Sterotactic Ablative Radiotherapy in a Multicentric Series of Oligometastatic SCLC: The SAMOS Cohort.

AIMS: SCLC is the most aggressive lung cancer histology with a 5-year OS <10%. At the diagnosis, almost two-thirds of the SCLC an Extended Disease presentation. Two randomized studies (CASPIAN and ImPower133) demonstrated an OS improvement, when immunotherapy was prescribed as maintenance therapy after standard chemotherapy. To date, SABR has had a limited indication in managing metastatic SCLC, although recent reports proposed it as a valid treatment option in selected patients. We propose a retrospective multicentric analysis of patients treated with SABR for oligometastatic SCLC. METHOD: Data of patients affected by oligometastatic-SCLC treated with SABR between 2017 and 2022 in 11 Italian centers were collected. Clinical and therapeutic variables together with OS and time to next treatment were analyzed. Univariate analysis with Kaplan-Meier curve were calculated, and log-rank test were applied. Cox proportional hazard model was used for multivariate analysis. RESULTS: Data from 93 patients and 132 metastatic lesions were analyzed. The median age was 64 years (36-86) and all but 1 had Performance Status 0 or 1. Fifty-two patients presented ED at diagnosis. The first line treatment was radiochemotherapy in 42%, CHT alone in 24% and CHT-IO in 28%, others treatment accounts for 4% and only 2% of patients underwent best supportive care. Of the 132 lesions treated with SBRT 55 were in brain, 27 in lung, 11 in liver, 10 in lymph nodes, 8 in bones and 20 in adrenal gland. Median OS was 14 months, 1 year-OS and 2 years OS were 53% and 27%, respectively. The median TtNT was 14 months for the entire population. Of all the analyzed variables only, the anatomical site of the metastases and their number showed statistical significance in the univariate analysist, confirmed in the subsequent multivariate. CONCLUSION: SABR seems to play a role in delaying further systemic lines in oligometastatic disease and to extend the use of ongoing treatment in oligoprogressive state. Prospective studies are needed to confirm these findings.

Preoperative Radiotherapy with a Simultaneous Integrated Boost Compared to Chemoradiotherapy for cT3-4 Rectal Cancer: Long-Term Results of a Multicenter Randomized Study.

BACKGROUND: Preoperative chemoradiotherapy (CRT) is the standard treatment for T3-4 rectal cancer. Here, we compared image-guided and intensity-modulated RT (IG-IMRT) with a simultaneous integrated boost (SIB) (instead of concomitant chemotherapy) versus CRT in a multi-centric randomized trial. METHODS: cT3-4 rectal cancer patients were randomly assigned to receive preoperative IG-IMRT 46 Gy/23 fractions plus capecitabine 825 mg/m² twice daily (CRT arm) or IG-IMRT 46 Gy/23 fractions with an SIB to the rectal tumor up to a total dose of 55.2 Gy (RTSIB arm). RESULTS: A total of 174 patients were randomly assigned between April 2010 and May 2014. Grade 3 acute toxicities were 6% and 4% in the CRT and RTSIB arms, respectively. The mean fractional change in SUVmax at 5 weeks after completion of preoperative RT were -55.8% (±24.0%) and -52.9% (±21.6%) for patients in the CRT arm and RTSIB arm, respectively (p = 0.43). The pathologic complete response rate was 24% with CRT compared to 14% with RTSIB. There were no differences in 5-year overall survival (OS), progression-free survival (PFS) or local control (LC). CONCLUSIONS: The preoperative RTSIB approach was not inferior to CRT in terms of metabolic response, toxicity, OS, PFS and LC, and could be considered an available option for patients unfit for fluorouracil-based CRT.

Total Marrow Irradiation for Second Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Advanced Acute Leukemia.

Second allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option for patients with acute leukemia who relapse after a first HSCT. Although myeloablative conditioning (MAC) regimens before the first HSCT are considered superior to reduced- intensity conditioning (RIC) in terms of disease control in acute leukemia patients, the optimal conditioning regimen for the second allogeneic HSCT remains controversial. The most important prognostic factors are the remission disease phase at the time of the second HSCT and an interval >12 months from the first HSCT to the second HSCT. Total marrow irradiation (TMI) is an advanced high-precision radiation treatment that delivers therapeutic doses over extensively selected targets while substantially reducing radiation to vital organs compared to conventional total body irradiation (TBI). Here we report the results of a retrospective analysis of second allogeneic HSCT treated with TMI as an MAC regimen with the intent of limiting toxicity. We investigated the efficacy of high dose per fraction TMI in combination with thiotepa, fludarabine, and melphalan in 13 consecutive patients with acute leukemia who had relapsed after a first allogeneic HSCT treated between March 2018 and November 2021. Donor type was haploidentical in 10 patients, unrelated in 2 patients, and HLA-identical sibling in 1 patient. The conditioning regimen consisted of 8 Gy TMI in 5 patients on days -8 and -7 and 12 Gy TMI in 8 patients on days -9 to -7, plus thiotepa 5 mg/kg on day -6, fludarabine 50 mg/day on days -5 to -3, and melphalan 140 mg/day on day -2. The TMI was delivered at the dosage og 4 GY for 2 consecutive days (total = 8 GY) or for 3 consecutive days (total = 12 GY). The median patient age was 45 years (range, 19 to 70 years); 7 patients were in remission, and 6 had active disease at the time of their second allogeneic HSCT. The median time to a neutrophil count of >.5 × 109/L was 16 days (range, 13 to 22 days), and the median time to a platelet count of >20 × 109/L was 20 days (range, 14 to 34 days). All patients showed complete donor chimerism on day +30 post-transplantation. The cumulative incidence of grade I-II acute graft-versus-host disease (GVHD) was 43%, and that of chronic GVHD was 30%. The median duration of follow-up was 1121 days (range, 200 to 1540 days). Day +30 and +100 transplantation-related mortality (TRM) was 0. The overall cumulative incidence of TRM, relapse rate, and disease free-survival were 27%, 7%, and 67%, respectively. This retrospective study demonstrates the safety and efficacy of a hypofractionated TMI conditioning regimen in patients with acute leukemia undergoing second HSCT with encouraging outcomes in terms of engraftment, early toxicity, GVHD, and relapse.

External validation of a composite bio-humoral index in anal cancer patients undergoing concurrent chemoradiation.

BACKGROUND AND PURPOSE: A prognostic scoring system based on laboratory inflammation parameters, [Hemo-Eosinophils-Inflammation (HEI) index], including baseline hemoglobin level, the systemic inflammatory index and eosinophil count was recently proposed in patients with squamous cell carcinoma of the anus (ASCC). HEI was shown to discriminate disease-free (DFS) and overall (OS) survival in ASCC patients treated with concurrent chemoradiation (CRT). We tested the accuracy of the model on a multicentric cohort for external validation. MATERIALS AND METHODS: Patients treated with CRT were enrolled. The Kaplan-Meier curves for DFS and OS based on HEI risk group were calculated and the log-rank test was used. Cox proportional hazards models were used to assess the prognostic factors for DFS and OS. The exponential of the regression coefficients provided an estimate of the hazard ratio (HR). For model discrimination, we determined Harrell's C-index, Gönen & Heller K Index and the explained variation on the log relative hazard scale. RESULTS: A total of 877 patients was available. Proportional hazards were adjusted for age, gender, tumor-stage, and chemotherapy. Two-year DFS was 77 %(95 %CI:72.0-82.4) and 88.3 %(95 %CI:84.8-92.0 %) in the HEI high- and low- risk groups. Two-year OS was 87.8 %(95 %CI:83.7-92.0) and 94.2 %(95 %CI:91.5-97). Multivariate Cox proportional hazards model showed a HR = 2.02(95 %CI:1.25-3.26; p = 0.004) for the HEI high-risk group with respect to OS and a HR = 1.53(95 %CI:1.04-2.24; p = 0.029) for DFS. Harrel C-indexes were 0.68 and 0.66 in the validation dataset, for OS and DFS. Gonen-Heller K indexes were 0.67 and 0.71, respectively. CONCLUSION: The HEI index proved to be a prognosticator in ASCC patients treated with CRT. Model discrimination in the external validation cohort was acceptable.

Exploring Response to Immunotherapy in Non-Small Cell Lung Cancer Using Delta-Radiomics.

Delta-radiomics is a branch of radiomics in which features are confronted after time or after introducing an external factor (such as treatment with chemotherapy or radiotherapy) to extrapolate prognostic data or to monitor a certain condition. Immune checkpoint inhibitors (ICIs) are currently revolutionizing the treatment of non-small cell lung cancer (NSCLC); however, there are still many issues in defining the response to therapy. Contrast-enhanced CT scans of 33 NSCLC patients treated with ICIs were analyzed; altogether, 43 lung lesions were considered. The radiomic features of the lung lesions were extracted from CT scans at baseline and at first reassessment, and their variation (delta, Δ) was calculated by means of the absolute difference and relative reduction. This variation was related to the final response of each lesion to evaluate the predictive ability of the variation itself. Twenty-seven delta features have been identified that are able to discriminate radiologic response to ICIs with statistically significant accuracy. Furthermore, the variation of nine features significantly correlates with pseudo-progression.

Corrigendum: A Real-World, Multicenter, Observational Retrospective Study of Durvalumab After Concomitant or Sequential Chemoradiation for Unresectable Stage III Non-Small Cell Lung Cancer.

[This corrects the article DOI: 10.3389/fonc.2021.744956.].

Ultra-hyper-fractionated radiotherapy for high-grade gliomas.

High-grade gliomas (HGGs; WHO grades III and IV) are invariably lethal brain tumors. Low-dose hyper-radiosensitivity (HRS) of HGG is a well-established phenomenon in vitro. However, possibly linked to the unavailability of accurate animal models of the diseases, this therapeutic effect could not be consistently translated to the animal setting, thus impairing its subsequent clinical development. The purpose of this study was to develop radiotherapeutic (RT) schedules permitting to significantly improve the overall survival of faithful animal models of HGG that have been recently made available. We used primary glioma initiating cell (GIC)-driven orthotopic animal models that accurately recapitulate the heterogeneity and growth patterns of the patients' tumors, to investigate the therapeutic effects of low radiation doses toward HGG. With the same total dose, RT fractions ≤0.5 Gy twice per week [ultra-hyper-fractionation (ultra-hyper-FRT)] started at early stages of tumor progression (a condition that in the clinical setting often occurs at the end of the guidelines treatment) improved the effectiveness of RT and the animal survival in comparison to standard fractions. For the same cumulative dose, the use of fractions ≤0.5 Gy may permit to escape one or more tumor resistance mechanisms thus increasing the effectiveness of RT and the overall animal survival. These findings suggest investigating in the clinical setting the therapeutic effect of an ultra-hyper-FRT schedule promptly extending the conventional RT component of the current guideline ("Stupp") therapeutic protocol.

A Real-World, Multicenter, Observational Retrospective Study of Durvalumab After Concomitant or Sequential Chemoradiation for Unresectable Stage III Non-Small Cell Lung Cancer.

INTRODUCTION: For unresectable stage III non-small cell lung cancer (NSCLC), the standard therapy consists of chemoradiotherapy (CRT) followed by durvalumab maintenance for responding patients. The present study reports on the safety and outcome of durvalumab use after CRT in a real-world, multicenter, retrospective cohort. METHODS: Two hundred thirty-eight patients have been included. We collected data on systemic therapy, radiation therapy, the timing between CRT and durvalumab, number of durvalumab cycles, reasons for non-starting or discontinuation, incidence and grade of adverse events (AEs), and progression-free survival (PFS) and overall survival (OS). RESULTS: One hundred fifty-five patients out of 238 (65.1%) received at least one durvalumab dose: 91 (58.7%) after concomitant CRT (cCRT) and 64 (41.3%) after sequential CRT (sCRT). Programmed-death ligand 1 (PD-L1) status was unknown in 7/155 (4.5%), negative in 14 (9.1%), and positive ≥1% in 134/155 (86.4%). The main reasons for non-starting durvalumab were progression (10.1%), PD-L1 negativity (7.5%), and lung toxicity (4.6%). Median follow-up time was 14 months (range 2­29); 1-year PFS and OS were 65.5% (95%CI: 57.6-74.4) and 87.9% (95%CI: 82.26.6-93.9), respectively. No significant differences in PFS or OS were detected for cCRT vs. sCRT, but the median PFS was 13.5 months for sCRT vs. 23 months for cCRT. Potentially immune-related AEs were recorded in 76/155 patients (49.0%). Pneumonitis was the most frequent, leading to discontinuation in 11/155 patients (7.1%). CONCLUSIONS: Durvalumab maintenenace after concurrent or sequential chemoradiation for unresectable, stage III NSCLC showed very promising short-term survival results in a large, multicenter, restrospective, real-world study. Durvalumab was the first drug obtaining a survival benefit over CRT within the past two decades, and the present study contributes to validating its use in clinical practice.

Thoracic re-irradiation with 3D-conformal or more advanced techniques: A systematic review of treatment safety by the Re-irradiation Study Group of the Italian Association of Radiation and Oncology AIRO.

Re-irradiation (re-RT) is a treatment modality that has been actively investigated in recurrent lung cancer or in lung metastases appeared in previously irradiated areas. A literature search, according PRISMA recommendations and a meta-analysis technique were performed with the aims to identify possible factors related to the toxicity incidence and severity of ≥ G3 acute toxicity. 1243 patients and 36 studies, met inclusion criteria. Our results, showed that there was no difference in ≥ G3 acute (10,5%) toxicity rate with respect to different radiation techniques, cumulative dose and re-irradiation total dose and fractionation. Factors eventually related to severe toxicity were described. The frequent lack of a sufficient description of the treatment's intent, the heterogeneity in technique and radiotherapy regimen, makes balancing risk and benefit of re-RT based on published data even more difficult.

Radiotherapy with Intensity-Modulated (IMRT) Techniques in the Treatment of Anal Carcinoma (RAINSTORM): A Multicenter Study on Behalf of AIRO (Italian Association of Radiotherapy and Clinical Oncology) Gastrointestinal Study Group.

A multi-institutional retrospective study was conducted to evaluate the pattern of care and clinical outcomes of anal cancer patients treated with intensity-modulated radiotherapy (IMRT) techniques. In a cohort of 987 patients, the clinical complete response (CR) rate (beyond 6 months) was 90.6%. The 3-year local control (LC) rate was 85.8% (95% CI: 84.4-87.2), and the 3-year colostomy-free survival (CFS) rate was 77.9% (95% CI: 76.1-79.8). Three-year progression-free survival (PFS) and overall survival (OS) rates were 80.2% and 88.1% (95% CI: 78.8-89.4) (95% CI: 78.5-81.9), respectively. Histological grade 3 and nodal involvement were associated with lower CR (p = 0.030 and p = 0.004, respectively). A statistically significant association was found between advanced stage and nodal involvement, and LC, CFS, PFS, OS and event-free survival (EFS). Overall treatment time (OTT) ≥45 days showed a trend for a lower PFS (p = 0.050) and was significantly associated with lower EFS (p = 0.030) and histological grade 3 with a lower LC (p = 0.025). No statistically significant association was found between total dose, dose/fraction and/or boost modality and clinical outcomes. This analysis reports excellent clinical results and a mild toxicity profile, confirming IMRT techniques as standard of care for the curative treatment of anal cancer patients. Lymph node involvement and histological grade have been confirmed as the most important negative prognostic factors.

The NIPRO Study: An Observational, Retrospective, Multicenter Study on the Safety of the Radiotherapy and Immunotherapy Combination for Advanced-Stage NSCLC.

INTRODUCTION: In this observational, retrospective, multicenter study, we aimed to assess the safety of the combination of local metastasis-directed radiotherapy (RT) and immunotherapy (IT) in a cohort of advanced non-small-cell lung cancer (aNSCLC) patients. MATERIAL AND METHODS: We collected clinical data of aNSCLC patients who received concomitant RT and anti-PD-1/PD-L1 inhibitors in seven Italian centers from September 2015 to June 2019. Concomitant RT was defined as delivered ≤4 weeks before or after the first or last administration of immunotherapy, or within two consecutive cycles of ICI. All adverse events apparently related to RT and/or IT were graded according to the Common Terminology Criteria for Adverse Events, version 4.0, and reported in terms of incidence and severity as immune related or RT related, or combined. RESULTS: We analyzed the clinical charts of 187 patients. Median follow-up time was 23 months, and median overall survival was 16.5 months (range, 3-162). Thirteen patients developed pure RT-related side effects, and 43 patients (23.9%) developed immune-related side effects. No additive toxic effects were observed. A case of grade 5 pulmonary toxicity was recorded as a possible consequence of a combined effect. CONCLUSION: This analysis suggests that the combination of concomitant RT and anti-PD-1/PD-L1 agents is safe, and the two toxicity profiles are independent.

The Prognostic Value of the New Combined Hemo-Eosinophil Inflammation Index (HEI Index): A Multicenter Analysis of Anal Cancer Patients Treated with Concurrent Chemo-Radiation.

Anal squamous cell carcinoma (SCC) is a rare tumor, and bio-humoral predictors of response to chemo-radiation (CT-RT) are lacking. We developed a prognostic score system based on laboratory inflammation parameters. We investigated the correlation between baseline clinical and laboratory variables and disease-free (DFS) and overall (OS) survival in anal SCC patients treated with CT-RT in five institutions. The bio-humoral parameters of significance were included in a new scoring system, which was tested with other significant variables in a Cox's proportional hazard model. A total of 308 patients was included. We devised a prognostic model by combining baseline hemoglobin level, SII, and eosinophil count: the Hemo-Eosinophils Inflammation (HEI) Index. We stratified patients according to the HEI index into low- and high-risk groups. Median DFS for low-risk patients was not reached, and it was found to be 79.5 months for high-risk cases (Hazard Ratio 3.22; 95% CI: 2.04-5.10; p < 0.0001). Following adjustment for clinical covariates found significant at univariate analysis, multivariate analysis confirmed the HEI index as an independent prognostic factor for DFS and OS. The HEI index was shown to be a prognostic parameter for DFS and OS in anal cancer patients treated with CT-RT. An external validation of the HEI index is mandatory for its use in clinical practice.

How Can Imaging Help the Radiation Oncologist in Multiple Myeloma Treatment.

Multiple myeloma is an incurable malignant tumor of plasma cells of the bone marrow; most patients present a disseminated disease with important bone involvement. Even though a chemotherapy-based approach is the major treatment, radiotherapy often has a supportive role for symptom relief but also a radical role for patients with indolent disease or localized forms. In both cases imaging is the basis for treatment planning and for correct patient classification. This paper aims to describe and summarize how radiation oncologists could use imaging information to personalize the treatment for each patient.

Current radiotherapy techniques in NSCLC: challenges and potential solutions.

Introduction: Radiotherapy is an important therapeutic strategy in the management of non-small cell lung cancer (NSCLC). In recent decades, technological implementations and the introduction of image guided radiotherapy (IGRT) have significantly increased the accuracy and tolerability of radiation therapy.Area covered: In this review, we provide an overview of technological opportunities and future prospects in NSCLC management.Expert opinion: Stereotactic body radiotherapy (SBRT) is now considered the standard approach in patients ineligible for surgery, while in operable cases, it is still under debate. Additionally, in combination with systemic treatment, SBRT is an innovative option for managing oligometastatic patients and features encouraging initial results in clinical outcomes. To date, in inoperable locally advanced NSCLC, the radical dose prescription has not changed (60 Gy in 30 fractions), despite the median overall survival progressively increasing. These results arise from technological improvements in precisely hitting target treatment volumes and organ at risk sparing, which are associated with better treatment qualities. Finally, for the management of NSCLC, proton and carbon ion therapies and the recent development of MR-Linac are new, intriguing technological approaches under investigation.

Fondazione Italiana Linfomi (FIL) expert consensus on the use of intensity-modulated and image-guided radiotherapy for Hodgkin's lymphoma involving the mediastinum.

AIM: Advances in therapy have resulted in improved cure rates and an increasing number of long-term Hodgkin's lymphoma (HL) survivors. However, radiotherapy (RT)-related late effects are still a significant issue, particularly for younger patients with mediastinal disease (secondary cancers, heart diseases). In many Centers, technological evolution has substantially changed RT planning and delivery. This consensus document aims to analyze the current knowledge of Intensity-Modulated Radiation Therapy (IMRT) and Image-Guided Radiation Therapy (IGRT) for mediastinal HL and formulate practical recommendations based on scientific evidence and expert opinions. METHODS: A dedicated working group was set up within the Fondazione Italiana Linfomi (FIL) Radiotherapy Committee in May 2018. After a first meeting, the group adopted a dedicated platform to share retrieved articles and other material. Two group coordinators redacted a first document draft, that was further discussed and finalized in two subsequent meetings. Topics of interest were: 1) Published data comparing 3D-conformal radiotherapy (3D-CRT) and IMRT 2) dose objectives for the organs at risk 3) IGRT protocols and motion management. RESULTS: Data review showed that IMRT might allow for an essential reduction in the high-dose regions for all different thoracic OAR. As very few studies included specific dose constraints for lungs and breasts, the low-dose component for these OAR resulted slightly higher with IMRT vs. 3D-CRT, depending on the technique used. We propose a set of dose objectives for the heart, breasts, lungs, and thyroid. The use of IGRT is advised for margin reduction without specific indications, such as the use of breath-holding techniques. An individual approach, including comparative planning and considering different risk factors for late morbidity, is recommended for each patient. CONCLUSIONS: As HL therapy continues to evolve, with an emphasis on treatment reduction, radiation oncologists should use at best all the available tools to minimize the dose to organs at risk and optimize treatment plans. This document provides indications on the use of IMRT/IGRT based on expert consensus, providing a basis for clinical implementation and future development.

Management of locally advanced non-small cell lung cancer in the modern era: A national Italian survey on diagnosis, treatment and multidisciplinary approach.

Concurrent chemotherapy and radiotherapy (cCRT) is considered the standard treatment of locally advanced non-small cell lung cancer (LA-NSCLC). Unfortunately, management is still heterogeneous across different specialists. A multidisciplinary approach is needed in this setting due to recent, promising results obtained by consolidative immunotherapy. The aim of this survey is to assess current LA-NSCLC management in Italy. From January to April 2018, a 15-question survey focusing on diagnostic/therapeutic LA-NSCLC management was sent to 1,478 e-mail addresses that belonged to pneumologists, thoracic surgeons, and radiation and medical oncologists. 421 answers were analyzed: 176 radiation oncologists, 86 medical oncologists, 92 pneumologists, 64 thoracic surgeons and 3 other specialists. More than a half of the respondents had been practicing for >10 years after completing residency training. Some discrepancies were observed in clinical LA-NSCLC management: the lack of a regularly planned multidisciplinary tumor board, the use of upfront surgery in multistation stage IIIA, and territorial diffusion of cCRT in unresectable LA-NSCLC. Our analysis demonstrated good compliance with international guidelines in the diagnostic workup of LA-NSCLC. We observed a relationship between high clinical experience and good clinical practice. A multidisciplinary approach is mandatory for managing LA-NSCLC.

Multi-institutional evaluation of MVCT guided patient registration and dosimetric precision in total marrow irradiation: A global health initiative by the international consortium of total marrow irradiation.

PURPOSE: Total marrow irradiation (TMI) is a highly conformal treatment of the human skeleton structure requiring a high degree of precision and accuracy for treatment delivery. Although many centers worldwide initiated clinical studies using TMI, currently there is no standard for pretreatment patient setup. To this end, the accuracy of different patient setups was measured using pretreatment imaging. Their impact on dose delivery was assessed for multiple institutions. METHODS AND MATERIALS: Whole body imaging (WBI) or partial body imaging (PBI) was performed using pretreatment megavoltage computed tomography (MVCT) in a helical Tomotherapy machine. Rigid registration of MVCT and planning kilovoltage computed tomography images were performed to measure setup error and its effect on dose distribution. The entire skeleton was considered the planning target volume (PTV) with five sub regions: head/neck (HN), spine, shoulder and clavicle (SC), and one avoidance structure, the lungs. Sixty-eight total patients (>300 images) across six institutions were analyzed. RESULTS: Patient setup techniques differed between centers, creating variations in dose delivery. Registration accuracy varied by anatomical region and by imaging technique, with the lowest to the highest degree of pretreatment rigid shifts in the following order: spine, pelvis, HN, SC, and lungs. Mean fractional dose was affected in regions of high registration mismatch, in particular the lungs. CONCLUSIONS: MVCT imaging and whole body patient immobilization was essential for assessing treatment setup, allowing for the complete analysis of 3D dose distribution in the PTV and lungs (or avoidance structures).

Extra-pleural pneumonectomy in the era of image-guided intensity-modulated radiotherapy.

PURPOSE: To assess the outcome of malignant pleural mesothelioma patients treated with extra-pleural pneumonectomy (EPP) and adjuvant radiotherapy (RT), using the most advanced radiotherapeutic techniques, namely image-guided intensity-modulated RT (IG-IMRT). METHODS AND MATERIALS: Fifty-four patients were analyzed. Minimum radiation dose was 50 Gy (2 Gy/fr). Planning target volume encompassed the entire hemithorax, including the ipsilateral mediastinum if interested by disease, the pericardium and diaphragm, and any drain sites. The study endpoints included loco-regional control (LRC), distant metastases free survival (DMFS), and overall survival (OS), as well as radiation-related toxicity. RESULTS: Major patients and treatment characteristics were the following: median age 62 years, epithelioid histology in 51 (94%) cases, locally advanced disease in 41 (90%) cases, and metastatic mediastinal lymph nodes in 27 patients (50%). Only 7 patients (13%) had gross residual disease after surgery. Chemotherapy was administered in 38 patients (70%). Median follow-up was 16 months (range 0-73 months). Median and 2-year OS were 21 months and was 43.8%, respectively. The predominant pattern of failure was distant: 34 patients (62.9%) developed some component of distant failure, and only 5 patients (9.2%) developed an isolated loco-regional recurrence. The estimates of LRC and DMFS at 2 years were 63.4% and 43.4%, respectively. Three fatal pneumonitis were documented. Other major toxicities included: Grade 2 and 3 pneumonitis in 1 and 2 cases, respectively, 1 case of bronchial fistula, pleural empyema, and Grade 3 esophagitis, respectively. CONCLUSIONS: Although executed in the era of high-technology radiotherapy (IG-IMRT), EPP should not be routinely performed.