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.
In their article in the August issue of ONCOLOGY, Klimm and colleagues review the data available for treatment of patients 60 years and older with Hodgkin's lymphoma (HL). They present convincing evidence that multiple variables determine the poor outcome described for older patients with this disease, and suggest that the disease may be a different kind of lymphoma than it is in patients who are younger than 60.
First, some authors have previously suggested that the disease is more aggressive in patients who are older, with more frequent presence of B symptoms and more extensive disease. Second, multiple authors have described retrospective analyses of patients who received chemotherapy in an attempt to determine why these older patients have a poor outcome-often using mechlorethamine (Mustargen)-based combinations-and have reported that dose reductions were often necessary, that complications were more frequent in this population, and that comorbid conditions often precluded curative-intent therapy.
Klimm and colleagues review in detail many of these studies, and rightly find that misdiagnoses were responsible in the past for many of the poor results reported for these patients. They also note that most trials do not include patients who are older, and that we probably do not know the true incidence of the disease in "older" patients, however that group is defined. They also comment on methods using novel agents that will hopefully improve results for these patients, and underscore the need for standard methods of assessing potential tolerability of therapy prior to embarking on a treatment program.
But the question remains: is this really a disease that is different in older patients? First, Klimm and colleagues fail to mention that the age cutoff in the International Prognostic Score (IPS) system for Hodgkin's lymphoma is 45, not 60, and the differences in results between patients 45 to 60 and those under 45 have not been addressed by any prior study. In ongoing trials that analyze results for patients with HL, age 45 is being used as an adverse prognostic factor, because of its inclusion in the IPS, and reasons for this cutoff are not clear. Prospective studies are needed to clarify this point.
Second, older age, although important in patients receiving radiotherapy alone in past studies, is not an important factor reported in patients with stage I/II HL who receive combined-modality therapy.[2-4] Part of this may be due to the small numbers of older patients who present with early-stage disease, and part may relate to the value of combined modality in treating early-stage disease.
Third, although some studies have reported more advanced disease in older patients, it is not clear that the disease is different in an older patient: perhaps it is something about the older patient that is different. Investigators still do not fully understand the role that the patient's immune response has in the development or progression of the disease, and until we have more sophisticated ways of understanding this phenomenon, we may not have answers to this question.
Another problem with past studies specifically reporting results for older patients is that, surprisingly, none of them studied primarily patients who received ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) alone. Currently, ABVD is the most frequently used chemotherapy combination in the United States to treat HL, and, although multiple investigators have determined that the use of doxorubicin improves results for older patients with HL, ABVD, with its limited capability for cardiac and marrow toxicity compared to MOPP (mechlorethamine, vincristine [Oncovin], procarbazine [Matulane], prednisone) or other more intensive regimens, appears to have been forgotten by those testing PVAG (prednisone, vinblastine, doxorubicin, gemcitabine [Gemzar]) and other regimens in older patients. Admittedly, bleomycin is not a good agent to include in therapy for the older patient, because of the high risk of death once pulmonary toxicity develops, but some authors have already suggested that this drug is not as important as the other drugs in the ABVD regimen, and one is quick to omit this drug from the ABVD regimen once early toxicity develops.[5-7]
In the one trial that randomized patients between MOPP and ABVD in the United States, two prognostic factors seemed to suggest worse results: age over 50 and at least two extranodal sites of involvement. The combination of both of these adverse features was associated with a higher failure rate in those treated with MOPP, but not for those treated with ABVD, suggesting that ABVD may be a better regimen for the patients at greatest risk, supporting conclusions reached by others regarding doxorubicin in the review by Klimm and colleagues. Perhaps ABVD should be tested specifically in older patients, perhaps without bleomycin, to determine its value in this population.
Finally, the authors themselves have published some interesting data supporting the concept that HL in the older patient is no different than it is in the younger patient. Engert and colleagues reported that patients aged 60 years or older more often have stage III/IV (combined) disease, masses measuring greater than 5 cm, elevated erythrocyte sedimentation rates, poor performance status, and mixed cellularity histology. However, none of these prognostic factors were reported by Hasenclever and Diehl as being important in their study used to develop the IPS. When they analyzed their results according to an age-adjusted IPS, 11% of those under 60 had a score of 4 to 6, compared with 13% of those who were 60 or older.
Admittedly, the older patient may need extra care when receiving chemotherapy, and comorbidities cannot be overlooked, but at the current time, there is little to suggest that-in the era of modern chemotherapy-HL in the "older" patient is different from the disease in a "younger" patient.
-Fredrick B. Hagemeister, MD
Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. 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 339:1506-1513, 1998.
2. Noordijk EM, Carde P, Dupouy N, et al: Combined-modality therapy for clinical stage I or II Hodgkin's lymphoma: Long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials.. J Clin Oncol 24:3128-3135, 2006.
3. Diehl V, Brillant A, Engert A, et al: HD10: Investigating reduction of combined modality treatment intensity in early stage Hodgkin's lymphoma. Interim analysis of a randomized trial of the German Hodgkin Study Group (GHSG) (abstract 6506). J Clin Oncol 23(16S):561s, 2005.
4. Bonadonna G, Bonfante V, Viviani S, et al: ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: Long-term results. J Clin Oncol 22:2835-2841, 2004.
5. Straus DJ, Portlock CS, Oin J, et al: Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood 104:3483-3489, 2004.
6. Canellos GP, Duggan D, Johnson J, et al: How important is bleomycin in the adriamycin + bleomycin + vinblastine + dacarbazine regimen? J Clin Oncol 22:1532-1533, 2004.
7. 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.
8. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478-1484, 1992.
9. 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.