The combination of doxorubicin, bleomycin, vinblastine and dacarbazine was originally used by Bonadonna et alr for treatment of advanced stage Hodgkin lymphoma. Initially ABVD was proven effective in advanced disease when it was shown to be superior to the previous standard regimen, MOPP, alonerrr and less toxic than the MOPP/ABVD combination, with minimal infertility and reduced rates of secondary malignancy compared with radiation therapy (RT) or MOPP.r Subsequently, combined modality therapy with ABVD and RT replaced RT alone for early stage disease and ABVD has now become the standard chemotherapy regimen for early stage Hodgkin lymphoma.rrr A Cochrane reviewr concluded that, in early stage Hodgkin lymphoma, combined modality therapy results in improved overall and disease free survival compared with either chemotherapy or RT alone. In addition, second malignancy rates were lower with combined therapy when compared with RT alone. The number of cycles of ABVD required depends on the stage of disease. A large German randomized trial (HD10) demonstrated that the intensity of therapy can be reduced in early favourable disease without altering outcome.r Two cycles of ABVD with 20Gy of involved field RT (IFRT) is equivalent to 4 cycles of ABVD with 30 Gy IFRT, the previous standard of care. Another question has been whether it is possible to eliminate radiation from the treatment of early stage disease altogether. There have been several randomized trialsrrrr but the trials have been limited in applicability.
The most recent trial showed improved overall survival when ABVD alone was used however an outmoded form of radiation (subtotal nodal irradiation) was used, potentially accounting for the increased death rate from non-lymphoma causes in those who received radiation.r In patients with higher risk disease (early unfavourable Hodgkin lymphoma) progression free and overall survival are inferior compared with early favourable disease.r The German Hodgkin Study Group has recently trialled (HD11) increasing the intensity of chemotherapy for the early unfavourable patients.r There was no benefit to giving 4 cycles of BEACOPP baseline compared with 4 cycles of ABVD, when followed by IFRT.
In the HD-14 trialr, patients with early unfavourable disease were randomized to either 4 cycles of ABVD + 30 Gy radiotherapy or 2 cycles of ABVD + 2 cycles esc BEACOPP + 30 Gy radiotherapy. Although the PFS improved with the 2+2 regimen, did not impact in OS. However a recent Cochrane reviewr concluded that “this meta-analysis provides moderate- to high-quality evidence that adult patients between 16 and 60 years of age with early unfavourable and advanced stage HL benefit regarding OS and PFS from first-line chemotherapy including escalated BEACOPP".
A further study investigated the possibility of PET directed omission of radiotherapy after initial ABVD treatment (3 cycles)r in the both the early favourable and early unfavourable risk groups. This study found only a modest improvement of 3 year Progression Free Survival in favour of radiotherapy in an intention-to-treat analysis (95% vs 91% without radiotherapy), however longer analysis is required to assess the late effects of radiotherapy. In a further study by the EORTC/LYSA/FIL H10 group, an increased number of events were noted in the non-radiotherapy arm in the early unfavourable risk group (PET directed after 2 cycles of ABVD) and the study was therefore closed early.r The latest Cochrane review publishedr of PET-directed therapy for early stage Hodgkin lymphoma concluded that “ to date, no robust data on OS, response rate, TRM, QoL, or short- and long-term AEs are available. However, this systematic review found moderate-quality evidence that PFS was shorter in individuals with early-stage HL and a negative PET scan receiving chemotherapy only (PET-adapted therapy) than in those receiving additional radiotherapy (standard therapy)".
In patients with early stage Hodgkin lymphoma, combined modality therapy using ABVD and involved field radiation therapy results in CR rates of 96-100 %.rrrr Long term (7-12 years) freedom from treatment failure is 87-95% and overall survival 94-96%.
© Journal of Clinical Oncology 2004
A study by the German Hodgkin study group investigated the outcomes of early favourable Hodgkin Lymphoma treated with ABVD with omission of either dacarbazine or bleomycin from the initial regime (2 cycles), followed by involved field radiotherapy. There were higher rates of progressive disease and relapse in the study arm without dacarbazine. The Complete Remission (CR) rates were comparable in the ABVD (control) and AVD (bleomycin omitted) arms (97.2% vs 98.1%), with similar overall survival. However late relapses were more common in the AVD arm. Dacarbazine is therefore not recommended to be omitted, however it may be feasible to omit bleomycin in certain patients but with a risk of a shorter Freedom from Treatment Failure.r
ABVD causes Grade 3-4 neutropenia in 30-34% of patients.rr Despite this, rates of significant infections are low (1-2%, Grade 3-4),rr Evens et alr demonstrated that G-CSF support is not required to maintain near 100% dose intensity during ABVD treatment. In their study 58% of 658 ABVD treatments were administered with an ANC <1.0 x 109/L without an increase in infection (incidence rate 0.44%) when compared with those given G-CSF (0.78%). Other Grade 3-4 early toxicities include alopecia 24-30%,rr nausea and vomiting 6-13%rr and pulmonary 6-10%rr Fertility is relatively preserved after ABVD. 30-54% of males experience transient oligoazospermia however most fully recover.rr Transient amenorrhoea occurs in around one third of women of reproductive age (<45 years) but permanent amenorrhoea secondary to ABVD alone is uncommon.rr Furthermore, female Hodgkin lymphoma survivors attempting pregnancy after ABVD had fertility comparable with case controls with a 12 month pregnancy rate of 70%.r Although second malignancies occur in patients post-ABVD (6% at 6-10 years follow up) rates of secondary MDS/AML are very low and do not appear to be significantly increased.rrrOther long term toxicities include bleomycin-induced lung injury (link to Pulmonary Toxicity associated with antineoplastic agents) and doxorubicin-related cardiac toxicity (link to Cardiac toxicity associated with anthracyclines).
In the most recent Cochrane reviewr, authors concluded that: “The risk of secondary acute myeloid leukaemia and myelodysplastic syndrome (AML/MDS) is increased but efficacy is improved among patients treated with intensified chemotherapy protocols. Treatment decisions must be tailored for individual patients. Consolidating radiotherapy is associated with an increased rate of secondary malignancies; therefore it appears important to define which patients can safely be treated without radiotherapy after chemotherapy, both for early and advanced stages. For early stages, treatment optimisation methods such as use of fewer chemotherapy cycles and reduced field or reduced-dose radiotherapy did not appear to markedly affect efficacy or secondary malignancy risk. Due to the limited amount of long-term follow-up in this meta-analysis, further long-term investigations of late events are needed, particularly with respect to secondary solid tumours. Since many older studies have been included, possible improvement of radiotherapy techniques must be considered when interpreting these results.