Managing advanced stage Hodgkin lymphoma.

Hodgkin lymphoma (HL) is a unique malignancy, both from the biology and response to therapy points of view.[1] Described initially by Thomas Hodgkin on its clinical behaviour and later by Dorothy Reed and Sternberg on the pathological features, we now understand its cellular origin (B cells) and the microenvironment in a somewhat better way. Studying the biology of R-S cells (Reed-Sternberg) has been a challenge due to their paucity in affected nodes and thus availability of sufficient material. The microenvironment is composed of a mixed population of cells and they too seem to direct the behaviour of the disease in a significant manner.[2]

It is also one of the first malignancies that showed significant response to combined modality chemotherapy (MOPP or similar regimens, ABVD, escalated BEACOPP, Standord V, etc) in advanced stage and prolonged freedom from relapse and cure in many.[345] Early stage HL can be managed with extended field radiation therapy alone following an exploratory laparotomy, but such practice has become obsolete now. Radiation therapy is now used as adjuvant to chemotherapy. At present, combination chemotherapy is the mainstay of treatment for all patients with HL.

In managing early stage disease, the focus now is to maintain the excellent response of combination chemotherapy followed by reduced dose radiation therapy (20-30 Gy) and minimise acute and long term toxicities with optimisation of both modalities. Even chemotherapy alone can be chosen for non-bulky disease. Over-treatment given in earlier days was found to have many unwanted effects in long term survivors. These include lung, cardiac diseases, infertility and second malignancies.

In last 4 decades, with the advent of combination chemotherapy, the number of patients with freedom from relapse and overall survival has increased significantly even in patients with advanced stage disease. First evidence came from the MOPP regimen and subsequently the real benefit in terms of safety and efficacy was achieved with the ABVD regimen. Advanced stage HL is not a homogeneous disease.[36] The IPI score, although not a perfect prognostic model, provides some information on outcome, overall survival varying from 42% to 77%, depending on a number of factors involved in a given individual.[5] It is obvious that there is much to be done for advanced stage HL patients. Escalated BEACOPP regimen can improve CR and OS, but at the cost of significant toxicity.[46] Moreover, it cannot be offered in many countries that have socio-economic restraints. Even in developed countries, toxicity remains unacceptable to many. Subsequent approach with 4 cycles of escalated BEACOPP followed by baseline BEACOPP produced equally good outcome.[7] Long term outcomes using ABVD × 3 cycles followed by escalated BEACOPP in FDG-PET positive patients are also being eagerly awaited. So, efforts are underway to find out the value of both de-escalation and escalation of treatment based on interim PET status.

In Indian context, not many studies have been reported till date. While a few retrospective studies have been reported, no prospective study has been carried out.[89] In this issue of the journal, Jain et al. are reporting a single institute's results of a retrospective study.[10] Patients were treated in the period 2004-07 with the standard ABVD regimen for 6 cycles in majority. The response rates were CR in 76% and 10% PR. Early mortality in 8 patients due to toxicity remains a cause of concern. Estimated 5- year PFS and OS were 58% and 60%. The small difference in PFS and OS appears to be due to failure of salvage chemotherapy and absence of high dose therapy with ASCT. Adjuvant or consolidation radiation therapy was given to 36% patients based on bulky disease at diagnosis or residual disease (CT based?). As often happens with retrospective analysis, the data on toxicity is scratchy. Nonetheless, it a valuable report. It brings out an important fact that administration of the ABVD regimen is feasible in most patients and the results are comparable with some published results. Another issue in the study is inability of many patients to undergo high dose chemotherapy after failure or relapse following ABVD. This would have probably improved overall survival outcome.

The role of radiation therapy in the management of advanced HL remains debatable.[11] Stanford University, the seat of radiation oncology, offered 36 Gy to all patients who presented with a largest node mass of more than 5 cm as adjuvant to Stanford V regimen. This is not practiced across the world. A randomised Indian study had shown its beneficial value.[9] The study had many paediatric patients, in whom the prognosis is always better even without radiation therapy. The study also had the drawback of documenting long term toxicities of such an approach. The EORTC 20884 study showed beneficial role of consolidation radiation therapy of 24 Gy, but the combination therapy in that era was MOPP/ABVD, an obsolete regimen now.[12] Also, CT scan was the standard for evaluating response then. Currently, FDG-PET scan has become the standard for evaluating response.[13] Looking at the data from various trials, it is reasonable to conclude that patients with a PET-CT positive residual disease after chemotherapy derive a benefit. To take this issue further, even consolidation high dose therapy with autologous stem cell transplantation produces excellent salvage. Hence, there are more than one ways to treat post-chemotherapy residual disease. Radiation therapy has a value in a country like India where high dose chemotherapy cannot be offered to all eligible patients.

The study does not comment on use of FDG- PET-CT scan as a part of staging or evaluating response to therapy but mentions that response was evaluated according to the proposed 2007 criteria.[13] This is somewhat misleading. It is quite possible that a good number of patients underwent this investigation. Probably, it was not employed in most. Should PET now be routinely used for staging, interim evaluation, at end of study and at follow up visits? PET scan certainly stages the disease at baseline and currently, most treating physicians would get one done if the facility is available within the geographical location. The value of PET negative status at interim analysis, after 2-3 cycles has been reported. However, the value of PET positive disease, with or without new lesions remains a matter of further research. Interpretation of FDG positivity requires constant refinement. It is still a learning tool. To this end, currently the Deauville 5-point scoring system is being employed.[14] Also, the role of radiation therapy in PET positive disease is under investigation. New lesions should always be biopsied to confirm the pathology. Once complete remission is documented, the need for frequent CT scans or PET scans is debatable but the general guideline is not to get a scan in the absence of clinical suspicion.[13]

Administering ABVD on scheduled time is desirable for an optimal outcome. The study does not comment on this. It is not an aggressive regimen and can be safely delivered with an ANC (absolute neutrophil count) of 1000/micro litre, without G-CSF support.[15] Only a small number of patients need such support. However, looking out for bleomycin lung injury at least clinically cannot be overemphasised.

In conclusion, the Indian retrospective result of a single centre experience is noteworthy and can be used as a benchmark for future prospective studies. It also warns us about detailed documentation needed even for retrospective analysis. Availability and effectiveness of a number of biological agents like rituximab (in a selected subset), brentuximab vedotin, PD-1 blocker, etc. will have an important role to play even in first line setting. These agents are under investigation in relapsed/refractory settings.[1617] We live in the hope of bettering the results of ABVD chemotherapy which has remained a benchmark for more than 3 decades.