A single institutional experience of combined carbon-ion radiotherapy and chemotherapy for unresectable locally advanced pancreatic cancer.

PURPOSE: The aim of this study was to evaluate the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for unresectable locally advanced pancreatic cancer (LAPC). METHODS AND MATERIALS: Patients with LAPC treated with definitive C-ion RT between April 2014 and July 2017 were analyzed retrospectively. The prescribed dose was 55.2 Gy (relative biological effectiveness [RBE] weighted absorbed dose) in 12 fractions. Overall survival (OS), local control (LC), progression free survival (PFS), and toxicity were evaluated. RESULTS: Sixty-four patients were enrolled. All patients completed planned course of C-ion RT. The median follow-up time for survivors from the initiation of C-ion RT was 24.4 months (range, 5.1-46.1 months). Median survival time was 25.1 months. Two-year OS, LC, and PFS were 53% (95% confidence interval [CI], 39%-66%), 82% (95% CI, 66%-91%), and 23% (95% CI, 14%-36%), respectively. Four patients experienced acute grade 3 toxicities including 3 gastrointestinal (GI) toxicities. There was no grade 3 or more late toxicity. CONCLUSIONS: The clinical results of C-ion RT for LAPC at our institution were comparable to those of a recent multi-institutional analysis.

A case of the cirrhotic patient performed living donor liver transplantation after carbon-ion radiotherapy for hepatocellular carcinoma.

The patient was a 50-year-old female with an initial diagnosis of a single hepatocellular carcinoma in liver cirrhosis. The tumor was located in the posterior liver segment (S7) and measured 5 cm with a rapid growth rate and portal invasion. The pre-treatment Child-Pugh (C-P) was grade A (six points). The total prescribed dose of carbon-ion radiotherapy (C-ion RT) was 60 Gy (relative biological effectiveness) given in 4 fractions. Thereafter, tumor shrinkage and rapid decrease of the serum alpha-fetoprotein level were observed. At 1-year follow-up a new lesion was diagnosed in the left lobe and the underlying liver failure had worsened to C-P grade B (eight points). Thus, she was recommended to undergo living-donor liver transplantation (LDLT). The postoperative course was uneventful. At pathological examination, no viable tumor cells in the region treated with C-ion RT were detected. At the time of the last follow-up, the patient was in overall good general condition with no signs of tumor recurrence.

Carbon-Ion Radiation Therapy for Pelvic Recurrence of Rectal Cancer.

PURPOSE: Investigation of the treatment potential of carbon-ion radiation therapy in pelvic recurrence of rectal cancer. METHODS AND MATERIALS: A phase 1/2 dose escalation study was performed. One hundred eighty patients (186 lesions) with locally recurrent rectal cancer were treated with carbon-ion radiation therapy (CIRT) (phase 1/2: 37 and 143 patients, respectively). The relapse locations were 71 in the presacral region, 82 in the pelvic sidewalls, 28 in the perineum, and 5 near the colorectal anastomosis. A 16-fraction in 4 weeks dose regimen was used, with total dose ranging from 67.2 to 73.6 Gy(RBE); RBE-weighted absorbed dose: 4.2 to 4.6 Gy(RBE)/fraction. RESULTS: During phase 1, the highest total dose, 73.6 Gy(RBE), resulted in no grade >3 acute reactions in the 13 patients treated at that dose. Dose escalation was halted at this level, and this dose was used for phase 2, with no other grade >3 acute reactions observed. At 5 years, the local control and survival rates at 73.6 Gy(RBE) were 88% (95% confidence interval [CI], 80%-93%) and 59% (95% CI, 50%-68%), respectively. CONCLUSION: Carbon-ion radiation therapy may be a safe and effective treatment option for locally recurrent rectal cancer and may serve as an alternative to surgery.

Decreased Expression of Fructose-1,6-bisphosphatase Associates with Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma.

Fructose-1,6-bisphosphatase (FBP1), the rate-limiting enzyme in gluconeogenesis, is reduced in expression in certain cancers where it has been hypothesized to act as a tumor suppressor, including in hepatocellular carcinoma (HCC). Here, we report functional evidence supporting this hypothesis, providing a preclinical rationale to develop FBP1 as a therapeutic target for HCC treatment. Three independent cohorts totaling 594 cases of HCC were analyzed to address clinical significance. Lower FBP1 expression associated with advanced tumor stage, poor overall survival, and higher tumor recurrence rates. In HCC cell lines, where endogenous FBP1 expression is low, engineering its ectopic overexpression inhibited tumor growth and intracellular glucose uptake by reducing aerobic glycolysis. In patient specimens, promoter methylation and copy-number loss of FBP1 were independently associated with decreased FBP1 expression. Similarly, FBP1 downregulation in HCC cell lines was also associated with copy-number loss. HCC specimens exhibiting low expression of FBP1 had a highly malignant phenotype, including large tumor size, poor differentiation, impaired gluconeogenesis, and enhanced aerobic glycolysis. The effects of FBP1 expression on prognosis and glucose metabolism were confirmed by gene set enrichment analysis. Overall, our findings established that FBP1 downregulation in HCC contributed to tumor progression and poor prognosis by altering glucose metabolism, and they rationalize further study of FBP1 as a prognostic biomarker and therapeutic target in HCC patients. Cancer Res; 76(11); 3265-76. ©2016 AACR.

Prognostic Significance of a Minute Amount of Ascites During Chemoradiotherapy for Locally Advanced Pancreatic Cancer.

AIM: The aim of this study was to investigate the clinical factors for predicting overall survival (OS) and the significance of a minute amount of ascites on computed tomography (CT) in patients with locally advanced pancreatic cancer (LAPC) treated with chemoradiotherapy (CRT). PATIENTS AND METHODS: Between 2003 and 2011, 48 consecutive patients with LAPC were treated with CRT. Various clinical factors, including ascites, were evaluated for correlation with OS. A subset analysis of 16 patients with a minute amount of ascites was also performed. RESULTS: The median survival duration and the 1-year OS rates were 11.5 months and 50%, respectively. A minute amount of ascites on CT and elevated carbohydrate antigen 19-9 (CA19-9) level were significantly associated with poorer OS. In 16 patients with ascites, the amount of ascites increased in the course of the disease, and these were considered to be cancerous clinically, regardless of the amount. CONCLUSION: A minute amount of ascites and CA19-9 were important prognostic factors in CRT. Any amount of ascites was considered an early indicator of peritoneal carcinomatosis in LAPC.

Carbon Ion Radiation Therapy With Concurrent Gemcitabine for Patients With Locally Advanced Pancreatic Cancer.

PURPOSE: To determine, in the setting of locally advanced pancreatic cancer, the maximum tolerated dose of carbon ion radiation therapy (C-ion RT) and gemcitabine dose delivered concurrently and to estimate local effect and survival. METHODS AND MATERIALS: Eligibility included pathologic confirmation of pancreatic invasive ductal carcinomas and radiographically unresectable disease without metastasis. Concurrent gemcitabine was administered on days 1, 8, and 15, and the dose levels were escalated from 400 to 1000 mg/m(2) under the starting dose level (43.2 GyE) of C-ion RT. The dose levels of C-ion RT were escalated from 43.2 to 55.2 GyE at 12 fractions under the fixed recommended gemcitabine dose determined. RESULTS: Seventy-six patients were enrolled. Among the 72 treated patients, dose-limiting toxicity was observed in 3 patients: grade 3 infection in 1 patient and grade 4 neutropenia in 2 patients. Only 1 patient experienced a late grade 3 gastric ulcer and bleeding 10 months after C-ion RT. The recommended dose of gemcitabine with C-ion RT was found to be 1000 mg/m(2). The dose of C-ion RT with the full dose of gemcitabine (1000 mg/m(2)) was safely increased to 55.2 GyE. The freedom from local progression rate was 83% at 2 years using the Response Evaluation Criteria in Solid Tumors. The 2-year overall survival rates in all patients and in the high-dose group with stage III (≥45.6 GyE) were 35% and 48%, respectively. CONCLUSIONS: Carbon ion RT with concurrent full-dose gemcitabine was well tolerated and effective in patients with unresectable locally advanced pancreatic cancer.

Treatment Outcome of Radiotherapy for Localized Primary Ocular Adnexal MALT Lymphoma--Prognostic Effect of the AJCC Tumor-Node-Metastasis Clinical Staging System.

AIM: To analyze the treatment outcome of radiotherapy for localized primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (POAML) and evaluate the prognostic effect of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) clinical staging system for POAML. PATIENTS AND METHODS: Seventy-three patients with Ann Arbor stage IE POAML who were treated with radiotherapy alone were analyzed. T-Factor based on the AJCC staging system was T1 in 28, T2 in 33 and T3 in 12 patients. RESULTS: Out of nine patients with relapse, six had distant and three had contralateral ocular adnexal relapse. One patient died of lymphoma progression. The 5-year local control and progression-free survival (PFS) rates were 100% and 81.5%, respectively. T-Factor was not significantly associated with PFS. CONCLUSION: Radiotherapy achieved excellent local control and survival rates for stage IE POAML. The AJCC TNM clinical staging system was not significantly predictive for PFS of stage IE POAML.

Clinical characteristics and outcome of pneumothorax after stereotactic body radiotherapy for lung tumors.

BACKGOUND: We retrospectively investigated the clinical characteristics and outcome of pneumothorax after stereotactic body radiotherapy (SBRT) for lung tumors. METHODS: Between April 2003 and July 2012, 473 patients with lung tumors were treated with SBRT. We identified 12 patients (2.5 %) with pneumothorax caused by SBRT, and evaluated the clinical features of pneumothorax. RESULTS: All of the tumors were primary lung cancers. The severity of radiation pneumonitis was grade 1 in 10 patients and grade 2 in two patients. Nine patients had emphysema. The planning target volume and pleura overlapped in 11 patients, and the tumors were attached to the pleura in 7 patients. Rib fractures were observed in three patients before or at the same time as the diagnosis of pneumothorax. The median time to onset of pneumothorax after SBRT was 18.5 months (4-84 months). The severity of pneumothorax was grade 1 in 11 patients and grade 3 in one patient. CONCLUSION: Although pneumothorax was a relatively rare late adverse effect after SBRT, some patients demonstrated pneumothorax after SBRT for peripheral lung tumors. Although most pneumothorax was generally tolerable and self-limiting, careful follow-up is needed.

Stereotactic body radiation therapy for primary lung cancers clinically diagnosed without pathological confirmation: a single-institution experience.

BACKGROUND: Pathological diagnosis of small lung lesions is sometimes difficult in medically inoperable patients. The purpose of this study was to evaluate the adverse events and the outcomes of stereotactic body radiation therapy (SBRT) for lung lesions which were clinically diagnosed as primary lung cancer without pathological confirmation. METHODS: Between April 2003 and April 2011, 88 patients with small lung lesions which were clinically diagnosed as primary lung cancer were treated with SBRT. The median tumor size was 19 mm (range 8-40 mm). The radiation dose was 48 Gy in four fractions in all patients. The median follow-up was 23 months (range 6-91 months). RESULTS: Recurrence was observed in 13 patients. The local control rate, progression-free survival rate, and overall survival rate at 3 years were 90, 67, and 80 %, respectively. Two patients (2.3 %) had Grade 2 radiation pneumonitis, and six patients (6.8 %) had Grade 2 rib fractures. There were no adverse events of Grade 3 or greater. CONCLUSIONS: SBRT appears to be a safe and effective treatment option for small lung lesions that are clinically diagnosed as primary lung cancer without pathological confirmation.

Recent advances in radiation oncology: intensity-modulated radiotherapy, a clinical perspective.

Radiotherapy plays an important role in the treatment of various malignancies, and intensity-modulated radiotherapy (IMRT) is an attractive option because it can deliver precise conformal radiation doses to the target while minimizing the dose to adjacent normal tissues. IMRT provides a highly conformal dose distribution by modulating the intensity of the radiation beam. A number of malignancies have been targeted by IMRT; this work reviews published data on the major disease sites treated with IMRT. The dosimetric advantage of IMRT has resulted in the significant reduction of adverse effects in some tumors. However, there are few clinical trials comparing IMRT and three-dimensional conformal radiotherapy (3D-CRT), and no definite increase in survival or the loco-regional control rate by IMRT has been demonstrated in many malignancies. IMRT also requires greater time and resources to complete compared to 3D-CRT. In addition, the cost-effectiveness of IMRT versus 3D-CRT has not yet been established.

Radiotherapy for early-stage primary ocular adnexal mucosa-associated lymphoid tissue lymphoma.

BACKGROUND: Primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (POAML) is a rare disease. The purpose of this study was to evaluate the treatment outcome and patterns of failure of patients with early-stage POAML treated with radiotherapy. PATIENTS AND METHODS: From 1995 to 2008, 53 patients with early-stage POAML were reviewed. Tumors were categorized as either superficial or mass-forming type. In principle, superficial lesions (n=11) were treated with 24 Gy, while the mass-forming lesions (n=42) were irradiated with 30 Gy. The median follow-up period was 3.9 years. RESULTS: All four cases of relapse had mass-forming lesions. The 5-year overall and progression-free survival rates were 100% and 91.5%, respectively. Although 30 patients experienced grade 2 or 3 late adverse events, no patients had radiation-related retinopathy. CONCLUSION: Early-stage POAML can be well-controlled with radiotherapy. However, the risk of distant relapse should be noted, in particular, for mass-forming tumors.

Definitive fractionated re-irradiation for local recurrence following stereotactic body radiotherapy for primary lung cancer.

AIM: To retrospectively evaluate the efficacy and safety of definitive fractionated re-irradiation for local recurrence following stereotactic body radiotherapy (SBRT) for primary lung cancer. PATIENTS AND METHODS: Between April 2003 and December 2011, 398 patients with primary lung tumor underwent SBRT at the Kyushu University Hospital, and 46 out of these developed local recurrence after SBRT. Definitive fractionated re-irradiation was performed for 17 out of the 46 patients. The median dose of re-irradiation was 60 Gy/ 30 fractions. Concurrent chemotherapy was given to four patients. RESULTS: The median follow-up duration was 12.6 months. At one year post-re-irradiation, local progression-free survival was 33.8%; progression-free survival, 30.9%; cause-specific survival, 79.3%; and overall survival, 74.7%. No severe adverse events were observed during the follow-up. CONCLUSION: Definitive fractionated re-irradiation is thought to be a safe alternative therapy for local recurrence following SBRT, although its efficacy may be not entirely satisfactory.

Stereotactic body radiation therapy for stage I non-small cell lung cancer patients with chronic respiratory insufficiency requiring domiciliary oxygen therapy.

BACKGROUND: The efficacy of stereotactic body radiation therapy (SBRT) for patients treated with domiciliary oxygen therapy is not well-known. PATIENTS AND METHODS: We collected the clinical records of 15 patients with chronic respiratory insufficiency requiring domiciliary oxygen therapy at 1-3 l/min who were treated with SBRT for stage I non-small cell lung cancer. All patients were fixed with a thermoplastic body cast system. SBRT was given in 7-8 fields with an isocenter dose of 40-60 Gy in 4-10 fractions (median, 48 Gy in 4 fractions). RESULTS: The overall 2-year and 5-year survival rates for all patients were 67.4% and 34.7%, while the disease-specific 2-year and 5-year survival rates were 90.0% and 72.0%, respectively. Pulmonary adverse effects were mild in the majority of the patients, although two patients had grade 2 radiation pneumonitis. The oxygen flow required increased slightly at follow-up periods greater than one year, but was still at an acceptable level. CONCLUSION: SBRT was feasible for patients requiring domiciliary oxygen therapy.

Radiation-induced rib fractures after hypofractionated stereotactic body radiation therapy: risk factors and dose-volume relationship.

PURPOSE: The purpose of this study was to clarify the incidence, the clinical risk factors, and the dose-volume relationship of radiation-induced rib fracture (RIRF) after hypofractionated stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: One hundred sixteen patients treated with SBRT for primary or metastatic lung cancer at our institution, with at least 6 months of follow-up and no previous overlapping radiation exposure, were included in this study. To determine the clinical risk factors associated with RIRF, correlations between the incidence of RIRF and the variables, including age, sex, diagnosis, gross tumor volume diameter, rib-tumor distance, and use of steroid administration, were analyzed. Dose-volume histogram analysis was also conducted. Regarding the maximum dose, V10, V20, V30, and V40 of the rib, and the incidences of RIRF were compared between the two groups divided by the cutoff value determined by the receiver operating characteristic curves. RESULTS: One hundred sixteen patients and 374 ribs met the inclusion criteria. Among the 116 patients, 28 patients (46 ribs) experienced RIRF. The estimated incidence of rib fracture was 37.7% at 3 years. Limited distance from the rib to the tumor (<2.0 cm) was the only significant risk factor for RIRF (p = 0.0001). Among the dosimetric parameters used for receiver operating characteristic analysis, the maximum dose showed the highest area under the curve. The 3-year estimated risk of RIRF and the determined cutoff value were 45.8% vs. 1.4% (maximum dose, ≥42.4 Gy or less), 51.6% vs. 2.0% (V40, ≥0.29 cm(3) or less), 45.8% vs. 2.2% (V30, ≥1.35 cm(3) or less), 42.0% vs. 8.5% (V20, ≥3.62 cm(3) or less), or 25.9% vs. 10.5% (V10, ≥5.03 cm(3) or less). CONCLUSIONS: The incidence of RIRF after hypofractionated SBRT is relatively high. The maximum dose and high-dose volume are strongly correlated with RIRF.

Successful hyperbaric oxygen therapy for laryngeal radionecrosis after chemoradiotherapy for mesopharyngeal cancer: case report and literature review.

Laryngeal radionecrosis is one of the most troublesome late complications of radiotherapy, because it is frequently resistant to treatment and laryngectomy is required in the worst case. Here, we report a case of laryngeal radionecrosis, successfully treated by use of hyperbaric oxygen (HBO) therapy, in which laryngectomy was avoided. A 67-year-old male received radical chemoradiotherapy (CRT) for mesopharyngeal cancer, which included radiotherapy with a total dose of 71.4 Gy/38 Fr and chemotherapy with CDDP + S-1. He developed dyspnea and throat pain 9 months after completion of CRT. Laryngoscopy revealed vocal cord impairment because of severe laryngeal edema. He was diagnosed as having laryngeal radionecrosis and initially received conservative therapy combined with antibiotics, steroids, and prostaglandins. Because his dyspnea was persistent despite this treatment, HBO therapy was administered 20 times, and resulted in complete remission of the dyspnea. HBO therapy, therefore, is regarded as an effective conservative therapeutic option for laryngeal radionecrosis.

Esophageal stenosis associated with tumor regression in radiotherapy for esophageal cancer: frequency and prediction.

PURPOSE: To determine clinical factors for predicting the frequency and severity of esophageal stenosis associated with tumor regression in radiotherapy for esophageal cancer. METHODS AND MATERIALS: The study group consisted of 109 patients with esophageal cancer of T1-4 and Stage I-III who were treated with definitive radiotherapy and achieved a complete response of their primary lesion at Kyushu University Hospital between January 1998 and December 2007. Esophageal stenosis was evaluated using esophagographic images within 3 months after completion of radiotherapy. We investigated the correlation between esophageal stenosis after radiotherapy and each of the clinical factors with regard to tumors and therapy. For validation of the correlative factors for esophageal stenosis, an artificial neural network was used to predict the esophageal stenotic ratio. RESULTS: Esophageal stenosis tended to be more severe and more frequent in T3-4 cases than in T1-2 cases. Esophageal stenosis in cases with full circumference involvement tended to be more severe and more frequent than that in cases without full circumference involvement. Increases in wall thickness tended to be associated with increases in esophageal stenosis severity and frequency. In the multivariate analysis, T stage, extent of involved circumference, and wall thickness of the tumor region were significantly correlated to esophageal stenosis (p = 0.031, p < 0.0001, and p = 0.0011, respectively). The esophageal stenotic ratio predicted by the artificial neural network, which learned these three factors, was significantly correlated to the actual observed stenotic ratio, with a correlation coefficient of 0.864 (p < 0.001). CONCLUSION: Our study suggested that T stage, extent of involved circumference, and esophageal wall thickness of the tumor region were useful to predict the frequency and severity of esophageal stenosis associated with tumor regression in radiotherapy for esophageal cancer.

A Case of Radiation Fibrosis Appearing as Mass-Like Consolidation after SBRT with Elevation of Serum CEA.

We report a case of radiation fibrosis appearing as mass-like consolidation, which was difficult to distinguish from local recurrence. A 72-year-old woman was diagnosed as having primary lung cancer (cT1N0M0 stage IA) in the right upper lobe and was treated with SBRT of 48 Gy in 4 fractions. After 12 months, mass-like consolidation appeared around the irradiated area, and after 13 months, it had increased in size. FDG-PET revealed high uptake (SUV max = 5.61) for the consolidation. CT-guided biopsy was performed, but we could not confirm the diagnosis. Considering her poor respiratory function and her age, short-interval follow-up was performed. After 15 months, the consolidation enlarged at the dorsal side, and carcinoembryonic antigen (CEA) became elevated (14.6 ng/mL). Serum KL-6 (436 U/mL) and SP-D (204 ng/mL) were also elevated. However, after 16 months, serum CEA slightly decreased. The consolidation gradually retracted on follow-up CT images. CEA, KL-6, and SP-D were also decreased by degrees. After 40 months, there is no evidence of local recurrence.

Concurrent chemoradiotherapy with S-1 for T2N0 glottic squamous cell carcinoma.

In this study, we evaluated the feasibility, efficacy and toxicity of concurrent chemoradiotherapy with S-1 (tegafur-gimeracil-oteracil potassium) for T2N0 glottic carcinoma. A total of 23 patients with T2N0 glottic carcinoma received chemoradiotherapy with S-1. Radiotherapy consisted of five daily fractions of 2 Gy per week, to a total median dose of 70 Gy. S-1 was administered 65 mg/m(2) per day for 4 weeks, beginning on the day therapy was started, followed by 2 weeks off the drug and twice a day until the end of radiotherapy. Initial local control rate of the primary tumor was achieved in all patients. The median follow-up period for all patients was 38 months. The 3-year local control rate was 95.4%. Regarding adverse reactions, grade 3 mucositis upon clinical examination, mucositis upon functional/symptomatic examination, dysphagia, hepatic toxicity and anemia were observed in 13, 2, 2, 1 and 1 patients, respectively. This chemoradiotherapy did not result in grade 4 acute toxicity or severe late toxicity. Chemoradiotherapy with S-1 was feasible, well tolerated and effective. This therapy is suggested as a possible regimen for improving local control of T2N0 glottic carcinoma.

Effective palliative radiotherapy in primary malignant melanoma of the esophagus: a case report.

INTRODUCTION: Primary malignant melanoma of the esophagus is a rare but highly aggressive tumor with poor prognosis. Surgical resection is the treatment of choice. However, some cases may be diagnosed with advanced inoperable disease. Palliative radiotherapy may be used to relieve symptoms caused by the esophageal tumor. CASE PRESENTATION: We report on a case of advanced inoperable primary malignant melanoma of the esophagus treated with palliative radiotherapy. The patient's dysphagia resolved with radiotherapy. CONCLUSION: Malignant melanoma of the esophagus is rare. Patients with advanced inoperable malignant melanomas of the esophagus benefit from radiation therapy. Radiation therapy is effective for palliation.