Treatment of advanced-stage Hodgkin lymphoma

https://doi.org/10.1053/j.seminhematol.2016.05.006Get rights and content

Abstract

There is now good evidence that the escalated BEACOPP regimen (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) is more effective in controlling advanced-stage Hodgkin lymphoma (HL) than the widely used ABVD regimen (adriamycin, bleomycin, vinblastine, dacarbazine), but the extra efficacy comes at the expense of both short- and long-term toxicity, and there is debate as to whether overall survival is affected. Baseline prognostic factors have proven of limited utility for determining which patients require more intensive therapy and recent studies have sought to use interim fluoro-deoxyglucose positron emission tomography (FDG-PET) evaluation as a means to guide the modulation of treatment, both upwards and downwards in intensity. These suggest that if treatment starts with ABVD then patients remaining PET-positive after 2 months can be salvaged with escalated BEACOPP in around 65% of cases, but those becoming PET-negative may still experience recurrences in 15%–20%, an event that is more common in those with more advanced disease at presentation. There are early data to suggest that starting with escalated BEACOPP may reduce the rate of recurrence after a negative interim PET to less than 10%. This may be an attractive approach for those with very high-risk features at presentation, but risks overtreating many patients if applied nonselectively. New regimens incorporating antibody–drug conjugates may shift the balance of efficacy and toxicity once again, and further studies are underway to evaluate this.

Introduction

The introduction of MOPP combination chemotherapy by De Vita in the mid-1960s was the first major step towards cure of advanced-stage Hodgkin lymphoma (HL) [1], [2], [3], [4], [5]. ABVD (adriamycin, bleomycin, vinblastine, dacarbazine), a regimen developed by Bonadonna in the 1970s [2], [6], [7] proved to be less toxic and more effective than MOPP (mechlorethamine, vincristine, procarbazine, prednisone), thus becoming the new standard of care [3], [4], [5], [6], [7], [8]. Despite initial enthusiasm, several attempts to improve results over ABVD with the introduction of alternating, hybrid, or 9–10 drug regimens proved unsuccessful [9], [10], [11], [12]. Following ABVD plus consolidation radiotherapy (RT) in selected patients, the long-term probability of tumor control is 65%–75%, depending on the definition of advanced disease.

In the 1990s, the German Hodgkin Study Group (GHSG) developed a theoretical model predicting that a time-intensified seven-drug regimen with higher drug doses compared to COPP (cyclophosphamide, vincristine, procarbazine, prednisone)/ABVD would improve the outcome of advanced HL [13]. BEACOPP-escalated (BEACOPP = bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) was designed on this basis [14] and the HD9 trial proved that indeed this regimen, but not its “baseline” version, improved progression-free survival (PFS) and overall survival (OS) over COPP/ABVD in patients up to 65 years old with advanced HL, defined as stage III/IV or IIB with bulky mediastinal and/or extranodal disease [15]. In the 10-year report, the absolute PFS and OS benefits with BEACOPP-escalated were 18% and 10%, respectively [16]. However, these benefits, achieved by eight cycles of BEACOPP-escalated, were associated with significant treatment-related mortality (TRM) and lethal secondary myelodysplasia and leukemia (sMDS/ANLL) rates of ~2%–3% each and much higher rates of severe hematologic toxicity.

Based on these results, the GHSG focused on the improvement of BEACOPP toxicity in the HD12 and HD15 trials. By limiting the number of cycles to six and the upper age limit to 60 years, results were further improved and TRM and sMDS/ANLL were minimized to 0.8% (comparable to ABVD) and 0.3%, respectively [17]. On the other hand, investigational groups outside Germany focused on the comparison of BEACOPP-escalated versus ABVD and similar regimens [18], [19], [20], [21].

Section snippets

Summary of trials comparing BEACOPP with ABVD or similar regimens

Based on the results of HD9 and HD15, there is good evidence that BEACOPP-escalated improves OS over alternating COPP/ABVD and that six cycles are better tolerated than eight cycles in patients up to 60 years old, minimizing toxic deaths and sMDS/ANLL [15], [16], [17]. However, no direct comparison was conducted in these trials with ABVD, which is less toxic than COPP/ABVD and may be more effective, providing as it does a greater dose-intensity of doxorubicin, one of the more important drugs in

Can baseline prognostic factors guide the selection of first-line treatment?

The standard tool for the prognostic assessment of advanced HL is the IPS [25]. In the HD9 trial, IPS was predictive for freedom from treatment failure (FFTF) and OS after either COPP/ABVD or eight cycles of BEACOPP-escalated, with differences between the two regimens being more pronounced in the intermediate- (IPS 2–3) and high-risk (IPS 4–7) groups [15]. The absolute difference between high and low-risk groups was narrower after BEACOPP-escalated than COPP/ABVD (13% v 25% for OS and 10% v 20%

Background

Positron emission tomography combined with computed tomography (PET/CT) is increasingly used in HL. In 2006–2007, two retrospective studies suggested that early interim PET assessment (iPET) after two cycles of ABVD could discriminate patients who are destined to fail from those who will achieve long-term remission [33], [34]. In patients with stage III/IV HL or stage II with adverse factors, the 5-year PFS was 95% for iPET-negative versus only 13% for iPET-positive patients [34]. This

Other regimens and novel agents in the first-line setting

The preceding discussion has focused on the use of iPET to spare the excessive toxicity of BEACOPP-based therapy in a proportion of patients with advanced stage HL. However, the use of other intensive regimens and the incorporation of novel agents in HL combination treatment may provide alternative, less toxic strategies for treatment intensification.

The dose-dense Stanford V regimen was developed in the early 1990s but ultimately failed to improve on the results of ABVD [11], [29], [31]. An

Conclusions

The treatment of advanced HL remains an area of active research, and the emphasis has shifted significantly in recent years from the principal pursuit of anti-lymphoma efficacy towards the additional consideration of long-term survival and the exclusion of avoidable toxicity. The testing of response-adapted therapy based upon interim PET has been helpful in this respect, but there remains scope for further improvement, by the application of more sophisticated models to determine those patients

Conflicts of interest

P.J. and T.P.V. have served on advisory boards for Takeda and Bristol-Myers Squibb. T.P.V. has received honoraria from Takeda.

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