Second Cancer Risk 40 Years After Hodgkin Lymphoma Treatment

Reporter: Gita Suneja, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 30, 2012

Presenter: Berthe Aleman, MD, PhD
Affiliation: The Netherlands Cancer Institute


  • Large studies have identified increased risk of breast and other cancers in survivors of Hodgkin lymphoma, partially due to late toxicity of chemotherapy and radiation.
  • Over the last several years, the treatment of Hodgkin lymphoma has evolved towards less toxic chemotherapy and lower doses of radiation to smaller treatment volumes in an effort to minimize normal tissue toxicity.
  • The study sought to characterize the impact of these changes on the risk of secondary malignancy following treatment for Hodgkin lymphoma.

Materials and Methods

  • The study cohort consisted of 3,390 patients ages 15-51 years diagnosed with Hodgkin lymphoma between 1965-2000.
  • Patients were followed for secondary malignancy, and standardized incidence ratios (SIR) were calculated to compare second cancer risk in those treated for Hodgkin lymphoma with the expected cancer risk based on the general population.
  • Comparisons of second cancer incidence were also made between treatment modalities and different time periods, 1965-1979, 1980-1990, and 1990-2000.


  • Median follow-up was 18.2 years, and 23% of the patients were followed for more than 25 years.
  • In the study period, 734 second cancers occurred.
  • The SIR for any cancer was 4.5, leading to an absolute excess risk of 114.4 cases per 10,000 persons/year.
  • SIR markedly decreased in more recent calendar years for hematologic malignancies diagnosed after treatment for Hodgkin lymphoma, and these differences were statistically significant.
  • Additionally, the risk of developing a secondary leukemia was far lower than the risk of developing a secondary solid tumor.
  • For solid malignancies, SIR did not decrease in more recent calendar years.
  • Patients treated with larger radiotherapy fields (full mantle vs. partial mantle) had a higher SIR for secondary breast cancers, 8.1 vs. 3.1.
  • Infra-diaphragmatic radiation increased the risk for secondary stomach, colon, and rectal malignancies with SIR of 2.5
  • Procarbazine administration at doses > 4.2 g/m2 had SIR of 2.3, except for breast cancer in which high procarbazine doses appeared to decrease the risk of breast cancer.
  • The effects of radiation therapy and procarbazine were independent of each other, and risks were additive in patients who received both.

Author's conclusions

  • Second cancer risk after Hodgkin lymphoma has decreased over time, with the observed difference largely accounted for by decrease in hematologic malignancies with treatment changes in the last decade.
  • Smaller radiation fields and procarbazine doses > 4.2 g/m2 are associated with lower breast cancer risk, while high procarbazine doses are associated with increased risk of gastrointestinal cancers.

Clinical Implications

  • The incidence and management of secondary cancers in survivors of Hodgkin lymphoma is a complex problem.
  • Given the high rates of control in Hodgkin lymphoma, many patients will live long enough to develop a secondary cancer associated with chemotherapy or radiation treatment.
  • Over the years, the treatment paradigms have changed to minimize the risk of late toxicity, including secondary malignancy. Reduction in radiation dose, treatment volume, and selectivity in chemotherapy regimens have all been attempted to minimize long-term treatment toxicity.
  • This study demonstrated that while the SIR for hematologic secondary malignancies have decreased in the modern era, the SIR for solid secondary malignancies have not decreased.
  • While this is a large, multicenter cohort study with detailed treatment information and very complete follow-up, the follow-up may not have been long enough to detect a reduction in risk of secondary solid cancers.
  • Analyses examining the impact of dose on secondary cancer incidence were not conducted, and dose may be an important factor influencing secondary cancer incidence.
  • Additionally, the effect of age at treatment on secondary cancer incidence was not examined, but young age at treatment has been found to contribute to excess secondary risk in other studies.
  • Another recently published study demonstrated that in addition to age at treatment and chemotherapy regimen, radiation dose does contribute to secondary malignancy risk (Omer, Br J Hematol, 2012).
  • The strengths of this study are the large sample size and near complete follow-up. With a longer follow-up interval, the effects of decreased radiation field size and dose may be more evident by reduction of SIR for secondary solid malignancies following treatment for Hodgkin lymphoma.