Publications by authors named "Suayib Yalcin"

93 Publications

A Phase II Study of the Combination of Oxaliplatin, Capecitabine, and Trastuzumab and Chemoradiotherapy in the Adjuvant Setting in Operated Patients With HER2-positive Gastric or Gastroesophageal Junction Cancer (TOXAG Study): A Turkish Oncology Group Study.

Am J Clin Oncol 2021 May 12. Epub 2021 May 12.

Department of Medical Oncology, Acibadem Adana Hospital Departments of Radiation Medical Oncology, Baskent University, Adana Department of Medical Oncology, Hacettepe University Department of Medical Oncology, Dr. A.Y. Ankara Oncology Training and Research Hospital Department of Medical Oncology, Gazi University Department of Medical Oncology, Medical Park Ankara Hospital Department of Medical Oncology, Ankara Yildirim Beyazit University, Ankara Department of Medical Oncology, Marmara University Department of Medical Oncology, Ethica Incirli Hospital Roche Pharmaceuticals Department of Medical Pharmacology, Bahcesehir University School of Medicine Department of Biostatistics and Medical Informatics, Koc University/MedStats Consulting, Istanbul Department of Medical Oncology, Necmettin Erbakan University Meram School of Medicine, Konya Department of Medical Oncology, Ege University, Izmir, Turkey.

Background: Trastuzumab prolonged the overall survival in patients with advanced gastric cancer with human epidermal growth factor receptor 2 (HER2) overexpression in combination with chemotherapy. In this phase II open-label prospective study, the tolerability and safety of trastuzumab with chemotherapy, and chemoradiotherapy for curatively resected patients with HER2-positive gastric carcinoma was investigated.

Methods: The patients with HER2-positive gastric, or gastroesophageal junction adenocarcinoma, after gastrectomy plus D2 dissection, were included. They received 3 cycles of oxaliplatin (100 mg/m2 intravenously day 1) plus capecitabine (850 mg/m2 orally days 1 to 14), trastuzumab (8 mg/kg intravenously day 1 in cycle 1, 6 mg/kg thereafter) every 21 days, followed by chemoradiotherapy. Trastuzumab was given for 1 year.

Results: Of the 212 patients screened, 35 were eligible, and 34 were treated. The median age was 56 years (minimum to maximum: 35 to 75 y), male patients constituted 73.5% (n=25), and 33 (97.1%) had gastric adenocarcinoma. R0 resection was performed in 30 (88.2%). The majority (26, 61.7%) were in stage III disease. Most of the adverse events were grade I/II, the most frequent grade III side effects were nausea (3, 8.8%), vomiting (3, 8.8%), diarrhea (2, 5.9%), and weight loss (n=2, 5.9%). Two patients died during the first 3 cycles of chemotherapy and chemoradiotherapy; 1 secondary to pulmonary thromboembolism, and the other due to cerebral ischemia. After excluding 2 with early progression and 1 consent withdrawal, of the remaining 31 patients, 28 (90.3%) were able to complete the chemotherapy and chemoradiotherapy part of the trial. After the 25 months follow-up period, 21 patients (61.8%) were alive. Overall survival at 12 and 24 months was 75.0% and 58.0%, while disease-free survival at 12 and 24 months was 65.7% and 55.0%, respectively.

Conclusions: Trastuzumab in combination with capecitabine, oxaliplatin following chemoradiotherapy as the adjuvant therapy for gastric or gastroesophageal junction adenocarcinoma was considered as safe and tolerable. The frequency of HER2 overexpression in curatively resected patients is comparable to that in patients with metastatic disease (trial registration: clinicaltrials.gov the identifier: NCT01748773, December 13, 2012, https://clinicaltrials.gov/ct2/show/NCT01748773).
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http://dx.doi.org/10.1097/COC.0000000000000825DOI Listing
May 2021

The burden of polypharmacy and drug-drug interactions in older cancer patients treated with immunotherapy.

J Oncol Pharm Pract 2021 Apr 20:10781552211012038. Epub 2021 Apr 20.

Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.

Introduction: Polypharmacy is a common problem in older cancer patients, although the data about polypharmacy and potentially inappropriate prescription practices is limited in patients treated with immune checkpoint inhibitors (ICIs). Therefore, we aimed to evaluate the polypharmacy frequency and drug-drug interactions in older cancer patients (≥65 years) treated with ICIs.

Methods: A total of 70 geriatric patients with advanced cancer were included. The polypharmacy was defined as regular use of 5 or more drugs. The START/STOPP Criteria Version 2 was used for the potentially inappropriate medications (PIM) and potential prescription omissions (PPO). The Medscape Drug Interaction Checker was used for potential drug-drug interactions.

Results: The patients had a median of 6 regular drugs, and polypharmacy was present in 77.1%. The polypharmacy risk was significantly increased in patients over 75 years of age (p = 0.028) and with opioid use (p = 0.048). The 50% of patients had category D or X interactions. Patients with higher Charlson Comorbidity Index had significantly increased risk for drug interactions (CCI ≤10 vs. >10, p = 0.017). The PIMs were present in 44.3% and the PPOs in 68.6% of the patients. While the overall survival and immune related adverse events were similar according to polypharmacy, in patients using seven or more drugs, the acute kidney injury risk was increased (HR: 4.667, p = 0.038).

Conclusion: In this study, we observed a high rate of polypharmacy and inappropriate prescription practices in ICI-treated patients. These issues pointed out the need for improved general medical care and attention for better comedication management in ICI-treated patients.
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http://dx.doi.org/10.1177/10781552211012038DOI Listing
April 2021

Poorer baseline performance status is associated with increased thromboembolism risk in metastatic cancer patients treated with immunotherapy.

Support Care Cancer 2021 Mar 11. Epub 2021 Mar 11.

Department of Medical Oncology, Hacettepe University Cancer Institute, 06100 Sıhhıye, Ankara, Turkey.

Purpose: Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in cancer patients. However, the association of VTE with immunotherapy remains poorly defined. We therefore evaluated the frequency of VTE in patients receiving immunotherapy and tried to determine predisposing factors.

Methods: A total of 133 adult metastatic cancer patients treated with immunotherapy for any cancer between were included. Baseline demographics, ECOG performance status, type of tumors, and baseline blood count parameters were recorded. Possible predisposing factors were evaluated with univariate and multivariate analyses.

Results: The median age was 60 (interquartile range (IQR) 48-66) years, and the median follow-up was 10.1 (IQR 5.8-18.5) months. Renal cell carcinoma (26.3%) and melanoma (24.1%) were most common diagnoses. Fifteen patients (11.3%) had an episode of VTE. Most of the VTEs were diagnosed as pulmonary emboli (10/15; 67%). Eighty percent (12/15) of these VTE cases were detected incidentally. Patients with a baseline ECOG performance status of 1 or more (29.3% of patients) had a significantly increased risk of venous thrombosis (ECOG ≥1 vs. 0, HR: 3.023, 95% CI: 1.011-9.039, p=0.048). Other factors, including patient age, tumor type, body mass index, baseline thrombocyte, neutrophil, and lactate dehydrogenase levels were not significantly associated with VTE risk.

Conclusions: In this study, we observed VTE development in more than 10% of immunotherapy-treated patients and increased VTE risk in patients with poorer ECOG status. With the asymptomatic nature of VTEs in most cases, a high index of suspicion level for VTE is required in patients treated with immunotherapy.
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http://dx.doi.org/10.1007/s00520-021-06139-3DOI Listing
March 2021

A Challenging Task: Identifying Patients with Cancer of Unknown Primary (CUP) According to ESMO Guidelines: The CUPISCO Trial Experience.

Oncologist 2021 May 25;26(5):e769-e779. Epub 2021 Mar 25.

Clinical Cooperation Unit Molecular Haematology/Oncology, German Cancer Research Center and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.

Background: CUPISCO is an ongoing randomized phase II trial (NCT03498521) comparing molecularly guided therapy versus platinum-based chemotherapy in patients newly diagnosed with "unfavorable" cancer of unknown primary (CUP).

Materials And Methods: Patients with an unfavorable CUP diagnosis, as defined by the European Society of Medical Oncology (ESMO), and available cancer tissue for molecular sequencing are generally eligible. Potential patients with CUP entering screening undergo a review involving reference histopathology and clinical work-up by a central eligibility review team (ERT). Patients with "favorable" CUP, a strongly suspected primary site of origin, lack of tissue, or unmet inclusion criteria are excluded.

Results: As of April 30, 2020, 628 patients had entered screening and 346 (55.1%) were screen failed. Screen fails were due to technical reasons (n = 89), failure to meet inclusion and exclusion criteria not directly related to CUP diagnosis (n = 89), and other reasons (n = 33). A total of 124 (35.8%) patients were excluded because unfavorable adeno- or poorly differentiated CUP could not be confirmed by the ERT. These cases were classified into three groups ineligible because of (a) histologic subtype, such as squamous and neuroendocrine, or favorable CUP; (b) evidence of a possible primary tumor; or (c) noncarcinoma histology.

Conclusion: Experience with CUPISCO has highlighted challenges with standardized screening in an international clinical trial and the difficulties in diagnosing unfavorable CUP. Reconfirmation of unfavorable CUP by an ERT in a clinical trial can result in many reasons for screen failures. By sharing this experience, we aim to foster understanding of diagnostic challenges and improve diagnostic pathology and clinical CUP algorithms.

Implications For Practice: A high unmet need exists for improved treatment of cancer of unknown primary (CUP); however, study in a trial setting is faced with the significant challenge of definitively distinguishing CUP from other cancer types. This article reports the authors' experience of this challenge so far in the ongoing CUPISCO trial, which compares treatments guided by patients' unique genetic signatures versus standard chemotherapy. The data presented will aid future decision-making regarding diagnosing true CUP cases; this will have far-reaching implications in the design, execution, and interpretation of not only CUPISCO but also future clinical studies aiming to find much-needed treatment strategies.
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http://dx.doi.org/10.1002/onco.13744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100559PMC
May 2021

The platelet to lymphocyte ratio predicts overall survival better than the neutrophil to lymphocyte ratio in metastatic renal cell carcinoma

Turk J Med Sci 2021 04 30;51(2):757-765. Epub 2021 Apr 30.

Department of Preventive Oncology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

Background/aim: The prognostic values of systemic inflammatory markers, neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) on overall survival (OS) of metastatic renal cell carcinoma patients (mRCC) treated with tyrosine kinase inhibitors (TKI) remain unclear. Thus, the present study aimed to investigate the prognostic impact of these markers on OS of mRCC patients.

Materials And Methods: A total of 150 patients receiving TKIs were retrospectively analyzed. Progression-free survival and OS times were analyzed with the Kaplan–Meier method, and the log‐rank test was used for comparison. Univariable and multivariable Cox regression models evaluated the impact of NLR and PLR on OS of the patients. The receiver operating characteristic curve analysis determined that the optimal cut-off values of NL, and PLR in predicting OS were 2 and 204, respectively.

Results: Patient with PLR > 204 had significantly lower median OS time than those with PLR ≤ 204 (14.6 months vs. 31.6 months, P < 0.001). While the univariate analyses showed that both NLR and PLR associated with OS (NLR: P = 0.002; PLR: P < 0.001), PLR, not NLR, was an independent determinant for OS in the multivariate analyses (Hazard Ratio: 2.535, 95% CI: 1.564-4.108, P < 0.001). Additionally, the presence of brain metastases and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic scoring system were identified as independent prognostic factors for OS (brain metastases: P = 0.040; IMDC: P < 0.001).

Conclusion: The PLR is a readily and inexpensively obtained marker, which may predict OS in patients with mRCC treated with TKIs.
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http://dx.doi.org/10.3906/sag-2009-75DOI Listing
April 2021

The Prognostic Value of Circulating VEGF-A Level in Patients With Hepatocellular Cancer.

Technol Cancer Res Treat 2020 Jan-Dec;19:1533033820971677

Department of Medical Oncology, 64005Hacettepe University, Hacettepe Cancer Institute, Ankara, Turkey.

Background: Neovascularization plays a crucial pathogenic role in tumor development and vascular endothelial growth factor (VEGF-A) is a key signaling element that drives angiogenesis, thereby facilitating hepatocellular cancer (HCC) growth and metastasis. We aimed to define the relationship between serum VEGF-A levels and clinical outcomes in a cohort of Turkish patients with HCC.

Methods: We enrolled and prospectively followed 84 patients with HCC in our study. Serum VEGF-A levels were measured and we assessed the association between VEGF-A levels and clinical features.

Results: Forty-eight patients had cirrhosis while 35 patients were noncirrhotic. Serum VEGF-A levels were significantly lower in HCC patients with cirrhosis compared to non-cirrhotic HCC patients (p = 0.03).In terms of viral hepatitis subtype, 36 (%42.8) of patients were hepatitis B virus (HBV) positive and 8 (%9.5) of patients were hepatitis C virus (HCV) positive. Patients with serum VEGF-A levels ≥100 pg/mL had significantly lower OS rates than patients with serum VEGF-A level <100 pg/mL (p = 0.01). The OS rates were 5.8 and 14.2 months, respectively (p = 0.02). The median OS was 7.38 months (95% CI: 5.89-13.79 months). We observed a significant relationship between serum VEGF-A level and tumor size. Patients with tumor size ≤ 5cm had lower VEGF-A levels than patients with VEGF-A levels <5 cm. The VEGF-A levels were 132.7 and 342.1 pg/mL, respectively (p < 0.001). The median follow-up was 32 months.

Conclusions: Serum VEGF-A level, a biological marker of angiogenesis, is an independent predictor of survival in patients with HCC. Serum VEGF-A levels may be utilized to predict response to treatment targeting serum VEGF-A in patients with HCC.
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http://dx.doi.org/10.1177/1533033820971677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705781PMC
November 2020

Impact of Integrating Insulin-Like Growth Factor 1 Levels into Model for End-Stage Liver Disease Score for Survival Prediction in Hepatocellular Carcinoma Patients.

Oncology 2020 7;98(12):836-846. Epub 2020 Oct 7.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA,

Background: Liver reserve affects survival in hepatocellular carcinoma (HCC). Model for End-Stage Liver Disease (MELD) score is used to predict overall survival (OS) and to prioritize HCC patients on the transplantation waiting list, but more accurate models are needed. We hypothesized that integrating insulin-like growth factor 1 (IGF-1) levels into MELD score (MELD-IGF-1) improves OS prediction as compared to MELD.

Methods: We measured plasma IGF-1 levels in training (n = 310) and validation (n = 155) HCC cohorts and created MELD-IGF-1 score. Cox models were used to determine the association of MELD and MELD-IGF-1 with OS. Harrell's c-index was used to compare the predictive capacity.

Results: IGF-1 was significantly associated with OS in both cohorts. Patients with an IGF-1 level of ≤26 ng/mL in the training cohort and in the validation cohorts had significantly higher hazard ratios than patients with the same MELD but IGF-1 >26 ng/mL. In both cohorts, MELD-IGF-1 scores had higher c-indices (0.60 and 0.66) than MELD scores (0.58 and 0.60) (p < 0.001 in both cohorts). Overall, 26% of training and 52.9% of validation cohort patients were reclassified into different risk groups by MELD-IGF-1 (p < 0.001).

Conclusions: After independent validation, the MELD-IGF-1 could be used to risk-stratify patients in clinical trials and for priority assignment for patients on liver transplantation waiting list.
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http://dx.doi.org/10.1159/000502482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704605PMC
December 2020

Prognostic Significance of Serum Insulin-Like Growth Factor-1 in Hepatocellular Cancer Patients: A Validation Study.

J Hepatocell Carcinoma 2020 16;7:143-153. Epub 2020 Sep 16.

University of Texas, MD Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, Houston, Texas, USA.

Background: The Child-Turcotte-Pugh score (CTP) is the most commonly used tool to assess hepatic reserve and predict survival in hepatocellular cancer (HCC). The CTP stratification accuracy has been questioned and attempts have been made to improve the objectivity of the system. Serum insulin-like growth factor-1 (IGF-1)-CTP has been proposed to improve CTP prognostic accuracy. We aimed to validate the IGF-CTP score in our patient population.

Patients And Methods: A total of 84 diagnosed HCC patients were enrolled prospectively. IGF-CTP scores in addition to CTP scores were calculated. C-index was used to compare the prognostic significance of the two scoring systems and overall survival (OS).

Results: Cirrhosis was present in 48 (57.1%) patients, 35 (41.7%) patients were non-cirrhotic, 36 (42.8%) patients were hepatitis B (HBV) positive, and 8 (9.5%) patients were hepatitis C (HCV) positive. Serum IGF-1 levels were significantly lower in cirrhotic compared with non-cirrhotic patients (p=0.04). There was a significant difference in OS rates of patients with serum IGF-1 level <50 ng/mL and patients with serum IGF-1 levels ≥50 ng/mL (p=0.02); the OS rates were 6.5 and 14.8 months, respectively (p=0.02). The median OS of all patients was 7.38 months (95% CI: 5.89-13.79). The estimated C-index for CTP and IGF-CTP scores was 0.605 (95% CI: 0.538, 0.672) and 0.599 (95% CI: 0.543, 0.655), respectively. The U statistics indicated that the C-indices between two scoring systems are not statistically different (P= 0.91).

Conclusion: This study evaluated IGF-1 levels and the IGF-CTP classification in a predominantly HBV (+) cohort of HCC patients with 41.7% non-cirrhotic. Although the prognostic value was similar, among patients with CTP-A, class those reclassified as IGF-CTP B had shorter OS than those with IGF-CTP score A. Thus, further validations of IGF-CTP score in similar populations may add additional value as a stratification tool to predict HCC outcome.
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http://dx.doi.org/10.2147/JHC.S258930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502406PMC
September 2020

Follow-Up Care for Breast and Colorectal Cancer Across the Globe: Survey Findings From 27 Countries.

JCO Glob Oncol 2020 09;6:1394-1411

Peking University Cancer Hospital, Beijing, People's Republic of China.

Purpose: The purpose of this study was to describe follow-up care for breast and colorectal cancer survivors in countries with varying levels of resources and highlight challenges regarding posttreatment survivorship care.

Methods: We surveyed one key stakeholder from each of 27 countries with expertise in survivorship care on questions including the components/structure of follow-up care, delivery of treatment summaries and survivorship care plans, and involvement of primary care in survivorship. Descriptive analyses were performed to characterize results across countries and variations between the WHO income categories (low, middle, high). We also performed a qualitative content analysis of narratives related to survivorship care challenges to identify major themes.

Results: Seven low- or /lower-middle-income countries (LIC/LMIC), seven upper-middle-income countries (UMIC), and 13 high-income countries (HICs) were included in this study. Results indicate that 44.4% of countries with a National Cancer Control Plan currently address survivorship care. Additional findings indicate that HICs use guidelines more often than those in LICs/LMICs and UMICs. There was great variation among countries regardless of income level. Common challenges include issues with workforce, communication and care coordination, distance/transportation issues, psychosocial support, and lack of focus on follow-up care.

Conclusion: This information can guide researchers, providers, and policy makers in efforts to improve the quality of survivorship care on a national and global basis. As the number of cancer survivors increases globally, countries will need to prioritize their long-term needs. Future efforts should focus on efforts to bridge oncology and primary care, building international partnerships, and implementation of guidelines.
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http://dx.doi.org/10.1200/GO.20.00180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529533PMC
September 2020

Lycopene sensitizes the cervical cancer cells to cisplatin via targeting nuclear factor- kappa B (NF-κB) pathway

Turk J Med Sci 2021 02 26;51(1):368-374. Epub 2021 Feb 26.

Department of Medical Oncology, Faculty of Medicine, Hacettepe University, Ankara, Turkey

Background/aim: Lycopene is associated with anticancer effects in various tumor types. However, the exact underlying mechanisms of action of lycopene in human cervical cancer remain to be determined. This study aimed to determine anticancer efficacy and mechanism of lycopene in human cervical carcinoma (HeLa) cells.

Materials And Methods: HeLa cells were treated with cisplatin (1 μM) alone, lycopene (10 μM) alone, and in combination for 72 h. The cell viability of HeLa cells was assessed via MTS assay. Western blot was used to analyze the expression levels of the nuclear factor-kappa B (NF-κB), B-cell-associated X protein (Bax), nuclear factor erythroid 2-related factor (Nrf2), and B-cell lymphoma 2 (Bcl-2).

Results: We found that lycopene acts as a synergistic agent with cisplatin in preventing the growth of HeLa cells. The rates of HeLa cells’ viability were 65.6% and 71.1% with lycopene and cisplatin treatment alone compared to the control group, respectively (P < 0.001). The inhibitory effect of cisplatin was enhanced with lycopene addition by declining the cell viability to 37.4% (P < 0.0001). Lycopene treatment significantly increased Bax expression (P < 0.0001) and decreased Bcl-2 expression (P < 0.0001) in HeLa cells. Furthermore, lycopene markedly activated the Nrf2 expression (P < 0.001) and suppressed the NF-κB signaling pathway (P < 0.0001).

Conclusion: Lycopene increases the sensitization of cervical cancer cells to cisplatin via inhibition of cell viability, up-regulation of Bax expression, and down-regulation of Bcl-2 expression. Furthermore, the anticancer effect of lycopene might be also associated with suppression of NF-κB-mediated inflammatory responses, and modulation of Nrf2-mediated oxidative stress. The results of the present study suggest that lycopene and concurrent cisplatin chemotherapy might have a role in improving the treatment of cervical cancer.
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http://dx.doi.org/10.3906/sag-2005-413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991865PMC
February 2021

COVID-19 pandemic: changes in cancer admissions.

BMJ Support Palliat Care 2020 Jul 14. Epub 2020 Jul 14.

Department of Medical Oncology, Cancer Institute, Hacettepe University, Ankara, Turkey.

Background: COVID-19 pandemic could create a collateral damage to cancer care denoting disruptions in care due to a significant burden on healthcare and resource allocations. Herein, we evaluate the early changes in the inpatient and outpatient oncology clinics to take a snapshot of this collateral damage at Hacettepe University Cancer Institute.

Methods: Patients applying the outpatient clinic and outpatient palliative care (OPC) clinic for the first time and patients admitted to inpatient wards in the first 30 days after the first case of COVID-19 in Turkey were evaluated. These data were compared with data from the same time frame in the previous 3 years.

Results: The mean number of daily new patient applications to the outpatient clinic (9.87±3.87 vs 6.43±4.03, p<0.001) and OPC clinic (3.87±1.49 vs 1.13±1.46, p<0.001) was significantly reduced compared with the previous years. While the number of inpatient admissions was similar for a month frame, the median duration of hospitalisation was significantly reduced. The frequency of hospitalisations for chemotherapy was higher than in previous years (p<0.001). By comparison, the rate of hospitalisations for palliative care (p=0.028) or elective interventional procedures (p=0.001) was significantly reduced.

Conclusion: In our experience, almost all domains of care were affected during the pandemic other than patients' systemic treatments. There were significant drops in the numbers of newly diagnosed patients, patients having interventional procedures and palliative care services, and these problems should be the focus points for the risk mitigation efforts for prevention of care disruptions.
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http://dx.doi.org/10.1136/bmjspcare-2020-002468DOI Listing
July 2020

Clinicopathologic Features of Gastroenteropancreatic Neuroendocrine Tumors: A Single-center Experience

Balkan Med J 2020 08 23;37(5):281-286. Epub 2020 Jun 23.

Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey

Background: Gastroenteropancreatic neuroendocrine tumors, a heterogeneous group of neoplasms, originates from the neuroendocrine system of the gastrointestinal tract and pancreas. There are limited number of studies investigating neuroendocrine tumors in Turkey.

Aims: To define the clinicopathologic, demographic, and survival features of patients with gastroenteropancreatic neuroendocrine tumors.

Study Design: A retrospective observational cohort study.

Methods: We reviewed hospital records of patients and data was analyzed retrospectively. We investigated the clinical, pathological, survival features, and prognosis of patients with gastroenteropancreatic neuroendocrine tumors (n=128) admitted to the medical oncology department between year 2003 and 2014. Survival estimation was performed by the Kaplan-Meier method. Univariate and multivariate Cox regression models were utilized to investigate the prognostic factors for survival.

Results: Of 128 patients with gastroenteropancreatic neuroendocrine tumors, 61 (47.7%) were female and 67 (52.3%) were male. The most common site of the tumor was stomach (36.7%), while the most common stage of tumor at diagnosis was stage 4 (40.9%). The median follow-up period was 37 months, while the 3- and 5-year overall survival rates were 78% and 69%, respectively. The factors significantly affecting overall survival rate were clinical stage, grade, presence of metastasis at diagnosis, and Ki-67 proliferation index. These factors were associated with the 3- and 5-year overall survival rate. Moreover, grade (hazard ratio: 8.34, 95% confidence interval: 2.16-32.22, p=0.01) and presence of metastasis at diagnosis (hazard ratio: 3.18, 95% confidence interval: 1.30-7.77, p=0.01) independently predicted overall survival in multivariate model following adjustment for age and gender.

Conclusion: Higher-grade and presence of metastasis at diagnosis are negative independent prognostic indicators of survival in patients with gastroenteropancreatic neuroendocrine tumors.
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http://dx.doi.org/10.4274/balkanmedj.galenos.2020.2020.1.126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424185PMC
August 2020

Stereotactic ablative radiotherapy for bone metastasis of gastrointestinal stromal tumor: Case report and review of the literature.

Rep Pract Oncol Radiother 2020 May-Jun;25(3):331-335. Epub 2020 Feb 24.

Hacettepe University Faculty of Medicine, Department of Radiation Oncology, Ankara, Turkey.

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors are rare and only make bone metastases at a rate of 5%.

Case Summary: A 31-year-old male with a GIST presented with solitary bone metastasis at the right iliac bone. We performed stereotactic ablative radiotherapy (SABR) and achieved excellent local control. Herein, our case is presented, and a short review of the literature is carried out.

Conclusion: SABR should be considered as a treatment option in GIST with bone metastasis.
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http://dx.doi.org/10.1016/j.rpor.2020.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114605PMC
February 2020

Quality of life study of patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma treated with gemcitabine+nab-paclitaxel versus gemcitabine alone: AX-PANC-SY001, a randomized phase-2 study.

BMC Cancer 2020 Mar 30;20(1):259. Epub 2020 Mar 30.

Hacettepe University Cancer Institute, Ankara, Turkey.

Background: Combination of gemcitabine and nab-paclitaxel has superior clinical efficacy than gemcitabine alone. Nevertheless, health-related quality of life. (QoL) associated with this combination therapy when administered at first-line in advanced pancreatic adenocarcinoma is unknown.

Methods: A total of 125 patients were randomized to combination therapy (1000 mg/m2 gemcitabine + 125 mg/m2 nab-paclitaxel) and single-agent gemcitabine (1000 mg/m2) arms to take treatment weekly for 7 of 8 weeks, and following 3 of 4 weeks, until progression or severe toxicity. Primary endpoints were three-months of definitive deterioration free percent of patients, and QoL.

Results: Overall QoL analyses showed that 34 and 58.3% of cases in gemcitabine and gemcitabine+nab-P arms had no deterioration in 3rd month QoL scores (p = 0.018). These proportions were 27.3 and 36.6% in 6 month assessments, respectively (p = 0.357). Median overall survivals in combination and single-agent arms were 9.92 months and 5.95 months, respectively (HR: 0.64, 95% CI: 0.42-0.86, p = 0.038). Median progression free survivals in these treatment arms were 6.28 and 3.22 months, respectively (HR: 0.58, 95% CI: 0.39-0.87, p = 0.008). Median time-to-deterioration were 5.36 vs 3.68 months, and objective response rates were 37.1% vs 23.7% (p = 0.009), respectively in combination and single-agent arms.

Conclusions: Combination therapy with gemcitabine + nab-paclitaxel had better overall and progression-free survival than gemcitabine alone. Also, combination therapy showed increased response rate without toxicity or deteriorated QoL. Combination treatment with gemcitabine and nab-paclitaxel may provide significant benefit for advanced pancreatic cancer.

Trial Registration: This study has been registered in ClinicalTrials.gov as NCT03807999 on January 8, 2019 (retrospectively registered).
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http://dx.doi.org/10.1186/s12885-020-06758-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106641PMC
March 2020

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

BMJ Open 2020 03 26;10(3):e027665. Epub 2020 Mar 26.

Division of Medical Oncology, Department of Internal Medicine, Marmara University Medical Faculty, Istanbul, Turkey.

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.
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http://dx.doi.org/10.1136/bmjopen-2018-027665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170555PMC
March 2020

Prognostic value of the 2017 World Health Organization Classification System for gastric neuroendocrine tumors: A single-center experience.

Turk J Gastroenterol 2020 02;31(2):91-98

Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.

Background/aims: Gastric neuroendocrine tumors (G-NETs) are rare tumors, but their incidence is gradually increasing. Despite the existence of many classification systems, determining prognosis and planning treatment in patients with G-NETs remains a clinical challenge. In this study, the prognostic value of the World Health Organization (WHO) 2017 grading system and the effect of surgery on survival in low grade neuroendocrine tumors were investigated.

Materials And Methods: G-NETs who were diagnosed between January 2000 and May 2017 were included in the study. Patients' demographic characteristics, treatment details, and survival data were obtained from medical charts. Pathological samples were re-classified according to the WHO 2017 grading system.

Results: Of the total 94 evaluated patients, 50 (53.2%) were classified with G1 NETs, 37(39.4%) with G2 NETs, 4(4.2%) with well-differentiated G3 NETs, and the remaining 3 patients with poorly differentiated G3 neuroendocrine carcinoma (NEC). The median follow-up time was 83.2 months. There was a statistically significant difference in 5-year progression free survival (PFS) between G1 tumors (100%) and G2 tumors (76%) (p<0.001). However, there was no statistically significant deference in 5-year overall survival rate (OS) for G1 (97%) and G2 (82%) tumors (p=0.141). When G2 and G1 NETs were compared according to their surgical approach, radical surgery was more frequently performed in patients with G2 tumors (p<0.001). However, radical surgery did not improve PFS in G1 and G2 NETs.

Conclusion: The WHO 2017 NET classification system may have low prognostic value for determining the prognosis of patients with G1 and G2 tumors. Radical surgery for G1 and G2 NETs did not improve PFS in our study.
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http://dx.doi.org/10.5152/tjg.2020.18919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062132PMC
February 2020

Health-related quality of life associated with trifluridine/tipiracil in heavily pretreated metastatic gastric cancer: results from TAGS.

Gastric Cancer 2020 07 4;23(4):689-698. Epub 2020 Mar 4.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: In TAGS, an international, double-blind, phase 3 trial, trifluridine/tipiracil significantly improved overall survival and progression-free survival compared with placebo in heavily pretreated metastatic gastric cancer patients. This paper reports pre-specified quality of life (QoL) outcomes for TAGS.

Methods: Patients were randomized 2:1 to trifluridine/tipiracil (35 mg/m twice daily on days 1-5 and 8-12 of each 28-day cycle) plus best supportive care (BSC) or placebo plus BSC. QoL was evaluated at baseline and at each treatment cycle, using the EORTC QLQ-C30 and EORTC QLQ-STO22 questionnaires; results were considered valid for analysis only if ≥ 10% of patients completed the questionnaires. Key QoL outcomes were mean changes from baseline and time to deterioration in QoL. A post hoc analysis assessed the association between QoL and time to deterioration of Eastern Cooperative Oncology Group performance score (ECOG PS) to ≥ 2.

Results: Of 507 randomized patients, 496 had baseline QoL data available. The analysis cut-off was 6 cycles for trifluridine/tipiracil and 3 cycles for placebo. In both treatment groups, there were no clinically significant deteriorations in the mean QLQ-C30 Global Health Status (GHS) score, or in most subscale scores. In a sensitivity analysis including death and disease progression as events, there was a trend towards trifluridine/tipiracil reducing the risk of deterioration of QoL scores compared with placebo. Deterioration in the GHS score was associated with deterioration in ECOG PS.

Conclusion: QoL was maintained in TAGS, and there was a trend towards trifluridine/tipiracil reducing the risk of QoL deterioration compared with placebo. Trial registration ClinicalTrials.gov number: NCT02500043.
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http://dx.doi.org/10.1007/s10120-020-01053-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305098PMC
July 2020

Anti-prostate cancer activity of a nanoformulation of the spleen tyrosine kinase (SYK) inhibitor C61.

Anticancer Drugs 2020 07;31(6):609-616

Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.

Patients with advanced or metastatic castration-resistant prostate cancer have a dismal prognosis and are therefore in urgent need for therapeutic innovations. Spleen tyrosine kinase has emerged as a new molecular target for castration-resistant prostate cancer. This study was done to test the cytotoxicity of the lead nanoformulation of a potent spleen tyrosine kinase inhibitor, C61-LNP, against the human prostatic carcinoma cell line, PC-3. PC-3 cells were treated with various concentrations of C61-LNP either alone or in combination with cisplatin (CDDP) for 24, 48 and 72 hours. The cell viability was evaluated by MTS assay. Cellular expression levels of various regulatory proteins in treated PC-3 cells were evaluated by Western blot analyses. C61-LNP exhibited dose-dependent cytotoxicity against PC-3 cells. C61-LNP, as well as C61-LNP + CDDP treatments, caused pro-apoptotic proteomic changes including an increase in cleaved fragments of caspases-3 and -9 consistent with caspase activation as well as an improvement in the anti-apoptotic Bcl2 and Bax levels. The combination of C61-LNP and CDDP changed in alterations of the cell cycle regulatory proteins p53, p21, p27, cyclin D1 and cyclin E levels. C61-LNP exhibited cytotoxicity against the castration-resistant prostate cancer cell line PC3. It also caused alterations in expression levels of regulatory proteins involved in apoptosis and cell cycle regulation and these effects were not abrogated by the standard chemotherapy drug CDDP. We are planning to further develop C61-LNP as a selective spleen tyrosine kinase inhibitor as part of a multi-modality treatment strategy for advanced/metastatic castration-resistant prostate cancer.
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http://dx.doi.org/10.1097/CAD.0000000000000910DOI Listing
July 2020

Nutritional Aspect of Cancer Care in Medical Oncology Patients.

Clin Ther 2019 11 4;41(11):2382-2396. Epub 2019 Nov 4.

Ege University Faculty of Medicine, Izmir, Turkey.

Purpose: Awareness of advances in the nutritional aspects of cancer care and translation of this information into clinical practice are important for oncology practitioners to effectively couple oncologic and nutritional approaches throughout the cancer journey. The goal of this consensus statement by a panel of medical oncologists was to provide practical and implementable guidance addressing nutritional aspects of cancer care from the perspective of the medical oncologist.

Methods: A panel of medical oncologists agreed on a series of statements supported by scientific evidence and expert clinical opinion.

Findings: Participating experts emphasized that both poor nutritional intake and metabolic alterations underlie cancer-related malnutrition. The use of liquid and high energy-dense oral nutritional supplements may enable better patient compliance, whereas higher efficacy is more likely with the use of pharmaconutrient-enriched oral nutritional supplements in terms of improved weight, lean body mass, functional status, and quality of life, as well as better tolerance to antineoplastic treatment. A multimodal approach is currently believed to be the best option to counteract the catabolism leading to cancer-related malnutrition; this treatment is scheduled in parallel with anticancer therapies and includes nutritional interventions, multitarget drug therapies, and exercise and rehabilitation programs. Participating experts emphasized the role of the oncologist as a reference professional figure in the coordination of nutritional care for patients with cancer within the context of complex and different clinical scenarios, particularly for permissive-adjunctive nutritional support.

Implications: This review article provides practical guidance addressing major nutritional aspects of cancer care from the medical oncologist's perspective. Thus, this document is expected to assist oncology practitioners in terms of awareness of advances in the nutritional aspects of cancer care and translation of this information into their clinical practice to effectively couple oncologic and nutritional approaches as part of the continuum of care for patients with cancer.
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http://dx.doi.org/10.1016/j.clinthera.2019.09.006DOI Listing
November 2019

Impact of tivozanib on patient outcomes in treatment of advanced renal cell carcinoma.

Cancer Manag Res 2019 16;11:7779-7785. Epub 2019 Aug 16.

University of Health Sciences, Diyarbakir Gazi Yasargil Training and Research Hospital, Department of Medical Oncology, Diyarbakir, Turkey.

Renal cell carcinoma (RCC) is the most common type of kidney malignancy, and the clear-cell subtype represents the majority of RCCs. RCC is a heterogeneous disease in terms of genetic and histological features which determine the behavior of the disease. The () is a tumor suppressor gene and mutations of this gene are seen in 95% of clear-cell RCCs. Inactivation of  causes the accumulation of hypoxia-inducible factor-1 (HIF-1), and in turn, accumulation of HIF-1 induces overexpression of vascular endothelial growth factor (VEGF); the increase in VEGF expression makes RCC a highly vascularized tumor, and forms the rationale for antiVEGF treatment. In the past decade, improvement in the survival of RCC patients has been observed due to new effective therapies, such as antiVEGF and mammalian target of rapamycin (mTOR) targeting agents and immune checkpoint inhibitors. The majority of VEGF targeted agents are not just selective to VEGF receptors, but usually also have inhibitory effects on other kinases, such as c-KIT and FLT3. Tivozanib is an extremely potent and selective tyrosine kinase inhibitor (TKI) of VEGFR-1, 2, and 3, with a relatively long half-life, that is approved by the European Commission for the treatment of advanced/metastatic RCC. Tivozanib, at very low serum concentration can inhibit phosphorylation of VEGFR -1, -2, and -3 tyrosine kinase activity. This article summarizes the clinical data on tivozanib in the treatment of advanced/metastatic RCC.
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http://dx.doi.org/10.2147/CMAR.S206105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701608PMC
August 2019

Aflibercept Plus FOLFIRI for Second-line Treatment of Metastatic Colorectal Cancer: Observations from the Global Aflibercept Safety and Health-Related Quality-of-Life Program (ASQoP).

Clin Colorectal Cancer 2019 09 15;18(3):183-191.e3. Epub 2019 May 15.

IRCCS Azienda Ospedaliera Universitaria San Martino, Genova, Italy.

Background: The objectives of this study were to evaluate the safety profile of aflibercept and health-related quality of life (HRQL) in patients with metastatic colorectal cancer (mCRC) provided with aflibercept access before marketing authorization.

Patients And Methods: Patients received aflibercept followed by FOLFIRI (fluorouracil, leucovorin, irinotecan) on day 1 of a 2-week cycle until disease progression, unacceptable toxicity, death, or patient/investigator decision to discontinue. Treatment-emergent adverse events (TEAEs) were evaluated, and HRQL was assessed at baseline, cycle 3, and every other cycle using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-CR29, and EuroQol 5-Dimensions 3-Levels questionnaires (NCT01571284).

Results: Overall, 779 adult patients with mCRC, who received ≥ 1 prior oxaliplatin-based regimen and had disease progression during or following their last administration of oxaliplatin-based chemotherapy, were enrolled. At data cutoff, all patients had discontinued treatment, mainly owing to disease progression (51.7%). The most common TEAEs of any grade were diarrhea (61.6%), hypertension (48.4%), and nausea (43.3%). The most common grade 3/4 TEAEs were hypertension (24.1%), neutropenia (23.1%), and diarrhea (15.3%). Clinically meaningful changes in HRQL were reported for all measures. Most patients either had an improvement in their HRQL scores or remained stable during the treatment period based on patient-reported outcomes.

Conclusion: The data from this study support the tolerability of the combination of aflibercept and FOLFIRI in a setting that more closely approximates real life in patients with mCRC who failed to respond to oxaliplatin-based chemotherapy, and also suggest an improvement in HRQL.
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http://dx.doi.org/10.1016/j.clcc.2019.05.003DOI Listing
September 2019

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

BMC Cancer 2019 Jun 3;19(1):535. Epub 2019 Jun 3.

Genekor Medical S.A, Athens, Greece.

Background: Hereditary cancer predisposition syndromes are responsible for approximately 5-10% of all diagnosed cancer cases. In the past, single-gene analysis of specific high risk genes was used for the determination of the genetic cause of cancer heritability in certain families. The application of Next Generation Sequencing (NGS) technology has facilitated multigene panel analysis and is widely used in clinical practice, for the identification of individuals with cancer predisposing gene variants. The purpose of this study was to investigate the extent and nature of variants in genes implicated in hereditary cancer predisposition in individuals referred for testing in our laboratory.

Methods: In total, 1197 individuals from Greece, Romania and Turkey were referred to our laboratory for genetic testing in the past 4 years. The majority of referrals included individuals with personal of family history of breast and/or ovarian cancer. The analysis of genes involved in hereditary cancer predisposition was performed using a NGS approach. Genomic DNA was enriched for targeted regions of 36 genes and sequencing was carried out using the Illumina NGS technology. The presence of large genomic rearrangements (LGRs) was investigated by computational analysis and Multiplex Ligation-dependent Probe Amplification (MLPA).

Results: A pathogenic variant was identified in 264 of 1197 individuals (22.1%) analyzed while a variant of uncertain significance (VUS) was identified in 34.8% of cases. Clinically significant variants were identified in 29 of the 36 genes analyzed. Concerning the mutation distribution among individuals with positive findings, 43.6% were located in the BRCA1/2 genes whereas 21.6, 19.9, and 15.0% in other high, moderate and low risk genes respectively. Notably, 25 of the 264 positive individuals (9.5%) carried clinically significant variants in two different genes and 6.1% had a LGR.

Conclusions: In our cohort, analysis of all the genes in the panel allowed the identification of 4.3 and 8.1% additional pathogenic variants in other high or moderate/low risk genes, respectively, enabling personalized management decisions for these individuals and supporting the clinical significance of multigene panel analysis in hereditary cancer predisposition.
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http://dx.doi.org/10.1186/s12885-019-5756-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547505PMC
June 2019

Analysis of and in saliva of colorectal cancer patients.

Biomark Med 2019 06 3;13(9):725-735. Epub 2019 Jun 3.

Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara 06230, Turkey.

The aim of the study was to examine the prevalence and amount of (), () and () in the saliva of colorectal cancer (CRC) patients and controls. PCR analyses performed in 71 CRC patients and 77 controls. Saliva samples of patients had higher amounts of (p = 0.001) and (p < 0.001) compared with controls. Amount of and were lower in the microsatellite instability (+) group. Evaluation of salivary amount by receiver operating characteristics analysis found to have diagnostic value for CRC (AUC: 0.84, 95% CI: 0.72-0.96). We found higher amounts of and in the saliva of CRC patients. Salivary could helpful in distinction of CRC.
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http://dx.doi.org/10.2217/bmm-2019-0020DOI Listing
June 2019

Concomitant RAS and BRAF mutation in colorectal cancer - A report of 7 cases.

Indian J Cancer 2019 Apr-Jun;56(2):176-179

Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.

Rat sarcoma viral oncogene homolog (RAS) and B-Raf murine sarcoma viral oncogene homolog B1 (BRAF) are members of the same signaling pathway (RAS-RAF-mitogen-activated protein kinase (MAPK) in colorectal cancer (CRC). It is generally assumed that BRAF mutations are seen only with wild-type RAS in CRC. But RAS and BRAF are not mutually exclusive. We have identified concomitant BRAF and RAS mutations in seven patients. DNA was extracted from formalin-fixed paraffin-embedded tumor tissue and the mutation status of the RAS gene (exons 2, 3, 4) and BRAF (exon 15 V600, V597) was assessed using a polymerase chain reaction enzyme-linked mini sequence assay-based DNA sequencing method. Three patients harbored Kirsten rat sarcoma viral oncogene homolog (KRAS) with a codon 13 mutation (gly13asp) along with a BRAF variation of L597V in exon 15 (p. leu597val, c.1789C>G (CTA>GTA). Two patients harbored KRAS with codon 12 mutations; one harbored the gly12val mutation with a variation of leu597val in the BRAF exon 15 codon, the other harbored a gly12asp mutation with p. leu597val, c.1789C>G (CTA>GTA) in the BRAF exon 15 codon. One patient harbored a codon 117 mutation with a BRAF V600E mutation. The last patient harbored a NRAS exon 2 (gly12asp) mutation with the GGT/GAT, V600G mutation in the BRAF exon 15 codon. Consequently, concomitant KRAS and BRAF mutations are very rare. Although it is known that the survival of concomitant RAS/BRAF mutation carriers is generally poor, we have shown that survival of concomitant RAS/BRAF mutation carriers is variable.
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http://dx.doi.org/10.4103/ijc.IJC_430_18DOI Listing
September 2019

Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience.

J Oncol 2019 20;2019:5483791. Epub 2019 Mar 20.

Department of Medical Oncology, Hacettepe University, Ankara, Turkey.

Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts' immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. The literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management.
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http://dx.doi.org/10.1155/2019/5483791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446118PMC
March 2019

First-line treatment choices of Turkish medical oncologists in metastatic colorectal cancer: A survey study.

J BUON 2019 Jan-Feb;24(1):68-76

Afyon Kocatepe University, Department of Medical Oncology, Afyonkarahisar, Turkey.

Purpose: Colorectal cancer is one of the most common malignancies in the World. RAS-BRAF mutational status and primary tumor location are also important factors for the selection of optimal combinations therapies. In this study, we aimed to evaluate the Turkish oncologists' treatment decisions depending on tumor location and mutational status in metastatic colorectal cancer.

Methods: An online survey link was sent to the medical oncologists who are registered to Turkish Society of Medical Oncology via e-mail and mobile applications.

Results: Ninety-four oncologists (85.5%) reported that tumor localization affects their treatment modality. In RAS-BRAF wild type left colon tumors, Turkish oncologists mostly use chemotherapy and anti-EGFR therapy (90.1%) for the first-line treatment, while on the right side, oncologists favored anti-VEGF therapy in combination with chemotherapy (65.5%). BRAF-mutant tumors in left colon had nearly the same rates of treatment tendency with both anti-VEGF and anti-EGFR antibodies in combination with chemotherapy, while in right-sided tumors the main treatment selection of the participants was anti-VEGF-based treatment (83.6%). In RAS-mutant patients, a great number of oncologists selected anti-VEGF-based treatment. On the right and left colon tumors, anti-VEGF treatment options ratios were 91.7 and 92.7%, respectively. Maintenance treatment is usually preferred by oncologists in both anti-VEGF and anti-EGFR-based treatment.

Conclusion: Turkish oncologists are considering tumor sidedness as an indicator for treatment individualization of patients. The selection of monoclonal antibodies is being affected by tumor localization and mutation status.
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August 2019

The frequency and predictors of persistent amenorrhea in premenopausal women with colorectal cancer who received adjuvant chemotherapy.

Anticancer Drugs 2019 03;30(3):289-294

Medical Oncology, Hacettepe University Cancer Institute.

The purpose of this study was to identify the frequency of chemotherapy-induced amenorrhea and associated factors thereof in premenopausal female patients diagnosed with colon cancer. Premenopausal female patients under the age of 50 years who were diagnosed with stages I, II, and III colon cancer were included. A questionnaire surveying personal history including menarche, comorbidities, drugs, other clinical features, and menstrual history during and after completion of chemotherapy was filled by the patients during outpatient visits. Patients who received pelvic radiotherapy were excluded from the study. A total of 60 patients were included in the study. Eleven patients had been treated with surgery alone, and 49 patients had received adjuvant chemotherapy with either fluorouracil (5-FU) alone (n=22) or 5-FU+oxaliplatin (n=27). The frequency of persistent amenorrhea 1 year after receiving chemotherapy was 20% in the whole group, 18% in patients who had received adjuvant chemotherapy with 5-FU alone, and 22% in patients who had received chemotherapy with 5-FU+oxaliplatin. Frequency of persistent amenorrhea was 3.5% in patients under the age of 44 years and 42.8% in patients aged 44 years and older. Multivariate analysis showed that age of 44 years and older (hazard ratio: 29.3; 95% confidence interval: 2.8-309.2, P=0.005) and menarche age of 14 years and older (hazard ratio: 7.6; 95% confidence interval: 1.2-49, P=0.076) were significantly associated with increased risk of persistent amenorrhea. In this study, we found that the frequency of persistent amenorrhea was 20% in patients who received 5-FU monotherapy or oxaliplatin-based adjuvant chemotherapy protocols in colon cancer treatment. Older age and later menarche were the factors that increased the risk of persistent amenorrhea 1 year after chemotherapy.
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http://dx.doi.org/10.1097/CAD.0000000000000728DOI Listing
March 2019

Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Oncol 2018 11 21;19(11):1437-1448. Epub 2018 Oct 21.

Vall d'Hebron University Hospital and Institute of Oncology, Barcelona, Spain.

Background: Trifluridine/tipiracil showed activity and was well tolerated in a phase 2 study of pretreated patients with advanced gastric cancer done in Japan. We investigated whether the treatment was efficacious compared with placebo in a global population.

Methods: TAGS was a randomised, double-blind, placebo-controlled, phase 3 trial done in 110 academic hospitals in 17 countries. Patients aged 18 years or older with histologically confirmed, non-resectable, metastatic gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) as defined by the American Joint Committee on Cancer staging classification (7th edition) who had received at least two previous chemotherapy regimens and had experienced radiological disease progression were eligible for inclusion. Patients were randomly assigned (2:1) via dynamic randomisation from a centralised interactive voice-response system to receive either oral trifluridine/tipiracil (35 mg/m twice daily on days 1-5 and days 8-12 every 28 days) plus best supportive care or placebo plus best supportive care. Participants were allocated to groups by study-site personnel. Randomisation was stratified by region (Japan vs rest of world), ECOG performance status (0 vs 1), and previous treatment with ramucirumab (yes vs no). Both patients and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy was assessed in the intention-to-treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT02500043. The trial, including follow-up of all participants, has been completed.

Findings: Between Feb 24, 2016, and Jan 5, 2018, 507 patients were enrolled and randomly assigned, 337 to the trifluridine/tipiracil group and 170 to the placebo group. Median overall survival was 5·7 months (95% CI 4·8-6·2) in the trifluridine/tipiracil group and 3·6 months (3·1-4·1) in the placebo group (hazard ratio 0·69 [95% CI 0·56-0·85]; one-sided p=0·00029, two-sided p=0·00058). Grade 3 or worse adverse events of any cause occurred in 267 (80%) patients in the trifluridine/tipiracil group and 97 (58%) in the placebo group. The most frequent grade 3 or worse adverse events of any cause were neutropenia (n=114 [34%]) and anaemia (n=64 [19%]) in the trifluridine/tipiracil group and abdominal pain (n=15 [9%]) and general deterioration of physical health (n=15 [9%]) in the placebo group. Serious adverse events of any cause were reported in 143 (43%) patients in the trifluridine/tipiracil group and 70 (42%) in the placebo group. One treatment-related death was reported in each group (because of cardiopulmonary arrest in the trifluridine/tipiracil group and because of toxic hepatitis in the placebo group).

Interpretation: Trifluridine/tipiracil significantly improved overall survival compared with placebo and was well tolerated in this heavily pretreated population of patients with advanced gastric cancer. Trifluridine/tipiracil could be a new treatment option in this population who represent a high unmet medical need.

Funding: Taiho Oncology and Taiho Pharmaceutical.
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http://dx.doi.org/10.1016/S1470-2045(18)30739-3DOI Listing
November 2018

Real world survival data of a rare malignancy: Anal cancer results in HIV negative patients from Turkey.

Turk J Gastroenterol 2018 07;29(4):411-418

Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.

Background/aims: An organ preservation approach using chemoradiotherapy has been established for anal cancer. This retrospective cohort study aimed to define the clinico-demographic characteristics and outcomes of cases of human immunodeficiency virus (HIV)-negative anal carcinoma during a period of 20 years in a single comprehensive cancer institute.

Materials And Methods: This was a single-center retrospective cohort study of patients who were treated between January 1995 and January 2015. The primary outcome measures that were investigated included overall survival (OS), progression-free survival (PFS), colostomy rates, and colostomy-free survival (CFS).

Results: A total of 28 patients who were principally treated with standard 5-fluorouracil + mitomycin combination chemoradiotherapy were eligible for analysis. The 3- and 5-year PFS rates were 92.4% and 63%, respectively. The lower T stage was found to be associated with a prolonged PFS (p=0.001). The 3- and 5-year CFS rates were 84.3% and 74.9%, respectively. A longer CFS was observed with lower T stages (p=0.05). At the last follow-up, 75% of the patients with anal cancer were alive, and 71.4% of the patients were disease free. The median OS was not reached with a median follow-up of 54 months (range, 6-115 months). The 3- and 5-year OS rates were 82% and 71.1%, respectively. No late toxicity was observed during the follow-up period.

Discussion: The short- and long-term prognoses of HIV-negative patients with anal squamous cell carcinoma were good, and low-grade toxicity was rare, thereby demonstrating that these patients can be successfully treated in a real-life setting with favorable outcomes.
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http://dx.doi.org/10.5152/tjg.2018.17660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284643PMC
July 2018

Prevalence of Complementary Medicine Use in Patients With Cancer: A Turkish Comprehensive Cancer Center Experience.

J Glob Oncol 2018 09 18;4:1-6. Epub 2017 Apr 18.

Suayib Yalcin and Pervin Hurmuz, Hacettepe University School of Medicine, Ankara, Turkey; and Lacey McQuinn and Aung Naing, University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Complementary and alternative medicine (CAM) has been popular among patients with cancer for several decades. The objectives of this study were to evaluate the prevalence of CAM use and to identify the factors affecting CAM use in a large patient cohort seen at a comprehensive cancer center in Turkey.

Patients And Methods: An investigator-designed survey was completed by volunteer patients who visited the outpatient clinic in the medical oncology department. CAM use encompassed pharmacologic agents including vitamins, dietary supplements, and herbal products or nonpharmacologic methods like prayer, meditation, hypnosis, massage, or acupuncture.

Results: Of 1,499 patients who answered the survey, 1,433 (96%) used nonpharmacologic CAM and 60 (4%) used pharmacologic CAM (pCAM). The most frequent types of CAM used were prayer (n = 1,433) followed by herbal products (n = 42). pCAM use was not significantly associated with age ( P = .63), sex ( P = .15), diagnosis ( P = .15), or income level ( P = .09). However, it was significantly associated with the level of education ( P = .0067) and employment status ( P < .001). Patients with higher education levels used more pCAM products ( P = .025). Among 60 pCAM users, six patients (10%) used pCAM for more than 2 years and 22 (36%) did not consult their physicians about their pCAM use. Only nine patients (15%) reported unpleasant adverse effects related to pCAM.

Conclusion: Although CAM use was high among our patients, prevalence of pCAM use was lower than expected. Patients with higher education levels tended to use more pCAM.
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http://dx.doi.org/10.1200/JGO.2016.008896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180833PMC
September 2018