Intervening on Reproductive Health in Young Breast Cancer Survivors
Phase: NA
Conditions: Breast Cancer, Hot Flashes, Sexual Dysfunction, Fertility, Contraception
Sponsor: University of California, San Diego

Reproductive Health Survivorship Care Plan 
Trial Protocol 
 
NCT02667626 
February 1, 2016 
 
 

Design of a randomized controlled trial on the efficacy of a reproductive health 
survivorship care plan in young breast cancer survivors 
 
Introduction  
There are nearly 3.5 million breast cancer survivors in the United States, with 19% of new 
cases occurring in women age 45 and younger. Most young breast cancer survivors (YBCS) 
undergo chemotherapy and/or endocrine therapy, treatments that can impair ovarian function and 
result in significant reproductive health issues. These include hot flashes, infertility, sexual 
dysfunction, and limited contraception options, which negatively impact quality of life in 
survivorship. Evidence-based clinical strategies to manage these late effects have been 
identified, but have limited dissemination among YBCS and their healthcare providers (HCPs), 
resulting in unmet informational needs among YBCS on reproductive health [3].  
Breast cancer survivors seek health information and advice from their HCPs and online. 
Information seeking in YBCS is associated with increased self-efficacy, satisfaction with 
treatment decisions, and improved quality of life [6,8]. Coupled to underinsurance, limited 
healthcare access and high mobility in YBCS, these information-seeking characteristics 
motivated us to develop a web-based intervention on reproductive health for YBCS and their 
HCPs. 
In 2006, the Institute of Medicine recommended development of survivorship care plans 
(SCPs) to support the transition of care from cancer treatment to survivorship. SCPs aim to 
inform patients about the effects of cancer treatment, guide follow-up care, and improve care 
coordination. Internet accessible SCPs for breast cancer survivors have been developed, but 
contain limited reproductive health guidance. Randomized controlled trials on the efficacy of 
SCPs on patient-reported and health services outcomes have included YBCS, but none have 
focused on reproductive health. 
The web-based Survivorship Care Plan in Reproductive Health (SCP-R) intervention was 
developed to address unmet informational and clinical management needs for hot flashes, 
fertility-related concerns, contraception, and sexual health in YBCS. Research findings, 
professional society guidelines and clinical expertise on these reproductive health issues were 
curated into screening and management strategies that will be delivered to YBCS and their HCPs 
via the SCP-R intervention. A web-based intervention and text message support were chosen to 
enhance intervention accessibility.  
This report details the design, recruitment, and baseline characteristics of YBCS and HCP 
participants of the randomized controlled trial testing the efficacy of the SCP-R intervention on 
improving reproductive health in YBCS. We hypothesize that YBCS who receive the SCP-R 
intervention will be more likely to improve on at least one of four targeted reproductive health 
outcomes (hot flashes, fertility-related concerns, sexual health, and contraception) compared to 
waitlist controls.  
 
Material and Methods 
The SCP-R trial will test the efficacy of a 24-week, web-based educational intervention with 
text message support in improving reproductive health issues experienced by female YBCS. 
 
 
 
 

Following online eligibility screening and consent, YBCS complete an enrollment questionnaire 
and undergo a 7-day run-in period for reporting daily hot flash frequency and severity via text 
messaging. Adherent participants are randomized in a 1:1 ratio to the intervention or waitlist 
control arm. Participants in the intervention arm receive access to the full web-based SCP-R 
intervention and reproductive health text message prompts, while participants in the waitlist 
control arm receive access to a list of curated web-based resources and study adherence text 
messages. All participants will be followed for 24 weeks, report daily hot flash frequency and 
severity via text messaging, and complete a 12-week and a final 24-week questionnaire.   
To support YBCS-HCP interactions, one HCP is nominated by each YBCS participant to 
receive the same study materials as their patient. Following eligibility screening and consent 
online or by paper, HCP participants whose YBCS patients are randomized to the intervention 
arm will receive access the full web-based educational intervention; HCP participants whose 
YBCS patients are randomized to the waitlist control arm will receive access to the list of curated 
web-based resources. HCP participants will complete an enrollment and a 24-week 
questionnaire. The UC San Diego institutional review board approved all study procedures, and 
the trial was registered at clinicaltrials.gov (NCT02667626).   
 
Intervention prototype development and refinement 
In line with community-based participatory research [22], a stakeholder panel was formed to 
design and conduct the study. The panel was comprised of 2 YBCS advocates and 6 
investigators with clinical and research expertise in reproductive health, primary care, breast 
oncology, health behavior and randomized trials. To develop the intervention, we conducted 
systematic reviews and searched professional medical society guidelines for evidence on 
managing hot flashes and sexual health, addressing contraception needs and predicting fertility 
potential [23–25]. Supplemented by clinical expertise and review of existing web-based 
resources from professional medical societies and cancer advocacy groups, these evidence- and 
guideline-based practices were summarized into the SCP-R prototype. SCP-R was designed to 
improve self-efficacy by providing both up-to-date evidence and actionable steps for symptom 
management. The multi-level intervention further promoted taking actionable steps by 
incorporating reinforcement from the YBCS’ HCP.  
Seven focus groups with 37 YBCS were conducted to refine the content and presentation of 
the SCP-R [26]. For the intervention arm, we initially planned to provide each participant with 
only the SCP-R sections relevant to her specific reproductive issue(s). Based on focus group 
feedback, we changed the intervention design to allow participants in the intervention arm to 
access to all SCP-R sections.  
The final SCP-R intervention included four sections for each of the four planned 
reproductive health issue (hot flashes, fertility-related concerns, vaginal symptoms and 
contraception) and an additional fifth issue on genetic cancer risk. For each issue, the four 
sections included: 1) a 1- to 2-page SCP framed in a question and answer format; 2) a detailed 
summary of the systematic review results with hyperlinks to primary research articles; 3) a 
summary of clinical guidelines with hyperlinks; 4) a list of curated web-based resources. This 
content was programmed into the study website. The intervention arm will be able to access all 4 
sections for all 5 issues (Appendix A); the waitlist control arm will only be able to access the list 
of curated web-based resources for all 5 issues.  
 
 

Website and text messaging platforms 
We collaborated with an experienced web architect to develop a HIPAA-compliant website 
that enabled online participant registration, consent, completion of questionnaires, automated 
randomization and access to group-specific intervention material, integration with MOSIO, a 
text messaging software, and pairing of YBCSs with their nominated HCPs. The web portal is 
programmed to send study gift cards and weekly reminders on incomplete tasks to YBCS and 
HCP participants.  
The text messaging platform is programmed to push daily text messages to all YBCS 
participants to ascertain hot flash frequency and severity. Natural language processing is 
embedded to minimize variation in how participants provide hot flash responses. In addition, 
biweekly text messages with reproductive health prompts will be sent to YBCS participants in 
the intervention arm, while biweekly study adherence text messages will be sent to YBCS 
participants in the waitlist control arm. The text messaging platform supports opt out by 
participants and two-way text messaging capabilities between participants and study staff.  
This web- and text message-based design supports streamlined YBCS screening, consent, 
follow-up, and data collection, enables geographically diverse recruitment and utilizes fewer 
resources compared to a traditional in-person RCTs. Daily hot flash text messages will provide 
near real-time data collection to minimize recall bias.  
  
YBCS eligibility, recruitment, consent and enrollment  
YBCS are eligible if they report experiencing at least one of the four targeted reproductive 
health issues: hot flashes (> 4 per day with > 1 at least moderate in severity), moderate to high 
pregnancy and/or fertility concerns (fertility or pregnancy subscale score >3 on the Reproductive 
Concerns After Cancer Scale), not using contraception or using a less effective method (barrier 
or fertility awareness methods, withdrawal, or spermicides), or vaginal atrophy symptoms (> 1 
symptom of vaginal dryness, irritation, soreness or dyspareunia over the past 4 weeks reported as 
at least moderate in severity). Additional eligibility criteria include: ages 18-50 at study 
enrollment, diagnosed with stage 0-III breast cancer between ages 18-45, completed primary 
cancer treatment including surgery, chemotherapy and radiation, are not pregnant at enrollment, 
are able to read English and access the Internet, and are able to complete daily text message hot 
flash diaries.  
YBCS are recruited from the following sources: (1) cancer advocacy organizations including 
the Young Survival Coalition, Susan G. Komen San Diego and Army of Women-a program by 
the Dr. Susan Love Research Foundation, (2) referrals from health care providers and patient 
advocates, (3) Research Match, (4) previous observational studies conducted by the 
investigators. Interested YBCS are directed to the study web portal to create a secure personal 
account, followed by online access to study description, screening for eligibility and consent.  
Consented participants complete the enrollment questionnaire and undergo a 7-day daily hot 
flash text message run-in period. Participants receive two daily text messages prompting them to 
report the number of hot flashes and severity of each hot flash (mild, moderate, severe, or very 
severe) in the previous 24 hours. Participants with at least 70% adherence over 7 days are then 
randomized.  
 
YBCS randomization 
Computerized, blocked randomization with equal allocation to intervention and waitlist control arms 
was undertaken. Randomization is stratified by the four a priori reproductive health issues in order to 

maintain balance between the intervention and waitlist control groups with regard to these factors. 
Fifteen unique strata were created based on possible combinations of experiencing one or more 
of the four late effects.  
 
HCP eligibility, recruitment, consent, enrollment and procedures  
At enrollment, each YBCS participant nominates a HCP with whom they wish to discuss 
reproductive health issues. Study staff contact nominated HCPs by email, phone and/or fax for 
study recruitment. After five contacts, non-responsive HCPs are mailed the study consent, 
enrollment questionnaire and their patient’s SCP materials. Interested HCPs are directed to the 
study web portal to create a secure personal account, followed by online access to study 
description, screening for eligibility and consent. Consented HCP participants complete the 
enrollment questionnaire and are provided with access to their patient’s intervention materials, 
i.e. full SCP-R or only curated web-based resource lists. HCPs will complete a 24-week 
questionnaire and may opt to complete all study procedures (consent, questionnaires) and access 
intervention materials in a paper format.  
 
Blinding 
Study staff and YBCS and HCP participants are blinded to treatment allocation. Automated 
computer allocation of participants into intervention or waitlist control arm within the study 
portal allow for study staff to be blinded to assignment. YBCS and HCP participants are 
informed about participant randomization in the trial but are not notified of assignment until they 
complete their final study tasks. YBCS and HCP participants assigned to the waitlist control arm 
will be able to access the full SCP-R materials following completion of their final study tasks. 
Although 3 HCPs were nominated by more than one YBCS participant, each HCP only had 
participants in the same study arm.  
 
YBCS outcome measures 
Hot flash frequency and severity over the prior 24 hours will be measured in each questionnaire 
and via daily via text messages using the following questions: “How many hot flashes have you 
had in the past 24 hours?” and “How many of your hot flashes in the past 24 hours would you 
categorize as mild, moderate, severe and/or very severe?”  The hot flash score is calculated as the 
weighted sum of the number of hot flashes in each severity category multiplied by a severity-
exclusive weight (1-mild, 2-moderate, 3-severe, 4-very severe). For the primary analysis, a 
decrease of 50% in the hot flash score will be defined as an improvement in hot flashes for the 
primary composite outcome. Secondary hot flash outcomes will include quality of life measured 
by the 29-item Menopause-specific Quality of Life (MENQOL) scale, confidence to talk with a 
HCP about hot flash management, plans to implement and implementation of a suggested tip 
from the intervention materials.   
 
Fertility-related concerns will be measured with the Reproductive Concerns After Cancer Scale 
(RCAC), specifically fertility potential and pregnancy subscales. The RCAC is an 18-item 
multidimensional scale composed of 6 subscales (fertility potential, pregnancy, child’s health, 
disclosure to partner of fertility status, personal health, acceptance of infertility) measuring 
reproductive health concerns of young adult female cancer survivors. The two subscales were 
chosen, because the SCP-R content addressed these constructs. Each subscale consists of 3 
questions with response options ranging from 1 “Strongly disagree” to 3 “Neither agree nor 

disagree” to 5 “Strongly agree”. Scores for the fertility and pregnancy subscales will be 
calculated by averaging responses (range 1-5), scores > 3 indicating concern. For the primary 
analysis, scores < 3 in follow up will be considered an improvement in fertility-related concerns 
for the primary composite outcome. Secondary fertility-related outcomes will include the overall 
RCAC score, referral, consultation and treatment with a fertility specialist, pregnancy planning, 
and confidence to talk with a HCP about fertility-related concerns and plans to implement and 
implementation of suggestions from the fertility SCP.   
 
Contraception outcomes will be analyzed in participants at risk of unintended pregnancy, defined 
as having a uterus and at least one ovary, sexually active in the 24 months prior to or during the 
study, ≤ 45 years old. For the primary analysis, use of highly effective birth control methods 
(intrauterine devices, female sterilization, male partner sterilization, combined hormonal 
contraception, progestin implants or injections) during follow up will be considered an 
improvement for the primary composite outcome. Secondary contraceptive outcomes will 
include confidence to talk with a HCP about contraception, plans to implement and 
implementation of suggestions from the contraception SCP.  
 
Sexual health will be measured the Vaginal Atrophy Symptoms Score, a 4-item scale on vaginal 
dryness, soreness, irritation and dyspareunia experienced in the prior 4 weeks [29]. Each item 
has a 4-point Likert scale response (0-none, 1-mild, 2-moderate, 3-severe). The scale will be 
summarized by averaging responses, with higher scores indicating a greater level of vaginal 
atrophy. For the primary analysis, a decrease of 50% in the score will be defined as an 
improvement in vaginal symptoms for the primary composite outcome. Secondary outcomes 
included sexual desire, arousal, orgasm and pain via the 19-item Female Sexual Function 
Inventory (FSFI), confidence to talk with a HCP about vaginal symptoms and sexual health 
management, plans to implement and implementation of a suggested tip from the intervention 
materials.   
 
HCP measures 
HCP preparedness and confidence in talking to their patients about each of the four reproductive 
health issues will be measured. Each preparedness item had a 4-point Likert scale response (very 
unprepared, unprepared, prepared, and very prepared). Each confidence item had a 7-point Likert 
scale response (not at all confident, slightly confident, somewhat confident, moderately 
confident, quite confident, very confident, and extremely confident). Demographic, medical 
specialty, and experience and volume of breast cancer patients, and satisfaction with SCP 
materials will also be measured.   
 
YBCS participant adherence and retention 
We will deploy several approaches to motivate YBCS participants to complete the study. 
Participants will receive up to $100 in Amazon gift cards for completing each of 3 questionnaires 
and daily hot flash text messages. Weekly, automated reminder emails to complete study tasks 
will be sent via the web platform. Telephone call and/or text message reminders will be 
undertaken for overdue tasks for up to 5 contacts. On hot flash text messages, daily reports will 
be generated to monitor responses and identify those who had not responded in ≥ 3 consecutive 
days for study staff contact.  
 

HCP participant adherence and retention 
HCP participants will receive up to $40 in Amazon gift cards for completing each of 2 
questionnaires. Weekly, automated email reminders to complete study tasks and view their 
patient’s SCP will be sent via the website platform. HCPs who opted to participate via paper 
materials will be contacted by telephone calls to their medical practice to confirm receipt and 
encourage completion overdue tasks for up to 5 contacts. If a final questionnaire is not received 
within two months of mailing, questionnaires will be resent.  
 
Statistical Analysis  
The primary analysis will be intent-to-treat. The primary composite outcome will be an 
improvement in at least one reproductive health issue over the 24 week study, defined as: > 50% 
improvement in enrollment hot flash score, > 50% improvement in enrollment vaginal atrophy 
symptom score, use of highly effective contraceptive methods (sterilization, long-acting 
reversible contraception, injectables, pills, patch or vaginal ring), and fertility and pregnancy 
concern subscale scores <3. Logistic regression models will be used to test for differences by 
intervention versus control arm; odds ratios with 95% confidence intervals for intervention effect 
will be reported.  
To quantify intervention effects on each of the four reproductive health issues, we will also 
undertake secondary analyses to compare changes in each issue separately. As participant 
responses will be measured at enrollment, 12 and 24 weeks, we will  compare each health issue  
outcome between the intervention and waitlist control groups using linear mixed effect models 
for the continuous outcomes (hot flash score, vaginal atrophy symptom score, fertility concerns 
score) and GEE models for binary outcomes (use of effective contraceptive method) . Best linear 
unbiased predictors from the mixed models will also be used to impute missing outcomes for the 
primary composite outcome. Similar analysis will be conducted for secondary outcomes, which 
include additional YBCS-reported symptoms and actions, as well as healthcare provider 
preparedness and confidence.  
 
Sample size 
YBCS participants will be randomized into two arms: intervention and waitlist control. We 
will measure outcomes at enrollment, 12 weeks, and 24 weeks. Leveraging published data on hot 
flashes [31], we based sample-size calculations on detecting meaningful changes in hot flash 
frequency and score. With a sample size of 50/arm, there will be 80% power to detect a 0.57 
effect-size between groups on hot flash score changes from baseline to 24 weeks based on a 2-
sided t-test with alpha =0.05. This effect-size translates to a group difference of 1.2 hot flashes or 
3 units in the hot flash score, if we assume the standard deviation of the change was 2 hot flashes 
or 5 score units per patient per day. Incorporating all the repeated measurements on each 
participant should ensure sufficient power to detect an even smaller effect size. In particular, 
assuming 2 post-randomization measures with autocorrelation 0.5, there is 80% power to detect a 
0.44 effect size with 50 samples in each arm and 2-sided significance level 0.05.  
Considering the composite primary outcome of improvement in at least 1 reproductive health 
issue, we have 80% power to detect a 27% group difference, e.g., 25% in the control arm and 
52% in the treatment improve on at least one outcome. Given that some participants may have 
the same healthcare provider, we account for a clustering effect as follows: we assume as a 
worst-case scenario that on average 3 participants shared a provider, and that intraclass 
correlations (ICC) of the study outcomes due to a shared physician is 0.1. This results in a design 

effect of 1.2, requiring us to inflate the sample-size by 20%.  We further anticipate 20% sample 
size loss due to the run-in period prior to randomization, and an additional 20% drop-out rate. 
Hence, we aim to enroll 196 participants and randomize 157 to ensure sufficient power.