A systematic review by Kaster et al. examined the use of radical intent hypofractionated radiation therapy in stage III NSCLC.r In total, 33 studies were included with heterogenous dose prescriptions ranging from 45 to 85.5 Gy in 15-35 fractions (dose per fraction ranged from 2.3-3.5 Gy). This review found overall survival was associated with tumour biological effective dose. There was also a prospective single institution phase I trial which was carried out to identify the maximum tolerated dose (MTD) for hypofractionated radiotherapy without concurrent chemotherapy.r The MTD was defined as maximum dose with ≤ 20% risk of severe toxicity. Doses ranged from 57-85.5 Gy in 25 daily fractions. There was no difference in local control in patients treated to 69.25 Gy and higher, compared with those treated at 57 Gy and 63.25 Gy dose levels (p = 0.81). An MTD was identified at 63.25 Gy in 25 fractions (EQD210 66 Gy, EQD23 70 Gy) with late grade 4-5 toxicity attributable to damage to central and perihilar structures, and correlated with dose to the proximal bronchial tree.
This protocol is for the fractionation prescription of 55 Gy in 20 fractions (EQD210 58 Gy, EQD23 63 Gy), a regimen commonly used in the UK.r Although the EQD2 is slightly lower than for 60 Gy, this does not account for the time factor with the advantage of radiation therapy being completed in ten fewer fractions.
There is a paucity of phase III randomised data for this regimen with most data based on phase II or series evidence. Two phase III studies using this regimen both failed to reach recruitment and were reported as phase II studies. The GRiN trial recruited 111 patients with medically inoperable T1-2 N0-1 M0 NSCLC, comparing 55 Gy in 20 fractions of radiation therapy alone (Arm A) versus the same radiation therapy fractionation with concurrent weekly gemcitabine (Arm B).r No significant difference in event-free or overall survival was found. Event-free survival was 42% and 46% at 2 years and 20% and 31% at 5 years (p = 0.72) for arm A and B, respectively. Overall survival was 56% and 52% at 2 years and 20% and 33% at 5 years (p = 0.87) for arm A and B, respectively. Two deaths were reported from accelerated interstitial lung disease in the chemotherapy arm. The SOCCAR study included 130 patients with inoperable stage III NSCLC and compared concurrent versus sequential chemotherapy (cisplatin and vinorelbine) with 55 Gy in 20 fraction radiation therapy.r There was no significant difference in overall survival between the 2 groups (2-year overall survival 50% vs. 46%, overall survival HR 0.92, 95% CI:0.6-1.39, p = 0.682). Treatment related mortality was 2/68 (2.9%) in the concurrent group and 1/58 (1.7%) in the sequential group.
Din et al. published retrospective series data from 4 UK centres, which included 609 patients of whom 98% received 55 Gy in 20 fractions. 49% had stage I disease and 27% received concurrent or sequential chemotherapy.r Median overall survival was 24 months and 2-year overall survival was 50%. The difference in overall survival of the chemotherapy group compared to those who did not receive chemotherapy was not statistically significant (21 months vs. 26 months, p = 0.332). No grade 3-5 toxicities were identified. This is similar to previously published series by Pemberton et al. 2009 (55 Gy in 20 fractions) and Lester et al. 2004 (50-55 Gy in 15-20 fractions), reporting 2-year overall survival of 45% and 44.4%, respectively.rr