Minimally Invasive Surgery and Risk of Capsule

Letters

Cancer Centre Singapore, Singapore (Chua); Oncology Academic Programme, Table 2. COVID-19 Pneumonia in Patients With NSCLC of Different Age Duke-NUS Medical School, Singapore (Chua). Groups Treated at the Zhongnan Hospital of Wuhan University Corresponding Authors: Conghua Xie, MD, Department of Radiation and No. (%) Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Age, Total No. of patients with NSCLC Patients with NSCLC with COVID-19 People’s Republic of China ([email protected]); Melvin L. K. Chua, MBBS, y (n = 228) (n=7) PhD, Division of Radiation Oncology, National Cancer Centre Singapore, 11 ≤60 111 (48.7) 2 of 111(1.8) Hospital Crescent, Singapore 169610 ([email protected]). >60 117 (51.3) 5 of 117 (4.3) Accepted for Publication: March 11, 2020. Published Online: March 25, 2020. doi:10.1001/jamaoncol.2020.0980 Abbreviations: COVID-19, 2019 novel coronavirus disease; NSCLC, non–small cell lung cancer. Open Access: This is an open access article distributed under the terms of the CC- BY License.©2020YuJetal.JAMA Oncology. Author Contributions: Drs Xie and Chua had full access to all of the data in the patients was 66 years (range, 48 to 78 years); 8 of 12 patients study and take responsibility for the integrity of the data and the accuracy of (66.7%) were older than 60 years. Seven of 12 (58.3%) pa- the data analysis. Drs Yu and Ouyang contributed equally as co–first authors. tients had non–small cell lung carcinoma (NSCLC). Five (41.7%) Drs Chua and Xie contributed equally as co–senior authors. Study concept and design: All authors. were being treated with either chemotherapy with or with- Acquisition, analysis, or interpretation of data: All authors. out immunotherapy (n = 3) or radiotherapy (n = 2). Three pa- Drafting of the manuscript: Yu, Chua. tients (25.0%) developed SARS; 1 patient required intensive- Critical revision of the manuscript for important intellectual content: Yu, Ouyang, Xie. level care. As of March 10, 2020, 6 patients (50.0%) had been Statistical analysis: Yu, Chua. discharged, whereas 3 deaths (25.0%) were recorded. Administrative, technical, or material support: All authors. We also interrogated the association of SARS-Cov-2 infec- Study supervision: Yu, Chua, Xie. tion with age and concurrent NSCLC diagnosis. Of the 1524 pa- Funding/Support: Dr Chua is supported by the National Medical Research tients with cancer who were screened, 228 had NSCLC. We Council Clinician-Scientist Award (CSA/0027/2018). found that patients with NSCLC older than 60 years had a Role of the Funder/Sponsor: The National Medical Research Council had no role in the design and conduct of the study; collection, management, analysis, higher incidence of COVID-19 than those aged 60 years or and interpretation of the data; preparation, review, or approval of the younger (4.3% vs 1.8%) (Table 2). manuscript; and decision to submit the manuscript for publication. Conflict of Interest Disclosures: No conflicts are reported. Discussion | It is hypothesized that patients with cancer may be Additional Contributions: We thank all the patients who consented to this susceptible to an infection during a viral epidemic owing to study, and the frontline healthcare professionals who are involved in patient their immunocompromised status.4 This study highlights the care during this pandemic. following observations: patients with cancer from the epicen- 1. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of ter of a viral epidemic harbored a higher risk of SARS-CoV-2 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513. doi:10.1016/S0140-6736(20)30211-7 infection (OR, 2.31; 95% CI, 1.89-3.02) compared with the com- 2. Wu YC, Chen CS, Chan YJ. The outbreak of COVID-19: an overview. J Chin Med munity. However, fewer than half of these infected patients Assoc. 2020;83(3):217-220. doi:10.1097/JCMA.0000000000000270 were undergoing active treatment for their cancers. Next, we 3. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients observed that older patients (>60 years) and patients with with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. NSCLC may be at risk of COVID-19. Nonetheless, a population Published online February 7, 2020. doi:10.1001/jama.2020.1585 study of 1099 patients with COVID-19 did not indicate that age 4. Kamboj M, Sepkowitz KA. Nosocomial infections in patients with cancer. was associated with susceptibility to infection.5 A larger sample Lancet Oncol. 2009;10(6):589-597. doi:10.1016/S1470-2045(09)70069-5 size in patients with cancer will resolve these potential asso- 5. Guan WJ, Ni ZY, Hu Y, et al; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. ciations. Finally, our findings imply that hospital admission and Published online February 28, 2020. doi:10.1056/NEJMoa2002032 recurrent hospital visits are potential risk factors for SARS- CoV-2 infection. Minimally Invasive Surgery and Risk of Capsule We propose that aggressive measures be undertaken to re- Rupture for Women With Early-Stage Ovarian Cancer duce frequency of hospital visits of patients with cancer dur- Ovarian cancer remains the deadliest gynecologic malignant ing a viral epidemic going forward. For patients who require neoplasm in the United States.1 Salpingo-oophorectomy with treatment, proper isolation protocols must be in place to miti- the intact removal of the ovary and fallopian tube is the stan- gate the risk of SARS-CoV-2 infection. dard approach for suspected ovarian malignant neoplasm ap- parently confined to the Jing Yu, MD ovary.2 Surgery for early- Wen Ouyang, MD Editorial page 991 stage ovarian cancer has his- Melvin L. K. Chua, MBBS, PhD torically been performed via Conghua Xie, MD Related article page 1019 laparotomy. However, in re-

Author Affiliations: Department of Radiation and Medical Oncology, Zhongnan cent years, more women with Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China (Yu, ovarian cysts and masses have been treated with minimally Ouyang, Chua, Xie); Hubei Key Laboratory of Tumor Biological Behaviors, invasive surgery (MIS), including laparoscopy.3 To date, there Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of are limited data to support the safety and oncologic out- China (Yu, Ouyang, Xie); Hubei Cancer Clinical Study Center, Zhongnan Hospital 4 of Wuhan University, Wuhan, Hubei, People’s Republic of China (Yu, Ouyang, comes of MIS for early-stage ovarian cancer. The objective of Xie); Division of Radiation Oncology, Division of Medical Sciences, National this study was to examine the association between MIS use,

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Figure. Trends and Outcomes Associated With Capsule Rupture in Stage I Epithelial Ovarian Cancer

A MIS use and capsule rupture 40 30 MIS P <.001

30 25 Capsule rupture, %

RRuptureupture 20 P ==.02.02 20 MIS use, %

10 15

0 10 2010 2011 2012 2013 2014 2015 Year

B Overall survival 100

95 A, Temporal trends of minimally MIS and no rupture 90 invasive surgery (MIS) use and Open surgery and no rupture capsule rupture in stage I epithelial MIS and rupture Open surgery and rupture ovarian cancer between 2010 and 85 Overall survival, % Overall 2015. Cochran-Armitage trend test for P value. Observed values and 95% 80 CIs are shown for MIS use (dark blue) 0 12 24 36 48 and stage I epithelial ovarian cancer Time, y with capsule rupture (light blue). B, No. at risk Overall survival of women with stage MIS and no rupture 19361633 1365 1014 679 MIS and rupture 664557 462 334 228 I epithelial ovarian cancer stratified by Open surgery and no rupture 49204186 3569 2799 1996 surgery type and capsule rupture Open surgery and rupture 3301122 942 714 505 status. The y-axis is truncated to 80% to 100%.

capsule rupture, and survival of women with stage I epithe- A total of 1994 women (22.5%) experienced capsule rup- lial ovarian cancer. ture. The rate of rupture increased from 20.2% (269 of 1330) in 2010 to 23.9% (379 of 1589) in 2015 (18.3% relative in- Methods | This is an observational study of women with stage crease; Cochran-Armitage trend test P = .02; Figure, A). In a I epithelial ovarian cancer who underwent surgery from 2010 multivariable analysis, MIS was independently associated with to 2015 and were registered in the National Cancer Database. capsule rupture (adjusted relative risk, 1.17; 95% CI, 1.06- All women underwent adnexectomy. The study used deiden- 1.29; Table). Larger tumor size was also associated with higher tified data and was deemed exempt by the Columbia Univer- risk of capsule rupture. Women with ruptured tumors were sity Institutional Review Board. more likely than women with nonruptured tumors to receive Procedures were stratified based on the surgical ap- chemotherapy (unilateral tumors: 1252 of 1869 [67.0%] vs 2500 proach as laparotomy vs MIS (including laparoscopic and ro- of 6484 [38.6%]; and bilateral tumors: 100 of 125 [80.0%] vs botic-assisted surgery). Trends in MIS use and capsule rup- 219 of 372 [58.9%]; P < .001). ture over time were examined. Factors associated with capsule The median follow-up was 39.4 months, and the 4-year rupture were examined using multivariable analyses. The as- overall survival rate decreased by 5.0% between 2010 (over- sociation between route of surgery, capsule rupture, and overall survival, 91.0%) and 2015 (overall survival, 86.0%). Women all survival were examined using Cox proportional hazards re- with ruptured tumors had lower overall survival compared with gression models. All P values were from 2-sided tests and those with nonruptured tumors in univariable analysis: 4-year results were deemed statistically significant at P < .05. rates, 86.8% for open surgery and ruptured tumors, 88.9% for MIS and ruptured tumors, 90.5% for open surgery and non- Results | Among 8850 women (mean [SD] age, 55.6 [13.7] years) ruptured tumors, and 91.5% for MIS and nonruptured tu- with stage I ovarian cancer, 2600 women (29.4%) underwent mors (log-rank test, P = .001; Figure, B). In the adjusted model, MIS. Use of MIS increased from 19.8% (263 of 1330) in 2010 to use of MIS with capsule rupture was independently associ- 34.9% (554 of 1589) in 2015 (1.8-fold increase; P < .001; Figure, ated with an increase in all-cause mortality compared with use A). In a multivariable model, more recent year of surgery and of MIS and nonruptured capsules (adjusted hazard ratio, 1.41; serous histologic characteristics were associated with use of 95% CI, 1.01-1.97). A similar association was observed for lapa- MIS (Table). rotomy, where use of laparotomy with capsule rupture was in-

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Table. Multivariable Analysis for MIS Use and Capsule Rupture

Characteristic No. MIS (%/row) aRR (95% CI) Rupture (%/row) aRR (95% CI) MISa No 6250 NA NA 1330 (21.3) 1 [Reference] Yes 2600 NA NA 664 (25.5) 1.17 (1.06-1.29)b Age, y <40 1036 421 (40.6) 1 [Reference] 216 (20.8) 1 [Reference] 40-49 1713 528 (30.8) 0.91 (0.71-1.17) 374 (21.8) 0.86 (0.61-1.21) 50-59 2727 722 (26.5) 0.80 (0.62-1.02) 655 (24.0) 0.92 (0.66-1.28) 60-69 2030 557 (27.4) 0.82 (0.64-1.06) 468 (23.1) 0.86 (0.62-1.21) 70-79 935 262 (28.0) 0.84 (0.64-1.09) 200 (21.4) 0.81 (0.57-1.15) ≥80 409 110 (26.9) 0.80 (0.60-1.07) 81 (19.8) 0.74 (0.50-1.08) Race Non-Hispanic: white 6929 2063 (29.8) 1 [Reference] 1557 (22.5) 1 [Reference] Non-Hispanic: black 478 112 (23.4) 0.84 (0.71-0.98)b 90 (18.8) 0.94 (0.76-1.15) Hispanic 574 167 (29.1) 0.96 (0.83-1.10) 120 (20.9) 1.00 (0.83-1.20) Other 567 180 (31.7) 1.02 (0.89-1.16) 149 (26.3) 1.13 (0.96-1.32) Unknown 302 78 (25.8) 0.90 (0.73-1.10) 78 (25.8) 1.15 (0.93-1.40) Year of diagnosis 2010 1330 263 (19.8) 1 [Reference] 269 (20.2) 1 [Reference] 2011 1317 322 (24.4) 1.26 (1.08-1.47)b 280 (21.3) 1.03 (0.89-1.21) 2012 1493 441 (29.5) 1.49 (1.30-1.72)b 355 (23.8) 1.15 (1.00-1.33) 2013 1584 543 (34.3) 1.76 (1.53-2.03)b 353 (22.3) 1.08 (0.92-1.25) 2014 1537 477 (31.0) 1.64 (1.43-1.88)b 358 (23.3) 1.13 (0.97-1.31) 2015 1585 554 (34.9) 1.85 (1.60-2.14)b 379 (23.9) 1.14 (0.99-1.32) Histology Serous 1567 557 (35.5) 1 [Reference] 373 (23.8) 1 [Reference] b b Mucinous 2211 541 (24.5) 0.74 (0.67-0.82) 342 (15.5) 0.75 (0.65-0.86) Abbreviations: aRR, adjusted relative Endometrioid 2389 742 (31.1) 0.87 (0.80-0.96)b 557 (23.3) 1.06 (0.94-1.19) risk; MIS, minimally invasive surgery; Clear cell 1549 441 (28.5) 0.85 (0.77-0.94)b 435 (28.1) 1.13 (0.99-1.28) NA, not applicable. a Other 1134 319 (28.1) 0.84 (0.75-0.94)b 287 (25.3) 1.10 (0.96-1.25) Data on route of surgery (MIS vs laparotomy) became available in Tumor differentiation 2010. Numbers and percentages Well 2397 754 (31.5) 1 [Reference] 437 (18.2) 1 [Reference] represent row totals (factors for MIS Moderate 2193 588 (26.8) 0.92 (0.84-1.01) 481 (21.9) 1.18 (1.05-1.33)b use or risk of capsule rupture). Cases with missing information b b Poorly 2709 765 (28.2) 0.90 (0.81-0.99) 754 (27.8) 1.31 (1.15-1.50) were analyzed as a discrete group. Unknown 1551 493 (31.8) 0.95 (0.86-1.06) 322 (20.8) 1.07 (0.92-1.23) Multivariable models adjusted for Laterality age, race/ethnicity, insurance status, area average household income, Unilateral 8353 2455 (29.4) 1 [Reference] 1869 (22.4) 1 [Reference] area educational level, facility Bilateral 497 145 (29.2) 0.94 (0.82-1.09) 125 (25.2) 1.04 (0.88-1.22) information (location and type), Tumor size, mm Charlson-Deyo comorbidity index, year, histologic characteristics, 0-20 1053 420 (39.9) 1 [Reference] 187 (17.8) 1 [Reference] laterality, tumor size, 21-40 628 250 (39.8) 1.05 (0.93-1.18) 135 (21.5) 1.17 (0.94-1.44) lymphadenectomy, hysterectomy, 41-60 522 230 (44.1) 1.15 (1.02-1.29)b 128 (24.5) 1.27 (1.03-1.56)b and MIS use in the final model in each analysis. Surgical factors were b b 61-80 607 262 (43.2) 1.13 (1.00-1.27) 176 (29.0) 1.46 (1.21-1.75) not entered in the model for MIS 81-100 722 277 (38.4) 1.01 (0.90-1.13) 244 (33.8) 1.74 (1.46-2.08)b use. Similar results were >100 4452 851 (19.1) 0.53 (0.48-0.59)b 946 (21.2) 1.19 (1.02-1.38)b demonstrated when outcome measures were analyzed in Unknown 866 310 (35.8) 0.97 (0.85-1.10) 178 (20.6) 1.13 (0.93-1.38) purposeful selection method and Lymphadenectomy backward selection method. Race No 2060 725 (35.2) NA 452 (21.9) 1 [Reference] was classified based on the National Cancer Database grouping. Yes 6771 1868 (27.6) NA 1540 (22.7) 0.92 (0.82-1.02) b P < .05. Unknown 19 Suppressedc NA Suppressedc 0.49 (0.12-1.99) c Number less than 10.

dependently associated with an increase in all-cause mortal- Discussion | There has been a significant increase in the use of ity compared with use of laparotomy and nonruptured capsules MIS among women with early-stage ovarian cancer in the (adjusted-hazard ratio, 1.43; 95% CI, 1.18-1.73). United States.3 In the present study, MIS was associated with

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an increased risk of capsule rupture, which was associated with Conflict of Interest Disclosures: Dr Matsuo reported receiving an honorarium increased mortality. An increased rate of capsular rupture from Chugai, textbook editorial expense from Springer, and investigator meeting attendance expense from VBL Therapeutics outside the submitted among women with benign adnexal cysts undergoing MIS has work. Dr Matsuzaki reported receiving research grants from MSD outside the been previously reported, but this association has received little submitted work. Dr Klar reported receiving consultation fees from Tesaro and attention for women with ovarian cancer.4 GSK outside the submitted work. Dr Roman reported receiving consultation Previous work on the prognostic significance of capsular fees from Quantgene outside the submitted work. Dr Sood reported receiving consultation fees from Merck and Kiyatec, being a shareholder for Bio-Path 5 rupture has reported mixed findings. Theoretically, rupture Holdings, and receiving research grants from M-Trap outside the submitted of the ovarian capsule may result in tumor seeding of the ab- work. Dr Wright reported receiving grants from Merck and consultation fees dominal cavity and may be associated with increased from Clovis Oncology outside the submitted work. No other disclosures were reported. mortality.5 We recognize a number of limitations of this study, Funding/Support: This study was funded by grant NCI R01CA169121-01A1 from including the inability to determine the timing of capsule rup- the National Cancer Institute (Dr Wright); grant NCI CA217685 from the ture and whether or not the rupture was contained within a National Cancer Institute, American Cancer Society, and the Frank McGraw tissue extraction bag at the time of occurrence. Some data, in- Memorial Chair in Cancer Research (Dr Sood); and Ensign Endowment for cluding preoperative diagnosis, tumor marker values, sub- Gynecologic Cancer Research (Dr Matsuo). stage, and body mass index, were not available. Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of Several factors, including widespread use of MIS for other the data; preparation, review, or approval of the manuscript; and decision to procedures, decreased perioperative morbidity, and availabil- submit the manuscript for publication. ity of improved technology, were likely associated with the up- Additional Information: The data on which this study is based are publicly take of MIS adnexal surgery.6 Guidelines by the National Com- available upon request at https://www.facs.org/quality-programs/cancer/ncdb. prehensive Cancer Network state that MIS for early-stage 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019; ovarian cancer should be limited to selected patients and ex- 69(1):7-34. doi:10.3322/caac.21551 perienced surgeons.2 Until more data become available, care- 2. National Comprehensive Cancer Network. Ovarian cancer including fallopian tube cancer and primary peritoneal cancer. NCCN guidelines. Accessed January ful preoperative patient selection and intraoperative assess- 5, 2020. https://www.nccn.org/ ment prior to endoscopic oophorectomy should be performed 3. Matsuo K, Chang EJ, Matsuzaki S, et al. Minimally invasive surgery for to minimize the risk of tumor disruption and spillage. early-stage ovarian cancer: association between hospital surgical volume and short-term perioperative outcomes. Gynecol Oncol. Published online May 10, 2020. doi:10.1016/j.ygyno.2020.04.045 Koji Matsuo, MD, PhD 4. Falcetta FS, Lawrie TA, Medeiros LR, et al. Laparoscopy versus laparotomy Yongmei Huang, MD, MPH for FIGO stage I ovarian cancer. Cochrane Database Syst Rev. 2016;10:CD005344. Shinya Matsuzaki, MD, PhD doi:10.1002/14651858.CD005344.pub4 Maximilian Klar, MD, MPH 5. Matsuo K, Machida H, Yamagami W, et al. Intraoperative capsule rupture, Lynda D. Roman, MD postoperative chemotherapy, and survival of women with stage I epithelial Anil K. Sood, MD ovarian cancer. Obstet Gynecol. 2019;134(5):1017-1026. doi:10.1097/AOG. 0000000000003507 Jason D. Wright, MD 6. Walker JL, Piedmonte MR, Spirtos NM, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Author Affiliations: Division of Gynecologic Oncology, Department of Oncology Group Study LAP2. J Clin Oncol. 2009;27(32):5331-5336. doi:10. Obstetrics and Gynecology, University of Southern California, Los Angeles 1200/JCO.2009.22.3248 (Matsuo, Matsuzaki, Roman); Norris Comprehensive Cancer Center, University of Southern California, Los Angeles (Matsuo, Roman); Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York (Huang, Wright); COMMENT & RESPONSE Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany (Klar); Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston (Sood) Immunotherapy With Programmed Cell Death 1 . vs Programmed Cell Death Ligand 1 Inhibitors Accepted for Publication: April 8, 2020. in Patients With Cancer 1 Corresponding Author: Jason D. Wright, MD, Division of Gynecologic To the Editor Duan et al conducted a well-designed meta- Oncology, Department of Obstetrics and Gynecology, Columbia University analysis comparing the efficacy and safety of programmed College of Physicians and Surgeons, 161 Fort Washington Ave, 8th Floor, New cell death 1 (PD-1) and programmed cell death ligand 1 (PD- York, NY 10032 ([email protected]). L1) inhibitors for treating cancer. Most analyses in their Published Online: June 11, 2020. doi:10.1001/jamaoncol.2020.1702 study focused on overall pooled outcomes for all cancer Author Contributions: Drs Huang and Wright had full access to all of the data in types. Subgroup analyses for tumor types could only be the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Matsuo and Huang contributed equally to the work. found in the OS Comparison: Frequentist Approach section Concept and design: Matsuo, Matsuzaki, Klar, Sood, Wright. in the Results. In other parts of the Results section, the sub- Acquisition, analysis, or interpretation of data: Matsuo, Huang, Klar, Roman, group of tumor type was only used to examine the source of Wright. heterogeneity and verify the stability of overall pooled out- Drafting of the manuscript: Matsuo, Matsuzaki, Klar, Wright. Critical revision of the manuscript for important intellectual content: Huang, Klar, comes in sensitivity analysis. Additionally, the authors did Roman, Sood, Wright. not mention their results concerning tumor types in the Dis- Statistical analysis: Matsuo, Huang, Matsuzaki, Klar, Wright. cussion or Conclusions sections. In the Conclusions, the Obtained funding: Matsuo. Administrative, technical, or material support: Matsuo, Roman, Wright. statement “anti–PD-1 exhibited better survival outcomes Supervision: Klar, Roman, Sood, Wright. than anti–PD-L1 in patients with solid tumors…with compa-

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