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The status and prognostic value of the disagreement between physician and patient assessments of symptomatic adverse events (AEs) remain unclear for patients with metastatic colorectal cancer treated with first‐line cetuximab plus chemotherapy. Paired data on patient‐reported outcomes using the EORTC QLQ‐C30 and physician‐reported outcomes using the NCI‐CTCAE for eight symptomatic AEs (fatigue, pain, insomnia, dyspnea, constipation, appetite loss, nausea/vomiting, and diarrhea) were collected from a prospective trial assessing the relationships between treatment efficacy, AEs, and quality of life. The overall agreement rates between patient and physician reporting at 4 weeks ranged from 40.2% to 76.5% for 129 patients. The level of agreement based on Cohen's κ statistics was slight to poor for dyspnea, pain, fatigue, and insomnia, while it was moderate to fair for the remaining AEs. No clinicopathological characteristics of disagreement were found. The underreporting by physicians ranged from 12.5% (nausea/vomiting) to 56.7% (fatigue). The 2‐year overall survival (OS) rate was more favorable for patients with high agreement than for those with low agreement (71.2% vs. 46.5%, p =.016), and the agreement status was an independent factor of OS (HR, 2.31; 95% CI, 1.13–4.71; p =.022). For patients who were reported as asymptomatic by the physician, the presence of patient‐reported symptoms resulted in a trend toward poor prognostic outcomes for appetite loss, dyspnea, diarrhea, and constipation. These findings provide the clinical importance of the monitoring of patient‐reported symptoms that can be complementary to physician‐reported data to ensure more accurate clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: It remains unclear whether patients' self‐perceptions of symptoms at baseline clinically impact the prognostic relevance, treatment efficacy, or toxicity profiles in metastatic colorectal cancer (mCRC) patients treated with the first‐line cetuximab and standard chemotherapy. Methods: The data were collected from a prospective trial that assessed the relationships between quality of life (QOL), treatment efficacy, and adverse events (AEs). Results: The analysis of 137 mCRC patients revealed a significant association between the presence of baseline tumor‐related symptoms and a lower overall survival (OS) compared to the absence of symptoms (HR, 2.49; 95% CI, 1.37‐4.62; P =.003). The asymptomatic responders had favorable outcomes compared to the symptomatic nonresponders (2‐year OS rates: 83.6% and 35.9%, respectively), while the symptomatic responders had similar outcomes to the asymptomatic nonresponders. The median postprogression survival differed significantly: 10.2 months for the symptomatic patients and 15.9 months for the asymptomatic patients (HR, 2.29; 95% CI, 1.25‐4.29, P =.008). The objective response rates and patient toxicity profiles were similar irrespective of the severity of baseline symptoms. Conclusion: Baseline symptoms were associated with worse OS but not with impaired treatment efficacy or more frequent AEs in mCRC patients treated with cetuximab in addition to chemotherapy. [ABSTRACT FROM AUTHOR]

Predicting tumor response prior to starting anti-epidermal growth factor receptor (EGFR) antibody therapy would benefit patients with advanced/metastatic colorectal cancer (mCRC). The present study investigated the association between efficacy of cetuximab treatment and gene polymorphisms of fragment C γ receptor (FcγR) 2A, FcγR3A and EGFR in patients with extended RAS/BRAF wild-type mCRC. Clinical data and specimens were obtained from 90 patients who participated in either of two clinical studies evaluating the first-line, cetuximab plus oxaliplatin-based treatment. It was hypothesized that polymorphisms H/H of FcγR2A, V/V of FcγR3A, K/K of EGFR and <36 CA repeats in the EGFR gene may be associated with a favorable tumor response. Multivariate analysis demonstrated that patients with the H/H polymorphism tended to have an improved tumor response compared with the non-H/H population, although the result was not significant [odds ratio, 2.25; 95% confidence interval (CI), 0.89–5.66; P=0.09]. Univariate analysis revealed increased tumor shrinkage in patients with the K/K polymorphism of EGFR compared with the other polymorphisms (mean ± standard deviation, −55.3±28.4 vs. −39.6±40.8%; P=0.04). Subsequent multivariate analysis confirmed that the K/K polymorphism of EGFR predicted greater tumor shrinkage (multiple linear regression analysis estimate, −19.3; 95% CI, −35.5 to 3.0; P=0.02), with the tendency toward a preferable response in patients with <36 CA EGFR gene repeats (estimate, −16.9; 95% CI; −34.4 to 0.6; P=0.06). However, other polymorphisms and clinical variables did not predict tumor shrinkage. In conclusion, the present study demonstrated that polymorphisms of EGFR, FcγR2A and FcγR3A may differentiate the patients that obtain the maximum benefit from cetuximab treatment. [ABSTRACT FROM AUTHOR]

Abstract: A prospective trial has not been performed to investigate associations between quality of life (QOL), adverse events (AEs), and overall survival (OS) in the first‐line treatment with cetuximab plus standard chemotherapy for advanced/metastatic colorectal cancer (mCRC). Associations between patient outcome and health‐related QOL (HRQOL) together with skin toxicity‐related QOL were prospectively evaluated using EORTC QLQ‐C30 and DLQI questionnaires. One hundred and forty mCRC patients were analyzed in this study, and 87.8% received pre‐emptive skin treatment. Skin toxicity had no clinical impact on HRQOL or skin‐related QOL during the first 8 weeks and throughout the study period. An early skin reaction with a grade ≥2 at 8 weeks was significantly associated with a favorable OS compared with a grade of ≤1 (HR, 0.50; 95% CI, 0.24‐0.95; P = .035) and was confirmed to be an independent predictor of OS (HR, 0.48; 95% CI, 0.21‐0.97; P = .040). Patients symptomatic at baseline who responded to treatment had improved HRQOL compared to nonresponding patients. Severe mucositis/stomatitis had a statistically significant and clinically meaningful negative impact on HRQOL (mean changes from baseline throughout the study period in global health status were −12.64 for a grade of ≥2 vs −0.35 for a grade of 0 or 1 (P = .005)). In conclusion, severe early skin reactions predict favorable OS for patients treated with cetuximab plus chemotherapy without impairing QOL. In addition, mucositis/stomatitis was the most substantial AE compromising both QOL and treatment compliance. [ABSTRACT FROM AUTHOR]

Bevacizumab(Avastin®), a humanized therapeutic monoclonal antibody that targets vascular endothelial growth factor, is widely used in cancer treatment. Patients who are treated with bevacizumab have an increased risk of developing systemic hypertension. However, the relationship between bevacizumab-induced hypertension and clinical outcome remains unclear. We aimed to evaluate the effect of bevacizumab-induced hypertension in terms of prognosis in patients with colorectal cancer and non-small cell lung cancer. The study included 632 patients, 317 patients with non-small cell lung cancer and 315 patients with colorectal cancer. All patients were treated with bevacizumab in combination with standard chemotherapy protocols, between April 2007 and December 2014. Blood pressure was measured before each treatment cycle. In the patient group with colorectal cancer, treated with bevacizumab, Grade 2-3 hypertension was present in 27.6%. In hypertensive patients with colorectal cancer, median overall survival was 42.6 months, compared with 20.6 months for normotensive patients in this group ( P = 0.00071). In the patient group with non-small cell lung cancer, treated with bevacizumab, Grade 2-3 hypertension was present in 20.5%. In hypertensive patients with non-small cell lung cancer, median overall survival was 43.0 months, compared with 26.3 months for normotensive patients in this group ( P = 0.00451). Patients who developed hypertension during treatment with bevacizumab for colorectal cancer and non-small cell lung cancer had significantly prolonged overall survival when compared with normotensive patients. Bevacizumab-induced hypertension may represent a biomarker for clinical benefit in cancer patients treated with bevacizumab. [ABSTRACT FROM AUTHOR]

A 74-year-old woman who developed schwannoma of the sigmoid colon was referred to our hospital for colonography to determine the cause of her stool occult blood. Colonoscopy revealed a submucosal tumor, which measured 3 cm in diameter, in the sigmoid colon. Endoscopic ultrasonography revealed a low echoic, homogeneous and demarcated submucosal tumor that continued into the fourth layer of the colonic wall. Gastrointestinal stromal, myogenic or neurogenic tumor was suspected, and thus, laparoscopic sigmoidectomy was carried out. We used two ports during the operation, a SILS Port in the umbilical region and a 12-mm port in the right lower abdominal wall, and performed sigmoidectomy with D2 lymph node dissection. Histological findings revealed spindle-like tumor cells with multiform nuclei. The tumor was diagnosed by immunostaining as benign schwannoma of the sigmoid colon. The conventional surgical treatment for schwannoma of the digestive tract is partial resection, but if preoperative diagnosis is unknown, radical resection with lymphadenectomy is acceptable for submucosal tumors in the digestive tract. In this case, laparoscopic reduced port surgery using only one or two ports may be more feasible and beneficial with regard to cosmesis and reduced postoperative pain than conventional laparoscopic colectomy. [ABSTRACT FROM AUTHOR]

Background: Oxaliplatin and capecitabine (CapeOX) combined with cetuximab is rarely used to treat advanced and metastatic colorectal cancer (mCRC). The present study aimed to clarify the clinical benefits of this treatment regimen when used as a first-line therapy in patients with expanded RAS/BRAF/PIK3CA wild-type mCRC, using the data and tumor specimens from two previously published Phase II clinical trials. Methods: The gene mutation status and clinical data of 102 patients with KRAS wild-type mCRC, who received either of CapeOX + cetuximab or FOLFOX + cetuximab, were analyzed. The primary endpoint was response rate (RR) of CapeOX + cetuximab treatment in patients with extended RAS/BRAF/PIK3CA wild-type mCRC. RR comparisons and maximum tumor size changes between different treatment regimens and gene mutation status were set as key secondary endpoints. Results: We identified 88 patients with extended RAS/BRAF/PIK3CA wild-type mCRC. Those treated with CapeOX + cetuximab (n = 52) had a 61.5% RR (95% CI, 47.0-74.7%), while those treated with FOLFOX + cetuximab (n = 36) had a 66.7% RR (95% CI, 49.0-81.4%). Patients with any mutation (n = 14) had a 42.9% RR (95% CI, 17.1-71.1%). There were no significant differences between these three groups ( P = 0.298). The disease control rate was 86.5% (95% CI, 74.2-94.4%) in the CapeOX + cetuximab group, and 88.9% (95% CI, 73.9-96.9%) in the FOLFOX + cetuximab group. Maximum tumor size changes were largest in patients with wild-type mCRC treated with FOLFOX + cetuximab followed by patients with wild-type mCRC treated with CapeOX + cetuximab, and then by those with any mutation (-63.2%, -52.6%, and -27.3%, respectively; P = 0.035). Conclusions: Patients with RAS/BRAF/PIK3CA wild-type mCRC had a sufficient RR following first-line treatment with CapeOX + cetuximab. These results suggest that this combination therapy should be considered as a treatment option for patients with advanced mCRC.

Background: FOLFOXIRI (Fluorouracil, folinate, oxaliplatin, and irinotecan) plus bevacizumab improved progression-free survival (PFS) and overall survival in patients with metastatic colorectal cancer (mCRC), compared with FOLFIRI (fluorouracil, folinate, and irinotecan) plus bevacizumab, but significantly increased the incidences of adverse events. The efficacy and safety profiles of FOLFOXIRI plus bevacizumab in ethnic Asian patients have not been established yet., Patients and Methods: This study was an open-label, single-arm, multi-centered phase II prospective clinical trial in patients with mCRC who received FOLFOXIRI plus bevacizumab. The primary endpoint was the PFS rate at 10 months. Secondary endpoints included overall survival, response rate, and safety., Results: A total of 69 patients received FOLFOXIRI plus bevacizumab as induction therapy and were assessed for efficacy and safety. The PFS rate at 10 months was 75.2% and the median PFS was 13.3 months. Complete response and partial response were achieved in 2 (2.9%) and 47 patients (69.1%), respectively. Grade 3 and 4 adverse events with incidence rates exceeding 20% were neutropenia (72.5%), hypertension (34.8%), leucopenia (33.3%), and febrile neutropenia (21.7%). Significantly more patients with grade 4 neutropenia had single-heterozygous UGT1A1*1/*6 or *1/*28 (46.2%) than UGT1A1 wild-type genotype (*1/*1) (13.3%) (P = .004)., Conclusions: FOLFOXIRI plus bevacizumab is considered an effective first-line regimen that improves the outcome of patients with mCRC regardless of ethnicity. In Asian patients, utmost attention should be paid to the possible onset of severe neutropenia or febrile neutropenia attributed to different types of UGT1A1*6 and *28 polymorphism, when FOLFOXIRI plus bevacizumab is administered., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite the comparable clinical benefit of XELOX (capecitabine with oxaliplatin) and FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin), the value of XELOX treatment in combination with cetuximab for metastatic colorectal cancer (mCRC) remains largely unknown., Patients and Methods: In this clinical trial we evaluated the efficacy and safety of weekly/biweekly cetuximab administration combined with biweekly XELOX in patients with previously untreated v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type mCRC. The primary end point was response rate (RR) with confirmation, and the secondary end points included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), dose intensity, and the safety of the protocol treatment., Results: Forty patients who fulfilled the inclusion criteria participated in this study. The median treatment cycle number was 8 and the median dose intensities were 218 mg/m 2 /wk for cetuximab, 34 mg/m 2 /wk for oxaliplatin, and 821 mg/m 2 /d for capecitabine. One patient showed complete response and partial response was observed in 19 patients, giving an overall RR of 50% (95% confidence interval [CI], 33.8%-66.2%). Stable disease was obtained in 13 patients, resulting in a DCR of 82.5% (95% CI, 67.2%-92.7%). The PFS was 6.5 months (95% CI, 3.5-9.6 months), and the OS was 24.3 months (95% CI, 14.9-33.7 months). The safety profile revealed the common Grade 3/4 adverse events to be acneiform eruption (12.5%), peripheral neuropathy (7.5%), and elevated alanine transaminase levels (7.5%). Grade 3/4 thrombocytopenia and neutropenia occurred only in 5.0% and 2.5% of the patients, respectively. Grade 1 hand-foot syndrome (HFS) was not uncommon (20%), whereas Grade 2/3 HFS occurred in only 3 patients (7.5%). No deaths were reported within 30 days of the last dose., Conclusion: Cetuximab with XELOX showed a confirmed overall RR of 50%, which was within the previously reported range of RR. The safety profile showed an acceptable rate and severity of adverse events. In light of the several advantages of XELOX, including convenience and the reported cost-saving aspects, further study of this combination therapy is warranted., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Patients with colorectal cancer treated with oxaliplatin are at risk of hypersensitivity reactions, with the incidence estimated to be 12%-20%. Coinfusion of dexamethasone and oxaliplatin could potentially reduce the incidence of these reactions, but oxaliplatin is reported to be incompatible with alkaline compounds in solution. However, in a previous retrospective study we found that the pH of a solution of dexamethasone and oxaliplatin was less than 7.4, and that hypersensitivity to oxaliplatin could have been prevented by coinfusion of dexamethasone. We aimed to evaluate the effectiveness of coinfusion of dexamethasone and oxaliplatin to prevent oxaliplatin-induced hypersensitivity reactions., Patients and Methods: The AVOID trial was a prospective, multicenter, open-label, single-arm Phase II trial conducted from January to September 2013. The study included 73 patients who received capecitabine plus oxaliplatin (XELOX) or XELOX plus bevacizumab therapy for colorectal cancer. In all patients, oxaliplatin was administered in combination with dexamethasone. The primary outcome measure was the presence of hypersensitivity reactions., Results: Hypersensitivity reactions occurred in three patients (4.1%); all three experienced a cutaneous reaction (grade 1 erythema). None of the 73 patients developed respiratory symptoms, ocular symptoms, or anaphylaxis. Grade 3 or higher hemotoxicity occurred in 13.7% of the patients and grade 3 or higher nonhematological toxicity occurred in 13.7%. The response rate to treatment was 64.4%., Conclusion: The coinfusion of dexamethasone and oxaliplatin effectively reduced oxaliplatin-induced hypersensitivity reactions in patients with colorectal cancer. This approach should be considered for all patients treated with oxaliplatin, allowing treatment to be completed as planned.

Background: This study was the first multicenter phase II study of cetuximab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) in KRAS wild-type mCRC as a second-line treatment in Japan including BRAF and PIK3CA genotyping., Patients and Methods: Tumors of 112 pre-registered patients were genotyped for KRAS, BRAF, and PIK3CA. The primary study end-point was response rate, and secondary end-points were progression-free survival (PFS), overall survival (OS), and safety., Results: Sixty-seven patients (59.8%) were EGFR-positive and KRAS wild-type. The mean age of the enrolled patients (n=60) was 62.6 years (range=37-82 years). The response rate was 31.7% and stable disease was observed in 53.3%. No objective response was observed in patients with BRAF or PIK3CA mutations. The median PFS and OS were 7.4 and 18.2 months, respectively. Grade-3/4 adverse events were leucopenia (26.7%), neutropenia (43.3%), paronychia (10.0%), fissure (10.0%) and acne-like rash (5.0%)., Conclusion: Second-line cetuximab plus FOLFIRI was effective and well-tolerated.