Future perspectives of radiation therapy for Hodgkin Lymphoma: Risk-adapted, response-adapted, and safer than before.

Classical Hodgkin lymphoma is a lymphoproliferative disease with a good prognosis mainly seen in young people. Nevertheless secondary malignancy, cardiac disease and infertility may affect the long survivors with significant impact on quality of life, morbidity and overall survival. In the last decades several treatment strategies were evaluated to reduce the toxicity of first line treatment such as avoiding radiotherapy or its reduction in terms of dosage and extension. Many trials including interim Positron Emission Tomography evaluation fail to compare efficacy between combined modality treatment versus chemotherapy alone in particular in early stage disease. In this review we analyze which subset of patients could take advantage from proton therapy in terms of toxicity and cost effectiveness.

Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET-CT: a collaborative study by ILROG.

Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40 to 50%. As 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography with computerized tomography (PET-CT) upstages 10 to 60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Inclusion criteria were: RT alone for untreated stage I to II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow-up ≥3 months. End points were freedom from progression (FFP), local control, and overall survival (OS). A total of 512 patients treated between 2000 and 2017 at 16 centers were eligible for analysis; median age was 58 years (range, 20-90); 410 patients (80.1%) had stage I disease; median RT dose was 30 Gy (24-52); and median follow-up was 52 months (3.2-174.6). Five-year FFP and OS were 68.9% and 95.7%. For stage I, FFP was 74.1% vs 49.1% for stage II (P < .0001). Eight patients relapsed in-field (1.6%). Four had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.44-3.10) and BCL2 expression (HR, 1.62; 95% CI, 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.

Local Therapies and Modulation of Tumor Surrounding Stroma in Malignant Pleural Mesothelioma: A Translational Approach.

Malignant Pleural Mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural mesothelium, mainly associated with asbestos exposure and still lacking effective therapies. Modern targeted biological strategies that have revolutionized the therapy of other solid tumors have not had success so far in the MPM. Combination immunotherapy might achieve better results over chemotherapy alone, but there is still a need for more effective therapeutic approaches. Based on the peculiar disease features of MPM, several strategies for local therapeutic delivery have been developed over the past years. The common rationale of these approaches is: (i) to reduce the risk of drug inactivation before reaching the target tumor cells; (ii) to increase the concentration of active drugs in the tumor micro-environment and their bioavailability; (iii) to reduce toxic effects on normal, non-transformed cells, because of much lower drug doses than those used for systemic chemotherapy. The complex interactions between drugs and the local immune-inflammatory micro-environment modulate the subsequent clinical response. In this perspective, the main interest is currently addressed to the development of local drug delivery platforms, both cell therapy and engineered nanotools. We here propose a review aimed at deep investigation of the biologic effects of the current local therapies for MPM, including cell therapies, and the mechanisms of interaction with the tumor micro-environment.

The growth of non-solid neoplastic lung nodules is associated with low PD L1 expression, irrespective of sampling technique.

BACKGROUND: Few data are known regarding the molecular features and patterns of growth and presentation which characterize those lung neoplastic lesions presenting as non-solid nodules (NSN). METHODS: We retrospectively reviewed two different cohorts of NSNs detected by CT scan which, after transthoracic fine-needle aspiration (FNA) and core needle biopsy (CNB) received a final diagnosis of malignancy. All the enrolled patients were then addressed to surgical removal of lung cancer nodules or to exclusive radiotherapy. Exhaustive clinical and radiological features were available for each case. RESULTS: In all 62 analysed cases the diagnosis of adenocarcinoma (ADC) was reached. In cytologic samples, EGFR activating mutations were identified in 2 of the 28 cases (7%); no case showed ALK/EML4 or ROS1 translocations. In the histologic samples EGFR activating mutation were found in 4 out of 25 cases (16%). PD-L1 immunostains could be evaluated in 30 cytologic samples, while the remaining 7 did not reach the cellularity threshold for evaluation. TPS was < 1% in 26 cases, > 1% < 50% in 3, and > 50% in 1. All surgical samples showed TPS < 1%. Of the 17 cases that could be evaluated on both samples, 15 were concordantly TPS 0, and 2 showed TPS > 1% < 50 on the biopsy samples. TPS was < 1% in 14 cases, > 1%/< 5% in 4 cases, > 5%/< 50% in 2 cases, > 50% in 1 case. CONCLUSIONS: Overall PD-L1 immunostaining documented the predominance of low/negative TPS, with high concordance in FNA and corresponding surgical samples. It can be hypothesized that lung ADC with NSN pattern and predominant in situ (i.e. lepidic) components represent the first steps in tumor progression, which have not yet triggered immune response, and/or have not accumulated a significant rate of mutations and neoantigen production, or that they belong to the infiltrated-excluded category of tumors. The negative prediction of response to immunomodulating therapy underlines the importance of rapid surgical treatment of these lesions. Notably, cell block cytology seems to fail in detecting EGFR mutations, thus suggesting that this kind of sampling technique should be not adequate in case of DNA direct sequencing.

Radiotherapy treatment volumes for oligorecurrent nodal prostate cancer: a systematic review.

BACKGROUND: Radiotherapy is an emerging treatment strategy for nodal oligorecurrent prostate cancer (PCa) patients. However, large heterogeneities exist in the RT regimens used, with series reporting the use of elective nodal radiotherapy (ENRT) strategies and others the delivery of focal treatments to the relapsing nodes with Stereotactic Body Radiotherapy (SBRT). In this systematic review of the literature we compared the oncological outcomes and toxicity of the different RT regimens for nodal oligorecurrent PCa patients, with the aim of defining the optimal RT target volume in this setting. METHODS: We performed a systemic search on the Pubmed database to identify articles reporting on the use of ENRT or SBRT for oligometastatic PCa with nodal recurrence. RESULTS: Twenty-two articles were analyzed, including four prospective phase II trials (3 with SBRT and 1 with ENRT). Focal SBRT, delivered with an involved node, involved site, and involved field modality, was the most commonly used strategy with 2-year progression-free survival (PFS) rates ranging from 16 to 58% and a very low toxicity profile. Improved PFS rates were observed with ENRT strategies (52-80% at 3 years) compared to focal SBRT, despite a slightly higher toxicity rate. One ongoing randomized phase II trial is comparing both modalities in patients with nodal oligorecurrent PCa. CONCLUSIONS: With a large variability in patterns of practice, the optimal RT strategy remains to be determined in the setting of nodal oligorecurrent PCa. Ongoing randomized trials and advances in translational research will help to shed light on the best management for these patients. .

Is multidisciplinary management possible in the treatment of lung cancer? A report from three Italian meetings.

PURPOSE: To report criticisms and barriers to the "real-life" application of international guidelines and recent developments in the management of locally advanced non-small cell lung cancer (NSCLC) in Italy. METHODS: Three 2-day courses were organized. During the first day, experts in different fields of thoracic oncology gave their lecture on diagnosis and therapy for locally advanced NSCLC. During the second day, all participants were divided into four groups to discuss on a clinical case as a multidisciplinary team (MDT). The aim was to stimulate the discussion on practical issues in the management of NSCLC patients in the real-life practice. RESULTS: A total of 196 physicians were involved in the courses as learners. Invasive diagnosis of nodal disease for staging purposes, a priori definition of "surgical resectability" and a regular MDT with all crucial participants available were the three main key points identified for a good management of these patients. The main barriers to the clinical application of a good diagnostic and therapeutic approach to the patient were the absence of a regular and complete MDT in the South and Centre of Italy, while in the North of Italy, time for discussion of clinical cases in the MDT and waiting lists for staging and therapeutic interventions were deemed as the major concerns. CONCLUSION: The meetings showed that diagnosis and treatment of locally advanced NSCLC are still extremely variable between different Italian regions. Logistic issues, waiting lists, paucity of well-trained staff and expertise seem to be the main barriers to international guidelines application.

Renewed interest for low-dose radiation therapy in follicular lymphomas: From biology to clinical applications.

Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoproliferative disorders. Treatment strategies for FL may include several therapeutic choices, ranging from a "watchful waiting" approach to stem cell transplantation, mostly depending on staging, age, risk factors, and disease burden at diagnosis. The high radiosensitivity of FL compared with other solid tumors has been known since the beginning of radiotherapy treatment in lymphoma patients. Doses of 24 to 40 Gy were considered appropriate in first line curative treatment for localized disease (stages I-II), but several publications investigating low-dose radiotherapy (LDRT) of 4Gy (2 × 2Gy) reported an overall response rate surprisingly high. Due to its high local efficacy and negligible toxicity, LDRT might be offered to both early and advanced stage FL patients in combination with new agents, at diagnosis or after several lines of systemic therapy. The aim of this review is to summarize and discuss the current knowledge on LDRT for FL and its potential application in a curative setting in combination with new drugs for both early and advanced disease.

Optimal Therapy for Early-Stage Hodgkin's Lymphoma: Risk Adapting, Response Adapting, and Role of Radiotherapy.

PURPOSE OF REVIEW: The aim of this article is to discuss the current role of radiotherapy (RT) for early-stage Hodgkin's lymphoma (HL) in the context of risk-adapted and response-adapted treatment strategy, and describe changes in RT technical approach. RECENT FINDINGS: In low-risk patients, RT could be omitted but, at the price of a lower progression-free survival, and its role is still debated. Ongoing trials are combining new agents with chemotherapy alone or response-adapted combined modality therapy, and results are awaited. Modern RT incorporates lower doses and smaller fields, together with the implementation of sophisticated delivery techniques aimed to reducing the dose to critical structures such as the heart. The role of RT for early-stage HL is still under debate, and new combinations are emerging; an individualized approach should be recommended, considering all RT technical opportunities to minimize toxicity while maintaining efficacy.

Stereotactic ablative radiation therapy prior to liver transplantation in hepatocellular carcinoma.

OBJECTIVE: Stereotactic ablative radiotherapy (SABR) is a safe treatment approach for hepatocellular carcinoma (HCC) with comparable effectiveness to other local therapies. Only scant information is available concerning the role of SABR prior to liver transplantation (LT) for HCC. We present a consecutive case series investigating the role of SABR as a bridge or downstaging option in HCC patients subsequently submitted to LT. MATERIALS AND METHODS: Between September 2012 and May 2014, 8 patients for a total of 13 lesions underwent SABR prior to LT. Inclusion criteria were a pathological or radiological diagnosis of HCC, lesion size ≤6 cm or lesion number ≤3 with a total diameter ≤6 cm, no extrahepatic metastases, Child-Pugh class A-B, ECOG performance status ≤1. Patients were prescribed 36-48 Gy in 3-5 fractions (8 Gy × 5 fractions or 16 Gy × 3 fractions), in 3-5 consecutive days according to clinical and dosimetric decision making. Radiological response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Pathological response was assessed through the rate of tumor necrosis relative to the total tumor volume. Acute and late toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 (CTCAE v 4.0). RESULTS: Among the 13 pathologically evaluated lesions, 8 (61.5 %) lesions had a complete response 2 (15.3 %) had a minimal pathological response and other 2 (15.3 %) showed stable disease. The remaining lesion had a significant pathological response. Maximum detected toxicity included a G2 GGT increase in two patients (at 1 and 3 months respectively). One patient developed a non-classic RILD with a fivefold increase in transaminase enzymes level and a shift in Child-Pugh category from B7 to C10 due to bilirubin increase. Only one modification in the surgical strategy was needed during LT. CONCLUSIONS: SABR proved to be a safe and effective local therapy prior to LT in HCC patients. Prospective controlled clinical trials are needed to evaluate its efficacy compared to other local therapies in this setting.

Three-dimensional ultrasound-based image-guided hypofractionated radiotherapy for intermediate-risk prostate cancer: results of a consecutive case series.

External beam radiotherapy (EBRT) is a standard of care in the treatment of prostate cancer. Hypofractionation is a valid option either radiobiologically and logistically in this context. Image-guidance procedures are strongly needed to provide ballistic precision to radiation delivery. The Clarity platform allows for the acquisition of three-dimensional ultrasound scans (3D-US) to perform image-guided radiotherapy. We treated a consecutive series of intermediate-risk prostate cancer patients (according to NCCN stratification) with a hypofractionated schedule (70.2 Gy/26 fractions at 2.7 Gy/daily to the prostate gland excluding the seminal vesicles at 62.1 Gy) under 3D-US guidance with the Clarity platform. The 3-year biochemical-relapse-free survival, distant-metastases-free, cancer-specific and overall survival were 98.6% (CI: 91.1-99.6%), 98.6% (CI: 91.1-99.6%), 97.5% (CI: 94.5-99.1%), and 94.3% (CI: 90.4-96.7%), respectively. Maximum detected acute GU toxicity was G0 in 22 patients (29.7%), G1 in 30 (22.7%), G2 in 19 (25.6%), G3 in 3 (4%). Maximum detected acute GI toxicity at the end of EBRT was G0 in 42 patients (56.8%), G1 in 22 (29.7%), G2 in 9 (12.1%), G3 in 1 (1.4%). The 3-year actuarial rates of ≥ G2 late toxicities were 6.1% for genito-urinary and 8.9% for gastrointestinal. The whole image-guidance workflow resulted in being robust and reliable. EBRT delivered employing a hypofractionated schedule under 3D-US-based image guidance proved to be a safe and effective treatment approach with consistent biochemical control and a mild toxicity profile. Hence, it has been transferred into daily clinical practice in our Department.

Impact of the observers' experience on daily prostate localization accuracy in ultrasound-based IGRT with the Clarity platform.

The aim of this study is to evaluate the accuracy of daily prostate localization with ultrasound imaging of various radiation oncologists with nonhomogeneous expertise. For ten patients who underwent radical radiotherapy for localized prostate cancer, 11 radiation oncologists reviewed daily ultrasound scans acquired during three different treatment sessions. The average values of two senior radiation oncologists, considered to be expert observers, were selected as reference. The remaining nine observers were divided into two groups, Group 1 and Group 2, with more and less than one year of experience, respectively. The recorded shifts in prostate position were divided in three classes: <3 mm, 3-5 mm, and > 5 mm. Deviations from reference were less than 3 mm in all directions in 91% and 81% of measurements in Groups 1 and 2, respectively. The maximum difference in terms of root mean square error (RMSE) was reported for superior-inferior (SI) direction, in particular a mean difference of 3.24 mm was observed for Group 2 in respect to the reference; moreover RMSE was 1 and 1.3 mm higher for Group 2 for anterior-posterior (AP) and left-right (LR) directions, respectively. The difference between Groups 1 and 2 was significant (p < 0.01) for all directions. The mean values for the shifts in all three directions between Group 1 and the references were 0.235 mm, 0.385 mm, and 0.009 mm for the LR, SI, and AP directions, respectively. The position of the prostate gland is more easily detectable (p = 0.956) in the AP direction, while the visibility is lower for LR (p = 0.105) and SI boundaries (p < 0.05). The observers' experience is essential for positioning the target correctly; therefore, a training period is recommended before putting the system into clinical practice.

Is stereotactic ablative radiotherapy an alternative to surgery in operable stage I non-small cell lung cancer?

Surgery is the gold therapeutic standard for patients affected with stage I non-small cell lung cancer. Stereotactic ablative radiotherapy is currently considered the preferred treatment option for inoperable patients, representing approximately 25%. Limited data are available directly comparing surgery and SABR in operable patients, none of them prospective. Preliminary results are encouraging, showing that the two treatment modalities are equally effective in terms of tumour control, with expected similar survival projections. Moreover, in elderly patients SABR could represent a valid treatment alternative in comparison to surgery due to the lower morbidity. We here review and discuss the potential role of SABR as an alternative to surgery in operable early stage lung cancer patients.

CT and MRI radiomic features of lung cancer (NSCLC): comparison and software consistency.

BACKGROUND: Radiomics is a quantitative approach that allows the extraction of mineable data from medical images. Despite the growing clinical interest, radiomics studies are affected by variability stemming from analysis choices. We aimed to investigate the agreement between two open-source radiomics software for both contrast-enhanced computed tomography (CT) and contrast-enhanced magnetic resonance imaging (MRI) of lung cancers and to preliminarily evaluate the existence of radiomic features stable for both techniques. METHODS: Contrast-enhanced CT and MRI images of 35 patients affected with non-small cell lung cancer (NSCLC) were manually segmented and preprocessed using three different methods. Sixty-six Image Biomarker Standardisation Initiative-compliant features common to the considered platforms, PyRadiomics and LIFEx, were extracted. The correlation among features with the same mathematical definition was analyzed by comparing PyRadiomics and LIFEx (at fixed imaging technique), and MRI with CT results (for the same software). RESULTS: When assessing the agreement between LIFEx and PyRadiomics across the considered resampling, the maximum statistically significant correlations were observed to be 94% for CT features and 95% for MRI ones. When examining the correlation between features extracted from contrast-enhanced CT and MRI using the same software, higher significant correspondences were identified in 11% of features for both software. CONCLUSIONS: Considering NSCLC, (i) for both imaging techniques, LIFEx and PyRadiomics agreed on average for 90% of features, with MRI being more affected by resampling and (ii) CT and MRI contained mostly non-redundant information, but there are shape features and, more importantly, texture features that can be singled out by both techniques. RELEVANCE STATEMENT: Identifying and selecting features that are stable cross-modalities may be one of the strategies to pave the way for radiomics clinical translation. KEY POINTS: • More than 90% of LIFEx and PyRadiomics features contain the same information. • Ten percent of features (shape, texture) are stable among contrast-enhanced CT and MRI. • Software compliance and cross-modalities stability features are impacted by the resampling method.

Management of patients with extensive small-cell lung cancer in the immunotherapy era: An Italian consensus through a Delphi approach.

BACKGROUND: Immunotherapy represented a turning point for treating extensive small-cell lung cancer (ES-SCLC). Although, many issues remain debated. METHODS: A group of Italian medical and radiation oncologists with expertise in managing patients with ES-SCLC developed a list of statements divided in six areas of interest. The Delphi method was used to assess the consensus on the defined list of statements. RESULTS: 32 statements were included in the final list to be voted by the Delphi panel, and 26 reached a consensus on the agreement. A prompt involvement of a multidisciplinary team is a priority to provide an integrated treatment strategy. First-line recommended treatment is immunotherapy in combination with platinum-based chemotherapy and etoposide for four cycles followed by maintenance immunotherapy. CONCLUSIONS: While awaiting new data from clinical trials and real-world studies, these recommendations can represent a useful tool to guide the management of ES-SCLC patients in daily practice.

The "BUONGIORNO" project: burnout syndrome among young Italian radiation oncologists.

Few data exist about the prevalence of burnout syndrome among young radiation oncologists. A national survey to assess its prevalence among junior members (under 40 yrs of age) of the Italian Society of Radiation Oncology was conducted. One hundred and twelve young radiation oncologists completed the questionnaire: the prevalence of burnout syndrome was 35%, and it was related to the presence of different personal, organizational, and work-related aspects, with an impact also on the private life (p<.005). Burnout syndrome is relatively common among young Italian radiation oncologists, and specific educational tools to help improve the management of workload and stress are needed.

Prostate-specific antigen kinetics after I125-brachytherapy for prostate adenocarcinoma.

PURPOSE: To investigate a potential correlation between the achievement of a cut-off of nadir PSA (nPSA) after brachytherapy (BRT) with biochemical Disease-Free Survival (bDFS) and to define the rate of post-BRT PSA bounces. METHODS: Retrospective analysis was carried out in 105 consecutive patients affected with early-stage prostate adenocarcinoma who underwent (125)I BRT. Only patients with a minimum follow-up ≥24 months were included. Biochemical DFS was chosen as primary endpoint. RESULTS: At a median follow-up of 51.2 months, 3- and 5-year bDFS were 96.8 and 91.2%, respectively. Median time to biochemical failure (BF) was 54 months. By Kaplan-Meier analysis, patients achieving nPSA ≤ 0.35 ng/mL had significantly higher bDFS (3- and 5-year bDFS: 100 and 98.5 % vs. 83.3 and 66.7 %, respectively; p = 0.001). Bounce PSA occurred in 28.6% of patients, at a median time of 21.5 months. No BFs were observed in the bounce group. Achieving a nPSA ≤ 0.35 ng/mL was the only factor independently associated with long-term bDFS on both univariate (p = 0.000) and multivariate analysis (HR 3.82; p = 0.003). CONCLUSIONS: Patients attaining a nPSA ≤ 0.35 ng/mL are significantly more likely to experience long-term freedom-from-biochemical failure. Bounce PSA occurs in approximately 30% of patients. Time to onset of PSA increase seems the most reliable feature to distinguish bounce from failure. Tailored follow-up strategies are needed for patients at higher risk of recurrence, and caution is advised in interpreting an early increase in PSA levels in the first 24-30 months after BRT.

Salvage external beam radiotherapy for recurrent prostate adenocarcinoma after high-intensity focused ultrasound as primary treatment.

INTRODUCTION: The main objective was to evaluate feasibility, toxicity and biochemical control rates of salvage external beam radiotherapy (EBRT) in recurrent localized prostate cancer after high-intensity focused ultrasound (HIFU) as primary therapy. PATIENTS AND METHODS: A total of 24 patients who underwent salvage EBRT after 1 or 2 HIFU sessions and with a minimum post-treatment follow-up of 24 months were retrospectively evaluated. Primary endpoints were toxicity and biochemical disease-free survival (bDFS, defined according to the ASTRO Phoenix definition). RESULTS: Median follow-up was 40.3 months. Gastrointestinal toxicity was low. Acute genitourinary (GU) toxicity grade ≤II rate was 45.8%, with only few patients presenting grade III (8.3%) and grade IV (4.2%) toxicity. Late grade ≥III GU toxicity was registered in 16.7% of patients. The 3-year bDFS rate was 77.8%. Patients achieving a nadir prostate-specific antigen (nPSA) of ≤0.35 ng/ml after EBRT had significantly higher bDFS (3-year bDFS: 87.7 vs. 50%, respectively; p = 0.001). Achieving nPSA ≤0.35 ng/ml was the only factor independently associated to long-term bDFS both on univariate (p = 0.01) and multivariate analysis (HR 7.06, p = 0.039). CONCLUSIONS: Salvage EBRT after HIFU failure is feasible and allows to obtain satisfactory biochemical control rates, especially in patients attaining a nPSA ≤0.35 ng/ml after EBRT.

The "PROCAINA (PROstate CAncer INdication Attitudes) Project" (Part II)--a survey among Italian radiation oncologists on radical radiotherapy in prostate cancer.

PURPOSE: Radiotherapy (RT) has an established role in the treatment of prostate cancer patients. Despite the large number of patients treated with RT, some issues about optimal techniques, doses, volumes, timing, and association with androgen deprivation are still subject of debate. The aim of this survey was to determine the patterns of choice of Italian radiation oncologists in two different clinical cases of prostate cancer patients treated with radical RT. STUDY DESIGN: During the 2010 Italian Association of Radiation Oncology (AIRO) National congress, four different clinical cases were presented to attending radiation oncologists. Two of them were prostate cancer cases that could be treated by RT +/- hormonal therapy (HT), different for T stage of primary tumour according to TNM, preoperative diagnostic procedures for staging, initial prostate specific antigen (iPSA), and Gleason Score sum of biopsy. For each clinical case, radiation oncologists were asked to: (a) give indication to pretreatment procedures for staging; (b) give indication to treatment; (c) define specifically, where indicated, total dose, type of fractionation, volumes of treatment, type of technique, type of image-guided setup control; (d) indicate if HT should be prescribed; (e) define criteria that particularly influenced prescription. A descriptive statistical analysis was performed. RESULTS: Three hundred questionnaires were given to radiation oncologists attending the congress, 128 questionnaires were completed and considered for this analysis (41%). Some important differences were shown in prescribing and delivering RT, particularly with regards to treatment volumes and fractionation. CONCLUSIONS: Despite the results of clinical trials, several differences still exist among Italian radiation oncologists in the treatment of prostate cancer patients. These patients probably deserve a more uniform approach, based on upto-date, detailed, and evidence-based recommendations.

Rationale and Design of a Single-Arm, Phase 2, Multi-Center Study of Chemo-Immunotherapy Followed by Hypo-Fractionated RT and Maintenance Immunotherapy in Patients With Unresectable Stage III NSCLC: The DEDALUS Trial.

INTRODUCTION/BACKGROUND: This single-arm, phase 2, multi-center, study aims to assess the safety and efficacy of a regimen of induction chemo-immunotherapy followed by de-intensified, hypo-fractionated thoracic radiotherapy (RT) given concurrently with durvalumab and maintenance durvalumab in patients with unresectable, stage III NSCLC. MATERIAL AND METHODS: we will enroll 45 patients with unresectable stage III NSCLC, any PD-L1, deemed ineligible for concurrent CRT by a thoracic oncology multidisciplinary team, and candidate to sequential chemoradiation followed by durvalumab. RESULTS: Primary endpoint is safety, defined by the incidence of grade 3 and 4 possibly related adverse events (PRAEs) within 6 months from the initiation of treatment. The secondary objectives are PFS and OS (median and 12 months). Ancillary endpoints are molecular response evaluated by cfDNA isolation baseline, after chemo-immuno RT and at progression, and radiomics analysis on CT scans at baseline and before maintenance. CONCLUSION: DEDALUS phase 2 trial explores the safety and efficacy of a novel sequence of chemo-radiation (with de-intensified RT) plus the anti-PD-L1 agent durvalumab in patients with stage III unresectable NSCLC who are candidates to sequential chemoradiation plus maintenance immunotherapy.

New options and open issues in the management of unresectable stage III and in early-stage NSCLC: A report from an expert panel of Italian medical and radiation oncologists - INTERACTION group.

IMPORTANCE: After the PACIFIC trial, concurrent chemo-radiotherapy followed by consolidation therapy with durvalumab for 1 year (limited to PD-L1 tumour proportion score ≥ 1% in the EMA region) is the firmly established standard of care treatment for unresectable NSCLC patients. Several relevant questions are emerging with the growing use of this approach, posing novel challenges in clinical practice. Treatment of oncogene-addicted NSCLCs, management of mediastinal disease recurrence after surgery and the optimal management of patients progressing during or after durvalumab are now some of the most clinically relevant issues. OBSERVATIONS: Patients with unresectable NSCLC harbouring EGFR and HER2 mutations or ALK/ROS1/RET /NTRK1,2,3 rearrangements are unresponsive to immunotherapy. Importance of knowing the tumour genotyping (NGS, preferable DNA and RNA) from the earliest stages of NSCLC, also for the possible use of immunotherapy both in the adjuvant and perioperative setting. In case of mediastinal disease recurrence after surgery, re-biopsy is essential to re-determine the histological and biological characteristics of the disease and the distinction of recurrence in curable and non-curable disease is of pivotal important for the optimal management of subsequent treatments. CONCLUSIONS AND RELEVANCE: Treatment of stage III NSCLC has always been controversial and challenging: Multidisciplinary approach is mandatory and defining resectability is a critical issue. Chemo-radiotherapy followed by maintenance Durvalumab is now the standard of treatment. Herein, we provide a comprehensive overview of the key challenges and open questions that we are currently facing in clinical practice, in unresectable stage III and in early-stage NSCLC, identifying the knowledge gaps and the possible solutions.