No Reduction of Ovarian Failure with the Use of GnRH-Analogues or Oral Contraceptives in Young Women Treated with Escalated BEACOPP for Advanced-Stage Hodgkin Lymphoma (HL). Final Results of the PROFE Trial, German Hodgkin Study Group (GHSG).

For ongoing trials of the German Hodgkin Study Group (GHSG), the reduction of treatment-related toxicities is the main goal. In this respect, the prevention of ovarian failure in young women is of major importance. This might be achieved with oral contraceptives and Gonadotropin-releasing hormone agonistic analoges (GnRH-a) by inhibiting follicular growth in the ovary. Unfortunately, only contradictory, mostly retrospective or non-controlled results on these protective effects have been published, Thus, the GHSG started a randomised phase-II trial (PROFE) for the reduction of ovarian failure with the use of GnRH-analogues and oral contraceptives in young women treated with intensive chemotherapy for advanced-stage HL. The aim of the trial was to develop a standard co-treatment for the reduction of infertility rates.

The study was designed for young female patients (18-40 years) with advanced-stage HL, including stage II with B symptoms and one of the following risk factors: extranodal disease and/or large mediastinal mass, stage III, and IV. The patients were randomly assigned either to receive daily oral contraceptive or to receive the GnRH-analogue given monthly during 8 cycles of polychemotherapy with escalated BEACOPP. Blood samples were drawn for determination of hormonal levels once before the beginning of therapy, monthly during therapy, and 6, 12, and 18 months after therapy. Hormonal profiles including follicle-stimulating hormone (FSH), luteinizing hormone (LH), E₂, Anti-Müllerian Hormone (AMH), prolactin, testosterone, DHEAS, SHBG, Inhibin A, Inhibin B, and progesterone were measured to document fertility status. The primary endpoint according to study protocol was the FSH level 6 months after the end of therapy. Because in the meantime AMH has been established as more valid indicator for ovarian function, we finally used AMH levels after minimally 12 months (<.46 μg/l) as more conclusive criterion for infertility. Individual courses for FSH, AMH and oestradiol in the 2 experimental groups will be presented.

The recruitment started in 2004 and was prematurely stopped in 2007 because of the following hindrances to participation: first, the application of the more intensive 8 cycles of escalated BEACOPP instead of less toxic treatment alternatives in the competing HD15 study (6 cycles of escalated BEACOPP or 8 cycles of BEACOPP-14). Second, to date, mostly all female patients in advanced stages already receive GnRH-analogue co-treatment, as recommended by their gynaecologists, and could therefore not be included into the PROFE trial. Consequently, a total of 23 patients are now evaluable for the final analysis of blood samples. Twelve patients were enrolled into arm A (oral contraceptive) and 11 into arm B (GnRH-analogue). At randomisation, women's mean age was 28 years in arm A and it was 26 years in arm B. FSH and AMH levels were correlated but also showed remarkable differences. In 8 cases FSH levels finally returned to normal values after therapy, whereas AMH levels remained reduced with exception of one woman receiving co-treatment with oral contraceptives (arm A). The respective infertility rates and 95% confidence intervals were 90% in arm A (62%-99%) and 100% in arm B (76%-100%). Combining arm A and arm B, the infertility rate in all 19 patients determined by AMH after minimally 12 months was 95% (78%-99%).

In this prospectively randomised study in HL patients, no meaningful ovarian protection with hormonal co-treatment during HL therapy consisting of 8 cycles of escalated BEACOPP has been achieved. Though the confidence interval in this study is large due to the limited number of patients, the results do certainly not support the use of oral contraceptives or GnRH analogues to prevent ovarian failure in young women during this intensive chemotherapy regimen. Thus, alternative strategies for the protection of ovarian function should be offered to young women before the start of treatment.

Off Label Use: Gonadotropin-releasing hormone agonistic analoges inhibiting follicular growth in the ovary with purpose to reduce infertility.