Long term outcome after 48 Gy stereotactic ablative body radiotherapy for peripheral stage I non-small cell lung cancer.

BACKGROUND: To evaluate the outcome of patients treated with stereotactic ablative body radiotherapy (SABR) with curative intent for stage I non-small cell lung cancer (NSCLC) with regard to local, regional and distant tumor control, disease-free survival (DFS), overall survival (OS) and toxicity. METHODS: Data of 300 patients treated with SABR for NSCLC cancer for the period of November 2007 to June 2016 were retrospectively analyzed. Of which, 189 patients had single primary lung lesion and were included in the study. The prescribed dose for the tumor was 48 Gy, given in 12 Gy × 4 fractions for all patients. In 2010, an improved protocol was established in advanced technology for the planning CT, dose calculation and imaging. Cumulative incidence function (CIF) of local, regional, distant or any recurrences were computed using competing risk analysis with death as a competing event. Survivals (DFS and OS) were estimated using the Kaplan-Meier method and Cox proportional regression was used for comparisons. Toxicities were graded according to the common terminology criteria for adverse events version 4.0 (CTCAE v.4). RESULTS: Diagnosis was histologically confirmed in 42% of the patients (N = 80). At 1, 2 and 4 years, the cumulative incidence function (CIF) of local relapses were 8% [4-13%], 15% [10-21%] and 18% [12-25%], the CIF of regional relapses were 4% [2-8%], 10% [6-16%] and 12% [8-19%], the CIF of distant relapses were 9% [5-14%], 15% [11-22%] and 20% [15-28%] and the CIF of any relapses were 14% [10-20%], 28% [22-36%], 34% [27-43%], respectively. After 1, 2 and 4 years, the OS rates were 83% [95% CI: 78-89%] (N = 128), 65% [95% CI: 57-73%] (N = 78) and 37% [95% CI: 29-47%] (N = 53), respectively. The median survival time was 37 months. The DFS after 1, 2 and 4 years reached 75% [95% CI: 68-81%] (N = 114), 49% [95% CI: 42-58%] (N = 60) and 31% [95% CI: 24-41%] (N = 41), respectively. No grade 4 or 5 toxicity was observed. CONCLUSIONS: We observed a long-term local control and survival after SABR for peripheral stage I NSCLC in this large series of patients with the expected low toxicity.

Complete tumor response of a locally advanced lung large-cell neuroendocrine carcinoma after palliative thoracic radiotherapy and immunotherapy with nivolumab.

Lung large-cell neuroendocrine carcinoma (L-LCNEC) is a rare subset of lung carcinoma associated with poor overall survival. Due to its rarity, little has been established about its optimal treatment in the advanced stage. We report the case of a 41-year-old woman diagnosed with an unresectable locally advanced L-LCNEC who presented an impressive tumor response to immunotherapy with nivolumab after non-curative thoracic radiotherapy. Salvage surgery was then performed, and pathologic analysis of the resected piece revealed the absence of residual viable tumor cells. Based on this case report, we discuss the literature regarding the efficacy of inhibitors of programmed death-1 protein (PD-1) in L-LCNEC and their use in association with radiotherapy and in the neoadjuvant setting.

An individualized radiation dose escalation trial in non-small cell lung cancer based on FDG-PET imaging.

AIM: The aim of the study was to assess the feasibility of an individualized 18F fluorodeoxyglucose positron emission tomography (FDG-PET)-guided dose escalation boost in non-small cell lung cancer (NSCLC) patients and to assess its impact on local tumor control and toxicity. PATIENTS AND METHODS: A total of 13 patients with stage II-III NSCLC were enrolled to receive a dose of 62.5 Gy in 25 fractions to the CT-based planning target volume (PTV; primary turmor and affected lymph nodes). The fraction dose was increased within the individual PET-based PTV (PTVPET) using intensity modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) until the predefined organ-at-risk (OAR) threshold was reached. Tumor response was assessed during follow-up by means of repeat FDG-PET/computed tomography. Acute and late toxicity were recorded and classified according to the CTCAE criteria (Version 4.0). Local progression-free survival was determined using the Kaplan-Meier method. RESULTS: The average dose to PTVPET reached 89.17 Gy for peripheral and 75 Gy for central tumors. After a median follow-up period of 29 months, seven patients were still alive, while six had died (four due to distant progression, two due to grade 5 toxicity). Local progression was seen in two patients in association with further recurrences. One and 2-year local progression free survival rates were 76.9% and 52.8%, respectively. Three cases of acute grade 3 esophagitis were seen. Two patients with central tumors developed late toxicity and died due to severe hemoptysis. CONCLUSION: These results suggest that a non-uniform and individualized dose escalation based on FDG-PET in IMRT delivery is feasible. The doses reached were higher in patients with peripheral compared to central tumors. This strategy enables good local control to be achieved at acceptable toxicity rates. However, dose escalation in centrally located tumors with direct invasion of mediastinal organs must be performed with great caution in order to avoid severe late toxicity.

Validation of the mid-position strategy for lung tumors in helical TomoTherapy.

PURPOSE: To compare the mid-position (MidP) strategy to the conventional internal target volume (ITV) for lung tumor management in helical TomoTherapy, using 4D Monte Carlo (MC) plan simulations. MATERIALS AND METHODS: For NSCLC patients treated by SBRT (n = 8) or SIB-IMRT (n = 7), target volumes and OARs were delineated on a contrast-enhanced CT, while 4D-CT was used to generate either ITV or MidP volumes with deformable registrations. PTV margins were added. Conformity indexes, volumetric and dosimetric parameters were compared for both strategies. Dose distributions were also computed using a 4D MC model (TomoPen) to assess how intra-fraction tumor motion affects tumor coverage, with and without interplay effect. RESULTS: PTVs derived from MidP were on average 1.2 times smaller than those from ITV, leading to lower doses to OARs. Planned dose conformity to TVs was similar for both strategies. 4D MC computation showed that ITV ensured adequate TV coverage (D95 within 1% of clinical requirements), while MidP failed in 3 patients of the SBRT group (D95 to the TV lowered by 4.35%, 2.16% and 2.61%) due to interplay effect in one case and to breathing motion alone in the others. CONCLUSIONS: Compared to the ITV, the MidP significantly reduced PTV and doses to OARs. MidP is safe for helical delivery except for very small tumors (<5 cc) with large-amplitude motion (>10mm) where the ITV might remain the most adequate approach.

Helical tomotherapy for SIB and hypo-fractionated treatments in lung carcinomas: a 4D Monte Carlo treatment planning study.

PURPOSE: To evaluate the impact of intra-fraction motion induced by regular breathing on treatment quality for helical tomotherapy treatments. MATERIAL AND METHODS: Four patients treated by simultaneous-integrated boost (SIB) and three by hypo-fractionated stereotactic treatments (hypo-fractionated, 18 Gy/fraction) were included. All patients were coached to ensure regular breathing. For the SIB group, the tumor volume was delineated using CT information only (CTV(CT)) and the boost region was based on PET information (GTV(PET), no CTV extension). In the hypo-fractionated group, a GTV based on CT information was contoured. In both groups, ITVs were defined according to 4D data. The PTV included the ITV plus a setup error margin. The treatment was planned using the tomotherapy TPS on 3D CT images. In order to verify the impact of intra-fraction motion and interplay effects, dose calculations were performed using a previously validated Monte Carlo model of tomotherapy (TomoPen): first on the planning 3D CT ("planned dose") and second, on the 10 phases of the 4D scan. For the latter, two dose distributions, termed "interplay simulated" or "no interplay" were computed with and without beamlet-phase correlation over the 10 phases and combined using deformable dose registration. RESULTS: In all cases, DVHs of "interplay simulated" dose distributions complied within 1% of the original clinical objectives used for planning, defined according to ICRU (report 83) and RTOG (trials 0236 and 0618) recommendations, for SIB and hypo-fractionated groups, respectively. For one patient in the hypo-fractionated group, D(mean) to the CTV(CT) was 2.6% and 2.5% higher than "planned" for "interplay simulated" and "no interplay", respectively. CONCLUSION: For the patients included in this study, assuming regular breathing, the results showed that interplay of breathing and tomotherapy delivery motions did not affect significantly plan delivery accuracy. Hence, accounting for intra-fraction motion through the definition of an ITV volume was sufficient to ensure tumor coverage.

Gradient-based delineation of the primary GTV on FDG-PET in non-small cell lung cancer: a comparison with threshold-based approaches, CT and surgical specimens.

PURPOSE: The aim of this study was to validate a gradient-based segmentation method for GTV delineation on FDG-PET in NSCLC through surgical specimen, in comparison with threshold-based approaches and CT. MATERIALS AND METHODS: Ten patients with stage I-II NSCLC were prospectively enrolled. Before lobectomy, all patients underwent contrast enhanced CT and gated FDG-PET. Next, the surgical specimen was removed, inflated with gelatin, frozen and sliced. The digitized slices were used to reconstruct the 3D macroscopic specimen. GTVs were manually delineated on the macroscopic specimen and on CT images. GTVs were automatically segmented on PET images using a gradient-based method, a source to background ratio method and fixed threshold values at 40% and 50% of SUV(max). All images were finally registered. Analyses of raw volumes and logarithmic differences between GTVs and GTV(macro) were performed on all patients and on a subgroup excluding the poorly defined tumors. A matching analysis between the different GTVs was also conducted using Dice's similarity index. RESULTS: Considering all patients, both lung and mediastinal windowed CT overestimated the macroscopy, while FDG-PET provided closer values. Among various PET segmentation methods, the gradient-based technique best estimated the true tumor volume. When analysis was restricted to well defined tumors without lung fibrosis or atelectasis, the mediastinal windowed CT accurately assessed the macroscopic specimen. Finally, the matching analysis did not reveal significant difference between the different imaging modalities. CONCLUSIONS: FDG-PET improved the GTV definition in NSCLC including when the primary tumor was surrounded by modifications of the lung parenchyma. In this context, the gradient-based method outperformed the threshold-based ones in terms of accuracy and robustness. In other cases, the conventional mediastinal windowed CT remained appropriate.