Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines.

BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.

The Italian version of the Pediatric Quality of Life Inventory™ (PEDSQL™) 3.0 healthcare satisfaction hematology/oncology module: reliability and validity in radiation oncology.

BACKGROUND: Health-related quality of life (HRQOL) measurement has become an important health care outcome even in oncological pediatric scenario. During radiation therapy care path, pediatric patients and their relatives may suffer from emotional and psychosocial distress not only related to cancer diagnosis, but also due to the procedure and the required daily routine. Despite the high prevalence of psychosocial consequences in this setting, instruments that inquire pediatric HRQOL and healthcare satisfaction have rarely been studied in Italy. Purpose of this study was to investigate reliability and linguistic validation of the PedsQL™ healthcare satisfaction Hematology/Oncology module from its original English version to Italian language. METHODS: Three phases standard procedure of cross-culture adaptation were used to create Italian version of PedsQL™ healthcare satisfaction Hematology/Oncology module. Forward translations and backward translations were performed. Finally, a pilot-testing for understandability of the 'pre-final' version was conducted with parents of children attending our Radiotherapy Center using two methodologies of Cognitive Interviewing ("Think-aloud Interviews" and "Respondent Debriefing"), in order to obtain the final Italian version of the PedsQL™ healthcare satisfaction Hematology/Oncology module. RESULTS: Twenty-five parents (2 father, 23 mothers) were recruited during their children's radiotherapy treatment and the grammatically and conceptually acceptable pre-final version of the PedsQL™ Healthcare Satisfaction Hematology/Oncology Module was administered. The questionnaire was well understood reflecting its linguistic adaptation. Compliance with questionnaire administration was optimal. All subjects stated that the questions were interesting to express their opinion, most of them reported that all the questions of each section were clearly comprehensible and easy to understand, suggesting minimal changes that were double-checked with back translation. Furthermore, six of them spontaneously asked to complete the questionnaire in order to review the assistance received during radiotherapy. CONCLUSION: Our Italian version of the PedsQL™ 3.0 Healthcare Satisfaction Hematology/Oncology Module seems to be a valid and functional instrument to indagate Healthcare Satisfaction.

THUNDER 2: THeragnostic Utilities for Neoplastic DisEases of the Rectum by MRI guided radiotherapy.

BACKGROUND: Neoadjuvant chemoradiation therapy (nCRT) is the standard treatment modality in locally advanced rectal cancer (LARC). Since response to radiotherapy (RT) is dose dependent in rectal cancer, dose escalation may lead to higher complete response rates. The possibility to predict patients who will achieve complete response (CR) is fundamental. Recently, an early tumour regression index (ERI) was introduced to predict pathological CR (pCR) after nCRT in LARC patients. The primary endpoints will be the increase of CR rate and the evaluation of feasibility of delta radiomics-based predictive MRI guided Radiotherapy (MRgRT) model. METHODS: Patients affected by LARC cT2-3, N0-2 or cT4 for anal sphincter involvement N0-2a, M0 without high risk features will be enrolled in the trial. Neoadjuvant CRT will be administered using MRgRT. The initial RT treatment will consist in delivering 55 Gy in 25 fractions on Gross Tumor Volume (GTV) plus the corresponding mesorectum and 45 Gy in 25 fractions on the drainage nodes. Chemotherapy with 5-fluoracil (5-FU) or oral capecitabine will be administered continuously. A 0.35 Tesla MRI will be acquired at simulation and every day during MRgRT. At fraction 10, ERI will be calculated: if ERI will be inferior than 13.1, the patient will continue the original treatment; if ERI will be higher than 13.1 the treatment plan will be reoptimized, intensifying the dose to the residual tumor at the 11th fraction to reach 60.1 Gy. At the end of nCRT instrumental examinations are to be performed in order to restage patients. In case of stable disease or progression, the patient will undergo surgery. In case of major or complete clinical response, conservative approaches may be chosen. Patients will be followed up to evaluate toxicity and quality of life. The number of cases to be enrolled will be 63: all the patients will be treated at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. DISCUSSION: This clinical trial investigates the impact of RT dose escalation in poor responder LARC patients identified using ERI, with the aim of increasing the probability of CR and consequently an organ preservation benefit in this group of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04815694 (25/03/2021).

Does restaging MRI radiomics analysis improve pathological complete response prediction in rectal cancer patients? A prognostic model development.

PURPOSE: Our study investigated the contribution that the application of radiomics analysis on post-treatment magnetic resonance imaging can add to the assessments performed by an experienced disease-specific multidisciplinary tumor board (MTB) for the prediction of pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). MATERIALS AND METHODS: This analysis included consecutively retrospective LARC patients who obtained a complete or near-complete response after nCRT and/or a pCR after surgery between January 2010 and September 2019. A three-step radiomics features selection was performed and three models were generated: a radiomics model (rRM), a multidisciplinary tumor board model (yMTB) and a combined model (CM). The predictive performance of models was quantified using the receiver operating characteristic (ROC) curve, evaluating the area under curve (AUC). RESULTS: The analysis involved 144 LARC patients; a total of 232 radiomics features were extracted from the MR images acquired post-nCRT. The yMTB, rRM and CM predicted pCR with an AUC of 0.82, 0.73 and 0.84, respectively. ROC comparison was not significant (p = 0.6) between yMTB and CM. CONCLUSION: Radiomics analysis showed good performance in identifying complete responders, which increased when combined with standard clinical evaluation; this increase was not statistically significant but did improve the prediction of clinical response.

Standardized data collection to build prediction models in oncology: a prototype for rectal cancer.

The advances in diagnostic and treatment technology are responsible for a remarkable transformation in the internal medicine concept with the establishment of a new idea of personalized medicine. Inter- and intra-patient tumor heterogeneity and the clinical outcome and/or treatment's toxicity's complexity, justify the effort to develop predictive models from decision support systems. However, the number of evaluated variables coming from multiple disciplines: oncology, computer science, bioinformatics, statistics, genomics, imaging, among others could be very large thus making traditional statistical analysis difficult to exploit. Automated data-mining processes and machine learning approaches can be a solution to organize the massive amount of data, trying to unravel important interaction. The purpose of this paper is to describe the strategy to collect and analyze data properly for decision support and introduce the concept of an 'umbrella protocol' within the framework of 'rapid learning healthcare'.

Impact of body composition parameters on radiation therapy compliance in locally advanced rectal cancer: A retrospective observational analysis.

Background: The impact of body composition and sarcopenia in locally advanced rectal cancer (LARC) is still unclear, even several studies have been published on this issue. Our study aims to analyze the impact of sarcopenia on neoadjuvant chemoradiotherapy (nCRT) tolerance and survival outcomes. Methods: This is a retrospective, monocentric study where LARC patients treated between 2010 and 2020 were enrolled. A single slice, from the pre-therapy simulation computed tomography (CT) scan, was used to perform the body composition analysis with dedicated software. The primary endpoint was the impact of body composition on radiotherapy (RT) interruption secondarily on overall survival (OS), disease-free survival (DFS), and local control (LC). Results: The study included 628 LARC patients (40.9 % female, mean age 63.4 years): 24 % had low skeletal muscle index (SMI), 30 % had low muscle density (MD) and 17 (10.3 % of obese) were sarcopenic obese. Higher BMI (OR 2.38, 95 % CI 1.36-4.01) and lower SMI (0.73, 95 % CI 0.55-0.94) resulted as independent predictors of RT interruption. Sarcopenic obesity (HR 2.83, 95 % CI 1.24-6.45) was related to worse OS, while MD (0.96, 95 % CI 0.93-0.98), and higher SMI (0.97, 95 % CI 0.95-0.99) were related to better OS; a lower MD remained also associated even in adjusted multivariable analysis (0.96, 95 % CI0.93-0.98). Moreover, higher visceral adipose tissue (VAT) resulted associated with worse DFS (1.02, 95 % CI 1.01-1.03), while higher SMI was related to better Local Control (0.96, 95 % CI 0.93-0.99). Conclusions: Body composition analysis, particularly of muscle and fat masses, may be a useful tool for better management of LARC patients undergoing RT. Increased collaboration between radiation oncologists and clinical nutritionists is advisable, to enable early nutritional support of LARC.

Rectal Sparing Approach after preoperative Radio- and/or Chemo-therapy (ReSARCh): a prospective, multicenter, observational study.

BACKGROUND: Rectal-sparing approaches for patients with rectal cancer who achieved a complete or major response following neoadjuvant therapy constitute a paradigm of a potential shift in the management of patients with rectal cancer; however, their role remains controversial. The aim of this study was to investigate the feasibility of rectal-sparing approaches to preserve the rectum without impairing the outcomes. METHODS: This prospective, multicenter, observational study investigated the outcomes of patients with clinical stage II-III mid-low rectal adenocarcinoma treated with any neoadjuvant therapy, and either transanal local excision or watch-and-wait approach, based on tumor response (major or complete) and patient/surgeon choice. The primary endpoint of the study was rectum preservation at a minimum follow-up of 2 years. Secondary endpoints were overall, disease-free, local and distant recurrence-free, and stoma-free survival at 3 years. RESULTS: Of the 178 patients enrolled in 16 centers, 112 (62.9%) were managed with local excision and 66 (37.1%) with watch-and-wait. At a median (interquartile range) follow-up of 36.1 (30.6-45.6) months, the rectum was preserved in 144 (80.9%) patients. The 3-year rectum-sparing, overall survival, disease-free survival, local recurrence-free survival, and distant recurrence-free survival was 80.6% (95% CI 73.9-85.8), 97.6% (95% CI 93.6-99.1), 90.0% (95% CI 84.3-93.7), 94.7% (95% CI 90.1-97.2), and 94.6% (95% CI 89.9-97.2), respectively. The 3-year stoma-free survival was 95.0% (95% CI 89.5-97.6). The 3-year regrowth-free survival in the watch-and-wait group was 71.8% (95% CI 59.9-81.2). CONCLUSIONS: In rectal cancer patients with major or complete clinical response after neoadjuvant therapy, the rectum can be preserved in about 80% of cases, without compromising the outcomes.

THeragnostic utilities for neoplastic DisEases of the rectum by MRI guided radiotherapy (THUNDER 2) phase II trial: interim safety analysis.

BACKGROUND: The THUNDER-2 phase II single institutional trial investigates the benefits of MRI-guided radiotherapy (MRIgRT) in treating locally advanced rectal cancer (LARC). This study focuses on evaluating the impact of escalating radiation therapy dose in non-responder patients using the Early Tumour Regression Index (ERI) for predicting complete response (CR). The trial's primary endpoint is to increase the CR rate in non-responders by 10% and assess the feasibility of the delta radiomics-based MRIgRT predictive model. This interim analysis assesses the feasibility and safety of the proposed MRIgRT dose escalation strategy in terms of acute toxicity (gastrointestinal, genitourinary and haematological) and treatment adherence. METHODS: Stage cT2-3, N0-2, or cT4 patients with anal sphincter involvement, N0-2a, M0, but without high-risk features were enrolled. MRIgRT treatment consisted of a standard dose of 55 Gy to the Gross Tumor Volume (GTV) and mesorectum, and 45 Gy to the mesorectum and drainage nodes in 25 fractions with concomitant chemotherapy. 0.35 T MRI was used for simulation imaging and daily alignment. ERI was calculated at the 10th fraction. Non-responders with an ERI above 13.1 received intensified dose escalation from the 11th fraction, resulting in a total dose of 60.1 Gy. Acute toxicity was assessed using the CTCAE v.5 scale. RESULTS: From March 2021 to November 2022, 33 out of the total number of 63 patients to be enrolled (52.4%) were included, with one withdrawal unrelated to treatment. Sixteen patients (50%) underwent dose escalation. Treatment was well tolerated, with only one patient (3.1%) in the standard treatment group experiencing acute Grade 3 diarrhea, proctitis, and cystitis. No significant differences in toxicity were observed between the two groups (p = 0.5463). CONCLUSIONS: MRIgRT treatment with dose escalation up to 60.1 Gy is well tolerated in LARC patients predicted as non-responders by ERI, confirming the feasibility and safety of this approach. The THUNDER-2 trial's primary and secondary endpoints will be fully analyzed when all planned patients will be enrolled.

Predictive and prognostic value of inflammatory markers in locally advanced rectal cancer (PILLAR) - A multicentric analysis by the Italian Association of Radiotherapy and Clinical Oncology (AIRO) Gastrointestinal Study Group.

Background: Patients (pts) affected with locally advanced rectal cancer (LARC) may respond differently to neoadjuvant chemoradiotherapy (nCRT). The identification of reliable biomarkers able to predict oncological outcomes could help in the development of risk-adapted treatment strategies. It has been suggested that inflammation parameters may have a role in predicting tumor response to nCRT and survival outcomes and in rectal cancer, but no definitive conclusion can be drawn at present. The aim of the current study is to evaluate the role of baseline inflammatory markers as prognostic and predictive factors in a large multicentric Italian cohort of LARC pts. Methods: Patients diagnosed with LARC from January 2002 to December 2019 in 9 Italian centers were retrospectively collected. Patients underwent long-course RT with chemotherapy based on fluoropyrimidine ± oxaliplatin followed by surgery. Inflammatory markers were retrieved based on a pre-treatment blood sample including HEI (hemo-eosinophils inflammation index), SII (systemic index of inflammation), NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio) and MLR (monocyte-to-lymphocyte ratio). Outcomes of interest were pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS). Results: 808 pts were analyzed. pCR rate was 22 %, 5yOS and 5yDFS were 84.0% and 63.1% respectively. Multivariate analysis identified that a NLR cut-off value >1.2 and SII cut-off value >500 could predict pCR (p = 0.05 and 0.009 respectively). In addition to age, extramesorectal nodes and RT dose, MLR >0.18 (p = 0.03) and HEI = 3 (p = 0.05) were independent prognostic factors for DFS. Finally, age, RT dose, MLR with a cut-off >0.35 (p = 0.028) and HEI = 3 (p = 0.045) were independent predictors of OS. Conclusions: Higher values of baseline composite inflammatory markers can serve as predictors of lower pCR rates and worse survival outcomes in LARC patients undergoing nCRT. More reliable data from prospective studies could lead to the integration of these inexpensive and easy-to-derive tools into clinical practice.

Preoperative Intensified Chemoradiation with Intensity-Modulated Radiotherapy and Simultaneous Integrated Boost Combined with Capecitabine in Locally Advanced Rectal Cancer: Long-Term Outcomes of a Real-Life Multicenter Study.

BACKGROUND: Despite the feasibility and promising activity data on intensity-modulated RT and simultaneous integrated boost (IMRT-SIB) dose escalation in preoperative chemoradiation (CRT) for locally advanced rectal cancer (LARC), few data are currently available on long-term outcomes. PATIENTS AND METHODS: A cohort of 288 LARC patients with cT3-T4, cN0-2, cM0 treated with IMRT-SIB and capecitabine from March 2013 to December 2019, followed by a total mesorectal excision (TME) or an organ-preserving strategy, was collected from a prospective database of 10 Italian institutions. A dose of 45 Gy in 25 fractions was prescribed to the tumor and elective nodes, while the SIB dose was prescribed according to the clinical practice of each institution on the gross tumor volume (GTV). Concurrent capecitabine was administered at a dose of 825 mg/m2 twice daily, 7 days a week. The primary objective of the study was to evaluate long-term outcomes in terms of local control (LC), progression-free survival (PFS) and overall survival (OS). The secondary objective was to confirm the previously reported feasibility, safety and efficacy (pCR, TRG1-2 and downstaging rates) of the treatment in a larger patient population. RESULTS: All patients received a dose of 45 Gy to the tumor and elective nodes, while the SIB dose ranged from 52.5 Gy to 57.5 Gy (median 55 Gy). Acute gastrointestinal and hematologic toxicity rates of grade 3-4 were 5.7% and 1.8%, respectively. At preoperative restaging, 36 patients (12.5%) with complete or major clinical responses (cCR or mCR) were offered an organ-preserving approach with local excision (29 patients) or a watch and wait strategy (7 patients). The complete pathologic response rate (pCR) in radically operated patients was 25.8%. In addition, 4 TME patients had pT0N1 and 19 LE patients had pT0Nx, corresponding to an overall pT0 rate of 31.3%. Of the 36 patients selected for organ preservation, 7 (19.5%) required the completion of TME due to unfavorable pathologic features after LE or tumor regrowth during W-W resulting in long-term rectal preservation in 29 of 288 (10.1%) of the total patient population. Major postoperative complications occurred in 14.2% of all operated patients. At a median follow-up of 50 months, the 5-year PFS and OS rates were 72.3% (95% CI: 66.3-77.4) and 85.9% (95% CI: 80.2-90.1), respectively. The 5-year local recurrence (LR) rate was 9.2% (95% CI: 6.0-13.2), while the distant metastasis (DM) rate was 21.3% (95% CI: 16.5-26.5). The DM rate was 24.5% in the high-risk subset compared to 16.2% in the low-intermediate risk group (p = 0.062) with similar LR rates (10% and 8%, respectively). On multivariable analysis, cT4 and TRG3-5 were significantly associated with worse PFS, OS and metastasis-free survival. CONCLUSIONS: Preoperative IMRT-SIB with the moderate dose intensification of 52.5-57.5 Gy (median 55 Gy) and the full dose of concurrent capecitabine confirmed to be feasible and effective in our real-life clinical practice. Organ preservation was shown to be feasible in carefully selected, responsive patients. The favorable long-term survival rates highlight the efficacy of this intensified treatment program. The incorporation of IMRT-SIB with a more effective systemic therapy component in high-risk patients could represent a new area of investigational interest.

An IT Platform Supporting Rectal Cancer Tumor Board Activities: Implementation Process and Impact Analysis.

Colorectal cancer (RC) is the third most common cancer, with an increasing incidence in recent years. Digital health solutions supporting multidisciplinary tumor boards (MTBs) could improve positive outcomes for RC patients. This paper describes the implementation process of a digital solution within the RC-MTB and its impact analysis in the context of the Fondazione Policlinico 'A. Gemelli' in Italy. Adopting a two-phase methodological approach, the first phase qualitatively describes each phase of the implementation of the IT platform, while the second phase quantitatively describes the analysis of the impact of the IT platform. Descriptive and inferential analyses were performed for all variables, with a p-value < 0.05 being considered statistically significant. The implementation of the platform allowed more healthcare professionals to attend meetings and resulted in a decrease in patients sent to the RC-MTB for re-staging and further diagnostic investigations and an increase in patients sent to the RC-MTB for treatment strategies. The results could be attributed to the facilitated access to the platform remotely for specialists, partly compensating for the restrictions imposed by the COVID-19 pandemic, as well as to the integration of the platform into the hospital's IT system. Furthermore, the early involvement of healthcare professionals in the process of customizing the platform to the specific needs of the RC-MTB may have facilitated its use and contributed to the encouraging quantitative results.

Impact of preoperative chemoradiation with higher dose intensity modulated radiotherapy on pathological complete response for locally advanced rectal cancer: a systematic review.

INTRODUCTION: Neoadjuvant chemoradiation (CRT) followed by total mesorectal excision is the current standard-of-care for locally advanced UICC II-III stage rectal cancer (LARC). A pathological complete response (pCR) correlates with survival. Improvements of pCR, including dose escalation, should be explored. The aim of this explorative analysis is to assess the impact on pCR of intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB). AREAS COVERED: A literature search via PICO (Population, Intervention, Comparison, Outcome) in MEDLINE/PubMed and EMBASE and a systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Metanalysis) methodology were performed. Studies that reported pCR rate in patients with LARC in clinical stage T2N+M0 or cT3/4 N0/+M0 treated with preoperative CRT with SIB-IMRT/VMAT (Volumetric Modulated Arc Therapy) were included. Sixty-two studies were identified, but only eight clinical trials with a total of 311 patients were included . Median follow-up was 16-61 months. pCR reached the value of 38%. Good survival outcomes were observed with a mild toxicity profile. EXPERT OPINION: Radiotherapy dose intensification in LARC showed a slight increase of pCR compared to historical studies. Prospective evaluations are necessary to define which patients would benefit most.

The Role of Simultaneous Integrated Boost in Locally Advanced Rectal Cancer Patients with Positive Lateral Pelvic Lymph Nodes.

Aims: Between 11 to 14% of patients with locally advanced rectal cancer (LARC) have positive lateral pelvic lymph nodes (LPLN) at diagnosis, related to a worse prognosis with a 5-year survival rate between 30 to 40%. The best treatment choice for this group of patients is still a challenge. The optimal radiotherapy (RT) dose for LPLN patients has been investigated. Methods: We retrospectively collected data from LARC patients with LPLN at the primary staging MRI, treated in our center from March 2003 to December 2020. Patients underwent a neoadjuvant concomitant chemo-radiotherapy (CRT) treatment on the primary tumor (T), mesorectum, and pelvic nodes, associated with a fluoride-based chemotherapy. The total reached dose was 45 Gy at 1.8 Gy/fr on the elective sites and 55 Gy at 2.2 Gy/fr on the disease and mesorectum. Patients were divided in two groups based on whether they received a simultaneous integrated RT boost on the LPLN or not. Overall Survival (OS), Disease Free Survival (DFS), Metastasis Free Survival (MFS), and Local Control (LC) were evaluated in the whole group and then compared between the two groups. Results: A total of 176 patients were evaluated: 82 were included in the RT boost group and 94 in the non-RT boost group. The median follow-up period was 57.8 months. All the clinical endpoint (OS, DFS, MFS, LC), resulted were affected by the simultaneous integrated boost on LPLN with a survival rate of 84.7%, 79.5%, 84.1%, and 92%, respectively, in the entire population. From the comparison of the two groups, there was a statistical significance towards the RT boost group with a p < 0.006, 0.030, 0.042, 0.026, respectively. Conclusions: Concomitant radiotherapy boost on positive LPLN has shown to be beneficial on the survival outcomes (OS, DFS, MFR, and LC) in patients with LARC and LPLN. This analysis demonstrates that a higher dose of radiotherapy on positive pelvic lymph nodes led not only to a higher local control but also to a better survival rate. These results, if validated by future prospective studies, can bring a valid alternative to the surgery dissection without the important side effects and permanent disabilities observed during the years.

BRIDGE -1 TRIAL: BReak Interval Delayed surgery for Gastrointestinal Extraperitoneal rectal cancer, a multicentric phase III randomized trial.

Design: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the standard of care for locally advanced rectal cancer (LARC).Several studies have shown a correlation between a longer interval between the end of nCRT and surgery (surgical interval - SI) and an increased pathological complete response (pCR) rate, with a maximum obtained between 10 and 13 weeks.The primary endpoint of this multicenter, 2-arm randomised trial is to investigate SI lengthening, evaluating the difference in terms of complete response (CR) and Tumor Regression Grade (TRG)1 rate in the two arms. Secondly, the impact of SI lengthening on survival outcomes and quality of life (QoL) will be investigated. Methods: Intermediate-risk LARC patients undergoing nCRT will be prospectively included in the study. nCRT will be administered with a total dose of 55 Gy in 25 fractions on Gross Tumor Volume (GTV) plus the corresponding mesorectum of 45 Gy in 25 fractions on the whole pelvis. Chemotherapy with oral capecitabine will be administered continuously.The patients achieving a clinical major or complete response assessed at clinical-instrumental re-evaluation at 7-8 weeks after treatment completion, will be randomized into two groups, to undergo surgery or local excision at 9-11 weeks (control arm) or at 13-16 weeks (experimental arm). Pathological response will be assessed on the surgical specimen using the AJCC TNM v.7 and the TRG according to Mandard. Patients will be followed up to evaluate toxicity and QoL.The promoter center of the trial will conduct the randomization process through an automated procedure to prevent any possible bias.For sample size calculation, using CR difference of 20% as endpoint, 74 patients per arm will be enrolled. Conclusions: The results of this study may prospectively provide a new time frame for the clinical re-evaluation for complete/major responders patients in order to increase the CR rate to nCRT.Trial registration:ClinicalTrials.gov Identifier: NCT03581344.

Bayesian network structure for predicting local tumor recurrence in rectal cancer patients treated with neoadjuvant chemoradiation followed by surgery.

Background and Purpose: Tumor recurrence, a characteristic of malignant tumors, is the biggest concern for rectal cancer survivors. The epidemiology of the disease calls for a pressing need to improve healthcare quality and patient outcomes. Prediction models such as Bayesian networks, which can probabilistically reason under uncertainty, could assist caregivers with patient management. However, some concerns are associated with the standard approaches to developing these structures in medicine. Therefore, this study aims to compare Bayesian network structures that stem from these two techniques. Patients and Methods: A retrospective analysis was performed on 6754 locally advanced rectal cancer (LARC) patients enrolled in 14 international clinical trials. Local tumor recurrence at 2, 3, and 5-years was defined as the endpoints of interest. Five rectal cancer treating physicians from three countries elicited the expert structure. The algorithmic structure was inferred from the data with the hill-climbing algorithm. Structural performance was assessed with calibration plots and area under the curve values. Results: The area under the curve for the expert structure on the training and validation data was above 0.9 and 0.8, respectively, for all the time points. However, the algorithmic structure had superior predictive performance over the expert structure for all time points of interest. Conclusion: We have developed and internally validated a Bayesian networks structure from experts' opinions, which can predict the risk of a LARC patient developing a tumor recurrence at 2, 3, and 5 years. Our result shows that the algorithmic-based structures are more performant and less interpretable than expert-based structures.

Fractal-Based Radiomic Approach to Tailor the Chemotherapy Treatment in Rectal Cancer: A Generating Hypothesis Study.

INTRODUCTION: The aim of this study was to create a radiomic model able to calculate the probability of 5-year disease-free survival (5yDFS) when oxaliplatin (OXA) is or not administered in patients with locally advanced rectal cancer (LARC) and treated with neoadjuvant chemoradiotherapy (nCRT), allowing physicians to choose the best chemotherapy (CT) regimen. METHODS: LARC patients with cT3-4 cN0 or cT1-4 cN1-2 were treated according to an nCRT protocol that included concomitant CT schedules with or without OXA and radiotherapy dose of 55 Gy in 25 fractions. Radiomic analysis was performed on the T2-weighted (T2-w) MR images acquired during the initial tumor staging. Statistical analysis was performed separately for the cohort of patients treated with and without OXA. The ability of every single radiomic feature in predicting 5yDFS as a univariate analysis was assessed using the Wilcoxon-Mann-Whitney (WMW) test or t-test. Two logistic models (one for each cohort) were calculated, and their performance was assessed using the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: A total of 176 image features belonging to four families (morphological, statistical, textural, and fractal) were calculated for each patient. At the univariate analysis, the only feature showing significance in predicting 5yDFS was the maximum fractal dimension of the subpopulation identified considering 30% and 50% as threshold levels (maxFD30-50). Once the models were developed using this feature, an AUC of 0.67 (0.57-0.77) and 0.75 (0.56-0.95) was obtained for patients treated with and without OXA, respectively. A maxFD30-50 >1.6 was correlated to a higher 5yDFS probability in patients treated with OXA. CONCLUSION: This study suggests that radiomic analysis of MR T2-w images can be used to define the optimal concomitant CT regimen for stage III LARC cancer patients. In particular, by providing an indication of the gross tumor volume (GTV) spatial heterogeneity at initial staging, maxFD30-50 seems to be able to predict the probability of 5yDFS. New studies including a larger cohort of patients and external validation sets are recommended to verify the results of this hypothesis-generating study.

Timing to achieve the highest rate of pCR after preoperative radiochemotherapy in rectal cancer: a pooled analysis of 3085 patients from 7 randomized trials.

PURPOSE: Optimal timing of surgery after neoadjuvant chemoradiotherapy (Nad-CRT) is still controversial in locally advanced rectal cancer (LARC). The primary goal of this study was to determine the best surgical interval (SI) to achieve the highest rate of pathological complete response (pCR) and secondly to evaluate the effect on survival outcomes according to the SI. PATIENTS AND METHODS: Patients data were extracted from the international randomized trials: Accord12/0405, EORTC22921, FFCD9203, CAO/ARO/AIO-94, CAO-ARO-AIO-04, INTERACT and TROG01.04. Inclusion criteria were: age≥ 18, cT3-T4 and cN0-2, no clinical evidence of distant metastasis at diagnosis, Nad-CRT followed by surgery. Pearson's Chi-squared test with Yates' continuity correction for categorical variables, the Mann-Whitney test for continuous variables, Mann-Kendall test, Kaplan-Meier curves with log-rank test, univariate and multivariate logistic regression model was used for data analysis. RESULTS: 3085 patients met the inclusion criteria. Overall, the pCR rate was 14% at a median SI of 6 weeks (range 1-31). The cumulative pCR rate increased significantly when SI lengthened, with 95% of pCR events within 10 weeks from Nad-CRT. At univariate and multivariate logistic regression analysis, lengthening of SI (p< 0.01), radiotherapy dose (p< 0.01), and the addition of oxaliplatin to Nad-CRT (p< 0.01) had a favorable impact on pCR. Furthermore, lengthening of SI was not impact on local recurrences, distance metastases, and overall survival. CONCLUSION: This pooled analysis suggests that the best time to achieve pCR in LARC is at 10 weeks, considering that the lengthening of SI is not detrimental concerning survival outcomes.

Could the conservative approach be considered safe in the treatment of locally advanced rectal cancer in case of a clinical near-complete or complete response? A retrospective analysis.

BACKGROUND: Conservative approach has emerged as an option for the management of rectal cancer (RC) patients with a near or complete clinical response after neoadjuvant chemoradiotherapy (nCRT). The aim of this study is to assess the impact of the conservative approach by comparing patients' survival outcomes and quality of life with those who had surgical resection. METHODS: A single-institution and retrospective study including RC patients who reached a near complete or complete clinical response after nCRT from January 2010 to September 2019. Conservative approaches included local excision or watch and wait strategy; surgery approaches included anterior resection or abdominal-perineal resection.Local regrowth (LR), overall survival, disease free survival, metastasis free survival and colostomy free survival were evaluated through Kaplan-Meier curves and compared trough log-rank tests. Quality of life was measured by the following validated questionnaires: EORTC QLC30, EORTC QLQ - CR29 and Fecal Incontinence Quality of Life scale. RESULTS: Overall 157 patients were analyzed: 105 (66,9%) underwent radical surgery and 52 (33,1%) had a conservative approach. With a median follow-up of 51 months, 2 patients in the surgical group had a local recurrence and 8 in the conservative group had a LR, respectively. Distance metastasis occurred in 7 and 1 patients of surgical and conservative group, respectively. No differences were detected in terms of survival outcomes except for colostomy free survival (p: 0,01). The conservative group showed better intestinal (p < 0.01) and sexual (p: 0,04) function and emotional status (p: 0,02). CONCLUSIONS: Conservative approach seems to be safe in terms of survival outcomes with a significant advantage on quality of life in RC patients who achieved clinical complete response after nCRT.

The Assisi Think Tank Meeting Breast Large Database for Standardized Data Collection in Breast Cancer-ATTM.BLADE.

Background: During the 2016 Assisi Think Tank Meeting (ATTM) on breast cancer, the panel of experts proposed developing a validated system, based on rapid learning health care (RLHC) principles, to standardize inter-center data collection and promote personalized treatments for breast cancer. Material and Methods: The seven-step Breast LArge DatabasE (BLADE) project included data collection, analysis, application, and evaluation on a data-sharing platform. The multidisciplinary team developed a consensus-based ontology of validated variables with over 80% agreement. This English-language ontology constituted a breast cancer library with seven knowledge domains: baseline, primary systemic therapy, surgery, adjuvant systemic therapies, radiation therapy, follow-up, and toxicity. The library was uploaded to the BLADE domain. The safety of data encryption and preservation was tested according to General Data Protection Regulation (GDPR) guidelines on data from 15 clinical charts. The system was validated on 64 patients who had undergone post-mastectomy radiation therapy. In October 2018, the BLADE system was approved by the Ethical Committee of Fondazione Policlinico Gemelli IRCCS, Rome, Italy (Protocol No. 0043996/18). Results: From June 2016 to July 2019, the multidisciplinary team completed the work plan. An ontology of 218 validated variables was uploaded to the BLADE domain. The GDPR safety test confirmed encryption and data preservation (on 5000 random cases). All validation benchmarks were met. Conclusion:BLADE is a support system for follow-up and assessment of breast cancer care. To successfully develop and validate it as the first standardized data collection system, multidisciplinary collaboration was crucial in selecting its ontology and knowledge domains. BLADE is suitable for multi-center uploading of retrospective and prospective clinical data, as it ensures anonymity and data privacy.

Delta Radiomics Can Predict Distant Metastasis in Locally Advanced Rectal Cancer: The Challenge to Personalize the Cure.

PURPOSE: Distant metastases are currently the main cause of treatment failure in locally advanced rectal cancer (LARC) patients. The aim of this research is to investigate a correlation between the variation of radiomics features using pre- and post-neoadjuvant chemoradiation (nCRT) magnetic resonance imaging (MRI) with 2 years distant metastasis (2yDM) rate in LARC patients. METHODS AND MATERIALS: Diagnostic pre- and post- nCRT MRI of LARC patients, treated in a single institution from May 2008 to June 2015 with an adequate follow-up time, were retrospectively collected. Gross tumor volumes (GTV) were contoured by an abdominal radiologist and blindly reviewed by a radiation oncologist expert in rectal cancer. The dataset was firstly randomly split into 90% training data, for features selection, and 10% testing data, for the validation. The final set of features after the selection was used to train 15 different classifiers using accuracy as target metric. The models' performance was then assessed on the testing data and the best performing classifier was then selected, maximising the confusion matrix balanced accuracy (BA). RESULTS: Data regarding 213 LARC patients (36% female, 64% male) were collected. Overall 2yDM was 17%. A total of 2,606 features extracted from the pre- and post- nCRT GTV were tested and 4 features were selected after features selection process. Among the 15 tested classifiers, logistic regression proved to be the best performing one with a testing set BA, sensitivity and specificity of 78.5%, 71.4% and 85.7%, respectively. CONCLUSIONS: This study supports a possible role of delta radiomics in predicting following occurrence of distant metastasis. Further studies including a consistent external validation are needed to confirm these results and allows to translate radiomics model in clinical practice. Future integration with clinical and molecular data will be mandatory to fully personalized treatment and follow-up approaches.