Single-fraction stereotactic ablative body radiation therapy for primary and metastasic lung tumor: A new paradigm?

Table 1 Prospective data, single fraction stereotactic ablative body radiotherapy early-stage peripheral non-small cell lung cancer

Ref.	Design	Arms	n	Toxicity rates > GIII	LC	PFS	OS	FU3	SABR technique/prescription
Le et al[29], 2006	Phase I, n = 32	15 Gy (1fr)	9	0	54	NSCLC1: 67%	NSCLC1: 85%	18	Cyberknife
									Gold fiducials
									Breathold or Synchrony (Accuray) respiratory tracking system/Isodose coverage: 95% of PTV
		20 Gy (1fr)	1	0
		25 Gy (1fr)	20	1p (GIII)3p (GV)	91
						Metastatic1: 25%	Metastatic1: 56%
		30 Gy (1fr)	2	0
Videtic et al[30], 2015	Phase II, n = 84	48 Gy (4fr)	45	6 (13.3%)	92.7%1	71.1%2	77.7%2	30.2	Abdominal compression, gating with the respiratory cycle, tumor tracking, and active breath-holding techniques were allowed. Image guidance was required/prescription isodose surface ≥ 60% and < 90% of the maximun dose.
RTOG 0915
		34 Gy (1fr)	39	4 (10.3%)	97%1	56.4%2	62.3%2
Singh et al[31], 2019	Phase II, n = 98	60 Gy (3fr)	49	6 (15%)	97.1%1	50%2	62%2	53.8	Body Fix (Elekta) immobilizer. Real-Time Position Management by Varían Medical System or abdominal compression. 3D-CRT was preferred. Image guidance was required/tumor coverage and normal tissue dose constraints followed RTOG 0915
		30 Gy (1fr)	49	8 (17%)	94.9%2	65%2	73%2

¹At 1 yr.

²At 2 yr.

³Median follow-up months.

Fr: Fraction; RTOG: Radiation Therapy Oncology Group.

Table 2 Single fraction stereotactic ablative body radiotherapy for pulmonary metastases

Ref.	Study design	Total lesions (n)/LM (n)	Mean, Dose Gy (range)/Location	SABR technique/prescription	Mean GTV (cc) (range) failing this, cm	FU (mo), median	LC	Toxicity ≥ GIII	Comments
Nakagawa et al[11]	P	22/12	22.8 (18-25)1/NR	Rotational or StaticTherapy 3D-CRT. Abdominal compression/PTV enclosing isodose.	4.8 (0.8-13)	10	100%1	0	Non actuarial LC
Hara et al[26]	P	59/48	30(20-34)/Periph	Static 3D-CRT. Gating/Minimal dose to GTV	5 (1-19)	12(mean)	1-yr 93%	1 GIII	LC 52% < 30 Gy
									LC 83% ≥ 30 Gy
									P = 0.068
							2-yr 78%
Wulf et al[54]	R	92/31	26/Central	Static 3D-CRT. Abdominal compression/65-80%-isodose enclosing PTV	NR	14	100%	NR	SF data are shown
Fritz et al[53]	P	64/31	30/Periph	Static 3D-CRT. Abdominal compression/Isocenter, 90% isodose enclosing GTV, 80% isodose enclosing PTV	Median: 6 (2.8-55.8)1	221	5-yr 80%1	0	No difference LC and OS LM vs primary lung cancer
Le et al [29]	Phase I	32/11	22.34 (15-30)/Periph	Cyberknife. Gold fiducials.Breathold or Synchrony (Accuray) respiratory tracking system / Isodose coverage: 95% of PTV	Median: 17.1 (2-103)	18	1-yr 91% (≥ 20 Gy)	1 GIII (pn)	LC primary vs LM: 78% vs 58%
									And OS (85% vs 56%)
							1-yr 54% (< 20 Gy)	3 GV (central)
									Higher toxicity in central tumors
Hof et al [63]	P	0/71	24.35 (12-30)/NR	Static 3D-CRT. Abdominal compression/Isocenter: 80% isodose enclosing PTV	10 (1-53)	14	1-yr 88.6%	3 GIII (pn)	LC 3 yr 78% 26-30 Gy
							2-yr 73.7%
							3-yr 63.1%
Gandhidasan et al [56]	R	186/95	18/Central26 or 28/Periph	Static 3D-CRT or IMRT/80% isodose enclosing PTV	NR	22	2yr 84%	0
Osti et al [57]	P	0/103	23Gy/Central30 Gy/Periph	Static 3D-CRT. 4DCT. 80% isodose enclosing PTV	NR	15	Central vs peripheral:1-yr 79.4% vs 94.7%	2 GIII (pn)	Prognostic factors for LC: sex and histology
							Global: 1-yr 89.1%, 2-yr 82.1%
Filippi et al[58]	R	0/90	26Gy/Periph	Static 3D-CRT or IMRT or VMAT. Abdominal compression/80% isodose enclosing PTV	< 5 cm	24	1-yr 93.4%	8 GII-IIIlate radiological toxicity	They suggest not to use a SF in lesions close to the chest wall
							2-yr 88.1%
								6 GII-IIIchest wall toxicity
Siva et al [44]	R	0/41	18/Central26/Periph	Static 3D-CRT or IMRT or VMAT. /70-80% isodose enclosing PTV	< 5 cm	25	2-yr 93%	0	LC, OS and toxicity rates between SF and multi-fraction SABR
Osti et al [59]	R	0/166	30/Periph	Static 3D-CRT. 4DCT/95% isodose enclosing PTV	3.46 (0.03-47.48)	38	3-yr 80.1%	6 GIII (pn)	Lesions ≤ 15 mm from mediastinum were not included in the study
								11 GIIIlung fibrosis
							5-yr 79.2%
								1 GV at 15 mm PBT
Sharma et al [61]	R	32	30/Periph	Cyberknife. Radiopaque markers Tumor traking.70-90% isodose enclosing PTV	< 3 cm	22	2-yr 68%	No details for SF	BED10 < 100, delivery of pre-SBRT chemo. and synchronous metastasis: independently < LC
							3-yr 63%
							4-yr 59%
Sogono et al [60]	R	167 (95% peripher)	16-18/Central26-28/Periph	Static 3D-CRT or IMRT or VMAT. 4DCT/99% isodose enclosing PTV	NR	37	1-yr 96%	NR	Several locations
							2-yr 92%
							5-yr 92%
Siva et al[55]	Phase II	133	28/NR	Static 3D-CRT or IMRT or VMAT. Abdominalo compression/70-80% isodose enclosing PTV	2.2 cm (mean)	12	1-yr 93%	2 GIII	Preliminary results (TROG 13.01 SAFRON II)
									1-3 metastases non-central targets < 5 cm

¹Data refer to subgroup pulmonary metastases; when not specified otherwise, data refer to the whole series.

FU: Follow up; LC: Local control; OS: Overall survival; G: Grade; LM: Lung metastases; P: Prospective; R: Retrospective; NR: No reported; pn: Pneumonitis; periph: Peripheral; 3D-CRT: Tridimensional conformal radiotherapy. 4DCT: Four-dimensional CT; IMRT: Intensity-modulated radiotherapy; VMAT: Volumetric-modulated arc therapy.

Table 3 Benefits and constraints to using single fraction stereotactic ablative body radiotherapy schemes

Benefits	Constraints
Low medium-long term toxicity	Fear of severe toxicity in initial studies
Prospective efficacy and toxicity data	Insufficient long-term data
Convenience for patient, fewer hospital visits (indirect costs), shorter treatment times
Less occupation of accelerators
Reduced positioning errors between fractions	Greater risk of positioning errors
Peripheral tumors	Central tumors
Reduction in direct costs
Less interference with systemic therapies	Cases of Neumonitis recall with some systemic therapies
Convenience for COVID-19 pandemic

Table 4 Biologically effective dose

	Early tumor effects α/β = 10	Late tumor effects α/β = 3
28 Gy in 1 fraction	106 Gy	289 Gy
48 Gy in 4 fractions	105 Gy	240 Gy

Table 5 Summary of indications for stereotactic ablative body radiotherapy in pandemic COVID-19 in patients with early stage non-small cell lung cancer

ESTRO-ASTRO	UK	GOECP/SEOR
45-54 Gy in 3 fx, 48 Gy in 4 fx; Maximum hypofractionation supported, 30-34 Gy in 1 fx (90% support if choosing hypofractionation)	Safe zone: 34 Gy in 1 fx	Safe zone: 30-34 Gy, 1 fx (first option); 54 Gy in 3 fx
	Tumours within 2.5 cm of the Chest Wall: 48-54 Gy in 3 fx
		Peripheral lesions: 48 Gy in 4 fx (first option)
	Moderately central: 50 Gy in 5 fx
		Central tumour: 50-60 Gy in 5 fx, 60 Gy in 8 fx
	Ultra-central: 45-50 Gy in 4-5 fx, 60 Gy in 8 fx
	Central/ultra-central early stage tumours not suitable for stereotactic ablative radiotherapy: 50-60 Gy in 15 fx

ESTRO: European Society for Radiotherapy and Oncology; ASTRO: American Society for Radiation Oncology; GOECP: Oncologic Group for the Study of Lung Cancer; SEOR: Spanish Society of Radiation Oncology; UK: United Kingdom.