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The purpose of the study is to externally validate publishedOutcome data and pre-radiotherapy PET images of 100 oropharyngeal cancer patients (stage IV:78) treated with concomitant chemotherapy to 66-69 Gy/30 fr were available. Tumors were segmented using a previously validated semi-automatic method; 450 radiomic features (RF) were extracted according to IBSI (Image Biomarker Standardization Initiative) guidelines. Only one model for cancer-specific survival (CSS) prediction was suitable to be independently tested, according to our criteria. This model, in addition to HPV status, SUVmean and SUVmax, included two independent meta-factors (FRegarding the analysis of the subgroup with HPV information, with a median follow-up of 41.6 months, seven patients died due to cancer. R was confirmed to be associated to CSS (p value = 0.05) with a C-index equal 0.75 (95% CI=0.62-0.85). The best cut-off value (equal to 0.15) showed high ability in patient stratification (p=0.01, HR=7.4, 95% CI=1.6-11.4). The 5-year CSS for R were 97% (95% CI: 93-100%) vs 74% (56-92%) for low- and high-risk groups, respectively. RA previously published PET radiomic model for CSS prediction was independently validated. Performances of the model were similar to the ones of using only the MTV, without improvement of prediction accuracy.

To assess the potential of radiomic features (RFs) extracted from simulation computed tomography (CT) images in discriminating local progression (LP) after stereotactic body radiotherapy (SBRT) in the management of lung oligometastases (LOM) from colorectal cancer (CRC).Thirty-eight patients with 70 LOM treated with SBRT were analyzed. The largest LOM was considered as most representative for each patient and was manually delineated by two blinded radiation oncologists. In all, 141 RFs were extracted from both contours according to IBSI (International Biomarker Standardization Initiative) recommendations. Based on the agreement between the two observers, 134/141 RFs were found to be robust against delineation (intraclass correlation coefficient [ICC] 0.80); independent RFs were then assessed by Spearman correlation coefficients. The association between RFs and LP was assessed with Mann-Whitney test and univariate logistic regression (ULR): the discriminative power of the most informative RF was quantified by receiver-operating characteristics (ROC) analysis through area under curve (AUC).In all, 15/38 patients presented LP. Median time to progression was 14.6 months (range 2.4-66 months); 5/141 RFs were significantly associated to LP at ULR analysis (p 0.05); among them, 4 RFs were selected as robust and independent: Statistical_Variance (AUC = 0.75, p = 0.002), Statistical_Range (AUC = 0.72, p = 0.013), Grey Level Size Zone Matrix (GLSZM) _zoneSizeNonUniformity (AUC = 0.70, p = 0.022), Grey Level Dependence Zone Matrix (GLDZM) _zoneDistanceEntropy (AUC = 0.70, p = 0.026). Importantly, the RF with the best performance (Statisical_Variance) is simply representative of density heterogeneity within LOM.Four RFs extracted from planning CT were significantly associated with LP of LOM from CRC treated with SBRT. Results encourage further research on a larger population aiming to define a usable radiomic score combining the most predictive RFs and, possibly, additional clinical features.

Simple Summary Several phase III randomized trials of moderate hypofractionation, including a higher proportion of high-risk prostate cancer patients treated only to the prostate, failed to demonstrate the superiority of hypofractionated regimens. There is only one randomized phase III trial, of moderately hypofractionated high-dose radiotherapy to the prostate-only versus pelvic irradiation and prostate boost, with a sufficiently long follow-up. It demonstrated better biochemical and disease-free survival when lymph nodal radiotherapy was added. Here we present the 10-year results of our experience based on an Institutional protocol adopted after a phase I–II study, on patients with unfavorable intermediate- (UIR), high- (HR), and very high-risk (VHR) prostate cancer (PCa) treated with pelvic lymph nodal irradiation (WPRT) and moderately hypofractionated high-dose (HD) simultaneous integrated boost (SIB) to the prostate. Prognostic factors for relapse, as well as acute and late gastro-intestinal (GI) and genito-urinary (GU) toxicity were also analyzed. Abstract Aims: To report 10-year outcomes of WPRT and HD moderately hypofractionated SIB to the prostate in UIR, HR, and VHR PCa. Methods: From 11/2005 to 12/2015, 224 UIR, HR, and VHR PCa patients underwent WPRT at 51.8 Gy/28 fractions and SIB at 74.2 Gy (EQD2 88 Gy) to the prostate. Androgen deprivation therapy (ADT) was prescribed in up to 86.2% of patients. Results: Median follow-up was 96.3 months (IQR: 71–124.7). Median age was 75 years (IQR: 71.3–78.1). At last follow up, G3 GI–GU toxicity was 3.1% and 8%, respectively. Ten-year biochemical relapse-free survival (bRFS) was 79.8% (95% CI: 72.3–88.1%), disease-free survival (DFS) 87.8% (95% CI: 81.7–94.3%), overall survival (OS) 65.7% (95% CI: 58.2–74.1%), and prostate cancer-specific survival (PCSS) 94.9% (95% CI: 91.0–99.0%). Only two patients presented local relapse. At univariate analysis, VHR vs. UIR was found to be a significant risk factor for biochemical relapse (HR: 2.8, 95% CI: 1.17–6.67, p = 0.021). After model selection, only Gleason Score ≥ 8 emerged as a significant factor for biochemical relapse (HR = 2.3, 95% CI: 1.12–4.9, p = 0.023). Previous TURP (HR = 3.5, 95% CI: 1.62–7.54, p = 0.001) and acute toxicity ≥ G2 (HR = 3.1, 95% CI = 1.45–6.52, p = 0.003) were significant risk factors for GU toxicity ≥ G3. Hypertension was a significant factor for GI toxicity ≥ G3 (HR = 3.63, 95% CI: 1.06–12.46, p = 0.041). ADT (HR = 0.31, 95% CI: 0.12–0.8, p = 0.015) and iPsa (HR = 0.37, 95% CI: 0.16–0.83, p = 0.0164) played a protective role. Conclusions: WPRT and HD SIB to the prostate combined with long-term ADT, in HR PCa, determine good outcomes with acceptable toxicity.

To report toxicity of hypofractionated whole-breast radiotherapy in a large cohort of early-stage breast cancer (BCaients.From 02/2009-05/2017, 1325 consecutive BCa patients were treated with 40.05 Gy/15 fractions, without boost. Median age was 62 (IQR:51.1-70.5) years. Chemotherapy was prescribed for 28% of patients, hormonal therapy for 80.3%, monoclonal antibodies for 8.2%.Median follow-up was 72.4 (IQR: 44.6-104.1) months. Acute RTOG toxicity was: 69.8% Grade (G) 1, 14.3% G2 and 1.7% G3. Late SOMA-LENT toxicities were: edema-hyperpigmentation (E-H): G1 28.67%, G2 4.41%, G3 0.15%; fibrosis-atrophy-telangiectasia-pain (F-A-T-P): G1 14.6%, G2 3.2%, G3 0.8%, G4 0.1%. Median time to first occurrence was 6 and 18 months, respectively. Aesthetic result after surgery was excellent in 28.7%, good in 41.5%, acceptable in 20.3% and poor in 9.5% of patients. Change in breast appearance after radiotherapy was mild in 6.9%, moderate in 2.3% and marked in 1.3% of patients. Concomitant chemotherapy, obesity, smoking, use of bolus and planning target volume (PTV) were associated with higher acute toxicity. Patients ≥55 years old were less likely to experience acute toxicity. PTV and acute G2 toxicity were associated with ≥G2 E-H. PTV, concomitant chemotherapy, hypertension and ≥G2 acute toxicity were associated with increased risk of F-A-T-P.Hypofractionated whole-breast radiotherapy without boost demonstrated mild acute and late toxicity in a large cohort of consecutive patients. Moderate and marked changes in breast appearance were registered for 3.6% of patients and occurred between 18 to 42 months.

An increase of skin dose during head and neck cancer (HNC) radiotherapy is potentially dangerous. Aim of this study was to quantify skin dose variation and to assess the need of planning adaptation (ART) to counteract it.Planning CTs of 32 patients treated with helical tomotherapy (HT) according to a Simultaneous Integrated Boost (SIB) technique delivering 54/66 Gy in 30 fractions were deformably co-registered to MVCTs taken at fractions 15 and 30; in addition, the first fraction was also considered. The delivered dose-of-the-day was calculated on the corresponding deformed images. Superficial body layers (SL) were considered as a surrogate for skin, considering a layer thickness of 2 mm. Variations of SL DVH (∆SL) during therapy were quantified, focusing on ∆SL95% (i.e., 62.7 Gy).Small changes (within ± 1 cc for ∆SL95%) were seen in 15/32 patients. Only 2 patients experienced ∆SL95% 1 cc in at least one of the two monitored fractions. Negative ∆SL95% 1 cc (up to 17 cc) were much more common (15/32 patients). The trend of skin dose changes was mostly detected at the first fraction. Negative changes were correlated with the presence of any overlap between PTV and SL at planning and were explained in terms of how the planning system optimizes the PTV dose coverage near the skin. Acute toxicity was associated with planning DVH and this association was not improved if considering DVHs referring to fractions 15/30.About half of the patients treated with SIB with HT for HNC experienced a skin-sparing effect during therapy; only 6% experienced an increase. Our findings do not support skin-sparing ART, while suggesting the introduction of improved skin-sparing planning techniques.ZWECK: Eine Erhöhung der Hautdosis während der Strahlentherapie von Kopf-Hals-Tumoren (HNC) ist potenziell gefährlich. Das Ziel dieser Studie war es, die Änderung der Hautdosis zu quantifizieren und den Bedarf einer Plananpassung (ART) zu bewerten, um dieser entgegenzuwirken.Planungs-CTs von 32 Patienten, die mittels helikaler Tomotherapie (HT) in einer „Simultaneous Integrated Boost“(SIB)-Technik mit 54/66 Gy bei 30 Fraktionen behandelt wurden, wurden nichtrigide registriert mit MVCTs, die bei Fraktion 15, 30 gefahren wurden; zusätzlich wurde auch die erste Fraktion berücksichtigt. Die verabreichte Tagesdosis wurde auf den entsprechenden deformierten Bildern berechnet. Die äußersten Schichten (SL) wurden als Ersatz für die Haut angesehen, mit einer Schichtdicke von 2 mm. Änderungen der SL-DVH (∆SL) während der Therapie wurden quantifiziert, mit einem Fokus auf ∆SL95 % (d. h. 62,7 Gy).Kleine Änderungen (innerhalb ± 1 cc für ∆SL95 %) ergaben sich bei 15 von 32 Patienten. Bei nur 2 Patienten wurde ein ∆SL95 % 1 cc in mindestens einer der beiden überwachten Fraktionen beobachtet. Negative ∆SL95 % 1 cc (bis zu 17 cc) waren weit häufiger (15 von 32). Der Trend von Hautdosisänderungen wurde zumeist bei der ersten Fraktion festgestellt. Negative Änderungen korrelierten mit der Anwesenheit einer Überlappung von PTV und SL bei der Planung und wurden dahingehend erklärt, wie das Planungssystem die PTV-Dosisabdeckung in der Nähe der Haut optimiert. Eine akute Toxizität war auf das Planungs-DVH zurückzuführen; dies wurde unter Berücksichtigung von DVH bei Fraktion 15 bzw. 30 nicht verbessert.Bei etwa der Hälfte der Patienten, die in SIB-Technik mittels HT für HNC behandelt wurden, ergab sich eine Hautschonung während der Therapie; nur 6 % erfuhren einen Anstieg. Unsere Erkenntnisse unterstützen keine hautschonende Plananpassung (ART), schlagen jedoch die Einführung verbesserter hautschonender Planungstechniken vor.

Background: The number of patients with cardiac implantable electronic devices (CIEDs) receiving radiotherapy (RT) is increasing. The management of CIED-carriers undergoing RT is challenging and requires a collaborative multidisciplinary approach. Aim: The aim of the study is to report the real-world, ten-year experience of a tertiary multidisciplinary teaching hospital. Methods: We conducted an observational, real-world, retrospective, single-center study, enrolling all CIED-carriers who underwent RT at the San Raffaele University Hospital, between June 2010 and December 2021. All devices were MRI-conditional. The devices were programmed to an asynchronous pacing mode for patients who had an intrinsic heart rate of less than 40 beats per minute. An inhibited pacing mode was used for all other patients. All tachyarrhythmia device functions were temporarily disabled. After each RT session, the CIED were reprogrammed to the original settings. Outcomes included adverse events and changes in the variables that indicate lead and device functions. Results: Between June 2010 and December 2021, 107 patients were enrolled, among which 63 (58.9%) were pacemaker carriers and 44 (41.1%) were ICD carriers. Patients were subjected to a mean of 16.4 (±10.7) RT sessions. The most represented tumors in our cohort were prostate cancer (12; 11%), breast cancer (10; 9%) and lung cancer (28; 26%). No statistically significant changes in device parameters were recorded before and after radiotherapy. Generator failures, power-on resets, changes in pacing threshold or sensing requiring system revision or programming changes, battery depletions, pacing inhibitions and inappropriate therapies did not occur in our cohort of patients during a ten-year time span period. Atrial arrhythmias were recorded during RT session in 14 patients (13.1%) and ventricular arrhythmias were observed at device interrogation in 10 patients (9.9%). Conclusions: Changes in device parameters and arrhythmia occurrence were infrequent, and none resulted in a clinically significant adverse event.

Aim We report molecular subtype impact on 1325 early breast cancer (BCa) patients treated with whole breast hypofractionated (WBH) adjuvant forward-planned intensity modulated radiotherapy (F-IMRT) without boost. Methods and materials From 02/2009-05/2017 1325 patients with pTis-pT3, pNx-N1aM0 BCa who underwent breast conservation surgery were treated with WBHF-IMRT in our institute, to a total dose of 40 Gy/15 fractions, without boost. Median age: 62 (interquartile range-IQR-:51.14–70.53) years. Histology: 8% in situ carcinoma (ISC), 92% invasive tumors. Molecular subtypes (invasive tumors): 49.9% Luminal A, 33.1% Luminal B Her2 negative (−), 6.2% Luminal B Her2 positive (+), 3.6% Hormone Receptor (HR)- Her2+, 7.1% Triple negative (TNBC), and 0.2% HR+. Chemotherapy (CT) was prescribed in 28% of patients, hormonal therapy in 80.3%, monoclonal antibodies (MAb) in 86.8% of Luminal B Her2+ and 97.7% of HR- Her2+ patients. Results Median follow up was 72.43 (IQR: 44.63–104.13) months. The 5-year Kaplan-Meier estimates of local relapse-free survival (LRFS) was 97.8%, regional-(RRFS) 98.6%, loco-regional- (LRRFS) 96.9%, distant- (DRFS) 96.6%, disease-free survival (DFS) 94.8% and overall survival (OS) 95.5%. Considering molecular subtypes, 5-year LRFS was: 99.8% for Luminal A, 96.7% for Luminal B Her2-, 94.1% for Luminal B Her2+, 87.9% for HR- Her2+, 95.1% for TNBC and 99.1% for in situ carcinoma. Conclusion While the overall estimated probability of LR within 5 years after WBHF-IMRT without boost is good (2.2%), molecular subtypes have a strong impact, despite MAb therapy in Her2+ patients, and CT for TNBC patients, and could be used as a parameter in deciding the boost prescription., Highlights • Hypofractionated three-weeks radiotherapy ensures good local control whitout boost. • In 1325 early stage breast cancers 5-year local relapse without boost was 2.2%. • Molecular subtypes have a strong impact on estimated probability of local relapse. • 5-year local control (LC) was 99.8% for Luminal A vs 87.9% for HR- Her2+. • 5-year LC was 96.7% for Luminal B Her2-, 94.1% for Luminal B Her2+, 95.1% for TNBC.

Simple Summary The therapeutic strategies employed for anaplastic thyroid cancer patients seems to be insufficient to prolong their survival, but some characteristics could predict a good prognosis, so that, starting from our experience we offer a systematic review of the literature to better understand anaplastic thyroid cancers behavior and their prognostic factors, in order to recognize and select the patients with the higher probability of better outcome even if metastatic. Moreover, we described an uncommon site of metastasis in order to improve scientific knowledge about this rare and highly aggressive pathology. Abstract Anaplastic thyroid carcinoma (ATC) is a very rare, highly aggressive malignant thyroid tumor with an overall survival from 3 to 5 months in most of the cases. Even the modern and intensive treatments seem not to be enough to provide a cure, also for the resectable ones, and the role of chemotherapy is still unclear but does not seem to prolong survival. Nevertheless, some patients survive longer and have a better outcome, even in the presence of metastasis, than what the literature reports. We present the case of a 64-year-old female affected by ATC, treated on February 2018 with surgery followed by chemoradiation. One year after surgery, the patient developed a subcutaneous recurrence that was radically resected and is still alive 29 months after the diagnosis. We propose a systematic review of the literature to deepen the knowledge of the prognostic factors of ATC with the aim to recognize and select the patients with a better outcome, even if metastatic, and to describe a very uncommon site of metastatization.

Purpose: The value of FDG PET-derived parameters in predicting overall survival (OS), local relapse-free survival (LRFS) and distant relapse-free survival (DRFS) in treated patients with malignant pleural mesothelioma (MPM) was evaluated. Methods: This retrospective evaluation included 55 MPM patients treated between March 2006 and February 2015 with FDG PET/CT-guided salvage helical tomotherapy (HTT) after previous surgery plus chemotherapy. Univariate Cox regression analysis was performed to assess the impact of the following FDG PET-derived parameters: biological target volume (BTV), mean and maximum standardized uptake values (SUVmean/max), metabolic tumour volume (MTV) and total lesion glycolysis (TLG), measured using different uptake thresholds (40%, 50% and 60%). Logistic regression was then performed to identify the best FDG PET-derived parameters for selecting patients with poorer survival. Results: The median OS was 9.1months (range 0.0 – 69.6months) after the end of HTT; 54/55 patients were dead at the last follow-up. BTV and TLG40, TLG50 and TLG60 were the most significant predictors of OS (p< 0.005). The median OS was 4.8months in patients with MTV60 >5cm3 and TLG40 >334.4, compared with 13.8months and 16.1months in patients with smaller values, respectively. The median LRFS and DRFS were 6.2months (range 1.2 – 39.4months) and 6.5months (0.0 – 66.4months), respectively. TLG40, TLG50 and TLG60 were significantly correlated with LRFS (p< 0.015). Median DRFS was 6.4months in patients with MTV40 >39.6cm3 and 6.2months in patients with TLG40 >334.4, compared with 17months and 18.8months in patients with smaller values. BTV, TLG40 and MTV40 were also found to be good predictors in patients with poor OS/LRFS/DRFS (median survival times less than the median values). Conclusion: FDG PET-derived parameters effectively discriminated patients with a poor prognosis and may be helpful in the selection of MPM patients for salvage HTT.

Objectives: stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) are a therapeutic option for Oligometastatic/Oligoprogressive (OM/OP) NSCLC. This retrospective multicentre analysis aims to analyse clinical outcomes and treatment related toxicity of patients treated to all sites of know disease with SRS and/or FSRT for OM/OP NSCLC in 8 Italian radiation oncology centres. Materials and methods: From January 2016 to January 2017 198 OM/OP NSCLC patients (pts) were treated in 8 Centres. Inclusion criteria were as follows: 1–5 lesions at onset or after previous systemic treatment; Pts must have all metastatic lesions treated. Endpoints analysed were local progression free survival (LPFS); out-of-field recurrence free survival (OFPS); progression free survival (PFS); overall survival (OS). Time to New systemic Therapy free survival (TNT) and toxicity were also analysed. Results: At the time of radiotherapy, 119 pts (60 %) were treated for a single lesion, 49 (25 %) for 2 lesions, 30 (15 %) for 3–5 metastases. Total number of lesions treated was 333: 204 brain, 68 lung, 24 bone, 16 nodal, 12 adrenal, 8 liver and 1 soft tissue. 83/198 pts (41.8 %) had the primary tumour controlled at the time of the SRT. After a median follow-up of 18 months, median OS and PFS were 29.6 months and 10.6 months, respectively. One year LPFS and OPFS were 90 % and 47 %, respectively. Median TNT was 10 months. At univariate analysis factors associated with better OS were PS 0–1; controlled primary tumour, 1–2 lesions; extracranial metastasis. Multivariate analysis confirmed number of lesions

Purpose: To explore the association between planning skin dose-volume data and acute cutaneous toxicity after Radio–chemotherapy for Head and Neck (HN) cancer patients. Methods: Seventy HN patients were treated with Helical Tomotherapy (HT) with radical intent (SIB technique: 54/66 Gy to PTV1/PTV2 in 30fr) ± chemotherapy superficial body layer 2 mm thick (SL2) was delineated on planning CT. CTCAE v4.0 acute skin toxicity data were available. Absolute average Dose-Volume Histograms (DVH) of SL2 were calculated for patients with severe (G3) and severe/moderate (G3/G2) skin acute toxicities. Differences against patients with none/mild toxicity (G0/G1) were analyzed to define the most discriminative regions of SL2 DVH; univariable and multivariable logistic analyses were performed on DVH values, CTV volume, age, sex, chemotherapy. Results: Sixty-one % of patients experienced G2/G3 toxicity (rate of G3 = 19%). Differences in skin DVHs were significant in the range 53-68Gy (p-values: 0.005–0.01). V56/V64 were the most predictive parameters for G2/G3 (OR = 1.12, 95%CI = 1.03–1.21, p = 0.001) and G3 (OR = 1.13, 95%CI = 1.01–1.26, p = 0.027) with best cut-off of 7.7cc and 2.7cc respectively. The logistic model for V56 was well calibrated being both, slope and R2, close to 1. Average V64 were 2.2cc and 6cc for the two groups (G3 vs G0-G2 toxicity); the logistic model for V64 was quite well calibrated, with a slope close to 1 and R2 equal to 0.60. Conclusion: SL2 DVH is associated with the risk of acute skin toxicity. Constraining V64 < 3cc (equivalent to a 4x4cm2 skin surface) should keep the risk of G3 toxicity below or around 10%.

Introduction: The objective of this study was to present the outcomes of moderately hypofractionated helical intensity-modulated radiation therapy (HT) with/without simultaneous integrated boost (SIB) on fluorodeoxyglucose-positron emission tomography (FDG-PET) positive areas (gross tumor volume [GTV]-PET) for patients with progressive malignant pleural mesothelioma (MPM) after previous treatments. Methods and Materials: From May 2006 to April 2014, 51 patients with a median age of 68.8 years (range, 38.6-82 years) were treated. There were 41 men and 10 women; 43 epithelioid MPM and 8 sarcomatoid, involving the left pleura in 25 patients and the right pleura in 26 patients. The initial stage was: I, 11 patients; II, 14 patients; III, 17 patients; and IV, 9 patients. Chemotherapy was prescribed for 46 patients, for 6 cycles (range, 0-18 cycles). Eighteen patients had pleurectomy/decortication, and 33 had talc pleurodesis. FDG-PET was used for target identification. A median dose of 56 Gy/25 fractions was prescribed to the involved pleura, and SIB to 62.5 Gy to GTV-PET was added in 38 patients. Results: The median survival from diagnosis was 25.8 months (range, 8.4-99.0 months). One patient, treated with SIB, was alive at the October 2017 follow-up. Two cases of grade 5 radiation pneumonitis were registered. A GTV-PET ≤ 205 cc was predictive of late ≥ grade 2 lung toxicity, but also of better survival in stage III and IV disease: 5.9 versus 11.7 months (P = .04). A GTV-PET ≥ 473 cc was predictive of early death (P = .001). Conclusions: Moderately hypofractionated, FDG-PET guided salvage HT in patients with progressive MPM after previous treatments showed acceptable toxicity and outcome results similar to adjuvant radiotherapy after pleurectomy/decortication, suggesting that the delay of radiotherapy is not detrimental to survival, and has the associated benefit of postponing inherent toxicity. Fifty-one patients with malignant pleural mesothelioma treated with helical intensity-modulated radiation therapy in presence of intact lungs were analyzed. A positron emission tomography positive volume ≥ 473 cc was found predictive of early death. A positron emission tomography positive volume < 205 cc was associated with longer survival in stage III to IV patients treated with simultaneous integrated boost, and also with higher late pulmonary ≥ grade 2 toxicity.

Simple Summary Small cell lung cancer (SCLC) remains the most aggressive form of neuroendocrine tumor of the lung, for which treatment options remain limited. The introduction of immune checkpoint inhibitors has modified for the first time the therapeutic strategies in patients with extensive disease after decades. New therapeutic approaches are required. Deeper knowledge of tumor biology is required to gain new insights into this complex disease. Abstract Several trials have tried for decades to improve the outcome of extensive disease small cell lung cancer (ED-SCLC) through attempts to modify the standard treatments. Nevertheless, platinum/etoposide combination and topotecan have remained respectively the first and the second line standard treatments for the last 40 years. With the advent of immunotherapy, this scenario has finally changed. Our review aims to provide an overview of the primary studies on the actual therapeutic strategies available for ED-SCLC patients, and to highlight emerging evidence supporting the use of immunotherapy in SCLC patients.

Aims To report 5 year outcome and late toxicity in prostate cancer patients treated with image-guided tomotherapy with a moderate hypofractionated simultaneous integrated boost approach. Materials and methods In total, 211 prostate cancer patients, 78 low risk, 53 intermediate risk and 80 high risk were treated between 2005 and 2011. Intermediate- and high-risk patients received 51.8 Gy to pelvic lymph nodes and concomitant simultaneous integrated boost to prostate up to 74.2 Gy/28 fractions, whereas low-risk patients were treated to the prostate only with 71.4 Gy/28 fractions. Daily megavoltage computed tomography (MVCT) image guidance was applied. Androgen deprivation was prescribed for a median duration of 6 months for low-risk patients (for downsizing), 12 months for intermediate-risk and 36 months for high-risk patients. The 5 year biochemical relapse-free survival (bRFS), cancer-specific survival (CSS), overall survival and late gastrointestinal and genitourinary CTCAE.v3 toxicity were assessed. The effect of several clinical variables on both outcome and gastrointestinal/genitourinary toxicity was tested by uni- and multivariate Cox regression analyses. Results After a median follow-up of 5 years, the late toxicity actuarial incidence was: genitourinary ≥ grade 2: 20.2%; genitourinary ≥ grade 3: 5.9%; gastrointestinal ≥ grade 2: 17%; gastrointestinal ≥ grade 3: 6.3% with lower prevalence at the last follow-up visit (≥ grade 3: genitourinary: 1.9%; gastrointestinal: 1.9%). Major predictors of ≥ grade 3 genitourinary and gastrointestinal late toxicity were genitourinary acute toxicity ≥ grade 2 (hazard ratio: 4.9) and previous surgery (hazard ratio: 3.4). The overall 5 year bRFS was 93.7% (low risk: 94.6%; intermediate risk: 96.2%; high risk: 91.1%), overall survival and CSS were 88.6% (low risk: 90.5%; intermediate risk: 87.4%; high risk: 87%) and 97.5% (low risk: 98.7%; intermediate risk: 95%; high risk: 94.3%), respectively. Risk classes and androgen deprivation were not significantly correlated with either bRFS, overall survival or CSS. Twelve patients experienced a biochemical relapse but none experienced clinically proven local and/or pelvic recurrence. Conclusion A satisfactory 5 year outcome with an acceptable toxicity profile was observed. The combination of image-guided radiotherapy–intensity-modulated radiotherapy, high equivalent 2 Gy dose (EQD2) with a moderate hypofractionated approach and extensive prophylactic lymph node irradiation also leads to very good outcome in high-risk patients.

To investigate the robustness of PET radiomic features (RF) against tumour delineation uncertainty in two clinically relevant situations.Twenty-five head-and-neck (HN) and 25 pancreatic cancer patients previously treated withA large disagreement between manual and SUV_max method was found for thresholds ≥50%. Inter-observer variability showed median DICE values between 0.81 (HN-T) and 0.73 (pancreas). Volumes defined by PET_Edge were better consistent with the manual ones compared to SUV40%. Regarding RF, 19%/19%/47% of the features showed ICC 0.80 between observers for HN-N/HN-T/pancreas, mostly in the Voxel-alignment matrix and in the intensity-size zone matrix families. RFs with ICC 0.80 against manual delineation (taking the worst value) increased to 44%/36%/61% for PET_Edge and to 69%/53%/75% for SUV40%.About 80%/50% of 72 RF were consistent between observers for HN/pancreas patients. PET_edge was sufficiently robust against manual delineation while SUV40% showed a worse performance. This result suggests the possibility to replace manual with semi-automatic delineation of HN and pancreas tumours in studies including PET radiomic analyses.

Purpose: To investigate the robustness of PET radiomic features (RF) against tumour delineation uncertainty in two clinically relevant situations. Methods: Twenty-five head-and-neck (HN) and 25 pancreatic cancer patients previously treated with18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT)-based planning optimization were considered. Seven FDG-based contours were delineated for tumour (T) and positive lymph nodes (N, for HN patients only) following manual (2 observers), semi-automatic (based on SUV maximum gradient: PET_Edge) and automatic (40%, 50%, 60%, 70% SUV_max thresholds) methods. Seventy-three RF (14 of first order and 59 of higher order) were extracted using the CGITA software (v.1.4). The impact of delineation on volume agreement and RF was assessed by DICE and Intra-class Correlation Coefficients (ICC). Results: A large disagreement between manual and SUV_max method was found for thresholds ≥50%. Inter-observer variability showed median DICE values between 0.81 (HN-T) and 0.73 (pancreas). Volumes defined by PET_Edge were better consistent with the manual ones compared to SUV40%. Regarding RF, 19%/19%/47% of the features showed ICC < 0.80 between observers for HN-N/HN-T/pancreas, mostly in the Voxel-alignment matrix and in the intensity-size zone matrix families. RFs with ICC < 0.80 against manual delineation (taking the worst value) increased to 44%/36%/61% for PET_Edge and to 69%/53%/75% for SUV40%. Conclusions: About 80%/50% of 72 RF were consistent between observers for HN/pancreas patients. PET_edge was sufficiently robust against manual delineation while SUV40% showed a worse performance. This result suggests the possibility to replace manual with semi-automatic delineation of HN and pancreas tumours in studies including PET radiomic analyses.

Background and Purpose: Head-Neck (HN) patients may experience severe acute skin complications that can cause treatment interruption and increase the risk of late fibrosis. This study assessed a method for accurately monitoring skin dose changes during helical tomotherapy for HN cancer based on deformable image registration of planning computed tomography (CT) and mega-voltage CT (MVCT). Materials and Methods: Planning CTs of nine patients were deformably registered to mid-treatment MVCT (MV15) images resulting in CTdef images. The original plans were recalculated on both CTdef and mid-treatment kilo-voltage CT (CT15) taken as ground truth. Superficial layers (SL) of the body with thicknesses of 2, 3 and 5 mm (SL2, SL3, SL5) were considered as derma surrogates. SL V95%, V97%, V98%, V100%, V102%, V105% and V107% of the prescribed PTV dose were extracted for CT15/CTdef and compared (considering patients with skin dose > 95%). For comparison, doses were calculated directly on the calibrated MVCT and analyzed in the same way. Results: Differences between SL2/SL3/SL5 V95%-V107% in CT15/CTdef were very small: for eight of nine patients the difference between the considered SL2 Vd% computed on CTdef and CT15 was less than 1.4 cm3 for all d%. A larger value was found when using MVCT for skin dose calculation (4.8 cm3 for SL2), although CTdef body contour matched CT15 body with accuracy similar to that of MV15. Conclusions: Deforming the planning CT-to-MVCT was shown to be accurate considering external body contours and skin DVHs. The method was able to accurately identify superficial overdosing. Keywords: Skin dose, DIR, MVCT, Dose of the day, Tomotherapy

Objective: To report the 3-year toxicity and outcomes of carbon 11 (11C)-choline-positron emission tomography (PET)/computed tomography (CT)-guided radiotherapy (RT), delivered via helical tomotherapy (HTT; Tomotherapy® Hi-Art II® Treatment System, Accuray Inc., Sunnyvale, CA, USA) after lymph node (LN) relapses in patients with prostate cancer. Patients and Methods: From January 2005 to March 2013, 81 patients with biochemical recurrence after surgery, with or without adjuvant/salvage RT or radical RT, and with evidence of LN 11C-choline-PET/CT pathological uptake, underwent HTT (median [range] prostate-specific antigen level 2.59 [0.61–187] ng/mL). Of the 81 patients, 72 were treated at the pelvic and/or lumbar-aortic LN chain with HTT at 51.8 Gy/28 fr and with simultaneous integrated boost to a median dose of 65.5 Gy on the pathological uptake sites detected by 11C-choline-PET/CT. Nine patients were treated without simultaneous integrated boost (50–65.5 Gy, 25–30 fr). Results: With a median (range) follow-up of 36 (9–116) months, 91.4% of the patients had a PSA reduction 3 months after HTT. The 3-year overall, local relapse-free and clinical relapse-free survival rates were 80.0, 89.8 and 61.8%, respectively. The 3-year actuarial incidences of ≥grade 2 rectal and ≥grade 2 genitourinary toxicity were 6.6% (±2.9%) and 26.3% (±5.5%), respectively. A PSA nadir of ≥0.26 ng/mL (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.7–7.7; P = 0.001), extrapelvic 11C-choline-PET/CT-positive LN location (HR 2.4, 95% CI 0.9–6.4; P = 0.07), RT previous to HTT (HR 2.7; 95% CI 1.07–6.9, P = 0.04) and number of positive LNs (HR 1.13, 95% CI 1.04–1.22; P = 0.003) were the main predictors of clinical relapse after HTT. Conclusions: 11C-choline-PET/CT-guided HTT is safe and effective in the treatment of LN relapses of prostate cancer in previously treated patients.

Purpose The aim of this study was to test the feasibility and dosimetric accuracy of a method that employs planning CT-to-MVCT deformable image registration (DIR) for calculation of the daily dose for head and neck (HN) patients treated with Helical Tomotherapy (HT). Methods For each patient, the planning kVCT (CTplan) was deformably registered to the MVCT acquired at the 15th therapy session (MV15) with a B-Spline Free Form algorithm using Mattes mutual information (open-source software 3D Slicer), resulting in a deformed CT (CTdef). On the same day as MVCT15, a kVCT was acquired with the patient in the same treatment position (CT15). The original HT plans were recalculated both on CTdef and CT15, and the corresponding dose distributions were compared; local dose differences

Purpose An increase of skin dose during RT for head-neck (HN) cancer due to anatomy deformation may potentially translate into an increased risk of skin toxicity, suggesting a potential benefit from planning adaptation (ART) to counteract this effect. Current study applied an original method for dose-of-the-day calculation in quantifying changes of skin dose during Tomotherapy for head and neck (HN) cancer in order to identify those patients that could benefit of ART. Methods Planning CTs of 32 patients (SIB: 54/66 Gy, 30 fractions) were deformable registered to MVCT images taken at fraction 15 and 30 using a constrained-intensity-based algorithm. Dose-of-the-day were calculated on the deformed images; this approach was previously validated by comparing dose distributions of deformed CT and diagnostic kVCT of the same day. Superficial body layers (SL) were considered as a surrogate of skin, considering a 2 mm thickness. Skin dose variation during therapy ( Δ SL) in terms of fraction of SL receiving at least 95%–105% of the prescribed PTV dose (66 Gy) were considered. Based on the previous validation, a change ≥ + 1 cc was assessed to define patients that may benefit of ART. Results Δ SL occurred during treatment with individually variable patterns, depending on several factors like the PTV location/dimension/shape/shrinkage. Only 3 patients experienced >1 cc change of SL95%-105% during treatment (maximum variation: 6 cc) while negative Δ SL95%-105% > 1 cc, up to 17 cc, were seen in 15/33 patients. A negative change was correlated with the presence of some overlap between PTV and SL at planning (p = 0.03). Δ SL 95% are shown for all patients in Fig. 1. Download : Download high-res image (301KB) Download : Download full-size image Conclusions Most patients treated with a SIB approach with Tomotherapy for HN cancer showed negative or irrelevant changes to the dose delivered to the skin. Less than 10% of patients seem to be candidate to ART to counteract any significant skin dose increase during therapy.

Purpose To assess the robustness of PET radiomic features (RF) against tumour/PET positive nodes (T/N) delineation uncertainty in two clinically relevant situations, namely head-and-neck (HNC) and pancreatic cancer. Methods Twenty-five HNC (T and N) and 25 pancreatic cancer (only T) patients previously treated with IMRT and 18FDG-PET/CT based planning optimization were included in the study. Seven contours were delineated for each lesion following manual (2 independent observers), semi-automatic (based on SUV_max gradient: PET_edge) and automatic (40%,50%,60%,70% SUV_max thresholds) methods using MIM software(MimVista). For each contour, 71 RF (12 of first and 59 of higher order) were extracted by using the CGITA (v1.4) software. The impact of delineation on volume agreement (DICE-index) and RF was assessed by Intra-class Correlation Coefficients (ICC), considering a threshold of 0.80. Semi-automatic contouring repeatability was also tested. Results A large disagreement between manual and automatic SUV_max method was found for threshold values ⩾50%. Inter-observer variability was moderately high with median DICE values between 0.81 (HN-T) and 0.73 (pancreas). Volumes defined by PET_Edge were in better agreement with the manual ones compared to SUV40%; the repeatability of PET_Edge was excellent (median DICE = 0.95). Regarding RF, 14/14/35 features showed an ICC Conclusions About 80%/50% of 72 RF extracted with the CGITA software were consistent with respect to manual delineation for HN/pancreas patients. PET_edge was sufficiently robust with about 60%/40% of RF consistent with manual delineation while a worse performance was found for SUV40%. This result suggests the possibility to replace manual delineation of HN and pancreas tumours in studies including PET radiomic analyses.

A number of studies have reported an increase in radiation sensitivity of pacemakers or implantable cardioverter defibrillators. The type, severity and extent of radiation damage to these devices depend on the total dose and rate. We report the case of a 70-year-old male patient with non-small cell lung cancer presenting as a sub-carinal paraesophageal lesion, and a history of dilated cardiomyopathy and cardioverter-defibrillator implantation. The decision of a multidisciplinary meeting was to keep the device in place and deliver radiotherapy using an intensity-modulated radiation therapy technique by means of helical tomotherapy. The radiotherapy was well tolerated and consistent device interrogation revealed no malfunction. Innovative irradiation techniques have made radiotherapy feasible despite the presence of technological sophistications of pacemakers and cardioverter defibrillators that have potentially changed the tolerance profiles.

To test the feasibility of salvage radiotherapy using PET-guided helical tomotherapy in patients with progressive malignant pleural mesothelioma (MPM).A group of 12 consecutive MPM patients was treated with 56 Gy/25 fractions to the planning target volume (PTV); FDG-PET/CT simulation was always performed to include all positive lymph nodes and MPM infiltrations. Subsequently, a second group of 12 consecutive patients was treated with the same dose to the whole pleura adding a simultaneous integrated boost of 62.5 Gy to the FDG-PET/CT positive areas (BTV).Good dosimetric results were obtained in both groups. No grade 3 (RTOG/EORTC) acute or late toxicities were reported in the first group, while 3 cases of grade 3 late pneumonitis were registered in the second group: the duration of symptoms was 2-10 weeks. Median overall survival was 8 months (1.2-50.5 months) and 20 months (4.3-33.8 months) from the beginning of radiotherapy, for groups I and II, respectively (p=0.19). A significant impact on local relapse from radiotherapy was seen (median time to local relapse: 8 vs 17 months; 1-year local relapse-free rate: 16% vs 81%, p=0.003).The results of this pilot study support the planning of a phase III study of combined sequential chemoradiotherapy with dose escalation to BTV in patients not able to undergo resection.

The Jacobian of the deformation field of elastic registration between images taken during radiotherapy is a measure of inter-fraction local deformation. The histogram of the Jacobian values (Jac) within an organ was introduced (JVH-Jacobian-volume-histogram) and first applied in quantifying parotid shrinkage. MVCTs of 32 patients previously treated with helical tomotherapy for head-neck cancers were collected. Parotid deformation was evaluated through elastic registration between MVCTs taken at the first and last fractions. Jac was calculated for each voxel of all parotids, and integral JVHs were calculated for each parotid; the correlation between the JVH and the planning dose-volume histogram (DVH) was investigated. On average, 82% (±17%) of the voxels shrinks (Jac1) and 14% (±17%) shows a local compression50% (Jac0.5). The best correlation between the DVH and the JVH was found between V10 and V15, and Jac0.4-0.6 (p0.01). The best constraint predicting a higher number of largely compressing voxels (Jac0.57.5%, median value) was V15 ≥ 75% (OR: 7.6, p = 0.002). Jac and the JVH are promising tools for scoring/modelling toxicity and for evaluating organ/contour variations with potential applications in adaptive radiotherapy.

We developed an efficient technique to auto-propagate parotid gland contours from planning kVCT to daily MVCT images of head-and-neck cancer patients treated with helical tomotherapy. The method deformed a 3D surface mesh constructed from manual kVCT contours by B-spline free-form deformation to generate optimal and smooth contours. Deformation was calculated by elastic image registration between kVCT and MVCT images. Data from ten head-and-neck cancer patients were considered and manual contours by three observers were included in both kVCT and MVCT images. A preliminary inter-observer variability analysis demonstrated the importance of contour propagation in tomotherapy application: a high variability was reported in MVCT parotid volume estimation (p = 0.0176, ANOVA test) and a larger uncertainty of MVCT contouring compared with kVCT was demonstrated by DICE and volume variability indices (Wilcoxon signed rank test, p < 10-4 for both indices). The performance analysis of our method showed no significant differences between automatic and manual contours in terms of volumes (p > 0.05, in a multiple comparison Tukey test), center-of-mass distances (p = 0.3043, ANOVA test), DICE values (p = 0.1672, Wilcoxon signed rank test) and average and maximum symmetric distances (p = 0.2043, p = 0.8228 Wilcoxon signed rank tests). Results suggested that our contour propagation method could successfully substitute human contouring on MVCT images. © 2011 Institute of Physics and Engineering in Medicine.

Purpose: Characterizing the changes of PET-positive lymphnodes (PNs) of head-neck cancer patients during image-guided Tomotherapy in order to verify if our clinical margin for PTV boost are adequate. Material and methods: Weekly MVCTs of 30 patients were matched with the planning kVCT (kVCT_pl) on bony anatomy: 42 visible PNs were contoured on kVCT_pl/MVCTs. Intra/inter-observer and inter-modality variability in contouring PNs was evaluated by blind re-delineation. Shrinkage of PNs and center-of-mass (CM) shifts were measured and Van Herk margins for the residual error were estimated. In addition, due to the PNs' shrinkage during therapy, probability coverage maps were considered to estimate the fraction of the high probability contours missed by the clinical PTV (5mm margin); larger margins were tried for PNs showing some missing. Results: MVCTs were adequate for PNs' delineation (DICE=0.85; range=0.79–0.91). Twenty-seven PNs showed a significant volume shrinkage at the end of therapy (median: 71%, range: 27–94%, ρ =−0.93). Time–trend of 3D-CM shift was significant for 38% of PNs (median: 5.1mm at the end of treatment, range: 1.0–8.9). The clinical PTV included 95% of the 90%/100% probability contours in 40/36 (95%/86%) PNs respectively. Van Herk margins (not considering shrinkage) were approximately 7mm for all three main axes. The clinical PTV included 95% of the 90%/100% probability contours in 40/36 (95%/86%) PNs respectively. Conclusions: The residual error relative to PNs after bone match is relatively small; the impact of CM shifts is partially counterbalanced by shrinkage. Our results do not seem to support an extensive use of adaptive re-planning to avoid the missing of PNs in dose-escalated protocols, although more information about the dosimetry impact of the reported changes is warranted.