Yohei Oku

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 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.

Severe COPD Is Correlated With Mild Radiation Pneumonitis Following Stereotactic Body Radiotherapy

BACKGROUND The primary cause of COPD and lung cancer is smoking. Thus, patients with COPD frequently have lung cancer that often is inoperable. Stereotactic body radiation therapy (SBRT) is anticipated to be the standard of care for inoperable early stage non-small cell lung cancer. The most critical toxicity following SBRT is radiation pneumonitis (RP). We analyzed predictive factors for RP following SBRT and investigated the degree and occurrence of RP in patients with severe COPD. METHODS We retrospectively evaluated 265 lung tumors treated with SBRT between 2005 and 2010 with a minimum follow-up of 6 months. Predictive factors for RP, including GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage and pack-years smoked, were evaluated by univariate and multivariate analyses. RP was graded according to the Common Terminology Criteria for Adverse Events version 3.0 scale. RESULTS Median follow-up was 19.2 months (range, 6.0-72.0 months). RP grades of 0, 1, 2, 3, 4, and 5 occurred in 101, 102, 49, 12, 0, and one of these patients, respectively. Multivariate analysis revealed that high normal lung volume receiving ≥ 20 Gy, fewer pack-years smoked, and high total dose were significant predictive factors for RP ≥ grade 1, and high normal lung volume receiving 20 Gy, fewer pack-years smoked, and a history of lung resection were predictive for RP ≥ grade 2. RP in patients with more severe COPD was relatively milder than in patients with normal lung function and with mild COPD. Pack-year scales were significantly correlated with GOLD stage. CONCLUSIONS RP following SBRT in patients with severe COPD was relatively mild. Heavy smoking was the strongest negative predictor for severe RP and was correlated with severe COPD. Further follow-up and quantitative analysis of lung function might be needed to ascertain longer tolerability to SBRT.

Maximum Standardized Uptake Value on FDG-PET Is a Strong Predictor of Overall and Disease-Free Survival for Non–Small-Cell Lung Cancer Patients after Stereotactic Body Radiotherapy

Introduction: The maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography is a predictor for overall survival (OS) in non–small-cell lung cancer (NSCLC) after resection. We investigated the association between SUVmax and outcomes in NSCLC after stereotactic body radiotherapy. Methods: Between 2005 and 2012, 283 patients with early NSCLC (T1a-2N0M0) were treated with stereotactic body radiotherapy; the total doses were 40 to 60 Gy in five fractions. Patients who underwent staging 18F-fluorodeoxyglucose positron emission tomography scans by a single scanner and were followed up for more than or who died within 6 months were eligible. The optimal threshold SUVmax was calculated for each outcome. Outcomes were analyzed using the Kaplan–Meier method and log-rank test. Prognostic significance was assessed by univariate and multivariate analyses. Results: One hundred fifty-two patients were eligible. Median follow-up was 25.3 (range, 1.3–77.4) months. Local, regional, and distant recurrences, cancer-specific deaths, and deaths from other reasons occurred in 14, 11, 27, 21, and 31 patients, respectively. The optimal threshold SUVmax for local, regional, and distant recurrences, and disease-free survival (DFS), cancer-specific survival, and OS were 2.47 to 3.64. Outcomes of patients with SUVmax lower than each threshold were significantly better than those with higher SUVmax (all p<0.005): 3-year DFS rates were 93.0% versus 58.3% (p<0.001) and 3-year OS rates were 86.5% versus 42.2% (p<0.001), respectively. By multivariate analysis, higher SUVmax was a significantly worse predictor for DFS (p<0.01) and OS (p=0.04). Conclusions: SUVmax was a predictor for DFS and OS. A high SUVmax may be considered for intensive treatment to improve outcomes.

Acceptable Toxicity After Stereotactic Body Radiation Therapy for Liver Tumors Adjacent to the Central Biliary System

PURPOSE To evaluate biliary toxicity after stereotactic body radiation therapy (SBRT) for liver tumors. METHODS AND MATERIALS Among 297 consecutive patients with liver tumors treated with SBRT of 35 to 50 Gy in 5 fractions, patients who were irradiated with >20 Gy to the central biliary system (CBS), including the gallbladder, and had follow-up times >6 months were retrospectively analyzed. Toxicity profiles, such as clinical symptoms and laboratory and radiologic data especially for obstructive jaundice and biliary infection, were investigated in relation to the dose volume and length relationship for each biliary organ. RESULTS Fifty patients with 55 tumors were irradiated with >20 Gy to the CBS. The median follow-up period was 18.2 months (range, 6.0-80.5 months). In the dose length analysis, 39, 34, 14, and 2 patients were irradiated with >20 Gy, >30 Gy, >40 Gy, and >50 Gy, respectively, to >1 cm of the biliary tract. Seven patients were irradiated with >20 Gy to >20% of the gallbladder. Only 2 patients experienced asymptomatic bile duct stenosis. One patient, metachronously treated twice with SBRT for tumors adjacent to each other, had a transient increase in hepatic and biliary enzymes 12 months after the second treatment. The high-dose area >80 Gy corresponded to the biliary stenosis region. The other patient experienced biliary stenosis 5 months after SBRT and had no laboratory changes. The biliary tract irradiated with >20 Gy was 7 mm and did not correspond to the bile duct stenosis region. No obstructive jaundice or biliary infection was found in any patient. CONCLUSIONS SBRT for liver tumors adjacent to the CBS was feasible with minimal biliary toxicity. Only 1 patient had exceptional radiation-induced bile duct stenosis. For liver tumors adjacent to the CBS without other effective treatment options, SBRT at a dose of 40 Gy in 5 fractions is a safe treatment with regard to biliary toxicity.

Evaluation for local failure by 18F-FDG PET/CT in comparison with CT findings after stereotactic body radiotherapy (SBRT) for localized non-small-cell lung cancer

PURPOSE Stereotactic body radiotherapy (SBRT) is the standard care for medically inoperable early non-small-cell lung cancer (NSCLC). However, it can be difficult to differentiate local recurrence from non-recurrence radiation-induced lung opacity. We retrospectively assessed (18)F-FDG PET/CT to detect local recurrence after SBRT for NSCLC. METHODS Between 2005 and 2011, 273 NSCLCs in 257 patients were treated with SBRT. Prescribed doses were 50Gy and 40Gy per 5 fractions for peripheral and central lesions, respectively. Tri-monthly follow-up CT scans were acquired. (18)F-FDG PET/CT scans were scheduled for screening at one year after SBRT or when recurrence was highly suspected. The dual-time-point maximum standardized uptake values (SUVmaxs) and their retention indexes (RIs) were obtained. RESULTS A total of 214 (18)F-FDG PET/CT scans were obtained for 164 localized NSCLC tumors in 154 patients. The median follow-up period was 24.9 months (range: 6.3-72.1). Among these, 21 scans of 17 tumors were diagnosed as local recurrence. The median SUVmaxs on early and late images of recurrence and their RI were 5.0 (range: 3.2-10.7), 6.3 (range: 4.2-13.4), and 0.20 (range; 0-0.41), respectively. These were significantly higher than the respective values of non-recurrence images of 1.8 (range: 0.5-4.6), 1.7 (range: 0.5-6.1), and 0.00 (range: -0.37-0.41) (all p<0.05). For SUVmaxs on early and late images, optimal thresholds were identified as 3.2 and 4.2. Using each threshold, the sensitivity and specificity were 100% and 96-98%, respectively. CT findings were classified into ground-glass opacity (N=9), scar or fibrotic change (N=96), consolidation with air-bronchogram (N=34), consolidation only (N=22), and nodule (N=17); the respective numbers of recurrence were 0, 0, 1, 3, and 17. CONCLUSION SUVmaxs of (18)F-FDG PET/CT could detect local recurrence after SBRT for localized NSCLC. In contrast, CT scan results had a limited ability to diagnose local recurrence.

Stereotactic body radiotherapy (SBRT) for solitary pulmonary nodules clinically diagnosed as lung cancer with no pathological confirmation: Comparison with non-small-cell lung cancer

INTRODUCTION In non-surgical candidates with solitary pulmonary nodules (SPNs) and no histological confirmation, optimal management remains uncertain. METHODS Between February 2005 and February 2011 we treated 298 lung cancers with stereotactic body radiotherapy (SBRT), including SPNs clinically diagnosed as lung cancer (CDLC). Among them, we extracted patients treated with a total dose of 40-50 Gy per 5 fractions and followed up more than 6 months. Patients who had a history of previously treated lung cancer, or were diagnosed pathologically, or suspected as having small-cell lung cancer or large cell neuroendcrine cancer were excluded from this study. The remaining patients were divided into two groups; CDLC and non-small-cell lung cancer (NSCLC) patients and their outcomes were assessed and compared. RESULTS Fifty-eight CDLC and 115 NSCLC patients were included in this study. The proportions of female and inoperable cases were significantly higher in the CDLC group. Other characteristics, including T stage and standard uptake value, were well balanced. Median follow-up durations were 20.2 (range, 6.0-58.8) and 21.2 (range, 6-63.7) months, respectively. The 3-year local control, regional-free, metastasis-free, progression-free, cause-specific survival, and overall survival rates were 80% and 87% (p = 0.73), 88% and 91% (p = 0.72), 70% and 74% (p = 0.57), 64% and 67% (p = 0.45), 74% and 71% (p = 0.17), 54% and 57% (p = 0.48), respectively. CONCLUSION These results indicate that the treatment outcome of CDLC group was almost identical to that of NSCLC and that few benign lesions seemed to be included. We advocate that SBRT can be legitimately applied to CDLC, provided that they are carefully diagnosed by integrating various clinical findings.

Toxicities of Organs at Risk in the Mediastinal and Hilar Regions Following Stereotactic Body Radiotherapy for Centrally Located Lung Tumors

Introduction: We investigated tolerable doses to organs at risk (OARs) in the mediastinum and pulmonary hilum following stereotactic body radiotherapy for centrally located lung tumors. Methods: Between 2005 and 2012, 381 patients with lung tumors were treated with stereotactic body radiotherapy of 40 to 60 Gy in five fractions. From among these patients, we extracted those who received greater than 25 Gy irradiation to OARs and analyzed dosimetric factors in relation to grade 3 to 5 toxicities. Results: In total, 398 OARs in 133 patients were analyzed, with a median follow-up of 33 (range, 3–87) months. The numbers receiving greater than 25 Gy irradiation to the aorta, vena cava, pulmonary artery, pulmonary vein, bronchus, trachea, heart, and esophagus were 72, 33, 73, 60, 55, 13, 69, and 23, respectively. The corresponding median Dmax 0.5 ml were 43.8, 32.0, 32.2, 29.1, 28.4, 28.7, 41.1, and 21.7 Gy. Of these patients, two developed grade 5 and one grade 3 hemoptysis, and two had grade 3 obstructive pneumonia. Two patients with grade 5 hemoptysis received high doses at the pulmonary artery and bronchus (59.2 and 54.4 Gy, and 61.3 and 59.6 Gy, respectively). No other grade 3 to 5 toxicities occurred. Conclusion: Therapeutic indications and dose-intensity should be carefully determined for patients with central tumors, especially when doses to the pulmonary artery and bronchus in the pulmonary hilum exceed 50 Gy. Tolerable doses for other OARs might, however, be higher than in this study, though longer follow-up is necessary to assess this possibility.