On the necessity of specialized knowledge-based models for SBRT prostate treatments plans.

PURPOSE: Test whether a well-grounded KBP model trained on moderately hypo-fractionated prostate treatments can be used to satisfactorily drive the optimization of SBRT prostate treatments. MATERIALS AND METHODS: A KBP model (SBRT-model) was developed, trained and validated using the first forty-seven clinically treated VMAT SBRT prostate plans (42.7 Gy/7fx or 36.25 Gy/5fx). The performance and robustness of this model were compared against a high-quality KBP-model (ST-model) that was already clinically adopted for hypo-fractionated (70 Gy/28fx and 60 Gy/20fx) prostate treatments. The two models were compared in terms of their predictions robustness, and the quality of their outcomes were evaluated against a set of reference clinical SBRT plans. Plan quality was assessed using DVH metrics, blinded clinical ranking, and a dedicated Plan Quality Metric algorithm. RESULTS: The plan libraries of the two models were found to share a high degree of anatomical similarity. The overall quality (APQM%) of the plans obtained both with the ST- and SBRT-models was compatible with that of the original clinical plans, namely (93.7 ± 4.1)% and (91.6 ± 3.9)% vs (92.8.9 ± 3.6)%. Plans obtained with the ST-model showed significantly higher target coverage (PTV V95%): (97.9 ± 0.8)% vs (97.1 ± 0.9)% (p < 0.05). Conversely, plans optimized following the SBRT-model showed a small but not-clinically relevant increase in OAR sparing. ST-model generally provided more reliable predictions than SBRT-model. Two radiation oncologists judged as equivalent the plans based on the KBP prediction, which was also judged better that reference clinical plans. CONCLUSION: A KBP model trained on moderately fractionated prostate treatment plans provided optimal SBRT prostate plans, with similar or larger plan quality than an embryonic SBRT-model based on a limited number of cases.

Artificial Intelligence-suggested Predictive Model of Survival in Patients Treated With Stereotactic Radiotherapy for Early Lung Cancer.

BACKGROUND/AIM: Overall survival (OS)-predictive models to clinically stratify patients with stage I Non-Small Cell Lung Cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT) are still unavailable. The aim of this work was to build a predictive model of OS in this setting. PATIENTS AND METHODS: Clinical variables of patients treated in three Institutions with SBRT for stage I NSCLC were retrospectively collected into a reference cohort A (107 patients) and 2 comparative cohorts B1 (32 patients) and B2 (38 patients). A predictive model was built using Cox regression (CR) and artificial neural networks (ANN) on reference cohort A and then tested on comparative cohorts. RESULTS: Cohort B1 patients were older and with worse chronic obstructive pulmonary disease (COPD) than cohort A. Cohort B2 patients were heavier smokers but had lower Charlson Comorbidity Index (CCI). At CR analysis for cohort A, only ECOG Performance Status 0-1 and absence of previous neoplasms correlated with better OS. The model was enhanced combining ANN and CR findings. The reference cohort was divided into prognostic Group 1 (0-2 score) and Group 2 (3-9 score) to assess model's predictions on OS: grouping was close to statistical significance (p=0.081). One and 2-year OS resulted higher for Group 1, lower for Group 2. In comparative cohorts, the model successfully predicted two groups of patients with divergent OS trends: higher for Group 1 and lower for Group 2. CONCLUSION: The produced model is a relevant tool to clinically stratify SBRT candidates into prognostic groups, even when applied to different cohorts. ANN are a valuable resource, providing useful data to build a prognostic model that deserves to be validated prospectively.

Redetermination of PD-L1 expression after chemio-radiation in locally advanced PDL1 negative NSCLC patients: retrospective multicentric analysis.

Background: Chemoradiation therapy (CRT) is the treatment of choice for locally advanced non-small cell lung cancer (LA-NSCLC). Several clinical trials that combine programmed cell death 1 (PD1) axis inhibitors with radiotherapy are in development for patients with LA-NSCLC. However, the effect of CRT on tumor cells programmed cell death ligand-1 (PD-L1) expression is unknown. Methods: In this multicentric retrospective study, we analyzed paired NSCLC specimens that had been obtained pre- and post-CRT. PD-L1 expression on tumor cells was studied by immunohistochemistry. The purpose of this study was to evaluate the feasibility, risk of complications, and clinical relevance of performing re-biopsy after CRT in patients with PD-L1 negative LA-NSCLC. Results: Overall, 31 patients from 6 centers with PD-L1 negative LA-NSCLC were analyzed. The percentage of tumor cells with PD-L1 expression significantly increased between pre- and post-CRT specimens in 14 patients (45%). Nine patients had unchanged PD-L1 expression after CRT, in five patients the rebiopsy material was insufficient for PD-L1 analysis and in two patients no tumor cells at rebiopsy were found. The post-rebiopsy complication rate was very low (6%). All patients with positive PD-L1 re-biopsy received Durvalumab maintenance after CRT, except one patient who had a long hospitalization for tuberculosis reactivation. Median PFS of patients with unchanged or increased PD-L1 expression was 10 and 16.9 months, respectively. Conclusion: CRT administration can induce PD-L1 expression in a considerable fraction of PD-L1 negative patients at baseline, allowing them receiving the maintenance Durvalumab in Europe. Hence, after a definitive CRT, PD-L1 redetermination should be considered in patients with LA-NSCLC PD-L1 negative, to have a better selection of maintenance Durvalumab candidates.

European Association of Urology Biochemical Recurrence Risk Classification as a Decision Tool for Salvage Radiotherapy-A Multicenter Study.

BACKGROUND: The European Association of Urology (EAU) has proposed a risk stratification for patients harboring biochemical recurrence (BCR) after radical prostatectomy (RP). OBJECTIVE: To assess whether this risk stratification helps in choosing patients for salvage radiotherapy (SRT). DESIGN, SETTING, AND PARTICIPANTS: Analyses of 2379 patients who developed BCR after RP (1989-2020), within ten European high-volume centers, were conducted. Early and late SRT were defined as SRT delivered at prostate-specific antigen values <0.5 and ≥0.5 ng/ml, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable Cox models tested the effect of SRT versus no SRT on death and cancer-specific death. The Simon-Makuch method tested for survival differences within each risk group. RESULTS AND LIMITATIONS: Overall, 805 and 1574 patients were classified as having EAU low- and high-risk BCR. The median follow-up was 54 mo after BCR for survivors. For low-risk BCR, 12-yr overall survival was 87% versus 78% (p = 0.2) and cancer-specific survival was 100% versus 96% (p = 0.2) for early versus no SRT. For high-risk BCR, 12-yr overall survival was 81% versus 66% (p < 0.001) and cancer-specific survival was 98% versus 82% (p < 0.001) for early versus no SRT. In multivariable analyses, early SRT decreased the risk for death (hazard ratio [HR]: 0.55, p < 0.01) and cancer-specific death (HR: 0.08, p < 0.001). Late SRT was a predictor of cancer-specific death (HR: 0.17, p < 0.01) but not death (p = 0.1). CONCLUSIONS: Improved survival was recorded within the high-risk BCR group for patients treated with early SRT compared with those under observation. Our results suggest recommending early SRT for high-risk BCR men. Conversely, surveillance might be suitable for low-risk BCR, since only nine patients with low-risk BCR died from prostate cancer during follow-up. PATIENT SUMMARY: The impact of salvage radiotherapy (SRT) on cancer-specific outcomes stratified according to the European Association of Urology biochemical recurrence (BCR) risk classification was assessed. While men with high-risk BCR should be offered SRT, surveillance might be a suitable option for those with low-risk BCR.

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.

Real-world Outcomes and Predictive Biomarkers for 177Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study.

BACKGROUND: The European Association of Urology guidelines include the lutetium-177 (177Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers. OBJECTIVE: To assess the performance of 177Lu PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective observational study including 233 patients with mCRPC treated with 177Lu PSMA in eight high-volume European centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline characteristics and clinical parameters during and after 177Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ2 and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models. RESULTS AND LIMITATIONS: A prostate-specific antigen (PSA) decrease of ≥30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease ≥30% after the first two cycles of 177Lu PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase ≤31 U/L at the start of 177Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). CONCLUSIONS: 177Lu PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease ≥30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice. PATIENT SUMMARY: 177Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that 177Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.

Additional Value of PET and CT Image-Based Features in the Detection of Occult Lymph Node Metastases in Lung Cancer: A Systematic Review of the Literature.

Lung cancer represents the second most common malignancy worldwide and lymph node (LN) involvement serves as a crucial prognostic factor for tailoring treatment approaches. Invasive methods, such as mediastinoscopy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), are employed for preoperative LN staging. Among the preoperative non-invasive diagnostic methods, computed tomography (CT) and, recently, positron emission tomography (PET)/CT with fluorine-18-fludeoxyglucose ([18F]FDG) are routinely recommended by several guidelines; however, they can both miss pathologically proven LN metastases, with an incidence up to 26% for patients staged with [18F]FDG PET/CT. These undetected metastases, known as occult LN metastases (OLMs), are usually cases of micro-metastasis or small LN metastasis (shortest radius below 10 mm). Hence, it is crucial to find novel approaches to increase their discovery rate. Radiomics is an emerging field that seeks to uncover and quantify the concealed information present in biomedical images by utilising machine or deep learning approaches. The extracted features can be integrated into predictive models, as numerous reports have emphasised their usefulness in the staging of lung cancer. However, there is a paucity of studies examining the detection of OLMs using quantitative features derived from images. Hence, the objective of this review was to investigate the potential application of PET- and/or CT-derived quantitative radiomic features for the identification of OLMs.

Role of radiomic analysis of [18F]fluoromethylcholine PET/CT in predicting biochemical recurrence in a cohort of intermediate and high risk prostate cancer patients at initial staging.

AIM: To study the feasibility of radiomic analysis of baseline [18F]fluoromethylcholine positron emission tomography/computed tomography (PET/CT) for the prediction of biochemical recurrence (BCR) in a cohort of intermediate and high-risk prostate cancer (PCa) patients. MATERIAL AND METHODS: Seventy-four patients were prospectively collected. We analyzed three prostate gland (PG) segmentations (i.e., PGwhole: whole PG; PG41%: prostate having standardized uptake value - SUV > 0.41*SUVmax; PG2.5: prostate having SUV > 2.5) together with three SUV discretization steps (i.e., 0.2, 0.4, and 0.6). For each segmentation/discretization step, we trained a logistic regression model to predict BCR using radiomic and/or clinical features. RESULTS: The median baseline prostate-specific antigen was 11 ng/mL, the Gleason score was > 7 for 54% of patients, and the clinical stage was T1/T2 for 89% and T3 for 9% of patients. The baseline clinical model achieved an area under the receiver operating characteristic curve (AUC) of 0.73. Performances improved when clinical data were combined with radiomic features, in particular for PG2.5 and 0.4 discretization, for which the median test AUC was 0.78. CONCLUSION: Radiomics reinforces clinical parameters in predicting BCR in intermediate and high-risk PCa patients. These first data strongly encourage further investigations on the use of radiomic analysis to identify patients at risk of BCR. CLINICAL RELEVANCE STATEMENT: The application of AI combined with radiomic analysis of [18F]fluoromethylcholine PET/CT images has proven to be a promising tool to stratify patients with intermediate or high-risk PCa in order to predict biochemical recurrence and tailor the best treatment options. KEY POINTS: • Stratification of patients with intermediate and high-risk prostate cancer at risk of biochemical recurrence before initial treatment would help determine the optimal curative strategy. • Artificial intelligence combined with radiomic analysis of [18F]fluorocholine PET/CT images allows prediction of biochemical recurrence, especially when radiomic features are complemented with patients' clinical information (highest median AUC of 0.78). • Radiomics reinforces the information of conventional clinical parameters (i.e., Gleason score and initial prostate-specific antigen level) in predicting biochemical recurrence.

A predictive model of polymetastatic disease from a multicenter large retrospectIve database on colorectal lung metastases treated with stereotactic ablative radiotherapy: The RED LaIT-SABR study.

Aim: Stereotactic ablative radiotherapy (SABR) showed increasing survival in oligometastatic patients. Few studies actually depicted oligometastatic disease (OMD) evolution and which patient will remain disease-free and which will rapidly develop a polymetastatic disease (PMD) after SABR. Therefore, apart from the number of active metastases, there are no clues on which proven factor should be considered for prescribing local treatment in OMD. The study aims to identify predictive factors of polymetastatic evolution in lung oligometastatic colorectal cancer patients. Methods: This international Ethical Committee approved trial (Prot. Negrar 2019-ZT) involved 23 Centers and 450 lung oligometastatic patients. Primary end-point was time to the polymetastatic conversion (tPMC). Additionally, oligometastases number and cumulative gross tumor volume (cumGTV) were used as combined predictive factors of tPMC. Oligometastases number was stratified as 1, 2-3, and 4-5; cumGTV was dichotomized to the value of 10 cc. Results: The median tPMC in the overall population was 26 months. Population was classified in the following tPMC risk classes: low-risk (1-3 oligometastases and cumGTV ≤ 10 cc) with median tPMC of 35.1 months; intermediate-risk (1-3 oligometastases and cumGTV > 10 cc), with median tPMC of 13.9 months, and high-risk (4-5 oligometastases, any cumGTV) with median tPMC of 9.4 months (p = 0.000). Conclusion: The present study identified predictive factors of polymetastatic evolution after SABR in lung oligometastatic colorectal cancer. The results demonstrated that the sole metastases number is not sufficient to define the OMD since patients defined oligometastatic from a numerical point of view might rapidly progress to PMD when the cumulative tumor volume is high. A tailored approach in SABR prescription should be pursued considering the expected disease evolution after SABR, with the aim to avoid unnecessary treatment and toxicity in those at high risk of polymetastatic spread, and maximize local treatment in those with a favorable disease evolution.

Secondary prevention and treatment innovation of early stage non-small cell lung cancer: Impact on diagnostic-therapeutic pathway from a multidisciplinary perspective.

Lung cancer (LC) is the leading cause of cancer-related death worldwide, mostly because the lack of a screening program so far. Although smoking cessation has a central role in LC primary prevention, several trials on LC screening through low-dose computed tomography (LDCT) in a high risk population showed a significant reduction of LC related mortality. Most trials showed heterogeneity in terms of selection criteria, comparator arm, detection nodule method, timing and intervals of screening and duration of the follow-up. LC screening programs currently active in Europe as well as around the world will lead to a higher number of early-stage Non Small Cell Lung Cancer (NSCLC) at the diagnosis. Innovative drugs have been recently transposed from the metastatic to the perioperative setting, leading to improvements in terms of resection rates and pathological responses after induction chemoimmunotherapy, and disease free survival with targeted agents and immune checkpoint inhibitors. The present review summarizes available evidence about LC screening, highlighting potential pitfalls and benefits and underlining the impact on the diagnostic therapeutic pathway of NSCLC from a multidisciplinary perspective. Future perspectives in terms of circulating biomarkers under evaluation for patients' risk stratification as well as a focus on recent clinical trials results and ongoing studies in the perioperative setting will be also presented.

Estimated Direct Costs of Renal Cancer by Stage of Disease at Diagnosis and Phase of Its Management: A Whole-Disease Model.

BACKGROUND: Renal cell carcinoma (RCC) is the seventh most common neoplasm in high-income countries. New clinical pathways have been developed to deal with this tumor, which includes costly drugs that pose an economic threat to the sustainability of healthcare services. This study provides an estimate of the direct costs of care for patients with RCC by stage of disease (early vs. advanced) at diagnosis, and disease management phase along the pathway recommended by local and international guidelines. MATERIALS AND METHODS: Considering the clinical pathway for RCC adopted in the Veneto region (north-east Italy) and the latest guidelines, we developed a very detailed "whole-disease" model that covers the probabilities of all potentially necessary diagnostic and therapeutic actions involved in the management of RCC. Based on the cost of each procedure according to the Veneto Regional Authority's official reimbursement tariffs, we estimated the total and average per-patient costs by stage of disease (early or advanced) and phase of its management. RESULTS: In the first year after diagnosis, the mean expected cost of a patient with RCC is €12,991 if it is localized or locally-advanced and reaches €40,586 if it is advanced. For early disease, the main cost is incurred by surgery, whereas medical therapy (first and second line) and supportive care become increasingly important for metastatic disease. CONCLUSION: It is crucially important to examine the direct costs of care for RCC, and to predict the burden on healthcare services of new oncological therapies and treatments, as the findings could be useful for policy-makers planning the allocation of resources.

Updating a clinical Knowledge-Based Planning prediction model for prostate radiotherapy.

BACKGROUND AND PURPOSE: Clinical knowledge-based planning (KBP) models dedicated to prostate radiotherapy treatment may require periodical updates to remain relevant and to adapt to possible changes in the clinic. This study proposes a paired comparison of two different update approaches through a longitudinal analysis. MATERIALS AND METHODS: A clinically validated KBP model for moderately hypofractionated prostate therapy was periodically updated using two approaches: one was targeted at achieving the biggest library size (Mt), while the other one at achieving the highest mean sample quality (Rt). Four subsequent updates were accomplished. The goodness, robustness and quality of the outcomes were measured and compared to those of the common ancestor. Plan quality was assessed through the Plan Quality Metric (PQM) and plan complexity was monitored. RESULTS: Both update procedures allowed for an increase in the OARs sparing between +3.9 % and +19.2 % compared to plans generated by a human planner. Target coverage and homogeneity slightly reduced [-0.2 %;-14.7 %] while plan complexity showed only minor changes. Increasing the sample size resulted in more reliable predictions and improved goodness-of-fit, while increasing the mean sample quality improved the outcomes but slightly reduced the models reliability. CONCLUSIONS: Repeated updates of clinical KBP models can enhance their robustness, reliability and the overall quality of automatically generated plans. The periodical expansion of the model sample accompanied by the removal of the unacceptable low quality plans should maximize the benefits of the updates while limiting the associated workload.

Renal cell carcinoma: the population, real world, and cost-of-illness.

BACKGROUND: The RCC treatment landscape has evolved dramatically over the past decade. The purpose of this study is to present a real-world data estimation of RCC's cost-of-illness for this tumour's clinical pathway. METHODS: This investigation is a population-based cohort study using real-world data, which considers all RCC incident cases diagnosed in Local Unit 6 of the Province of Padua in 2016 and 2017 as registered by the Veneto Cancer Registry. Data on drug prescriptions, the use of medical devices, hospital admissions, and visits to outpatient clinics and emergency departments were collected by means of administrative databases. We evaluated the costs of all healthcare procedures performed in the 2 years of follow-up post-RCC diagnosis. The overall and annual average real-world costs per patient, both as a whole and by single item, were calculated and stratified by stage of disease at diagnosis. RESULTS: The analysis involved a population of 148 patients with a median age of 65.8 years, 66.22% of whom were male. Two years after diagnosis, the average total costs amounted to €21,429 per patient. There is a steady increment in costs with increasing stage at diagnosis, with a total amount of €41,494 spent 2 years after diagnosis for stage IV patients, which is 2.44 times higher than the expenditure for stage I patients (€17,037). In the first year, hospitalization appeared to be the most expensive item for both early and advanced disease. In the second year, however, outpatient procedures were the main cost driver in the earlier stages, whereas anticancer drugs accounted for the highest costs in the advanced stages. CONCLUSIONS: This observational study provides real-world and valuable estimates of RCC's cost-of-illness, which could enable policymakers to construct dynamic economic cost-effectiveness evaluation models based on real world costs' evaluation.

The Multidisciplinary Approach in Stage III Non-Small Cell Lung Cancer over Ten Years: From Radiation Therapy Optimisation to Innovative Systemic Treatments.

Background: About 30% of new non-small cell lung cancer (NSCLC) cases are diagnosed at a locally advanced stage, which includes a highly heterogeneous group of patients with a wide spectrum of treatment options. The management of stage III NSCLC involves a multidisciplinary team, adequate staging, and a careful patient selection for surgery or radiation therapy integrated with systemic treatment. Methods: This is a single-center observational retrospective and prospective study including a consecutive series of stage III NSCLC patients who were referred to the Veneto Institute of Oncology and University Hospital of Padova (Italy) between 2012 and 2021. We described clinico-pathological characteristics, therapeutic pathways, and treatment responses in terms of radiological response in the entire study population and in terms of pathological response in patients who underwent surgery after induction therapy. Furthermore, we analysed survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS). Results: A total of 301 patients were included. The majority of patients received surgical multimodality treatment (n = 223, 74.1%), while the remaining patients (n = 78, 25.9%) underwent definitive CRT followed or not by durvalumab as consolidation therapy. At data cut-off, 188 patients (62.5%) relapsed and the median RFS (mRFS) of the entire population was 18.2 months (95% CI: 15.83−20.57). At the time of analyses 140 patients (46.5%) were alive and the median OS (mOS) was 44.7 months (95% CI: 38.4−51.0). A statistically significant difference both in mRFS (p = 0.002) and in mOS (p < 0.001) was observed according to the therapeutic pathway in the entire population, and selecting patients treated after 2018, a significant difference in mRFS (p = 0.006) and mOS (p < 0.001) was observed according to treatment modality. Furthermore, considering only patients diagnosed with stage IIIB-C (N = 131, 43.5%), there were significant differences both in mRFS (p = 0.047) and in mOS (p = 0.022) as per the treatment algorithm. The mRFS of the unresectable population was 16.3 months (95% CI: 11.48−21.12), with a significant difference among subgroups (p = 0.030) in favour of patients who underwent the PACIFIC-regimen; while the mOS was 46.5 months (95% CI: 26.46−66.65), with a significant difference between two subgroups (p = 0.003) in favour of consolidation immunotherapy. Conclusions: Our work provides insights into the management and the survival outcomes of stage III NSCLC over about 10 years. We found that the choice of radical treatment impacts on outcome, thus suggesting the importance of appropriate staging at diagnosis, patient selection, and of the multidisciplinary approach in the decision-making process. Our results confirmed that the PACIFIC trial and the following introduction of durvalumab as consolidation treatment may be considered as a turning point for several improvements in the diagnostic-therapeutic pathway of stage III NSCLC patients.

The Overall Survival and Progression-Free Survival in Patients with Advanced Adrenocortical Cancer Is Increased after the Multidisciplinary Team Evaluation.

We aimed to evaluate the role of adrenal multidisciplinary team evaluation (MTE) in affecting the overall survival (OS) and progression-free survival (PFS) in patients with adrenocortical carcinoma (ACC). We included in a retrospective monocentric study 47 patients with ACC. We divided our cohort into group 1 (without adrenal-MTE discussion, ACC diagnosis from 2004 to 2012, n = 14) and group 2 (diagnosis and beginning of treatments after 2013, all discussed in the adrenal MTE, n = 33). OS was defined by the survival between the first and the last visit, while PFS as the time from the first visit to the progression of the disease. Kaplan−Meier curves were used to compare OS and PFS between Group 1 and Group 2. Group 1stages III−IV (n = 10) presented a shorter median OS than Group 2stages III−IV (25 patients, 4 vs. 31 months, p = 0.023). Likewise, the median PFS was lower in Group 1 as compared to Group 2 (2.9 vs. 17.2 months, p < 0.001). The gain in PFS (6 months) was also confirmed in stage III-IV patients (2.9 vs. 8.7 months, respectively, for Group 1 and Group 2, p = 0.02). Group 1 presented a median PFS of 4 months, while the median PFS of Group 2 was 14.7 months (p = 0.128). In conclusion, we found a significant gain in terms of survival in patients after the MTE discussion in 2013. Therefore, ACC patients should be referred to a tertiary center, ideally from the time of diagnosis, to promptly apply all available treatments, according to the single patient's clinical history and based on multidisciplinary management.

Novel Harmonization Method for Multi-Centric Radiomic Studies in Non-Small Cell Lung Cancer.

The purpose of this multi-centric work was to investigate the relationship between radiomic features extracted from pre-treatment computed tomography (CT), positron emission tomography (PET) imaging, and clinical outcomes for stereotactic body radiation therapy (SBRT) in early-stage non-small cell lung cancer (NSCLC). One-hundred and seventeen patients who received SBRT for early-stage NSCLC were retrospectively identified from seven Italian centers. The tumor was identified on pre-treatment free-breathing CT and PET images, from which we extracted 3004 quantitative radiomic features. The primary outcome was 24-month progression-free-survival (PFS) based on cancer recurrence (local/non-local) following SBRT. A harmonization technique was proposed for CT features considering lesion and contralateral healthy lung tissues using the LASSO algorithm as a feature selector. Models with harmonized CT features (B models) demonstrated better performances compared to the ones using only original CT features (C models). A linear support vector machine (SVM) with harmonized CT and PET features (A1 model) showed an area under the curve (AUC) of 0.77 (0.63-0.85) for predicting the primary outcome in an external validation cohort. The addition of clinical features did not enhance the model performance. This study provided the basis for validating our novel CT data harmonization strategy, involving delta radiomics. The harmonized radiomic models demonstrated the capability to properly predict patient prognosis.

Stereotactic prostate radiotherapy with or without androgen deprivation therapy, study protocol for a phase III, multi-institutional randomized-controlled trial.

Objective: The therapeutic landscape for localized prostate cancer (PC) is evolving. Stereotactic radiotherapy (SRT) has been reported to be at least not inferior to standard radiotherapy, but the effect of androgen deprivation therapy (ADT) in this setting is still unknown and its use is left to clinical judgment. There is therefore the need to clarify the role of ADT in association with SRT, which is the aim of the present study. Methods: We present a study protocol for a randomized, multi-institutional, Phase III clinical trial, designed to study SRT in unfavorable intermediate and a subclass of high-risk localized PC. Patients (pts) will be randomized 1:1 to SRT + ADT or SRT alone. SRT will consists in 36.25 Gy in 5 fractions, ADT will be a single administration of Triptorelin 22.5 mg concurrent to SRT. Primary end point will be biochemical disease-free survival. Secondary end points will be disease-free survival, freedom from local recurrence, freedom from regional recurrence, freedom from distant metastasis and overall survival (OS); quality of life QoL and patient reported outcomes will be an exploratory end point and will be scored with EPIC-26, EORTC PR 25, IPSS, IIEF questionnaires in SRT + ADT and SRT alone arms. Moreover, clinician reported acute and late toxicity, assessed with CTCAE v. 5.0 scales will be safety end points. Results: Sample size is estimated of 310 pts. For acute toxicity and quality of life results are awaited after 6 months since last patient in, whereas, for efficacy end points and late toxicity mature results will be available 3-5 years after last patient in. Conclusion: Evidence is insufficient to guide decision making concerning ADT administration in the new scenario of prostate ultra-hypofractionation. Hence, the need to investigate the ADT role in SRT specific setting. Advances in knowledge: The stereotactic prostate radiotherapy with or without ADT trial (SPA Trial) has been designed to establish a new standard of care for SRT in localized unfavorable intermediate and a subclass of localized high risk PC.

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.].

The role of stereotactic body radiation therapy and its integration with systemic therapies in metastatic kidney cancer: a multicenter study on behalf of the AIRO (Italian Association of Radiotherapy and Clinical Oncology) genitourinary study group.

Although systemic therapy represents the standard of care for polymetastatic kidney cancer, stereotactic body radiation therapy (SBRT) may play a relevant role in the oligometastatic setting. We conducted a multicenter study including oligometastatic kidney cancer treated with SBRT. We retrospectively analyzed 207 patients who underwent 245 SBRT treatments on 385 lesions, including 165 (42.9%) oligorecurrent (OR) and 220 (57.1%) oligoprogressive (OP) lesions. Most common sites were lung (30.9%) for OR group, and bone (32.7%) for OP group. Among 78 (31.8%) patients receiving concomitant systemic therapy, sunitinib (61.5%) and pazopanib (15.4%) were the most common for OR patients, while sunitinib (49.2%) and nivolumab (20.0%) for OP patients. End points were local control (LC), progression free survival (PFS), overall survival (OS), time to next systemic therapy (TTNS) and toxicity. Median follow-up was 18.6 months. 1, 2 and 3-year LC rates were 89.4%, 80.1% and 76.6% in OR patients, and 82.7%, 76.9% and 64.3% in those with OP, respectively. LC for OP group was influenced by clear cell histology (p = 0.000), total number of lesions (p = 0.004), systemic therapy during SBRT (p = 0.012), and SBRT dose (p = 0.012). Median PFS was 37.9 months. 1, 2- and 3-year OS was 92.7%, 86.4% and 81.8%, respectively. Median TTNS was 15.8 months for OR patients, and 13.9 months for OP patients. No grade 3 or higher toxicities were reported for both groups. SBRT may be considered an effective safe option in the multidisciplinary management of both OR and OP metastases from kidney cancer.

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.