Another step towards improving oncofertility counselling of young women with Hodgkin's lymphoma
Authors: Matteo Lambertini, Isabelle Demeestere
Journal: The Lancet Oncology (2018)

Possible chemotherapy-induced premature ovarian in-sufficiency is of great concern for female premenopausal patients with cancer. Therefore, appropriate counselling on the risk of premature ovarian insufficiency is now mandatory in all countries.1Peccatori FA Azim Jr, HA Orecchia R et al.Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2013; 24: vi160-vi170Crossref PubMed Scopus (491) Google Scholar, 2Oktay K Harvey BE Partridge AH et al.Fertility preservation in patients with cancer: ASCO Clinical Practice Guideline update.J Clin Oncol. 2018; 36: 1994-2001Crossref PubMed Scopus (703) Google Scholar Oncofertility counselling is of particular importance for women who have Hodgkin's lymphoma, who are often diagnosed at a young age. However, the counselling of these women can be quite complex because of the paucity of accurate data to estimate the effect of different chemotherapy regimens on their gonadal function. Previous studies in this setting were mostly retrospective or relied only on menstrual function after treatment to define premature ovarian insufficiency, a measure that is not an optimal surrogate for assessing gonadal damage associated with treatment. In The Lancet Oncology, Richard A Anderson and colleagues3Anderson RA Remedios R Kirkwood AA et al.Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial.Lancet Oncol. 2018; (published Sept 13.)http://dx.doi.org/10.1016/S1470-2045(18)30500-XSummary Full Text Full Text PDF Scopus (44) Google Scholar report important results for helping physicians informing premenopausal women with advanced Hodgkin's lymphoma about the risk of chemotherapy-induced premature ovarian insufficiency associated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or AVD, or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) chemotherapy.3Anderson RA Remedios R Kirkwood AA et al.Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial.Lancet Oncol. 2018; (published Sept 13.)http://dx.doi.org/10.1016/S1470-2045(18)30500-XSummary Full Text Full Text PDF Scopus (44) Google Scholar In this substudy, done within the RATHL trial (NCT00678327), biomarkers of ovarian function during and up to 3 years after chemotherapy were assessed in women younger than 45 years at the time of diagnosis. Specifically, 67 participants were monitored for serum antimüllerian hormone concentrations and 321 participants for follicle-stimulating hormone concentrations Despite a few limitations, including the small sample size of the antimüllerian hormone analysis, particularly of those who were treated with BEACOPP, and the lack of collection of participant information from the main RATHL cohort that could have had a potential effect on outcomes (eg, use of hormonal contraceptives, previous fertility preservation procedures, and menstrual status after chemotherapy), this study provides more precise information than previous reports to counsel women with Hodgkin's lymphoma on gonadal damage induced by ABVD, AVD, or BEACOPP. The results from this study raise several factors for consideration by patients and physicians. First, the study confirms that both the type of chemotherapy and patient's age at the time of treatment remain the two major determinants of risk of premature ovarian insufficiency for all patients with cancer.4Behringer K Mueller H Goergen H et al.Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials.J Clin Oncol. 2013; 31: 231-239Crossref PubMed Scopus (180) Google Scholar, 5Lambertini M Campbell C Bines J et al.Adjuvant Anti-HER2 therapy, treatment-related amenorrhea, and survival in premenopausal HER2-positive early breast cancer patients.J Natl Cancer Inst. 2018; (published online June 5.)DOI:10.1093/jnci/djy094Crossref Scopus (58) Google Scholar Antimüllerian hormone concentrations decreased substantially during both chemotherapy regimens; however, while antimüllerian hormone concentrations recovered to before treatment levels in those patients given ABVD or AVD by 1 year after treatment, little recovery of antimüllerian hormone concentrations was seen after treatment with BEACOPP.3Anderson RA Remedios R Kirkwood AA et al.Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial.Lancet Oncol. 2018; (published Sept 13.)http://dx.doi.org/10.1016/S1470-2045(18)30500-XSummary Full Text Full Text PDF Scopus (44) Google Scholar In Anderson and colleagues' study, age was shown to be a crucial factor, with increased risk of chemotherapy-induced premature ovarian insufficiency after both regimens in women aged 35 years and older at the time of diagnosis. Second, these results highlight the need for a standardised definition of premature ovarian insufficiency. Different endpoints (menstrual function only, ovarian biomarkers only—as in the present study—or a combination of the two) and timing of its assessment (ranging from a few months up to several years after chemotherapy) have been used to define chemotherapy-induced premature ovarian insufficiency. Therefore, cross-study comparisons remain difficult, even when the same chemotherapy regimens have been assessed. Guidelines suggest use of a composite endpoint that includes both amenorrhoea and a hormone profile after menopause,6European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POIESHRE guideline: management of women with premature ovarian insufficiency.Hum Reprod. 2016; 31: 926-937Crossref PubMed Scopus (688) Google Scholar, 7Paluch-Shimon S Pagani O Partridge AH et al.ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3).Breast. 2017; 35: 203-217Summary Full Text Full Text PDF PubMed Scopus (175) Google Scholar and assessing chemotherapy-induced premature ovarian insufficiency at least 2 years after the end of treatment.7Paluch-Shimon S Pagani O Partridge AH et al.ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3).Breast. 2017; 35: 203-217Summary Full Text Full Text PDF PubMed Scopus (175) Google Scholar In the present study, recovery of ovarian function, as measured by follicle-stimulating hormone concentrations, occurred by 1 year after the end of treatment for most patients (75% treated with ABVD or AVD and 33% treated with BEACOPP), but recovery can also happen during the second year (18% of participants treated with ABVD or AVD and 50% with BEACOPP) with little chance of recovery thereafter. These results support the expert opinion-based indication to assess ovarian function after chemotherapy no earlier than 2 years after treatment completion.7Paluch-Shimon S Pagani O Partridge AH et al.ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3).Breast. 2017; 35: 203-217Summary Full Text Full Text PDF PubMed Scopus (175) Google Scholar Third, although this study provides further evidence on the role of antimüllerian hormone as a biomarker of gonadotoxicity, the clinical utility of its assessment during treatment and subsequent follow-up remains to be fully determined. As shown in other studies,8Steiner AZ Pritchard D Stanczyk FZ et al.Association between biomarkers of ovarian reserve and infertility among older women of reproductive age.JAMA. 2017; 318: 1367-1376Crossref PubMed Scopus (205) Google Scholar, 9Demeestere I Brice P Peccatori FA et al.No evidence for the benefit of gonadotropin-releasing hormone agonist in preserving ovarian function and fertility in lymphoma survivors treated with chemotherapy: final long-term report of a prospective randomized trial.J Clin Oncol. 2016; 34: 2568-2574Crossref PubMed Scopus (153) Google Scholar both resumption of menstrual function and spontaneous conception can be observed in women with low concentrations of antimüllerian hormone.8Steiner AZ Pritchard D Stanczyk FZ et al.Association between biomarkers of ovarian reserve and infertility among older women of reproductive age.JAMA. 2017; 318: 1367-1376Crossref PubMed Scopus (205) Google Scholar, 9Demeestere I Brice P Peccatori FA et al.No evidence for the benefit of gonadotropin-releasing hormone agonist in preserving ovarian function and fertility in lymphoma survivors treated with chemotherapy: final long-term report of a prospective randomized trial.J Clin Oncol. 2016; 34: 2568-2574Crossref PubMed Scopus (153) Google Scholar Similarly, in Anderson and colleagues' study,3Anderson RA Remedios R Kirkwood AA et al.Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trial.Lancet Oncol. 2018; (published Sept 13.)http://dx.doi.org/10.1016/S1470-2045(18)30500-XSummary Full Text Full Text PDF Scopus (44) Google Scholar some pregnancies were observed in women with very low antimüllerian hormone levels. Hence, the best predictor of infertility in cancer survivors remains to be identified. Finally, this study raises the crucial issue of discussing the possibility of reducing the risk of premature ovarian insufficiency.1Peccatori FA Azim Jr, HA Orecchia R et al.Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2013; 24: vi160-vi170Crossref PubMed Scopus (491) Google Scholar, 2Oktay K Harvey BE Partridge AH et al.Fertility preservation in patients with cancer: ASCO Clinical Practice Guideline update.J Clin Oncol. 2018; 36: 1994-2001Crossref PubMed Scopus (703) Google Scholar Preservation of ovarian function (ie, reducing the risk of chemotherapy-induced premature ovarian insufficiency) should be distinguished from preservation of fertility (ie, improving the chances of pregnancy after treatment) and can be considered of important value also by women without childbearing desire. While cryopreservation of gametes is the first option to preserve fertility, the use of temporary ovarian suppression with gonadotropin-releasing hormone agonists during chemotherapy can now be offered for ovarian function preservation in patients with breast cancer, but its efficacy has not yet been shown in patients with Hodgkin's lymphoma.9Demeestere I Brice P Peccatori FA et al.No evidence for the benefit of gonadotropin-releasing hormone agonist in preserving ovarian function and fertility in lymphoma survivors treated with chemotherapy: final long-term report of a prospective randomized trial.J Clin Oncol. 2016; 34: 2568-2574Crossref PubMed Scopus (153) Google Scholar, 10Lambertini M Moore HCF Leonard RCF et al.Gonadotropin-Releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: a systematic review and meta-analysis of individual patient-level data.J Clin Oncol. 2018; 36: 1981-1990Crossref PubMed Scopus (193) Google Scholar The results of Anderson and colleagues' study highlight the importance of discussing access to these options in women older than 35 years, irrespective of chemotherapy type, and among candidates to the BEACOPP regimen, irrespective of their age. Very young women undergoing ABVD or AVD chemotherapy probably do not need to access these options, but they could be proposed later in life if additional treatments are required. Results from the ovarian function biomarker analysis ongoing within the AHL 2011 trial (NCT01358747) are awaited to provide further evidence on the gonadotoxicity of BEACOPP chemotherapy in premenopausal women with Hodgkin's lymphoma. We declare no competing interests. Determinants of ovarian function after response-adapted therapy in patients with advanced Hodgkin's lymphoma (RATHL): a secondary analysis of a randomised phase 3 trialReduced recovery of ovarian function observed in women older than 35 years treated with ABVD or AVD compared with younger women indicates that treatment could reduce their reproductive lifespan and supports discussion of fertility preservation before treatment. Women treated with BEACOPP should be informed of its potential high gonadotoxicity. These findings warrant further investigation in large, prospective studies with fertility and reproductive lifespan as outcomes. Full-Text PDF Open Access