Comparing interplay effects in scanned proton therapy of lung cancer: Free breathing with various layer and volume rescanning versus respiratory gating with different gate widths.

PURPOSE: We investigated interplay effects and treatment time (TT) in scanned proton therapy for lung cancer patients. We compared free-breathing (FB) approaches with multiple rescanning strategies and respiratory-gating (RG) methods with various gating widths to identify the superior irradiation technique. METHODS: Plans were created with 4/1, 2/2, and 1/4 layered/volume rescans of FB (L4V1, L2V2, and L1V4), and 50%, 30%, and 10% gating widths of the total respiratory curves (G50, G30, and G10) of the RG plans with L4V1. We calculated 4-dimensional dynamic doses assuming a constant sinusoidal curve for six irradiation methods. The reconstructed doses per fraction were compared with planned doses in terms of dose differences in 99% clinical-target-volume (CTV) (ΔD99%), near-maximum dose differences (ΔD2%) at organs-at-risk (OARs), and TT. RESULTS: The mean/minimum CTV ΔD99% values for FB were -1.0%/-4.9%, -0.8%/-4.3%, and -0.1%/-1.0% for L4V1, L2V2, and L1V4, respectively. Those for RG were -0.3%/-1.7%, -0.1%/-1.0%, and 0.0%/-0.5% for G50, G30, and G10, respectively. The CTV ΔD99% of the RGs with less than 50% gate width and the FBs of L1V4 were within the desired tolerance (±3.0%), and the OARs ΔD2% for RG were lower than those for FB. The mean TTs were 90, 326, 824, 158, 203, and 422 s for L4V1, L2V2, L1V4, G50, G30, and G10, respectively. CONCLUSIONS: FB (L4V1) is the most efficient treatment, but not necessarily the optimal choice due to interplay effects. To satisfy both TT extensions and interplay, RG with a gate width as large as possible within safety limits is desirable.

Dose-volume comparisons of proton therapy for pencil beam scanning with and without multi-leaf collimator and passive scattering in patients with lung cancer.

This study evaluated the dose distributions of proton pencil beam scanning (PBS) with/without a multileaf collimator (MLC) compared to passive scattering (PS) for stage I/II lung cancers. Collimated/uncollimated (PBS+/PBS-) and PS plans were created for 20 patients. Internal-clinical-target-volumes (ICTVs) and planning-target-volumes (PTVs) with a 5 mm margin were defined on the gated CTs. Organs-at-risk (OARs) are defined as the normal lungs, spinal cord, esophagus, and heart. The prescribed dose was 66 Gy relative-biological-effectiveness (RBE) in 10 fractions at the isocenter and 50% volume of the ICTVs for the PS and PBS, respectively. We compared the target and OAR dose statistics from the dose volume histograms. The PBS+ group had a significantly better mean PTV conformity index than the PBS- and PS groups. The mean dose sparing for PBS+ was better than those for PBS- and PS. Only the normal lung doses of PBS- were worse than those of PS. The overall performance of the OAR sparing was in the order of PBS+, PBS-, and PS. The PBS+ plan showed significantly better target homogeneity and OAR sparing than the PBS- and PS plans. PBS requires collimating systems to treat lung cancers with the most OAR sparing while maintaining the target coverage.

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.

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.

Formation of spread-out Bragg peak for helium-ion beam using microdosimetric kinetic model.

PURPOSE: To evaluate the applicability of microdosimetric kinetic model (MKM) to helium-ion therapy by forming a spread-out Bragg peak (SOBP) of a helium-ion beam using the MKM developed for carbon-ion radiotherapy and confirming the predictions in biological experiments. METHODS: Using a ridge filter, a 90-mm wide SOBP for a 210 MeV/u helium-ion beam was created in a broad beam delivery system. The ridge filter was designed such that a uniform biological response was achieved with a cell survival rate of 7% over the SOBP region. Biological experiments were then performed using the SOBP beam in a human salivary gland (HSG) cell line to measure the cell survival rates. RESULTS: The biological responses were uniform in the SOBP region, as expected by the MKM; however, the mean of the measured cell survival rates was (11.2 ± 0.6) % in the SOBP region, which was 60% higher than the designed rate. When investigating the biological parameters of the HSG cell line used in the experiments, we found that they were altered slightly from the MKM parameters used for carbon-ion radiotherapy. The new ß parameter reproduced the measured survival rates within 6.5% in the SOBP region. CONCLUSION: We produced biologically uniform SOBP using MKM for carbon-ion radiotherapy. The measured survival rates in the SOBP region were higher than expected, and the survival rates were reproduced by modifying the MKM parameter. This study was limited to one SOBP, and further investigations are required to prove that MKM is generally applicable to helium-ion radiotherapy.

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.

Six Cases of Hemoptysis with Angiogenesis from Non-Bronchial Systemic Arteries.

BACKGROUND Although bronchial arteries are the most common cause of hemoptysis, other systemic arteries can cause hemoptysis and are potential pitfalls for successful embolization. CASE REPORT We present 6 cases of hemoptysis showing vascularization from systemic arteries other than bronchial arteries that presented to our department between 2013 and 2020. Chronic inflammatory diseases such as tuberculosis and pulmonary aspergillosis were the underlying diseases in 4 of the 6 cases. In all 6 cases, the lesions were close to the pleura. The abnormal non-bronchial systemic arteries were the internal thoracic artery in 4 cases, intercostal artery in 2 cases, lateral thoracic artery in 2 cases, and the subclavian, thyrocervical, and inferior phrenic arteries in 1 case each, all of which formed a shunt with the pulmonary artery. Additionally, depending on the location of the lesion, the non-bronchial systemic arteries near the lesion proliferated into the lung parenchyma through the adherent pleura. CONCLUSIONS When lesions are in contact with the pleura, various non-bronchial systemic arteries near the lesion can develop in the pulmonary parenchyma via the adherent pleura, which can cause hemoptysis. In patients with hemoptysis, it may be useful to evaluate chest contrast-enhanced computed tomography and angiography, while always accounting for the potential involvement of non-bronchial systemic arteries to ensure a safer and more reliable treatment.

Electrophysiological and Pathological Impact of Medium-Dose External Carbon Ion and Proton Beam Radiation on the Left Ventricle in an Animal Model.

Background Medium-dose (25 gray) x-ray radiation therapy has recently been performed on patients with refractory ventricular tachyarrhythmias. Unlike x-ray, carbon ion and proton beam radiation can deliver most of their energy to the target tissues. This study investigated the electrophysiological and pathological changes caused by medium-dose carbon ion and proton beam radiation in the left ventricle (LV). Methods and Results External beam radiation in the whole LV was performed in 32 rabbits. A total of 9 rabbits were not irradiated (control). At the 3-month or 6-month follow-up, the animals underwent an open-chest electrophysiological study and were euthanized for histological analyses. No acute death occurred. Significant LV dysfunction was not seen. The surface ECG revealed a significant reduction in the P and QRS wave voltages in the radiation groups. The electrophysiological study showed that the local conduction times in each LV site were significantly longer and that the local LV bipolar voltages were significantly lower in the radiation groups than in the control rabbits. Histologically, apoptosis, fibrotic changes, and a decrease in the expression of the connexin 43 protein were seen in the LV myocardium. These changes were obvious at 3 months, and the effects were sustained 6 months after radiation. No histological changes were seen in the coronary artery and esophagus, but partial radiation pneumonitis was observed. Conclusions Medium-dose carbon ion and proton beam radiation in the whole LV resulted in a significant electrophysiological disturbance and pathological changes in the myocardium. Radiation of the arrhythmogenic substrate would modify the electrical status and potentially induce the antiarrhythmic effect.

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.

Successful transcatheter arterial embolization in an asymptomatic patient with primary racemose hemangioma of the bronchial artery.

An asymptomatic 70-year-old woman presented with a nodular lesion overlapping the pulmonary artery at the right hilar region on a chest X-ray. Bronchial arteriography revealed an aneurysmal dilation of the long segment of the right bronchial artery and a shunt from the right bronchial artery to the right lower pulmonary artery. She was diagnosed with primary racemose hemangioma of the bronchial artery (RHBA). Considering the risk of hemoptysis, we performed a bronchial arterial embolization (BAE) using coils and N-butyl-2-cyanoacrylate. She had no complication after the BAE and no recurrences of hemoptysis at the 36-month follow-up. RHBA should be considered in case of aneurysmal dilation in the long segment of the bronchial artery, and BAE should be considered as a treatment strategy despite the absence of symptoms.

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.

Space-Making Particle Therapy with Surgical Spacer Placement in Patients with Sacral Chordoma.

BACKGROUND: Sacral chordomas are rare malignant bone tumors and are often very large for complete resection. Particle therapy for these tumors, which are adjacent to the gastrointestinal tract, is restricted because the tolerance dose of the intestine is low. This study aimed to demonstrate the technical aspects and treatment results of space-making particle therapy with surgical spacer placement for sacral chordoma. We aimed to investigate the dosimetric change in the particle therapy before and after spacer placement and the safety, efficacy, and long-term outcomes of space-making particle therapy. STUDY DESIGN: Twenty-one patients with sacral chordomas who were excluded from typical particle therapy were enrolled between 2007 and 2015. Gore-Tex sheets (WL Gore & Assoc) were folded and placed between the sacral and rectum. Particle therapy with 70.4 Gy (relative biologic effectiveness) was then performed. RESULTS: The mean volume that allows 95% of the treatment plan dose of the gross tumor volume and clinical tumor volume after spacer placement was improved to 97.7% and 96.4% from preoperative values of 91.0% and 89.5%, respectively. The recurrence rate within the gross tumor volume was only 4.8%. The 4-year local progression-free survival rate was 68.4%. The 5-year overall survival rate was 100% and the adverse events were acceptable. CONCLUSIONS: Considering improvements in the dose-volume histogram after spacer placement, low recurrence rates within the gross tumor volume, good survival rates, and low incidences of side effects, treatment of sacral chordoma with space-making particle therapy shows promise.

Characterization of pulmonary intimal sarcoma cells isolated from a surgical specimen: In vitro and in vivo study.

Pulmonary intimal sarcoma (PIS) constitutes a rare sarcoma originating from the intimal cells of pulmonary arteries. The pathogenesis of PIS remains to be elucidated and specific treatments have not been established; therefore, prognosis is generally poor. The purpose of our study was to isolate and characterize PIS cells from a specimen resected from a patient with PIS. The surgical specimen was minced and incubated, and spindle-shaped and small cells were successfully isolated and designated as PIS-1. PIS-1 cells at passages 8-9 were used for all in vitro and in vivo experiments. Immunocytochemistry showed that PIS-1 cells were positive for vimentin, murine double minute 2, and CD44 and negative for α-smooth muscle actin, CD31, von Willebrand factor, and desmin. PIS-1 cells exhibited the hallmarks of malignant cells including the potential for autonomous proliferation, anchorage-independent growth, invasion, genetic instability, and tumorigenicity in severe combined immunodeficiency mice. The PIS-1 cells highly expressed tyrosine kinase receptors such as platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2. Pazopanib, a multi-targeted tyrosine kinase inhibitor, suppressed the proliferation of PIS-1 cells in vitro and the growth of tumors formed from xenografted PIS-1 cells. A PIS cell line was thus successfully established. The PIS-1 cells highly expressed tyrosine kinase receptors, which may be a target for treatment of PIS.

External dosimetry audit for quality assurance of carbon-ion radiation therapy clinical trials.

PURPOSE: The QA team of the Japan carbon-ion radiation oncology study group (J-CROS) was organized in 2015 to enhance confidence in the accuracy of clinical dosimetry and ensure that the facility QA procedures are adequate. The team conducted onsite dosimetry audits in all the carbon-ion radiation therapy centers in Japan. MATERIALS AND METHODS: A special phantom was fabricated for the onsite dosimetry audit. Target volumes such as the GTV, CTV, and PTV were contoured to the obtained CT images, and two plans with different isocenter depths were created. The dose at the isocenter was measured by an ionization chamber, in the onsite audit and compared with the calculated dose. RESULTS: For all the centers, the average of the percentage ratio between the measured and calculated doses (measured/calculated) was 0.5% (-2.7% to +2.6%) and the standard deviation, 1.7%. In all the centers, the beams were within the set tolerance level of 3%. CONCLUSIONS: The audit demonstrated that the dose at a single point in the water phantom was within tolerance, but it is a big step to say that all doses are correct. In addition, this external dosimetry audit encouraged centers to improve the quality of their dosimetry systems.

Treatment outcomes of proton or carbon ion therapy for skull base chordoma: a retrospective study.

BACKGROUND: The usefulness of particle therapy for skull base chordoma has not been established. The aim of this retrospective study was to analyse the treatment outcomes of proton therapy (PT) and carbon ion therapy (CIT) in patients with skull base chordoma at a single institution. METHODS: All patients who underwent PT or CIT with curative intent between 2003 and 2014 at Hyogo Ion Beam Medical Center were included in this study. Twenty-four patients were enrolled. Eleven (46%) received PT and 13 (54%) received CIT. Overall survival (OS), progression-free survival (PFS) and local control (LC) were calculated using the Kaplan-Meier method. Late toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The median follow-up was 71.5 months (range, 14-175 months). The five-year LC, PFS and OS rates were 85, 81, and 86%, respectively. The LC (P = 0.048), PFS (P = 0.028) and OS (P = 0.012) were significantly improved in patients who had undergone surgery before particle therapy. No significant differences were observed in the LC rate and the incidence of grade 2 or higher late toxicities between patients who received PT and CIT. CONCLUSIONS: Both PT and CIT appear to be effective and safe treatments and show potential to become the standard treatments for skull base chordoma. To increase the local control, surgery before particle therapy is preferable.

Radiosensitizing Effect of 5-Aminolevulinic Acid and Protoporphyrin IX on Carbon-ion Beam Irradiation.

BACKGROUND/AIM: Carbon-ion beam is one of the most advanced radiations used for cancer treatment. However, there are tumors that are difficult to suppress with carbon-ion beam alone, thus necessitating development of drugs that can enhance its therapeutic effect. In this regard, the radiosensitizing effect of 5-aminolevulinic acid (ALA) and protoporphyrin IX (PpIX), that is a metabolic intermediate of ALA, on carbon-ion beam was investigated. MATERIALS AND METHODS: Radiosensitizing activity, mitochondrial ROS and DNA double-strand break production of ALA and PpIX were evaluated by irradiation with 1.0 or 1.5-Gy carbon-ion beam to mouse mammary EMT6 tumor cells. RESULTS: Combination of carbon-ion beam and ALA or PpIX showed a significant enhancement of its cytotoxic activity through a significant increase in ROS production in mitochondria. Furthermore, the combined activity of carbon-ion beam and ALA resulted in a significant increase in DNA double-strand breakage. CONCLUSION: ALA selectively accumulates in the mitochondria and PpIX synthesized from ALA reacts with carbon-ion beam to produce ROS that exert antitumor activity.

Outcomes of Patients With Primary Sacral Chordoma Treated With Definitive Proton Beam Therapy.

PURPOSE: To evaluate the efficacy and safety of definitive proton beam therapy (PBT) for primary sacral chordoma. METHODS AND MATERIALS: We conducted a retrospective analysis of the clinical outcomes of eligible patients with primary sacral chordoma who had undergone definitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions at our institution from September 2009 to October 2015. Local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival were evaluated. To explore the factors that influenced local progression, the following parameters were analyzed: sex, the presence of a spacer (Gore-Tex sheets), gross tumor volume, and extent of cranial tumor extension. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. To assess the impact of PBT on pain relief, the change in pain grades was investigated between the initiation of PBT and the last follow-up visit. RESULTS: Thirty-three eligible patients were analyzed. The median follow-up period was 37 months. The 3-year estimated local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival rates were 89.6%, 88.2%, 81.9%, 95.7%, and 92.7%, respectively. No significant association was between the patients' clinicopathologic characteristics and local progression-free survival. Four patients developed grade 3 adverse events, including acute dermatitis (n = 1), ileus (n = 1), and pain due to sacral insufficiency fractures (n = 2). The pain grades had improved, were unchanged, or had deteriorated in 15, 7, and 11 patients, respectively. CONCLUSIONS: Definitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions is an effective treatment with acceptable toxicity for primary sacral chordoma and has the potential to reduce pain.