Chemotherapy-Induced Ovarian Damage: Prevention and Impact

Institution: University of California, San Francisco
Investigator(s): Lucy Berlin, M.S. - Hope Rugo, M.D. - Lynn Westphal, M.D. -
Award Cycle: 2002 (Cycle VIII) Grant #: 8AB-1701 Award: $64,189
Award Type: CRC Pilot Award
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

This is a collaboration with: 8AB-1700 -

Initial Award Abstract (2002)
For many young women with breast cancer, the realization that chemotherapy will most likely render them infertile is devastating. Chemotherapy-related menopause in young women produces intensely unpleasant symptoms and results in low libido and rapid bone loss. The ovarian damage increases with age and drug dose, such that 40-70% of 40-year olds will develop menopause within one year. Data in primates and patients with lymphoma suggest that shutting down the ovaries during chemotherapy with GnRH-analogues (G) reduces ovarian failure, but this has not yet been demonstrated in a breast cancer clinical trial.

The main questions to be addressed in the research are: We will open a phase II clinical trial of the GnRH-analogue triptorelin before and during breast cancer chemotherapy in 32 women aged 35-44. Because we will include women up to their early 40s, we expect not only to document tolerability and young women's interest, but also to give a preliminary estimate of the effectiveness of the ovarian protection.

Complementary to the clinical trial, we will have 100 young survivors complete a pilot survey about the information they received, the emotional effect of this risk, and their post-chemotherapy menstrual function. We will interview a subset of these to obtain a deeper understanding of their experiences, attitudes, and needs.

By focusing on women aged 35-44, this will be the first clinical trial of GnRH-analog based ovarian protection in breast cancer patients who have a significant risk of visible ovarian damage after chemotherapy. Unlike other studies, we will focus on quality of life outcomes important to women--the hormonal and menstrual signs of low fertility and peri-menopause, not just immediate menopause. Our survey will add to the scant data on menstrual problems after modern chemotherapy regimens, and the qualitative component will give much needed insights into the attitudes of young women regarding childbearing after breast cancer, their information needs regarding ovarian function and early menopause, and the information and advice they currently receive from their oncologists.

Final Report (2006)
Introduction: Early menopause is also associated with rapid bone loss (median loss 7.8% by 1 year), increased risk of cardiovascular disease, low libido and vaginal atrophy. Preventing early ovarian failure is important to young women with breast cancer, including women who have completed childbearing.

Purpose: The purpose of this study was to evaluate whether premature menopause can be avoided by administration of the GnRHa (G) triptorelin, during adjuvant chemotherapy (aCTx) for breast cancer. aCTx results in reduced ovarian reserve, with symptoms including infertility and premature menopause. It appears that younger women experience more severe quality of life disruption and clinical distress from breast cancer diagnosis and treatment and unwanted infertility is severely distressing, especially when it is a result of cancer treatment. Its potential is sufficiently distressing that some women may consider forgoing or abbreviating life-saving chemotherapy.

Topic addressed: First, we designed a phase II clinical trial targeting women aged 35-44 (at higher risk for aCTx induced menopause due to age) scheduled for aCTX for early stage breast cancer to see if concurrent use of ovarian suppression would preserve ovarian function in this group at high risk for ovarian failure. Consenting patients received G to temporarily suppress ovarian function. Hormone levels (estradiol and FSH) were measured during and after aCTX; quality of life (QOL) and recovery of menses were tracked. Second, we wanted to gain a detailed understanding of how chemotherapy-induced ovarian toxicity influences treatment decisions and post-treatment life of young women with breast cancer, and, how the path to these outcomes is influenced by information and choices given after diagnosis. Specifically we wanted to learn (a) how serious is the impact of ovarian toxicity on young women? (b) what information do they need after diagnosis about ovarian-related issues and options? (c) given a clinical trial of CT+G, what would affect young women's interest in participating? We designed ethnographic interview questions that covered these issues, and iteratively developed a retrospective survey, with decision-making vignettes to probe attitudes and information needs.

Progress toward specific aims:
Phase II clinical trial. We enrolled 12 patients in the clinical trial. Three patients were not evaluable for recovery of menses due to disease progression or oophorectomy. All 9 patients recovered menses within 15 months following aCTx. Treatment was generally well tolerated; the major side effects were menopausal. One patient carried a pregnancy to term.

Qualitative study. We recruited 41 participants with a broad sampling. 24 women participated in audiotaped interviews, and 31 completed the surveys. Most women experienced at least temporary CRA. Women in their 30s had more severe menopausal symptoms, and felt unprepared for the QOL impact of chemotherapy related amenorrhea (CRA). MDs rarely mentioned the symptoms women found most distressing: low libido, vaginal dryness, disturbed sleep, and mood swings. 25% had tried to preserve fertility. 45% of women diagnosed under age 40 assumed that a pregnancy would be risky; most of those did not tell MDs their fertility goals. 40% of women diagnosed in their 30s had unwanted CRA within 2 years. Despite more uncertainty in survival benefit, an ovary-sparing regimen was the 1st choice for 67% of women with hormone receptor positive disease, and 83% of women with receptor negative tumors. 54% chose ovary-sparing regimens for their top 3 choices. Women were highly interested in a trial of G+CTX: Overall 23/37 expressed interest in participating if their doctor approved. If CT+G were known to be safe, this proportion rose to 33/37. 50% would have chosen 2-4% lower absolute recurrence-free survival odds in order to get a regimen with low odds of infertility/menopause.

Future direction and impact: Treatment with the GnRH agonist triptorelin in order to preserve ovarian function during aCTx in premenopausal women appears safe and well tolerated. The feasibility of this trial was limited by concerns regarding primary treatment of breast cancer, and the age restrictions within the trial. The study raised awareness of fertility and menopause concerns within the patient and oncology community, established relationships between breast oncology and the fertility specialists at UCSF and Stanford, and began to explore one option that might improve that chance of preserving ovarian function. Womens’ preference for ovary-sparing regimens and for G+CTX suggests that young women facing treatment decisions need information on CRA and pregnancy safety, and would welcome even preliminary data on the survival benefits and menopause/infertility risks of chemotherapy regimens with less toxicity to ovarian function such as doxorubicin followed by a taxane, or G plus chemotherapy, as studied in this trial. An ongoing national trial is investigating G in women with receptor negative disease.

Symposium Abstract (2003)
Introduction: Young women who receive chemotherapy to treat breast cancer experience ovarian damage. This damage may prevent subsequent childbearing and may cause side effects of early menopause, e.g., accelerated bone loss, hot flashes, and vaginal dryness. The magnitude of benefit of chemotherapy depends on a woman’s stage and tumor characteristics, while a woman’s odds of infertility or menopause after chemotherapy is primarily influenced by two key factors: age at diagnosis, and the total dose of alkylating drugs (Cytoxan). The principles of informed consent and participatory decision-making require that women receive good information about different treatment options, the risks and benefits of chemotherapy, early menopause and of any post-treatment pregnancies, and adequate time to process the risk and benefits. However, anecdotally, many women report ignorance of (a) their risks of infertility (b) the side effects of menopause, and © of options for freezing their eggs or minimizing the ovarian toxicity.

Goals: We have designed and are conducting a self-administered retrospective survey of the information women received about chemotherapy-related menopause and post-treatment childbearing, their attitudes toward various treatment options, and post-chemotherapy menstrual function. We will survey 130 women aged 20-45 at diagnosis who had had chemotherapy for early breast cancer, and will interview some of these to get more in-depth data on how they conceptualized their tradeoffs and options.

Status: After IRB approval we began iteratively testing the survey. To date we have obtained data from 14 women with varied demographics, and have recruited over 30 other survivors. We obtained feedback on the survey’s clarity, flow, content validity, length, and interest and conducted one formal interview. This early group already represents a broad sample: aged 28-44 at diagnosis (median 36), stage I – IIIb; 8 months – 9 years post diagnosis; one pregnant, four with infants or toddlers at diagnosis, and four who had been uninterested in future childbearing. We will soon mail the survey to the few dozen more women who have already signed up. We expect to present preliminary data at the conference.

Through this rich data on young women’s information needs and attitudes toward early menopause and post-treatment pregnancies, we hope to inform oncologists’ dialogues with newly diagnosed women about the women’s goals, values and options. By documenting the importance to some women of maintaining ovarian function, we also hope to raise researchers’ awareness of the impact of this toxicity, increase the tracking of age-based post-chemotherapy ovarian toxicity, and motivate research in less ovary-toxic regimens.

Symposium Abstract (2005)
Background: In young women, chemotherapy frequently causes infertility and the symptoms of premature menopause. Less ovary-toxic regimens exist, but are not standard in the US. For young women, access to high quality care must include information about treatment options that minimize undesirable permanent side effects. Thus doctors and activists need to learn whether menopause and infertility risks matter to young women, and if they do, physicians need data on less-ovary-toxic alternatives. In our pilot grant we are documenting how the current ovary-toxic chemotherapies affect young women’s experience of breast cancer, and what they wish they had known after diagnosis. We are also conducting a pilot clinical trial of GnRHa for ovary preservation during chemotherapy. The interviews also explored which factors would influence women’s interest in participating in such a trial.

Methods: We conducted in-depth semi-structured interviews with 23 breast cancer survivors who had all had chemotherapy. We chose these via “theoretical sampling” to get a breadth of demographics which might influence their attitudes and goals. Median age at diagnosis was 35 years (27-45). At diagnosis 78% were married, 65% had children. 61% had ER+ tumors. Interviews were audiotaped and transcribed.

Results: 83% had at least temporary chemo-induced menopause, including 8 of 10 women aged 31-35. Most were unprepared for the symptoms of sudden menopause. Most distressing were vaginal dryness, low sex drive, hot flashes, and severe mood swings. Three of the women aged <35 reported infertility. Women needed specific information about their individual odds of benefiting from chemotherapy, their odds of infertility or menopause after standard treatments the safety of pregnancy after cancer, the likely symptoms of menopause, and especially the differences in the ovarian damage likely with different regimens. We identified choices in the design of a trial of GnRHa during chemotherapy that will likely greatly affect enrollment, and the information women need to make informed decisions.

Conclusions: Starting in the early 30s, women are frequently affected by the ovarian toxicity of chemotherapy, not only unwanted infertility but also the sexual and emotional side effects of chemo-induced menopause. Many young women did not get the accurate, individualized information they need to make informed decisions. A trial of GnRHa for ovarian preservation might have very low -- or high -- accrual, depending on (a) whether women understand a set of key facts, and (b) choices made in the study protocol. Our research also demonstrates a value of community-research collaborations: by listening to the perspectives and needs of young survivors we learned valuable insights for researchers designing a clinical trial and also for clinicians counseling newly diagnosed young women.

(Funded by a Community-Research Collaboration (CRC) Grant of the California Breast Cancer Research Program.)

Symposium Abstract (2005)
Background: Women with early stage breast cancer frequently receive combination adjuvant chemotherapy. Recent data suggests that the addition of taxanes, and dose density improves outcome. However, CIA is a common complication that limits fertility options; risk of CIA increases with age. Data from small studies suggest that GnRH agonists (GA) might preserve ovarian function; trials have included very young women, and have not tracked hormone levels or quality of life.

Study Design: We designed a study targeted to women aged 35 and older scheduled for adjuvant chemotherapy (aCTX) for early stage breast cancer. Consenting patients received the GnRH agonist triptorelin starting at least 10 days prior to aCTX. Estradiol and FSH levels were measured during and after aCTX; quality of life (QOL) and recovery of menses were tracked.

Results: To date, 13 women have been enrolled in our study, all evaluable patients recovered menses within 7-15 months. QOL and hormone data as well as barriers to enrollment and the importance of the community collaboration will be discussed.