Endoscopic resection of residual rectal neoplasia after definitive chemoradiotherapy for rectal cancer.

The conventional approach to treating locally advanced rectal cancer, commonly defined as cT3 or cT4 primary tumors or with nodal metastases, involves chemoradiation (CRT) followed by surgical resection. There is a growing recognition of the potential for nonsurgical management following CRT or total neoadjuvant therapy (TNT), which allows for organ preservation. "Watch and wait" strategy may be considered if complete clinical response is achieved. In cases when adenoma or superficial cancer is present, a novel approach known as "salvage endoscopic resection of the residual disease" is emerging as a viable nonsurgical option for carefully selected patients. This review discusses available evidence and future potential for endoscopic management of residual neoplasia after oncological treatment of rectal cancer.

Which tumour factors preclude organ preservation in patients with rectal cancer?

BACKGROUND: cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes, extramural vascular invasion (EMVI) and mesorectal fascia threatening (MRF+) have been utilized as exclusion criteria in several studies on the watch-and-wait (w&w) strategy. Here, our aim was to validate these criteria through a post hoc analysis of two pooled prospective studies on w&w following routine radio(chemo)therapy. METHODS: A review of baseline magnetic resonance imaging was performed in a subgroup of 223 patients treated at a single institution. Of these, 17.9 % started w&w, 12.6 % achieved clinical complete response (cCR) and 9.0 % sustained cCR during median follow-up of 54 months. RESULTS: The multivariable logistic analysis showed that the proportion of circumferential bowel involvement and EMVI significantly influenced the chance of sustained cCR; odds ratios were 0.063 (95 % confidence interval [CI] 0.008-0.489, p = 0.008), and 0.109 (95 % CI 0.014-0.850, p = 0.034), respectively. Sustained cCR was observed in none of the 57 patients with 90 %-100 % circumferential bowel involvement and in only one of the 89 patients with EMVI. In contrast, cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes or MRF+ were not independently associated with sustained cCR. Among the subgroups of patients with these features but without (near-)circular tumour or EMVI+, sustained cCR was observed in 12 %-25 % of patients. CONCLUSION: Sustained cCR after routine preoperative radio(chemo)therapy is unlikely in patients with (near-)circular tumour or EMVI, whereas patients with cT3cdT4, cN2, mesorectal nodes > 8 mm, clinically positive lateral nodes and MRF+ should not be denied w&w.

The ultimate local failure rate after the watch-and-wait strategy for rectal cancer: a systematic review of literature and meta-analysis.

BACKGROUND: We hypothesise that a high rate of tumour regrowth after the watch-and-wait (w&w) strategy may lead, despite salvage surgery, to a significant impairment of ultimate local control compared with immediate surgery. MATERIALS AND METHODS: To test this hypothesis, we conducted meta-analyses of studies on the w&w strategy (both opportunistic and planned) with an ultimate local failure rate as an endpoint in three patient groups: (1) in all starting radio(chemo)therapy as potential w&w candidates, (2) in a subgroup starting w&w, and (3) in a subgroup with regrowth. RESULTS: We identified eight studies for evaluation of local failure in group 1 (N = 837) and 36 studies in group 2 (N = 1914) and in group 3 (N = 439). The meta-analysis revealed an ultimate local failure rate of 8.0% (95% CI 4.8%-12.1%) in group 1 and 5.4% (95% CI 3.9%-7.1) in group 2. These rates are similar to those reported in the literature following preoperative chemoradiation and surgery. However, in the most unfavourable group 3 (with regrowth), the rate of ultimate local failure was 24.1% (95% CI 17.9%-30.9%), with the most common causes being patients' refusal of salvage total mesorectal excision (TME) (9.1%), recurrence after salvage TME (7.8%), distant metastases (4.1%), frailty (2.4%), and pelvic tumour unresectability (1.7%). CONCLUSION: Nearly 25% of patients with regrowth (unfavourable subgroup) experienced ultimate local failure, primarily due to refusing salvage TME. The risk of ultimate local failure in patients initiating radio(chemo)therapy as potential w&w candidates, or in patients starting w&w, appears comparable to that reported after preoperative chemoradiation and surgery. However, this comparison may be biased, because w&w studies included more early tumours compared with surgical studies.

pCR and 2-Year Disease-Free Survival: A Combination of the Two Endpoints as a New Classification for Locally Advanced Rectal Cancer Patients-An Updated Pooled Analysis of Eleven International Randomized Trials.

LARC is managed by multimodal treatments whose intensity can be highly modulated. In this context, we need surrogate endpoints to help predict long-term outcomes and better personalize treatments. A previous study identified 2yDFS as a stronger predictor of OS than pCR in LARC patients undergoing neoadjuvant RT. The aim of this pooled analysis was to assess the role of pCR and 2yDFS as surrogate endpoints for OS in a larger cohort. The pooled and subgroup analyses were performed on large rectal cancer randomized trial cohorts who received long-course RT. Our analysis focused on the evaluation of OS in relation to the pCR and 2-year disease status. A total of 4600 patients were analyzed. Four groups were identified according to intermediate outcomes: 12% had both pCR and 2yDFS (the better); 67% achieved 2yDFS but not pCR (the good); 1% had pCR but not 2yDFS; and 20% had neither pCR nor 2yDFS (the bad). The pCR and 2yDFS were favorably associated with OS in the univariate analysis, and 2yDFS maintained a statistically significant association in the multivariate analysis independently of the pCR status. The combination of the pCR and 2yDFS results in a strong predictor of OS, whereas failure to achieve 2yDFS carries a poor prognosis regardless of the pCR status. This new stratification of LARC patients could help design predictive models where the combination of 2yDFS and pCR should be employed as the primary outcome.

Does the Gain of Total Neoadjuvant Therapy Outweigh the Harm in Rectal Cancer? Importance of the ATRESS (neoAdjuvant Therapy-RElated Shortening of Survival) Phenomenon: A Systematic Review.

BACKGROUND: We aimed to evaluate whether total neoadjuvant therapy (TNT) results in long-term overall survival (OS) or quality of life (QoL) benefit compared with chemoradiation if all patients are being considered for radical resection, and whether the ATRESS phenomenon (i.e., reduction in post-metastatic survival) impacts OS after TNT. METHODS: Systematic review of randomised trials comparing TNT with neoadjuvant (chemo)radiation. RESULTS: Six trials were identified. Follow-ups were too short to resolve whether TNT improves long-term OS. QoL analysis in one trial showed worse long-term neurotoxicity-related QoL (any neurotoxicity: 14% vs. 3%), higher rate of grade III+ acute toxicity (48% vs. 25%), longer duration of neoadjuvant treatment (19 vs. 6 weeks) and higher rate of locoregional failure (10% vs. 7%) in TNT vs. chemoradiation. This should be weighed against an absolute 8% reduction in the incidence of distant metastases (DM) after TNT. ATRESS could explain a discrepancy between reduction of DM and the absence of OS improvement after TNT in one trial. CONCLUSION: In the light of unproven OS benefit, the gain of TNT (reduction of DM) does not seem to outweigh the harm (excess of toxicity). ATRESS can be a reason for the absence of the OS benefit despite the reduction in DM.

The importance of measuring baseline tumour volume (or alternatively tumour length along with its rectal circumferential extent) in the watch-and-wait strategy in rectal cancer: a review.

BACKGROUND: The impact of the tumour volume or size on achieving clinical complete response (cCR) after radio(chemo)therapy is poorly understood. MATERIALS AND METHODS: A literature search was performed to gather data on the predictive value of baseline tumour volume or size in achieving cCR. RESULTS: In total, nine reports were identified. In two of three studies evaluating the baseline tumour volumetry, the tumour volume was the most powerful predictor for cCR. In four of six studies evaluating baseline tumour size without volumetry, tumour dimension was significantly associated with cCR, in one study reached borderline significance and in one report was insignificant. In three of four studies where a multivariable analysis was performed, the cT category did not show an independent predictive value for cCR. Because the tumour shape is often (semi)annular, its circumferential rectal extent along with the tumour length probably impact the tumour volume most, and thus, could be considered an acceptable alternative for time-consuming volumetry. CONCLUSIONS: Our review suggests that baseline tumour volume (or alternatively, tumour length along with its circumferential rectal extent) is the most relevant clinical predictor of cCR. Therefore, we postulate assessing and reporting these parameters in studies on the watch-and-wait strategy.

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.

International consensus recommendations on key outcome measures for organ preservation after (chemo)radiotherapy in patients with rectal cancer.

Multimodal treatment strategies for patients with rectal cancer are increasingly including the possibility of organ preservation, through nonoperative management or local excision. Organ preservation strategies can enable patients with a complete response or near-complete clinical responses after radiotherapy with or without concomitant chemotherapy to safely avoid the morbidities associated with radical surgery, and thus to maintain anorectal function and quality of life. However, standardization of the key outcome measures of organ preservation strategies is currently lacking; this includes a lack of consensus of the optimal definitions and selection of primary end points according to the trial phase and design; the optimal time points for response assessment; response-based decision-making; follow-up schedules; use of specific anorectal function tests; and quality of life and patient-reported outcomes. Thus, a consensus statement on outcome measures is necessary to ensure consistency and facilitate more accurate comparisons of data from ongoing and future trials. Here, we have convened an international group of experts with extensive experience in the management of patients with rectal cancer, including organ preservation approaches, and used a Delphi process to establish the first international consensus recommendations for key outcome measures of organ preservation, in an attempt to standardize the reporting of data from both trials and routine practice in this emerging area.

Watch-and-wait strategy in rectal cancer: Is there a tumour size limit? Results from two pooled prospective studies.

BACKGROUND: Frequency and predictive factors for a clinical complete response (cCR) in unselected patients are unclear. MATERIAL AND METHODS: Two prospective observational studies were designed and pooled to explore predictive factors for cCR. Both studies evaluated the watch-and-wait strategy in consecutive patients; the first single-institutional study in elderly with a small tumour, the second multi-institutional study in all the patients receiving standard of care preoperative radiotherapy. RESULTS: Four hundred and ninety patients were analysed. Short-course radiotherapy alone, or with consolidation chemotherapy or chemoradiation was given to 40.6%, 40.2% and 19.2% of the patients, respectively. The median interval from the radiation start to the first tumour response assessment was 10.2 weeks for short-course radiation and 13.2 weeks for chemoradiation. Seventy-three patients had cCR and 71 underwent w&w with the median follow-up of 24 months. The regrowth rate was 26.8%. cCR rate was 39.0% for low-risk cancer (cT1-2N0), 16.8% for intermediate-risk (cT3 with unthreatened mesorectal fascia [MRF-] or cT2N+) and 5.4% for high-risk (cT4 or MRF+). In the multivariable analysis, tumour volume (or tumour length and circumferential extent) and cN status were significant predictors for cCR. In circular cancers or with a length ≥7 cm (n = 184), cCR rate was only 2.7%, sustained cCR 1.6% and the sensitivity of cCR diagnosis 23.1%. None of 27 patients with a tumour larger than 120 cm3 achieved cCR. CONCLUSIONS: Considering watch-and-wait strategy is questionable in patients with circular tumours or with tumour length ≥7 cm.

Should Short-Course Neoadjuvant Radiation Therapy Be Applied for Low-Lying Rectal Cancer? A Systematic Review and Meta-Analysis of the Randomized Trials.

PURPOSE: National Comprehensive Cancer Network guidelines recommend either long-course chemoradiation (LC) or short-course radiation (SC, 5 × 5 Gy) for rectal cancer before total mesorectal excision. However, they do not recommend SC for low-lying tumors. As early toxicity of SC is lower than that of LC, and postoperative complications as well as late toxicity are similar, the probable reason is a notion that for low-lying tumors LC may be more effective than SC in assuring local control. METHODS AND MATERIALS: A systematic review and meta-analysis of the randomized trials comparing SC with LC was performed to test the hypothesis that for low-lying tumors, LC is superior to SC in reducing the risk of local failure. RESULTS: The systematic search identified 4 trials including, in total, 421 patients with tumors <5 cm from the anal verge; 221 were randomized to SC and 200 to LC. The meta-analysis showed that the difference in local failure rate between SC and LC was insignificant; the pooled odds ratio was 0.87, 95% confidence interval 0.53 to 1.44, P = .59. Heterogeneity between trials was insignificant; I2 = 0.0%, P = .47. CONCLUSIONS: Our meta-analysis does not support the notion that LC given before total mesorectal excision is superior to SC in reducing the risk of local failure in low-lying tumors.

Neoadjuvant chemotherapy with or without oxaliplatin after short-course radiotherapy in high-risk rectal cancer: A subgroup analysis from a prospective study.

AIM: To evaluate the role of oxaliplatin in neoadjuvant chemotherapy delivered after short-course irradiation. BACKGROUND: Using oxaliplatin in the above setting is uncertain. PATIENTS AND METHODS: A subgroup of 136 patients managed by short-course radiotherapy and 3 cycles of consolidation chemotherapy within the framework of a randomised study was included in this post-hoc analysis. Sixty-seven patients received FOLFOX4 (oxaliplatin group) while oxaliplatin was omitted in the second period of accrual in 69 patients because of protocol amendment (fluorouracil-only group). RESULTS: Grade 3+ acute toxicity from neoadjuvant treatment was observed in 30% of patients in the oxaliplatin group vs. 16% in the fluorouracil-only group (p = 0.053). The corresponding proportions of patients having radical surgery or achieving complete pathological response were 72% vs. 77% (odds ratio [OR] = 0.88; 95% confidence interval [CI]: 0.39-1.98; p = 0.75) and 15% vs. 7% (OR = 2.25; 95% CI: 0.83-6.94; p = 0.16), respectively. The long-term outcomes were similar in the two groups. Overall and disease-free survival rates at 5 years were 63% vs. 56% (p = 0.78) and 49% vs. 44% (p = 0.59), respectively. The corresponding numbers for cumulative incidence of local failure or distant metastases were 33% vs. 38% (hazard ratio [HR] = 0.89; 95% CI: 0.52-1.52; p = 0.68) and 33% vs. 33% (HR = 0.78; 95% CI: 0.43-1.40; p = 0.41), respectively. CONCLUSION: Our findings do not support adding oxaliplatin to three cycles of chemotherapy delivered after short-course irradiation.

The 2017 Assisi Think Tank Meeting on rectal cancer: A positioning paper.

BACKGROUND AND PURPOSES: To describe current practice in the management of rectal cancer, to identify uncertainties that usually arise in the multidisciplinary team (MDT)'s discussions ('grey zones') and propose next generation studies which may provide answers to them. MATERIALS AND METHODS: A questionnaire on the areas of controversy in managing T2, T3 and T4 rectal cancer was drawn up and distributed to the Rectal-Assisi Think Tank Meeting (ATTM) Expert European Board. Less than 70% agreement on a treatment option was indicated as uncertainty and selected as a 'grey zone'. Topics with large disagreement were selected by the task force group for discussion at the Rectal-ATTM. RESULTS: The controversial clinical issues that had been identified within cT2-cT3-cT4 needed further investigation. The discussions focused on the role of (1) neoadjuvant therapy and organ preservation on cT2-3a low-middle rectal cancer; (2) neoadjuvant therapy in cT3 low rectal cancer without high risk features; (3) total neoadjuvant therapy, radiotherapy boost and the best chemo-radiotherapy schedule in T4 tumors. A description of each area of investigation and trial proposals are reported. CONCLUSION: The meeting successfully identified 'grey zones' and, in the light of new evidence, proposed clinical trials for treatment of early, intermediate and advanced stage rectal cancer.