Treatment results of proton beam therapy with chemo-radiotherapy for stage I-III esophageal cancer Nobukazu Fuwa 1, Akinori Takada 2 and Takahiro Kato 3 1;Departments of Radiology, Hyogo Ion Beam Medical Center, Tatsuno, Hyogo, Japan 2;Department of Radiation Oncology, Mie University Graduate School of Medicine, Tsu, Mie, Japan 3;Department of Radiation Physics, Southern Tohoku Proton Therapy Center, Koriyama, Fukushima, Japan
Background:Although the standard treatment for esophageal cancer is surgery, it is highly invasive and often makes the patient s QOL decreased. Chemo-radiotherapy (CRT) for esophageal cancer has been significantly progressed and this treatment has been acknowledged to be one of the standard treatment. However, the serious late adverse effects such as pulmonary dysfunction and heart damage due to high dose to lung and heart have been raised as a critical issue. Proton beam therapy (PBT) can significantly reduce dose to the normal tissues compared with photon therapy. Therefore, the higher effectiveness and lesser late adverse effects in lung and heart would be expected. Purpose: The aim of our study was to evaluate the outcomes of PBT with CRT in patients with esophageal cancer.
Evaluated Items Completion rate of the treatment, Primary effect Patterns of recurrence, Adverse effect Local control rate, Overall survival rate, and Progression survival rate Univariate and multivariate analyses of the prognostic factors on overall survival Comparison with conventional CRT, and previously reported proton therapy
Alternating Chemo-Radiation Methods 5-FU:700mg/m 2,d1-5 NDP:130mg/m 2,d6 5-FU:700mg/m 2,d1-5 NDP:130mg/m 2,d6 X ray36gy (1.8Gyx20) Proton 33GyE (2.2GyEx15-18)
Patients n=47 2009.1-2012.12 Age: 47~77 yrs (median: 63 yrs) Pathology: Squamous cell ca. 46 (98%), adenoca. 1 (2%) Gender: male 37 (79%) female 10 (21%) PS: 0/1/2 ; 6 (13%) /39 (83%) /2 (4%) Stage (UICC2009):I/II/III ; 10(21%) /12 (26%) /25 (53%) Reasons of chemo radiotherapy: Refusal of surgery 35 (74%) Inoperable 12 (25%) T4 n=8
Results n=47 2009.1-2012.12 Completion rate of the treatment: 1 st chemo. 46 (98%), RT 46 (98%) 2 nd chemo. 43 (91%), RT 47 (100%) X ray dose: 12.6-40Gy (median 36Gy) Proton dose: 23.8-63.8GyE (median 37.4GyE) Primary effect: CR 37 (79%), PR 10 (21%) Patterns of recurrence: local recurrence (within GTV) 11 (23%) distant metastasis 5 (11%) prophylactic area of lymph node 2 (4%)
Hematologic Leukopenia Adverse effects( Grade3)CTC ver.4 Neutropenia Anemia Thrombocytopenia 26 (55%) 20 (43%) 2 (4%) 13 (27%) Non-Hematologic Esophagitis 5 (10%) Stenosis, fistula 3 (6%) Pneumonitis 2 (4%) Pericardial effusion 0 (0%) Treatment related death 2 (4%)
Local control curve n=47 Local Overall Contol Survival Probability Probability 0.0 0.0 0.2 0.2 0.4 0.4 0.6 0.6 0.8 0.8 1.0 1.0 3y:68% 0 1 2 3 4 5 0 1 2 3 4 5 Time in Year Time in Year
Overall survival curve Stage I - III n=47 Stage II - III n=37 Overall Survival Probability 0.0 0.2 0.4 0.6 0.8 1.0 3y:59% Overall Survival Probability 0.0 0.2 0.4 0.6 0.8 1.0 3y:55% 0 1 2 3 4 5 0 1 2 3 4 5 Time in Year Time in Year
Progression free survival curve Stage I - III n=47 Stage II - III n=37 Progression-free Survival Probability 0.0 0.2 0.4 0.6 0.8 1.0 3y:56% Progression-free Survival Probability 0.0 0.2 0.4 0.6 0.8 1.0 3y:54% 0 1 2 3 4 5 Time in Year 0 1 2 3 4 5 Time in Year
Results of the Univariate Analysis of the Prognostic Factor on Overall Survival Based on Log rank test Factor Variable Adjusted P value T classification T1, 2 T3, 4 N classification Stage Location Findings of GIF N0 N1-3 I, II III Ut-Mt Lt-AE Clear margin Unclear margin Adjusted HR (95% CI) 0.018 1.000 [referent] 4.999 (1.117, 22.37) 0.146 1.000 [referent] 2.857 (0.639, 1.754) 0.028 1.000 [referent] 3.732 (1.040, 13.395) 0.299 1.000 [referent] 0.550 (1.040, 13.395) 0.014 1.000 [referent] 3.387(1.184, 9.691) Passage of GIF Yes No SUV max <14.5 14.5 <0.001 1.000 [referent] 7.397 (2.627, 23.986) 0.024 1.000 [referent] 2.429 (0.730, 8.080)
Results of the Multivariate Analysis of the Prognostic Factor on Overall Survival Based on Cox Proportion - Hazard Model Factor Variable Adjusted P value T classification T1, 2 T3, 4 Stage Findings of GIF I, II III Clear margin Unclear margin Adjusted HR (95% CI) 0.017 1.000 [referent] 14.843 (1.612, 136.703) 0.550 1.000 [referent] 1.828 (0.253, 13.200) 0.101 1.000 [referent] 0.295(0.068, 1.268) Passage of GIF Yes No SUV max <14.5 14.5 0.045 1.000 [referent] 5.331 (1.035, 27.443) 0.624 1.000 [referent] 1.490 (0.302, 7.339)
Institute N CR rate National Cancer Center(Japan) Comparison with conventional CRT; Stage Ⅱ/Ⅲ(except T4)esophageal ca. Survival rate 3 Years 5 Years Remarks 88 66% 48% 35% Except T4 Tohoku univ. 40 68% 58% Except T4 Salvage Operation:38% JCOG9906 76 62% 45% 37% Except T4 This study 37 74% 55% T4 (n=8) included
Comparison with other proton therapy institutes N Stage chemo X-ray dose Proton dose Survival rate 3 Y OS 3 PFS Remarks Tsukuba univ. 1) 51 T1-4 N0-1 - 46Gy n=33 36GyE n=33 79GyE n=18 34.3% 24.6% Most cases; II-III MD Anderson.2) 62 I-IV + - 50.4GyE 51.7% 40.5% Most cases; II-III, adenoca. Pre-op.; n=29 This study 47 I-III + 36Gy 37.4GyE 59% 56% Most cases; II-III 1) Mizumoto H.et al.strahlen Ther Onkol, 2010 2) Lin SH.et al. Int J Radiat oncol Biol Phys, 2012
Summary Treatment results of proton beam therapy with chemo-radiotherapy for stage I-III esophageal cancer were favorable. These results are superior to those of conventional CRT, and might be equal to those of surgery. Proton beam therapy combined with CRT can reduce late adverse effects. This method will play an important role for esophageal cancer, and may replace surgery in treating some lesions. In case of operable patient, the optimum dose (e.g. 50.4 Gy ±surgery or over 70Gy) will be an important problem.