Efficacy
Evidence for radiation prescription
The evidence supporting this protocol is provided by the German Hodgkin Study Group (GHSG) phase III multicentre international randomised trials HD7, HD10, HD16 and HD11.rrrr
The GHSG HD11 trial compared ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with either 20 Gy or 30 Gy IFRT, to BEACOPP with either 20 Gy or 30 Gy IFRT. r Between 1998 and 2003, 1395 patients were randomised into four groups:
- Group 1: 4 cycles of ABVD plus 30 Gy IFRT
- Group 2: 4 cycles of ABVD plus 20 Gy IFRT
- Group 3: 4 cycles of BEACOPP plus 30 Gy IFRT
- Group 4: 4 cycles of BEACOPP plus 20 Gy 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-radiation therapy 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.r
Figure 1: Kaplan-Meier curves for all four trial arms of HD11 - (A) ABVD plus 30 Gy, (B) ABVD plus 20 Gy, (C) BEACOPP plus 30 Gy.
© J Clin Oncol 2010r
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 30 Gy RT
- Group 2 - 4 cycles of ABVD plus 20 Gy RT
- Group 3 - 2 cycles of ABVD plus 30 Gy RT
- Group 4 - 2 cycles of ABVD plus 20 Gy 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 cycles of ABVD and then underwent a PET scan. Those with a negative PET result (Deauville score 1-2) were randomised to either 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% vs 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 non-significant rate ratios for the RT group as compared with the no RT group of 1.57 (95% CI:0.84-2.97, p = 0.16) and 0.51 (95% CI:0.15-1.68, 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 outcomes in ePET positive patients.
F-group patients in the standard arm received one additional cycle of ABVD and INRT, regardless of ePET results. F-group patients in the experimental arm with ePET negative results received an additional 2 cycles of ABVD and no INRT. For F-group 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) respectively.
U-group patients in the standard arm received an additional 2 cycles of ABVD and INRT, regardless of ePET results. U-group patients in the experimental arm with ePET negative results received an additional 4 cycles of ABVD and no INRT. For U-group 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) respectively.
For ePET positive patients the standard arm (n = 361) received 1 additional cycle of ABVD plus INRT (F-group) or 2 additional cycles of ABVD plus INRT (U-group). In the experimental arm, U-group and F-group patients with ePET positive results received 2 additional cycles of BEACOPPesc plus 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.
Figure 3: Progression free survival in PET negative patients in ABVD plus INRT and ABVD only groups (A - Favourable; B - Unfavourable)
© J Clin Oncol 2017r
Figure 4: PFS (A) and OS (B) in PET-positive patients in ABVD plus INRT vs BEACOPPesc plus INRT groups
© J Clin Oncol 2017r
The H10 trial demonstrated ePET-negative patients have excellent overall outcome with either chemotherapy plus RT or chemotherapy alone, but non-inferiority of chemotherapy alone was not demonstrated in favourable or unfavourable groups. This study also showed patients who are ePET positive after 2 cycles of ABVD, intensification with 2 cycles of BEACOPPesc, plus INRT produced a significant improvement in 5-year PFS, and therefore should be considered.r
The GHSG HD16 trial was a randomised control non-inferiority study of standard therapy versus PET-directed therapy for favourable early-stage Hodgkin lymphoma patients.r Patients were randomised to standard therapy of combined modality treatment (CMT) (2 cycles of ABVD plus 20 Gy IFRT), or PET-guided treatment of 2 cycles of ABVD for all patients and 20 Gy IFRT only for PET positive patients after two chemotherapy cycles (PET-2-positive). The study aimed to assess whether IFRT could be omitted in PET negative patients (PET-2-negative) after 2 cycles of ABVD. The second aim was to ascertain whether PET-2-positive was a risk factor for PFS after combined modality treatment. A Deauville Score of ≥3 was considered positive.
A total of 628 patients were PET-2-negative, of these, 328 received CMT and 300 received 2 cycles of ABVD alone. Among these, 5-year PFS was 93.4% (95% CI:90.4-96.5%) in the CMT group compared with 86.1% (95% CI:81.4-90.9%) for the experimental group receiving ABVD alone. Non-inferiority of chemotherapy alone was not demonstrated. There was no difference in 5-year OS, 98.1% (95% CI:96.5-99.8%) with CMT and 98.4% (95% CI:96.5-100.0%) with ABVD alone.
There were 693 patients assigned to IFRT after chemotherapy, PET-2-negative (n = 353) or PET-2-positive (n = 340). PFS at 5 years was 93.2% (95% CI:90.2-96.2%) in the PET-2-negative subgroup and 88.4% (95% CI:84.2-92.6%) in the PET-2-positive subgroup (HR = 1.71, 95% CI:1.00-2.93, p = 0.047).
Figure 5: Kaplan-Meier estimates for PET-2-negative (PET after two cycles of chemotherapy) per-protocol population. (A) Progression-free survival; (B) Overall survival
© J Clin Oncol 2019r
RAPID, H10, and HD16 trials did not demonstrate non-inferiority of omitting RT for PFS, and there was no significant difference in OS. Favourable early-stage Hodgkin lymphoma patients have a very good prognosis with or without consolidation radiation therapy. A PET-adapted approach may be utilised on an individual basis where the risk of late toxicity from radiation therapy is considered to outweigh the incremental benefit in tumour control.
A longer follow-up period is required for these trials to determine whether a PET-adapted approach reduces the risk of secondary cancers and cardiovascular disease.
The GHSF HD17 trial was the first study to show that radiation therapy can be omitted in patients with a negative end of treatment PET scan after 2 x ABVD + 2 x eBEACOPP (2+2) without compromising on PFS.r 1,100 patients with early-stage unfavourable HD were randomly assigned 2+2 followed by 30 Gy involved field or 2+2 followed by 30 Gy of involved node RT only to patients with a positive PET at the end of four cycles of chemotherapy. A positive PET scan was defined as a Deauville score of 3 or more with 160 of 493 patients in the PET guided treatment group meeting this definition. At a median follow up of 46.2 months the 5-year progression-free survival was 97.3% (95%CI 94.5-98.7) in the standard combined modality group and 95.1% (95%CI 92.0-97.0) in the PET guided treatment group demonstrating non-inferiority with this approach.
Figure 6: Kaplan-Meier estimates of 5-year progression-free survival in the per-protocol analysis population (A) and in a subset of PET4-negative patients in the per-protocol analysis population (B).
PET4-PET scan at the end of four cycles of chemotherapy.
© Lancet Oncolr