The Unique Characteristics and Management of Patients Over 60 Years of Age with Classic Hodgkin Lymphoma
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- Halbsguth, T.V., Böll, B., Borchmann, P. et al. Curr Hematol Malig Rep (2011) 6: 164. doi:10.1007/s11899-011-0089-7
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In recent decades, the prognosis of Hodgkin lymphoma has been substantially improved, but these successes have been restricted to younger patients and could not be translated into a major benefit for older patients, especially those with advanced-stage disease. Major problems in treating older patients include a different biology, frailty, comorbidities, and poorer tolerance of therapy. Additionally, these patients are often excluded from randomized trials, so an evidence-based standard of care is lacking. Importantly, the proportion of older patients with HL will increase over the next 50 years. Currently, ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) is considered to be the gold standard, even though it has some toxicity in older patients and prospective data are not available. Thus, further studies are required, including the assessment of comorbidities and the incorporation of new drugs such as immunomodulatory agents, antibody-drug conjugates, mTOR inhibitors, or histone deacetylase (HDAC) inhibitors.
KeywordsHodgkin lymphomaHodgkin diseaseOlderElderlyManagementTreatmentComorbidityToxicity, therapy-associated deathTreatment-related morbidityABVD
The prognosis of Hodgkin lymphoma (HL) has been substantially improved in recent decades. To date, the use of stage-adapted polychemotherapy and modern radiation techniques has lead to a progression-free survival (PFS) at 5 years of almost 90% in young patients [1–3]. Unfortunately, these improvements do not apply to patients over 60 years of age, particularly those presenting in advanced stages [4–8]. These “older” patients are often excluded from randomized controlled trials (RCTs) because of their poorer tolerance of aggressive polychemotherapy and their comorbidities. Thus, the percentage of older patients is underestimated in data from RCTs, and information is lacking to define a standard of care, as RCTs include only a minority of older patients [9, 10]. Population-based studies estimate that about 20% of the HL population is older than 60 years. The lack of improvement in this cohort of patients is becoming an increasing problem, as the number of older patients will double over the next 50 years . This article describes the unique characteristics of older patients with classic HL and summarizes the available data on their management.
The incidence of HL is constant at 2 to 3 cases per 100,000 people over the past decades [12, 13]. Recent analyses do not confirm the previous model of a bimodal age distribution with a first peak of incidence around 30 years and a second around 50 years. Reasons may be the improvement in hematopathology, including immunohistochemistry, and the involvement of reference pathologists in most study groups. Thus, more cases initially identified as HL could be reclassified as non-Hodgkin lymphoma (NHL) .
A proper assessment of the HL incidence in older patients is difficult, as most RCTs have excluded these patients because of age or fitness level. In RCTs, only 5% to 10% of all patients are older than 60 years [5, 15, 16]. To date, data of population-based studies appear to deliver the most accurate estimates. Two Swedish studies showed a proportion of 37% from 1979 to 1988 and 26% from 1973 to 1994 [8, 17]. The analysis of the British National Lymphoma Investigation Group (BNLI) documented that about 15% of all patients were older than 65 years, but only a minority of 5% had been included in BNLI studies . In the data collected by the Scotland and Newcastle Lymphoma Group (SNLG) covering a period from 1979 to 2003, 674 (20%) of 3,373 patients registered on the population registry were over 60 years of age . The proportion of 20% was also found in a study conducted by Stark et al. .
A comprehensive retrospective review of older HL patients published by the German Hodgkin Study Group (GHSG) was able to reveal different patterns of histologic subtypes. In contrast to younger patients, mixed cellularity was more frequent in older HL patients than in younger patients (35% vs 19%, P < 0.001), whereas nodular sclerosis was less frequent (41% vs 66%, P < 0.001). However nodular sclerosis remained the most common subtype in both groups, and there was no difference in frequency for the other histologic subtypes. The Nebraska Study Group and the Cancer and Leukemia Group B also reported a higher frequency of the mixed cellularity subtype [6, 7, 15], but this difference did not result in a distinct clinical outcome [19, 20].
Epstein-Barr virus (EBV) infection has long been proposed as a potential causative agent in HL, and the association between tumor EBV status and clinical outcome in HL is controversial. In a recent study by Jarrett et al. , EBV association was more common in patients aged 50 years or older than in younger patients. Interestingly, EBV positivity was a poor prognostic factor for patients aged 50 years or older but not for other groups . Diepstra et al. confirmed these data by a retrospective analysis of 412 patients. EBV positivity was associated with a worse failure-free survival (FFS) in patients aged between 50 and 74 years, but not in younger patients. Even after adjusting in multivariate analysis for histology, HLA class II expression by tumor cells, stage, presence of extranodal localizations, and treatment, the effect of positive EBV tumor status remained significant [22•]. In the study by Stark et al., EBV-positive status was also associated with advanced-stage disease . Although the reason remains elusive, the investigators speculated that EBV-positive patients have a defective immune response to EBV and present with an advanced stage of immunodeficiency and hence more advanced HL disease .
In previous studies, a larger proportion of patients presented with advanced-stage disease [4, 8]. In contrast, Stark et al. reported more early stages among HL patients older than 70 years than among those 60 to 69 years old . As the sample sizes of these studies have been rather small and the results are very heterogeneous, the GHSG performed a comprehensive retrospective analysis among 372 patients aged 60 years and older who were treated within GHSG trials. This analysis found a significant difference in clinical stage, with more pronounced incidence of the very early and very advanced stages in the older population, a finding that is line with other studies [4, 5, 8, 19]. Furthermore, the analysis showed significantly more female patients, more patients presenting with B symptoms, elevated sedimentation rate, and higher Eastern Cooperative Oncology Group (ECOG) score (indicating poorer function) in the older group, and fewer patients with a large mediastinal mass or bulky disease . The Nebraska Group and another study by Mir et al. confirmed a higher proportion of older HL patients presenting with B symptoms and lower performance status, and fewer patients with bulky disease [7, 15].
Comorbidity is evidently more common in older patients and has therefore been proposed as a crucial element contributing to the reduced survival of older HL patients. Between 1993 and 1996, 194 HL patients and 904 NHL patients were registered and analyzed by van Sprosen et al. with regard to their age-specific comorbidities and the potential impact on outcome. In the HL cohort, the most frequent comorbidities were cardiovascular disease (18%), hypertension (13%), chronic obstructive lung disease (13%), and diabetes mellitus (10%). In total, 56% of the HL patients who were age 60 or older suffered from severe comorbidity, with no significant difference in prevalence for advanced or early stages. Furthermore, patients with a high burden of comorbidities were less frequently treated by chemotherapy and showed a poorer overall survival (OS), especially within the first 4 months after diagnosis of HL—a finding that could be regarded as a clear indicator of the impact of comorbidities on survival . This conclusion is supported by a report of Levis et al. , who found comorbidities in 35% of 105 older HL patients treated with VEPEMB (vinblastine, cyclophosphamide, procarbazine, etoposide, mitoxantrone, and bleomycin). The multivariate analysis demonstrated that comorbidities were an independent prognostic factor for poorer survival, as were stage and the presence of B symptoms . Guinee et al.  compared the outcome of patients between 60 and 70 years of age with patients in the group 40 to 59 years of age in the period from 1977 to 1983. Older patients showed a twofold risk of death from HL and a fourfold risk of death due to other causes. Interestingly, the response rate (RR) for treatment did not differ between the two cohorts (84% for the older patients and 88% for the younger patients) . Based on these data, the assessment of comorbidities should be included in the treatment and management of older HL patients. To date, only two studies have incorporated comorbidity assessment, the AVD-Rev study by the GHSG and the SHIELD trial. In the SHIELD approach, a modified ACE-27 comorbidity score excludes patients who fail the assessment from aggressive chemotherapy . The data from this study are expected soon and may confirm the urgent need for future inclusion of comorbidity assessment. In addition, there are now recommendations from the International Society of Geriatric Oncology on the use of comprehensive geriatric assessment tools for studies in older patients .
Not only comorbidities but also therapy-associated toxicities have a major impact on the treatment of older HL patients. Reduced tolerability of conventional chemotherapy resulting in more severe toxicities (including fatal outcomes), the inability to maintain dose density, and a shorter survival after relapse or progression are jointly responsible for the poor outcome observed in older patients [6–8, 17, 27–29]. An increased proportion of therapy-associated toxicity was also seen in the GHSG analysis . Reduced dose density and increased mortality during therapy were identified as major determinants of an inferior outcome of older HL patients. Older patients were less likely than younger patients to complete the whole chemotherapy and radiotherapy regimen. Especially in advanced stages, the failure to maintain dose density and the early termination of therapy showed a negative impact on the prognosis of older HL patients [5, 17]. As in younger patients, the most prominent toxicities were leukopenia, infections, and cardiopulmonary events [5, 27, 30, 31]. In the literature, the incidence of severe therapy-associated toxicity with commonly used polychemotherapy regimens varies between 8% and 20% [6–8, 20, 30, 31]. For MOPP/ABVD (mechlorethamine, vincristine, procarbazine, prednisone/Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine), a rate of 19% for acute toxic deaths was reported by Levis et al. . This rate was confirmed by Enblad et al., with 18% toxic deaths for the same regimen . The GHSG detected a lower rate of 8% using COPP (cyclophosphamide, vincristine, procarbazine, prednisone)/ABVD . Nowadays, ABVD has replaced these regimens. Unfortunately, no prospectively randomized studies using ABVD in older patients have been published, and a reliable statement on its toxicity for this cohort of patients cannot be given. Only one study (which is still ongoing) is available that uses ABVD as a standard arm and compares it with VEPEMB. The most recent interim analysis did not show any therapy-associated deaths, but the final analysis should be awaited before drawing further conclusions .
Other new regimens particularly designed for older HL patients showed low toxicity but also low efficacy [33–35]. Another approach to overcome the apparent problem of neutropenic infections to lower toxicity was the use of granulocyte colony-stimulating factor (G-CSF) [27, 36, 37]. However, in randomized trials conducted in older NHL patients, no impact on the incidence of severe infections and mortality could be documented . A recent meta-analysis of the Cochrane Haematological Malignancies Group (CHMG) strongly supports this result . Further data are required to elucidate the role of G-CSF in preventing severe infections in older patients.
Early stages in patients younger than age 60 are mainly subdivided into the early favorable and early unfavorable stages. For older patients, there are currently insufficient data to discriminate between the early stages, but a smaller study conducted by Kim et al. has shown some advantage of combined-modality treatment in these patients . Between 1969 and 1995, 52 early-stage patients older than 60 years of age were analyzed. Of this group, 37 received radiotherapy only, 9 received chemotherapy only, and 6 received a combination. Even though the sample size was too small to reach statistical significance, the lowest relapse rate (20%) was found in the combined-modality group. This rate was 33% in the group receiving chemotherapy alone and 46% in the radiotherapy-only group .
The recent analysis of the GHSG HD8 trial for early unfavorable stages focused on comparing the outcome of patients over 60 years of age versus younger patients. In both groups, patients were treated with four cycles COPP/ABVD followed by either extended-field radiotherapy (EF-RT) or involved-field radiotherapy (IF-RT) as randomized. In the group of older patients, there was a significantly lower 5-year freedom from treatment failure (FFTF) (64% vs 87%; P < 0.001) and OS (70% vs 94%; P < 0.001). Interestingly the outcome in older patients was poorer when they were treated with EF-RT instead of IF-RT (FFTF, 58% vs 70%, P = 0.034; OS, 59% vs 81%, P = 0.008). Furthermore, increased toxicity was documented when the older patients received EF-RT . In conclusion, EF-RT should be avoided in treating older patients.
A new regimen, VEPEMB, was designed for older patients and tested by Levis et al., who treated 48 patients in early stages with three cycles of VEPEMB followed by IF-RT. The approach showed a complete remission (CR) rate of 98% with OS at 5 years of 94% and FFS of 79% .
Another approach was investigated by Kolstad and colleagues . In this study, the CHOP-21 regimen was used to treat 29 HL patients, 11 of them presenting with stage I or stage IIA disease. According to their risk profile, these patients received two to four cycles of CHOP-21 followed by IF-RT. The CR rate was 91%, with OS at 3 years of 91% and PFS of 82% . Unfortunately, the number of patients is much too small to judge the use in HL of this NHL treatment scheme.
Recently, the GHSG published the results of the HD10 trial, which included 1,370 early-stage HL patients, some as old as 75 years [42•]. In this prospective trial, patients were randomized to receive either two or four cycles of ABVD followed by 20 Gy or 30 Gy of IF-RT. In the final analysis, treatment with two cycles of ABVD followed by 20 Gy IF-RT were just as effective and less toxic than four cycles of ABVD followed by 30 Gy IF-RT. Outside of clinical trials, the GHSG therefore recommends two cycles of ABVD followed by 20 Gy IF-RT for early favorable-stage patients and four cycles of ABVD followed by 30 Gy IF-RT for early unfavorable-stage patients. However, these recommendations are based largely on results in younger patients, and the use of FDG-PET may reduce the proportion of patients requiring radiotherapy in the future.
Selected studies of chemotherapy regimens for older patients with advanced-stage Hodgkin lymphoma
Therapy-associated death rate
Levis et al. 
CR rate = 61%
8-y OS = 48%
8-y RFS = 75%
8-y EFS = 36%
Levis et al. 
CR-rate = 73%
5-y OS = 65%
5-y RFS = 47%
Weekes et al. 
5-y OS = 30%
5-y EFS = 24%
5-y OS = 67%
5-y EFS = 52%
Macpherson et al. 
5-y OS = 42%
5-y DFS = 49%
Levis et al. 
CR rate = 58%
5-y OS = 32%
5-y RFS = 66%
Ballova et al. 
CR rate = 77%
5-y OS = 50%
5-y HD-FFTF = 55%
Relapse rate = 23%
CR rate = 76%
5-y OS = 50%
5-y HD-FFTF = 74%
Relapse rate = 12%
Levis et al. 
CR rate = 86%
3-y OS = 79%
3-y RFS = 57%
CR rate = 77%
3-y OS = 60%
3-y RFS = 50%
Kolstad et al. a
CR rate = 72%
3-y OS = 67%
3-y PFS = 72%
Halbsguth et al. 
CR rate = 85%
2-y OS = 76%
2-y PFS = 71%
Relapse rate = 13%
A study conducted by Landgren et al.  compared ABVD with MOPP-based chemotherapy and investigated the influence of relative dose intensity (RDI) on the OS of 88 older HL patients. Patients with an RDI of 65% or higher had significantly better cause-specific survival and OS than patients whose RDI was less than 65%. Additionally, the use of an ABVD-based chemotherapy with an RDI of 65% or higher showed significantly better OS than treatment with an RDI below 65% or treatment with MOPP-based regimens regardless of the RDI (P = 0.001). Interestingly, 92% of patients treated with ABVD-like regimens had an RDI over 65%, whereas the proportion was only 24% for patients who received an MOPP-based therapy . In conclusion, the use of anthracyclines and a high dose density improved the outcome in older patients.
On the other hand, it was unclear whether an increase of intensity would improve the outcome. Thus, the GHSG subtrial HD9elderly was designed for patients between 65 and 75 years of age with first diagnosis of advanced-stage HL. Patients were randomized between eight cycles of COPP/ABVD and eight cycles of BEACOPP baseline; patients with bulky or residual disease received additional radiotherapy. In contrast to younger patients, intensification of therapy failed to improve the outcome. There was no significant difference in terms of CR rate or progressive disease. Interestingly, the disease-specific FFTF at 5 years was better for the BEACOPP arm (74% vs 55%; P = 0.13), but this did not translate to better OS at 5 years (50% in both arms). A major explanation was found in the high rate of therapy-associated deaths in the BEACOPP arm (21% vs 8%) . Consequently, the GHSG developed the BACOPP regimen, a variant of the BEACOPP schedule in which etoposide was omitted to improve tolerability and the dose of anthracycline was increased to maintain effectiveness [43•]. In total, among the 60 patients (92%) eligible for the final analysis, 75% of treatment courses were administered according to protocol, and 51 patients achieved a CR/CRunknown (85%), 2 (3%) achieved a partial remission, and 4 (7%) showed a progression of disease. In 52 patients (87%), WHO grade III/IV toxicities were documented. With a median observation of 33 months, 18 deaths (including 7 therapy-associated fatal outcomes) were recorded. Thus, the rate of 12% therapy-associated death was still unsatisfactory and needed further improvement [43•]. A different approach investigated the incorporation of gemcitabine into first-line treatment of older HL patients. Here, the bleomycin and dacarbazine of the ABVD schedule were replaced by gemcitabine and prednisone, resulting in the PVAG regimen. The final analysis of a phase II trial evaluating PVAG is awaited for 2011.
Another strategy of therapy intensification was investigated by the Vancouver Group with the introduction of the ODBEP schedule (vincristine, doxorubicin, bleomycin, etoposide, and prednisone) . This regimen tried to increase dose intensity by delivery of treatment without delays and to escalate the number of non–cross-resistant drugs that were selected for minimal cumulative myelotoxicity. Compared with a MOPP/ABVD-like treatment, the patients treated with ODBEP had higher 5-year disease-free survival (49% vs 37%) and OS (42% vs 32%), but the differences were not statistically significant .
In contrast, an Italian group focused on the development of a less-intensive chemotherapy especially for older HL patients. The first approach was the CVP/CEB regimen, which was administered to 25 patients and was well tolerated. The CR rate was 73%, but unfortunately this result was compromised by a high relapse rate, leading to EFS of 32% and OS of 55% at 5 years .
In the following years, the VEPEMB schedule was designed and administered to 57 patients in advanced stages, who received six cycles of the regimen followed by radiotherapy on bulky disease or residual mass. The CR rate was 58%, with FFS of 34% and OS of 32% at 5 years. The rate of therapy-associated death was as low as 3% . In 2007, an interim analysis of a prospectively randomized phase III trial comparing VEPEMB and ABVD was presented. The CR rate was slightly better for the ABVD arm (86% vs 77%), though the difference was not statistically significant. At 3 years, the relapse-free survival rates were 57% and 50% (P = ns), the OS was 79% versus 60% (P = ns), and the EFS was 52% versus 24% (P = 0.08) for the ABVD arm versus VEPEMB, respectively . The final analysis should be awaited, but currently the data do not support the use of VEPEMB outside clinical trials.
In a recent analysis by Kolstad et al., the well known CHOP-21 schedule, which is well tolerated in older NHL patients, was tested for the treatment of older HL patients . Among 29 patients, 18 were in advanced stages and were treated with six to eight cycles of CHOP-21 followed by radiotherapy to any residual mass. The CR rate was 72% and the 3-year OS was 67%. Only one patient death was due to therapy . A larger study will be necessary to confirm these results before further conclusions can be drawn.
In summary, the use of anthracycline-based chemotherapy is of great value for older HL patients in advanced stages. Even though randomized data on the use of ABVD in this special cohort is currently lacking, six to eight cycles of ABVD followed by radiotherapy to residual disease are regarded as the standard of care [9, 10]. On the other hand, the SNLG is currently running the SHIELD study, a phase II, international, multicenter trial. This study has two components: a VEPEMB treatment arm and a registration arm, in which details of eligible patients receiving treatments other than VEPEMB are recorded. Recruitment closed in September 2009 with 232 patients. By collecting data on all patients with HL in this age group, regardless of treatment, the study will provide a clearer overall picture of outcome in this cohort [18, 25].
Nevertheless, further studies are warranted to find the balance between efficacy and tolerability. As in younger patients, FDG-PET scans should be used to adapt treatment to therapy response. The initial results in younger patients, presented by Kobe et al., are very promising, showing that radiotherapy could be avoided in patients with a negative PET scan in a residual mass measuring 2.5 cm or larger after completion of therapy .
For patients with relapsing disease, second-line therapies are feasible but usually have a palliative intent. As there are no studies specifically focusing on this objective, conclusions must be drawn based on fewer old studies or in analogy to results from studies in younger HL or older NHL patients. Thus, no general recommendations can be given. If the treatment goals have been clarified, in limited stages the option of radiotherapy should be explored. For patients who need systemic therapy, treatment decisions can be guided by the duration of response to first-line therapy. Patients in a good general condition who have been in remission for more than 1 year after first-line treatment may benefit from a second chemotherapy. Unfortunately, anthracyclines cannot be given to most of these patients, as their cumulative dose has been reached. Thus, drugs with known single-agent activity, such as ifosfamide, trofosfamide, procarbazine, gemcitabine, vinca alkaloids, or platinum derivates may be a feasible therapeutic option in this setting. In older NHL patients, promising results were reported for the combination of gemcitabine and oxaliplatin , but there are no published data on HL patients. An oral schedule called PECC, consisting of prednisolone, etoposide, chlorambucil, and CCNU, was used in HL patients by the SNLG and was very well tolerated . In a recent update, 12 patients above 60 years of age who received PECC for the treatment of relapsed HL were analyzed. The schedule induced a CR in 7 of the 12 patients, suggesting that regimens containing CCNU may be beneficial in this situation [47•].
If the duration of remission is less than 1 year or the patient cannot tolerate polychemotherapy, single-agent chemotherapy should be evaluated. Gemcitabine has shown promising results in younger patients and has been extensively used in refractory or relapsed disease . In older patients, dose reductions may be necessary because of thrombopenia, the most prominent adverse effect of gemcitabine. In addition, oral alkylating agents like trofosfamide can induce remission in HL patients, with good tolerability [49, 50].
Currently, evidence-based recommendations for the treatment of older HL patients cannot be provided because of a lack of prospective randomized trials. The results in older HL patients are still disappointing, particularly in patients presenting with advanced-stage disease. Although the intensification of chemotherapy and dose density was a major achievement in the treatment of young HL patients, most studies indicate that delivery of intensive doses is compromised in patients older than 65 years, with a major effect on their outcome. In this cohort of patients, clinical research needs to focus on developing new approaches with better tolerability.
Based on the available data, older patients with early-stage HL (stage I and II without risk factors) should be treated with short courses of chemotherapy followed by IF-RT. Although ABVD has some toxicity in older HL patients and data on therapy-related deaths are scarce, this schedule is considered as standard of care for older HL patients. A treatment with two cycles of ABVD plus 20 Gy IF-RT for early stages is supported by the recently published GHSG trial HD10 [42•]. A comparison with the data of the SHIELD study (once these data become available) will be interesting.
For advanced-stage disease, six to eight cycles of ABVD are regarded as standard of care, though the relative dose intensity is often less than the critical limit of 65% in older HL patients, who have a poorer outcome than younger patients. Especially for these patients, innovative approaches incorporating new drugs should be evaluated; these may include immunomodulatory agents such as lenalidomide, antibody-drug conjugates like SGN-35, histone deacetylase (HDAC) inhibitors, or mTOR inhibitors. Currently, the GHSG is conducting the AVD-Rev trial for older HL patients, replacing bleomycin by lenalidomide in order to test the tolerability and efficacy of an innovative approach in older HL patients.
No potential conflicts of interest relevant to this article were reported.