Hospital Volume for Rectal Cancer Resection Plays a Pivotal Role in Improving Outcomes: A Population-based Analysis.

OBJECTIVE: Assessing the association between hospital surgical volume (SV) and outcomes after rectal cancer surgery (RCS), using national population-based data. SUMMARY BACKGROUND DATA: For RCS, the association of higher SV with improved short- and/or long-term outcomes remains controversial. METHODS: National cancer registry data and administrative data were used to select patients diagnosed with stage I-III rectal cancer in 2009-2018 and who underwent RCS. The average annual SV of RCS was categorised as low (<15; LV), medium (15-29; MV) or high (≥30; HV). The association between SV and 90-day and 1-year excess postoperative mortality (90DPM and 1YEPM) and 5-year observed survival (5YOS) was evaluated. RESULTS: From the 11,519 patients , RCS was performed in LV (4,088; 36%), MV (2,795; 24%) or HV (4,636; 40%) hospitals. Observed 90DPM was significantly better in HV (2.3% 95%CI[1.9,2.8]) than in LV (3.7% 95%CI[3.2,4.4]) and MV (3.5% 95%CI[2.9,4.3]) with adjusted OR 1.4, P<0.0001. Continuous regression analysis showed significantly higher 90DPM in annual SV <35 compared to ≥35 (OR 1.6 95%CI[1.21,2.11]; P=0.0009). Observed 1YEPM was significantly better in HV (2.9% 95%CI[2.2,3.6]) compared to LV (4.7% 95%CI [3.9,5.6]) with adjusted excess HR 1.31 95%CI[1.00,1.73] and P=0.05, and to MV (5.0% 95%CI[4.0,6.1]) with adjusted excess HR 1.45 95%CI[1.09,1.94] and P=0.01. The 5YOS was significantly better in HV (75.9% 95%CI[74.6,77.2]) than in LV (70.3% 95%CI[68.8,71.8]) and MV (71.5% 95%CI[69.7,73.2]) with adjusted HR 1.4 in both LV and MV versus HV, P≤0.003. CONCLUSIONS: This population-based study identified robustly superior outcomes at 90-days, 1-year and 5-years after RCS in hospitals with higher volumes.

A Population-Based Study Using Belgian Cancer Registry Data Supports Centralization of Esophageal Cancer Surgery in Belgium.

BACKGROUND: Esophageal cancer surgery outcomes benefit from higher hospital volumes. Despite the evidence, organization of national health care often is complex and depends on various factors. The volume-outcome results of this population-based study supported national health policy measures regarding concentration of esophageal resections in Belgium. METHODS: The Belgian Cancer Registry (BCR) database was linked to administrative data on cancer treatment. All Belgian patients with newly diagnosed esophageal cancer in 2008-2018 undergoing resection were allocated to the hospital at which surgery was performed. The study assessed hospital volume association with 90-day mortality and 5-year overall survival, classifying average annual hospital volume of resections as low (LV, <6), medium (MV, 6-19), or high (HV, ≥20) and as a continuous covariate in the regression models. RESULTS: The study included 4156 patients who had surgery in 79 hospitals (2 HV hospitals [37% of all surgeries], 12 MV hospitals [30% of all surgeries], and 65 LV hospitals [33% of all surgeries]). Adjusted 90-day mortality in HV hospitals was lower than in LV hospitals (odds ratio [OR], 0.37; 95% CI, 0.21-0.65; p = 0.001). Case-mix adjusted 5-year survival was superior in HV versus LV (hazard ratio [HR], 0.43; 95% CI, 0.31-0.60; p < 0.001). The continuous model demonstrated a lower 90-day mortality (OR, 0.40; 95% CI, 0.23-0.71; p = 0.002) and a superior 5-year survival (HR, 0.45; 95% CI, 0.33-0.63; p < 0.001) in hospitals with volumes of 40 or more resections annually. CONCLUSION: Population-based data from the BCR confirmed a strong volume-outcome association for esophageal resections. Improved 5-year survival in centers with annual volumes of 20 or more resections was driven mainly by the achievement of superior 90-day mortality. These findings supported centralization of esophageal resections in Belgium.

Clinical implications of dose to functional lung volumes in the trimodality treatment of esophageal cancer.

BACKGROUND: Trimodality treatment, i.e., neoadjuvant chemoradiotherapy (nCRT) followed by surgery, for locally advanced esophageal cancer (EC) improves overall survival but also increases the risk of postoperative pulmonary complications. Here, we tried to identify a relation between dose to functional lung volumes (FLV) as determined by 4D-CT scans in EC patients and treatment-related lung toxicity. MATERIALS AND METHODS: All patients with EC undergoing trimodality treatment between 2017 and 2022 in UZ Leuven and scanned with 4D-CT-simulation were selected. FLVs were determined based on Jacobian determinants of deformable image registration between maximum inspiration and expiration phases. Dose/volume parameters of the anatomical lung volume (ALV) and FLV were compared between patients with versus without postoperative pulmonary complications. Results of pre- and post-nCRT pulmonary function tests (PFTs) were collected and compared in relation to radiation dose. RESULTS: Twelve out of 51 EC patients developed postoperative pulmonary complications. ALV was smaller while FLV10Gy and FLV20Gy were larger in patients with complications (respectively 3141 ± 858mL vs 3601 ± 635mL, p = 0.025; 360 ± 216mL vs 264 ± 139mL, p = 0.038; 166 ± 106mL vs 118 ± 63mL, p = 0.030). No differences in ALV dose-volume parameters were detected. Baseline FEV1 and TLC were significantly lower in patients with complications (respectively 90 ± 17%pred vs 102 ± 20%pred, p = 0.033 and 93 ± 17%pred vs 110 ± 13%pred, p = 0.001), though no other PFTs were significantly different between both groups. DLCO was the only PFT that had a meaningful decrease after nCRT (85 ± 17%pred vs 68 ± 15%pred, p < 0.001) but was not related to dose to ALV/FLV. CONCLUSION: Small ALV and increasing FLV exposed to intermediate (10 to 20 Gy) dose are associated to postoperative pulmonary complications. Changes of DLCO occur during nCRT but do not seem to be related to radiation dose to ALV or FLV. This information could attribute towards toxicity risk prediction and reduction strategies for EC.

Potential Molecular Mechanisms behind the Ultra-High Dose Rate "FLASH" Effect.

FLASH radiotherapy, or the delivery of a dose at an ultra-high dose rate (>40 Gy/s), has recently emerged as a promising tool to enhance the therapeutic index in cancer treatment. The remarkable sparing of normal tissues and equivalent tumor control by FLASH irradiation compared to conventional dose rate irradiation­the FLASH effect­has already been demonstrated in several preclinical models and even in a first patient with T-cell cutaneous lymphoma. However, the biological mechanisms responsible for the differential effect produced by FLASH irradiation in normal and cancer cells remain to be elucidated. This is of great importance because a good understanding of the underlying radiobiological mechanisms and characterization of the specific beam parameters is required for a successful clinical translation of FLASH radiotherapy. In this review, we summarize the FLASH investigations performed so far and critically evaluate the current hypotheses explaining the FLASH effect, including oxygen depletion, the production of reactive oxygen species, and an altered immune response. We also propose a new theory that assumes an important role of mitochondria in mediating the normal tissue and tumor response to FLASH dose rates.

Optimal 68Ga-PSMA and 18F-PSMA PET window levelling for gross tumour volume delineation in primary prostate cancer.

PURPOSE: This study proposes optimal tracer-specific threshold-based window levels for PSMA PET-based intraprostatic gross tumour volume (GTV) contouring to reduce interobserver delineation variability. METHODS: Nine 68Ga-PSMA-11 and nine 18F-PSMA-1007 PET scans including GTV delineations of four expert teams (GTVmanual) and a majority-voted GTV (GTVmajority) were assessed with respect to a registered histopathological GTV (GTVhisto) as the gold standard reference. The standard uptake values (SUVs) per voxel were converted to a percentage (SUV%) relative to the SUVmax. The statistically optimised SUV% threshold (SOST) was defined as those that maximises accuracy for threshold-based contouring. A leave-one-out cross-validation receiver operating characteristic (ROC) curve analysis was performed to determine the SOST for each tracer. The SOST analysis was performed twice, first using the GTVhisto contour as training structure (GTVSOST-H) and second using the GTVmajority contour as training structure (GTVSOST-MA) to correct for any limited misregistration. The accuracy of both GTVSOST-H and GTVSOST-MA was calculated relative to GTVhisto in the 'leave-one-out' patient of each fold and compared with the accuracy of GTVmanual. RESULTS: ROC curve analysis for 68Ga-PSMA-11 PET revealed a median threshold of 25 SUV% (range, 22-27 SUV%) and 41 SUV% (40-43 SUV%) for GTVSOST-H and GTVSOST-MA, respectively. For 18F-PSMA-1007 PET, a median threshold of 42 SUV% (39-45 SUV%) for GTVSOST-H and 44 SUV% (42-45 SUV%) for GTVSOST-MA was found. A significant pairwise difference was observed when comparing the accuracy of the GTVSOST-H contours with the median accuracy of the GTVmanual contours (median, - 2.5%; IQR, - 26.5-0.2%; p = 0.020), whereas no significant pairwise difference was found for the GTVSOST-MA contours (median, - 0.3%; IQR, - 4.4-0.6%; p = 0.199). CONCLUSIONS: Threshold-based contouring using GTVmajority-trained SOSTs achieves an accuracy comparable with manual contours in delineating GTVhisto. The median SOSTs of 41 SUV% for 68Ga-PSMA-11 PET and 44 SUV% for 18F-PSMA-1007 PET form a base for tracer-specific window levelling. TRIAL REGISTRATION: Clinicaltrials.gov ; NCT03327675; 31-10-2017.

Automated treatment planning of prostate stereotactic body radiotherapy with focal boosting on a fast-rotating O-ring linac: Plan quality comparison with C-arm linacs.

PURPOSE: The integration of auto-segmentation and automated treatment planning methods on a fast-rotating O-ring linac may improve the time efficiency of online adaptive radiotherapy workflows. This study investigates whether automated treatment planning of prostate SBRT with focal boosting on the O-ring linac could generate plans that are of similar quality as those obtained through manual planning on clinical C-arm linacs. METHODS: For 20 men with prostate cancer, reference treatment plans were generated on a TrueBeam STx C-arm linac with HD120 MLC and a TrueBeam C-arm linac with Millennium 120 MLC using 6 MV flattened dual arc VMAT. Manual planning on the Halcyon fast-rotating O-ring linac was performed using 6 MV FFF dual arc VMAT (HA2-DL10) and triple arc VMAT (HA3-DL10) to investigate the performance of the dual-layer MLC system. Automated planning was performed for triple arc VMAT on the Halcyon linac (ET3-DL10) using the automated planning algorithms of Ethos Treatment Planning. The prescribed dose was 35 Gy to the prostate and 30 Gy to the seminal vesicles in five fractions. The iso-toxic focal boost to the intraprostatic tumor nodule(s) was aimed to receive up to 50 Gy. Plan deliverability was verified using portal image dosimetry measurements. RESULTS: Compared to the C-arm linacs, ET3-DL10 shows increased seminal vesicles PTV coverage (D99% ) and reduced high-dose spillage to the bladder (V37Gy ) and urethra (D0.035cc ) but this came at the cost of increased high-dose spillage to the rectum (V38Gy ) and a higher intermediate dose spillage (D2cm). No statistically significant differences were found when benchmarking HA2-DL10 and HA3-DL10 with the C-arm linacs. All plans passed the patient-specific QA tolerance limit. CONCLUSIONS: Automated planning of prostate SBRT with focal boosting on the fast-rotating O-ring linac is feasible and achieves similar plan quality as those obtained on clinical C-arm linacs using manual planning.

Outcome measures in multimodal rectal cancer trials.

There is a large variability regarding the definition and choice of primary endpoints in phase 2 and phase 3 multimodal rectal cancer trials, resulting in inconsistency and difficulty of data interpretation. Also, surrogate properties of early and intermediate endpoints have not been systematically assessed. We provide a comprehensive review of clinical and surrogate endpoints used in trials for non-metastatic rectal cancer. The applicability, advantages, and disadvantages of these endpoints are summarised, with recommendations on clinical endpoints for the different phase trials, including limited surgery or non-operative management for organ preservation. We discuss how early and intermediate endpoints, including patient-reported outcomes and involvement of patients in decision making, can be used to guide trial design and facilitate consistency in reporting trial results in rectal cancer.

Development and External Validation of a Multiparametric Magnetic Resonance Imaging and International Society of Urological Pathology Based Add-On Prediction Tool to Identify Prostate Cancer Candidates for Pelvic Lymph Node Dissection.

PURPOSE: We sought to expand current prediction tools for lymph node invasion in patients with prostate cancer using current state-of-the-art available tumor information, including multiparametric magnetic resonance imaging based tumor stage and detailed biopsy information. MATERIALS AND METHODS: We selected patients with prostate cancer for study who had available registered information on ISUP (International Society of Urological Pathology) based biopsy grading and multiparametric magnetic resonance imaging, and who had undergone radical prostatectomy with extended pelvic lymph node dissection. We developed a lymph node invasion prediction tool in 420 patients and externally validated it in 187. A concordance index was estimated to quantify the discriminative performance of the model. RESULTS: In the development cohort a median of 21 lymph nodes were removed per patient and 71 patients (16.9%) were diagnosed with lymph node invasion. Statistically significant predictors of lymph node invasion were the initial prostate specific antigen value, multiparametric magnetic resonance imaging based T stage, maximum tumor length in 1 core in mm and ISUP grade group corresponding to the maximum tumor involvement in 1 core. The predictive accuracy of this lymph node invasion prediction tool was 79.7% after fivefold internal cross validation and 72.5% after external validation. CONCLUSIONS: We report a contemporary, externally validated prediction tool for lymph node invasion in patients with prostate cancer. This prediction tool is a response to the paradigm shift from systematic to targeted biopsies by incorporating additional core specific biopsy information instead of the percent of positive cores. This new tool will also overcome stage migration, which is a potential risk when multiparametric magnetic resonance imaging information is used in digital rectal examination based nomograms.

Metastasis-directed therapy in castration-refractory prostate cancer (MEDCARE): a non-randomized phase 2 trial.

BACKGROUND: Patients diagnosed with metastatic castration-refractory prostate cancer (mCRPC) rely on a limited number of therapeutic agents resulting in a median survival of 2-3 years. A subgroup of those patients with mCRPC presents with oligoprogressive disease, with a limited number of progressive lesions while other metastases are still controlled by ongoing systemic treatment. METHODS: In this single arm prospective phase II trial, we aim to include 18 patients with oligoprogressive mCRPC (1-3 metastases and/or local recurrence) who will be treated with metastasis-directed therapy to all visible progressive lesions. Progression is based on conventional imaging, as the use of PSMA PET-CT is considered investigational. However all patients will undergo PSMA PET-CT and the images will be blinded until progression. Primary endpoint is the postponement of the start of next-line systemic treatment (NEST) and the additional clinical value of PSMA PET-CT. Recruitment of patients for this trial started in January 2020 and will be completed approximately by December 2020. DISCUSSION: In this phase 2 trial on oligoprogressive mCRPC, we will investigate the benefit of progression-directed therapy while continuing ongoing systemic treatment. We hypothesize that progression-directed therapy (PDT) with surgery or stereotactic body radiation therapy for these oligoprogressive lesions will postpone the start of next-line systemic treatment and therefore serve as a new or add-on therapy in the spectrum of treatments available for mCRPC. The results of this trial will serve as guidance for a later randomized phase 3 trial. All participants are given an information sheet and are required to give written informed consent. Results will be published in a peer-reviewed journal. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov: NCT04222634 (December 18th 2019).

Histopathological Features of MRI-Invisible Regions of Prostate Cancer Lesions.

BACKGROUND: Previous studies have reported tumor volume underestimation with multiparametric (mp)MRI in prostate cancer diagnosis. PURPOSE: To investigate why some parts of lesions are not visible on mpMRI by comparing their histopathology features to those of visible regions. STUDY TYPE: Retrospective. POPULATION: Thirty-four patients with biopsy-proven prostate cancer scheduled for prostatectomy (median 68.7 years). FIELD STRENGTH/SEQUENCE: T2 -weighted, diffusion-weighted imaging, T2 mapping, and dynamic contrast-enhanced MRI on two 3T systems and one 1.5T system. ASSESSMENT: Two readers delineated suspicious lesions on mpMRI. A pathologist delineated the lesions on histopathology. A patient-customized mold enabled the registration of histopathology and MRI. On histopathology we identified mpMRI visible and invisible lesions. Subsequently, within the visible lesions we identified regions that were visible and regions that were invisible on mpMRI. For each lesion and region the following characteristics were determined: size, location, International Society of Urological Pathology (ISUP) grade, and Gleason subpatterns (density [dense/intermediate], tumor morphology [homogeneous/heterogeneous], cribriform growth [yes/no]). STATISTICAL TESTS: With generalized linear mixed-effect modeling we investigated which features explain why a lesion or a region was invisible on MRI. We compared imaging values (T2 , ADC, and Ktrans ) for these features with one-way analysis of variance (ANOVA). RESULTS: Small, anterior, and ISUP grade 1-2 lesions (n = 34) were missed more frequent than large, posterior, ISUP grade ≥ 3 lesions (n = 35). Invisible regions on mpMRI had lower tumor density, heterogeneous tumor morphology, and were located in the transition zone. Both T2 and ADC values were higher in "intermediate" compared with "dense" regions (P = 0.002 and < 0.001) and in regions with heterogeneous compared with homogeneous morphology (P < 0.001 and 0.03). Ktrans was not significantly different (P = 0.24 and 0.99). DATA CONCLUSION: Regions of prostate cancer lesions that are invisible on mpMRI have different histopathology features than visible regions. This may have implications for monitoring during active surveillance and focal treatment strategies. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:1235-1246.

Variation in adjuvant and early salvage radiotherapy after robot-assisted radical prostatectomy for prostate cancer: a population-based cohort study.

Purpose: The primary aim of the study was to assess the association between having a radiotherapy (RT) department on-site at the surgical centre and the performed postoperative treatment strategy for prostate cancer (PCa) patients. According to the current international guidelines, adjuvant radiotherapy (ART) or a regular prostate-specific antigen (PSA)-based follow-up with (early) salvage radiotherapy ((e)SRT) if needed is recommended in case of adverse pathological characteristics.Material and methods: Prospective data on consecutive robot-assisted radical prostatectomy (RARP) patients in Belgium from 2009 to 2016 were identified in the Belgian Robotic-Assisted-Laparoscopic-Prostatectomy (Be-RALP) database. Multivariable regression was used to evaluate patient- and facility-related factors associated with postoperative radiation treatment.Results: 2072 patients undergoing a RARP, suffering at least one of the following adverse pathological features, i.e., extracapsular extension (ECE), seminal vesicle invasion (SVI) or positive section margins (PSM), and with registered follow-up until 24 months were enrolled. After RARP, ART was applied to 9.1% and (e)SRT to 12.6% of the patients. Multivariable analysis demonstrated that patients were more likely to receive ART or (e)SRT if they were operated in a hospital with a RT department on-site (odds ratio, ART: 1.49 [1.07-2.07]; (e)SRT: 1.55 [1.16-2.06]). Furthermore, the presence of higher tumour category (T-category) and/or PSM on final pathology was associated with a higher chance of getting ART and (e)SRT (p < .01).Conclusion: Variations in ART and (e)SRT are not only driven by patient-related characteristics. In our nationwide cohort, the availability of a RT department on-site at the surgical centre was found to be an independent predictor for ART and (e)SRT, with a 1.5 times higher odds of receiving postoperative RT during the first 24 months after surgery.

Long- versus short-term androgen deprivation therapy with high-dose radiotherapy for biochemical failure after radical prostatectomy: a randomized controlled trial.

Radical prostatectomy is a well-established treatment option in the management of localized and locally advanced prostate cancer. An extended lymphadenectomy is performed in case of substantial risk for lymph node involvement. When biochemical recurrence (BCR) occurs, salvage radiotherapy (SRT) is performed. The benefit in terms of BCR-free survival (FS) and metastasis-FS by adding 6 months of androgen deprivation therapy (ADT) compared with SRT only has already been established. Retrospective evidence suggests that a longer schedule of ADT may be more beneficial compared with 6 months. This multicenter open-label randomized trial will include patients who need SRT after experiencing BCR post-radical prostatectomy with lymphadenectomy and pN0-status. Patients will be randomized for ADT duration (6 vs 24 months). Primary end point is distant metastasis-FS. Clinical Trial Registration: NCT04242017 (ClinicalTrials.gov).

Improved repeatability of dynamic contrast-enhanced MRI using the complex MRI signal to derive arterial input functions: a test-retest study in prostate cancer patients.

PURPOSE: The arterial input function (AIF) is a major source of uncertainty in tracer kinetic (TK) analysis of dynamic contrast-enhanced (DCE)-MRI data. The aim of this study was to investigate the repeatability of AIFs extracted from the complex signal and of the resulting TK parameters in prostate cancer patients. METHODS: Twenty-two patients with biopsy-proven prostate cancer underwent a 3T MRI exam twice. DCE-MRI data were acquired with a 3D spoiled gradient echo sequence. AIFs were extracted from the magnitude of the signal (AIFMAGN ), phase (AIFPHASE ), and complex signal (AIFCOMPLEX ). The Tofts model was applied to extract Ktrans , kep and ve . Repeatability of AIF curve characteristics and TK parameters was assessed with the within-subject coefficient of variation (wCV). RESULTS: The wCV for peak height and full width at half maximum for AIFCOMPLEX (7% and 8%) indicated an improved repeatability compared to AIFMAGN (12% and 12%) and AIFPHASE (12% and 7%). This translated in lower wCV values for Ktrans (11%) with AIFCOMPLEX in comparison to AIFMAGN (24%) and AIFPHASE (15%). For kep , the wCV was 16% with AIFMAGN , 13% with AIFPHASE , and 13% with AIFCOMPLEX . CONCLUSION: Repeatability of AIFPHASE and AIFCOMPLEX is higher than for AIFMAGN , resulting in a better repeatability of TK parameters. Thus, use of either AIFPHASE or AIFCOMPLEX improves the robustness of quantitative analysis of DCE-MRI in prostate cancer.

Patched 1 Expression Correlates with Biochemical Relapse in High-Risk Prostate Cancer Patients.

There is an unmet clinical need for adequate biomarkers to aid risk stratification and management of prostate cancer (PCa) patients. Even within the high-risk PCa category, not all patients will invariably have a poor prognosis, and improved stratification of this heterogeneous group is needed. In this context, components of the hedgehog (Hh) pathway may have promise as biomarkers, because the available evidence suggests increased Hh pathway activity may confer a poorer outcome in advanced and castrate-resistant PCa. In this study, potential associations between Hh pathway protein expression and clinicopathological factors, including time to biochemical recurrence (BCR), were investigated using a tissue microarray constructed from benign and malignant prostate samples from 75 predominantly high-risk PCa patients who underwent radical prostatectomy. Hh signaling activity was found to differ between benign and malignant prostate tissue, with a greater amount of active Hh signaling present in malignant than benign prostate epithelium. High expression of Patched 1 in malignant prostate epithelium was found to be an independent predictor of BCR in high-risk PCa patients. Glioma-associated oncogene 1 may potentially represent a clinically useful biomarker of an aggressive tumor phenotype. Evaluation of Hh signaling activity in PCa patients may be useful for risk stratification, and epithelial Patched 1 expression, in particular, may be a prognostic marker for BCR in high-risk PCa patients.

Radiation dose and pathological response in oesophageal cancer patients treated with neoadjuvant chemoradiotherapy followed by surgery: a multi-institutional analysis.

Purpose: To explore whether a higher neoadjuvant radiation dose increases the probability of a pathological complete response (pCR) or pathological major response (pMR) response in oesophageal cancer patients. Material and methods: Between 2000 and 2017, 1048 patients from four institutions were stratified according to prescribed neoadjuvant radiation doses of 36.0 Gy (13.3%), 40.0 Gy (7.4%), 41.4 Gy (20.1%), 45.0 Gy (25.5%) or 50.4 Gy (33.7%) in 1.8-2.0 Gy fractions. Endpoints were pCR (tumour regression grade (TRG) 1) and pMR (TRG 1 + 2). Multivariable binary (TRG 1 + 2 vs. TRG > 2) and ordinal (TRG 1 vs. TRG 2 vs. TRG > 2) logistic regression analyses were performed, with subgroup analyses according to histology (squamous cell carcinoma (SCC) vs. adenocarcinoma (AC)). Variables entered in the regression model along with neoadjuvant radiation dose were clinical tumour stage (cT), histology, chemotherapy regimen, induction chemotherapy and time from neoadjuvant chemoradiation to surgery. Results: A pCR was observed in 312 patients (29.8%); in 22.7% patients with AC and in 49.6% patients with SCC. No radiation dose-response relation was observed for pCR (OR = 1.01, 95% CI: 0.98-1.05 for AC and OR = 1.03, 95% CI: 0.96-1.10 for SCC). A pMR was observed in 597 patients (57.0%); in 53.4% patients with AC and in 67.2% patients with SCC. A higher radiation dose increased the probability of achieving pMR (OR = 1.04, 95% CI: 1.02-1.05). Factors reducing this probability were advanced cT stage (reference = cT1-2; cT3: OR = 0.54, 95% CI: 0.37-0.80; cT4: OR = 0.45, 95% CI: 0.24-0.84), AC histology (reference = SCC; OR = 0.62, 95% CI: 0.44-0.88), the use of non-platinum based chemotherapy in SCC patients (OR = 0.30, 95% CI: 0.10-0.91) and platinum based chemotherapy without induction chemotherapy in patients with AC (OR = 0.56, 95% CI: 0.42-0.76). The radiation dose-response relation was confirmed in a subgroup analysis of histologic subtypes (OR = 1.02, 95% CI: 1.01-1.04 for AC and OR = 1.05, 95% CI: 1.02-1.08 for SCC). Conclusions: Neoadjuvant radiation dose impacts pathological response in terms of pMR in oesophageal cancer patients. No radiation dose-response effect was observed for pCR. Further prospective trials are needed to investigate the dose-response relation in terms of pCR.

Analysis of patients scheduled for neoadjuvant therapy followed by surgery for esophageal cancer, who never made it to esophagectomy.

BACKGROUND: Neoadjuvant treatment followed by esophagectomy is standard practice in locally advanced esophageal cancer. However, not all patients who started neoadjuvant treatment will undergo esophageal resection. The purpose of our study was to investigate the group of patients, scheduled for neoadjuvant treatment followed by esophagectomy, who never made it to esophageal resection. METHODS: We retrospectively analyzed patients treated between 2002 and 2015 for locally advanced esophageal cancer, who did not undergo esophagectomy after neoadjuvant treatment. Subanalysis was performed according to time period (2002-2010 versus 2011-2015) and histology (adenocarcinoma versus squamous cell carcinoma). RESULTS: In 114 of 679 patients (16.8%), surgery was not performed after neoadjuvant treatment. Reasons for cancelation were disease progression (50 patients, 43.9%), poor general condition (26 patients, 22.8%), irresectability (14 patients, 12.3%), patients' own decision (15 patients, 13.2%), and death during neoadjuvant treatment (9 patients, 7.9%). In the second time period, there were less irresectable tumors (17.7% versus 5.8%; p = 0.044). Median overall survival was not different over time (9.2 versus 12.5 months; p = 0.937). Irresectability (p = 0.032), patients' refusal (p = 0.012), and poor general condition (p = 0.002) were more frequent as reasons for cancelation in squamous cell carcinoma patients. Median overall survival was, respectively, 12.5 and 9.9 months for adenocarcinoma and squamous cell carcinoma patients (p = 0.441). The majority of patients refusing surgery had a clinical complete response (73.3%). They had a median overall survival of 33.2 months. CONCLUSIONS: One in six patients starting neoadjuvant treatment for locally advanced esophageal cancer never made it to esophagectomy, more than half of them for oncological reasons, but also 1.3% because of death during treatment. Over time, irresectability as reason decreased. As a result, the relative weight of medical inoperability increased, indicating the importance of upfront testing of medical operability. Cancelation of surgery was significantly more common in patients with a squamous cell carcinoma, and this histology seems to represent a more complex oncological and functional entity. Refusal of esophagectomy based on clinical complete response showed a significant survival benefit compared to those who did not undergo esophagectomy because of other reasons.

Neoadjuvant degarelix with or without apalutamide followed by radical prostatectomy for intermediate and high-risk prostate cancer: ARNEO, a randomized, double blind, placebo-controlled trial.

BACKGROUND: Recent retrospective data suggest that neoadjuvant androgen deprivation therapy can improve the prognosis of high-risk prostate cancer (PCa) patients. Novel androgen receptor pathway inhibitors are nowadays available for treatment of metastatic PCa and these compounds are promising for early stage disease. Apalutamide is a pure androgen antagonist with a very high affinity with the androgen receptor. The combination of apalutamide with degarelix, an LHRH antagonist, could increase the efficacy compared to degarelix alone. OBJECTIVE: The primary objective is to assess the difference in proportions of minimal residual disease at prostatectomy specimen between apalutamide + degarelix vs placebo + degarelix. Various secondary endpoints are assessed: variations of different biomarkers at the tumour level (tissue microarrays to evaluate DNA-PKs, PARP, AR and splice variants, PSMA, etc.), whole transcriptome sequencing, exome sequencing and clinical (PSA and testosterone kinetics, early biochemical recurrence free survival, quality of life, safety, etc.) and radiological endpoints. METHODS: ARNEO is a single centre, phase II, randomized, double blind, placebo-controlled trial. The plan is to include at least 42 patients per each of the two study arms. Patients with intermediate/high-risk PCa and who are amenable for radical prostatectomy with pelvic lymph node dissection can be included. After signing an informed consent, every patient will undergo a pelvic 68Ga -PSMA-11 PSMA PET/MR and receive degarelix at standard dosage and start assuming apalutamide/placebo (60 mg 4 tablets/day) for 12 weeks. Within thirty days from the last study medication intake the same imaging will be repeated. Every patient will undergo PSA and testosterone testing the day of randomization, before the first drug intake, and after the last dose. Formalin fixed paraffin embedded tumour samples will be collected and used for transcriptome analysis, exome sequencing and immunohistochemistry. DISCUSSION: ARNEO will allow us to answer, first, whether the combined treatment can result in an increased proportion of patients with minimal residual disease. Secondly, It will enable the study of the molecular consequences at the level of the tumour. Thirdly, what the consequences are of new generation androgen receptor pathway inhibitors on 68Ga -PSMA-11 PET/MR. Finally, various clinical, safety and quality of life data will be collected. TRIAL REGISTRATION: EUDRaCT number: 2016-002854-19 (authorization date 3rd August 2017). clinicalTrial.gov: NCT03080116 .

PET imaging in adaptive radiotherapy of gastrointestinal tumors.

INTRODUCTION: Radiotherapy is a cornerstone in the multimodality treatment of several gastrointestinal (GI) tumors. Positron-emission tomography (PET) has an established role in the diagnosis, response assessment and (re-)staging of these tumors. Nevertheless, the value of PET in adaptive radiotherapy remains unclear. This review focuses on the role of PET in adaptive radiotherapy, i.e. during the treatment course and in the delineation process. EVIDENCE ACQUISITION: The MEDLINE database was searched for the terms ("Radiotherapy"[Mesh] AND "Positron-Emission Tomography"[Mesh] AND one of the site-specific keywords, yielding a total of 1710 articles. After abstract selection, 27 papers were identified for esophageal neoplasms, 1 for gastric neoplasms, 9 for pancreatic neoplasms, 6 for liver neoplasms, 1 for biliary tract neoplasms, none for colonic neoplasms, 15 for rectal neoplasms and 12 for anus neoplasms. EVIDENCE SYNTHESIS: The use of PET for truly adaptive radiotherapy during treatment for GI tumors has barely been investigated, in contrast to the potential of the PET-defined metabolic tumor volume for optimization of the target volume. The optimized target definition seems useful for treatment individualization such as focal boosting strategies in esophageal, pancreatic and anorectal cancer. Nevertheless, for all GI tumors, further investigation is needed. CONCLUSIONS: In general, too little data are available to conclude on the role of PET imaging during radiotherapy for ART strategies in GI cancer. On the other hand, based on the available evidence, the use of biological imaging for target volume adaptation seems promising and could pave the road towards individualized treatment strategies.

Gastric cancer.

Gastric cancer is one of the leading causes of cancer-related death worldwide. Many patients have inoperable disease at diagnosis or have recurrent disease after resection with curative intent. Gastric cancer is separated anatomically into true gastric adenocarcinomas and gastro-oesophageal-junction adenocarcinomas, and histologically into diffuse and intestinal types. Gastric cancer should be treated by teams of experts from different disciplines. Surgery is the only curative treatment. For locally advanced disease, adjuvant or neoadjuvant therapy is usually implemented in combination with surgery. In metastatic disease, outcomes are poor, with median survival being around 1 year. Targeted therapies, such as trastuzumab, an antibody against HER2 (also known as ERBB2), and the VEGFR-2 antibody ramucirumab, have been introduced. In this Seminar, we present an update of the causes, classification, diagnosis, and treatment of gastric cancer.

TOPGEAR: A Randomized, Phase III Trial of Perioperative ECF Chemotherapy with or Without Preoperative Chemoradiation for Resectable Gastric Cancer: Interim Results from an International, Intergroup Trial of the AGITG, TROG, EORTC and CCTG.

BACKGROUND: Postoperative chemoradiation and perioperative chemotherapy using epirubicin/cisplatin/5-fluorouracil (ECF) represent two standards of care for resectable gastric cancer. In the TOPGEAR (Trial Of Preoperative therapy for Gastric and Esophagogastric junction AdenocaRcinoma) trial, we hypothesized that adding preoperative chemoradiation to perioperative ECF will improve survival; however, the safety and feasibility of preoperative chemoradiation have yet to be determined. METHODS: TOPGEAR is an international phase III trial in which patients with adenocarcinoma of the stomach were randomized to perioperative ECF alone or with preoperative chemoradiation. The ECF-alone group received three preoperative cycles of ECF, while the chemoradiation group received two cycles of preoperative ECF followed by chemoradiation. Both groups received three postoperative cycles of ECF. A planned interim analysis of the first 120 patients was conducted, and was reviewed by the Independent Data Safety Monitoring Committee to assess treatment compliance, toxicity/safety, and response rates. RESULTS: The proportion of patients who received all cycles of preoperative chemotherapy was 93% (ECF group) and 98% (chemoradiation group), while 65 and 53%, respectively, received all cycles of postoperative chemotherapy. Overall, 92% of patients allocated to preoperative chemoradiation received this treatment. The proportion of patients proceeding to surgery was 90% (ECF group) and 85% (chemoradiation group). Grade 3 or higher surgical complications occurred in 22% of patients in both groups. Furthermore, grade 3 or higher gastrointestinal toxicity occurred in 32% (ECF group) and 30% (chemoradiation group) of patients, while hematologic toxicity occurred in 50 and 52% of patients. CONCLUSIONS: These results demonstrate that preoperative chemoradiation can be safely delivered to the vast majority of patients without a significant increase in treatment toxicity or surgical morbidity.