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Journal of Clinical Oncology, Vol 25, No 12 (April 20), 2007: pp. 1630-1631 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.3666
Assessment of the Effect of Chemotherapy on Ovarian Function in Women With Breast CancerDivision of Reproduction and Developmental Science, Centre for Reproductive Biology, University of Edinburgh, United Kingdom
Department of Oncology, University of Edinburgh, United Kingdom To the Editor: Petrek and colleagues1 recently reported a large survey of menstrual function in women during and after breast cancer treatment. This is a valuable addition to the literature, particularly due to the prospective design and number of women recruited. However, its limitation, as the authors acknowledge, is that it only indirectly addresses its stated purpose—to assess ovarian function. In their comments on Petrek's study, Oktay and colleagues2 highlight new hormonal markers of the ovarian reserve. The most promising of these is anti-Müllerian hormone (AMH), as it reflects earlier stages of follicle development than inhibin B and estradiol, and thus, is believed to more closely approximate the number of primordial follicles in the ovary.3 Ultrasound measurement of both ovarian volume and antral follicle count (the number of small follicles present) are also of value.4 Most data arise from the clinical context of improving prediction of outcome during assisted reproduction, but may also be applied to ageing and the effects of chemotherapy, which can be regarded as inducing an accelerated form of ovarian ageing. It is also important to have accurate information on the gonadotoxicity of different cancer treatment regimens to improve patient information and optimize approaches for fertility preservation.5 Oktay and colleagues suggest that there have been no prospective studies assessing ovarian reserve in adult cancer patients. This is not the case as we have recently published just such a study in women with breast cancer.6 We recruited 56 women at the time of diagnosis, of whom 42 had chemotherapy after surgery. The remaining women received hormone treatment, most commonly goserelin with tamoxifen. A number of different chemotherapy regimens were represented, but most women received a regimen of sequential single-agent anthracycline followed by cyclophosphamide, methotrexate, and fluorouracil (CMF; n = 25), with 11 treated with epirubicin plus cyclophosphamide followed by docetaxel or paclitaxel. The data demonstrate a rapid and profound decrease in AMH during chemotherapy, often to undetectable concentrations. Most of the decrease occurs within the first 3 months of chemotherapy, during which time women received the anthracycline component of their therapy. Comparison of ovarian reserve markers at 6 months, the end of chemotherapy administration, for the four most commonly used regimens suggested that the docetaxel-containing regimen was the most gonadotoxic, with those women having the highest follicle-stimulating hormone concentrations and lowest AMH and inhibin B concentrations. This regimen included a markedly lower cyclophosphamide dose (2.4 g/m2 over 12 weeks) versus the epirubicin and CMF regimens (3.0 to 4.8 g/m2 over 12 to 16 weeks). The Bonadonna doxorubicin and CMF regimen appeared the least gonadotoxic of these four regimens, despite the highest cumulative dose of cyclophosphamide (4.8 g/m2 over 24 weeks). These observations suggest re-evaluation of whether cyclophosphamide should still be regarded as the main cytotoxic cause of premature ovarian failure.7 These hormone differences were also reflected in the prevalence of amenorrhoea, with the docetaxel regimen inducing amenorrhoea within 6 months in a significantly higher proportion of women than with the other main regimens (Fig 1). Interestingly, Petrek et al1 also report differences in bleeding patterns with different chemotherapy regimens. Their data indicate that more women continued menstruating in the initial months with CMF than with doxorubicin and cyclophosphide with or without a taxane, but that this was reversed with longer monitoring. The difficulty of interpreting these data confirm the value of direct assessment of ovarian function.
We also detected changes in the ultrasound markers of the ovarian reserve, with decreases in both ovarian volume and antral follicle count during chemotherapy.6 However, these are already low in this population compared with younger women reflecting the demographics of breast cancer and are likely to be of insufficient sensitivity to be of value comparing different treatment regimens in this context. Administration of endocrine agents, such as tamoxifen and increasingly aromatase inhibitors, complicates interpretation, but as suggested by Oktay,2 AMH may still have some value. Figure 2 shows AMH concentrations in five women treated with taxoxifen alone (ages 42 to 51 years) demonstrating no significant change over 12 months. Gonadotropin and estradiol concentrations showed the expected marked elevations. We have no data on the effects of aromatase inhibitors on AMH concentrations in premenopausal women.
Therefore, this study demonstrates the feasibility and value of prospective analysis of ovarian function using direct hormone measures of ovarian activity during and after treatment for breast cancer. We and others have previously performed analyses of the ovarian reserve in adult survivors of childhood cancer.8-10 These data complement the approach of Petrek and colleagues1 using menses as a surrogate for ovarian activity, which has the advantage of being less invasive and costly, and thus more suitable for larger studies. However, a detailed prospective approach is necessary for a more precise understanding of the effect of chemotherapy on the ovary, and for comparisons between regimens. This is of growing importance with the improved survival of women with breast and other cancers, who are increasingly interested in their fertility after treatment, as well as the consequences of loss of ovarian function, such as osteoporosis. Our preliminary data suggest that taxanes may increase gonadal toxicity compared with anthracycline and CMF regimens, but this needs to be confirmed.11 Taxane regimes are now recognized to confer survival advantages12; further detailed analyses will be required to confirm whether this is at the cost of increased damage to the ovary. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: David A. Cameron, Pfizer, Sanofi-Aventis, Bristol-Myers Squibb Research Funds: N/A Testimony: N/A Other: N/A
ACKNOWLEDGMENTS The study from which data are presented here was supported by the Medical Research Council. REFERENCES
1. Petrek JA, Naughton MJ, Case LD, et al: Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: A prospective study. J Clin Oncol 24:1045-1051, 2006 2. Oktay K, Oktem O, Reh A, et al: Measuring the impact of chemotherapy on fertility in women with breast cancer. J Clin Oncol 24:4044-4046, 2006 3. van Rooij IAJ, Broekmans FJM, Scheffer GJ, et al: Serum antimüllerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: A longitudinal study. Fertil Steril 83:979-987, 2005[CrossRef][Medline] 4. Scheffer GJ, Broekmans FJ, Looman CW, et al: The number of antral follicles in normal women with proven fertility is the best reflection of reproductive age. Hum Reprod 18:700-706, 2003 5. Lee SJ, Schover LR, Partridge AH, et al: American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 24:2917-2931, 2006 6. Anderson RA, Themmen APN, Al Qahtani A, et al: The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Human Reprod 10:2583-2592, 2006 7. Meirow D, Nugent D: The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update 7:535-543, 2001 8. Bath LE, Anderson RA, Critchley HOD, et al: Hypothalamic–pituitary-ovarian dysfunction after prepubertal chemotherapy and cranial irradiation for acute leukaemia. Hum Reprod 16:1838-1844, 2001 9. Bath LE, Wallace WHB, Fitzpatrick C, et al: Depletion of the ovarian reserve in young women following treatment for cancer in childhood: Detection by anti-Müllerian hormone, inhibin B and ovarian ultrasound. Hum Reprod 18:2368-2374, 2003 10. Larsen EC, Muller J, Rechnitzer C, et al: Diminished ovarian reserve in female childhood cancer survivors with regular menstrual cycles and basal FSH <10 IU/l. Hum Reprod 18:417-422, 2003 11. Fornier MN, Modi S, Panageas KS, et al: Incidence of chemotherapy-induced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane. Cancer 104:1575-1579, 2005[CrossRef][Medline] 12. Martin M, Pienkowski T, Mackey J, et al: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302-2313, 2005
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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