Table 4.

Interventional trials involving functional lung avoidance

Study first author	N	Anatomic cohort?	FLI modality: Definition	RT modality	Technical results	Clinical outcomes	PTV and OAR, as compared with anatomic plan
Bucknell82	25	No (anatomic plans included for reference)	V/Q PET: 70th percentile threshold	VMAT with midtreatment adaptation	Perfusion No statistically significant difference in fV20 or fMLD fV5 ↓ 5.1* in the functional plan No statistically significant benefit to midtreatment functional adaptation. V, no statistically significant difference in fMLD fV20 ↓ 1.4* in the functional plan fV5 ↓ 5.0* in the functional plan No statistically significant benefit to midtreatment functional adaptation	The majority of patients with late-stage cancer benefitted from avoidance planning	Q, mean esophagus ↓ 0.6* V, no significant differences reported
Follacchio76	19	No (anatomic plans included for reference)	SPECT Q: 60% of maximum threshold	IMRT: Choice of functional or anatomic plan was made individually for each patient	The best plan for patients in all cases was judged to be the functional plan	Two cases of grade 2 RP were observed during follow-up. A significant correlation was found between perfusion score and early-onset RILT.	All functional plans were clinically acceptable.
Huang136	36	No (anatomic plans included for reference)	Xe CT V: Automated contouring	IMRT or VMAT	fV20 ↓ 1.7* in the functional plan fMLD ↓ 2.9* in the functional plan	4 grade 2+ RP cases diagnosed at follow-up, found to be statistically significantly lower than historical control. 1 case of grade 3 esophagitis. 50% of patients developed disease progression.	Maximum dose ↑ 1.5* V20 ↓ 2* MLD ↓ 1.1*
Miller124	56	No	CT V (HU-based): 15% of maximum threshold	N/A	Not reported	Avoidance planning reduces PFT results by less than standard anatomic plans compared with historical control.	Not reported
Thomas126	39	No	SPECT Q: N/A	19 IMRT/VMAT 20 Proton	Not reported	16 patients developed grade 2+ RP. COPD was the only significant predictor of grade 2+ RP development. No functional parameters were found to be significant.	Not reported
Thomas102	28 (8:20)	Yes	SPECT Q: 70% of maximum threshold	Anatomic plan: 6 IMRT/VMAT 2 proton functional plan: 12 IMRT/VMAT 2 proton	Medians reported. fMLD ↓ 7.9* in the functional cohort fV20 ↓ 12* in the functional cohort fV20 ↓ 23* in the functional cohort fV5 ↓ 24* in the functional cohort (all units EQD2)	Significant perfusion changes between cohorts were found cohort only in the 0-5 Gy dose bin. The functional cohort had increased cohort perfusion in this region.	No statistically significant differences found between cohorts.
Vinogradskiy119	67	No (anatomic plans included for reference)	CT V: 15% of maximum threshold	IMRT	fMLD ↓ 1.3* in the functional plan fV5 ↓ 3.4* in the functional plan fV10 ↓ 6.4* in the functional plan fV20 ↓3.5* in the functional fV30 ↓ 1.8* in the functional plan	10 grade 2+ RP events 33 grade 2+ esophagitis events 14 grade 2+ dyspnea events 13 grade 2+ cough events 14 grade 2+ fatigue events RP reduction was statistically significant compared with plan historical control.	PTV coverage ↓ 0.8* MLD ↓ 0.7* V20 ↓ 2* Cord max ↑ 1.4* Mean esophagus ↓ 0.7*
Yamamoto148	14	No (anatomic plans included for reference)	CT V: Weighted	IMRT with midtreatment adaptation	fMLD ↓ 0.7* in functional adapted plan fV10 ↓ 2.8* in functional adapted plan fV20 ↓ 2.5* in functional adapted plan fV30 ↓ 1.1* in functional adapted plan	Not reported	No significant differences found
Yaremko133	27 (11:16)	Yes	He-MRI: Threshold unspecifid	VMAT	No statistically significant reductions in dose-function parameters between cohorts.	No statistically significant differences in quality-of-life scores, RILT events, or disease progression statistics between cohorts.	No significant differences found between cohorts.

Abbreviations: COPD = chronic obstructive pulmonary disease; CT = computed tomography; EQD2 = equivalent dose in 2 Gy fractions; FLI = functional lung imaging; fMLD = mean dose to functional lung; fVx = dose parameter (x) to functional lung, defined as in the modality column; He = helium; HU = Hounsfield unit; IMRT = intensity modulated radiation therapy; MLD = mean dose to non-PTV lung; Vx = dose parameter (x) to non-PTV lung; MRI = magnetic resonance imaging; OAR = organs at risk; PET = positron emission tomography; PFT = pulmonary function test; PTV = planning target volume; Q = perfusion; RILT = radiation-induced lung toxicities; RP = radiation pneumonitis; RT = radiation therapy; SPECT = single-photon emission computed tomography; V = ventilation; VMAT = volumetric modulated arc therapy; Xe = xenon.

^*Statistically significant.