Elderly Hodgkin lymphoma, typically defined as affecting individuals ≥ 60 years of age, remains a disease for which no standard treatment recommendation exists. This population is underrepresented in clinical studies, and survival rates in older patients with Hodgkin lymphoma are significantly and disproportionately inferior compared with younger patients.
Surveillance, Epidemiology and End Results (SEER) data reported by Brenner et al showed that Hodgkin lymphoma outcomes in elderly patients improved from 1980 to 2004.1 However, that study and others reported 5‑year progression-free survival and freedom from treatment failure rates of 30% to 45%, with 5-year overall survival rates of 40% to 55% for elderly patients.2,3 This compares with 5-year overall survival rates of > 80% to 90% for Hodgkin lymphoma populations under age 45 years.
Prior Studies
A number of analyses conducted in the 1970s to 1990s examined a variety of chemotherapy regimens, documenting modest outcomes for elderly patients with Hodgkin lymphoma.4-14 These treatments included less intensive regimens as well as therapy tailored to individual patients based on comorbidities. More intense regimens, such as BEACOPP-baseline (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], and prednisone), have been studied in elderly patients with Hodgkin lymphoma and shown to be too toxic.10,15,16 Inadequate treatment delivery for older patients may compromise the rate of cure, while comorbidities may preclude the delivery of standard chemotherapy.13,17,18
Treatment delivery and comorbidity, however, do not appear to completely explain the observed differences in the outcome of elderly patients with Hodgkin lymphoma, implicating in part a different disease biology.19 Indeed, elderly subjects with Hodgkin lymphoma frequently present with mixed-cellularity subtype, EBV positivity, advanced-stage disease, and low incidence of bulky disease. Additionally, a paucity of prognostic data exists for elderly Hodgkin lymphoma, while the potential impact of functional status on survival is largely unexplored.20 The most commonly used prognostic tool in Hodgkin lymphoma is the International Prognostic Score (IPS), which utilizes seven adverse clinical prognostic factors (including age ≥ 45 years) to predict outcome. However, only 9% of patients in that pivotal analysis were over age 55, and none were over 65 years.21
Recent Analyses
We recently conducted a multicenter retrospective analysis of elderly patients consecutively diagnosed and treated with Hodgkin lymphoma between 1999 and 2009 at five medical centers.22 We documented that that the majority of patients had a severe (ie, grade 3 or 4) comorbidity in at least one category (as scored by the Cumulative Illness Rating Scale–Geriatric system),23,24 while a significant minority of subjects had a geriatric syndrome and/or loss of activities of daily living at diagnosis.
The presence of comorbidity as a prognostic factor is particularly relevant for older patients. In a population-based study, van Spronsen et al reported that among elderly patients with Hodgkin lymphoma, 56% had a serious comorbid condition vs 13% in younger patients (P < .0001).18 Additionally, Levis et al reported results of elderly patients with Hodgkin lymphoma who received lower-intensity chemotherapy6; the presence of comorbidity independently correlated with lower disease-specific and overall survival.
The most common treatment in our series was ABVD-based therapy. The overall and complete remission rates were good, with a complete remission rate of 73%; however, the incidence of bleomycin lung toxicity was 32%, which had an associated mortality rate of 25%. Moreover, the incidence of bleomycin lung toxicity was 38% vs 0% among patients who received G‑CSF (filgrastim, Neupogen) vs not, respectively (P = .0001). G-CSF may induce bleomycin lung toxicity in part through recruitment of pulmonary neutrophils with associated free radical–induced pulmonary damage.25 Other series have reported an increased incidence of bleomycin lung toxicity when G-CSF was used during bleomycin-containing chemotherapy, with an associated mortality rate of 40% in patients ≥ age 40 years.26
With a median follow-up of 66 months, the 5-year overall survival for advanced-stage Hodgkin lymphoma in our series of elderly patients with Hodgkin lymphoma was < 50%. Further, most IPS factors (eg, anemia, WBC, sex, lymphopenia) were not significant on univariate analysis. On multivariate Cox regression analysis, only two factors were associated with inferior survival: (1) age ≥ 70 years and (2) loss of activities of daily living. Furthermore, we created a new survival model based on the number of these risk factors present at initial diagnosis (0, 1, or 2), showing a differential 2-year overall survival of 83%, 70%, 13%, respectively (P < .0001), and 5-year overall survival of 73%, 51%, 0%, respectively (P < .0001).
We also recently presented data among the subset of elderly patients with Hodgkin lymphoma (n = 43) who were treated on the E2496 Intergroup trial that randomly assigned patients with advanced-stage disease to six to eight cycles ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) vs Stanford V (doxorubicin, vinblastine, mechlorethamine [Mustargen], etoposide, bleomycin, vincristine, and prednisone).27 Not surprisingly, the failure-free and overall survival rates were significantly inferior for elderly patients compared with those under 60 years old, with survival rates > 30% to 35% lower for the former. Further, treatment-related mortality was comparatively higher for the elderly Hodgkin lymphoma population. The incidence rate of bleomycin lung toxicity in this prospective trial (26%) was remarkably consistent with the aforementioned retrospective series, while the bleomycin lung toxicity–related mortality rate in E2496 was 18%.
Treatment Toxicities and Alternatives
Hodgkin lymphoma is a malignancy that does not have an expected appreciable rate of treatment-related mortality. However, due in part to bleomycin and other chemotherapy-related toxicities, treatment-associated mortality is likely more common than suggested, despite the contemporary era of supportive care measures. In fact, use of granulocyte growth factors concurrently with bleomycin may exacerbate pulmonary toxicity, as noted before.
Outside of a clinical trial, I typically advocate treatment with AVD chemotherapy (doxorubicin, vinblastine, dacarbazine) for elderly Hodgkin lymphoma, withholding bleomycin a priori in most subjects over ages 60 to 65 years old. Retrospective data from Cancer and Leukemia Group B (CALGB) research suggests that bleomycin may not be needed as a component of ABVD therapy.28 If bleomycin is not administered, G‑CSF may then be used with impunity.
Another systemic therapeutic option for elderly Hodgkin lymphoma includes CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone). In a small study, Kolstad et al reported encouraging results with CHOP in this setting.29
Additionally, with respect to number of cycles of chemotherapy and use of radiotherapy (ie, for early-stage disease), I follow stage-based guidelines similar to those applied for younger patients.30
Ongoing Research
New therapeutic options, including biologically based strategies, are actively being investigated in Hodgkin lymphoma. This includes brentuximab vedotin (Adcetris), the antibody-drug conjugate, which has shown significant single-agent activity in relapsed/refractory disease.31 This and other novel agents should be explored in front-line therapy of elderly Hodgkin lymphoma through prospective clinical trials.
In addition, continued examination of the biology of the disease in elderly patients, especially the impact of Epstein-Barr virus, is warranted. Finally, results from the recently completed SHIELD study conducted by Proctor and colleagues, which included analysis of a large cohort of elderly Hodgkin patients (with functional assessments) in addition to completion of a prospective clinical trial, are eagerly awaited.32 ■
Disclosure: Dr. Evens has received research funding from Seattle Genetics.
References
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