Preoperative systemic chemotherapy alters the histopathological growth patterns of colorectal liver metastases.

Histopathological growth patterns (HGPs) are a reliable, reproducible, and strong prognostic biomarker that can be assessed on haematoxylin and eosin-stained sections of resected colorectal liver metastases (CRLM). Assessment estimates the relative fraction of the tumour-liver interface for each of the three growth patterns; the desmoplastic HGP reflects good prognosis. Whether preoperative chemotherapy affects the HGP is currently unclear. The present international multicentre study evaluates this in an original cohort of 877 consecutive patients treated in the Netherlands, an external validation cohort of 1,203 consecutive patients treated in the USA, and a post hoc analysis from the phase III randomised controlled European Organization for Research and Treatment of Cancer (EORTC) 40983 trial (n = 70). All patients underwent resection of CRLM with or without preoperative systemic chemotherapy. Trial patients were randomised between perioperative chemotherapy and resection or resection alone. HGPs were determined according to consensus guidelines and compared for preoperative treatment status. Data from three separate tumour regression grading systems were available for the trial cohort. These were correlated with HGP stratified for treatment arm. In the original cohort, the average presence of desmoplastic HGP was 43% for chemo-naïve versus 67% for preoperatively treated patients (p < 0.001). A significant association between chemotherapy and desmoplastic HGP was found on multivariable analysis (ß [95% confidence interval, CI]: 24.57 [18.28-30.87], p < 0.001). In the validation cohort, the average presence of desmoplastic HGP was 40% for chemo-naïve versus 63% for preoperatively treated patients (p < 0.001). This association remained on multivariable analysis (ß [95% CI]: 24.18 [18.70-29.66], p < 0.001). In the EORTC 40983 trial, the average desmoplastic HGP presence was 33% in the resection arm versus 61% in the chemotherapy arm (p = 0.005). Chemotherapy was independently associated with an increase in desmoplastic HGP (ß [95% CI]: 23.29 [1.78-44.79], p = 0.022). All three tumour regression gradings were significantly associated with the desmoplastic HGP in the chemotherapy arm (all p < 0.04). None were associated in the resection arm (all p > 0.11). Preoperative chemotherapy induces histopathological changes that alter the HGP of CRLM.

Pre- and Postoperative Capecitabine Without or With Oxaliplatin in Locally Advanced Rectal Cancer: PETACC 6 Trial by EORTC GITCG and ROG, AIO, AGITG, BGDO, and FFCD.

PURPOSE: The PETACC 6 trial investigates whether the addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative capecitabine improves disease-free survival (DFS) in locally advanced rectal cancer. METHODS: Between November 2008 and September 2011, patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node positive, were randomly assigned to 5 weeks preoperative capecitabine-based chemoradiation (45-50.4 Gy) followed by six cycles of adjuvant capecitabine, both without (control arm, 1) or with (experimental arm, 2) oxaliplatin. The primary end point was improvement of 3-year DFS by oxaliplatin from 65% to 72% (hazard ratio [HR], 0.763). RESULTS: A total of 1,094 patients were randomly assigned (intention to treat), and 1,068 eligible patients started their allocated treatment (arm 1, 543; arm 2, 525), with completion of protocol treatment in 68% (arm 1) v 54% (arm 2). A higher rate of grade 3/4 adverse events was reported in the experimental arm (14.4% v 37.3% and 23.4% v 46.6% for neoadjuvant and adjuvant treatment, respectively). At a median follow-up of 68 months (interquartile range, 58-74 months), 157 and 156 DFS events were observed in arms 1 and 2, respectively (adjusted HR, 1.02; 95% CI, 0.82 to 1.28; P = .835). Three-year DFS rate was not different, with 76.5% (95% CI, 72.7% to 79.9%) in arm 1, which is higher than anticipated, and 75.8% (95% CI, 71.9% to 79.3%) in arm 2. The 7-year DFS and overall survival (OS) rates were not different as well, with DFS of 66.1% v 65.5% (HR, 1.02) and OS of 73.5% v 73.7% (HR, 1.19) in arms 1 and 2, respectively. Subgroup analyses revealed heterogeneity in treatment effect according to German versus non-German site location, without detectable confounding factors in multivariable analysis. CONCLUSION: The addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative adjuvant chemotherapy impairs tolerability and feasibility and does not improve efficacy.

Shanghai international consensus on diagnosis and comprehensive treatment of colorectal liver metastases (version 2019).

The liver is the most common anatomical site for hematogenous metastases from colorectal cancer. Therefore effective treatment of liver metastases is one of the most challenging elements in the management of colorectal cancer. However, there is rare available clinical consensus or guideline only focusing on colorectal liver metastases. After six rounds of discussion by 195 clinical experts of the Shanghai International Consensus Expert Group on Colorectal Liver Metastases (SINCE) from 29 countries or regions, the Shanghai Consensus has been finally completed, based on current research and expert experience. The consensus emphasized the principle of multidisciplinary team, provided detailed diagnosis approaches, and guided precise local and systemic treatments. This Shanghai Consensus might be of great significance to standardized diagnosis and treatment of colorectal liver metastases all over the world.

Author Correction: Deep Learning and Radiomics predict complete response after neo-adjuvant chemoradiation for locally advanced rectal cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Deep Learning and Radiomics predict complete response after neo-adjuvant chemoradiation for locally advanced rectal cancer.

Treatment of locally advanced rectal cancer involves chemoradiation, followed by total mesorectum excision. Complete response after chemoradiation is an accurate surrogate for long-term local control. Predicting complete response from pre-treatment features could represent a major step towards conservative treatment. Patients with a T2-4 N0-1 rectal adenocarcinoma treated between June 2010 and October 2016 with neo-adjuvant chemoradiation from three academic institutions were included. All clinical and treatment data was integrated in our clinical data warehouse, from which we extracted the features. Radiomics features were extracted from the tumor volume from the treatment planning CT Scan. A Deep Neural Network (DNN) was created to predict complete response, as a methodological proof-of-principle. The results were compared to a baseline Linear Regression model using only the TNM stage as a predictor and a second model created with Support Vector Machine on the same features used in the DNN. Ninety-five patients were included in the final analysis. There were 49 males (52%) and 46 females (48%). Median tumour size was 48 mm (15-130). Twenty-two patients (23%) had pathologic complete response after chemoradiation. One thousand six hundred eighty-three radiomics features were extracted. The DNN predicted complete response with an 80% accuracy, which was better than the Linear Regression model (69.5%) and the SVM model (71.58%). Our model correctly predicted complete response after neo-adjuvant rectal chemoradiotherapy in 80% of the patients of this multicenter cohort. Our results may help to identify patients who would benefit from a conservative treatment, rather than a radical resection.

Radiofrequency ablation for colorectal cancer liver metastases initially greater than 25 mm but downsized by neo-adjuvant chemotherapy is associated with increased rate of local tumor progression.

BACKGROUND: Radiofrequency ablation (RFA) is a valid treatment for liver metastases from colorectal cancer (CRLM) smaller than 25 mm and unsuitable for surgical resection. Tumor size is predictive for local tumor progression (LTP). The aim of this study was to evaluate whether RFA is indicated for lesions >25 mm at presentation but <25 mm after chemotherapy. METHOD: Patients who underwent RFA for CRLM after chemotherapy (January 2004-December 2012) were reviewed. Metastases were classified according to their size. Group 1: ≤25 mm before and after chemotherapy. Group 2A: >25 mm before but ≤25 mm after chemotherapy. Group 2B: >25 mm before and after chemotherapy. RESULTS: 133 CRLM were ablated in 83 patients (median follow-up 56 months). At 1-year, the LTP rate was higher in group 2A than in group 1 (32% vs. 16%, p ≤ 0.001). The highest rate of 1-year LTP was 64% in group 2B. Time to LTP (TLTP) was shorter in group 2A than in group 1 (HR: 2.89; 95% CI [1.04-8.01]; p = 0.004). Following multivariate analysis, the group type was the only predictive factor for TLTP (p < 0.001). CONCLUSIONS: RFA is not the optimal treatment for CRLM > 25 mm at presentation.

Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial.

Background: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach. Methods: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n < 10 and no extrahepatic disease) received systemic treatment alone or systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection. Previously, we reported that the primary end point (30-month overall survival [OS] > 38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat. Results: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm. Conclusions: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases.

What can we learn from oncology surgical trials?

Conducting high-quality prospective clinical trials in surgical oncology remains a challenge, and many seemingly well-designed trials lack this high quality because of inadequate recruitment accrual, lack of clinician interest, or evolution of treatment strategy during the many years over which such trials are conducted. In this Perspectives we examine some of the failures in published surgical oncology trials and discuss why they failed, and we make a critical assessment of the established prospective trial methodology in oncological practice (that is, phase 0, I, II, III and IV trials, and large prospective comparative audits) and how these methods might be used more effectively in future evaluation of cancer-surgery practice.

Prognostic impact of immune response in resectable colorectal liver metastases treated by surgery alone or surgery with perioperative FOLFOX in the randomised EORTC study 40983.

AIM: To investigate whether the immune response in colorectal liver metastases is related to progression free survival (PFS) and if this may be influenced by systemic therapy. METHODS: A retrospective central collection of tumour tissue was organised for the European Organisation for Research and Treatment of Cancer (EORTC) study 40983, where patients with colorectal liver metastases were treated by either resection alone or resection with perioperative FOLFOX. Immunostaining on whole slides was performed to recognise T-lymphocytes (CD3+, CD4+, CD8+), B-lymphocytes (CD20+), macrophages (CD68+) and mast cells (CD117+) inside the tumour, at the tumour border (TNI) and in normal liver tissue surrounding the tumour (0.5-2mm from the TNI). Immunological response was compared between treatment arms and correlated to PFS. RESULTS: Tumour tissue and immune response profiles were available for 82 resected patients, 38 in the perioperative chemotherapy arm and 44 in the surgery alone arm. Baseline patient and disease characteristics were similar between the treatment arms. In response to chemotherapy, we observed increased CD3+ lymphocyte and mast cell counts inside the tumour (p<0.01), lower CD4+ lymphocytes in the normal liver tissue (p=0.02) and lower macrophage counts in normal tissue (p<0.01) and at the TNI (p=0.02). High number of CD3+ lymphocyte and mast cells, and high T-cell score were correlated with tumour regression grade (TRG). Prolonged PFS correlated with the presence of mast cells in the tumour (9.8 versus 16.5 months, Hazard ratio (HR) 0.54 p=0.03), higher CD3+ lymphocyte count at the TNI (10.8 versus 22.8 months, HR 0.57, p=0.03) and T-cell score >2 (10.8 versus 38.6 months, HR 0.51, p=0.04). CONCLUSION: Our analyses in the context of a randomised study suggest that chemotherapy influences immune cell profiles, independent of patient characteristics. Immune responses of lymphocytes and mast cells were associated with pathological response to chemotherapy and to increased PFS. High CD3+ lymphocytes at the tumour front and intratumoural mast cells appear to be prognostic for patients with colorectal liver metastases.

Can we predict complete or major response after chemoradiotherapy for rectal cancer by noninvasive methods? Results of a prospective study on 61 patients.

Rectal preservation has been proposed as an alternative to radical resection in patients with presumed complete or major response to chemoradiotherapy (CRT). The aim of this prospective study was to evaluate the accuracy of digital rectal examination (DRE) and magnetic resonance imaging (MRI) to predict major or complete rectal cancer response to CRT. Over 2 years, 61 patients underwent radical resection after CRT for rectal cancer. DRE and MRI were carried out before and 6 to 8 weeks after the end of CRT. Data from DRE and MRI post-CRT were compared with pathological examinations. At pathological examination, major/complete responses were recorded for tumors classified ypT1N0 and ypT0N0, respectively. DRE post-CRT showed major/complete response in 26 cases, of which 14 (54%) were confirmed by pathology. The positive (PPV) and negative (NPV) predictive values of DRE to predict major/complete response were 54 and 88 per cent, respectively. MRI post-CRT showed major/complete response in 12 cases, of which nine (75%) were confirmed by pathology. The PPV and NPV of MRI to predict major/complete response were 75 and 82 per cent, respectively. Data from DRE and RMI post-CRT were concordant in 45 patients. The PPV and NPV of concordant DRE and MRI to predict major/complete response were 82 and 91 per cent, respectively. DRE and MRI do not appear to be sufficiently accurate for safe selection of patients appropriate for a rectum-sparing strategy because the risk of leaving an invasive tumor untreated is 18 per cent.

Management of patients over 80 years of age treated with resection for localised colon cancer: results from a French referral centre.

BACKGROUND: Few data are available on management of very elderly colon cancer patients, especially concerning the parameters of therapeutic decisions and the role of geriatricians. METHODS: We retrospectively reviewed the charts of patients over 80 years of age who underwent surgery for a localised colon cancer in a French academic hospital. RESULTS: A total of 176 patients underwent surgery (postoperative morbidity and mortality rates: 25% and 6.7%). Adjuvant chemotherapy was discussed at a multidisciplinary team meeting for 91% of stage III patients, but only 13.5% of them were treated. Twenty-five patients relapsed: 19 were discussed at the multidisciplinary meeting and 16 were treated (5 had a metastasectomy). Despite their increase with time, geriatric assessments were infrequent, 17% (33% after 2006), and had no impact on postoperative morbi-mortality. Median overall survival and recurrence-free survival were 65.3 months and 65.1 months, respectively. Age, emergency surgery, and Charlson comorbidity index were independent prognostic factors. CONCLUSION: Selected elderly colon cancer patients have significant access to surgery. However, postoperative morbi-mortality rates remain high and adjuvant chemotherapy rarely prescribed. Perioperative geriatric assessment, especially before surgery, should be routinely proposed to these patients to evaluate its impact on postoperative morbi-mortality and prescription of adjuvant treatment.

Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial.

BACKGROUND: Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. METHODS: This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m(2) (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. FINDINGS: Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6-9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68-1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0-83·4) in the perioperative chemotherapy group and 54·3 months (41·9-79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6-58·3) in the perioperative chemotherapy group versus 47·8% (40·3-55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. INTERPRETATION: We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients. FUNDING: Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.

Multicenter validation study of pathologic response and tumor thickness at the tumor-normal liver interface as independent predictors of disease-free survival after preoperative chemotherapy and surgery for colorectal liver metastases.

BACKGROUND: To validate pathologic markers of response to preoperative chemotherapy as predictors of disease-free survival (DFS) after resection of colorectal liver metastases (CLM). METHODS: One hundred seventy-one patients who underwent resection of CLM after preoperative chemotherapy at 4 centers were studied. Pathologic response-defined as the proportion of tumor cells remaining (complete, 0%; major, <50%; minor, ≥50%) and tumor thickness at the tumor-normal liver interface (TNI) (<0.5 mm, 0.5 to <5 mm, ≥5 mm)-was assessed by a central pathology reviewer and local pathologists. RESULTS: Pathologic response was complete in 8% of patients, major in 49% of patients, and minor in 43% of patients. Tumor thickness at the TNI was <0.5 mm in 21% of patients, 0.5 to <5 mm in 56% of patients, and ≥5 mm in 23% of patients. On multivariate analyses, using either pathologic response or tumor thickness at TNI, pathologic response (P = .002, .009), tumor thickness at TNI (P = 0.015, <.001), duration of preoperative chemotherapy (P = .028, .043), number of CLM (P = .038, . 037), and margin (P = .011, .016) were associated with DFS. In a multivariate analysis using both parameters, tumor thickness at TNI (P = .004, .015), duration of preoperative chemotherapy (P = .025), number of nodules (P = .027), and margin (P = .014) were associated with DFS. Tumor size by pathology examination was the predictor of pathologic response. Predictors of tumor thickness at the TNI were tumor size and chemotherapy regimen. There was near perfect agreement for pathologic response (κ = .82) and substantial agreement (κ = .76) for tumor thickness between the central reviewer and local pathologists. CONCLUSIONS: Pathologic response and tumor thickness at the TNI are valid predictors of DFS after preoperative chemotherapy and surgery for CLM.