GnRH Agonist Fails to Save Fertility in Lymphoma Patients

Fran Lowry

May 31, 2016

In young lymphoma survivors, treatment with a gonadotropin-releasing hormone agonist (GnRHa) did not prevent chemotherapy-induced premature ovarian failure and did not influence future pregnancy rate.

These new results "reopen the debate" about using GnRHa to preserve fertility in cancer patients, and suggest that "it should not be recommended as standard for fertility preservation in patients with lymphoma," lead author Isabelle Demeestere, MD, PhD, from Université Libre de Bruxelles (ULB) in Belgium, told Medscape Medical News.

The results from the prospective randomized trial were published online May 23 in the Journal of Clinical Oncology.

These results are in contrast to those from a number of recent studies that showed the benefit of GnRHa in preserving fertility in breast cancer survivors, which prompted the American Society of Clinical Oncology (ASCO) to update its clinical guidelines on ovarian suppression in patients with breast cancer in February.

Dr Isabelle Demeestere

For instance, the phase 3 Prevention of Early Menopause Study (POEMS), from the Southwest Oncology Group, was hailed as "practice changing" at the 2014 ASCO annual meeting, as reported by Medscape Medical News. Treatment with the GnRHa goserelin (Zoladex, AstraZeneca) reduced the risk for ovarian failure in breast cancer patients whose chemotherapy regimens included cyclophosphamide and resulted in more pregnancies than no treatment.

In POEMS, only 8% (5 of 66) of the women treated with chemotherapy plus goserelin experienced premature ovarian failure 2 years after treatment, compared with 22% (15 of 69) of the women treated with chemotherapy alone (odds ratio, 0.30; P = .04).

And in the more recent Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients – Gruppo Italiano Mammella 6 (PROMISE-GIM6) (JAMA. 2015;314:2632-2640), researchers reported similar results with the GnRHa triptorelin in follow-up that ranged from 6 to 8 years, as reported by Medscape Medical News.

In PROMISE-GIM6, the long-term probability of menstrual resumption, defined as the occurrence of at least one menstrual cycle, was higher in women who received triptorelin while on chemotherapy than in women who did not (72.6% vs 72.8%). In addition, there were more pregnancies in the triptorelin group than in the control group (8 vs 3), and a higher 5-year cumulative incidence estimate of pregnancy (2.1% vs 1.6%).

Different Populations, Different Chemotherapies

"The studies that show that gonadotropin-releasing hormone agonists work have been done in breast cancer patients who are older, with a mean age of 39 years, than the lymphoma patients in our study, who were 26 years old, so it's a completely different population," Dr Demeestere explained. "Also, the treatment is completely different."

"It is possible that in these breast cancer patients, there may be a benefit of the GnRH analog treatment because their chemotherapy is less gonadotoxic," she said.

GnRH analog treatment might be efficient in preserving ovarian function and fertility in breast cancer patients, but not in lymphoma patients.

"But what is important for me is that our study is the largest and the only one that has 5 years of follow-up in lymphoma patients. GnRH analog treatment might be efficient in preserving ovarian function and fertility in breast cancer patients, but not in lymphoma patients. It is important to separate the populations. We do not have any biological support to prove that it is working in lymphoma patients," Dr Demeestere said.

"There is no evidence for its mechanism of action, which is still hypothetical. It is difficult to reassure the patient and tell her that if she takes this medication, it will protect her ovaries. At least it should not replace other fertility preservation procedures, such as oocyte and ovarian tissue preservation," she said.

Dr Demeestere, who heads the research laboratory on human reproduction at ULB, and her team previously reported that after 1 year of follow-up, GnRHa treatment did not prevent chemotherapy-induced premature ovarian failure in lymphoma patients. But they still thought that it could protect ovarian reserve.

However, their latest study shows this is not the case.

In the current study, they followed 129 patients out to 7 years. The patients were randomly assigned to either triptorelin (Decapeptyl LP, Ipsen Pharma) plus birth control with norethisterone or norethisterone alone during chemotherapy.

The primary end point — premature ovarian failure — was defined as at least one follicle-stimulating hormone (FSH) level of 40 IU/L or more during long-term follow-up.

Secondary end points were the ovarian function recovery rate, defined as a FSH level of 15 IU/L or less during follow-up; ovarian reserve, evaluated with anti-Müllerian hormone (AMH) levels; fertility rate; and disease-free survival rate.

Of the original cohort, 67 patients (mean age, 26.21 years) completed at least 2 years of follow-up and had data that could be analyzed. The median follow-up time was 5.33 years in the GnRH analog group and 5.58 years in the control group (P = .452).

Premature ovarian failure was experienced by six of 31 patients (19.4%) in the GnRHa group and in eight of 32 patients (25.0%) in the control group (P = .763). This risk was significantly elevated in patients who received a conditioning regimen for hematopoietic stem cell transplantation (HSCT) (P = .002) or a cumulative dose of cyclophosphamide greater than 5 g/m² (P = .019).

An increased risk for premature ovarian failure was associated with age (P = .047) but not type of disease (P = .281) or the coadministration of GnRHa during chemotherapy (P = .651).

A total of 37 patients had AMH levels available at least once during follow-up. Mean AMH values decreased significantly from baseline to 2 to 4 years after treatment (3.14 vs 1.26 ng/mL; P = .039) and remained at similar levels 5 to 7 years after treatment.

The researchers also analyzed ovarian function restoration rate, defined as a FSH level of 15 IU/L or less, which they saw in 21 of 31 patients in the GnRHa group and 16 of 32 control patients throughout follow-up.

Additionally, there was a significantly decreased risk for low FSH values in patients who received the conditioning regimen for HSCT or a cumulative dose of cyclophosphamide greater than 5 g/m².

There was no difference in the risk for low FSH values according to age, type of disease, or administration of GnRH.

Some Pregnancies Did Occur

Slightly more than half (17 of 32 patients; 53.1%) of patients in the GnRHa group and 15 of 35 patients (42.8%) in the control group achieved pregnancy (P = .467).

A "surprising" finding was that five pregnancies (two in the GnRH group and three in the control group) were reported in patients who experienced premature ovarian failure during follow-up.

"These data confirm the possibility of incidental ovarian cycle recovery, leading to fertility restoration after several years of treatment in this young population," Dr Demeestere said.

Ovarian Suppression by GnRHa Unlikely

"A medical, noninvasive method of fertility preservation would be highly desirable for patients," Kutluk Oktay, MD, and Giuliano Bedoschi, MD, from the New York Medical College and the Innovation Institute for Fertility Preservation in New York City, write in an accompanying editorial.

"However, when carefully scrutinized from a scientific point of view and considered together with ovarian biology, ovarian suppression by GnRHa is highly unlikely to be the answer, especially given the current strong study," the editorialists write.

The original idea that GnRHa could preserve fertility during cancer treatment came from "misinterpreted observations that children are less likely to develop ovarian failure after chemotherapy," they note.

"This led to a number of retrospective and inadequately controlled studies, which suggested some benefit of ovarian suppression in the preservation of menstrual function during chemotherapy," they write.

Studies that have shown benefit with GnRHa treatment have used amenorrhea or menstrual resumption rates to indicate success, which is "troublesome," the editorialists write.

Irregular menstruation, rather than amenorrhea, is the most common symptom of premature ovarian failure. "The most established definition of POF is irregular periods or amenorrhea with FSH levels greater than 40 mIU/mL in women younger than age 40 years. None of the studies, except the current, original study by Demeestere et al, has used an appropriate definition of POF," they write.

And the study has numerous other strengths.

"It used an established biologic description of POF with long-term follow-up...and validated its findings by secondary outcome measures such as the lack of diminished ovarian reserve reflected by serum FSH levels less than 15 mIU/mL, longitudinal serum anti-Mullerian hormone measurements, and fertility rates," they write.

'Incredibly Important' Survivorship Issue

All clinicians treating young women with breast cancer would like to offer them something that would reduce their risk of developing amenorrhea and infertility, said Claudine J. Isaacs, MD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

"This is obviously an incredibly important survivorship issue," she told Medscape Medical News. "It is possible that the effects of a GnRH agonist could be different in breast cancer and lymphoma. But I don't think the underlying malignancy as such should alter the effect of the drug and the risk of amenorrhea. Certainly, the type of treatment could, and the type of chemotherapy that is given for lymphoma is different from what is administered for breast cancer and has a greater potential to cause amenorrhea," Dr Isaacs said.

"It is certainly possible that the GnRH agonists are ineffective in this setting. As was pointed out in the editorial by Oktay and Bedoschi, the mechanism by which GnRH agonists could act to preserve ovarian function is not at all clear. Age could be a factor, as could the type of treatment they get for lymphoma," she said.

"We want this to work because this is such an important survivorship issue. We're robbing these young women of so much. The good news about lymphoma and breast cancer is that most patients are cured. We want them to live a normal life, and part of a normal life is being able to have a family. This is not simple, I don't think we have an answer," Dr Isaacs said.

The study was supported by the Fonds National de la Recherche Scientifique and by an unconditional grant from the Ipsen Pharmaceutical Group. Triptorelin was provided by the Ipsen Pharmaceutical Group. Dr Demeestere reports that her research received a grant from Ipsen. Dr Oktay, Dr Bedoschi, and Dr Isaacs have disclosed no relevant financial relationships.

J Clin Oncol. Published online May 23, 2016. Abstract, Editorial


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