The neoadjuvant rectal score and a novel magnetic resonance imaging based neoadjuvant rectal score are stage independent predictors of long-term outcome in locally advanced rectal cancer.

AIM: Neoadjuvant rectal (NAR) score is an early surrogate for longer-term outcomes in rectal cancer undergoing radiotherapy and resection. In an era of increasing organ preservation, resection specimens are not always available to calculate the NAR score. Post-treatment magnetic resonance imaging (MRI) re-staging of regression is subjective, limiting reproducibility. We explored the potential for a novel MRI-based NAR score (mrNAR) adapted from the NAR formula. METHODS: Locally advanced rectal cancer patients undergoing neoadjuvant therapy (nCRT) and surgery were retrospectively identified between 2008 and 2020 in a single cancer network. mrNAR was calculated by adapting the NAR formula, replacing pathological (p) stages with post-nCRT MR stages (ymr). Cox regression assessed relationships between clinicopathological characteristics, NAR and mrNAR with overall survival (OS) and recurrence-free survival (RFS). RESULTS: In total, 381 NAR and 177 mrNAR scores were calculated. On univariate analysis NAR related to OS (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.33-3.14, p = 0.001) and RFS (HR 2.52, 95% CI 1.77-3.59, p = 0.001). NAR 3-year OS <8 was 95.3%, 8-16 was 88.6% and >16 was 80%. mrNAR related to OS (HR 2.96, 95% CI 1.38-6.34, p = 0.005) and RFS (HR 2.99, 95% CI 1.49-6.00, p = 0.002). 3-year OS for mrNAR <8 was 96.2%, 8-16 was 92.4% and >16 was 78%. On multivariate analysis, mrNAR was a stage-independent predictor of OS and RFS. mrNAR corresponded to NAR score category in only 15% (positive predictive value 0.23) and 47.5% (positive predictive value 0.48) of cases for categories <8 and >16, respectively. CONCLUSIONS: Neoadjuvant rectal score is validated as a surrogate end-point for long-term outcomes. mrNAR categories do not correlate with NAR but have stage-independent prognostic value. mrNAR may represent a novel surrogate end-point for future neoadjuvant treatments that focus on organ preservation.

Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME-RT).

BACKGROUND: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response. METHODS: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m2 oxaliplatin, 350 mg folinic acid and 400 mg/m2 bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m2 5-FU infusion over 46-48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m2 twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease. DISCUSSION: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020).

C-reactive protein as a predictor of postoperative infective complications after curative resection in patients with colorectal cancer.

BACKGROUND: Infective complications particularly in the form of surgical site infections including anastomotic leak represent a serious morbidity after colorectal cancer surgery. Systemic inflammation markers, including C-reactive protein (CRP) and white cell count, have been reported to provide early detection. However, their relative predictive value is unclear. The aim of the present study was to examine the diagnostic accuracy of serial postoperative WCC, albumin and CRP in detecting infective complications. METHODS: White cell count, albumin and CRP were measured postoperatively for 7 days in 454 consecutive patients undergoing surgery for colorectal cancer. All postoperative complications were recorded. The diagnostic accuracy of the white cell count, albumin and CRP values were analyzed by receiver operating characteristics curve analysis with surgical site infective complications as outcome measures. RESULTS: One hundred four patients (23 %) developed infective complications, and 26 of them developed an anastomotic leak. CRP was most sensitive to the development of an infective complication, surgical site or at a remote site. On postoperative day 3 CRP the area under the receiver operating characteristic curve was 0.80 (p < 0.001) and the optimal cutoff value was 170 mg/L. This threshold was also associated with an increase in the length of hospital stay (p < 0.001), 30 day mortality (p < 0.05) and 12 month mortality (p < 0.10). CONCLUSIONS: Postoperative CRP measurement on day 3 postoperatively is clinically useful in predicting surgical site infective complications, including an anastomotic leak, in patients undergoing surgery for colorectal cancer.

The impact of perioperative risk, tumor pathology and surgical complications on disease recurrence following potentially curative resection of colorectal cancer.

OBJECTIVE: The objective of the study was to identify determinants of disease recurrence after potentially curative resection of colorectal cancer. SUMMARY BACKGROUND DATA: The identification of patients at increased risk of disease recurrence is currently based on pathological factors. Recently, there has been considerable interest in the potential impact of perioperative factors on long-term colorectal cancer outcome. Few studies have examined pre-, intra-, and postoperative variables in a single cohort. METHODS: Four hundred and twenty-three patients with histologically confirmed colorectal cancer who underwent surgery with curative intent between 1997 and 2007 were included. Pre-, intra-, and postoperative variables were recorded. Logistic and Cox regression analyses were performed to identify predictors of surgical complications and disease recurrence, respectively. RESULTS: The postoperative mortality rate was 4% and the morbidity rate 34%. The most important predictors of complications were smoking (odd ratio [OR] 1.32), ASA grade (OR 1.90) and POSSUM operative score (OR 1.32). During follow up (median 80 months), 35% of patients developed disease recurrence. Predictors of recurrence, independent of tumor stage, were POSSUM physiology score (hazard ratio [HR] 1.31) and systemic inflammatory response (HR 1.31). CONCLUSIONS: Preoperative risk factors, but not postoperative complications, are associated with early disease recurrence after potentially curative resection of colorectal cancer.