Fertility outcomes following beacopp and ebeacopp chemotherapy in Hodgkin's lymphoma: A systematic review

Abstract Background: Hodgkin's disease has a high survival rate, especially if caught and treated in early stages. It can be effectively treated with bleomycin sulfate, etoposide phosphate, doxorubicin hydrochloride (Adriamycin), cyclophosphamide, vincristine sulfate (Oncovin), procarbazine hydrochloride, and prednisone (BEACOPP) and escalated-BEACOPP chemotherapy. However, through these treatment options, fertility is at high risk. Since it mainly affects the population at the peak reproductive age, we aim to conduct a systematic review on the fertility outcomes after treatment of Hodgkin's lymphoma with these regimens. Methods Eligible articles were retrieved from Embase, Cochrane Library, Clinicaltrials.gov, PubMed, and various conference papers per PRISMA guidelines using search terms related to “Hodgkin's disease” and “Fertility outcomes” After primary and secondary screening of the articles from search, 15 were included reporting patients aged 16-60 who underwent BEACOPP or EBEACOPP treatment for Hodgkin's lymphoma. The effects of treatment of Hodgkin's lymphoma on their fertility and reproductive abilities are reported descriptively. Results A total of 12,515 patients aged 16–60 years, who received BEACOPP or eBEACOPP chemotherapy for Hodgkin's lymphoma, were included from 15 studies, with follow-up ranging from 32 months to 8.7 years. 51.4% females undergoing eight cycles of eBEACOPP experienced amenorrhea, considerably more than with BEACOPP or other regimens. Menstrual recovery was age-dependent: 82% women under 30, 45% women over 30, resumed cycles. In early-stage HL, 90% women recovered menstrual function within 12 months. Fertility was mostly affected by: low ovarian reserve, older age, and higher cumulative alkylating agent doses. Post-treatment, Low ovarian reserve (AMH<0.5 ng/ml), low AMH levels with low recovery at 3 years, increased FSH levels (during and post-treatment), increased LH levels, and low oestradiol levels were observed, which pointed towards premature ovarian insufficiency (POI). 46.1% eBEACOPP arm patients experienced POI, compared to 14.5% in the PET-adapted arm. AMH levels decreased from 6.8 to 0.08 pmol/L after BEACOPP in 5 of 7 patients at 3 years. PET-guided therapy reduced the risk of POI. In males, treatment with eBEACOPP therapy resulted in 96.3% azoospermia, whereas the PET-driven arm achieved 33.3%, with better sperm recovery compared to eBEACOPP. Hormonal analysis revealed elevated FSH and decreased inhibin B levels post-treatment, both for eBEACOPP and advanced stage HL. Testosterone levels remained within normal range, especially in younger males, who had higher levels. Spermatogenesis recovery occurred in 4 patients, with a median recovery time of 3.6 years. 4-year gonadal function recovery rates were much lower for eBEACOPP patients (males 39.7%, females 73.3%) as compared to BrECADD (males 85.6%, females 95.3%) Parenthood occurred in 15/91 women in the eBEACOPP group and 4/133 men. Another study showed that out of 84 reported pregnancies, 35 occurred in the standard arm and 49 in the PET-driven arm. In HD21, 108 childbirths were reported, with pregnancies more common in early stage as compared to advanced-stage HL survivors: 6.5% women, 3.3% men. Use of fertility preservation methods was common. Males who preserved sperm, using cryopreserved samples, had high assisted reproduction success. Fertility recovery occurred in 30% of patients treated with alkylating regimens after a median of 19 months, compared to 82% in patients treated with non-alkylating regimens. Conclusion HL treatment can be done with BEACOPP/ eBEACOPP, but it can result in significant gonadotoxicity. Both male and female patients showed signs of infertility, with significant hormonal disturbances. PET-adapted regimens reduced POI and improved recovery of gonadal function in both sexes; many survivors, especially young patients with fertility preservation, were able to achieve pregnancies and parenthood. Fertility counselling should be integrated into reproductive-aged HL patients undergoing BEACOPP or eBEACOPP chemotherapy.