Organ sparing potential and inter-fraction robustness of adaptive intensity modulated proton therapy for lung cancer.

Background: The aim of this study was to compare adaptive intensity modulated proton therapy (IMPT) robustness and organ sparing capabilities with that of adaptive volumetric arc photon therapy (VMAT).Material and methods: Eighteen lung cancer patients underwent a planning 4DCT (p4DCT) and 5 weekly repeated 4DCT (r4DCT) scans. Target volumes and organs at risk were manually delineated on the three-dimensional (3D) average scans of the p4DCT (av_p4DCT) and of the r4DCT scans (av_r4DCT). Planning target volume (PTV)-based VMAT plans and internal clinical target volume (ICTV)-based robust IMPT plans were optimized in 3D on the av_p4DCT and re-calculated on the av_r4DCTs. Re-planning on av_r4DCTs was performed when indicated and accumulated doses were evaluated on the av_p4DCT.Results: Adaptive VMAT and IMPT resulted in adequate ICTV coverage on av_r4DCT in all patients and adequate accumulated-dose ICTV coverage on av_p4DCT in 17/18 patients (due to a shrinking target in one patient). More frequent re-planning was needed for IMPT than for VMAT. The average mean heart dose reduction with IMPT compared with VMAT was 4.6 Gy (p = .001) and it was >5 Gy for five patients (6, 7, 8, 15, and 22 Gy). The average mean lung dose reduction was 3.2 Gy (p < .001). Significant reductions in heart and lung V5 Gy were observed with IMPT.Conclusion: Robust-planned IMPT required re-planning more often than VMAT but resulted in similar accumulated ICTV coverage. With IMPT, heart and lung mean dose values and low dose regions were significantly reduced. Substantial cardiac sparing was obtained in a subgroup of five patients (28%).

Does VMAT for treatment of NSCLC patients increase the risk of pneumonitis compared to IMRT ? - a planning study.

BACKGROUND: Volumetric modulated arc therapy (VMAT) for treatment of non-small cell lung cancer (NSCLC) patients potentially changes the risk of radiation-induced pneumonitis (RP) compared to intensity modulated radiation therapy (IMRT) if the dose to the healthy lung is changed significantly. In this study, clinical IMRT plans were used as starting point for VMAT optimization and differences in risk estimates of RP between the two plan types were evaluated. MATERIAL AND METHODS: Fifteen NSCLC patients prescribed 66 Gy in 2 Gy fractions were planned with IMRT and subsequently with single arc VMAT. Dose metrics were evaluated for target and lung together with population averaged dose volume histograms. The risk of RP was calculated using normal tissue complication probability (NTCP) models. Finally, applicability of the plans was tested through delivery on an Elekta accelerator. RESULTS: When changing from IMRT to VMAT only modest differences were observed in the dose to the lung and target volume. On average, fractions of lung irradiated to doses between 18 Gy and 48 Gy were statistically significant reduced using VMAT compared to IMRT. For the fraction of lung receiving more than 20 Gy the reduction was 1.2% percentage points: (range -0.6 -2.6%). The evaluated toxicity were smaller with VMAT compared to IMRT, however only modest differences were observed in the NTCP values. The plans were delivered without any problems. The average beam on time with VMAT was 83 s. This was a reduction of 141 s (ranging from 37 s to 216 s) compared to IMRT. CONCLUSIONS: Using IMRT as reference for the VMAT optimization it was possible to implement VMAT in the clinic with no increase in estimated risk of RP. Thus, toxicity is not expected to be a hindrance to using VMAT and will profit from the shorter delivery time with VMAT compared to IMRT.

Evaluation of active breathing control-moderate deep inspiration breath-hold in definitive non-small cell lung cancer radiotherapy.

The purpose of this study is to evaluate the effect of Active Breathing Control-moderate deep inspiration breath-hold (ABC-mDIBH) on tumor motion and critical organ doses in non-small cell lung cancer (NSCLC) radiotherapy. 23 patients with locally advanced NSCLC were included in the study. All patients were scanned at free breathing and ABC-mDIBH for radiation treatment planning. 3 separate treatment plans were generated for each patient including one plan with ABC-mDIBH and uniform margins, one plan with free breathing and uniform margins, and one plan with free breathing and 3-dimensional non-uniform margins determined by Cone Beam Computed Tomography (CBCT) and XVI Motion View (X-ray Volume Imaging, Elekta, UK). Critical organ dose-volumes and physical lung parameters were comparatively evaluated on 3 separate dose-volume histograms of each patient acquired from planning software. Individual tumor motion of each patient with and without ABC-mDIBH was documented and compared. Use of ABC-mDIBH resulted in statistically significant improvement in physical lung parameters of V20 (lung volume receiving ≥ 20 Gy) and mean lung dose (MLD) which are predictors of radiation pneumonitis (p<0.001). Reduction in spinal cord dose and tumor motion with ABC-mDIBH was also statistically significant (p<0.001). ABC-mDIBH increases normal lung tissue sparing in definitive NSCLC radiotherapy by improving physical lung parameters along with spinal cord dose reduction through exact tumor immobilization. The incorporation of ABC-mDIBH into NSCLC radiotherapy may have implications for potential margin reduction and dose escalation to improve treatment outcomes.

Neuroendocrine prostate cancer xenografts with large-cell and small-cell features derived from a single patient's tumor: morphological, immunohistochemical, and gene expression profiles.

BACKGROUND: Small-cell carcinoma (SCC) of the prostate is an AR-negative variant of prostate cancer found at progression in 10-20% of castrate-resistant disease. Its finding predicts a distinct clinical course and a poor prognosis. Large-cell neuroendocrine carcinoma (LCNEC) is a much rarer variant that behaves similarly to SCC. The biological mechanisms that drive these disease variants are poorly understood. METHODS: Eight tumor fragments from the salvage pelvic exenteration specimen of a patient with castrate-resistant prostate carcinoma were subcutaneously implanted into 6- to 8-week-old male CB17 SCID mice. Serial tissue sections and tissue microarrays of the resulting MDA PCa 144 xenograft lines were used for histopathologic and immunohistochemical characterization of the xenografts and their tissue of origin. RNA from two representative xenograft sublines was used for gene-expression profiling. RESULTS: All eight fragments formed tumors: four of the MDA PCa 144 xenograft sublines had morphologic characteristics of SCC and four, of LCNEC. All retained high fidelity to their parent tumor tissue, which remained stable through serial passages. Morphological transitions in the specimen of origin suggested LCNEC represents an intermediate step between adenocarcinoma and SCC. Over 2,500 genes were differentially expressed between the SCC (MDA PCa 144-13) and the LCNEC (MDA PCa 144-4) sublines and enriched in "Nervous System Development" Gene Ontology subtree. CONCLUSION: The eight xenograft models described represent the spectrum of neuroendocrine carcinomas in prostate cancer and will be valuable preclinical tools to study the pathogenesis of and therapy targets for this increasingly recognized subset of lethal prostate cancer.

Prognostic impact of VEGF and VEGF receptor 1 (FLT1) expression in patients irradiated for stage II/III non-small cell lung cancer (NSCLC).

BACKGROUND AND PURPOSE: The prognostic value of the tumor expression of vascular endothelial growth factor (VEGF) and VEGF receptor 1 (FLT1) is still unclear. This study investigated the impact of tumor expression of VEGF and FLT1 on outcomes in 61 patients irradiated for stage II/III non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: The impact of tumor VEGF and FLT expression and twelve additional potential prognostic factors on locoregional control (LC), metastases-free survival (MFS), and overall survival (OS) were retrospectively evaluated. These factors included age, gender, performance status, histology, histological grade, T-category, N-category, surgery, chemotherapy, pack-years, smoking during radiotherapy, and hemoglobin levels during radiotherapy. RESULTS: On univariate analysis, improved LC was associated with lower T-category (p = 0.046), lower N-category (p = 0.047), and not smoking during radiotherapy (p = 0.012). VEGF (p = 0.26) and FLT1 expression (p = 0.70) had no significant impact. On multivariate analysis, lower N-category (p = 0.037) maintained significance; not smoking during radiotherapy was almost significant (p = 0.052). On univariate analysis, improved MFS was associated with lower T-category (p = 0.034) and lower N-category (p = 0.027), and almost with hemoglobin >or= 12 g/dl during radiotherapy (p = 0.053). VEGF (p = 0.80) and FLT1 expression (p = 0.61) had no significant impact. On multivariate analysis, lower N-category (p = 0.040) maintained significance. On univariate analysis, improved OS was associated with lower T-category (p = 0.028), lower N-category (p = 0.003), not smoking during radiotherapy (p = 0.047), and hemoglobin levels >or= 12 g/dl during radiotherapy (p = 0.019). VEGF (p = 0.59) and FLT1 expression (p = 0.85) had no significant impact. On multivariate analysis, lower N-category (p = 0.011) maintained significance. CONCLUSION: Tumor expression of VEGF and FLT1 appear to have no significant impact on LC, MFS, or OS in patients irradiated for NSCLC.

Surgical resection versus stereotactic body radiation therapy in early stage bronchopulmonary large cell neuroendocrine carcinoma.

BACKGROUND: Surgery is the standard of care for early stage non-small cell lung cancer (NSCLC). Stereotactic body radiotherapy (SBRT) is another definitive treatment option for those patients who have not been treated surgically. Comparison of approaches is being explored in NSCLC, but has yet to be compared exclusively in large cell neuroendocrine carcinoma (LCNEC) of the lung. We used the National Cancer Database (NCDB) to conduct such a comparison. METHODS: We accessed the NCDB for patients with LCNEC who were recorded as having lung stage T1-2N0M0 treated with lobectomy/pneumonectomy or SBRT. Multivariable logistic regression identified predictors of SBRT. Multivariable Cox regression was used to identify predictors of survival propensity matching and account for indication bias. RESULTS: A total of 3209 patients met the criteria, of which 238 (7%) received SBRT. The median SBRT dose was 50 Gy (48-60) in four fractions (3-5). Predictors of SBRT were age >68, T1 disease, and most recent year of treatment. Predictors of survival were younger age, surgical treatment, female sex, and T1 disease. After propensity matching, median survival was 57 months versus 35 months in favor of surgical resection, P < 0.0001. CONCLUSION: Surgical resection in comparison to SBRT has improved survival for patients with early stage LCNEC of the lung. SBRT represents a viable treatment alternative for those patients who do not meet the criteria for surgery.

The role of postoperative radiotherapy (PORT) in pulmonary large cell neuroendocrine carcinoma (PLCNEC).

PURPOSE: To assess the long-term survivals and related prognostic indicators of patients with pulmonary large cell neuroendocrine carcinoma (PLCNEC), and determine the prognostic value of post-operative radiotherapy in PLCNEC. MATERIALS AND METHODS: Patients diagnosed with PLCNEC between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were included in our study. Cox proportional hazard model was used to evaluate the factors related to overall survival (OS). Propensity score matching analysis (PSM analysis) was used to balance the variables differences between postoperative radiotherapy (PORT) and non-PORT groups. RESULTS: A total of 701 postoperative cases were identified, with the median follow-up time of 23 months. The 3- and 5-year OS were 50.7%, and 41.2%, respectively. Multivariate analysis revealed that stage I (P<0.001), age <65 years old (P<0.001), chemotherapy (P<0.001) were independent favorable prognostic factors. There is no significant difference in survival between patients with or without postoperative radiotherapy (PORT) after PSM analysis (P=0.489). No survival benefit in favor of PORT were displayed, even when subgroups were deeply analyzed. CONCLUSIONS: Age, stage, and chemotherapy were significantly associated with OS of patients with resected PLCNEC. However, PORT after resection did not improve long-term outcome of PLCNEC patients.

Large-cell neuroendocrine carcinoma of the uterine cervix complicating pregnancy.

Large-cell neuroendocrine cervical carcinoma is a rare and aggressive cancer that tends to spread and recur early despite intensive multimodal treatment. The optimal mode of therapy is still controversial and management during pregnancy is challenging because foetal well-being must also be considered. We report a patient with clinically stage IIB large-cell neuroendocrine cervical carcinoma who presented with a cervical polyp and vaginal bleeding at 18 weeks of pregnancy. The patient received concurrent chemotherapy and radiation after termination of pregnancy and remained in complete remission 21 months after completion of treatment.

Large Cell Neuroendocrine Carcinoma of the Mediastinum Successfully Treated with Systemic Chemotherapy after Palliative Radiotherapy.

Large cell neuroendocrine carcinoma (LCNEC) is a highly malignant cancer originally found in lung in 1991. In extremely rare occasions, primary LCNEC is found in the mediastinum; approximately 40 of such cases have been reported. Due to the limited number of reported cases, a standardized treatment protocol has yet to be established. We report a case of a 66-year-old woman with primary mediastinal LCNEC who presented with superior vena cava syndrome. Emergent radiotherapy was performed, followed by systemic chemotherapy with cisplatin and etoposide, which resulted in a dramatic tumor reduction. This is the first report describing the achievement of a complete response after systemic chemotherapy in a patient with primary LCNEC.

Quantitative assessment of range fluctuations in charged particle lung irradiation.

PURPOSE: Water equivalent path length (WEL) variations due to respiration can change the range of a charged particle beam and result in beam overshoot to critical organs or beam undershoot to tumor. We have studied range fluctuations by analyzing four-dimensional computed tomography data and quantitatively assessing potential beam overshoot. METHODS AND MATERIALS: The maximal intensity volume is calculated by combining the gross tumor volume contours at each respiratory phase in the four-dimensional computed tomography study. The first target volume calculates the maximal intensity volume for the entire respiratory cycle (internal target volume [ITV]-radiotherapy [RT]), and the second target volume is the maximal intensity volume corresponding to gated RT (gated-RT, approximately 30% phase window around exhalation). A compensator at each respiratory phase is calculated. Two "composite" compensators for ITV-RT and gated-RT are then designed by selecting the minimal compensator depth at the respective respiratory phase. These compensators are then applied to the four-dimensional computed tomography data to estimate beam penetration. Analysis metrics include range fluctuation and overshoot volume, both as a function of gantry angle. We compared WEL fluctuations observed in treating the ITV-RT versus gated-RT in 11 lung patients. RESULTS: The WEL fluctuations were <21.8 mm-WEL and 9.5 mm-WEL for ITV-RT and gated-RT, respectively for all patients. Gated-RT reduced the beam overshoot volume by approximately a factor of four compared with ITV-RT. Such range fluctuations can affect the efficacy of treatment and result in an excessive dose to a distal critical organ. CONCLUSION: Time varying range fluctuation analysis provides information useful for determining appropriate patient-specific treatment parameters in charged particle RT. This analysis can also be useful for optimizing planning and delivery.

High dose rate endobronchial brachytherapy in the management of lung cancer: response and toxicity evaluation in 158 patients.

The aim of this study was to evaluate the symptomatic and endoscopic responses as well as the toxicities in 158 patients with endobronchial lung cancer treated with high dose rate endobronchial brachytherapy (HDR-EB). Forty-three patients with stage III NSCLC were treated with 60Gy external beam radiotherapy (ERT) and three applications of 5Gy each of HDR-EB (group A). Seventy-four patients who did not receive previous RT were treated with 30Gy ERT and two applications of 7.5Gy HDR-EB with palliative intent (group B). Forty-one patients with recurrent tumor who were irradiated previously were treated with three applications of 7.5Gy HDR-EB, with palliative intent (group C). In group A, bronchoscopic complete (CR) and overall response rates (ORR) were 67% and 86%, respectively. Symptomatic improvement was obtained in 58% of patients with cough, 77% of patients with dyspnea and 100% of patients with hemoptysis. Two and 5-year survival rates were 25.5% and 9.5%, respectively and the median survival time (MST) was 11 months. In group B, the bronchoscopic CR and ORR were 39% and 77%, respectively and 28% and 72% in group C. The symptomatic response rates were 57% and 55% for cough, 90% and 78% for dyspnea and 94% and 77% for hemoptysis, with a MST of 7 and 6 months in Groups B and C, respectively. Eighteen patients (11%) died of fatal hemoptysis (FH) with the median time to this event of 7 months. Treatment intent (p<0.001), total BED (p<0.001) and the number of HDR-EB fractions (p<0.001) were significant prognostic factors for FH. HDR-EB provides effective palliation in relieving the symptoms of patients with endobronchial lung cancer, however, there is a risk of developing FH that is associated with a high BED and multiple HDR-EB applications.

Survival impact of postoperative radiotherapy timing in pediatric and adolescent medulloblastoma.

Background: Radiation therapy (RT) remains a critical component of multimodality treatment for medulloblastoma. Traditionally, clinicians strive to start RT within 4-5 weeks of surgery, but the optimal timing after surgery remains unclear. Methods: Using the National Cancer Database, we identified pediatric and adolescent patients with medulloblastoma treated with curative-intent surgery, RT, and chemotherapy. Factors associated with early or delayed RT were identified using Pearson chi-squared tests. Overall survival (OS) differences based on RT timing were compared using the Kaplan-Meier estimator with log-rank tests. Patient, tumor, and treatment characteristics associated with OS were analyzed with univariate and multivariate Cox proportional hazards models. Results: Among the 1338 patients analyzed, early RT (defined as initiation ≤3 wk after surgery) was associated with younger age, M1-3 disease, and subtotal resection. Patients who initiated RT early had decreased 5-year OS compared with patients who initiated RT 3.1-4, 4.1-5, or >5 weeks after surgery (72.5% vs. 80.5%, 79.4%, and 77.8%, respectively; P = 0.019), but there was no significant difference in OS among the latter 3 groups (P = 0.788). On multivariate analysis, early RT versus the 3.1- to 4-week interval was significantly associated with poorer OS (adjusted hazard ratio, 1.72; 95% CI: 1.19-2.48; P = 0.004), while time to RT of >5 weeks but within 90 days of surgery did not adversely impact OS (P = 0.563). Conclusions: In this large national database analysis, delaying RT within 90 days of surgery was not associated with inferior outcomes. Although clinical judgment remains paramount, postoperative RT timing should allow for healing and the development of an optimal treatment plan.

Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer.

BACKGROUND: Emerging data support aggressive local treatment of oligometastatic non-small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker. MATERIALS AND METHODS: We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS). RESULTS: On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014). CONCLUSION: The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.

Re-irradiation in lung disease by SBRT: a retrospective, single institutional study.

BACKGROUND: The loco regional relapse is frequent in the lung disease. The aim of this study was to evaluate the outcomes of re-irradiation by SBRT in terms of Local Control (LC) and toxicities. METHODS: From April 2011 to December 2016, twenty-two patients received a re-irradiation by SBRT. Twenty- seven lesions were treated. The medium BED(10) of re-irradiation was 100.6 Gy (range: 48-151.2 Gy) and the medium EQD2(10) was 93.8 Gy (range: 40-126 Gy). In the previous treatment the medium BED(10) was 97.2 Gy (range: 40-120 Gy), the medium EQD2(10) was 81 Gy (range: 32.5-100 Gy). The median time between the first and the second treatment was 18 months. RESULTS: Local Control was reached in 18 out of 27 (66%) re-irradiated lesions, with rates of 67 and 54% at 1- year and 2- years respectively. The treatment was well tolerated; the maximum recorded toxicity was Grade 3. CONCLUSIONS: Re- irradiation by SBRT may represent an option for the treatment of lung disease with good results in terms of LC and toxicity.

Is pulmonary artery a dose-limiting organ at risk in non-small cell lung cancer patients treated with definitive radiotherapy?

PURPOSE: Our previous study suggested that some pulmonary artery (PA) dosimetric parameters were associated with mortality in unresectable non-small cell lung cancer (NSCLC) treated with definitive radiotherapy. The present study aims to analyze the impact of both PA and heart dosimetric parameters on survival of patients with NSCLC treated with definitive conventional fractionated radiotherapy (CFRT) in another independent research center and further determine whether the PA should be considered a dose-limiting organ at risk (OAR) for patients receiving thoracic CFRT. METHODS: We performed a retrospective analysis of successive patients with medically inoperable or unresectable NSCLC treated with definitive radiotherapy or chemoradiotherapy from August 2010 to September 2014. Clinical and pathological information, PA and heart dosimetric factors, and follow-up data were collected from each patient's records and evaluated as potential prognostic factors for survival. Survival probabilities were estimated by the Kaplan-Meier method and compared by the log rank test. Cox proportional hazards regression models were performed to determine the independent predicators of survival. The optimal cutoff points of continuous dosimetric variables were determined by Youden index in receiver operating characteristic (ROC) analysis. RESULTS: This study analyzed the records of 141 patients, 50.4% had adenocarcinoma, 71.6% had stage III disease, and 55% patients received concurrent chemoradiotherapy. Radiation dose ranged from 60 to 76 Gy in 30-38 fractions. Median follow up was 16.9 months. Median overall survival (OS) was 20.5 months (95% confidence interval [CI] 10.3-30.7 months), and 1-, 2-, 3-year OS rates were 75.2%, 58.2% and 56%, respectively. Univariate and multivariate analysis showed that Karnofsky Performance Status (KPS) score, Charlson's Comorbidity Index (CCI), T and N stage, PA invasion grade and the percentage of PA volume that received 40 to 55 Gy (PA V40-55) were significantly associated with OS. No significant associations were found between heart dosimetric factors and OS. Median OS of patients with PA invasion grade 0, 1, 2, and 3 were 41.8, 27.8, 12.7 and 7.5 months, respectively (P < 0.001). PA V40, V45, V50 and V55, using thresholds of 80%, 68%, 45%, and 32%, respectively, were independent predictors for OS. CONCLUSIONS: PA invasion grade and PA V40-55 appear associated with OS in patients with NSCLC treated with definitive CFRT. We propose that PA be considered as a dose-limiting OAR for such patients.

Prognostic analysis of radiation pneumonitis: carbon-ion radiotherapy in patients with locally advanced lung cancer.

BACKGROUND: Carbon-ion radiotherapy (CIRT) is a promising treatment for locally advanced non-small-cell lung cancer, especially for patients with inoperable lung cancer. Although the incidence of CIRT-induced radiation pneumonitis (RP) ≥ grade 2 ranges from 2.5 to 9.9%, the association between CIRT-induced RP and dosimetric parameters is not clear. Herein, we identified prognostic factors associated with symptomatic RP after CIRT for patients with non-small-cell lung cancer. METHODS: Clinical results of 65 patients treated with CIRT between 2000 and 2015 at the National Institute of Radiological Sciences were retrospectively analyzed. Clinical stage II B disease (TNM classification) was the most common stage among the patients (45%). The median radiation dose was 72 Gy (68-76) relative biological effectiveness (RBE) in 16 fractions. In cases involving metastatic lymph nodes, prophylactic irradiation of mediastinal lymph nodes was performed at a median dose of 49.5 Gy (RBE). The median follow-up was 22 months. RESULTS: Grade 2 and grade 3 RP occurred in 6 and 3 patients (9 and 5%), respectively. No patients developed grade 4 or 5 RP. Using univariate analysis, vital capacity as a percentage of predicted (%VC), forced expiratory volume in 1 s (FEV1), mean lung dose (MLD), volume of lung receiving ≥5 Gy (RBE) (V5), V10, V20 and V30 were determined to be the significant predictive factors for ≥ grade 2 RP. The receiver operating characteristic (ROC) analysis revealed the cutoff values for %VC, FEV1, MLD, V5, V10, V20 and V30 for ≥ grade 2 RP, which were 86.9%, 1.16 L, 12.5 Gy (RBE), 28.8, 29.9, 20.1 and 15.0%, respectively. In addition, the multivariate analysis revealed that %VC <86.9% (odds ratio = 13.7; p = 0.0041) and V30 ≥ 15% (odds ratio = 6.1; p = 0.0221) were significant risk factors. CONCLUSIONS: Our study demonstrated the risk factors for ≥ grade 2 RP after carbon-ion radiotherapy for patients with locally advanced lung cancer.

A Dose Escalation Clinical Trial of Single-Fraction Carbon Ion Radiotherapy for Peripheral Stage I Non-Small Cell Lung Cancer.

OBJECTIVES: Our objective was to report initial results of a dose escalation trial of single-fraction carbon ion radiotherapy for peripheral stage I NSCLC. METHODS: Between April 2003 and February 2012, a total of 218 patients were treated. The total dose was raised from 28 to 50 Gy (relative biological effectiveness [RBE]). There were 157 male and 61 female patients, with a median age of 75 years. Of the tumors, 123 were stage T1 and 95 were stage T2. A total of 134 patients (61.5%) were medically inoperable. By histological type, there were 146 adenocarcinomas, 68 squamous cell carcinomas, three large cell carcinomas, and one mucoepidermoid carcinoma. RESULTS: The median follow-up was 57.8 months (range 1.6-160.7). The overall survival rate at 5 years was 49.4%. The local control (LC) rate was 72.7%. A statistically significant difference in LC rate (p = 0.0001, log-rank test) was seen between patients receiving 36 Gy (RBE) or more and those receiving less than 36 Gy (RBE). In 20 patients irradiated with 48 to 50 Gy (RBE), the LC rate at 5 years was 95.0%, the overall survival rate was 69.2%, and the progression-free survival rate was 60.0% (median follow-up was 58.6 months). With dose escalation, LC tended to improve. As for adverse lung and skin reactions, there were no patients with grade 3 or higher reactions, and less than 2% had a grade 2 reaction. Regarding chest wall pain, only one patient had grade 3 late toxicity. CONCLUSIONS: We have reported the outcome of a dose escalation study of single-fraction carbon ion radiotherapy for stage I NSCLC, showing the feasibility of obtaining excellent results comparable to those with previous fractionated regimens.

CT scan prior to radiotherapy in unresectable, locally advanced, non-small cell carcinoma of the lung: is it always necessary?

PURPOSE: There is broad consensus regarding evaluating response to chemotherapy (CHT) by means of computerized tomography (CT) in patients with localized or locally advanced non-small cell lung carcinoma (NSCLC). We present a study comparing the usefulness of CT versus chest X-ray (XR) and clinical findings when indicating radiotherapy (RT) following CHT. METHODS: Ninety-eight of 150 subjects with unresectable locally advanced NSCLC were blindly and independently evaluated by XR and CT, with pairs of chest XR and CT (before and after CHT). A null hypothesis (H0) was established of the conditioned probability of detecting progression by CT and not by XR of 10 % or more, with a statistical power of 80 %. RESULTS: Sensitivity, specificity, positive and negative predictive value of XR versus CT were 98, 89, 99, and 80 % respectively. A 4 % (p = 0.0451) probability of improvement of CT versus XR was calculated, enabling the H0 to be ruled out. CONCLUSION: The CT failed to prove to be significantly superior to the chest XR + clinical picture in indicating a change in treatment approach in patients with unresectable locally advanced NSCLC after CHT.

Choice of postoperative radiation for stage IIIA pathologic N2 non-small cell lung cancer: impact of metastatic lymph node number.

BACKGROUND: Postoperative radiation (PORT) is an option for non-small cell lung cancer (NSCLC) patients with resectable stage IIIA pathological N2 status (pN2). For patients with PORT, this study aims to investigate the impact of the exact number of positive lymph nodes (LNs) on overall survival (OS) and lung cancer-specific survival (LCSS). METHODS: Within the Surveillance, Epidemiology, and End Results database, we identified 3373 patients with stage IIIA pathological N2 status (pN2) NSCLC who underwent a lobectomy or pneumonectomy from 2004 to 2013. OS and LCSS were compared among patients coded as receiving PORT or observation. The proportional hazards model was applied for investigation. RESULTS: OS and LCSS favored PORT for patients with stage IIIA (pN2) NSCLC. Multivariable analyses showed that PORT and the exact number of positive LNs (n ≤ 3) were independently associated with better OS and LCSS. Both better OS and LCSS emerged for positive LNs (n > 3) after the use of PORT in survival analyses, whereas the benefits of OS and LCSS were not observed anymore for positive LNs (n ≤ 3) group. More importantly, multivariable analyses showed that the use of PORT is an independent risk factor of survival for positive LNs (n > 3) but not for positive LNs (n ≤ 3). CONCLUSIONS: In Stage IIIA (pN2) NSCLC, the use of PORT demonstrated better survival results than no PORT for patients with positive LNs (n > 3), but not for patients with positive LNs (n ≤ 3).