Evidence for radiation prescription
The evidence supporting this protocol is provided by the German Hodgkin Study Group (GHSG) phase III multicentre international randomised trials HD7r, HD10r and HD11r.
The GHSG HD11 trial compared ABVD with either 20Gy or 30Gy IFRT to BEACOPP with either 20Gy or 30Gy IFRT. r Between 1998 and 2003, 1395 patients were randomised into four groups:
- Group 1: 4 cycles of ABVD + 30Gy IFRT
- Group 2: 4 cycles of ABVD + 20Gy IFRT
- Group 3: 4 cycles of BEACOPP + 30Gy IFRT
- Group 4: 4 cycles of BEACOPP + 20Gy IFRT
The primary end point was freedom from treatment failure (FFTF) and secondary endpoints included overall survival (OS), progression free survival (PFS) and treatment-associated toxicity.
After a median follow-up of 82 months, the trial showed that 4 cycles of ABVD followed by 30 Gy IFRT was equivalent to more intensive BEACOPP chemotherapy-radiotherapy regimens, and less toxic. However, dose reduction to 20 Gy IFRT was inferior to 30 Gy with lower rates of FFTF and PFS, unless more intensive chemotherapy was used.
Further follow-up through the HD11 trial showed no significant superiority in progression free survival of BEACOPP over ABVD when combined with 30 or 20 Gy IFRT.18
Figure 1: Kaplan-Meier curves for all four trial arms of HD11: ABVD+30 Gy, ABVD+20 Gy, BEACOPP+30 Gy, BEACOPP+20 Gy
© J Clin Oncol 2007r
The GHSG HD10 trial demonstrated that less chemotherapy and lower radiation doses may be used.r This trial randomised 1370 patients (favourable risk according to GHSG criteria) into four groups:
- Group 1 - 4 cycles of ABVD plus 30Gy RT
- Group 2 - 4 cycles of ABVD plus 20Gy RT
- Group 3 - 2 cycles of ABVD plus 30Gy
- Group 4 - 2 cycles of ABVD plus 20Gy RT
The comparison of freedom from failure rates showed no difference between these four arms.
Evidence for prognostic role of interim PET and treatment stratification
The RAPID trial was a randomised control non-inferiority study of PET-directed therapy for early-stage Hodgkin Lymphoma.r It aimed to determine if treatment can be de-escalated by omitting RT in PET negative patients in order to avoid late radiotoxicities. Approximately 60% of patients were favourable as per GSHG and EORTC criteria.
Patients received 3 x ABVD and then underwent a PET scan. Those with a negative PET result (Deauville score 1-2) were randomised to either to RT of 30 Gy IFRT (n=209) or no RT (n=211). The results demonstrated a 3 year progression free survival (PFS) of 94.6% in the RT arm vs 90.8% in the no RT arm (97.1% v 90.8% in per-protocol analysis), and an overall survival (OS) rate of 97.1% in the RT arm vs 99.0% in the no RT arm, with nonsignificant rate ratios for the RT group as compared with the no RT group of 1.57 (95% CI, 0.84 to 2.97; P=0.16) and 0.51 (95% CI, 0.15 to 1.68; P-0.27) respectively. Therefore, the non- inferiority criterion for omitting RT was not met.
Figure 2. Kaplan–Meier plots of progression-free survival and overall survival. Included are data from patients with negative PET findings who underwent randomisation and were included in the intention to treat analysis
© New Eng J Med 2015r
The EORTC H10 trial was an RCT that assessed PET-directed therapy for EORTC favourable (F) and unfavourable (U) early-stage Hodgkin Lymphoma.r The study aimed to determine if treatment can be de-escalated by omitting INRT in patients with a negative early PET (ePET) after 2 cycles of ABVD. ePET negative was defined as Deauville 1-2. This study also assessed if intensification of treatment with escalated doses of BEACOPPesc chemotherapy after 2 cycles of ABVD would improve outcome in ePET positive patients.
F group patients in the standard arm received one additional cycle ABVD and INRT, regardless of ePET results. F patients in the experimental arm with ePET negative results received an additional 2 cycles of ABVD and no INRT. For F patients with ePET negative results, the 5 year PFS was 99% (standard arm) and 87% (experimental arm). The 5 year OS was 100% (standard arm) and 99.6% (experimental arm).
U group patients in the standard arm received an additional 2 cycles of ABVD and INRT, regardless of ePET results. U patients in the experimental arm with ePET negative results received an additional 4 cycles of ABVD and no INRT. For U patients with ePET negative results, the 5 year PFS was 92.1% (standard arm) and 89.6% (experimental arm). The 5 year OS was 96.7% (standard arm) and 98.3% (experimental arm).
For ePET-positive patients the standard arm (n=361) received 1 additional cycle of ABVD + INRT (F group) or 2 additional cycles of ABVD + INRT (U group). U and F patients in the experimental arm with ePET positive results would receive 2 additional cycles of BEACOPPesc + INRT. The 5 year PFS was 77.4% (standard arm) and 90.6% (experimental arm). The 5 year OS was 89.3% (standard arm) and 96% (experimental arm) respectively.
Image 4. Progression free survival in PET negative patients in ABVD + INRT and ABVD only groups (A Favourable; B Unfavourable)
© J Clin Oncol 2017r
Image 5. PFS (A) and OS (B) in PET-positive patients in ABVD+INRT vs BEACOPPesc+INRT groups.
© J Clin Oncol 2017r
The H10 trial demonstrated that the outcome of ePET-negative patients have excellent overall outcome with either chemotherapy + RT or chemotherapy alone, but non-inferiority of chemotherapy alone was not demonstrated in both favourable and unfavourable groups. This study also showed that patients who are ePET-positive after 2 x ABVD, intensification with 2 x BEACOPPesc + INRT produced a significant improvement in 5 year PFS, and therefore should be considered.
Both the RAPID and H10 trials did not demonstrate non-inferiority of omitting RT for PFS, but there was no significant difference in OS. Favourable early stage Hodgkin Lymphoma patients have a very good prognosis with or without consolidation radiotherapy. PET-adapted approach may be utilised on an individualised basis where the risk of late toxicity from radiotherapy is felt to outweigh the incremental benefit in tumour control.
A longer follow up period is required for both trials to determine whether this PET-adapted approach would lead to fewer secondary cancers and cardiovascular disease.