Daniel K. Ebner

The Immunoregulatory Potential of Particle Radiation in Cancer Therapy

Cancer treatment, today, consists of surgery, chemotherapy, radiation, and most recently immunotherapy. Combination immunotherapy-radiotherapy (CIR) has experienced a surge in public attention due to numerous clinical publications outlining the reduction or elimination of metastatic disease, following treatment with specifically ipilimumab and radiotherapy. The mechanism behind CIR, however, remains unclear, though it is hypothesized that radiation transforms the tumor into an in situ vaccine which immunotherapy modulates into a larger immune response. To date, the majority of attention has focused on rotating out immunotherapeutics with conventional radiation; however, the unique biological and physical benefits of particle irradiation may prove superior in generation of systemic effect. Here, we review recent advances in CIR, with a particular focus on the usage of charged particles to induce or enhance response to cancerous disease.

Predictors for long-term survival free from whole brain radiation therapy in patients treated with radiosurgery for limited brain metastases

Purpose To identify predictors for prolonged survival free from salvage whole brain radiation therapy (WBRT) in patients with brain metastases treated with stereotactic radiosurgery (SRS) as their initial radiotherapy approach. Materials and methods Patients with brain metastases treated with SRS from 2001 to 2013 at our institution were identified. SRS without WBRT was typically offered to patients with 1–4 brain metastases, Karnofsky performance status ≥70, and life expectancy ≥3 months. Three hundred and eight patients met inclusion criteria for analysis. Medical records were reviewed for patient, disease, and treatment information. Two comparison groups were identified: those with ≥1-year WBRT-free survival (N = 104), and those who died or required salvage WBRT within 3 months of SRS (N = 56). Differences between these groups were assessed by univariate and multivariate analyses. Results Median survival for all patients was 11 months. Among patients with ≥1-year WBRT-free survival, median survival was 33 months (12–107 months) with only 21% requiring salvage WBRT. Factors significantly associated with prolonged WBRT-free survival on univariate analysis (p < 0.05) included younger age, asymptomatic presentation, RTOG RPA class I, fewer brain metastases, surgical resection, breast primary, new or controlled primary, absence of extracranial metastatic disease, and oligometastatic disease burden (≤5 metastatic lesions). After controlling for covariates, asymptomatic presentation, breast primary, single brain metastasis, absence of extracranial metastases, and oligometastatic disease burden remained independent predictors for favorable WBRT-free survival. Conclusion A subset of patients with brain metastases can achieve long-term survival after upfront SRS without the need for salvage WBRT. Predictors identified in this study can help select patients that might benefit most from a treatment strategy of SRS alone.

Stereotactic radiosurgery for large brain metastases

We evaluated patient outcomes following stereotactic radiosurgery (SRS)-treatment of large brain metastasis (⩾3 cm) at our institution. SRS is an established treatment for limited brain metastases. However, large tumors pose a challenge for this approach. For this study, 343 patients with 754 total brain metastases were treated with SRS, of which 93 had large tumors. The tumor size was 3-3.5, 3.5-4, and ⩾4 cm in 29%, 32%, and 39% of these patients. Surgical resection was performed prior to SRS in 68% of patients, and 53% achieved a gross total resection. The local control of large metastases was inferior compared to smaller tumors, with 1 year local control of 68 versus 86%, respectively (p<0.001). Among the patients with large metastases, no correlation between local control and surgical resection (p=0.747), or extent of surgery (gross total versus subtotal resection; p=0.120), was identified. Histology (p=0.939), tumor size (3-4 versus >4 cm; p=0.551), and SRS dose (⩽16 versus >16 Gy; p=0.539) also showed no correlation with local failure. The overall survival at 1, 2, and 5 years was 46%, 29% and 5%, respectively. Prolonged survival was seen in patients with age <65 years (p=0.009), primary treatment compared with salvage (p=0.077), and controlled primary tumors (p=0.022). Radiation necrosis developed in 10 patients (11.8%). For patients with large brain metastases, SRS is well tolerated and can achieve local central nervous system disease control in the majority of patients, and extended survival in some, though the local control rate is suboptimal. Further strategies to improve the outcomes in this subgroup of patients are needed.

Progressive hypofractionated carbon-ion radiotherapy for hepatocellular carcinoma: Combined analyses of 2 prospective trials.

The objective of this study was to evaluate the safety and efficacy of carbon‐ion radiotherapy (CIRT) in patients with hepatocellular carcinoma (HCC) with stepwise dose escalation and hypofractionation in 2 combined prospective trials.

Lifestyle-related diseases following the evacuation after the Fukushima Daiichi nuclear power plant accident: a retrospective study of Kawauchi Village with long-term follow-up

Objectives Kawauchi Village lies 20 km west of the Fukushima Daiichi nuclear power plant. On 16 March 2011, evacuation was ordered due to the threat of radiological exposure, and was lifted in April 2012. In this study, we aimed to evaluate the predisaster and postdisaster health status of the Kawauchi Villagers, measured by routine yearly physical examinations. Methods We analysed the annual health examination data of residents of Kawauchi Village from 2008 to 2013, as available from the Japanese National Health Insurance system. Data from 2011 were not available due to the disaster. Since the health data included the same participants repeatedly from year to year, the sample was non-independent and generalised estimated equation modelling was used. A predisaster time period (2008–2010) was categorised for comparison with postdisaster 2012 and 2013. The outcome examined was the prevalence of metabolic disease, and was adjusted for confounding factors. Results Data for 20.6%–25.9% of the total residents were available in this period. In 2013, the prevalence of metabolic syndrome (from 17.0% to 25.2%, p<0.001), diabetes (from 11.3% to 17.0%, p<0.001), dyslipidaemia (from 43.2% to 56.7%, p<0.0001), hyperuricaemia (from 5.2% to 8.4%, p=0.006) and chronic kidney disease (from 16.1% to 26.7%, p<0.001) was found to be elevated significantly compared to predisaster years, while that of obesity or hypertension did not change. Conclusions The present follow-up study for Kawauchi Village revealed an increase in lifestyle-related disease following the March 2011 disaster and subsequent evacuation, and this trend still continues 2 years later.

Respiration-gated fast-rescanning carbon-ion radiotherapy

Phase-controlled rescanning of the carbon-ion beam offers fast and precise dose application with decreased irradiation of normal tissue. However, organ movement with respiration remains a unique challenge. Technological development has enabled the simultaneous application of beam-energy-modulated markerless phase-controlled rescanning with respiration gating, allowing scanning treatment of respiration-mobile tumors with carbon. A total of 10 patients with tumors in the liver or lung were treated in a feasibility study at our facility using this combination. At a median of 10.5 months, follow-up examination including computed tomography/magnetic resonance imaging revealed no grade 2+ acute adverse effects with this new therapy. Two patients with complex disease experienced local recurrence, which may be improved with increased dose delivery. One patient died of unrelated causes. All other patients are alive with good control at the time of writing. Though long-term observation is pending, these are promising initial results for use of the carbon-beam phase-controlled rescanning method in respiration-mobile disease.

Prognostic factors of adenoid cystic carcinoma of the head and neck in carbon-ion radiotherapy: The impact of histological subtypes

PURPOSE The aim of this study was to evaluate the effect of histological subtypes of head and neck adenoid cystic carcinoma (ACC) on the results of carbon-ion radiotherapy (CIRT). MATERIAL AND METHODS Of the 113 patients with ACC who were treated with CIRT between December 2006 and July 2013, 100 patients with identified histological subtypes were enrolled in this study. CIRT at a total dose of 57.6 or 64.0Gy (RBE) was administered in 16 fractions. Histological grading was defined as the presence or absence of a solid growth pattern. RESULTS Median follow-up was 60 months. 5-Year local control (LC), overall survival (OS) and distant metastasis free survival (DMFS) of all patients were 68.6%, 74.8% and 65.7%, respectively. On multivariate analysis, the prescribed dose (p=0.001) and gross tumor volume (p=0.002) were significant independent risk factors for LC. No significant difference for local control of solid/non-solid growth patterns was found (p=0.093). Solid growth pattern was an independent risk factor for both OS (p=0.033) and DMFS (p=0.024). CONCLUSIONS CIRT appears able to locally control solid growth pattern ACC in the head and neck. Improved intervention is needed to extend DMFS and OS.

Cancer‐specific mortality of high‐risk prostate cancer after carbon‐ion radiotherapy plus long‐term androgen deprivation therapy

The treatment outcomes of patients with high‐risk localized prostate cancer (PC) after carbon‐ion radiotherapy (CIRT) combined with long‐term androgen deprivation therapy (LTADT) were analyzed, and compared with those of other treatment modalities, focusing on PC‐specific mortality (PCSM). A total of 1247 patients were enrolled in three phase II clinical trials of fixed‐dose CIRT between 2000 and 2013. Excluding patients with T4 disease, 608 patients with high‐risk or very‐high‐risk PC, according to the National Comprehensive Cancer Network classification system, who received CIRT with LTADT were evaluated. The median follow‐up time was 88.4 months, and the 5‐/10‐year PCSM rates were 1.5%/4.3%, respectively. T3b disease, Gleason score of 9–10 and percentage of positive biopsy cores >75% were associated with significantly higher PCSM on univariate and multivariate analyses. The 10‐year PCSM rates of patients having all three (n = 16), two (n = 74) or one of these risk factors (n = 217) were 27.1, 11.6 and 5.7%, respectively. Of the 301 patients with none of these factors, only 1 PCSM occurred over the 10‐year follow‐up (10‐year PCSM rate, 0.3%), and significant differences were observed among the four stratified groups (P <0.001). CIRT combined with LTADT yielded relatively favorable treatment outcomes in patients with high‐risk PC and very favorable results in patients without any of the three abovementioned factors for PCSM. Because a significant difference in PCSM among the high‐risk PC patient groups was observed, new categorization and treatment intensity adjustment may be required for high‐risk PC patients treated with CIRT.

Carbon-ion radiotherapy for isolated para-aortic lymph node recurrence from colorectal cancer

The safety and effectiveness of carbon‐ion radiotherapy (CIRT) for isolated para‐aortic lymph node (PALN) metastasis was evaluated retrospectively.

Particle Radiation Therapy for Gastrointestinal Cancers

Particle irradiation of cancerous disease has gained great traction in recent years. The ability for particle therapy centers to deliver radiation with a highly conformal dose distribution while maintaining minimal exit or excess dose delivered to normal tissue, coupled with various biological advantages particularly found with heavy-ion beams, enables treatment of diseases inapproachable with conventional radiotherapy. Here, we present a review of the current status of particle therapy with regard to cancers of the gastrointestinal tract, including esophagus, liver, pancreas, and recurrent rectal cancer.