Second Cancer Risk Remains Elevated After Treatment of Hodgkin’s Lymphoma Interview with:
Dr. Michael van Leeuwen PhD
Department of Epidemiology
Netherlands Cancer Institute
Amsterdam, the Netherlands

Medical Research: What is the background for this study? What are the main findings?

Response: Over the last decades cure rates for Hodgkin’s lymphoma patients have increased dramatically. Cure and long-term survival may, however, come at a price, in the form of an increased risk of second cancers and other late effects. Since the late 1980’s treatment of Hodgkin’s lymphoma has been changed towards smaller radiation target volumes and more effective, generally less toxic chemotherapy.

In a study which included 3905 Hodgkin’s lymphoma patients treated between 1965 and 2000 in the Netherlands, the impact of these treatment changes on second malignancy risk was evaluated. Hodgkin’s lymphoma patients were between the ages of 15 and 50 years and had survived at least 5 years after treatment.

During follow-up, 1055 second cancers were diagnosed in 908 survivors, corresponding to a risk of 4.6 times as high as the occurrence of cancer in the general population. Up to at least 40 years after treatment for Hodgkin’s lymphoma, survivors remained at increased risk for second cancers.

The cumulative incidence of a second cancer was 33.2% at 30 years, compared with 9.6% in the general population, and 48.5% at 40 years, compared with 19.0% in the general population.

Breast cancer was the most common second cancer reported followed by lung and gastrointestinal cancers. Thirty-year cumulative incidence was 16.6% for breast cancer, 7.1% for lower respiratory tract cancers, 7.0% for gastrointestinal cancers, and 3.7% for non-Hodgkin’s lymphomas.

The risk of solid cancer after treatment for Hodgkin’s lymphoma was not lower among more recently treated patients (patients treated between 1989 and 2000) than among those who were treated in earlier time periods, despite changes in treatment. Nonetheless, patients treated with smaller radiation fields (e.g., a supradiaphragmatic field radiotherapy not including the axilla) were at a 63% lower relative risk of breast cancer as a second malignancy than if they received complete mantle-field radiotherapy. The lack of change in the cumulative incidence of solid cancers could be due to an incomplete adoption of the more modern radiotherapy concepts but may also be explained on the basis of a change in the chemotherapy regimens used in the 1990s. Because in the 1970’s many women exposed to high doses of alkylating agents were experiencing premature menopause, doses of alkylating agents were lowered over time to preserve fertility. However, early menopause introduced with the alkylating regimens was likely responsible for decreasing the breast cancer incidence. With the lower doses of the alkylating agents, this protection was taken away.

The cumulative incidence of non-Hodgkin’s lymphoma and of leukemia (and the myelodysplastic syndrome) was, however, much lower among patients who were treated in the period from 1989 through 2000 than among those who were treated in the period from 1965 through 1976. For leukemia, the decrease in cumulative incidence is likely due to the much lower doses of alkylating agents used in Hodgkin’s lymphoma treatment in the 1990’s compared to earlier decades.

It is important to realize that current common practice in radiation oncology, including involved-node or involved-site radiotherapy, three-dimensional conformal radiation treatment planning, and radiation doses of less than 36 Gy, was not applied in our study population. It is hoped that these changes may reduce the risk of solid cancer among patients treated after 2000.

Medical Research: What should clinicians and patients take away from your report?

Response: For current survivors of Hodgkin’s lymphoma, information about second cancer risk should be provided, screening should be made available where proven useful and any emerging symptoms should be investigated without delay in order to rule out second-cancer diagnosis. Survivors should be recommended to stop smoking as this strongly increases their risk of radiation-induced lung cancer.

In the Netherlands, we have set up survivor clinics, in which – besides providing information on risk of late complications of Hodgkin’s lymphoma treatment – we offer intensive screening for breast cancer (from early ages onwards) to Hodgkin’s lymphoma, survivors. In addition, while treating new patients clinicians should carefully balance the risks of both radiation-related and chemotherapy-related late toxic effects against the risk of failing to control the primary disease.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: Future research should aim at refining Hodgkin’s lymphoma treatment, providing more individualized treatment to patients to optimize the chance of cure while limiting the risks of late complications.

Furthermore we should evaluate whether the burden, in terms of morbidity and mortality, of second cancers can be reduced by extending screening towards other cancer types such as colorectal cancer and possibly lung cancer. It also remains important to evaluate the risk of second cancers in patients treated with contemporary treatments after 2000.     


Second Cancer Risk Up to 40 Years after Treatment for Hodgkin’s Lymphoma

Michael Schaapveld, Ph.D., Berthe M.P. Aleman, M.D., Ph.D., Anna M. van Eggermond, M.Sc., Cécile P.M. Janus, M.D., Augustinus D.G. Krol, M.D., Ph.D., Richard W.M. van der Maazen, M.D., Ph.D., Judith Roesink, M.D., Ph.D., John M.M. Raemaekers, M.D., Ph.D., Jan Paul de Boer, M.D., Ph.D., Josée M. Zijlstra, M.D., Ph.D., Gustaaf W. van Imhoff, M.D., Ph.D., Eefke J. Petersen, M.D., Ph.D., Philip M.P. Poortmans, M.D., Ph.D., Max Beijert, M.D., Marnix L. Lybeert, M.D., Ina Mulder, Ph.D., Otto Visser, Ph.D., Marieke W.J. Louwman, Ph.D., Inge M. Krul, M.Sc., Pieternella J. Lugtenburg, M.D., Ph.D., and Flora E. van Leeuwen, Ph.D.

N Engl J Med 2015; 373:2499-2511

December 24, 2015
DOI: 10.1056/NEJMoa1505949

Dr. Michael van Leeuwen PhD (2015). Second Cancer Risk Remains Elevated After Treatment of Hodgkin’s Lymphoma 

Last Updated on December 24, 2015 by Marie Benz MD FAAD