Treatment of advanced stage Hodgkin lymphoma – it's all about risk‐benefit (2012)

In formulating treatment protocols for Hodgkin lymphoma (HL), one will find a wealth of randomized clinical trials trying to define what the standard of care should be. Yet, more than ever, the answer to the question of which therapy should be initiated in a patient with newly diagnosed advanced stage HL is not as straight forward as it should be. For all the many publications comparing the combination of bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine and prednisolone (BEACOPP) versus adriamycin, bleomycin, vinblastine and dacarbazine (ABVD), there have been none that have directly compared ABVD versus eight cycles of escalated BEACOPP (8 × Besc), which, up until this month's publication in the Lancet (Engert et al, 2012) was still considered the standard of treatment by the German Hodgkin Study Group (GHSG). The National Comprehensive Cancer Network (NCCN) gives some guidance on treatment of advanced-stage HL (NCCN Clinical Practice Guidelines in Oncology, 2012), although it is unclear why they have recommended that selected cases with an International Prognostic Score (IPS) of 4 or more be considered for BEACOPP therapy. Hasenclever et al (1998), published data on the IPS and found that the overall survival (OS) decreased sharply from approximately 78% in IPS 3 to 61% in IPS four groups. However, the BEACOPP regimen has never been shown to improve OS in the latter group. The GHSG HD9 study (Engert et al, 2009) is the only randomized study to have shown significant OS advantage of 8 × Besc over an ABVD-like regimen [COPP (cyclophosphamide, vincristine, procarbazine, prednisolone)/ABVD hybrid], but this finding was confined to patients in IPS groups 2 and 3. In the HD2000 trial (Federico et al, 2009), the progression-free survival (PFS) advantage with BEACOPP (over ABVD) was mostly seen in IPS groups 3 to 7. A Cochrane review last year that included data from the aforementioned HD9 and HD2000 trials, as well as abstracts from HD14 and GSM-HD2008 studies concluded that there was a significant improvement in PFS but not OS with BEACOPP, compared with other chemotherapy regimens, including ABVD (Bauer et al, 2011). The higher PFS came at the expense of a significantly higher risk of secondary acute myeloid leukaemia (sAML) and myelodysplastic syndrome. We know from the GHSG HD12 trial (Borchmann et al, 2011) that four cycles of escalated BEACOPP (4 × Besc) followed by four cycles of baseline BEACOPP (as recommended by NCCN) may not be as effective as 8 × Besc; the former strategy being discarded by the pioneers of the BEACOPP regimen. Yet in the HD2000 trial, 4 × Besc + 2 × Bbaseline was used to compare the efficacy of the GHSG BEACOPP regimen with ABVD. Viviani et al (2011) also used the 4 × Besc + 4 × Bbaseline regimen in place of the recommended 8 × Besc to compare BEACOPP versus ABVD. This trial set out to examine freedom from first progression as their primary objective and found their version of the BEACOPP regimen to be superior to ABVD (85% vs. 73%, P = 0·004) in that respect. However, in view of an absence of OS advantage, the authors concluded that BEACOPP exposed patients to an unnecessarily high risk of toxicity. It is worth highlighting that more patients in the ABVD arm had to be salvaged with ifosfamide-based chemotherapy followed by high-dose therapy/autologous stem cell transplantation (ASCT) compared with the BEACOPP arm due to greater rates of progression (15% vs. 7%) and relapse (16% vs. 6%). Even though upfront therapy with BEACOPP has a higher rate of acute toxicity and sAML, we must not discount the fact that ASCT in HL carries a treatment-related mortality of approximately 9%, a rate of second malignancy of about 17% at 15 years (Lavoie et al, 2005), and high risk of infertility, and if we use ABVD over BEACOPP, we must expect more of our patients to require salvage therapy. The argument of using a less effective regimen upfront must also take into account these complications associated with salvage therapy. The findings of the recently published GHSG HD15 trial (Engert et al, 2012) unequivocally proves that six cycles of escalated BEACOPP (6 × Besc) is better than 8 × Besc with similar efficacy but a higher survival rate due to less acute toxicity and fewer secondary malignancies. This trial also showed that when 6 × Besc is used, consolidation radiotherapy (RT) can be omitted in patients whom have negative positron emission tomography (PET) scans at completion of chemotherapy, even if computerized tomography (CT) scans show a residual mass. With this strategy, the number of patients who had to undergo RT was reduced to 11%, compared to a figure of 71% from the GHSG HD9 trial (Engert et al, 2009). Furthermore, data from the HD12 study supports the omission of RT in patients with initial bulky disease who have been treated with BEACOPP and achieved a complete remission based on CT scans (Borchmann et al, 2011). Whether omission of consolidation RT based on PET imaging can be used in the setting of ABVD remains to be determined. As it stands, consolidation RT should be given to all patients who have bulky disease at presentation and/or have residual disease post-chemotherapy, irrespective of fludeoxyglucose-avidity on PET imaging, if ABVD chemotherapy is used. Data from the UK Lymphoma Group LY09 study emphasized this, with better PFS and OS seen in patients who were given consolidation RT after ABVD (Johnson et al, 2005). Mediastinal and cardiac toxicity risk may be higher with ABVD due to a higher total doxorubicin dose (300 mg/m2 if given for six cycles) combined with this need for consolidation RT. With a reduction of escalated BEACOPP to six cycles and using a PET-guided consolidation RT strategy, the good balance of risk-benefit may have tipped in favour of the GHSG BEACOPP protocol. Trials directly comparing 6 × Besc (and not variations of BEACOPP) against ABVD are needed. With PET imaging coming to the forefront of prognostication, we may soon be adjusting HL treatment protocols based not on regional preference but on a risk-adapted PET-2 strategy. Unfortunately, based on current evidence, that time has not yet arrived. Colin Phipps performed the analyis and wrote the paper. Yuh Shan Lee provided input and data. William Hwang provided input and data.