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

Table 1 Level of evidence and grades of recommendation

Level of evidence
I	Evidence from at least one large randomised controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity
II	Small randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity
III	Prospective cohort studies
IV	Retrospective cohort studies or case-control studies
V	Studies without control groups; case reports; expert opinions
Grades of recommendation
A	Strong evidence for efficacy with a substantial clinical benefit, strongly recommended
B	Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended
C	Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, etc.), optional
D	Moderate evidence against efficacy or for adverse outcomes, generally not recommended
E	Strong evidence against efficacy or for adverse outcome, never recommended

Table 2 Recommended stereotactic body radiation therapy dose in early-stage disease

Localization	Dose	Ref.	Evidence level
Central tumour	50/5 fx-60/5 fx	Bezjak et al[43], 2019	II, B
	60 Gy/8 fx	Haasbeek et al[46], 2011
Chest wall	48 Gy/4 fx	Guckenberger et al[47], 2017	II, B
	60 Gy/5 fx	Nagata et al[48], 2015
	45 Gy/3 fx	Nyman et al[49], 2006
Safe zone	30 Gy/1 fx	Singh et al[50], 2019	II, B
	34 Gy/1 fx	Videtic et al[31], 2019
	54 Gy/3 fx	Timmerman et al[36], 2018

SBRT: Stereotactic body radiation therapy; fx: Fractions.

Table 3 Accelerated fractionation-hyperfractionation studies

Ref.	Study type	Number of patients	Radiotherapy	Chemotherapy	Results	Toxicity
[65,66]	Phase III RCT	n = 563: Stage I (29%), II (7%), IIIA (38%), IIIB (23%). Similar in both arms	[cRT: 60 Gy, 2 Gy/d (6 wk). INP 44 Gy + boost 16 Gy tumour and involved nodes] vs (CHART: 54 Gy, 1.5 Gy/3 times/d, 6 h apart, on 12 consecutive days). INP 37.5 Gy in 25 fx + boost 16.5 Gy in 11 Gy to tumour and involved nodes	No	Absolute 2-yr survival improvement of 9%: 20% cRT vs 29% CHART. 21% relative risk reduction for PL. Major improvement in squamous cell disease: 13% 2-yr survival: 20% cRT vs 33% CHART. 25% relative risk reduction of PL	Clinical pneumonitis 19% cRT and 10% CHART
[67]	Phase III RCT	n = 141: Stage III A-B unresectable. ECOG 0-1	[cRT: 64 Gy, 2 Gy/d (6 ½ wk)] vs [HART: 57.6 Gy, 1.5 Gy 2 times/d (2.5 wk)]	Induction: Carboplatin AUC 6 + paclitaxel 225 mg/m2 2 cycles prior to RT	2-yr OS: 44% HART vs 24% cRT; 3 yr: 34% vs 14%. Non-significant trend towards better survival with HART. Feasible treatment. Trial close early due to slow recruitment	Esophagitis ≥ G3: 23% HART vs 15% cRT. Pneumonitis ≥ G3: 0 HART vs 10% cRT
[68]	Phase III RCT	n = 406: Stage I 10%, II 5%, IIIA 38%, IIIB 46%. Similar in both arms	(CHARTWEL: 60 Gy, 1.5 Gy 2 times/d in 2.5 wk) vs (cRT: 66 Gy, 2 Gy/d, 6.5 wk)	Neoadjuvant 27%. Similar in both arms	Better LC in CHARTWEL. No difference between arms in OS at 2, 3, 5 yr. Better LC CHARTWEL trend in advanced stages and after neoadjuvant ChT	Greater acute dysphagia CHARTWEL. Greater radiological pneumonitis CHARTWEL, no differences in clinical pneumonitis
[69]	Retrospective	n = 849, 9 United Kingdom centres. Stage I 33%, II 13%, IIIA 24%, IIIB 24%, IV 1%	CHART: 54 Gy, 1.5 Gy/3 times/d, 6 h apart, in 12 d	Induction: 27% patients, 82% stage III (96% platinum doublets: Cisplatin or carboplatin with vinorelbine, gemcitabine or paclitaxel)	OS 2 and 3 yr: 47% and 32%. OS 3 yr: 38% stage I and 27% stage III. Tendency to better survival in stage III after ChT	Esophagitis, pneumonitis ≥ G3 5%

RCT: Randomised controlled trial; cRT: Conventional radiotherapy; ENI: Elective nodal irradiation; CHART: Continuous Hyperfractionated Accelerated Radiotherapy Trial; OS: Overall survival; RT: Radiotherapy; LC: Local control; CHARTWEL: Continuous Hyperfractionated Accelerated Radiotherapy Weekend Less.

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.

Table 5 Radiation therapy in patients with oligometastatic non-small cell lung cancer

Ref.	Type	Design	Palliative treatment	Histology	Presentation	No. of metastases/location	RT type	Follow-up (mo)	PFS (mo)	MFS (mo)	OS (mo)
Gomez et al[93], 2019	Phase II RCT. Multicentre	Induct. ChT: (RT + MT) vs MT	49	NSCLC (No EGFR, ALK)	Synchronous. Metachronous	≤ 3 (1%:65%)/lung, CNS, bone, liver SSRR, nodes	SABR/SBRT (MTX) hypofra. RT (primary)	38.8	14.2 (SABR/SBRT + MT) vs 4.4 (MT)	11.9 (SABR/SBRT + MT) vs 5.7	41 (SABR/SBRT + MT) vs 17
Iyengar et al[95], 2018	Phase II RCT. Multicentre	Induct. ChT: (SBRT + mChT) vs mChT	29	NSCLC (No GFR, ALK)	Synchronous	≤ 5 (1%:21%, 2%-3%:76%)/lung, lymph, bone, SSRR	SABR/SBRT (MTX) hypofra. RT (primary)	9.61	9.7 (SABR/SBRT + MT) vs 3.5 (MT)	NR	NR (SABR/SBRT + MT) vs 17
Palma et al[94], 2020	Phase II RCT. Multicentre	(ChT + PT) vs (ChT + SABR/SBRT)	99	Lung (18/99)	Synchronous. Metachronous	≤ 5 (1%-3%:93%)/lung, bone, CNS, liver, SSRR	SABR/SBRT	51	11.6 (SABR/SBRT + MT) vs 5.4 (TP-MT)	NR	50 (SABR/SBRT + MT) vs 22

¹Study stopped early due to significant difference in progression-free survival between the two arms.

RT: Radiotherapy; MT: Maintenance treatment; mChT: Maintenance chemotherapy; SABR: Stereotactic ablative radiotherapy; SBRT: Stereotactic body radiotherapy; EGFR: Epidermal growth factor receptor; ALK: Anaplastic lymphoma kinase; MTX: Metastasis; NR: Not reported; PFS: Progression-free survival; MFS: Metastasis-free survival; OS: Overall survival; PT: Palliative treatment; NSCLC: Non-small cell lung cancer.

Table 6 Prognostic factors associated with better survival in oligometastatic patients with non-small cell lung cancer

Factor	Comments
Gender	Female > male
Histology	Adenocarcinoma > squamous cell carcinoma
Presentation	Metachronous > synchronous
Karnofsky index - ECOG	80% < - ≤ 100%
Number of lesions	1 > 2-3 > 4-10
Size	< 3 cm
Location	Lung, bone > adrenal glands, lymph nodes > liver, brain

ECOG: Eastern Cooperative Oncology Group.

Table 7 Dose constraints in normofractionated radiotherapy

Organ	Volume	Endpoint	Dose (Gy), dose/volume	Rate, %	Ref.
Spinal cord	Partial	Myelopathy	Dmax 50, Dmax 60, Dmax 69	0.2%, 6%, 50%
Lung	Whole organ, both lungs	Pneumonitis	V20 ≤ 30%, MD = 7, MD = 13, MD = 20, MD = 24, MD = 27	< 20%, 5%, 10%, 20%, 30%, 40%	Palma et al[133], 2013 Marks et al[130], 2010
Esophagus	Whole organ	≥ Grade 3 acute esophagitis, ≥ grade 2 acute esophagitis	MD < 34, V60 ≤ 17%, V35 < 50%, V50 < 40%, V70 < 20%	5%-20%, < 30%, < 30%, < 30%	Al-Halabi et al[135], 2015
Heart	Pericardium. Whole organ	Pericarditis. Cardiac mortality long term	MD < 26, V30 < 46%, V25 < 10%, V50 ≤ 25%	< 15%, < 15%, < 1%	Speirs et al[136], 2017
Brachial plexus	Whole organ	Brachial plexopathy	MD > 69 Gy. Dosis maximum 75 Gy to 2 cc of the brachial plexus		Amini et al[137], 2012

Dmax: Maximum dose; MD: Median dose.

Table 8 Dose constraints for moderate hypofractionation

Organ	Concurrent RT/ChT (55 Gy/20 fx)	Sequential RT/ChT (55 Gy/20 fx)	RT (50-58 Gy/15 fx)	RT (50-60 Gy/15 fx)[138]
Spinal cord	MD 44 Gy (0.1 cc)	Dmax ≤ 36	MD 42 Gy (0.1 cc)	MD < 38 Gy
Esophagus1	MD < 55 Gy (1 cc)	V42 < 32%	MD < 52 Gy (1 cc)	MD < 50 Gy (1 cc), V45 < 10 cc
Lungs-GTV	V20 < 35%, MD < 18 Gy	V20 < 25%-30%, MD ≤ 15 Gy	V19 < 35%, MD < 16 Gy	V20 < 30%, V5 < 60%, MD < 20 Gy
Heart	V30 < 36%	V33 < 25%	D100% < 33 Gy, D67% < 40 Gy, D33% < 52 Gy	MD 63 Gy, V57 < 10 cc
Great vessels	NA	NA	MD 58 Gy	MD 63 Gy, V57 < 10 cc
Trachea, carina and main bronchus	NA	NA	MD 58 Gy	MD 63 Gy, V57 < 10cc
Rib	MD < 63 Gy	NA	V30 < 30 cc	MD 63 Gy; V30 < 30cc

¹Esophagus within the planning target volume ≤ 12 cm.

MD: Median dose; Dmax: Maximum dose; Fx: Fraction; ChT: Chemotherapy; NA: Not available.

Table 9 The constraints to organs at risk s in stereotactic body radiotherapy based on the studies

Organ	Single fraction (30-34 Gy)		Three fractions (54-60 Gy)		Four fractions (48 Gy)		Five fractions (50-60 Gy)		Eight fractions (60 Gy)		Ref.
	Optimal	Mandatory	Optimal	Mandatory	Optimal	Mandatory	Optimal	Mandatory	Optimal	Mandatory
Brachial plexus	14 Gy < 3 cc	17.5 Gy ≤ 0.035 cc	20.4 Gy < 3cc	24 Gy ≤ 0.035 cc			27 Gy < 3 cc	30.5 Gy ≤ 0.035 cc			Benedict et al[139], Grimm et al[140]
	14.4 Gy < 3cc	17.5 Gy Dmax	22.5 Gy < 3 cc	24 Gy			30 Gy < 3 cc	32 Gy			Bezjak et al[43]
					23.6 Gy < 3 cc, 30 Gy < 10 cc, 35 Gy < 1 cc	27.2 Gy Dmax, 40 Gy Dmax					Videtic et al[31], Chang et al[146]
			24 Gy ≤ 0.5 cc	26 Gy ≤ 0.5 cc			27 Gy ≤ 0.5 cc	29 Gy ≤ 0.5 cc	27 Gy ≤ 0.5 cc	38 Gy ≤ 0.5 cc	Hanna et al[141]
Spinal cord	10 Gy < 0.35 cc, 7 Gy < 1.2 cc	14 Gy ≤ 0.035 cc	14 Gy < 0.35 cc, 12.3 Gy < 1.2 cc	18 Gy ≤ 0.035 cc			23 Gy < 0.35 cc, 14.5 Gy < 1.2 cc	30 Gy ≤ 0.035 cc			Benedict et al[139]
	7 Gy < 1.2 cc	7 Gy < 1.2 cc	18 Gy < 0.25 cc, 11.1 Gy < 1.2 cc	18 Gy	20.8 Gy < 0.35 cc, 13.6 Gy < 1.2 cc	26 Gy Dmax	22.5 Gy < 0.25 cc, 13.5 Gy < 1.2 cc, 13.5 Gy < 0.5 cc				Bezjak et al[43], Videtic et al[31], Timmerman et al[36]
			18 Gy < 0.1 cc	21.9 Gy < 0.1 cc			23 Gy < 0.1 cc	30 Gy < 0.1 cc	25 Gy < 0.1 cc	32 Gy < 0.1 cc	Hanna et al[141]
Esophagus	11.9 Gy < 5 cc, 14.5 Gy < 5 cc	15.4 Gy Dmax	17.7 Gy < 5 cc	25.2 Gy			19.5 Gy < 5 cc	35 Gy			Videtic et al[31]
			21 Gy < 5 cc	27 Gy	18.8 Gy < 5 cc, 30 Gy < 10 cc, 35 Gy < 1 cc	30 Gy Dmax, 50 Gy Dmax	27.5 Gy < 5 cc	35 Gy, 52.5 Gy			Timmerman et al[36], Bezjak et al[43], Chang et al[146]
				25.2 Gy < 0.5 cc			32 Gy < 0.5 cc	34 Gy < 0.5 cc		40 Gy < 0.5 cc	Hanna et al[141]
Heart	16 Gy < 15 cc, 16 Gy < 15 cc	22 Gy Dmax, 22 Gy Dmax	24 Gy < 15 cc, 24 Gy < 15 cc	30 Gy Dmax, 30 Gy Dmax	28 Gy < 15 cc, 35 Gy < 10 cc, 40 Gy < 1 cc	34 Gy Dmax, 50 Gy Dmax	32 Gy < 15 cc, 32 Gy < 15 cc	38 Gy Dmax, 38 Gy Dmax, 52.5 Gy Dmax			Benedict et al[139], Timmerman et al[36], Bezjak et al[43], Chang et al[146]
			24 Gy < 0.5 cc	26 Gy < 0.5 cc			27 Gy < 0.5 cc	29 Gy < 0.5 cc	50 Gy < 0.5 cc	60 Gy	Hanna et al[141]
Great Vessels	31 Gy < 10 cc	37 Gy Dmax	39 Gy < 10 cc	45 Gy Dmax			47 Gy < 10 cc	53 Gy Dmax			Benedict et al[139]
	31 Gy < 10 cc	37 Gy < 0.035 cc	39 Gy < 10 cc	45 Gy Dmax	43 Gy < 10 cc, 35 Gy < 10 cc, 40 Gy < 1 cc	49 Gy Dmax	47 Gy < 10 cc	52.5 Gy Dmax			Bezjak et al[43], Videtic et al[31], Chang et al[146]
				45 Gy < 0.5 cc		53 Gy < 5 cc					Hanna et al[141]
Trachea and bronchus	10.5 Gy < 4 cc	20.2 Gy Dmax	15 Gy < 4 cc	30 Gy Dmax			16.5 Gy < 4 cc	40 Gy Dmax			Benedict et al[139]
	8.8 Gy < 4 cc, 10.5 Gy < 4 cc	22 Gy Dmax, 20.2 Gy < 0.035 cc	21 Gy < 5 cc	30 Gy Dmax	30 Gy < 10 cc, 35 Gy < 1 cc, 15.6 Gy < 4 cc	50 Gy Dmax, 34.8 Gy Dmax					Bezjak et al[43], Videtic et al[31], Timmerman et al[36], Chang et al[146]
			30 Gy < 0.5 cc	32 Gy < 0.5 cc			32 Gy < 0.5 cc	35 Gy < 0.5 cc	32 Gy < 0.5 cc	44 Gy < 0.5 cc	Hanna et al[141]
Skin	23 Gy < 10 cc, 14.4 Gy < 10 cc	26 Gy Dmax, 16 Gy Dmax	30 Gy < 10 cc, 22.5 Gy < 10 cc	33 Gy Dmax, 24 Gy Dmax	35 Gy < 10 cc, 40 Gy < 1 cc, 33.2 Gy < 10 cc	36 Gy Dmax	36.5 Gy < 10 cc, 30 Gy < 10 cc	39.5 Gy Dmax, 32 Gy Dmax			Benedict et al[139], Chang et al[146], Videtic et al[31]
Chest wall	22 Gy < 1 cc	30 Gy Dmax	28.8 Gy < 1 cc, 30 Gy < 30 cc	36.9 Gy Dmax			35 Gy < 1 cc	43 Gy Dmax			Benedict et al[139]
	22 Gy < 1 cc	30 Gy Dmax	30 Gy < 30 cc, 50 Gy < 2.3 cc		35 Gy < 10 cc, 32 Gy < 1 cc	40 Gy Dmax	30 Gy < 30 cc, 50 Gy < 2.3 cc, 60 Gy < 1.4 cc				Videtic et al[31], Kong et al[145], Liao et al[147]
			37 Gy < 0.5 cc, 30 Gy < 30 cc				39 Gy < 0.5 cc, 32 Gy < 30 cc		39 Gy < 0.5 cc, 35 Gy < 30 cc		Hanna et al[141], Dunlap et al[142], Ma et al[143]
			40 Gy < 5 cc, 60 Gy < 0.5 cc				V30 < 30 cc, V30 < 70 cc				Herth et al[19]
Normal lungs	Minimal critical volume under threshold. 1500 cc, 1000 cc	Threshold dose: 7 Gy, 7.4 Gy		Threshold dose: 11.6 Gy, 12.4 Gy			Threshold dose: 12.5 Gy, 13.5 Gy				Benedict et al[139]
	Minimal critical volume under threshold. 1500 cc, 1000 cc, 1500 cc, 1000 cc	7 Gy, 7.4 Gy	20 Gy < 10%, 20 Gy < 15%	10.5 Gy, 11.4 Gy	11.6 Gy, 12.4 Gy, 20 Gy < 20%, 30 Gy < 10%		12.5 Gy, 13.5 Gy, 20 Gy < 20%, 30 Gy < 10%				Bezjak et al[43], Videtic et al[31], Chang et al[146]
				V20 < 10%, V12.5 < 15%			V20 < 10%, V12.5 < 15%		V20 < 10%, V12.5 < 15%		Hanna et al[141]
	Treatment on lesion: V20 < 10%; treatment 2-3 lesions: V20 < 12.5% (optimal); V20 < 15% (acceptable); V20 < 20% (selected cases) 3-8 fractions on alternating days. If the lesions are not included in the treatment field, alternate the treatment days for the different lesions										Hanna et al[141]
	In 3-5 fraction Dmean ≤ 8 Gy and V20 ≤ 10%-15%										Kong et al[145]

Table 10 Summary of recommendations

Diagnosis	Level of evidence, grade of recommendation
If lung cancer is suspected, refer patient to a rapid diagnostic service for evaluation by a multidisciplinary team	II, C
PET-CT is recommended for initial staging in patients with stage I-III disease who are candidates for radical treatment	I, A
EBUS/EUS is recommended for clinical staging in patients with enlarged lymph nodes without distant metastases, with or without PET uptake	I, C
EBUS/EUS is recommended for stating in patients with positive PET-CT scans and normal-sized lymph nodes without distant metastases	I, A
Histological confirmation of the mediastinum by EBUS/EUS is recommended in central tumours, tumours > 3 cm, and N1 cases	I, C
Histological confirmation is required in cases with a single metastatic lesion and positive PET-CT	II, A
Brain MRI is recommended in candidates for curative-intent treatment	II, A
VAMS should be performed when EBUS/EUS findings are not evaluable	I, B
Differentiation between adenocarcinomas and squamous cell carcinomas is recommended even for small biopsies or cytology	I, B
EGFR mutations and ALK rearrangements should be assessed in patients with stage IV, non-squamous cell carcinomas. This determination should be performed in all cases (regardless of smoking status) and in all non-smokers independently of tumour histology	I, B
Early stage NSCLC - SBRT
Inoperable	II, A
Operable	III, C
High surgical risk	III, A
Locally-advanced disease
Concomitant radiotherapy: This is the treatment of choice for unresectable stage IIIA/IIIB with ECOG 0-1 and weight loss < 5% in 3 mo	I, A
60-66 Gy in 30-33 daily fractions of 2 Gy/fx and 2-4 ChT cycles	I, A
Platinum-based ChT	I, A
Treatment should be completed in < 7 wk	III, B
Sequential radiotherapy
If concomitant treatment is not possible, the alternative is sequential CRT	I, A
Treatment should be completed in a short period of time	I, A
Neoadjuvant radiotherapy
Assessment by a multidisciplinary team is recommended	IV, C
In potentially-resectable upper sulcus tumours, the recommended approach is neoadjuvant CRT followed by surgery	III, A
This approach can be considered in potentially-resectable T3/T4 tumours, but only in well-selected cases at experienced centres	III, B
Surgery must be performed within 4 wk after completion of RT	III, B
Adjuvant radiotherapy
Not recommended in early stage disease with complete resection (R0)	I, A
It should be considered if resection is incomplete or margins are involved (R1)	IV, B
Not recommended as standard in R0 cases with N2 involvement	I, A
In N2 disease, adjuvant RT could be considered based on risk factors for local recurrence	IV, C
If adjuvant ChT and RT are both administered, the recommended sequence is ChT followed by RT	V, C
Altered fractionation schemes
Accelerated hyperfractionation schemes provide better disease control than conventional RT	I, A
Recommended fractionation schemes for RT administered alone or sequentially after ChT: 55 Gy (20 fx, 2.75 Gy), 60 Gy (20 fx, 3 Gy), 60 Gy (15 fx, 4 Gy), 45-50 Gy (15 fx, 3-3.33 Gy)	II, A
If RT administered concurrently with ChT in patients with good performance status: 55 Gy (20 fx 2.75 Gy)	II, B
General considerations: There is no evidence to support prophylactic WBRT in stage III disease	II, A

PET-CT: Positron emission tomography-computed tomography; fx: Fractions; MRI: Magnetic resonance imaging; EGFR: Epidermal growth factor receptor; ALK: Anaplastic lymphoma kinase; NSCLC: Non-small cell lung cancer; ECOG: Eastern Cooperative Oncology Group; ChT: Chemotherapy; CRT: Conformal radiotherapy; RT: Radiotherapy; WBRT: Whole-brain radiotherapy.