Etsuo Kunieda

Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study

BACKGROUND We aimed to examine whether stereotactic radiosurgery without whole-brain radiotherapy (WBRT) as the initial treatment for patients with five to ten brain metastases is non-inferior to that for patients with two to four brain metastases in terms of overall survival. METHODS This prospective observational study enrolled patients with one to ten newly diagnosed brain metastases (largest tumour <10 mL in volume and <3 cm in longest diameter; total cumulative volume ≤15 mL) and a Karnofsky performance status score of 70 or higher from 23 facilities in Japan. Standard stereotactic radiosurgery procedures were used in all patients; tumour volumes smaller than 4 mL were irradiated with 22 Gy at the lesion periphery and those that were 4-10 mL with 20 Gy. The primary endpoint was overall survival, for which the non-inferiority margin for the comparison of outcomes in patients with two to four brain metastases with those of patients with five to ten brain metastases was set as the value of the upper 95% CI for a hazard ratio (HR) of 1·30, and all data were analysed by intention to treat. The study was finalised on Dec 31, 2012, for analysis of the primary endpoint; however, monitoring of stereotactic radiosurgery-induced complications and neurocognitive function assessment will continue for the censored subset until the end of 2014. This study is registered with the University Medical Information Network Clinical Trial Registry, number 000001812. FINDINGS We enrolled 1194 eligible patients between March 1, 2009, and Feb 15, 2012. Median overall survival after stereotactic radiosurgery was 13·9 months [95% CI 12·0-15·6] in the 455 patients with one tumour, 10·8 months [9·4-12·4] in the 531 patients with two to four tumours, and 10·8 months [9·1-12·7] in the 208 patients with five to ten tumours. Overall survival did not differ between the patients with two to four tumours and those with five to ten (HR 0·97, 95% CI 0·81-1·18 [less than non-inferiority margin], p=0·78; pnon-inferiority<0·0001). Stereotactic radiosurgery-induced adverse events occurred in 101 (8%) patients; nine (2%) patients with one tumour had one or more grade 3-4 event compared with 13 (2%) patients with two to four tumours and six (3%) patients with five to ten tumours. The proportion of patients who had one or more treatment-related adverse event of any grade did not differ significantly between the two groups of patients with multiple tumours (50 [9%] patients with two to four tumours vs 18 [9%] with five to ten; p=0·89). Four patients died, mainly of complications relating to stereotactic radiosurgery (two with one tumour and one each in the other two groups). INTERPRETATION Our results suggest that stereotactic radiosurgery without WBRT in patients with five to ten brain metastases is non-inferior to that in patients with two to four brain metastases. Considering the minimal invasiveness of stereotactic radiosurgery and the fewer side-effects than with WBRT, stereotactic radiosurgery might be a suitable alternative for patients with up to ten brain metastases. FUNDING Japan Brain Foundation.

STEREOTACTIC BODY RADIOTHERAPY FOR PRIMARY LUNG CANCER AT A DOSE OF 50 GY TOTAL IN FIVE FRACTIONS TO THE PERIPHERY OF THE PLANNING TARGET VOLUME CALCULATED USING A SUPERPOSITION ALGORITHM

PURPOSE To retrospectively analyze the clinical outcomes of stereotactic body radiotherapy (SBRT) for patients with Stages 1A and 1B non-small-cell lung cancer. METHODS AND MATERIALS We reviewed the records of patients with non-small-cell lung cancer treated with curative intent between Dec 2001 and May 2007. All patients had histopathologically or cytologically confirmed disease, increased levels of tumor markers, and/or positive findings on fluorodeoxyglucose positron emission tomography. Staging studies identified their disease as Stage 1A or 1B. Performance status was 2 or less according to World Health Organization guidelines in all cases. The prescribed dose of 50 Gy total in five fractions, calculated by using a superposition algorithm, was defined for the periphery of the planning target volume. RESULTS One hundred twenty-one patients underwent SBRT during the study period, and 63 were eligible for this analysis. Thirty-eight patients had Stage 1A (T1N0M0) and 25 had Stage 1B (T2N0M0). Forty-nine patients were not appropriate candidates for surgery because of chronic pulmonary disease. Median follow-up of these 49 patients was 31 months (range, 10-72 months). The 3-year local control, disease-free, and overall survival rates in patients with Stages 1A and 1B were 93% and 96% (p = 0.86), 76% and 77% (p = 0.83), and 90% and 63% (p = 0.09), respectively. No acute toxicity was observed. Grade 2 or higher radiation pneumonitis was experienced by 3 patients, and 1 of them had fatal bacterial pneumonia. CONCLUSIONS The SBRT at 50 Gy total in five fractions to the periphery of the planning target volume calculated by using a superposition algorithm is feasible. High local control rates were achieved for both T2 and T1 tumors.

Stereotactic body radiotherapy for small hepatocellular carcinoma: A retrospective outcome analysis in 185 patients

Abstract Background. Since 2005, we have treated hepatocellular carcinoma (HCC) with stereotactic body radiotherapy (SBRT) uniformly at two dose levels, according to baseline liver function and normal liver dose. We retrospectively examined the outcomes for these patients. Material and methods. Between 2005 and 2012, 221 HCC patients were treated with SBRT. Eligibility criteria for SBRT included a single (either solitary or recurrent) HCC lesion; unfeasible, difficult or refusal to undergo other surgery or percutaneous ablative therapies; Child-Pugh Classification (CPC) A or B; tumors ≤ 5 cm; dose to the bowels < 25 Gy/5 fractions; curative intent. Patients followed up ≥ 6 months were eligible. The prescribed dose depended on liver function and liver dose: 40 Gy for CPC-A and 35 Gy for CPC-B, in 5 fractions, requiring a 5-Gy dose reduction if the proportion of the liver receiving ≥ 20 Gy exceeded 20%. Treatment outcomes and safety were analyzed. Results. A total of 185 patients (n = 48 in the 35-Gy group; n = 137 in the 40-Gy group) were eligible, with a median follow-up duration of 24 months (range 3–80). The three-year local control and overall survival rates were 91% and 70%, respectively. There were no significant differences in outcomes between dose levels: the three-year local control and overall survival rates in the 35-Gy and 40-Gy groups were 91% and 89% (log-rank p = 0.99) and 66% and 72% (p = 0.54), respectively. Acute toxicities ≥ grade 3 were observed in 24 (13.0%) patients, and 19 (10.3%) patients had worsening of CPC score by two points. All but three (1.6%) patients promptly recovered to grade 1–2. Grade 5 liver failure occurred in two patients in the 35-Gy group. Conclusion. SBRT for HCC was safe and provided equivalent outcomes when administered either in 35 or 40 Gy/5 fractions.

Stereotactic body radiotherapy (SBRT) for oligometastatic lung tumors from colorectal cancer and other primary cancers in comparison with primary lung cancer

PURPOSE To analyze local control of oligometastatic lung tumors (OLTs) compared with that of primary lung cancer after stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS Retrospective record review of patients with OLTs who received SBRT with 50Gy in 5 fractions. Local control rates (LCRs), toxicities, and factors of prognostic significance were assessed. RESULTS Twenty-one colorectal OLTs, 23 OLTs from other origins, and 188 primary lung cancers were included. Multivariate analysis revealed only tumor origin was prognostically significant (p<0.05). The 1-year/2-year LCRs in colorectal OLTs and OLTs from other origins were 80%/72% and 94%/94%, respectively. The LCR in colorectal OLTs was significantly worse than that in OLTs from the other origins and primary lung cancers with pathological and clinical diagnosis (p<0.05, p<0.0001 and p<0.005). Among 44 OLT patients, Grades 2 and 3 radiation pneumonitis were identified in 2 and 1 patients, respectively. No other toxicities of more than Grade 3 occurred. CONCLUSION SBRT for OLTs is tolerable. The LCR for OLTs from origins other than colorectal cancer is excellent. However, LCR for colorectal OLTs is worse than that from other origins. Therefore dose escalation should be considered to achieve good local control for colorectal OLTs.

Proportion-corrected scaled voxel models for Japanese children and their application to the numerical dosimetry of specific absorption rate for frequencies from 30 MHz to 3 GHz

The development of high-resolution anatomical voxel models of children is difficult given, inter alia, the ethical limitations on subjecting children to medical imaging. We instead used an existing voxel model of a Japanese adult and three-dimensional deformation to develop three voxel models that match the average body proportions of Japanese children at 3, 5 and 7 years old. The adult model was deformed to match the proportions of a child by using the measured dimensions of various body parts of children at 3, 5 and 7 years old and a free-form deformation technique. The three developed models represent average-size Japanese children of the respective ages. They consist of cubic voxels (2 mm on each side) and are segmented into 51 tissues and organs. We calculated the whole-body-averaged specific absorption rates (WBA-SARs) and tissue-averaged SARs for the child models for exposures to plane waves from 30 MHz to 3 GHz; these results were then compared with those for scaled down adult models. We also determined the incident electric-field strength required to produce the exposure equivalent to the ICNIRP basic restriction for general public exposure, i.e., a WBA-SAR of 0.08 W kg(-1).

The maximum standardized uptake value (SUVmax) on FDG-PET is a strong predictor of local recurrence for localized non-small-cell lung cancer after stereotactic body radiotherapy (SBRT)

BACKGROUND The maximum standardized uptake value (SUVmax) of FDG-PET may predict local recurrence for localized non-small-cell lung cancer (NSCLC) after stereotactic body radiotherapy (SBRT). METHODS Among 195 localized NSCLCs that were treated with total doses of either 40Gy or 50Gy in 5 SBRT fractions, we reviewed those patients who underwent pre-treatment FDG-PET using a single scanner for staging. Local control rates (LCRs) were obtained by the Kaplan-Meier method and a log-rank test. Prognostic significance was assessed by univariate and multivariate analyses. RESULTS A total of 95 patients with 97 lesions were eligible. Median follow-up was 16.0months (range: 6.0-46.3months). Local recurrences occurred in 9 lesions. By multivariate analysis, only the SUVmax of a primary tumor was a significant predictor (p=0.002). Two years LCRs for lower SUVmax (<6.0; n=78) and higher SUVmax (⩾6; n=19) were 93% and 42%, respectively. In subgroups with T1b and T2, LCRs were significantly better for lower SUVmax than for higher SUVmax (p<0.0005 and p<0.01). In both subgroups that received 40Gy and 50Gy, LCRs were also significantly better for lower SUVmax than for higher SUVmax (p<0.001 and p<0.01). CONCLUSIONS SUVmax was the strongest predictor for local recurrence. A high SUVmax may be considered for dose escalation to improve local control. Additional follow-up is needed to determine if SUVmax is correlated with regional recurrence, distant metastasis, and survival.

Hypofractionated stereotactic radiotherapy with and without transarterial chemoembolization for small hepatocellular carcinoma not eligible for other ablation therapies: Preliminary results for efficacy and toxicity

Aim:  To investigate the efficacy and toxicity of hypofractionated stereotactic radiotherapy for the treatment of patients presenting with hepatocellular carcinoma (HCC) in a single institutional setting.

Acute exacerbation of subclinical idiopathic pulmonary fibrosis triggered by hypofractionated stereotactic body radiotherapy in a patient with primary lung cancer and slightly focal honeycombing

Hypofractionated stereotactic body radiotherapy (SBRT) for pulmonary lesions provides a high local control rate, allows completely painless ambulatory treatment, and is not associated with adverse reactions in most cases. Here we report a 70-year-old lung cancer patient with slight focal pulmonary honeycombing in whom subclinical idiopathic pulmonary fibrosis was exacerbated by SBRT. This experience has important implications for the development of selection criteria prior to SBRT for pulmonary lesions. For SBRT candidates with lung tumors, attention must be paid to the presence of co-morbid interstitial pneumonia even if findings are minimal. Such patients must be informed of potential risks, and careful decision-making must take place when SBRT is being considered.

Stereotactic Ablative Body Radiation Therapy for Octogenarians With Non-Small Cell Lung Cancer

PURPOSE To retrospectively investigate treatment outcomes of stereotactic ablative body radiation therapy (SABR) for octogenarians with non-small cell lung cancer (NSCLC). METHODS AND MATERIALS Between 2005 and 2012, 109 patients aged ≥80 years with T1-2N0M0 NSCLC were treated with SABR: 47 patients had histology-unproven lung cancer; 62 patients had pathologically proven NSCLC. The prescribed doses were either 50 Gy/5 fractions for peripheral tumors or 40 Gy/5 fractions for centrally located tumors. The treatment outcomes, toxicities, and the correlating factors for overall survival (OS) were evaluated. RESULTS The median follow-up duration after SABR was 24.2 (range, 3.0-64.6) months. Only limited toxicities were observed, except for 1 grade 5 radiation pneumonitis. The 3-year local, regional, and distant metastasis-free survival rates were 82.3%, 90.1%, and 76.8%, respectively. The OS and lung cancer-specific survival rates were 53.7% and 70.8%, respectively. Multivariate analysis revealed that medically inoperable, low body mass index, high T stage, and high C-reactive protein were the predictors for short OS. The OS for the operable octogenarians was significantly better than that for inoperable (P<.01). CONCLUSIONS Stereotactic ablative body radiation therapy for octogenarians was feasible, with excellent OS. Multivariate analysis revealed that operability was one of the predictors for OS. For medically operable octogenarians with early-stage NSCLC, SABR should be prospectively compared with resection.

DOSE DISTRIBUTION ANALYSIS IN STEREOTACTIC BODY RADIOTHERAPY USING DYNAMIC CONFORMAL MULTIPLE ARC THERAPY

PURPOSE We have used dynamic conformal multiple arc therapy (DCMAT) for stereotactic body radiotherapy (SBRT) since 2001. We investigated the consistency of DCMAT for SBRT using dose-volume histogram analysis. METHODS AND MATERIALS A total of 50 patients with peripheral lung tumors underwent SBRT. The median tumor diameter was 2.4 cm (range, 0.9-5.9). Treatment planning was performed using a superposition algorithm. The prescribed 50 Gy dose was divided into five fractions. The prescribed dose was defined as 80% of the maximal dose in the planning target volume (PTV), and the leaf margins were modified to ensure the PTV was included in the 80% isodose surface. The dose-volume histogram analysis was used to assess the PTV and normal lung volume. RESULTS The median dose covering 95% of the PTV was 50.27 Gy (range, 46.14-52.67), essentially consistent with the prescribed dose. The median homogeneity and conformity index was 1.41 (range, 1.31-1.53) and 1.73 (range, 1.41-2.21), respectively. The median volume of lung receiving > or =20 Gy (V(20)) was 4.2% (range, 1.4-10.2%). A linear correlation was found between the tumor diameter and V(20), and an even stronger correlation was found between the PTV/(normal lung volume) and V(20). The estimated V(20) was 7.1% (range, 3.9-10.4%) for a 5-cm-diameter tumor, assumed to be the maximal size limitation for SBRT. CONCLUSION SBRT with DCMAT achieved high conformity and delivered adequate doses within the PTV. The median dose covering 95% of the PTV was consistent with the prescribed dose. V(20) can be estimated using the tumor diameter and normal lung volume. DCMAT was thus both a feasible and a reproducible method of SBRT delivery.