High-dose Proton Beam Therapy Research Articles

High-dose proton beam therapy versus conventional fractionated radiation therapy for newly diagnosed glioblastoma: a propensity score matching analysis

BackgroundHigh-dose proton beam therapy (PBT) uses excellent dose concentricity based on the unique characteristic termed the Bragg peak. PBT is a highly feasible treatment option that improves survival in select patients with newly diagnosed glioblastoma (GBM). However, selection bias remains an issue in prior studies that evaluated the efficacy of PBT. The aim of the present study was to compare the survival outcomes and toxicities of high-dose PBT and conventional radiation therapy (CRT) using propensity score-matched treatment cohorts.MethodsThe analysis included patients with newly diagnosed GBM treated with high-dose PBT of 96.6 Gy (RBE) or CRT of 60 Gy from 2010 to 2020. Propensity score generation and 1:1 matching of patients were performed based on the following covariates: age, sex, tumor location, extent of resection, chemotherapy, immunotherapy, and pre-radiation Karnofsky performance scale score.ResultsFrom a total of 235 patients, 26 were selected in each group by propensity score matching. The median overall survival (OS) of the PBT group was 28.3 months, while the median OS of the CRT group was 21.2 months. Although acute radiation-related toxicities were equivalent between the PBT and CRT groups, radiation necrosis as a late radiation-related toxicity was observed significantly more frequently in the PBT group.ConclusionsHigh-dose PBT provided significant survival benefits for patients with newly diagnosed GBM compared to CRT as shown by propensity score matching analysis. Radiation necrosis remains an issue in high-dose PBT; thus, the establishment of an effective treatment strategy centered on bevacizumab would be essential.

Detection of Pretreatment Circulating Tumor DNA Predicts Recurrence after High-Dose Proton Beam Therapy for Early-Stage Non-Small Cell Lung Cancer

Circulating tumor DNA (ctDNA) has been studied as a rapid and noninvasive biomarker for predicting cancer treatment outcomes. However, published data on the usefulness of pretreatment ctDNA in patients with non-small cell lung cancer (NSCLC) who underwent radiotherapy are currently limited, especially in patients who received proton beam therapy. This study included patients with cT1-2N0M0 nonsquamous NSCLC treated with proton beam therapy. Pretreatment plasma and matched white blood cell samples were subjected to targeted sequencing. The incidence of tumor recurrence and prognosis of patients with and without ctDNA detection were statistically evaluated. Forty-three patients with nonsquamous NSCLC were analyzed in this study. Pretreatment ctDNA was detectable in 8 of 43 patients (18.6%). At the median follow-up of 59 months (range, 15-97 months) in the surviving patients, detectable ctDNA was associated with inferior progression-free survival (HR, 5.2; 95% CI, 1.9-14.6; P <0.01) and overall survival (HR, 4.7; 95% CI, 1.1-20.6; P=0.02). There was no significant difference in the cumulative incidence of in-field recurrence according to the ctDNA detection status (P=0.92), but the ctDNA-positive group showed a significantly higher cumulative incidence of out-of-field recurrence (P<0.01) than the ctDNA-negative group. These results suggest that pretreatment ctDNA detection can predict out-of-field recurrence in patients with cT1-2N0M0 nonsquamous NSCLC treated with high-dose proton beam therapy.

A phase II trial of hypofractionated high-dose proton beam therapy for unresectable liver metastases

Background and purposeProton beam therapy (PBT) is an effective treatment option for primary malignant liver disease. However, evidence regarding liver metastasis is insufficient. We aimed to investigate the efficacy and safety of hypofractionated high-dose PBT in the treatment of metastatic liver disease. Materials and methodsFrom January 2019 to January 2021, patients with unresectable liver metastases were enrolled. For PBT, the dose schemes of 60 Gy relative biological effectiveness (GyRBE) in 5 fractions (fx) (biologically effective dose [BED] 132 GyE) or 70 GyRBE in 10 fx (BED 119 GyE) were used. Either a passive scattered beam or pencil beam scanning (PBS)-based intensity-modulated proton therapy (IMPT) was performed with proper respiratory management. The primary endpoint of the study was 6-month freedom from local progression (FFLP) rate; and the Kaplan–Meier method was used to calculate the FFLP and survival rates. ResultsOf the 49 liver metastases in 46 patients, the colorectum accounted for 60% of the primary cancer sites, followed by the gastrointestinal organs and pancreas/biliary tract. Forty patients presented only 1 liver metastasis, while the other 6 patients had 2 to 4 metastases. The Six-month FFLP rate was 95.2%. The 1-year FFLP rate in patients with <3 cm liver metastasis was 87.4%, while that was 74.1% in patients with > 3 cm group (p = 0.087). With regard to systemic treatment, the 1-year FFLP rate after PBT was better (94.1%) than that without systemic treatment (75.8%; p = 0.051). Regarding PBT-related toxicity, one patient developed a grade 2 gastric ulcer, while none of the patients developed grade ≥3 toxicities. ConclusionsHypofractionated PBT with a BED > 100 GyRBE for liver metastasis is safe and effective, given the high rate of 6-month FFLP without grade ≥3 treatment-related toxicities. However, further improvements are required for larger tumors and/or those without prior systemic therapy.

RT-4 Treatment outcome of proton beam therapy for glioblastoma

Introduction: Proton beam therapy enables high dose irradiation for tumors while reducing the dose to surrounding normal tissue due to the sharp energy peak called the Bragg peak. We retrospectively analyzed the efficacy of the high dose radiotherapeutic strategy using proton beam for glioblastoma (GBM) in our institution. Methods: Twenty-nine patients with newly diagnosed GBM who underwent high dose proton beam therapy concomitant with temozolomide were investigated. All patients received hyperfractionated concomitant radiotherapy consisting of X-ray radiotherapy (50.4Gy in 28 fractions) and proton beam therapy (46.2Gy [RBE] in 28 fractions). The survival outcome and adverse events were analyzed. Results: The median overall survival time and progression free survival time for all 29 patients were 31.0 months (95%CI, 25.9–36.1) and 11.0 months (95%CI, 7.8–14.2), respectively. No significant survival difference according to the MGMT methylation status was shown. Failure patterns after proton beam therapy included 17 cases of local recurrence, 3 cases of distant recurrence, and 5 cases of dissemination. Although there was no significant difference in time to recurrence according to the failure pattern, there was a tendency of longer survival in the local recurrence group. Regarding adverse events, radiation necrosis was observed in 8 cases (including 2 asymptomatic cases). The median time to onset of necrosis after radiation was 18.2 months (95%CI, 10.3–26.2). There were 5 cases of long survivor over 5 years out of 29 cases (17.2%). Of these, 4 cases developed radiation necrosis. Conclusions: Our results indicate that high dose proton beam therapy of 96.6Gy (RBE) prolonged survival in selected GBM patients. Particularly in long survivors, special attention and effective treatment to radiation necrosis is a remaining problem.

Optimal Androgen Deprivation Therapy Combined with Proton Beam Therapy for Prostate Cancer: Results from a Multi-Institutional Study of the Japanese Radiation Oncology Study Group.

Background: Androgen deprivation therapy (ADT) combined with radiation therapy benefits intermediate- and high-risk prostate cancer (PC) patients. The optimal ADT duration in combination with high-dose proton beam therapy (PBT) remains unknown. Methods: Intermediate- and high-risk PC patients treated with PBT combined with ADT for various durations were analyzed retrospectively. To assess the relationship between ADT and biochemical relapse-free (bRF) rate, Cox proportional hazards models including T stage, prostate specific antigen (PSA) level, Gleason score (GS), and total radiation dose were used. Results: In the intermediate-risk PC patients (n = 520), ADT use improved bRF (HR 0.49, 95% CI 0.26–0.93; p = 0.029), especially in those with multiple intermediate-risk factors (T2b–2c, PSA 10–20 ng/mL, and GS 7). In the high-risk PC patients (n = 555), a longer ADT duration (>6 months) conferred a benefit for bRF (HR 0.54, 95% CI 0.32–0.90; p = 0.018), which was most apparent in patients with multiple high-risk factors (T3a–4, PSA > 20 ng/mL, and GS ≥ 8) treated with ADT for ≥21 months. Conclusions: Short-term (≤6 months) ADT is beneficial for intermediate-risk PC patients, but likely unnecessary for those with a single risk factor, whereas ADT for >6 months is necessary for high-risk PC patients and ADT for ≥21 months might be optimal for those with multiple risk factors in combination of high-dose PBT.

Successful two-stage operation for esophageal necrosis due to proton beam therapy followed by sorafenib in a case of large hepatocellular carcinoma

BackgroundLocally advanced hepatocellular carcinoma (HCC), which is unsuitable for standard locoregional therapies, remains a challenge to manage. Among the recently developed treatments, proton beam therapy (PBT) has been reported to achieve good local control. However, in patients with large HCC adjacent to the esophagus, high-dose PBT may rarely lead to radiation-induced esophageal necrosis or perforation. Furthermore, the optimal strategy to safely treat these fatal complications remains unclear.Case presentationA 49-year-old man who was diagnosed with a large (16 cm) HCC in the right lobe with tumor thrombosis in the main trunk of the portal vein (PVTT) received high-dose hypofractionated PBT in another hospital. A total dose of 66 GyE in 10 fractions was administered to the primary tumor and the PVTT. After 5 months, a 1-cm solitary nodule was noted in the upper lobe of the right lung. Therefore, sorafenib was started. About 6 months after the PBT, lower esophageal mucosal inflammation that progressed to an ulcer was noted. About 7 months after the PBT, the lower esophagus developed full-thickness necrosis. Therefore, emergency thoracoscopic esophagectomy was performed, followed by two-stage reconstruction 2 months later. The operation and postoperative clinical course were mostly uneventful, except for a minor anastomotic leakage. The outcome of the primary HCC, including the PVTT, was graded as a complete response, which has been maintained for 51 months after the PBT.ConclusionPBT is a promising option for patients with locally advanced HCC; however, for large tumors adjacent to the esophagus, ischemic esophageal necrosis due to antiangiogenic effects may occur, particularly with the combined use of PBT and sorafenib. In such a life-threatening condition, the thoracoscopic esophagectomy and the two-stage reconstruction are a safe option that can prevent critical postoperative complications due to the poor general condition, effects of PBT on the remnant gastric conduit, and use of sorafenib.

Proton beam therapy for liver cancers.

Proton beam therapy (PBT) delivers less dose to nearby normal organs compared to X-ray therapy (XRT), which is particularly relevant for treating liver cancers given that both mean and low liver dose are among the most significant predictors of radiation induced liver disease (RILD). High-dose PBT has been shown to achieve excellent long-term tumor control with minimal toxicity in hepatocellular carcinoma (HCC) patients. Increasing data support ablative PBT for patients with unresectable cholangiocarcinoma or liver metastases, especially those with larger tumors not suitable for XRT.

Proton Therapy for Primary Renal Cell Carcinoma: The First Nationwide Retrospective Study in Japan.

This multi-institutional study aimed to investigate the efficacy and feasibility of proton beam therapy (PBT) for renal cell carcinoma (RCC) in Japan. The survival, local control, and toxicities in 22 RCC patients treated between 2001 and 2016 at 6 Japanese PBT institutes were analyzed. The 22 patients comprised 20 men and had a median age of 67 (range=42-88) years. The total irradiation dose was 60-79.6 Gy (relative biological effectiveness). Over a median follow-up of 37 months, the 3-year overall and disease-specific survival rates were 95% and 100%, respectively, and no recurrence occurred. No patient experienced grade 3 or higher adverse events. The serum blood urea nitrogen (p=0.25) and creatinine levels (p=0.95) were not significantly affected, although the mean estimated glomerular filtration rate was reduced by 7.1±11.2 ml/min/1.73 m2 Conclusion: Despite the small number of patients, high-dose PBT can control RCC while maintaining their renal function with high probability, and could be and alternative curative therapy especially for inoperable patients.

RT-02 POTENTIAL OF PROTON BEAM THERAPY FOR THE TREATMENT OF GLIOBLASTOMA

INTRODUCTIONRecently, proton beam therapy has attracted increasing interest in the Japanese neuro-oncological field because of the insurance approval for pediatric brain tumor, chordoma, and chondrosarcoma. We have developed the high dose radiotherapeutic strategy using proton beam for malignant glioma in our institution since long before. Here we retrospectively analyzed the efficacy of this treatment strategy.METHODSThirty-four patients with newly diagnosed GBM who underwent high dose proton beam therapy were investigated. All patients received hyperfractionated concomitant radiotherapy consisting of X-ray radiotherapy (50.4Gy in 28 fractions) and proton beam therapy (46.2Gy [RBE] in 28 fractions). Concurrent chemotherapy consisted of ACNU in the early 6 cases or TMZ in the late 28 cases. The survival outcome and adverse events were analyzed.RESULTSThe median overall survival time and progression free survival time for all 34 patients were 35.7 months (95%CI, 28.1–43.4) and 11.2 months (95%CI, 6.8–15.7), respectively. No significant survival difference according to the chemotherapy regimen was shown. Failure patterns after proton beam therapy include 19 cases of local recurrence, 3 cases of distant recurrence, and 5 cases of dissemination. Although there was no significant difference in time to recurrence according to the failure pattern, there was a tendency of longer survival in the local recurrence group. As for adverse events, symptomatic radiation necrosis was observed in 9 cases. The median time to onset of necrosis after radiation was 18.2 months (95%CI, 10.2–26.2). There were 8 cases of long survivors over 5 years out of 34 cases (23.5%). Of these, 6 cases developed symptomatic radiation necrosis.CONCLUSIONSOur results indicate that high dose proton beam therapy of 96.6Gy (RBE) prolonged survival in selected GBM patients. With appropriate patient selection and potent treatment for radiation necrosis, high dose proton beam therapy has a great potential to improve survival in GBM patients.

Prognostic analysis of patients who underwent gross total resection of newly diagnosed glioblastoma

Despite cumulative evidence supporting the idea that gross total resection (GTR) contributes to prolonged survival of patients with glioblastoma (GBM), the survival outcome of such patients remains unsatisfactory. To develop more effective postoperative therapeutic strategies for patients who underwent GTR, identification of prognostic factors influencing survival is urgently needed. Here we retrospectively analyzed prognostic factors for patients who underwent GTR of newly diagnosed GBM, with a particular focus on the influence of the subventricular zone (SVZ) as the tumor location. Forty-eight consecutive patients with newly diagnosed GBM who underwent GTR during the initial operation were investigated. Tumor involvement of the SVZ was significantly associated with overall survival (OS). The SVZ-positive group had a significantly shorter median OS of 12.2 months, compared to 34.9 months for the SVZ-negative group. The occurrence of leptomeningeal dissemination was significantly influenced by tumor involvement of the SVZ, but was not significantly influenced by ventricular opening during surgery. We observed a statistically significant difference in OS according to radiation modality. The median OS was 36.9 months for patients treated with high-dose proton beam therapy, compared with 26.2 months for patients treated with conventional radiotherapy. We demonstrated that tumor involvement of the SVZ was associated with poor survival of patients who underwent GTR of newly diagnosed GBM, suggesting the potential need for therapeutic strategies that specifically target tumors in the SVZ. Further prospective studies to evaluate whether radiotherapy targeting the SVZ improves survival of patients with tumor involvement of the SVZ who had undergone GTR are warranted.

Preliminary Result of Hyperfractionated High-Dose Proton Beam Radiotherapy for Pediatric Skull Base Chordomas

Objective: Proton beam therapy (PBT) may provide good local control for skull base chordoma and reduced toxicities, especially for pediatric patients. Methods: We evaluated the efficacy and safety of hyperfractionated high-dose PBT in6 pediatric patients with newly-diagnosed skull basechordoma who were treated with PBT at our institute from 2011 to 2015. The patients were 5 males and one female, and the median age was 9 years old (range: 5 - 13). All patients received surgery before PBT. The median period between surgery and PBT was 57 days (range: 34 - 129 days). The treatment dose was 78.4 GyE in 56 fractions (twice per day). Results: All patients received PBT without severe acute toxicity. The median follow-up period was 27 months (range: 21 - 71 months). At the last follow-up, all patients were alive and all tumors were well controlled. Acute and late toxicities were generally acceptable, with only grade 1 and 2 events. Late toxicities included growth hormone abnormality and cortical hormone abnormality. One patient needed growth hormone and cortical hormone replacement therapy. Conclusion: Although the number of pediatric patients was small, our overall findings in the 6 cases indicate that hyperfractionated high-dose PBT is safe and effective for pediatric patients with skull base chordoma.

Hyperfractionated high-dose proton beam radiotherapy for clival chordomas after surgical removal.

To evaluate the hyperfractionated high-dose proton beam therapy (PBT) for patients with clival chordomas. Records for 19 patients with pathologically verified clival chordomas treated with surgery followed by hyperfractionated PBT were retrospectively reviewed. The first 9 consecutive patients were treated with 77.44 cobalt gray equivalents (CGEs) in 64 fractions, and the latter 10 patients were treated with 78.4 CGE in 56 fractions. The median follow-up period of all 19 cases was 61.7 months with a range from 31.5 to 115.4 months. At 5 years, the local control, cause-specific and overall survival rates for all 19 cases were 75%, 94% and 83.2%, respectively. Whereas the 5-year local control, cause-specific and over all survival rates of the latter 10 cases were 100%, 100% and 88.9%, respectively, with a median follow-up period of 59.5 months. One of the first nine patients demonstrated bilateral temporal lobe radiation necrosis, who were successfully treated conservatively. In the latter cohort, two cases showed transient neurological symptoms probably due to brain stem ischaemia, but both cases recovered completely with conservative treatment. The hyperfractionated high-dose scheme combined with maximum surgical removal was shown to be efficient for patients with clival chordomas. High-dose proton beam radiotherapy using a hyperfractionation scheme yielded a more favourable outcome than previous reports.

Clinical Outcomes and Prognostic Factors of High-Dose Proton Beam Therapy for Peripheral Stage I Non-Small-Cell Lung Cancer

BackgroundThe efficacy, toxicity, and prognostic factors of high-dose proton beam therapy (PBT) for peripheral stage I non-small-cell lung cancer were assessed in this retrospective study. Materials and MethodsFifty patients with peripheral stage I non-small-cell lung cancer, two of whom had heterochronic multiple lung cancers, underwent high-dose PBT between January 2009 and September 2014. The relative biological effectiveness of the proton beam was defined as 1.1. The beam energy and spread-out Bragg peak were fine-tuned for the 90% isodose volume of the prescribed dosage to encompass the planning target volume. The cumulative survival curves were calculated using the Kaplan-Meier method. Treatment toxicities were evaluated using version 4 of the Common Terminology Criteria for Adverse Events, version 4. ResultsThe study included 35 males and 15 females with a median age of 72.5 years. The median follow-up period was 22.8 months. The clinical stage was IA in 44 (85%) and IB in eight (15%) tumors. The total dose of PBT was 66 GyE in 10 fractions in all tumors. Three-year overall survival rate among all patients was 87.9% (95% confidence interval [CI], 94.8%-73.2%). Forty-five patients were alive, and 5 were dead. Three-year local control and progression-free survival rates were 95.7% (95% CI, 98.9%-83.8%) and 76.3% (95% CI, 86.9%-59.3%), respectively. Only one patient experienced Grade 2 pneumonitis. ConclusionHigh-dose PBT may be an effective and safe treatment option for patients with stage I non-small-cell lung cancer.

High Dose (74 GyE) Proton Beam Therapy With Concurrent Chemotherapy for Stage III Non-Small Cell Lung Cancer

Purpose/Objective(s)To evaluate the clinical outcome of high-dose (74 Gy RBE) proton beam therapy (PBT) with concurrent chemotherapy for unresectable locally advanced non-small cell lung cancer (NSCLC).Materials/MethodsBetween 2007 and 2013, 31 patients with locally advanced NSCLC were treated with PBT and chemotherapy concurrently. The prescribed dose was 74 Gy RBE to the primary tumor and 66 Gy RBE to the metastatic lymph nodes. Adapted planning was made during the treatment. Cisplatin- or carboplatin-based chemotherapy was used. Twenty-four of 31 patients were men, and the median age was 63 years (range, 40-79 years). The clinical stage was Stage IIIA in 8 patients and Stage IIIB in 23 patients.ResultsAt the last follow-up, 13 of 31 patients were dead of disease, 2 patients were dead of other diseases, 11 patients were alive with disease, and 5 patients were alive without disease. The median follow-up time was 21 months for all patients and 37 months for surviving patients. The 2-year overall survival, disease-specific survival, and progression-free survival rates were 61%, 65%, and 22%, respectively. The median survival time was 39 months. Sixteen patients developed locoregional recurrences at intra-thorax and/or supraclavicular node (inside the field: 12, outside the field: 3, inside and outside the field: 1). The 2-year locoregional control rate was 53%. No Grade 4 or 5 acute and late non-hematologic toxicities were observed. Grade 3 acute dermatitis and esophagitis were seen in 3 and 2 patients, respectively. Three patients experienced Grade 3 radiation pneumonitis.ConclusionHigh-dose PBT with concurrent chemotherapy for locally advanced NSCLC is a safe and effective treatment option. Purpose/Objective(s)To evaluate the clinical outcome of high-dose (74 Gy RBE) proton beam therapy (PBT) with concurrent chemotherapy for unresectable locally advanced non-small cell lung cancer (NSCLC). To evaluate the clinical outcome of high-dose (74 Gy RBE) proton beam therapy (PBT) with concurrent chemotherapy for unresectable locally advanced non-small cell lung cancer (NSCLC). Materials/MethodsBetween 2007 and 2013, 31 patients with locally advanced NSCLC were treated with PBT and chemotherapy concurrently. The prescribed dose was 74 Gy RBE to the primary tumor and 66 Gy RBE to the metastatic lymph nodes. Adapted planning was made during the treatment. Cisplatin- or carboplatin-based chemotherapy was used. Twenty-four of 31 patients were men, and the median age was 63 years (range, 40-79 years). The clinical stage was Stage IIIA in 8 patients and Stage IIIB in 23 patients. Between 2007 and 2013, 31 patients with locally advanced NSCLC were treated with PBT and chemotherapy concurrently. The prescribed dose was 74 Gy RBE to the primary tumor and 66 Gy RBE to the metastatic lymph nodes. Adapted planning was made during the treatment. Cisplatin- or carboplatin-based chemotherapy was used. Twenty-four of 31 patients were men, and the median age was 63 years (range, 40-79 years). The clinical stage was Stage IIIA in 8 patients and Stage IIIB in 23 patients. ResultsAt the last follow-up, 13 of 31 patients were dead of disease, 2 patients were dead of other diseases, 11 patients were alive with disease, and 5 patients were alive without disease. The median follow-up time was 21 months for all patients and 37 months for surviving patients. The 2-year overall survival, disease-specific survival, and progression-free survival rates were 61%, 65%, and 22%, respectively. The median survival time was 39 months. Sixteen patients developed locoregional recurrences at intra-thorax and/or supraclavicular node (inside the field: 12, outside the field: 3, inside and outside the field: 1). The 2-year locoregional control rate was 53%. No Grade 4 or 5 acute and late non-hematologic toxicities were observed. Grade 3 acute dermatitis and esophagitis were seen in 3 and 2 patients, respectively. Three patients experienced Grade 3 radiation pneumonitis. At the last follow-up, 13 of 31 patients were dead of disease, 2 patients were dead of other diseases, 11 patients were alive with disease, and 5 patients were alive without disease. The median follow-up time was 21 months for all patients and 37 months for surviving patients. The 2-year overall survival, disease-specific survival, and progression-free survival rates were 61%, 65%, and 22%, respectively. The median survival time was 39 months. Sixteen patients developed locoregional recurrences at intra-thorax and/or supraclavicular node (inside the field: 12, outside the field: 3, inside and outside the field: 1). The 2-year locoregional control rate was 53%. No Grade 4 or 5 acute and late non-hematologic toxicities were observed. Grade 3 acute dermatitis and esophagitis were seen in 3 and 2 patients, respectively. Three patients experienced Grade 3 radiation pneumonitis. ConclusionHigh-dose PBT with concurrent chemotherapy for locally advanced NSCLC is a safe and effective treatment option. High-dose PBT with concurrent chemotherapy for locally advanced NSCLC is a safe and effective treatment option.

High-dose proton beam therapy for stage I non-small cell lung cancer: Clinical outcomes and prognostic factors

Background. Evidence has suggested that radiation therapy with a lower dose per fraction may be a reasonable option for the treatment of centrally located non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of two proton beam therapy (PBT) protocols for stage I NSCLC and to determine prognostic factors.Material and methods. This study included patients clinically diagnosed with stage I NSCLC. Based on the location of the tumor, one of the two PBT protocols was administered. Patients with peripherally located tumors were given 66 Gy relative biological dose effectiveness (RBE) over 10 fractions (Protocol A) while patients with centrally located tumors were given 80 Gy (RBE) over 25 fractions (Protocol B).Results. Between January 2009 and May 2012, 56 eligible patients were enrolled (protocol A: 32 patients; protocol B: 24 patients). The three-year overall survival (OS), progression-free survival (PFS), and local control (LC) rates were 81.3% [95% confidence interval (CI) 75.9–86.7%], 73.4% (95% CI 67.2–79.6%), and 96.0% (95% CI 93.2–98.8%), respectively. There were no significant differences in outcomes between the two protocols. Late grade 2 and 3 pulmonary toxicities were observed in nine patients (13.4%) and one patient (1.5%), respectively; no grade 4 or 5 toxicities were observed. Sex, age, performance status, T-stage, operability, and tumor pathology were not associated with OS and PFS. Only maximum standardized uptake value (SUVmax; < 5 vs. ≥ 5) was identified as a significant prognostic factor for OS and PFS.Conclusion. Both high-dose PBT protocols achieved high LC rates with tolerable toxicities in stage I NSCLC patients, and SUVmax was a significant prognostic factor.

High-dose proton beam therapy for sinonasal mucosal malignant melanoma.

BackgroundThe significance of definitive radiotherapy for sinonasal mucosal melanoma (SMM) is sill controvertial. This study was to evaluate the role of high-dose proton beam therapy (PBT) in patients with SMM.MethodsThe cases of 20 patients with SMM localized to the primary site who were treated by PBT between 2006 and 2012 were retrospectively analyzed. The patterns of overall survival and morbidity were assessed.ResultsThe median follow-up time was 35 months (range, 6–77 months). The 5-year overall and disease-free survival rates were 51% and 38%, respectively. Four patients showed local failure, 2 showed regrowth of the primary tumor, and 2 showed new sinonasal tumors beyond the primary site. The 5-year local control rate after PBT was 62%. Nodal and distant failure was seen in 7 patients. Three grade 4 late toxicities were observed in tumor-involved optic nerve.ConclusionOur findings suggested that high-dose PBT is an effective local treatment that is less invasive than surgery but with comparable outcomes.

Long-term survival after treatment of glioblastoma multiforme with hyperfractionated concomitant boost proton beam therapy

PurposeAlthough conventional x-ray therapy of 60 Gy in 30 fractions is generally used in our institute as well as others, the prognosis of patients with glioblastoma multiforme (GBM) is poor. The purpose of this study was to evaluate the characteristics of long-term GBM survivors after postoperative hyperfractionated concomitant boost x-ray radiation therapy and proton beam therapy. Methods and materialsTwenty-three of 81 GBM patients who met the eligible criteria and consented to the protocol were treated with x-ray radiation therapy (50.4 Gy in 28 fractions in T2-high areas) and proton beam therapy (46.2 GyE in 28 fractions in gadolinium-enhanced volumes >6 hours after x-ray radiation therapy) concurrent with nimustine hydrochloride or temozolomide. ResultsTreatment was completed in all patients within 38-50 days (median, 43 days). Six currently living patients (median follow-up period, 70.9 months) developed radiation necrosis without tumor recurrence. Of these, 5 underwent necrotomy and 2 received bevacizumab after necrotomy. Compared with the pretreatment status, the Karnofsky performance scale (KPS) for the 6 survivors decreased by 10%-30% at the last follow-up. However, radiation necrosis had been well controlled and 5 of 6 patients maintained a stable KPS without hospital care. ConclusionsThe results suggest that high-dose proton beam therapy could control GBM pathogenesis if the treatment area completely covers tumor infiltration. Although radiation necrosis was inevitable, the remaining brain volume was fairly well preserved in the long-term survivors.

Outcomes and Prognostic Factors for Recurrence After High-Dose Proton Beam Therapy for Centrally and Peripherally Located Stage I Non–Small-Cell Lung Cancer

IntroductionThis study was conducted to determine disease control rates and prognostic factors associated with recurrence of centrally and peripherally located stage I NSCLC treated using high-dose PBT. Patients and MethodsSeventy-four patients with 80 centrally or peripherally located stage I NSCLCs were treated with PBT. A protocol using 72.6 Gy (RBE) in 22 fractions was used for centrally located tumors, and 66 Gy (RBE) in 10 or 12 fractions was used for peripherally located tumors. Data were collected and control rates and prognostic factors for recurrence were evaluated retrospectively. ResultsThe median follow-up period was 31.0 months. The overall survival, disease-specific survival, and progression-free survival rates were 76.7%, 83.0%, and 58.6% at 3 years, respectively. Disease recurrence was noted in 30 patients and local recurrence of 11 tumors occurred. The 3-year local control rate was 86.2% for stage IA tumors and 67.0% for stage IB tumors. Radiation dose was identified as a significant prognostic factor for disease recurrence and local recurrence. Tumor diameter and age were only significantly associated with disease recurrence. The 3-year local control rate was 63.9% for centrally located tumors irradiated with 72.6 Gy (RBE) and 88.4% for peripherally located tumors irradiated with 66 Gy (RBE). ConclusionRadiation dose was shown to be the most significant prognostic factor for tumor control in stage I NSCLC treated using high-dose PBT. Tumor diameter was not significant for local control. Further evaluation of PBT for centrally located tumors is warranted.

Proton Beam Therapy for Inoperable Recurrence of Bronchial High-grade Mucoepidermoid Carcinoma

We report the case of a 17-year-old patient who received four courses of proton beam therapy for inoperable recurrent high-grade bronchial mucoepidermoid carcinoma of the chest wall and lymph nodes. The equivalent doses in conventional fractionation of 79.2-80.6 Gy were applied to the tumor from the first to third courses of proton beam therapy; the hemi-chest wall was also irradiated prophylactically in the third course. The irradiated tumor recurred marginally and liver metastasis developed, but tumor size within the irradiated field was suppressed. Proton beam therapy was also applied to the marginally recurrent tumor in the fourth course. The patient died of cancer about 5 years after the first course of proton beam therapy-about 9 years after the initial diagnosis and surgery. Repeated irradiation of the mediastinum and chest wall with photon radiotherapy is often limited by side-effects in the heart, esophagus and spinal cord. However, no severe late complications in critical organs were detected in this case. Only a Grade 2 skin reaction and lymphatic edema were observed. Therefore, high-dose proton beam therapy may be an option as a salvage therapy with less toxicity to normal tissues compared with photon radiotherapy and provide an alternative to repeated surgery.

Results of Proton Beam Therapy without Concurrent Chemotherapy for Patients with Unresectable Stage III Non-small Cell Lung Cancer

This study was performed retrospectively to evaluate the outcome of patients with stage III non-small cell lung cancer (NSCLC) after proton beam therapy (PBT) alone. The subjects were 57 patients with histologically confirmed NSCLC (stage IIIA/IIIB: 24/33) who received PBT without concurrent chemotherapy. The cohort included 32 cases of squamous cell carcinoma, 18 adenocarcinoma, and 7 non-small cell carcinoma. Lymph node metastases were N0 7, N1 5, N2 30, and N3 15. Planned total doses ranged from 50 to 84.5 GyE (median, 74 GyE). Planned treatment was completed in 51 patients (89%). At the time of analysis, 20 patients were alive, and the median follow-up periods were 16.2 months for all patients and 22.2 months for survivors. The median overall survival period was 21.3 months (95% confidence interval: 14.2-28.4 months), and the 1- and 2-year overall survival rates were 65.5% (52.9-78.0%) and 39.4% (25.3-53.5%), respectively. Disease progression occurred in 38 patients, and the 1- and 2-year progression-free survival rates were 36.2% (23.1-49.4%) and 24.9% (12.7-37.2%), respectively. Local recurrence was observed in 13 patients, and the 1- and 2-year local control rates were 79.1% (66.8-91.3%) and 64.1% (47.5-80.7%), respectively. Grade ≥ 3 lung toxicity was seen in six patients, esophageal toxicity occurred at grade ≤ 2, and there was no cardiac toxicity. The prognosis of patients with unresectable stage III NSCLC is poor without chemotherapy. Our data suggest that high-dose PBT is beneficial and tolerable for these patients.