The evidence supporting the use of this protocol is supported by three phase III multicentre international randomised trials (Borchmann,r Laskerr and Fermer) and multiple Phase II, observational and retrospective studies.
There is clear evidence for a Freedom From Treatment Failure (FFTF) benefit of consolidation radiotherapy in the setting of a partial response to chemotherapy in patients with advanced stage Hodgkin Lymphoma. There is good evidence that radiotherapy can be safely omitted in patients with a complete response following BEACOPP or MOPP-ABV chemotherapy (even in the setting of bulky initial disease).r,r,r There is less data on the omission of radiotherapy in patients who achieve a complete response after ABVD chemotherapy.r Longer follow-up data from the RATHL study should assist with this question. There is scanty randomized evidence for the benefit of consolidation RT for areas of bulky disease and extranodal sites. Difficulties arise due to the inconsistency in the definition of “bulky” and the reporting of bulky and extranodal disease. Two international guidelines, however, recommend radiotherapy in those settings. Most current trials do not recommend radiotherapy if there has been a CR to chemotherapy.
The HD 12 trialr was a 2 x 2 factorial design. It randomized patients to 8 cycles of escalated BEACOPP chemotherapy or to 4 cycles of escalated BEACOPP followed by 4 cycles of baseline dose BEACOPP chemotherapy. Patients in each arm with bulky and/or residual disease (but with = 50% response) and/or extranodal disease were randomized to RT (30Gy) or no RT. Patients with an inadequate response to chemotherapy (i.e. <50% tumour response) were not randomized). Between January 1999 and January 2003, 755 patients were randomized to a receive-RT arm and 765 patients were randomized to a no-RT arm. The primary radiotherapy objective was to evaluate the impact of consolidation RT in patients responding to chemotherapy who had initial bulky disease (defined as >5cm) or had residual disease = 1.5cm.
After a median follow-up of 78 months the FFTF was 87% in the non-RT arm compared to 90.4% in the RT arm (difference -3.4%; 95% CI -6.6% to -0.1%). Subgroup analysis confirmed a superior FFTF for patients with residual disease after CT who received RT (difference -5.8%; 95% CI, -10.7% to -1%). In contrast, not giving RT to patients who presented with bulky disease and then achieved a CR with CT did not give a detrimental outcome. There was no difference in OS between the two groups.
Laskar et alr published a randomized controlled trial involving 251 patients with all stages of Hodgkin’s disease. Patients received 6 cycles of ABVD and underwent post-treatment CT staging. 179 of the 251 patients (71%) achieved a CR and this group was then randomized to receive no further treatment or consolidation radiotherapy. Among the 179 patients, 80 patients had advanced stage disease. Between 1993 and 1996 84 patients were randomized to an observation arm (no RT) and 95 patients were randomized to a consolidation RT arm.
After a median follow-up of 64 months, the 8 year EFS and OS in the whole group Non-RT arm was 76% and 89% respectively, versus 88% and 100% in the RT arm (p=0.01, p=0.002). Subset analysis identified significantly improved outcomes with the addition of RT in patients with advanced stage disease. The 8-year EFS was 59% in the no-RT arm versus 78% in the RT arm (p=0.03). The 8-year OS was 80% in the no-RT arm versus 100% in the RT arm (p=0.006). This is the only randomized trial that shows a survival benefit to consolidation RT in advanced disease. The published data from the UKLG LY09 large randomized UK trialr showed that the omission of consolidation radiotherapy following ABVD was associated with a poorer survival. This is despite the fact that the patients in the irradiated group had worse risk features i.e. more bulky disease and less complete responses.
Aleman et alr examined 421 patients who achieved a complete response after MOPP-ABV chemotherapy. 161 of these patients were randomized to an observation (no RT) arm and 172 patients were randomized to an involved field RT arm. After a median follow-up of 79 months there was no statistically significant difference in event-free survival or overall-survival in the two arms.
Given the difference in effect of RT based on the response to chemotherapy it is evident that using FDG-PET should improve our ability to choose those patients most likely to benefit from escalated treatment. In the HD15 study9 2126 patients were randomised to three different BEACOPP chemotherapy regimens. All patients with a mass =2.5cm that was FDG avid received 30Gy consolidation radiotherapy (11% of patients). Progression free survival in patients with a residual mass that was PET-negative was similar to those with a complete response on CT imaging. This highlights the importance of FDG-PET in the assessment of residual masses.