Safety and efficacy of trifluridine/tipiracil in previously treated metastatic colorectal cancer: PRECONNECT Turkey.

Background: The efficacy and safety of trifluridine/tipiracil (FTD/TPI) for third-line treatment of metastatic colorectal cancer have been demonstrated. The authors present the Turkish post hoc analysis of the PRECONNECT study. Methods: An international, multicenter, single-arm, open-label, phase IIIb trial evaluating FTD/TPI in patients with ≥2 previous lines of chemotherapy for metastatic colorectal cancer was conducted. The primary end point was safety. Results: In this Turkish cohort (n = 100; eight centers), the most frequent treatment-emergent adverse event was neutropenia (48%). Median progression-free survival was 3.0 months; disease control rate was 36%; quality of life remained stable. Conclusion: Outcomes with FTD/TPI in Turkey are consistent with previous studies and confirm the efficacy and safety of FTD/TPI treatment in the third-line setting. Clinical Trial Registration: NCT03306394 (ClinicalTrials.gov).

The View of Turkish Oncologists Regarding MSI Status and Tumor Localization in Stage II and III Colon Cancer.

INTRODUCTION: Although several clinical factors which show the benefit of adjuvant chemotherapy (AC) in early-stage colon cancer use for evaluating the risk of relapse, there is no consensus on which risk factors are more reliable. In this study, we evaluated both the utility of MSI and the daily practice of the Turkish oncologists in stage II and III colon cancer. MATERIAL AND METHOD: We conducted an online questionnaire which was consisting of twenty questions including the treatment choices and duration about stage II-III colon cancer depending on sidedness and risk factors for relapse. RESULTS: More than 65% of the oncologists declared the use of MSI testing in stage II colon cancer without considering any risk factors. In stage 3 colon cancer oncologists had an equal decision "to do or not to do" in MSI testing. More than 50% of the oncologists had preferred XELOX protocol in high-risk stage II (T4N0) colon cancer, while three out of four preferred observation in low-risk stage II (T3N0) patients without risk factors. Two-thirds of the oncologists had preferred 6 months of treatment in stage II colon cancer with at least one risk factor. CONCLUSION: Turkish oncologists participating to this trial had declared conflicting results about adjuvant treatment in early-stage colorectal cancer in their daily practice compared with the updated guidelines, especially, MSI evaluation utility in stage III colon cancers, adjuvant chemotherapy (AC) duration, and oxaliplatin adding to AC in elderly and stage II patients.

Objective response rate assessment in oncology: Current situation and future expectations.

The tumor objective response rate (ORR) is an important parameter to demonstrate the efficacy of a treatment in oncology. The ORR is valuable for clinical decision making in routine practice and a significant end-point for reporting the results of clinical trials. World Health Organization and Response Evaluation Criteria in Solid Tumors (RECIST) are anatomic response criteria developed mainly for cytotoxic chemotherapy. These criteria are based on the visual assessment of tumor size in morphological images provided by computed tomography (CT) or magnetic resonance imaging. Anatomic response criteria may not be optimal for biologic agents, some disease sites, and some regional therapies. Consequently, modifications of RECIST, Choi criteria and Morphologic response criteria were developed based on the concept of the evaluation of viable tumors. Despite its limitations, RECIST v1.1 is validated in prospective studies, is widely accepted by regulatory agencies and has recently shown good performance for targeted cancer agents. Finally, some alternatives of RECIST were developed as immune-specific response criteria for checkpoint inhibitors. Immune RECIST criteria are based essentially on defining true progressive disease after a confirmatory imaging. Some graphical methods may be useful to show longitudinal change in the tumor burden over time. Tumor tissue is a tridimensional heterogenous mass, and tumor shrinkage is not always symmetrical; thus, metabolic response assessments using positron emission tomography (PET) or PET/CT may reflect the viability of cancer cells or functional changes evolving after anticancer treatments. The metabolic response can show the benefit of a treatment earlier than anatomic shrinkage, possibly preventing delays in drug approval. Computer-assisted automated volumetric assessments, quantitative multimodality imaging in radiology, new tracers in nuclear medicine and finally artificial intelligence have great potential in future evaluations.

Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study.

OBJECTIVES: Regorafenib improved overall survival in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies in two randomised, phase III trials, but has not been evaluated in Turkey. REGARD evaluated the safety and efficacy of regorafenib in Turkish patients with treatment-refractory mCRC. DESIGN: Open-label, single-arm, phase IIIb study conducted between July 2013 and April 2015. SETTING: 11 tertiary centres in Turkey. PARTICIPANTS: Eligible patients were adults with mCRC who had disease progression within 3 months after receiving their last dose of approved standard therapies and who had an Eastern Cooperative Oncology Group performance status ≤1. Patients were excluded if they had previously received regorafenib. Of 139 patients screened, 100 were treated and completed the study, and all 100 were analysed. Fifty-eight per cent were male. INTERVENTIONS: Patients received oral regorafenib, 160 mg once daily, for the first 3 weeks of each 4-week cycle until disease progression, death or unacceptable toxicity. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was safety, assessed by incidence of treatment-emergent adverse events (TEAEs). Progression-free survival (PFS) per investigator was the primary efficacy endpoint. There were no secondary endpoints. RESULTS: The median treatment duration was 2.5 months (range 0.1 to 20.6). Ninety-six per cent of patients had at least one TEAE and 77% had a grade ≥3 TEAE. The most common grade ≥3 regorafenib-related TEAEs were hypophosphataemia (11%), fatigue (8%), hyperbilirubinaemia (6%), hand-foot skin reaction (5%), hypertension (5%), anorexia (5%) and increased alanine aminotransferase (5%). TEAEs led to dose reduction in 30% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 17% of patients. Median PFS was 3.1 months (95% CI 2.9 to 3.8). CONCLUSION: The regorafenib safety profile and PFS in REGARD were consistent with the results of previous trials of regorafenib in mCRC. Regorafenib is an option for patients in Turkey with treatment-refractory mCRC. TRIAL REGISTRATION NUMBER: NCT01853319, ClinicalTrials.gov.

Bevacuzimab May Be Less Effective in Obese Metastatic Colorectal Cancer Patients.

PURPOSE: The purpose of this study was to investigate whether obesity affects survival in metastatic colorectal cancer (mCRC) patients treated with bevacizumab combined with chemotherapy. METHODS: A total of 563 patients with mCRC who had received first-line chemotherapy in combination with bevacizumab were studied. Patients were grouped as obese (BMI levels > 30) or non-obese (BMI levels < 30). Progression-free survival (PFS) and overall survival (OS) were analyzed. Primary tumor location was also investigated in terms of PFS and OS. RESULTS: The median age of the patients was 59 years. The non-obese group had longer PFS than the obese group (P = 0.030). The 2-year survival rate of the non-obese group was also significantly higher (P = 0.036). The median PFS of non-obese patients was significantly longer in Kras wild-type patients (10.1 vs. 8.1 months, P = 0.010). Among patients with left-sided primary tumor location, median PFS and OS were significantly higher in the non-obese group (PFS non-obese, 11.5 months; obese, 8.8 months; P = 0.002) (OS non-obese, 29.4 months; obese, 21.4 months; P = 0.026). CONCLUSIONS: Efficacy of bevacizumab may be lower in obese patients. Among patients with Kras wild-type left-sided tumors treated with bevacizumab-based regimens, the prognosis could be worse for obese patients than that for non-obese patients. There is a need for prospectively designed studies of obese patients to prove the efficacy and dosages of bevacizumab in treatment of mCRC.

Kras-mutation influences outcomes for palliative primary tumor resection in advanced colorectal cancer-a Turkish Oncology Group study.

PURPOSE: We aimed to investigate the prognostic effect of primary tumor resection (PTR) prior to bevacizumab-based treatments in unresectable metastatic colorectal cancer (mCRC). METHODS: We retrospectively collected 341 mCRC cases with unresectable metastases at diagnosis. PTR was performed in 210 cases (the surgery group) and the other patients (n = 131) were followed without PTR (the no-surgery group). All the patients were treated with bevacizumab combined chemotherapy regimens. RESULTS: The median progression free survival (PFS) of the surgery group was 10.4 months (95% CI: 8.9-11.9), which was significantly better than that of the no-surgery group (7.6 months, 95% CI: 6.4-8.8, P=0.000). The median overall survival (OS) of the surgery group was longer than that of the no-surgery group (27.4 months vs. 18.3 months, respectively, P=0.000). The median PFS and OS of the surgery group were 10.4 months and 28.2 months, which were significantly longer than that of the no-surgery group in Kras-mutant patients (7.8 months and 18.3 months; P=0.004, P=0.028, respectively). There was no difference in terms of PFS and OS between the surgery and the no-surgery groups in Kras-wild type patients. CONCLUSION: Palliative PTR may improve the survival outcomes for unresectable mCRC patients. PTR may be preferred, particularly in Kras-mutant patients.

Evaluation of epidermal growth factor receptor serum levels and their association with clinicopathological characteristics in patients with colorectal cancer.

Colorectal cancer (CRC) is a major public health concern and one of the leading causes of cancer-related mortality worldwide. The aim of the present study was to determine the serum epidermal growth factor receptor (sEGFR) levels in healthy volunteers and patients with CRC, to determine the association between tumor marker levels and clinicopathological findings, and investigate its prognostic value. A total of 140 patients with CRC were enrolled in the present study. Pre-treatment sEGFR levels were determined using ELISA. A total of 40 age- and sex-matched healthy controls were included in the analysis. The median age of patients was 60 years (range, 24-84 years); the majority of the tumor localization was to the colon (n=81, 58%). The median follow-up time was 14 months, while 43 (31%) patients experienced disease progression and 31 (22%) succumbed to the disease. A total of 81 patients (58%) were in the early stages of disease (stage II and III), and 42% of the patients had stage IV disease. The estimated 2-year overall and 1-year progression-free survival rates for the whole patient group were 70% [95% confidence interval (CI): 58.8-81.2] and 26.2% (95% CI: 12.9-39.5), respectively. The number of patients who received neoadjuvant treatment was 37. Of the patients who were administered palliative treatment, 24 received oxaliplatin, whereas 22 received irinotecan and 9 received fluorouracil/capecitabine. A total of 36 and 15 of the patients who received targeted therapy were administered bevacizumab and cetuximab, respectively. Of the 55 patients with metastatic disease who received palliative chemotherapy (CTx), 31% were CTx-responsive. The baseline median sEGFR levels were significantly higher in patients with CRC compared with the healthy control group (P=0.002). In addition, established clinical variables, including no surgical resection, metastatic stage, higher pathological tumor stage, poorer regression score (3-4) and higher lactate dehydrogenase levels, were found to be associated with higher sEGFR levels (P=0.03, P=0.009, P=0.05, P=0.05 and P=0.05, respectively). The results of the present study did not reveal statistically significant associations between sEGFR concentrations and overall and progression-free survival rates. In conclusion, sEGFR concentrations may be diagnostic markers in patients with CRC; however, their predictive and prognostic values were not determined.

Imatinib response of gastrointestinal stromal tumor patients with germline mutation on KIT exon 13: A family report.

Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant disorder associated with mutations in the KIT gene in the majority of cases. Although, exon 11 appears to be the hot spot region for approximately 95% of germline mutations, pathogenic variations have also been identified in exon 8, 13 and 17. Exon 13 germline mutations are extremely rare amongst familial GISTs and seven families with a germline mutation have been reported to date. Moreover, the role of imatinib mesylate in this rare familiar settings is not completely known so far. We describe here clinical, imaging, pathological and genetic findings of a family with four affected members; grandmother, his son and two grand-sons having a germline gain-of-function mutation of KIT in exon 13 and discuss the imatinib mesylate treatment surveillance outcomes towards disease management.

Evaluation of Serum Interleukin-17 (IL-17) Levels as a Diagnostic Marker in Pancreatic Adenocarcinoma.

BACKGROUND: Inflammatory cytokines modulate immune responses in the tumor microenvironment during progression. The role of interleukin (IL-17) in cancer is currently under debate. This study was conducted to investigate the serum levels of IL-17 in patients with pancreatic adenocarcinoma (PA) and the relationship with tumor progression and known prognostic parameters. MATERIAL AND METHODS: Thirty-five patients with PA were investigated. Serum samples were obtained on first admission before treatment and follow-up. Both serum IL-17 levels were determined using enzyme-linked immunosorbent assay (ELISA). Age- and sex-matched 35 healthy controls were included in the analysis. RESULTS: The median age at diagnosis was 61 years, range 38-84 years; 21 (60%) patients were men. The tumor was located in the head of pancreas in 24 (69%) patients. The most common metastatic site was liver in 20 patients with metastasis (n = 18, 90%). The median follow-up time was 24.0 weeks (range 1.0-191.0 weeks). At the end of the observation period, 12 (34%) patients experienced disease progression and 23 patients (66%) were dead. Forty-four percent of 18 metastatic patients who received palliative chemotherapy (CTx) were CTx-responsive. Median progression-free survival and overall survival of the whole group were 13.7 ± 2.3 weeks [95% confidence interval (CI) = 9-18 weeks] and 48.0 ± 12.8 weeks (95% CI = 23-73 weeks), respectively. The baseline serum IL-17 levels were significantly higher in patients with PA than in the control group (p = 0.001). Moreover, serum IL-17 levels were significantly higher in the patients with large pathologic tumor status and low albumin levels (p = 0.04 and p = 0.03, respectively). However, serum IL-17 assays had no prognostic roles on outcome. CONCLUSION: Although serum levels of IL-17 assays were found to be diagnostic value, no predictive and prognostic value was determined in PA patients.

Serum neural precursor cell-expressed, developmentally down regulated 9 (NEDD9) level may have a prognostic role in patients with gastric cancer.

BACKGROUND: Neural precursor cell-expressed, developmentally down regulated 9 (NEDD9), a member of Crk-associated substrate (CAS) family, is highly expressed in multiple cancer types and involved in cancer cell adhesion, migration and invasion. The prognostic value of NEDD9 has been evaluated before and its expression is a predictor of poor prognosis in cancer patients. The objective of this study was to determine the clinical significance of the serum levels of NEDD9 in gastric cancer (GC) patients. PATIENTS AND METHODS: A total of 68 patients with a pathologically confirmed diagnosis of GC were enrolled into this study. Serum NEDD9 concentrations were determined by the solid-phase sandwich (ELISA) method. Twenty-eight healthy age- and sex-matched controls were included into the analysis. RESULTS: The median age at diagnosis was 60years, range 21 to 84years. Forty-nine (72%) patients were male and cardia was the most common tumor localization (n=37, 77%) in GC patients. The most frequent histologic subtype was adenocarcinoma (n=45, 66%). Liver was the most common metastatic site in 32 patients with metastasis (n=14, 44%). Sixty-one percent of 23 metastatic patients who received palliative chemotherapy (CTx) were CTx-responsive. The median follow-up time was 8months (range 1 to 23months). At the end of the observation period, 17 patients (25%) experienced disease progression and 28 of the remaining patients (41%) died. Median progression-free survival (PFS) and overall survival (OS) of the whole group were 4.0±0.7months [95% confidence interval (CI)=3-5months] and 14.6±1.2months (95% CI=12-17months), respectively. One-year and 2-year OS rates were 54.4% (95% CI=41.3-67.5) and 51.2% (95% CI=37.3-65.1), respectively. The median serum NEDD9 levels of GC patients were significantly higher than controls (1339.51 vs. 1187.91pg/mL, P=0.02). There was no significant difference according to known disease-related clinicopathological or laboratory parameters (P>0.05). Serum NEDD9 levels had a significant impact on PFS (P=0.04). On the other hand, serum NEDD9 levels showed no significantly adverse effect on OS (P=0.50). CONCLUSION: Serum NEDD9 level may be a diagnostic marker for GC patients. Moreover, our study results showed that it was elevated in GC patients and had an unfavorable prognostic effect. However, it has no predictive role on CTx response.

Epidemiology of colorectal cancer in Turkey: A cross-sectional disease registry study (A Turkish Oncology Group trial).

BACKGROUND/AIMS: This study aimed to determine the epidemiological characteristics of colorectal cancer in Turkey. MATERIALS AND METHODS: In this multicenter, prospective, and cross-sectional registry study, data for 968 patients with colorectal cancer from 21 centers in 7 geographic regions were analyzed. RESULTS: Diagnosis was colon cancer in 662 (68.4%) and rectum cancer in 306 (31.6%) patients. In total, 60.9% of patients was male; mean age was 58.9±12.6 years. Among patients, 15.0% was drinking alcohol, 17.5% was smoking, 1.5% had familial history of polyposis, 15.0% had diabetes mellitus, 1.0% had inflammatory bowel disease. Fruit and vegetable consumption was low (<3 times/week) in 35.5% and red meat consumption was high (≥3 times/week) in 47.4% of the patients. Median time-to diagnosis was 3.0 months and 4.0 months for patients with colon and rectum cancer, respectively. Mean body mass index was >25 in all group of patients. Distal rectum (61.3%) and sigmoid colon (36.8%) were the most common locations of cancer, for rectum and colon respectively. In total, 85.6% of patients were operated; 25.8% had emergency surgery. Low anterior resection rate was 64.2% in rectum cancer. In majority (89.8%) of the patients with rectum cancer who received preoperative treatment, conventional chemo-radiotherapy regimen was given. pTNM staging at diagnosis showed that stage III and IV patients were in majority (35.9% and 29.7%, respectively). CONCLUSION: Colon cancer is more frequent than rectum cancer in Turkey. Colorectal cancer patients are diagnosed at later stages. Most of the cases were operated. Interregional differences for risk factors are worthwhile for evaluation in future trials.

Clinical significance of serum claudin-1 and claudin-7 levels in patients with colorectal cancer.

The present study aimed to investigate the serum levels and clinical relevance of claudin (CLDN) 1 and CLDN7 in patients with colorectal cancer (CRC). A total of 140 patients with a pathologically confirmed diagnosis of CRC were enrolled in this study. The serum levels of CLDN1 and CLDN7 were determined using the solid-phase sandwich ELISA method. A total of 40 healthy age- and gender-matched controls were included in the analysis. The median age of the patients was 60 years (range, 24-84 years). The localization of the tumor in the majority of the patients was the colon (n=81, 58%). Of the 55 metastatic patients who received palliative chemotheraphy, 31% were chemotherapy-responsive. The baseline median serum CLDN1 and CLDN7 levels were significantly lower in non-metastatic and metastatic patients compared with those in healthy controls (CLND1, P=0.008 and 0.002; and CLND7, P=0.002 and 0.002, respectively). Moreover, known clinical variables, including poor performance status and high carcinoembryonic antigen (CEA) levels were found to be associated with lower serum CLDN1 concentrations for all patients (P=0.03 and P=0.03, respectively). High T stage and high CEA levels were found to be correlated with lower serum CLDN7 concentrations for all patients (P=0.04 and 0.03, respectively). A correlation was identified between CLDN1 and CLDN7 levels in non-metastatic and metastatic CRC patients (both P-values <0.001). Our study results did not reveal any statistical significance for serum CLDN1 or CLND7 concentrations regarding progression-free and overall survival rate. Therefore, reduced serum levels of CLDN1 and CLND7 may be useful markers in the differential diagnosis of CRC.

Red Meat and Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide. More than half of cases occur in more developed countries. The consumption of red meat (beef, pork, lamb, veal, mutton) is high in developed countries and accumulated evidence until today demonstrated a convincing association between the intake of red meat and especially processed meat and CRC risk. In this review, meta-analyses of prospective epidemiological studies addressed to this association, observed link of some subtypes of red meat with CRC risk, potential carcinogenic compounds, their mechanisms and actual recommendations of international guidelines are presented.