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Background: Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) for colorectal cancer peritoneal metastases (CRPM) is associated with improved survival in patients with historically dismal prognosis. Nonetheless, peritoneal recurrences remain common and represent a difficult challenge in these patients' management. Repeat CRS/HIPEC is associated with even greater morbidity and its survival benefit has not yet been clearly demonstrated., Methods: We retrospectively reviewed our prospectively maintained database and aimed to assess the safety and oncological efficacy of repeat CRS/HIPEC., Results: Two hundred thirty-two patients underwent an initial CRS/HIPEC, whereas 30 subsequently had repeat CRS/HIPEC for CRPM. Groups were similar in demographics, comorbidities, and peritoneal cancer index (PCI). No significant difference in morbidity, hospital stay, or reoperation rate was noted between initial and repeat procedures. Patients who underwent repeat CRS/HIPEC had a median overall survival of 68 months versus 51 months in patients who did not undergo repeat procedure for their peritoneal recurrence (p = 0.03). Disease-free survival (DFS) in patients after repeat and after initial procedure were similar with median of 9.6 versus 12 months, respectively (p = 0.083). Univariate analysis demonstrated that PCI, DFS, and repeat procedure displayed significant factors on outcomes in patients with peritoneal recurrences, whereas PCI > 16 and DFS remained independent predictors on multivariable analysis., Conclusions: Our analysis, which represents the largest series to date of repeat CRS/HIPEC for CRPM, indicates that this approach as a part of multimodal therapy is both safe and efficacious in appropriately selected patients., (© 2021. Society of Surgical Oncology.)

Background: Synchronous peritoneal and liver metastasis in colorectal cancer is a relative contraindication for curative surgery. We aimed to evaluate the safety and oncological outcomes of combined treatment of peritoneal and liver metastasis., Methods: We conducted a retrospective analysis of metastatic colorectal cancer patients from two prospective databases: peritoneal surface malignancy (n = 536) and hepatobiliary (n = 286). We compared 60 patients treated with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) and hepatectomy; 80 patients treated with cytoreduction and HIPEC only; and 63 patients treated with hepatectomy alone., Results: No differences in demographics were observed between the groups. Median hospital and intensive care unit (ICU) stay was shorter in group C (7 and 1 days, respectively) versus groups A and B (13 and 1 days, and 12 and 1 days, respectively; p < 0.001). Postoperative complications were not significantly different. Median follow-up was 18.6, 23.1, and 30.6 months for groups A, B, and C, respectively. Estimated 5-year overall survival (OS) was 48.8% (group A), 55.4% (group B), and 60.2% (group C) [p = 0.043 for group A vs. group C], and estimated 5-year disease-free survival (DFS) was 14.2% (group A), 23.0% (group B), and 18.6% (group C). Five-year OS was superior in group C compared with group A (p = 0.043), and DFS was superior in group C compared with groups A and B (p = 0.043 and 0.03, respectively). The peritoneum was the site of first recurrence in groups A and B (23.3% and 32.5%, respectively), and the liver was the site of first recurrence in group C (44.4%)., Conclusions: We report favorable perioperative and oncological outcomes in combined cytoreduction/HIPEC and hepatectomy for patients with peritoneal and liver metastasis. Surgical intervention after multidisciplinary discussion should be considered in patients with both peritoneal and hepatic lesions when complete cytoreduction is feasible.

Background: FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined., Patients and Methods: In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan-Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method., Results: CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n = 592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P = 0.051), PFS (P < 0.001), and OS (P < 0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy., Conclusions: CMS classification is prognostic for mCRC. Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. CMS classification provides deeper insights into the biology to CRC, but at present time has no direct impact on clinical decision-making.The FIRE-3 (AIO KRK-0306) study had been registered at ClinicalTrials.gov: NCT00433927., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Previous studies have shown that prognosis in metastatic colorectal cancer (mCRC) might vary according to sites of metastasis. We evaluated prognosis in individuals with mCRC and single-site metastasis, according to several clinical and genetic variables., Patients and Methods: Using the National Cancer Database we identified 58,044 mCRC patients with a synchronous single site of metastasis. We first examined the effect of metastasis site on prognosis. In a secondary analysis, among individuals who had not undergone surgery or received radiotherapy, we examined the prognostic value of chemotherapy intensity, Kirsten ras (KRAS) status, primary tumor location and carcinoembryonic antigen (CEA) levels., Results: Individuals with lung metastasis had the best prognosis (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.77-0.83), followed by those with liver metastasis (HR, 1.11; 95% CI, 1.07-1.15), whereas those with bone or brain metastasis had the worse prognosis. In a subgroup analysis, we assessed prognosis among individuals who received multiagent chemotherapy and had not undergone surgery or received radiotherapy. Individuals with lung metastasis and mutant KRAS had better prognosis compared with those with liver metastasis (HR, 0.69; 95% CI, 0.54-0.88), regardless of primary tumor location or CEA levels., Conclusion: Single-site metastasis to the lungs is associated with better prognosis in mCRC, specifically among patients with KRAS mutant tumors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We propose a working hypothesis that integrates data from the CALGB/SWOG 80405 and FIRE-3 studies to explain apparent discrepancies in their results. Both trials assessed the combination of either cetuximab or bevacizumab with a different chemotherapy backbone: irinotecan in all patients in the FIRE-3 study, or oxaliplatin in 75% of the patients in the CALGB/SWOG 80405 study. The hypothesis is divided into three parts. Firstly, in addition to the biology or microenvironment of the tumour and the selection of the biologically targeted agents common to both trials, chemotherapy itself is an important variable that determines treatment efficacy because of a complex interplay between the biological therapy, the chemotherapy, and the microenvironment. Secondly, the tumour microenvironment, as defined by the Consensus Molecular Subtypes (CMS) classification, determines the interaction of chemotherapeutic agents with biologically targeted agents such as bevacizumab and cetuximab. Whereas irinotecan synergises with cetuximab across all CMS subtypes, oxaliplatin might have variable effects, synergising with cetuximab in fibroblast-poor microenvironments, such as CMS2 and CMS3, but activating fibroblast-rich microenvironments, such as CMS1 and CMS4, to release cytokines that might antagonise some of the cetuximab effects. Thirdly, the previous assumptions integrate into a final concept, which is that overall survival is determined not only by the biological therapy or the first-line treatment, but specifically by the sequence of first-line and second-line regimens, and the degree of synergism between them. In a clinical setting, the optimal first-line combination of biological therapy and chemotherapy predetermines the crossover to a specific second-line treatment, which affects the overall survival of a patient with a specific tumour subtype. Our working hypothesis suggests that the CALGB/SWOG 80405 and FIRE-3 studies are complementary rather than discrepant, and it provides an explanation for their opposing interpretations. In conclusion, proper interpretation of the CALGB/SWOG 80405 and FIRE-3 results requires an in-depth examination of the complex interplay, not only between the targeted biological agents and chemotherapeutic drugs, but also between therapies and the tumour biology and microenvironment, for each line of treatment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting., (© The Author 2016. 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.)

Background: We report our initial experience combining cytoreductive surgery (CRS) plus intraperitoneal chemotherapy with hyperthermia (HIPEC) in a selected group of patients presenting with disseminated peritoneal carcinomatosis (PC) of colorectaL or appendiceaL origin at a single tertiary referral institution., Methods: The study included patients who underwent CRS with HIPEC at the Sheba Medical Center between April 2009 and December 2011. The HIPEC technique was administered with the open Coliseum technique reaching a steady state of mitomycin-C delivery at 410 C for perfusion duration of 90 minutes., Results: AnaLysis included 45 patients (18 males) incorporating 42 cases of primary colorectal cancer (CRC) or appendiceal cancer and 3 cases of pseudomyxoma peritonei. Thirty-seven patients (82%) underwent CC-0 resections with a median overall hospital stay of 8 days (range 5-43). There was one perioperative death at 90 days. The perioperative complication rate was 31.1%. The median follow-up was 12 months (range 2-36) during which 13 patients died. Among the CRC and appendiceal cancer group the median overall survival was 20.2 months and the median progression free survival was 16.4 months (Kaplan-Meier analysis). During follow-up, 23 patients experienced disease progression., Conclusion: The selective use of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for patients with peritoneal carcinomatosis from colorectal or appendiceal origin is safe with acceptable morbidity and low mortality.

Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. Treatment decisions must be based on the available evidence, which has been the basis for this consensus conference-based guideline delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations. This ESMO guideline is recommended to be used as the basis for treatment and management decisions.

Background: Prognosis of patients following resection of CRC metastases to the liver has traditionally been predicted by clinical risk factors. In the era of neoadjuvant chemotherapy, determination of new prognostic indicators of outcome are necessary., Methods: This retrospective study includes patients with CRC liver metastases, who received oxaliplatin or irinotecan based neoadjuvant chemotherapy and underwent R0 resection. Patients were followed by CT and PET-CT, before, during and after chemotherapy and surgery. The predictive value of the Memorial Sloan-Kettering Cancer Center Clinical Score (MSKCC-CS) and degree of response to chemotherapy (measured by CT and PET-CT), were analyzed by univariate and multivariate COX regression., Results: Included are 54 patients. Overall 1-, 2-, 3-year survival rates 88%, 70%, and 39%. Response to chemotherapy on CT was a significant predictor of survival on univariate (P = 0.03) and multivariate analysis (P = 0.03), whereas MSKCC-CS and response to chemotherapy on PET-CT were not. Multivariate analysis demonstrated response to chemotherapy as a predictor of time to recurrence on CT (P = 0.02) and PET-CT (P = 0.03), while the MSKCC-CS (P = 0.64) was not., Conclusions: In this cohort of patients treated by neoadjuvant chemotherapy, the outcome was not predicted by the traditional clinical scoring system, but rather by response to chemotherapy as evaluated by CT and PET-CT.

Abdominal wall metastases from colorectal cancer (CRC) may be resected with curative results. Such lesions, often indicators of additional intra-abdominal lesions, may appear in surgical scars, stomas and port site metastases after laparoscope-assisted surgery (LAS). Post-operative changes, primarily surgical scars, alter local physical findings making early detection of small lesions challenging. The purpose of this study was to retrospectively evaluate the contribution of PET/CT to the diagnosis of recurrent colorectal cancer in the post-operative abdominal wall. 120 patients were referred for PET/CT with suspected recurrent CRC based on clinical, radiological or laboratory findings. All underwent whole body PET/CT imaging. 12 of these 120 (10%), were found to have abdominal wall lesions. A total of 16 abdominal wall lesions were detected, located to surgical scars, stomas, drain and laparoscope ports. Additional findings on PET/CT in this group included liver metastases, intra-abdominal lesions and retroperitoneal lymph node involvement. In general, the patients in this small group were young with high grade tumours presenting in advanced stages. In conclusion, PET/CT appears to be a sensitive tool for the diagnosis of abdominal wall recurrence of CRC. The accuracy of localization afforded by the fused functional and anatomic images makes PET/CT a likely tool for diagnosing abdominal wall lesions, including port site metastases of other aetiologies.

The present approach at our institution for the treatment of patients with colorectal (CRC) cancer and with liver metastases planned for metastasectomy is the neoadjuvant administration of Bevacizumab with Irinotecan based therapy. Metabolic imaging of tumor viability with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and simultaneous anatomic localization provided by low-dose non-enhanced computed tomography (CT), can be obtained in a combined modality FDG-PET/CT scan. The purpose of this study was to evaluate the possible contribution of FDG-PET/CT as a surrogate marker to evaluate treatment response of liver metastases in vivo. This is a retrospective evaluation of 18F-FDG PET and CT findings in the first seven consecutive patients. FDG-PET/CT scans were performed before the start of the neoadjuvant and after four cycles of therapy, just prior to surgery. Results were compared to concurrent contrast-enhanced CT, when required, and pathology. Response to treatment was determined according to RECIST size criteria obtained from data from thin (3-5mm) slice CT, and changes in uptake of 18F-FDG uptake on PET. A total of 20 liver lesions were evaluated in seven patients. Overall, 6/7 patients had favorable response to treatment, and only one had progression of disease. One patient was found to be inoperable at surgery. Biopsy was obtained in 1/4 lesions in this patient, while pathology was unable for the remaining three lesions. As such, pathologic validation of findings was available for 17/20 lesions. Complete response (CR) was evident on FDG-PET in 10/17 (58%) lesions, whereas only 4/17(23%) were deemed CR by CT. Similarly, only 1/17 (6%) lesion appeared stable by FDG-PET criteria, whereas three (18%) were termed stable disease (SD) according to size on CT. FDG-PET findings correlated better than CT with pathology, and were more indicative of pathology. Overall PET/CT correctly predicted necrosis at pathology in 70% vs. 35% by CT. Our results suggest that 18F-FDG PET may be instrumental for predicting the pathologic response to Bevacizumab based therapy.