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Introduction: Historically, multimodal therapeutic strategies involving preoperative chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (CT) have been employed to treat locally advanced rectal cancer (LARC). Total Neoadjuvant Therapy (TNT) is showing promise in improving outcomes. Despite its benefits, the optimal sequencing within TNT-whether induction chemotherapy should precede or follow chemoradiotherapy-remains a critical question. This study endeavors to explore the effects of different TNT sequencing strategies on patient outcomes, including tumor downstaging, pathological response, organ preservation, and the balance between efficacy and tolerability., Methods: Our methodology entailed a comprehensive literature review conducted on Medline, focusing on recent research, including retrospective studies, systematic reviews, and clinical trials. The review emphasized the comparison of induction chemotherapy versus consolidation chemotherapy within TNT regimens, assessing outcomes such as pathological response, organ preservation rates, and adverse effects. To ensure the selection of appropriate and high-quality studies, specific inclusion and exclusion criteria were applied., Results: The analysis revealed that induction chemotherapy might lead to decreased adherence to subsequent chemoradiotherapy while offering an early intervention against micrometastasis and potentially improving overall chemotherapy compliance. Conversely, consolidation chemotherapy has been associated with higher pathological complete response (pCR) rates and improved tolerability, indicating its potential for patients requiring local symptom relief or those eligible for a nonoperative management approach. Comparative studies like CAO/ARO/AIO-12 and the OPRA trials have significantly contributed to our understanding, suggesting that while both strategies have distinct advantages, the choice between induction and consolidation chemotherapy should be tailored based on individual patient profiles and tumor characteristics., Conclusion: This narrative review underscores the importance of a nuanced approach to TNT sequencing in locally advanced rectal cancer, highlighting the need for further research to refine treatment strategies., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

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., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Neoadjuvant therapy has an established role in the treatment of patients with colorectal cancer. However, its role continues to evolve due to both advances in the available treatment modalities, and refinements in the indications for neoadjuvant treatment and subsequent surgery., Methods: A narrative review of the most recent relevant literature was conducted., Results: Short-course radiotherapy and long-course chemoradiotherapy have an established role in improving local but not systemic disease control in patients with rectal cancer. Total neoadjuvant therapy offers advantages over short-course radiotherapy and long-course chemoradiotherapy, not only in terms of increased local response but also in reducing the risk of systemic relapses. Non-operative management is increasingly preferred to surgery in patients with rectal cancer and clinical complete responses but is still associated with some negative impacts on functional outcomes. Neoadjuvant chemotherapy may be of some benefit in patients with locally advanced colon cancer with proficient mismatch repair, although patient selection is a major challenge. Neoadjuvant immunotherapy in patients with deficient mismatch repair cancers in the colon or rectum is altering the treatment paradigm for these patients., Conclusion: Neoadjuvant treatments for patients with colon or rectal cancers continue to evolve, increasing the complexity of decision-making for patients and clinicians alike. This review describes the current guidance and most recent developments., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Purpose: The aim of this study is to determine if radiomics features extracted from staging magnetic resonance (MR) images could predict 2-year long-term clinical outcome in patients with locally advanced cervical cancer (LACC) after neoadjuvant chemoradiotherapy (NACRT)., Materials and Methods: We retrospectively enrolled patients with LACC diagnosis who underwent NACRT followed by radical surgery in two different institutions. Radiomics features were extracted from pre-treatment 1.5 T T2w MR images. The predictive performance of each feature was quantified in terms of Wilcoxon-Mann-Whitney test. Among the significant features, Pearson correlation coefficient (PCC) was calculated to quantify the correlation among the different predictors. A logistic regression model was calculated considering the two most significant features at the univariate analysis showing the lowest PCC value. The predictive performance of the model created was quantified out using the area under the receiver operating characteristic curve (AUC)., Results: A total of 175 patients were retrospectively enrolled (142 for the training cohort and 33 for the validation one). 1896 radiomic feature were extracted, 91 of which showed significance (p < 0.05) at the univariate analysis. The radiomic model showing the highest predictive value combined the features calculated starting from the gray level co-occurrence-based features. This model achieved an AUC of 0.73 in the training set and 0.91 in the validation set., Conclusions: The proposed radiomic model showed promising performances in predicting 2-year overall survival before NACRT. Nevertheless, the observed results should be tested in larger studies with consistent external validation cohorts, to confirm their potential clinical use., (© 2022. The Author(s).)

Background: Rectum-preservation for locally advanced rectal cancer has been proposed as an alternative to total mesorectal excision (TME) in patients with major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The purpose of this study was to report on the short-term outcomes of ReSARCh (Rectal Sparing Approach after preoperative Radio- and/or Chemotherapy) trial, which is a prospective, multicenter, observational trial that investigated the role of transanal local excision (LE) and watch-and-wait (WW) as integrated approaches after neoadjuvant therapy for rectal cancer., Methods: Patients with mid-low rectal cancer who achieved mCR or cCR after neoadjuvant therapy and were fit for major surgery were enrolled. Clinical response was evaluated at 8 and 12 weeks after completion of chemoradiotherapy. Treatment approach, incidence, and reasons for subsequent TME were recorded., Results: From 2016 to 2019, 160 patients were enrolled; mCR or cCR at 12 weeks was achieved in 64 and 96 of patients, respectively. Overall, 98 patients were managed with LE and 62 with WW. In the LE group, Clavien-Dindo 3+ complications occurred in three patients. The rate of cCR increased from 8- to 12-week restaging. Thirty-three (94.3%) of 35 patients with cCR had ypT0-1 tumor. At a median 24 months follow-up, a tumor regrowth was found in 15 (24.2%) patients undergoing WW., Conclusions: LE for patients achieving cCR or mCR is safe. A 12-week interval from chemoradiotherapy completion to LE is correlated with an increased cCR rate. The risk of ypT > is reduced when LE is performed after cCR., (© 2021. Society of Surgical Oncology.)

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 11 th 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)., (© 2022. The Author(s).)

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., (© 2021. Italian Society of Medical Radiology.)

Background: Local excision might represent an alternative to total mesorectal excision for patients with locally advanced rectal cancer who achieve a major or complete clinical response after neoadjuvant chemoradiotherapy., Methods: Between August 2005 and July 2011, 63 patients with mid-low rectal adenocarcinoma who had a major/complete clinical response after neoadjuvant chemoradiotherapy were enrolled in a multicenter prospective phase 2 trial and underwent transanal full thickness local excision. The main endpoint of this study was to evaluate the 5- and 10-year overall, relapse-free, local, and distant relapse-free survival, which were calculated by applying the Kaplan-Meier method. The rate of patients with rectum preserved and without stoma were also calculated., Results: Of 63 patients, 38 (60%) were male and 25 (40%) were female, with a median (range) age of 64 (25-82) years. At baseline, the following clinical stages were found: cT2, n = 21 (33.3%); cT3, n = 42 (66.6%), 39 (61.9%) patients were cN+. At a median (range) follow-up of 108 (32-166) months, the estimated cumulative 5- and 10-year overall survival, relapse-free survival, local recurrence-free survival, and distant recurrence-free survival were 87% (95% CI 76-93) and 79% (95% CI 66-87), 89% (95% CI 78-94) and 82% (95% CI 66-91), both 91% (95% CI 81-96), and 90% (95% CI 80-95) and 86% (95% CI 73-93), respectively. Overall, 49 (77.8%) patients had their rectum preserved, and 54 (84.1%) were stoma-free., Conclusion: In highly selected patients, the local excision approach after neoadjuvant chemoradiotherapy is associated with excellent long-term outcomes, high rates of rectum preservation and absence of permanent stoma.

Background: The standard approach for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME). After nCRT 20% of patients achieve a clinical complete response (pCR) and could be treated with a non-operative management (NOM)., Methods: The panel of the Italian Association of Medical Oncology (AIOM) Guidelines on rectal cancer applied the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach addressing the following question: Should NOM vs. TME be used for patients with rectal cancer with clinical complete response after nCRT? Five outcomes were identified: disease-free survival (DFS), mortality, local recurrence, colostomy rate, and functional outcomes., Results: Nine studies were included in the analysis. A higher risk of disease recurrence was observed in the NOM group compared to the TME group (RR = 1.69, 95% CI 1.08, 2.64) on the other hand, we observed a slightly positive but not significant effect on mortality of NOM (RR = 0.82, 95% CI 0.46, 1.45). Patients in the NOM group were more likely to experience local recurrence (RR = 5.37, 95% CI 2.56, 11.27) and patients in the TME group were more likely to have a permanent colostomy (RR = 0.15, 95% CI 0.08, 0.29). Only one study evaluated functional outcomes. The overall certainty of evidence was rated as very low., Conclusions: NOM was found to correlate with a higher risk of local recurrence which did not translate in worse OS and a lower colostomy rate. Due to the paucity of evidences, no recommendations are possible. NOM remains an experimental treatment; thus, patients managed with NOM should be enrolled in clinical trials with a dedicated follow-up schedule.

Purpose: The aim of this Phase II, non-randomized study was to assess activity and safety of neoadjuvant chemotherapy (NACT) before chemoradiation (CT/RT) followed by radical surgery (RS) in locally advanced cervical cancer (LACC) patients., Methods and Materials: The primary end point was rate of pathologic complete response (pCR). FIGO Stage IB2-IVA patients were administered NACT chemotherapy (paclitaxel 80 mg/m 2 , carboplatin AUC 2), for 6 weeks, followed by Intensity Modulated Radiotherapy plus simultaneous boost (total dose of 50.4 Gy to CTV1, and 39.6 Gy to CTV2). Clinical response was assessed according to RECIST criteria. Responsive patients were triaged to RS. The regimen would be considered active if >20 pCRs were registered in 39 patients., Results: 45 patients were enrolled into the study; 25 patients (55.5%) were FIGO stage IIB, 9 cases (20.0%) had stage III disease. At work up, pelvic lymph node involvement was documented in 38 (84.4%) patients; pCR was documented in 18 out of 40 patients (45.0%). Grade 3-4 hematological toxicity after NACT occurred in 4 patients; CT/RT associated grade 3 toxicity was found in 7 patients. Early and late postoperative complications were detected in 16, and 11 cases, respectively. Three-year PFS and OS were 66.0% and 86.0%, respectively., Conclusions: NACT followed by CT/RT by IMRT and RS, is feasible and safe; failure to achieve the primary endpoint has to be recognized; however, enrollment of a higher rate of poor prognosis patients compared to historical data used to calculate sample size, could have resulted in reduced activity., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Preoperative radiotherapy (RT) in combination with fluoropyrimidine-based chemotherapy (CT) is the standard of care in patients with locally advanced, T3-T4 N0-2, rectal cancer (LARC). Given the correlation between RT dose-tumor response and the prognostic role of the tumor regression grade (TRG), treatment intensification represents an area of active investigation. The aim of the study was to analyze the role of RT dose-intensification in the preoperative treatment of LARC in terms of feasibility, efficacy and toxicity., Methods: We retrospectively analyzed patients with LARC treated with intensity-modulated radiotherapy (IMRT) and simultaneous integrated boost (SIB) at five Italian radiation oncology centers. Concurrent Capecitabine was administered. Treatment response was evaluated in terms of disease down-staging and TRG. Acute toxicity was evaluated according to the CTC-AE 4.0 scale., Results: A total of 76 patients were identified for this analysis. A dose of 45 Gy was prescribed to the entire mesorectum and pelvic lymph nodes with a median SIB dose of 54 Gy (range 52.5-57.5) to the tumor and corresponding mesorectum. Overall, 74/76 (97.4%) patients completed the planned RT, whereas 64/76 (84.2%) patients completed the prescribed CT. Eight (10.5%) patients developed grade 3-4 acute toxicity. Overall, 72/76 patients underwent surgery. The tumor and nodal down-staging was documented in 51 (70.8%) and 43 (67%) patients, respectively. Twenty (27.8%) patients obtained a pathologic complete response. Surgical morbidity was reported in 13/72 patients (18.1%)., Conclusions: Although retrospective in design, this study indicates that IMRT-SIB with a dose range of 52.5-57.5 Gy (median 54 Gy) and concomitant Capecitabine appears feasible, well tolerated and effective in terms of disease down-staging and pathological complete response. Long-term toxicity and the impact on disease control and patient survival will be evaluated with a longer follow-up time., Trial Registration: NA.

Background: In many European countries, short-term 5 × 5 Gy radiotherapy has become the standard preoperative treatment of patients with resectable rectal cancer. Individualized risk assessment might allow a better selection of patients who will benefit from postoperative treatment and intensified follow-up., Patients and Methods: From patient's data from three European rectal cancer trials (N = 2881), we developed multivariate cox nomograms reflecting the risk for local recurrence (LR), distant metastases (DM) and overall survival (OS). Evaluated variables were age, gender, tumour distance from the anal verge, the use of radiotherapy, surgical technique (total mesorectal excision/conventional surgery), surgery type (low anterior resection/abdominoperineal resection), time from randomization to surgery, residual disease (R0 versus R1 + 2), pT-stage, pN-stage and surgical complications., Results: Pathological T- and N-status are of vital importance for an accurate prediction of LR, DM and OS. Short-course radiotherapy reduces the rate of LR. The developed nomograms are capable of predicting events with a validation c-index of 0.79 (LR), 0.76 (DM) and 0.75 (OS). The proposed stratification in risk groups allowed significant distinction between Kaplan-Meier curves for outcome., Conclusion: The developed nomograms can contribute to better individual risk prediction for LR, DM and OS for patients operated on rectal cancer. The practicality of the defined risk groups makes decision support in the consulting room feasible, assisting physicians to select patients for adjuvant therapy or intensified follow-up., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Neoadjuvant chemoradiation (CRT), tailored mesorectal excision, and intraoperative radiotherapy (IORT) have become the leading measures for rectal cancer treatment. The objective of this study was to evaluate early and long-term results of a multimodal treatment model for rectal cancer followed by curative surgery. Prospectively collected hospital records of 338 patients surgically treated for rectal cancer between January 1998 and December 2008 were retrospectively reviewed. Patients with high rectum level cancers and those with middle and low rectum cancers with clinical stage T1 to T2 underwent surgery, whereas those with T3 to T4 and N+ disease at the middle and low rectum received neoadjuvant CRT in 96.2 per cent of cases. Short-course neoadjuvant radiotherapy was not considered for neoadjuvant treatment. Postoperative major complications and mortality rates were 12.7 and 2.3 per cent, respectively. Overall 5-year disease-specific and disease-free survival were 80 and 73.1 per cent, respectively, whereas local recurrence rate was 6.1 per cent. At multivariate analysis, nodal status and circumferential margin status were independently associated with poor survival; local recurrence rates were independently affected by nodal and marginal status and tumor stage. The extent of mesorectal excision should be tailored depending on tumor location and the use of neoadjuvant chemotherapy, combined with IORT in advanced middle and low rectal cancer, leading to remarkable tumor downstaging with excellent prognosis in responding patients.

Purpose: To prospectively monitor the response in patients with locally advanced nonmucinous rectal cancer after chemoradiotherapy (CRT) using diffusion-weighted magnetic resonance imaging. The histopathologic finding was the reference standard., Methods and Materials: The institutional review board approved the present study. A total of 62 patients (43 men and 19 women; mean age, 64 years; range, 28-83) provided informed consent. T(2)- and diffusion-weighted magnetic resonance imaging scans (b value, 0 and 1,000 mm(2)/s) were acquired before, during (mean 12 days), and 6-8 weeks after CRT. We compared the median apparent diffusion coefficients (ADCs) between responders and nonresponders and examined the associations with the Mandard tumor regression grade (TRG). The postoperative nodal status (ypN) was evaluated. The Mann-Whitney/Wilcoxon two-sample test was used to evaluate the relationships among the pretherapy ADCs, extramural vascular invasion, early percentage of increases in ADCs, and preoperative ADCs., Results: Low pretreatment ADCs (<1.0 × 10(-3)mm(2)/s) were correlated with TRG 4 scores (p = .0011) and associated to extramural vascular invasion with ypN+ (85.7% positive predictive value for ypN+). During treatment, the mean percentage of increase in tumor ADC was significantly greater in the responders than in the nonresponders (p < .0001) and a >23% ADC increase had a 96.3% negative predictive value for TRG 4. In 9 of 16 complete responders, CRT-related tumor downsizing prevented ADC evaluations. The preoperative ADCs were significantly different (p = .0012) between the patients with and without downstaging (preoperative ADC ≥1.4 × 10(-3)mm(2)/s showed a positive and negative predictive value of 78.9% and 61.8%, respectively, for response assessment). The TRG 1 and TRG 2-4 groups were not significantly different., Conclusion: Diffusion-weighted magnetic resonance imaging seems to be a promising tool for monitoring the response to CRT., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Our objective was evaluate the outcome of primary clinical T4M0 extraperitoneal rectal cancer treated by neoadjuvant radiochemotherapy. Prognosis of clinical T4 rectal cancer is poor. Preoperative chemoradiation therapy may be beneficial. The results obtained are unclear due to lack of objective and strictly applied staging methods., Methods: Patients with primary, clinical, T4MO, extraperitoneal rectal cancer, defined by transrectal ultrasonography, computed tomography or magnetic resonance imaging, were considered. Intraoperative radiotherapy and adjuvant chemotherapy were employed in some patients after curative resection (R0). Variables influencing the possibility to perform an R0 resection and a sphincter-saving procedure were investigated as predictors of outcome., Results: 100 patients were included. R0 resection was performed in 78 patients. R0 resection rate was greater in females (93% vs 67%) and in responders to neoadjuvant chemoradiation (94% vs 60%). The ability to perform a sphincter-saving procedure was 57%, greater in middle rectal location (85% vs 51%) and in responders to the chemoradiation (70% vs 47%). Median follow-up was 31 months (range, 4-136). Local recurrences were found in 7 patients (10%). Five-year local control in R0 patients was 90% and better in the IORT group (100%). Distant relapse occurred in 24 patients (30%). Five-year overall survival was 59%, and was better after an R0 versus an R1 or R2 resection (68% vs 22%). Overall and disease free survival in R0 patients improved after overall downstaging. Adjuvant chemotherapy given in addition to the neoadjuvant therapy did not appear to offer benefit in improving survival., Conclusion: A multimodal approach enabled us to obtain a 5-year overall survival of about 60%. IORT increased local control. The role of adjuvant chemotherapy needs to be further investigated.

Purpose: In the literature, a favorable prognosis was observed for complete pathologic response after preoperative therapy (ypCR) in patients with locally advanced rectal cancer. The aim of this study is to verify whether ypCR predicts a favorable outcome in a large series of patients., Methods and Materials: The Gastro-Intestinal Working Group of the Italian Association of Radiation Oncology collected clinical data for 566 patients with ypCR (ypT0N0) after neoadjuvant therapy. Eligibility criteria included locally advanced rectal cancer with no evidence of metastases at the time of diagnosis, evidence of ypCR after preoperative radiotherapy +/- chemotherapy (CT)., Results: Median radiation dose was 50 Gy. A total of 527 patients (93%) received one of 12 different neoadjuvant CT schedules. Sphincter preservation, anteroposterior resection, and endoscopic surgery were performed in 73%, 22%, and 5% of patients, respectively. Adjuvant CT was administered to 22% of patients. Median follow-up was 46.4 months. Locoregional recurrence occurred in 7 patients (1.6%). Distant metastases occurred in 49 patients (8.9%). Overall, 5-year rates of disease-free survival, overall survival, and cancer-specific survival were 85%, 90%, and 94%, respectively. In multivariate analysis, only age and clinical stage statistically correlated with survival outcome. Adjuvant CT was still of borderline significance (worse for adjuvant CT). No relation was found between survival and neoadjuvant CT schedules., Conclusion: A ypCR after neoadjuvant therapy identified a favorable group of patients, even in this large series of 566 patients collected in 61 centers. Locoregional recurrence occurred only in 1.6% patients.

When the surgeon analyzes the ongoing literature on the evidence of the neoadjuvant approaches to rectal cancer finds a true paradox: from one side they seem to offer a relative less relevant contribute through the time, in fact whereas in the Swedish trial preoperative radiation yielded a significant improvement of local control and survival, after the introduction of TME the contribution of preoperative chemoradiation is relegate to local control with no or poor influence on survival, even if the absolute 5-year survival rate moved from 40% of the '70 to 60-65% of the latest years. From other side the growing evidence of an incidence of pCR approaching to 30%, seems to identify a subset of patients with more favourable prognosis to neoadjuvant treatments. Furthermore, the overall evidence that 30-35% of rectal cancer patients treated with multimodality therapy still die from cancer namely by distant metastases in spite of the 4-8% of absolute benefit of adjuvant 5Fu based adjuvant chemotherapy, seems to vanish the efforts of the further optimization of the local treatments (surgery and radiotherapy) and of the ongoing modality of delivery the chemotherapeutic agents. We would like to address the main evidences from the literature and the main uncertainties that the surgeon could face to propose a combined treatment to his rectal cancer patient.

Correlation between pathological response of primary tumour and mesorectal lymph node involvement was prospectively evaluated to assess the role of local excision (LE) in rectal cancer after complete response to neoadjuvant treatment. A series of 272 consecutive rectal cancer, submitted to neoadjuvant radiochemotherapy (RCT) and surgery with total mesorectal excision (TME) were analysed. Tumour downstaging (pT) and tumour regression grade (TRG) together with sex, age, location of the tumour, pre-treatment clinical stage, type of chemoradiation and operation performed entered in an univariate and multivariate analysis. Pathological complete response on primary tumour was found in 56 patients (20.6%). Lymph node metastases were found in 72 patients (26.5%). The rate of positive nodes was 1.8% for pT0 and TRG1 cases, respectively, to go up to 6.3% for pT1 and 24.1% for TRG 2 cases, respectively. At the univariate analysis, factors with a statistically significant correlation with the risk of lymph node metastasis were: clinical pre-treatment N stage (p<0.05), pT stage (p<0.001) and TRG (p<0.001). At the multivariate analysis, the best predictors of pathologic lymph node involvement were pT stage (p=0.0013 ) and TRG (p=0.0011). Because LE is an adequate technique to assess the tumour pathological response and nodal involvement in pT0 or TRG1 cases seems extremely infrequent, radical resection is probably not justified after pathological complete response. Prospective randomized trials are necessary to establish if, in these cases, LE can guarantee the same oncologic results offered by the currently adopted protocols of RCT followed by radical resections.

Background: Neoplastic microfoci have frequently been found in the mesorectum, with poor outcome. In this study, incidence and clinical significance of mesorectal microfoci (MMF) were analyzed in patients operated on for rectal cancer following neoadjuvant chemoradiation., Methods: A case series of 68 patients with extraperitoneal rectal cancer treated with neoadjuvant chemoradiation and surgery (including total mesorectal excision) were investigated for presence of neoplastic MMF., Results: MMF were found in 26 cases (38.2%). Increasing incidence of microfoci was statistically related to pathologic involvement of the bowel wall (P = 0.0006), Mandard's tumor regression grading (P = 0.0006), and pathologic neoplastic mesorectal involvement (P < 0.00001). None of the nine patients with complete tumor disappearance displayed both microfoci and lymph node metastasis. Only one local recurrence developed in a patient with multiple MMF. One out of nine pT0 or TRG1 patients (11.1%) had distant metastases compared with 15 out of 59 pT1-4 or TRG2-5 (25.4%, P = 0.70)., Conclusions: A remarkable incidence of MMF was found following chemoradiation. However, when this therapy induced complete regression of primary tumor (pT0-TRG1), we found that node metastases and neoplastic MMF also disappeared. These features should be confirmed to assess the impact of these microfoci in treatment decision making in rectal cancers.

Purpose: This study was designed to evaluate long-term outcome in locally advanced resectable extraperitoneal rectal cancer treated by preoperative radiochemotherapy., Methods: Eighty-three consecutive patients who developed locally advanced resectable extraperitoneal rectal cancer underwent preoperative concomitant radiochemotherapy followed by surgery, including total mesorectal excision., Results: Median follow-up was 108 (range, 10-169) months. The living patients underwent complete follow-up of, at least, nine years. Fourteen patients developed local recurrence. The time to detection was longer than two years in eight cases and longer than five years in four. Twenty-one patients developed metastases, 19 within the first five years from surgery. At the univariate analysis, clinical stage at presentation, lymph node involvement at clinical restaging after neoadjuvant therapy, and pT and pN stage were found positively correlated to the incidence of metastases. At the multivariate analysis, the only factors which confirmed a positive correlation were pT stage and pN stage. The actuarial overall survival at five, seven, and ten years was 75.5, 67.8, and 60.4 percent, respectively. The same figures for cancer-related survival were 77.9, 70, and 65.8 percent. At the univariate analysis, factors directly correlated with worse survival were: TNM stage at clinical restaging after neoadjuvant therapy (in particular lymph node involvement) pTNM, pT, and pN. At the multivariate analysis the only factors that confirmed a correlation with worse survival were pTNM, pT, and pN., Conclusions: Long- term follow-up allows to individuate 28 percent of all local relapses after the first five years from surgery. Postoperative stage is highly predictive of prognosis.

Background: Improving the response to preoperative therapy may increase the likelihood of successful resection of locally advanced rectal cancers. Historically, the pathologic complete response (pCR) rate has been < approximately 10% with preoperative radiation therapy alone and < approximately 20% with concurrent chemotherapy and radiation therapy., Methods and Materials: Thirty-seven patients were enrolled on a prospective Phase I/II protocol conducted jointly at Washington University, St. Louis and the Catholic University of the Sacred Heart, Rome evaluating a three-dimensionally (3D) planned boost as part of the preoperative treatment of patients with unresectable or recurrent rectal cancer. Preoperative treatment consisted of 4500 cGy in 25 fractions over 5 weeks to the pelvis, with a 3D planned 90 cGy per fraction boost delivered once or twice a week concurrently (no time delay) with the pelvic radiation. Thus, on days when the boost was treated, the tumor received a dose of 270 cGy in one fraction while the remainder of the pelvis received 180 cGy. When indicated, nonaxial beams were used for the boost. The boost treatment was twice a week (total boost dose 900 cGy) if small bowel could be excluded from the boost volume, otherwise the boost was delivered once a week (total boost dose 450 cGy). Patients also received continuous infusion of 5-fluorouracil (1500 mg/m(2)-week) concurrently with the radiation as well as postoperative 5-FU/leucovorin., Results: All 37 patients completed preoperative radiotherapy as planned within 32--39 elapsed days. Twenty-seven underwent proctectomy; reasons for unresectability included persistent locally advanced disease (6 cases) and progressive distant metastatic disease with stable or smaller local disease (4 cases). Actuarial 3-year survival was 82% for the group as a whole. Among resected cases the 3-year local control and freedom from disease relapse were 86% and 69%, respectively.Twenty-four of the lesions (65%) achieved an objective clinical response by size criteria, including 9 (24%) with pCR at the primary site (documented T0 at surgery). The most important factor for pCR was tumor volume: small lesions with planning target volume (PTV) < 200 cc showed a 50% pCR rate (p = 0.02). There were no treatment associated fatalities. Nine of the 37 patients (24%) experienced Grade 3 or 4 toxicities (usually proctitis) during preoperative treatment. There were an additional 7 perioperative and 2 late toxicities. The most important factors for small bowel toxicity (acute or late) were small bowel volume (> or = 150 cc at doses exceeding 4000 cGy) and large tumor (PTV > or = 800 cc). For rectal toxicity the threshold is PTV > or = 500 cc., Conclusion: 3D planned boost therapy is feasible. In addition to permitting the use of nonaxial beams for improved dose distributions, 3D planning provides tumor and normal tissue dose-volume information that is important in interpreting outcome. Every effort should be made to limit the treated small bowel to less than 150 cc. Tumor size is the most important predictor of response, with small lesions of PTV < 200 cc most likely to develop complete responses.