EROS: Engendering Reproductive Health Within Oncologic Survivorship
Phase: NA
Conditions: Malignant Neoplasm
Sponsor: ECOG-ACRIN Cancer Research Group

 
E1Q11 
1 
EROS: Engendering Reproductive Health within Oncologic Survivorship 
STUDY CHAIR: 
Ashlesha Patel, MD, MPH 
STUDY CO CHAIR: 
Howard A. Zaren, MD FACS 
STUDY CO-CHAIR: 
Erika K. Radeke, MPS 
STUDY STATISTICIAN: 
Ju-Whei Lee, PhD 
CANCER CONTROL & SURVIVORSHIP CHAIR: 
Lynne I. Wagner, PhD 
SYMPTOM MANAGEMENT COMMITTEE CHAIR: 
Michael J. Fisch, MD 
LABORATORY CO-CHAIR: 
Ashlesha Patel, MD, MPH 
Version Date:  March 17, 2021 
STUDY PARTICIPANTS FOR PATIENT ENROLLMENT 
ACTIVATION DATE 
Limited to invited and selected sites (including affiliate sites) that 
agree to participate from the following: 
September 30, 2015 
PRE-ACTIVATION DATE 
MU NCORP / NCORP Minority Underserved sites: 
September 17, 2014 
BAPTIST / Baptist Memorial Health Care / Mid-South MU 
NCORP (ECOG-ACRIN) 
Addendum #1 – Incorporated Prior to Activation 
Addendum #2 – Incorporated Prior to Activation 
GACARES / Georgia Cares MU NCORP (ECOG-ACRIN) (COG) 
Addendum #3 – Incorporated Prior to Activation 
GULFSOUTH / Gulf South MU NCORP (ECOG-ACRIN) 
Addendum #4 – 11/16 
HAWAII / Hawaii MU NCORP  
(Alliance, SWOG, NRG) 
Addendum #5 – 5/17 
Addendum #6 – 11/17 
MONTEFIORE / Montefiore Medical Center MU NCORP (ECOG-
ACRIN) 
Addendum #7 
Addendum #8 
MUSC / Medical University of South Carolina MU NCORP 
(ECOG-ACRIN) 
Addendum #9 
Addendum #10 
NEWMEXICO / New Mexico MU NCORP (Alliance, SWOG, NRG) 
Addendum #11 
TXPED / Texas Pediatric MU NCORP (COG) 
Addendum #12 
STROGER / Stroger Hospital of Cook County MU NCORP 
(ECOG-ACRIN) 
Addendum #13 
VCU / VCU Massey Cancer Center MU NCORP  
(ECOG-ACRIN) 
 
NCORP / NCORP sites: 
 
AURORA / Aurora NCORP (ECOG-ACRIN) 
 
CARLE / Carle Cancer Center NCORP (ECOG-ACRIN) 
 
WESTERN / Western States Cancer Research NCORP  
(ECOG-ACRIN) 
 
COLUMBUS / Columbus NCORP (ECOG-ACRIN) 
 
CORA / Catholic Health Initiatives NCORP (ECOG-ACRIN) 
 
FLPED / Florida Pediatric NCORP (COG) 
 
GEORGIA / Georgia NCORP (ECOG-ACRIN) 
 
METROMIN / Metro Minnesota NCORP (ECOG-ACRIN) 
 
NCFR / Nevada Cancer Research Foundation NCORP  
(ECOG-ACRIN) 
 
NEMOURS / NEMOURS NCORP (COG) 
 
PCRC / Pacific Cancer Research Consortium NCORP (ECOG-
ACRIN) 
 
SCOR / Southeast Clinical Oncology Research Consortium 
NCORP (SWOG) 
 
UPSTATE / Upstate Carolina Consortium Community Oncology 
Research Program NCORP (ECOG-ACRIN) 
 
MAINE / MaineHealth Cancer Care Network 
(ALLIANCE/NRG/COG) 
 
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Table of Contents 
EROS: Engendering Reproductive Health within Oncologic Survivorship ................. 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 Study Foundation ...................................................................................... 7 
1.2 Study Overview ......................................................................................... 7 
1.3 Study Aims................................................................................................. 7 
1.4 Hypotheses ................................................................................................ 7 
1.5 Background ............................................................................................... 7 
1.6 Summary and Rationale for Proposed Study ............................................ 8 
1.7 Reproductive Health Related Endocrine Disruption in Cancer Care ......... 9 
1.8 Quality of Life (QOL) Assessment: Longitudinal Study of Sexuality in 
Females with Newly Diagnosed Cancer .................................................. 10 
2. Objectives ......................................................................................................... 12 
2.1 Primary Objective .................................................................................... 12 
2.2 Secondary Objectives .............................................................................. 12 
2.3 Correlative Objective .............................................................................. 12 
2.4 Quality of Life Objective .......................................................................... 12 
3. Selection of Patients ......................................................................................... 13 
3.1 Eligibility Criteria ..................................................................................... 13 
4. CTEP Registration Procedures ........................................................................... 14 
4.1 Selection and Randomization of Sites ..................................................... 15 
4.2 Registration of Patients ........................................................................... 16 
4.3 Protocol Number ..................................................................................... 19 
4.4 Investigator Identification ....................................................................... 19 
4.5 Patient Identification .............................................................................. 19 
4.6 Eligibility Verification .............................................................................. 20 
4.7 COG Patient Registration Enrollment Information ................................. 20 
4.8 Additional Requirements ........................................................................ 20 
5. Methodology..................................................................................................... 23 
5.1 Randomization ........................................................................................ 23 
5.2 Study Arms and Intervention .................................................................. 23 
5.3 Provider Survey Administration Instructions - Using Assessment Center™23 
5.4 Patient Recruitment ................................................................................ 24 
5.5 Data Collection ........................................................................................ 24 
5.6 Administration Instructions .................................................................... 25 
5.7 On-Study and Follow Up Assessment Schedule ...................................... 25 
5.8 Provision of Appropriate Care for Patients ............................................. 27 
5.9 Reproductive Health Related Endocrine Disruption in Cancer Care ....... 27 
5.10 Quality of Life (QOL) Assessment ............................................................ 27 
5.11 Duration of Study .................................................................................... 27 

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5.12 Duration of Follow-up ............................................................................. 28 
6. Measures .......................................................................................................... 29 
6.1 Study Tools .............................................................................................. 29 
7. Study Parameters (For Arm A only) .................................................................. 30 
8. Statistical Considerations .................................................................................. 35 
8.1 Design and Randomization ..................................................................... 35 
8.2 Selection of Participating Clinics ............................................................. 36 
8.3 Sample Size ............................................................................................. 37 
8.4 Accrual Goal and Accrual Period ............................................................. 38 
8.5 Power for the Important Second Endpoint (the LTC Usage at 6 Month 
Assessment) ............................................................................................ 39 
8.6 Analysis Plan ............................................................................................ 41 
8.7 Randomization Scheme........................................................................... 44 
8.8 Monitoring Plan ...................................................................................... 44 
8.9 Race and Ethnicity ................................................................................... 44 
8.10 Handling Missing Data ............................................................................ 45 
9. Correlative Studies ............................................................................................ 46 
9.1 Study-Specific Account Set Up for Quest Diagnostics ............................. 46 
9.2 Sample Submission Schedule .................................................................. 47 
9.3 Sample Preparation Guidelines ............................................................... 47 
9.4 ECOG-ACRIN Sample Tracking System .................................................... 50 
9.5 Banking .................................................................................................... 50 
9.6 Sample Inventory Submission Guidelines ............................................... 50 
9.7 Lab Data Transfer Guidelines .................................................................. 51 
10. Electronic Data Capture .................................................................................... 52 
11. Patient Consent and Peer Judgment ................................................................ 52 
12. References ........................................................................................................ 52 
Appendix I  Patient Thank You Letter ...................................................................... 55 
Appendix II  Patient Log ........................................................................................... 56 
Appendix III Quest Diagnostics Sub-Account Information Sheet ............................ 57 
Appendix IV  INFORMATION SHEET REGARDING RESEARCH STUDY E1Q11 (for 
teens from 15 through 17 years of age) ........................................................... 58 
 

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STUDY CHAIR 
Ashlesha Patel MD MPH 
John H. Stroger, Jr. Hospital of Cook County 
1901 W Polk 5th Floor 
Chicago, IL 60622 
Tel: 312-864-5240 
Fax: 312.864.9782 
Email: apatel2@cookcountyhhs.org 
 
STUDY CO-CHAIRS 
H.A. Zaren, M.D.,FACS 
Nancy N. and J.C. Lewis Cancer & Research 
Pavilion at St. Joseph's/Candler Hospital, 
Savannah GA. 
College of Georgia 
Tel: 912.819.5758 
Fax:  912.819.5705 
Email: hazaren@msn.com 
 
Erika K. Radeke, MPS 
SHCC MU NCORP 
1900 W. Polk, Room 449 
Chicago, IL 60612 
Tel: 312.864.5204 
Fax: 312.864.9782 
Email: eradeke@cookcountyhhs.org 
 
 
 
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CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Data collection will be 
performed exclusively in 
Medidata Rave. :  
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal: 
Regulatory Submission Portal (Sign in 
at www.ctsu.org, and select the 
Regulatory Submission sub-tab under 
the Regulatory tab.)  
Institutions with patients waiting that 
are unable to use the Portal should 
alert the CTSU Regulatory Office 
immediately at 1-866-651-2878 to 
receive further instruction and support. 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for regulatory 
assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network 
(OPEN)  which can be 
accessed at . 
https://www.ctsu.org/OPEN
_SYSTEM/ or 
https://OPEN.ctsu.org. 
Contact the CTSU Help 
Desk with any OPEN-
related questions at 
ctsucontact@westat.com. 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy the 
CTSU on data submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS). 
For clinical questions (i.e., patient eligibility) Contact the Study PI of the Lead Protocol Organization. 
For non-clinical questions (i.e., unrelated to patient eligibility or data submission) contact the 
CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 
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Schema 
R
A
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D
O
M
I
Z
E
I
N
S
T
I
T
U
T
I
O
N
Non-Intervention
Standard Practice
Arm A
Arm B
Total Accrual Goal: 425
Intervention
Training Modules Algorithm, 
Referral Development
P
A
T
I
E
N
T
R
E
G
I
S
T
R
A
T
I
O
N
Assessments
• Clinician Forms
• Patient Forms
(Without RHA Form)
Arm A
Arm B
Selected and 
invited 
institutions
Assessments
• Clinician Forms
• Patient Forms
(With RHA Form)
 
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1. 
Introduction 
1.1 
Study Foundation 
Reproductive health goals of females with cancer in the 15-55-year age range 
are poorly understood and overlooked. Reproductive health issues that include 
oncofertility, oncocontraception and sexuality are important to females regardless 
of cancer diagnosis.  Evaluation and treatment of cancer should include an 
assessment of goals for fertility and family planning in order to optimize a 
patient’s cancer treatment and her future reproductive health. 
1.2 
Study Overview  
We propose the EROS trial “Engendering Reproductive Health within Cancer 
Survivorship.”  The primary study is a cluster randomized controlled trial 
examining an intervention of a reproductive health assessment and algorithm to 
improve the adoption of appropriate reproductive health management.  Two 
important secondary objectives are to (1) examine reproductive health related 
endocrine disruption through longitudinal study of endocrine markers during the 
first five years after cancer diagnosis and (2) perform longitudinal study of sexual 
function during the first five years after cancer diagnosis.  
1.3 
Study Aims 
This study will add valuable interventional and observational data to this largely 
unexplored area of research and could have a tremendous impact on the care of 
young cancer survivors to maintain tenable reproductive health goals.  
Additionally, tools validated from this study may be utilized by the National 
Cancer Institute (NCI) to assist clinicians navigating through reproductive health 
issues in the context of cancer care. 
1.4 
Hypotheses 
1.4.1 
The reproductive health needs for females with cancer are not 
adequately assessed and addressed by cancer care providers.  
1.4.2 
The implementation of the proposed reproductive health assessment 
and algorithm will optimize the reproductive health objectives of 
females with cancer. 
1.4.3 
Patients and clinicians have different perspectives regarding 
reproductive health objectives of females with cancer. 
1.4.4 
There are certain clinical, demographic, healthcare delivery, and 
socioeconomic factors that affect patients with regards to adequacy of 
reproductive health management. 
1.5 
Background 
In 2009, approximately 719,000 females in the United States were newly 
diagnosed with various types of cancer.1 Nearly 17% of these new cancer cases 
were diagnosed in reproductive age females.1 The most common cancers 
diagnosed in females of childbearing age are breast and cervical carcinoma, 
melanoma, non-Hodgkin’s lymphoma, leukemia and colon cancer.2-4 Of these, 
breast is the most common malignancy site for females and is the second 
leading cause of cancer-related deaths in females.  
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Approximately 4 in 100 adults today is a cancer survivor.5 With the recent 
advancements in cancer detection and treatment, survival rates are increasing 
for cancer patients. Over the past 30 years, the number of cancer survivors in the 
United States has increased to almost 14 million.5 As a result; there is a 
tremendous focus on improvement of quality of life in cancer survivors. When a 
female is diagnosed with cancer, particularly a young female, issues regarding 
survival are paramount; however, the magnitude of reproductive health and 
quality of life issues cannot be neglected.6 
The definition of reproductive health is widely accepted as “the state of complete 
physical, mental and social well-being, and not merely the absence of 
reproductive disease or infirmity.”7 The components that define reproductive 
health are broad and not well defined in the literature. For the purpose of this 
proposal, we define the components of reproductive health as it pertains to 
females with cancer as oncofertility, oncocontraception, and sexuality. The initial 
period of cancer diagnosis and treatment is fraught with much uncertainty 
regarding reproductive health issues related to prognosis of disease, iatrogenic 
loss of fertility, endocrine disruption, and exposure to teratogenic treatment 
agents. 
Fertility preservation for young cancer survivors has obtained research and 
public interest; however, reproductive health is not only limited to fertility 
preservation but also includes sexuality and family planning, ranging from 
oncocontraception, preconception counseling, and optimization of present or 
future pregnancy.8  The full scope of reproductive health is often omitted from the 
discussion of cancer treatment planning. 
While organizations, such as the American Cancer Society (ACS) and American 
Society of Clinical Oncologists (ASCO) have recommendations regarding 
reproductive health in cancer, ASCO states that there is a paucity of literature in 
the area of reproductive health particularly randomized controlled trials, as well 
as information that relates to diverse populations and socioeconomic groups.3 
Our proposal is a cluster randomized controlled trial design to address aspects of 
reproductive health in cancer care. An integrated cancer management and 
reproductive health plan will be developed and implemented for females in this 
study. Success of the reproductive health plan will be evaluated. Outcomes to be 
investigated are contraceptive utilization, pregnancy outcomes, and attention to 
sexuality related issues. Since this study will accrue patients with cancer of the 
colon/rectum, breast, lung, and others, a secondary analysis of the previously 
stated objectives will also be conducted to study the differences and similarities 
among these patients with respect to their disease sites. Study sites will be 
sought to include patients from across the country with diversity of ethnicity and 
sociodemographics. The sample size was constructed to allow for the evaluation 
of the success of the reproductive health programming among females aged 
between 15-55 years old with initial diagnosis of any form of cancer. 
1.6 
Summary and Rationale for Proposed Study 
Uncertainties regarding future fertility, pregnancy and cancer survival are intricate 
and challenging for a patient and a cancer care team. The goals of 
comprehensive reproductive health care at times may come in conflict with the 
primary objective of cancer care. However, with appropriate counseling and 
preventive measures, this conflict can be absolved to unify objectives. Work from 

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this study should inform leading organizations in cancer care and treatment to 
improve guidelines and to include a reproductive health assessment for all young 
females with cancer. It would also aid informed decision making and 
management plans. 
This interventional study involves an initial assessment of reproductive health for 
females with cancer. Various modalities will provide data on the prevalence of 
reproductive health care needs during the course of cancer care. Based on this 
reproductive health assessment, a management plan pertaining to reproductive 
and sexual health is developed in conjunction with the cancer management plan. 
Measurable outcomes pertaining to management and treatment implementation 
and modification are the cornerstones of this study. Study tools have been tested 
by our research group at four institutions and are feasible for administration. 
As this is a behavior study, details pertaining to the intervention are included in 
addendum I and are only accessible to those sites randomized to receive the 
intervention. It is requested that the details of the intervention remain confidential 
to maintain the integrity of the randomized cluster-controlled design. If local IRBs 
have questions or concerns regarding the intervention, they are instructed to 
contact ECOG-ACRIN or the study team directly. 
1.7 
Reproductive Health Related Endocrine Disruption in Cancer Care 
We propose a 2-year observational study following tumor markers for fertility 
status and endocrine disruption of the first 200 individuals who agree to 
participate. 
Primary Hypothesis 
At least 80% of females will have significant endocrine disruption during 
chemotherapy. 
Background 
The sequelae of endocrine disruption may include loss of fertility. Although some 
cancer therapy modalities induce amenorrhea, many patients undergoing 
treatment remain fertile. After a short period of chemotherapy-induced 
amenorrhea, 50% of females younger than 35 years resume menstruation, 
whereas in older females the risk of amenorrhea is increased due to reduced 
follicular reserve.9 The absence of menstruation does not necessarily indicate 
lack of ovarian function. Additionally, the possibility of spontaneous recovery of 
ovarian function has been observed, particularly in cases of ovarian germ cell 
cancer. A study by Fossa found that cisplatin-based chemotherapy is followed by 
a recovery of ovarian function in almost all patients.9 
For patients on chemotherapy who desire fertility, ovarian function should be 
reassessed periodically.  Since menstrual activity is not a reliable index to assess 
ovarian function, various tests like FSH level, inhibin A or B levels or 
antimullerian hormone (AMH) and vaginal ultrasonography assessment for 
number of antral follicles can be used.10  
Knowledge of the functional ovarian reserve may benefit females with cancer 
prior to making important decisions regarding treatment, fertility preservation, and 
contraception. An ideal marker for fertility status has not yet been identified.  
Recent literature (2009) indicates the best biochemical indicators of ovarian 
reserve are serum FSH levels, AMH and Inhibin B.11 In the reproductive 
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endocrinology literature, AMH is emerging as the optimal marker to determine 
ovarian reserve and subsequent pregnancy success.12 Experience with AMH in 
cancer survivors is limited, however this marker has potential as an indicator of 
ovarian function post chemotherapy.11,13 FSH as a marker may be less reliable as 
it is ovulatory cycle dependent and affected by tamoxifen and other hormonal 
therapies.13  
Additionally alterations in thyroid function have been noted in females with breast 
cancer with a baseline rate of autoimmune thyroid disease 2-3 times the general 
population.14 Thyroid function may be affected by chemotherapy and radiation 
treatment, particularly when treatment is localized to the vicinity of the thyroid.15 
Such disruption may lead to symptoms that may affect quality of life indicators 
related to sexuality and sexual health. Repercussions of these effects remain an 
important aspect of research within oncology care. Given the available data, 
many questions remain unanswered; therefore, the laboratory ancillary included 
in this proposal would provide important data during the course of our primary 
study. 
This data will provide a foundation for future research to aid prediction of fertility 
status throughout the course of cancer care and treatment.  
This analysis will be performed at Quest Diagnostics. 
1.8 
Quality of Life (QOL) Assessment: Longitudinal Study of Sexuality in Females 
with Newly Diagnosed Cancer 
We propose a prospective observational study performing interval sexuality 
surveys for reproductive aged females throughout 2 years post diagnosis of 
cancer. 
Hypothesis 
Primary Hypothesis: Cancer survivors’ sexual function decreases during initial 
cancer treatment then increases with time after treatment completion. 
Secondary Hypothesis: Cancer survivors have lower levels of satisfaction with 
their sex lives compared to the age-matched general population at baseline. 
Background 
Sexuality remains an important aspect of reproductive health that is greatly 
influenced by cancer diagnosis and treatment.  The extent of impact of cancer 
diagnosis and treatment is poorly understood.  Sexuality encompasses gender 
roles, patterns of affection, social and family roles, and genital sex, and affects a 
survivor physically, psychologically, and emotionally.16 It should be understood 
that sexuality is “an ever-changing, lived experience affecting the way in which 
people view themselves, their body and their ability to intimately connect with 
significant others throughout life, rather than limiting it to fertility status or 
capacity for sexual intercourse.”17  
In a study of females post-trachelectomy for cervical cancer, it was observed that 
many patients’ fears of intercourse and dyspareunia were reported prior to 
surgery.18 Furthermore, information suggests that females with gynecologic 
cancers may have a higher risk of psychological distress.19 In a review by Fossa, 
the diagnosis of cancer affects sexual life more so in females than in males, and 
was found to strongly influence emotional aspects of partnership.9  
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Hordern and Street analyzed the quality of discussions regarding sexuality 
between patients and healthcare providers.  Not only did they find that patients 
felt their needs were unmet, but there were also “mismatched expectations.17  
Among the barriers are clinician embarrassment, lack of time, and inexperience. 
These can be addressed with proper training, thereby increasing comfort with 
these conversations. 
The National Institutes of Health (NIH) established the Patient-Reported 
Outcomes Measurement Information System (PROMIS) Network with the goal of 
developing a comprehensive, standardized, and efficient means of measuring 
patient–reported outcomes in persons with chronic diseases. As one of the 7 
original research sites, Duke University led the development of 2 domains of 
measurement for patients with cancer, including sexual function. The first phase 
of PROMIS supported research toward the development of the sexual function 
domain for cancer populations. Early testing suggests the PROMIS Sexual 
Function Brief Profile v1.0 - Female is superior to alternative patient-reported 
outcomes measures in terms of understandability, comprehensiveness, and 
appropriateness for many types of people. Sexual functioning and intimacy were 
considered important to quality of life. While most effects of cancer were 
considered negative, many participants identified improvements to intimacy after 
cancer.20 We propose conducting an observational study as part of this trial to 
gain valuable data on the trajectory of sexual function among females (15-55 
years of age) with cancer using the PROMIS Sexual Function Brief Profile v1.0 - 
Female. 
The incorporation of NIH PROMIS Sexual Function Brief Profile v 1.0 - Female 
within this study will leverage NIH-funded advances in measurement science 
while contributing to the ongoing development of this measure. The ongoing 
evaluation psychometric properties of the NIH Sexual Function Brief Profile v 1.0 
- Female is a research aim for the NIH PROMIS network. Through collaborating 
with PROMIS investigators, we will support the attainment of this aim by 
collecting longitudinal data on the NIH PROMIS Sexual Function Brief Profile v 
1.0 - Female from trial participants. Questions from the NIH PROMIS Sexual 
Function Brief Profile v1.0 – Female have been incorporated into the E1Q11 
Sexual Function Survey. 
 

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2. 
Objectives 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the success of the 
implementation of reproductive health programming (Didactics, EROS 
Reproductive Health Assessment and EROS Trial Algorithm) among 
reproductive aged females (15-55) with cancer. 
2.2 
Secondary Objectives 
2.2.1 
To assess the degree of discrepancy between patients and their 
clinicians in estimates of significance of the reproductive health goals 
for the patient 
2.2.2 
To evaluate baseline and follow-up reproductive health assessments 
for trends in reproductive health choices relating to oncofertility, 
oncocontraception and pregnancy over the 2 year study period 
2.2.3 
To identify clinical and demographic factors that predict the adequacy 
of reproductive health care management 
2.3 
Correlative Objective 
2.3.1 
To perform a longitudinal study following endocrine markers of fertility 
in a cohort of the first 200 registered EROS trial patients who agree to 
participate 
2.4 
Quality of Life Objective 
2.4.1 
To perform a longitudinal study of sexual function using the PROMIS 
sexual function survey in all subjects participating in the EROS Trial 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration by the treating 
physician. 
3.1 
Eligibility Criteria 
3.1.1 
Female patients presenting with initial diagnosis of any type of cancer, 
including patients with DCIS. 
3.1.2 
Patients must not have initiated chemotherapy, radiation therapy or 
endocrine therapy prior to registration to this study. 
3.1.3 
Patients must not have had a prior hysterectomy, bilateral 
oophorectomy or sterilization of any method. 
3.1.4 
Patients must be pre-menopausal patients within the reproductive age 
range of 15-55 years. 
Please note, pre-menopausal will be defined as females meeting the 
following criteria: 
• 
Patients not currently on hormonal contraception with the 
presence of menses in the past 6 months.  
• 
If no menstruation in the past 6 months, without hormonal 
manipulation, then confirmed FSH < 23mlU/mL 
• 
If age < 47 years and on hormonal contraception, then patient will 
be eligible regardless of menstrual history 
• 
If age ≥ 47 years and on hormonal contraception, then FSH 
confirmed < 23mIU/mL 
3.1.5 
Pregnant females are eligible to participate in this study. 
3.1.6 
Patients must have the cognitive ability to participate in the study. 
______ 
______ 
______ 
______ 
______ 
______ 
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4. 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System (RUMS), OPEN, Rave,); 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, 
employment, license, and 
certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug 
shipment, or as the CI on the DTL must be rostered at the enrolling site with a 
participating organization (i.e., Alliance). Additional information can be found on the 
CTEP website at <https://ctep.cancer.gov/investigatorResources/default.htm>. For 
questions, please contact the RCR Help Desk by email at <RCRHelpDesk@nih.gov>. 
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CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by emailing the email address above or calling 1-888-651-
CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
4.1 
Selection and Randomization of Sites 
To ensure patient diversity in this study, all Minority/Underserved National 
Cancer Institute Community Oncology Research Programs (MU NCORP) sites 
will be invited to participate. The remainder of sites will be filled by NCORPs. 
All MU NCORPS and selected NCORPs will receive an invitation letter from the 
Group Chair together with the study chair including a brief description of the 
study. Potential sites will be asked to respond to several questions related to site 
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characteristics, including patient volume and possible accrual and reproductive-
related services available in the areas of each site, to determine feasibility of 
utilizing the site for trial recruitment and the site’s level of interest in serving as a 
study site. Information from sites that respond will be reviewed by the study chair 
and the study team. Sites that express interest in participating and that report 
adequate patient volume to meet the protocol accrual goal will be sent a formal 
invitation to participate in this study. Depending on the number of participating 
MU NCORPs, other NCORPs will be randomly selected to participate in this 
study. Once sites have been selected, they will be randomized to the intervention 
or non-intervention arm. Sites randomized to the intervention arm will receive 
access to additional materials and information specific to the intervention 
including the intervention content. 
A notice of randomized intervention assignment will be forwarded by the ECOG-
ACRIN Operations Office - Boston.  Each participating institution will be sent a 
notice confirming the assignment of the intervention or non-intervention arm. 
4.2 
Registration of Patients 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Prior to the recruitment of a patient for this study, investigators must be 
registered members of a Cooperative Group.  Each investigator must have an 
NCI investigator number and must maintain an “active” investigator registration 
status through the annual submission of a complete investigator registration 
packet (FDA Form 1572 with original signature, current CV, Supplemental 
Investigator Data Form with signature, and Financial Disclosure Form with 
original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, 
NCI. These forms are available on the CTSU Web site (enter credentials at 
https://www.ctsu.org; then click on the Register tab) or by calling the PMB at 240-
276-6575 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can enroll patients. Study centers can 
check the status of their registration packets by querying the Regulatory Support 
System (RSS) site registration status page of the CTSU member web site by 
entering credentials at https://www.ctsu.org. 
Submitting Regulatory Documents 
Once your site is authorized to begin the IRB approval process, please apply to 
the CIRB for participation approval and follow local IRB submission requirements 
as outlined by your institution.  If local IRBs have questions or concerns 
regarding the intervention, they are instructed to contact ECOG-ACRIN or the 
study team directly. Once approval is received, you may move forward with study 
initiation if you are randomized to Arm A (control). If you are randomized to Arm 
B (intervention), you are required to submit all intervention materials (addendum 
I) to your IRB, if you have not already done so, for the next phase of approval 
before moving forward with study initiation. 
Before an Institution may enter patients, protocol specific documents must be 
submitted to the CTSU Regulatory Office. Submit required forms and documents 
to the CTSU Regulatory Office via the Regulatory Submission Portal on the 
CTSU website. 
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To access the Regulatory Submission Portal log on to the CTSU members’ 
website  Regulatory  Regulatory Submission 
Institutions with patients waiting that are unable to use the Regulatory 
Submission Portal should alert the CTSU Regulatory Office immediately at 1-
866-651-2878 in order to receive further instruction and support. 
Checking Your Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website. 
• 
Click on the Regulatory at the top of the screen; 
• 
Click on the Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go 
• 
Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type 
NOTE: 
The status shown only reflects institutional compliance with site 
registration requirements as outlined within the protocol. It does not 
reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with 
NCI or their affiliated networks. 
Downloading Site Registration Documents:  
Download the site registration forms from the protocol-specific page located on 
the CTSU members’ website. Permission to view and download this protocol and 
its supporting documents is restricted based on person and site roster 
assignment. To participate, the institution and its associated investigators and 
staff must be associated with the LPO or a PO on the protocol. 
• 
Log on to the CTSU members’ website https://www.ctsu.org  using your 
CTEP-IAM username and password 
• 
Click on the Protocols in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol #E1Q11 
• 
Click on Documents, select the Site Registration, and download and 
complete the forms provided.  
NOTE: 
For sites under the CIRB initiative, IRB data will load automatically 
to the CTSU as described above.) 
Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning 
risks or alternative procedures contained in the sample informed 
consent document must be justified in writing by the investigator 
and approved by the IRB. 
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2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review 
• 
Signature of IRB official 
4. E1Q11 Study Participation Interest and Feasibility Form (See Section 4.7.4) 
5. Site Signature Log and Delegation of Responsibilities (ECOG-ACRIN 
website) 
6. Site Training Record (ECOG-ACRIN website)-Required only for Arm B 
sites 
7. Site Referral Network Form (ECOG-ACRIN website) – Required only for 
Arm B sites 
Patients must not start protocol prior to registration. 
Patient registration can occur only after eligibility criteria have been met, and the 
study site is listed as ‘approved’ in the CTSU RSS. Patients must have signed 
and dated all applicable consents and authorization forms.   
The Oncology Patient Enrollment Network (OPEN) is a web-based registration 
system available on a 24/7 basis. OPEN is integrated with CTSU regulatory and 
roster data and with the Lead Protocol Organization (LPOs) 
registration/randomization systems or Theradex Interactive Web Response 
System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data 
management system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Be on a LPO roster, 
ETCTN Corresponding roster, or PO roster with the role of Registrar. 
Registrars must hold a minimum of an AP registration type; 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, drug shipment (IVR only), or receiving investigator 
for a patient transfer in OPEN, the IVR or NPIVR must list the IRB number used 
on the site’s IRB approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria have been met within the protocol stated timeframes. 

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• 
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 and a ‘Registrar’ role on either the LPO or participating 
organization roster. 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 relevant Group or CTSU roster and hold a minimum of 
an AP registration type.  
• 
To perform registrations on protocols for which you are a member of the Lead 
Group, you must have an equivalent 'Registrar' role and hold an account of 
AP or higher on the Lead Group roster. Role assignments are handled 
through the Groups in which you are a member  
• 
To perform registrations to trials accessed via the CTSU mechanism (i.e., 
non-Lead Group registrations) you must have the role of Registrar on the 
CTSU roster and hold a minimum of an AP registration type. 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration. Please print this confirmation for your records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU 
members’ website. Further instructional information is provided on the OPEN tab 
of the CTSU members’ side of the CTSU website at https://www.ctsu.org or at 
https://open.ctsu.org. For any additional questions contact the CTSU Help Desk 
at 1-888-823-5923 or ctsucontact@westat.com. 
The following information will be requested 
4.3 
Protocol Number  
4.4 
Investigator Identification  
4.4.1 
Institution and affiliate name (Institution CTEP ID) 
4.4.2 
Investigator’s name (NCI number) 
4.4.3 
Cooperative Group Credit 
4.4.4 
Credit Investigator 
4.4.5 
Protocol specific contact information 
4.5 
Patient Identification  
4.5.1 
Patient’s initials (first and last) 
4.5.2 
Patient’s Hospital ID and/or Social Security number 
4.5.3 
Patient demographics 
4.5.3.1 
Gender 
4.5.3.2 
Birth date 
4.5.3.3 
Race 
4.5.3.4 
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4.5.3.5 
Nine-digit ZIP code 
4.5.3.6 
Method of payment 
4.5.3.7 
Country of residence 
4.6 
Eligibility Verification  
4.6.1 
Patients must meet all of the eligibility requirements listed in Section 
3. 
4.7 
COG Patient Registration Enrollment Information 
For COG Credited Enrollments ONLY: Prior to enrollment on this study, patients 
enrolling must be assigned a COG patient ID number. This number is obtained 
via the Patient Registry module in OPEN once authorization for the release of 
protected health information (PHI) has been obtained. The COG patient ID 
number is used to identify the patient in all future interactions with COG. If you 
have problems with the registration, please refer to the online help. For additional 
help or information, please contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. See Appendix IV for the Information Sheet for teens 
from 15 through 17 years of age. 
4.8 
Additional Requirements  
4.8.1 
Patients and clinicians must provide a signed and dated, written 
informed consent form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office -Boston. 
4.8.2 
Blood samples for the endocrine markers should be submitted as 
outlined in Section 9 per patient consent. 
NOTE: 
ECOG-ACRIN requires that biological samples submitted 
from patients participating in E1Q11 be entered and 
tracked via the online ECOG Sample Tracking System 
(STS). See Section 9.5. 
NOTE: 
Institutions must complete and submit the Quest 
Diagnostics Sub-Account Information Sheet (Appendix III) 
to create their study-specific account number in order to 
obtain supplies and arrange for courier service for the 
blood sample collections. 
4.8.3 
Medidata Rave 
Medidata Rave is a clinical data management system being used for 
data collection for this trial/study. Access to the trial in Rave is 
controlled through the CTEP-IAM system and role assignments. 
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site 
of: Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave 
SLA, or Rave Investigator.  
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• 
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a 
minimum of an Associate Plus (AP) registration type;  
• 
Rave Investigator role must be registered as an Non-
Physician Investigator (NPIVR) or Investigator (IVR); and  
• 
Rave Read Only role must have at a minimum an 
Associates (A) registration type. 
Refer to 
https://ctep.cancer.gov/investigatorResources/default.htm for 
registration types and documentation required. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. If an eLearning is required and has not yet been 
taken, the link to the eLearning will appear under the study name in 
iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study 
in Rave will be granted, and a Rave EDC link will display under the 
study name. 
Users that have not previously activated their iMedidata/Rave 
accounts will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on 
the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on the CTSU 
website under the Rave tab at http://www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com.  
Provider data collection will be done in the PROMIS Assessment 
Center, a web-based application.   
4.8.4 
Site Credentialing 
Sites interested in participating in E1Q11 must have an active CTEP 
ID number. Site staff who do not have a CTEP ID number must first 
register with the Pharmaceutical Management Branch (PMB, CTEP) 
at https://eapps-ctep.nci.nih.gov/iam/.  For additional information on 
obtaining a CTEP ID number and joining ECOG, go to http://ecog-
acrin.org/about-us/membership/how-to-join. If you have any 
questions, please contact ecog.membership@jimmy.harvard.edu. 
To express interest in participating, sites must email 
e1q11interest@jimmy.harvard.edu with the following information: 
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First and Last Name of the Primary Contact at your Institution 
Email address for Primary Contact 
Site Name 
CTEP Site ID 
Street Address 
City, State, Zip 
NOTE: 
The person identified as the Primary Contact will be the 
person responsible for data entry in Rave. 
The Primary Contact will receive an email letting them know their site 
has been registered in Rave and that they can access the “E1Q11 
Study Participation and Feasibility” study to complete the Study 
Participation and Feasibility Interest Form in Medidata Rave. (Please 
note that only the Primary Contact at each NCORP group will need to 
complete the E1Q11 Study Participant and Feasibility Interest Form. It 
will not be necessary for each affiliate to complete the form.) 
4.8.5 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff 
to manage unanswered queries and form delinquencies, monitor data 
quality and timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data 
Management. The Rave Home section displays a table providing 
summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms and the DQP Reports modules are 
available to access details and reports of unanswered queries, 
delinquent forms, and timeliness reports. Review the DQP modules 
on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and 
have access to the CTSU website. Staff that have Rave study access 
can access the Rave study data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon 
displayed on the Rave Home, DQP Queries, and DQP Delinquent 
Forms modules. 
NOTE: 
Some Rave protocols may not have delinquent form 
details or reports specified on the DQP. A protocol must 
have the Calendar functionality implemented in Rave by 
the Lead Protocol Organization (LPO) for delinquent form 
details and reports to be available on the DQP. Site staff 
should contact the LPO Data Manager for their protocol 
regarding questions about Rave Calendaring functionality. 
 
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5. 
Methodology 
5.1 
Randomization 
Participating sites will be randomized to standard practice (Arm A) or intervention 
(Arm B).  Due to logistical challenges of having both intervention and non-
intervention programs within a single institution, the unit of randomization will be 
the institution (i.e., a cluster randomized approach) rather than individual patient. 
Institutions (i.e., the NCORP groups) participating in the study will be randomized 
to one of the two arms: Arm A without intervention and Arm B with intervention. 
Upon registration to this study, patients will be assigned to a study arm 
depending on the institutional assignment. Training for those randomized to Arm 
B will be offered at ECOG-ACRIN Group meetings and/or through a webinar on 
the ECOG website to enhance feasibility of site participation. Trainings specific to 
the intervention will be provided only to Arm B sites. 
5.2 
Study Arms and Intervention 
5.2.1 
Arm A – Non-intervention  
Sites randomized to non-intervention will function with usual standard 
practice related to reproductive health. 
5.2.2 
Arm B – Intervention 
Sites randomized to the intervention will receive training and 
intervention materials. Information specific to the intervention can be 
found in Addendum I. 
5.3 
Provider Survey Administration Instructions - Using Assessment Center™ 
5.3.1 
Electronic administration of the Provider Surveys will be done using 
the study’s website in the PROMIS Assessment Center. 
http://www.assessmentcenter.net/ac1/Assessments/E1Q11. 
5.3.2 
Prior to accessing the website, each provider will need to know his/her 
own physician’s CTEP ID and site name/site CTEP ID. 
5.3.3 
User-friendly instructions will then be shown on the screen.  
5.3.4 
For providers who complete assessments using the Assessment 
Center, sites will log completion of these assessments in Medidata 
Rave. If the provider needed assistance or was unable to complete 
assessments at a given timepoint, the reason or type of assistance 
should be provided. 
5.3.5 
For sites with troubleshooting inquiries regarding the use of 
Assessment Center, the following steps should be followed: 1) All 
sites should direct troubleshooting inquiries directly to the E1Q11 
Data Associate; 2) ECOG-ACRIN will forward unresolved inquiries to 
Northwestern University research staff; 3) Research staff at 
Northwestern University may forward unresolved inquiries to 
Assessment Center for final resolution. NOTE: Assessment Center 
should not receive any troubleshooting inquiries directly from sites. 
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5.4 
Patient Recruitment 
Patients from oncology clinics with newly diagnosed cancer are possible 
candidates for the study.  Complete eligibility criteria are included in Section 3.  
After the diagnosis of cancer is given to the patient, the primary provider will refer 
the patient to the study personnel for initial contact. The primary provider is 
defined as the clinician (MD, nurse practitioner, PA-C) that is clinically assessing 
the oncology patient.  Subjects must enroll prior to initiation of chemotherapy or 
radiation, if applicable. 
Institutions will identify a clinical research nurse (CRN)/CRA that will be 
responsible for all aspects of this study. The designated (CRN)/CRA from each 
institution will be available to work with physicians during the clinical session to 
identify and recruit patients. This person will discuss the details of this study with 
appropriate care and thoughtfulness as she has recently received the diagnosis 
of a cancer.  If the patient agrees, she will be screened for study eligibility at that 
time or at a subsequent visit as deemed appropriate by study personnel. This 
person will also be available to answer any questions regarding the study. 
Patients will either be enrolled in the study or listed on the “Patient Log” 
(Appendix II), which requires a reason for the patient’s decision not to participate. 
Please keep a copy of the Patient Log in patient chart at institution. 
5.5 
Data Collection 
Patients will be followed over time and all surveys will be administered as 
described in Table 1 (Section 7). 
5.5.1 
Following site randomization and local IRB approval, a consent form 
will be given to each provider (oncology staff, i.e. MD, nurse 
practitioner or PA-C, that clinically assesses the patient). A signed 
provider consent form is required for participation. 
5.5.2 
Upon site study activation a delegation of responsibility log should be 
completed and submitted to CTSU prior to enrolling the first patient 
5.5.3 
Patients will be recruited to participate at their scheduled provider 
appointment. Study staff will approach patients who are possible 
candidates to determine interest. If interested, eligibility will be 
confirmed (Section 3). 
5.5.4 
A consent form will be given to interested and eligible patients. The 
consent form should be completed on the same day eligibility is 
confirmed, however, it must be signed prior to treatment initiation (See 
Section 7 Patient-specific timeline). 
5.5.5 
Patient will have the baseline provider visit, complete baseline 
surveys and be registered to the trial on the same day of consent. If 
this is not feasible, then all baseline requirements (including 
registration) must be completed within one week of patient consent. 
Baseline provider visits, completion of baseline surveys and study 
registration must be completed on same day. (Table 1). 
5.5.6 
The designated research staff person (CRN or CRA) from each 
institution will administer questionnaires and assist with the 
completion of form(s) at the baseline and follow-up visits, as 
necessary. A CRN or CRA must review form(s) for completeness as 
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soon as the patient finishes them to ensure all items have been 
marked appropriately. 
5.5.7 
The scheduled study tools must be completed during the visit. 
5.5.8 
Completed clinician and patient form(s) will be entered into Medidata 
Rave within 7 days of collection. 
5.6 
Administration Instructions 
5.6.1 
The forms must be administered at the time points noted in Table 1 
(Section 7). 
5.6.2 
The CRA should read the instructions at the beginning of each 
questionnaire and administer to the patient unless the patient chooses 
to complete the survey on her own. The patient should be instructed 
to respond to questions in terms of her experience during the time 
frame specified on the form.  It is permissible to assist the patient with 
completion of the forms, as long as the staff person does not influence 
the patient’s response. 
5.6.3 
The completed forms must be reviewed by the designated CRN or 
CRA, as soon as the patient completes them, to ensure all items were 
marked appropriately. If more than one answer was marked, the 
patient should be asked to choose the answer which best reflects how 
she is feeling. If a question was not answered, the patient should be 
asked if she would like to answer it. The patient should always have 
the option to refuse. If the patient refuses, it should be indicated on 
the form that she declined to answer the item. 
5.6.4 
If the patient cannot complete the baseline form properly, the reason 
should be noted on the Assessment Compliance Form. If a patient 
cannot complete the follow-up questionnaire because she is too sick 
AND the CRN/CRA learns of it, it will be documented on the 
Assessment Compliance Form. 
5.6.5 
The clinician responsible for filling out the Provider Reproductive 
Health Values Surveys (Specific to Patient) may be the treating 
MD, the nurse practitioner, or PA-C involved in the clinical care of the 
patient.  This will be determined per patient by the CRA/CRN. 
5.6.6 
If overlap occurs between the patient study follow-up visit and 
chemotherapy/radiation treatment visit, the Patient Follow-up 
Interviews should be completed rather than the Patient Follow-up 
Interview During Chemotherapy.   
5.7 
On-Study and Follow Up Assessment Schedule 
5.7.1 
Provider Assessment Schedule 
Providers (oncology staff, i.e. MD, nurse practitioner or PA-C, that 
clinically assesses the patient) from both arms will complete two 
surveys, the Provider Reproductive Health Values Survey 
(General) and the Provider Reproductive Health Values Survey 
(Specific to Patient). The general survey consists of 18 questions 
which assess provider opinion regarding reproductive health and 
cancer care and referral practices. The patient specific survey 
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consists of 8 questions assessing provider opinion regarding the 
reproductive health care needs of a specific patient. 
Providers will complete the Provider Reproductive Health Values 
Survey (General) at the following two timepoints. This survey will 
take approximately 5 minutes to complete. 
1. Pre-Study (0 months) 
2. 30 months from site initiation 
Additionally, the provider will complete the Provider Reproductive 
Health Values Survey (Specific to Patient) at the following eight 
timepoints: 
1. Baseline - (0 months) 
2. 3 Months from Baseline Visit 
3. 6 Months from Baseline Visit 
4. 12 Months from Baseline Visit 
5. 24 Months from Baseline Visit 
Study Staff will complete forms according to the following schedule:  
Medical Record Abstraction Form - Baseline  
1. Baseline 
Medical Record Abstraction Form – Follow-up 
NOTE: 
The term ‘regimen’ is defined as anytime a patient starts a 
new course of medical treatment. 
1. Within one week prior to the start of each chemotherapy regimen 
for patients undergoing chemotherapy or every four weeks of RT 
for patients undergoing radiation therapy alone  
2. 3 Months from Baseline Visit 
3. 6 Months from Baseline Visit 
4. 12 Months from Baseline Visit 
5. 24 Months from Baseline Visit 
5.7.2 
Patient Reported Outcomes Assessment Schedule 
If a patient is eligible to participate in this study and the physician 
approves, the study is further discussed with the patient.  Patients 
providing consent will be registered on trial. Participants will complete 
a total of 8 assessment visits (including baseline). Structured 
interviews will be administered to participants at the timepoints listed 
below. At each time point, two questionnaires will be administered by 
a study team member.  Completion of these forms on a given visit 
should take about 10-20 minutes. Patient interviews are designed to 
assess the patient’s reproductive health history, management and 
goals at baseline and as they progress through cancer treatment. 
Additionally, the Sexual Function Survey, which includes the PROMIS 
Sexual Function Brief Profile v1.0 – Female, is designed to assess 
sexual health at diagnosis and throughout treatment. 
Patients will be assessed according to the following schedule:  
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Patient Baseline Interview (51 Questions) 
Baseline  
Patient Follow-Up Interview (34 Questions) 
1. 3 Months from Baseline Visit 
2. 6 Months from Baseline Visit 
3. 12 Months from Baseline Visit 
4. 24 Months from Baseline Visit 
Patient Interview - During Chemotherapy/Radiation Treatment (11 
Questions) 
In addition to the above forms, each patient will complete the Patient 
Interview During Chemo/Radiation Treatment as well according to 
the following schedule: 
Within one week prior to the start of each chemotherapy regimen for 
patients undergoing chemotherapy or every four weeks of RT for 
patients undergoing radiation therapy alone  
Sexual Function Survey (16 Questions) 
1. Baseline 
2. Within one week prior to the start of each chemotherapy regimen 
for patients undergoing chemotherapy or every four weeks of RT 
for patients undergoing radiation therapy alone  
3. 3 Months from Baseline Visit 
4. 6 Months from Baseline Visit 
5. 12 Months from Baseline Visit 
6. 24 Months from Baseline Visit 
5.8 
Provision of Appropriate Care for Patients 
The clinical management of all patients (regardless of symptom severity) will be 
determined by the treating physician. 
5.9 
Reproductive Health Related Endocrine Disruption in Cancer Care  
This part of the study will be conducted on the first 200 patients enrolled in the 
EROS study who agree to participate. Blood samples will be drawn and 
laboratory tests (AMH, FSH, Thyroperoxidase antibody and TSH) will be 
evaluated to assess fertility status and endocrine disruption at baseline and at 3, 
6,12, and 24 months from Baseline Visit. 
5.10 
Quality of Life (QOL) Assessment  
The Sexual Function Survey will be administered to all patients recruited for the 
EROS study over the 2 year study period (as specified in Table 1). The PROMIS 
Sexual Function Brief Profile v1.0 - Female measures are included in the Sexual 
Function Survey. 
5.11 
Duration of Study  
Patients will participate on this study for 24 months from registration.  
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Patient will complete surveys in this study unless:  
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient’s health, administration of protocol 
surveys should be discontinued. In this event submit data through Medidata 
Rave according to the schedule in the E1Q11 Forms Completion Guidelines.  
• 
Patient withdraws consent.  
5.12 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue study participation 
early, will be followed for survival for 2 years from the date of registration. 
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6. 
Measures 
6.1 
Study Tools   
Forms completed by clinical staff: 
6.1.1 
The EROS Trial: Engendering Reproductive Health Within Oncologic 
Survivorship Provider Reproductive Health Values Survey (General*). 
6.1.2 
The EROS Trial: Engendering Reproductive Health Within Oncologic 
Survivorship Provider Reproductive Health Values Survey (Specific to 
Patient*). 
6.1.3 
The EROS Trial: Engendering Reproductive Health Within Oncologic 
Survivorship Medical Record Abstraction Form – Baseline. 
6.1.4 
The EROS Trial: Engendering Reproductive Health Within Oncologic 
Survivorship Medical Record Abstraction Form – Follow-up. 
6.1.5 
The EROS Trial: Engendering Reproductive Health Within Oncologic 
Survivorship Pregnancy Supplement Form. 
6.1.6 
The EROS Trial: Engendering Reproductive Health Within Oncologic 
Survivorship Reproductive Health Assessment. (for intervention sites 
only) 
Semi-Structured Interviews to be administered to study participants: 
6.1.7 
The EROS Trial: Engendering Reproductive Health Within Oncologic 
Survivorship Patient Baseline Interview. 
6.1.8 
The EROS Trial: Engendering Reproductive Health Within Oncologic 
Survivorship Sexual Function Survey. 
6.1.9 
The EROS Trial: Engendering Reproductive Health Within Oncologic 
Survivorship Patient Interview – During Chemotherapy/Radiation 
Treatment. 
6.1.10 
The EROS Trial: Engendering Reproductive Health Within Oncologic 
Survivorship Patient Follow-up Interview. 
* Providers (oncology staff, i.e. MD, nurse practitioner or PA-C, that clinically 
assesses the patient) are required to review, sign, and submit a Provider Consent 
Form prior to site initiation of this study. 
 
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7. 
Study Parameters (For Arm A only) 
NOTE: 
THE ASSESSMENT SCHEDULE FOR THE INTERVENTION ARM B (WITH SOME EXTRA ITEMS) IS 
AVAILABLE IN ADDENDUM I. 
 
Site Specific Timeline
Site Acceptance 
Letter
Randomization 
Allocation 
(to Control Arm)
Site 
Activated
Complete: 
1) Provider Consent Form
2) Reproductive Health 
Values Survey (General)
3) Delegation of 
Responsibilities Log 
CIRB
Approval of 
Primary 
Protocol
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Subject Specific Timeline  
Recruitment Timeframe
 Prior to initiation of cancer treatment
 
 
 
 
 
Patient Recruitment
1) CRA/CRN 
approach 
preliminarily 
eligible patient to 
determine interest
2) If interested, 
confirm eligibility 
(Section 3)
 
Patient Baseline
1) Consent Signed
2) Baseline visit with provider
3) Baseline surveys completed after visit
4) Patient registered
Baseline provider visit, baseline surveys 
and registration should be completed on 
the same day as consent, if this is not 
feasible baseline visit, baseline forms, 
and registration must be completed on 
the same day, within 1 week of consent 
and before treatment initiation.
 
 
3 Month 
Visit  
6 Month 
Visit  
12 Month 
Visit  
24 Month Visit 
 
 
 
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Table 1. Non-Intervention (Arm A) Engendering Reproductive Health within Oncologic Survivorship: Data Collection 
For Intervention Arm (Arm B) data collection table includes four additional items located in Addendum I 
NOTE: 
The term ‘regimen’ is defined as anytime a patient starts a new course of medical treatment. 
 
Pre-
study1 
Baseline4 
0 and 30 
Months 
from Site 
Initiation 
Within one week prior to 
start of each Chemotherapy 
Regimen or Every Four 
Weeks during RT10,11 
At the end of 3, 6, 
12, 24 Months 
from Baseline 
Visit11,12 
SITE2  
 
 
 
 
 
Provider Consent Form 
X 
 
 
 
 
Delegation of Responsibilities Log 
X 
 
 
 
 
CLINICIAN 
 
 
 
 
 
Provider Reproductive Health Values Survey (General)3 
X 
 
X 
 
 
Provider Reproductive Health Values Survey (Specific to 
Patient)5  
 
X 
 
 
X 
Medical Record Abstraction Form – Baseline6 
 
X 
 
 
 
Medical Record Abstraction Form – Follow-up6,13 
 
 
 
X 
X 
Pregnancy Test7  
 
X 
 
X 
X 
Pregnancy Supplemental Form8 
 
X 
 
X 
X 
 
PATIENT 
 
 
 
 
 
Patient Baseline Interview9 
 
X 
 
 
 
Sexual Function Survey 
 
X 
 
X 
X 
Patient Interview - During Chemotherapy/Radiation 
Treatment10 
 
 
 
X 
 
Patient Follow-up Interview11, 12 
 
 
 
 
X 
1. Pre-Study documents should be completed prior to participant recruitment. 
2. These documents need to be updated based on staffing and provider changes over the course of this study. We define provider as the clinician 
(MD, nurse practitioner or PA-C) that clinically assesses the oncology patient. 
3. Each primary clinician should complete this form once at 0 (Prior to Study Training) and 30 months from site initiation. It is not necessary to fill 
out the form for each patient at each of these time points. As staffing changes over the course of this study new clinicians will complete this form 
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upon signing provider consent and at 30 months from site initiation. The date for site initiation is defined as the time when the site is approved to 
enroll patients into this study. 
4. Patient will have the baseline provider visit, complete baseline surveys and be registered to the trial on the same day of consent. If this is not 
feasible, then all baseline requirements (including registration) must be completed within one week of patient consent and before treatment 
initiation as part of their standard of care (i.e., chemotherapy or radiation therapy). Baseline provider visits, completion of baseline surveys and 
study registration must be completed on same day. 
5. This form should be completed by the primary clinician after each office visit (as determined by the CRN/CRA) 
6. Complete the medical record abstraction forms from the medical chart of each eligible participant after visit with the patient. Form must be 
completed and entered electronically in Medidata Rave within one week of patient visit.  
7. Pregnancy Test requirements. All patients must be counseled about pregnancy precautions, risks of fetal exposure and other risk as per 
standard of care. Pregnancy tests should be administered at Baseline, 3, 6, 12, and 24 months from Baseline Visit and within one (1) week prior 
to each chemotherapy regimen. For patients on radiation therapy (RT) alone, pregnancy tests should be administered within one (1) week prior 
to the initiation of radiation therapy then every four (4) weeks until the end of radiation treatment. For patients who aged past 55 after enrollment 
may discontinue pregnancy tests if menopause is confirmed FSH < 23mlU/mL. Patients who have had a hysterectomy after enrollment may also 
discontinue pregnancy tests. Pregnant patients may discontinue pregnancy tests until delivery 
8. If patient is pregnant or has been pregnant since her last study visit, one Pregnancy Supplement Form should be completed for each pregnancy. 
9. Interview done after visit with the provider. 
10. Study surveys should be completed at the beginning of each regimen of cancer treatment. For patients undergoing chemotherapy, surveys 
should be administered within one (1) week prior to each chemotherapy regimen. For patients on radiation therapy (RT) alone, surveys should 
be administered within one (1) week prior to the initiation of radiation therapy then every four (4) weeks until the end of radiation treatment.  
Patients receiving both chemotherapy and RT must follow the chemotherapy reporting schedule; if patient's treatment overlaps (+/- 2 weeks), 
the questionnaires do not have to be repeated. 
11. Sites must complete the study surveys within the following windows: 
• 
3-month visit: +/- one month 
• 
6-month visit: +/- one month 
• 
starting from 12-month visits: +/- 2 months 
12. If there is an overlap (+/- 2 weeks) of visits at 3, 6, 12, and 24 months and visits relating to chemotherapy or RT, the Medical Record 
Abstraction-Follow up, Patient Follow-up Interview, the Sexual Function Survey and the Pregnancy Test only need to be completed once at the 
3, 6, 12, and 24 month visits and not at the chemotherapy or RT visits. 
13. The term ‘regimen’ is defined as anytime a patient starts a new course of medical treatment 
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Table 2. Biological Sample Submissions 
NOTE: 
Effective March 10, 2021 the endocrine marker sub-study is closed to further 
accrual. This sub study has met its targeted accrual goal. 
Serum specimens should continue to be collected from previously enrolled 
patients that have consented to provide serum specimens at the time points 
outlined below. 
Do not submit serum specimens from patients registered to E1Q11 after March 
10, 2021. 
NOTE: 
THIS SECTION APPLIES TO BOTH STUDY ARMS.  
Blood samples should be submitted for the endocrine markers as outlined in Section 
9. Submit only from patients who have given written consent to participate in the 
optional laboratory studies. 
NOTE: 
It is required that biological sample submissions be logged into the ECOG-ACRIN 
Sample Tracking System (STS) for purposes of monitoring compliance.  
NOTE: 
Institutions must complete and submit the Quest Diagnostics Sub-Account 
Information Sheet (Appendix III) to create their study specific account number in 
order to obtain supplies and arrange for courier service for the collection of the blood 
samples. See Section 9 for further instructions. 
Biological Materials 
Day of 
Registration 
[prior to 
treatment]1 
Within One Week Prior to Start of 
Each Chemotherapy Regimen or 
Every Four Weeks during RT1 
At the end of 3, 6, 12, 24 
Months from Baseline 
Visit 
From Patients Who Answer “Yes” to “I agree to participate in the laboratory research studies that are 
being done as part of this clinical trial.”3 
Serum (one 7.5mL red 
top tube)2,3,4 
X 
X 
X 
Serum, SST (one 
7.5mL red/black top 
tube)2,3,4 
X 
X 
X 
1. For patients undergoing chemotherapy, blood samples will also be collected in conjunction with 
chemotherapy within one (1) week prior to the start of each chemotherapy regimen. For patients 
undergoing radiation therapy (RT) alone, blood samples will be collected within one (1) week prior to 
the initiation of radiation therapy and every four (4) weeks until the end of radiation treatment. 
2. When possible, blood draws will be timed with the collection of blood draws for routine clinical 
purposes thus minimizing participant burden. 
3. Ship blood samples to Quest Diagnostics as outlined in Section 9. 
4. Supplies are available for the collection of the blood samples.  
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8. 
Statistical Considerations 
The primary objective of this study is to evaluate the success of implementation of the 
reproductive health programming among females aged between 15-55 years old with 
initial diagnosis of any form of cancer (before chemotherapy or radiation has started). 
Secondary objectives include (1) assessing the degree of discrepancy between patients 
and their clinicians in estimates of significance of the reproductive health goals for the 
patient, (2) evaluating baseline and follow-up reproductive health assessments for trends 
in reproductive health choices relating oncofertility, oncocontraception, and pregnancy 
over the 2 year study period, (3) identifying clinical and demographic factors that predict 
the adequacy of reproductive health management. 
E1Q11 is a cluster randomized trial (CRT) with patients in one site all receiving the same 
intervention. This study was originally designed with a paired-matching cluster 
randomization, paired mainly by the type of institution (MU NCORP vs. NCORP) and 
geographical region (Northeast vs. Midwest vs. South vs. West). However, this design 
falls apart as some sites originally invited to participate in this study dropped from the 
study (at various time points). Consequently, the study design is now changed to a 
parallel cluster randomization (i.e., with clusters randomized to one of treatment arms). 
To have a manageable number of patients in this study and have this study completed in 
a reasonable timeline, the sample size was re-calculated based mainly on the primary 
endpoint of the primary objective (instead of the important secondary endpoint of the 
primary objective) and the patient’s age limit was lowered to 15 years. Due to an 
oversight in previous sample size calculations, the sample size was re-calculated in 
amendment 13. 
8.1 
Design and Randomization 
In this study, the patient population will include all female patients initially 
diagnosed with any form of cancer and within the reproductive age of 15-55 
years old.  All enrolled female patients will be categorized into one of the four 
strata (Figure 1) – Stratum 1 with patients who are not pregnant, sexually active, 
and have not completed childbearing, Stratum 2 with patients who are not 
pregnant, sexually active, and have completed childbearing, Stratum 3 with 
patients who are not pregnant and not sexually active, and Stratum 4 with 
pregnant females and females who are interested in becoming pregnant within 
one year of study enrollment. 
Given that E1Q11 adopts a cluster randomized design, the details of endpoints 
can be found in the statistical analysis plan (located in Addendum II) in order to 
avoid contaminating control sites and to preserve the integrity of the intervention. 
To evaluate the success of the intervention, appropriate reproductive health 
management will be used as the primary endpoint and the sample size will be 
calculated based on this endpoint. It is expected that the intervention can 
increase appropriate reproductive health management from 50% to 80% (across 
all four strata). The baseline rate of 50% was determined by Pilot Study 1 
data.21,22 In the “Reproductive Health Algorithm,” 100% of females had 
appropriate reproductive health management after the intervention.23 Therefore, 
with this study, we expect to detect an improvement from 50% to 80%. 
For the secondary endpoint of LTC, it is hypothesized that for patients in Stratum 
1, intervention will increase the contraception usage rate from 1% to 22% (based 
on Pilot Study 1). For patients in Stratum 2, the intervention will increase the 
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contraception usage rate from 20% to 60% (based on Pilot Study 1 and the 
“Reproductive Health Algorithm”)23,21,22. Stratum 3 and Stratum 4 are 
observational groups and no specific hypothesis is given for them. 
Institutions will be selected and invited to participate in this study. Because of the 
logistical difficulties of having both intervention and no intervention programs 
within a single institution, the unit of randomization will be the institution (i.e., a 
cluster randomized approach) rather than the individual patient. Thus, institutions 
participating in the study will be randomized to one of the two arms, Arm A 
without intervention and Arm B with intervention. Patients being accrued to the 
study, regardless of stratum, will be assigned to one of the two arms depending 
on the institutional assignment. 
Figure 1. Patient Strata 
 
1. Defined as within one year from study enrollment) for the phrase “Immediate 
Pregnancy. 
8.2 
Selection of Participating Clinics 
To ensure patient diversity in this study, all NCI MU NCORPs will be invited to 
participate in this study. Once participating MU NCORPs have been identified, 
the remainder of sites will be filled by NCORPS. All institutions will be equally 
randomized to either the non-intervention group (Arm A) or the intervention group 
(Arm B). Each institution will have patients enrolled in one of the four strata 
depending on the patient’s pregnancy status, sexual activity status, and/or her 
birth intention. 
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8.3 
Sample Size 
To have a manageable number of patients in this study, the sample size is re-
calculated based on the primary endpoint. For a cluster randomized trial, we 
must take into account the similarity among responses within a cluster (known as 
the intracluster correlation coefficient (ICC); ICC=0 indicating individuals 
completely independent; ICC=1 indicating individuals completely dependent), the 
required number of clusters per arm (denoted as k), and the number of patients 
per cluster (denoted as m) for the sample size calculations. To account for the 
possibility of variable cluster size in real accrual, coefficient of variation (CV) of 
cluster sizes (defined as the ratio of standard deviation of cluster sizes to mean 
of cluster sizes) was considered in sample size calculations as well. In this 
section, the power is computed assuming equal enrollment per arm. As of 
January 4, 2021, though, 66% (268/406) of the enrollment is from sites on the 
control arm and 34% from sites in the intervention group (with recent accrual 
closer to 50% in each group, due to site accrual caps). The number of 
intervention arm cases needed under equal enrollment will then be used to 
determine the overall sample size under the enrollment proportions seen in this 
study. The actual power should then be higher than stated, given the additional 
enrollment on the control arm. 
To detect an increase from 50% to 80% (across all four strata) in the adoption of 
appropriate reproductive health management within 3 months consistent with 
patient’s initial reproductive health goals (the primary endpoint),Table 1 shows 
the power with respect to various parameter values (including intra-cluster 
correlation coefficient, number of clusters, coefficient of variation, and mean 
cluster size), assuming an exchangeable within-cluster correlation structure, t-
distribution, and type I error rate (⍺) at 0.10 (two-sided). The sample size and 
power calculations were conducted using the Shiny CRT Calculator, a web-
based tool (https://clusterrcts.shinyapps.io/rshinyapp/)24,25. 
Table 1: Power for Various Plausible Parameter Values (assuming an 
exchangeable within-cluster correlation structure, t-distribution, and ⍺=0.10) 
Number of 
Clusters (k, 
per arm) 
Coefficient of 
Variation (CV) 
Mean Cluster 
Size (m) 
ICC 
0.05 
0.10 
0.15 
8 
0.0 
11 
0.96 
0.90 
0.84 
 
0.5 
14 
0.97 
0.90 
0.82 
 
0.6 
16 
0.97 
0.90 
0.81 
 
0.7 
20 
0.98 
0.90 
0.81 
 
0.8 
15 
0.95 
0.85 
0.75 
 
0.8 
27 
0.98 
0.90 
0.80 
9 
0.0 
9 
0.95 
0.90 
0.85 
 
0.5 
11 
0.96 
0.90 
0.83 
 
0.6 
12 
0.96 
0.90 
0.82 
 
0.7 
14 
0.97 
0.90 
0.82 
 
0.8 
17 
0.97 
0.90 
0.81 
10 
0.0 
8 
0.96 
0.91 
0.87 
 
0.5 
9 
0.96 
0.90 
0.84 
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Number of 
Clusters (k, 
per arm) 
Coefficient of 
Variation (CV) 
Mean Cluster 
Size (m) 
ICC 
0.05 
0.10 
0.15 
 
0.6 
10 
0.96 
0.90 
0.84 
 
0.7 
11 
0.97 
0.90 
0.83 
 
0.8 
12 
0.97 
0.90 
0.81 
Based on the results in the Verma and Lê’s study26, it is estimated that the intra-
cluster correlation coefficient for the primary endpoint is 0.10. As of January 4, 
2021, 9 Arm A sites and 8 Arm B sites have had enrolled patients for the EROS 
trial (n=268 for Arm A and 138 for Arm B) with CV=0.78 (=23.9/18.6). Assuming 
ICC=0.10, 16 institutions in total (i.e., 8 clusters per arm) and CV=0.8, Table 1 
indicates an average of 27 eligible patients per cluster can detect an 
improvement from 50% to 80% while keeping 0.10 two-sided type I error rate and 
90% power. Due to the slow accrual in Arm B, the study power was lowered to 
85% with an average of 15 eligible patients per cluster, keeping the other 
parameters constant. In this case, this study requires 240 eligible patients in total 
enrolled into this study (average of 15 per cluster, 120 per arm) in order to keep 
0.10 type I error rate and 85% chance of detecting the proposed 50% to 80% 
improvement on the primary endpoint. Assuming a 5% ineligibility rate and an 
additional 15% of attrition rate at 3 months (based on the fourth interim analysis 
with data pulled in July 2019), the sample size for the primary endpoint of this 
study is inflated to 298 patients in total (149 patients per arm, across the four 
strata), under equal enrollment on the two arms. To obtain 149 intervention arm 
cases, total enrollment will need to be 425 patients (see below). 
8.4 
Accrual Goal and Accrual Period 
To help safeguard 10 enrolling sites per intervention group (as originally 
proposed), we have invited more than 20 MU NCORPs/NCORPs to participate in 
this study (as listed on the cover page of the protocol). To further help accrual, 
we lowered the age limit to 15 years in Addendum 9 (effective from February 6, 
2019). Besides the original participating MU NCORPs/NCORPs, interested 
pediatric MU NCORPs/NCORPs are allowed to participate in the EROS trial as 
well. 
To have adequate power to detect the difference from 50% to 80% in the primary 
endpoint, the accrual goal of this study was re-calculated to ensure 149 patients 
in the intervention arm, assuming 16 sites enrolling patients for this trial (8 to the 
non-intervention group (Arm A) and the other 8 to the intervention group (Arm 
B)). Patients from each site will be enrolled into one of the four strata depending 
on the patient’s pregnancy status, sexual activity status, and/or her birth 
intention. Given some sites accrue much faster than the others, a NCORP 
accrual cap of 45 patients was implemented per Addendum 8. 
As of January 4, 2021, 268 patients from 9 Arm A sites and 138 patients from 8 
Arm B sites have had been enrolled to this trial. As this is a comparative study, 
the trial will continue accrual for both arms until Arm B meets its accrual goal of 
149 patients which is projected to take another 5 months. Taking into account the 
site accrual up to January 4, 2021 and the accrual rate in the past three months 
(i.e., the last three months of 2020, with the top three accrual sites met the 
accrual cap of 45 patients and closed accrual to Arm A), the final accrual of this 
study, thus, is expected to be 425 patients (276 from Arm A and 149 from Arm 
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B). The mean cluster size is projected to be 25 patients assuming 17 enrolling 
sites in total (~30 patients per cluster for Arm A and ~18 patients per cluster for 
Arm B). As suggested by Table 1, this study is equipped with more power if the 
cluster size is larger than the average of 18-19 patients per cluster and/or if the 
number of clusters per arm is greater than the stated 8 sites per arm in the 
sample size calculations. The additional patients and sites in Arm A imply the 
power of this study will be a little larger than stated (i.e., 85% power) to detect a 
change from 50% to 80% on the primary endpoint with the projected final accrual 
of 425 patients. 
Based on E5103, PACT1, E4599, and E4402, it is projected that the accrual rate 
for this patient population (female patients initially diagnosed with any form of 
cancer within the reproductive age of 15-55) is 50 patients per month. Since only 
limited institutions will be invited to participate in this study, it is further assumed 
that 13 patients per month will be accrued via these institutions for this study. 
8.5 
Power for the Important Second Endpoint (the LTC Usage at 6 Month 
Assessment) 
8.5.1 
Stratum 1 with patients who are not pregnant, sexually active, and 
have not completed childbearing. 
It is expected that intervention can increase the LTC usage rate at 6 
months after baseline visit from 1% (without intervention) to 22% for 
patients in Stratum 1. 
Table 2 shows the power with various parameter values to detect 
such an improvement, assuming ICC=0.10, an exchangeable within-
cluster correlation structure, t-distribution, and type I error rate at 0.10 
(two-sided). As indicated in Table 2, this study needs an average of 
10 eligible patients enrolled into stratum 1 per cluster in order to have 
84% power to detect an improvement in the LTC usage rate at 6 
months from 1% to 22%, assuming ICC=0.10, 8 institutions per arm, 
and CV=0.8. The power drops to 47% if an average of 3 eligible 
patients is enrolled into stratum 1 per cluster, keeping all other 
parameters constant. 
Results from the fourth interim analysis suggest that approximately 
20% of eligible patients can be categorized into Stratum 2 and the 6-
month attrition rate is approximately 20%. With the stated 15 eligible 
patients to detect a change from 50% to 80% on the primary endpoint 
(assuming 8 sites per arm), the projected average cluster size is 2-3 
eligible patients in stratum 1 (=15x0.2x0.80). Thus, the new study 
design is not adequately powered to detect the proposed difference in 
LTC usage rate in Stratum 1. 
Table 2: Power for Various Plausible Parameter Values (assuming 
improvement from 1% to 22%, ICC=0.10, an exchangeable within-
cluster correlation structure, t-distribution, and ⍺=0.10). 
Number of 
Clusters (k, per 
arm) 
Coefficient of 
Variation (CV) 
Mean Cluster 
Size (m) 
Power 
8 
0.5 
3 
0.50 
 
0.5 
4 
0.65 
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Number of 
Clusters (k, per 
arm) 
Coefficient of 
Variation (CV) 
Mean Cluster 
Size (m) 
Power 
 
0.5 
5 
0.73 
 
0.5 
10 
0.89 
 
0.8 
3 
0.47 
 
0.8 
4 
0.61 
 
0.8 
5 
0.69 
 
0.8 
10 
0.84 
10 
0.5 
3 
0.59 
 
0.5 
5 
0.82 
 
0.5 
10 
0.94 
 
0.8 
3 
0.56 
 
0.8 
5 
0.77 
 
0.8 
10 
0.90 
8.5.2 
Stratum 2 with patients who are not pregnant, sexually active, and 
have completed childbearing 
It is expected that intervention can increase the LTC usage rate at 6 
months after baseline visit from 20% (without intervention) to 60% for 
patients in Stratum 2. Table 3 summarizes the power with various 
parameter values, assuming ICC=0.10, an exchangeable within-
cluster correlation structure, t-distribution, and type I error rate at 0.10 
(two-sided). As indicated in Table 3, this study needs an average of 5 
eligible patients enrolled into stratum 2 per cluster in order to have 
85% power to detect an improvement in the LTC usage rate at 6 
months from 20% to 60%, assuming ICC=0.10, 8 institutions per arm, 
and CV=0.8. 
Results from the fourth interim analysis suggest that approximately 
40% of eligible patients can be categorized into Stratum 2 and the 6-
month attrition rate is approximately 20%. With the stated 15 eligible 
patients to detect a change from 50% to 80% on the primary endpoint 
(assuming 8 sites per arm), the projected average cluster size is 
expected to be 4-5 eligible patients in stratum 2 (=15x0.4x0.8). 
Consequently, the new study design has at least 80% power to detect 
an increase from 20% to 60% in the LTC usage rate at 6 month 
between the two arms. 
Table 3: Power for Various Plausible Parameter Values (assuming 
improvement from 20% to 60%, ICC=0.10, an exchangeable within-
cluster correlation structure, t-distribution, and ⍺=0.10) 
Number of 
Clusters (k, per 
arm) 
Coefficient of 
Variation (CV) 
Mean Cluster 
Size (m) 
Power 
8 
0.5 
3 
0.71 
 
0.5 
4 
0.84 
 
0.5 
5 
0.89 
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Number of 
Clusters (k, per 
arm) 
Coefficient of 
Variation (CV) 
Mean Cluster 
Size (m) 
Power 
 
0.5 
10 
0.97 
 
0.8 
3 
0.67 
 
0.8 
4 
0.80 
 
0.8 
5 
0.86 
 
0.8 
10 
0.95 
10 
0.5 
3 
0.79 
 
0.5 
5 
0.94 
 
0.5 
10 
0.99 
 
0.8 
3 
0.76 
 
0.8 
5 
0.92 
 
0.8 
10 
0.98 
8.5.3 
Stratum 3 with patients who are not pregnant and not sexually active 
Stratum 3 is an observational group and no specific hypothesis is 
proposed for it. 
8.5.4 
Stratum 4 with pregnant patients and patients who are interested in 
becoming pregnant within one year of study enrollment. 
Stratum 4 is an observational group and no specific hypothesis is 
proposed for it.  
8.6 
Analysis Plan 
8.6.1 
Plan for the primary objective 
With a cluster randomized design, the generalized estimating 
equations (GEEs) method will be used to evaluate the intervention 
effect. The GEEs method can be used to construct an extension of 
standard logistic regression27. For the primary endpoint, appropriate 
reproductive health management, a GEE model with an exchangeable 
correlation structure (i.e., assuming every patient within a cluster is 
equally correlated with every other patient from that cluster) and 
registering institution as the cluster variable will be fitted to compare 
the rates between the intervention group and the no intervention 
group by combining patients in all strata.  The appropriate 
reproductive health management rate at each time point will be 
summarized, by arm, with frequency and percentage along with its 
95% confidence interval. This rate in the non-intervention arm will 
indicate whether reproductive health needs are adequately addressed 
(Hypothesis 1, Section 1.4.1). Whether the intervention can improve 
reproductive health care (Hypothesis 2, Section 1.4.2) can be 
determined by comparing this rate between the non-intervention arm 
and the intervention arm. 
The same method will be used to evaluate the intervention effect on 
contraception usage for Stratum 1 and Stratum 2, separately. Since it 
is expected that contraception usage will be influenced by the number 
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of children (0, 1-2, >2), type of treatment (chemo vs. RT vs. surgery 
vs. combination), and disease stage (nonmetastatic vs. metastatic) as 
well, these factors will be included in the model as covariates. The 
contraception usage rate at each time point will be reported with 
frequency and percentage along with its 95% confidence interval. 
Similar analysis method will be applied to the proportion of patients 
with pregnancy by the end of 2 years after baseline visit on the study. 
The analysis will be applied to patients by stratum for each of these 
secondary endpoints. 
8.6.2 
Plan for secondary objectives 
Objective 1: To assess the degree of discrepancy between patients 
and their clinicians in estimates of significance of the reproductive 
health goals for the patient. 
Assume the rating (1-10) on the reproductive health value questions is 
on a continuous scale. For each question, mean and standard 
deviation in terms of rating will be computed by arm for patients and 
their clinicians, respectively. The difference in ratings between the 
patient and his/her clinician will also be computed and summarized 
with descriptive statistics. The ratings between patients and clinicians 
will be compared using a linear mixed-effect model. Only data 
available from both the patient and his/her clinician will be included in 
this part of analysis. This analysis can address Hypothesis 3 that 
patients and clinicians have different perspectives regarding 
reproductive health objectives of females with cancer (Section 1.4.3). 
Objective 2: To evaluate baseline and follow-up reproductive health 
assessments.  
Frequency/percentage will be used to summarize results collected at 
each time point. Longitudinal analysis will be applied when 
appropriate.  
Objective 3: To identify clinical and demographic factors predictive of 
the adequacy of reproductive health management. 
To identify clinical and demographic factors predictive of the 
adequacy of reproductive health management (Hypothesis 4, Section 
1.4.4), the GEE method will be used. 
8.6.3 
Plan for Endocrine Disruption in Cancer Care 
A longitudinal observational study is proposed to examine 
reproductive health biomarkers in a subgroup of participants (first 200 
subjects who agree to participate in this part of study) in the EROS 
Trial. Participants will be asked to provide blood samples for 
laboratory correlates (AMH, FSH, TSH, TPO), indicating reproductive 
health, fertility status, and endocrine disruption. Blood samples will be 
obtained at baseline and periodically at 3, 6, 12, and 24 months from 
baseline visit on the study, which totals 8 blood draws. In addition, 
blood samples will be acquired in conjunction with chemotherapy 
(within one week of each regimen, prior to chemotherapy) or radiation 
therapy (within one week prior to the initiation of radiation therapy 
then every four weeks until the end of radiation treatment). This will 
increase the number of samples for that population as we attempt to 
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assess impact of chemotherapy on endocrine function. The hormonal 
levels at each measurement point will be summarized (by median and 
range) and plotted across time by marker. All analysis will be 
performed for patients with chemotherapy and without chemotherapy 
separately. To assess the impact of chemotherapy on endocrine 
function, a linear mixed-effect model will be used to make 
comparisons between the two groups with respect to each marker. 
To determine the percent of females having significant endocrine 
disruption during chemotherapy, Table 7 below summarizes the 
abnormal level for each marker. 
Table 7: Endocrine Markers and Associated Threshold Values for 
Endocrine Disruption 
Marker 
Age Range 
Abnormal Range 
FSH 
15-55  
≥ 23.0 mIU/mL 
TPO 
15-55 
< 35 IU/mL 
TSH 
≤ 19 
≥ 20 
0.50-4.30 mIU/mL 
0.40-4.50 mlU/mL 
AMH 
≤ 19 
0.76 – 11.34 ng/mL 
 
20-29 
0.76- 11.34 ng/mL 
 
30-39 
< 9.24 ng/mL 
 
40-49 
≤ 50 
< 4.50 ng/mL 
< 0.45 ng/mL 
Quest Diagnostics Laboratory reference ranges 
For each marker, the patient with the observed lab value falling into 
the abnormal range is considered to represent a case with endocrine 
disruption. Frequency and percentage (along with its 95% confidence 
interval) will be used to summarize patients with endocrine disruption 
during chemotherapy for each marker.  
8.6.4 
Plan for Longitudinal Study of Sexuality 
Measurement of PROMIS Sexual Function Survey Brief Profile v1.0 - 
Female will be used to evaluate the hypotheses that (1) cancer 
survivors’ sexual function decreases during primary cancer treatment 
then increases after treatment completion and (2) cancer survivors 
have lower levels of satisfaction with their sex lives compared to the 
age-matched general population at baseline. All patients recruited for 
the EROS study will be included in this part of analysis. Data collected 
in PROMIS Sexual Function Survey Brief Profile v1.0 - Female in the 
EROS study will be summarized and plotted across time with respect 
to each of the subdomains (global satisfaction with sex life, interest in 
sexual activity, lubrication, vaginal discomfort, and orgasm). A linear 
mixed-effect model will be used to study changes in each of the 
subdomain scores of PROMIS Sexual Function Survey Brief Profile 
v1.0 - Female over time, with institution as the random effect (by 
stratum and across all patients if there is no difference between 
strata). For the secondary hypothesis, our comparative group is the 
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age-matched population of non-cancer females in the reproductive 
age range surveyed by the Duke Clinical Research Institute. The 
collaborator at Duke Clinical Research Institute will provide summary 
data on age-matched non-cancer patients. The PROMIS study uses a 
T score method with a mean of 50 and a standard deviation of 10. 
Results from the Sexual Function Survey in the EROS trial will be 
transformed into T scores as well then comparison between the 
groups will be performed using the two-sample t test. 
8.7 
Randomization Scheme 
Institutions that are selected to participate will be randomly assigned (with a 1:1 
allocation ratio) to either the non-intervention arm or the intervention arm. 
8.8 
Monitoring Plan 
Study Progress and Safety Reports are prepared twice yearly for all ECOG-
ACRIN studies. Reports of these analyses are sent to the ECOG-ACRIN 
Principal Investigator or Senior Investigator at the participating institutions. The 
ECOG-ACRIN Data Safety Monitoring Committee (DSMC) will semi-annually 
review this randomized trial as well. 
An interim analysis plan is proposed to monitor study progress instead of early 
stopping for efficacy or futility. 
The survey compliance rates (considering both Medical Record Abstraction Form 
and Patient Interview Form are completed), considering both baseline/3 months 
and baseline/6 months will be reported separately in each of the interim analysis, 
starting after every 100 patients enrolled on this study and synchronizing with the 
DSMC meeting. The proportion of patients who adopts appropriate reproductive 
health management within 3 months from baseline visit (the primary endpoint, 
across all evaluable patients) will also be reported in the interim analysis, 
together with the 90% confidence interval. All these results will be presented to 
the DSMC. 
8.9 
Race and Ethnicity 
Patients in this study will be females only. The slow accrual in Arm B led to over-
accrual in Arm A (n=268, as of January 4, 2021) with respect to the new accrual 
goal (n=149 per arm). Taking into account the site accrual up to January 4, 2021 
and the accrual rate in the past three months (i.e., the last three months of 2020), 
the final accrual of this study is projected to be approximately 425 patients in total 
when Arm B meets its accrual goal. According to historic data for ECOG studies 
(E5103, PACT1, E4599, E4402, and E1A11), the anticipated accrual in 
subgroups defined by ethnicity and race is as follows: 
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Racial Categories 
Not Hispanic/Latino 
Hispanic/Latino 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
2 
0 
0 
0 
2 
Asian 
14 
0 
0 
0 
14 
Native Hawaiian or Other 
Pacific Islander 
2 
0 
0 
0 
2 
Black or African American 
43 
0 
2 
0 
45 
White 
315 
0 
47 
0 
362 
Total 
376 
0 
49 
0 
425 
The accrual targets in individual cells are not large enough for definitive 
comparisons to be made within these subgroups. Therefore, overall accrual to 
the study will not be extended to meet individual subgroup targets. 
8.10 
Handling Missing Data 
The primary analysis will treat missing data as missing at random then analyze 
cases with complete data. The method of multiple imputation will be used to 
handle missing data if more than 20% of the cases have missing data in the 
variables of interest. If so, sensitivity analysis will be performed to compare 
results from the complete case analysis and imputation analysis. In case of 
discrepancies, possible explanations will be discussed. For longitudinal data, 
given the expected high level of missingness in these data, data will be analyzed 
according to the methods described in Schluchter and in Schluchter, Greene, 
and Beck28,29. These methods take into account the possibility of informative 
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9. 
Correlative Studies 
NOTE:  Effective March 10, 2021 the endocrine marker sub-study is closed to 
further accrual. This sub study has met its targeted accrual goal. 
Serum specimens should continue to be collected from previously 
enrolled patients that have consented to provide serum specimens at the 
time points outlined below.  
Do not submit serum specimens from patients registered to E1Q11 after 
March 10, 2021. 
NOTE: 
THIS SECTION APPLIES TO BOTH STUDY ARMS. 
NOTE: 
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System. An STS 
shipping manifest form must be generated and shipped with the sample 
submissions. See Section 9.4. 
NOTE: 
An informed consent must be signed prior to the submission of any samples 
for laboratory studies. Samples for the optional laboratory studies should be 
submitted only from patients who have given written consent for the use of 
their samples for these purposes. 
9.1 
Study-Specific Account Set Up for Quest Diagnostics 
The following steps should be completed prior to consenting or registering 
patients to the study, as account creation and initial supply delivery takes about 
two (2) weeks. 
• 
Institutions must complete and submit the Quest Diagnostics Sub-Account 
Information Sheet (Appendix III) to create their study-specific account 
number.  
• 
E-mail the completed form to Andrea.P.Pogue@questdiagnostics.com or Fax 
to (855) 848-4237. 
• 
Quest will provide each institution with a study-specific account name and 
number and ship an initial allocation of supplies (collection tubes, specimen 
labels, specimen transport bags, serum transport vials/caps, pre-printed 
custom requisitions forms) using the contact information listed on Account 
Set Up Information section of the Sub-Account Information Sheet (Appendix 
III). The study-specific account number will be included on a laminated form 
with the initial supplies shipment.   
• 
Upon receipt of the study-specific account number, institutions should contact 
Quest at (866) 697-8378 to obtain courier and pick-up details for their 
institution.  Institutions will be given a specific cut-off time for calling in to 
receive same day pick-up and to determine if Saturday service is available (if 
needed). The courier service will provide dry ice. If your institution is not 
eligible for Quest courier pick-up Quest will provide supplies for shipping via 
FedEx.  
• 
To order additional supplies contact Quest Diagnostics at (866) 226-8046 or 
e-mail DGXNational@QuestDiagnotics.com. Supplies will be shipped via 
ground delivery to arrive within three to five working days.   
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9.2 
Sample Submission Schedule 
Blood samples are being collected for the correlative studies outlined in Section 
1.7 and analyzed by Quest Diagnostics. 
NOTE: 
Results of these laboratory tests will not be returned to the institutions 
or reported to the patient. 
NOTE: 
Blood samples should be collected as outlined in the table and 
sections below.  
Biological 
Materials 
Day of 
Registration 
[prior to 
treatment]1 
Within One Week Prior to Start of Each 
Chemotherapy Regimen or Every Four 
Weeks during RT1 
At the end of 3, 6, 
12, 24 Months 
from Baseline Visit 
From Patients Who Answer “Yes” to “I agree to participate in the laboratory research 
studies that are being done as part of this clinical trial.”3 
Serum (one 
7.5mL red 
top tube)2 
X 
X 
X 
Serum, SST 
(one 7.5mL 
red/black 
top)2 
X 
X 
X 
1. For patients undergoing chemotherapy, blood samples will also be collected 
in conjunction with chemotherapy within one (1) week prior to the start of 
each chemotherapy regimen. For patients undergoing radiation therapy (RT) 
alone, blood samples will be collected within one (1) week prior to the 
initiation of radiation therapy and every four (4) weeks until the end of 
radiation treatment. 
2. When possible, blood draws will be timed with the collection of blood draws 
for routine clinical purposes thus minimizing participant burden. 
9.3 
Sample Preparation Guidelines 
If you have any questions concerning sample collection and shipment, please 
contact Quest Diagnostics National Clinical Call Center at (866) 226-8046 or 
DGXNational@QuestDiagnostics.com Monday-Friday 7AM-7PM CST, please 
have your national account number ready when calling. 
9.3.1 
Red Top Tube Collection 
1. Draw 7.5mL of blood into the Red Top tube. 
2. Invert tube gently no more than eight (8) times to mix the blood 
with the clot activator. 
3. Do not remove stopper at any time. Do not centrifuge immediately 
after drawing blood. Allow the blood to coagulate in an upright 
position at room temperature for at least 30 minutes, but no longer 
than one (1) hour before centrifugation. 
4. Centrifuge tube for at least 15 minutes at speeds between 2200 
and 2500rpm within one (1) hour of collection. 
5. Separate serum from clot and dispense at least 1mL of serum into 
the plastic transport screw cap vial.  
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6. Screw the cap to the vial securely and freeze at ≤ -20oC 
immediately until pick-up. 
9.3.2 
SST Tube Collection 
1. Draw 7.5mL of blood into the SST tube. 
2. Invert tube gently no more than eight (8) times to mix the blood 
with the clot activator. 
3. Do not remove stopper at any time. Do not centrifuge immediately 
after drawing blood. Allow the blood to coagulate in an upright 
position at room temperature for at least 30 minutes, but no longer 
than one (1) hour before centrifugation. 
4. Centrifuge tube for at least 15 minutes at speeds between 2200 
and 2500rpm within one (1) hour of collection. 
5. Store at ambient temperature until pick-up. 
9.3.3 
Labeling and Custom Test Requisition Form Completion  
All specimens should be labeled at the time of collection with at least 
two patient identifiers.   
Each tube must be clearly labeled in ball point pen to include: 
• 
ECOG-ACRIN Five-Digit Patient Sequence Number (required, if 
not available at baseline visit Patient Initials must be used) 
• 
Patient Gender 
The tubes must also be labeled with the specimen labels from the test 
requisition forms. See packaging guidelines below. 
Specimens must be accompanied by custom paper test requisition 
forms. Custom test requisition forms will be included with the supplies. 
Two pre-printed test requisition forms must be submitted with the 
blood samples (one for each tube type). 
Complete the patient information section on the requisition and select 
the tests to be performed. Please be sure to keep a copy of each test 
requisition form within the patient’s chart. 
The tests to be ordered with corresponding codes are as follows: 
Frozen Red Top Tube 
• 
Anti-Mullerian Hormone AssessR [#37227] 
Ambient SST Tube 
• 
Thyroid Peroxidase Antibodies (TPO) [#5081] 
• 
TSH [#899] 
• 
FSH [#470] 
The requisition should contain the following patient information: 
• 
ECOG-ACRIN Five-Digit Sequence Number (enter under Patient 
ID#) (if not available at baseline visit Patient Initials must be used) 
• 
Do NOT write in the patient’s name 
• 
Sex 
• 
Name of Insured/Responsible Party (enter as ECOG-ACRIN) 
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• 
Name and Address of Physician Ordering the Test 
• 
Tests Requested (see codes above) 
• 
Date and Time of Specimen Collection 
• 
Fasting or Non Fasting 
Please do NOT fill out information related to results reporting, patient 
social security number and date of birth, patient phone number and 
street address. 
9.3.4 
Packaging Guidelines  
1. Ensure that all specimen container caps and lids are properly 
tightened to prevent leakage.  
2. Complete the test requisition forms, one for the frozen blood 
sample in the transport tube and one for the blood sample in the 
SST tube. 
3. Collect the specimens and transfer to a proper transport container, 
if needed.  
4. Double check the specimen container to ensure that the device is 
not beyond its stated expiration date.  
5. Remove a self-stick label from the bottom of the pre-printed paper 
test requisition and securely affix this label to the specimen 
transport container. Fold the top copy (original) of the test 
requisition in half widthwise (top to bottom) with the bar code 
facing out. Retain the second copy for your files.  
6. The specimen transport bag has two pouches. Place the 
specimen containers in the front pocket. Insert the test requisition 
into the rear pocket with the bar code visible in the bottom corner 
of the bag.  
7. Frozen specimens should be transported in plastic screw--cap 
containers only. Frozen specimens must be placed in a separate 
specimen bag along with a separate test requisition.  
8. Remove the protective strip and seal the specimen bag. The 
protective strip must not obstruct the bar code. This will protect the 
test requisition from leakage and help ensure that the patient 
information can be entered directly into the laboratory computer by 
scanning of the bar code. 
9.3.5 
Quest Courier Service 
The blood samples should be transported using the Quest 
Diagnostics courier service. Please contact Quest Diagnostics at 
(866) 697-8378 to schedule the courier pick-up within 24 hours of 
the blood draw. You will be given a specific cut-off time for calling in 
to receive same day pick-up, if calls are made past this time, the pick-
up will be scheduled for the following day. Please provide your 
account number when calling. If courier service is not available in your 
location, FedEx air bill labels will be provided to you with your 
supplies, be sure to request two FedEx air bill labels for each of the 
tube shipments. 
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9.4 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password. 
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Important: 
Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using 
the software.  A user manual and interactive demo are available by 
clicking this link: http://www.ecog.org/general/stsinfo.html Please 
take a moment to familiarize yourself with the software prior to 
using the system. 
An STS shipping manifest form must be generated and shipped with all sample 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
9.4.1 
Study Specific Notes 
An ECOG-ACRIN Generic Specimen Submission Form (#2981) will 
be required only if STS is unavailable at the time of sample 
submission. Indicate the appropriate Lab ID # on the submission form: 
• 
0169 = Quest Diagnostics  
NOTE: 
Quest Diagnostics will not be utilizing the STS; 
therefore blood samples submitted will not be marked 
as received in STS. 
Retroactively enter all collection and shipping information when STS 
is available. 
9.5 
Banking 
The blood samples submitted will be used for the embedded laboratory research 
studies as outlined in Section 9. No residuals will be stored for future research 
studies. 
9.6 
Sample Inventory Submission Guidelines 
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS and receipt and usability verified by the receiving laboratory.  
Inventories of samples forwarded and utilized for approved laboratory research 
studies will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis in an electronic format defined by 
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9.7 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secure data transfer to the ECOG–ACRIN 
Operations Office – Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. 
 

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10. 
Electronic Data Capture 
Please refer to the E1Q11 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office-Boston to CTEP by electronic means. 
11. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
12. 
References 
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Health and Human Services, Centers for Disease Control and Prevention and 
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Jemal A, Siegel R, Ward E, et al. Cancer Statistics 2007. CA Cancer J Clin. 2007; 
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Lee SJ, Schover LR, Partridge AH, et al. American society of clinical oncology 
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Minter A, Malik R, Ledbetter L, Winokur TS, Hawn MT, Saif MW. Colon cancer in 
pregnancy. Cancer Control 2005; 12(3):196-202. PMID: 16062167 
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Abdallah RT, Muasher SJ. Surviving cancer, saving fertility-the promise of 
cryopreservation.Sexuality, Reproduction and Menopause. 2006; 4(1):7-12. 
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2501/PIIS1546250106000053.pdf 
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Schover LR. Sexuality and fertility after cancer. Hematology Am Soc Hematol Educ 
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Fossa SD, Dahl AA. Fertility and sexuality in young cancer survivors who have 
adult-onset malignancies. Hematol Oncol Clin North Am. 2008; 22(2):291-303, vii. 
PMID: 18395151 
10. Mastro LD, Catzeddu T, Venturini M. Infertility and pregnancy after breast cancer: 
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11. Rosendahl, M, Andersen, CY, Freiesleben, NC, et al. Dynamics and mechanisms 
of chemotherapy-induced ovarian follicular depletion in women of fertile age. Fertil 
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12. Gleicher N, Weghofer A, and Barad DH. Anti-Mullerian hormone (AMH) defines, 
independent of age, low versus good live-birth chances in women with severely 
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20538269 
13. Su HI, Sammel MD, Green J, et al. Antimullerian hormone and inhibin B are 
hormone measures of ovarian function in late reproductive-aged breast cancer 
survivors. Cancer. 2010; 116(3):592-9. PMID: 19918920 
14. Reinertsen KV, Cvancarova M, Wist E, Bjøro T, Dahl AA, Danielsen T, Fosså SD. 
Thyroid function in women after multimodal treatment for breast cancer stage II/III: 
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Martino E, Pinchera A Relationship between breast cancer and thyroid disease: 
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16. Hughes, MK. Sexuality and the cancer survivor. Cancer Nurs. 2000;23(6):477-82. 
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17. Hordern, AJ, Street, AF. Let’s talk about sex: risky business for cancer and 
palliative care clinicians. Contemp Nurse. 2007;27(1):49-60. PMID: 18386955 
18. Carter J, Sonoda Y, Chi DS, et al. Radical trachelectomy for cervical cancer: 
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19. Carpenter, KM, Andersen, BL, Fowler, JM, et al. Sexual self schema as a 
moderator of sexual and psychological outcomes for gynecologic cancer survivors. 
Arch Sex Behav. 2009;38:828-41. PMID: 18418707 
20. Weinfurt KP. Duke University, Durham, N.C.; Validating and Extending the 
PROMIS Sexual Function Measure for Clinical Research. 
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21. Patel A, Sreedevi M. Sutaria RP, et al. Reproductive health issues in women with 
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Biometrika. 1986; 73(1):13-22. 
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29. Schluchter MD, Greene T, Beck GJ. Analysis of change in the presence of 
informative censoring: application to a longitudinal clinical trial of progressive renal 
disease. Statistics in Medicine 2001; 20:989-1007. 
 

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Appendix I 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we will improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN, we thank you again and look 
forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

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Appendix II 
 
Patient Log 
INSTITUTION:  Use this form to record the oncology out-patients who have been asked and elected not to participate in this study. 
Institution:__________________________________________ 
CRA:__________________________________________ 
Patient Initials (L, F) 
Date Approached 
(M/D/Y) 
Reason Given for Not Participating 
1.______________________________________________________/_____/____ ________________________________________ 
2.______________________________________________________/_____/____ ________________________________________ 
3.______________________________________________________/_____/____ ________________________________________ 
4.______________________________________________________/_____/____ ________________________________________ 
5.______________________________________________________/_____/____ ________________________________________ 
6.______________________________________________________/_____/____ ________________________________________ 
7.______________________________________________________/_____/____ ________________________________________ 
8.______________________________________________________/_____/____ ________________________________________ 
9._________________________________________________ _____/_____/___ _________________________________________
10.________________________________________________ _____/_____/___ _________________________________________
11.________________________________________________ _____/_____/___ _________________________________________
12.________________________________________________ _____/_____/___ _________________________________________
13.________________________________________________ _____/_____/___ _________________________________________
14.________________________________________________ _____/_____/___ _________________________________________
15.________________________________________________ _____/_____/___ _________________________________________
Page ____________ of __________________________________’s Patient Log 
Institution/site name 
 

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Appendix III 
Quest Diagnostics Sub-Account Information Sheet 
 
All of the information requested below is required to set-up a new sub-account for an 
existing NCTS client. 
Account Set-Up Information: 
Account Name 
 
Attn 
 
Address  
City, State, Zip 
 
Phone 
 
Fax 
ECOG-ACRIN Fax: 617-589-0914  
(all results to ECOG-ACRIN via Care360) 
Rep Name and Sales ID   
Andi Pogue/AH24 
RSM Name and Sales ID 
Dave Stella/DS16 
Ordering Physician (Name, License 
Number and State, UPIN Number, NPI) 
 
National ID Code 
NEFS 
If existing accounts are group billed, 
what is the Group Bill Number? 
97513507 
Billing Information:  
(Bill to the following statement address, complete only if different from information above) 
Bill To Name 
ECOG-ACRIN E1Q11 
Attn 
Chris Schleyer 
Address  
City, State, Zip 
ECOG-ACRIN Medical Research Foundation 
1818 Market Street, Suite #1100 
Philadelphia, PA 19103 
Reporting Options: 
Final Reports or Partial Reports – Final Reports 
Fax Final (faxed report only, no mailed copy) – Care360 (All Results for Sub-Account to go back 
to ECOG-ACRIN) 
Care360 – LO&R or Physician Portal 
The Secure Fax letter must be filled out for either option, signed and faxed to Quest 
Diagnostics. 
If Care 360, user request forms must be completed and authorized by ordering physician. 
All information must be complete before submitting.   
Email Completed Form to Andrea.P.Pogue@questdiagnostics.com or Fax to (855) 848-4237. 
What Custom Panels (if any) are to be activated for this account?    
INTERNAL INFORMATON ONLY:  Use Account #
Rev. 5/17 

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Appendix IV 
 
INFORMATION SHEET REGARDING RESEARCH STUDY E1Q11 
(for teens from 15 through 17 years of age) 
A study about reproductive health care needs for female patients who are treated for cancer 
1. 
We have been talking with you about your cancer and the side effects of cancer 
treatment, including possible effects on reproductive health. 
2. 
We are asking you to take part in a research study because you are receiving treatment 
for cancer. A research study is when doctors work together to try out new ways to help 
people who are sick. The purpose of this study is to learn more about how female 
patients are usually being helped with their reproductive health needs during cancer 
treatment. This study will also look at tools and information that could be added to help 
more. 
3. 
You do not have to be in this study. No one will be disappointed in or angry with you if 
you decide not to join after learning about the details of the study. If, after understanding 
the nature of the study, you decide to join today you can change your mind later. Once 
you read, discuss, and understand the study, and if you and your parent/guardian agree, 
you will be asked to sign your name on this form. You will be given a copy of this form to 
keep. 
4. 
The study staff will talk with you and your parent/guardian about this study and answer 
your questions, as needed. 
5. 
Teens who are part of this study will be asked to complete questionnaires at about eight 
to ten time points during their regular medical visits. The questions will be about your 
reproductive health interests. Each time, a study team member will give you 
questionnaires and ask you the questions listed. This will be done in private, without 
anyone else besides the study team member with you in the room. The questions should 
take about 10-15 minutes at each visit. 
6. 
Sometimes good things can happen to people when they are in a research study. These 
good things are called “benefits.” We hope that a benefit to you of being part of this 
study is that communication between you and your doctor will better help treatment 
planning fit your future reproductive health goals. We hope the information learned from 
this study will benefit other cancer patients in the future. But we don’t know for sure if 
there is any benefit of being part of this study. 
7. 
Sometimes bad things can happen to people when they are in a research study. These 
bad things are called “risks.” The risks to you from this study are that some of the 
questions or topics that come up during this study may cause you to feel embarrassed, 
or may upset you. You can choose to fill in the survey questions in private or to not 
answer questions. Other things may happen to you that we don’t yet know about. 
8. 
Your family can choose to be part of this study or not. Your family can also decide to 
stop being in this study at any time once you start. There may be other options that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
9. 
We are asking your permission to collect additional blood. We want to study changes to 
reproductive hormone levels that may happen throughout and after treatment. 
Researchers will perform tests on the blood in order to look at how chemotherapy 
impacts the endocrine (hormone) system. These samples would be taken when other 
standard blood tests are being performed, so there should not be any extra blood sticks 
Rev. Add9 

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beyond your usual care. You can still be a part of this study even if you don't allow us to 
collect the extra blood samples for research.