• prognostic markers
• colon cancer
• targeted therapies

• Humans
• Antibodies, Monoclonal/therapeutic use
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Proto-Oncogene Proteins B-raf/genetics
• Proto-Oncogene Proteins p21(ras)/genetics
• Fluorouracil
• Colonic Neoplasms/drug therapy
• Rectal Neoplasms/drug therapy
• ErbB Receptors/genetics
• Liver Neoplasms/drug therapy
• Mutation
• Cetuximab

• 1085364 Department of Health | National Health and Medical Research Council (NHMRC)

• Anti-EGFR antibody
• Colorectal cancer
• Molecular subtype
• Predictive factors
• Primary side
• Prognostic factors
• Treatment

• colorectal neoplasms
• population register
• primary tumor location
• survival
• tumor biomarkers

• Colorectal neoplasms
• Multidetector computed tomography
• Neoplasm metastasis
• ROC curve
• Response Evaluation Criteria in Solid Tumors

• cecum cancer
• colon cancer
• compare
• prognosis
• sigmoid colon cancer

• Humans
• Sigmoid Neoplasms/surgery
• Sigmoid Neoplasms/pathology
• Neoplasm Staging
• Prognosis
• Survival Analysis
• Cecum/pathology
• Retrospective Studies

• efficacy
• maintenance therapy
• metastatic colorectal cancer
• metronomic chemotherapy
• safety

• Humans
• Bevacizumab/adverse effects
• Colorectal Neoplasms/pathology
• Randomized Controlled Trials as Topic
• Colonic Neoplasms/drug therapy
• Rectal Neoplasms/drug therapy
• Lymphoma, Follicular/drug therapy

Background and Objectives: The aim of this study was to evaluate the role of the pathologic complete response ratio of liver metastases (PCRRLM) in predicting the prognosis and recurrence of colorectal cancer liver metastases (CRLM).

Methods: A total of 305 CRLM patients who underwent preoperative chemotherapy followed by hepatectomy were included. PCRRLM was defined as the number of liver metastases exhibiting pathologic complete response (PCR) divided by the number of total resected liver metastases. The Kaplan–Meier method was used to calculate survival, and differences were examined by the log-rank test. Univariate and multivariate analyses were performed to identify the predictors of PCRRLM, recurrence-free survival (RFS) and overall survival (OS).

Results: Among the 305 included patients, 44 (14.4%) achieved a PCRRLM ≥0.50 (including PCRRLM = 1), and 261 (85.6%) achieved a PCRRLM <0.50 (including PCRRLM = 0). Patients of an older age (≥55 years old) and those with higher carcinoembryonic antigen (CEA) levels (≥5 ng/ml) were less likely to achieve a PCRRLM ≥0.50. In the multivariate analysis, PCRRLM≥ 0.50 (vs. < 0.50, HR [95% CI]: 0.67 [0.46–0.99], p = 0.043) was associated with better RFS. Positive lymph node status (vs. negative, HR [95% CI]: 1.46 [1.04–2.05], p = 0.028) and TBS ≥5 (vs. < 5, HR [95% CI]: 1.44 [1.02–2.04], p = 0.038) were associated with worse RFS.

Conclusion: PCRRLM was significantly associated with long-term RFS after preoperative chemotherapy and CRLM resection. Thus, it may be a valuable indicator of recurrence in CRLM patients.

• Colorectal cancer
• Incidence
• Mortality
• Outcome
• Primary tumor localization

• Humans
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Cetuximab
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/therapy
• Panitumumab/therapeutic use
• Prognosis
• Proto-Oncogene Proteins p21(ras)/genetics

• 25350 Cancer Research UK

• Colorectal cancer
• Treatment sequencing
• Tumor location

• EGFR
• HNSCC
• Interferon response
• Transcriptional reprogramming
• Tyrosine kinase inhibitor

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Carcinoma, Squamous Cell/drug therapy
• Cell Line, Tumor
• Cetuximab/pharmacology
• Cetuximab/therapeutic use
• ErbB Receptors
• Head and Neck Neoplasms/drug therapy
• Humans
• Interferons
• Mice
• Mice, Inbred BALB C
• Squamous Cell Carcinoma of Head and Neck/drug therapy

• I01 BX004751 BLRD VA
• U.S. Department of Veterans Affairs

Primary tumor location is a prognostic factor for metastatic colorectal cancer (mCRC). Post hoc analyses of mCRC clinical trials, including FIRE-3, CALGB/SWOG 80405, suggest that primary tumor location is also predictive of survival benefit with cetuximab or bevacizumab in combination with 5-fluorouracil-based chemotherapy.

Evaluate prognostic/predictive roles of primary tumor location in real-world mCRC patients treated with cetuximab or bevacizumab plus 5-fluorouracil-based chemotherapy.

This retrospective cohort study selected patients with KRAS wild-type mCRC who initiated first-line therapy with cetuximab or bevacizumab in combination with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) or 5-fluorouracil/ leucovorin/oxaliplatin (FOLFOX) between January 2013 and April 2017 from the Flatiron Health electronic health record-derived database of de-identified patient-level data in the United States. Primary tumor location was abstracted from patients’ charts. Left-sided primary tumor location (LPTL) was defined as tumors that originated in the splenic flexure, descending colon, sigmoid colon, or rectum; right-sided primary tumor location (RPTL) was defined as tumors that originated from the appendix, cecum, ascending colon, hepatic flexure, or transverse colon. Propensity score matching was used to balance the baseline demographic and clinical characteristics between patients treated with cetuximab and patients treated with bevacizumab. Kaplan-Meier and Cox regression methods were used for survival analyses.

A total of 1312 patients met the selection criteria. Of 248 cetuximab plus FOLFIRI or FOLFOX patients, 164 had LPTL and 84 had RPTL; of 1064 bevacizumab plus FOLFIRI or FOLFOX patients, 679 had LPTL and 385 had RPTL. Cetuximab LPTL and RPTL patients were more likely to receive FOLFIRI vs bevacizumab patients (LPTL: 64.0% vs 24.3%; RPTL: 76.2% vs 24.9%, P < 0.001). Stage at initial diagnosis was different between cetuximab RPTL vs bevacizumab RPTL patients (P < 0.001); cetuximab RPTL patients were more likely to have stage III disease (44.0% vs 22.6%), while bevacizumab RPTL patients were more likely to have stage IV disease (65.7% vs 48.8%). Cetuximab RPTL patients were more likely to have a documented history of adjuvant chemotherapy vs bevacizumab RPTL patients (47.6% vs 22.3%, P < 0.001). In the propensity score-matched sample, median overall survival (OS) was 29.7 mo (95%CI: 26.9-35.2) for LPTL patients vs 18.3 mo (95%CI: 15.8-21.3) for RPTL patients (P < 0.001). Median OS was 29.7 mo (95%CI: 27.4-NA) for cetuximab LPTL patients vs 29.1 mo (95%CI: 26.6-35.6) for bevacizumab LPTL patients (HR = 0.87; 95%CI: 0.63-1.19; P = 0.378) and 17.0 mo (95%CI: 12.0-32.6) for cetuximab RPTL patients vs 18.8 mo (95%CI: 15.8-22.3) for bevacizumab RPTL patients (HR = 1.00; 95%CI: 0.68-1.46; P = 0.996). The interaction of treatment and primary tumor location was not significant in the Cox regression.

In this real-world mCRC cohort, the prognostic role of primary tumor location was substantiated, but not the predictive role for treatment with cetuximab vs bevacizumab in combination with 5-fluorouracil-based chemotherapy.

• Bevacizumab
• Cetuximab
• Cohort study
• Colorectal neoplasms
• Electronic health records
• Prognosis
• Retrospective studies
• Survival

• bevacizumab
• mCRC
• primary tumor sidedness
• prognosis
• survival

Clinicians often encounter cases of pulmonary lymphangitic carcinomatosis when treating patients with cancer. When such a condition develops before the diagnosis of cancer, its diagnosis is often challenging. Herein, we report about two patients with colorectal carcinoma diagnosed after the identification of lymphangitic carcinomatosis, which achieved complete remission with combination anti-epidermal growth factor receptor (anti-EGFR) antibody therapy. In case 1, a 74-year-old woman presented with cough and dyspnea that had persisted for 1 month. She had unresectable advanced carcinoma of the sigmoid colon with lymphangitic carcinomatosis. Her respiratory status gradually deteriorated due to the disease. Thus, FOLFIRI plus cetuximab therapy was initiated. Her dyspnea rapidly resolved with the treatment, and complete remission of lymphangitic carcinomatosis was achieved. In case 2, a 46-year-old man presented with fever and dyspnea that had persisted for 1 month. He had unresectable advanced carcinoma of the transverse colon with lymphangitic carcinomatosis. FOLFOXIRI therapy was then initiated. However, his respiratory status did not improve. Therefore, his treatment was immediately switched to FOLFIRI plus panitumumab. His dyspnea rapidly resolved with the treatment, and complete remission of lymphangitic carcinomatosis was achieved. In oncologic emergencies, such as lymphangitic carcinomatosis, requiring an early response to treatment, the administration of anti-EGFR antibodies may be a highly effective treatment option.

• Pan-Asian adapted ESMO consensus guidelines
• anti-epidermal growth factor receptor antibody
• chemotherapy
• depth of response
• early tumor shrinkage
• tumor location

• Colonic neoplasms
• Survival
• Treatment outcome

Previous studies have demonstrated that left-sided tumors have better prognoses than right-sided tumors in RAS wild-type mCRC (metastatic colorectal cancer) patients, while anti-EGFR mAbs appear to have no advantage compared with bevacizumab for right-sided tumors in these patients. Nevertheless, it remains unclear whether primary tumor location affects patients’ options for potentially curative resection.

PubMed, the Cochrane Library, Embase, ASCO, and ESMO conference abstracts were searched. The inclusion criteria were RCT (randomized controlled trials) studies that evaluated the efficacy of anti-EGFR mAbs based on primary tumor location. The outcomes included ORR, ETS, and DpR. ORs for ORR were calculated with 95% confidence intervals by Comprehensive Meta-Analysis, version 2.0.

Nine studies including nine RCTs were analyzed. Regardless of left- or right-sided tumors, the ORRs for anti-EGFR mAb (left-sided: 80.2%, 95% CI, 47–95%; I² = 76.9%; right-sided: 46.1%, 95% CI, 39.4–53.0%; I² = 18.9%) were both higher than the control arm including chemotherapy with or without bevacizumab. The ORs for anti-EGFR mAbs have a significant benefit compared with chemotherapy with or without bevacizumab in left-sided tumors (OR = 2.19, 95% CI, 1.41–3.38; P < 0.001). For right-sided tumors, anti-EGFR mAbs still significantly improved the ORR compared with chemotherapy alone (OR = 1.75, 95% CI, 1.05–2.90; P = 0.03), and the OR numerically favored the anti-EGFR mAbs compared with bevacizumab (OR = 1.281, 95% CI, 0.77–2.12; P = 0.335). The data of ETS and DpR from three RCTs also favored the EGFR antibody irrespective of tumor location. Resection data on differentiating tumor locations is inconclusive. For right-sided tumors, it should be noted that median PFS and OS were comparable for patients who achieved ETS in both treatment arms.

Anti-EGFR mAbs have advantages in the tumor shrinkage regardless of left- or right-sided tumors, which is important for conversion therapy. For right-sided tumors, anti-EGFR mAbs should remain the first choice for potentially curative resection in RAS wild-type mCRC patients. ETS may represent a subgroup of patients with right-sided tumors who might benefit from the anti-EGFR mAb.

The online version of this article (10.1186/s12957-018-1502-7) contains supplementary material, which is available to authorized users.

• Anti-EGFR mAb
• Conversion therapy
• Metastatic colorectal cancer
• Primary tumor location
• Resection

Human epidermal growth factor receptor 2 (HER2) signaling pathway activation has been identified as a contributor to de novo or acquired resistance to epidermal growth factor receptor (EGFR) inhibitors in a small subset of patients with metastatic colorectal cancer (mCRC). Dual anti-HER2-targeted treatment exhibits strong antitumor activity in preclinical models of HER2-positive mCRC, supporting its testing in clinical trials. The HERACLES trial at four Italian academic cancer centers has confirmed the effectiveness of dual blockage of HER2 with trastuzumab plus lapatinib in patients with heavily pretreated HER2-positive mCRC, refractory to the anti-EGFR antibodies cetuximab or panitumumab. Here, we reviewed the preclinical studies exploring the role of HER2 signaling in the development of anti-EGFR therapy resistance and discussed the status of clinical trials assessing the activity of HER2 inhibitors in this setting.

• Epidermal growth factor receptor
• Cetuximab
• Panitumumab
• Human epidermal growth factor receptor 2
• Anti-epidermal growth factor receptor resistance
• Trastuzumab
• Dual inhibition

Cetuximab-induced skin disorder is common in colorectal cancer (CRC), and is known to affect prolonged overall survival (OS). Patients with left-sided CRC survive longer than those with right-sided CRC, among those treated with combination cetuximab and chemotherapy. However, no study has evaluated patient prognosis in terms of OS and progression-free survival (PFS) in relation to both tumor location and skin disorder. This study aimed to determine the incidence of skin disorder according to tumor location and analyze the relationship of tumor location and skin disorder with OS.

Patients with metastatic colorectal cancer (mCRC) treated with standard chemotherapy and cetuximab as first-line therapy were included. Differences in the incidence of skin disorders due to the location of the primary tumors were compared in the same patient. The OS and PFS in relation to the location of the primary tumors and presence or absence of skin disorder were also compared.

Total frequency of each skin disorder as rash acneiform, paronychia, and dry skin in patients with left- and right-sided mCRC was 70%, 70%, and 43% and 27%, 36%, and 27%, respectively. The median OS was 8.9 months for mCRC on the left-sided without skin disorder and 56.3 months for mCRC on the left-sided with skin disorder. In comparison, the median OS was 10.4 months for mCRC on the right-sided without skin disorder and 11.3 months for mCRC on the right-sided with skin disease (left-sided with skin disorder versus other three group; P<0.001).

Primary tumor location and the presence of skin disorder are important factors in patients with mCRC who receive cetuximab. In particular, our results show the new fact that the left-sided and right-sided mCRC survival time were comparable if there is no skin disorder caused by cetuximab.

• Colorectal cancer
• cetuximab
• skin disease

• anti-egfr monoclonal antibody
• folfoxiri
• metastatic colorectal cancer
• panitumumab
• triplet

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 has been demonstrated to confer a prognostic value in colorectal cancer (CRC), but no studies have investigated whether this association differs according to tumour location. In this study, immunohistochemical expression of PD-1 and PD-L1 was analysed in tissue microarrays with primary tumours from 557 incident CRC cases from a prospective population-based cohort. Univariable and multivariable Cox regression analyses, adjusted for age, sex, TNM stage, differentiation grade and vascular invasion, were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. High PD-L1 expression on tumour-infiltrating immune cells was an independent factor of a prolonged OS in the entire cohort (hazard ratio [HR] = 0.49; 95% confidence interval [CI] CI 0.35 – 0.68), and in tumours of the right colon (HR = 0.43; 95% CI 0.25 – 0.74) and the left colon (HR = 0.28; 95% CI 0.13 – 0.61), but not in rectal cancer. Tumour-specific PD-L1-expression was not prognostic, neither in the full cohort nor according to tumour location. High immune cell-specific PD-1 expression was associated with a prolonged OS in the entire cohort and in tumours of the right colon, but not in the left colon or rectum, and only in univariable analysis. In conclusion, these results demonstrate that immune cell-specific PD-L1 and PD-1 expression is prognostic in a site-dependent manner, whereas tumour-specific PD-L1-expression is not prognostic in CRC.

• PD-1
• PD-L1
• colorectal cancer
• prognosis
• programmed cell death receptor
• sidedness
• tumour location

• Metastatic colorectal cancer
• Next generation sequencing
• Panitumumab
• TP53
• Tumor sidedness

• colorectal neoplasms
• hepatectomy
• liver metastasi
• sidedness

• Meta-analysis
• Metastatic colorectal cancer
• RAS wild-type
• Sidedness
• Systemic chemotherapy

This study aims at evaluating the prognostic significance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation indexes (SII) in metastatic colorectal cancer (mCRC) patients treated with cetuximab. Ninety-five patients receiving cetuximab for mCRC were categorized into the high or low NLR, PLR, LMR, and SII groups based on their median index values. Univariate and multivariate survival analysis were performed to identify the indexes’ correlation with progression-free survival (PFS) and overall survival (OS). In the univariate analysis, ECOG performance status, neutrphil counts, lymphocyte counts, monocyte counts, NLR, PLR, and LDH were associated with survival. Multivariate analysis showed that ECOG performance status of 0 (hazard ratio [HR] 3.608, p < 0.001; HR 5.030, p < 0.001, respectively), high absolute neutrophil counts (HR 2.837, p < 0.001; HR 1.922, p = 0.026, respectively), low lymphocyte counts (HR 0.352, p < 0.001; HR 0.440, p = 0.001, respectively), elevated NLR (HR 3.837, p < 0.001; HR 2.467, p = 0.006) were independent predictors of shorter PFS and OS. In conclusion, pre-treatment inflammatory indexes, especially NLR were potential biomarkers to predict the survival of mCRC patients with cetuximab therapy.

• Anti-EGFR therapy
• Anti-VEGF therapy
• Biomarkers
• Predictive value
• Primary tumor location

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Asian People
• Bevacizumab/pharmacology
• Bevacizumab/therapeutic use
• China
• Colonic Neoplasms/drug therapy
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/pathology
• Female
• Humans
• Male
• Middle Aged
• Mutation
• Prognosis
• Proto-Oncogene Proteins p21(ras)/genetics
• Proto-Oncogene Proteins p21(ras)/metabolism
• Rectal Neoplasms/drug therapy
• Retrospective Studies
• Treatment Outcome
• ras Proteins/genetics

• Chemotherapy
• Colorectal cancer
• Liver metastases
• Pathologic response

• Kras
• cetuximab
• colorectal cancer
• meta-analysis
• primary tumor location

• P30 CA014089 NCI NIH HHS