Abstract: In total, 80%–90% of Hodgkin’s lymphoma (HL) patients are curable with combination chemoradiotherapy. Due to improvements in therapeutic strategies, 50% of all relapsed/refractory patients may undergo complete clinical responses and have long-term survival. Treatment options for HL are effective, but may have a negative impact on post-chemotherapy fertility. Thus, cryopreservation of semen prior to treatment is recommended for male patients. For female patients, assisted reproductive techniques (ART) consult and fertility preservation should be offered as a therapeutical option. In the last years, new targeted molecules have been available for HL treatment. These new drugs showed a high rate of overall responses in the setting of heavily pretreated patients, most of them in relapse after autologous stem cell transplantation, a group previously considered very poor risk. Up to 50% of patients have a complete response and an improved overall survival. Future studies will address the usefulness of novel molecules as a frontline therapy. Considering the high response and survival rates with monoclonal antibody-based therapeutics, fertility has become a concerning issue for long-term HL survivors. As progress has been made regarding ART, with the rigorous steps planned for HL patients, more survivors will become parents.
Keywords: Hodgkin’s lymphoma, infertility, pregnancy, fertility preservation
Due to modern combined chemoradiotherapy strategies, Hodgkin’s lymphoma (HL) is now considered to be a malignant disease with a high curability rate and a 5-year progression free survival of 87%.1Patients diagnosed with early stage HL are generally treated with short courses of chemotherapy plus consolidation radiotherapy. Patients with an advanced stage disease are treated with combination chemotherapy.2–4 The progress made in the last few years with intensive chemotherapy, autologous stem cell transplantation (ASCT), and novel targeted molecules has improved the response and survival rates, even for advanced stage of relapsed/refractory HL.5–9 Patients with progressive disease after salvage therapy were considered, a decade ago, to be a very poor prognosis group. Eligible patients are now being offered the chance of undergoing an allogeneic stem cell transplantation, in association with an increased risk of therapy related-mortality.10–12 Targeted molecules show unprecedented response rates in present-day chemotherapy.13–17 Still, large cohort studies have yet to address the concerning issue of long-term complications. One such complication is infertility in both men and women. In women, infertility may be due to chemotherapy-induced diminished ovarian reserve (chDOR) or to premature ovarian failure (POF). chDOR manifests as secondary amenorrhea and persisting high levels of gonadotropins.18 POF is defined as the loss of ovarian function of peripheral origin before the age of 40. In men, chemotherapy may be complicated by temporary or definitive azoospermia. Even more, there is the issue of subfertility, a known complication of HL that affects both sexes, predominantly men. A possible explanation would be the disturbed cellular immunity.19–21
In the current paper, we aim to review the current know-how on fertility complications induced by chemotherapy and radiotherapy, as well as by novel drugs approved for HL therapy. Other possible treatment options, such as assisted reproductive techniques (ART) for HL patients with fertility problems and long-term survivors, are discussed, with the purpose of designing an algorithm with distinct steps on HL diagnosis, treatment, and tissue/sperm preservation.
The analysis was made following an extensive search of the National Library of Medicine’s MEDLINE database using PubMed and Google Scholar, as previously described.22 Papers included in the analysis were limited to English, German, Romanian, and French language publications, but were not limited to any geographical region, from January 1976 to July 2017. Only papers published between 1976 and 2017 were considered in order to avoid any inconsistencies in diagnostic criteria and also cover the period of publications on HL. The search strategy was based on the combination of the keywords “Hodgkin’s lymphoma”, “infertility”, “pregnancy”, “fertility preservation”. Subsequently, an additional manual search of the citations of the previously selected papers was performed.
We identified 268 candidate papers, of which nine papers were excluded as they were related to pediatric oncology. Nine other papers related to other types of lymphoma and solid cancers, being excluded, raised the number of analyzed papers to 250.