ABSTRACT: 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.
Treatment and prognosis of patients with Hodgkin's lymphoma (HL) has substantially improved during the past few decades, rendering this entity one of the most curable of human cancers. This success is mainly attributed to the introduction and optimization of effective chemotherapy regimens and progress in radiation techniques. However, these improvements have so far not been extended to the group of elderly patients presenting with HL.
In contrast to younger patients, elderly patients with HL still have an unsatisfactory prognosis. Advanced age at presentation is one of the strongest negative risk factors. Different study groups showed significantly poorer outcome for elderly HL patients compared with younger patients when similar treatments were given.[1-14] 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. But 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,[6-9] shorter survival after relapse,[10,11] and death due to other causes also contribute to the poorer outcome in elderly patients.
Within population-based studies, the proportion of patients older than 60 years ranges from 20% to 44%.[6,9,15] However, the number of elderly patients participating in prospective trials is considerably lower than that of younger patients. This is mainly due to the fact that most clinical trials have age limits or study entry criteria that exclude older patients with severe comorbidity or poor performance status. Although some retrospective analyses have enrolled selected elderly patients in standard treatment protocols, data from larger randomized studies designed for this age group are lacking.
Thus, besides the evaluation of toxicity, response, and outcome of established therapies, new strategies with sufficient efficacy and better tolerability are needed for elderly patients. Different modified or new regimens specifically targeted at elderly patients are currently being evaluated by different study groups.[16-19]
Here, we review the literature on elderly HL patients, including biologic and clinical prognostic factors as well as clinical studies and future approaches for this group of patients.
Biologic Differences in the Elderly
In Europe and the United States, the annual incidence of HL is about 2 to 3 per 100,000 persons at risk, and has remained remarkably constant over the past few decades. In industrialized countries, the age at onset has historically shown two peaks—one in the third decade and a second for patients older than 50 years. However, in more recent analyses, the second peak seems to disappear, since many cases of non-Hodgkin's lymphoma (NHL) were misclassified as HL in the past.
The incidence of HL in patients older than 60 years is still not exactly clear. The proportion of elderly patients participating in prospective trials is usually low, mostly due to age restraints for the trials or the fact that exclusion criteria are not met. Generally, more elderly HL patients were represented in studies performed in the 1970s or 1980s. For example, in earlier Cancer and Leukemia Group B (CALGB) studies, 19% of patients were older than 60 years. However, central pathology review was not performed in these studies. Given that a more recent retrospective reevaluation of elderly HL patients diagnosed decades ago indicates that a substantial proportion of elderly patients with B-cell lymphomas were initially misdiagnosed as having HL, meaningful studies in elderly patients require a reference pathology expert diagnosis. Accordingly, elderly patients represented 8% of all diagnoses in the follow-up CALGB trial, which included pathology review.
Within population-based studies, the proportion of elderly HL patients ranges from 20% to 44%: In a Swedish study, 163 of 202 patients treated between 1979 and 1988 were confirmed HL cases after histopathologic review. Of these, 61 (31%) were older than 60 years. Another study from England prospectively evaluated the incidence and outcome of HL patients in the Northern Health Region (population of 3 million) between 1991 and 1998, irrespective of entry into a specific trial. Of the newly diagnosed HL patients, 20% were older than 60 years. The age-specific incidence was 1.97/100,000 for those aged 60 to 69 and 2,18/100,000 for those aged 70 years or older.[15,23]
Histologic Subtype and Disease Characteristics
A retrospective analysis from the German Hodgkin Study Group (GHSG) revealed statistically significant differences in disease-related characteristics between younger and older HL patients. Elderly patients presented more frequently with B symptoms, elevated sedimentation rate, mixed cellularity (MC) histologic subtype, and poorer Karnofsky performance score. Less frequently found in this group were bulky disease, large mediastinal mass, and nodular sclerosis (NS) subtype. Although the MC subtype was present more often in elderly patients (35% vs 19%), NS histology was most frequently observed in both age groups (41% vs 66%).
In smaller case series, others have reported similar findings.[5,8,22] As an example, a recent study from the Nebraska Lymphoma Study Group found sex, stage, Karnofsky performance score, lactate dehydrogenase, number of extranodal sites, B symptoms, size of largest mass and histologic subtype prognostically relevant. More recent studies or those using pathology expert review[7,12,22] observed fewer patients with lymphocyte-predominant and lymphocyte-depleted subtypes.[1,3,8,24] This reflects improved histomorphology allowing a more precise classification of different HL subtypes and the distinction of HL from NHL.
In accordance with the findings of the GHSG and the Nebraska Group, the difference in outcome between young and elderly patients seems to be due, at least in part, to an intrinsic difference in the disease. Elderly patients present more often with poorer risk factors such as B symptoms or a shorter history of disease.[24-27] Furthermore, although staging procedures have usually been more comprehensive in the young, many studies found advanced stages more often in elderly patients.[2,9]
Clinical Differences in the Elderly
It is unlikely that biology and disease-related factors alone explain the differences in outcome between younger and elderly HL patients. Treatment-related factors such as reduced tolerability of conventional therapy, more severe toxicity and treatment-related deaths, failure to maintain dose intensity,[6-9] and shorter survival after relapse[10,11] further worsen the prognosis of the elderly age group.
The GHSG analysis including 373 elderly HL patients (≥ 60 years) found more treatment-associated toxicity. Higher mortality during treatment as well as lower dose intensity were the major factors explaining the poorer overall outcome. Elderly patients were less likely to complete the full intended course of treatment. The most frequent reason for premature termination of chemotherapy or radiotherapy was excessive toxicity. Considering only the intended number of treatment cycles, fewer elderly patients received the full number of cycles. Dose adjustment was necessary significantly more often in older patients, especially during treatment for advanced-stage disease. The administration of more intensive treatment resulted in even more dose reductions and early withdrawals in elderly patients. Thus, the dose intensity delivered was generally lower, explaining the poorer outcome of elderly patients, particularly those in advanced stages of disease. All relevant adverse effects occur more often in elderly patients. Above all, leukopenia, infections, and cardiopulmonary toxicity were the limiting factors in treatment delivery and contributed substantially to the higher treatment-related mortality in the elderly.
Other investigators have also observed this increased toxicity and reduced tolerance of treatment associated with higher mortality and a worse outcome in elderly HL patients.[3,7-9,12,27] Levis et al showed that in the group of elderly patients treated with a conventional hybrid MOPP/ABVD regimen (mechlorethamine [Mustargen], vincristine [Oncovin], procarbazine(Drug information on procarbazine) [Matulane], prednisone(Drug information on prednisone), doxorubicin(Drug information on doxorubicin) [Adriamycin], bleomycin, vinblastine, dacarbazine(Drug information on dacarbazine)), acute toxic death occurred in 19% of patients compared with 4% in the group treated with CVP/CEP (cyclophosphamide, vincristine, prednisone, carboplatin, etoposide(Drug information on etoposide), bleomycin(Drug information on bleomycin)). Among patients treated with VEPEMB (vinblastine, cyclophosphamide(Drug information on cyclophosphamide), procarbazine, prednisolone(Drug information on prednisolone), etoposide, mitoxantrone(Drug information on mitoxantrone), bleomycin), 3% died during therapy. Another population-based study reported a 21% treatment-related death rate in patients over 60 years old treated with curative intent.
In the HD9elderly study of the GHSG, elderly patients with advanced-stage HL suffered from considerably more severe hematologic toxicity than younger patients when being treated with intensified chemotherapy (BEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) compared to a standard treatment (COPP-ABVD; cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine(Drug information on vinblastine), and dacarbazine). Acute toxic deaths occurred in 21% of patients treated with BEACOPP compared with 8% for COPP-ABVD recipients. As a result, in contrast to younger patients, there was no benefit in changing to the more effective treatment for the older age group.
Comorbidity and Death From Other Causes
Although most authors describe treatment-related toxicity and mortality as major obstacles in this age group, patient-related factors such as comorbidity and death from unrelated causes further contribute to the poorer outcome of elderly patients.
In a population-based series comprising more patients with serious comorbidity than allowed in clinical trials, van Spronsen et al studied the age-specific prevalence of comorbidity and its relationship to treatment and outcome in 194 HL and 904 NHL patients diagnosed between 1993 and 1996. The most common comorbid conditions were cardiovascular disease (18%), hypertension (13%), chronic obstructive pulmonary disease (13%), and diabetes mellitus (10%) for elderly HL patients. Serious comorbidity was found in more than half of all lymphoma patients who were 60 years and older. Elderly patients with serious comorbidity received chemotherapy less often, which is likely to adversely affect survival, as was especially indicated by a decreased survival within the first 4 months after diagnosis.
Guinee et al compared the clinical course of 136 previously untreated HL patients aged 60 to 79 years with that of 223 patients aged 40 to 59 years, treated between 1977 and 1983. When the prognosis of all patients was examined, a definite change in the pattern of survival appeared in the 60- to 69-year-old cohort. The entire group of elderly patients (60 to 79) had twice the risk of dying from HL and four times the risk of dying from other causes, compared with the younger group. The authors concluded that HL should have the same natural history and similar risk factor pattern in the elderly and should be amenable to existing therapeutic approaches. Thus, the prognosis of older patients with HL has been obscured in previous studies by the inclusion of deaths due to other causes in survival estimates.
Another adverse factor might be an inadequate staging and treatment in elderly patients. In a study of 52 patients 60 to 75 years old who were treated for HL at Stanford between 1968 and 1980, the 5-year survival rate in the adequately staged and treated group was 86%, compared with only 35% in the inadequately staged group. Another study found that patients over the age of 50 years were more likely to receive suboptimal doses of chemotherapy, which was associated with more treatment failure and relapse.