Chemotherapy-Induced Ovarian Damage: Prevention and Impact

Institution: Stanford University
Investigator(s): Lynn Westphal, M.D. - Lucy Berlin, M.S. - Hope Rugo, M.D. -
Award Cycle: 2002 (Cycle VIII) Grant #: 8AB-1700 Award: $82,027
Award Type: CRC Pilot Award
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

This is a collaboration with: 8AB-1701 -

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:
  1. Are women who receive G during breast cancer chemotherapy more likely to keep their menstrual function, and is the protection of G affected by a woman's age?
  2. Are there factors other than age and total dose of cyclophosphamide that affect a woman's odds of developing abnormal or absent menses?
  3. What are the experiences, attitudes, and information needs of newly diagnosed young women regarding ovarian damage and post-treatment childbearing?
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)
ntroduction: 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 (c) 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.