Extreme-hypofractionated RT with concomitant boost to the DIL in PCa: a 5-year update on oncological and patient-reported outcomes for the phase II trial "GIVE ME FIVE".

AIM: The present work reports updated oncological results and patients-reported outcomes at 5 years of phase II trial "Short-term high precision RT for early prostate cancer with SIB to the dominant intraprostatic lesion (DIL) for patients with early-stage PCa". METHODS: Data from patients enrolled within AIRC IG-13218 (NCT01913717) trial were analyzed. Clinical and GU/GI toxicity assessment and PSA measurements were performed every 3 months for at least 2 years after RT end. QoL of enrolled patients was assessed by IPSS, EORTC QLQ-C30, EORTC QLQ-PR25, and IIEF-5. Patients' score changes were calculated at the end of RT and at 1, 12, and 60 months after RT. RESULTS: A total of 65 patients were included. At a median follow-up of 5 years, OS resulted 86%. Biochemical and clinical progression-free survival at 5 years were 95%. The median PSA at baseline was 6.07 ng/ml, while at last follow-up resulted 0.25 ng/ml. IPSS showed a statistically significant variation in urinary function from baseline (p = 0.002), with the most relevant deterioration 1 month after RT, with a recovery toward baseline at 12 months (p ≤ 0.0001). A numerical improvement in QoL according to the EORTC QLQ-C30 has been reported although not statistically significant. No change in sexual activity was recorded after RT. CONCLUSIONS: The study confirms that extreme hypofractionation with a DIL boost is safe and effective, with no severe effects on the QoL. The increasing dose to the DIL does not worsen the RT toxicity, thus opening the possibility of an even more escalated treatment.

Correlation between radiological and biological features and clinical outcomes in early prostate cancer: an exploratory subgroup analysis.

PTEN deletion and Ki-67 expression are two of the most promising biomarkers in prostate cancer (PCa). In the same manner, multiparametric magnetic resonance imaging (mp-MRI) guided core biopsy is a powerful tool for PCa detection and staging. The aim of the study is to assess whether a correlation can be identified between the pathological stage defined by an mp-MRI-guided core biopsy and Ki-67 expression and PTEN deletion. Such correlation might be useful for staging and treatment personalization in PCa. This investigation was conducted in the context of phase II clinical study "Short-term radiotherapy for early prostate cancer with a concomitant boost to the dominant lesion" (AIRC IG-13218), ClinicalTrials.gov identifier: NCT01913717. Nineteen patients underwent a further in-bore MRI-targeted core biopsy (MRI-TBx) on the dominant intraprostatic lesion (DIL); on this basis, an additional Gleason Score (GS) was determined. PTEN loss and Ki-67 expression on these samples were analyzed and correlated with both risk categories modifications and oncological outcomes (overall survival, biochemical and clinical relapse). GS was upgraded in 5 cases, with 4 patients re-classified as intermediate-risk and 1 patient as high-risk. The latter experienced a clinical local relapse. No correlations between up/down-staging, PTEN deletion, and Ki-67 expression were observed in this cohort. Further investigations are needed towards the identification of a pattern in the tumor aggressiveness-response in PCa treated with ultra-hypofractionated radiotherapy. Moreover, a possible relationship between biomarker analysis and imaging textural features could be explored.

Adjuvant radiotherapy in node positive prostate cancer patients: a debate still on. when, for whom?

OBJECTIVE: To evaluate the impact of adjuvant radiotherapy (aRT) in patients with prostate cancer (PCa) found to have pathological positive lymph nodes (pN1s) after radical prostatectomy (RP) and extended pelvic lymph node dissection (ePLND) with regard to distant recurrence-free survival (RFS), according to both main tumour pathological characteristics and number of positive lymph nodes. Biochemical RFS, local RFS, overall survival (OS) and acute and late toxicity were assessed as secondary endpoints. PATIENTS AND METHODS: A retrospective cohort of 187 consecutive patients with pN1 PCa were treated with aRT at the IEO, European Institute of Oncology IRCCS, Milan, Italy. aRT on the tumour bed and pelvis was administered within 6 months of RP. Androgen deprivation therapy was administered according to the guidelines. Univariate and multivariate Cox regression analyses predicting biochemical RFS, local RFS, distant RFS and OS rates were performed to assess whether the number of pN1s represented an independent prognostic factor. The Youden index was computed to find the optimal threshold for the number of pN1s able to discriminate between patients with or without biochemical and clinical relapse. RESULTS: At 5 years, local RFS, distant RFS, biochemical RFS and OS were 68%, 71%, 56% and 94%, respectively. The median follow-up was 49 months. The number of pN1s was significantly associated with biochemical RFS, local RFS and distant RFS. The best threshold for discriminating between patients with or without biochemical and clinical relapse was five pN1s. In multivariate analyses, the number of pN1s was confirmed to be an independent predictor of biochemical RFS, local RFS and distant RFS, but not of OS. Multivariate analyses also showed an increased risk of biochemical relapse for increasing values of initial prostate-specific antigen and for patients with tumour vascular invasion. Local and distant RFS were also inversely correlated with significantly reduced risk for International Society of Urological Pathology grade group <3 (group 1 or 2 compared to group 3). CONCLUSIONS: Our data confirmed the encouraging outcomes of patients with pN1 PCa treated with adjuvant treatments and the key role represented by the number of pN1s in predicting biochemical RFS, clinical RFS and distant RFS. Large prospective cohort studies and randomized clinical trials are needed to confirm these results and to identify the subgroup of patients with pN1 PCa who would most benefit from aRT.

MRI-based radiomics signature for localized prostate cancer: a new clinical tool for cancer aggressiveness prediction? Sub-study of prospective phase II trial on ultra-hypofractionated radiotherapy (AIRC IG-13218).

OBJECTIVES: Radiomic involves testing the associations of a large number of quantitative imaging features with clinical characteristics. Our aim was to extract a radiomic signature from axial T2-weighted (T2-W) magnetic resonance imaging (MRI) of the whole prostate able to predict oncological and radiological scores in prostate cancer (PCa). METHODS: This study included 65 patients with localized PCa treated with radiotherapy (RT) between 2014 and 2018. For each patient, the T2-W MRI images were normalized with the histogram intensity scale standardization method. Features were extracted with the IBEX software. The association of each radiomic feature with risk class, T-stage, Gleason score (GS), extracapsular extension (ECE) score, and Prostate Imaging Reporting and Data System (PI-RADS v2) score was assessed by univariate and multivariate analysis. RESULTS: Forty-nine out of 65 patients were eligible. Among the 1702 features extracted, 3 to 6 features with the highest predictive power were selected for each outcome. This analysis showed that texture features were the most predictive for GS, PI-RADS v2 score, and risk class; intensity features were highly associated with T-stage, ECE score, and risk class, with areas under the receiver operating characteristic curve (ROC AUC) ranging from 0.74 to 0.94. CONCLUSIONS: MRI-based radiomics is a promising tool for prediction of PCa characteristics. Although a significant association was found between the selected features and all the mentioned clinical/radiological scores, further validations on larger cohorts are needed before these findings can be applied in the clinical practice. KEY POINTS: • A radiomic model was used to classify PCa aggressiveness. • Radiomic analysis was performed on T2-W magnetic resonance images of the whole prostate gland. • The most predictive features belong to the texture (57%) and intensity (43%) domains.

Correction to: Late toxicity of image-guided hypofractionated radiotherapy for prostate: non-randomized comparison with conventional fractionation.

Unfortunately, the denomination of the IEO was incorrectly published in the affiliation of this original.

Radioablation +/- hormonotherapy for prostate cancer oligorecurrences (Radiosa trial): potential of imaging and biology (AIRC IG-22159).

BACKGROUND: Prostate cancer (PCa) is the second most common cancer among men. New imaging-modalities have increased the diagnosed patients with limited number of metastasis after primary curative therapy, introducing so-called oligometastatic state. Stereotactic body radiotherapy (SBRT) is emerging as a low-toxicity treatment to erase PCa localizations and postpone androgen deprivation therapy (ADT). A deeper understanding of the predictive role of biomarkers is desirable for a targeted treatment selection and surveillance programs. The aims of the RADIOSA trial are: 1. Compare SBRT +/- ADT for oligorecurrent-castration-sensitive PCa (OCS-PCa) in terms of efficacy, toxicity and Quality of Life (QoL). 2. Develop biology/imaging based prognostic tool that allows identifying OCS-PCa subclasses. METHODS: This is a randomized phase II clinical trial, recruiting 160 OCS-PCa in 3 years, with progression-free survival (PFS) as primary endpoint. Three tasks will be developed: 1. Randomized clinical study (3 years for accrual and 2 years for follow-up and data analysis); 2. Imaging study, including imaging registration and METastasis Reporting and Data System (MET-RADS) criteria; 3. Pre-clinical study, development of a biobank of blood samples for the analysis of neutrophil-to-lymphocyte ratio and preparatory for a subsequent miRNA profiling. We aim to determine which arm is justified for testing in a subsequent Phase III trial. A decision-tree algorithm, based on prognosis, biological phenotype and imaging profile, will be developed. DISCUSSION: Recruiting will start in July 2019. SBRT will allow obtaining excellent PFS, local control, QoL and low toxicity. In SBRT arm, ADT deferral will allow for a drug-holiday, delaying the detrimental impact on QoL. A sufficient number of blood samples will be collected to perform biological patient profiling. A stratification tool will be established with an analysis of morphological and functional imaging, based on the use of MET-RADS criteria. So, in conclusion, RADIOSA aims to define the optimal management of bone/nodal PCa relapses in a SBRT regimen. This study will increase our knowledge on low-burden metastatic PCa in the era of high precision and high technology personalized medicine, offering highly effective therapy in terms of clinical outcome and cost-effectiveness. TRIAL REGISTRATION: The RADIOSA study was prospectively registered at clinicaltrials.gov ( NCT03940235 , May 2019).

Late toxicity of image-guided hypofractionated radiotherapy for prostate: non-randomized comparison with conventional fractionation.

PURPOSE: To evaluate the incidence and predictors for late toxicity and tumor outcome after hypofractionated radiotherapy using three different image-guided radiotherapy (IGRT) systems (hypo-IGRT) compared with conventional fractionation without image guidance (non-IGRT). METHODS AND MATERIALS: We compared the late rectal and urinary toxicity and outcome in 179 prostate cancer patients treated with hypo-IGRT (70.2 Gy/26 fractions) and 174 non-IGRT patients (80 Gy/40 fractions). Multivariate analysis was performed to define predictors for late toxicity. 5- and 8-year recurrence-free survival (RFS) and overall survival (OS) were analyzed. RESULTS: Mean follow-up was 81 months for hypo-IGRT and 90 months for non-IGRT group. Mainly mild late toxicity was observed: Hypo-IGRT group experienced 65 rectal (30.9% G1/G2; 6.3% G3/G4) and 105 urinary events (56% G1/G2; 4% G3/G4). 5- and 8-year RFS rates were 87.5% and 86.8% (hypo-IGRT) versus 80.4% and 66.8% (non-IGRT). 5- and 8-year OS rates were 91.3% and 82.7% in hypo-IGRT and 92.2% and 84% in non-IGRT group. Multivariate analysis showed that hypo-IGRT is a predictor for late genitourinary toxicity, whereas hypo-IGRT, acute urinary toxicity and androgen deprivation therapy are predictors for late rectal toxicity. Advanced T stage and higher Gleason score (GS) were correlated with worse RFS. CONCLUSIONS: A small increase in mild late toxicity, but not statistically significant increase in severe late toxicity in the hypo-IGRT group when compared with conventional non-IGRT group was observed. Our study confirmed that IGRT allows for safe moderate hypofractionation, offering a shorter overall treatment time, a good impact in terms of RFS and providing potentially more economic health care.

Variability in axillary lymph node delineation for breast cancer radiotherapy in presence of guidelines on a multi-institutional platform.

AIM: To quantify the variability between radiation oncologists (ROs) when outlining axillary nodes in breast cancer. MATERIAL AND METHODS: For each participating center, three ROs with different levels of expertise, i.e., junior (J), senior (S) and expert (E), contoured axillary nodal levels (L1, L2, L3 and L4) on the CT images of three different patients (P) of an increasing degree of anatomical complexity (from P1 to P2 to P3), according to contouring guidelines. Consensus contours were generated using the simultaneous truth and performance level estimation (STAPLE) method. RESULTS: Fifteen centers and 42 ROs participated. Overall, the median Dice similarity coefficient was 0.66. Statistically significant differences were observed according to the level of expertise (better agreement for J and E, worse for S); the axillary level (better agreement for L1 and L4, worse for L3); the patient (better agreement for P1, worse for P3). Statistically significant differences in contouring were found in 18% of the inter-center comparison. Less than a half of the centers could claim to have a good agreement between the internal ROs. CONCLUSIONS: The overall intra-institute and inter-institute agreement was moderate. Central lymph-node levels were the most critical and variability increased as the complexity of the patient's anatomy increased. These findings might have an effect on the interpretation of results from multicenter and even mono-institute studies.

Reporting combined outcomes with Trifecta and survival, continence, and potency (SCP) classification in 337 patients with prostate cancer treated with image-guided hypofractionated radiotherapy.

OBJECTIVE: To report the image-guided hypofractionated radiotherapy (hypo-IGRT) outcome for patients with localised prostate cancer according to the new outcome models Trifecta (cancer control, urinary continence, and sexual potency) and SCP (failure-free survival, continence and potency). PATIENTS AND METHODS: Between August 2006 and January 2011, 337 patients with cT1-T2N0M0 prostate cancer (median age 73 years) were eligible for a prospective longitudinal study on hypo-IGRT (70.2 Gy/26 fractions) in our Department. Patients completed four questionnaires before treatment, and during follow-up: the International Index of Erectile Function-5 (IIEF-5), the International Prostate Symptom Score (IPSS), and the European Organization for Research and Treatment of Cancer prostate-cancer-specific Quality of Life Questionnaires (QLQ) QLQ-PR25 and QLQ-C30. Baseline and follow-up patient data were analysed according to the Trifecta and SCP outcome models. Cancer control, continence and potency were defined respectively as no evidence of disease, score 1 or 2 for item 36 of the QLQ-PR25 questionnaire, and total score of >16 on the IIEF-5 questionnaire. Patients receiving androgen-deprivation therapy (ADT) at any time were excluded. RESULTS: Trifecta criteria at baseline were met in 72 patients (42% of all ADT-free patients with completed questionnaires). Both at 12 and 24 months after hypo-IGRT, 57% of the Trifecta patients at baseline were still meeting the Trifecta criteria (both oncological and functional success according to the SCP model). The main reason for failing the Trifecta criteria during follow-up was erectile dysfunction: in 18 patients after 6 months follow-up, in 12 patients after 12 months follow-up, and in eight patients after 24 months. Actuarial 2-year Trifecta failure-free survival rate was 44% (95% confidence interval 27-60%). In multivariate analysis no predictors of Trifecta failure were identified. Missing questionnaires was the main limitation of the study. CONCLUSION: The Trifecta and SCP classifications can be used as tools to report RT outcome.

Muscle-invasive bladder cancer in elderly and frail people: Is hypofractionated radiotherapy a feasible approach when no other local options are available?

AIM: The study aims to report the feasibility and safety of palliative hypofractionated radiotherapy targeting macroscopic bladder tumors in a monocentric cohort of frail and elderly bladder cancer patients not eligible for curative treatments. METHODS: Patients who underwent hypofractionated radiotherapy to the gross disease or to the tumor bed after transurethral resection of bladder tumor from 2017 to 2021 at the European Institute of Oncology IRCCS, were retrospectively considered. Schedules of treatment were 30 and 25 Gy in 5 fractions (both every other day, and consecutive days). Treatment response was evaluated with radiological investigation and/or cystoscopy. Toxicity assessment was carried out according to RTOG/EORTC v2.0 criteria. RESULTS: A total of 16 patients were included in the study, of these 11 received hypofractionated radiotherapy on the macroscopic target volume and five on the tumor bed after transurethral resection of bladder tumor. No grade (G) >2 acute toxicities were described after treatment for both groups. Only one patient in the group receiving radiotherapy on the macroscopic disease reported G4 GU late toxicity. Ten patients had available follow-up status (median FU time 18 months), of them six had complete response, one had stable disease, and three had progression of disease. The overall response rate and disease control rate were 60% and 70%, respectively. CONCLUSION: Our preliminary data demonstrate that palliative hypofractionated radiotherapy for bladder cancer in a frail and elderly population is technically feasible, with an acceptable toxicity profile. These outcomes emphasize the potential of this approach in a non-radical setting and could help to provide more solid indications in this underrepresented setting of patients.

Photon vs proton hypofractionation in prostate cancer: A systematic review and meta-analysis.

BACKGROUND: High-level evidence on hypofractionated proton therapy (PT) for localized and locally advanced prostate cancer (PCa) patients is currently missing. The aim of this study is to provide a systematic literature review to compare the toxicity and effectiveness of curative radiotherapy with photon therapy (XRT) or PT in PCa. METHODS: PubMed, Embase, and the Cochrane Library databases were systematically searched up to April 2022. Men with a diagnosis of PCa who underwent curative hypofractionated RT treatment (PT or XRT) were included. Risk of grade (G) ≥ 2 acute and late genitourinary (GU) OR gastrointestinal (GI) toxicity were the primary outcomes of interest. Secondary outcomes were five-year biochemical relapse-free survival (b-RFS), clinical relapse-free, distant metastasis-free, and prostate cancer-specific survival. Heterogeneity between study-specific estimates was assessed using Chi-square statistics and measured with the I2 index (heterogeneity measure across studies). RESULTS: A total of 230 studies matched inclusion criteria and, due to overlapped populations, 160 were included in the present analysis. Significant lower rates of G ≥ 2 acute GI incidence (2 % vs 7 %) and improved 5-year biochemical relapse-free survival (95 % vs 91 %) were observed in the PT arm compared to XRT. PT benefits in 5-year biochemical relapse-free survival were maintained for the moderate hypofractionated arm (p-value 0.0122) and among patients in intermediate and low-risk classes (p-values < 0.0001 and 0.0368, respectively). No statistically relevant differences were found for the other considered outcomes. CONCLUSION: The present study supports that PT is safe and effective for localized PCa treatment, however, more data from RCTs are needed to draw solid evidence in this setting and further effort must be made to identify the patient subgroups that could benefit the most from PT.

Image guided hypofractionated radiotherapy and quality of life for localized prostate cancer: prospective longitudinal study in 337 patients.

PURPOSE: We prospectively analyzed quality of life in a cohort of patients with prostate cancer undergoing a course of hypofractionated image guided radiotherapy. MATERIALS AND METHODS: Between August 2006 and January 2011, 337 patients with a median age of 73 years who had cT1-T2N0M0 prostate cancer were eligible for this prospective, longitudinal study of hypofractionated image guided radiotherapy (70.2 Gy/26 fractions) using 1 of 3 image guided radiotherapy modalities (transabdominal ultrasound, x-ray or cone beam computerized tomography) available in our radiation oncology department. Patients completed 4 questionnaires before treatment, and 6, 12 and 24 months later, including the International Index of Erectile Function-5, International Prostate Symptom Score, and EORTC (European Organization for Research and Treatment of Cancer) prostate cancer specific QLQ-PR25 and QLQ-C30. RESULTS: Patient followup was updated to at least the last questionnaire time point. Median followup was 19 months. Significant deterioration in erectile function on the International Index of Erectile Function-5 was documented with time only in patients without androgen deprivation (p = 0.0002). No change with time was observed in urinary symptom related quality of life on the QLQ-PR25 or International Prostate Symptom Score. Slight deterioration in QLQ-PR25 bowel symptom related quality of life was observed (p = 0.02). Overall QLQ-C30 Global Health Status improved with time (p = 0.03). On univariate analysis it significantly correlated with the maximum RTOG (Radiation Therapy Oncology Group)/EORTC urinary and bowel late toxicity scores after radiotherapy. CONCLUSIONS: The regimen of hypofractionated image guided radiotherapy with multiple imaging modalities adopted in our radiation oncology department for localized prostate cancer might be a successful strategy for dose escalation with a limited impact on different aspects of quality of life with time.

Can Ki-67 predict radiotherapy response in neuroendocrine tumors? Retrospective analysis of a monocentric series of patients.

BACKGROUND: The impact of radiotherapy (RT) in neuroendocrine neoplasms is still unknown, and outcomes could be improved by a better insight in RT response predictors. This retrospective analysis investigates the potential correlation between Ki-67 and RT response to evaluate its role as biological marker of radiosensitivity. MATERIAL AND METHODS: Data from patients treated at an Italian NET-referral center between 2015 and 2020 were retrieved. Inclusion criteria included: histologically-proven diagnosis of NEN, Ki-67 status, indication (symptomatic and/or ablative) and at least one post-RT radiological assessment. RESULTS: Forty-two patients and 63 different treatment lines were included. Primary tumors presented Ki-67 values < 3% in 21% of cases, between 3 and 20% in 45% and >20% in the remaining 33%. Almost all patients were metastatic at the time of RT, which was performed with symptomatic purpose in 43% of cases. At a median time of three months, a complete response on the target lesion was observed in nine cases (14%), a partial response in 17 (27%), stability in 23 (37%) and local progression in 14 (22%). With median FU of 22.8 months, OS does not show statistically significant differences among three Ki-67 groups. Considering all lines of therapy, the relationship between ORR and Ki-67, did not show statistically significant differences, even following adjustments for drug types and delivered RT doses. CONCLUSION: No association between Ki67 and local tumor response to RT could be observed in the present cohort, regardless of whether the evaluation was performed on a categorical or continuous scale.

Cyberknife Radiosurgery for Prostate Cancer after Abdominoperineal Resection (CYRANO): The Combined Computer Tomography and Electromagnetic Navigation Guided Transperineal Fiducial Markers Implantation Technique.

In this technical development report, we present the strategic placement of fiducial markers within the prostate under the guidance of computed tomography (CT) and electromagnetic navigation (EMN) for the delivery of ultra-hypofractionated cyberknife (CK) therapy in a patient with localized prostate cancer (PCa) who had previously undergone chemo-radiotherapy for rectal cancer and subsequent abdominoperineal resection due to local recurrence. The patient was positioned in a prone position with a pillow under the pelvis to facilitate access, and an electromagnetic fiducial marker was placed on the patient's skin to establish a stable position. CT scans were performed to plan the procedure, mark virtual points, and simulate the needle trajectory using the navigation system. Local anesthesia was administered, and a 21G needle was used to place the fiducial markers according to the navigation system information. A confirmatory CT scan was obtained to ensure proper positioning. The implantation procedure was safe, without any acute side effects such as pain, hematuria, dysuria, or hematospermia. Our report highlights the ability to use EMN systems to virtually navigate within a pre-acquired imaging dataset in the interventional room, allowing for non-conventional approaches and potentially revolutionizing fiducial marker positioning, offering new perspectives for PCa treatment in selected cases.

Nodal Merkel Cell Carcinoma with Unknown Primary Site and No Distant Metastasis: A Single-Center Series.

Merkel cell carcinoma (MCC) is a very rare and aggressive neuroendocrine carcinoma originating from Merkel cells, typically with a skin nodule; however, it exceptionally presents with only a basin lymph node localization, with neither a cutaneous primary site nor distant metastases. From 1996 to 2020, among patients with histologically confirmed MCC managed at a neuroendocrine neoplasm-referral center, we selected those with an exclusive nodal basin, no distant metastasis, and an unknown primary site defined by cross-sectional and physical examination. A total of 55 out of 310 patients fulfilled the selection criteria. The median age was 64 years and the majority were males. Inguinal lymph-nodes were the most common anatomic site. With a median follow-up of 4.3 years, the 5-year relapse-free survival (RFS) rate was 56.6 (95% CI 42.0-68.8%) and the 5-year cancer specific survival (CSS) rate was 68.5 (95% CI 52.8-79.9%) for the whole population. The 36 patients (65.5%) undergoing lymphadenectomy (LND) + radiotherapy (RT) ± chemotherapy had a 5-year RFS rate of 87.2% (95% CI 65.5-95.7%) and a 5-year CSS rate of 90.5% (95% CI 67.0-97.5), which were better than those receiving LND alone. In a multivariable analysis, the survival benefit for LND + RT remained significant. Results from one of the largest single-center series of nMCC-UP suggest that a curative approach including RT can be effective, similar to what is observed for stage IIIB MCC. Multicentric studies with homogenous populations should be carried out in this controversial clinical entity, to minimize the risk of biases and provide robust data.

Ultrahypofractionated radiotherapy for localized prostate cancer with simultaneous boost to the dominant intraprostatic lesion: a plan comparison.

OBJECTIVE: To compare different stereotactic body techniques-intensity-modulated radiotherapy with photons and protons, applied to radiotherapy of prostatic cancer-with simultaneous integrated boost (SIB) on the dominant intraprostatic lesion (DIL). METHODS: Ten patients were selected for this planning study. Dosimetric results were compared between volumetric modulated arc therapy, intensity-modulated radiation therapy (IMRT), and intensity-modulated proton therapy both with two (IMPT 2F) and five fields (IMPT 5F) planning while applying the prescription schemes of 7.25 Gy/fraction to the prostate gland and 7.5 Gy/fraction to the DIL in 5 fractions. RESULTS: Comparison of the coverages of the planning target volumes showed that small differences exist. The IMPT-2F-5F techniques allowed higher doses in the targets; conformal indexes resulted similar; homogeneity was better in the photon techniques (2%-5%). Regarding the organs at risk, all the techniques were able to maintain the dose well below the prescribed constraints: in the rectum, the IMPT-2F-5F and IMRT were more efficient in lowering the intermediate doses; in the bladder, the median dose was significantly better in the case of IMPT (2F-5F). In the urethra, the best sparing was achieved only by IMPT-5F. CONCLUSIONS: Stereotactic radiotherapy with SIB for localized prostate cancer is feasible with all the investigated techniques. Concerning IMPT, the two-beam technique does not seem to have a greater advantage compared to the standard techniques; the 5-beam technique seems more promising also accounting for the range uncertainty.

Physical and clinical implications of radiotherapy treatment of prostate cancer using a full bladder protocol.

PURPOSE: To assess the dosimetric and clinical implication when applying the full bladder protocol for the treatment of the localized prostate cancer (PCA). PATIENTS AND METHODS: A total of 26 consecutive patients were selected for the present study. Patients underwent two series of CT scans: the day of the simulation and after 40 Gy. Each series consisted of two consecutive scans: (1) full bladder (FB) and (2) empty bladder (EB). The contouring of clinical target volumes (CTVs) and organs at risk (OAR) were compared to evaluate organ motion. Treatment plans were compared by dose distribution and dose-volume histograms (DVH). RESULTS: CTV shifts were negligible in the laterolateral and superior-inferior directions (the maximum shift was 1.85 mm). Larger shifts were recorded in the anterior-posterior direction (95% CI, 0.83-4.41 mm). From the dosimetric point of view, shifts are negligible: the minimum dose to the CTV was 98.5% (median; 95%CI, 95-99%). The potential advantage for GU toxicity in applying the FB treatment protocol was measured: the ratio between full and empty bladder dose-volume points (selected from our protocol) is below 0.61, excluding the higher dose region where DVHs converge. CONCLUSION: Having a FB during radiotherapy does not affect treatment effectiveness, on the contrary it helps achieve a more favorable DVH and lower GU toxicities.

Use of machine learning methods for prediction of acute toxicity in organs at risk following prostate radiotherapy.

PURPOSE: The goal of this study is to investigate the advantages of large scale optimization methods vs conventional classification techniques in predicting acute toxicity for urinary bladder and rectum due to prostate irradiation. METHODS: Clinical and dosimetric data of 321 patients undergoing prostate conformal radiotherapy were recorded. Gastro-intestinal and genito-urinary acute toxicities were scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale. Patients were classified in two categories to separate mild (Grade < 2) from severe toxicity levels (Grade > 2). Machine learning methods at different complexity were implemented to predict toxicity as a function of multiple variables. The first approach consisted of a large scale optimization method, based on genetic algorithms (GAs) and artificial neural networks (ANN). The second approach was a binary classifier based on support vector machines (SVM). RESULTS: The ANN and SVM-based solutions showed comparable prediction accuracy, exhibiting an area under the receiver operating characteristic (ROC) curve of 0.7. Different sensitivity and specificity features were measured for the two approaches. The ANN algorithm showed enhanced sensitivity if combined with appropriate classification criteria. CONCLUSIONS: The results demonstrate that high sensitivity in toxicity prediction can be achieved with optimized ANNs, that are put forward to represent a valuable support in medical decisions. Future studies will be focused on enlarging the available patient database to increase the reliability of toxicity prediction algorithms and to define optimal classification criteria.

Multidisciplinary team approach for Merkel cell carcinoma: the European Institute of Oncology experience with focus on radiotherapy.

OBJECTIVE: To review the therapeutic strategy in Merkel cell carcinoma (MCC) treated with radiotherapy (RT) discussed in a multidisciplinary tumour board. METHODS: Clinical records of patients with a diagnosis of MCC and with an indication to undergo RT at the European Institute of Oncology between 2003 and 2018 were reviewed retrospectively. RESULTS: Twenty-six patients were included in the analysis (median age 65 years, range 42-87). Nineteen received adjuvant RT, 4 exclusive RT, and the remainder palliative RT. Intensity-modulated RT was used in 13 cases, a 3D conformal technique in 11 cases, and stereotactic RT in 2 cases. No major toxicities were recorded. The median relapse-free survival (RFS) after adjuvant RT was 20.5 months, while for unknown primary MCC, it was 23 months. In the adjuvant setting, median polyomavirus-positive RFS was 21.5 months (range 1-49) and median polyomavirus-negative RFS was only 14 months (range 4-45). Overall, RFS of polyomavirus-positive and polyomavirus-negative patients was 10.5 and 8 months, respectively. After adjuvant RT, only 1 out of 10 patients had a recurrence in the RT field. At the time of data collection, 16 patients were alive with no evidence of disease, 1 patient was alive with advanced status of disease, 8 patients died of disease progression, and 1 patient died of other causes. CONCLUSIONS: The management of unknown primary and polyomavirus-positive cases, which had a better prognosis in our series, may benefit from a multidisciplinary approach, given the limited data available regarding optimal treatment.

Finding safe dose-volume constraints for re-irradiation with SBRT of patients with prostate cancer relapse: The IEO experience.

AIM: The primary aim of this study is to provide preliminary indications for safe constraints of rectum and bladder in patients re-irradiated with stereotactic body RT (SBRT). METHODS: Data from patients treated for prostate cancer (PCa) and intraprostatic relapse, from 1998 to 2016, were retrospectively collected. First RT course was delivered with 3D conformal RT techniques, SBRT or volumetric modulated arc therapy (VMAT). All patients underwent re-irradiation with SBRT with heavy hypofractionated schedules. Cumulative dose-volume values to organs at risk (OARs) were computed and possible correlation with developed toxicities was investigated. RESULTS: Twenty-six patients were included. Median age at re-irradiation was 75 years, mean interval between the two RT courses was 5.6 years and the median follow-up was 47.7 months (13.4-114.3 months). After re-irradiation, acute and late G ≥ 2 GU toxicity events were reported in 3 (12%) and 10 (38%) patients, respectively, while late G ≥ 2 GI events were reported in 4 (15%) patients. No acute G ≥ 2 GI side effects were registered. Patients receiving an equivalent uniform dose of the two RT treatments < 131 Gy appeared to be at higher risk of progression (4-yr b-PFS: 19% vs 33%, p = 0.145). Cumulative re-irradiation constraints that appear to be safe are D30% < 57.9 Gy for bladder and D30% < 66.0 Gy, D60% < 38.0 Gy and V122.1 Gy < 5% for rectum. CONCLUSION: Preliminary re-irradiation constraints for bladder and rectum have been reported. Our preliminary investigation may serve to clear some grey areas of PCa re-irradiation.