Initial disease stage, presence of bulky disease and response to initial treatment can guide de-escalation or escalation chemotherapy and indication for consolidation radiation therapy (RT). Treatment response is assessed with FDG-PET. Interpretation of FDG-PET response is based on the Deauville criteria. In the RATHL design where patients with a positive scan received escalation from ABVD to BEACOPP, investigators preferred to use the liver threshold to avoid the risk of over treating patients (score = 3).rr In some trials designed to explore de-escalation strategies, a lower mediastinal threshold has been used to avoid the risk of under treating patients (score = 2).r
There is clear evidence for a freedom from treatment failure (FFTF) benefit of consolidation RT in the setting of a partial response to chemotherapy in patients with advanced stage Hodgkin lymphoma.
The HD 12 trial randomised patients to 8 cycles of escalated BEACOPP chemotherapy or to 4 cycles of escalated BEACOPP followed by 4 cycles of baseline dose BEACOPP chemotherapy.r Patients in each arm with bulky and/or residual disease (but with ≥ 50% response) and/or extranodal disease were randomised to RT (30Gy) or no RT. Patients with an inadequate response to chemotherapy (i.e. <50% tumour response) were not randomised. Between January 1999 and January 2003, 755 patients were randomised to a receive-RT arm and 765 patients were randomised to a no-RT arm. The primary radiation therapy objective was to evaluate the impact of consolidation RT in patients responding to chemotherapy who had initial bulky disease (defined as >5 cm) or had residual disease ≥1.5 cm.
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 al. 2004 published a randomised controlled trial involving 251 patients with all stages of Hodgkin’s disease. Patients received 6 cycles of ABVD and underwent post-treatment CT staging.r Of the 251 patients, 179 (71%) achieved a CR and this group was then randomised to receive no further treatment or consolidation RT. Among the 179 patients, 80 patients had advanced stage disease. Between 1993 and 1996, 84 patients were randomised to an observation arm (no RT) and 95 patients were randomised to a consolidation RT arm.
After a median follow-up of 63 months, the 8 year event free survival (EFS) and overall survival (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 randomised trial that shows a survival benefit to consolidation RT in advanced disease.
Complete response to chemotherapy
There is good evidence that radiation therapy can be safely omitted in patients with a complete response following BEACOPP or MOPP-ABV chemotherapy (even in the setting of bulky initial disease).rr r
Aleman et al. 2003 examined 421 patients who achieved a complete response after MOPP-ABV chemotherapy. Of these patients, 161 were randomised to an observation (no RT) arm and 172 were randomised to an involved field RT arm.r After a median follow-up of 79 months there was no statistically significant difference in EFS or OS in the two arms.
The HD15 trial showed omission of RT in PET negative residual nodal mass (≥2.5cm) after 6 or 8 cycles of eBEACOPP or BEACOPP14 is non-inferior to those with complete remission who were also not offered consolidation RT (4 year PFS 92.1% for PET negative residual disease and complete metabolic response).r
Trotman et al. (RATHL) separately analysed patients with bulky stage II disease. RT appeared to not add any benefit and hence it was considered safe to omit RT in those with initial bulky disease.r The 3 year progression free survival (PFS) of this group was 89% (82.5 – 93.0) with no significant difference between ABVD and AVD, RT or no RT, presence or absence of a residual mass, or Deauville score (1‐3). This is relative and overall PFS of all stage IIB to IV at 3 years for ABVD was 85.4% (95% CI 81.9 – 88.4), and for AVD 84.0% (95% CI 80.3‐87.1).r
An abstract by Savage et al. report that stage IIB to IV patients with negative FDG PET scans following ABVD chemotherapy are at low risk of relapse and do not routinely require additional consolidative RT.r In the PET negative patients, there was no difference in the 3-year TTP in those with bulky versus non-bulky disease at diagnosis (86% versus 91%, p = 0.71). In the PET positive group, 25 (81%) received the planned RT and of these, 10 (40%) have relapsed. Bulk at diagnosis was not predictive of time to progression. Time to progression is reflected by residual disease on interim FDG PET. Regardless of the presence of bulky disease at diagnosis, it is the presence of disease after chemotherapy that is representative of the risk of progression.
Radiation therapy to bulky disease in PET driven studies
The GITIL/FIL HD 0607 trial investigated the PFS of patients with advanced Hodgkin’s lymphoma after a risk-adapted treatment strategy that was based on a positive interim FDG PET.r The primary objective was to assess whether interim FDG-PET could be used to de-escalate therapy for those with a high probability of cure and escalation for those at higher risk of failure. With respect to consolidation RT, results suggest that omitting RT based on a negative PET after chemotherapy is appropriate. The study showed that the addition of RT to initial bulky disease (>5 cm) did not improve PFS when both interim PET and post-ABVD x 6 PET were negative. Among 296 randomly assigned patients, the largest diameter of LNM at baseline was 5-7 cm in 101 (34%; subgroup A) and 8-10 cm in 96 (32%; subgroup B), whereas classic bulky (diameter >10 cm) was detected in 99 (33%; subgroup C). 280 patients (88%) showed a post-chemotherapy RM. The median dose of cRT was 30.6 Gy (range, 24-36 Gy). After a median follow-up of 5.9 years (range, 0.5-10 years), the 6-year PFS rate of patients who underwent cRT or NFT was, respectively, 91% (95% CI, 84% to 99%) and 95% (95% CI, 89% to 100%; p = .62) in subgroup A; 98% (95% CI, 93% to 100%) and 90% (95% CI, 80% to 100%; p = .24) in subgroup B; 89% (95% CI, 81% to 98%) and 86% (95% CI, 77% to 96%; p = .53) in subgroup C (classic bulky).r
© J Clin Oncol 2020r
In the HD 0801 trial patients with a bulky lesion at baseline (a mass with largest diameter ≥5 cm) who had CMR after 2 and 6 ABVD cycles were randomly assigned 1:1 to RT vs observation (OBS) with a primary endpoint of event-free survival (EFS) at 2 years.r The sample size was calculated estimating an EFS improvement for RT of 20% (from 60% to 80%). The secondary end point was PFS. 116 patients met the inclusion criteria and were randomly assigned to RT or OBS. Intention-to-treat (ITT) analysis showed a 2-year EFS of 87.8% vs 85.8% for RT vs OBS (hazard ratio [HR], 1.5; 95% CI 0.6-3.5; p = .34). At 2 years, ITT-PFS was 91.3% vs 85.8% (HR, 1.2; 95% CI 0.5-3; p = .7). Patients in CMR randomly assigned to OBS had a good outcome, and the primary end point of a 20% benefit in EFS for RT was not met. However, the sample size was underpowered to detect a benefit of 10% or less, keeping open the question of a potential, more limited role of RT in this setting.