Age at the Time of Hodgkin’s Disease Treatment and the Occurrence of Second Malignancies

Abstract & Commentary

Synopsis: With the advent of effective chemotherapy and radiotherapy approaches for the treatment of Hodgkin’s disease introduced several decades ago, there is now a large cohort of patients with a remote history of such treatment. In this report of a large series of such survivors, second malignancies of all types (including lung, colon and breast, as well as leukemia) were discovered at an increased rate. The risk of developing second malignancies was greatest for those who were treated for their Hodgkin’s disease at a young age. Patients cured of Hodgkin’s disease are at increased risk for second malignancy, and the risk appears to increase rather than recede with time.

Source: Swerdlow AJ, et al. J Clin Oncol 2000;18:
498-509.

Inasmuch as curative therapies for hodgkin’s disease have been available for over three decades, the long-term side effects of treatment are now becoming increasingly apparent. To further describe the later consequences of treatment, a large cohort of British patients (n = 5519) treated from 1963 to 1993 were evaluated for the development of second malignancy and mortality. The data, derived from the British National Lymphoma Investigation, the Royal Marsden Hospital, and St. Bartholomew’s Hospital registries, were available for 97% of patients.

There were 322 second malignancies in this group. All major types of tumors were more frequent in Hodgkin’s disease survivors than the general population. For example, the relative risks of gastrointestinal, lung, breast, and of leukemia increased significantly. Although the absolute excess risks of second malignancy were greater for older patients, the relative risks (RR) were more pronounced for individuals who had Hodgkin’s disease treated at a young age. Furthermore, there now emerges a trend toward certain types of second tumors depending on the type of Hodgkin’s disease therapy. For example, after mixed modality treatment, the relative risk for gastrointestinal cancer was 3.3 (95% CI, 2.1-4.8), whereas the risk of lung cancer was greater for those that received chemotherapy alone (RR = 3.3; 95% CI, 2.4-4.7) and the risk of breast cancer was increased for those that had received radiotherapy (without chemotherapy) (RR = 2.5; 95% CI, 1.4-4.0).

As mentioned, these risks were greater after treatment at younger ages: for patients treated at ages younger than 25 years, there were RRs of 18.7 (95% CI, 5.8-43.5) for gastrointestinal cancer after mixed-modality treatment, 14.4 (95% CI, 5.7-29.3) for breast cancer after radiotherapy, and 85.2 (95% CI, 45.3 to 145.7) for leukemia after chemotherapy (with or without radiotherapy).

This analysis highlights the major effect of age at treatment on the appearance of second malignancy after Hodgkin’s disease. The association of type of treatment and the occurrence of specific second tumors is an observation that may eventually provide clues to the mechanisms of tumor development in those organ systems.

COMMENT by william b. ershler, md

This analysis is by far the most comprehensive description of second malignancies in Hodgkin’s disease survivors. Treatment-related leukemias have been appreciated for many years,1-3 and most believe that alkylating agents are primarily responsible.4 These leukemias tend to occur within a few years of Hodgkin’s disease treatment. Solid tumors occur more gradually, but eventually constitute the great majority of second malignancies.5,6

There have been other reports that would suggest that, at least for certain cancers, the risks are greater after childhood than after adult Hodgkin’s disease treatment.7-9 This comprehensive report supports this conclusion. It is curious that gastrointestinal malignancies seem to occur more commonly in individuals treated with mixed modalities, whereas breast cancer occurs more commonly in patients previously treated with radiation alone. Chemotherapy is clearly associated with the development of leukemias and probably lung cancer as well. Why this should be the case is clearly conjecture at this point, but the roles of specific treatments in the etiology of second malignancies needs further and intense exploration.

The report also highlights the importance of patient age at the time of treatment, and now, with many survivors having been treated 30 or more years ago, there is an emergence of lung and gastrointestinal second malignancies with rates that exceed those for leukemia. It may well be that the increased risk for these solid tumors will increase even more with succeeding decades.

The take-home message for clinicians is that patients cured of Hodgkin’s disease are in a high-risk category for just about all types of cancer, and such patients should be examined and screened as rigorously as rigorously as any high-risk group.

References

1. Tucker MA, et al. N Engl J Med 1988;318:76-81.

2. Kaldor JM, et al. N Engl J Med 1990;322:7-13.

3. Boivin JF, et al. J Natl Cancer Inst 1995;87:732-741.

4. Swerdlow AJ, et al. BMJ 1992;304:1137-1143.

5. Kaldor JM, et al. Int J Cancer 1987;39:571-585.

6. Mauch PM, et al. Blood 1996;87:3625-3632.

7. Bhatia S, et al. N Engl J Med 1996;334:745-751.

8. Sankila R, et al. J Clin Oncol 1996;14:1442-1446.

9. Rodriguez MA, et al. Ann Oncol 1993;4:125-131.

Which of the following statements about the risk of second malignancy after treatment for Hodgkin’s disease is not true?

a. The older the patient at the time of treatment, the greater the risk for leukemia development.

b. Younger patients have a greater relative risk for the development of solid tumors.

c. Lung, colon, and breast cancer occur at increased frequency in Hodgkin’s disease survivors.

d. Solid tumors occur later after Hodgkin’s disease therapy than do leukemias.