PROTOCOL GOG-0278 EVALUATION OF PHYSICAL FUNCTION AND QUALITY OF LIFE (QOL) BEFORE AND AFTER NON-RADICAL SURGICAL THERAPY (EXTRA FASCIAL HYSTERECTOMY OR CONE BIOPSY WITH PELVIC LYMPHADENECTOMY) FOR STAGE IA1 (LVSI+) and IA2-IB1 (≤ 2CM) CERVICAL CANCER NCI Version Date 05/09/2013 Includes Revision #1
POINTS: PER CAPITA - 20 MEMBERSHIP - 6
STUDY CHAIR STUDY CO-CHAIR ALLAN COVENS, MD JEANNE CARTER, PH.D. ODETTE CANCER CENTER See GOG Website Directory 2075 BAYVIEW AVE, T2051 TORONTO, ONTARIO M4N 3M5 STATISTICIAN PHONE: (416) 480-4378 SHAMSHAD ALI, MS FAX: (416) 480-6002 See GOG Website Directory Email:[email protected]
NURSE CONTACT JILLIAN KNAZEK, RN UNIVERSITY HOPSITALS CASE MEDICAL CTR DEPT OF GYN ONCOLOGY 11100 EUCLID AVE, ROOM MAC-7128 CLEVELAND, OH 44106 216-844-8787 FAX: 216-844-8596 Email: [email protected]
This protocol was designed and developed by the Gynecologic Oncology Group (GOG). It is intended to be used only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized by GOG nor does GOG assume any responsibility for unauthorized use of this protocol.
OPEN TO PATIENT ENTRY OCTOBER 1, 2012 REVISED JUNE 3, 2013 GOG-0278
SCHEMA (06/03/2013)
Women with IA1- IB1 (≤2cm) carcinoma of the cervix who have been consented for surgery will be approached for study participation. Pre-entry cone biopsy/LEEP (depth of invasion ≤ 10mm)
Study Entry
Pre-operative QOL Study Survey1
Fertility Preservation Group: No Wish for Future Fertility Group: Conization with pelvic lymphadenectomy Simple hysterectomy with pelvic (If the lateral margins were positive on the first lymphadenectomy (If the lateral margins were con e biopsy/LEEP, patients must have a second positive on the first cone biopsy/LEEP, patients cone biopsy/LEEP at the time of the pelvic must have a second cone biopsy/LEEP prior to lymphadenectomy) hysterectomy)
If depth of invasion If any of the following criteria are met, If depth of invasion (sum of the pre and patient will be followed for survival only: (sum of the pre and post entry biopsies) Depth of invasion (sum of the pre and post post entry biopsies) is ≤10 mm, only entry biopsies) is >10 mm is ≤10 mm, proceed ECC is required. Positive pelvic lymph nodes on final pathology to hysterectomy. Adjuvant therapy required
Post-Operative
Follow-up Visits and QOL Study Surveys1 4-6 weeks Post-Op and every 6 months (6, 12, 18, 24, 30, 36) for three years
1. QOL Study Survey includes: Bladder and Bowel Function Items, Female Functioning Index and 2 PROMIS items, GCLQ-Gyn Cancer Lymphedema Questionnaire, Functional Assessment Cancer Therapy FACT-Cx, and Impact of Events Scale (IES). Patients in the Fertility Preservation Group will also complete the Reproductive Items (ICF & RCS) in addition to the items above. See section 7.4 for additional information regarding the QOL Study Survey. GOG-0278
TABLE OF CONTENTS
PAGE
1.0 OBJECTIVES - 1 -
2.0 BACKGROUND AND RATIONALE - 2 -
3.0 PATIENT ELIGIBILITY AND EXCLUSIONS - 8 -
4.0 STUDY MODALITIES - 9 -
5.0 TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE - 10 -
6.0 TREATMENT MODIFICATIONS - 13 -
7.0 STUDY PARAMETERS - 14 -
8.0 EVALUATION CRITERIA - 18 -
9.0 DURATION OF STUDY - 19 -
10.0 STUDY MONITORING AND REPORTING PROCEDURES - 20 -
11.0 STATISTICAL CONSIDERATIONS - 25 -
12.0 BIBLIOGRAPHY - 39 -
SUGGESTED PATIENT INFORMATION/INFORMED CONSENT
APPENDIX I - Clinical Staging (FIGO) APPENDIX II - Cervical Conization Procedure APPENDIX III - Pelvic Lymphadenectomy Procedure APPENDIX IV - Extrafascial Hysterectomy Procedure - 1 - GOG-0278
1.0 OBJECTIVES
1.1 Primary Objectives 1.11 To examine the changes before and after non-radical surgical treatment (simple hysterectomy or cone biopsy [fertility preservation]) and pelvic lymphadenectomy) on functional outcomes of bladder, bowel and sexual function for stage IA1 (LVSI+) and IA2-IB1 (<2cm) carcinoma of the cervix. 1.12 To evaluate incidence and severity of lymphedema after non-radical surgery (simple hysterectomy or cone biopsy [fertility preservation] and pelvic lymphadenectomy) for stage IA1 (LVSI+) and IA2-IB1 (<2cm) carcinoma of the cervix. 1.2 Secondary Objectives 1.21 To investigate if non-radical surgery (simple hysterectomy or cone biopsy [fertility preservation] with pelvic lymphadenectomy) demonstrates greater physical function and less toxicity in comparison to historical data on radical surgery (radical hysterectomy or radical trachelectomy). 1.22 To evaluate incidence and severity of treatment-related adverse events, including surgical complications among the entire cohort and by treatment type. 1.23 To evaluate changes in QOL (FACT-Cx), cancer worries (IES) and sexual (FSFI)/reproductive concerns (RCS) among the entire cohort and by treatment type. 1.24 To explore relationships (correlation, interaction, independence) between functional outcomes (i.e. bladder function, bowel function, sexual function), adverse events (including and surgical complication lymphedema (GCLQ)), cancer worry (IES), surgical complications and overall quality of life (FACT-Cx). 1.25 To determine participants’ intention for conception & fertility rates (ICF) and assess the reproductive concerns (RCS) of women following cone biopsy and pelvic lymphadenectomy for stage IA1 (LVSI+) and IA2-IB1 (<2cm) carcinoma of the cervix. 1.26 To estimate the efficacy of non-radical surgery (simple hysterectomy or cone biopsy [fertility preservation] and pelvic lymphadenectomy) for stage IA1 (LVSI+) and IA2-IB1 (<2cm) carcinoma of the cervix.
- 2 - GOG-0278
2.0 BACKGROUND AND RATIONALE
Cervical cancer is one of the most common cancers in women under the age of 40. Women faced with the diagnosis of cervical cancer must not only face difficult treatment choices and possible outcomes, but also consider the possible impact of treatment on issues of future fertility, sexual health, and risk of complications (i.e. bladder/ bowel issues, lymphedema).
Radical hysterectomy has been the standard method of surgical management for early stage cervical cancer since the middle of the 20th century. It is associated with an excellent survival in appropriate patients. However, it is also associated with substantial toxicity including: blood loss (and transfusion); vessel and nerve injury; short and long term bladder and bowel dysfunction, including fistula requiring surgical intervention;2,3 lymphedema;4-6 loss of fertility;1 and sexual dysfunction.1,7
Multiple studies have demonstrated that the morbidity of radical hysterectomy is associated with the radicality of the surgery, in particular the extent of parametrial resection. Typical indices of morbidity (and their magnitude), associated with radical hysterectomy include blood loss (600cc), and postop non-infectious complications (6%).8 The anticipated postoperative complications following radical hysterectomy include bladder dysfunction (75-80%), vesico-vaginal fistula and uretero-vaginal fistula (2%).9,10 Many of these include both questionnaires as well as objective measurements of the various metrics. Bladder dysfunction is a late morbidity of radical hysterectomy that has been studied using prospective and retrospective study designs. The most frequent complaint of patients is bladder dysfunction12 including urinary incontinence (29- 41%),13,6 impairment of bladder sensation (6-26%),6,13 and straining to void (61%).13 Bowel dysfunction after radical hysterectomy is commonly described as constipation (4- 28%)6,13 and flatulence incontinence (17%).13 Findings from a retrospective study demonstrate that women treated with radical hysterectomy for cervical cancer were at an eight-fold increased risk of developing lymphedema.9 Long-term cervical cancer survivors have also been found to have chronic leg lymphedema.14 Secondary lymphedema after radical hysterectomy is reported to be 20-25% in some studies4,5 and one study noted a 19% incidence of lower extremity lymphedema up to 24 months post surgical treatment.6 Nodal sampling has also been documented as a factor in the development of symptomatic lymphedema15-17 with an increased risk with the greater number of nodes removed.18 Research on sexual function after radical hysterectomy found sexual dysfunction to include vaginal changes of decreased lubrication (10- 26%)1,6,7 and shortening of the vagina (25-26%),1,6 lack of libido (25-57%),6,7 lack of sensation in labia (71%)6 and dyspareunia (18%).6 Predictors of sexual health after treatment among women treated for stage I to II cervical cancer were vaginal changes, time since treatment, receipt of RT, perceived physical appearance, and partnered relationship.19 Studies with long-term cervical cancer survivors in comparison to controls note increased anxiety about sexual performance and sexual worry14 and for those reporting sexual function difficulties (i.e. vaginal dryness and/or problems with sexual arousal) poorer QOL.20
- 3 - GOG-0278
Studies investigating methods to reduce the side effects of radical hysterectomy have been ongoing for decades. Cone biopsy alone (or simple hysterectomy for patients not wishing preservation of fertility) as a method of managing microinvasive squamous cell cancer has been proposed as an acceptable method of management since 1985.33 More recently, radical trachelectomy has been described to preserve fertility while maintaining efficacy for stage I (more than microinvasive) cervical cancer.21 However, recent studies indicate that surgical morbidity can be associated with this fertility preserving surgery. Some radical trachelectomy patients have experienced issues of dysmenorrhea (24%), cervical stenosis (10-40%), and dyspareunia (10-30%).22,23 The development of cervical stenosis after surgical resection is significantly associated with the volume of tissue resected and history of previous excisions.25,26 Factors of cervical stenosis or adhesion formation may create subfertility.19-22 Consequently, this may present challenges for the young cervical cancer patient following fertility-preserving treatment since the procedure may lead to infertility,31 as well as distress and reproductive concerns in cancer survivorship.24
The existing research highlights the treatment morbidity corresponding with radical surgery, thus presenting a strong argument for empirical investigations with more conservative approaches (non-radical surgery). The potential for better physical function (sexual, bladder) and QOL is crucial in the cost/benefit ratio for patients seeking the benefit of adequate surgical treatment but without a significant cost on these important domains. Treatment sequelae and quality of life concerns have influenced decisions about the extent of surgical procedures over the past decade and now non-radical surgical procedures are being considered in the treatment of early stage cervical cancer;24 however, prospective data is greatly needed.
Target Group Newly diagnosed early stage cervical cancer patients will be the focus of this study. This study will evaluate the physical function (bladder, bowel, and sexual function) and quality of life changes before and after non-radical surgical treatment for early stage cervical cancer. When survival rates are excellent irrespective of radicality of surgery, treatment choice then becomes a major consideration in regards to potential side-effects and impact on quality of life. We know the significant changes associated with quality of life after radical surgery. If the changes in physical function, QOL, and survivorship are substantially less after non-radical surgery than established rates described for early stage cervical cancer patients undergoing radical surgical approaches (radical hysterectomy or radical trachelectomy), future treatment may be able to be simplified using a conservative simple hysterectomy surgery with lymph node sampling. It would also provide additional options (or benefits) for fertility preservation, such as conization with lymph node sampling.
The best method of evaluating the efficacy of non-radical surgery in this patient population would be a randomized study. However, due to the low incidence of relapse, the need for an equivalence or non-inferior study, the feasibility of such is poor. The sample size required to test equivalence for a relapse rate of 5% to 8%, with a 90% power (one sided alpha=0.05) is approximately 2300 pts. Therefore, similar to the data on cone - 4 - GOG-0278 biopsy for microinvasive cervical cancer, and radical trachelectomy, (both accepted as standards of care for appropriate patients without any randomized data), clinicians will have to rely on data from large prospective cohort studies.33,34 The potential consequences of these results may be analogous to sentinel lymph node biopsy in vulvar cancer; GOG-0173 was a single arm cohort study that has changed practice. We propose to study physical function (bladder, bowel and sexual function), quality of life, survivorship, and recurrence rates in non-radical cervical cancer surgery (simple hysterectomy or cone biopsy [in women wishing preservation of fertility]) with pelvic lymphadenectomy. This study will provide key information on a multicenter prospective surgical cohort of non-radically treated cervical cancer patients that has never been accomplished to date. This data will serve as a barometer for future studies in this area and enhance our understanding of what changes in treatment morbidity occur, including bladder, bowel and sexual function, complications (lymphedema- LE), and QOL after non-radical surgical treatments in comparison to the documented and established treatment side-effects (as detailed above) associated with radical surgery.
Rationale Recognizing the physical treatment toxicities of radical surgery, including bladder and bowel difficulties, and sexual dysfunction, in addition to cancer-related infertility with radical hysterectomy and cervical stenosis with radical trachelectomy, investigations with non-radical surgical procedures for treatment of early stage cervical cancer warrant further investigation. It is proposed that radical and non-radical surgical treatment will have similar recurrence rates but long-term complications or treatment side-effects will differ substantially with the radicality of the procedure. Potential physical function and QOL are paramount factors in the treatment decision making process for these young women who are expected to have excellent prognosis and may live for decades with side- effects from treatment.
With the conservative non-radical surgery proposed in this study, we predict that young women will be able to receive cancer treatment (and preserve their fertility if desired) without an increase in recurrence. Interim monitoring will be used to assess adverse events and risk of recurrence. This will be monitored semi-annually, and any indication of increased risk will be reported to the GOG SRC. We also believe these women will experience fewer side-effects (complications) than what has been documented in the radical surgery literature, which is an important issue in determining the quality of cancer survivorship in cervical cancer patients.
Therefore we propose to document the changes in QOL indices including postoperative complications in a cohort of patients with early stage cervical cancer undergoing non- radical surgery. Unlike radical surgery, non-radical surgery does not remove the parametrium, does not require dissecting and unroofing the ureter out of its tunnel into the bladder, does not involve resecting the cardinal and/or uterosacral ligaments (which includes blood vessels and autonomic nerves which innervate the bowel and bladder), and does not remove a cuff of vagina. It is precisely all of the above which contribute to indices of morbidity: blood loss (and transfusion); vessel and nerve injury; short and long-term bladder and bowel dysfunction, including fistula requiring surgical - 5 - GOG-0278 intervention; sexual dysfunction; and possible lymphedema. It is unclear if the non- radical surgery patients will exhibit any changes in rates of lower extremity lymphedema risk from that reported for radical surgery, as all patients (simple hysterectomy and cone biopsy patients) will undergo a nodal dissection (documented risk factor).18
The treatment toxicities of radical surgery are multifactorial with factors such as pelvic lymphadenectomy and the radicality of the cervical surgery contributing to issues of bladder/rectal dysfunction, lymphedema and infertility. Autonomic nerve disruption has also been cited as a factor. Adverse effects of radical surgery are commonly described and include bladder dysfunction, infertility (radical hysterectomy), vascular/nerve injuries, and rectal and sexual dysfunction.8,42-44
We propose that non-radical surgery (simple hysterectomy and conization) patients will demonstrate minimal to small changes in vaginal toxicities than what has been noted in the radical surgery literature consisting of vaginal dryness10-26%,1,6,7 dyspareunia 18%,6 and shortened vagina 25-26%.1,6 Physical function difficulties are also predicted to be less frequent after non-radical surgery in comparison to established rates in the radical hysterectomy and radical trachelectomy literatures with rates of bowel dysfunction (constipation) (4-28%),6,13flatulence incontinence (17%),13 bladder dysfunction (urinary incontinence) (29-41%),13,6 impairment of bladder sensation (6-26%),6,13 and straining to void (61%).13
The incidence of parametrial involvement is an important consideration. Covens reported on 824 patients treated radically for stages IA1-IB1 cervical cancer.35 In patients with tumors ≤2cm, depth of invasion <10mm, and negative pelvic lymph nodes, the incidence of parametrial involvement was 0.6%, and the relapse rate at 5yrs was 4%. Other data sets have confirmed similar incidences of parametrial involvement with similar pathological characteristics.36-41 However, it is predicted that less radicality could be a protective factor, translating into a lower incidence of lymphedema, which will be investigated within this study design by assessing lower extremity lymphedema rates in these patients in comparison to the cited 19-25% in the radical hysterectomy literature. The specific incidences of lower extremity lymphedema following treatment for gynecologic cancer, as well as risk factors for development of lymphedema are not well known due to the lack of prospective studies. As this proposal includes non-radical surgery (conization or simple hysterectomy) with pelvic lymphadenectomy it would be important to investigate any potential risk.
As cancer worry has been identified in women experiencing abnormal pap smears,46 undergoing colposcopy and large loop excision of the transformation zone47 and radical trachelectomy,24 as well as in long-term cervical cancer survivors,20 this will be examined. Since non-radical surgery is not the current standard of care for the treatment of early stage cervical cancer, it is possible that participants in this study may experience greater cancer worry or distress. It will be important to determine if this is the case since cancer worry can have an influence on quality of life.
- 6 - GOG-0278
In recent years, fertility sparing options (i.e. radical trachelectomy) have been established as an alternative to radical hysterectomy in the management of cervical cancer.21 Yet, as cited above this is still a radical surgical procedure with its own toxicity (cervical stenosis, dyspareunia) connected with the benefit of fertility preservation. Wenzel and colleagues evaluated the relationship between fertility and long-term quality of life in female cancer survivors, and found reproductive concerns are of great importance and centrally linked to psychosocial outcomes.45 This proposal will assess if the non-radical fertility preserving procedure of conization with lymph node sampling has the benefit of fertility preservation without the vaginal difficulties and reproductive concerns described with radical trachelectomy.
Significance Possible treatment sequelae (bladder, bowel and sexual function) and quality of life become paramount factors in the decision making process when considering treatments, especially if survival outcomes are expected to be comparable. Despite the documented morbidity associated with radical surgery, no prospective studies have been conducted to examine non-radical surgical treatment in this young cohort of patients with early stage disease. As these women are expected to have an excellent prognosis, this translates into many years of cancer survivorship which could be negatively impacted by treatment side- effects and poor QOL. Therefore the aims of this study are to empirically assess the impact of non-radical surgery with lymphadenectomy on issues of sexual health, bladder and bowel function, possible complications (lymphedema- LE), quality of life, and emotional well-being, in addition to examining recurrence rates in both groups. We will also compare non-radical rates on these domains with the existing historical data on radical surgery. As this population of young survivors has been shown to be within childbearing age and at risk of distress from cancer-related infertility, we will also examine the intention to conceive, degree of reproductive concerns and fertility rates within the arm of the fertility preservation (conization) group in our study.
We propose to formally study the changes before and after non-radical surgical treatment on Bladder and Bowel function (FACT-Cx subscale specific bladder and bowel function are 3-Bladder function items [controlling urine, burn when urinate and discomfort when urinate] & 1 Bowel function [constipation] item plus 3 supplemental items [addressing strain to void, bladder sensation and flatulence incontinence] based difficulties experienced after radical hysterectomy cited in the literature), sexual function (FSFI), possible complications (lymphedema [GCLQ]), quality of life (FACT-Cx), and emotional adjustment (IES), and determine the efficacy of nonradical surgery (simple hysterectomy or conization) and pelvic lymphadenectomy for stage IA1 (LVSI+) and IA1–IB1 cervical cancer. We will also examine any potential group changes by non-radical surgical type. Reproductive outcomes (exploratory items) and concerns (RCS) will also be examined within the fertility preservation (conization) group. Our goal is to document the predicted low rates of bladder, bowel and sexual dysfunction, and complications in addition to the expected positive quality of life and emotional adjustment, in contrast to published treatment sequelae associated with radical surgical approaches. In addition, since this is not the current standard of care we will investigate if women undergoing non-radical surgery experience heightened cancer worry, in order to determine if psychosocial - 7 - GOG-0278 interventions are needed in the future. Although we expect comparable rates of recurrence within this cohort, in comparison to rates documented with the standard of care (radical surgery), prospective data is greatly needed to confirm safety/efficacy (recurrence rates) in this population [as defined in Section 3.1] before clinical care strategies can be considered for change. Additionally, surgical therapy for early stage cervical cancer in the future may be able to be simplified,8,42,43,44 with a non-radical instead of a radical surgical approach if the study results support low risk (recurrence) and positive benefit (better physical function i.e. sexual/ bladder/bowel and QOL).
2.1 Inclusion of Women and Minorities
The Gynecologic Oncology Group and GOG participating institutions will not exclude potential subjects from participating in this or any study solely on the basis of ethnic origin or socioeconomic status. Every attempt will be made to enter all eligible patients into this protocol and therefore address the study objectives in a patient population representative of the entire cervical cancer population treated by participating institutions.
- 8 - GOG-0278
3.0 PATIENT ELIGIBILITY AND EXCLUSIONS
3.1 Eligible Patients (06/03/2013)
3.11 Patient must consent for the appropriate surgery (see Section 4.0).
3.12 Patients with a histologic diagnosis of squamous cell carcinoma, adenocarcinoma or adenosquamous cell carcinoma of the cervix, Stage IA1 (LVSI+), IA2, and IB1 (tumor size [maximum visible or palpable]) ≤ 2cm), any grade.
3.13 All patients must have undergone a cone biopsy or LEEP procedure. Depth of invasion must be ≤ 10 mm.
3.14 Patients must have no evidence of metastasis on MRI or CT scan of the pelvis and chest imaging.
3.15 Patients who have met the pre-entry requirements specified in Section 7.0.
3.16 Patients must have signed an approved informed consent and authorization permitting release of personal health information.
3.17 Patients must be > 18 years of age.
3.18 Patient must have GOG performance status of 0, 1, or 2.
3.2 Ineligible Patients (06/03/2013)
3.21 Patients with Stage IA1 disease who are LVSI negative.
3.22 Patients with Stage IB1 with tumor size (maximum visible or palpable) > 2 cm.
3.23 Patients with ≥ Stage IB2 disease.
3.24 Patients with clear cell or neuroendocrine cell types.
3.25 Patients with depth of invasion >10mm on first cone biopsy (or LEEP).
3.26 Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol therapy.
- 9 - GOG-0278
4.0 STUDY MODALITIES
4.1 Surgery
4.11 Total abdominal hysterectomy and pelvic lymphadenectomy, or a cone biopsy (if fertility preservation is desired) and pelvic lymphadenectomy. These procedures can be done by minimally invasive technique, or by laparotomy. (See Appendices II, III and IV.)
- 10 - GOG-0278
5.0 TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE
Sites must submit all IRB approvals (initial and continuing) on NCI-sponsored adult Cooperative Group phase I, II & III prevention and treatment studies to the CTSU Regulatory Office, at the Coalition of Cancer Cooperative Groups in Philadelphia. A CTSU IRB/Regulatory Approval Transmittal Sheet should be submitted along with the CTSU IRB Certification Form or its equivalent. (CTSU forms can be downloaded at https://www.ctsu.org/public/rss2_page.aspx). IRB submissions can be faxed or e-mailed (preferred methods) or mailed to:
Cancer Trials Support Unit (CTSU) ATTN: Coalition of Cancer Cooperative Groups (CCCG) Suite1100 1818 Market Street Philadelphia, PA 19103 FAX: 1-215-569-0206 [email protected]
5.1 Patient Entry and Registration
When a suitable candidate has been identified for protocol entry, the following steps should be taken:
OPEN Registration: All site staff will use OPEN to enroll patients to this study. OPEN can be accessed on the GOG web menu page by clicking on the OPEN link. OPEN is integrated with the CTSU Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient position in the Rave database.
Prior to accessing OPEN site staff should verify the following:
All eligibility criteria have been met within the protocol stated timeframes. Site staff should use the registration forms provided on the group web site as a tool to verify eligibility. All patients have signed an appropriate consent form and HIPAA authorization form (if applicable).
Access requirements for OPEN:
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM account. This is the same account (user id and password) used for the CTSU members' web site. To perform registrations, the site user must have been assigned the 'Registrar' role on the GOG or CTSU roster. - 11 - GOG-0278
To perform registrations you must have an equivalent 'Registrar' role on the Lead Group roster. Role assignments are handled through the Groups in which you are a member.
Note: The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records.
Further instructional information is provided on the CTSU members' web site OPEN tab or within the OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or [email protected].
5.2 Treatment Plan
Patients will be stratified according to their fertility wishes to either cone biopsy and pelvic lymphadenectomy (fertility preservation) or simple hysterectomy and pelvic lymphadenectomy (fertility preservation not desired).
5.21 Regimens
5.211 Fertility Preservation Group/Cone Biopsy and Pelvic Lymphadenectomy (06/03/2013)
If the lateral margins were negative on the first cone biopsy/LEEP, only ECC is required.
If the lateral margins were positive on the first cone biopsy/LEEP, patients MUST have a second cone biopsy/LEEP at the time of the pelvic lymphadenectomy. If the depth of invasion (sum of the pre- and post-entry biopsies) is ≤10 mm, only ECC is required.
If any of the following criteria are met, the patient will be followed for survival only: Depth of invasion (sum of the pre- and post-entry biopsies is >10mm Positive pelvic lymph nodes on final pathology Adjuvant therapy required
5.212 No Wish for Future Fertility Group/Simple Hysterectomy and pelvic lymphadenectomy (06/03/2013)
If the lateral margins were negative on the first cone biopsy/LEEP, proceed directly to hysterectomy and pelvic lymphadenectomy.
- 12 - GOG-0278
If the lateral margins were positive on the first cone biopsy/LEEP, patients MUST have a second cone biopsy/LEEP prior to hysterectomy.
If the depth of invasion (sum of the pre- and post-entry biopsies) is ≤10 mm, proceed to hysterectomy.
If any of the following criteria are met, the patient will be followed for survival only: Depth of invasion (sum of the pre- and post-entry biopsies is >10mm Positive pelvic lymph nodes on final pathology Adjuvant therapy required
5.22 Quality of Life Assessment
See Section 7.4 for complete overview. - 13 - GOG-0278
6.0 TREATMENT MODIFICATIONS
6.1 No treatment modifications are allowed on this protocol.
6.2 Sentinel lymph node mapping is allowed, but all patients must undergo a complete pelvic lymphadenectomy.
6.3 Insertion of a cervical cerclage is permissible at time of surgery.
6.4 Adjuvant Therapy Consideration
Radiation (+/- chemo) is recommended for patients with positive lymph nodes, positive surgical margins, or deep invasion (>10mm). These patients will not be evaluable for the study objectives, but will be followed for survival. (06/03/2013)
- 14 - GOG-0278
7.0 STUDY PARAMETERS
7. 1 Observations and Tests
The following observations and tests are to be performed and recorded on the appropriate form(s):
Parameter Pre-op OR Post-operative Year 1 Year 2 Year 3
4-6wks 3m 6m 9m 12m 18m 24m 30m 36m
History & Physical 1 X1 X1 X1 X1 X1 X1 X1 X1 X1 X1
Tumor measurement X1 X1 X1 X1 X1 X1 X1 X1 X1 X1
Toxicity Assessment X5 Pathology – cone biopsy X or LEEP CBC/Diff/platelets X3 Creatinine X3 CT scan or MRI of the X3 X2 Abdomen/Pelvis Chest Imaging X3 X2 (x-ray or CT scan) Blood Loss & X4 Complications QOL Study Survey6 X X X X X X X X (06/03/2013) 1. QOL (FACT-Cx) & Cancer Worry (IES) 2. Physical Function (Bladder & Bowel Items; FSFI; GCLQ) Reproductive Items X X X X X X X X (cone biopsy group) 1. Intention for Conception and Fertility rates(ICF) 2. Reproductive Concerns (RCS)
1. To be done every visit and will include a pelvic exam 2. Only if concerned about possible recurrence 3. Must be done within 28 days prior to surgery 4. Please report this information in the comment section of the Toxicity Report – Section 1 Form. 5. Please collect information regarding adverse events which occurred within 30 days after the surgery. - 15 - GOG-0278
6. Patients who meet any of the following criteria will be followed for survival only, and will not be required to complete post-surgery questionnaires:
Depth of invasion (sum of the pre- and post-entry biopsies is >10mm) Positive pelvic lymph nodes on final pathology Adjuvant therapy required (06/03/2013)
7.2 STAINED PATHOLOGY SLIDE REQUIREMENTS FOR CENTRAL REVIEW TO CONFIRM ELIGIBILITY
Not applicable.
7.3 Translational Research
Not applicable.
7.4 Quality of Life (06/03/2013)
Patients who meet any of the following criteria will be followed for survival only, and will not be required to complete post-surgery questionnaires:
Depth of invasion (sum of the pre- and post-entry biopsies is >10mm Positive pelvic lymph nodes on final pathology Adjuvant therapy required
The measures selected to comprise the Quality of Life Study Survey will include: 1) an overall quality of life measure addressing physical symptoms, functional well-being, social well-being and emotional well-being plus cervix subscale assessing symptoms specific to cervical cancer [FACT-CX], 2) Cancer worry [IES], 3) physical functioning assessment of bladder and bowel function [supplemental items] and sexual function [FSFI + PROMIS screening items] and lymphedema symptoms [GCLQ] and 4) for the cone biopsy group only – items addressing Intention for Conception and Fertility (ICF) rates [Pregnancy history & intent to conceive] and reproductive concerns [RCS]
7.41 The Functional Assessment of Cancer Therapy(FACT-Cx): The FACT-Cx is the FACT-G plus cervix subscale with 42 quality of life items assessing the Physical Well Being, Functional Well Being and Cervix specific concerns of cervical cancer patients. The Fact-G Version 4 is a 27-item scale (score range from 0 to 108) and cervix subscale consists of 15 items (score range from 0 to 60) specific to symptoms related to cervical cancer. The FACT-Cx (score range from 0-168) instrument takes approximately 5-10 minutes to complete and will be used to assess overall QOL
7.42 Impact of Events Scale (IES): The IES is a 15-item self-report measure focusing on intrusive thoughts and avoidance associated with cancer. - 16 - GOG-0278
Participants rate on a 4-point Likert type scale how true each statement has been for them during the past month. Both Intrusion and Avoidance subscale scores are computed. Internal consistency estimates for both the Intrusion subscale (Cronbach's alpha of .87) and the Avoidance subscale (alpha = .86) are good. The IES takes approximately 2 minutes to complete. This instrument will be used to assess CWS.
7.43 Physical Functioning Assessment: Bladder and Bowel Function Items (FACT-Cx subscale specific bladder and bowel function are 3-Bladder function items [controlling urine, burn when urinate and discomfort when urinate] & 1 Bowel function [constipation] item. It will also include 3 supplemental items [addressing strain to void, bladder sensation and flatulence incontinence] based difficulties experienced after radical hysterectomy cited in the literature)
Female Sexual Function Index (FSFI): The FSFI is a self-report measure of female sexual function. This is a 19-item scale assessing sexual functioning in women with sub-domains of: desire, arousal, lubrication, orgasm, satisfaction, and pain. The FSFI, which takes approximately 10 minutes to complete, will be used to assess SD. PROMIS supplemental items - 2 screener items have been added to assess sexuality activity.
Gynecologic Cancer Lymphedema Questionnaire (GCLQ): The GCLQ is a modification of the validated Lymphedema Breast Cancer Questionnaire (LBCQ). This scale has been modified for lower extremity edema and is currently being used in studies with gynecologic cancer populations. The patient self-reported lymphedema questionnaire assesses 20 symptoms associated with lymphedema, measured as present within the past 4 weeks. GCLQ responses have been dichotomized. Scores for total current patient self-reported lymphedema symptoms and symptom groups can be calculated to describe the most prominent symptoms associated with the diagnosis of lymphedema and the change in lymphedema measurement over time. Items will be combined into symptoms of heaviness, swelling (general), swelling (limb), infection-related, aching, numbness, and physical functioning. Exploratory supplemental items have been added to determine the utilization of lymphedema-specific treatment. GCLQ was recently tested with 58 gyn cancer survivors (28 w/LLE and 30 with no history of LLE) to test the efficacy and feasibility of using the GCLQ as an LLE measurement tool, using the same criteria as the proposed study. Responses were dichotomized and will be used in this study. Findings noted the distribution of GCLQ total score and multi-item subscales differed significantly by LLE diagnosis; LLE patients had higher scores (all Wilcoxon rank sum test P<0.01). One-item subscales also distinguished between the groups effectively, with significantly more LLE patients endorsing these items (Fisher’s exact test P<0.01).
- 17 - GOG-0278
7.44 Reproductive Items:
Intention for Conception and Fertility rates (ICF): The ICF tool (4 items pre-op and 12 items post-op) will be used to assess participants’ desire and intention for conception during the study period, in addition to rates of fertility success.
The Reproductive Concerns Scale (RCS): The RCS is a 14-item scale to assess the female cancer survivor whose reproductive ability was impaired or removed by cancer treatment and takes approximately 2 minutes to complete.
- 18 - GOG-0278
8.0 EVALUATION CRITERIA
8.1 Recurrence
Recurrence is defined as newly evident disease for patients who have no evidence of disease at baseline or progressive disease for patients who have strictly non- measurable disease at baseline.
8.2 Recurrence-Free Survival
Recurrence-Free Survival (RFS) is defined as the duration of time from study entry to time of recurrence or death, whichever occurs first.
8.3 Survival
Survival is defined as the duration of time from study entry to time of death or the date of last contact.
- 19 - GOG-0278
9.0 DURATION OF STUDY
9.1 Each patient entered on study will be followed for 3 years. Follow-up will evaluate disease recurrence and functional outcomes. Fertility parameters will be evaluated in patients undergoing cone biopsy (attempting pregnancy and pregnancy outcomes).
- 20 - GOG-0278
10.0 STUDY MONITORING AND REPORTING PROCEDURES
10.1 ADVERSE EVENT REPORTING FOR A TRIAL EVALUATING A SURGICAL PROCEDURE
10.11 Definition of Adverse Events (AE)
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease that occurs in a patient administered a pharmaceutical product or protocol procedure, whether the event is considered related or unrelated to the study treatment.
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). The CTCAE v4.0 Manual is also available on the GOG member web site (http://www.gog.org under MANUALS).
10.12 Reporting Expedited Adverse Events
All CTCAE v4.0 expedited AEs must be reported to the GOG. All expedited AE reports should be submitted by using the CTEP automated system for expedited reporting (AdEERS). Submitting a report through ADEERS serves as notification to GOG, and satisfies the GOG requirements for expedited AE reporting.
10.13 Expedited Reporting of Adverse Events occurring within 30 Days of the Study Procedure
The following table summarizes the GOG requirements for expedited reporting of AEs that occur within 30 days of the surgical procedure.
- 21 - GOG-0278
Reporting Requirements for Adverse Events that occur within 30 Days¹ of the Study Procedure:
Grades Grades Grade 1 Grade 2 Grade 2 Grade 3 Grade 3 4 & 52 4 & 52 Unexpected Expected Unexpected With Without With Without Unexpected Expected and Expected Unexpected Expected Hospitali- Hospitali- Hospitali- Hospitali- zation zation zation zation
Not Not Not Not Required 7 Days Not Required 7 Days 7 Days 7 Days Unrelated Required Required Required Unlikely Possible Not Not Not Probable Not Required 7 Days Not Required 7 Days 7 Days 7 Days Required Required Required Definite 1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after surgery require reporting as follows:
AdEERS 7 calendar day report: At least Grade 3 with hospitalization or prolongation of hospitalization, or Persistent causes, significant disabilities/incapacities
2 Grade 5: All deaths within 30 days of the surgical procedure must be reported within 7 calendar days using expedited reporting regardless of causality.
Please see exceptions below under the section entitled, “Additional Instructions or Exceptions to Expedited Reporting Requirements for Surgical Trials.” March 2005
Note: All deaths on study require both routine and expedited reporting regardless of causality. Attribution to treatment or other cause must be provided.
Expedited AE reporting timelines defined: “7 calendar days” – A complete AdEERS report on the AE must be submitted within 7 calendar days of the investigator learning of the event.
Any medical event equivalent to CTCAE grades 3, 4, or 5 that precipitates hospitalization (or prolongation of existing hospitalization) must be reported regardless of attribution and designation as expected or unexpected with the exception of any events identified as protocol-specific expedited adverse event reporting exclusions.
Any event that results in persistent or significant disabilities and/or incapacities must be reported via AdEERS if the event occurs following a protocol procedure.
Use the NCI protocol number and the protocol-specific patient ID provided during trial registration on all reports.
- 22 - GOG-0278
Additional Instructions or Exceptions to AdEERS Expedited Reporting Requirements for Surgical Trials: There are no additional instructions or exceptions to AdEERS expedited reporting requirements for this protocol.
10.14 Procedures for Expedited Adverse Event Reporting
10.141 AdEERS Expedited Reports: Expedited reports are to be submitted using AdEERS available at http://ctep.cancer.gov. The CTEP, NCI Guidelines: Adverse Event Reporting Requirements for expedited adverse event reporting requirements are also available at this site.
In the rare event when Internet connectivity is disrupted a 24-hour notification is to be made to GOG by telephone at: 215-854-0770. An electronic report MUST be submitted immediately upon re- establishment of internet connection. Please note that all paper AdEERS forms have been removed from the CTEP website and will NO LONGER be accepted.
- 23 - GOG-0278
10.2 GOG DATA MANAGEMENT FORMS
The following forms must be completed for all patients registered and submitted to the GOG Statistical and Data Center (SDC) according to the schedule below. GOG electronic case report forms must be submitted through the Medidata Rave Electronic Data Entry System. All amendments to forms submitted through Medidata Rave must also be submitted through Medidata Rave. The operative report, discharge summary and pathology reports can be sent to the GOG Statistical and Data Center via postal mail or uploaded in Medidata Rave. The upload option is an alternative method for submitting paper reports. Quality of Life questionnaires are to be completed on the original Scantron forms and submitted via postal mail. Form Due within Copies* Comments Weeks Event Registration Form 2 Registration N/A Mandatory submission via Medidata Rave Primary Cervical - On Study Form 2 Registration N/A Mandatory submission via Medidata Rave Pre-Treatment Summary Form 2 Registration N/A Mandatory submission via Medidata Rave Pregnancy and Intention to Conceive 2 Surgery N/A ♦♦ and Fertility Pre-Op Checklist Mandatory submission via (06/03/2013) Medidata Rave
Labs and Chemistries Form (pre- 2 Surgery N/A Mandatory submission via operative labs) Medidata Rave Tumor Measurement Form 2 Surgery N/A 4-6 weeks post-op N/A 6 months post-op N/A 12 months post-op N/A Mandatory submission via 18 months post-op N/A Medidata Rave 24 months post-op N/A 30 months post-op N/A 36 months post-op N/A Surgical Forms:
- Surgical Reporting Form 6 Surgery N/A - Summary of Operative Findings – 6 Surgery N/A Pelvis Mandatory submission via - Summary of Operative Findings – 6 Surgery N/A Medidata Rave Nodes - Summary of Operative Findings – 6 Surgery N/A Abdominal Organs - Post-Surgical Evaluability 6 Surgery N/A Checklist (06/03/2013) Pathology Reports: Submit to SDC via postal - Pathology Report (pre-registration mail or upload online via - 24 - GOG-0278
biopsy) 6 Registration 1 Medidata Rave - Pathology Report (protocol surgery) 6 Surgery 1 Toxicity Reporting: **
- Section 1 Form 6 Surgery N/A Mandatory submission via - NADIRS Form 6 Surgery N/A Medidata Rave ♦ - Adverse Event – AE Form 6 Surgery N/A ♦ 6 Surgery N/A - Adverse Event - AE Grades Form Pregnancy and Intention to Conceive 4 4-6 weeks post-op N/A ♦♦ and Fertility Post-Op Checklist 6 months post-op N/A 12 months post-op N/A (06/03/2013) Mandatory submission via 18 months post-op N/A Medidata Rave 24 months post-op N/A 30 months post-op N/A 36 months post-op N/A Quality of Life Scantron Form*** 4 Registration 1 4-6 weeks post-op 1 6 months post-op 1 Submit the original 12 months post-op 1 Scantron form to SDC via 18 months post-op 1 postal mail 24 months post-op 1 30 months post-op 1 36 months post-op 1 Treatment Completion Form 2 Completion of N/A Mandatory submission via study Rx and Medidata Rave change in Rx Follow-Up Form 2 Disease N/A progression; Mandatory submission via death; normal Medidata Rave quarterly follow-up for 2 years, semi-annually for 1 more year
* The number of required copies including the original form which must be sent to the Statistical and Data Center. ** Please report adverse events which occurred within 30 days of the surgery. *** Quality of Life Study Survey includes: 1) Overall QOL - FACT –Cx 2) Cancer Worry - IES 3) Physical function – Bladder & Bowel items, FSFI and GCLQ 4) Reproductive Items – ICF and RCS (cone biopsy group only) ♦ Appropriate forms will load based upon the answers reported on the Surgical Status Form. ♦♦ Required for the Fertility Preservation group only. (06/03/2013)
This study will be monitored by the Abbreviated Clinical Data System (CDUS) Version 3.0 CDUS data will be submitted quarterly to CTEP by electronic means.
- 25 - GOG-0278
11.0 STATISTICAL CONSIDERATIONS
This is a multi-center prospective cohort study to evaluate bladder (BL), bowel (BW) and sexual /reproductive (SX) dysfunction, surgical complications including lymphedema (LE), and quality of life (QOL); following non radical surgery (simple hysterectomy [SH] or cone biopsy [CB]) and pelvic lymphadenectomy (PL) for stage IA1 (LVSI+) and IA2 – IB1 (≤ 2.0cm) carcinoma of the cervix.
Patient registration will be conducted centrally at GOG Statistical and Data Center (SDC) prior to surgery after proper consent and eligibility verification. The GOG SDC is responsible for data collection, study monitoring, analysis, and reporting.
11.1 Study objectives: the primary focus of this study is to assess bladder, bowel and sexual dysfunction, and lymphedema based on observed incidence and severity of related adverse events.
11.11 Primary objectives
11.111 To evaluate incidence and severity of BL, BW and SX dysfunction among the entire study cohort and by treatment type.
11.112 To evaluate incidence and severity of Lymphedema (LE) among the entire study cohort and by treatment type.
11.12 Secondary objectives
11.121 To investigate if non-radical surgery (simple hysterectomy or cone biopsy [fertility preservation] with pelvic lymphadenectomy) demonstrates greater physical function and less toxicity in comparison to historical data on radical surgery (radical hysterectomy or radical trachelectomy).
11.122 To summarize incidence and severity of treatment-related adverse events, including surgical complications among the entire cohort and by treatment type.
11.123 To evaluate changes in QOL, cancer worries (CWS) and sexual/reproductive concerns (SRC) among the entire cohort and by treatment type.
11.124 To explore relationships (correlation, interaction, independence) between functional outcomes (i.e. bladder function, bowel function, sexual function), adverse events (including surgical complication lymphedema), cancer worry, surgical complications and overall quality of life.
- 26 - GOG-0278
11.125 To assess intention for conception and fertility rate following cone biopsy and pelvic lymphadenectomy.
11.126 To estimate local failure rate, progression/recurrence-free survival and overall survival among the entire cohort and by treatment type.
11.2 Endpoints, data elements and assessment time points
The following data elements and endpoints will be collected for evaluation of study objectives:
11.21 Endpoints and data elements specific to primary objectives
11.211 Bladder and bowel function score based on SBB questions plus 4 items from the FACT-Cx (3 bladder and 1 bowel question) – used to assess bladder and bowel dysfunction.
11.212 FSFI (19 items) score plus 2 PROMIS screener items – used to assess sexual function and activity.
11.213 GCLQ (gynecologic cancer lymphedema questionnaire, 24 items) score used to assess lymphedema.
11.214 Maximum grade (according to CTCAE v 4.0) and duration of severe (>grade 2, chronic) adverse events associated with BL, BW and SX dysfunction and LE.
11.22 Endpoints and data elements specific to secondary objectives
11.221 Maximum grade of treatment-related adverse events according to CTCAE v 4.0.
11.222 FACT-Cx (42 items) score to assess overall QOL.
11.223 IES (15 items) score to assess cancer worry.
11.224 RCS (14 items) score to assess reproductive concerns.
11.225 Site of first recurrence, classified as either local (pelvis regions, including vaginal) or distant (abdomen, lung, bone, brain and other).
11.226 Recurrence free survival (RFS) and overall survival (OS).
11.23 Baseline (prior to surgery) characteristics
- 27 - GOG-0278
a. Disease: clinical tumor size, FIGO clinical stage (IA1 (LSVI+), IA2, or IB1), tumor histology (squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma), Grade, LVSI status, depth of invasion, pelvic lymph node status b. Patient: age, performance status, race and ethnicity
11.24 Assessment time points: Patients will consent to completing study questionnaires at the following time points a. T0: baseline, just prior to study entry (pre-op) b. T1: 1st post-op visit c. T2: 6 month follow-up d. T3: 12 month follow-up e. T4: 18 month follow-up f. T5: 24 month follow-up g. T6: 30 month follow-up (if feasible) h. T7: 36 month follow-up (if feasible)
11.3 Accrual and study duration The minimum sample size is 200 eligible patients. Depending on results from interim analyses and feasibility assessments, this study may accrue up to 600 patients over three stages of accrual. Rationale and criterion for accruing additional patients beyond the first stage (200 eligible patients) is outlined below.
Based on GOG-0071, GOG-0141 and collaboration from Gynecologic Cancer Inter Group (GCIG) members (the GCIG currently comprises a cooperative of 20 member groups) the accrual rate is estimated to be least 60 eligible patients per annum. The first stage accrual objective is 200 eligible patients. Assuming at least 1.5 years for post accrual follow-up, this study will take at least 5 years to complete.
If during quarters 5 – 6 accrual is ≤ 20% of the projected, the study will be closed and deemed not feasible. If accrual is between 20% and50% of the projected during quarters 5 – 6, the study team will be allowed an addition 6 months to improve accrual too at least 50% of the projected. If the average accrual rate in quarter 8 is below 50%, then the trial will either be amended to reflect the actual accrual rate with justification of the new accrual rate on study relevance and feasibility or terminated.
11.4 Sample size justification
The primary focus is to estimate incidence and severity of BL, BW and SX dysfunction and/or lymphedema among an initial cohort of 200 treated patients. Consider the frequency of severe (at treatment related, at least grade 3, occurred
within 6 months of treatment) post treatment BL dysfunction, and let BL be the anticipated incidence rate. Also, let A be the number of patients who experienced - 28 - GOG-0278
at least one severe BL dysfunction event. Furthermore let, H0: BL ≤ 0.20 and A
< 33 and HA: > 0.20 and A ≥ 33. The probability that fewer than 33 patients will experience at least one severe BL dysfunction event, in a sample of 200 patients with anticipated incidence rate of 0.20 is 0.1153 ( ). That is, power (1 - ) = 0.8847. These probabilities are derived using PASS (power analysis sample size software) based on the method of Machin et al (1997) 56. The relationship between the type II error rate ( ), the anticipated incidence rate, the critical value (A) and sample size is shown in figure 1.
Adverse Events (A) = 33 Incidence rate = 0.20
0.4 0.5
0.4 0.3
0.19 33 0.3 0.2 34
0.20
Incidence Probability
Probability 0.2 35 Adverse Events Adverse 0.21 0.1 36 0.1
0.0 180 190 200 210 220 0.0 180 190 200 210 220 Sample Size (N) Sample Size (N)
Figure 1: Probability of type II error ( ), sample size (N), incidence rate and adverse events (A)
Assuming incidence rate of 0.20, A = 33, a cohort study with at least 200 evaluable
patients will have adequate power to independently estimate , BW , SX and LE , for severe bladder, bowel and sexual dysfunction and lymphedema respectively.
However, incidence of BL, BW, SX dysfunction and LE may be correlated outcomes. In particular; LE may be more related to the disease and pelvic lymphadenectomy (PL); while BL and or BW dysfunction may be more related to the extent of surgery. Thus, it is necessary to compare the proportion of patients with severe BL or BW dysfunction that experience severe LE with the proportion of patients without severe BL and/or BW that experience severe LE. This will be done using McNemar’s test 2 which basically compares the proportions for two correlated dichotomous variables.
Consider table 11.42. The relevant research hypotheses are, H0: p1 = p2 versus HA: p1 ≠ p2, where: p1 = (n11+ n12) ∕ N and p2 = (n11+ n21) ∕ N. Note that p1 = p2 is equivalent to p12 = p21. Thus, the null hypothesis for McNemar’s test is p12 = p21 and the alternate is that they are unequal.The null hypothesis may also be stated in terms of the odds ratio (OR), i.e. H0: OR = 1.
- 29 - GOG-0278
Counts Proportions No Severe BL No Severe BL or or BW dysfunction BW dysfunction Severe LE Severe LE Total Total Yes No Yes No With severe BL n11 n12 n1 With severe BL p11 p12 p1 or or n n 1-n p p 1-p BW dysfunction 21 22 1 BW dysfunction 21 22 1 Total n2 1-n2 N Total p 1-p 1 2 2
Table 1
Suppose the OR of interest is the ratio of the odds of an event occurring in patients with severe BL or BW dysfunction to the odds of it occurring in patients without severe BL or BW dysfunction. To test H0: OR = 1 versus HA: OR ≠ 1; a sample size of 200 achieves 48% power to detect an odds ratio of 1.7 using a two-sided McNemar test 57 with a significance level of 0.05. This power analysis further justifies the need for conducting a larger cohort study (i.e. justification for the multistage accrual strategy). Figure 2 shows the relationship between power, odds ratio, and sample size for McNemar’s test.
1.00
0.91
0.82 200
0.72
Power 250
0.63 Sample(N)Size 300
0.54
0.45 1.5 1.6 1.7 1.8 1.9 2.0 Odds Ratio (OR)
Figure 2: Power of McNemar’s test
11.41 Sample size and secondary objectives QOL, CWS and SRC will be evaluated using FACT-Cx, IES and FSFI assessment tools respectively. Summary statistics and graphs will be used to describe distribution of scores at each assessment time points (see 11.24). Also change in QOL, CWS and SRC between pre and post surgical assessment time points will be evaluated. - 30 - GOG-0278
As a result of environmental and social factors, noncompliance, lost to follow-up, and the high cure rate within the population, change in patients’ scores from T0 and any time points beyond T2, relative to study intervention would be uninformative and difficult to interpret. Therefore observed differences, mean differences and simultaneous 90% confidence interval will only be determined among patients who complete baseline and at least one of the first two subsequent assessments (i.e. T0 and T1 or T2).
Suppose assessment tools for QOL, CWS and SRC are indexed by subscript k, where k = 1, 2, or 3 respectively and let Dijk be the observed difference in assessment k (k =1, 2, 3) scores, between baseline and time point j ( j = 1, 2) for patient i (i = 1, 2,…). Let Ajk be the observed average difference in assessment k score between baseline and time j. If the mean difference in the entire population is ajk, then Ajk is a point estimate for parameter ajk.
Evaluation of the QOL, CWS and SRC will require estimation of simultaneous confidence bounds for six parameters, ajk (j = 1, 2 and k = 1, 2, 3). To ensure that the overall confidence level is 10%, each of the six mean differences will be assessed at 98% confidence level (using Dunn- Sidak correction). If all patients have complete data up to time point T2 (i.e. i = 1, 2, …, 200) then this study will be able to provide two sided 98% confidence interval for each mean difference, ajk with a distance from the true mean difference to the confidence limit (1/2 width of CI) equal to 0.170 when the estimated standard deviation of differences is 1.0
Given the study population and recent GOG experience, compliance for this study is estimated to be at least 80% during the first year of follow up. That is, at least 80% of patients are expected to have complete data at T0, T1, and T2.
Figure 3 shows the relationship between the sample size and precision (1/2 of the width of 98% CI) when estimated standard deviation varies from 1 to 3. Therefore if at least 160 patients (80% of the planned sample size) have complete data at time points T0, T1 andT2, then this study will be able to provide two sided 98% confidence interval for each mean difference, ajk with a distance from the true mean difference to the confidence limit (1/2 width of CI) equal to 0.190 when the estimated standard deviation of differences is 1.0 - 31 - GOG-0278
Precsion of 98% CI vs. Sample Size 0.60
0.55
0.50
0.45 1.000 0.40 1.500
0.35 SD 2.000 Precision 0.30 2.500 0.25 3.000 0.20
0.15
0.10 140 150 160 170 180 190 200 Sample Size
Figure 3 11.43 Accrual, sample size and subgroup analyses If fewer than 30 (<50% of the anticipated accrual rate) patients enrolled during the first four quarters of accrual, the study will be re-evaluated for feasibility. The study team will either implement strategies to improve accrual or recommend study termination. If poor accrual persists the study will be closed and deemed not feasible due to inadequate accrual.
Two hundred evaluable patients may be sufficient to evaluated incidence of severe BL, BW and SX dysfunctions among the entire cohort. However, the ability to assess fertility preservation is limited since the proportion of patients electing for fertility preserving (FP) treatment (cone biopsy + PL) is unknown.
Clearly fertility preservation is an important outcome and therefore should be evaluated with the maximum feasible sample size. Thus if feasible this study may re-open to two additional stages of accrual of up to 200 eligible patients per stage. The decision to open second and third stage must be deemed necessary, safe and feasible, by the study team and the GOG DSMB. 11.5 Analysis Plan (06/03/2013) Patients recommended for post-surgical adjuvant therapy (positive nodes, positive margins or >10mm invasion on final pathology will not be required to complete post-surgery questionnaires and hence will not be evaluable.
- 32 - GOG-0278
These patients are still expected to comply with all other aspect of the protocol including post-surgery follow-up visits for physical exam and imaging thus providing valuable outcome information for future studies.
Centralized GOG modality review may result in post registration exclusion for a variety of reasons, including incorrect baseline risk assessment, inadequate pathology, wrong stage, and improper surgery. Accordingly, the analysis set will consist of all non-excluded evaluable cases not requiring adjuvant therapy.
Results will be presented for the entire study cohort and by treatment (simple hysterectomy or cone biopsy, plus pelvic lymphadenectomy). Since this is a non- randomized study, there will be bias in choice of treatment and distribution of known prognostic. If the study completes three stages of accrual, it may be possible to adjust for confounding factors and known prognostic factors and even perform reliable subgroup comparisons.
Distribution of known prognostic factors will be summarized for the entire cohort and by treatment. Subgroups will be compared using ANOVA for continuous variables and Fisher’s exact test or the chi-square test for discrete variables.
Patient reported outcomes will be captured using scantron forms which should take no more than 20-30 minutes to complete. Instruments (tools) to be utilized include:
11.51 Entire cohort a. The Functional Assessment of Cancer Therapy(FACT-Cx): The FACT-Cx is the FACT-G plus cervix subscale with 42 quality of life items assessing the Physical Well Being, Functional Well Being and Cervix specific concerns of cervical cancer patients. The Fact-G Version 4 is a 27-item scale (score range from 0 to 108) and cervix subscale consists of 15 items (score range from 0 to 60) specific to symptoms related to cervical cancer. The FACT-Cx (score range from 0-168) instrument takes approximately 5-10 minutes to complete and will be used to assess overall QOL
b. Impact of Events Scale (IES): The IES is a 15-item self-report measure focusing on intrusive thoughts and avoidance associated with cancer. Participants rate on a 4-point Likert type scale how true each statement has been for them during the past month. Both Intrusion and Avoidance subscale scores are computed. Internal consistency estimates for both the Intrusion subscale (Cronbach's alpha of .87) and the Avoidance subscale (alpha = .86) are good. The IES takes approximately 2 minutes to complete. This instrument will be used to assess CWS
- 33 - GOG-0278
c. Female Sexual Function Index (FSFI): The FSFI is a self-report measure of female sexual function. This is a 19-item scale assessing sexual functioning in women with sub-domains of: desire, arousal, lubrication, orgasm, satisfaction, and pain. Two PROMIS screener questions have been added to assess sexual activity. These items take approximately 10 minutes to complete and will be used to assess SDF.
d. Gynecologic Cancer Lymphedema Questionnaire (GCLQ): is a patient self-reported lymphedema questionnaire that assesses 20 symptoms associated with lymphedema, measured as present within the past 4 weeks. GCLQ responses have been dichotomized and take approximately 5 minutes to complete.
e. Bladder and Bowel Function Items consist of supplemental bladder and bowel (SBB) questions (3 items) and 4 items from the FACT-Cx (3 bladder and 1 bowel questions) to assess Bladder and Bowel dysfunction and should take approximately 2 minutes to complete.
11.52 Conization group only a. The Reproductive Concerns Scale (RCS): The RCS is a 14 item scale to assess the female cancer survivor whose reproductive ability was impaired or removed by cancer treatment and takes approximately 2 minutes to complete.
b. Intention for Conception and Fertility rates (ICF): The ICF tool (4 items pre-op and 12 items post-op) will be used to assess participants’ desire and intention for conception during the study period, in addition to rates of fertility success.
11.53 Construct and Scoring Within an individual assessment, one or more items may not be answered. A subscale score will be computed as long as more than 50% of subscale items have been answered. A subscale score Si with Ni items will be calculated as:
ij sij j1 Si N i ij j1
th Where ij is equal to 1 when the j item has a valid response, otherwise it th is equal to 0 and sijis the response score of the j item. The total score for a given will be used if at least 80% of the subscale items provide valid answers. The FACT-Cx, IES, FSFI, and RCS total scores ranged 0 – 168, 0 – 45, 0 – 95, and 0– 56 respectively. - 34 - GOG-0278
Descriptive statistics (e.g. means and standard deviations of subscale scores, correlation between assessments) and graphics (box plots, line plots, noodle plots) will be used to display trends over time for the entire cohort and for each subgroup.
For each instrument, ANOVA methods with repeated measurements and a time component will initially be used to determine whether there are significant changes over time. If so, we will then investigate the subject- specific graphs of the QOL instruments over time and develop appropriate classifications. For example, (1) trending upward; (2) trending downward; (3) initially trending upward and then leveling off, (4) initially trending downward and then leveling off; (5) increasing and then decreasing; (6) decreasing and then increasing; (7) variable ("numerous" ups and downs); and (8) reasonably flat, i.e., constant. These categories may very well need to be collapsed, if there are few graphs in one or more of them. We will determine, using univariate methods, whether any covariates are more closely associated with specific categories of graph classification than others.
Multivariate Methods: we will also use a family of multivariate methods commonly referred to as generalized estimating equations, random regression models, or general linear mixed models to investigate longitudinal associations. These methods can deal with serial correlation, time-varying covariates, irregular measurement occasions, person-specific deviations from the average time trend, missing data, etc.
Handling Missing Data: we have reason to believe that the number of missing values will be minimal because questionnaires will be collected at each patient’s regularly scheduled visit as part of the treatment and follow- up protocol. Education and sensitization of data managers and nurses on the importance of obtaining complete assessments, data manager reporting of specific reasons for missed assessment, and regular accrual rate monitoring will help to further minimize incidence of missing data. Also, the clinic staff may use the GOG SDC web-based forms tracking system to obtain reminders of upcoming assessments.
Anticipating, nevertheless, that there will be some unavoidable missing data, we must also acknowledge that some of it might not be missing at random. For example patients with lower QOL (either because they have greater post-treatment illness or for some intrinsic reason) may be more prone to have missing values. If a subject misses a data collection point, but not the next one, we will determine the reasons for the missing observational point and whether it might have had something to do with quality of life complications. We note that random regression models do not require longitudinal observations to be collected at the same time points. When all subsequent data are missing after a given time point, the - 35 - GOG-0278
patient may be deceased or otherwise too ill to complete the questionnaire. Thus, we may presume that completion of the questionnaire is no longer relevant. (However, quality of death may be relevant, but beyond the scope of this study.) If the patient simply no longer is willing to complete the questionnaire for reasons independent of health status (which we will likely know), then we are faced with the problem of attempting to determine whether the refusal is directly related to objective functional outcomes and/ or quality of life. To address this, we plan to investigate the within subject patterns to assess whether identified patterns are associated with functional outcomes, QOL or disease status. Lack of an association would indicate time point data missing at random. If time point data are not missing at random, we will then know the patterns associated with “missing-ness” and can use this knowledge to estimate the degree and direction of possible biases in the analyses of the available data.
11.54 Evaluation of RFS, OS and LC Product-limit estimates according to the method of Kaplan and Meier will be used to estimate survival endpoints (RFS and OS). In addition, Cox proportional hazard (CPH) regression will be employed to evaluate relative risk (hazard ratio) adjusting for known prognostic factors. Trellis plots will be used to display point estimates of hazard ratio and respective 95% confidence intervals from subgroup analyses. Gompertz hazard regression will also be employed to evaluate relative risk (hazard ratio) and cure rates, adjusting for known prognostics factors. Local recurrence will be summarized using frequency tables and plot of cumulative incidence of local recurrence over time
11.55 Evaluation of Site(s) of Recurrence The site(s) of first disease recurrence will be classified and summarized as pelvic-only, extra-pelvic only or pelvic-and-extra-pelvic
11.56 Toxicity analysis Adverse events (AE) will be classified as either acute (occurring and resolved within 60 days of treatment) or chronic (unresolved acute events or any delayed treatment related event with an onset date greater than 60 days from treatment and duration greater than 30 days). Adverse events will be graded according to CTCAE v. 4 (Grades 0 - 5). Grades will be categorized into three groups; none (0), mild (1 or 2) and severe (3 or 4). Detailed narratives will be provided for any treatment related deaths (grade 5). In addition to displaying frequency of AE for each grade category for the entire cohort, if feasible, Fishers’ exact test will be used to assess significance of observed differences between subgroups.
- 36 - GOG-0278
11.6 Study monitoring and data quality control The GOG SDC is responsible for the secure, efficient and accessible storage of the data. To assure the best possible data quality, the study statistician in collaboration with the data manager/coordinator (DM) will execute regular data checks. Inconsistencies and errors will be queried and sites will notify the DM upon resolution. In turn the DM will repeat data checks to make certain that query was indeed resolved. Every effort will be made to resolve outstanding queries promptly. Unresolved queries will be documented and briefly cited in the study scientific table.
Depending on accrual rate, new patients’ case report forms (CRFs) will be reviewed by the study chair (and/or co-chairs) in May and November of each year of active accrual. The purpose of these reviews is to assess protocol compliance and possibly make recommendations. After data checks, study chair (and/or co- chairs) reviews and data updates, a locked dataset void of protected patient information will be saved using standardized GOG SDC dataset achieving convention.
Reports will be generated periodically from the most recent locked information by the study statistician for inclusion into the GOG’s Semi-annual Statistical Report (SR). The SR is distributed (via the GOG member access website) to GOG members at each GOG Semi-annual Business Meeting. The purpose of the SR is to assess study progress regarding accrual (patient accession), distribution of baseline traits, treatment compliance, patient safety and to facilitate the formulation of possible amendments as needed.
11.61 Interim Safety Analyses
The first goal is to recruit at least 200 evaluable patients. The decision to open second and third stage accrual will depend on interim results and must be deemed necessary, safe and feasible.
Radical hysterectomy, despite significant toxicity effects, is associated with excellent survival. In particular, 5 year recurrence free survival (RFS) rate for patients treated with radical hysterectomy is at least 85%. Thus, risk of recurrence (and toxicity) is a concern in this study. Recurrence and adverse events will be monitored throughout the trial and any evidence of excessive risk, including all serious adverse events (SAE) will be reported promptly and to the study team, the GOG DSMB and relevant regulatory agencies.
Formal stopping rules will be implemented during the first stage accrual based on an extension of methods formulated by Chen et al (1997)58. Suppose p is the recurrence free survival rate. To monitor risk of recurrence among the first cohort of 200 patients, the optimal three-stage design to test the null hypothesis that p ≤ 0.80 versus the alternative that p - 37 - GOG-0278
≥ 0.90 has an expected sample size of 80, a probability of early termination after the first stage of 0.787, and a probability of early termination after the second stage of 0.945. If the treatment is ineffective there is a 0.044 probability of concluding that it is (the target for this value was α = 0.050). If the treatment is actually effective, there is a 0.089 probability of concluding that it is not (the target for this value was β = 0.100). After observing 60 treated patients for at least two years, the trial will be terminated (conclude p < 0.800) if 10 or more patients recurred, otherwise continue accruing. If 20 or more patients recurred among the first 130 with at least 2 years of follow-up, the trial will be terminated (conclude p < 0.800), otherwise continue accruing. If 35 or more patients recurred among the first cohort of 200, the trial will be terminated (conclude p < 0.800). Otherwise accrual to second stage (2nd cohort of 200) may be considered.
Note: temporary stoppage (e.g. for interim analyses) is not expected during the accrual of the first 200 patients unless there is evidence of excessive risk of recurrence and/or toxicity.
11.62 GOG’s DSMB and SRC The GOG Data Monitoring Committee (DSMB) will review AE reports in January and July each year. The database is locked two months prior to prepare a progress report. This progress report includes: the patient accrual rate, projected completion data, institutional accrual, pretreatment characteristics, compliance rates, and the frequency and severity of SAEs and AEs due to protocol therapy. The decision to terminate accrual includes considerations of accrual rate, toxicities, treatment compliance and results from external studies. Additionally the GOG Safety Review Committee (SRC) will review accumulating summaries of toxicities and all severe adverse event (SAE) reports on an ongoing basis. This committee will also perform detailed reviews of all deaths in which the study treatment may have been a contributing cause. The SRC will report to the DSMB and it may recommend study amendments pertaining to patient safety.
- 38 - GOG-0278
11.7 Planned Gender and Minority Inclusion (based on 200 evaluable patients) The Gynecologic Oncology Group and GOG participating institutions will not exclude potential subjects from participating in this or any study solely on the basis of ethnic origin or socioeconomic status. The population of interest is women with stage IA1-IB1 (≤2.0 cm) cervical cancer. Table 2 shows race and ethnicity distribution anticipated for this trial:
Accrual Targets Sex/Gender Ethnic Category Females Males Total Hispanic or Latino 21 + 0 = 21 Not Hispanic or Latino 179 + 0 = 179 Ethnic Category: Total of all subjects 200 (A1) + 0 (B1) = 200 (C1) Racial Category
American Indian or Alaskan Native 2 + 0 = 2 Asian 18 + 0 = 18 Black or African American 47 + 0 = 47 Native Hawaiian or other Pacific Islander 2 + 0 = 2 White 131 + 0 = 131 Racial Category: Total of all subjects 200 (A2) + 0 (B2) = 200 (C2) (A1 = A2) (B1 = B2) (C1 = C2) - 39 - GOG-0278
12.0 BIBLIOGRAPHY
1. Bergmark k, Avall-Lundqvist E, Dickman PW, et al. Vaginal changes and sexuality in women with a history of cervical cancer N Eng J Med 340:1383-9. 1999
2. Sasaki H, Yoshida T, Noda K et al. Urethral pressure profiles following radical hysterectomy. Obstet Gyn 59:101-4. 1982.
3. Vervest HA, Barents JW, Haspels AA et al. Radical hysterectomy and the function of the lower urinary tract. Urodynamic quantification of changes in storage and evacuation function. Acta Obstet Gyn Scand 68:331-40. 1989.
4. Martimbeau PW, Kjorstad KE, Kolstad. Stage IB carcinoma of the cervix, the Norwegian Radium Hospital, 1968-1970: results of treatment and major complications. I Lymphedema Am J Obste Gynecol 131:389-94. 1978
5. Werngren-Elgstrom M, Lidman D. Lymphoedema of the lower extremitiesafter surgery and radiotherapy for cancer of the cervix. Scad J Plast Reconstr Hand Surgery 28:289-93. 1980
6. Pieterse QD, Maas CP, Ter Kuile MM, et al. An observational longitudinal study to evaluate miction, defecation and sexual function after radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer. Int J Gyn Ca 16:1119-29. 2006
7. Jensen PT, Groenvold M, Klee MC et al. Early stage cervical carcinoma, radical hysterectomy, and sexual function. A longitudinal study. Cancer. 100:97-106.
8. Covens A, Rosen B, Murphy J, Laframboise S, DePetrillo A, Lickrish G, Colgan T, Chapman W, Shaw P. Changes in the Demographics and Perioperative Care of Stage IA2/IB1 Cervical Cancer over the Past 16 Years. Gynecol Oncol 81:133, 2001.
9. Bergmark K, Avall-Lundqvist E, Dickman PW, et al. Lymphedema and bladder- emptying difficulties after radical hysterectomy for early cervical cancer and among population controls. Int J Gynecol Cancer. 2006;16:1130-1139.
10. Jackson KS, Naik R. Pelvic floor dysfunction and radical hysterectomy. Int J Gynecol Cancer. 2006 Jan-Feb;16(1):354-6319. Grumann M, Robertson R, Hacker NF, Sommer. Sexual functioning in patients following radical hysterectomy for stage IB cancer of the cervix. Int J Gynecol Cancer. 11:372-380. 2001
11. Benedetti-Panici P, Zullo MA et al. Long-term bladder function in patients with locally advanced cervical carcinoma treated with neoadjuvant chemotherapy and type 3-4 radical hysterectomy. Cancer 100:2110-7. 2004.
- 40 - GOG-0278
12. Zullo MA, Manci N, Angioli R, et al. Versical dysfunctions after radical hysterectomy for cervical cancer: a critical review. Critical Reviews in Oncology/ Hematology. 48:287-93. 2003
13. Cibula D, Velechovska P, Slama J et al. Late morbidity following nerve-sparing radical hysterectomy. Gyn Onc 116:506-11. 2010
14. Park SY, Bae DS, Nam JH, et al Quality of life and Sexual Problems in Disease- Free Survivors of Cervical Cancer Compared with the General Population. Cancer 2007;110(12):2716-2725.
15. Ohara K, Tsunoda H, Satoh T, et al. Use of the small pelvic field instead of the classic whole pelvic field in postoperative radiotherapy for cervical cancer: reduction of adverse events. Int J Radiat Oncol Biol Phys. 2004;60:258-264.
16. Judson PL, Jonson AL, Paley PJ, et al. A prospective, randomized study analyzing sartorius transposition following inguinal-femoral lymphadenectomy. Gynecol Oncol. 2004;95:226-230
17. Gaarenstroom KN, Kenter GG, Trimbos JB, et al. Postoperative complications after vulvectomy and inguinofemoral lymphadenectomy using separate groin incisions. Int J Gyn Cancer. 2003;13:522-527.
18. Abu-Rustum NR, Alektiar K, Iasonos A, et al. The incidence of symptomatic lower- extremity lymphedema following treatment of uterine corpus malignancies: a 12-year experience at Memorial-Sloan Kettering Cancer Center. Gynecol Oncol. 2006;103:714-718.
19. Donovan KA, Taliaferro LA. Alvarez EM et al. Sexual health in women treated for cervical cancer: Characteristics and correlates. Gyn Onc 2007; 104:428-434.
20. Wenzel L, De Alba I, Habbal R., et al. Quality of life in long-term cervical cancer survivors. Gyn Onc 2005;97:310-317.
21. Dargent D, Brun L, Roy M, Mathevet P, Remy I. La Trache - lectomie E largie (T.E.). ne alternative a l’hyste rectomie radicale dans le traitement des cancers infiltrants developpes sur la face externe du col uterin. J. Obstet Gynecol 2:285, 1994.
22. Alexander-Sefre F, Chee N, Spencer C, Menon U, Shepherd JH. Surgical morbidity associated with radical trachelectomy and radical hysterectomy. Gynecol Oncol 2006;101:450-4.
23. Carter J, Sonoda Y, Chi DS, Raviv L, Abu-Rustum NR. Radical trachelectomy for cervical cancer: Postoperative physical and emotional adjustment concerns. Gynecol Oncol 2008;111:151-7.
- 41 - GOG-0278
24. Carter J, Sonoda Y, Abu-Rustum NR. Reproductive concerns of women treated with radical trachelectomy for cervical cancer. Gynecol Oncol 2007;105:13-6.
25. Hagen B, Skeldestad FE, Bratt H, Tingulstad S, Lie AK. CO2 laser conization for cervical intraepithelial neoplasia grade II-III: Complications and efficacy. Acta Obstet Gynecol Scand 1998;77:558-63.
26. Suh-Burgmann E, Whall-Strojwas D, Chang Y, Hundley D, Goodman A.Risk factors for cervical stenosis after loop electrocautery excision procedure. Obstet Gynecol 2000;96:657-60.
27. Covens A, Shaw P, Murphy J, DePetrillo D, Lickrish G, Laframboise S, Rosen B. Is radical trachelectomy a safe alternative to radical hysterectomy for patients with stage Ia-B carcinoma of the cervix? Cancer 1999;86:2273-9.
28. Shepherd JH. Mould T, Oram DH. Radical trachelectomy in early stage carcinoma of the cervix: outcome as judged by recurrence and fertility rates. BJOG 2001;108:882- 5.
29. Plante M, Renaud MC, Hoskins IA, Roy M. Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of early-stage cervical cancer. A series of 50 pregnancies and review of the literature. Gyn Oncol 2005;98:3-10.
30. Boss EA, van Golde RJ, Beerendonk CC, Massuger LF. Pregnancy after radical trachelectomy: a real option? Gynecol Oncol 2005;99(3 Suppl 1):S152-6.
31. Noyes N. Hysteroscopic cervical canal shaving: a new therapy for cervical stenosis before embryo transfer in patients undergoing in vitro fertilization. Fertil Steril 1999;71:965-6.
32. Wright JD, Nathavithrana R, Lewin SN et al. Fertility-Conserving Surgery for Young Women With Stage IA1 Cervical Cancer: Safety and Access. Ob & Gyn 2010:115(3):585-590.
33. Creasman WT, Fetter BF, Clarke-Pearson DL, Kaufmann L, Parker RT. Management of stage la carcinoma of the cervix. Am J Obstet Gynecol 153:164, 1985.
34. Beiner M, Hauspy J, Rosen B, Murphy J, Laframboise S, Nofech-Mozes S, Ismiil N, Rasty G, Khalifa M, Covens A. Radical vaginal trachelectomy vs. radical hysterectomy for small early stage cervical cancer: a matched case-control study. Gynecol Oncol. 110:168, 2008.
35. Covens A, Rosen B, Murphy J, Laframboise S, DePetrillo A, Lickrish G, Colgan T, Chapman W, Shaw P. How Important Is Removal of the Parametrium at Surgery for Carcinoma of the Cervix? Gynecol Oncol 84:145, 2002.
- 42 - GOG-0278
36. Kinney WK, Hodge DO, Egorshin EV, Ballard DJ, Podratz KC. Identifi- cation of a low risk subset of patients with stage lb invasive squamous cancer of the cervix possibly suited to less radical surgical treatment. Gynecol Oncol 57:3, 1995.
37. Frumovitz M, Sun CC, Schmeler KM, Deavers MT, Dos Reis R, Levenback CF, Ramirez PT. Parametrial involvement in radical hysterectomy specimens for women with early-stage cervical cancer.Obstet Gynecol. 114:93, 2009.
38. Stegeman M, Louwen M, van der Velden J, ten Kate FJ, den Bakker MA, Burger CW, Ansink AC. The incidence of parametrial tumor involvement in select patients with early cervix cancer is too low to justify parametrectomy. Gynecol Oncol. 105:475, 2007.
39. van Meurs H, Visser O, Buist MR, Ten Kate FJ, van der Velden J. Frequency of pelvic lymph node metastases and parametrial involvement in stage IA2 cervical cancer: a population-based study and literature review. Int J Gynecol Cancer. 19:21, 2009.
40. Strnad P, Robova H, Skapa P, Pluta M, Hrehorcak M, Halaska M, Rob L. A prospective study of sentinel lymph node status and parametrial involvement in patients with small tumor volume cervical cancer. Gynecol Oncol. 109:280, 2008.
41. Wright JD, Grigsby PW, Brooks R, Powell MA, Gibb RK, Gao F, Rader JS, Mutch DG. Utility of parametrectomy for early stage cervical cancer treated with radical hysterectomy. Cancer. 110:1281, 2007.
42. Averette HE, Nguyen HN, Donato DM, Penalver MA, Sevin BU, Estape R, Little WA. Radical hysterectomy for invasive cervical cancer. A 25 year prospective experience with the Miami technique. Cancer 71: 1422, 1993.
43. Underwood PB, Jr, Wilson WC, Kreutner A, Miller MC, Murphy E. Radical hysterectomy: a critical review of twenty-two years’ experience. Am Obstet Gynecol 134:889, 1979.
44. Ralph G, Winter R, Michelitsch L, Tamussino K. Radicality of parametrial resection and dysfunction of the lower urinary tract after radical hysterectomy. Eur J Gynecol Oncol 12:27, 1991.
45. Wenzel L, Dogan-Ates A, Habbal R, Berkowitz R, Goldstein DP, Bernstein M, et al. Defining and measuring reproductive concerns of female cancer survivors. J Natl Cancer Inst Monogr 2005;34:94-8.
46. Gray NM, Sharp L, Cotton SC et al. Psychological effects of a low-grade abnormal cervical smear test result: anxiety and associated factors. Br J Cancer 2006;94:1253- 1262.
- 43 - GOG-0278
47. Kola S and Walsh C. Patients’ psychological reactions to colposcopy and LLETZ treatment for cervical intraepithelial neoplasia. Eur J Ob & Gyn and Reprod Bio 2009;146: 96-99.
48. Cella D, Wiklund I, Shumaker SA, et al. Integrating health-related quality of life into cross-sectional clinic trials. Qual Life Res. 1993;2:433-440.
49.Moore DH, Blessing JA, McQuellon R et al. Phase III study ofCisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol. 2004;22(15):3113-9.
50. Horowitz, M, Wilner, N, & Alvarez, W (1979). Impact of Events scale: a measure of subjective distress. Psychosomatic Medicine, 41: 209-218.
51. Valdimarsdottir HB, Bovbjerg DH, Kash KM. Psychological distress in women with a familial risk of breast cancer. Psycho-Oncology. 1995;4:133-141.
52. Lesko, LM, Ostroff JS, Mumma GH, et al. Long-term psychological adjustment of acute leukemia survivors: impact of bone marrow transplantation versus conventional chemotherapy. Psychosom Med. 1992;54:30-47.
53. Cordova, MJ, Andrykowski MA, Kenady DE, et al. Frequency and correlates of posttraumatic-stress-disorder-like symptoms after treatment for breast cancer. J Consult Clin Psychol. 1995;63:981-986.
54. Rosen, R, et al. (2000). The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. Journal of Sex & Marital Therapy, 26(2): 191-208
55. Carter J, Raviv L, Appollo K, Baser RE, Iasonos A, and Barakat RR. A Pilot Study Using the Gynecologic Cancer Lymphedema Questionnaire (GCLQ) as a Clinical Care Tool to Identify Lower Extremity Lymphedema in Gynecologic Cancer Survivors. Gynecol Oncol 117(2):317-23. 2010. 56. Machin, D. et al. 1997. Sample Size Tables for Clinical Studies, 2nd Edition. Blackwell Science, Malden Mass, Page 147 57. Sheskin, David (2004). "Test 20, the McNemar Test". Handbook of parametric and nonparametric statistical procedures. CRC Press. pp. 1193
58. Chen, T. T. 1997. Optimal three stage designs for phase II cancer clinical trials, Statistics in Medicine, Volume 16, pages 2701 – 2711