Saving ovaries during chemotherapy for breast cancer: mixed results

Saving ovaries during chemotherapy for breast cancer: mixed results

6 Sep 2014

Women who received a medication during chemotherapy had a very small increase in pregnancies, and resumption of menstruation, which was considered non-significant. The medication did not negatively affect the chemotherapy's effect.

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This medication, called triptorelin, contains a substance called a "luteinizing hormone-releasing hormone" (LHRH) analog, and its effectiveness was assessed in a randomized clinical trial.

Results of the clinical trial

The addition of triptorelin to breast cancer chemotherapy did not adversely affect disease control or survival compared with chemotherapy alone, reported Matteo Lambertini, MD, of Azienda Ospedaliera Universitaria San Martino in Genova, Italy, and colleagues.

The results mean that a previously reported significant reduction in chemotherapy-induced premature menopause in triptorelin-treated women did not translate into a significantly increased likelihood of pregnancy, they said in a presentation at the Breast Cancer Symposium.

"The use of the LHRH analog triptorelin showed a trend towards an increased probability for becoming pregnant and a trend towards an increased probability for menstrual resumption at longer follow-up, although neither finding was significant," Lambertini said, adding that the lack of difference in 5-year disease-free survival (DFS) between the two arms was "reassuring regarding the safety of the procedure."

Earlier this year, investigators in a different trial reported a significant reduction in ovarian failure, a significant increase in pregnancies, and significant improvement in DFS among breast cancer patients treated with the LHRH agonist goserelin during chemotherapy. That trial was limited to patients who had hormone receptor-negative breast cancer, whereas 80% of the Italian study's patient population had hormone-sensitive disease, Lambertini noted.

Taken together, results of the two clinical trials make a case for offering an LHRH analog to younger breast cancer patients concerned about preserving their fertility, he added.

Guidelines and trials focusing on fertility preservation

Several randomized trials and systematic reviews have evaluated use of LHRH analogs to prevent ovarian failure in younger women with early-stage breast cancer. The trials have contributed minimal long-term data to document pregnancies, survival, and long-term ovarian function.

Clinical guidelines from the American Society of Clinical Oncology and the European Society for Medical Oncology characterize use of LHRH analogs for fertility preservation as investigational, Lambertini said.

To address the lack of long-term data to inform clinical decision-making, Italian investigators performed a multicenter, randomized, clinical trial to evaluate triptorelin in premenopausal women scheduled to receive chemotherapy (adjuvant or neoadjuvant) for early breast cancer.

Trial details: 72% reduction in ovarian failure risk

The trial's primary objective was to determine the effect of the LHRH analog on the frequency of chemotherapy-induced premature ovarian failure. The primary analysis showed a 72% reduction in the likelihood of ovarian failure in women randomized to receive triptorelin. Lambertini reported findings from planned long-term follow-up.

The trial involved 281 patients, including 268 who remained in follow-up to the primary analysis and 246 in the long-term data analysis. During a median follow-up of 7.3 years, three pregnancies occurred among women who received chemotherapy alone, and all three culminated in live births.

Patients who received chemotherapy plus triptorelin had eight pregnancies and five live births; two pregnancies ended in miscarriage and one was aborted.

Improved likelihood of return of menstruation

Analysis of long-term ovarian function showed that menstruation resumed in 72.6% of patients who received the LHRH agonist and 64.0% of patients who received chemotherapy alone (statistical details: Hazard Ratio 1.28, 95% Confidence Interval 0.98-1.68, P=0.071).

The survival analysis showed a 5-year DFS of 83.7% in patients who received chemotherapy only and 80.3% in patients who received triptorelin in addition to chemotherapy. An exploratory analysis identified nodal status (positive versus negative) as the only independent predictor of DFS (statistical details: Hazard Ratio 1.75, 95% Confidence Interval 1.04-2.97, P=0.032).

"97% of breast cancer patients could be at risk for infertility and premature ovarian failure"

Ovarian preservation is an important issue for oncologists and patients, said invited discussant Hope Rugo, MD, of the University of California San Francisco. Each year more than 20,000 women younger than 45 have newly diagnosed breast cancer in the U.S., and as many as 97% of them could be at risk for infertility and premature ovarian failure.

Current options for fertility preservation include ovarian stimulation and cryopreservation of embryos and oocytes, experimental oocyte retrieval and cryopreservation techniques, and early referral to reproductive specialists.

On the flip side of the issue, "Do we really want to universally preserve ovarian function?" Rugo asked.

A large study conducted by the National Surgical Adjuvant Breast and Bowel Project showed that treatment-induced amenorrhea for 6 months or longer predicted better overall survival and DFS in women with hormone receptor-positive disease.

Studies conducted to date have shown that assessing the impact of cancer therapy on fertility versus amenorrhea can be difficult. The studies have employed different definitions of ovarian failure, and estimated rates of failure might be overestimates for current therapies.

"The use of [LHRH] agonists during chemotherapy to protect ovarian function remains controversial," Rugo said. "Given the lack of apparent risk, they could be considered for patients with estrogen receptor-negative disease, after a discussion of unknown benefits. This is not a substitute for established methods."

"Fertility options should be discussed with all women of child-bearing age who are diagnosed with breast cancer -- before starting treatment," she added. "This is universally recommended by multiple international guidelines. Early referral is critical to maximize the yield."

 

Source: MedPage Today

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