GOECP/SEOR radiotheraphy guidelines for non-small-cell lung cancer

Table 4 Studies of moderate hypofractionated radiotherapy

Ref.	Type of study	Number of patients	Radiotherapy	Chemotherapy	Results	Toxicity
[76]	Prospective	30, stage III-IVA. ECOG ≥ 2	60 Gy (20 fx 3 Gy); (BED10 79.4 Gy)	Sequential (80% patients)	LR 37%. OS 2-yr 38.1%. LR 37%. Distant relapse 57%	Acute esophagitis G3 7%. Acute pneumonitis G3 3%. No chronic toxicity
[77]	Prospective	83 (32 stage III)	66 Gy (24 fx 2.75 Gy); (BED10 84 Gy)	Sequential 90.6% stage III (platinum + vinorelbine)	OS 2 yr 37.5%. SCE 2 yr 41.5%	No toxicity ≥ G3
[78]	Retrospective	300, stage III, inoperable, MEG	3 arms: 45 Gy (15 fx 3 Gy); 60-63 Gy (6 wk); > 63 Gy (6 wk)		No significant differences in LC, distant control, or OS. > DFS in 60-63 Gy	Lower in hypofractionated arm
[79]	Retrospective	609 (9 centres). Stage IA (18%), IB (30.7%), II (14.8%), IIIA (16.4%), IIIB (19.2%). Unresectable or inoperable	55 Gy (20 fx 2.75 Gy)	ChT 28% (83% stage III). Platinum doublets. Most neoadjuvant	OS at 2, 3 and 5 yr: 50%, 36% and 20%. 2 yr OS: stage IA, 72%, stage Ib 51%, stage IIIA 40%. Adenocarcinoma better median survival (31 m) vs squamous (20.4 m). No difference in OS between ChT vs no ChT. Stage III, trend towards better OS with ChT	No toxicity ≥ G3. Pneumonitis G1-2, 15%
[80,82]	Retrospective	31, stage I (15), II (15), IIIA (57), IIIB (43). Medically inoperable or unresectable	3 arms: 66 Gy (24 fx 2.75 Gy) + daily cisplatin (6 mg/m2); same sequential RT after 2 cycles cisplatin/gemcitabine; RT alone 66 Gy (24 fx 2.75 Gy) or 60 Gy (20 fx 3 Gy)	Concurrent: Cisplatin daily (6 mg/m2). Sequential: (2 cycles cisplatin/gemcitabine) prior to RT	LR 36%, DM 46%. Better RT + ChT than RT alone. 5 yr OS: Concurrent CRT, 23%. No significant difference between concurrent and sequential CRT. LR 36%, DM 46%	Severe late toxicity greater in CRT (27% concurrent, 23% sequential) than in RT alone (8%)
[81]	Phase III RCT1	60, stage II/III (11.6%/88.3%). ECOG ≥ 2. Not candidates for ChT/RT	cRT 60-66 Gy/30-33 fx vs accelerated hypofx 60 Gy/15 fx 4 Gy	Non-concurrent ChT. Possible neoadjuvant or adjuvant	OS and PFS without significant differences between cRT and hypofx	No G4 toxicity. G3 toxicity: 35% cRT and 18.75% hypofx
[82]	Phase III RCT	158, stage I (3% sequential, 1% concurrent), II (4% sequential, 5% concurrent), IIIA (45% sequential, 30% concurrent), IIIB (47% sequential, 64% concurrent). Inoperable ECOG 0-1	66 Gy (24 fx 2.75 Gy)	Concurrent: Daily cisplatin (6 mg/m2) + RT 66 Gy (24 fx 2.75 Gy) vs sequential: 2 cycles gemcitabine 1250 mg/m2 days 1, 8 and cisplatin (75 mg/m2 day 2, prior to RT 66 Gy (24 fx 2.75 Gy)	No significant differences between the 2 groups in DM, OS, PFS. OS 2 and 3 yr: 39%-34% concurrent and 34%-22% sequential. Both schemes well tolerated. Due to early closure, no conclusions drawn	Acute esophagitis G3/4 more common in concurrent (14% vs 5%). Late esophagitis G3 = 4% in both arms. Pneumonitis G3/4 = 18% concurrent and 14% sequential
[83]	Phase II RCT	130, stage III inoperable. ECOG 0-1	55 Gy (20 fx 2.75 Gy)	Concurrent: Cisplatin 20 mg/m2 days 1-4 and 16-19 and vinorelbine 15 mg/m2 days 1, 6, 15 and 20 RT and 1 or 2 post ChT cycles (CDDP) 80 mg/m2 day 1 and vinorelbine 25 mg/m2 days 1 and 8). Sequential: Cisplatin 80 mg/m2 day 1 and vinorelbine 25 mg/m2 days 1 and 8, x 3-4 cycles before RT	No significant differences. OS 1 yr: 70% concurrent vs 83% sequential and 2 yr: 50% concurrent vs 46% sequential. PFS 1 yr: 74% concurrent vs 85% sequential; 2 yr: 47% concurrent vs 45% sequential. Both safe and effective treatments. Non-significant trend towards better survival with concurrent RT/ChT	Similar esophagitis ≥ G3 in both arms (8.8% concurrent and 8.5% sequential. Pneumonitis ≥ G3: 3.1% concurrent vs 5.2% sequential. No grade 4/5 esophagitis. G3 neutropenia lower in concurrent (37%) vs sequential (55%)
[84]	Retrospective	100, stages IIIA-B 95%, II 5%. ECOG 0/1	55 Gy (20 fx 2.75 Gy)	Concurrent: Cisplatin 20 mg/m2 days 1-4 and 16-19 RT and vinorelbine 15 mg/m2 days 1, 6, 15, 20 and 2 cycles post RT/ChT	OS 2 yr 58%. PFS 2 yr 49%	Esophagitis G3/4 14%. Pneumonitis G3/4 4%

¹Interim analysis of NCT01459497 with 226 patients: Arm A (experimental), 60 Gy in 15 fractions (3 wk) with image-guided radiotherapy versus arm B, conventional radiotherapy 60-66 Gy in 30-33 fractions (6 wk) with optional concurrent carboplatin/taxol. Final data expected in December 2021 and December 2022.

RT: Radiotherapy; cRT: Conventional radiotherapy; LR: Local recurrence; DM: Distant metastases; LC: Local control; G: Grade; ChT: Chemotherapy; PFS: Progression-free survival; MFS: Metastasis-free survival; OS: Overall survival; CDDP: Concurrent cisplatin.