For Peer Review Only

BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from

POPULATION-BASED CANCER STATISTICS FOR THE LAHORE DISTRICT, PAKISTAN

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-011828

Article Type: Research

Date Submitted by the Author: 08-Mar-2016

Complete List of Authors: Badar, Farhana; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Mahmood, Shahid; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Yusuf, Mohammed; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Internal Medicine Mahmood, Mohammad ; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pathology Masood, Misbah; The Institute of Nuclear Medicine and Oncology, Oncology Sial, Ghulam; Ittefaq Hospital(Trust), Pathology Mustafa, Tanveer; Fatima Jinnah Medical University, Pathology Chughtai, Omar; Chughtais Lahore Lab Chughtai, Nasir; Sheikh Zayed Hospital , Pathology Riaz, Sabiha; Fatima Memorial Hospital, Pathology

Anis, Tazeen; Allama Iqbal Medical College, Pathology http://bmjopen.bmj.com/ Hanif, Ghazala; The Children’s Hospital & the Institute of Child Health, Pathology Bajwa, Rakhshindah; Services Institute of Medical Sciences, Pathology Suleman, Bilquis; Nawaz Sharif Social Security Hospital, Pathology Aziz, Zeba; Hameed Latif Hospital, Oncology Khokhar, Muhammad; King Edward Medical University, Oncology and Radiotherapy Siddiqui, Neelam; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Medical Oncology on October 2, 2021 by guest. Protected copyright. Mushtaq, Sajid; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pathology Loya, Asif; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pathology Faraz, Raqib; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Yousaf, Aneel; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Quader, Ainul; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Ali, Kamran; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Sultan, Faisal; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Internal Medicine

Primary Subject Public health Heading:

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 Secondary Subject Heading: Epidemiology 5 Keywords: PUBLIC HEALTH, EPIDEMIOLOGY, ONCOLOGY 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 POPULATION-BASED CANCER STATISTICS FOR THE LAHORE DISTRICT, PAKISTAN 4 5 6 Farhana Badar, Shahid Mahmood, Muhammed Aasim Yusuf, Mohammad Tariq Mahmood, Misbah 7 Masood, Ghulam Rasool Sial, Tanveer Mustafa, Omar Rasheed Chughtai, Nasir Chughtai, Sabiha Riaz, 8 Tazeen Anis, Ghazala Hanif, Rakhshindah Bajwa, Bilquis A. Suleman, Zeba Aziz, Muhammad Abbas 9 Khokhar, Neelam Siddiqui, Sajid Mushtaq, Asif Loya, Raqib Faraz, Aneel Yousaf, Ain ul Quader, Kamran 10 11 Liaqat Ali , Faisal Sultan. 12 13 14 15 Corresponding authorFor peer review only 16 17 Farhana Badar-MBBS, MPH 18 19 20 Sr. Biostatistician & Cancer Epidemiologist 21 22 Cancer Registry & Clinical Data Management 23 24 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 25 26 7-A, Block R-3 27 28 Johar Town, Lahore 29 30 Pakistan 31 32 33 Ph.: +92 42 35905000 Ext. 4240 | Email: [email protected]

34 http://bmjopen.bmj.com/ 35 36 37 Shahid Mahmood-MBA, CPC 38 39 Medical Coder/Cancer Registry Officer 40 41 Cancer Registry & Clinical Data Management

42 on October 2, 2021 by guest. Protected copyright. 43 44 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 45 46 47 48 Mohammed Aasim Yusuf-FRCP 49 50 Consultant Gastroenterologist | Chief Medical Officer 51 52 Department of Internal Medicine 53 54 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 55 56 57 58 59 60 Page 1 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 3 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Mohammad Tariq Mahmood-DABP 4 5 6 Consultant Pathologist 7 8 Department of Pathology 9 10 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 11 12 13 14 Misbah Masood-FCPS 15 For peer review only 16 Consultant Clinical Oncologist 17 18 19 Oncology Division 20 21 The Institute of Nuclear Medicine and Oncology, Lahore, Pakistan. 22 23 24 25 Ghulam Rasool Sial-FCPS 26 27 Consultant Pathologist 28 29 30 Department of Pathology 31 32 Ittefaq Hospital, Lahore, Pakistan. 33

34 http://bmjopen.bmj.com/ 35 36 Tanveer Mustafa-MPhil 37 38 Senior Demonstrator 39 40 Department of Pathology 41

42 on October 2, 2021 by guest. Protected copyright. 43 Fatima Jinnah Medical University, Lahore, Pakistan. 44 45 46 47 Omar Rasheed Chughtai-FCAP 48 49 Consultant Pathologist 50 51 Chughtais Lahore Lab., Lahore, Pakistan. 52 53

54 55 56 Nasir Chughtai-MPhil 57 58 59 60 Page 2 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open Page 4 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Consultant Pathologist 4 5 6 Department of Pathology 7 8 Sheikh Zayed Hospital, Lahore, Pakistan. 9 10 11 12 Sabiha Riaz-FRCPath 13 14 Consultant Pathologist 15 For peer review only 16 Department of Pathology 17 18 19 Fatima Memorial Hospital, Lahore, Pakistan. 20 21 22 23 Tazeen Anis-DCP 24 25 Senior Demonstrator 26 27 Department of Pathology 28 29 30 Allama Iqbal Medical College, Lahore, Pakistan. 31 32 33

34 Ghazala Hanif-MPhil http://bmjopen.bmj.com/ 35 36 Consultant Pathologist 37 38 Department of Pathology 39 40 The Children’s Hospital & the Institute of Child Health, Lahore, Pakistan. 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 Rakhshindah Bajwa-MPhil 46 47 Consultant Pathologist 48 49 Department of Pathology 50 51 The Services Institute of Medical Sciences, Lahore, Pakistan. 52 53

54 55 56 Bilquis A Suleman-FRCPath 57 58 59 60 Page 3 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 5 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Consultant Pathologist 4 5 6 Department of Pathology 7 8 Nawaz Sharif Social Security Hospital, Lahore, Pakistan. 9 10 11 12 Zeba Aziz-DABM 13 14 Consultant Oncologist 15 For peer review only 16 Department of Oncology 17 18 19 Hameed Latif Hospital, Lahore, Pakistan. 20 21 22 23 Muhammad Abbas Khokhar-FCPS 24 25 Consultant Oncologist 26 27 Department of Oncology and Radiotherapy 28 29 30 King Edward Medical University, Lahore, Pakistan. 31 32 33

34 Neelam Siddiqui-FRCP http://bmjopen.bmj.com/ 35 36 Consultant Oncologist 37 38 Department of Medical Oncology 39 40 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 Sajid Mushtaq-FRCPath 46 47 Consultant Pathologist 48 49 Department of Pathology 50 51 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 52 53

54 55 56 Asif Loya-DABP 57 58 59 60 Page 4 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open Page 6 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Consultant Pathologist 4 5 6 Department of Pathology 7 8 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 9 10 11 12 Raqib Faraz-BSc 13 14 Medical Coder/Cancer Registry Officer 15 For peer review only 16 Cancer Registry & Clinical Data Management 17 18 19 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 20 21 22 23 Aneel Yousaf-MBA 24 25 Medical Coder/Cancer Registry Officer 26 27 Cancer Registry & Clinical Data Management 28 29 30 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 31 32 33

34 Ain ul Quader-BSc http://bmjopen.bmj.com/ 35 36 Medical Coder/Cancer Registry Officer 37 38 Cancer Registry & Clinical Data Management 39 40 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 Kamran Liaqat Ali-BSc 46 47 Medical Coder/Cancer Registry Officer 48 49 Cancer Registry & Clinical Data Management 50 51 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 52 53

54 55 56 Faisal Sultan-FRCP 57 58 59 60 Page 5 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 7 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Consultant Physician | Chief Executive Officer 4 5 6 Department of Internal Medicine 7 8 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 9 10 11 12 Keywords: 13 14 Population-based, cancer registration, incidence, Lahore 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 6 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open Page 8 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 POPULATION-BASED CANCER STATISTICS FOR THE LAHORE DISTRICT, PAKISTAN 4 5 6 ABSTRACT 7 8 Objectives 9 10 To estimate the population-level cancer estimates for the Lahore district, which is part of the Punjab 11 Cancer Registry (PCR), Pakistan. The population of Lahore was estimated at 9.5 million in 2010. 12 13 Design 14 15 For peer review only 16 A cross-sectional study. 17 18 Setting 19 20 The Registry has nineteen collaborating centers in Lahore that report their data to the Central Office 21 located within a tertiary care cancer treatment facility in Lahore, Pakistan. 22 23 Participants 24 25 26 Patients belonging to Lahore, of any age-group, and diagnosed with cancer in 2010, were included in the 27 study. Patients were followed-up between July and October 2015 to determine their vital status. 28 29 Outcome measures 30 31 Summaries were generated for gender, diagnoses, deaths, and the basis of diagnosis. Five-year age 32 33 categories were created from 0-4 till 70-74, followed by 75+ years. The Age-Standardized Incidence

34 Rates (ASIR) were computed per 100,000 population. Death counts were reported by site. http://bmjopen.bmj.com/ 35 36 Results 37 38 In 2010, in Lahore, a total of 5,302 new cancers were diagnosed-43% male and 57% female; 88·6% 39 40 microscopically confirmed and 11·4% non-microscopically. The ASIR amongst males was 70·9 and 41 amongst females 107·6. ASIRs of leading cancers, amongst men, were: prostate 6·2, urinary bladder 5·2,

42 and Non-Hodgkin Lymphoma (NHL) 5·1, and amongst women: breast 49·9, ovary 4·6, and corpus uteri on October 2, 2021 by guest. Protected copyright. 43 44 and NHL 3·5, each. A total of 1,656 deaths were recorded. 45 46 Conclusions 47 48 In Lahore, the ASIR was higher in women than in men. Amongst men, prostate cancer and in women 49 breast cancer was the leading cancer types. These estimates can also be used for health promotion and 50 51 policy making in the region. 52 53 54 55 56 57 58 59 60 Page 7 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 9 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 6 7 8 ARTICLE SUMMARY 9 10 STRENGTHS AND LIMITATIONS OF THIS STUDY 11 12 • This is the first time that the age-standardized incidence rates have been presented for the 13 Lahore district. 14 15 For peer review only 16 • A comparison has been made with the incidence rates reported by other registries around the 17 world. 18 19 • There are follow-up issues related to determining the vital status of the patients, once they are 20 21 registered as new cancer patients. Therefore, the limitation of the study is that the vital status 22 of the vast majority of patients could not be determined. 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 8 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open Page 10 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 PAPER 4 5 6 7 8 POPULATION-BASED CANCER STATISTICS FOR THE LAHORE DISTRICT, PAKISTAN 9 10 11 12 INTRODUCTION 13 14 In the area of public health research, conducting high-quality, population-level studies, is hailed as the 15 For peer review only 16 gold standard, as the outcomes truly represent the disease status of the community on whom the 17 studies are being conducted. This includes the practice of population-based cancer registration, which 18 not only assists in providing statistics and trends on incidence, mortality, and survival, it can also provide 19 20 information on putative risk factors associated with various diseases within a defined population, living 21 in a geographically demarcated area, over a specified period of time. However, cancer registration can 22 only be undertaken if there is appropriate infrastructure to enable it, and suitable, well-trained staff to 23 24 perform the tasks associated with it. Understandably, there is a cost associated with conducting this 25 type of epidemiologic work, and in a resource-constrained country like Pakistan, governments are less 26 likely to focus on the area of cancer registration than other areas deemed more immediately critical. 27 Further, there is no legislation in the country that requires health-care practitioners to report diagnoses 28 29 of cancer. 30 31 The question whether cancer registration is a necessity or a luxury in developing countries has been 32 debated extensively over the years. A paper published in 2008 stated that in low-income countries, 33

34 cancer registration is urgently needed so as to gauge the cancer burden in the region[1]. Given that http://bmjopen.bmj.com/ 35 Pakistan is categorized as a ‘lower-middle income country’ by the World Bank, with its population 36 estimated to be 185·0 million in the year 2014, and the life expectancy at birth being 66 years (65 years 37 38 for males and 67 years for females), it seems unlikely that registration of all cancer diagnoses will be 39 accurate and complete at the national level in the near future[2]. However, there is no denying the fact 40 that knowing the cancer burden in the region helps in projecting estimates, establishing the required 41 numbers of health-care facilities to cater to the needs of the patients, training sufficient numbers of

42 on October 2, 2021 by guest. Protected copyright. 43 health-care practitioners to manage the conditions, addressing health education, and assisting in 44 developing prevention, early detection, and cancer control programs in the region. Figure 1 is a map of 45 46 Pakistan showing the provinces of Pakistan and countries adjacent to Pakistan[3]. 47 48 Population-level statistics cannot be computed without the availability of figures for the population 49 under review, or the catchment population. In Pakistan, publications describing the population structure 50 are available for the census that was conducted in 1998[4]. However, the most recent population 51 52 census, initiated a year ago, has not yet been completed[5]; therefore, accurate figures describing the 53 Pakistani population are not available. As a result, for this study, population estimates are based on 54 population figures determined by using the average annual growth rates provided by the Government of 55 56 Pakistan[4]. 57 58 59 60 Page 9 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 11 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Even though accurate population figures are not available, enthusiastic professionals have, over the 4 5 years, endeavored to determine cancer estimates for Pakistan. In the past, the regional registry of the 6 Karachi South district, in the province of Sindh, was established and managed for several years by a 7 dedicated pathologist, Dr. Yasmin Bhurgri[6]. This registry was widely recognized at an international 8 9 level for its data quality[6]. However, due to the sudden death of Dr. Bhurgri in January 2012, this 10 registry is no longer active. Another registry in Pakistan is the Punjab Cancer Registry (PCR), which was 11 founded collaboratively by a group of health-professionals in 2005, pioneered by the administrators of a 12 13 complete cancer treatment facility in Lahore called the Shaukat Khanum Memorial Cancer Hospital and 14 Research Center (SKMCH & RC)[7-10]. The Punjab Cancer Registry, herein, referred to as the Registry, is 15 registered with, andFor regulated peer under, the Societies review Registration Act, 1860,only of Pakistan[11]. It is also a 16 17 member of the International Association of Cancer Registries, France[12]. The purpose of establishing 18 the Registry was to determine the cancer estimates in the province of Punjab. Punjab is the most 19 populous province of Pakistan, with a population estimated at 100M, and 36 administrative districts, of 20 21 which Lahore is the most populous, with a population of some 9M[4,13]. For about a decade, data have 22 been captured in a systematic and pre-defined manner, in accordance with the minimum data items 23 required for cancer registries as well as some additional optional data items[7,10,14]. The quality of data 24 25 collected for the Lahore district and the level of completeness have improved with the passage of time, 26 with the number of cases reported to the Registry going up from 2,006 in the year 2005 to 5,123 in the 27 year 2015 (Figure 2). Data are collected using both the active and passive methods of data collection 28 from nineteen collaborating centers within the Lahore district, both in the government and private 29 30 sectors (Appendix A). Information collected on paper-based forms is subsequently entered into the 31 database developed within the computerized Hospital Information System, after checking for 32 duplication. Some of the fields are automatically populated by linkages with the pathology records of 33

34 the SKMCH & RC pathology department. Cancers are coded using the International Classification of http://bmjopen.bmj.com/ 35 Diseases, Clinical Modification, 10th revision[15]. Over recent years, six other districts have been 36 included for the purpose of data collection, with the idea being to include 1-2 contiguous district(s) of 37 38 Punjab every year in order to expand cancer registration. This approach has been adopted because the 39 sponsor, SKMCH & RC, is a charitable organization, and it is logistically not possible to initiate data 40 collection from 36 districts of Punjab simultaneously. 41

42 on October 2, 2021 by guest. Protected copyright. 43 In the past, PCR data have been reported to the International Agency for Research on Cancer (IARC) in 44 response to a call for data by the Agency. The data have been used, along with data from Dr. Yasmin 45 Bhurgri’s paper, and the Federal Bureau of Statistics, Pakistan, to provide cancer estimates for Pakistan 46 47 in the Globocan 2012 report[16]. Between July and October 2015, an attempt was made to obtain 48 follow-up data, by making phone calls to patients in order to determine their vital status; these data 49 were again reported to IARC. We were able to contact only 60% of patients in this way. 50 51 This manuscript provides population-level cancer estimates for the Lahore district, based on cases 52 53 diagnosed in 2010 and reported to the Registry. This is the first time that the Lahore district population- 54 level data have been computed and are being reported. 55 56 57 58 59 60 Page 10 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open Page 12 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 METHODS 4 5 6 The population denominator 7 8 The population of the Lahore district was estimated at 9,503,871 in the year 2010, determined using an 9 average annual growth rate of 3·46%[4,13]. The total area of the Lahore district is 1,772 square 10 kilometers, its population density being calculated as 5,363 persons, per square kilometer, in the year 11 12 under study[4]. Figure 3 is a population pyramid showing the population distribution of the Lahore 13 district by age-group and gender, for the year 2010. These population estimates were used as the 14 population-at-risk denominator, for calculating the incidence rates for this study. 15 For peer review only 16 Data collection 17 18 19 The Punjab Cancer Registry data were reviewed retrospectively to retrieve information on cancer 20 patients belonging to the Lahore district and having been diagnosed in the year 2010. Information was 21 collected on new cancer diagnoses (by histology and gender), the most valid basis of diagnosis as 22 23 microscopically versus non-microscopically confirmed, and deaths recorded. Five-year age categories 24 were created beginning from 0-4 years and ending on 70-74 years, with all those above 75 included as 25 75+. Cases were stratified by age-group and histology/site. 26 27 Data analysis 28 29 30 Counts were determined and ASIRs computed according to 5-year age-group, weighted by the Segi 31 World Standard population[17]. ASIRs were expressed per 100,000 population, separately for male and 32 female patients. For mortality data, counts were stratified by site. Overall survival interval was 33

34 computed between the dates of diagnosis and last contact and analyzed using the Kaplan-Meier http://bmjopen.bmj.com/ 35 method. Of a total of 5,302 cases recorded in the year 2010, survival intervals could not be computed 36 for 2,530 cases (47·7%). This is because, of these 2,530 cases, attendants of 128 patients could only 37 38 communicate that the patients had died but could not recall their dates of death; in 21 cases, patients 39 died on the day of cancer diagnoses and their intervals were set at naught; and in 2,381 cases, no 40 contact could be established on the phone numbers provided. Accordingly, the survival intervals of 41 these 2,530 patients could not be confirmed and these patients were not included in the survival

42 on October 2, 2021 by guest. Protected copyright. 43 analysis. Although extensive survival analysis was subsequently done on the fifty percent of cases on 44 whom the duration of survival was available, the survival estimates generated were not considered 45 46 valid. Therefore, survival results are not being presented in this manuscript. 47 48 Data were analyzed using the Microsoft Excel, version 2010, and SPSS, version 19. The local Institutional 49 Review Board (IRB) granted exemption from full IRB evaluation. 50 51 52 53 RESULTS 54 55 56 The population of the Lahore district was estimated to stand at 9,503,871 in the year 2010, with males 57 accounting for 52·7% and females 47·3% of the population. Further, of a total of 5,302 cancer patients 58 59 60 Page 11 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 13 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 belonging to the district of Lahore and registered in the PCR database against the same year, 3,000 4 5 (56·6%) were female and 2,302 (43·4%) were male patients. Of all the cancers diagnosed, about 88·6% 6 were microscopically and 11·4% were non-microscopically confirmed (Table 1). Skin cancer had the 7 highest figure in the microscopically confirmed group (98·7%), whereas, liver and intrahepatic bile 8 9 duct(s) had the highest figure in the non-microscopically confirmed category (76·1%). The ASIR for all 10 sites combined amongst male patients was 70·9 per 100,000 men and in female patients, 107·6, per 11 100,000 women. Tables 2-3 show the ASIRs for all the cancers recorded in the Registry, for males and 12 13 females, respectively. Amongst men, the highest ASIRs were recorded for the following sites and 14 malignancies: prostate 6·2, bladder 5·2, NHL 5·1, trachea, bronchus, and lung 4·8, liver 4·2, and brain 15 and CNS 4·2, whereas,For amongst peer females, the highestreview ASIRs were: breast only 49·9, ovary 4·6, corpus uteri 3·5, 16 17 NHL 3·5, cervix uteri 3·1, and brain and CNS 2·7. 18 19 Table 1. The basis of diagnosis, categorized as being microscopically and non-microscopically confirmed 20 (N=5,302). 21 22 The basis of diagnosis Microscopic Non-Microscopic 23 Cancer site (%) (%) 24 Lip & oral cavity 92.4 7.6 25 Esophagus 97.4 2.6 26 Stomach 97.6 2.4 27 Colorectal 92.6 7.4 Liver & intrahep. bile ducts 23.9 76.1 28 Gall bladder 75.0 25.0 29 Larynx 90.5 9.5 30 Bronchus & lung 90.1 9.9 31 Bone 92.6 7.4 32 Connective tissue 93.2 6.8 Leukemia 77.1 22.9 33 Breast 91.7 8.3 34 Cervix uteri 91.9 8.1 http://bmjopen.bmj.com/ 35 Corpus uteri 94.0 6.0 36 Testis 96.8 3.2 37 Prostate 94.5 5.5 NHL 89.5 10.5 38 Hodgkin lymphoma 93.3 6.7 39 Urinary bladder 94.4 5.6 40 Brain 95.2 4.8 41 Skin 98.7 1.3 Ovary 87.0 13.0

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 12 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open Page 14 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 Table 2. Age-specific and age-standardized incidence rates of cancers diagnosed in the Lahore district in 6 7 2010, amongst males. 8 9 Male Age-specific incidence rates All ages 10Site (years) 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75+ Crude % ASIR ICD-10 11Lip 10 0.0 0.0 0.0 0.0 0.2 0.0 0.0 0.3 0.0 0.0 1.1 0.9 3.9 1.6 0.0 0.0 0.2 0.4 0.3 C00 12Tongue 72 0.0 0.0 0.0 0.0 0.8 0.2 1.4 1.7 4.8 4.8 4.0 5.2 6.8 9.6 14.7 3.6 1.4 3.1 2.2 C01-C02 13Mouth 83 0.0 0.2 0.2 0.0 0.2 0.2 0.9 1.4 3.6 6.4 5.7 9.5 13.7 16.0 9.2 1.8 1.7 3.6 2.7 C03-C06 14Salivary gland 16 0.0 0.0 0.2 0.0 0.0 0.2 0.6 0.7 0.4 0.5 1.1 0.9 1.0 1.6 3.7 1.8 0.3 0.7 0.5 C07-C08 15Tonsil 1 0.0 For0.0 0.0 0.0 peer 0.0 0.0 0.0 review 0.0 0.0 0.0 0.0 0.0only 0.0 1.6 0.0 0.0 0.0 0.0 0.0 C09 16Other oropharynx 2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.9 0.0 0.0 1.8 0.0 0.0 0.1 0.1 C10 17Nasopharynx 7 0.0 0.0 0.0 0.0 0.2 0.0 0.6 0.0 0.0 0.0 0.6 0.9 2.0 0.0 0.0 0.0 0.1 0.3 0.2 C11 18Hypopharynx 10 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.3 0.0 0.0 1.1 0.9 1.0 0.0 3.7 3.6 0.2 0.4 0.3 C12-C13 19Pharynx 4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.4 1.1 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.2 0.1 C14 20Esophagus 43 0.0 0.0 0.0 0.0 0.0 0.0 0.9 0.0 0.8 3.8 2.3 2.6 4.9 9.6 11.0 12.4 0.9 1.9 1.5 C15 21Stomach 61 0.0 0.0 0.0 0.0 0.0 2.0 0.9 1.7 2.0 4.3 4.6 5.2 3.9 16.0 5.5 1.8 1.2 2.6 1.9 C16 22Small intestine 10 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.7 0.0 0.5 1.1 0.9 1.0 1.6 0.0 3.6 0.2 0.4 0.3 C17 23Colon 84 0.0 0.0 0.0 0.2 0.4 0.7 0.6 1.4 2.0 6.4 6.9 8.6 9.8 22.5 7.4 8.9 1.7 3.6 2.8 C18 24Rectum 59 0.0 0.0 0.0 0.0 0.6 0.7 1.4 1.0 1.6 3.2 5.7 4.3 5.9 16.0 3.7 3.6 1.2 2.6 1.9 C19-C20 25Anus 17 0.0 0.0 0.0 0.2 0.2 0.0 0.0 0.0 0.4 0.0 2.9 2.6 2.0 4.8 1.8 0.0 0.3 0.7 0.6 C21 26Liver 117 0.0 0.0 0.0 0.0 0.0 0.0 0.0 2.4 1.6 4.8 12.0 13.8 16.6 35.3 20.3 17.8 2.3 5.1 4.2 C22 27Gall bladder 26 0.0 0.0 0.0 0.0 0.0 0.2 0.3 0.3 0.0 0.0 2.9 3.5 2.0 9.6 3.7 7.1 0.5 1.1 0.9 C23-C24 28Pancreas 17 0.0 0.0 0.0 0.0 0.2 0.0 0.3 0.0 1.6 1.6 0.0 3.5 0.0 3.2 3.7 0.0 0.3 0.7 0.5 C25 29Nose, sinus 8 0.0 0.2 0.0 0.0 0.2 0.0 0.0 0.3 0.4 0.0 0.0 2.6 0.0 0.0 1.8 0.0 0.2 0.3 0.2 C30-31 30Larynx 66 0.0 0.0 0.0 0.0 0.4 0.0 0.0 0.7 1.2 6.4 4.6 9.5 11.7 12.8 12.9 1.8 1.3 2.9 2.3 C32 31Trachea, bronchus, lung 132 0.0 0.0 0.0 0.0 0.0 0.2 0.9 1.0 1.6 4.3 5.7 19.0 21.5 32.1 35.0 35.5 2.6 5.7 4.8 C33-C34 32Other thoracic organ(s) 11 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.0 2.9 0.0 1.0 0.0 5.5 1.8 0.2 0.5 0.4 C37-C38 33Bone 49 0.0 0.6 0.9 3.2 1.4 0.5 1.2 0.3 0.0 0.0 0.6 0.0 2.9 0.0 3.7 1.8 1.0 2.1 0.9 C40-C41 Melanoma of the skin 2 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 C43 34 http://bmjopen.bmj.com/ Other skin 92 0.0 0.2 0.3 0.4 0.2 1.2 2.3 1.7 1.6 3.2 2.9 9.5 11.7 22.5 14.7 14.2 1.8 4.0 3.0 C44 35 Connective & soft tissue 55 0.3 0.3 0.2 1.4 1.0 0.7 0.9 2.1 0.4 4.8 1.1 2.6 2.9 3.2 5.5 3.6 1.1 2.4 1.4 C47,C49 36 Breast 19 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.3 1.2 0.5 0.6 2.6 2.0 9.6 0.0 3.6 0.4 0.8 0.7 C50 37Prostate 165 0.0 0.0 0.0 0.0 0.2 0.2 0.0 0.0 0.0 1.1 2.9 13.0 22.5 36.9 70.0 101.3 3.3 7.2 6.2 C61 38Testis 31 0.2 0.0 0.0 0.9 0.6 0.7 0.6 2.1 2.0 0.5 1.1 0.0 1.0 1.6 0.0 1.8 0.6 1.3 0.7 C62 39Kidney 53 0.8 0.2 0.0 0.0 0.0 0.2 0.3 0.7 2.4 3.2 2.3 7.8 6.8 8.0 3.7 7.1 1.1 2.3 1.7 C64 40Bladder 142 0.0 0.0 0.0 0.0 0.0 0.2 0.6 0.3 1.6 4.8 6.3 17.3 24.4 40.1 33.1 46.2 2.8 6.2 5.2 C67 41Eye 25 1.0 0.5 0.0 0.2 0.2 0.2 0.0 0.3 0.0 1.1 0.6 0.9 2.0 1.6 7.4 1.8 0.5 1.1 0.7 C69

42Brain, CNS 160 0.3 1.4 0.6 0.7 1.2 3.7 5.5 3.8 5.2 7.0 14.3 14.7 10.7 9.6 5.5 3.6 3.2 7.0 4.2 C70-C72 on October 2, 2021 by guest. Protected copyright. 43Thyroid 23 0.0 0.0 0.0 0.4 0.2 1.0 0.6 0.0 1.2 1.1 0.6 2.6 1.0 1.6 5.5 0.0 0.5 1.0 0.6 C73 44Adrenal 2 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.8 0.0 0.0 0.1 0.1 C74 45Hodgkin lymphoma 77 0.3 1.8 0.5 1.4 0.2 1.7 1.4 2.4 3.2 2.7 2.3 6.1 2.0 6.4 3.7 0.0 1.5 3.3 1.8 C81 46NHL 179 0.5 1.1 1.4 1.3 2.2 1.0 4.0 3.1 4.8 5.9 11.4 8.6 26.4 22.5 20.3 17.8 3.6 7.8 5.1 C82-C88 47Multiple myeloma 20 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.3 0.0 1.1 1.7 3.5 3.9 3.2 3.7 1.8 0.4 0.9 0.7 C90 48Lymphoid leukemia 64 3.1 1.5 2.3 0.7 0.8 0.7 0.3 0.0 1.2 0.0 0.0 0.0 1.0 3.2 1.8 1.8 1.3 2.8 1.2 C91 49Myeloid leukemia 27 0.3 0.5 0.2 0.4 1.0 0.5 0.6 0.7 0.4 0.5 1.1 0.9 2.0 0.0 0.0 1.8 0.5 1.2 0.6 C92-93 50Leukemia unspecified 22 0.7 0.6 0.0 0.4 1.0 0.2 0.9 0.0 0.0 1.1 0.0 0.9 0.0 0.0 0.0 0.0 0.4 1.0 0.4 C95 51 Other & 52Other & unspecified 172 0.0 0.2 0.9 0.9 0.4 2.0 2.9 4.2 4.0 6.4 12.6 10.4 20.5 17.7 31.3 40.9 3.4 7.5 5.3 unspecified 53Benign CNS 67 0.2 0.2 0.3 0.5 0.6 1.7 2.9 3.1 2.0 4.8 1.7 0.9 7.8 3.2 5.5 0.0 1.3 2.9 1.7 Benign CNS All sites (total) 2302 7.7 9.1 7.9 13.3 14.7 21.6 34.2 40.9 53.8 98.2 129.2 197.1 259.9 385.2 362.8 353.7 46.0 100.0 70.9 54 55 56 57 58 59 60 Page 13 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 15 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Table 3. Age-specific and age-standardized incidence rates of cancers diagnosed in the Lahore district in 4 2010, amongst females. 5 6 7 8 Female Age-specific incidence rates 9 All ages (years) 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75+ Crude % ASIR ICD-10 10 Lip 4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 2.2 0.0 0.0 4.9 0.0 0.1 0.1 0.2 C00 11 Tongue 43 0.0 0.0 0.0 0.0 0.2 0.0 0.3 1.2 1.0 3.7 6.9 5.4 7.2 9.9 9.8 0.0 1.0 1.4 1.7 C01-C02 12 Mouth 34 0.0 0.0 0.0 0.4 0.2 0.6 0.0 0.4 1.9 0.6 4.1 4.4 6.0 2.0 12.3 4.5 0.8 1.1 1.3 C03-C06 13Salivary gland 14 0.0 0.0 0.2 0.0 0.0 0.6 0.3 1.2 0.0 0.0 2.1 2.2 0.0 4.0 0.0 0.0 0.3 0.5 0.5 C07-C08 14Tonsil 2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.7 1.1 0.0 0.0 0.0 0.0 0.0 0.1 0.1 C09 15Nasopharynx 6 0.0For 0.0 0.0 0.2peer 0.0 0.0 0.3review 0.0 1.0 0.0 0.0 only 1.1 0.0 0.0 2.5 0.0 0.1 0.2 0.2 C11 16Hypopharynx 12 0.0 0.0 0.0 0.0 0.4 0.0 0.3 0.8 0.0 0.6 0.7 1.1 1.2 0.0 4.9 2.3 0.3 0.4 0.4 C12-C13 17Esophagus 33 0.0 0.0 0.0 0.0 0.0 0.3 0.0 1.2 2.4 4.3 2.8 0.0 7.2 6.0 7.4 2.3 0.7 1.1 1.3 C15 18Stomach 24 0.0 0.0 0.0 0.0 0.0 0.3 0.3 0.4 1.0 3.1 2.1 2.2 6.0 6.0 0.0 2.3 0.5 0.8 1.0 C16 19Small intestine 6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.5 0.0 0.0 1.1 0.0 0.0 7.4 2.3 0.1 0.2 0.3 C17 20Colon 64 0.0 0.0 0.2 0.6 0.4 1.1 1.7 2.5 1.4 2.5 6.9 7.6 4.8 19.8 7.4 4.5 1.4 2.1 2.4 C18 21Rectum 42 0.0 0.0 0.2 0.2 0.9 1.7 1.3 0.8 2.9 0.0 2.8 4.4 4.8 6.0 4.9 2.3 0.9 1.4 1.4 C19-C20 22Anus 4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 1.0 0.0 0.0 0.0 0.0 0.0 2.5 0.0 0.1 0.1 0.1 C21 23Liver 59 0.0 0.0 0.0 0.0 0.2 0.3 0.3 0.0 0.5 7.4 6.9 15.2 8.4 15.9 7.4 2.3 1.3 2.0 2.5 C22 24Gall bladder 46 0.0 0.0 0.0 0.0 0.0 0.0 0.7 0.8 2.4 3.1 4.1 6.5 12.1 4.0 4.9 13.5 1.0 1.5 1.9 C23-C24 25Pancreas 13 0.0 0.0 0.0 0.0 0.0 0.3 0.0 0.4 0.5 0.6 0.7 2.2 0.0 9.9 2.5 0.0 0.3 0.4 0.6 C25 26Nose, sinus 9 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.0 0.6 0.7 0.0 4.8 2.0 2.5 0.0 0.2 0.3 0.4 C30-31 27Larynx 8 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.2 1.4 1.1 1.2 0.0 0.0 4.5 0.2 0.3 0.3 C32 28Trachea, bronchus, lung 30 0.0 0.0 0.2 0.4 0.0 0.3 0.7 0.4 1.4 2.5 1.4 3.3 4.8 4.0 7.4 4.5 0.7 1.0 1.1 C33-C34 29Other thoracic organ(s) 5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.4 0.5 1.2 0.0 1.1 0.0 0.0 0.0 0.0 0.1 0.2 0.2 C37-C38 30Bone 32 0.2 0.2 1.2 1.7 1.3 0.3 0.3 1.7 0.5 0.0 0.0 0.0 0.0 0.0 2.5 0.0 0.7 1.1 0.6 C40-C41 31Melanoma of the skin 3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.1 0.0 2.0 0.0 2.3 0.1 0.1 0.1 C43 32Other skin 59 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.8 2.9 5.0 3.5 3.3 10.8 21.8 19.6 13.5 1.3 2.0 2.6 C44 33Connective & soft tissue 40 0.3 0.2 0.3 0.2 0.9 1.7 1.0 1.7 1.0 0.6 3.5 1.1 2.4 4.0 2.5 6.8 0.9 1.3 1.2 C47,C49

34Breast 1390 0.0 0.0 0.0 0.2 3.1 14.2 35.8 60.3 93.3 131.8 145.9 167.6 149.5 148.8 135.0 103.5 30.9 46.3 49.9 C50 http://bmjopen.bmj.com/ 35Vulva 3 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.1 0.0 0.0 0.0 2.3 0.1 0.1 0.1 C51 36Vagina 5 0.0 0.0 0.0 0.0 0.0 0.3 0.0 0.4 0.0 0.6 0.0 0.0 1.2 0.0 0.0 2.3 0.1 0.2 0.2 C52 37Cervix uteri 86 0.0 0.0 0.0 0.0 0.4 0.3 1.3 5.0 5.3 11.8 6.2 12.0 13.3 2.0 4.9 6.8 1.9 2.9 3.1 C53 38Corpus uteri 83 0.0 0.0 0.0 0.0 0.0 0.3 0.7 2.9 1.4 6.2 9.0 13.1 20.5 17.9 14.7 6.8 1.8 2.8 3.5 C54 39Uterus, unspecified 34 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.4 2.9 5.0 3.5 3.3 7.2 4.0 4.9 0.0 0.8 1.1 1.3 C55 Ovary 138 0.0 0.2 0.5 0.4 1.8 2.3 2.7 5.8 9.6 10.5 13.1 14.2 16.9 13.9 9.8 0.0 3.1 4.6 4.6 C56 40 Other female gen. organ(s) 5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.5 0.0 0.7 0.0 2.4 0.0 2.5 0.0 0.1 0.2 0.2 C57 41 Placenta 3 0.0 0.0 0.0 0.0 0.2 0.3 0.0 0.4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.1 C58

42 on October 2, 2021 by guest. Protected copyright. Kidney 35 0.5 0.2 0.0 0.0 0.4 0.0 0.0 0.8 2.4 2.5 3.5 7.6 2.4 2.0 2.5 4.5 0.8 1.2 1.2 C64 43 Bladder 35 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.8 1.4 1.9 2.1 4.4 6.0 7.9 12.3 13.5 0.8 1.2 1.5 C67 44Eye 8 0.3 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.6 0.0 0.0 1.2 2.0 0.0 2.3 0.2 0.3 0.3 C69 45Brain, CNS 84 0.2 0.8 0.7 0.6 0.9 1.4 1.3 2.1 5.3 6.2 8.3 8.7 6.0 9.9 2.5 2.3 1.9 2.8 2.7 C70-C72 46Thyroid 71 0.0 0.2 0.2 0.4 1.8 1.4 1.7 3.7 5.3 4.3 5.5 1.1 10.8 2.0 4.9 2.3 1.6 2.4 2.2 C73 47Hodgkin lymphoma 27 0.3 0.3 0.2 0.4 1.1 1.4 0.0 1.7 1.0 1.2 0.0 1.1 0.0 0.0 2.5 0.0 0.6 0.9 0.6 C81 48NHL 96 0.2 0.5 0.0 1.0 0.7 0.3 1.3 2.9 4.8 7.4 7.6 6.5 10.8 9.9 19.6 24.8 2.1 3.2 3.5 C82-C88 49Multiple myeloma 13 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.0 1.2 0.0 1.1 2.4 7.9 4.9 0.0 0.3 0.4 0.6 C90 50Lymphoid leukemia 30 1.2 1.4 1.3 0.0 0.2 0.0 0.3 0.0 0.5 0.0 0.0 2.2 1.2 0.0 0.0 0.0 0.7 1.0 0.6 C91 51Myeloid leukemia 15 0.0 0.2 0.0 0.2 0.2 0.3 0.0 0.8 0.5 0.6 2.1 3.3 0.0 0.0 2.5 0.0 0.3 0.5 0.5 C92-93 52Leukemia unspecified 8 0.2 0.2 0.3 0.0 0.2 0.3 0.3 0.0 0.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.3 0.2 C95 53 Other & 54Other & unspecified 166 0.2 0.0 0.2 0.4 0.7 1.7 2.7 5.8 7.2 9.9 15.9 20.7 19.3 33.7 34.4 24.8 3.7 5.5 6.4 unspecified Benign 55Benign CNS 73 0.3 0.2 0.5 1.1 0.4 2.3 2.0 5.4 3.8 3.7 3.5 4.4 4.8 4.0 4.9 2.3 1.6 2.4 2.1 CNS 56All sites (total) 3000 3.9 4.7 6.1 8.2 17.0 34.1 58.5 114.9 169.2 242.6 278.0 339.6 358.0 383.0 375.6 265.6 66.7 100.0 107.6 57 58 59 60 Page 14 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open Page 16 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 6 Of the 5,302 patients, death was recorded in 1,656 (31·2%) cases by the cut-off date for this study; this 7 included 791 male and 865 female patients. One-thousand, two-hundred and sixty-five patients were 8 still alive (23·9%) at the time of review, whereas, the vital status of 2,381 patients (44·9%) could not be 9 determined. Death certificates were available for only 8% of patients (127/1,656), representing just one 10 11 collaborating center. Table 4 displays death counts and proportion by cancer sites. 12 13 Table 4. Distribution of deaths recorded (1,656 (791 male and 865 female patients)), of the patients diagnosed 14 with cancer in the Lahore district in 2010, according to gender and cancer type (top 10 cancers only). 15 For peer review only 16 Males Count % Female Count % 17 Brain 74 9 Breast 330 38 18 19 Lip & oral cavity 58 7 Ovary 47 5 20 Liver & intrahep. bile ducts 56 7 Colorectal 42 5 21 Colorectal 53 7 Brain 41 5 22 Bronchus & lung 51 6 NHL 33 4 23 NHL 51 6 Liver & intrahep. bile ducts 28 3 24 25 Prostate 49 6 Lip & oral cavity 25 3 26 Urinary bladder 46 6 Leukemia 20 2 27 Leukemia 45 6 Cervix 19 2 28 Larynx 22 3 Corpus uteri 17 2 29 30 31 32 33 Of the deaths recorded, in male patients, 9% were in those who had brain tumor, 7% each in those with 34 lip & oral cavity, liver & intrahepatic bile ducts, and colorectal tumors, 6% each in cancers of the http://bmjopen.bmj.com/ 35 36 bronchus & lung, NHL, prostate, urinary bladder, and leukemia, and 3% in laryngeal carcinoma. Amongst 37 females, 38% deaths were recorded in those who had breast cancer, 5% each in those who had ovarian, 38 colorectal, and brain tumors, 4% in NHL, 3% each in those who had liver & intrahepatic bile ducts and lip 39 40 & oral cavity tumors, and 2% each in those who had leukemia and cancer of the cervix and corpus uteri. 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 DISCUSSION 45 46 The results reported for the population of the Lahore district show that over 5,000 cancer cases were 47 48 reported in 2010. The ASIR for all-cancers combined was higher amongst females (107·6) than in males 49 (70·9). These results also included the ASIRs for benign CNS tumors and other/unspecified sites. The 50 ASIRs reported by the Surveillance, Epidemiology, and End Results (SEER) Program of the United States 51 52 of America (USA), are very high (359·4 for females and 282·6 for males)[18,19]. These figures represent 53 SEER 18 registries compiling data from all cases diagnosed since 2000 and covering approximately 30% 54 of the US population[18,19]. The ASIRs published in the CI5-X report for Delhi in India and Riyadh in 55 Saudi Arabia, are close to the Lahore district figures as opposed to the SEER rates; in fact, the ASIRs for 56 57 females in these three regions are quite similar to one another. It is important to point out that Delhi, 58 59 60 Page 15 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 17 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 located in India, to the east of Lahore, is closer to Lahore than is Karachi located in Southern Pakistan. As 4 5 far as the South Karachi Registry is concerned, based on the last report (1998-2002) released in CI5-IX, it 6 can be seen that the ASIRs for Karachi were relatively high (192·0 for females and 166·6 for males) as 7 compared to those for the Lahore district. Further, in the region of Golestan in Iran (2005-2007), and for 8 9 Israel, again the ASIRs were high compared to those reported for the Lahore district[19]. For the SEER 10 Program, Delhi, Iran, and Saudi Arabia, data were reported for the 2003-2007 time period. Table 5 11 shows a comparison of the ASIRs according to cancer sites, though not all sites, in the aforementioned 12 13 regions of the world. In women belonging to the Lahore district, the ASIR of breast cancer ranked the 14 highest (49·9) of all the cancers, and was higher than that for Delhi (31·6), but relatively low compared 15 to that reported forFor the Israeli peer Jews (89·4). Amongst review men in the Lahore only district, the ASIR of prostate 16 17 cancer was the highest (6·2) of all the cancers, but was lower than that reported for Delhi (10·1) and 18 Riyadh (7·9). The ASIR of cervical cancer in Lahore was 3·1 but in Delhi it was much higher, at 17·7; this is 19 despite the fact that the screening levels are low in the general population of India[20]. Other than this, 20 21 of the factors implicated in the etiology of cervical cancer in the Indian population (early age at 22 marriage, having multiple sexual partners and pregnancies, poor genital hygiene, malnourishment, use 23 of oral contraceptives, low level of awareness, and prevalence of specific oncogenic types of Human 24 25 Papilloma Viruses (HPV) 16 and 18 that can be easily spread through direct sexual contact), some are 26 also found in the Pakistani population. Although, not many population-level studies have been 27 conducted to determine the HPV prevalence in Pakistan, one study reports HPV positivity to be nearly 28 2·8% in the general population (25/899) and about 92% in patients with invasive cervical cancer 29 30 (83/91)[21]. These figures demonstrate that extensive population-level studies are needed to decipher 31 the role of HPV in causing cervical cancer in Pakistan. However, in India, it has been reported that HPV 32 prevalence varies from 7·5% to 16·9% in women without cervical cancer as opposed to 87·8% to 96·7% 33

34 amongst cervical cancer patients[20]. http://bmjopen.bmj.com/ 35 36 As far as the mortality data are concerned, since the vital status of all the patients could not be 37 recorded, our results have to be interpreted with caution. The highest mortality was recorded in 38 39 patients diagnosed with breast cancer amongst females, and amongst those with brain tumors in males. 40 Due to the non-availability of the vital status of nearly half of the patients, the survival statistics could 41 not be reported either. The establishment of a death registry in the region could help in collecting the

42 on October 2, 2021 by guest. Protected copyright. 43 mortality data and determining the cause-specific mortality, along with the survival estimates for the 44 study population. 45 46 The fact that nearly 13% were non-microscopically confirmed cancers as opposed to nearly 87% that 47 were microscopically confirmed, is a quality index for the data. 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 16 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open Page 18 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Table 5. ASIRs, per 100,000 population, for selected cancer sites, in Pakistan, India, Iran, Israel, and USA. 4 5 Pakistan Pakistan India Iran Saudi Arabia Israel USA 6 Lahore Karachi New Delhi Golestan Riyadh Jews SEER 7 2010 1998-2002 2003-2007 2005-2007 2003-2007 2003-2007 2003-2007 8 Oral cavity & salivary gland-C00-C08 9 Male 5.7 22.5 14.0 1.7 1.6 3.3 6.9 10 Female 3.7 20.4 4.7 1.3 1.4 2.3 3.1 11 Pharynx-C09-C14 12 Male 0.7 8.2 6.6 1.0 2.4 1.5 4.4 13 Female 0.7 3.4 1.5 0.7 1.3 0.5 1.1 14 Oesophagus-C15 15 Male For peer1.5 6.7 review 4.9 23.2 only 1.6 1.8 5.1 16 Female 1.3 8.6 2.9 18.8 1.3 0.9 1.2 17 Stomach-C16 18 Male 1.9 6.0 3.2 30.4 4.4 10.0 6.6 19 Female 1.0 3.6 1.5 12.6 2.3 5.4 3.3 20 Small intestine-C17 21 Male 0.3 0.2 0.2 1.4 0.5 1.0 1.5 22 Female 0.3 0.4 0.1 0.9 0.3 0.7 1.1 23 Colo-rectum-C18-C21 24 Male 5.3 7.1 5.5 13.6 12.5 42.8 35.3 25 Female 3.9 5.2 3.7 10.4 10.6 32.6 26.5 26 Liver-C22 27 Male 4.2 5.4 2.6 3.6 3.0 3.1 7.6 28 Female 2.5 3.7 1.5 2.0 6.0 1.4 2.4 29 Gall bladder-C23-C24 30 Male 0.9 1.3 4.0 1.2 1.2 1.7 1.7 31 Female 1.9 4.9 8.0 1.6 2.5 1.4 1.7 32 Pancreas-C25 33 Male 0.5 0.9 1.9 2.8 3.2 8.6 8.2 34 Female 0.6 0.5 1.1 1.0 1.9 6.4 6.2 http://bmjopen.bmj.com/ 35 Nose & sinus-C30-C31 36 Male 0.2 0.7 0.3 0.0 0.2 0.4 0.6 37 Female 0.4 0.4 0.2 0.2 0.2 0.3 0.4 38 Larynx-C32 39 Male 2.3 10.7 8.0 4.1 1.7 4.1 4.3 40 Female 0.3 1.8 1.1 1.4 0.1 0.6 0.9 41 Trachea, bronchus, & lung-C33-C34

42 Male 4.8 25.2 13.7 17.5 6.3 29.8 48.3 on October 2, 2021 by guest. Protected copyright. 43 Female 1.1 3.6 3.6 5.6 2.2 13.4 33.8 44 Bone-C40-C41 45 Male 0.9 1.3 2.0 1.3 0.8 1.3 1.0 46 Female 0.6 1.5 1.2 1.5 0.5 1.0 0.8 47 Melanoma of the skin-C43 48 Male 0.0 0.5 0.2 0.9 0.3 13.7 16.8 49 Female 0.1 0.3 0.2 0.7 0.4 11.2 12.0 50 Skin-C44 51 Male 3.0 4.3 1.3 11.0 3.8 2.8 1.3 52 Female 2.6 4.1 1.0 7.7 3.2 1.9 1.0 53 Connective & soft tissue-C47-C49 54 Male 1.4 2.4 1.5 2.1 1.3 3.2 3.0 55 Female 1.2 2.3 1.2 2.1 0.9 2.2 2.1 56 Breast-C50 57 Male 0.7 1.0 1.3 0.1 0.5 1.3 0.7 58 59 60 Page 17 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 19 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Female 49.9 69.0 31.6 28.0 21.1 89.4 86.6 4 Cervix-C53 5 Female 3.1 7.5 17.7 5.4 2.0 5.5 6.4 6 Uterus-C54 7 Female 3.5 6.7 4.5 1.7 4.4 14.4 16.7 8 Ovary-C56-C57.0-4 9 Female 4.8 8.8 8.6 6.1 3.3 9.2 9.6 10 Other female genital organ(s)-C51-C52, C55, C58 11 Female 1.7 1.0 1.6 1.4 0.9 1.8 2.5 12 Penis-C60 13 Male - 0.1 1.0 0.0 0.1 0.3 0.7 14 Prostate-C61 15 Male For peer6.2 10.1 review 10.1 10.6 only 7.9 68.3 106.8 16 Testis-C62 17 Male 0.7 1.2 0.6 2.3 0.6 4.7 4.9 18 Kidney, etc.-C64, C66, C68 19 Male 1.7 1.9 2.7 2.2 3.8 13.9 137.0 20 Female 1.2 0.8 1.2 1.2 2.5 6.5 7.1 21 Bladder-C67 22 Male 5.2 9.3 6.5 8.5 5.6 25.5 20.8 23 Female 1.5 2.6 1.5 2.8 1.3 4.8 5.3 24 Eye-C69 25 Male 0.7 0.6 0.3 0.4 0.4 0.6 0.8 26 Female 0.3 0.3 0.2 0.2 0.2 0.4 0.6 27 Brain, CNS-C70-C72 28 Male 4.2 3.3 3.8 7.8 3.5 6.7 6.4 29 Female 2.7 2.7 2.4 5.3 2.1 5.0 4.6 30 Thyroid-C73 31 Male 0.6 0.7 1.1 1.2 2.5 4.8 3.9 32 Female 2.2 2.9 2.5 3.0 10.2 14.7 12.3 33 Adrenal & other endocrine-C74-C75 34 Male 0.1 0.2 0.2 0.7 0.3 0.6 0.5 http://bmjopen.bmj.com/ 35 Female - 0.3 0.2 0.4 0.2 0.5 0.4 36 Hodgkin lymphoma-C81 37 Male 1.8 2.0 1.6 1.8 2.2 3.6 2.7 38 Female 0.6 1.0 0.7 1.1 2.0 3.4 2.2 39 NHL-C82-C86, C96 40 Male 5.1 7.6 5.6 7.2 8.6 17.9 15.5 41 Female 3.5 5.1 3.0 3.3 7.1 14.4 10.8

42 Multiple myeloma-C88, C90 on October 2, 2021 by guest. Protected copyright. 43 Male 0.7 1.8 2.0 2.4 1.8 4.8 4.7 44 Female 0.6 1.3 1.2 2.2 1.0 3.0 3.1 45 Leukemia-C91-C95 46 Male 2.2 4.8 5.6 10.8 5.7 10.6 11.1 47 Female 1.2 4.1 3.6 7.7 4.3 6.9 7.1 48 All sites-C00-C96 49 Male 70.9 166.6 119.7 165.3 104.1 273.1 359.4 50 Female 107.6 192.0 118.4 142.0 103.9 308.5 282.6 51 52 53 CONCLUSION 54 55 56 This is the first time that an attempt has been made to determine and report the population-based 57 cancer statistics for the Lahore district. This collaborative study highlights cancer registration and follow- 58 59 60 Page 18 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open Page 20 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 up issues in a developing country like Pakistan, along with the non-availability of recent, accurate 4 5 population estimates required as denominators in computation of the incidence rates. Over 5,300 new 6 cancer cases were reported in the Lahore district, in the year 2010 (Figure 2). Although it is likely that all 7 the cases have not been reported for the year 2010, it is not possible to gauge the extent of under- 8 9 reporting at this stage. The cancer statistics reported in this manuscript can be used as baseline figures 10 for comparison with studies to be undertaken in the future. These statistics can also assist in highlighting 11 the putative risk factors associated with cancers commonly diagnosed in the region, as part of a health 12 13 promotion and education program. Finally, this report can play an important role in developing 14 prevention, early detection, and cancer control strategies in the region. 15 For peer review only 16 17 18 FOOTNOTES 19 20 Contributors 21 22 23 FB conceived the idea of the study, designed it, supervised the statistical analysis, did literature search, 24 interpreted the results, and drafted the manuscript. FB further did the survival analysis for this study. 25 SMa did the case-finding, coding, and indexing of cases from SKMCH & RC and computed the incidence 26 27 rates and created figures and tables; RF and AY validated the data, checked for duplication, and 28 followed-up on the patients; and AQ and KLA worked on the comparison of the incidence rates with 29 other regions. MAY reviewed the paper critically. MM was responsible for reporting the cancers 30 31 recorded at the Institute of Nuclear Medicine and Oncology, Lahore; GRS from Ittefaq Hospital, Lahore; 32 TM from Fatima Jinnah Medical University, Lahore; ORC from Chughtais Lahore Lab., Lahore; NC from 33 Sheikh Zayed Hospital, Lahore; SR from Fatima Memorial Hospital, Lahore; TA from Allama Iqbal Medical 34 http://bmjopen.bmj.com/ 35 College, Lahore; GH from the Children’s Hospital & the Institute of Child Health, Lahore; RB from the 36 Services Institute of Medical Sciences, Lahore; BAS from Nawaz Shairf Social Security Hospital, Lahore; 37 and ZA and MAK from Jinnah Hospital, Lahore. NS contributed intellectually to the study. MTM, SMu, 38 39 and AL did the pathologic confirmation of cases at SKMCH & RC, Lahore. SMa supervised, FB managed, 40 and MAY and FS established and directed the Punjab Cancer Registry. 41

42 Funding on October 2, 2021 by guest. Protected copyright. 43 44 None for this study. 45 46 Competing interests 47 48 49 We declare no competing interests. 50 51 Data sharing statement 52 53 No additional data available. 54 55 56 57 ACKNOWLEDGEMENTS 58 59 60 Page 19 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 21 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 We thank the professionals representing various centers in the region for reporting their data to the 4 5 Punjab Cancer Registry. We also thank the staff of the unit Cancer Registry and Clinical Data 6 Management, SKMCH & RC, on making additional efforts to complete cancer registration, following 7 international guidelines, thus, enabling us to complete the study. 8 9

10 11 12 REFERENCES 13 14 1 Valsecchi MG, Steliarova-Foucher E. Cancer registration in developing countries: luxury or 15 necessity?For Lancet Oncol peer [Internet]. 2008 review Feb [cited 2016 Feb only16]; 9: 159-67. Available from: 16 http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70028-7/fulltext DOI: 17 10.1016/S1470-2045(08)70028-7. 18

19 20 2 The World Bank [Internet]. Washington, DC, USA; 2016 [cited 2016 Jan 25]. Available from: 21 http://databank.worldbank.org/data/reports.aspx?source=2&type=metadata&series=EN.POP.D 22 NST# and http://wdi.worldbank.org/table/1.5 23 24 3 Survey of Pakistan (Map) [Internet]. Pakistan; 2015 [cited 2015 Dec 17]. Available from: 25 http://www.surveyofpakistan.gov.pk/ 26 27 28 4 Pakistan Bureau of Statistics-Government of Pakistan [Internet]. Islamabad, Pakistan; 2015 29 [cited 2015 Dec 16]. Available from: http://www.pbs.gov.pk/content/population-census 30 31 5 Census in Pakistan by Wikipedia [Internet]. Wikimedia Foundation, San Francisco, CA, USA; 2016 32 [cited 2016 Jan 22]. Available from: https://en.wikipedia.org/wiki/Census_in_Pakistan 33 34 http://bmjopen.bmj.com/ 35 6 Bhurgri Y. Epidemiology of cancers in Karachi 1995-1999. Karachi: Pharmacia and Upjohn; 2001. 36 37 7 Punjab Cancer Registry [Internet]. SKMCH & RC, Lahore, Pakistan; 2011 [cited 2015 Dec 16]. 38 Available from: http://punjabcancerregistry.org.pk 39 40 8 Shaukat Khanum Memorial Cancer Hospital and Research Center [Internet]. Lahore, Pakistan; 41 2015 [cited 2015 Dec 16]. Available from: http://www.shaukatkhanum.org.pk/

42 on October 2, 2021 by guest. Protected copyright. 43 44 9 Badar F. Cancer Registration in Pakistan. J Coll Physicians Surg Pak 2013; 23(8): 611–12. 45 46 10 Badar F, Mahmood S. The state of cancer registration in Pakistan. J Ayub Med Coll Abbottabad 47 2015; 27(2): 507–508. 48 49 11 The Societies Registration Act, 1860 (Act XXI of 1860) [Internet]. Pakistan; 2015 [cited 2015 Dec 50 51 16]. Available from: http://punjablaws.gov.pk/laws/1.html#_ftn2 52 53 12 IACR-International Association of Cancer Registries [Internet]. Lyon, France; 2015 [cited 2015 54 Dec 16]. Available from: http://www.iacr.com.fr/ 55 56 57 58 59 60 Page 20 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open Page 22 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 13 Census-Publication No. 125-Population Census Organization-Statistics Division, Government of 4 Pakistan, Islamabad (2000). Statistical Tables of 1998 Population and Housing Census. In: ‘1998 5 6 District Census Report of Lahore.’ Islamabad: Government of Pakistan: 2000. P. 77–305. 7 8 14 MacLennan R. Chapter 6-Items of patient information which may be collected by registries. In: 9 Jensen OM, Parkin DM, MacLennan R, Muir CS, Skeet RG, editor. Cancer Registration: Principles 10 and Methods-IARC Scientific Publications No. 95. Lyon, France: International Agency for 11 Research on Cancer; 1991 [cited 2016 Feb 16]. Available from: 12 13 https://www.iarc.fr/en/publications/pdfs-online/epi/sp95/SP95.pdf 14 15 15 Holden K,For editor. ICD-10-CM peer Expert for review Hospitals. The complete only official code set. Codes valid 16 October 1, 2015 through September 30, 2016. Salt Lake City, UT, USA: Optum360, LLC; 2015. 17 18 16 GLOBOCAN 2012: Estimated Cancer Incidence, Mortality, and Prevalence Worldwide in 2012 19 [Internet]. Lyon, France; 2015 [cited 2015 Dec 17]. Available from: 20 21 http://globocan.iarc.fr/Default.aspx 22 23 17 Boyle P, Parkin DM. Chapter 11-Statistical Methods for Registries-IARC. In: Jensen OM, Parkin 24 DM, MacLennan R, Muir CS, Skeet RG, editors. Cancer Registration: Principles and Methods. 25 IARC Scientific Publication No. 95. Lyon, France: International Agency for Research on Cancer; 26 27 1991 [cited 2016 Feb 16]. Available from: https://www.iarc.fr/en/publications/pdfs- 28 online/epi/sp95/SP95.pdf 29 30 18 The Surveillance, Epidemiology, and End Results (SEER) Program [Internet]. NCI, Bethesda, 31 Maryland; 2016 [cited 2016 Feb 4]. Available from: http://seer.cancer.gov/registries/terms.html 32 33 19 Cancer Incidence in Five Continents Volumes I to X-IACR; International Agency for Research on 34 http://bmjopen.bmj.com/ 35 Cancer [Internet]. Lyon, France; 2016 [cited 2016 Feb 3]. Available from: http://ci5.iarc.fr/CI5I- 36 X/Pages/table4_sel.aspx 37 38 20 Sreedevi A, Javed R, Dinesh A. Epidemiology of cervical cancer with special focus on India. Int J 39 Womens Health [Internet]. 2015 Apr [cited 2016 Feb 16]; 7: 405–414. Available from: 40 41 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404964/ DOI: 10.2147/IJWH.S50001.

42 on October 2, 2021 by guest. Protected copyright. 43 21 Raza SA, Franceschi S, Pallardy S, et al. Human papillomavirus infection in women with and 44 without cervical cancer in Karachi, Pakistan. Br J Cancer [Internet]. 2010 Apr [cited 2016 Feb 16]; 45 46 102: 1657–1660. Available from: https://researchonline.lshtm.ac.uk/448554/1/6605664a.pdf 47 DOI:10.1038/sj.bjc.6605664. 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 21 of 21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Page 23 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 59x51mm (300 x 300 DPI) 38 39 40 41

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 Appendix A-List of collaborating centers: Centers 1-13 contributed data in 2010 and are listed in descending 6 7 order of the number of cases reported, to the Punjab Cancer Registry. 8 9 S. No. Center name 10 1 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore. 11 12 2 Institute of Nuclear Medicine and Oncology, Lahore. 13 3 Ittefaq Hospital, Lahore. 14 15 4For Fatima peerJinnah Medical University, review Lahore. only 16 5 Chughtais Lahore Lab., Lahore. 17 6 Sheikh Zayed Hospital, Lahore. 18 19 7 Fatima Memorial Hospital, Lahore. 20 8 The Children's Hospital & the Institute of Child Health, Lahore. 21 22 9 Allama Iqbal Medical College, Lahore. 23 10 Services Institute of Medical Sciences, Lahore. 24 25 11 Nawaz Sharif Social Security Hospital, Lahore. 26 12 Jinnah Hospital, Lahore. 27 13 King Edward Medical University, Lahore. 28 29 14 Shalamar Hospital, Lahore. 30 15 Combined Military Hospital, Lahore. 31 32 16 Akhtar Saeed Medical & Dental College, Lahore. 33 17 Post Graduate Medical Institute, Lahore.

34 http://bmjopen.bmj.com/ 35 18 Pride Lab., Lahore. 36 19 Indus Lab., Lahore. 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 27 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 STROBE Statement—checklist of items that should be included in reports of observational studies 3 4 5 Item No Recommendation 6 7 Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the 8 abstract-page 7 9 (b) Provide in the abstract an informative and balanced summary of what was done 10 and what was found- page 7 11 12 Introduction 13 Background/rationale 2 Explain the scientific background and rationale for the investigation being reported- 14 page 9-10 15 Objectives For3 peer State specific objectives, review including any pre-specified only hypotheses-page 10 16 17 Methods 18 Study design 4 Present key elements of study design early in the paper-page 11 19 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, 20 21 exposure, follow-up, and data collection-page 11 22 Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of 23 selection of participants. Describe methods of follow-up 24 Case-control study—Give the eligibility criteria, and the sources and methods of 25 26 case ascertainment and control selection. Give the rationale for the choice of cases 27 and controls 28 Cross-sectional study—Give the eligibility criteria, and the sources and methods of 29 selection of participants-pages 9-11 30 (b) Cohort study—For matched studies, give matching criteria and number of 31 32 exposed and unexposed 33 Case-control study—For matched studies, give matching criteria and the number of

34 controls per case http://bmjopen.bmj.com/ 35 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect 36 37 modifiers. Give diagnostic criteria, if applicable-pages 11-15 38 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 39 measurement assessment (measurement). Describe comparability of assessment methods if there 40 is more than one group-pages 15-18 41 Bias 9 Describe any efforts to address potential sources of bias-page 19

42 on October 2, 2021 by guest. Protected copyright. 43 Study size 10 Explain how the study size was arrived at-page 11 44 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, 45 describe which groupings were chosen and why-page 11 46 Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding- 47 48 page 11 49 (b) Describe any methods used to examine subgroups and interactions-page 11 50 (c) Explain how missing data were addressed-page 11 51 (d) Cohort study—If applicable, explain how loss to follow-up was addressed 52 53 Case-control study—If applicable, explain how matching of cases and controls was 54 addressed 55 Cross-sectional study—If applicable, describe analytical methods taking account of 56 sampling strategy- not applicable 57 (e) Describe any sensitivity analyses 58 59 Continued on next page 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 BMJ Open Page 28 of 27 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Results 4 5 Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, 6 examined for eligibility, confirmed eligible, included in the study, completing follow-up, and 7 analysed-pages 11-15 8 (b) Give reasons for non-participation at each stage-pages 11-15 9 (c) Consider use of a flow diagram-none 10 11 Descriptive 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information 12 data on exposures and potential confounders-page 11 13 (b) Indicate number of participants with missing data for each variable of interest-page 11 14 (c) Cohort study—Summarise follow-up time (e.g., average and total amount) 15 For peer review only 16 Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time 17 Case-control study—Report numbers in each exposure category, or summary measures of 18 exposure 19 Cross-sectional study—Report numbers of outcome events or summary measures- pages 11-15 20 21 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their 22 precision (e.g., 95% confidence interval). Make clear which confounders were adjusted for and 23 why they were included-pages 11-15 24 (b) Report category boundaries when continuous variables were categorized 25 26 (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful 27 time period 28 Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity 29 analyses 30 31 Discussion 32 Key results 18 Summarise key results with reference to study objectives-pages 15-18 33 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision.

34 http://bmjopen.bmj.com/ Discuss both direction and magnitude of any potential bias-pages 18-19 35 36 Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity 37 of analyses, results from similar studies, and other relevant evidence-pages 18-19 38 Generalisability 21 Discuss the generalisability (external validity) of the study results- pages 18-19 39 40 Other information 41 Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable,

42 for the original study on which the present article is based-pages 10 & 19 on October 2, 2021 by guest. Protected copyright. 43 44 *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and 45 46 unexposed groups in cohort and cross-sectional studies. 47 48 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 49 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 50 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 51 52 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 53 available at www.strobe-statement.org. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml2 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from

THE EPIDEMIOLOGY OF CANCERS IN LAHORE, PAKISTAN, 2010-2012: A CROSS-SECTIONAL STUDY

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-011828.R1

Article Type: Research

Date Submitted by the Author: 06-May-2016

Complete List of Authors: Badar, Farhana; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Mahmood, Shahid; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Yusuf, Mohammed; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Internal Medicine Mahmood, Mohammad ; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pathology Masood, Misbah; The Institute of Nuclear Medicine and Oncology, Oncology Sial, Ghulam; Ittefaq Hospital(Trust), Pathology Chughtai, Nasir; Sheikh Zayed Hospital , Pathology Chughtai, Omar; Chughtais Lahore Lab Mustafa, Tanveer; Fatima Jinnah Medical University, Pathology Aziz, Zeba; Hameed Latif Hospital, Oncology

Khokhar, Muhammad; King Edward Medical University, Oncology & http://bmjopen.bmj.com/ Radiotherapy Hanif, Ghazala; The Children’s Hospital & the Institute of Child Health, Pathology Ahmad, Alia; The Children’s Hospital & the Institute of Child Health, Hematology/Oncology Bajwa, Rakhshindah; Services Institute of Medical Sciences, Pathology Riaz, Sabiha; Fatima Memorial College of Medicine & Dentistry, Pathology Tanvir, Imrana; Fatima Memorial College of Medicine & Dentistry, Pathology on October 2, 2021 by guest. Protected copyright. Aziz, Farooq; Shalamar Medical & Dental College, Pathology Anis, Tazeen; Allama Iqbal Medical College, Pathology Niazi, Shahida; King Edward Medical University, Pathology Suleman, Bilquis; Nawaz Sharif Social Security Hospital, Pathology Siddiqui, Neelam; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Medical Oncology Mushtaq, Sajid; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pathology Loya, Asif; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pathology Hussain, Mudassar; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pathology Faraz, Raqib; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Yousaf, Aneel; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Quader, Ainul; Shaukat Khanum Memorial Cancer Hospital and Research

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 Centre, Cancer Registry & Clinical Data Management 5 Ali, Kamran; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management 6 Asif, Hina; Shaukat Khanum Memorial Cancer Hospital and Research 7 Centre, Cancer Registry & Clinical Data Management 8 Atif, Adna; Shaukat Khanum Memorial Cancer Hospital and Research 9 Centre, Cancer Registry & Clinical Data Management 10 Sultan, Faisal; Shaukat Khanum Memorial Cancer Hospital and Research 11 Centre, Internal Medicine 12 Primary Subject Public health 13 Heading: 14 15 Secondary SubjectFor Heading: peerEpidemiology review only 16 17 Keywords: PUBLIC HEALTH, EPIDEMIOLOGY, ONCOLOGY 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 THE EPIDEMIOLOGY OF CANCERS IN LAHORE, PAKISTAN, 2010-2012: A CROSS-SECTIONAL STUDY 4 5 6 Farhana Badar, Shahid Mahmood, Muhammed Aasim Yusuf, Mohammad Tariq Mahmood, Misbah 7 Masood, Ghulam Rasool Sial, Nasir Chughtai, Omar Rasheed Chughtai, Tanveer Mustafa, Zeba Aziz, 8 Muhammad Abbas Khokhar, Ghazala Hanif, Alia Ahmad, Rakhshindah Bajwa, Sabiha Riaz, Imrana Tanvir, 9 Farooq Aziz, Tazeen Anis, Shahida Niazi, Bilquis A. Suleman, Neelam Siddiqui, Sajid Mushtaq, Asif Loya, 10 11 Mudassar Hussain, Raqib Faraz, Aneel Yousaf, Ain ul Quader, Kamran Liaqat Ali, Hina Asif, Adna Atif, 12 Faisal Sultan. 13 14 15 For peer review only 16 Corresponding author 17 18 19 Farhana Badar-MBBS, MPH 20 21 Sr. Biostatistician & Cancer Epidemiologist 22 23 Cancer Registry & Clinical Data Management 24 25 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 26 27 7-A, Block R-3 28 29 30 Johar Town, Lahore 31 32 Pakistan 33

34 Ph.: +92 42 35905000 Ext. 4240 | Email: [email protected] http://bmjopen.bmj.com/ 35 36 37 38 Shahid Mahmood-MBA, CPC 39 40 Medical Coder/Cancer Registry Officer 41

42 on October 2, 2021 by guest. Protected copyright. 43 Cancer Registry & Clinical Data Management 44 45 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 46 47 48 49 Mohammed Aasim Yusuf-FRCP 50 51 Consultant Gastroenterologist | Chief Medical Officer 52 53 54 Department of Internal Medicine 55 56 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 29 Page 3 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 6 Mohammad Tariq Mahmood-DABP 7 8 Consultant Pathologist 9 10 Department of Pathology 11 12 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 13 14 15 For peer review only 16 Misbah Masood-FCPS 17 18 19 Consultant Clinical Oncologist 20 21 Oncology Division 22 23 The Institute of Nuclear Medicine & Oncology, Lahore, Pakistan. 24 25 26 27 Ghulam Rasool Sial-FCPS 28 29 30 Consultant Pathologist 31 32 Department of Pathology 33

34 Ittefaq Hospital, Lahore, Pakistan. http://bmjopen.bmj.com/ 35 36 37 38 Nasir Chughtai-MPhil 39 40 Consultant Pathologist 41

42 on October 2, 2021 by guest. Protected copyright. 43 Department of Pathology 44 45 Sheikh Zayed Hospital, Lahore, Pakistan. 46 47 48 49 Omar Rasheed Chughtai-FCAP 50 51 Consultant Pathologist 52 53 Chughtais Lahore Lab, Lahore, Pakistan. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 2 of 29 BMJ Open Page 4 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Tanveer Mustafa-MPhil 4 5 6 Senior Demonstrator 7 8 Department of Pathology 9 10 Fatima Jinnah Medical University, Lahore, Pakistan. 11 12 13 14 Zeba Aziz-DABM 15 For peer review only 16 Consultant Oncologist 17 18 19 Department of Oncology 20 21 Hameed Latif Hospital, Lahore, Pakistan. 22 23 24 25 Muhammad Abbas Khokhar-FCPS 26 27 Assistant Professor 28 29 30 Department of Oncology and Radiotherapy 31 32 King Edward Medical University, Lahore, Pakistan. 33

34 http://bmjopen.bmj.com/ 35 36 Ghazala Hanif-MPhil 37 38 Consultant Pathologist 39 40 Department of Pathology 41

42 on October 2, 2021 by guest. Protected copyright. 43 The Children’s Hospital & the Institute of Child Health, Lahore, Pakistan. 44 45 46 47 Alia Ahmad-MRCPCH 48 49 Associate Professor 50 51 Department of Hematology/Oncology 52 53 The Children’s Hospital & the Institute of Child Health, Lahore, Pakistan. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 29 Page 5 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Rakhshindah Bajwa-MPhil 4 5 6 Consultant Pathologist 7 8 Department of Pathology 9 10 The Services Institute of Medical Sciences, Lahore, Pakistan. 11 12 13 14 Sabiha Riaz-FRCPath 15 For peer review only 16 Consultant Pathologist 17 18 19 Department of Pathology 20 21 Fatima Memorial College of Medicine & Dentistry, Lahore, Pakistan. 22 23 24 25 Imrana Tanvir-FCPS 26 27 Assistant Professor 28 29 Department of Pathology 30 31 Fatima Memorial College of Medicine & Dentistry, Lahore, Pakistan. 32 33

34 http://bmjopen.bmj.com/ 35 Farooq Aziz-MPhil 36 37 Professor 38 39 Department of Pathology 40 41 Shalamar Medical & Dental College, Lahore, Pakistan.

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 Tazeen Anis-DCP 46 47 48 Senior Demonstrator 49 50 Department of Pathology 51 52 Allama Iqbal Medical College, Lahore, Pakistan. 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 4 of 29 BMJ Open Page 6 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Shahida Niazi-MPhil 4 5 Associate Professor 6 7 Department of Pathology 8 9 King Edward Medical University, Lahore, Pakistan. 10 11 12 13 14 Bilquis A. Suleman-FRCPath 15 For peer review only 16 Consultant Pathologist 17 18 Department of Pathology 19 20 Nawaz Sharif Social Security Hospital, Lahore, Pakistan. 21 22

23 24 25 Neelam Siddiqui-FRCP 26 27 Consultant Oncologist 28 29 Department of Medical Oncology 30 31 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 32 33 34 http://bmjopen.bmj.com/ 35 36 Sajid Mushtaq-FRCPath 37 38 Consultant Pathologist 39 40 Department of Pathology 41

42 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. on October 2, 2021 by guest. Protected copyright. 43 44 45 46 Asif Loya-DABP 47 48 49 Consultant Pathologist 50 51 Department of Pathology 52 53 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 29 Page 7 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Mudassar Hussain-FCPS 4 5 Consultant Pathologist 6 7 Department of Pathology 8 9 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 10 11 12 13 14 Raqib Faraz-BSc 15 For peer review only 16 Medical Coder/Cancer Registry Officer 17 18 Cancer Registry & Clinical Data Management 19 20 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 21 22 23 24 Aneel Yousaf-MBA 25 26 27 Medical Coder/Cancer Registry Officer 28 29 Cancer Registry & Clinical Data Management 30 31 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 32 33 34 http://bmjopen.bmj.com/ 35 Ain ul Quader-BSc 36 37 38 Medical Coder/Cancer Registry Officer 39 40 Cancer Registry & Clinical Data Management 41

42 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. on October 2, 2021 by guest. Protected copyright. 43 44 45 46 Kamran Liaqat Ali-BSc 47 48 Medical Coder/Cancer Registry Officer 49 50 51 Cancer Registry & Clinical Data Management 52 53 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 6 of 29 BMJ Open Page 8 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Hina Asif-MSc 4 5 6 Medical Coder/Cancer Registry Officer 7 8 Cancer Registry & Clinical Data Management 9 10 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 11 12 13 14 Adna Atif-BA 15 For peer review only 16 Medical Coder/Cancer Registry Officer 17 18 19 Cancer Registry & Clinical Data Management 20 21 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 22 23 24 25 Faisal Sultan-FRCP 26 27 Consultant Physician | Chief Executive Officer 28 29 30 Department of Internal Medicine 31 32 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

34 Standardized Incidence Rates (ASIR) were computed per 100,000 population, by gender and cancer site. http://bmjopen.bmj.com/ 35 Five-year age categories were created from 0-4 till 70-74, followed by 75+ years. Death counts were 36 37 reported by site. 38 39 Results 40 41 Between 2010 and 2012, in Lahore, a total of 15,840 new cancers were diagnosed-43% in male and 57%

42 female patients; 93.5% microscopically confirmed and 6.5% non-microscopically. The ASIR amongst on October 2, 2021 by guest. Protected copyright. 43 44 females was 105.1 and in males 66.7. ASIRs of leading cancers, amongst women, were: breast 47.6, 45 ovary 4.9, and corpus uteri 3.6, whereas, amongst men: prostate 6.4, bladder 5.0, and, trachea, 46 bronchus, & lung 4.6. A total of 5,134 deaths were recorded. 47 48 Conclusions 49 50 51 In Lahore, the ASIR was higher in women than in men. Amongst women, breast cancer, and in men, 52 prostate cancer, were the leading cancer types. These estimates can be used for health promotion and 53 policy making in the region. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 8 of 29 BMJ Open Page 10 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 6 7 8 ARTICLE SUMMARY 9 10 STRENGTHS AND LIMITATIONS OF THIS STUDY 11 12 • This is the first time that the age-standardized incidence rates have been presented for the 13 Lahore district. 14 15 For peer review only 16 • A comparison has been made with the incidence rates reported by other registries around the 17 world. 18 19 • There are follow-up issues related to determining the vital status of the patients, once they are 20 21 registered as new cancer patients. Therefore, the limitation of the study is that the vital status 22 of the vast majority of patients could not be determined. 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 29 Page 11 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 PAPER 4 5 6 7 8 THE EPIDEMIOLOGY OF CANCERS IN LAHORE, PAKISTAN, 2010-2012: A CROSS-SECTIONAL STUDY 9 10 INTRODUCTION 11 12 In the area of public health research, conducting high-quality, population-level studies, is hailed as the 13 gold standard, as the outcomes truly represent the disease status of the community on whom the 14 15 studies are being Forconducted. Thispeer includes the review practice of population-based only cancer registration, which 16 not only assists in providing statistics and trends on incidence, mortality, and survival, it can also provide 17 information on putative risk factors associated with various diseases within a defined population, living 18 19 in a geographically demarcated area, over a specified period of time. However, cancer registration can 20 only be undertaken if there is appropriate infrastructure to enable it, and suitable, well-trained staff to 21 perform the tasks associated with it. Understandably, there is a cost associated with conducting this 22 23 type of epidemiologic work, and in a resource-constrained country like Pakistan, governments are less 24 likely to focus on the area of cancer registration than other areas deemed more immediately critical. 25 Further, there is no legislation in the country that requires health-care practitioners to report diagnoses 26 27 of cancer. Moreover, the health-care delivery in Pakistan is quite complex, and is as depicted in Figure 1. 28 A large part of the population is served through a mixed system via multiple health providers[1]. 29 30 The question whether cancer registration is a necessity or a luxury in developing countries has been 31 debated extensively over the years. A paper published in 2008 stated that in low-income countries, 32 33 cancer registration is urgently needed so as to gauge the cancer burden in the region[2]. Given that

34 Pakistan is categorized as a ‘lower-middle income country’ by the World Bank, with its population http://bmjopen.bmj.com/ 35 estimated to be 185·0 million in the year 2014, and the life expectancy at birth being 66 years (65 years 36 37 for males and 67 years for females), it seems unlikely that registration of all cancer diagnoses will be 38 accurate and complete at the national level in the near future[3]. However, there is no denying the fact 39 that knowing the cancer burden in the region helps in projecting regional cancer trends, establishing the 40 41 required numbers of health-care facilities to cater to the needs of the patients, training sufficient

42 numbers of health-care practitioners to manage the conditions, addressing health education, and on October 2, 2021 by guest. Protected copyright. 43 assisting in developing prevention, early detection, and cancer control programs in the region. Figure 2 44 45 is a map of Pakistan showing the provinces of Pakistan and countries adjacent to Pakistan[4]. Even 46 though accurate population figures are not available, enthusiastic professionals have, over the years, 47 endeavored to determine cancer estimates for Pakistan. In the past, the regional registry of the Karachi 48 49 South district, in the province of Sindh, was established and managed for several years by a dedicated 50 pathologist, Dr. Yasmin Bhurgri[5]. This registry was widely recognized at an international level for its 51 data quality[5]. However, due to the sudden death of Dr. Bhurgri in January 2012, this registry is no 52 53 longer active. Another registry in Pakistan is the Punjab Cancer Registry (PCR), which was founded 54 collaboratively by a group of health-professionals in 2005, pioneered by the administrators of a 55 complete cancer treatment facility in Lahore called the Shaukat Khanum Memorial Cancer Hospital and 56 57 Research Center (SKMCH & RC)[6-9]. The Punjab Cancer Registry, herein, referred to as the Registry, is 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 10 of 29 BMJ Open Page 12 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 registered with, and regulated under, the Societies Registration Act, 1860, of the Government of 4 5 Pakistan[10]. It is also a member of the International Association of Cancer Registries, France[11]. 6 Appendix A shows the list of collaborating centers of the Registry. 7 8 The reporting of cancer cases to population-based cancer registries is not required by law, in Pakistan. It 9 is, in fact, a voluntary task undertaken by professionals representing many institutions of the region. 10 11 When the Registry was established in 2005, a memorandum outlining the structure and governance 12 mechanisms was signed by the stake-holders representing both the government and private 13 laboratories and hospitals of the city. The purpose of establishing the Registry was to determine the 14 15 cancer estimates Forin the province peer of Punjab. Punjab review is the most populous only province of Pakistan, with a 16 population estimated at 100 M, and 36 administrative districts, of which Lahore is the most populous, 17 with a population of some 10 M[12,13]. For about a decade, data have been captured in a systematic 18 19 and pre-defined manner, in accordance with the minimum data items required for cancer registries as 20 well as some additional optional data items[6,9,14]. 21 22 In the past, PCR data have been reported to the International Agency for Research on Cancer (IARC) in 23 24 response to a call for data by the Agency. The data have been used, along with data from Dr. Yasmin 25 Bhurgri’s paper, and the Federal Bureau of Statistics, Pakistan, to provide cancer estimates for Pakistan 26 in the Globocan 2012 report[15]. 27 28 This manuscript provides population-level cancer estimates for the Lahore district, based on cases 29 30 diagnosed in 2010-2012 and reported to the Registry. This is the first time that the Lahore district 31 population-level data have been computed and are being reported. 32 33 34 http://bmjopen.bmj.com/ 35 METHODS 36 37 38 The population denominator 39 40 Population-level statistics cannot be computed without the availability of figures for the population 41 under review, or the catchment population. In Pakistan, publications describing the population structure

42 are available for the census that was conducted in 1998[12]. However, the most recent population on October 2, 2021 by guest. Protected copyright. 43 44 census, initiated a year ago, has not yet been completed[16]; therefore, accurate figures describing the 45 Pakistani population are not available. As a result, for this study, population estimates are based on 46 population figures determined by using the average annual growth rates provided by the Government of 47 48 Pakistan[12]. 49 50 In the years 2010, 2011, and 2012, the population of the Lahore district was estimated at 9,503,871, 51 9,832,705, and 10,172,916 respectively, computed using an average annual growth rate of 52 53 3·46%[12,13]. The total area of the Lahore district is 1,772 square kilometers, with its average 54 population density being calculated as 5,551 persons, per square kilometer, in the years under 55 study[12]. Figure 3 is a population pyramid showing the combined population distribution of the Lahore 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 29 Page 13 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 district by age-group and gender, for the years 2010-2012. These population estimates were used as the 4 5 population-at-risk denominator, for calculating the incidence rates for this study. 6 7 Data collection 8 9 As routine cancer registration practice, the information is collected on the PCR data collection forms 10 11 developed collaboratively, following international guidelines on recording cancers (Appendix B). The 12 pertinent question on the form states whether a patient is a resident of Lahore or has come to Lahore 13 for diagnosis or treatment only. This has helped to identify the residents of Lahore. 14 15 For peer review only 16 Each center is allocated a separate center identification number. The forms are distributed to, and 17 collected from, each participating center on a regular basis. Both the active and passive methods of data 18 19 collection are used[14]. Registry Staff educates relevant personnel at each center with regard to data 20 capture, missing information and answers any other queries that arise. At the Cancer Registry & Clinical 21 Data Management unit, only authorized personnel are allowed to enter data from forms, into the 22 database. The forms collected are stored securely and remain confidential. The information is 23 24 subsequently entered into the Punjab Cancer Registry database, developed as part of the computerized 25 Hospital Information System of SKMCH & RC (Appendices C-CCC). All authorized Staff members are 26 given specific usernames and passwords to turn the computers on and another username-password to 27 28 access the system, and thence, the PCR software. Any form of transmission of the information including 29 printing and saving it on portable electronic devices, and aspects related to document retention, are 30 strictly regulated by the Governing Council of the Registry and SKMCH & RC, the latter being the sponsor 31 32 of the Registry. For the cases diagnosed or treated at SKMCH & RC, linkages have been developed with 33 the pathology department and clinics to facilitate date capture.

34 http://bmjopen.bmj.com/ 35 36 For the purpose of recording cancers, incidence date on the PCR form is defined as the date of 37 cytologic/histologic confirmation of a malignancy on a pathology report, date of evaluation at an 38 outpatient clinic only, or date of clinical investigation(s) as imaging or tumor markers, confirming the 39 40 diagnosis. A check for multiple primaries is done, as per IARC rules[17]. In case of duplicate registration 41 identified by checking various combinations of name/age/sex/phone number/address/tumor

42 morphology, the case is registered with the center where the first diagnosis was made. Edits, for the on October 2, 2021 by guest. Protected copyright. 43 44 validity and for the consistency between variables, are also carried out (age/incidence, 45 age/site/histology, site/histology, sex/site, sex/histology, behavior/site, behavior/histology, 46 grade/histology, and basis of diagnosis/histology). Initially, cancers were coded using the International 47 Classification of Disease for Oncology-Third Edition[18]. For this manuscript, cancers were categorized 48 49 using the International Classification of Diseases, Clinical Modification, 10th revision[19]. 50 51 Data access and follow-up 52 53 54 Release of confidential information is governed by the rules approved by the Registry, and is always 55 without any identifiers[6]. For maintaining confidentiality of the information recorded, Staff members 56 57 are made to sign a confidentially pledge at the time of employment, which remains in force after 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 12 of 29 BMJ Open Page 14 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 cessation of employment with SKMCH & RC. For the purpose of reporting the data to IARC and to 4 5 determine the vital status, patients diagnosed in the time-period 2010-2012 were followed-up 6 telephonically between July and October 2015. We were able to establish contact with only sixty 7 percent of the cases in this way. 8 9 10 Cancers reported 11 12 Cancer notifications for the Lahore district have improved with the passage of time, with the cases 13 reported to the Registry going up from 2,006 in the year 2005 to 5,123 in the year 2015. In chronologic 14 15 order, the numbersFor reported arepeer as follows: 2,006;review 2,987; 3,617; 3,990; only 5,109; 5,302; 4,949; 5,589; 16 6,009; 5,943; and 5,123. We are still receiving information on cases diagnosed in 2014 and 2015. Over 17 recent years, six other districts have been included for the purpose of data collection, with the idea 18 19 being to include 1-2 contiguous district(s) of Punjab every year in order to expand cancer registration. 20 The data collection form is modified accordingly to ascertain resident status of the patients[6]. The 21 approach related to including 1-2 districts on a regular basis has been adopted because the sponsor, 22 23 SKMCH & RC, is a charitable organization, and it is logistically not possible to initiate data collection from 24 36 districts of Punjab simultaneously. 25 26 2010-2012 study 27 28 A cross-sectional study was conducted and the Punjab Cancer Registry data were reviewed 29 30 retrospectively to retrieve information on cancer patients belonging to the Lahore district and having 31 been diagnosed in 2010-2012. Information was collected on new cancer diagnoses (by histology and 32 gender), the most valid basis of diagnosis as microscopically versus non-microscopically confirmed, 33

34 multiple primaries, and deaths recorded. Five-year age categories were created beginning from 0-4 http://bmjopen.bmj.com/ 35 years and ending on 70-74 years, with all those above 75 included as 75+. Cases were stratified by year 36 of diagnosis/gender/age-group and histology/site. 37 38 Data analysis 39 40 41 Counts were determined and ASIRs computed according to 5-year age-group, weighted by the Segi

42 World Standard population[20]. ASIRs were expressed per 100,000 population, per year, separately for on October 2, 2021 by guest. Protected copyright. 43 male and female patients. For mortality data, counts were stratified by histology/site. Overall survival 44 45 interval was computed between the dates of diagnosis and last contact and analyzed using the Kaplan- 46 Meier method. Of a total of 15,825 patients registered in the years 2010-2012, survival intervals could 47 not be computed for nearly 43 percent of the cases. Of these, in the vast majority of cases, no contact 48 49 could be established with the patients on the phone numbers provided; in some of the cases, the 50 attendants of the patients could only communicate that the patients had died but could not recall their 51 dates of death; and, in a few cases, the patients died on the day of cancer diagnoses and their intervals 52 were set at naught. Although extensive survival analysis was subsequently done on the fifty-seven 53 54 percent of cases on whom the duration of survival was available, the survival estimates generated were 55 not considered valid. Therefore, survival results are not being presented in this manuscript. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 29 Page 15 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Data were analyzed using the Microsoft Excel, version 2010, and SPSS, version 19. The Institutional 4 5 Review Board (IRB) of the Shaukat Khanum Memorial Cancer Hospital & Research Center granted 6 exemption from full IRB evaluation. 7 8 9 10 RESULTS 11 12 13 The total population of the Lahore district, in 2010-2012, was estimated to be 29,509,492, with males 14 accounting for 52·7% and females 47·3% of the population (Figure 3). The number of cases reported in 15 each of the three-yearsFor under peerstudy, 2010, 2011, review & 2012, along with onlytheir population denominators, 16 were: 5,302/9,503,871, 4,949/9,832,705, and 5,589/10,172,916, respectively. Of a total of 15,840 17 18 cancers diagnosed in 15,825 patients belonging to the district of Lahore and registered in the PCR 19 database against the corresponding years, 9,069 (57·3%) were in female and 6,771 (42·7%) in male 20 patients. Nearly ten percent were identified to have been registered twice and were eventually assigned 21 22 to the center where the first diagnosis was made, thereby, counted just once. The age-range of the 23 patients was 0-106 years. Of all the cancers diagnosed, about 93·5% were microscopically and 6·5% 24 were non-microscopically confirmed (Table 1). None were registered on the basis of death certificates 25 26 only. Skin cancer had the highest figure in the microscopically confirmed group (99·6%), whereas, liver & 27 intrahepatic bile duct(s) had the highest figure in the non-microscopically confirmed category (69·5%). 28 Multiple primary cancers, upto two, were identified in 15 patients (Table 2). The ASIR for all sites 29 30 combined amongst female patients was 105·1 per 100,000 women and amongst male patients, it was 31 66·7 per 100,000 men, per year. Tables 3-6 show the ASIRs for all the cancers recorded in the Registry, 32 by the year of diagnosis and gender, and the age-specific rates for the 5-year age-group, separately for 33

34 female and male patients. Amongst females, the highest ASIRs were recorded for the following sites and http://bmjopen.bmj.com/ 35 malignancies: breast 47·6, ovary 4·9, corpus uteri 3·6, Non-Hodgkin Lymphoma (NHL) 3·3, cervix uteri 36 2·9, and brain & CNS 2·2, whereas, in men, the highest ASIRs were: prostate 6·4, bladder 5·0, trachea, 37 38 bronchus, & lung 4·6, NHL 4·5, brain & CNS 3·8, and liver 3·7. 39 40 Table 1. The basis of diagnosis, categorized as being microscopically and non-microscopically confirmed, 41 2010-2012, in the Lahore district (N=15,840).

42 on October 2, 2021 by guest. Protected copyright. 43 The basis of diagnosis 44 Microscopic Non-Microscopic Cancer site (%) (%) 45 Lip & oral cavity 97.0 3.0 46 Esophagus 99.1 0.9 47 Stomach 99.2 0.8 48 Colorectal 96.9 3.1 49 Liver & intrahep. bile ducts 30.5 69.5 50 Gall bladder 92.6 7.4 51 Larynx 96.6 3.4 52 Bronchus & lung 94.7 5.3 53 Bone 97.0 3.0 54 Connective tissue 94.4 5.6 55 Leukemia 92.8 7.2 56 Breast 95.8 4.2 57 Cervix uteri 96.8 3.2 Corpus uteri 97.8 2.2 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 14 of 29 BMJ Open Page 16 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Testis 98.9 1.1 4 Prostate 97.5 2.5 5 NHL 95.8 4.2 6 Hodgkin lymphoma 97.5 2.5 7 Urinary bladder 97.3 2.7 8 Brain 96.6 3.4 9 Skin 99.6 0.4 10 Kidney 93.4 6.6 11 Thyroid 97.6 2.4 12 Ovary 93.7 6.3 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

17 Breast 18 4 Female 45 Alive Breast 19 20 Illdefined 21 5 Male 45 Alive Lung 22 23 Breast

24 6 Female 46 Alive Ovary 25

26 Spinal cord

27 7 Male 55 Alive NHL 28 Brain 29 30 8 Male 56 Dead Unknown primary 31 Breast 32 33 9 Female 59 Alive Liver

http://bmjopen.bmj.com/ 34 Breast 35 10 Female 60 Dead Breast 36

Rectum 37 38 11 Male 62 Dead Bone 39 40 Breast 41 12 Female 64 Alive Breast

42 on October 2, 2021 by guest. Protected copyright. Thyroid 43 44 13 Male 67 Dead Stomach 45 Connective tissue 46 14 Male 70 Dead Liver 47 48 Breast 49 15 Female 91 Dead Ovary 50 51 52 53 54

56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 16 of 29 BMJ Open Page 18 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 Table 3. Cancer counts and the age-standardized incidence rates of cancers diagnosed in the Lahore district, 5 2010-2012, according to year of diagnosis. 6 2010 2011 2012 7 Site ICD10 code Count ASIR Count ASIR Count ASIR 8 Lip C00 13 0.2 5 0.1 4 0.1 9 Tongue C01C02 115 2.0 92 1.5 102 1.6 10 Mouth C03C06 117 2.1 110 1.8 115 1.9 Salivary glands C07C08 30 0.5 32 0.5 29 0.4 11 Tonsil C09 3 0.1 3 0.1 10 0.1 12 Other oropharynx C10 2 0.0 3 0.1 1 0.0 13 Nasopharynx C11 13 0.2 11 0.1 14 0.2 14 Hypopharynx C12C13 22 0.4 12 0.2 19 0.3 15 Pharynx C14 4 0.1 3 0.0 3 0.0 Esophagus ForC15 peer 76review 1.4 61only 1.1 85 1.4 16 Stomach C16 85 1.5 86 1.4 96 1.5 17 Small intestine C17 15 0.3 15 0.3 13 0.2 18 Colon C18 148 2.6 106 1.7 135 2.2 19 Rectum C19C20 101 1.6 89 1.4 133 2.0 20 Anus C21 21 0.4 22 0.3 21 0.3 Liver C22 176 3.4 184 3.4 145 2.6 21 Gall bladder etc. C23C24 72 1.3 76 1.4 84 1.6 22 Pancreas C25 30 0.6 30 0.6 37 0.7 23 Other illdefined digestive C26 7 0.1 11 0.2 12 0.2 24 Nose, sinuses C3031 17 0.3 23 0.4 19 0.3 25 Larynx C32 74 1.4 55 1.0 82 1.4 Trachea, bronchus, & lung C33C34 162 3.2 156 2.9 170 3.2 26 Other thoracic organs C37C38 14 0.2 11 0.2 17 0.2 27 Bone C40C41 80 0.8 74 0.8 80 0.8 28 Melanoma of skin C43 4 0.1 11 0.2 11 0.1 29 Other skin C44 152 2.8 141 2.5 174 2.9 30 Connective & soft tissue C47,C49 95 1.3 95 1.2 62 0.8 Breast C50 1409 22.9 1339 21.4 1404 21.5 31 Vulva C51 3 0.1 7 0.2 9 0.4 32 Vagina C52 5 0.2 6 0.2 5 0.2 33 Cervix uteri C53 86 3.1 69 2.4 92 3.2

34 Corpus uteri C54 83 3.5 84 3.3 100 4.1 http://bmjopen.bmj.com/ Uterus, unspecified C55 34 1.3 27 1.1 28 1.0 35 Ovary C56 138 4.6 124 4.1 180 5.8 36 Other female genital organ C57 5 0.2 7 0.3 6 0.2 37 Placenta C58 3 0.1 2 0.0 2 0.0 38 Penis C60 1 0.0 39 Prostate C61 165 6.2 193 7.1 168 6.0 Testis C62 31 0.7 24 0.5 35 0.7 40 Other male genital organs C63 3 0.1 2 0.1 41 Kidney C64 88 1.5 97 1.5 89 1.4

42 Renal pelvis C65 2 0.0 on October 2, 2021 by guest. Protected copyright. 43 Ureter C66 1 0.0 1 0.0 44 Bladder C67 177 3.6 150 2.8 223 4.0 Other urinary organs C68 2 0.0 45 Eye C69 33 0.5 29 0.4 35 0.4 46 Brain, nervous system C70C72 248 3.5 203 2.8 234 3.0 47 Thyroid C73 94 1.3 92 1.3 110 1.5 48 Adrenal C74 2 0.0 3 0.0 6 0.1 49 Hodgkin lymphoma C81 104 1.3 86 1.0 92 0.9 NonHodgkin lymphoma C82C88 274 4.4 234 3.6 262 3.9 50 Multiple myeloma C90 33 0.7 26 0.5 30 0.5 51 Lymphoid leukemia C91 91 0.9 71 0.7 157 1.4 52 Myeloid leukemia C9293 42 0.5 31 0.4 96 1.1 53 Other Leukemias C95 30 0.3 25 0.3 45 0.4 54 Leukemia unspecified C94 3 0.0 2 0.0 3 0.0 Other & unspecified 335 5.7 369 6.2 393 6.4 55 Benign CNS 138 1.9 125 1.6 107 1.3 56 All sites 5302 97.8 4949 89.1 5589 96.8 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 29 Page 19 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 Table 4. Cancer counts and age-standardized incidence rates of cancers diagnosed in the Lahore district in 5 2010-2012, by gender and cancer site/type. 6 FEMALE MALE 7 Site ICD-10-code Count % Crude ASIR Count % Crude ASIR 8 Lip C00 9 0.1 0.1 0.1 13 0.2 0.1 0.1 9 Tongue C01-C02 129 1.4 0.9 1.7 180 2.7 1.2 1.8 Mouth C03-C06 130 1.4 0.9 1.6 212 3.1 1.4 2.2 10 Salivary glands C07-C08 41 0.5 0.3 0.5 50 0.7 0.3 0.5 11 Tonsil C09 8 0.1 0.1 0.1 8 0.1 0.1 0.1 12 Other oropharynx C10 - - - - 6 0.1 0.0 0.1 13 Nasopharynx C11 19 0.2 0.1 0.2 19 0.3 0.1 0.2 Hypopharynx C12-C13 32 0.4 0.2 0.4 21 0.3 0.1 0.2 14 Pharynx C14 5 0.1 0.0 0.1 5 0.1 0.0 0.0 15 Esophagus For peerC15 review95 1.0 0.7 1.2only 127 1.9 0.8 1.4 16 Stomach C16 105 1.2 0.8 1.3 162 2.4 1.0 1.6 17 Small intestine C17 17 0.2 0.1 0.2 26 0.4 0.2 0.3 Colon C18 159 1.8 1.1 1.9 230 3.4 1.5 2.4 18 Rectum C19-C20 137 1.5 1.0 1.5 186 2.7 1.2 1.9 19 Anus C21 23 0.3 0.2 0.3 41 0.6 0.3 0.4 20 Liver C22 177 2.0 1.3 2.4 328 4.8 2.1 3.7 21 Gall bladder etc. C23-C24 139 1.5 1.0 1.9 93 1.4 0.6 1.0 Pancreas C25 40 0.4 0.3 0.5 57 0.8 0.4 0.6 22 Other ill-defined digestive C26 14 0.2 0.1 0.1 16 0.2 0.1 0.2 23 Nose, sinuses C30-31 27 0.3 0.2 0.3 32 0.5 0.2 0.3 24 Larynx C32 28 0.3 0.2 0.3 183 2.7 1.2 2.0 25 Trachea, bronchus & lung C33-C34 92 1.0 0.7 1.2 396 5.8 2.5 4.6 Other thoracic organs C37-C38 16 0.2 0.1 0.2 26 0.4 0.2 0.2 26 Bone C40-C41 91 1.0 0.7 0.6 143 2.1 0.9 0.9 27 Melanoma of skin C43 13 0.1 0.1 0.1 13 0.2 0.1 0.1 28 Other skin C44 196 2.2 1.4 2.7 271 4.0 1.7 2.8 29 Connective & soft tissue C47,C49 108 1.2 0.8 1.0 144 2.1 0.9 1.2 Breast C50 4082 45.0 29.2 47.6 70 1.0 0.5 0.8 30 Vulva C51 19 0.2 0.1 0.2 - - - - 31 Vagina C52 16 0.2 0.1 0.2 - - - - 32 Cervix uteri C53 247 2.7 1.8 2.9 - - - - 33 Corpus uteri C54 267 2.9 1.9 3.6 - - - - Uterus unspecified C55 89 1.0 0.6 1.1 - - - - 34 Ovary C56 442 4.9 3.2 4.9 - - - - http://bmjopen.bmj.com/ 35 Other female genital organ C57 18 0.2 0.1 0.2 - - - - 36 Placenta C58 7 0.1 0.1 0.0 - - - - 37 Penis C60 - - - - 1 0.0 0.0 0.0 Prostate C61 - - - - 526 7.8 3.4 6.4 38 Testis C62 - - - - 90 1.3 0.6 0.6 39 Other male genital organs C63 - - - - 5 0.1 0.0 0.1 40 Kidney C64 102 1.1 0.7 1.1 172 2.5 1.1 1.7 41 Renal Pelvis C65 1 0.0 0.0 0.0 1 0.0 0.0 0.0 Ureter C66 1 0.0 0.0 0.0 1 0.0 0.0 0.0 42 Bladder C67 109 1.2 0.8 1.5 441 6.5 2.8 5.0 on October 2, 2021 by guest. Protected copyright. 43 Other urinary organs C68 - - - - 2 0.0 0.0 0.0 44 Eye C69 40 0.4 0.3 0.4 57 0.8 0.4 0.5 45 Brain, nervous system C70-C72 227 2.5 1.6 2.2 458 6.8 2.9 3.8 Thyroid C73 215 2.4 1.5 2.2 81 1.2 0.5 0.7 46 Adrenal C74 4 0.0 0.0 0.0 7 0.1 0.0 0.1 47 Hodgkin disease C81 80 0.9 0.6 0.7 202 3.0 1.3 1.4 48 Non-Hodgkin lymphoma C82-C88 277 3.1 2.0 3.3 493 7.3 3.2 4.5 49 Multiple myeloma C90 36 0.4 0.3 0.5 53 0.8 0.3 0.6 Lymphoid leukemia C91 112 1.2 0.8 0.7 207 3.1 1.3 1.2 50 Myeloid leukemia C92-93 62 0.7 0.4 0.5 107 1.6 0.7 0.8 51 Other Leukemias C94 2 0.0 0.0 0.0 6 0.1 0.0 0.0 52 Leukemia unspecified C95 40 0.4 0.3 0.3 60 0.9 0.4 0.4 53 Other & unspecified 536 5.9 3.8 6.6 561 8.3 3.6 5.7 54 Benign CNS 188 2.1 1.3 1.8 182 2.7 1.2 1.4 All sites 9069 100.0 64.9 105.1 6771 100.0 43.6 66.7 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 18 of 29 BMJ Open Page 20 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Table 5. Age-specific & age-standardized incidence rates of cancers diagnosed in the Lahore district, 2010-2012, amongst females. 4 5 Total ICD-10 6 Site cases 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75+ Crude % ASIR codes 7 Lip 9 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.0 1.1 0.4 0.6 1.6 0.7 0.1 0.1 0.1 C00 8 Tongue 129 0.0 0.0 0.0 0.0 0.1 0.1 0.2 1.2 1.4 5.4 4.7 4.9 6.6 5.8 8.7 5.1 0.9 1.4 1.7 C01-C02 9 Mouth 130 0.0 0.0 0.0 0.2 0.2 0.3 0.2 1.5 2.9 1.6 6.0 4.6 3.5 7.0 11.1 5.1 0.9 1.4 1.6 C03-C06 10Salivary glands 41 0.0 0.0 0.1 0.0 0.1 0.5 0.2 0.8 0.5 0.6 1.1 0.7 2.7 1.9 0.8 0.0 0.3 0.5 0.5 C07-C08 11Tonsil 8 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.2 0.7 0.4 0.0 0.0 0.8 0.7 0.1 0.1 0.1 C09 12Nasopharynx 19 0.0 0.0 0.1 0.1 0.1 0.2 0.3 0.0 0.3 0.6 0.2 0.4 0.4 0.0 1.6 0.0 0.1 0.2 0.2 C11 Hypopharynx 32 0.0 0.0 0.0 0.1 0.2 0.1 0.2 0.5 0.3 0.6 0.7 1.4 1.9 0.6 1.6 0.7 0.2 0.4 0.4 C12-C13 13 Pharynx 5 0.0 0.0 0.1 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.4 0.0 0.0 0.8 0.7 0.0 0.1 0.1 C14 14 Esophagus 95 0.0 0.0 0.0 0.1 0.0 0.3 0.3 0.9 1.9 4.0 1.8 2.8 5.8 4.5 4.7 3.6 0.7 1.0 1.2 C15 15Stomach 105 0.0 For 0.0 0.0 0.0peer 0.3 0.1 1.0 review 1.3 2.2 3.8 2.5 3.9only 2.7 8.9 0.0 3.6 0.8 1.2 1.3 C16 16Small intestine 17 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.6 0.0 0.0 0.4 1.9 1.3 2.4 0.7 0.1 0.2 0.2 C17 17Colon 159 0.0 0.0 0.1 0.3 0.1 0.7 1.3 2.0 2.0 3.4 3.3 7.0 5.0 9.6 9.5 8.0 1.1 1.8 1.9 C18 18Rectum 137 0.0 0.0 0.1 0.2 0.9 0.9 1.4 1.2 1.7 3.0 3.1 4.2 5.0 4.5 6.3 5.1 1.0 1.5 1.5 C19-C20 19Anus 23 0.0 0.0 0.0 0.0 0.1 0.0 0.3 0.1 0.9 0.6 0.2 0.0 0.8 0.6 2.4 0.7 0.2 0.3 0.3 C21 20Liver 177 0.1 0.1 0.0 0.1 0.1 0.1 0.2 0.3 1.4 4.4 6.2 11.2 12.0 16.6 8.7 5.1 1.3 2.0 2.4 C22 21Gall bladder, etc. 139 0.0 0.0 0.0 0.1 0.0 0.0 0.5 0.4 1.5 2.6 4.9 6.7 8.9 14.1 7.1 8.7 1.0 1.5 1.9 C23-C24 22Pancreas 40 0.0 0.0 0.0 0.1 0.0 0.2 0.1 0.5 0.3 0.8 0.9 2.1 0.8 5.8 2.4 1.4 0.3 0.4 0.5 C25 23Other ill-defined digestive 14 0.0 0.0 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.9 0.0 1.2 0.0 0.8 0.0 0.1 0.2 0.1 C26 24Nose, sinuses 27 0.1 0.0 0.0 0.1 0.0 0.0 0.1 0.3 0.0 0.6 0.7 1.8 2.3 1.3 0.8 0.7 0.2 0.3 0.3 C30-31 25Larynx 28 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.1 0.6 0.8 1.3 1.4 1.2 0.6 0.0 2.2 0.2 0.3 0.3 C32 26Trachea, bronchus, & lung 92 0.0 0.0 0.1 0.2 0.1 0.1 0.5 0.4 0.9 1.4 1.8 4.6 5.4 8.3 6.3 5.8 0.7 1.0 1.2 C33-C34 27Other thoracic organs 16 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.3 0.2 0.8 0.0 0.4 1.6 0.6 0.8 0.7 0.1 0.2 0.2 C37-C38 28Bone 91 0.2 0.5 0.9 1.4 0.9 0.3 0.4 1.3 0.3 0.6 0.4 0.4 0.0 0.0 1.6 0.0 0.7 1.0 0.6 C40-C41 29Melanoma of skin 13 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.3 0.2 0.4 0.4 0.7 0.0 0.0 0.8 0.7 0.1 0.1 0.1 C43 30Other skin 196 0.1 0.0 0.0 0.1 0.1 0.3 0.2 1.3 2.9 2.2 5.1 6.3 11.3 16.6 19.0 19.6 1.4 2.2 2.7 C44 Connective & soft tissue 108 0.4 0.3 0.3 0.6 0.6 0.8 0.8 1.2 1.7 1.2 1.8 1.4 1.6 3.8 2.4 2.9 0.8 1.2 1.0 C47,C49 31 Breast 4082 0.0 0.1 0.1 0.1 3.3 14.0 32.2 55.9 86.2 126.8 130.3 158.5 154.1 157.9 124.9 92.1 29.2 45.0 47.6 C50 32 Vulva 19 0.0 0.0 0.1 0.0 0.0 0.0 0.1 0.4 0.2 0.2 0.0 1.4 0.8 0.6 0.8 2.9 0.1 0.2 0.2 C51 33Vagina 16 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.1 0.3 0.8 0.2 0.7 0.4 0.0 0.8 1.4 0.1 0.2 0.2 C52 34Cervix uteri 247 0.0 0.0 0.0 0.0 0.2 0.4 1.3 3.9 5.7 9.4 7.1 10.5 10.1 8.3 5.5 5.1 1.8 2.7 2.9 C53 http://bmjopen.bmj.com/ 35Corpus uteri 267 0.0 0.0 0.0 0.0 0.0 0.2 0.6 1.5 1.9 6.0 9.8 16.5 22.1 16.0 18.2 7.2 1.9 2.9 3.6 C54 36Uterus, unspecified 89 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.9 1.5 3.4 4.0 2.8 5.8 3.8 4.7 0.0 0.6 1.0 1.1 C55 37Ovary 442 0.0 0.1 0.6 0.8 1.6 1.9 3.0 4.9 7.9 12.2 13.4 15.4 19.4 12.1 11.1 7.2 3.2 4.9 4.9 C56 38Other female genital organ 18 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.3 0.5 0.2 0.2 0.7 2.3 0.6 0.8 0.0 0.1 0.2 0.2 C57 39Placenta 7 0.0 0.0 0.0 0.0 0.1 0.1 0.3 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.0 C58 40Kidney 102 0.7 0.1 0.1 0.0 0.2 0.0 0.2 1.6 2.0 1.6 2.7 4.9 3.1 3.2 3.2 4.3 0.7 1.1 1.1 C64 41Renal pelvis 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C65 Ureter 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.8 0.0 0.0 0.0 C66 42 0.0 on October 2, 2021 by guest. Protected copyright. 43Bladder 109 0.1 0.0 0.0 0.1 0.0 0.1 0.2 1.1 1.2 1.6 2.7 4.9 5.0 8.9 10.3 10.1 0.8 1.2 1.5 C67 44Eye 40 0.9 0.3 0.1 0.0 0.0 0.0 0.0 0.0 0.3 0.4 0.0 0.0 0.8 4.5 0.8 2.2 0.2 0.4 0.4 C69 45Brain, nervous system 227 0.3 0.7 0.6 0.9 0.9 2.0 1.4 2.5 3.3 4.4 4.9 5.3 5.0 7.7 4.0 2.9 1.6 2.5 2.2 C70-C72 46Thyroid 215 0.0 0.1 0.1 0.2 1.9 1.6 2.8 2.9 3.3 4.6 6.5 3.5 6.6 3.2 7.9 2.9 1.5 2.4 2.2 C73 47Adrenal 4 0.1 0.1 0.0 0.0 0.1 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C74 48Hodgkin lymphoma 80 0.2 0.4 0.3 0.4 0.9 1.0 0.4 1.1 0.3 1.0 0.2 1.8 1.6 0.6 2.4 0.0 0.6 0.9 0.7 C81 Non-Hodgkin lymphoma 277 0.2 0.3 0.5 0.5 0.5 0.8 0.9 2.0 3.6 5.8 7.4 12.3 10.9 14.1 13.4 18.1 2.0 3.1 3.3 C82-C88 49 Multiple myeloma 36 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.3 1.6 1.1 0.7 2.7 3.2 4.0 0.7 0.3 0.4 0.5 C90 50 Lymphoid leukemia 112 2.0 1.3 1.4 0.3 0.1 0.2 0.2 0.0 0.5 0.2 0.2 0.7 1.2 0.6 0.8 0.0 0.8 1.2 0.7 C91 51Myeloid leukemia 62 0.3 0.2 0.2 0.2 0.5 0.6 0.6 0.7 0.5 0.6 1.1 1.4 0.8 0.6 1.6 0.0 0.4 0.7 0.5 C92-93 52Other Leukemias 2 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C94 53Leukemia, unspecified 40 0.3 0.5 0.3 0.3 0.1 0.3 0.1 0.1 0.2 0.2 0.7 0.0 0.0 0.6 0.8 0.0 0.3 0.4 0.3 C95 54 Other & 55Other & unspecified 536 0.5 0.2 0.2 0.2 1.1 1.8 2.7 4.7 7.0 12.6 14.9 24.9 24.1 33.9 26.9 18.8 3.8 5.9 6.6 unspecified 56Benign CNS 188 0.2 0.1 0.3 0.7 0.3 1.6 2.2 3.9 4.0 4.8 3.6 2.1 4.3 4.5 2.4 0.7 1.3 2.1 1.8 Benign CNS 57All sites 9069 6.7 5.0 6.5 8.4 16.4 32.1 58.3 104.7 155.6 237.8 259.9 337.6 364.1 398.2 348.7 259.5 64.9 100.0 105.1 All sites 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 29 Page 21 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Table 6. Age-specific & age-standardized incidence rates of cancers diagnosed in the Lahore district, 2010-2012, amongst males. 4 5 Total ICD-10 6 Site cases 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75+ Crude % ASIR codes 7 Lip 13 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.2 0.0 0.0 0.2 0.6 1.3 0.5 0.6 0.0 0.1 0.2 0.1 C00 8 Tongue 180 0.0 0.0 0.0 0.0 0.3 0.6 0.6 2.0 3.5 3.6 4.4 5.0 7.2 6.2 9.5 2.3 1.2 2.7 1.8 C01-C02 9 Mouth 212 0.0 0.0 0.0 0.0 0.1 0.2 1.2 1.1 3.0 5.4 4.8 9.7 10.1 8.8 7.7 4.0 1.4 3.1 2.2 C03-C06 10 Salivary glands 50 0.0 0.0 0.1 0.1 0.1 0.2 0.3 0.7 0.6 0.7 0.7 1.1 1.9 1.6 3.0 1.7 0.3 0.7 0.5 C07-C08 Tonsil 8 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.1 0.0 0.2 0.3 0.6 0.5 0.0 0.0 0.1 0.1 0.1 C09 11 Other oropharynx 6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.0 0.6 0.3 0.0 0.6 0.0 0.0 0.1 0.1 C10 12 Nasopharynx 19 0.0 0.0 0.0 0.1 0.1 0.0 0.2 0.1 0.3 0.3 0.2 0.8 1.3 0.5 0.0 0.0 0.1 0.3 0.2 C11 13 Hypopharynx 21 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.1 0.3 0.0 0.6 0.3 0.9 1.0 1.2 2.9 0.1 0.3 0.2 C12-C13 14 Pharynx 5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.3 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 C14 15 Esophagus 127 0.0 0.0For 0.0 0.1 peer 0.1 0.2 0.3 review 0.8 0.5 3.1 3.1 4.5only 5.3 6.2 9.5 6.9 0.8 1.9 1.4 C15 16 Stomach 162 0.0 0.0 0.0 0.0 0.1 0.8 0.9 1.4 2.2 3.8 3.3 4.7 4.4 10.3 8.3 3.4 1.0 2.4 1.6 C16 17 Small intestine 26 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.3 0.1 0.5 0.6 0.8 0.9 0.5 1.8 2.3 0.2 0.4 0.3 C17 Colon 230 0.0 0.0 0.0 0.4 0.8 0.6 0.7 1.5 2.1 4.8 4.4 5.8 11.6 14.5 9.5 6.3 1.5 3.4 2.4 C18 18 Rectum 186 0.0 0.0 0.0 0.4 0.7 0.9 1.4 1.0 1.0 3.3 3.9 5.0 8.2 11.9 4.2 6.3 1.2 2.7 1.9 C19-C20 19 Anus 41 0.0 0.0 0.0 0.1 0.1 0.1 0.5 0.0 0.6 0.5 1.3 0.8 2.2 1.6 0.6 1.1 0.3 0.6 0.4 C21 20 Liver 328 0.0 0.0 0.0 0.1 0.1 0.2 0.0 1.5 1.9 5.2 10.1 17.0 14.8 24.3 17.2 14.9 2.1 4.8 3.7 C22 21 Gall bladder, etc. 93 0.0 0.0 0.0 0.1 0.1 0.1 0.1 0.3 0.5 0.5 2.9 3.6 5.0 7.2 4.2 7.4 0.6 1.4 1.0 C23-C24 22 Pancreas 57 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.0 0.8 1.4 1.3 3.1 1.3 4.7 4.7 1.1 0.4 0.8 0.6 C25 23 Other ill-defined digestive 16 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.1 0.5 0.4 0.3 0.6 2.1 0.0 1.1 0.1 0.2 0.2 C26 24 Nose, sinuses 32 0.0 0.0 0.0 0.1 0.2 0.2 0.0 0.2 0.1 0.5 0.6 1.4 0.9 1.6 2.4 0.0 0.2 0.5 0.3 C30-31 25 Larynx 183 0.0 0.0 0.0 0.0 0.3 0.0 0.2 0.5 1.5 3.8 4.6 7.8 10.4 12.4 11.3 5.7 1.2 2.7 2.0 C32 Trachea, bronchus, & lung 396 0.0 0.0 0.0 0.0 0.1 0.1 0.6 1.9 1.8 5.7 4.8 13.1 21.4 32.0 37.4 32.6 2.5 5.8 4.6 C33-C34 26 Other thoracic organs 26 0.0 0.0 0.0 0.1 0.0 0.0 0.1 0.2 0.3 0.2 1.1 0.0 0.6 0.5 1.8 2.9 0.2 0.4 0.2 C37-C38 27 Bone 143 0.2 0.5 1.2 2.4 1.0 0.5 0.6 0.7 0.6 0.9 0.6 0.3 3.1 0.5 1.8 0.6 0.9 2.1 0.9 C40-C41 28 Melanoma of skin 13 0.0 0.0 0.0 0.1 0.0 0.1 0.1 0.1 0.0 0.0 0.0 1.1 0.0 0.5 0.0 1.7 0.1 0.2 0.1 C43 29 Other skin 271 0.1 0.1 0.1 0.2 0.3 0.9 1.6 2.0 2.3 2.8 4.1 8.6 11.3 16.5 10.1 21.2 1.7 4.0 2.8 C44 30 Connective & soft tissue 144 0.4 0.5 0.1 0.9 0.8 1.1 0.7 1.1 0.5 2.8 1.1 2.5 2.8 3.6 4.2 2.9 0.9 2.1 1.2 C47,C49 31 Breast 70 0.0 0.0 0.0 0.1 0.1 0.1 0.0 0.3 0.9 2.1 1.5 1.9 1.9 8.8 2.4 1.7 0.5 1.0 0.8 C50 32 Penis 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C60 33 Prostate 526 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.3 1.0 4.4 13.1 27.1 46.0 69.4 87.0 3.4 7.8 6.4 C61 Testis 90 0.2 0.0 0.0 0.5 1.1 1.2 1.2 1.1 1.0 0.7 0.6 0.3 0.3 1.6 0.6 0.6 0.6 1.3 0.6 C62 http://bmjopen.bmj.com/ 34 Other male genital organs 5 0.1 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.0 0.6 0.0 0.0 0.1 0.1 C63 35 Kidney 172 0.6 0.2 0.0 0.1 0.1 0.2 0.3 0.9 2.7 3.3 3.3 5.6 6.3 7.2 9.5 5.7 1.1 2.5 1.7 C64 36 Renal pelvis 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C65 37 Ureter 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C66 38 Bladder 441 0.1 0.0 0.0 0.0 0.1 0.2 0.4 1.8 2.2 5.9 7.5 19.2 23.0 30.0 29.7 42.4 2.8 6.5 5.0 C67 39 Other urinary organs 2 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.6 0.0 0.0 0.0 C68 40 Eye 57 1.2 0.2 0.0 0.1 0.1 0.1 0.0 0.1 0.1 0.7 0.6 0.3 1.6 2.1 2.4 1.1 0.4 0.8 0.5 C69 41 Brain, nervous system 458 0.7 1.0 0.7 1.2 1.6 2.9 4.5 4.4 5.0 7.3 8.8 10.6 11.3 9.8 8.3 3.4 2.9 6.8 3.8 C70-C72 Thyroid 81 0.0 0.0 0.0 0.2 0.2 0.7 0.8 0.3 0.8 1.4 1.8 3.3 1.6 2.6 3.0 1.1 0.5 1.2 0.7 C73 42 Adrenal 7 0.1 0.0 0.0 0.1 0.1 0.0 0.0 0.0 0.0 0.2 0.0 0.3 0.0 0.0 0.6 0.0 0.0 0.1 0.1 C74 on October 2, 2021 by guest. Protected copyright. 43 Hodgkin lymphoma 202 0.7 1.8 0.7 1.0 0.9 1.4 1.2 1.4 1.5 1.6 1.5 3.3 1.9 4.1 3.6 0.6 1.3 3.0 1.4 C81 44 Non-Hodgkin lymphoma 493 0.4 1.4 1.1 1.3 2.0 1.6 2.5 2.5 4.6 5.9 10.1 11.7 18.3 18.1 16.6 14.3 3.2 7.3 4.5 C82-C88 45 Multiple myeloma 53 0.1 0.0 0.0 0.0 0.0 0.0 0.2 0.2 0.5 1.2 1.3 2.5 3.1 1.6 2.4 2.3 0.3 0.8 0.6 C90 46 Lymphoid leukemia 207 3.1 2.2 2.6 0.7 0.5 0.2 0.3 0.1 0.8 0.3 0.9 0.6 0.6 2.1 0.0 1.7 1.3 3.1 1.2 C91 47 Myeloid leukemia 107 0.3 0.3 0.4 0.4 0.7 0.8 0.9 1.4 1.0 1.0 0.7 1.9 1.9 2.1 0.0 0.6 0.7 1.6 0.8 C92-93 48 Other Leukemias 6 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.1 0.0 0.4 0.0 0.0 0.0 0.6 0.0 0.0 0.1 0.0 C94 49 Leukemia, unspecified 60 0.5 0.4 0.7 0.2 0.5 0.2 0.3 0.1 0.3 0.3 0.2 0.3 0.6 0.0 0.6 0.0 0.4 0.9 0.4 C95 Other & 50 Other & unspecified 561 0.3 0.1 0.6 0.9 0.4 2.0 2.6 2.9 4.8 6.0 12.2 18.7 23.9 28.4 25.5 34.9 3.6 8.3 5.7 unspecified 51 Benign CNS 182 0.3 0.4 0.2 0.5 0.8 2.0 1.9 2.4 2.1 3.3 3.3 1.1 3.1 1.6 3.0 0.6 1.2 2.7 1.4 Benign CNS 52 All sites 6771 9.2 9.5 9.1 12.2 14.8 20.6 27.4 38.0 53.7 93.1 118.4 194.0 255.2 337.0 329.7 328.0 43.6 100.0 66.7 All sites 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 20 of 29 BMJ Open Page 22 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Of the 15,825 patients, death was recorded in 5,134 (32·4%) cases by the cut-off date for this study; this 4 5 included 2,726 female and 2,408 male patients. Four-thousand, three-hundred and forty-seven patients 6 were still alive (27·5%) at the time of review, whereas, the vital status of 6,344 patients (40·1%) could 7 not be determined. Death certificates were available in each record of a hospital death for about 8% of 8 9 patients (400/5,134), representing just one collaborating center, which is SKMCH & RC. Table 7 displays 10 death counts and proportion by cancer sites. Since the follow-up information was not available for 11 nearly 40% of the patients, the mortality to incidence ratio was not calculated either. 12 13 Table 7. Distribution of deaths recorded (5,134 (2,726 female and 2,408 male patients)), in patients diagnosed 14 with cancer, in the Lahore district, in 2010-2012, according to gender and cancer type (top 10 cancers only). 15 For peer review only 16 17 Females Count % Males Count % 18 Breast 987 36 Brain 213 9 19 20 Ovary 137 5 Bronchus & lung 207 9 21 Colorectum 127 5 NHL 169 7 22 23 NHL 109 4 Prostate 168 7 24 Lip & oral cavity 106 4 Colorectum 155 6 25 26 Brain 99 4 Lip & oral cavity 152 6 27 28 Leukemia 87 3 Liver & intrahep. bile ducts 151 6 29 Liver & intrahep. bile ducts 85 3 Leukemia 144 6 30 31 Cervix uteri 65 2 Urinary bladder 133 6 32 Corpus uteri 53 2 Stomach 73 3 33

34 http://bmjopen.bmj.com/ 35 36 Of the deaths recorded, amongst females, 36% were reported in those who had breast cancer, 5% each 37 in those who had ovarian and colo-rectal carcinoma, 4% each in NHL, lip & oral cavity, and brain tumor, 38 3% each in those with leukemia and liver & intrahepatic bile ducts tumors, and 2% each in those who 39 had cancer of the cervix and corpus uteri. In male patients, 9% each were in those who had tumor of the 40 41 brain and, bronchus & lung, 7% each in those with NHL and prostate cancer, 6% each in cancers of the

42 colo-rectum, lip & oral cavity, liver & intrahepatic bile ducts, bladder, and leukemia, and 3% in stomach on October 2, 2021 by guest. Protected copyright. 43 carcinoma. 44 45 46 47 48 DISCUSSION 49 50 The Registry has been in existence since 2005 but was in an evolving phase in the initial years of its 51 52 functioning. Therefore, conducting a comparison of the cases recorded over the initial years did not 53 appear to be useful. Further, as there are notification delays and the Registry is still receiving 54 information on cases diagnosed in the most recent years (2014-2015), mainly from one center, this 55 56 time-period has not been included in the study either. It is hoped that a study conducted at a 57 subsequent stage will cover the 2013-2015 period. For the time-period 2010-2012, the results reported 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 29 Page 23 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 for the population of the Lahore district show that on average, over 5,200 new cancer cases were 4 5 diagnosed, every year. The fact that nearly seven percent were non-microscopically confirmed cancers 6 as opposed to nearly 93% that were microscopically confirmed, supports that there was no over-reliance 7 on the pathology laboratory as the source of information. These figures are similar to those reported for 8 9 the Karachi Cancer Registry[5]. The ASIR for all-cancers combined was higher amongst females (105·1) 10 than in males (66·7). These results also include the ASIRs for benign CNS tumors and other/unspecified 11 sites. The ASIRs reported by the Surveillance, Epidemiology, and End Results (SEER) Program of the 12 13 United States of America (USA), are very high (359·4 for females and 282·6 for males)[21,22]. These 14 figures represent SEER 18 registries compiling data from all cases diagnosed since 2000 and covering 15 approximately 30%For of the US population[21,22].peer review The ASIRs published only in the CI5-X report for Delhi in 16 17 India and Riyadh in Saudi Arabia, are close to the Lahore district figures as opposed to the SEER rates; in 18 fact, the ASIRs for females in these three regions are quite similar to one another. It is important to 19 point out that Delhi, located in India, to the east of Lahore, is closer to Lahore than is Karachi located in 20 21 southern Pakistan. As far as the South Karachi Registry is concerned, based on the last report (1998- 22 2002) released in CI5-IX, it can be seen that the ASIRs for Karachi were relatively high (192·0 for females 23 and 166·6 for males) as compared to those for the Lahore district. Further, in the region of Golestan in 24 25 Iran (2005-2007), and for Israel, again the ASIRs were high compared to those reported for the Lahore 26 district[19]. For the SEER Program, Delhi, Iran, and Saudi Arabia, data were reported for the 2003-2007 27 time period. Table 8 shows a comparison of the ASIRs according to cancer sites, though not all sites, in 28 the aforementioned regions of the world. In women belonging to the Lahore district, the ASIR of breast 29 30 cancer ranked the highest (47·6) of all the cancers, and was higher than that for Delhi (31·6), but 31 relatively low compared to that reported for the Israeli Jews (89·4). Amongst men in the Lahore district, 32 the ASIR of prostate cancer was the highest (6·4) of all the cancers, but was lower than that reported for 33

34 Delhi (10·1) and Riyadh (7·9). Even though breast and prostate cancer were the most common diagnoses http://bmjopen.bmj.com/ 35 in the Lahore district, the point to be noted is that organized screening programs for early detection of 36 these diseases do not exist in Pakistan. The ASIR of cervical cancer in Lahore was 2·9 but in Delhi it was 37 38 much higher, at 17·7; this is despite the fact that the screening levels are low in the general population 39 of India[23]. Of the factors implicated in the etiology of cervical cancer in the Indian population, the 40 presence of specific oncogenic types of the Human Papilloma Viruses (HPV), namely types 16 and 18, 41 plays an important role in the development of cancer of the cervix. In Pakistan, one population-based 42 on October 2, 2021 by guest. Protected copyright. 43 study reports HPV positivity to be nearly 2·8% in the general population (25/899) and about 92% in 44 patients with invasive cervical cancer (83/91)[24]. However, in India, it has been reported that HPV 45 46 prevalence varies from 7·5% to 16·9% in women without cervical cancer as opposed to 87·8% to 96·7% 47 amongst cervical cancer patients[23]. Further, in the latest Globocan report, the ASIR for cancer of the 48 cervix in Pakistan was estimated at 7·9 per 100,000 females with 5,233 cases identified in 2012[15]; in 49 50 the same year, in Saudi Arabia, 241 cases were diagnosed, with the ASIR at 2·7 per 100,000 women; in 51 contrast to this, in India, 122,844 cervical cancer cases were diagnosed, with a relatively high ASIR of 52 22·0 per 100,000 females[15]. Since the ASIR is low in the aforementioned Muslim countries compared 53 54 to a non-Muslim country, circumcision of men may be a plausible explanation in reducing the 55 transmission of HPV infection to their female sexual partners. Circumcision of men is the norm amongst 56 Muslim males. The role of circumcision has been demonstrated in three separate randomized trials done 57 58 in Africa[25]. Since the incidence of cervical cancer in Pakistan is relatively low and the 5-year 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 22 of 29 BMJ Open Page 24 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 prevalence is 15,323, setting-up a formal screening program may have lower yields, therefore, a low 4 5 priority in resource allocation and decision making in our setting[15]. 6 7 As shown in Table 8, the ASIRs per 100,000 population, per year, for ten common cancers in Pakistan, as 8 9 reported in the Globocan 2012, compared to Lahore, are as follows: In women: breast 50·3, 47·6; lip & 10 oral cavity 9·1, 3·9; cervix uteri 7·9, 2·9; ovary 5·6, 5·1; esophagus 4·4, 1·2; corpus uteri 3·6, 3·6; NHL 3·4, 11 3·3; colo-rectum 3·3, 3·7; liver 2·5, 2·4; and stomach 2·2, 1·3, while, amongst men: lip & oral cavity 10·5, 12 4·6; lung 9·8, 4·6; NHL 5·3, 4·5; prostate 6·6, 6·4; bladder 5·1, 5·0; larynx 5·0, 2·0; colo-rectum 4 7, 4·7; 13 14 liver 4·7, 3·7; esophagus 3·9, 1·4; stomach 3·8, 1·6; and brain & nervous system 3·4, 3·8. The comparison 15 shows that rates areFor somewhat peer higher for tobacco-related review cancers (liponly & oral cavity, lung, larynx, and 16 esophagus), and cervical cancer, though for the latter, the rates are still lower than those reported in 17 18 countries with a high HPV prevalence rate. Since the Globocan 2012 report included data from the 19 Punjab Cancer Registry, Karachi South district, and Dr. Yasmin’s paper, the relatively high cancer rates 20 for certain cancers may be attributed to the high consumption of tobacco-related products in that part 21 22 of Pakistan, in the form of cigarettes and bidi and also of smokeless tobacco as betel quid and 23 niswar[26]. Further, Karachi South is one of the 29 districts of the province of Sindh[12], located in the 24 south of the country and its population was 1·72 M during the period under study. Its last report 25 26 published in the CI-5, IX, shows a high incidence rate for tobacco related cancers[22]. Therefore, the 27 dissimilarity in the incidence rates could be attributed to the geographic and lifestyle differences 28 between these two regions. Table 8, depicting the ASIRs, highlights the differences between these two 29 30 regions and other regions of the world as well. 31 32 As far as the mortality data in our study are concerned, since the vital status of all the patients could not 33 be recorded, our results have to be interpreted with caution. The highest mortality was recorded in 34 http://bmjopen.bmj.com/ 35 patients diagnosed with breast cancer amongst females, and amongst those with brain tumors in males. 36 Due to the non-availability of the vital status of nearly half of the patients, the survival statistics could 37 not be reported either. Death certificates were available from just one collaborating center for each 38 39 record of a hospital death and accounted for nearly 8% of the deaths recorded in the Registry. However, 40 the point to be noted is that the cancer diagnoses were not merely reported from hospitals, they were 41 also reported on patients identified as new cancer cases, from different laboratories/collection centers

42 on October 2, 2021 by guest. Protected copyright. 43 within the district. The establishment of a central death registry in the region could help in collecting the 44 mortality data and determining the cause-specific mortality, along with the survival estimates for the 45 study population. While the Government of Pakistan maintains the National Database Registration 46 47 Authority with all citizens’ data and biometric information, the capture of death information is variable 48 and typically done at the local government level[27,28]. Deaths within hospitals have documented death 49 certificates which get communicated to local government, but the recording of death diagnosis likely 50 51 over-reports final mechanisms of death (‘cardio respiratory failure’), rather than underlying causes. In 52 view of this, death data and thus survival data have inherent inaccuracies in it. 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 29 Page 25 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Table 8. ASIRs, per 100,000 population, per year, for selected cancer sites, in Pakistan, India, Iran, Israel, and USA. 4 5 Pakistan Globocan Pakistan India Iran Saudi Arabia Israel USA 6 Lahore Pakistan Karachi New Delhi Golestan Riyadh Jews SEER 7 2010-2012 2012 1998-2002 2003-2007 2005-2007 2003-2007 2003-2007 2003-2007 8 Oral cavity & salivary glands-C00-C08 9 Male 4.6 10.5 22.5 14.0 1.7 1.6 3.3 6.9 10 Female 3.9 9.1 20.4 4.7 1.3 1.4 2.3 3.1 11 Pharynx-C09-C14 12 Male 0.6 3.8 8.2 6.6 1.0 2.4 1.5 4.4 13 Female 0.8 1.3 3.4 1.5 0.7 1.3 0.5 1.1 14 Esophagus-C15 15 Male For1.4 3.9peer 6.7 review 4.9 23.2 only1.6 1.8 5.1 16 Female 1.2 4.4 8.6 2.9 18.8 1.3 0.9 1.2 17 Stomach-C16 18 Male 1.6 3.8 6.0 3.2 30.4 4.4 10.0 6.6 19 Female 1.3 2.2 3.6 1.5 12.6 2.3 5.4 3.3 20 Small intestine-C17 21 Male 0.3 - 0.2 0.2 1.4 0.5 1.0 1.5 22 Female 0.2 - 0.4 0.1 0.9 0.3 0.7 1.1 23 Colo-rectum-C18-C21 24 Male 4.7 4.7 7.1 5.5 13.6 12.5 42.8 35.3 25 Female 3.7 3.3 5.2 3.7 10.4 10.6 32.6 26.5 26 Liver-C22 27 Male 3.7 4.7 5.4 2.6 3.6 3.0 3.1 7.6 28 Female 2.4 2.5 3.7 1.5 2.0 6.0 1.4 2.4 29 Gall bladder-C23-C24 30 Male 1.0 0.9 1.3 4.0 1.2 1.2 1.7 1.7 31 Female 1.9 2.2 4.9 8.0 1.6 2.5 1.4 1.7 32 Pancreas-C25 33 Male 0.6 0.5 0.9 1.9 2.8 3.2 8.6 8.2

34 Female 0.5 0.4 0.5 1.1 1.0 1.9 6.4 6.2 http://bmjopen.bmj.com/ 35 Nose & sinuses-C30-C31 36 Male 0.3 - 0.7 0.3 0.0 0.2 0.4 0.6 37 Female 0.3 - 0.4 0.2 0.2 0.2 0.3 0.4 38 Larynx-C32 39 Male 2.0 5.0 10.7 8.0 4.1 1.7 4.1 4.3 40 Female 0.3 0.7 1.8 1.1 1.4 0.1 0.6 0.9 41 Trachea, bronchus, & lung-C33-C34 Male 4.6 9.8 25.2 13.7 17.5 6.3 29.8 48.3 42 on October 2, 2021 by guest. Protected copyright. 43 Female 1.2 1.7 3.6 3.6 5.6 2.2 13.4 33.8 44 Bone-C40-C41 45 Male 0.9 - 1.3 2.0 1.3 0.8 1.3 1.0 46 Female 0.6 - 1.5 1.2 1.5 0.5 1.0 0.8 47 Melanoma of the skin-C43 48 Male 0.1 0.3 0.5 0.2 0.9 0.3 13.7 16.8 49 Female 0.1 0.2 0.3 0.2 0.7 0.4 11.2 12.0 50 Skin-C44 51 Male 2.8 - 4.3 1.3 11.0 3.8 2.8 1.3 52 Female 2.7 - 4.1 1.0 7.7 3.2 1.9 1.0 53 Connective & soft tissue-C47-C49 54 Male 1.2 - 2.4 1.5 2.1 1.3 3.2 3.0 55 Female 1.0 - 2.3 1.2 2.1 0.9 2.2 2.1 56 Breast-C50 57 Male 0.8 - 1.0 1.3 0.1 0.5 1.3 0.7 58 Female 47.6 50.3 69.0 31.6 28.0 21.1 89.4 86.6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 24 of 29 BMJ Open Page 26 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Cervix uteri-C53 4 Female 2.9 7.9 7.5 17.7 5.4 2.0 5.5 6.4 5 Corpus uteri-C54 6 Female 3.6 3.6 6.7 4.5 1.7 4.4 14.4 16.7 7 Ovary-C56-C57.0-4 8 Female 5.1 5.6 8.8 8.6 6.1 3.3 9.2 9.6 9 Other female genital organs-C51-C52, C55, C58 10 Female 1.5 - 1.0 1.6 1.4 0.9 1.8 2.5 11 Penis-C60 12 Male - - 0.1 1.0 0.0 0.1 0.3 0.7 13 Prostate-C61 14 Male 6.4 6.6 10.1 10.1 10.6 7.9 68.3 106.8 15 Testis-C62 For peer review only 16 Male 0.6 0.9 1.2 0.6 2.3 0.6 4.7 4.9 17 Kidney, etc.-C64, C66, C68 18 Male 1.7 1.7 1.9 2.7 2.2 3.8 13.9 137.0 19 Female 1.1 0.9 0.8 1.2 1.2 2.5 6.5 7.1 20 Bladder-C67 21 Male 5.0 5.1 9.3 6.5 8.5 5.6 25.5 20.8 22 Female 1.5 1.6 2.6 1.5 2.8 1.3 4.8 5.3 23 Eye-C69 24 Male 0.5 - 0.6 0.3 0.4 0.4 0.6 0.8 25 Female 0.4 - 0.3 0.2 0.2 0.2 0.4 0.6 26 Brain, CNS-C70-C72 27 Male 3.8 3.4 3.3 3.8 7.8 3.5 6.7 6.4 28 Female 2.2 2.1 2.7 2.4 5.3 2.1 5.0 4.6 29 Thyroid-C73 30 Male 0.7 0.7 0.7 1.1 1.2 2.5 4.8 3.9 31 Female 2.2 2.2 2.9 2.5 3.0 10.2 14.7 12.3 32 Adrenal & other endocrine-C74-C75 33 Male 0.1 - 0.2 0.2 0.7 0.3 0.6 0.5 34 Female 0.0 - 0.3 0.2 0.4 0.2 0.5 0.4 http://bmjopen.bmj.com/ 35 Hodgkin lymphoma-C81 36 Male 1.4 2.2 2.0 1.6 1.8 2.2 3.6 2.7 37 Female 0.7 0.8 1.0 0.7 1.1 2.0 3.4 2.2 38 NHL-C82-C88, C96 39 Male 4.5 5.3 7.6 5.6 7.2 8.6 17.9 15.5 40 Female 3.3 3.4 5.1 3.0 3.3 7.1 14.4 10.8 41 Multiple myeloma-C88, C90

42 Male 0.6 0.7 1.8 2.0 2.4 1.8 4.8 4.7 on October 2, 2021 by guest. Protected copyright. 43 Female 0.5 0.6 1.3 1.2 2.2 1.0 3.0 3.1 44 Leukemia-C91-C95 45 Male 2.4 3.3 4.8 5.6 10.8 5.7 10.6 11.1 46 Female 1.5 2.2 4.1 3.6 7.7 4.3 6.9 7.1 47 All sites-C00-C96 48 Male 66.7 96.0 166.6 119.7 165.3 104.1 273.1 359.4 49 Female 105.1 127.7 192.0 118.4 142.0 103.9 308.5 282.6 50 51 52 CONCLUSION 53 54 55 This is the first time that an attempt has been made to determine and report the population-based 56 cancer statistics for the Lahore district. This collaborative study highlights cancer registration and follow- 57 up issues in a developing country like Pakistan, along with the non-availability of recent, accurate 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 29 Page 27 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 population estimates required as denominators in computation of the incidence rates. On average, 4 5 annually, 5,200 new cases were reported in the Lahore district, in 2010-2012. Although it is likely that all 6 the cases have not been reported, it is not possible to gauge the extent of under-reporting at this stage. 7 The cancer statistics reported in this manuscript can be used as baseline figures for comparison with 8 9 studies to be undertaken in the future. These statistics can also assist in exploring, thus, highlighting the 10 putative risk factors associated with cancers commonly diagnosed in the region, as part of a health 11 promotion and education program. Finally, this report can play an important role in developing 12 13 prevention, early detection, and cancer control strategies in the region. 14 15 For peer review only 16 17 FOOTNOTES 18 19 Contributors 20 21 FB conceived the idea of the study, designed it, supervised the statistical analysis, did literature search, 22 23 interpreted the results, and drafted the manuscript. FB further did the survival analysis for this study. 24 SMa did the case-finding, coding, and indexing of cases from SKMCH & RC and computed the incidence 25 rates and created figures and tables; RF, AY, HA, and AA validated the data, checked for duplication, and 26 27 followed-up on the patients; and AQ and KLA worked on the comparison of the incidence rates with 28 other regions. MAY and FS reviewed the paper critically and advised. MM was responsible for reporting 29 the cancers recorded at the Institute of Nuclear Medicine & Oncology, Lahore; GRS from Ittefaq 30 31 Hospital, Lahore; NC from Sheikh Zayed Hospital, Lahore; ORC from Chughtais Lahore Lab, Lahore; TM 32 from Fatima Jinnah Medical University, Lahore; ZA and MAK from Jinnah Hospital, Lahore; GH and AA 33 from the Children’s Hospital & the Institute of Child Health, Lahore; RB from the Services Institute of 34 http://bmjopen.bmj.com/ 35 Medical Sciences, Lahore; SR and IT from Fatima Memorial College of Medicine & Dentistry, Lahore; FA 36 from Shalamar Medical & Dental College, Lahore; TA from Allama Iqbal Medical College, Lahore; SN 37 from King Edward Medical University, Lahore; and BAS from Nawaz Sharif Social Security Hospital, 38 39 Lahore. NS contributed intellectually to the study. MTM, SMu, AL, and MH did the pathologic 40 confirmation of cases at SKMCH & RC, Lahore. SMa supervised, FB managed, and MAY and FS 41 established and directed the Punjab Cancer Registry.

42 on October 2, 2021 by guest. Protected copyright. 43 Funding 44 45 46 None for this study. 47 48 Competing interests 49 50 We declare no competing interests. 51 52 Data sharing statement 53 54 No additional data available. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 26 of 29 BMJ Open Page 28 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 ACKNOWLEDGEMENTS 4 5 6 We thank the professionals representing various centers in the region for reporting their data to the 7 Punjab Cancer Registry. We also thank the Staff of the unit Cancer Registry and Clinical Data 8 Management, SKMCH & RC, on making additional efforts to complete cancer registration, following 9 international guidelines, thus, enabling us to complete the study. 10 11 12 13 14 REFERENCES 15 For peer review only 16 17 1 Sania Nishtar. Pakistan’s health systems. In: Choked Pipes: Reforming Pakistan’s Mixed Health 18 Systems. Karachi, Oxford University Press 2010: Fig 4, Page 37. 19

20 21 2 Valsecchi MG, Steliarova-Foucher E. Cancer registration in developing countries: luxury or 22 necessity? Lancet Oncol 2008 Feb;9(2):159-67. URL: 23 http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70028-7/fulltext 24 (accessed 16 Feb 2016). DOI: 10.1016/S1470-2045(08)70028-7. 25 26 3 The World Bank [Internet]. Washington, DC, USA 2016. URL: 27 28 http://databank.worldbank.org/data/reports.aspx?source=2&type=metadata&series=EN.POP.D 29 NST# and http://wdi.worldbank.org/table/1.5 (accessed 25 Jan 2015). 30 31 4 Survey of Pakistan (Map). Pakistan 2015. URL: http://www.surveyofpakistan.gov.pk/ (accessed 32 17 Dec 2015). 33 34 http://bmjopen.bmj.com/ 5 Bhurgri Y. Epidemiology of cancers in Karachi 1995-1999. Karachi, Pharmacia and Upjohn 2001. 35 36 37 6 Punjab Cancer Registry. SKMCH & RC, Lahore, Pakistan 2011. URL: 38 http://punjabcancerregistry.org.pk (accessed 16 Dec 2015). 39 40 7 Shaukat Khanum Memorial Cancer Hospital and Research Center. Lahore, Pakistan 2015. URL: 41 http://www.shaukatkhanum.org.pk/ (accessed 16 Dec 2015).

42 on October 2, 2021 by guest. Protected copyright.

43 44 8 Badar F. Cancer Registration in Pakistan. J Coll Physicians Surg Pak 2013;23(8):611–12. 45 46 9 Badar F, Mahmood S. The state of cancer registration in Pakistan. J Ayub Med Coll Abbottabad 47 2015;27(2):507–508. 48 49 10 The Societies Registration Act, 1860 (Act XXI of 1860). Pakistan 2015. URL: 50 51 http://punjablaws.gov.pk/laws/1.html#_ftn2 (accessed 16 Dec 2016). 52 53 11 IACR-International Association of Cancer Registries. Lyon, France 2015. URL: 54 http://www.iacr.com.fr/ (accessed 16 Dec 2015). 55 56 12 Pakistan Bureau of Statistics-Government of Pakistan. Islamabad, Pakistan 2015. URL: 57 http://www.pbs.gov.pk/content/population-census (accessed 16 Dec 2015). 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 29 Page 29 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 13 Census-Publication No. 125-Population Census Organization-Statistics Division, Government of 5 6 Pakistan, Islamabad (2000). Statistical Tables of 1998 Population and Housing Census. In: ‘1998 7 District Census Report of Lahore.’ Islamabad: Government of Pakistan 2000. 77–305. 8 9 14 MacLennan R. Chapter 6-Items of patient information which may be collected by registries. In: 10 Jensen OM, Parkin DM, MacLennan R, et al, eds. Cancer Registration: Principles and Methods- 11 IARC Scientific Publications No. 95. International Agency for Research on Cancer, Lyon, France 12 13 1991. URL: https://www.iarc.fr/en/publications/pdfs-online/epi/sp95/SP95.pdf (accessed 16 14 Feb 2016). 15 For peer review only 16 15 GLOBOCAN 2012: Estimated Cancer Incidence, Mortality, and Prevalence Worldwide in 2012. 17 Lyon, France 2015. URL: http://globocan.iarc.fr/Default.aspx (accessed 17 Dec 2015). 18 19 16 Census in Pakistan by Wikipedia. Wikimedia Foundation, San Francisco, CA, USA 2016. URL: 20 21 https://en.wikipedia.org/wiki/Census_in_Pakistan (accessed 22 Jan 2016). 22 23 17 Program for Multiple Primaries- IARC/IACR Multiple Primary Rules. Appendix 3. In: Ferlay J, 24 Burkhard C, Whelan S, et al, eds. International Agency for Research on Cancer. Check and 25 Conversion Programs for Cancer Registries (IARC/IACR Tools for Cancer Registries). IARC 26 Technical Report No. 42. Lyon 2005;38-45. 27 28 29 18 Fritz A, Percy C, Jack A, et al, eds. 6th Digit Code for Histologic Grading and Differentiation. In: 30 Fritz A. International Classification of Diseases for Oncology. 3rd ed. WHO, Geneva 2000:31. 31 32 19 Holden K, ed. ICD-10-CM Expert for Hospitals. The complete official code set. Codes valid 33 October 1, 2015 through September 30, 2016. Salt Lake City, UT, USA: Optum360, LLC 2015. 34 http://bmjopen.bmj.com/ 35 36 20 Boyle P, Parkin DM. Chapter 11-Statistical Methods for Registries-IARC. In: Jensen OM, Parkin 37 DM, MacLennan R, et al, eds. Cancer Registration: Principles and Methods. IARC Scientific 38 Publication No. 95. International Agency for Research on Cancer, Lyon, France 1991. URL: 39 https://www.iarc.fr/en/publications/pdfs-online/epi/sp95/SP95.pdf (accessed 16 Feb 2016). 40 41 21 The Surveillance, Epidemiology, and End Results (SEER) Program. NCI, Bethesda, Maryland 2016.

42 on October 2, 2021 by guest. Protected copyright. URL: http://seer.cancer.gov/registries/terms.html (accessed 4 Feb 2016). 43 44 45 22 Cancer Incidence in Five Continents Volumes I to X-IACR; International Agency for Research on 46 Cancer, Lyon, France 2016. URL: http://ci5.iarc.fr/CI5I-X/Pages/table4_sel.aspx (accessed 3 Feb 47 2016). 48 49 23 Sreedevi A, Javed R, Dinesh A. Epidemiology of cervical cancer with special focus on India. Int J 50 51 Womens Health. 2015 Apr;7:405–414. URL: 52 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404964/ (accessed 16 Feb 2016). 53 DOI: 10.2147/IJWH.S50001. 54 55 24 Raza SA, Franceschi S, Pallardy S, et al. Human papillomavirus infection in women with and 56 without cervical cancer in Karachi, Pakistan. Br J Cancer 2010 Apr;102:1657–1660. URL: 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 28 of 29 BMJ Open Page 30 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 https://researchonline.lshtm.ac.uk/448554/1/6605664a.pdf (accessed 16 Feb 2016). 4 DOI:10.1038/sj.bjc.6605664. 5 6 7 25 Giuliano AR, Schim van der Loeff MF, Nyitray AG. Circumscribed HIV-infected men and HPV 8 transmission. Lancet Infect Dis. 2011 Aug;11(8):581-2. DOI: 10.1016/S1473-3099(11)70073-1. 9 Epub 2011 Apr 12. 10 11 26 Imam SZ, Nawaz H, Sepah YJ, et al. Use of smokeless tobacco among groups of Pakistani medical 12 13 students-a cross-sectional study. BMC Public Health. 2007 Sep;7:231. URL: 14 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1995212/ (accessed 26 Apr 2016). DOI: 15 10.1186/1471-2458-7-231.For peer review only 16 17 27 National Database and Registration Authority (NADRA). URL: https://www.nadra.gov.pk/ 18 (accessed 26 Apr 2016). 19

20 21 28 Local Government and Community Development-Registration of Death. URL: 22 https://lgcd.punjab.gov.pk/FAQ (accessed 26 Apr 2016).

23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

34 254x190mm (300 x 300 DPI) http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 Figure 2. Map of Pakistan showing the provinces and location of the Lahore and Karachi districts and neighboring countries. 41 344x337mm (300 x 300 DPI) 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Figure 3. Population structure of the Lahore district, 2010-2012, by gender. 152x97mm (300 x 300 DPI) 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Appendix A-List of collaborating centers in Lahore. Centers are listed in descending order of the number of 4 cases reported, to the Punjab Cancer Registry, 2010-2012. 5 6 S. No. Center name 7 8 1 Shaukat Khanum Memorial Cancer Hospital & Research Center 9 2 Institute of Nuclear Medicine & Oncology 10 11 3 Ittefaq Hospital 12 4 Sheikh Zayed Hospital 13 14 5 Chughtais Lahore Lab 15 6 ForFatima Jinnahpeer Medical Universityreview only 16 7 Jinnah Hospital 17 18 8 The Children's Hospital & the Institute of Child Health 19 9 Services Institute of Medical Sciences 20 21 10 Fatima Memorial College of Medicine & Dentistry 22 11 Shalamar Medical & Dental College 23 24 12 Allama Iqbal Medical College 25 13 King Edward Medical University 26 27 14 Nawaz Sharif Social Security Hospital 28 15 Akhtar Saeed Medical & Dental College 29 16 Post Graduate Medical Institute 30 31 17 Combined Military Hospital 32 18 Indus Lab 33

34 19 Pride Lab http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Page 1 of 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Appendix B-Data collection form used for the Lahore district, the Punjab Cancer Registry. 4 5 6

LAHORE 7 CHAPTER 8 9 10 PUNJAB CANCER REGISTRY 11 DATA COLLECTION FORM 12 13 CENTER I.D. NO.______PATIENT I.D NUMBER: ______← (To be allocated by 14 †PCR Central Office) → 15 For peer review only 16 HISTOLOGY NO.______HISTOLOGY DATE: ______/_____/______17 18 PATIENT’S NAME______FIRST MIDDLE 19 LAST 20 21 SEX: MALE FEMALE NEUTER (MUKHANNAS) FATHER'S NAME 22 ______23 BIRTH DATE ______AGE ______24 25 26 N.I.C. NUMBER (FOR CHILDREN ≤ 18 YEARS, ID OF MOTHER/ FATHER) ______27 PERMANENT ADDRESS (HOUSE AND STREET NO.) ______28 29 ______30 31 CITY/TOWN ______POSTAL CODE______

32 HOME/CELL TELEPHONE WITH AREA CODE______33

34 ↓RESIDENT OF LAHORE: YES NO IF YES, duration of stay in Lahore (Months/Years) _____ http://bmjopen.bmj.com/ 35

36 ↓COME TO LAHORE FOR TREATMENT/DIAGNOSIS ONLY______(YES/NO) 37

38 39 Procedure/surgery done at (hospital)………………………. 40 Name of surgeon…………………………………………… 41 Cytology/histopathology done at (lab.) …………………….

42 on October 2, 2021 by guest. Protected copyright. 43 PRIMARY SITE______DATE OF DIAGNOSIS ______44 SITE OF BIOPSY______METASTATIC______(YES/NO) 45 46 LATERALITY (where applicable) _____ MORPHOLOGY ______BEHAVIOR______47 GRADE ______STAGE (when available) ______48 49 *MOST VALID BASIS OF DIAGNOSIS (Please see the list below)______50 FOR PCR CENTRAL OFFICE USE ONLY 51 STATUS AT LAST FOLLOW-UP ______52 53 DATE OF DEATH ______PLACE OF DEATH † ______54 PCR is an acronym for the Punjab Cancer Registry. *0. Death Certificate Only 1. Clinical; 2. Clinical investigation; 4. Specific tumor markers; 5. Cytology; 6. Histology of 55 a metastasis; 7. Histology of primary tumor; and 9. Unknown.

56 xx END xx 57 58 59 Page 1 of 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 39

BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Appendix C-Screen shot of the PCR data capture form in the Hospital Information System, SKMCH & RC, 4 Lahore, Pakistan. 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Page 1 of 3 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 39 BMJ Open

BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Appendix CC-Screen shot of the PCR data capture form in the Hospital Information System, SKMCH & RC, 4 Lahore, Pakistan. 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Page 2 of 3 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 39

BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Appendix CCC-Screen shot of the PCR data capture form in the Hospital Information System, SKMCH & RC, 4 Lahore, Pakistan. 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Page 3 of 3 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 STROBE Statement—checklist of items that should be included in reports of observational studies 3 4 5 Item No Recommendation 6 7 Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the 8 abstract-page 8 9 (b) Provide in the abstract an informative and balanced summary of what was done 10 and what was found- page 8 11 12 Introduction 13 Background/rationale 2 Explain the scientific background and rationale for the investigation being reported- 14 page 9-11 15 Objectives For3 peer State specific objectives, review including any pre-specified only hypotheses-page 11 16 17 Methods 18 Study design 4 Present key elements of study design early in the paper-page 11-14 19 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, 20 21 exposure, follow-up, and data collection-page 11-14 22 Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of 23 selection of participants. Describe methods of follow-up 24 Case-control study—Give the eligibility criteria, and the sources and methods of 25 26 case ascertainment and control selection. Give the rationale for the choice of cases 27 and controls 28 Cross-sectional study—Give the eligibility criteria, and the sources and methods of 29 selection of participants-pages 11-14 30 (b) Cohort study—For matched studies, give matching criteria and number of 31 32 exposed and unexposed 33 Case-control study—For matched studies, give matching criteria and the number of

34 controls per case http://bmjopen.bmj.com/ 35 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect 36 37 modifiers. Give diagnostic criteria, if applicable-pages 11-14 38 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 39 measurement assessment (measurement). Describe comparability of assessment methods if there 40 is more than one group-pages 14-21 41 Bias 9 Describe any efforts to address potential sources of bias-page 21

42 on October 2, 2021 by guest. Protected copyright. 43 Study size 10 Explain how the study size was arrived at-page 11-14 44 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, 45 describe which groupings were chosen and why-page 11 46 Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding- 47 48 page 11-14 49 (b) Describe any methods used to examine subgroups and interactions-page 11-14 50 (c) Explain how missing data were addressed-page 11-14 51 (d) Cohort study—If applicable, explain how loss to follow-up was addressed 52 53 Case-control study—If applicable, explain how matching of cases and controls was 54 addressed 55 Cross-sectional study—If applicable, describe analytical methods taking account of 56 sampling strategy- not applicable 57 (e) Describe any sensitivity analyses 58 59 Continued on next page 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 BMJ Open Page 40 of 39 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Results 4 5 Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, 6 examined for eligibility, confirmed eligible, included in the study, completing follow-up, and 7 analysed-pages 11-14 8 (b) Give reasons for non-participation at each stage-pages 11-14 9 (c) Consider use of a flow diagram-one to indicate the health systems in Pakistan (Figure 10 11 1). 12 Descriptive 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information 13 data on exposures and potential confounders-page 11-14 14 (b) Indicate number of participants with missing data for each variable of interest-page 11-21 15 For peer review only 16 (c) Cohort study—Summarise follow-up time (e.g., average and total amount) 17 Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time 18 Case-control study—Report numbers in each exposure category, or summary measures of 19 exposure 20 21 Cross-sectional study—Report numbers of outcome events or summary measures- pages 11-21 22 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their 23 precision (e.g., 95% confidence interval). Make clear which confounders were adjusted for and 24 why they were included-pages 11-15 25 (b) Report category boundaries when continuous variables were categorized 26 27 (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful 28 time period 29 Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity 30 analyses 31 32 Discussion 33 Key results 18 Summarise key results with reference to study objectives-pages 14-21

34 http://bmjopen.bmj.com/ Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. 35 36 Discuss both direction and magnitude of any potential bias-pages 21-26 37 Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity 38 of analyses, results from similar studies, and other relevant evidence-pages 21-26 39 Generalisability 21 Discuss the generalisability (external validity) of the study results- pages 21-26 40 41 Other information

42 Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, on October 2, 2021 by guest. Protected copyright. 43 for the original study on which the present article is based-pages 12 & 26 44

45 46 *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and 47 unexposed groups in cohort and cross-sectional studies. 48 49 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 50 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 51 52 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 53 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 54 available at www.strobe-statement.org. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml2 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from

THE EPIDEMIOLOGY OF CANCERS IN LAHORE, PAKISTAN, 2010-2012: A CROSS-SECTIONAL STUDY

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-011828.R2

Article Type: Research

Date Submitted by the Author: 27-May-2016

Complete List of Authors: Badar, Farhana; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Mahmood, Shahid; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management Yusuf, Mohammed; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Internal Medicine Mahmood, Mohammad ; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pathology Masood, Misbah; The Institute of Nuclear Medicine and Oncology, Oncology Sial, Ghulam; Ittefaq Hospital(Trust), Pathology Chughtai, Nasir; Sheikh Zayed Hospital , Pathology Chughtai, Omar; Chughtais Lahore Lab Mustafa, Tanveer; Fatima Jinnah Medical University, Pathology Aziz, Zeba; Hameed Latif Hospital, Oncology

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 Centre, Cancer Registry & Clinical Data Management 5 Ali, Kamran; Shaukat Khanum Memorial Cancer Hospital and Research Centre, Cancer Registry & Clinical Data Management 6 Asif, Hina; Shaukat Khanum Memorial Cancer Hospital and Research 7 Centre, Cancer Registry & Clinical Data Management 8 Atif, Adna; Shaukat Khanum Memorial Cancer Hospital and Research 9 Centre, Cancer Registry & Clinical Data Management 10 Sultan, Faisal; Shaukat Khanum Memorial Cancer Hospital and Research 11 Centre, Internal Medicine 12 Primary Subject Public health 13 Heading: 14 15 Secondary SubjectFor Heading: peerEpidemiology review only 16 17 Keywords: PUBLIC HEALTH, EPIDEMIOLOGY, ONCOLOGY 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 THE EPIDEMIOLOGY OF CANCERS IN LAHORE, PAKISTAN, 2010-2012: A CROSS-SECTIONAL STUDY 4 5 6 Farhana Badar, Shahid Mahmood, Muhammed Aasim Yusuf, Mohammad Tariq Mahmood, Misbah 7 Masood, Ghulam Rasool Sial, Nasir Chughtai, Omar Rasheed Chughtai, Tanveer Mustafa, Zeba Aziz, 8 Muhammad Abbas Khokhar, Ghazala Hanif, Alia Ahmad, Rakhshindah Bajwa, Sabiha Riaz, Imrana Tanvir, 9 Farooq Aziz, Tazeen Anis, Shahida Niazi, Bilquis A. Suleman, Neelam Siddiqui, Sajid Mushtaq, Asif Loya, 10 11 Mudassar Hussain, Raqib Faraz, Aneel Yousaf, Ain ul Quader, Kamran Liaqat Ali, Hina Asif, Adna Atif, 12 Faisal Sultan. 13 14 15 For peer review only 16 Corresponding author 17 18 19 Farhana Badar-MBBS, MPH 20 21 Sr. Biostatistician & Cancer Epidemiologist 22 23 Cancer Registry & Clinical Data Management 24 25 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 26 27 7-A, Block R-3 28 29 30 Johar Town, Lahore 31 32 Pakistan 33

34 Ph.: +92 42 35905000 Ext. 4240 | Email: [email protected] http://bmjopen.bmj.com/ 35 36 37 38 Shahid Mahmood-MBA, CPC 39 40 Medical Coder/Cancer Registry Officer 41

42 on October 2, 2021 by guest. Protected copyright. 43 Cancer Registry & Clinical Data Management 44 45 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 46 47 48 49 Mohammed Aasim Yusuf-FRCP 50 51 Consultant Gastroenterologist | Chief Medical Officer 52 53 54 Department of Internal Medicine 55 56 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 28 Page 3 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 6 Mohammad Tariq Mahmood-DABP 7 8 Consultant Pathologist 9 10 Department of Pathology 11 12 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 13 14 15 For peer review only 16 Misbah Masood-FCPS 17 18 19 Consultant Clinical Oncologist 20 21 Oncology Division 22 23 The Institute of Nuclear Medicine & Oncology, Lahore, Pakistan. 24 25 26 27 Ghulam Rasool Sial-FCPS 28 29 30 Consultant Pathologist 31 32 Department of Pathology 33

34 Ittefaq Hospital, Lahore, Pakistan. http://bmjopen.bmj.com/ 35 36 37 38 Nasir Chughtai-MPhil 39 40 Consultant Pathologist 41

42 on October 2, 2021 by guest. Protected copyright. 43 Department of Pathology 44 45 Sheikh Zayed Hospital, Lahore, Pakistan. 46 47 48 49 Omar Rasheed Chughtai-FCAP 50 51 Consultant Pathologist 52 53 Chughtais Lahore Lab, Lahore, Pakistan. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 2 of 28 BMJ Open Page 4 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Tanveer Mustafa-MPhil 4 5 6 Senior Demonstrator 7 8 Department of Pathology 9 10 Fatima Jinnah Medical University, Lahore, Pakistan. 11 12 13 14 Zeba Aziz-DABM 15 For peer review only 16 Consultant Oncologist 17 18 19 Department of Oncology 20 21 Hameed Latif Hospital, Lahore, Pakistan. 22 23 24 25 Muhammad Abbas Khokhar-FCPS 26 27 Assistant Professor 28 29 30 Department of Oncology and Radiotherapy 31 32 King Edward Medical University, Lahore, Pakistan. 33

34 http://bmjopen.bmj.com/ 35 36 Ghazala Hanif-MPhil 37 38 Consultant Pathologist 39 40 Department of Pathology 41

42 on October 2, 2021 by guest. Protected copyright. 43 The Children’s Hospital & the Institute of Child Health, Lahore, Pakistan. 44 45 46 47 Alia Ahmad-MRCPCH 48 49 Associate Professor 50 51 Department of Hematology/Oncology 52 53 The Children’s Hospital & the Institute of Child Health, Lahore, Pakistan. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 28 Page 5 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Rakhshindah Bajwa-MPhil 4 5 6 Consultant Pathologist 7 8 Department of Pathology 9 10 The Services Institute of Medical Sciences, Lahore, Pakistan. 11 12 13 14 Sabiha Riaz-FRCPath 15 For peer review only 16 Consultant Pathologist 17 18 19 Department of Pathology 20 21 Fatima Memorial College of Medicine & Dentistry, Lahore, Pakistan. 22 23 24 25 Imrana Tanvir-FCPS 26 27 Assistant Professor 28 29 Department of Pathology 30 31 Fatima Memorial College of Medicine & Dentistry, Lahore, Pakistan. 32 33

34 http://bmjopen.bmj.com/ 35 Farooq Aziz-MPhil 36 37 Professor 38 39 Department of Pathology 40 41 Shalamar Medical & Dental College, Lahore, Pakistan.

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 Tazeen Anis-DCP 46 47 48 Senior Demonstrator 49 50 Department of Pathology 51 52 Allama Iqbal Medical College, Lahore, Pakistan. 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 4 of 28 BMJ Open Page 6 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Shahida Niazi-MPhil 4 5 Associate Professor 6 7 Department of Pathology 8 9 King Edward Medical University, Lahore, Pakistan. 10 11 12 13 14 Bilquis A. Suleman-FRCPath 15 For peer review only 16 Consultant Pathologist 17 18 Department of Pathology 19 20 Nawaz Sharif Social Security Hospital, Lahore, Pakistan. 21 22

42 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. on October 2, 2021 by guest. Protected copyright. 43 44 45 46 Asif Loya-DABP 47 48 49 Consultant Pathologist 50 51 Department of Pathology 52 53 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 28 Page 7 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Mudassar Hussain-FCPS 4 5 Consultant Pathologist 6 7 Department of Pathology 8 9 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 10 11 12 13 14 Raqib Faraz-BSc 15 For peer review only 16 Medical Coder/Cancer Registry Officer 17 18 Cancer Registry & Clinical Data Management 19 20 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 21 22 23 24 Aneel Yousaf-MBA 25 26 27 Medical Coder/Cancer Registry Officer 28 29 Cancer Registry & Clinical Data Management 30 31 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 32 33 34 http://bmjopen.bmj.com/ 35 Ain ul Quader-BSc 36 37 38 Medical Coder/Cancer Registry Officer 39 40 Cancer Registry & Clinical Data Management 41

42 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. on October 2, 2021 by guest. Protected copyright. 43 44 45 46 Kamran Liaqat Ali-BSc 47 48 Medical Coder/Cancer Registry Officer 49 50 51 Cancer Registry & Clinical Data Management 52 53 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 6 of 28 BMJ Open Page 8 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Hina Asif-MSc 4 5 6 Medical Coder/Cancer Registry Officer 7 8 Cancer Registry & Clinical Data Management 9 10 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 11 12 13 14 Adna Atif-BA 15 For peer review only 16 Medical Coder/Cancer Registry Officer 17 18 19 Cancer Registry & Clinical Data Management 20 21 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 22 23 24 25 Faisal Sultan-FRCP 26 27 Consultant Physician | Chief Executive Officer 28 29 30 Department of Internal Medicine 31 32 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 female patients; 93·5% microscopically confirmed and 6·5% non-microscopically. The ASIR amongst on October 2, 2021 by guest. Protected copyright. 43 44 females was 105·1 and in males 66·7. ASIRs of leading cancers, amongst women, were: breast 47·6, 45 ovary 4·9, and corpus uteri 3·6, whereas, amongst men: prostate 6·4, bladder 5·0, and, trachea, 46 bronchus, & lung 4·6. A total of 5,134 deaths were recorded. 47 48 Conclusions 49 50 51 In Lahore, the ASIR was higher in women than in men. Amongst women, breast cancer, and in men, 52 prostate cancer, were the leading cancer types. These estimates can be used for health promotion and 53 policy making in the region. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 8 of 28 BMJ Open Page 10 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 6 7 8 ARTICLE SUMMARY 9 10 STRENGTHS AND LIMITATIONS OF THIS STUDY 11 12 • This is the first time that the age-standardized incidence rates have been presented for the 13 Lahore district. 14 15 For peer review only 16 • A comparison has been made with the incidence rates reported by other registries around the 17 world. 18 19 • There are follow-up issues related to determining the vital status of the patients, once they are 20 21 registered as new cancer patients. Therefore, the limitation of the study is that the vital status 22 of the vast majority of patients could not be determined. 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 28 Page 11 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 PAPER 4 5 6 7 8 THE EPIDEMIOLOGY OF CANCERS IN LAHORE, PAKISTAN, 2010-2012: A CROSS-SECTIONAL STUDY 9 10 INTRODUCTION 11 12 In the area of public health research, conducting high-quality, population-level studies, is hailed as the 13 gold standard, as the outcomes truly represent the disease status of the community on whom the 14 15 studies are being Forconducted. Thispeer includes the review practice of population-based only cancer registration, which 16 not only assists in providing statistics and trends on incidence, mortality, and survival, it can also provide 17 information on putative risk factors associated with various diseases within a defined population, living 18 19 in a geographically demarcated area, over a specified period of time. However, cancer registration can 20 only be undertaken if there is appropriate infrastructure to enable it, and suitable, well-trained staff to 21 perform the tasks associated with it. Understandably, there is a cost associated with conducting this 22 23 type of epidemiologic work, and in a resource-constrained country like Pakistan, governments are less 24 likely to focus on the area of cancer registration than other areas deemed more immediately critical. 25 Further, there is no legislation in the country that requires health-care practitioners to report diagnoses 26 27 of cancer. Moreover, the health-care delivery in Pakistan is quite complex, and is as depicted in Figure 1. 28 A large part of the population is served through a mixed system via multiple health providers[1]. 29 30 The question whether cancer registration is a necessity or a luxury in developing countries has been 31 debated extensively over the years. A paper published in 2008 stated that in low-income countries, 32 33 cancer registration is urgently needed so as to gauge the cancer burden in the region[2]. Given that

42 numbers of health-care practitioners to manage the conditions, addressing health education, and on October 2, 2021 by guest. Protected copyright. 43 assisting in developing prevention, early detection, and cancer control programs in the region. Figure 2 44 45 is a map of Pakistan showing the provinces of Pakistan and countries adjacent to Pakistan[4]. Even 46 though accurate population figures are not available, enthusiastic professionals have, over the years, 47 endeavored to determine cancer estimates for Pakistan. In the past, the regional registry of the Karachi 48 49 South district, in the province of Sindh, was established and managed for several years by a dedicated 50 pathologist, Dr. Yasmin Bhurgri[5]. This registry was widely recognized at an international level for its 51 data quality[5]. However, due to the sudden death of Dr. Bhurgri in January 2012, this registry is no 52 53 longer active. Another registry in Pakistan is the Punjab Cancer Registry (PCR), which was founded 54 collaboratively by a group of health-professionals in 2005, pioneered by the administrators of a 55 complete cancer treatment facility in Lahore called the Shaukat Khanum Memorial Cancer Hospital and 56 57 Research Center (SKMCH & RC)[6-9]. The Punjab Cancer Registry, herein, referred to as the Registry, is 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 10 of 28 BMJ Open Page 12 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 registered with, and regulated under, the Societies Registration Act, 1860, of the Government of 4 5 Pakistan[10]. It is also a member of the International Association of Cancer Registries, France[11]. 6 Appendix A shows the list of collaborating centers of the Registry. 7 8 The reporting of cancer cases to population-based cancer registries is not required by law, in Pakistan. It 9 is, in fact, a voluntary task undertaken by professionals representing many institutions of the region. 10 11 When the Registry was established in 2005, a memorandum outlining the structure and governance 12 mechanisms was signed by the stake-holders representing both the government and private 13 laboratories and hospitals of the city. The purpose of establishing the Registry was to determine the 14 15 cancer estimates Forin the province peer of Punjab. Punjab review is the most populous only province of Pakistan, with a 16 population estimated at 100 M, and 36 administrative districts, of which Lahore is the most populous, 17 with a population of some 10 M[12,13]. For about a decade, data have been captured in a systematic 18 19 and pre-defined manner, in accordance with the minimum data items required for cancer registries as 20 well as some additional optional data items[6,9,14]. 21 22 In the past, PCR data have been reported to the International Agency for Research on Cancer (IARC) in 23 24 response to a call for data by the Agency. The data have been used, along with data from Dr. Yasmin 25 Bhurgri’s paper, and the Federal Bureau of Statistics, Pakistan, to provide cancer estimates for Pakistan 26 in the Globocan 2012 report[15]. 27 28 This manuscript provides population-level cancer estimates for the Lahore district, based on cases 29 30 diagnosed in 2010-2012 and reported to the Registry. This is the first time that the Lahore district 31 population-level data have been computed and are being reported. 32 33 34 http://bmjopen.bmj.com/ 35 METHODS 36 37 38 The population denominator 39 40 Population-level statistics cannot be computed without the availability of figures for the population 41 under review, or the catchment population. In Pakistan, publications describing the population structure

42 are available for the census that was conducted in 1998[12]. However, the most recent population on October 2, 2021 by guest. Protected copyright. 43 44 census, initiated a year ago, has not yet been completed[16]; therefore, accurate figures describing the 45 Pakistani population are not available. As a result, for this study, population estimates are based on 46 population figures determined by using the average annual growth rates provided by the Government of 47 48 Pakistan[12]. 49 50 In the years 2010, 2011, and 2012, the population of the Lahore district was estimated at 9,503,871, 51 9,832,705, and 10,172,916 respectively, computed using an average annual growth rate of 52 53 3·46%[12,13]. The total area of the Lahore district is 1,772 square kilometers, with its average 54 population density being calculated as 5,551 persons, per square kilometer, in the years under 55 study[12]. Figure 3 is a population pyramid showing the combined population distribution of the Lahore 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 28 Page 13 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 district by age-group and gender, for the years 2010-2012. These population estimates were used as the 4 5 population-at-risk denominator, for calculating the incidence rates for this study. 6 7 Data collection 8 9 As routine cancer registration practice, the information is collected on the PCR data collection forms 10 11 developed collaboratively, following international guidelines on recording cancers (Appendix B). The 12 pertinent question on the form states whether a patient is a resident of Lahore or has come to Lahore 13 for diagnosis or treatment only. This has helped to identify the residents of Lahore. 14 15 For peer review only 16 Each center is allocated a separate center identification number. The forms are distributed to, and 17 collected from, each participating center on a regular basis. Both the active and passive methods of data 18 19 collection are used[14]. Registry Staff educates relevant personnel at each center with regard to data 20 capture, missing information and answers any other queries that arise. At the Cancer Registry & Clinical 21 Data Management unit, only authorized personnel are allowed to enter data from forms, into the 22 database. The forms collected are stored securely and remain confidential. The information is 23 24 subsequently entered into the Punjab Cancer Registry database, developed as part of the computerized 25 Hospital Information System of SKMCH & RC (Appendices C-CCC). All authorized Staff members are 26 given specific usernames and passwords to turn the computers on and another username-password to 27 28 access the system, and thence, the PCR software. Any form of transmission of the information including 29 printing and saving it on portable electronic devices, and aspects related to document retention, are 30 strictly regulated by the Governing Council of the Registry and SKMCH & RC, the latter being the sponsor 31 32 of the Registry. For the cases diagnosed or treated at SKMCH & RC, linkages have been developed with 33 the pathology department and clinics to facilitate date capture.

42 morphology, the case is registered with the center where the first diagnosis was made. Edits, for the on October 2, 2021 by guest. Protected copyright. 43 44 validity and for the consistency between variables, are also carried out (age/incidence, 45 age/site/histology, site/histology, sex/site, sex/histology, behavior/site, behavior/histology, 46 grade/histology, and basis of diagnosis/histology). Initially, cancers were coded using the International 47 Classification of Disease for Oncology-Third Edition[18]. For this manuscript, cancers were categorized 48 49 using the International Classification of Diseases, Clinical Modification, 10th revision[19]. 50 51 Data access and follow-up 52 53 54 Release of confidential information is governed by the rules approved by the Registry, and is always 55 without any identifiers[6]. For maintaining confidentiality of the information recorded, Staff members 56 57 are made to sign a confidentially pledge at the time of employment, which remains in force after 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 12 of 28 BMJ Open Page 14 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 cessation of employment with SKMCH & RC. For the purpose of reporting the data to IARC and to 4 5 determine the vital status, patients diagnosed in the time-period 2010-2012 were followed-up 6 telephonically between July and October 2015. We were able to establish contact with only sixty 7 percent of the cases in this way. 8 9 10 Cancers reported 11 12 Cancer notifications for the Lahore district have improved with the passage of time, with the cases 13 reported to the Registry going up from 2,006 in the year 2005 to 5,123 in the year 2015. In chronologic 14 15 order, the numbersFor reported arepeer as follows: 2,006;review 2,987; 3,617; 3,990; only 5,109; 5,302; 4,949; 5,589; 16 6,009; 5,943; and 5,123. We are still receiving information on cases diagnosed in 2014 and 2015. Over 17 recent years, six other districts have been included for the purpose of data collection, with the idea 18 19 being to include 1-2 contiguous district(s) of Punjab every year in order to expand cancer registration. 20 The data collection form is modified accordingly to ascertain resident status of the patients[6]. The 21 approach related to including 1-2 districts on a regular basis has been adopted because the sponsor, 22 23 SKMCH & RC, is a charitable organization, and it is logistically not possible to initiate data collection from 24 36 districts of Punjab simultaneously. 25 26 2010-2012 study 27 28 A cross-sectional study was conducted and the Punjab Cancer Registry data were reviewed 29 30 retrospectively to retrieve information on cancer patients belonging to the Lahore district and having 31 been diagnosed in 2010-2012. Information was collected on new cancer diagnoses (by histology and 32 gender), the most valid basis of diagnosis as microscopically versus non-microscopically confirmed, 33

42 World Standard population[20]. ASIRs were expressed per 100,000 population, per year, separately for on October 2, 2021 by guest. Protected copyright. 43 male and female patients. For mortality data, counts were stratified by histology/site. Overall survival 44 45 interval was computed between the dates of diagnosis and last contact and analyzed using the Kaplan- 46 Meier method. Of a total of 15,825 patients registered in the years 2010-2012, survival intervals could 47 not be computed for nearly 43 percent of the cases. Of these, in the vast majority of cases, no contact 48 49 could be established with the patients on the phone numbers provided; in some of the cases, the 50 attendants of the patients could only communicate that the patients had died but could not recall their 51 dates of death; and, in a few cases, the patients died on the day of cancer diagnoses and their intervals 52 were set at naught. Although extensive survival analysis was subsequently done on the fifty-seven 53 54 percent of cases on whom the duration of survival was available, the survival estimates generated were 55 not considered valid. Therefore, survival results are not being presented in this manuscript. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 28 Page 15 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Data were analyzed using the Microsoft Excel, version 2010, and SPSS, version 19. The Institutional 4 5 Review Board (IRB) of the Shaukat Khanum Memorial Cancer Hospital & Research Center granted 6 exemption from full IRB evaluation. 7 8 9 10 RESULTS 11 12 13 The total population of the Lahore district, in 2010-2012, was estimated to be 29,509,492, with males 14 accounting for 52·7% and females 47·3% of the population (Figure 3). The number of cases reported in 15 each of the three-yearsFor under peerstudy, 2010, 2011, review & 2012, along with onlytheir population denominators, 16 were: 5,302/9,503,871, 4,949/9,832,705, and 5,589/10,172,916, respectively. Of a total of 15,840 17 18 cancers diagnosed in 15,825 patients belonging to the district of Lahore and registered in the PCR 19 database against the corresponding years, 9,069 (57·3%) were in female and 6,771 (42·7%) in male 20 patients. Multiple primary cancers, up to two, were identified in 15 patients (Table 1), explaining the 21 22 discrepancy between the number of cases recorded and the patients registered. Nearly ten percent 23 were identified to have been registered twice and were eventually assigned to the center where the first 24 diagnosis was made, thereby, counted just once. The age-range of the patients was 0-106 years. Of all 25 26 the cancers diagnosed, about 93·5% were microscopically and 6·5% were non-microscopically confirmed 27 (Table 2). None were registered on the basis of death certificates only. Skin cancer had the highest figure 28 in the microscopically confirmed group (99·6%), whereas, liver & intrahepatic bile duct(s) had the 29 30 highest figure in the non-microscopically confirmed category (69·5%). The ASIR for all sites combined 31 amongst female patients was 105·1 per 100,000 women and amongst male patients, it was 66·7 per 32 100,000 men, per year. Tables 3-6 show the ASIRs for all the cancers recorded in the Registry, by the 33

34 year of diagnosis and gender, and the age-specific rates for the 5-year age-group, separately for female http://bmjopen.bmj.com/ 35 and male patients. Amongst females, the highest ASIRs were recorded for the following sites and 36 malignancies: breast 47·6, ovary 4·9, corpus uteri 3·6, Non-Hodgkin Lymphoma (NHL) 3·3, cervix uteri 37 38 2·9, and brain & CNS 2·2, whereas, in men, the highest ASIRs were: prostate 6·4, bladder 5·0, trachea, 39 bronchus, & lung 4·6, NHL 4·5, brain & CNS 3·8, and liver 3·7. 40 41

8 1. Male 20 Alive Colon & brain 9 10 2. Male 23 Alive Larynx & testis 11 3. Male 34 Dead Kidney & thyroid

12 4. Female 45 Alive Breast & breast 13 5. Male 45 Alive Illdefined & lung 14 6. Female 46 Alive Breast & ovary 15 For peer review only 16 7. Male 55 Alive Spinal cord & NHL 17 8. Male 56 Dead Brain & unknown primary 18 9. Female 59 Alive Breast & liver 19 20 10. Female 60 Dead Breast & breast

21 11. Male 62 Dead Rectum & bone

22 12. Female 64 Alive Breast & breast 23 13. Male 67 Dead Thyroid & stomach 24 14. Male 70 Dead Connective tissue & liver 25 26 15. Female 91 Dead Breast & ovary 27 28 Table 2. The basis of diagnosis, categorized as being microscopically and non-microscopically confirmed, 2010- 29 2012, in the Lahore district (N=15,840). 30 31 The basis of diagnosis 32 Microscopic Non-Microscopic 33 Cancer site (%) (%)

34 Lip & oral cavity 97.0 3.0 http://bmjopen.bmj.com/ 35 Esophagus 99.1 0.9 36 Stomach 99.2 0.8 37 Colorectal 96.9 3.1 Liver & intrahep. bile ducts 30.5 69.5 38 Gall bladder 92.6 7.4 39 Larynx 96.6 3.4 40 Bronchus & lung 94.7 5.3 41 Bone 97.0 3.0

42 Connective tissue 94.4 5.6 on October 2, 2021 by guest. Protected copyright. 43 Leukemia 92.8 7.2 44 Breast 95.8 4.2 45 Cervix uteri 96.8 3.2 Corpus uteri 97.8 2.2 46 Testis 98.9 1.1 47 Prostate 97.5 2.5 48 NHL 95.8 4.2 49 Hodgkin lymphoma 97.5 2.5 50 Urinary bladder 97.3 2.7 51 Brain 96.6 3.4 52 Skin 99.6 0.4 53 Kidney 93.4 6.6 Thyroid 97.6 2.4 54 Ovary 93.7 6.3 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 28 Page 17 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 Table 3. Cancer counts and the age-standardized incidence rates of cancers diagnosed in the Lahore district, 5 2010-2012, according to year of diagnosis. 6 2010 2011 2012 7 Site ICD-10 code Count ASIR Count ASIR Count ASIR 8 Lip C00 13 0.2 5 0.1 4 0.1 9 Tongue C01C02 115 2.0 92 1.5 102 1.6 Mouth C03C06 117 2.1 110 1.8 115 1.9 10 Salivary glands C07C08 30 0.5 32 0.5 29 0.4 11 Tonsil C09 3 0.1 3 0.1 10 0.1 12 Other oropharynx C10 2 0.0 3 0.1 1 0.0 13 Nasopharynx C11 13 0.2 11 0.1 14 0.2 Hypopharynx C12C13 22 0.4 12 0.2 19 0.3 14 Pharynx C14 4 0.1 3 0.0 3 0.0 15 Esophagus For C15peer 76review 1.4 61 only 1.1 85 1.4 16 Stomach C16 85 1.5 86 1.4 96 1.5 17 Small intestine C17 15 0.3 15 0.3 13 0.2 Colon C18 148 2.6 106 1.7 135 2.2 18 Rectum C19C20 101 1.6 89 1.4 133 2.0 19 Anus C21 21 0.4 22 0.3 21 0.3 20 Liver C22 176 3.4 184 3.4 145 2.6 Gall bladder, etc. C23C24 72 1.3 76 1.4 84 1.6 21 Pancreas C25 30 0.6 30 0.6 37 0.7 22 Other illdefined digestive C26 7 0.1 11 0.2 12 0.2 23 Nose, sinuses C3031 17 0.3 23 0.4 19 0.3 24 Larynx C32 74 1.4 55 1.0 82 1.4 Trachea, bronchus, & lung C33C34 162 3.2 156 2.9 170 3.2 25 Other thoracic organs C37C38 14 0.2 11 0.2 17 0.2 26 Bone C40C41 80 0.8 74 0.8 80 0.8 27 Melanoma of the skin C43 4 0.1 11 0.2 11 0.1 28 Other skin C44 152 2.8 141 2.5 174 2.9 Connective & soft tissue C47,C49 95 1.3 95 1.2 62 0.8 29 Breast C50 1409 22.9 1339 21.4 1404 21.5 30 Vulva C51 3 0.1 7 0.2 9 0.4 31 Vagina C52 5 0.2 6 0.2 5 0.2 Cervix uteri C53 86 3.1 69 2.4 92 3.2 32 Corpus uteri C54 83 3.5 84 3.3 100 4.1 33 Uterus, unspecified C55 34 1.3 27 1.1 28 1.0

34 Ovary C56 138 4.6 124 4.1 180 5.8 http://bmjopen.bmj.com/ 35 Other female genital orgs. C57 5 0.2 7 0.3 6 0.2 Placenta C58 3 0.1 2 0.0 2 0.0 36 Penis C60 1 0.0 37 Prostate C61 165 6.2 193 7.1 168 6.0 38 Testis C62 31 0.7 24 0.5 35 0.7 39 Other male genital organs C63 3 0.1 2 0.1 Kidney C64 88 1.5 97 1.5 89 1.4 40 Renal pelvis C65 2 0.0 41 Ureter C66 1 0.0 1 0.0 Bladder C67 177 3.6 150 2.8 223 4.0 42 on October 2, 2021 by guest. Protected copyright. 43 Other urinary organs C68 2 0.0 Eye C69 33 0.5 29 0.4 35 0.4 44 Brain, nervous system C70C72 248 3.5 203 2.8 234 3.0 45 Thyroid C73 94 1.3 92 1.3 110 1.5 46 Adrenal C74 2 0.0 3 0.0 6 0.1 Hodgkin lymphoma C81 104 1.3 86 1.0 92 0.9 47 NonHodgkin lymphoma C82C88 274 4.4 234 3.6 262 3.9 48 Multiple myeloma C90 33 0.7 26 0.5 30 0.5 49 Lymphoid leukemia C91 91 0.9 71 0.7 157 1.4 50 Myeloid leukemia C9293 42 0.5 31 0.4 96 1.1 Other leukemias C95 30 0.3 25 0.3 45 0.4 51 Leukemia, unspecified C94 3 0.0 2 0.0 3 0.0 52 Other & unspecified 335 5.7 369 6.2 393 6.4 53 Benign CNS 138 1.9 125 1.6 107 1.3 54 All sites 5302 97.8 4949 89.1 5589 96.8 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 16 of 28 BMJ Open Page 18 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 Table 4. Cancer counts and age-standardized incidence rates of cancers diagnosed in the Lahore district in 6 2010-2012, by gender and cancer site/type. 7 FEMALE MALE 8 Site ICD-10-code Count % Crude ASIR Count % Crude ASIR 9 Lip C00 9 0.1 0.1 0.1 13 0.2 0.1 0.1 10 Tongue C01-C02 129 1.4 0.9 1.7 180 2.7 1.2 1.8 Mouth C03-C06 130 1.4 0.9 1.6 212 3.1 1.4 2.2 11 Salivary glands C07-C08 41 0.5 0.3 0.5 50 0.7 0.3 0.5 12 Tonsil C09 8 0.1 0.1 0.1 8 0.1 0.1 0.1 13 Other oropharynx C10 - - - - 6 0.1 0.0 0.1 14 Nasopharynx C11 19 0.2 0.1 0.2 19 0.3 0.1 0.2 Hypopharynx C12-C13 32 0.4 0.2 0.4 21 0.3 0.1 0.2 15 Pharynx For peerC14 review5 0.1 0.0 0.1only 5 0.1 0.0 0.0 16 Esophagus C15 95 1.0 0.7 1.2 127 1.9 0.8 1.4 17 Stomach C16 105 1.2 0.8 1.3 162 2.4 1.0 1.6 18 Small intestine C17 17 0.2 0.1 0.2 26 0.4 0.2 0.3 Colon C18 159 1.8 1.1 1.9 230 3.4 1.5 2.4 19 Rectum C19-C20 137 1.5 1.0 1.5 186 2.7 1.2 1.9 20 Anus C21 23 0.3 0.2 0.3 41 0.6 0.3 0.4 21 Liver C22 177 2.0 1.3 2.4 328 4.8 2.1 3.7 22 Gall bladder, etc. C23-C24 139 1.5 1.0 1.9 93 1.4 0.6 1.0 Pancreas C25 40 0.4 0.3 0.5 57 0.8 0.4 0.6 23 Other ill-defined digestive C26 14 0.2 0.1 0.1 16 0.2 0.1 0.2 24 Nose, sinuses C30-31 27 0.3 0.2 0.3 32 0.5 0.2 0.3 25 Larynx C32 28 0.3 0.2 0.3 183 2.7 1.2 2.0 26 Trachea, bronchus, & lung C33-C34 92 1.0 0.7 1.2 396 5.8 2.5 4.6 Other thoracic organs C37-C38 16 0.2 0.1 0.2 26 0.4 0.2 0.2 27 Bone C40-C41 91 1.0 0.7 0.6 143 2.1 0.9 0.9 28 Melanoma of the skin C43 13 0.1 0.1 0.1 13 0.2 0.1 0.1 29 Other skin C44 196 2.2 1.4 2.7 271 4.0 1.7 2.8 30 Connective & soft tissue C47,C49 108 1.2 0.8 1.0 144 2.1 0.9 1.2 Breast C50 4082 45.0 29.2 47.6 70 1.0 0.5 0.8 31 Vulva C51 19 0.2 0.1 0.2 - - - - 32 Vagina C52 16 0.2 0.1 0.2 - - - - 33 Cervix uteri C53 247 2.7 1.8 2.9 - - - -

34 Corpus uteri C54 267 2.9 1.9 3.6 - - - - http://bmjopen.bmj.com/ Uterus, unspecified C55 89 1.0 0.6 1.1 - - - - 35 Ovary C56 442 4.9 3.2 4.9 - - - - 36 Other female genital organs C57 18 0.2 0.1 0.2 - - - - 37 Placenta C58 7 0.1 0.1 0.0 - - - - 38 Penis C60 - - - - 1 0.0 0.0 0.0 Prostate C61 - - - - 526 7.8 3.4 6.4 39 Testis C62 - - - - 90 1.3 0.6 0.6 40 Other male genital organs C63 - - - - 5 0.1 0.0 0.1 41 Kidney C64 102 1.1 0.7 1.1 172 2.5 1.1 1.7 Renal pelvis C65 1 0.0 0.0 0.0 1 0.0 0.0 0.0

42 on October 2, 2021 by guest. Protected copyright. Ureter C66 1 0.0 0.0 0.0 1 0.0 0.0 0.0 43 Bladder C67 109 1.2 0.8 1.5 441 6.5 2.8 5.0 44 Other urinary organs C68 - - - - 2 0.0 0.0 0.0 45 Eye C69 40 0.4 0.3 0.4 57 0.8 0.4 0.5 46 Brain, nervous system C70-C72 227 2.5 1.6 2.2 458 6.8 2.9 3.8 Thyroid C73 215 2.4 1.5 2.2 81 1.2 0.5 0.7 47 Adrenal C74 4 0.0 0.0 0.0 7 0.1 0.0 0.1 48 Hodgkin lymphoma C81 80 0.9 0.6 0.7 202 3.0 1.3 1.4 49 Non-Hodgkin lymphoma C82-C88 277 3.1 2.0 3.3 493 7.3 3.2 4.5 50 Multiple myeloma C90 36 0.4 0.3 0.5 53 0.8 0.3 0.6 Lymphoid leukemia C91 112 1.2 0.8 0.7 207 3.1 1.3 1.2 51 Myeloid leukemia C92-93 62 0.7 0.4 0.5 107 1.6 0.7 0.8 52 Other leukemias C94 2 0.0 0.0 0.0 6 0.1 0.0 0.0 53 Leukemia, unspecified C95 40 0.4 0.3 0.3 60 0.9 0.4 0.4 54 Other & unspecified - 536 5.9 3.8 6.6 561 8.3 3.6 5.7 55 Benign CNS - 188 2.1 1.3 1.8 182 2.7 1.2 1.4 56 All sites 9069 100.0 64.9 105.1 6771 100.0 43.6 66.7 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 28 Page 19 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Table 5. Age-specific & age-standardized incidence rates of cancers diagnosed in the Lahore district, 2010-2012, amongst females. 4 5 Total ICD-10 Site 0- 5- 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- Crude % ASIR 6 cases codes 7 Lip 9 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.0 1.1 0.4 0.6 1.6 0.7 0.1 0.1 0.1 C00 8 Tongue 129 0.0 0.0 0.0 0.0 0.1 0.1 0.2 1.2 1.4 5.4 4.7 4.9 6.6 5.8 8.7 5.1 0.9 1.4 1.7 C01-C02 9 Mouth 130 0.0 0.0 0.0 0.2 0.2 0.3 0.2 1.5 2.9 1.6 6.0 4.6 3.5 7.0 11.1 5.1 0.9 1.4 1.6 C03-C06 10Salivary glands 41 0.0 0.0 0.1 0.0 0.1 0.5 0.2 0.8 0.5 0.6 1.1 0.7 2.7 1.9 0.8 0.0 0.3 0.5 0.5 C07-C08 Tonsil 8 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.2 0.7 0.4 0.0 0.0 0.8 0.7 0.1 0.1 0.1 C09 11Nasopharynx 19 0.0 0.0 0.1 0.1 0.1 0.2 0.3 0.0 0.3 0.6 0.2 0.4 0.4 0.0 1.6 0.0 0.1 0.2 0.2 C11 12Hypopharynx 32 0.0 0.0 0.0 0.1 0.2 0.1 0.2 0.5 0.3 0.6 0.7 1.4 1.9 0.6 1.6 0.7 0.2 0.4 0.4 C12-C13 13Pharynx 5 0.0 0.0 0.1 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.4 0.0 0.0 0.8 0.7 0.0 0.1 0.1 C14 14Esophagus 95 0.0 0.0 0.0 0.1 0.0 0.3 0.3 0.9 1.9 4.0 1.8 2.8 5.8 4.5 4.7 3.6 0.7 1.0 1.2 C15 15Stomach 105 0.0 For 0.0 0.0 0.0peer 0.3 0.1 1.0 review 1.3 2.2 3.8 2.5 3.9only 2.7 8.9 0.0 3.6 0.8 1.2 1.3 C16 16Small intestine 17 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.6 0.0 0.0 0.4 1.9 1.3 2.4 0.7 0.1 0.2 0.2 C17 17Colon 159 0.0 0.0 0.1 0.3 0.1 0.7 1.3 2.0 2.0 3.4 3.3 7.0 5.0 9.6 9.5 8.0 1.1 1.8 1.9 C18 18Rectum 137 0.0 0.0 0.1 0.2 0.9 0.9 1.4 1.2 1.7 3.0 3.1 4.2 5.0 4.5 6.3 5.1 1.0 1.5 1.5 C19-C20 19Anus 23 0.0 0.0 0.0 0.0 0.1 0.0 0.3 0.1 0.9 0.6 0.2 0.0 0.8 0.6 2.4 0.7 0.2 0.3 0.3 C21 Liver 177 0.1 0.1 0.0 0.1 0.1 0.1 0.2 0.3 1.4 4.4 6.2 11.2 12.0 16.6 8.7 5.1 1.3 2.0 2.4 C22 20 Gall bladder, etc. 139 0.0 0.0 0.0 0.1 0.0 0.0 0.5 0.4 1.5 2.6 4.9 6.7 8.9 14.1 7.1 8.7 1.0 1.5 1.9 C23-C24 21Pancreas 40 0.0 0.0 0.0 0.1 0.0 0.2 0.1 0.5 0.3 0.8 0.9 2.1 0.8 5.8 2.4 1.4 0.3 0.4 0.5 C25 22Other ill-defined digestive 14 0.0 0.0 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.9 0.0 1.2 0.0 0.8 0.0 0.1 0.2 0.1 C26 23Nose, sinuses 27 0.1 0.0 0.0 0.1 0.0 0.0 0.1 0.3 0.0 0.6 0.7 1.8 2.3 1.3 0.8 0.7 0.2 0.3 0.3 C30-31 24Larynx 28 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.1 0.6 0.8 1.3 1.4 1.2 0.6 0.0 2.2 0.2 0.3 0.3 C32 25Trachea, bronchus, & lung 92 0.0 0.0 0.1 0.2 0.1 0.1 0.5 0.4 0.9 1.4 1.8 4.6 5.4 8.3 6.3 5.8 0.7 1.0 1.2 C33-C34 26Other thoracic organs 16 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.3 0.2 0.8 0.0 0.4 1.6 0.6 0.8 0.7 0.1 0.2 0.2 C37-C38 27Bone 91 0.2 0.5 0.9 1.4 0.9 0.3 0.4 1.3 0.3 0.6 0.4 0.4 0.0 0.0 1.6 0.0 0.7 1.0 0.6 C40-C41 28Melanoma of the skin 13 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.3 0.2 0.4 0.4 0.7 0.0 0.0 0.8 0.7 0.1 0.1 0.1 C43 29Other skin 196 0.1 0.0 0.0 0.1 0.1 0.3 0.2 1.3 2.9 2.2 5.1 6.3 11.3 16.6 19.0 19.6 1.4 2.2 2.7 C44 Connective & soft tissue 108 0.4 0.3 0.3 0.6 0.6 0.8 0.8 1.2 1.7 1.2 1.8 1.4 1.6 3.8 2.4 2.9 0.8 1.2 1.0 C47,C49 30Breast 4082 0.0 0.1 0.1 0.1 3.3 14.0 32.2 55.9 86.2 126.8 130.3 158.5 154.1 157.9 124.9 92.1 29.2 45.0 47.6 C50 31Vulva 19 0.0 0.0 0.1 0.0 0.0 0.0 0.1 0.4 0.2 0.2 0.0 1.4 0.8 0.6 0.8 2.9 0.1 0.2 0.2 C51 32Vagina 16 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.1 0.3 0.8 0.2 0.7 0.4 0.0 0.8 1.4 0.1 0.2 0.2 C52 33Cervix uteri 247 0.0 0.0 0.0 0.0 0.2 0.4 1.3 3.9 5.7 9.4 7.1 10.5 10.1 8.3 5.5 5.1 1.8 2.7 2.9 C53

34Corpus uteri 267 0.0 0.0 0.0 0.0 0.0 0.2 0.6 1.5 1.9 6.0 9.8 16.5 22.1 16.0 18.2 7.2 1.9 2.9 3.6 C54 http://bmjopen.bmj.com/ 35Uterus, unspecified 89 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.9 1.5 3.4 4.0 2.8 5.8 3.8 4.7 0.0 0.6 1.0 1.1 C55 36Ovary 442 0.0 0.1 0.6 0.8 1.6 1.9 3.0 4.9 7.9 12.2 13.4 15.4 19.4 12.1 11.1 7.2 3.2 4.9 4.9 C56 37Other female genital organs 18 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.3 0.5 0.2 0.2 0.7 2.3 0.6 0.8 0.0 0.1 0.2 0.2 C57 38Placenta 7 0.0 0.0 0.0 0.0 0.1 0.1 0.3 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.0 C58 Kidney 102 0.7 0.1 0.1 0.0 0.2 0.0 0.2 1.6 2.0 1.6 2.7 4.9 3.1 3.2 3.2 4.3 0.7 1.1 1.1 C64 39 Renal pelvis 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C65 40Ureter 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.8 0.0 0.0 0.0 0.0 C66 41Bladder 109 0.1 0.0 0.0 0.1 0.0 0.1 0.2 1.1 1.2 1.6 2.7 4.9 5.0 8.9 10.3 10.1 0.8 1.2 1.5 C67

42Eye 40 0.9 0.3 0.1 0.0 0.0 0.0 0.0 0.0 0.3 0.4 0.0 0.0 0.8 4.5 0.8 2.2 0.2 0.4 0.4 C69 on October 2, 2021 by guest. Protected copyright. 43Brain, nervous system 227 0.3 0.7 0.6 0.9 0.9 2.0 1.4 2.5 3.3 4.4 4.9 5.3 5.0 7.7 4.0 2.9 1.6 2.5 2.2 C70-C72 44Thyroid 215 0.0 0.1 0.1 0.2 1.9 1.6 2.8 2.9 3.3 4.6 6.5 3.5 6.6 3.2 7.9 2.9 1.5 2.4 2.2 C73 45Adrenal 4 0.1 0.1 0.0 0.0 0.1 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C74 46Hodgkin lymphoma 80 0.2 0.4 0.3 0.4 0.9 1.0 0.4 1.1 0.3 1.0 0.2 1.8 1.6 0.6 2.4 0.0 0.6 0.9 0.7 C81 47Non-Hodgkin lymphoma 277 0.2 0.3 0.5 0.5 0.5 0.8 0.9 2.0 3.6 5.8 7.4 12.3 10.9 14.1 13.4 18.1 2.0 3.1 3.3 C82-C88 48Multiple myeloma 36 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.3 1.6 1.1 0.7 2.7 3.2 4.0 0.7 0.3 0.4 0.5 C90 Lymphoid leukemia 112 2.0 1.3 1.4 0.3 0.1 0.2 0.2 0.0 0.5 0.2 0.2 0.7 1.2 0.6 0.8 0.0 0.8 1.2 0.7 C91 49Myeloid leukemia 62 0.3 0.2 0.2 0.2 0.5 0.6 0.6 0.7 0.5 0.6 1.1 1.4 0.8 0.6 1.6 0.0 0.4 0.7 0.5 C92-93 50Other leukemias 2 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C94 51Leukemia, unspecified 40 0.3 0.5 0.3 0.3 0.1 0.3 0.1 0.1 0.2 0.2 0.7 0.0 0.0 0.6 0.8 0.0 0.3 0.4 0.3 C95 52 Other & 53Other & unspecified 536 0.5 0.2 0.2 0.2 1.1 1.8 2.7 4.7 7.0 12.6 14.9 24.9 24.1 33.9 26.9 18.8 3.8 5.9 6.6 unspecified 54Benign CNS 188 0.2 0.1 0.3 0.7 0.3 1.6 2.2 3.9 4.0 4.8 3.6 2.1 4.3 4.5 2.4 0.7 1.3 2.1 1.8 Benign CNS 55All sites 9069 6.7 5.0 6.5 8.4 16.4 32.1 58.3 104.7 155.6 237.8 259.9 337.6 364.1 398.2 348.7 259.5 64.9 100.0 105.1 All sites 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 18 of 28 BMJ Open Page 20 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Table 6. Age-specific & age-standardized incidence rates of cancers diagnosed in the Lahore district, 2010-2012, amongst males. 4 5 Total ICD-10 Site 0- 5- 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- Crude % ASIR 6 cases codes 7 Lip 13 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.2 0.0 0.0 0.2 0.6 1.3 0.5 0.6 0.0 0.1 0.2 0.1 C00 8 Tongue 180 0.0 0.0 0.0 0.0 0.3 0.6 0.6 2.0 3.5 3.6 4.4 5.0 7.2 6.2 9.5 2.3 1.2 2.7 1.8 C01-C02 9 Mouth 212 0.0 0.0 0.0 0.0 0.1 0.2 1.2 1.1 3.0 5.4 4.8 9.7 10.1 8.8 7.7 4.0 1.4 3.1 2.2 C03-C06 Salivary glands 50 0.0 0.0 0.1 0.1 0.1 0.2 0.3 0.7 0.6 0.7 0.7 1.1 1.9 1.6 3.0 1.7 0.3 0.7 0.5 C07-C08 10 Tonsil 8 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.1 0.0 0.2 0.3 0.6 0.5 0.0 0.0 0.1 0.1 0.1 C09 11 Other oropharynx 6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.0 0.6 0.3 0.0 0.6 0.0 0.0 0.1 0.1 C10 12 Nasopharynx 19 0.0 0.0 0.0 0.1 0.1 0.0 0.2 0.1 0.3 0.3 0.2 0.8 1.3 0.5 0.0 0.0 0.1 0.3 0.2 C11 13 Hypopharynx 21 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.1 0.3 0.0 0.6 0.3 0.9 1.0 1.2 2.9 0.1 0.3 0.2 C12-C13 14 Pharynx 5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.3 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 C14 Esophagus 127 0.0 0.0 0.0 0.1 0.1 0.2 0.3 0.8 0.5 3.1 3.1 4.5 5.3 6.2 9.5 6.9 0.8 1.9 1.4 C15 15 Stomach 162 0.0 For 0.0 0.0 0.0 peer 0.1 0.8 0.9 review 1.4 2.2 3.8 3.3 4.7only 4.4 10.3 8.3 3.4 1.0 2.4 1.6 C16 16 Small intestine 26 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.3 0.1 0.5 0.6 0.8 0.9 0.5 1.8 2.3 0.2 0.4 0.3 C17 17 Colon 230 0.0 0.0 0.0 0.4 0.8 0.6 0.7 1.5 2.1 4.8 4.4 5.8 11.6 14.5 9.5 6.3 1.5 3.4 2.4 C18 18 Rectum 186 0.0 0.0 0.0 0.4 0.7 0.9 1.4 1.0 1.0 3.3 3.9 5.0 8.2 11.9 4.2 6.3 1.2 2.7 1.9 C19-C20 19 Anus 41 0.0 0.0 0.0 0.1 0.1 0.1 0.5 0.0 0.6 0.5 1.3 0.8 2.2 1.6 0.6 1.1 0.3 0.6 0.4 C21 Liver 328 0.0 0.0 0.0 0.1 0.1 0.2 0.0 1.5 1.9 5.2 10.1 17.0 14.8 24.3 17.2 14.9 2.1 4.8 3.7 C22 20 Gall bladder, etc. 93 0.0 0.0 0.0 0.1 0.1 0.1 0.1 0.3 0.5 0.5 2.9 3.6 5.0 7.2 4.2 7.4 0.6 1.4 1.0 C23-C24 21 Pancreas 57 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.0 0.8 1.4 1.3 3.1 1.3 4.7 4.7 1.1 0.4 0.8 0.6 C25 22 Other ill-defined digestive 16 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.1 0.5 0.4 0.3 0.6 2.1 0.0 1.1 0.1 0.2 0.2 C26 23 Nose, sinuses 32 0.0 0.0 0.0 0.1 0.2 0.2 0.0 0.2 0.1 0.5 0.6 1.4 0.9 1.6 2.4 0.0 0.2 0.5 0.3 C30-31 24 Larynx 183 0.0 0.0 0.0 0.0 0.3 0.0 0.2 0.5 1.5 3.8 4.6 7.8 10.4 12.4 11.3 5.7 1.2 2.7 2.0 C32 25 Trachea, bronchus, & lung 396 0.0 0.0 0.0 0.0 0.1 0.1 0.6 1.9 1.8 5.7 4.8 13.1 21.4 32.0 37.4 32.6 2.5 5.8 4.6 C33-C34 Other thoracic organs 26 0.0 0.0 0.0 0.1 0.0 0.0 0.1 0.2 0.3 0.2 1.1 0.0 0.6 0.5 1.8 2.9 0.2 0.4 0.2 C37-C38 26 Bone 143 0.2 0.5 1.2 2.4 1.0 0.5 0.6 0.7 0.6 0.9 0.6 0.3 3.1 0.5 1.8 0.6 0.9 2.1 0.9 C40-C41 27 Melanoma of the skin 13 0.0 0.0 0.0 0.1 0.0 0.1 0.1 0.1 0.0 0.0 0.0 1.1 0.0 0.5 0.0 1.7 0.1 0.2 0.1 C43 28 Other skin 271 0.1 0.1 0.1 0.2 0.3 0.9 1.6 2.0 2.3 2.8 4.1 8.6 11.3 16.5 10.1 21.2 1.7 4.0 2.8 C44 29 Connective & soft tissue 144 0.4 0.5 0.1 0.9 0.8 1.1 0.7 1.1 0.5 2.8 1.1 2.5 2.8 3.6 4.2 2.9 0.9 2.1 1.2 C47,C49 30 Breast 70 0.0 0.0 0.0 0.1 0.1 0.1 0.0 0.3 0.9 2.1 1.5 1.9 1.9 8.8 2.4 1.7 0.5 1.0 0.8 C50 Penis 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C60 31 Prostate 526 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.3 1.0 4.4 13.1 27.1 46.0 69.4 87.0 3.4 7.8 6.4 C61 32 Testis 90 0.2 0.0 0.0 0.5 1.1 1.2 1.2 1.1 1.0 0.7 0.6 0.3 0.3 1.6 0.6 0.6 0.6 1.3 0.6 C62 33 Other male genital organs 5 0.1 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.0 0.6 0.0 0.0 0.1 0.1 C63

34 Kidney 172 0.6 0.2 0.0 0.1 0.1 0.2 0.3 0.9 2.7 3.3 3.3 5.6 6.3 7.2 9.5 5.7 1.1 2.5 1.7 C64 http://bmjopen.bmj.com/ 35 Renal pelvis 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C65 36 Ureter 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C66 Bladder 441 0.1 0.0 0.0 0.0 0.1 0.2 0.4 1.8 2.2 5.9 7.5 19.2 23.0 30.0 29.7 42.4 2.8 6.5 5.0 C67 37 Other urinary organs 2 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.6 0.0 0.0 0.0 C68 38 Eye 57 1.2 0.2 0.0 0.1 0.1 0.1 0.0 0.1 0.1 0.7 0.6 0.3 1.6 2.1 2.4 1.1 0.4 0.8 0.5 C69 39 Brain, nervous system 458 0.7 1.0 0.7 1.2 1.6 2.9 4.5 4.4 5.0 7.3 8.8 10.6 11.3 9.8 8.3 3.4 2.9 6.8 3.8 C70-C72 40 Thyroid 81 0.0 0.0 0.0 0.2 0.2 0.7 0.8 0.3 0.8 1.4 1.8 3.3 1.6 2.6 3.0 1.1 0.5 1.2 0.7 C73 41 Adrenal 7 0.1 0.0 0.0 0.1 0.1 0.0 0.0 0.0 0.0 0.2 0.0 0.3 0.0 0.0 0.6 0.0 0.0 0.1 0.1 C74 Hodgkin lymphoma 202 0.7 1.8 0.7 1.0 0.9 1.4 1.2 1.4 1.5 1.6 1.5 3.3 1.9 4.1 3.6 0.6 1.3 3.0 1.4 C81 42 Non-Hodgkin lymphoma 493 0.4 1.4 1.1 1.3 2.0 1.6 2.5 2.5 4.6 5.9 10.1 11.7 18.3 18.1 16.6 14.3 3.2 7.3 4.5 C82-C88 on October 2, 2021 by guest. Protected copyright. 43 Multiple myeloma 53 0.1 0.0 0.0 0.0 0.0 0.0 0.2 0.2 0.5 1.2 1.3 2.5 3.1 1.6 2.4 2.3 0.3 0.8 0.6 C90 44 Lymphoid leukemia 207 3.1 2.2 2.6 0.7 0.5 0.2 0.3 0.1 0.8 0.3 0.9 0.6 0.6 2.1 0.0 1.7 1.3 3.1 1.2 C91 45 Myeloid leukemia 107 0.3 0.3 0.4 0.4 0.7 0.8 0.9 1.4 1.0 1.0 0.7 1.9 1.9 2.1 0.0 0.6 0.7 1.6 0.8 C92-93 46 Other leukemias 6 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.1 0.0 0.4 0.0 0.0 0.0 0.6 0.0 0.0 0.1 0.0 C94 Leukemia, unspecified 60 0.5 0.4 0.7 0.2 0.5 0.2 0.3 0.1 0.3 0.3 0.2 0.3 0.6 0.0 0.6 0.0 0.4 0.9 0.4 C95 47 Other & 48 Other & unspecified 561 0.3 0.1 0.6 0.9 0.4 2.0 2.6 2.9 4.8 6.0 12.2 18.7 23.9 28.4 25.5 34.9 3.6 8.3 5.7 unspecified 49 Benign CNS 182 0.3 0.4 0.2 0.5 0.8 2.0 1.9 2.4 2.1 3.3 3.3 1.1 3.1 1.6 3.0 0.6 1.2 2.7 1.4 Benign CNS 50 All sites 6771 9.2 9.5 9.1 12.2 14.8 20.6 27.4 38.0 53.7 93.1 118.4 194.0 255.2 337.0 329.7 328.0 43.6 100.0 66.7 All sites 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 28 Page 21 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Of the 15,825 patients, death was recorded in 5,134 (32·4%) cases by the cut-off date for this study; this 4 5 included 2,726 female and 2,408 male patients. Four-thousand, three-hundred and forty-seven patients 6 were still alive (27·5%) at the time of review, whereas, the vital status of 6,344 patients (40·1%) could 7 not be determined. Death certificates were available in each record of a hospital death for about 8% of 8 9 patients (400/5,134), representing just one collaborating center, which is SKMCH & RC. Table 7 displays 10 death counts and proportion by cancer sites. Since the follow-up information was not available for 11 nearly 40% of the patients, the mortality to incidence ratio was not calculated either. 12 13 Table 7. Distribution of deaths recorded (5,134 (2,726 female and 2,408 male patients)), in patients diagnosed 14 with cancer, in the Lahore district, in 2010-2012, according to gender and cancer type (top 10 cancers only). 15 For peer review only 16 17 Females Count % Males Count % 18 Breast 987 36 Brain 213 9 19 20 Ovary 137 5 Bronchus & lung 207 9 21 Colorectum 127 5 NHL 169 7 22 23 NHL 109 4 Prostate 168 7 24 Lip & oral cavity 106 4 Colorectum 155 6 25 26 Brain 99 4 Lip & oral cavity 152 6 27 28 Leukemia 87 3 Liver & intrahep. bile ducts 151 6 29 Liver & intrahep. bile ducts 85 3 Leukemia 144 6 30 31 Cervix uteri 65 2 Urinary bladder 133 6 32 Corpus uteri 53 2 Stomach 73 3 33

42 colo-rectum, lip & oral cavity, liver & intrahepatic bile ducts, bladder, and leukemia, and 3% in stomach on October 2, 2021 by guest. Protected copyright. 43 carcinoma. 44 45 46 47 48 DISCUSSION 49 50 The Registry has been in existence since 2005 but was in an evolving phase in the initial years of its 51 52 functioning. Therefore, conducting a comparison of the cases recorded over the initial years did not 53 appear to be useful. Further, as there are notification delays and the Registry is still receiving 54 information on cases diagnosed in the most recent years (2014-2015), mainly from one center, this 55 56 time-period has not been included in the study either. It is hoped that a study conducted at a 57 subsequent stage will cover the 2013-2015 period. For the time-period 2010-2012, the results reported 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 20 of 28 BMJ Open Page 22 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 for the population of the Lahore district show that on average, over 5,200 new cancer cases were 4 5 diagnosed, every year. The fact that nearly seven percent were non-microscopically confirmed cancers 6 as opposed to nearly 93% that were microscopically confirmed, supports that there was no reliance on 7 the pathology laboratory as the only source of information. These figures are similar to those reported 8 9 for the Karachi Cancer Registry[5]. However, some of the cases diagnosed clinically might not have been 10 reported to the Registry but we have no way of knowing that, at present. The ASIR for all-cancers 11 combined was higher amongst females (105·1) than in males (66·7). These results also include the ASIRs 12 13 for benign CNS tumors and other/unspecified sites. The ASIRs reported by the Surveillance, 14 Epidemiology, and End Results (SEER) Program of the United States of America (USA), are very high 15 (359·4 for femalesFor and 282·6 forpeer males)[21,22]. review These figures represent only SEER 18 registries compiling 16 17 data from all cases diagnosed since 2000 and covering approximately 30% of the US population[21,22]. 18 The ASIRs published in the CI5-X report for Delhi in India and Riyadh in Saudi Arabia, are close to the 19 Lahore district figures as opposed to the SEER rates; in fact, the ASIRs for females in these three regions 20 21 are quite similar to one another. It is important to point out that Delhi, located in India, to the east of 22 Lahore, is closer to Lahore than is Karachi located in southern Pakistan. As far as the South Karachi 23 Registry is concerned, based on the last report (1998-2002) released in CI5-IX, it can be seen that the 24 25 ASIRs for Karachi were relatively high (192·0 for females and 166·6 for males) as compared to those for 26 the Lahore district. Further, in the region of Golestan in Iran (2005-2007), and for Israel, again the ASIRs 27 were high compared to those reported for the Lahore district[19]. For the SEER Program, Delhi, Iran, and 28 Saudi Arabia, data were reported for the 2003-2007 time period. Table 8 shows a comparison of the 29 30 ASIRs according to cancer sites, though not all sites, in the aforementioned regions of the world. In 31 women belonging to the Lahore district, the ASIR of breast cancer ranked the highest (47·6) of all the 32 cancers, and was higher than that for Delhi (31·6), but relatively low compared to that reported for the 33

34 Israeli Jews (89·4). Amongst men in the Lahore district, the ASIR of prostate cancer was the highest (6·4) http://bmjopen.bmj.com/ 35 of all the cancers, but was lower than that reported for Delhi (10·1) and Riyadh (7·9). Even though breast 36 and prostate cancer were the most common diagnoses in the Lahore district, the point to be noted is 37 38 that organized screening programs for early detection of these diseases do not exist in Pakistan. The 39 ASIR of cervical cancer in Lahore was 2·9 but in Delhi it was much higher, at 17·7; this is despite the fact 40 that the screening levels are low in the general population of India[23]. Of the factors implicated in the 41 etiology of cervical cancer in the Indian population, the presence of specific oncogenic types of the 42 on October 2, 2021 by guest. Protected copyright. 43 Human Papilloma Viruses (HPV), namely types 16 and 18, plays an important role in the development of 44 cancer of the cervix. In Pakistan, one population-based study reports HPV positivity to be nearly 2·8% in 45 46 the general population (25/899) and about 92% in patients with invasive cervical cancer (83/91)[24]. 47 However, in India, it has been reported that HPV prevalence varies from 7·5% to 16·9% in women 48 without cervical cancer as opposed to 87·8% to 96·7% amongst cervical cancer patients[23]. Further, in 49 50 the latest Globocan report, the ASIR for cancer of the cervix in Pakistan was estimated at 7·9 per 51 100,000 females with 5,233 cases identified in 2012[15]; in the same year, in Saudi Arabia, 241 cases 52 were diagnosed, with the ASIR at 2·7 per 100,000 women; in contrast to this, in India, 122,844 cervical 53 54 cancer cases were diagnosed, with a relatively high ASIR of 22·0 per 100,000 females[15]. Since the ASIR 55 is low in the aforementioned Muslim countries compared to a non-Muslim country, circumcision of 56 men may be a plausible explanation in reducing the transmission of HPV infection to their female sexual 57 58 partners. Circumcision of men is the norm amongst Muslim males. The role of circumcision has been 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 28 Page 23 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 demonstrated in three separate randomized trials done in Africa[25]. Since the incidence of cervical 4 5 cancer in Pakistan is relatively low and the 5-year prevalence is 15,323, setting-up a formal screening 6 program may have lower yields, therefore, a low priority in resource allocation and decision making in 7 our setting[15]. 8 9 10 As shown in Table 8, the ASIRs per 100,000 population, per year, for ten common cancers in Pakistan, as 11 reported in the Globocan 2012, compared to Lahore, are as follows: In women: breast 50·3, 47·6; lip & 12 oral cavity 9·1, 3·9; cervix uteri 7·9, 2·9; ovary 5·6, 5·1; esophagus 4·4, 1·2; corpus uteri 3·6, 3·6; NHL 3·4, 13 14 3·3; colo-rectum 3·3, 3·7; liver 2·5, 2·4; and stomach 2·2, 1·3, while, amongst men: lip & oral cavity 10·5, 15 4·6; lung 9·8, 4·6; ForNHL 5·3, 4·5; peer prostate 6·6, 6·4;review bladder 5·1, 5·0; larynx only 5·0, 2·0; colo-rectum 47, 4·7; 16 liver 4·7, 3·7; esophagus 3·9, 1·4; stomach 3·8, 1·6; and brain & nervous system 3·4, 3·8. The comparison 17 18 shows that rates are somewhat higher for tobacco-related cancers (lip & oral cavity, lung, larynx, and 19 esophagus), and cervical cancer, though for the latter, the rates are still lower than those reported in 20 countries with a high HPV prevalence rate. Since the Globocan 2012 report included data from the 21 22 Punjab Cancer Registry, Karachi South district, and Dr. Yasmin’s paper, the relatively high cancer rates 23 for certain cancers may be attributed to the high consumption of tobacco-related products in that part 24 of Pakistan, in the form of cigarettes and bidi and also of smokeless tobacco as betel quid and 25 26 niswar[26]. Further, Karachi South is one of the 29 districts of the province of Sindh[12], located in the 27 south of the country and its population was 1·72 M during the period under study. Its last report 28 published in the CI-5, IX, shows a high incidence rate for tobacco related cancers[22]. Therefore, the 29 30 dissimilarity in the incidence rates could be attributed to the geographic and lifestyle differences 31 between these two regions. Table 8, depicting the ASIRs, highlights the differences between these two 32 regions and other regions of the world as well. 33

34 http://bmjopen.bmj.com/ 35 As far as the mortality data in our study are concerned, since the vital status of all the patients could not 36 be recorded, our results have to be interpreted with caution. The highest mortality was recorded in 37 patients diagnosed with breast cancer amongst females, and amongst those with brain tumors in males. 38 39 Due to the non-availability of the vital status of nearly half of the patients, the survival statistics could 40 not be reported either. Death certificates were available from just one collaborating center for each 41 record of a hospital death and accounted for nearly 8% of the deaths recorded in the Registry. However,

42 on October 2, 2021 by guest. Protected copyright. 43 the point to be noted is that the cancer diagnoses were not merely reported from hospitals, they were 44 also reported on patients identified as new cancer cases, from different laboratories/collection centers 45 within the district. The establishment of a central death registry in the region could help in collecting the 46 47 mortality data and determining the cause-specific mortality, along with the survival estimates for the 48 study population. While the Government of Pakistan maintains the National Database Registration 49 Authority with all citizens’ data and biometric information, the capture of death information is variable 50 51 and typically done at the local government level[27,28]. Deaths within hospitals have documented death 52 certificates which get communicated to local government, but the recording of death diagnosis likely 53 over-reports final mechanisms of death (‘cardio respiratory failure’), rather than underlying causes. In 54 55 view of this, death data and thus survival data have inherent inaccuracies in it. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 22 of 28 BMJ Open Page 24 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Table 8. ASIRs, per 100,000 population, per year, for selected cancer sites, in Pakistan, India, Iran, Israel, and USA. 4 5 Saudi 6 Pakistan Globocan Pakistan India Iran Arabia Israel USA New 7 Lahore Pakistan Karachi Delhi Golestan Riyadh Jews SEER 8 2010- 1998- 2003- 2005- 2003- 2003- 9 2012 2012 2002 2007 2007 2003-2007 2007 2007 10 Oral cavity & salivary glands-C00-C08 11 Male 4.6 10.5 22.5 14.0 1.7 1.6 3.3 6.9 12 Female 3.9 9.1 20.4 4.7 1.3 1.4 2.3 3.1 13 Pharynx-C09-C14 14 Male 0.6 3.8 8.2 6.6 1.0 2.4 1.5 4.4 15 Female For0.8 peer 1.3 3.4 review 1.5 0.7 only 1.3 0.5 1.1 16 Esophagus-C15 Male 1.4 3.9 6.7 4.9 23.2 1.6 1.8 5.1 17 Female 1.2 4.4 8.6 2.9 18.8 1.3 0.9 1.2 18 Stomach-C16 19 Male 1.6 3.8 6.0 3.2 30.4 4.4 10.0 6.6 20 Female 1.3 2.2 3.6 1.5 12.6 2.3 5.4 3.3 21 Small intestine-C17 22 Male 0.3 - 0.2 0.2 1.4 0.5 1.0 1.5 23 Female 0.2 - 0.4 0.1 0.9 0.3 0.7 1.1 24 Colo-rectum-C18-C21 25 Male 4.7 4.7 7.1 5.5 13.6 12.5 42.8 35.3 26 Female 3.7 3.3 5.2 3.7 10.4 10.6 32.6 26.5 27 Liver-C22 28 Male 3.7 4.7 5.4 2.6 3.6 3.0 3.1 7.6 29 Female 2.4 2.5 3.7 1.5 2.0 6.0 1.4 2.4 30 Gall bladder-C23-C24 31 Male 1.0 0.9 1.3 4.0 1.2 1.2 1.7 1.7 Female 1.9 2.2 4.9 8.0 1.6 2.5 1.4 1.7 32 33 Pancreas-C25 Male 0.6 0.5 0.9 1.9 2.8 3.2 8.6 8.2 http://bmjopen.bmj.com/ 34 Female 0.5 0.4 0.5 1.1 1.0 1.9 6.4 6.2 35 Nose & sinuses-C30-C31 36 Male 0.3 - 0.7 0.3 0.0 0.2 0.4 0.6 37 Female 0.3 - 0.4 0.2 0.2 0.2 0.3 0.4 38 Larynx-C32 39 Male 2.0 5.0 10.7 8.0 4.1 1.7 4.1 4.3 40 Female 0.3 0.7 1.8 1.1 1.4 0.1 0.6 0.9 41 Trachea, bronchus, & lung-C33-C34

42 Male 4.6 9.8 25.2 13.7 17.5 6.3 29.8 48.3 on October 2, 2021 by guest. Protected copyright. 43 Female 1.2 1.7 3.6 3.6 5.6 2.2 13.4 33.8 44 Bone-C40-C41 45 Male 0.9 - 1.3 2.0 1.3 0.8 1.3 1.0 46 Female 0.6 - 1.5 1.2 1.5 0.5 1.0 0.8 47 Melanoma of the skin-C43 48 Male 0.1 0.3 0.5 0.2 0.9 0.3 13.7 16.8 Female 0.1 0.2 0.3 0.2 0.7 0.4 11.2 12.0 49 Skin-C44 50 Male 2.8 - 4.3 1.3 11.0 3.8 2.8 1.3 51 Female 2.7 - 4.1 1.0 7.7 3.2 1.9 1.0 52 Connective & soft tissue-C47-C49 53 Male 1.2 - 2.4 1.5 2.1 1.3 3.2 3.0 54 Female 1.0 - 2.3 1.2 2.1 0.9 2.2 2.1 55 Breast-C50 56 Male 0.8 - 1.0 1.3 0.1 0.5 1.3 0.7 57 Female 47.6 50.3 69.0 31.6 28.0 21.1 89.4 86.6 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 28 Page 25 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Cervix uteri-C53 4 Female 2.9 7.9 7.5 17.7 5.4 2.0 5.5 6.4 5 Corpus uteri-C54 6 Female 3.6 3.6 6.7 4.5 1.7 4.4 14.4 16.7 7 Ovary-C56-C57.0-4 8 Female 5.1 5.6 8.8 8.6 6.1 3.3 9.2 9.6 9 Other female genital organs-C51-C52, C55, C58 10 Female 1.5 - 1.0 1.6 1.4 0.9 1.8 2.5 11 Penis-C60 12 Male - - 0.1 1.0 0.0 0.1 0.3 0.7 13 Prostate-C61 14 Male 6.4 6.6 10.1 10.1 10.6 7.9 68.3 106.8 15 Testis-C62 Male For0.6 peer 0.9 1.2 review 0.6 2.3 only 0.6 4.7 4.9 16 Kidney, etc.-C64, C66, C68 17 Male 1.7 1.7 1.9 2.7 2.2 3.8 13.9 137.0 18 Female 1.1 0.9 0.8 1.2 1.2 2.5 6.5 7.1 19 Bladder-C67 20 Male 5.0 5.1 9.3 6.5 8.5 5.6 25.5 20.8 21 Female 1.5 1.6 2.6 1.5 2.8 1.3 4.8 5.3 22 Eye-C69 23 Male 0.5 - 0.6 0.3 0.4 0.4 0.6 0.8 24 Female 0.4 - 0.3 0.2 0.2 0.2 0.4 0.6 25 Brain, CNS-C70-C72 26 Male 3.8 3.4 3.3 3.8 7.8 3.5 6.7 6.4 27 Female 2.2 2.1 2.7 2.4 5.3 2.1 5.0 4.6 28 Thyroid-C73 29 Male 0.7 0.7 0.7 1.1 1.2 2.5 4.8 3.9 30 Female 2.2 2.2 2.9 2.5 3.0 10.2 14.7 12.3 31 Adrenal & other endocrine-C74-C75 Male 0.1 - 0.2 0.2 0.7 0.3 0.6 0.5 32 Female 0.0 - 0.3 0.2 0.4 0.2 0.5 0.4 33 Hodgkin lymphoma-C81 34 Male 1.4 2.2 2.0 1.6 1.8 2.2 3.6 2.7 http://bmjopen.bmj.com/ 35 Female 0.7 0.8 1.0 0.7 1.1 2.0 3.4 2.2 36 NHL-C82-C88, C96 37 Male 4.5 5.3 7.6 5.6 7.2 8.6 17.9 15.5 38 Female 3.3 3.4 5.1 3.0 3.3 7.1 14.4 10.8 39 Multiple myeloma-C88, C90 40 Male 0.6 0.7 1.8 2.0 2.4 1.8 4.8 4.7 41 Female 0.5 0.6 1.3 1.2 2.2 1.0 3.0 3.1

42 Leukemia-C91-C95 on October 2, 2021 by guest. Protected copyright. 43 Male 2.4 3.3 4.8 5.6 10.8 5.7 10.6 11.1 44 Female 1.5 2.2 4.1 3.6 7.7 4.3 6.9 7.1 45 All sites-C00-C96 46 Male 66.7 96.0 166.6 119.7 165.3 104.1 273.1 359.4 47 Female 105.1 127.7 192.0 118.4 142.0 103.9 308.5 282.6 48 49 50 CONCLUSION 51 52 This is the first time that an attempt has been made to determine and report the population-based 53 cancer statistics for the Lahore district. This collaborative study highlights cancer registration and follow- 54 55 up issues in a developing country like Pakistan, along with the non-availability of recent, accurate 56 population estimates required as denominators in computation of the incidence rates. On average, 57 annually, 5,200 new cases were reported in the Lahore district, in 2010-2012. Although it is likely that all 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 24 of 28 BMJ Open Page 26 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 the cases have not been reported, it is not possible to gauge the extent of under-reporting at this stage. 4 5 The cancer statistics reported in this manuscript can be used as baseline figures for comparison with 6 studies to be undertaken in the future. These statistics can also assist in exploring, thus, highlighting the 7 putative risk factors associated with cancers commonly diagnosed in the region, as part of a health 8 9 promotion and education program. Finally, this report can play an important role in developing 10 prevention, early detection, and cancer control strategies in the region. 11 12 13 14 FOOTNOTES 15 For peer review only 16 Contributors 17 18 19 FB conceived the idea of the study, designed it, supervised the statistical analysis, did literature search, 20 interpreted the results, and drafted the manuscript. FB further did the survival analysis for this study. 21 SMa did the case-finding, coding, and indexing of cases from SKMCH & RC and computed the incidence 22 23 rates and created figures and tables; RF, AY, HA, and AA validated the data, checked for duplication, and 24 followed-up on the patients; and AQ and KLA worked on the comparison of the incidence rates with 25 other regions. MAY and FS reviewed the paper critically and advised. MM was responsible for reporting 26 27 the cancers recorded at the Institute of Nuclear Medicine & Oncology, Lahore; GRS from Ittefaq 28 Hospital, Lahore; NC from Sheikh Zayed Hospital, Lahore; ORC from Chughtais Lahore Lab, Lahore; TM 29 from Fatima Jinnah Medical University, Lahore; ZA and MAK from Jinnah Hospital, Lahore; GH and AA 30 31 from the Children’s Hospital & the Institute of Child Health, Lahore; RB from the Services Institute of 32 Medical Sciences, Lahore; SR and IT from Fatima Memorial College of Medicine & Dentistry, Lahore; FA 33 from Shalamar Medical & Dental College, Lahore; TA from Allama Iqbal Medical College, Lahore; SN 34 http://bmjopen.bmj.com/ 35 from King Edward Medical University, Lahore; and BAS from Nawaz Sharif Social Security Hospital, 36 Lahore. NS contributed intellectually to the study. MTM, SMu, AL, and MH did the pathologic 37 confirmation of cases at SKMCH & RC, Lahore. SMa supervised, FB managed, and MAY and FS 38 39 established and directed the Punjab Cancer Registry. 40 41 Funding

42 on October 2, 2021 by guest. Protected copyright. 43 None for this study. 44 45 Competing interests 46 47 We declare no competing interests. 48 49 Data sharing statement 50 51 52 No additional data available. 53 54 55 56 ACKNOWLEDGEMENTS 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 28 Page 27 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 We thank the professionals representing various centers in the region for reporting their data to the 4 5 Punjab Cancer Registry. We also thank the Staff of the unit Cancer Registry and Clinical Data 6 Management, SKMCH & RC, on making additional efforts to complete cancer registration, following 7 international guidelines, thus, enabling us to complete the study. 8 9

10 11 12 REFERENCES 13 14 15 1 Sania Nishtar.For Pakistan’s peer health systems. review In: Choked Pipes: Reformingonly Pakistan’s Mixed Health 16 Systems. Karachi, Oxford University Press 2010: Fig 4, Page 37. 17 18 2 Valsecchi MG, Steliarova-Foucher E. Cancer registration in developing countries: luxury or 19 20 necessity? Lancet Oncol 2008 Feb;9(2):159-67. URL: 21 http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(08)70028-7/fulltext 22 (accessed 16 Feb 2016). DOI: 10.1016/S1470-2045(08)70028-7. 23 24 3 The World Bank [Internet]. Washington, DC, USA 2016. URL: 25 http://databank.worldbank.org/data/reports.aspx?source=2&type=metadata&series=EN.POP.D 26 27 NST# and http://wdi.worldbank.org/table/1.5 (accessed 25 Jan 2015). 28 29 4 Survey of Pakistan (Map). Pakistan 2015. URL: http://www.surveyofpakistan.gov.pk/ (accessed 30 17 Dec 2015). 31 32 5 Bhurgri Y. Epidemiology of cancers in Karachi 1995-1999. Karachi, Pharmacia and Upjohn 2001. 33 34 http://bmjopen.bmj.com/ 35 6 Punjab Cancer Registry. SKMCH & RC, Lahore, Pakistan 2011. URL: 36 http://punjabcancerregistry.org.pk (accessed 16 Dec 2015). 37 38 7 Shaukat Khanum Memorial Cancer Hospital and Research Center. Lahore, Pakistan 2015. URL: 39 http://www.shaukatkhanum.org.pk/ (accessed 16 Dec 2015). 40 41 8 Badar F. Cancer Registration in Pakistan. J Coll Physicians Surg Pak 2013;23(8):611–12.

42 on October 2, 2021 by guest. Protected copyright. 43 44 9 Badar F, Mahmood S. The state of cancer registration in Pakistan. J Ayub Med Coll Abbottabad 45 2015;27(2):507–508. 46 47 10 The Societies Registration Act, 1860 (Act XXI of 1860). Pakistan 2015. URL: 48 http://punjablaws.gov.pk/laws/1.html#_ftn2 (accessed 16 Dec 2016). 49 50 51 11 IACR-International Association of Cancer Registries. Lyon, France 2015. URL: 52 http://www.iacr.com.fr/ (accessed 16 Dec 2015). 53 54 12 Pakistan Bureau of Statistics-Government of Pakistan. Islamabad, Pakistan 2015. URL: 55 http://www.pbs.gov.pk/content/population-census (accessed 16 Dec 2015). 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 26 of 28 BMJ Open Page 28 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 13 Census-Publication No. 125-Population Census Organization-Statistics Division, Government of 4 Pakistan, Islamabad (2000). Statistical Tables of 1998 Population and Housing Census. In: ‘1998 5 6 District Census Report of Lahore.’ Islamabad: Government of Pakistan 2000. 77–305. 7 8 14 MacLennan R. Chapter 6-Items of patient information which may be collected by registries. In: 9 Jensen OM, Parkin DM, MacLennan R, et al, eds. Cancer Registration: Principles and Methods- 10 IARC Scientific Publications No. 95. International Agency for Research on Cancer, Lyon, France 11 1991. URL: https://www.iarc.fr/en/publications/pdfs-online/epi/sp95/SP95.pdf (accessed 16 12 13 Feb 2016). 14 15 15 GLOBOCANFor 2012: Estimated peer Cancer Incidence,review Mortality, and only Prevalence Worldwide in 2012. 16 Lyon, France 2015. URL: http://globocan.iarc.fr/Default.aspx (accessed 17 Dec 2015). 17 18 16 Census in Pakistan by Wikipedia. Wikimedia Foundation, San Francisco, CA, USA 2016. URL: 19 https://en.wikipedia.org/wiki/Census_in_Pakistan (accessed 22 Jan 2016). 20 21 22 17 Program for Multiple Primaries- IARC/IACR Multiple Primary Rules. Appendix 3. In: Ferlay J, 23 Burkhard C, Whelan S, et al, eds. International Agency for Research on Cancer. Check and 24 Conversion Programs for Cancer Registries (IARC/IACR Tools for Cancer Registries). IARC 25 Technical Report No. 42. Lyon 2005;38-45. 26 27 28 18 Fritz A, Percy C, Jack A, et al, eds. 6th Digit Code for Histologic Grading and Differentiation. In: 29 Fritz A. International Classification of Diseases for Oncology. 3rd ed. WHO, Geneva 2000:31. 30 31 19 Holden K, ed. ICD-10-CM Expert for Hospitals. The complete official code set. Codes valid 32 October 1, 2015 through September 30, 2016. Salt Lake City, UT, USA: Optum360, LLC 2015. 33 34 20 Boyle P, Parkin DM. Chapter 11-Statistical Methods for Registries-IARC. In: Jensen OM, Parkin http://bmjopen.bmj.com/ 35 36 DM, MacLennan R, et al, eds. Cancer Registration: Principles and Methods. IARC Scientific 37 Publication No. 95. International Agency for Research on Cancer, Lyon, France 1991. URL: 38 https://www.iarc.fr/en/publications/pdfs-online/epi/sp95/SP95.pdf (accessed 16 Feb 2016). 39 40 21 The Surveillance, Epidemiology, and End Results (SEER) Program. NCI, Bethesda, Maryland 2016. 41 URL: http://seer.cancer.gov/registries/terms.html (accessed 4 Feb 2016).

42 on October 2, 2021 by guest. Protected copyright.

43 44 22 Cancer Incidence in Five Continents Volumes I to X-IACR; International Agency for Research on 45 Cancer, Lyon, France 2016. URL: http://ci5.iarc.fr/CI5I-X/Pages/table4_sel.aspx (accessed 3 Feb 46 2016). 47 48 23 Sreedevi A, Javed R, Dinesh A. Epidemiology of cervical cancer with special focus on India. Int J 49 Womens Health. 2015 Apr;7:405–414. URL: 50 51 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404964/ (accessed 16 Feb 2016). 52 DOI: 10.2147/IJWH.S50001. 53 54 24 Raza SA, Franceschi S, Pallardy S, et al. Human papillomavirus infection in women with and 55 without cervical cancer in Karachi, Pakistan. Br J Cancer 2010 Apr;102:1657–1660. URL: 56 https://researchonline.lshtm.ac.uk/448554/1/6605664a.pdf (accessed 16 Feb 2016). 57 DOI:10.1038/sj.bjc.6605664. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 28 Page 29 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 25 Giuliano AR, Schim van der Loeff MF, Nyitray AG. Circumscribed HIV-infected men and HPV 5 6 transmission. Lancet Infect Dis. 2011 Aug;11(8):581-2. DOI: 10.1016/S1473-3099(11)70073-1. 7 Epub 2011 Apr 12. 8 9 26 Imam SZ, Nawaz H, Sepah YJ, et al. Use of smokeless tobacco among groups of Pakistani medical 10 students-a cross-sectional study. BMC Public Health. 2007 Sep;7:231. URL: 11 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1995212/ (accessed 26 Apr 2016). DOI: 12 13 10.1186/1471-2458-7-231. 14 15 27 National DatabaseFor and peer Registration Authority review (NADRA). URL: onlyhttps://www.nadra.gov.pk/ 16 (accessed 26 Apr 2016). 17 18 28 Local Government and Community Development-Registration of Death. URL: 19 https://lgcd.punjab.gov.pk/FAQ (accessed 26 Apr 2016). 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

34 254x190mm (300 x 300 DPI) http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 Figure 2. Map of Pakistan showing the provinces and location of the Lahore and Karachi districts and neighboring countries. 41 344x337mm (300 x 300 DPI) 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Figure 3. Population structure of the Lahore district, 2010-2012, by gender. 152x97mm (300 x 300 DPI) 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 Evaluation Edition of activePDF DocConverter 57 58 59 60 Visit www.activePDF.com for more details. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 38 BMJ Open

34 19 Pride Lab http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Page 1 of 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 34 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Appendix B-Data collection form used for the Lahore district, the Punjab Cancer Registry. 4 5 6

32 HOME/CELL TELEPHONE WITH AREA CODE______33

34 ↓RESIDENT OF LAHORE: YES NO IF YES, duration of stay in Lahore (Months/Years) _____ http://bmjopen.bmj.com/ 35

36 ↓COME TO LAHORE FOR TREATMENT/DIAGNOSIS ONLY______(YES/NO) 37

56 xx END xx 57 58 59 Page 1 of 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 38 BMJ Open

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Page 3 of 3 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 38 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 STROBE Statement—checklist of items that should be included in reports of observational studies 3 4 5 Item No Recommendation 6 7 Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the 8 abstract-page 8 9 (b) Provide in the abstract an informative and balanced summary of what was done 10 and what was found- page 8 11 12 Introduction 13 Background/rationale 2 Explain the scientific background and rationale for the investigation being reported- 14 page 9-11 15 Objectives For3 peer State specific objectives, review including any pre-specified only hypotheses-page 11 16 17 Methods 18 Study design 4 Present key elements of study design early in the paper-page 11-14 19 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, 20 21 exposure, follow-up, and data collection-page 11-14 22 Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of 23 selection of participants. Describe methods of follow-up 24 Case-control study—Give the eligibility criteria, and the sources and methods of 25 26 case ascertainment and control selection. Give the rationale for the choice of cases 27 and controls 28 Cross-sectional study—Give the eligibility criteria, and the sources and methods of 29 selection of participants-pages 11-14 30 (b) Cohort study—For matched studies, give matching criteria and number of 31 32 exposed and unexposed 33 Case-control study—For matched studies, give matching criteria and the number of

34 controls per case http://bmjopen.bmj.com/ 35 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect 36 37 modifiers. Give diagnostic criteria, if applicable-pages 11-14 38 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 39 measurement assessment (measurement). Describe comparability of assessment methods if there 40 is more than one group-pages 14-21 41 Bias 9 Describe any efforts to address potential sources of bias-page 21

42 on October 2, 2021 by guest. Protected copyright. 43 Study size 10 Explain how the study size was arrived at-page 11-14 44 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, 45 describe which groupings were chosen and why-page 11 46 Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding- 47 48 page 11-14 49 (b) Describe any methods used to examine subgroups and interactions-page 11-14 50 (c) Explain how missing data were addressed-page 11-14 51 (d) Cohort study—If applicable, explain how loss to follow-up was addressed 52 53 Case-control study—If applicable, explain how matching of cases and controls was 54 addressed 55 Cross-sectional study—If applicable, describe analytical methods taking account of 56 sampling strategy- not applicable 57 (e) Describe any sensitivity analyses 58 59 Continued on next page 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 Page 39 of 38 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Results 4 5 Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, 6 examined for eligibility, confirmed eligible, included in the study, completing follow-up, and 7 analysed-pages 11-14 8 (b) Give reasons for non-participation at each stage-pages 11-14 9 (c) Consider use of a flow diagram-one to indicate the health systems in Pakistan (Figure 10 11 1). 12 Descriptive 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information 13 data on exposures and potential confounders-page 11-14 14 (b) Indicate number of participants with missing data for each variable of interest-page 11-21 15 For peer review only 16 (c) Cohort study—Summarise follow-up time (e.g., average and total amount) 17 Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time 18 Case-control study—Report numbers in each exposure category, or summary measures of 19 exposure 20 21 Cross-sectional study—Report numbers of outcome events or summary measures- pages 11-21 22 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their 23 precision (e.g., 95% confidence interval). Make clear which confounders were adjusted for and 24 why they were included-pages 11-15 25 (b) Report category boundaries when continuous variables were categorized 26 27 (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful 28 time period 29 Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity 30 analyses 31 32 Discussion 33 Key results 18 Summarise key results with reference to study objectives-pages 14-21

THE EPIDEMIOLOGY OF CANCERS IN LAHORE, PAKISTAN, 2010-2012: A CROSS-SECTIONAL STUDY

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-011828.R3

Article Type: Research

Date Submitted by the Author: 02-Jun-2016

Primary Subject Public health Heading:

Secondary Subject Heading: Epidemiology

Keywords: PUBLIC HEALTH, EPIDEMIOLOGY, ONCOLOGY http://bmjopen.bmj.com/

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 THE EPIDEMIOLOGY OF CANCERS IN LAHORE, PAKISTAN, 2010-2012: A CROSS-SECTIONAL STUDY 4 5 6 Farhana Badar, Shahid Mahmood, Muhammed Aasim Yusuf, and Faisal Sultan. 7 8 Corresponding author 9 10 Farhana Badar-MBBS, MPH 11 12 Sr. Biostatistician & Cancer Epidemiologist 13 14 Cancer Registry & Clinical Data Management 15 For peer review only 16 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 17 18 19 7-A, Block R-3, Johar Town, Lahore 20 21 Pakistan 22 23 Ph.: +92 42 35905000 Ext. 4240 | Email: [email protected] 24 25 26 27 Shahid Mahmood-MBA, CPC 28 29 30 Medical Coder/Cancer Registry Officer 31 32 Cancer Registry & Clinical Data Management 33

34 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. http://bmjopen.bmj.com/ 35 36 37 38 Muhammed Aasim Yusuf-FRCP 39 40 Consultant Gastroenterologist | Chief Medical Officer 41

42 on October 2, 2021 by guest. Protected copyright. 43 Department of Internal Medicine 44 45 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 46 47 48 49 Faisal Sultan-FRCP 50 51 Consultant Physician | Chief Executive Officer 52 53 Department of Internal Medicine 54 55 56 Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 22 BMJ Open Page 2 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 THE EPIDEMIOLOGY OF CANCERS IN LAHORE, PAKISTAN, 2010-2012: A CROSS-SECTIONAL STUDY 4 5 6 ABSTRACT 7 8 Objectives 9 10 To estimate the population-level cancer estimates for the Lahore district, which is part of the Punjab 11 Cancer Registry (PCR), Pakistan. The average population, per year, of Lahore was estimated at 9.8 million 12 13 in 2010-2012. 14 15 Design For peer review only 16 17 A cross-sectional study. 18 19 Setting 20 21 The Registry has nineteen collaborating centers in Lahore that report their data to the Central Office 22 23 located within a tertiary care cancer treatment facility in Lahore, Pakistan. 24 25 Participants 26 27 Patients belonging to Lahore, of any age-group, and diagnosed with cancer in 2010-2012, were included 28 in the study. Patients were followed-up between July and October 2015 to determine their vital status. 29 30 Outcome measures 31 32 33 Summaries were generated for gender, the basis of diagnosis, diagnoses, and deaths. The Age-

42 female patients; 93·5% microscopically confirmed and 6·5% non-microscopically. The ASIR amongst on October 2, 2021 by guest. Protected copyright. 43 44 females was 105·1 and in males 66·7. ASIRs of leading cancers, amongst women, were: breast 47·6, 45 ovary 4·9, and corpus uteri 3·6, whereas, amongst men: prostate 6·4, bladder 5·0, and, trachea, 46 bronchus, & lung 4·6. A total of 5,134 deaths were recorded. 47 48 Conclusions 49 50 51 In Lahore, the ASIR was higher in women than in men. Amongst women, breast cancer, and in men, 52 prostate cancer, were the leading cancer types. These estimates can be used for health promotion and 53 policy making in the region. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 2 of 22 Page 3 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 6 7 8 ARTICLE SUMMARY 9 10 STRENGTHS AND LIMITATIONS OF THIS STUDY 11 12 • This is the first time that the age-standardized incidence rates have been presented for the 13 Lahore district. 14 15 For peer review only 16 • A comparison has been made with the incidence rates reported by other registries around the 17 world. 18 19 • There are follow-up issues related to determining the vital status of the patients, once they are 20 21 registered as new cancer patients. Therefore, the limitation of the study is that the vital status 22 of the vast majority of patients could not be determined. 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 22 BMJ Open Page 4 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 PAPER 4 5 6 7 8 THE EPIDEMIOLOGY OF CANCERS IN LAHORE, PAKISTAN, 2010-2012: A CROSS-SECTIONAL STUDY 9 10 INTRODUCTION 11 12 In the area of public health research, conducting high-quality, population-level studies, is hailed as the 13 gold standard, as the outcomes truly represent the disease status of the community on whom the 14 15 studies are being Forconducted. Thispeer includes the review practice of population-based only cancer registration, which 16 not only assists in providing statistics and trends on incidence, mortality, and survival, it can also provide 17 information on putative risk factors associated with various diseases within a defined population, living 18 19 in a geographically demarcated area, over a specified period of time. However, cancer registration can 20 only be undertaken if there is appropriate infrastructure to enable it, and suitable, well-trained staff to 21 perform the tasks associated with it. Understandably, there is a cost associated with conducting this 22 23 type of epidemiologic work, and in a resource-constrained country like Pakistan, governments are less 24 likely to focus on the area of cancer registration than other areas deemed more immediately critical. 25 Further, there is no legislation in the country that requires health-care practitioners to report diagnoses 26 27 of cancer. Moreover, the health-care delivery in Pakistan is quite complex, and is as depicted in Figure 1. 28 A large part of the population is served through a mixed system via multiple health providers[1]. 29 30 The question whether cancer registration is a necessity or a luxury in developing countries has been 31 debated extensively over the years. A paper published in 2008 stated that in low-income countries, 32 33 cancer registration is urgently needed so as to gauge the cancer burden in the region[2]. Given that

42 numbers of health-care practitioners to manage the conditions, addressing health education, and on October 2, 2021 by guest. Protected copyright. 43 assisting in developing prevention, early detection, and cancer control programs in the region. Figure 2 44 45 is a map of Pakistan showing the provinces of Pakistan and countries adjacent to Pakistan[4]. Even 46 though accurate population figures are not available, enthusiastic professionals have, over the years, 47 endeavored to determine cancer estimates for Pakistan. In the past, the regional registry of the Karachi 48 49 South district, in the province of Sindh, was established and managed for several years by a dedicated 50 pathologist, Dr. Yasmin Bhurgri[5]. This registry was widely recognized at an international level for its 51 data quality[5]. However, due to the sudden death of Dr. Bhurgri in January 2012, this registry is no 52 53 longer active. Another registry in Pakistan is the Punjab Cancer Registry (PCR), which was founded 54 collaboratively by a group of health-professionals in 2005, pioneered by the administrators of a 55 complete cancer treatment facility in Lahore called the Shaukat Khanum Memorial Cancer Hospital and 56 57 Research Center (SKMCH & RC)[6-9]. The Punjab Cancer Registry, herein, referred to as the Registry, is 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 4 of 22 Page 5 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 registered with, and regulated under, the Societies Registration Act, 1860, of the Government of 4 5 Pakistan[10]. It is also a member of the International Association of Cancer Registries, France[11]. 6 Appendix A shows the list of collaborating centers of the Registry. 7 8 The reporting of cancer cases to population-based cancer registries is not required by law, in Pakistan. It 9 is, in fact, a voluntary task undertaken by professionals representing many institutions of the region. 10 11 When the Registry was established in 2005, a memorandum outlining the structure and governance 12 mechanisms was signed by the stake-holders representing both the government and private 13 laboratories and hospitals of the city. The purpose of establishing the Registry was to determine the 14 15 cancer estimates Forin the province peer of Punjab. Punjab review is the most populous only province of Pakistan, with a 16 population estimated at 100 M, and 36 administrative districts, of which Lahore is the most populous, 17 with a population of some 10 M[12,13]. For about a decade, data have been captured in a systematic 18 19 and pre-defined manner, in accordance with the minimum data items required for cancer registries as 20 well as some additional optional data items[6,9,14]. 21 22 In the past, PCR data have been reported to the International Agency for Research on Cancer (IARC) in 23 24 response to a call for data by the Agency. The data have been used, along with data from Dr. Yasmin 25 Bhurgri’s paper, and the Federal Bureau of Statistics, Pakistan, to provide cancer estimates for Pakistan 26 in the Globocan 2012 report[15]. 27 28 This manuscript provides population-level cancer estimates for the Lahore district, based on cases 29 30 diagnosed in 2010-2012 and reported to the Registry. This is the first time that the Lahore district 31 population-level data have been computed and are being reported. 32 33 34 http://bmjopen.bmj.com/ 35 METHODS 36 37 38 The population denominator 39 40 Population-level statistics cannot be computed without the availability of figures for the population 41 under review, or the catchment population. In Pakistan, publications describing the population structure

42 are available for the census that was conducted in 1998[12]. However, the most recent population on October 2, 2021 by guest. Protected copyright. 43 44 census, initiated a year ago, has not yet been completed[16]; therefore, accurate figures describing the 45 Pakistani population are not available. As a result, for this study, population estimates are based on 46 population figures determined by using the average annual growth rates provided by the Government of 47 48 Pakistan[12]. 49 50 In the years 2010, 2011, and 2012, the population of the Lahore district was estimated at 9,503,871, 51 9,832,705, and 10,172,916 respectively, computed using an average annual growth rate of 52 53 3·46%[12,13]. The total area of the Lahore district is 1,772 square kilometers, with its average 54 population density being calculated as 5,551 persons, per square kilometer, in the years under 55 study[12]. Figure 3 is a population pyramid showing the combined population distribution of the Lahore 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 22 BMJ Open Page 6 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 district by age-group and gender, for the years 2010-2012. These population estimates were used as the 4 5 population-at-risk denominator, for calculating the incidence rates for this study. 6 7 Data collection 8 9 As routine cancer registration practice, the information is collected on the PCR data collection forms 10 11 developed collaboratively, following international guidelines on recording cancers (Appendix B). The 12 pertinent question on the form states whether a patient is a resident of Lahore or has come to Lahore 13 for diagnosis or treatment only. This has helped to identify the residents of Lahore. 14 15 For peer review only 16 Each center is allocated a separate center identification number. The forms are distributed to, and 17 collected from, each participating center on a regular basis. Both the active and passive methods of data 18 19 collection are used[14]. Registry Staff educates relevant personnel at each center with regard to data 20 capture, missing information and answers any other queries that arise. At the Cancer Registry & Clinical 21 Data Management unit, only authorized personnel are allowed to enter data from forms, into the 22 database. The forms collected are stored securely and remain confidential. The information is 23 24 subsequently entered into the Punjab Cancer Registry database, developed as part of the computerized 25 Hospital Information System of SKMCH & RC (Appendices C-CCC). All authorized Staff members are 26 given specific usernames and passwords to turn the computers on and another username-password to 27 28 access the system, and thence, the PCR software. Any form of transmission of the information including 29 printing and saving it on portable electronic devices, and aspects related to document retention, are 30 strictly regulated by the Governing Council of the Registry and SKMCH & RC, the latter being the sponsor 31 32 of the Registry. For the cases diagnosed or treated at SKMCH & RC, linkages have been developed with 33 the pathology department and clinics to facilitate date capture.

42 morphology, the case is registered with the center where the first diagnosis was made. Edits, for the on October 2, 2021 by guest. Protected copyright. 43 44 validity and for the consistency between variables, are also carried out (age/incidence, 45 age/site/histology, site/histology, sex/site, sex/histology, behavior/site, behavior/histology, 46 grade/histology, and basis of diagnosis/histology). Initially, cancers were coded using the International 47 Classification of Disease for Oncology-Third Edition[18]. For this manuscript, cancers were categorized 48 49 using the International Classification of Diseases, Clinical Modification, 10th revision[19]. 50 51 Data access and follow-up 52 53 54 Release of confidential information is governed by the rules approved by the Registry, and is always 55 without any identifiers[6]. For maintaining confidentiality of the information recorded, Staff members 56 57 are made to sign a confidentially pledge at the time of employment, which remains in force after 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 6 of 22 Page 7 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 cessation of employment with SKMCH & RC. For the purpose of reporting the data to IARC and to 4 5 determine the vital status, patients diagnosed in the time-period 2010-2012 were followed-up 6 telephonically between July and October 2015. We were able to establish contact with only sixty 7 percent of the cases in this way. 8 9 10 Cancers reported 11 12 Cancer notifications for the Lahore district have improved with the passage of time, with the cases 13 reported to the Registry going up from 2,006 in the year 2005 to 5,123 in the year 2015. In chronologic 14 15 order, the numbersFor reported arepeer as follows: 2,006;review 2,987; 3,617; 3,990; only 5,109; 5,302; 4,949; 5,589; 16 6,009; 5,943; and 5,123. We are still receiving information on cases diagnosed in 2014 and 2015. Over 17 recent years, six other districts have been included for the purpose of data collection, with the idea 18 19 being to include 1-2 contiguous district(s) of Punjab every year in order to expand cancer registration. 20 The data collection form is modified accordingly to ascertain resident status of the patients[6]. The 21 approach related to including 1-2 districts on a regular basis has been adopted because the sponsor, 22 23 SKMCH & RC, is a charitable organization, and it is logistically not possible to initiate data collection from 24 36 districts of Punjab simultaneously. 25 26 2010-2012 study 27 28 A cross-sectional study was conducted and the Punjab Cancer Registry data were reviewed 29 30 retrospectively to retrieve information on cancer patients belonging to the Lahore district and having 31 been diagnosed in 2010-2012. Information was collected on new cancer diagnoses (by histology and 32 gender), the most valid basis of diagnosis as microscopically versus non-microscopically confirmed, 33

42 World Standard population[20]. ASIRs were expressed per 100,000 population, per year, separately for on October 2, 2021 by guest. Protected copyright. 43 male and female patients. For mortality data, counts were stratified by histology/site. Overall survival 44 45 interval was computed between the dates of diagnosis and last contact and analyzed using the Kaplan- 46 Meier method. Of a total of 15,825 patients registered in the years 2010-2012, survival intervals could 47 not be computed for nearly 43 percent of the cases. Of these, in the vast majority of cases, no contact 48 49 could be established with the patients on the phone numbers provided; in some of the cases, the 50 attendants of the patients could only communicate that the patients had died but could not recall their 51 dates of death; and, in a few cases, the patients died on the day of cancer diagnoses and their intervals 52 were set at naught. Although extensive survival analysis was subsequently done on the fifty-seven 53 54 percent of cases on whom the duration of survival was available, the survival estimates generated were 55 not considered valid. Therefore, survival results are not being presented in this manuscript. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 22 BMJ Open Page 8 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Data were analyzed using the Microsoft Excel, version 2010, and SPSS, version 19. The Institutional 4 5 Review Board (IRB) of the Shaukat Khanum Memorial Cancer Hospital & Research Center granted 6 exemption from full IRB evaluation. 7 8 9 10 RESULTS 11 12 13 The total population of the Lahore district, in 2010-2012, was estimated to be 29,509,492, with males 14 accounting for 52·7% and females 47·3% of the population (Figure 3). The number of cases reported in 15 each of the three-yearsFor under peerstudy, 2010, 2011, review & 2012, along with onlytheir population denominators, 16 were: 5,302/9,503,871, 4,949/9,832,705, and 5,589/10,172,916, respectively. Of a total of 15,840 17 18 cancers diagnosed in 15,825 patients belonging to the district of Lahore and registered in the PCR 19 database against the corresponding years, 9,069 (57·3%) were in female and 6,771 (42·7%) in male 20 patients. Multiple primary cancers, up to two, were identified in 15 patients (Table 1), explaining the 21 22 discrepancy between the number of cases recorded and the patients registered. Nearly ten percent 23 were identified to have been registered twice and were eventually assigned to the center where the first 24 diagnosis was made, thereby, counted just once. The age-range of the patients was 0-106 years. Of all 25 26 the cancers diagnosed, about 93·5% were microscopically and 6·5% were non-microscopically confirmed 27 (Table 2). None were registered on the basis of death certificates only. Skin cancer had the highest figure 28 in the microscopically confirmed group (99·6%), whereas, liver & intrahepatic bile duct(s) had the 29 30 highest figure in the non-microscopically confirmed category (69·5%). The ASIR for all sites combined 31 amongst female patients was 105·1 per 100,000 women and amongst male patients, it was 66·7 per 32 100,000 men, per year. Tables 3-6 show the ASIRs for all the cancers recorded in the Registry, by the 33

8 1. Male 20 Alive Colon & brain 9 10 2. Male 23 Alive Larynx & testis 11 3. Male 34 Dead Kidney & thyroid

21 11. Male 62 Dead Rectum & bone

42 Connective tissue 94.4 5.6 on October 2, 2021 by guest. Protected copyright. 43 Leukemia 92.8 7.2 44 Breast 95.8 4.2 45 Cervix uteri 96.8 3.2 Corpus uteri 97.8 2.2 46 Testis 98.9 1.1 47 Prostate 97.5 2.5 48 NHL 95.8 4.2 49 Hodgkin lymphoma 97.5 2.5 50 Urinary bladder 97.3 2.7 51 Brain 96.6 3.4 52 Skin 99.6 0.4 53 Kidney 93.4 6.6 Thyroid 97.6 2.4 54 Ovary 93.7 6.3 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 22 BMJ Open Page 10 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 Table 3. Cancer counts and the age-standardized incidence rates of cancers diagnosed in the Lahore district, 5 2010-2012, according to year of diagnosis. 6 2010 2011 2012 7 Site ICD-10 code Count ASIR Count ASIR Count ASIR 8 Lip C00 13 0.2 5 0.1 4 0.1 9 Tongue C01C02 115 2.0 92 1.5 102 1.6 Mouth C03C06 117 2.1 110 1.8 115 1.9 10 Salivary glands C07C08 30 0.5 32 0.5 29 0.4 11 Tonsil C09 3 0.1 3 0.1 10 0.1 12 Other oropharynx C10 2 0.0 3 0.1 1 0.0 13 Nasopharynx C11 13 0.2 11 0.1 14 0.2 Hypopharynx C12C13 22 0.4 12 0.2 19 0.3 14 Pharynx C14 4 0.1 3 0.0 3 0.0 15 Esophagus For C15peer 76review 1.4 61 only 1.1 85 1.4 16 Stomach C16 85 1.5 86 1.4 96 1.5 17 Small intestine C17 15 0.3 15 0.3 13 0.2 Colon C18 148 2.6 106 1.7 135 2.2 18 Rectum C19C20 101 1.6 89 1.4 133 2.0 19 Anus C21 21 0.4 22 0.3 21 0.3 20 Liver C22 176 3.4 184 3.4 145 2.6 Gall bladder, etc. C23C24 72 1.3 76 1.4 84 1.6 21 Pancreas C25 30 0.6 30 0.6 37 0.7 22 Other illdefined digestive C26 7 0.1 11 0.2 12 0.2 23 Nose, sinuses C3031 17 0.3 23 0.4 19 0.3 24 Larynx C32 74 1.4 55 1.0 82 1.4 Trachea, bronchus, & lung C33C34 162 3.2 156 2.9 170 3.2 25 Other thoracic organs C37C38 14 0.2 11 0.2 17 0.2 26 Bone C40C41 80 0.8 74 0.8 80 0.8 27 Melanoma of the skin C43 4 0.1 11 0.2 11 0.1 28 Other skin C44 152 2.8 141 2.5 174 2.9 Connective & soft tissue C47,C49 95 1.3 95 1.2 62 0.8 29 Breast C50 1409 22.9 1339 21.4 1404 21.5 30 Vulva C51 3 0.1 7 0.2 9 0.4 31 Vagina C52 5 0.2 6 0.2 5 0.2 Cervix uteri C53 86 3.1 69 2.4 92 3.2 32 Corpus uteri C54 83 3.5 84 3.3 100 4.1 33 Uterus, unspecified C55 34 1.3 27 1.1 28 1.0

34 Ovary C56 138 4.6 124 4.1 180 5.8 http://bmjopen.bmj.com/ 35 Other female genital orgs. C57 5 0.2 7 0.3 6 0.2 Placenta C58 3 0.1 2 0.0 2 0.0 36 Penis C60 1 0.0 37 Prostate C61 165 6.2 193 7.1 168 6.0 38 Testis C62 31 0.7 24 0.5 35 0.7 39 Other male genital organs C63 3 0.1 2 0.1 Kidney C64 88 1.5 97 1.5 89 1.4 40 Renal pelvis C65 2 0.0 41 Ureter C66 1 0.0 1 0.0 Bladder C67 177 3.6 150 2.8 223 4.0 42 on October 2, 2021 by guest. Protected copyright. 43 Other urinary organs C68 2 0.0 Eye C69 33 0.5 29 0.4 35 0.4 44 Brain, nervous system C70C72 248 3.5 203 2.8 234 3.0 45 Thyroid C73 94 1.3 92 1.3 110 1.5 46 Adrenal C74 2 0.0 3 0.0 6 0.1 Hodgkin lymphoma C81 104 1.3 86 1.0 92 0.9 47 NonHodgkin lymphoma C82C88 274 4.4 234 3.6 262 3.9 48 Multiple myeloma C90 33 0.7 26 0.5 30 0.5 49 Lymphoid leukemia C91 91 0.9 71 0.7 157 1.4 50 Myeloid leukemia C9293 42 0.5 31 0.4 96 1.1 Other leukemias C95 30 0.3 25 0.3 45 0.4 51 Leukemia, unspecified C94 3 0.0 2 0.0 3 0.0 52 Other & unspecified 335 5.7 369 6.2 393 6.4 53 Benign CNS 138 1.9 125 1.6 107 1.3 54 All sites 5302 97.8 4949 89.1 5589 96.8 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 10 of 22 Page 11 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 Table 4. Cancer counts and age-standardized incidence rates of cancers diagnosed in the Lahore district in 6 2010-2012, by gender and cancer site/type. 7 FEMALE MALE 8 Site ICD-10-code Count % Crude ASIR Count % Crude ASIR 9 Lip C00 9 0.1 0.1 0.1 13 0.2 0.1 0.1 10 Tongue C01-C02 129 1.4 0.9 1.7 180 2.7 1.2 1.8 Mouth C03-C06 130 1.4 0.9 1.6 212 3.1 1.4 2.2 11 Salivary glands C07-C08 41 0.5 0.3 0.5 50 0.7 0.3 0.5 12 Tonsil C09 8 0.1 0.1 0.1 8 0.1 0.1 0.1 13 Other oropharynx C10 - - - - 6 0.1 0.0 0.1 14 Nasopharynx C11 19 0.2 0.1 0.2 19 0.3 0.1 0.2 Hypopharynx C12-C13 32 0.4 0.2 0.4 21 0.3 0.1 0.2 15 Pharynx For peerC14 review5 0.1 0.0 0.1only 5 0.1 0.0 0.0 16 Esophagus C15 95 1.0 0.7 1.2 127 1.9 0.8 1.4 17 Stomach C16 105 1.2 0.8 1.3 162 2.4 1.0 1.6 18 Small intestine C17 17 0.2 0.1 0.2 26 0.4 0.2 0.3 Colon C18 159 1.8 1.1 1.9 230 3.4 1.5 2.4 19 Rectum C19-C20 137 1.5 1.0 1.5 186 2.7 1.2 1.9 20 Anus C21 23 0.3 0.2 0.3 41 0.6 0.3 0.4 21 Liver C22 177 2.0 1.3 2.4 328 4.8 2.1 3.7 22 Gall bladder, etc. C23-C24 139 1.5 1.0 1.9 93 1.4 0.6 1.0 Pancreas C25 40 0.4 0.3 0.5 57 0.8 0.4 0.6 23 Other ill-defined digestive C26 14 0.2 0.1 0.1 16 0.2 0.1 0.2 24 Nose, sinuses C30-31 27 0.3 0.2 0.3 32 0.5 0.2 0.3 25 Larynx C32 28 0.3 0.2 0.3 183 2.7 1.2 2.0 26 Trachea, bronchus, & lung C33-C34 92 1.0 0.7 1.2 396 5.8 2.5 4.6 Other thoracic organs C37-C38 16 0.2 0.1 0.2 26 0.4 0.2 0.2 27 Bone C40-C41 91 1.0 0.7 0.6 143 2.1 0.9 0.9 28 Melanoma of the skin C43 13 0.1 0.1 0.1 13 0.2 0.1 0.1 29 Other skin C44 196 2.2 1.4 2.7 271 4.0 1.7 2.8 30 Connective & soft tissue C47,C49 108 1.2 0.8 1.0 144 2.1 0.9 1.2 Breast C50 4082 45.0 29.2 47.6 70 1.0 0.5 0.8 31 Vulva C51 19 0.2 0.1 0.2 - - - - 32 Vagina C52 16 0.2 0.1 0.2 - - - - 33 Cervix uteri C53 247 2.7 1.8 2.9 - - - -

42 on October 2, 2021 by guest. Protected copyright. Ureter C66 1 0.0 0.0 0.0 1 0.0 0.0 0.0 43 Bladder C67 109 1.2 0.8 1.5 441 6.5 2.8 5.0 44 Other urinary organs C68 - - - - 2 0.0 0.0 0.0 45 Eye C69 40 0.4 0.3 0.4 57 0.8 0.4 0.5 46 Brain, nervous system C70-C72 227 2.5 1.6 2.2 458 6.8 2.9 3.8 Thyroid C73 215 2.4 1.5 2.2 81 1.2 0.5 0.7 47 Adrenal C74 4 0.0 0.0 0.0 7 0.1 0.0 0.1 48 Hodgkin lymphoma C81 80 0.9 0.6 0.7 202 3.0 1.3 1.4 49 Non-Hodgkin lymphoma C82-C88 277 3.1 2.0 3.3 493 7.3 3.2 4.5 50 Multiple myeloma C90 36 0.4 0.3 0.5 53 0.8 0.3 0.6 Lymphoid leukemia C91 112 1.2 0.8 0.7 207 3.1 1.3 1.2 51 Myeloid leukemia C92-93 62 0.7 0.4 0.5 107 1.6 0.7 0.8 52 Other leukemias C94 2 0.0 0.0 0.0 6 0.1 0.0 0.0 53 Leukemia, unspecified C95 40 0.4 0.3 0.3 60 0.9 0.4 0.4 54 Other & unspecified - 536 5.9 3.8 6.6 561 8.3 3.6 5.7 55 Benign CNS - 188 2.1 1.3 1.8 182 2.7 1.2 1.4 56 All sites 9069 100.0 64.9 105.1 6771 100.0 43.6 66.7 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 22 BMJ Open Page 12 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Table 5. Age-specific & age-standardized incidence rates of cancers diagnosed in the Lahore district, 2010-2012, amongst females. 4 5 Total ICD-10 Site 0- 5- 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- Crude % ASIR 6 cases codes 7 Lip 9 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.0 1.1 0.4 0.6 1.6 0.7 0.1 0.1 0.1 C00 8 Tongue 129 0.0 0.0 0.0 0.0 0.1 0.1 0.2 1.2 1.4 5.4 4.7 4.9 6.6 5.8 8.7 5.1 0.9 1.4 1.7 C01-C02 9 Mouth 130 0.0 0.0 0.0 0.2 0.2 0.3 0.2 1.5 2.9 1.6 6.0 4.6 3.5 7.0 11.1 5.1 0.9 1.4 1.6 C03-C06 10Salivary glands 41 0.0 0.0 0.1 0.0 0.1 0.5 0.2 0.8 0.5 0.6 1.1 0.7 2.7 1.9 0.8 0.0 0.3 0.5 0.5 C07-C08 Tonsil 8 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.2 0.7 0.4 0.0 0.0 0.8 0.7 0.1 0.1 0.1 C09 11Nasopharynx 19 0.0 0.0 0.1 0.1 0.1 0.2 0.3 0.0 0.3 0.6 0.2 0.4 0.4 0.0 1.6 0.0 0.1 0.2 0.2 C11 12Hypopharynx 32 0.0 0.0 0.0 0.1 0.2 0.1 0.2 0.5 0.3 0.6 0.7 1.4 1.9 0.6 1.6 0.7 0.2 0.4 0.4 C12-C13 13Pharynx 5 0.0 0.0 0.1 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.4 0.0 0.0 0.8 0.7 0.0 0.1 0.1 C14 14Esophagus 95 0.0 0.0 0.0 0.1 0.0 0.3 0.3 0.9 1.9 4.0 1.8 2.8 5.8 4.5 4.7 3.6 0.7 1.0 1.2 C15 15Stomach 105 0.0 For 0.0 0.0 0.0peer 0.3 0.1 1.0 review 1.3 2.2 3.8 2.5 3.9only 2.7 8.9 0.0 3.6 0.8 1.2 1.3 C16 16Small intestine 17 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.6 0.0 0.0 0.4 1.9 1.3 2.4 0.7 0.1 0.2 0.2 C17 17Colon 159 0.0 0.0 0.1 0.3 0.1 0.7 1.3 2.0 2.0 3.4 3.3 7.0 5.0 9.6 9.5 8.0 1.1 1.8 1.9 C18 18Rectum 137 0.0 0.0 0.1 0.2 0.9 0.9 1.4 1.2 1.7 3.0 3.1 4.2 5.0 4.5 6.3 5.1 1.0 1.5 1.5 C19-C20 19Anus 23 0.0 0.0 0.0 0.0 0.1 0.0 0.3 0.1 0.9 0.6 0.2 0.0 0.8 0.6 2.4 0.7 0.2 0.3 0.3 C21 Liver 177 0.1 0.1 0.0 0.1 0.1 0.1 0.2 0.3 1.4 4.4 6.2 11.2 12.0 16.6 8.7 5.1 1.3 2.0 2.4 C22 20 Gall bladder, etc. 139 0.0 0.0 0.0 0.1 0.0 0.0 0.5 0.4 1.5 2.6 4.9 6.7 8.9 14.1 7.1 8.7 1.0 1.5 1.9 C23-C24 21Pancreas 40 0.0 0.0 0.0 0.1 0.0 0.2 0.1 0.5 0.3 0.8 0.9 2.1 0.8 5.8 2.4 1.4 0.3 0.4 0.5 C25 22Other ill-defined digestive 14 0.0 0.0 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.9 0.0 1.2 0.0 0.8 0.0 0.1 0.2 0.1 C26 23Nose, sinuses 27 0.1 0.0 0.0 0.1 0.0 0.0 0.1 0.3 0.0 0.6 0.7 1.8 2.3 1.3 0.8 0.7 0.2 0.3 0.3 C30-31 24Larynx 28 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.1 0.6 0.8 1.3 1.4 1.2 0.6 0.0 2.2 0.2 0.3 0.3 C32 25Trachea, bronchus, & lung 92 0.0 0.0 0.1 0.2 0.1 0.1 0.5 0.4 0.9 1.4 1.8 4.6 5.4 8.3 6.3 5.8 0.7 1.0 1.2 C33-C34 26Other thoracic organs 16 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.3 0.2 0.8 0.0 0.4 1.6 0.6 0.8 0.7 0.1 0.2 0.2 C37-C38 27Bone 91 0.2 0.5 0.9 1.4 0.9 0.3 0.4 1.3 0.3 0.6 0.4 0.4 0.0 0.0 1.6 0.0 0.7 1.0 0.6 C40-C41 28Melanoma of the skin 13 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.3 0.2 0.4 0.4 0.7 0.0 0.0 0.8 0.7 0.1 0.1 0.1 C43 29Other skin 196 0.1 0.0 0.0 0.1 0.1 0.3 0.2 1.3 2.9 2.2 5.1 6.3 11.3 16.6 19.0 19.6 1.4 2.2 2.7 C44 Connective & soft tissue 108 0.4 0.3 0.3 0.6 0.6 0.8 0.8 1.2 1.7 1.2 1.8 1.4 1.6 3.8 2.4 2.9 0.8 1.2 1.0 C47,C49 30Breast 4082 0.0 0.1 0.1 0.1 3.3 14.0 32.2 55.9 86.2 126.8 130.3 158.5 154.1 157.9 124.9 92.1 29.2 45.0 47.6 C50 31Vulva 19 0.0 0.0 0.1 0.0 0.0 0.0 0.1 0.4 0.2 0.2 0.0 1.4 0.8 0.6 0.8 2.9 0.1 0.2 0.2 C51 32Vagina 16 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.1 0.3 0.8 0.2 0.7 0.4 0.0 0.8 1.4 0.1 0.2 0.2 C52 33Cervix uteri 247 0.0 0.0 0.0 0.0 0.2 0.4 1.3 3.9 5.7 9.4 7.1 10.5 10.1 8.3 5.5 5.1 1.8 2.7 2.9 C53

42Eye 40 0.9 0.3 0.1 0.0 0.0 0.0 0.0 0.0 0.3 0.4 0.0 0.0 0.8 4.5 0.8 2.2 0.2 0.4 0.4 C69 on October 2, 2021 by guest. Protected copyright. 43Brain, nervous system 227 0.3 0.7 0.6 0.9 0.9 2.0 1.4 2.5 3.3 4.4 4.9 5.3 5.0 7.7 4.0 2.9 1.6 2.5 2.2 C70-C72 44Thyroid 215 0.0 0.1 0.1 0.2 1.9 1.6 2.8 2.9 3.3 4.6 6.5 3.5 6.6 3.2 7.9 2.9 1.5 2.4 2.2 C73 45Adrenal 4 0.1 0.1 0.0 0.0 0.1 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C74 46Hodgkin lymphoma 80 0.2 0.4 0.3 0.4 0.9 1.0 0.4 1.1 0.3 1.0 0.2 1.8 1.6 0.6 2.4 0.0 0.6 0.9 0.7 C81 47Non-Hodgkin lymphoma 277 0.2 0.3 0.5 0.5 0.5 0.8 0.9 2.0 3.6 5.8 7.4 12.3 10.9 14.1 13.4 18.1 2.0 3.1 3.3 C82-C88 48Multiple myeloma 36 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.3 1.6 1.1 0.7 2.7 3.2 4.0 0.7 0.3 0.4 0.5 C90 Lymphoid leukemia 112 2.0 1.3 1.4 0.3 0.1 0.2 0.2 0.0 0.5 0.2 0.2 0.7 1.2 0.6 0.8 0.0 0.8 1.2 0.7 C91 49Myeloid leukemia 62 0.3 0.2 0.2 0.2 0.5 0.6 0.6 0.7 0.5 0.6 1.1 1.4 0.8 0.6 1.6 0.0 0.4 0.7 0.5 C92-93 50Other leukemias 2 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C94 51Leukemia, unspecified 40 0.3 0.5 0.3 0.3 0.1 0.3 0.1 0.1 0.2 0.2 0.7 0.0 0.0 0.6 0.8 0.0 0.3 0.4 0.3 C95 52 Other & 53Other & unspecified 536 0.5 0.2 0.2 0.2 1.1 1.8 2.7 4.7 7.0 12.6 14.9 24.9 24.1 33.9 26.9 18.8 3.8 5.9 6.6 unspecified 54Benign CNS 188 0.2 0.1 0.3 0.7 0.3 1.6 2.2 3.9 4.0 4.8 3.6 2.1 4.3 4.5 2.4 0.7 1.3 2.1 1.8 Benign CNS 55All sites 9069 6.7 5.0 6.5 8.4 16.4 32.1 58.3 104.7 155.6 237.8 259.9 337.6 364.1 398.2 348.7 259.5 64.9 100.0 105.1 All sites 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 12 of 22 Page 13 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Table 6. Age-specific & age-standardized incidence rates of cancers diagnosed in the Lahore district, 2010-2012, amongst males. 4 5 Total ICD-10 Site 0- 5- 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- Crude % ASIR 6 cases codes 7 Lip 13 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.2 0.0 0.0 0.2 0.6 1.3 0.5 0.6 0.0 0.1 0.2 0.1 C00 8 Tongue 180 0.0 0.0 0.0 0.0 0.3 0.6 0.6 2.0 3.5 3.6 4.4 5.0 7.2 6.2 9.5 2.3 1.2 2.7 1.8 C01-C02 9 Mouth 212 0.0 0.0 0.0 0.0 0.1 0.2 1.2 1.1 3.0 5.4 4.8 9.7 10.1 8.8 7.7 4.0 1.4 3.1 2.2 C03-C06 Salivary glands 50 0.0 0.0 0.1 0.1 0.1 0.2 0.3 0.7 0.6 0.7 0.7 1.1 1.9 1.6 3.0 1.7 0.3 0.7 0.5 C07-C08 10 Tonsil 8 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.1 0.0 0.2 0.3 0.6 0.5 0.0 0.0 0.1 0.1 0.1 C09 11 Other oropharynx 6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.0 0.6 0.3 0.0 0.6 0.0 0.0 0.1 0.1 C10 12 Nasopharynx 19 0.0 0.0 0.0 0.1 0.1 0.0 0.2 0.1 0.3 0.3 0.2 0.8 1.3 0.5 0.0 0.0 0.1 0.3 0.2 C11 13 Hypopharynx 21 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.1 0.3 0.0 0.6 0.3 0.9 1.0 1.2 2.9 0.1 0.3 0.2 C12-C13 14 Pharynx 5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.3 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 C14 Esophagus 127 0.0 0.0 0.0 0.1 0.1 0.2 0.3 0.8 0.5 3.1 3.1 4.5 5.3 6.2 9.5 6.9 0.8 1.9 1.4 C15 15 Stomach 162 0.0 For 0.0 0.0 0.0 peer 0.1 0.8 0.9 review 1.4 2.2 3.8 3.3 4.7only 4.4 10.3 8.3 3.4 1.0 2.4 1.6 C16 16 Small intestine 26 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.3 0.1 0.5 0.6 0.8 0.9 0.5 1.8 2.3 0.2 0.4 0.3 C17 17 Colon 230 0.0 0.0 0.0 0.4 0.8 0.6 0.7 1.5 2.1 4.8 4.4 5.8 11.6 14.5 9.5 6.3 1.5 3.4 2.4 C18 18 Rectum 186 0.0 0.0 0.0 0.4 0.7 0.9 1.4 1.0 1.0 3.3 3.9 5.0 8.2 11.9 4.2 6.3 1.2 2.7 1.9 C19-C20 19 Anus 41 0.0 0.0 0.0 0.1 0.1 0.1 0.5 0.0 0.6 0.5 1.3 0.8 2.2 1.6 0.6 1.1 0.3 0.6 0.4 C21 Liver 328 0.0 0.0 0.0 0.1 0.1 0.2 0.0 1.5 1.9 5.2 10.1 17.0 14.8 24.3 17.2 14.9 2.1 4.8 3.7 C22 20 Gall bladder, etc. 93 0.0 0.0 0.0 0.1 0.1 0.1 0.1 0.3 0.5 0.5 2.9 3.6 5.0 7.2 4.2 7.4 0.6 1.4 1.0 C23-C24 21 Pancreas 57 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.0 0.8 1.4 1.3 3.1 1.3 4.7 4.7 1.1 0.4 0.8 0.6 C25 22 Other ill-defined digestive 16 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.1 0.5 0.4 0.3 0.6 2.1 0.0 1.1 0.1 0.2 0.2 C26 23 Nose, sinuses 32 0.0 0.0 0.0 0.1 0.2 0.2 0.0 0.2 0.1 0.5 0.6 1.4 0.9 1.6 2.4 0.0 0.2 0.5 0.3 C30-31 24 Larynx 183 0.0 0.0 0.0 0.0 0.3 0.0 0.2 0.5 1.5 3.8 4.6 7.8 10.4 12.4 11.3 5.7 1.2 2.7 2.0 C32 25 Trachea, bronchus, & lung 396 0.0 0.0 0.0 0.0 0.1 0.1 0.6 1.9 1.8 5.7 4.8 13.1 21.4 32.0 37.4 32.6 2.5 5.8 4.6 C33-C34 Other thoracic organs 26 0.0 0.0 0.0 0.1 0.0 0.0 0.1 0.2 0.3 0.2 1.1 0.0 0.6 0.5 1.8 2.9 0.2 0.4 0.2 C37-C38 26 Bone 143 0.2 0.5 1.2 2.4 1.0 0.5 0.6 0.7 0.6 0.9 0.6 0.3 3.1 0.5 1.8 0.6 0.9 2.1 0.9 C40-C41 27 Melanoma of the skin 13 0.0 0.0 0.0 0.1 0.0 0.1 0.1 0.1 0.0 0.0 0.0 1.1 0.0 0.5 0.0 1.7 0.1 0.2 0.1 C43 28 Other skin 271 0.1 0.1 0.1 0.2 0.3 0.9 1.6 2.0 2.3 2.8 4.1 8.6 11.3 16.5 10.1 21.2 1.7 4.0 2.8 C44 29 Connective & soft tissue 144 0.4 0.5 0.1 0.9 0.8 1.1 0.7 1.1 0.5 2.8 1.1 2.5 2.8 3.6 4.2 2.9 0.9 2.1 1.2 C47,C49 30 Breast 70 0.0 0.0 0.0 0.1 0.1 0.1 0.0 0.3 0.9 2.1 1.5 1.9 1.9 8.8 2.4 1.7 0.5 1.0 0.8 C50 Penis 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C60 31 Prostate 526 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.3 1.0 4.4 13.1 27.1 46.0 69.4 87.0 3.4 7.8 6.4 C61 32 Testis 90 0.2 0.0 0.0 0.5 1.1 1.2 1.2 1.1 1.0 0.7 0.6 0.3 0.3 1.6 0.6 0.6 0.6 1.3 0.6 C62 33 Other male genital organs 5 0.1 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.0 0.6 0.0 0.0 0.1 0.1 C63

34 Kidney 172 0.6 0.2 0.0 0.1 0.1 0.2 0.3 0.9 2.7 3.3 3.3 5.6 6.3 7.2 9.5 5.7 1.1 2.5 1.7 C64 http://bmjopen.bmj.com/ 35 Renal pelvis 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C65 36 Ureter 1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 C66 Bladder 441 0.1 0.0 0.0 0.0 0.1 0.2 0.4 1.8 2.2 5.9 7.5 19.2 23.0 30.0 29.7 42.4 2.8 6.5 5.0 C67 37 Other urinary organs 2 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.6 0.0 0.0 0.0 C68 38 Eye 57 1.2 0.2 0.0 0.1 0.1 0.1 0.0 0.1 0.1 0.7 0.6 0.3 1.6 2.1 2.4 1.1 0.4 0.8 0.5 C69 39 Brain, nervous system 458 0.7 1.0 0.7 1.2 1.6 2.9 4.5 4.4 5.0 7.3 8.8 10.6 11.3 9.8 8.3 3.4 2.9 6.8 3.8 C70-C72 40 Thyroid 81 0.0 0.0 0.0 0.2 0.2 0.7 0.8 0.3 0.8 1.4 1.8 3.3 1.6 2.6 3.0 1.1 0.5 1.2 0.7 C73 41 Adrenal 7 0.1 0.0 0.0 0.1 0.1 0.0 0.0 0.0 0.0 0.2 0.0 0.3 0.0 0.0 0.6 0.0 0.0 0.1 0.1 C74 Hodgkin lymphoma 202 0.7 1.8 0.7 1.0 0.9 1.4 1.2 1.4 1.5 1.6 1.5 3.3 1.9 4.1 3.6 0.6 1.3 3.0 1.4 C81 42 Non-Hodgkin lymphoma 493 0.4 1.4 1.1 1.3 2.0 1.6 2.5 2.5 4.6 5.9 10.1 11.7 18.3 18.1 16.6 14.3 3.2 7.3 4.5 C82-C88 on October 2, 2021 by guest. Protected copyright. 43 Multiple myeloma 53 0.1 0.0 0.0 0.0 0.0 0.0 0.2 0.2 0.5 1.2 1.3 2.5 3.1 1.6 2.4 2.3 0.3 0.8 0.6 C90 44 Lymphoid leukemia 207 3.1 2.2 2.6 0.7 0.5 0.2 0.3 0.1 0.8 0.3 0.9 0.6 0.6 2.1 0.0 1.7 1.3 3.1 1.2 C91 45 Myeloid leukemia 107 0.3 0.3 0.4 0.4 0.7 0.8 0.9 1.4 1.0 1.0 0.7 1.9 1.9 2.1 0.0 0.6 0.7 1.6 0.8 C92-93 46 Other leukemias 6 0.0 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.1 0.0 0.4 0.0 0.0 0.0 0.6 0.0 0.0 0.1 0.0 C94 Leukemia, unspecified 60 0.5 0.4 0.7 0.2 0.5 0.2 0.3 0.1 0.3 0.3 0.2 0.3 0.6 0.0 0.6 0.0 0.4 0.9 0.4 C95 47 Other & 48 Other & unspecified 561 0.3 0.1 0.6 0.9 0.4 2.0 2.6 2.9 4.8 6.0 12.2 18.7 23.9 28.4 25.5 34.9 3.6 8.3 5.7 unspecified 49 Benign CNS 182 0.3 0.4 0.2 0.5 0.8 2.0 1.9 2.4 2.1 3.3 3.3 1.1 3.1 1.6 3.0 0.6 1.2 2.7 1.4 Benign CNS 50 All sites 6771 9.2 9.5 9.1 12.2 14.8 20.6 27.4 38.0 53.7 93.1 118.4 194.0 255.2 337.0 329.7 328.0 43.6 100.0 66.7 All sites 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 22 BMJ Open Page 14 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Of the 15,825 patients, death was recorded in 5,134 (32·4%) cases by the cut-off date for this study; this 4 5 included 2,726 female and 2,408 male patients. Four-thousand, three-hundred and forty-seven patients 6 were still alive (27·5%) at the time of review, whereas, the vital status of 6,344 patients (40·1%) could 7 not be determined. Death certificates were available in each record of a hospital death for about 8% of 8 9 patients (400/5,134), representing just one collaborating center, which is SKMCH & RC. Table 7 displays 10 death counts and proportion by cancer sites. Since the follow-up information was not available for 11 nearly 40% of the patients, the mortality to incidence ratio was not calculated either. 12 13 Table 7. Distribution of deaths recorded (5,134 (2,726 female and 2,408 male patients)), in patients diagnosed 14 with cancer, in the Lahore district, in 2010-2012, according to gender and cancer type (top 10 cancers only). 15 For peer review only 16 17 Females Count % Males Count % 18 Breast 987 36 Brain 213 9 19 20 Ovary 137 5 Bronchus & lung 207 9 21 Colorectum 127 5 NHL 169 7 22 23 NHL 109 4 Prostate 168 7 24 Lip & oral cavity 106 4 Colorectum 155 6 25 26 Brain 99 4 Lip & oral cavity 152 6 27 28 Leukemia 87 3 Liver & intrahep. bile ducts 151 6 29 Liver & intrahep. bile ducts 85 3 Leukemia 144 6 30 31 Cervix uteri 65 2 Urinary bladder 133 6 32 Corpus uteri 53 2 Stomach 73 3 33

42 colo-rectum, lip & oral cavity, liver & intrahepatic bile ducts, bladder, and leukemia, and 3% in stomach on October 2, 2021 by guest. Protected copyright. 43 carcinoma. 44 45 46 47 48 DISCUSSION 49 50 The Registry has been in existence since 2005 but was in an evolving phase in the initial years of its 51 52 functioning. Therefore, conducting a comparison of the cases recorded over the initial years did not 53 appear to be useful. Further, as there are notification delays and the Registry is still receiving 54 information on cases diagnosed in the most recent years (2014-2015), mainly from one center, this 55 56 time-period has not been included in the study either. It is hoped that a study conducted at a 57 subsequent stage will cover the 2013-2015 period. For the time-period 2010-2012, the results reported 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 14 of 22 Page 15 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 for the population of the Lahore district show that on average, over 5,200 new cancer cases were 4 5 diagnosed, every year. The fact that nearly seven percent were non-microscopically confirmed cancers 6 as opposed to nearly 93% that were microscopically confirmed, supports that there was no reliance on 7 the pathology laboratory as the only source of information. These figures are similar to those reported 8 9 for the Karachi Cancer Registry[5]. However, some of the cases diagnosed clinically might not have been 10 reported to the Registry but we have no way of knowing that, at present. The ASIR for all-cancers 11 combined was higher amongst females (105·1) than in males (66·7). These results also include the ASIRs 12 13 for benign CNS tumors and other/unspecified sites. The ASIRs reported by the Surveillance, 14 Epidemiology, and End Results (SEER) Program of the United States of America (USA), are very high 15 (359·4 for femalesFor and 282·6 forpeer males)[21,22]. review These figures represent only SEER 18 registries compiling 16 17 data from all cases diagnosed since 2000 and covering approximately 30% of the US population[21,22]. 18 The ASIRs published in the CI5-X report for Delhi in India and Riyadh in Saudi Arabia, are close to the 19 Lahore district figures as opposed to the SEER rates; in fact, the ASIRs for females in these three regions 20 21 are quite similar to one another. It is important to point out that Delhi, located in India, to the east of 22 Lahore, is closer to Lahore than is Karachi located in southern Pakistan. As far as the South Karachi 23 Registry is concerned, based on the last report (1998-2002) released in CI5-IX, it can be seen that the 24 25 ASIRs for Karachi were relatively high (192·0 for females and 166·6 for males) as compared to those for 26 the Lahore district. Further, in the region of Golestan in Iran (2005-2007), and for Israel, again the ASIRs 27 were high compared to those reported for the Lahore district[19]. For the SEER Program, Delhi, Iran, and 28 Saudi Arabia, data were reported for the 2003-2007 time period. Table 8 shows a comparison of the 29 30 ASIRs according to cancer sites, though not all sites, in the aforementioned regions of the world. In 31 women belonging to the Lahore district, the ASIR of breast cancer ranked the highest (47·6) of all the 32 cancers, and was higher than that for Delhi (31·6), but relatively low compared to that reported for the 33

34 Israeli Jews (89·4). Amongst men in the Lahore district, the ASIR of prostate cancer was the highest (6·4) http://bmjopen.bmj.com/ 35 of all the cancers, but was lower than that reported for Delhi (10·1) and Riyadh (7·9). Even though breast 36 and prostate cancer were the most common diagnoses in the Lahore district, the point to be noted is 37 38 that organized screening programs for early detection of these diseases do not exist in Pakistan. The 39 ASIR of cervical cancer in Lahore was 2·9 but in Delhi it was much higher, at 17·7; this is despite the fact 40 that the screening levels are low in the general population of India[23]. Of the factors implicated in the 41 etiology of cervical cancer in the Indian population, the presence of specific oncogenic types of the 42 on October 2, 2021 by guest. Protected copyright. 43 Human Papilloma Viruses (HPV), namely types 16 and 18, plays an important role in the development of 44 cancer of the cervix. In Pakistan, one population-based study reports HPV positivity to be nearly 2·8% in 45 46 the general population (25/899) and about 92% in patients with invasive cervical cancer (83/91)[24]. 47 However, in India, it has been reported that HPV prevalence varies from 7·5% to 16·9% in women 48 without cervical cancer as opposed to 87·8% to 96·7% amongst cervical cancer patients[23]. Further, in 49 50 the latest Globocan report, the ASIR for cancer of the cervix in Pakistan was estimated at 7·9 per 51 100,000 females with 5,233 cases identified in 2012[15]; in the same year, in Saudi Arabia, 241 cases 52 were diagnosed, with the ASIR at 2·7 per 100,000 women; in contrast to this, in India, 122,844 cervical 53 54 cancer cases were diagnosed, with a relatively high ASIR of 22·0 per 100,000 females[15]. Since the ASIR 55 is low in the aforementioned Muslim countries compared to a non-Muslim country, circumcision of 56 men may be a plausible explanation in reducing the transmission of HPV infection to their female sexual 57 58 partners. Circumcision of men is the norm amongst Muslim males. The role of circumcision has been 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 22 BMJ Open Page 16 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 demonstrated in three separate randomized trials done in Africa[25]. Since the incidence of cervical 4 5 cancer in Pakistan is relatively low and the 5-year prevalence is 15,323, setting-up a formal screening 6 program may have lower yields, therefore, a low priority in resource allocation and decision making in 7 our setting[15]. 8 9 10 As shown in Table 8, the ASIRs per 100,000 population, per year, for ten common cancers in Pakistan, as 11 reported in the Globocan 2012, compared to Lahore, are as follows: In women: breast 50·3, 47·6; lip & 12 oral cavity 9·1, 3·9; cervix uteri 7·9, 2·9; ovary 5·6, 5·1; esophagus 4·4, 1·2; corpus uteri 3·6, 3·6; NHL 3·4, 13 14 3·3; colo-rectum 3·3, 3·7; liver 2·5, 2·4; and stomach 2·2, 1·3, while, amongst men: lip & oral cavity 10·5, 15 4·6; lung 9·8, 4·6; ForNHL 5·3, 4·5; peer prostate 6·6, 6·4;review bladder 5·1, 5·0; larynx only 5·0, 2·0; colo-rectum 47, 4·7; 16 liver 4·7, 3·7; esophagus 3·9, 1·4; stomach 3·8, 1·6; and brain & nervous system 3·4, 3·8. The comparison 17 18 shows that rates are somewhat higher for tobacco-related cancers (lip & oral cavity, lung, larynx, and 19 esophagus), and cervical cancer, though for the latter, the rates are still lower than those reported in 20 countries with a high HPV prevalence rate. Since the Globocan 2012 report included data from the 21 22 Punjab Cancer Registry, Karachi South district, and Dr. Yasmin’s paper, the relatively high cancer rates 23 for certain cancers may be attributed to the high consumption of tobacco-related products in that part 24 of Pakistan, in the form of cigarettes and bidi and also of smokeless tobacco as betel quid and 25 26 niswar[26]. Further, Karachi South is one of the 29 districts of the province of Sindh[12], located in the 27 south of the country and its population was 1·72 M during the period under study. Its last report 28 published in the CI-5, IX, shows a high incidence rate for tobacco related cancers[22]. Therefore, the 29 30 dissimilarity in the incidence rates could be attributed to the geographic and lifestyle differences 31 between these two regions. Table 8, depicting the ASIRs, highlights the differences between these two 32 regions and other regions of the world as well. 33

42 on October 2, 2021 by guest. Protected copyright. 43 the point to be noted is that the cancer diagnoses were not merely reported from hospitals, they were 44 also reported on patients identified as new cancer cases, from different laboratories/collection centers 45 within the district. The establishment of a central death registry in the region could help in collecting the 46 47 mortality data and determining the cause-specific mortality, along with the survival estimates for the 48 study population. While the Government of Pakistan maintains the National Database Registration 49 Authority with all citizens’ data and biometric information, the capture of death information is variable 50 51 and typically done at the local government level[27,28]. Deaths within hospitals have documented death 52 certificates which get communicated to local government, but the recording of death diagnosis likely 53 over-reports final mechanisms of death (‘cardio respiratory failure’), rather than underlying causes. In 54 55 view of this, death data and thus survival data have inherent inaccuracies in it. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 16 of 22 Page 17 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Table 8. ASIRs, per 100,000 population, per year, for selected cancer sites, in Pakistan, India, Iran, Israel, and USA. 4 5 Saudi 6 Pakistan Globocan Pakistan India Iran Arabia Israel USA New 7 Lahore Pakistan Karachi Delhi Golestan Riyadh Jews SEER 8 2010- 1998- 2003- 2005- 2003- 2003- 9 2012 2012 2002 2007 2007 2003-2007 2007 2007 10 Oral cavity & salivary glands-C00-C08 11 Male 4.6 10.5 22.5 14.0 1.7 1.6 3.3 6.9 12 Female 3.9 9.1 20.4 4.7 1.3 1.4 2.3 3.1 13 Pharynx-C09-C14 14 Male 0.6 3.8 8.2 6.6 1.0 2.4 1.5 4.4 15 Female For0.8 peer 1.3 3.4 review 1.5 0.7 only 1.3 0.5 1.1 16 Esophagus-C15 Male 1.4 3.9 6.7 4.9 23.2 1.6 1.8 5.1 17 Female 1.2 4.4 8.6 2.9 18.8 1.3 0.9 1.2 18 Stomach-C16 19 Male 1.6 3.8 6.0 3.2 30.4 4.4 10.0 6.6 20 Female 1.3 2.2 3.6 1.5 12.6 2.3 5.4 3.3 21 Small intestine-C17 22 Male 0.3 - 0.2 0.2 1.4 0.5 1.0 1.5 23 Female 0.2 - 0.4 0.1 0.9 0.3 0.7 1.1 24 Colo-rectum-C18-C21 25 Male 4.7 4.7 7.1 5.5 13.6 12.5 42.8 35.3 26 Female 3.7 3.3 5.2 3.7 10.4 10.6 32.6 26.5 27 Liver-C22 28 Male 3.7 4.7 5.4 2.6 3.6 3.0 3.1 7.6 29 Female 2.4 2.5 3.7 1.5 2.0 6.0 1.4 2.4 30 Gall bladder-C23-C24 31 Male 1.0 0.9 1.3 4.0 1.2 1.2 1.7 1.7 Female 1.9 2.2 4.9 8.0 1.6 2.5 1.4 1.7 32 33 Pancreas-C25 Male 0.6 0.5 0.9 1.9 2.8 3.2 8.6 8.2 http://bmjopen.bmj.com/ 34 Female 0.5 0.4 0.5 1.1 1.0 1.9 6.4 6.2 35 Nose & sinuses-C30-C31 36 Male 0.3 - 0.7 0.3 0.0 0.2 0.4 0.6 37 Female 0.3 - 0.4 0.2 0.2 0.2 0.3 0.4 38 Larynx-C32 39 Male 2.0 5.0 10.7 8.0 4.1 1.7 4.1 4.3 40 Female 0.3 0.7 1.8 1.1 1.4 0.1 0.6 0.9 41 Trachea, bronchus, & lung-C33-C34

42 Male 4.6 9.8 25.2 13.7 17.5 6.3 29.8 48.3 on October 2, 2021 by guest. Protected copyright. 43 Female 1.2 1.7 3.6 3.6 5.6 2.2 13.4 33.8 44 Bone-C40-C41 45 Male 0.9 - 1.3 2.0 1.3 0.8 1.3 1.0 46 Female 0.6 - 1.5 1.2 1.5 0.5 1.0 0.8 47 Melanoma of the skin-C43 48 Male 0.1 0.3 0.5 0.2 0.9 0.3 13.7 16.8 Female 0.1 0.2 0.3 0.2 0.7 0.4 11.2 12.0 49 Skin-C44 50 Male 2.8 - 4.3 1.3 11.0 3.8 2.8 1.3 51 Female 2.7 - 4.1 1.0 7.7 3.2 1.9 1.0 52 Connective & soft tissue-C47-C49 53 Male 1.2 - 2.4 1.5 2.1 1.3 3.2 3.0 54 Female 1.0 - 2.3 1.2 2.1 0.9 2.2 2.1 55 Breast-C50 56 Male 0.8 - 1.0 1.3 0.1 0.5 1.3 0.7 57 Female 47.6 50.3 69.0 31.6 28.0 21.1 89.4 86.6 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 22 BMJ Open Page 18 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Cervix uteri-C53 4 Female 2.9 7.9 7.5 17.7 5.4 2.0 5.5 6.4 5 Corpus uteri-C54 6 Female 3.6 3.6 6.7 4.5 1.7 4.4 14.4 16.7 7 Ovary-C56-C57.0-4 8 Female 5.1 5.6 8.8 8.6 6.1 3.3 9.2 9.6 9 Other female genital organs-C51-C52, C55, C58 10 Female 1.5 - 1.0 1.6 1.4 0.9 1.8 2.5 11 Penis-C60 12 Male - - 0.1 1.0 0.0 0.1 0.3 0.7 13 Prostate-C61 14 Male 6.4 6.6 10.1 10.1 10.6 7.9 68.3 106.8 15 Testis-C62 Male For0.6 peer 0.9 1.2 review 0.6 2.3 only 0.6 4.7 4.9 16 Kidney, etc.-C64, C66, C68 17 Male 1.7 1.7 1.9 2.7 2.2 3.8 13.9 137.0 18 Female 1.1 0.9 0.8 1.2 1.2 2.5 6.5 7.1 19 Bladder-C67 20 Male 5.0 5.1 9.3 6.5 8.5 5.6 25.5 20.8 21 Female 1.5 1.6 2.6 1.5 2.8 1.3 4.8 5.3 22 Eye-C69 23 Male 0.5 - 0.6 0.3 0.4 0.4 0.6 0.8 24 Female 0.4 - 0.3 0.2 0.2 0.2 0.4 0.6 25 Brain, CNS-C70-C72 26 Male 3.8 3.4 3.3 3.8 7.8 3.5 6.7 6.4 27 Female 2.2 2.1 2.7 2.4 5.3 2.1 5.0 4.6 28 Thyroid-C73 29 Male 0.7 0.7 0.7 1.1 1.2 2.5 4.8 3.9 30 Female 2.2 2.2 2.9 2.5 3.0 10.2 14.7 12.3 31 Adrenal & other endocrine-C74-C75 Male 0.1 - 0.2 0.2 0.7 0.3 0.6 0.5 32 Female 0.0 - 0.3 0.2 0.4 0.2 0.5 0.4 33 Hodgkin lymphoma-C81 34 Male 1.4 2.2 2.0 1.6 1.8 2.2 3.6 2.7 http://bmjopen.bmj.com/ 35 Female 0.7 0.8 1.0 0.7 1.1 2.0 3.4 2.2 36 NHL-C82-C88, C96 37 Male 4.5 5.3 7.6 5.6 7.2 8.6 17.9 15.5 38 Female 3.3 3.4 5.1 3.0 3.3 7.1 14.4 10.8 39 Multiple myeloma-C88, C90 40 Male 0.6 0.7 1.8 2.0 2.4 1.8 4.8 4.7 41 Female 0.5 0.6 1.3 1.2 2.2 1.0 3.0 3.1

42 Leukemia-C91-C95 on October 2, 2021 by guest. Protected copyright. 43 Male 2.4 3.3 4.8 5.6 10.8 5.7 10.6 11.1 44 Female 1.5 2.2 4.1 3.6 7.7 4.3 6.9 7.1 45 All sites-C00-C96 46 Male 66.7 96.0 166.6 119.7 165.3 104.1 273.1 359.4 47 Female 105.1 127.7 192.0 118.4 142.0 103.9 308.5 282.6 48 49 50 CONCLUSION 51 52 This is the first time that an attempt has been made to determine and report the population-based 53 cancer statistics for the Lahore district. This collaborative study highlights cancer registration and follow- 54 55 up issues in a developing country like Pakistan, along with the non-availability of recent, accurate 56 population estimates required as denominators in computation of the incidence rates. On average, 57 annually, 5,200 new cases were reported in the Lahore district, in 2010-2012. Although it is likely that all 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 18 of 22 Page 19 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 the cases have not been reported, it is not possible to gauge the extent of under-reporting at this stage. 4 5 The cancer statistics reported in this manuscript can be used as baseline figures for comparison with 6 studies to be undertaken in the future. These statistics can also assist in exploring, thus, highlighting the 7 putative risk factors associated with cancers commonly diagnosed in the region, as part of a health 8 9 promotion and education program. Finally, this report can play an important role in developing 10 prevention, early detection, and cancer control strategies in the region. 11 12 13 14 FOOTNOTES 15 For peer review only 16 Contributors 17 18 19 FB conceived the idea of the study, designed it, supervised the statistical analysis, did literature search, 20 interpreted the results, drafted the manuscript, and finalized it. FB further did the survival analysis for 21 this study. SM did the case-finding, indexing, and coding of cases, computed the incidence rates, and 22 23 created figures and tables. MAY and FS reviewed the paper critically for important intellectual content, 24 interpretation of the results, and final approval of the version to be published. 25 26 Funding 27 28 None for this study. 29 30 31 Competing interests 32 33 We declare no competing interests.

34 http://bmjopen.bmj.com/ 35 Data sharing statement 36 37 No additional data available. 38 39 40 41 ACKNOWLEDGEMENTS

42 on October 2, 2021 by guest. Protected copyright. 43 44 Clinical and participating investigators: Misbah Masood was responsible for reporting the cancers 45 recorded at the Institute of Nuclear Medicine & Oncology, Lahore; Ghulam Rasool Sial from Ittefaq 46 Hospital, Lahore; Nasir Chughtai from Sheikh Zayed Hospital, Lahore; Omar Rasheed Chughtai from 47 48 Chughtais Lahore Lab, Lahore; Tanveer Mustafa from Fatima Jinnah Medical University, Lahore; Zeba 49 Aziz and Muhammad Abbas Khokhar from Jinnah Hospital, Lahore; Ghazala Hanif and Alia Ahmad from 50 the Children’s Hospital & the Institute of Child Health, Lahore; Rakhshindah Bajwa from the Services 51 52 Institute of Medical Sciences, Lahore; Sabiha Riaz and Imrana Tanvir from Fatima Memorial College of 53 Medicine & Dentistry, Lahore; Farooq Aziz from Shalamar Medical & Dental College, Lahore; Tazeen Anis 54 from Allama Iqbal Medical College, Lahore; Shahida Niazi from King Edward Medical University, Lahore; 55 and Bilquis A. Suleman from Nawaz Sharif Social Security Hospital, Lahore. Neelam Siddiqui contributed 56 57 intellectually to the study. Mohammad Tariq Mahmood, Sajid Mushtaq, Asif Loya, and Mudassar 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 22 BMJ Open Page 20 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Hussain did the pathologic confirmation of cases at SKMCH & RC, Lahore. Raqib Faraz, Aneel Yousaf, 4 5 Hina Asif, and Adna Atif validated the data, checked for duplication, and followed-up on the patients; 6 and Ain ul Quader and Kamran Liaqat Ali worked on the comparison of the incidence rates with other 7 regions. 8 9

42 on October 2, 2021 by guest. Protected copyright. 43 44 9 Badar F, Mahmood S. The state of cancer registration in Pakistan. J Ayub Med Coll Abbottabad 45 2015;27(2):507–508. 46 47 10 The Societies Registration Act, 1860 (Act XXI of 1860). Pakistan 2015. URL: 48 http://punjablaws.gov.pk/laws/1.html#_ftn2 (accessed 16 Dec 2016). 49 50 51 11 IACR-International Association of Cancer Registries. Lyon, France 2015. URL: 52 http://www.iacr.com.fr/ (accessed 16 Dec 2015). 53 54 12 Pakistan Bureau of Statistics-Government of Pakistan. Islamabad, Pakistan 2015. URL: 55 http://www.pbs.gov.pk/content/population-census (accessed 16 Dec 2015). 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 20 of 22 Page 21 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 13 Census-Publication No. 125-Population Census Organization-Statistics Division, Government of 4 Pakistan, Islamabad (2000). Statistical Tables of 1998 Population and Housing Census. In: ‘1998 5 6 District Census Report of Lahore.’ Islamabad: Government of Pakistan 2000. 77–305. 7 8 14 MacLennan R. Chapter 6-Items of patient information which may be collected by registries. In: 9 Jensen OM, Parkin DM, MacLennan R, et al, eds. Cancer Registration: Principles and Methods- 10 IARC Scientific Publications No. 95. International Agency for Research on Cancer, Lyon, France 11 1991. URL: https://www.iarc.fr/en/publications/pdfs-online/epi/sp95/SP95.pdf (accessed 16 12 13 Feb 2016). 14 15 15 GLOBOCANFor 2012: Estimated peer Cancer Incidence,review Mortality, and only Prevalence Worldwide in 2012. 16 Lyon, France 2015. URL: http://globocan.iarc.fr/Default.aspx (accessed 17 Dec 2015). 17 18 16 Census in Pakistan by Wikipedia. Wikimedia Foundation, San Francisco, CA, USA 2016. URL: 19 https://en.wikipedia.org/wiki/Census_in_Pakistan (accessed 22 Jan 2016). 20 21 22 17 Program for Multiple Primaries- IARC/IACR Multiple Primary Rules. Appendix 3. In: Ferlay J, 23 Burkhard C, Whelan S, et al, eds. International Agency for Research on Cancer. Check and 24 Conversion Programs for Cancer Registries (IARC/IACR Tools for Cancer Registries). IARC 25 Technical Report No. 42. Lyon 2005;38-45. 26 27 28 18 Fritz A, Percy C, Jack A, et al, eds. 6th Digit Code for Histologic Grading and Differentiation. In: 29 Fritz A. International Classification of Diseases for Oncology. 3rd ed. WHO, Geneva 2000:31. 30 31 19 Holden K, ed. ICD-10-CM Expert for Hospitals. The complete official code set. Codes valid 32 October 1, 2015 through September 30, 2016. Salt Lake City, UT, USA: Optum360, LLC 2015. 33 34 20 Boyle P, Parkin DM. Chapter 11-Statistical Methods for Registries-IARC. In: Jensen OM, Parkin http://bmjopen.bmj.com/ 35 36 DM, MacLennan R, et al, eds. Cancer Registration: Principles and Methods. IARC Scientific 37 Publication No. 95. International Agency for Research on Cancer, Lyon, France 1991. URL: 38 https://www.iarc.fr/en/publications/pdfs-online/epi/sp95/SP95.pdf (accessed 16 Feb 2016). 39 40 21 The Surveillance, Epidemiology, and End Results (SEER) Program. NCI, Bethesda, Maryland 2016. 41 URL: http://seer.cancer.gov/registries/terms.html (accessed 4 Feb 2016).

42 on October 2, 2021 by guest. Protected copyright.

43 44 22 Cancer Incidence in Five Continents Volumes I to X-IACR; International Agency for Research on 45 Cancer, Lyon, France 2016. URL: http://ci5.iarc.fr/CI5I-X/Pages/table4_sel.aspx (accessed 3 Feb 46 2016). 47 48 23 Sreedevi A, Javed R, Dinesh A. Epidemiology of cervical cancer with special focus on India. Int J 49 Womens Health. 2015 Apr;7:405–414. URL: 50 51 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404964/ (accessed 16 Feb 2016). 52 DOI: 10.2147/IJWH.S50001. 53 54 24 Raza SA, Franceschi S, Pallardy S, et al. Human papillomavirus infection in women with and 55 without cervical cancer in Karachi, Pakistan. Br J Cancer 2010 Apr;102:1657–1660. URL: 56 https://researchonline.lshtm.ac.uk/448554/1/6605664a.pdf (accessed 16 Feb 2016). 57 DOI:10.1038/sj.bjc.6605664. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 22 BMJ Open Page 22 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 25 Giuliano AR, Schim van der Loeff MF, Nyitray AG. Circumscribed HIV-infected men and HPV 5 6 transmission. Lancet Infect Dis. 2011 Aug;11(8):581-2. DOI: 10.1016/S1473-3099(11)70073-1. 7 Epub 2011 Apr 12. 8 9 26 Imam SZ, Nawaz H, Sepah YJ, et al. Use of smokeless tobacco among groups of Pakistani medical 10 students-a cross-sectional study. BMC Public Health. 2007 Sep;7:231. URL: 11 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1995212/ (accessed 26 Apr 2016). DOI: 12 13 10.1186/1471-2458-7-231. 14 15 27 National DatabaseFor and peer Registration Authority review (NADRA). URL: onlyhttps://www.nadra.gov.pk/ 16 (accessed 26 Apr 2016). 17 18 28 Local Government and Community Development-Registration of Death. URL: 19 https://lgcd.punjab.gov.pk/FAQ (accessed 26 Apr 2016). 20 21 22 23 24 25 26 27 28 29 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

34 254x190mm (300 x 300 DPI) http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 Figure 2. Map of Pakistan showing the provinces and location of the Lahore and Karachi districts and neighboring countries. 41 344x337mm (300 x 300 DPI) 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Figure 3. Population structure of the Lahore district, 2010-2012, by gender. 152x97mm (300 x 300 DPI) 30 31 32 33

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

34 19 Pride Lab http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Page 1 of 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Appendix B-Data collection form used for the Lahore district, the Punjab Cancer Registry. 4 5 6

32 HOME/CELL TELEPHONE WITH AREA CODE______33

34 ↓RESIDENT OF LAHORE: YES NO IF YES, duration of stay in Lahore (Months/Years) _____ http://bmjopen.bmj.com/ 35

36 ↓COME TO LAHORE FOR TREATMENT/DIAGNOSIS ONLY______(YES/NO) 37

56 xx END xx 57 58 59 Page 1 of 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 32

34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41

42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Page 3 of 3 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 32 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 STROBE Statement—checklist of items that should be included in reports of observational studies 3 4 5 Item No Recommendation 6 7 Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the 8 abstract-page 8 9 (b) Provide in the abstract an informative and balanced summary of what was done 10 and what was found- page 8 11 12 Introduction 13 Background/rationale 2 Explain the scientific background and rationale for the investigation being reported- 14 page 9-11 15 Objectives For3 peer State specific objectives, review including any pre-specified only hypotheses-page 11 16 17 Methods 18 Study design 4 Present key elements of study design early in the paper-page 11-14 19 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, 20 21 exposure, follow-up, and data collection-page 11-14 22 Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of 23 selection of participants. Describe methods of follow-up 24 Case-control study—Give the eligibility criteria, and the sources and methods of 25 26 case ascertainment and control selection. Give the rationale for the choice of cases 27 and controls 28 Cross-sectional study—Give the eligibility criteria, and the sources and methods of 29 selection of participants-pages 11-14 30 (b) Cohort study—For matched studies, give matching criteria and number of 31 32 exposed and unexposed 33 Case-control study—For matched studies, give matching criteria and the number of

34 controls per case http://bmjopen.bmj.com/ 35 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect 36 37 modifiers. Give diagnostic criteria, if applicable-pages 11-14 38 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 39 measurement assessment (measurement). Describe comparability of assessment methods if there 40 is more than one group-pages 14-21 41 Bias 9 Describe any efforts to address potential sources of bias-page 21

42 on October 2, 2021 by guest. Protected copyright. 43 Study size 10 Explain how the study size was arrived at-page 11-14 44 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, 45 describe which groupings were chosen and why-page 11 46 Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding- 47 48 page 11-14 49 (b) Describe any methods used to examine subgroups and interactions-page 11-14 50 (c) Explain how missing data were addressed-page 11-14 51 (d) Cohort study—If applicable, explain how loss to follow-up was addressed 52 53 Case-control study—If applicable, explain how matching of cases and controls was 54 addressed 55 Cross-sectional study—If applicable, describe analytical methods taking account of 56 sampling strategy- not applicable 57 (e) Describe any sensitivity analyses 58 59 Continued on next page 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 BMJ Open Page 32 of 32 BMJ Open: first published as 10.1136/bmjopen-2016-011828 on 28 June 2016. Downloaded from 1 2 3 Results 4 5 Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, 6 examined for eligibility, confirmed eligible, included in the study, completing follow-up, and 7 analysed-pages 11-14 8 (b) Give reasons for non-participation at each stage-pages 11-14 9 (c) Consider use of a flow diagram-one to indicate the health systems in Pakistan (Figure 10 11 1). 12 Descriptive 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information 13 data on exposures and potential confounders-page 11-14 14 (b) Indicate number of participants with missing data for each variable of interest-page 11-21 15 For peer review only 16 (c) Cohort study—Summarise follow-up time (e.g., average and total amount) 17 Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time 18 Case-control study—Report numbers in each exposure category, or summary measures of 19 exposure 20 21 Cross-sectional study—Report numbers of outcome events or summary measures- pages 11-21 22 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their 23 precision (e.g., 95% confidence interval). Make clear which confounders were adjusted for and 24 why they were included-pages 11-15 25 (b) Report category boundaries when continuous variables were categorized 26 27 (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful 28 time period 29 Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity 30 analyses 31 32 Discussion 33 Key results 18 Summarise key results with reference to study objectives-pages 14-21