Aug 10, 2021
Dr. Lindsay Morton of the National Cancer Institute at the National Institutes of Health reflects on research findings by Øvlisen et al that leverage large-scale linked registries in Denmark to suggest that improvements in both chemotherapy treatments and assisted reproductive technologies have made it possible for more survivors of Hodgkin lymphoma to become parents.
This JCO podcast provides observations and commentary on the JCO article “Rates and Use of Assisted Reproduction Techniques in Younger Hodgkin Lymphoma Survivors: A Danish Population-Based Study of 793 Patients and 3965 Matched Comparators” by Øvlisen and colleagues. My name is Lindsay Morton, and I am a Senior Investigator and Deputy Chief of the Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, at the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. I am trained in epidemiology, and my oncologic specialty is in hematologic malignancies and cancer survivorship research. I have no relevant conflicts to disclose.
The adverse effects of treatment among patients with Hodgkin lymphoma have long been at the forefront of oncology research. In the late 1960s, patients with Hodgkin lymphoma were some of the first to receive combination chemotherapy with a four-drug regimen called “MOPP,” consisting of mechlorethamine, vincristine, procarbazine, and prednisone. MOPP resulted in dramatic improvements in patient outcomes following diagnosis with Hodgkin lymphoma. But in subsequent decades, the toxicities of MOPP came to be understood, including both acute toxicities – most notably myelosuppression – as well as longer-term toxicities such as second cancers and sterility, especially in males. Around the same timeframe, long-term toxicities of radiotherapy also were increasingly recognized, which set off a search for effective Hodgkin lymphoma treatment approaches with fewer short- and long-term toxicities. I often think of how research on adverse effects in patients with Hodgkin lymphoma has been at the vanguard in cancer survivorship: this focus has helped to drive development of new therapies and changes in clinical practice. This has occurred in part because Hodgkin lymphoma is frequently diagnosed in early adulthood and patients now have such a good prognosis; this means there is a longer window in which to experience any long-term effects of cancer treatments, and patients face unique issues, such as impacts on fertility, which aren’t relevant for older cancer patients.
In the paper accompanying this podcast, Øvlisen and colleagues present novel data on parenthood rates and use of assisted reproduction techniques in Danish patients with Hodgkin lymphoma. Importantly, the results of this study are very relevant to current patients because all the patients in the study were treated between 2000 and 2015 using standard treatment approaches that are still frequently used today. About one-third of the study population received radiotherapy plus 2-4 cycles of the combination chemotherapy regimen called “ABVD,” which consists of doxorubicin, bleomycin, vinblastine, and dacarbazine, and is the preferred front-line therapy approach for Hodgkin lymphoma patients in the United States. Another third of the study population received 6-8 cycles of ABVD, while in the remaining third, about half received either “BEACOPP” (a seven-drug regimen, which includes bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, and which is commonly used in Europe) or some other chemotherapy regimen.
In this study, the authors compared the rates of parenthood in patients with Hodgkin lymphoma to individuals in the general population who were matched to the patients by age, sex, and parenthood status. Overall, the news was good: both male and female survivors of Hodgkin lymphoma had similar parenthood rates as the matched individuals from the general population. But the details of this bigger picture finding are really worth understanding because of their important impact on patients. In particular, a larger number of patients with Hodgkin lymphoma than the comparison individuals from the general population used assisted reproductive technology in order to become parents. Specifically, nearly 22% of male and 14% of female survivors of Hodgkin lymphoma used assisted reproductive technology compared with only about 6% of those in the general population. When the authors looked at various predictors of parenthood in subgroup analyses, one other finding stood out: male survivors of Hodgkin lymphoma who had received BEACOPP therapy had about half the rate of parenthood compared with other Hodgkin lymphoma survivors and the general population. In contrast, for female survivors, parenthood rates were similar among the different treatment groups, but the numbers of female survivors treated with BEACOPP was small, so we should be cautious about drawing conclusions for females.
The results from Øvlisen and colleagues seem to reflect two important changes from previous studies, most of which included patients who were treated with older chemotherapy regimens, like MOPP. First, Hodgkin lymphoma treatments have continued to evolve, and adverse effects on fertility seem to be declining for the newer regimens. Second, of course, there also have been important advances in assisted reproductive technology, so that individuals who have trouble with conception initially can be helped by these technological advances.
In addition to hearing this good news for patients with Hodgkin lymphoma, the way the authors collected the information for this study was also exciting because it was large-scale, long-term, and systematic. Most of the data on fertility in patients with Hodgkin lymphoma previously has come from clinical trials. Those data have been invaluable, and in fact, provided some of the first signs several decades ago that patients with Hodgkin lymphoma treated with MOPP could face fertility issues. But we also know that clinical trials often have incomplete information on outcomes that occur more than a few years out, which raises some questions about the validity or generalizability of the study results for those outcomes.
In this report, the authors collected information on patients with Hodgkin lymphoma and the matched individuals from the general population from nationwide birth and patient registries. In countries like the United States, this study design would be virtually impossible because our healthcare system is fragmented – patients receive different types of care, like their cancer treatment and fertility treatments, in different places, and there is no easy way to link information on these different types of care for a specific individual. In this Danish study, the authors were able to leverage the centralized nature of the healthcare system in Denmark to capture not only all the information on the Hodgkin lymphoma treatments but also the birth registries and use of assisted reproductive techniques – connecting this information from different sources for all the individuals in the study. Because of the linkages that are possible among all these different sources of data, we are confident that the study provides complete, unbiased information even on longer-term outcomes.
While this study demonstrates both the importance of long-term patient follow-up and the power of registries, it also highlights the need to continue efforts to reduce toxicities and improve outcomes in patients with Hodgkin lymphoma, particularly those diagnosed in childhood, adolescence, or young adulthood. Fertility is just one aspect of quality of life that may be impacted by cancer treatment, and the more high-quality data we bring to bear on cancer survivorship, the better we will be at not just treating cancer but also taking care of the whole patient for the many years they have ahead of them.
This concludes this JCO Podcast. Thank you for listening.