Local excision in rectal cancer patients with major or complete clinical response after neoadjuvant therapy: a case-matched study.

PURPOSE: To assess the long-term oncological outcomes in patients with locally advanced rectal cancer who underwent neoadjuvant therapy followed by local or total mesorectal excision. METHODS: Patients with locally advanced rectal adenocarcinoma who received neoadjuvant therapy from 2005 to 2017 were evaluated. Those with major or complete clinical response underwent a full-thickness local excision. Kaplan-Meier estimates were used to evaluate overall, disease-free, and local recurrence-free survival of patients who underwent local excision (LE group) and were compared with a matched cohort of patients who underwent total mesorectal excision (TME group). RESULTS: Among 252 patients who received neoadjuvant therapy for rectal cancer, 51 (20.2%) underwent a local excision. At a median follow-up of 61 months, patients who underwent local excision were stoma-free in 88.2% of cases and with rectum preserved in 78.5% of cases, respectively. The estimated 5-year local, disease-free, and overall survival was 91.8% vs 97.6% (95% CI: 79.5-96.8 vs 84.6-99.6), 86.7% vs 86.4% (95% CI: 72.5-93.9 vs 70.1-94.1), and 85% vs 90% (95% CI: 69.0-93.0% vs 75.3-96.2), in the study and matched control group, respectively. None of the differences was statistically significant. CONCLUSIONS: One-fifth of patients with locally advanced rectal cancer are manageable with a rectum-sparing approach after neoadjuvant therapy. With this strategy, about 80% patients will have their rectum preserved and 90% will be without stoma at long term.

Multicentre randomized clinical trial of colonic J pouch or straight stapled colorectal reconstruction after low anterior resection for rectal cancer.

BACKGROUND: Colonic J pouch reconstruction has been found to be associated with a lower incidence of anastomotic leakage than straight anastomosis. However, studies on this topic are underpowered and retrospective. This randomized trial evaluated whether the incidence of anastomotic leakage was reduced after colonic J pouch reconstruction compared with straight colorectal anastomosis following anterior resection for rectal cancer. METHODS: This multicentre RCT included patients with rectal carcinoma who underwent low anterior resection followed by colorectal anastomosis. Patients were assigned randomly to receive a colonic J pouch or straight colorectal anastomosis. The main outcome measure was the occurrence of major anastomotic leakage. The incidence of global (major plus minor) anastomotic leakage and general complications were secondary outcomes. Risk factors for anastomotic leakage were identified by regression analysis. RESULTS: Of 457 patients enrolled, 379 were evaluable (colonic J pouch arm 190, straight colorectal arm 189). The incidence of major and global anastomotic leakage, and general complications was 14·2, 19·5 and 34·2 per cent respectively in the colonic J pouch group, and 12·2, 19·0 and 27·0 per cent in the straight colorectal anastomosis group. No statistically significant differences were observed between the two arms. In multivariable logistic regression analysis, male sex (odds ratio 1·79, 95 per cent c.i. 1·02 to 3·15; P = 0·042) and high ASA fitness grade (odds ratio 2·06, 1·15 to 3·71; P = 0·015) were independently associated with the occurrence of anastomotic leakage. CONCLUSION: Colonic J pouch reconstruction does not reduce the incidence of anastomotic leakage and postoperative complications compared with conventional straight colorectal anastomosis. Registration number NCT01110798 (http://www.clinicaltrials.gov).

Metastatic pattern and new primary tumours after neoadjuvant therapy and surgery in rectal cancer.

AIM: Current follow-up guidelines for distant tumour recurrence after rectal cancer surgery are not defined or agreed. The aim was to elucidate the pattern of recurrence over time and provide information that could help direct a strategy for surveillance. METHOD: In all, 378 patients with locally advanced rectal cancer were treated with preoperative chemoradiotherapy and surgery with curative intent. Patients were followed up with a standard protocol, and data were prospectively collected in a dedicated database. Disease-free survival and overall survival were calculated. RESULTS: Within a median follow-up time of 75 months, rates of local and distant recurrence were 2.6% and 21.7%, respectively. Risk factors for recurrence were a baseline carcinoembryonic antigen > 5.0 ng/ml, a distance from the anal verge ≤ 5 cm, R1 resection margins, G3 grading, ypT staging > 2, positive lymph node status and a tumour regression grade of 3-5. Disease-free survival did not vary significantly between patients with lung and extra-pulmonary metastases (P = 0.59). The only factor associated with increased risk of lung metastases was a distance of the tumour from the anal verge of ≤ 5 cm (P = 0.01). Most recurrences occurred within the first 3 years after surgery (74.4%). The first site of recurrence was most frequently the lung (52.0%). The most frequent new primary malignancy was lung cancer (22.5%). CONCLUSIONS: Patients undergoing curative therapy for rectal cancer often experience distant recurrence; the majority of recurrences occur within the first 3 years after surgery and lung metastases are the most common. A predictive factor for pulmonary recurrence is a tumour in the lower rectum.

T1 colon cancer in the era of screening: risk factors and treatment.

BACKGROUND: The aim of this study was to identify risk factors for lymph node positivity in T1 colon cancer and to carry out a surgical quality assurance audit. METHODS: The sample consisted of consecutive patients treated for early-stage colon lesions in 15 colorectal referral centres between 2011 and 2014. The study investigated 38 factors grouped into four categories: demographic information, preoperative data, indications for surgery and post-operative data. A univariate and multivariate logistic regression analysis was performed to analyze the significance of each factor both in terms of lymph node (LN) harvesting and LN metastases. RESULTS: Out of 507 patients enrolled, 394 patients were considered for analysis. Thirty-five (8.91%) patients had positive LN. Statistically significant differences related to total LN harvesting were found in relation to central vessel ligation and segmental resections. Cumulative distribution demonstrated that the rate of positive LN increased starting at 12 LN harvested and reached a plateau at 25 LN. CONCLUSIONS: Some factors associated with an increase in detection of positive LN were identified. However, further studies are needed to identify more sensitive markers and avoid surgical overtreatment. There is a need to raise the minimum LN count and to use the LN count as an indicator of surgical quality.

Clinical and molecular features of attenuated adenomatous polyposis in northern Italy.

BACKGROUND: Attenuated familial adenomatous polyposis (AFAP) is characterized by the presence of 10-99 colorectal adenomas. The disease may be associated with mutations in either APC or MUTYH genes. We purposed to evaluate the contribution of adenomatous polyposis coli (APC) and MutY homologue (MUTYH) germline alterations to the AFAP phenotype and to identify genotype/phenotype correlations. METHODS: During counselling for familial adenomatous polyposis (FAP), 91 probands (and 107 affected individuals) who met the criteria of AFAP were identified. Eighty-two families were screened for constitutional mutations of the APC and MUTYH genes. RESULTS: MUTYH mutations were detected in 21 families (25.6 % of the 82 tested), and APC mutations in 7 (8.5 %). Overall, constitutional alterations were found in 34.1 % of the probands. Patients with APC mutations were younger at cancer onset and had a higher mean number of polyps (48.5 ± 33.0 in APC+ individuals vs. 35.7 ± 24.9 in MUTYH+ individuals, and 33.2 ± 18.4 in the "no mutation" group). Clinical features rendered the "no mutation" group closer to MUTYH+ than to the APC+ group. Colorectal cancer at diagnosis was detected in 40 % of AFAP individuals. CONCLUSIONS: AFAP is a new clinical entity with its frequency in the general population still undefined. The number of adenomas varies greatly, with an average of 30-40 lesions. The molecular basis of AFAP can be established in approximately 1/3 of the patients. Both MUTYH and APC genes are implicated in AFAP, though the role of MUTYH is of considerably greater relevance.

A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer.

BACKGROUND: Oxaliplatin (OXA) significantly enhanced the antitumour activity of 5-fluorouracil (FUra) in patients with advanced colorectal cancer and displayed radiosensitising properties in preclinical studies. This study was thus performed to test the feasibility, identify the recommended doses (RDs) and explore preliminarily the clinical activity of weekly OXA and infused FUra combined with preoperative pelvic radiotherapy. PATIENTS AND METHODS: Forty-six patients with recurrent or locally advanced (cT3-4 and/or N+) adenocarcinomas of the mid-low rectum were treated with escalating doses of OXA (25, 35, 45, 60 mg/m2, weekly for 6 weeks) and FUra (200-225 mg/m2/day, 6-week infusion) concurrent to preoperative pelvic radiotherapy (50.4 Gy/28 fractions). The RDs for the phase II part of the study were immediately below the level resulting in dose-limiting toxicities in more than one third of the patients, or corresponded to the last planned dose level. RESULTS: In the escalation phase, dose-limiting toxicities only occurred in one patient at the fourth level and one of six patients treated at the last planned dose level (grade III diarrhoea). OXA 60 mg/m2 and FUra 225 mg/m2/day are therefore the RDs for the regimen. Among 25 patients globally treated at these doses (phase II part), the incidence of grade III diarrhoea was 16% with no grade IV toxicity. Neurotoxicity did not exceed grade II (12%). All patients completed radiotherapy and were operated on as scheduled. Twenty-one of 25 patients had the tumour down-staged after chemoradiation with seven (28%) pathological complete responses and 12 (48%) residual tumours limited to ypT1-2N0. CONCLUSIONS: Weekly OXA, at doses potentially active systemically, can be combined with full-dose, infused FUra and radiotherapy. Given the low toxicity and promising activity, this regimen is being compared to standard FUra-based pelvic chemoradiation in a randomised study.