Occurrence of Second Malignancies after Treatment for Hodgkin's Lymphoma: Who's at Fault?

Abstract & Commentary

By William B. Ershler, MD

Synopsis: Capitalizing on a large cohort of British patients followed after treatment for Hodgkin's lymphoma, the risk of occurrence of second malignancy was assessed in the context of treatment with chemotherapy alone vs treatment with combined chemotherapy and radiation. Chemotherapy treatment alone was found to be associated with an increased risk of leukemia, non-Hodgkin's lymphoma, and lung cancer, whereas treatment with combined modality was associated with an even greater risk of these three malignancies as well as cancers arising at a number of other anatomic sites. Furthermore, whereas the risk of malignancy after chemotherapy alone peaked at 5-9 years and was minimal at 15 years, the risk of malignancy after combined modality remained elevated at 25 years after treatment.

Source: Swerdlow AJ, et al. Second cancer risk after chemotherapy for Hodgkin's lymphoma: A collaborative British cohort study. J Clin Oncol 2011;29:4096-4104.

Long-term survival is now the expected outcome for patients with Hodgkin's lymphoma (HL), but the occurrence of second malignancies is becoming a well-recognized late effect.1 The risks associated with radiation therapy are clearly established,2 as well as those associated with certain chemotherapeutic agents.3 However, for patients with HL, the absolute risk for those treated with chemotherapy alone has been difficult to establish, primarily because most patients in published large cohorts had been treated with radiation, either alone or in combination with chemotherapy. In the United Kingdom, chemotherapy alone has been undertaken more often as initial HL treatment, and the current investigation examining a large cohort of patients aimed to determine the absolute excess risk (AER) of second malignancy with an emphasis on patients treated with chemotherapy alone.

For this, Swerdlow and colleagues reported on 5798 HL patients (of whom 3432 also received radiotherapy treated from 1963 to 2001). Second primary malignancy risk was determined and compared with general population-based expectations.

Second malignancies occurred in 459 cohort members. Relative risk (RR) of second cancer was raised after chemotherapy alone (RR, 2.0; 95% confidence interval [CI], 1.7 to 2.4) but was significantly lower than after combined modalities (RR, 3.9; 95% CI, 3.5 to 4.4). For those receiving chemotherapy alone, the analysis revealed significantly raised risks of lung cancer, non-HL, and leukemia — each contributing approximately equally to the absolute excess risk. For those receiving combined chemotherapy/radiation, there were raised risks of these and several other cancers. Second cancer risk peaked 5-9 years after chemotherapy alone, but it remained raised for 25 years and longer after combined modalities. It appeared that the risk was raised after each common chemotherapy regimen except ABVD, although the numbers and follow-up of patients receiving ABVD alone was limited.

The RR for the development of acute leukemia after either chemotherapy alone or combined chemotherapy/radiation therapy was greater in women than men, was not related to age at first treatment, reached a peak at 5-9 years after treatment, and was virtually non-existent after 14 years.

Other than leukemia and lung cancer, the risk of all other solid tumors combined was raised significantly only for those receiving radiation therapy combined with MOPP, MVPP, or ChlVPP.

The 20-year cumulative risk of second malignancy was 13% for chemotherapy only compared with 18% for combined chemotherapy/radiation patients. Among the chemotherapy-only patients, the risk for second malignancy when initially treated at age 25 years or younger was 3%, but it rose to 46% in those treated at age 55 years or older.

Commentary

The study expands our knowledge by providing data on a large cohort of patients treated for HL with chemotherapy alone. The data show that unlike radiotherapy, which affects cancer risk at almost all sites, chemotherapy is followed by substantial risks for only three malignancies: leukemia, non-Hodgkin lymphoma, and lung cancer. Furthermore, for those treated with ABVD alone, the data did not demonstrate any raised cancer risk, although, as the authors suggest, the period of follow-up was significantly less for this subgroup. This is notable because other studies suggested ABVD/radiation when compared to MOPP/radiation, although associated with lower risk for leukemia, resulted in a greater risk for solid tumors.4 This does not appear to be the case observed in this large British cohort, although a longer follow-up will be needed to establish this with confidence.

References

1. Baxi SS, Matasar MJ. State-of-the-art issues in Hodgkin's lymphoma survivorship. Curr Oncol Rep 2010;12:366-373.

2. Longo DL. Radiation therapy in Hodgkin disease: Why risk a pyrrhic victory? J Natl Cancer Inst 2005;97:1394-1395.

3. Swerdlow AJ, et al. Risk of second primary cancers after Hodgkin's disease by type of treatment: Analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 1992;304:1137-1143.

4. Bonadonna G, et al. Survival in Hodgkin's disease patients—Report of 25 years of experience at the Milan Cancer Institute. Eur J Cancer 2005;41: 998-1006.