Table 1. Description of Prognosis and Toxic Effects After Treatment With Proton or Photon Radiotherapy in Patients With Esophageal Cancer.

Source	Patients, No.		Study Type	Characteristics (proton vs photon)				RT technology/prescription dose (proton vs photon)	Follow-up, median, mo	Outcome (proton vs photon)	Toxic effects
	Proton	Photon		Age, median, y	Stage	Thoracic site	Pathological type
Suh et al,25 2021	48	29	RO	69 vs 73	cT1-3N0M0	Lower: 58% vs 28%a	SCC: 100%	PBT vs 3D-CRT/IMRT (24/5); Median PTV: 66 Gy/33 F; Radical RT (CCRT: 17% vs 31%) and salvage-therapy (33.8%)	46	OS: 1 y, 100% vs 97%; 2 y, 88% vs 79%; 3 y, 69% vs 69%; 5 y, 69% vs 62%b; PFS: 1 y, 88% vs 93%; 2 y, 70% vs 74%; 3 y, 63% vs 66%; 5 y, 57% vs 58%b	Acute: G≥2: RE, 29.9%; RP, 1.3% G≥3: PE, 0% vs 0%; PCE, 0% vs 0%
Ebrahimi et al,26 2021	30	15	RO	NA	NA	NA	NA	PBT (IMPT/PSPT) vs IMRT; PTV: 50.4 Gy/28 F; Radical CCRT	NA	NA	Mean minimum ALC: 390/330/μL vs 170/μL; change in ALC: 970/1080/μL vs 1250/μL
Sumiya et al,27 2021	54	15	RO	70	I-IV (III-IV: 41% vs 80%)a	Middle and lower: 80% vs 67%	SCC: 96% vs 93%	PBT vs PRT; PTV: 56-70 Gy/28-35 F; Radical CCRT (43% vs 52%: 5-FU + cisplatin)	NA	OS: 1 y, 86% vs 60%; 2 y, 77% vs 48%a,b PBT OS: 3 y, 75%; 5 y, 75%	Late: G≥2: RP, 0% vs 0%; PE, 5.6% vs 0%; PCE, 7.4% vs 13.3%; G≥3: LT and HET, 0%
Lin et al,28 2020	46	61	RCT (II)	67 vs 67	I-III (III: 59% vs 54%)	Lower: 83% vs 84%	AC: 91% vs 87%	PBT (80% PSPT) vs IMRT; PTV: 50.4 Gy/28 F: 87% vs 95%; Neoadjuvant and radical CCRT (61% vs 51%: 5-FU/capecitabine + taxane) + surgery (46% vs 49%)	44.1	OS: 1 y, 79% vs 89%; 2-y, 60% vs 66%; 3 y, 51% vs 53%; 5 y, 47% vs 51%b; PFS: 1 y, 56% vs 60%; 2 y, 50% vs 45%; 3 y, 45% vs 45%; 5 y, 41% vs 41%b; pCR: 14 vs 18	Acute: G≥2: RP, 2.2% vs 4.9%; G≥3: RE, 13% vs 13%; RP, 0% vs 2%; PE, 0% vs 5%; PCE, 0% vs 2%; lymphocytopenia, 0% vs 2%; G≥4: lymphocytopenia, 27% vs 52%a
Wang et al,29 2020	159	320	PO	62	I-III	Lower: 89%	AC: 87.1%	PBT (91% PSPT) vs IMRT; Median PTV: 50.4 Gy/28 F; Neoadjuvant and radical CCRT (FU+ platinum- and taxane-based) + surgery (59.3%)	76	NA	Late: G≥3: 2-y HET, 11% vs 18%; 3-y HET, 13% vs 21%
DeCesaris et al,30 2020	18	36	RO	62	II-IV (II: 33% vs 61%)a	Middle and lower: 100%	AC: 100%	PBT (IMPT) vs PRT (4-D CT); Median PTV: 50.4 Gy/28 F; Neoadjuvant CCRT (98%: carboplatin + paclitaxel) + surgery	25	OS: 1 y, 93% vs 72%; 2 y, 71% vs 55%b pCR: 3 vs 8	Acute: G≥2: RE, 33% vs 28%; HT, 6% vs 17%; G≥4, 0%
Bhangoo et al,31 2020	32	32	RO	71.5 vs 71.4	T1-3N0-3M0 (T3: 63% vs 56%)	Lower: 78% vs 94%	AC: 63% vs 91%a	PBT (IMPT) vs IMRT (4-D CT); Median PTV: 50 Gy/25 F; Neoadjuvant and radical CCRT (91% vs 100%: carboplatin + paclitaxel) + surgery (47% vs 56%)	10 vs 14	OS: 1 y, 74% vs 71%; 2 y, 40% vs 67%b PFS: 1 y, 71% vs 46%; 2 y, 60% vs 37%b pCR: 5 vs 7	Acute: G≥2: RE, 41% vs 25%; lymphocytopenia, 100% vs 94%; G≥3: RE, 3% vs 0%; lymphocytopenia, 84% vs 81%; G≥4: lymphocytopenia, 19% vs 28%
Routman et al,32 2019	50	50c	RO	66 vs 64.5	I-IV (III-IV: 61% vs 37%)a	Lower: 88% vs 90%	AC: 88% vs 86%	PBT (IMPT) vs 3D-CRT/VMAT Median PTV: 50 Gy/25 F; Radical CCRT (carboplatin + paclitaxel) + surgery (88%)	NA	NA	Acute: G≥4 lymphocytopenia, 24.0% vs 60.0%a
Shiraishi et al,33 2018	136	136c	RO	63 vs 60	I-IV (III-IV: 64% vs 60%)	Lower: 96% vs 97%	AC: 96% vs 98%	PBT vs IMRT (4-D CT); PTV: 50.4 Gy/28 F; Neoadjuvant CCRT (80.2%: FU + taxane/platinum) + surgery	NA	NA	Acute: G≥4 lymphocytopenia, 17.6% vs 40.4%a
Macomber et al,34 2018	16	39	RO	62	II-III (III: 56% vs 70%)	Lower: 78% vs 84%	AC: 94% vs 76%a	PBT vs 3-D CRT/IMRT (16/21); PTV: 50.4 Gy/28 F; Neoadjuvant CCRT (100% vs 78%: carboplatin + paclitaxel) + surgery	20	Overall OS: 1 y, 92%; 2 y, 77% pCR: 3 vs 8	NA
Xi et al,35 2017	132	211	RO	≥67: 71% vs 38%a	I-III (III: 64% vs 67%)	Lower: 71% vs 73%	AC: 68% vs 74%	PBT (95% PSPT) vs IMRT; Median PTV: 50.4 Gy/28 F; Radical CCRT (FU+ platinum/taxane) + salvage surgery (7.6% vs 12.8%)	44.8 vs 65.1	OS: 1 y, 87% vs 84%; 2 y, 67% vs 52%; 3 y, 55% vs 39%; 5 y, 42% vs 32%a,b PFS: 1 y, 62% vs 48%; 2 y, 49% vs 32%; 3 y, 43% vs 28%; 5 y, 35% vs 20%a,b	G≥2: RE, 45.5% vs 46.0%; RP, 3.9% vs 6.7%; PE, 5.3% vs 6.6%; PCE, 0.8% vs 2.4%; G≥3: RE, 11.4% vs 14.7%; RP, 1.6% vs 2.9%; PE, 0.8% vs 1.9%; PCE, 0.8% vs 2.4%; G≥4: RE, 0% vs 0.5%; RP, 0.8% vs 1.0%; PE, 0% vs 0%; PCE 0% vs 0%
Fang et al,36 2018	110	110c	RO	70 vs 69	I-IV (III-IV: 61% vs 60%)	Lower: 76.4% vs 76.4%	AC: 72% vs 76%	PBT vs IMRT (4-D CT); Median PTV: 50.4 Gy/28 F; Radical CCRT	NA	Stage III-IV OS: 1 y, 73% vs 75%; 2 y, 66% vs 49%; 3 y, 47% vs 38%; 5 y, 44% vs 16%b	Acute: G≥4 lymphocytopenia, 30.9% vs 47.3%a
Lin et al,37 2017	111	469	RO	>65: 32% vs 36%/ 26%	III-IV: 64% vs 63%/64%	Lower: 98% vs 88%/95%a;	AC: 96% vs 90%/94%;	PBT vs 3D-CRT/IMRT (214/ 255); PTV: 50.4 Gy/28 F; Neoadjuvant CCRT + surgery	NA	NA	Acute: LT, 16.2% vs 39.5%/24.2%; HET, 11.7% vs 11.7%/27.4%
Makishima et al,38 2015	25	19	PO	NA	0-III (III: 36% vs 74%)a	88% vs 63%	SCC: 100%	PBT vs 3D-CRT; Median PTV: 60 Gy/30 F; Radical CCRT (5-FU + cisplatin)	24 vs 20	NA	Late: G≥2: RP, 0% vs 21.1%; PE, 0% vs 10.6%; PCE, 4% vs 52.6%; G≥3: RP, 0% vs 5.3%; PE, 0% vs 5.3%; PCE, 0% vs 0%; G≥4: RP, 0% vs 0%; PE, 0% vs 0%; PCE, 0% vs 0%
Zhu et al,46 2021	246	500	RO	65 vs 62a	I-III (III: 65% vs 64%)	Lower: 88% vs 86%	NA	PBT vs PRT; PTV: 50.4 Gy/NA; Neoadjuvant and radical CCRT (platinum; or taxane-based)	NA	NA	Acute: G≥4 lymphocytopenia, 22.0% vs 46.2%a
Lin et al,48 2022	81	156	RO	61	I-V (III-IV: 34% vs 66%)	NA	NA	PBT vs IMRT; PTV: 50.4 Gy/28 F; Neoadjuvant CCRT + surgery	NA	NA	LT, 14.8% vs 19.9%; HET, 7.4% vs 9.6%
Choi et al,49 2022	15	16	RO	Age: 62.3 vs 59.4	T1-4N1-3M0 (T3: 73% vs 44%)	Middle and lower: 73% vs 69%;	SCC	PBT vs PRT; Median PTV: 40.4 Gy/23 F; Neoadjuvant CCRT (platinum + paclitaxel or capecitabine) + surgery (93% vs 88%)	17	OS: 1 y, 86% vs 94%; 2 y, 69% vs 68%; 3 y, 69% vs 58%; pCR: 4 vs 5	Acute: G≥4 lymphocytopenia, 12.5% vs 20%

Abbreviations: AC, adenocarcinoma; ALC, absolute lymphocyte count; CCRT, concurrent chemoradiotherapy; CRT, chemoradiotherapy; CT, computed tomography; D, dimensional; F, fraction; FU, fluoropyrimidine; G, grade; HET, heart toxic effects; HT, hematological toxic effects; IMPT, intensity modulate proton therapy; LT, lung toxic effects; NA, not available or not applicable; OS, overall survival; PBT, proton beam therapy; PCE, pericardial effusion; pCR, pathologic complete response; PE, pleural effusion; PFS, progression-free survival; PO, prospective; PRT, photon radiotherapy; PSPT, passive scattering proton therapy; PTV, planning target volume; RCT, randomized clinical trial; RE, radiation esophagitis; RO, retrospective; RP, radiation pneumonitis; RT, radiotherapy; SCC, squamous cell carcinoma.

^a Statistically significant at P < .05.

^b Data obtained from graphic.

^c Propensity-matched analysis.