Table 3. Results of PBT for hepatobiliary cancer.
| Reference & date | Number of patients | Tumor type & characteristics | Child-Pugh class | PBT dose, fractionation, technique | Chemotherapy | Median follow-up (months) | Survival outcomes | Toxicity |
|---|---|---|---|---|---|---|---|---|
| Chiba et al., 2005 (28) | 162 (192 lesions) | Primary HCC, 80/162 (49%) single nodule; 82/162 (51%) multiple. Stage I (66/162, 41%); stage II (70/162, 43%); stage IIIA (25/162, 15%); stage IIIB (1/162, 1%), size <3 cm (51/162, 27%); 3–5 cm (108/162, 56%); >5 cm (33/162, 17%) |
A (82/154, 51%); B (62/154, 38%); C (10/154, 4%) |
Median 72 CGE in 16 fractions, AP or PA & right lateral beam unless close to gut | For recurrence only | 32 | 5 y LC 87%; 5 y OS 24%, 5 y OS stage I 45%, stage II 11%, stage IIIA 27% | Grade 2+ nonhematologic acute toxicities: transaminitis (18/185, 10%), hyperbilirubinemia (3/185, 2%). Grade 2+ late toxicities: infection biloma (2/185, 1%), GI bleeding (2/185, 1%), CBD stenosis (1/185, 1%) |
| Hashimoto et al., 2006 (29) | 27 (68 lesions) | Recurrent HCC, Previously treated using PBT with (22/27, 81%) or without (5/27, 19%) TACE | A (21/27, 78%); B (6/27, 22%) | Median initial PBT dose 72 CGE in 16 fractions, Median re-RT dose 66 CGE in 16 fractions, AP and right lateral fields | Previous TACE in 22/27 (81%) patients | 62 | After re-RT, 5 y LC 86% and 5 y OS 26% | Acute toxicities: grade 4 hyperbilirubinemia (1/27, 4%), grade 4 hepatic coma (1/27, 4%). Late toxicities: grade 4 rib fracture (1/27, 4%), grade 3 infectious biloma (1/27, 4%), grade 3 obstructive cholangitis (1/27, 4%) |
| Hata et al., 2007 (30) | 3 (4 lesions) | Hypofractionation for HCC with uncontrollable ascites, median tumor size 3.0 cm | B (2/3, 67%); C (1/3, 33%) |
24 CGE in 1 fraction, 4–5 fields unique to each patient | None | 13 | CR in 2/3 (67%) patients; PR in 1/3 (33%) patients; 2/3 (67%) alive at 30 months |
No acute toxicities. Late toxicity: grade 2 rib fracture (1/3, 33%) |
| Nakayama et al., 2009 (31) | 318 | HCC, stage I (150/318, 47%); stage II (107/318, 34%); stage III (61/318, 19%) | A (234/318, 74%); B (77/318, 24%); C (7/318, 2%) |
77 CGE in 35 fractions if within 2 cm of gut (66/318, 21%); 72.6 CGE in 22 fractions if within 2 cm of porta hepatis (85/318, 27%); 66 CGE in 10 fractions if >2 cm (104/318, 33%), remainder varied |
36/318 (11%) treated with pre-PBT TACE/TAE, 144/318 (45%) with pre-PBT PEI/RFA | 19 | 5 y LC 83%; 1 y OS 90%; 3 y OS 65%; 5 y OS 45%, predictors of OS: T-stage, performance status, Child-Pugh class; not pre-PBT treatment | Grade 2 nonhematologic toxicities: skin (28/318, 9%), rib fracture (3/318, 1%), GI ulcers (3/318, 1%). Grade 3 nonhematologic toxicities: skin (4/418, 1%), colonic hemorrhage (1/318, 0%) |
| Ohtsubo et al., 2009 (32) | 1 | LR of HCC after surgery after PEI & microwave coagulation, Treated with HAI and PBT | – | 70 CGE in 35 fractions | Previous HAI with 5-FU, cisplatin, isovorin; followed by epirubicin & mitomycin C; Just prior to PBT HAI with irinotecan & docetaxel |
14 | Died of liver failure and DM 14 months after PBT | No grade 3+ nonhematologic toxicities |
| Kawashima et al., 2011 (33) | 60 | HCC, 45/60 (75%) single nodule; remainder multiple/diffuse. Median 45 mm |
A (47/60, 78%); B (13/60, 22%) | Median 76 CGE in 20 fractions, AP & right lateral fields | 26/43 (40%) with prior TACE | 43 | 3 y LC 90%; 5 y LC 86%; 3 y DFS 18%; 5 y DFS 4%; 3 y OS 56%, 5 y OS 25% | Grade 2+ GI toxicities: hemorrhagic duodenitis (1/60, 2%), grade 3 hemorrhagic colonic ulcer (1/60, 2%), grade 2 esophagitis (1/60, 2%) |
| Komatsu et al., 2011 (34) | 343 (386 lesions, n=278 PBT, n=108 CIT) | HCC, 333/386 (86%) single nodule; remainder multiple/diffuse. <5 cm (277/386, 72%); 5–10 cm (87/386, 22%); >10 cm (22/386, 6%) | A (262/386, 76%); B (75/386, 22%); C (6/386, 2%) | Most common PBT regimens: 60 CGE in 10 fractions (89/242, 37%), 76 CGE in 20 fractions (70/242, 29%), 66 CGE in 10 fractions (53/242, 22%) | – | 31 | 3 y LC 91%; 5 y LC 91%; 5 y LC 90% PBT; 93% CIT (P= NS). 3 y OS 59%, 5 y OS 38%; 5 y OS 38% PBT; 36% CIT (P= NS) | Grade 3 late toxicities: dermatitis (4/242, 2%), transaminitis (1/242, 1%), upper GI ulcer (1/242, 1%) biloma (1/242, 1%). Grade 4 late toxicity: dermatitis (1/242, 1%) |
| Bush et al., 2011 (35) | 76 | HCC, 65/76 (86%) single nodule; remainder multiple/diffuse. <5 cm (39/76, 51%); 5–10 cm (33/76, 43%); >10 cm (4/76, 5%) | A (22/76, 29%); B (36/76, 47%); C (18/76, 24%) | 63 CGE in 15 fractions, PA and left lateral fields | None | – | 15/76 (20%) patients with LR; 23/76 (36%) patients with other intrahepatic failure; 13/76 (17%) patients with extrahepatic failure. Median PFS 36 months; 3 y OS 70% in those with transplant (18/76, 24%); 3 y OS 10% without | No grade 3+ acute or late toxicity |
| Abei et al., 2013 (36) | 9 | Recurrent HCC treated with BCG extract vaccine, 7/9 (78%) single nodule; remainder multiple/diffuse. <5 cm (4/9, 44%); ≥5 cm (5/9, 56%) |
A (8/9, 89%); B (1/9, 11%) | Median 72.6 CGE in 22 fractions | 7/9 (78%) received TACE, chemotherapy, or sorafenib for recurrence | 12+ | LR in 8/9 (89%) patients; 6/9 (67%) died | No grade 3+ acute or late toxicity |
| Lee et al., 2014 (37) | 27 | HCC with portal vein tumor thrombosis. ≤7 cm (14/27, 52%); >7 cm (13/27, 48%) |
A (18/27, 67%); B (9/27, 33%) | Median 55 CGE in 21 fractions | Previous TACE and/or sorafenib in 20/27 (74%); concurrent sorafenib in 6/27 (22%); post-PBT TACE or sorafenib in 11/27 (41%) | 13 | 27/27 (100%) with intrahepatic recurrence, 14/27 (52%) with DM; 1 y LPFS 71%, 1 y RFS 11%, 1 y OS 56%; 2 y LPFS 62%, 2 y RFS 4%, 2 y OS 33% | No grade 3+ acute or late toxicity |
| Ohkawa et al., 2010 (38) | 14 | Intrahepatic cholangiocarcinoma. Stage II (1/14, 7%); stage IIIA (4/14, 29%); stage IIIC (5/14, 36%); stage IV (4/14, 29%) | – | Median 72.6 CGE in 26 fractions | 7/14 (50%); 5/14 (36%) with S1 | 12 | 1 y OS 50%; 1 y PFS 36%, LP in 6/14 (43%); LR in 2/14 (14%); Out-of-field recurrence in 7/14 (50%); DM in 4/14 (28%) | Grade 3 nonhematologic toxicities: elevated transaminases (1/14, 7%) |
| Makita et al., 2014 (39) | 28 | Cholangiocarcinoma. Intrahepatic (6/28, 21%); hilar (6/28, 21%); distal extrahepatic (3/28, 11%); gallbladder (3/28, 11%); local/nodal recurrence (10/28, 36%) |
– | Median 68.2 CGE/31 fractions | 10/28 (36%) prior, 3/28 (11%) concurrent, 15/28 (54%) adjuvant, gemcitabine and/or S1 | 12 | 1 y LC 68%, 1 y PFS 30%, 1 y OS 49%. Increased LC with BED >70 Gy (P=0.002) | Grade 3 acute toxicity: cholangitis (1/28, 4%). Grade 3 late toxicities: cholangitis (2/28, 7%), duodenal hemorrhage (2/28, 7%), CBD stenosis (1/28, 4%), duodenal stenosis (1/28, 4%), duodenal ulcer (1/28, 4%) |
| Hong et al., 2015 (40) | 83 | HCC (n=44); intrahepatic cholangiocarcinoma (n=37); mixed (n=2). Median size 5 cm in HCC, 6 cm cholangiocarcinoma |
A (66/83, 80%); B (15/83, 16%) | Median 58 CGE/15 fractions | Any chemotherapy (including TACE) in 27/83 (33%) | 19.5 | HCC, 2 y LC 95%; 1 y PFS 56%; 2 y PFS 40%; 1 y OS 77%; 2 y OS 63%. Cholangiocarcinoma: 2 y LC 94%; 1 y PFS 41%; 2 y PFS 26%; 1 y OS 70%; 2 y OS 47% |
Grade 3 toxicities: thrombocytopenia (1/83, 1.2%), liver disease (1/83, 1.2%), gastric ulcer (1/83, 1.2%), hyperbilirubinemia (1/83, 1.2%) |
| Bush et al., 2016 (41) | 69 | HCC, phase III PBT vs. TACE; 31/69 (45%) single nodule; remainder multiple/diffuse. Largest tumor 3.2 cm in both groups |
– | 70.2 CGE/15 fractions | 36 patients randomized to TACE, 33 patients to PBT | 28 | 2 y LC PBT 88% vs. TACE 45% (P=0.06); a2 y PFS PBT 48% vs. TACE 31% (P=0.06); 2 y OS 59%, no differences between groups |
Toxicities not specified. Hospitalizations 30 days post-treatment: TACE 62 vs. PBT 2 (P<0.001). Total hospitalization days: TACE 166 vs. PBT 24 (P<0.001) |
PBT, proton beam radiotherapy; CGE, cobalt gray equivalent; 5-FU, 5-fluorouracil; GI, gastrointestinal; PA, posteroanterior; MS, median survival; OS, overall survival; LP, local progression; DM, distant metastasis; FFLP, freedom from local progression; PFS, progression-free survival; DGE, delayed gastric emptying.