Hodgkin Lymphoma and the Impact of Age

In this issue of ONCOLOGY, Evens et al present a thoughtful and compelling argument that Hodgkin lymphoma in elderly patients deserves to be a focus for clinical research. This same argument could be made for many other cancers. In his American Society of Clinical Oncology (ASCO) Presidential Address in 1988, B.J. Kennedy argued that older patients have been unfairly and unreasonably discriminated against in clinical cancer studies.[1] He made a strong case that cancer in older patients would be an increasing clinical problem in the future and that it should be specifically addressed in clinical research and in medical education.

Age and Prognosis

Age is an important prognostic factor in the International Prognostic Index (IPI) for aggressive non-Hodgkin lymphoma,[2] in the Follicular Lymphoma in the International Prognostic Index (FLIPI)[3] for patients with the most common indolent non-Hodgkin lymphoma, and in the most widely used Prognostic Index in Hodgkin lymphoma.[4] However, multiple potential explanations may account for the poorer outcome in elderly patients. These include comorbid illnesses, altered metabolism of chemotherapeutic agents, diagnosis later in the course of the disease, different histologic subtypes, and many others. All of these might apply to patients with any type of lymphoma, or almost any other malignancy.

However, the argument has been made that Hodgkin lymphoma is unique when it occurs in elderly patients and that it might actually represent a different disease.[5,6] Those who favor this interpretation use the bimodal incidence curve with peaks in young adulthood and in patients over 60 years of age and the higher incidence of a mixed-cellularity histologic appearance of lymphoma in older patients to suggest that Hodgkin lymphoma in older patients is a typical malignancy, whereas the disease in younger patients might be related to an infectious process.

Despite the differences seen in older patients with Hodgkin lymphoma, investigators have reported for many years that elderly patients with Hodgkin lymphoma who receive the same evaluation and the same therapy as younger patients can have a comparable outcome.[7,8] In contrast, other investigators have found that elderly patients tolerate intensive therapies less well than younger patients, even when administered as part of a clinical trial.[9]

One point that can be lost in the argument about the appropriate management for patients over 60 years of age with Hodgkin lymphoma (or other cancers) is the distinction between chronologic age and “biologic” age. There is no question that a 45-year-old with long-standing brittle diabetes, or chronic renal failure and coronary artery disease, or long-standing, severe rheumatoid arthritis on immunosuppressive therapy all present difficult management problems and probably will be more difficult to treat and have a poorer outlook than an active, healthy 68-year-old. When making decisions in the clinic, these factors, and not just the number of years a particular patient has lived, need to be taken into account.

Underrepresentation in Clinical Trials

As pointed out by Evens et al, we don’t have as much information about the care of older patients with Hodgkin lymphoma as we need to provide optimal care. Numerous authors have pointed out that older patients are less likely to be treated for a particular cancer, or less likely to be treated with “optimal” regimens than young patients.[10,11] Goodwin et al reported that New Mexican patients enrolled in Southwest Oncology Group studies substantially underrepresented the elderly.[12] While 31% of adult patients with cancer were over 70 years of age, only 7% of the patients enrolled in the studies were in that age group.

Chen et al looked at a phase II randomized trial of patients with aggressive-histology lymphoma and reviewed all patients over age 65 who might have been included in the study. A total of 68 consecutive patients met inclusion criteria, but 30 patients (44%) were not entered. Patients excluded from the clinical trial were older, had a poorer performance status, were less likely to ever be given treatment with curative intent, and were less likely to complete therapy.[13] The conclusion of the investigators was that the results reported for elderly patients in clinical trials are not generalizable to the whole population because only the healthiest patients actually participate.

Conclusions

Evans et al are, in my estimation, correct in arguing that a new focus needs to be given to the study of Hodgkin lymphoma in elderly patients. Better understanding of the biology of the disease, the appropriate evaluation of the patient, and identification of the most effective treatments would likely be the result of this effort. A very similar argument could be made for the study of elderly patients with other malignancies.

-James O. Armitage, MD

References:

References

1. Kennedy BJ: Aging and cancer. J Clin Oncol 6:1903-1911, 1988.
2. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329:987-994, 1993.
3. Solal-Celigny P, Roy P, Colombat P, et al: Follicular Lymphoma International Prognostic Index. Blood 104:1258-1265, 2004.
4. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 339:1506-1514, 1998.
5. MacMahon B: Epidemiology of Hodgkin’s disease. Cancer Res 26:1189-1201, 1966.
6. MacMahon B: Epidemiological considerations in staging of Hodgkin’s disease. Cancer Res 31:1854-1857, 1971.
7. Diaz-Pavon JR, Cabanillas F, Majlis A, et al: Outcome of Hodgkin’s disease in elderly patients. Hematol Oncol 13:19-27, 1995.
8. Austin-Seymour MM, Hoppe RT, Cox RS, et al: Hodgkin’s disease in patients over sixty years old. Ann Intern Med 100:13-18, 1984.
9. Klimm B, Eich HT, Haverkamp H, et al: Poorer outcome of elderly patients treated with extended-field radiotherapy compared with involved-field radiotherapy after chemotherapy for Hodgkin’s lymphoma: An analysis from the German Hodgkin Study Group. Ann Oncol 18:357-363, 2007.
10. Samet J, Hunt WC, Key C, et al: Choice of cancer therapy varies with age of patient. JAMA 255:3385-3390, 1986.
11. Mor V, Masterson-Allen S, Goldberg RJ, et al: Relationship between age at diagnosis and treatments received by cancer patients. J Am Geriatr Soc 33:585-589, 1985.
12. Goodwin JS, Hunt WC, Humble CG, et al: Cancer treatment protocols. Who gets chosen? Arch Intern Med 148:2258-2260, 1988.
13. Chen CI, Skingley P, Meyer RM: A comparison of elderly patients with aggressive histology lymphoma who were entered or not entered on to a randomized phase II trial. Leuk Lymphoma 38:327-334, 2000.