Proton Beam Therapy for Intrahepatic Cholangiocarcinoma: A Multicenter Prospective Registry Study in Japan.

Introduction: Intrahepatic cholangiocarcinoma (ICC) can be treated with chemotherapy in unresectable cases, but outcomes are poor. Proton beam therapy (PBT) may provide an alternative treatment and has good dose concentration that may improve local control. Methods: Fifty-nine patients who received initial PBT for ICC from May 2016 to June 2018 at nine centers were included in the study. The treatment protocol was based on the policy of the Japanese Society for Radiation Oncology. Forty patients received 72.6-76 Gy (RBE) in 20-22 fr, 13 received 74.0-76.0 Gy (RBE) in 37-38 fr, and 6 received 60-70.2 Gy (RBE) in 20-30 fr. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results: The 59 patients (35 men, 24 women; median age: 71 years; range: 41-91 years) had PS of 0 (n = 47), 1 (n = 10), and 2 (n = 2). Nine patients had hepatitis and all 59 cases were considered inoperable. The Child-Pugh class was A (n = 46), B (n = 7), and unknown (n = 6); the median maximum tumor diameter was 5.0 cm (range 2.0-15.2 cm); and the clinical stage was I (n = 12), II (n = 19), III (n = 10), and IV (n = 18). At the last follow-up, 17 patients were alive (median follow-up: 36.7 months; range: 24.1-49.9 months) and 42 had died. The median OS was 21.7 months (95% CI: 14.8-34.4 months). At the last follow-up, 37 cases had recurrence, including 10 with local recurrence. The median PFS was 7.5 months (95% CI: 6.1-11.3 months). In multivariable analyses, Child-Pugh class was significantly associated with OS and PFS, and Child-Pugh class and hepatitis were significantly associated with local recurrence. Four patients (6.8%) had late adverse events of grade 3 or higher. Conclusion: PBT gives favorable treatment outcomes for unresectable ICC without distant metastasis and may be particularly effective in cases with large tumors.

Novel concept of "sequential particle radiotherapy" with atezolizumab plus bevacizumab for hepatocellular carcinoma with portal vein tumor thrombus.

Owing to the high objective response rate of atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC), the concept of sequential conversion to local treatment has recently become mainstream. The conversion concept is mainly applied to Barcelona Clinic for Liver Cancer (BCLC) stage B cases, and radiotherapy is rarely considered as a conversion local treatment. We herein report three patients who were treated with the novel concept of "sequential particle radiotherapy," consisting of Atez/Bev therapy followed by particle radiotherapy (PRT) for HCC with advanced portal vein tumor thrombus (Vp3/4 PVTT). All patients achieved partial response radiologically and were switched to PRT. All patients were recurrence free at 1 year after the introduction of Atez/Bev therapy without any additional treatment. This upcoming combination strategy includes the advocacy of sequential concepts for BCLC stage C cases and the introduction of PRT as a local treatment after Atez/Bev.

Proton Beam Therapy for Hepatocellular Carcinoma: Multicenter Prospective Registry Study in Japan.

PURPOSE: A prospective multicenter registry study was started May 2016 in Japan to evaluate the efficacy and safety of proton beam therapy (PBT) for hepatocellular carcinoma (HCC). METHODS AND MATERIALS: Patients who received PBT for HCC from May 2016 to June 2018 were registered in the database of the Particle Beam Therapy Committee and Subcommittee of the Japanese Society for Radiation Oncology. Overall survival (OS), progression-free survival (PFS), and local recurrence were evaluated. RESULTS: Of the 755 registered patients, 576 with initial PBT and no duplicate cancer were evaluated. At final follow-up, 322 patients were alive and 254 had died. The median follow-up period for survivors was 39 months (0-58 months). The median OS time of the 576 patients was 48.8 months (95% CI, 42.0-55.6 months) and the 1-, 2-, 3-, and 4-year OS rates were 83.8% (95% CI, 80.5%-86.6%), 68.5% (64.5%-72.2%), 58.2% (53.9%-62.2%), and 50.1% (44.9%-55.0%), respectively. Recurrence was observed in 332 patients, including local recurrence in 45 patients. The median PFS time was 14.7 months (95% CI, 12.4-17.0 months) and the 1-, 2-, 3-, and 4-year PFS rates were 55.2% (95% CI, 51.0%-59.2%), 37.5% (33.5%-41.5%), 30.2% (26.3%-34.2%), and 22.8% (18.5%-27.4%), respectively. The 1-, 2-, 3-, and 4-year OS rates were significantly higher for tumor size <5 versus 5 to 10 cm (P < .001) and <5 versus ≥10 cm (P < .001); Child-Pugh score A/B versus C (P < .001); and distance of the tumor from the gastrointestinal tract <1 versus 1 to 2 cm (P < .008) and <1 versus >2 cm (P < .001). At final follow-up, 27 patients (4.7%) had late adverse events of grade 3 or higher, with liver failure (n = 7), and dermatitis (n = 7) being most common. CONCLUSIONS: This multicenter prospective data registry indicated that PBT for HCC gives good therapeutic effects (3-year local control rate of 90%) with a low risk of severe late adverse events.

Innovative Combination Treatment to Expand the Indications of Particle Therapy: Spacer Placement Surgery Using Bio-Absorbable Polyglycolic Acid Spacer.

BACKGROUND: Particle therapy has favorable dose distribution and high curability. However, radiotherapy for malignant tumors adjacent to the gastrointestinal tract is contraindicated owing to its low tolerance. To overcome this, combination treatment with surgery to make a space between the tumor and adjacent gastrointestinal tract followed by particle therapy has been developed. Several materials have been used for the spacer and recently, we developed the absorbable polyglycolic acid (PGA) spacer, which has been used since 2019. This study is the first report of consecutive case series of spacer placement surgery using the PGA spacer. STUDY DESIGN: Fifty consecutive patients undergoing spacer placement surgery with the PGA spacer were evaluated. Postoperative laboratory data, morbidity related to the treatment, and spacer volume after treatment were evaluated. RESULTS: There were no treatment-related deaths, and all but 2 patients completed combination treatment. The median ratios of postoperative PGA spacer volume to the pretreatment volume were 96.9%, 87.7%, and 74.6% at weeks 2, 4, and 8, respectively. The spacer volume was maintained at 80% at 7 weeks and was predicted to be 50% at 15 weeks and 20% in 24 weeks. CONCLUSIONS: Spacer placement surgery using the PGA spacer was feasible and tolerable. The PGA spacers maintained sufficient thickness during the duration of subsequent particle therapy. Combination treatment using the PGA spacer is innovative and has the potential to become a new standard curative local treatment.

Clinical impact of spacer placement surgery with expanded polytetrafluoroethylene sheet for particle therapy.

BACKGROUND: Spacer placement surgery is useful in particle therapy (PT) for patients with abdominopelvic malignant tumors located adjacent to the gastrointestinal tract. This study aimed to assess the safety, efficacy, and long-term outcomes of spacer placement surgery using an expanded polytetrafluoroethylene (ePTFE) spacer. METHODS: This study included 131 patients who underwent ePTFE spacer placement surgery and subsequent PT between September 2006 and June 2019. The overall survival (OS) and local control (LC) rates were calculated using Kaplan-Meier method. Spacer-related complications were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). RESULTS: The median follow-up period after spacer placement surgery was 36.8 months. The 3-year estimated OS and LC rates were 60.5% and 76.5%, respectively. A total of 130 patients (99.2%) were able to complete PT. Spacer-related complications of ≥ grade 3 were observed in four patients (3.1%) in the acute phase and 13 patients (9.9%) in the late phase. Ten patients (7.6%) required removal of the ePTFE spacer. CONCLUSIONS: Spacer placement surgery using an ePTFE spacer for abdominopelvic malignant tumors is technically feasible and acceptable for subsequent PT. However, severe spacer-related late complications were observed in some patients. Since long-term placement of a non-absorbable ePTFE spacer is associated with risks for morbidity and infection, careful long-term follow-up and prompt therapeutic intervention are essential when complications associated with the ePTFE spacer occur. TRIAL REGISTRATION: retrospectively registered.

Proton radiotherapy as a treatment strategy to increase survival in locally advanced pancreatic cancer in the body and tail: a retrospective study.

BACKGROUND: Long-term outcomes and prognostic factors of proton radiotherapy for locally advanced pancreatic cancer (LAPC) in the body and tail are still unknown. The aim of this study was to determine the prognostic factors after proton radiotherapy in a large group of patients with LAPC in the body and tail. METHODS: The medical records of 200 patients with LAPC in the body and tail who underwent proton radiotherapy between February 2009 and January 2021 at the Hyogo Ion Beam Medical Center were retrospectively reviewed to identify prognostic factors that contribute to long-term survival. RESULTS: The overall survival rate at 1- and 2-year after PT was 69.6% and 35.4% with a median overall survival of 18.4 months. The 1- and 2-year local progression-free, and progression-free survival rates were 84.3% and 68.0%, and 44.3% and 19.4%, respectively. In multivariate analysis, superior mesenteric artery (SMA) invasion (SMA only invasion vs. celiac artery only invasion; P = 0.049: SMA and celiac artery invasion vs. celiac artery only invasion; P = 0.017), carbohydrate antigen 19-9 (CA 19-9) level ≥ 231.9 U/mL (P = 0.001), anterior peripancreatic invasion (P = 0.006), and incomplete scheduled concurrent chemotherapy (P = 0.009) were statistically significant prognostic factors for overall survival. There was no significant difference in local progression-free survival; however, distant metastasis-free survival was statistically worse in patients with prognostic factors than in those without. CONCLUSIONS: Proton radiotherapy for LAPC in the body and tail may be a valuable multidisciplinary treatment option. Patients with SMA invasion, higher pre-proton radiotherapy serum CA 19-9 level, anterior peripancreatic invasion, or incomplete scheduled concurrent chemotherapy had worse overall survival because of worse distant metastasis-free survival, suggesting that distant metastases have a significant impact on overall survival in such patients. TRIAL REGISTRATION: Retrospectively registered.

Carbon-ion radiotherapy for oligometastatic liver disease: A national multicentric study by the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS).

Reports on the therapeutic efficacy and safety of carbon-ion radiotherapy (C-ion RT) for oligometastatic liver disease are limited, with insufficient evidence. This study aimed to evaluate the clinical outcomes of C-ion RT for oligometastatic liver disease at all Japanese facilities using the nationwide cohort data. We reviewed the medical records to obtain the nationwide cohort registry data on C-ion RT between May 2016 and June 2020. Patients (1) with oligometastatic liver disease as confirmed by histological or diagnostic imaging, (2) with ≤3 synchronous liver metastases at the time of treatment, (3) without active extrahepatic disease, and (4) who received C-ion RT for all metastatic regions with curative intent were included in this study. C-ion RT was performed with 58.0-76.0 Gy (relative biological effectiveness [RBE]) in 1-20 fractions. In total, 102 patients (121 tumors) were enrolled in this study. The median follow-up duration for all patients was 19.0 months. The median tumor size was 27 mm. The 1-year/2-year overall survival, local control, and progression-free survival rates were 85.1%/72.8%, 90.5%/78.0%, and 48.3%/27.1%, respectively. No patient developed grade 3 or higher acute or late toxicity. C-ion RT is a safe and effective treatment for oligometastatic liver disease and may be beneficial as a local treatment option in multidisciplinary treatment.

Proton beam therapy for extrahepatic biliary tract cancer: Analysis with prospective multi-institutional patients' registration database, Proton-Net.

Background and purpose: To examine the role of proton beam therapy (PBT) in the treatment of extrahepatic biliary tract cancer (EBC). Methods and materials: We analyzed the data accumulated in the Proton-Net database, which prospectively registered all individual patient data treated with PBT in all Japanese proton institutions from May 2016 to June 2019. The primary endpoint was overall survival (OS), and the secondary endpoints were local control (LC), progression-free survival (PFS), and toxicity. Results: Ninety-three patients with unresectable and/or recurrent EBC were treated with PBT using a median prescribed dose of 67.5 Gy (RBE) (range, 50-72.6 Gy) in 25 (22-30 fractions). With a median follow-up of 16.3 months, the median survival time was 20.1 months and the 2-year OS was 37.8%. Two-year PFS and LC rates were 20.6% and 66.5%, respectively. Poor liver function (Child-Pugh B, C), a narrower distance between the tumor and digestive tract (2 cm >), and a larger tumor diameter (2 cm <) were identified as poor prognostic factors for OS. PBT-related grade 3 ≤ acute and late adverse events occurred in 5.4% and 4.3% of patients, respectively, including one gastrointestinal late toxicity (duodenal ulcer). Conclusions: This is the largest prospectively accumulated series of PBT for EBC, and PBT showed favorable outcomes with acceptable toxicity profiles.

Particle beam therapy versus photon radiotherapy for extrahepatic biliary cancer-systemic review and meta-analysis.

Particle beam therapy (PT) is a potentially promising approach to the treatment of extrahepatic biliary cancer (EBC) because of its unique dose distribution using the Bragg peak. However, the superiority of PT to photon radiotherapy (XT) remains unclear. Therefore, we conducted a systematic review and meta-analysis to compare PT and XT for the treatment of EBC. The primary endpoint was overall survival (OS), which was pooled using a random-effects model. Nine articles comprising a total of 1558 patients (seven XT articles, n = 1488 patients; two PT articles, n = 70 patients) were screened. In addition, we compared the outcomes of XT and PT with the outcomes available from a prospective data registry (proton-net). The 1-year OS probability rates were 55, 65 and 72% for the XT group, PT group and PT registry, respectively. The 2-year OS probability rates were 26, 38 and 38% for the XT group, PT group and PT registry, respectively. The 3-year OS probability rates were 12, 35 and 18% for the XT group, PT group and PT registry, respectively. Although the difference between the 1-year OS rates of the XT group and PT registry was statistically significant, no other significant superiority was observed among these groups. In conclusion, the efficacy of PT was not superior to that of XT during this meta-analysis.

Hepatic Resection vs Particle Therapy as an Initial Treatment for Single Hepatocellular Carcinoma: Bi-institutional Propensity Score-Matched Analysis.

BACKGROUND: Curative treatment for hepatocellular carcinoma (HCC) is limited to hepatic resection (HR), radiofrequency ablation, and liver transplantation, but the value of particle therapy (PT) as an initial treatment remains unclear. This study aimed to compare the outcomes of HR and PT for single HCC. STUDY DESIGN: A total of 554 patients with single HCC without vascular invasion were enrolled from January 2000 to December 2015. Patients underwent either HR (n = 279) or PT (n = 275) as initial treatments. A one-to-one propensity score-matching analysis was performed to evaluate the overall survival (OS) and progression-free survival after dividing patients according to liver function as assessed by the modified albumin-bilirubin grade. RESULTS: The median OS (130 vs 85 months, p = 0.001) and progression-free survival (47 vs 30 months HR, p = 0.004) of HR were also significantly better than that of PT in the propensity score-matching cohort with modified albumin-bilirubin grade 1/2a (n = 145 per group). Meanwhile, in a propensity score-matching cohort with modified albumin-bilirubin grade 2b/3 (n = 53 per group), there were no significant differences in median OS and progression-free survival between HR and PT. CONCLUSIONS: HR may be preferable as an initial treatment for patients with single HCC without vascular invasion, especially those with preserved liver function. PT can be an acceptable alternative to HR for patients without surgical indication and/or impaired liver function.

Space-Making Particle Therapy for Unresectable Hilar Cholangiocarcinoma.

INTRODUCTION: Although the primary treatment option for hilar cholangiocarcinoma (HC) has been surgical resection, most patients present with unresectable advanced tumors at the time of diagnosis. Particle therapy (PT) holds great potential for HC, even though the anatomical proximity to the gastrointestinal tract prevents delivering a radical dose to the tumor. Space-making PT (SMPT), consisting of spacer placement surgery and subsequent PT, has been developed to minimize complications and maximize the therapeutic benefit of dose escalation for HC. This study aimed to conduct a dosimetric evaluation and examine the effectiveness of SMPT for the treatment of HC. METHODS: Between 2007 and 2018, 12 patients with unresectable HC treated with SMPT were enrolled. The treatment outcomes and effectiveness of spacer placement surgery were evaluated through analyses of pre- and post-surgical parameters of dose-volume histograms. RESULTS: All patients completed the planned SMPT protocol. The median survival time was 29.6 months, and the 1- and 3-year overall survival rates were 82.5% and 45.8%, respectively. The mean V95% value (volume irradiated with 95% of the planned treatment dose) of the gross tumor volume and clinical target volume after spacer placement surgery improved to 98.5% and 96.6% from preoperative values of 85.6% and 78.1%, respectively (p = 0.0196 and p = 0.0053, respectively). Grade 3 or higher adverse events after SMPT were seen in 6 patients. DISCUSSION/CONCLUSION: SMPT led to improvements in dosimetric parameters and showed good feasibility and excellent outcomes. SMPT can be a promising novel alternative for unresectable HC.

Factors associated with long-term survival in gemcitabine-concurrent proton radiotherapy for non-metastatic locally advanced pancreatic cancer: a single-center retrospective study.

BACKGROUND: Factors associated with long-term survival in gemcitabine-concurrent proton radiotherapy (GPT) for non-metastatic, locally advanced pancreatic cancer (LAPC) remain unclear. This study aimed to determine the factors associated with long-term survival in GPT for non-metastatic LAPC. METHODS: The medical records of 123 patients with LAPC treated with GPT between February 2009 and December 2019 at Hyogo Ion Beam Medical Center were retrospectively reviewed to assess the factors associated with long-term survival outcomes. RESULTS: The median overall survival of the total cohort treated with GPT was 18.7 months. The 1- and 2-year overall, local progression-free, and progression-free survival rates were 70.4% and 35.7%, 78.2% and 59.0%, and 38.6% and 20.8%, respectively. Multivariate analysis revealed that LAPCs at the pancreatic body-tail and those without anterior peripancreatic invasion were independently associated with longer overall survival (P = 0.040 and P = 0.015, respectively). The median overall survival of patients with LAPC at the pancreatic body-tail and those with LAPC without anterior peripancreatic invasion were 24.1 and 28.1 months, respectively. LAPCs at the pancreatic body-tail had a higher volume ratio irradiated over 60 Gy equivalents at gross tumor volume than those at the pancreatic head (P < 0.001). LAPCs with anterior peripancreatic invasion had more peritoneal recurrence within 6 months after GTP than those without anterior peripancreatic invasion (P = 0.039). CONCLUSIONS: GPT is a promising treatment option for patients with LAPC at the pancreatic body-tail and those with LAPC without anterior peripancreatic invasion.

Predicted probabilities of brain injury after carbon ion radiotherapy for head and neck and skull base tumors in long-term survivors.

BACKGROUND AND PURPOSE: We aimed to determine the risk factors for radiation-induced brain injury (RIBI1) after carbon ion radiotherapy (CIRT) to predict their probabilities in long-term survivors. MATERIALS AND METHODS: We evaluated 104 patients with head, neck, and skull base tumors who underwent CIRT in a regimen of 32 fractions and were followed up for at least 24 months. RIBI was assessed using the Common Terminology Criteria for Adverse Events. RESULTS: The median follow-up period was 45.5 months; 19 (18.3 %) patients developed grade ≥2 RIBI. The maximal absolute dose covering 5 mL of the brain (D5ml) was the only significant risk factor for grade ≥2 RIBI in the multivariate logistic regression analysis (p = 0.001). The tolerance doses of D5ml for the 5% and 50% probabilities of developing grade ≥2 RIBI were estimated to be 55.4 Gy (relative biological effectiveness [RBE]) and 68.4 Gy (RBE) by a logistic model, respectively. CONCLUSION: D5ml was most significantly associated with grade ≥2 RIBI and may enable the prediction of its probability.

Salvage hepatectomy for local recurrence after particle therapy using proton and carbon ion beams for liver cancer.

AIM: With the increased use of particle therapy for liver cancer, local recurrence after particle therapy increased. Salvage hepatectomy is an acceptable treatment option for local recurrence following particle therapy; however, its safety and effectiveness remain unclear. Therefore, this multi-center study aimed to verify the feasibility and efficacy of salvage hepatectomy and assess clinical issues associated with its application. METHODS: We retrospectively assessed the perioperative outcomes, prognosis, and pathological characteristics of 15 patients who underwent salvage hepatectomy for local recurrence after particle therapy between 2006 and 2019. RESULTS: Hepatocellular carcinoma and metastatic liver tumors were noted in eight and seven patients, respectively. The mean total dose and number of fractions were 66.5 Gy and 12, respectively, and the mean interval between particle therapy and surgery was 30.1 months. Major hepatectomy was performed in seven cases. Moreover, the mortality rate was 0%, and surgical complications of Clavien-Dindo grade IIIa or higher were observed in four cases (27%)-two bile leakages, one pleural effusion, and one refractory skin fistula. The median overall survival time and 5-year overall survival rate after salvage hepatectomy were 29.9 months and 43.1%, respectively. Histological examination of the irradiated liver tissue surrounding the tumor showed sinusoidal dilatation, loss of hepatocyte, and fibrosis in most cases. CONCLUSION: Salvage hepatectomy after particle therapy is a feasible therapy; however, the risk of refractory complications associated with particle therapy is relatively high. Therefore, the first-line treatment for resectable liver cancer should be carefully determined considering second-line treatment after local recurrence.

Surgical spacer placement for proton radiotherapy in locally advanced pancreatic body and tail cancers: initial clinical results.

BACKGROUND: Particle radiotherapy has increasingly gained acceptance for locally advanced pancreatic cancers owing to superior tumor conformity and dosimetry compared to conventional photon radiotherapy. However, the close proximity of the pancreas to the stomach and duodenum leads to radiation-induced gastrointestinal toxicities, which hinder the delivery of curative doses to the tumor. To overcome this problem, a surgical spacer was placed between the tumor and gastrointestinal tract, and subsequent proton radiotherapy was performed in this study. METHODS: Data from 9 patients who underwent surgical spacer placement and subsequent proton radiotherapy were analyzed. The safety and feasibility of the spacer placement surgery were evaluated; the impact of the spacer on dosimetry was also assessed using dose volume histogram (DVH) analyses, before and after surgical spacer placement. RESULTS: Surgical spacer placement and subsequent proton radiotherapy were successfully completed in all cases. Surgical spacer placement significantly improved the dose intensity covering 95%, mean, and minimum doses for the gross tumor volume, and the clinical and planning target volume based on the DVH, while respecting the dose constraints of the gastrointestinal tract. Based on the Common Terminology Criteria for Adverse Events, two patients (22.2%) developed gastrointestinal ulcer (Grade 2) at 1 and 35 months, and one patient (11.1%) developed gastric perforation (Grade 4) at 4 months after proton radiotherapy. CONCLUSIONS: Surgical spacer placement in the locally advanced pancreatic body and tail cancers is relatively safe and technically feasible. Comparing radiation plans, surgical spacer placement seems to improve the dose distribution in the locally advanced pancreatic body and tail cancers, which are close to the gastrointestinal tract.

Targeted 1,3-dipolar cycloaddition with acrolein for cancer prodrug activation.

Cytotoxic anticancer drugs used in chemotherapy are often antiproliferative agents that preferentially kill rapidly growing cancer cells. Their mechanism relies mainly on the enhanced proliferation rate of cancer cells and is not genuinely selective for cancer cells. Therefore, these drugs can also significantly affect healthy cells. Prodrug therapy provides an alternative approach using a less cytotoxic form of anticancer drug. It involves the synthesis of inactive drug derivatives which are converted to an active form inside the body and, preferably, only at the site of cancerous tissues, thereby reducing adverse drug reaction (ADR) events. Herein, we demonstrate a prodrug activation strategy by utilizing the reaction between aryl azide and endogenous acrolein. Since acrolein is generally overproduced by most cancer cells, we anticipate our strategy as a starting point for further applications in mouse models with various cancers. Furthermore, cancer drugs that have had therapeutic index challenges might be reconsidered for application by utilizing our strategy.

Proton Therapy for Localized Prostate Cancer: Long-Term Results From a Single-Center Experience.

PURPOSE: Although proton therapy is controversial, it has been used to treat localized prostate cancer over the past 2 decades. The purpose of this study is to examine the long-term efficacy and toxicity of proton therapy for localized prostate cancer. METHODS AND MATERIALS: This was a retrospective observational study of 2021 patients from 2003 to 2014 at a single institution. Patients were classified using the risk groups defined by the National Comprehensive Cancer Network guidelines, version 4.2019. Ninety-eight percent of the patients received 74 Gy (relative biological effectiveness) in 37 fractions. Fifty-one and 6% of the patients received neoadjuvant and adjuvant androgen deprivation therapy, respectively. The outcomes were the time of freedom from biochemical relapse and the time to late toxicity by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The outcomes were estimated using the Kaplan-Meier method and were analyzed using multivariable Cox proportional hazards models. RESULTS: The median follow-up period was 84 months (interquartile range, 60-110). The 5- and 10-year freedom from biochemical relapse rates were 100% and 100%, 99% and 88%, 93% and 86%, 90% and 79%, 88% and 68%, and 76% and 63% for the very low, low, favorable intermediate, unfavorable intermediate, high, and very high-risk groups, respectively. Patients with higher risk experienced biochemical relapse after shorter periods. The 5-year rates of grade 2 or higher late genitourinary and gastrointestinal toxicity were 2.2% and 4.0%, respectively. The results of multivariable analyses indicate that younger patients more often experienced biochemical relapse. CONCLUSIONS: This study demonstrates the favorable biochemical controls of proton therapy even in advanced localized prostate cancer patients with a low incidence of late toxicities, supporting the feasibility of conducting prospective clinical trials. The risk groups defined by the National Comprehensive Cancer Network guidelines, version 4.2019, are useful to classify patients with localized prostate cancer. Our findings might suggest the necessity to develop a treatment strategy that accounts for the patient's age.

Disease-associated acrolein: A possible diagnostic and therapeutic substrate for in vivo synthetic chemistry.

Acrolein, a highly reactive α,ß-unsaturated aldehyde, is a compound to which humans are exposed in many different situations and often causes various human diseases. This paper summarizes the reports over the past twenty-five years regarding disease-associated acrolein detected in clinical patients and the role acrolein plays in various diseases. In several diseases, it was found that the increased acrolein acts as a pathogenetic factor. Thus, we propose the utility of over-produced acrolein as a substrate for a promising therapeutic or diagnostic method applicable to a wide range of diseases based on an in vivo synthetic chemistry strategy.

Phase I dose-escalation trial of S-1 combined with carbon-ion radiotherapy for sinonasal squamous cell carcinoma.

This study aimed to determine the maximum tolerance dose (MTD) and to estimate the recommended dose (RD) of concomitant S-1 with carbon-ion radiotherapy (RT) for sinonasal squamous cell carcinoma (SCC). Nine patients with sinonasal SCC received carbon-ion RT with escalating doses of S-1 according to phase I methods. Doses of 40, 60 and 80 mg/m2/day were administered twice daily in dose levels 1, 2 and 3, respectively, from days 1 to 14 and 22 to 35. Carbon-ion RT was administered at a dose of 70.4 Gy (relative biological effectiveness) in 32 fractions, 5 days a week. Two patients developed grade 3 acute dermatitis. However, none developed dose-limiting toxicities. Therefore, the MTD of S-1 could not be determined; the RD was estimated to be 80 mg/m2/day with concurrent carbon-ion RT. Partial response and stable disease were noted in 5 and 4 patients, respectively. The 2-year overall survival and local control rates were 56 and 74%, respectively. Overall, 2 patients developed ≥grade 3 late toxicities; among them, 1 patient developed grade 3 cataract and the other developed grade 4 cataract, optic nerve disorder and hearing impairment. To the best of our knowledge, this phase I study is the first clinical trial to evaluate concomitant S-1 with carbon-ion RT for sinonasal SCC. The MTD of S-1 could not be determined, and the RD was estimated to be 80 mg/m2/day. This study demonstrated a manageable safety profile for this combination. The observed outcomes may facilitate further evaluation of this novel therapy.

Space-making particle therapy for sarcomas derived from the abdominopelvic region.

BACKGROUND: The primary definitive treatment for abdominopelvic sarcomas (APSs) is resection, although incomplete resection has a negative prognostic impact. Although the effectiveness of particle therapy (PT) as a treatment for APS has already been demonstrated, its application for tumors adjacent to the gastrointestinal tract is frequently restricted, due to extremely low tolerance. Space-making PT, consisting of surgical spacer placement and subsequent PT, has been developed to overcome this limitation. MATERIALS AND METHODS: Between June 2006 and June 2018, a total of 75 patients with 12 types of APS underwent space-making PT. RESULTS: The 3-year local control rate of all patients was 90.3%. Fourteen surgery-related complications were observed in 12 patients (16%), and complications of Grade 3b or higher were observed in 3 patients. Ninety-five PT-related complications were seen in 66 patients (88.0%), and 13 patients (17.3%) had complications of Grade 3 or higher. The median V95% (volume irradiated with 95% of the treatment planning dose) of the gross tumor volume and clinical target volume were 99.9% and 99.5%, respectively. The median D95% (dose intensity covering 95% of the target volume) of the gross tumor volume/planned dose and clinical target volume/planned dose were 99.4%, and 99.1%, respectively. CONCLUSION: The feasibility and effectiveness of space-making PT have been demonstrated via dosimetric evaluation, and our results indicate that this new strategy may potentially provide an effective and innovative treatment option for advanced APS.