Shintaro Shiba

Clinical outcomes using carbon-ion radiotherapy and dose-volume histogram comparison between carbon-ion radiotherapy and photon therapy for T2b-4N0M0 non-small cell lung cancer—A pilot study

The safety and efficacy of carbon-ion radiotherapy for advanced non-small cell lung cancer have not been established. We evaluated the clinical outcomes and dose-volume histogram parameters of carbon-ion radiotherapy compared with photon therapy in T2b–4N0M0 non-small cell lung cancer. Twenty-three patients were treated with carbon-ion radiotherapy between May 2011 and December 2015. Seven, 14, and 2 patients had T2b, T3, and T4, respectively. The median age was 78 (range, 53−91) years, with 22 male patients. There were 12 adenocarcinomas, 8 squamous cell carcinomas, 1 non-small cell lung carcinoma, and 2 clinically diagnosed lung cancers. Eleven patients were operable, and 12 patients were inoperable. Most patients (91%) were treated with carbon-ion radiotherapy of 60.0 Gy relative biological effectiveness (RBE) in 4 fractions or 64.0 Gy (RBE) in 16 fractions. Local control and overall survival rates were calculated. Dose-volume histogram parameters of normal lung and tumor coverages were compared between carbon-ion radiotherapy and photon therapies, including three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT). The median follow-up of surviving patients was 25 months. Three patients experienced local recurrence, and the 2-year local control rate was 81%. During follow-up, 5 patients died of lung cancer, and 1 died of intercurrent disease. The 2-year overall survival rate was 70%. Operable patients had a better overall survival rate compared with inoperable patients (100% vs. 43%; P = 0.04). There was no grade ≥2 radiation pneumonitis. In dose-volume histogram analysis, carbon-ion radiotherapy had a significantly lower dose to normal lung and greater tumor coverage compared with photon therapies. Carbon-ion radiotherapy was effectively and safely performed for T2b–4N0M0 non-small cell lung cancer, and the dose distribution was superior compared with those for photon therapies. A Japanese multi-institutional study is ongoing to prospectively evaluate these patients and establish the use of carbon-ion radiotherapy.

Difference in distant failure site between locally advanced squamous cell carcinoma and adenocarcinoma of the uterine cervix after C-ion RT.

We investigated the first site of distant failure after carbon ion radiotherapy (C-ion RT) for locally advanced cervical cancer in three clinical trials. A total of 91 cases were enrolled in the three trials (Protocol 9702, 9704 and 9902). Histologically, 36 cases had squamous cell carcinoma (SqCC) and 55 cases had adenocarcinoma (AC), including 13 with adenosquamous cell carcinoma. The number of cases with Stage IIB, IIIB and IVA disease was 21, 59 and 11, respectively. Of the 91 cases, 42 had positive pelvic lymph nodes (PLNs). The median tumor size was 6.0 cm (range, 3.0–12.0 cm). The median follow-up duration for all cases was 40 months (range, 7–181 months). A total of 40 cases developed distant failure as the first site of failure: 13 of 36 (36.1%) SqCC cases had distant failure, with 9 of them with para-aortic lymph node (PALN) failure; 27 of 55 (44.0%) AC cases had distant failure, and 23 of them had distant failure excluding PALN metastasis. Distant failure rates of SqCC cases who had positive and negative PLNs before C-ion RT were 61.1% and 11.1%, respectively (P = 0.0045). Those of AC cases were 54.2% and 45.2%, respectively (P = 0.507). In conclusion, there were high rates of distant failure after C-ion RT in AC cases regardless of PLN status, and there were high rates of distant failure after C-ion RT, especially PALN failure, in SqCC cases with positive PLNs.

Carbon-ion radiotherapy for locally advanced cervical cancer with bladder invasion

The purpose of this study was to evaluate the efficacy and toxicities of carbon-ion radiotherapy (C-ion RT) for locally advanced cervical cancer with bladder invasion by a subset analysis of pooled data from eight prospective clinical trials at the National Institute of Radiological Sciences. Between June 1995 and January 2014, 29 patients with locally advanced cervical cancer with bladder invasion were identified. The median age was 56 years old (range 31–79 years old). The median tumor size at diagnosis on magnetic resonance imaging was 6.7 cm (range 3.5–11.0 cm). Histologically, 20 patients had squamous cell carcinoma and 9 had adenocarcinoma. C-ion RT was performed as a dose-escalation study in the initial trials. All patients received prophylactic whole-pelvic or extended-field irradiation and local boost. The total dose to the cervical tumor was 52.8–74.4 Gy (relative biological effectiveness) in 20 or 24 fractions. Weekly cisplatin (40 mg/m2/week, five cycles) was concurrently given to four patients. The median follow-up of all patients was 28.6 months (range 8.8–238.6 months). Grade 2 or higher late complications in the bladder were observed in eight patients, with seven developing vesicovaginal fistula. Six patients had Grade 2 or higher complications in the rectosigmoid colon. The 3-year overall survival rate was 47%, the 3-year local control rate was 66%, and the 3-year disease-free survival rate was 28%. In this study, C-ion RT showed favorable local control with reasonable toxicities, but the results were still unsatisfactory. We have the expectation of improvement of therapeutic effects by using C-ion RT with concurrent chemotherapy.

Clinical outcomes of carbon ion radiotherapy with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma in a phase 1/2 clinical trial (Protocol 1001)

We conducted a phase 1/2 study to evaluate the efficacy and safety of carbon ion radiotherapy (C‐ion RT) with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma. Thirty‐three patients were enrolled between April 2010 and March 2014. Treatment consisted of C‐ion RT with concurrent weekly cisplatin at a dose of 40 mg/m2. In the phase 1 component, the total dose was escalated from 68.0 Gy (relative biological effectiveness [RBE]) to 74.4 Gy (RBE) to determine the maximum tolerated dose of C‐ion RT. In the phase 2 component, the efficacy and safety of C‐ion RT with concurrent chemotherapy were evaluated using the dose determined in the phase 1 component. The median follow‐up duration was 30 months. Two patients did not receive chemotherapy because of anemia or leukocytopenia immediately prior to commencing treatment; 31 patients were analyzed. None of the patients developed dose‐limiting toxicities. The recommended dose (RD) was determined to be 74.4 Gy (RBE). In the phase 2 component, two patients developed Grade 3–4 toxicities in the gastrointestinal tract, due to repeated laser coagulation or peritonitis caused by appendicitis. In the patients treated with the RD, the 2‐year local control, progression‐free survival, and overall survival rates were 71%, 56%, and 88%, respectively. C‐ion RT with concurrent weekly cisplatin was well tolerated in patients with locally advanced uterine cervical adenocarcinoma. Our findings support further investigations into the efficacy of this strategy.

Maximum standardized uptake value on FDG‑PET predicts survival in stage I non‑small cell lung cancer following carbon ion radiotherapy

The present study (University Hospital Medical Information Network study no. UMIN000003797) aimed to evaluate whether the maximum standardized uptake value (SUVmax) of pretreatment 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) is prognostic factor for stage I non-small cell lung cancer (NSCLC) treated with carbon ion radiotherapy (C-ion RT). Patients treated between June 2010 and June 2013 at Gunma University Heavy Ion Medical Center (Maebashi, Japan) on a prospective protocol were included in the present study. Patients with T1a-b and T2a NSCLC were treated with C-ion RT at a dose of 52.8 Gy [relative biological effectiveness (RBE)] and 60.0 Gy (RBE), respectively, in four fractions. Prior to treatment, all patients underwent FDG-PET, in which the SUVmax of primary tumors was evaluated. Local control, progression-free survival (PFS), and overall survival (OS) were calculated. A total of 45 patients were analyzed and the median follow-up period was 28.9 months. The 2-year local control, PFS and OS rates for all patients were 93, 78 and 89%, respectively. The mean SUVmax of primary tumors was 5.5, and patients were divided into higher (≥5.5) and lower (<5.5) SUVmax groups. The 2-year PFS rates were 61 and 89% for the higher and lower SUVmax groups, respectively (P=0.01), and the 2-year OS rates for the higher and lower SUVmax groups were 76 and 96%, respectively (P=0.01). The higher SUVmax group exhibited a significantly worse PFS and OS compared with the lower SUVmax group; however, the SUVmax was not associated with the local control rate. In total, 2 patients (4%) experienced grade 2 or 3 radiation pneumonitis, with their symptoms improved through conservative treatment. No patients experienced any grade 4 or 5 toxicities. The results of the present study indicate that pretreatment SUVmax is a prognostic indicator for outcomes in patients with stage I NSCLC treated with C-ion RT.

Clinical Advantage of Chest-wall Post-mastectomy Radiation Therapy Without Bolus

Background/Aim: The clinical outcomes of post-mastectomy radiation therapy (PMRT) without bolus remain to be fully examined, so that we evaluated clinical outcomes of PMRT without bolus and to measure the chest-wall dose surface histogram (DSH) parameters. Patients and Methods: Fifty-two patients with breast cancer who received PMRT without bolus were retrospectively analyzed. DSH values of the percentage of maximum dose (Dmax) were measured. Results: All patients completed the treatment; the median follow-up period was 22.1 months. The 2-year overall survival and local control rates were 85% and 95%. Five patients developed grade 2 acute radiation dermatitis, and none developed grade 2 or higher late radiation dermatitis. The median Dmax in patients who developed grade 0-1 and grade 2 acute radiation dermatitis was 5,178 and 5,365 cGy (p=0.03). Conclusion: PMRT without bolus resulted in a low frequency of grade 2 or higher radiation dermatitis without increasing locoregional recurrences, and the Dmax was the contributing factor for developing acute radiation dermatitis.

A feasibility study of high-dose hypofractionated carbon ion radiation therapy using four fractions for localized hepatocellular carcinoma measuring 3 cm or larger

BACKGROUND AND PURPOSE To evaluate the safety of carbon-ion radiotherapy (C-ion RT) using 60 Gy (relative biological effectiveness, RBE) in four fractions for patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS The primary outcome was acute toxicities within 90 days. The secondary outcomes were late toxicities, local control, and progression-free survival and overall survival rates. The key inclusion criteria were as follows: (1) 3 cm or larger HCC without major vascular invasion and not adjacent to the alimentary tract; (2) Child-Pughs grade A/B; and (3) without extrahepatic metastasis. RESULTS A total of 21 cases were analyzed between October 2012 and April 2016. The median follow-up period among the 17 survivors was 24.2 (range: 6.3-43.7) months. Grade 3 or higher acute toxicity was not observed, while three (14.3%) of the 21 patients experienced grade 3 late toxicities. The 1- and 2-year local control, progression-free survival, and overall survival rates were 100% and 92.3%, 81.0% and 50.0%, and 90.5% and 80.0%, respectively. CONCLUSION C-ion RT using 60 Gy (RBE) in four fractions was safe and achieved promising local tumor control.

Comparison of passive and scanning irradiation methods for carbon-ion radiotherapy for breast cancer

Abstract The dose distribution of passive and scanning irradiation for carbon-ion radiotherapy for breast cancer was compared in order to determine the preferred treatment method. Eleven Japanese patients who received carbon-ion radiotherapy for breast cancer were retrospectively analyzed. The original clinical plans were used for the passive irradiation method, while the plans for the scanning irradiation method were more recently made. Statistical analysis suggested that there was no significant difference in superiority in terms of dose distribution between the passive and scanning irradiation methods. The present study found that the scanning irradiation method was not always superior to the passive method, despite a previous study having reported the superiority of scanning irradiation. The present result is considered to arise from characteristics of breast cancer treatment, such as the simplicity of the organ at risk and the shallow depth point of the target from the skin. It is noteworthy that the present study suggests that the passive irradiation method can provide better dose distribution, depending on the case.

No Deterioration in Clinical Outcomes of Carbon Ion Radiotherapy for Sarcopenia Patients with Hepatocellular Carcinoma

Background/Aim: The relationship between sarcopenia and prognosis in carbon ion radiotherapy (C-ion RT) for hepatocellular carcinoma (HCC) has not yet been reported, therefore we analyzed the presence or absence of sarcopenia before C-ion RT as a prognostic factor for patients with HCC. Patients and Methods: Data were retrospectively collected for patients who had undergone C-ion RT for HCC between September 2010 and December 2016. For defining the presence or absence of sarcopenia, skeletal muscles in the third lumbar vertebrae level were measured. Clinical outcomes were compared in the sarcopenia and non-sarcopenia groups. Results: Of the 68 patients who were analyzed, 22 were classified into the sarcopenia and 46 into the non-sarcopenia groups. Median follow-up of patients was 33.5 months. The three-year overall survival (OS) rates in the sarcopenia and non-sarcopenia groups were 66% and 77%, respectively (p=0.51). Conclusion: Sarcopenia was not a prognostic factor for patients with HCC treated with C-ion RT, which was effective in HCC patients with sarcopenia without worsening the OS.