Table 1. Results of PBT for gastroesophageal cancers.
| Reference & date | Number of patients | Tumor type & stage | Tumor & management characteristics | PBT dose, fractionation, technique | Chemotherapy | Median follow-up (months) | Survival outcomes | Toxicity |
|---|---|---|---|---|---|---|---|---|
| Koyama et al., 1990 (6) | 1 | Stomach | Inoperable, lesser curvature | 61 CGE in 2–3 CGE fractions; AP | Concurrent 5-FU, tegafur | 2 | Died at two months with endoscopic & histologic evidence of tumor regression | – |
| Shibuya et al., 1991 (7) | 2 | Stomach; T1N0M0 | Inoperable, lesser curvature (n=1) & antrum (n=1) | 86 CGE in 22 fractions; AP field (n=1); 83 Gy in 28 fractions; AP & left lateral fields (n=1) | None | 21 | 100% survival at 21 months | Persistent gastric ulcers, negative for malignancy (2/2, 100%) |
| Sugahara et al., 2005 (8) | 46 | Esophagus, 45/46 (98%) squamous cell carcinoma. 23/46 (50%) T1; 23/46 (50%) T2–T4; 39/46 (85%) N0 | 29/46 (63%) middle thoracic; 12/46 (26%) lower thoracic; 4/46 (9%) upper thoracic. All treated definitively (22/46, 48%) inoperable | 40/46 (87%) received both PBT and XRT; median XRT ose 48 Gy in 24 fractions; median PBT dose 32 CGE in 10 fractions; if PBT alone, median dose 82 CGE in 26 fractions; single PA field | None | 35 | 5 y LC 57%, 5 y LC for T1 83%, 5 y LC for T2–T4; 5 y DSS 67%, 5 y DSS for T1 95%, 5 y DSS for T2–T4 33%; 29%; 5 y OS 34%, 5 y OS for T1 55%, 5 y OS for T2–T4 13%; DMs in 3/23 (13%) of T2–T4, 2/23 (9%) of T1 |
Grade 3 acute toxicities: esophagitis (5/46, 11%); late toxicities: grade 3 esophageal (3/46, 7%); grade 5 esophageal (2/46, 4%); post-PBT esophageal ulcers in 22/46 (48%) patients |
| Xiaomao et al., 2009 (9) | 71 (53 IMRT, 18 PBT) | Esophagus, all locally advanced | Patients in PBT group older, better performance status, more N1 disease, more alcohol use | Median IMRT dose 50.4 Gy in 28 fractions, median PBT dose 50.4 CGE in 28 fractions | All patients | – | No differences in OS or DSS between IMRT and PBT |
No differences in esophagitis, pneumonitis, dermatitis rates between IMRT and PBT |
| Mizumoto et al., 2010 (10) | 51 | Esophagus, 50/51 (98%) squamous cell carcinoma. 8/51 (16%) T1N1; 26/51 (51%) T2–T4N0; 17/51 (33%) T2–T4N1 |
All treated definitively (24/51, 47%) inoperable | 33/51 (65%) received both PBT and XRT; median XRT dose 46 Gy in 23 fractions; median PBT dose 36 CGE in 12 fractions; if PBT alone, median dose 79 CGE in 44 fractions; AP/PA fields | None | 23 | 1 y LC 65%, 1 y PFS 46%, 1 y OS 62%; 3 y LC 43%, 3 y PFS 25%, 3 y OS 34%; 5 y LC 38%, 5 y PFS 14%, 5 y OS 21% |
Grade 3 acute toxicities: esophagitis (6/51, 12%); late toxicity: grade 5 esophageal (1/51, 2%); post-PBT esophageal ulcers in 25/51 (49%) patients |
| Mizumoto et al., 2011 (11) | 19 | Esophagus, 18/19 (95%) squamous cell; carcinoma. 9/19 (47%) T1–3N0; 10/19 (53%) T1–4N1 |
All treated definitively with hyperfractionated RT | 7/19 (37%) patients with 45 Gy XRT/25 fractions, concomitant 13 CGE/10 fraction PBT boost, followed by 19.8 CGE/9 fraction PBT boost (total dose 78 CGE); remainder with different schedules, 74–80 CGE (median 78 CGE) | None | 111 | 1 y LC 94%, 5 y LC 84%; 1 y OS 79%, 5 y OS 43% |
Grade 3 acute toxicity: esophagitis (1/19, 5%); grade 3 late toxicity: esophageal (1/19, 5%) |
| Hashimoto et al., 2012 (12) | 14 | Esophagus, 14/14 (100%) squamous cell carcinoma. Stage I (3/14, 21%); IIA (5/14, 36%); IIB (2/14, 14%); III (4/14, 28%) | 13/14 (93%) in thoracic esophagus | Median 60 CGE in 30 fractions | 5-FU & cisplatin | 15 | 1 y LC 90%, 1 y OS 93%; 11/14 (79%) with complete response, 3/14 (21%) partial response; 4/14 (29%) developed DM | Grade 3+ toxicities: esophageal (5/14, 36%) |
| Echeverria et al., 2012 (13) | 100 (80 with smoking history) | Esophagus, 83/100 (83%) adenocarcinoma. Stage I (3/100, 3%); IIA (24/100, 24%); IIB (6/100, 6%); III (51/100, 51%); IV (7/100, 7%); recurrent (9/100, 9%) |
82/100 (82%) in distal esophagus/GEJ; 16/100 (16%) middle; 2/100 (2%) proximal; 67/100 (67%) underwent surgery |
Median 50.4 CGE in 28 fractions | All patients | 2 if operated, 8 if not | – | Grade 2 toxicities: pneumonitis (20/100, 20%); grade 3 toxicities: pneumonitis (7/100, 7%) |
| Lin et al., 2012 (14) | 62 | Esophagus, 47/62 (76%) adenocarcinoma. Stage I (2/62, 3%); II (20/62, 32%); III (32/62, 52%); IV (8/62, 13%) |
48/62 (78%) in lower esophagus; 11/62 (18%) middle; 3/62 (5%) upper; 33/62 (53%) definitive; 29/62 (47%) neoadjuvant | Median 50.4 CGE in 28 fractions; AP/PA, PA/left lateral, left lateral/LPO/RPO or PA | Concurrent in all with 5-FU and taxane or platinum-based; induction chemotherapy in 26/62 (42%) | 20 | 3 y LRC 57%, 3 y RFS 52%, 3 y DMFS 67%, 3 y OS 52% | Grade 3 toxicities: esophagitis (6/62, 10%); dysphagia (6/62, 10%); nausea/vomiting (5/62, 8%); dermatitis (2/62, 3%); fatigue (5/62, 8%); anorexia (3/62, 5%); pneumonitis (1/62, 2%); mean hospital stay 8 days. Postoperative complications: pulmonary (4/62, 6%); anastomotic leak (4/62, 6%); atrial fibrillation (5/62, 8%); wound infection (2/62, 3.2%) |
| Wang et al., 2013 (15) | 444 (n=208 3DCRT, n=164 IMRT, n=72 PBT) | Esophagus. 395/444 (89%) adenocarcinoma. Stage I (7/444, 2%); II (164/444, 37%); III (252/444, 57%); IVa (21/444, 5%) | 413/444 (93%) in lower esophagus; 27/444 (6%) middle; 4/444 (1%) proximal; 412/444 (93%) with planned surgery | Median 50.4 Gy in 28 fractions for 3DCRT & IMRT, 50.4 CGE in 28 fractions for PBT; PA & left lateral fields | Concurrent in all with 5-FU and taxane or platinum-based; induction chemotherapy in 221/444 (50%) but 27/72 (38%) in PBT group | – | – | Pulmonary complications: 30% 3DCRT; 24% IMRT; 14% PBT (OR 2.23 IMRT vs. PBT). GI complications: 28% 3DCRT; 18% IMRT; 18% PBT (OR 1.25 IMRT vs. PBT). Median length of hospital stay: 12 days 3DCRT; 10 days IMRT; 8 days PBT (P<0.0001) |
| Fernandes et al., 2014 (16) | 11 | Esophagus, 9/11 (81%) adenocarcinoma | Re-irradiation after history of thoracic RT for previous esophageal cancer (n=8) or other primary (n=3) | 9/11 (81%) patients treated with PBT only; remainder with 14–30% IMRT; median prior dose 54 Gy, median re-RT dose 54 CGE | 9/11 (81%) concurrently | 11 | MS 11 months; 8/11 (72%) patients died; 5/11(45%) patients developed DM; 6/11 (54%) patients with in-field LRR |
Grade 3 nonhematologic acute toxicities: dysphagia & dyspnea (3/11, 27%). Grade 5 acute toxicities: esophagopleural fistula (1/11, 9%). Late toxicities: heart failure, esophageal stenosis, grade 3 dysphagia (3/11, 27%) |
| Kang et al., 2014 (17) | 5 | Esophagus, T1–3N0–1M0 adenocarcinoma or squamous cell carcinoma | – | 40 CGE in 20 fractions | Concurrent capecitabine/paclitaxel | 11 | 3/5 (60%) underwent surgery and remain alive; 1/5 (20%) had DM and 1/5 (20%) refused surgery | No significant acute toxicities |
| Ishikawa et al., 2015 (18) | 40 | Esophagus, 40/40 (100%) squamous cell carcinoma. Stage I (16/40, 40%); II (9/40, 22%); III (15/40, 38%) | 2/40 (5%) cervical; 10/40 (25%) upper thoracic; 21/40 (53%) middle thoracic; 7/40 (12%) lower thoracic. All treated definitively (24/40, 60%) inoperable | 60 CGE in 30 fractions; When clinically suspected, boost of 4–10 CGE; AP field, boost with right lateral and/or right anterior oblique fields | Cisplatin & 5-FU | 24 | 2 y LRC 66%, 2 y DSS 77%; 2 y OS 75%, 3 y OS 70% | Grade 3 nonhematologic acute toxicities: esophagitis (9/40, 22%); skin (2/40, 5%). Grade 3 late toxicities: esophageal ulcer (2/40, 5%) |
| Hallemeier et al., Chuong et al., 2015 (19,20) | 582 (n=217 3DCRT, n=255 IMRT, n=110 PBT) | Esophagus, 535/582 (92%) adenocarcinoma | 541/582 (93%) with distal tumors. All underwent surgery; open thoracotomy/laparotomy; greater smoking pack-years in PBT group (P=0.04) | Median 50.4 Gy in 28 fractions XRT, 50.4 CGE in 28 fractions PBT | Induction chemotherapy more in PBT group 5-FU/docetaxel most common in PBT group, 5-FU/cisplatin in XRT group | 28 | 90-day mortality 4.2% XRT vs. 0.9% PBT (P=0.15) 3 y OS 58% XRT vs. 70% PBT (P= NS) |
Grade 2+ nausea: 50% XRT vs. 29% PBT (P<0.001). Grade 2+ fatigue: 33% XRT vs. 27% PBT (P<0.001). Grade 2+ hematologic toxicity: 26% XRT vs. 2% PBT (P<0.001). Postoperative complications, cardiac: 19% XRT vs. 12% PBT (P=0.10). Postoperative complications pulmonary: 28% XRT vs. 14% PBT (P=0.003). Postoperative complications, GI: 22% XRT vs. 19% PBT (P=0.5). Postoperative complications, wound: 15% XRT vs. 5% PBT (P=0.002). Postoperative complications, total: 56% XRT vs. 41% PBT (P=0.005). Mean hospital length of stay: 12 days XRT vs. 9 days PBT (P<0.0001) |
PBT, proton beam radiotherapy; CGE, cobalt gray equivalent; 5-FU, 5-fluorouracil; AP, anteroposterior; XRT, X-ray (photon) radiotherapy; LC, local control; DSS, disease-specific survival; OS, overall survival; DM, distant metastasis; IMRT, intensity-modulated radiotherapy; PA, posteroanterior; PFS, progression-free survival; RT, radiotherapy; GEJ, gastroesophageal junction; LPO, left posterior oblique; RPO, right posterior oblique; LRC, locoregional control; RFS, recurrence-free survival; DMFS, distant metastasis-free survival; 3DCRT, three-dimensional conformal radiotherapy; MS, median survival; LRR, locoregional recurrence; NS, nonsignificant.