In an effort to limit ABVD toxicity other less intensive regimens have been tried but with limited success. Levis et al. tested the CVP/CEB regimen which although producing less treatment related mortality resulted in higher relapse rates and a 5 year relapse free survival of 43 % [27]. A further retrospective study carried out by the Nebraska Lymphoma Study Group investigated the importance of anthracyline in drug combinations and randomised ChlVPP (Chlorambucil, vinblastine, procarbazine and prednisolone) versus the combination of ChlVPP/ABV. The 5 year event free survival (EFS) was 24 % treated with ChlVPP alone versus 52 % for those treated with the combination regimen (p = 0.011) and 5 Year OS was 30 % versus 67 %. In a subsequent multivariate analysis the use of Doxorubicin was the only factor associated with superior outcomes and therefore remains important in the treatment of elderly HL patients [2]. A further study tested the VEPMB regimen (Vinblastine, cyclosphamide, procarabazine, etoposide, mitoxoantrone, Bleomycin) in which 57/105 patients with advanced disease received 6 cycles of treatment with consolidation radiotherapy to either bulky disease or residual mass. A reported a CR rate of 58 % at the end of treatment was noted with a 5 year FFS and OS of 34 and 32 % [18]. A further study randomised VEPEMB against ABVD and reported a 3 Year OS and EFS for ABVD and VEPMB of 79 % vs. 60 % (p = ns) and 52 % vs. 24 % (p = 0.08) [28].

In a search to develop tailor made elderly specific regimens to aim to deliver with curative intent, the GHSG have reported on two newer regimens in the elderly; BACOPP (Bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone and PVAG (prednisolone, vinblastine, doxorubicin, and gemcitabine) in elderly untreated patients with HL. In the BACOPP regimen where etoposide was omitted to improve treatment related mortality the CR rate attained was 85 % and the 3 year PFS and OS 60 and 71 % respectively. However the regimen was associated with significant toxicity with 30 % of patient experiencing early termination (87 % with adverse grade III-IV adverse events) and a still reported TRM of 12 % making the regimen unsuitable [23]. The PVAG regimen replaced the Bleomycin and Dacarabazine in ABVD with Gemcitabine and Prednisolone. A CR rate of 78 % was achieved and the 3 year PFS and OS of 58 and 66 % was achieved with a lower TRM of 2 % [29].

Kolstad and colleagues reported excellent results using the NHL regimen CHOP for elderly patients. 29 patients were treated with CHOP-21 for both early stage (2–4 cycles with IFRT) and advanced stage (6–8 cycles +/− IFTR). The CR rate was an impressive 93 % with a median follow up of 41 months and 3 year PFS and OS for advanced stage patients of 67 and 72 % respectively. This regimen may be useful in elderly patients where significant pulmonary co-morbidity is present and where avoidance of Bleomycin is desirable [30]. In a further effort to reduce cardiotoxicity, the use of VEPEMB (vinblastine, cyclosphosphamide, procacarabazine, etoposide, mitoxoantrone, bleomycin) regimen was tested in early and late stage disease reporting a CR rate of 98 % for early stage disease and 58 % for advanced stage patients. Five year FFS was 79 and 34 % for early and late stage disease respectively [18]. In a multivariate analysis stage, B symptoms and co morbidity maintained their independent prognostic value in affecting OS, DSS, and FFS. A follow on UK phase II study further tested the VEPEMB protocol and incorporated a co-morbidity assessment to define patients into a curative treatment approach (non-frail group) or define those as too frail to enter the treatment arm. This study permitted treating centres to record “all” patients in a population based study. A total of 103 patients of which 72 with advanced disease were designated non frail and eligible for VEPMB treatment. The reported CR rate was 61 % and 3 year PFS and OS for the advanced stage patients was 58 and 66 % respectively. Overall treatment related mortality was 7 %. A further 54 non frail patients either received ABVD, or ChlVPP chemotherapy. In all arms of the study with treatment with curative intent (n = 157), achievement of CR remained significant for OS and CR plus co-morbidity and age for PFS. Although the regimen contains Bleomycin pulmonary toxicity demonstrated was minimal [17]. None of those designated as frail completed or responded to chemotherapy, and the authors concluded that a novel agent approach may afford better outcomes in this group compared to chemotherapy. A further advance afforded by this study is that the suitability of patients to receive curative multi [31] agent chemotherapy was stratified by co-morbid assessment and other well defined measures such as ADL, IADL and ECOG which ensured a consistent assessment to stratify patient groups.