With improved prognosis for patients with Hodgkin's lymphoma (HL), interest has increasingly focused on high-risk groups such as elderly patients. Advanced age at presentation is still one of the strongest negative risk factors. Many different factors influence the prognosis in elderly patients. These include biologic differences such as more aggressive histology, different distribution of disease, more frequent diagnosis of advanced stage, and shorter history of disease. In addition, however, aging itself and associated factors such as comorbidity, reduced tolerability of conventional therapy, more severe toxicity and treatment-related deaths, failure to maintain dose intensity, shorter survival after relapse, and death due to other causes contribute to the poorer outcome in elderly patients. Besides the evaluation of specific causes and risk factors, this review highlights recent and ongoing studies for elderly patients with HL as well as international approaches and recommendations for this age group.
Drs. Klimm, Diehl, and Engert draw upon their extensive experience in the treatment of Hodgkin's lymphoma (HL) in this thorough review of the many issues related to the disease in the elderly. As pointed out in the article, the study of Hodgkin's and its treatment has centered on young people, where there has been dramatic progress and success over the past 40 years. Although the elderly make up a significant proportion of patients with HL, they have been underrepresented in prospective studies and have generally had a much poorer outcome than younger patients.
The most recent Surveillance, Epidemiology, and End Results (SEER) analysis of HL evaluated patients diagnosed between 1995 and 2002. The 5-year survival rate for that period was 88% among patients aged 0 to 64, compared to 55% for patients aged 65 and older. This 5-year survival in older patients had improved from < 45% in the 1980s but remains significantly worse than that in younger patients. Given the aging populace in the United States and around the world, this is likely to become a more prevalent problem that requires improved understanding and study.
As discussed in the review and previously reported in a retrospective analysis by the German Hodgkin Study Group (GHSG), elderly patients with HL have a poorer risk profile at the time of diagnosis. This includes disease-specific characteristics (more mixed cellularity subtype, B symptoms, and elevated erythrocyte sedimentation rate) and patient-related characteristics (performance status, comorbid conditions).
In addition, a number of studies have documented increased toxicity from chemotherapy, resulting in lower doses or fewer cycles of chemotherapy administered. As the authors report, the use of the BEACOPP regimen (bleomycin, etoposide, doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], procarbazine, prednisone) in the GHSG HD9elderly trial resulted in an acute death rate of 21%, compared to 8% in the COPP-ABVD arm (cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine). This trial and others indicate that efforts at increased dose intensity that have favorable results in young patients cannot be directly applied to older patients. It may be that with improved stratification of the older population by comprehensive geriatric assessment or other tool, we could better identify candidates for aggressive therapy vs a more palliative approach.
The authors discuss the potential for increased use of granulocyte colony-stimulating factor (G-CSF, Leukine) in elderly patients to allow increased dose intensity or dose density. A recent retrospective review from the Mayo Clinic raises potential concerns about this approach due to the possibility of increased pulmonary toxicity. Of 141 patients treated with bleomycin-containing regimens, decreased overall survival was noted for patients experiencing bleomycin pulmonary toxicity (BPT). Patients older than 40 years were three times more likely to develop BPT (33% vs 11%, P = .001) and those treated with G-CSF also had a higher rate of BPT (26% vs 9%, P = .014). In addition, 40% of patients > 40 years old who developed BPT died of their pulmonary disease. Although these data are retrospective, they raise further questions about the routine use of prophylactic growth factors in older patients with HL receiving bleomycin-containing regimens.
A significant impediment to improvement in the treatment of older patients with HL has been the lack of participation in randomized clinical trials. As reviewed recently in this journal by Arti Hurria, insufficient numbers of older patients are participating in cancer clinical trials. Efforts to improve the risk stratification of elderly patients can result in improved tolerability of chemotherapy, which is a clear need in the study of HL. Prospective, randomized clinical trials dedicated to older patients, such as the HD9elderly trial of the GHSG, are necessary to improve patient outcome. It will be difficult to obtain reasonable response and toxicity data (for application to the general elderly population) from trials in which older adults make up only 10% to 20% of the total enrollment. There appear to be enough data to indicate that elderly patients with HL are not the same as younger patients, and trials are needed that approach the elderly as a separate population.
The authors identify a number of issues that need to be addressed to improve the outcome of elderly patients with HL. Primary among these should be the inclusion of more patients into well-designed, elderly-specific clinical trials. Risk stratification by comprehensive geriatric assessment or other mechanism may allow for the identification of patients who are candidates for aggressive therapy. This would also help identify those who are at significant risk for excess toxicity and should be treated more conservatively. Such trials will also provide information that is more easily utilized by oncologists caring for older patients with HL.
A second high priority should be the evaluation of novel agents with less potential toxicity. A number of biologic agents are under study in HL, as summarized by Re and colleagues. These include monoclonal antibodies, small molecules, and oligonucleotides, all of which have the potential to provide therapeutic activity with decreased toxicity. Such approaches have demonstrated activity in a number of malignancies and have particularly benefited the elderly by providing more tolerable treatment options. Phase II trials of several novel agents are currently open in the United States, and elderly patients who are not candidates for standard therapies should be encouraged to participate.
-John J. Densmore, MD, PHD
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence-SEER 17 Regs Public-Use, Nov 2005 Sub (1973-2003 varying), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2006, based on the November 2005 submission. Accessed March 26, 2007.
2. Engert, A, Ballova V, Haverkamp H, et al: Hodgkin's lymphoma in elderly patients: A comprehensive retrospective analysis from the German Hodgkin's Study Group. J Clin Oncol 23:5052-5060, 2005.
3. Repetto L, Fratino L, Audisio RA, et al: Comprehensive geriatric assessment adds information to Eastern Cooperative Oncology Group performance status in elderly cancer patients: An Italian Group for Geriatric Oncology Study. J Clin Oncol 20:494-502, 2002.
4. Martin WG, Ristow KM, Habermann TM, et al: Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma. J Clin Oncol 23:7614-7620, 2005.
5. Hurria A: Clinical trials in older adults with cancer: Past and future. Oncology (Williston Park) 21:351-358, 2007.
6. Re D, Thomas RK, Behringer K, et al: From Hodgkin disease to Hodgkin lymphoma: Biologic insights and therapeutic potential. Blood 105:4553-4560, 2005.