Publications by authors named "Bulent Karabulut"

54 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

Older adults with colon cancer are not different from younger ones, but treated differently: Retrospective analysis from single centre.

J Oncol Pharm Pract 2021 Mar 22:10781552211002912. Epub 2021 Mar 22.

Division of Medical Oncology, Department of Internal Medicine, Ege University School of Medicine, Izmir, Turkey.

Aim: Decision- making of the treatment of colon cancer for the older patients becomes more complicated in consequence of comorbidities and geriatric syndromes, most importantly frailty. In the present study, we aimed to investigate whether there is a difference between tumour characteristics, treatment choices, and outcomes between the younger and older adults.

Method: The patients who were diagnosed with colorectal carcinoma in our centre between 2010 and 2015 included. Clinicopathological features of tumour, treatment choices and survivals of the patients were recorded. Patients were separated into two groups according to their chronological age.

Results: The present study included 465 patients, there were 173 patients aged 65 years and older. Clinicopathological features were similar in both groups. Adjuvant chemotherapy was given in similar rates. Whereas combination chemotherapies were preferred in younger patients as first-line therapy, single agents were given to the older group(p-value < 0.001). No significant differences were observed between combination therapy and monotherapy as progression-free and overall survival in older adults(p value > 0.05). It was observed that 53.2% of the older patients was not treated with any biological treatment (p-value < 0.001).

Discussion: Geriatric people are underrepresented in clinical trials,because of the presence of the limitations in the older patients. The results of our study revealed older patients with colon cancer patients underwent surgery less than the younger ones, they recieved monotherapy more frequently as first-line chemotherapy, and less frequently targeted therapy. Their mortality was higher. It was shown that decision-making of colon cancer therapy is influenced by age according to our results.
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http://dx.doi.org/10.1177/10781552211002912DOI Listing
March 2021

Safety and efficacy of everolimus (EVE) plus exemestane (EXE) in postmenopausal women with locally advanced or metastatic breast cancer: final results from EVEREXES.

Breast Cancer Res Treat 2021 Mar 16. Epub 2021 Mar 16.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: This study was conducted to collect clinical safety, tolerability, and efficacy data with the use of everolimus (EVE) combined with exemestane (EXE) in patients with advanced breast cancer (ABC).

Methods: The EVEREXES trial initiated in 2012, provided early access to the first dual blockade treatment with EVE + EXE in patients with HR+, HER2 - ABC in Asia and other emerging growth countries. Postmenopausal women with HR+, HER2 - ABC who had documented recurrence or progression, following a nonsteroidal aromatase inhibitor therapy, were treated with EVE (10 mg/day) + EXE (25 mg/day) orally.

Results: A total of 235 patients received ≥ 1 dose of study medication. At the end of the study, all patients ceased the treatment. Disease progression (66.0%) was the primary reason of discontinuation. The most common AEs (≥ 20%) were stomatitis, decreased appetite, hyperglycemia, rash, aspartate aminotransferase increased, anemia, alanine aminotransferase increased, cough, and fatigue. No new safety concerns were identified in the current study. Median progression-free survival (PFS) in the Asian subset was similar to that of the overall population (9.3 months in both groups). Confirmed overall response rate (ORR) was achieved for 19.6% of the patients. Efficacy of EVE + EXE across subgroups (prior CT, line of treatment, and presence of visceral metastases) was maintained.

Conclusion: The safety and efficacy results from EVEREXES trial are consistent to data previously reported in BOLERO-2. These results support that EVE + EXE could be a viable treatment option for the postmenopausal women with HR+, HER2 - ABC in Asian region.
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http://dx.doi.org/10.1007/s10549-021-06173-zDOI Listing
March 2021

The effectiveness of cetuximab and panitumumab when combined with FOLFIRI in second-line treatment of KRAS wild type metastatic colorectal cancers. Single centre experience.

J Chemother 2021 May 21;33(3):180-186. Epub 2020 Dec 21.

Tulay Aktas Oncology Hospital, Ege University School of Medicine, IZMIR, Turkey.

Panitumumab and cetuximab are monoclonal antibodies known to be effective in metastatic colorectal cancer (mCRC). Although the survival benefits when combined with chemotherapy have been determined, there are no studies comparing the two agents with chemotherapy in the second-line treatment. In this study, we aimed to compare the efficacy of cetuximab vs panitumumab in patients who previously received chemotherapy. Who progressed after first-line treatment for K-ras wild type mCRC were analyzed. The efficacy of cetuximab vs panitumumab on overall survival (OS) and progression-free survival (PFS) when combined with FOLFIRI regimen was compared retrospectively. Median PFS was 6.9 months in the cetuximab group and 4.7 months in the panitumumab group. Median OS cetuximab and panitumumab groups were 18.4 and 12.2 months, respectively. In the second-line treatment of K-ras wild type mCRC, both PFS and OS were found to be longer in patients receiving cetuximab than in patients receiving panitumumab, but no statistically significant difference was found.
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http://dx.doi.org/10.1080/1120009X.2020.1861531DOI Listing
May 2021

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

Evaluation of sarcopenia, sarcopenic obesity, and phase angle in geriatric gastrointestinal cancer patients: before and after chemotherapy

Turk J Med Sci 2019 Apr 18;49(2):583-588. Epub 2019 Apr 18.

Background/aim: The purpose of this study was to determine sarcopenia, sarcopenic obesity and phase angle (PA) and the influence of chemotherapy (CT) on anthropometric measurements and and the PA in in geriatric patients with gastrointestinal (GI) cancer.

Materials And Methods: The anthropometric measurements, calf circumference (CC), upper midarm circumference (UMAC), and hand grip strength (HGS), have been measured to understand muscle function of 153 patients (mean age of 70.5 ± 5.6 years, 28.8% female, 71.2% male). Sarcopenia and PA measurements have been evaluated by bioelectrical impedance analyses. The same evaluations were checked again after 1 cycle of CT (min: 4, max: 6 weeks).

Results: Patient population consisted of colorectal (51,6%), gastric (26.8%), pancreas (11.8%), liver (7.2%), and biliary tract cancer (2%). UMAC (28.5 ± 4.4 before, 28.1 ± 4.9, P = 0.034 after CT), and HGS measurements (27.5 ± 8.6 before, 26.8 ± 8.8 after CT, P = 0.007) have significantly decreased after CT. CC measurement < 31 cm at first visit was seen in 13.1% of patients, but the ratio raised to 20.3% after CT (χ², P = 0.003). Severe sarcopenia was determined in 33% of all patients, and 30.0% of them have been considered as sarcopenic obese.

Conclusion: Sarcopenia and sarcopenic obesity were prevalent in this group patients. The CT caused a decrease in muscle functions, UMAC, and CC. Patients should be followed up carefully for sarcopenia, sarcopenic obesity, and nutritional aspect and it would be proper to intervene before sarcopenia has not occurred yet.
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http://dx.doi.org/10.3906/sag-1808-114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018239PMC
April 2019

The Impact of Subtype Distribution in Inflammatory Breast Cancer Outcome.

Eur J Breast Health 2018 Oct 1;14(4):211-217. Epub 2018 Oct 1.

Division of Medical Oncology, Tülay Aktaş Oncology Hospital, Ege University School of Medicine, İzmir, Turkey.

Objective: Inflammatory breast cancer (IBC) has an unfavourable prognosis despite the advances made in the treatment of breast cancer. Our study aimed to define immunohistochemistry-based surrogate subtype distribution to determine whether the breast cancer subtype accompanied survival outcome differences in IBC.

Materials And Methods: Medical records of female breast cancer patients with non-metastatic inflammatory breast cancer admitted to our clinic between March 2000 and December 2015 were retrospectively reviewed. Patient demographics, clinical and pathological feature of the primary tumour, adjuvant treatment options and survival data were analysed. Intrinsic breast cancer subtypes were defined according to ER, PR, HER-2 and ki-67 status.

Results: We identified 129 non-metastatic inflammatory breast cancer patients. Median follow-up was 73 months. 10 (7.7%) were luminal A-like, 67 (51.9%) were luminal B-like, 37 (28.6%) were HER-2 positive, and 15 (11.6%) were triple negative (TNBC) by immunohistochemistry. There were no statistically significant differences between subtypes in terms of histological type, grade, tumour size and lymph node status. Median disease-free survival was 47 months (95% confidence interval [CI] 29.2-82.6) and median overall survival was 75 months (95% CI 64.7-90.8). Triple negative breast cancer showed poorer outcome than other subgroups. Presence of TNBC disease was associated with poorer outcome compared to luminal A (HR: 0.19, 95% CI 0.04-0.92, p: 0.039), luminal B (HR: 0.34, 95% CI 0.15-0.74, p: 0.007) and HER-2 positive subgroups (HR: 0.40, 95% CI 0.17-0.94, p:0.037). Luminal A patients had a trend to have a better overall survival which did not reach to a statistical significant difference.

Conclusion: Our study put forth that IBC have a poor prognosis irrespective of breast cancer surrogate subtype distribution. Luminal A, the most frequent subtype of breast cancer was the least common in our IBC patient group. TNBC had the worst outcome when compared to other breast cancer subtypes.
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http://dx.doi.org/10.5152/ejbh.2018.4170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170018PMC
October 2018

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

Surg Oncol 2018 Sep 30;27(3):485-489. Epub 2018 May 30.

Department of Medical Oncology, NecmettinErbakan University, Meram Faculty of Medicine, Konya, Turkey. Electronic address:

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.
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http://dx.doi.org/10.1016/j.suronc.2018.05.032DOI Listing
September 2018

The effect of chemotherapy on nutritional status and weakness in geriatric gastrointestinal system cancer patients.

Nutrition 2018 03 12;47:39-42. Epub 2017 Oct 12.

Ege University School of Medicine, Department of Geriatric, Bornova, Izmir, Turkey.

Objectives: Malnutrition is common in patients with geriatric gastrointestinal system (GIS) cancer. This study aimed to evaluate patients with geriatric GIS cancer in terms of nutritional status and weakness and determine the changes caused by chemotherapy (CT).

Methods: Patients with geriatric GIS cancer who received CT were included in the study. Their nutritional status was assessed with the Mini Nutritional Assessment, and weakness was assessed with the handgrip strength/body mass index ratio. After CT (minimum 4 wk and maximum 6 wk later), patients were assessed for the same parameters.

Results: A total of 153 patients aged ≥65 y (mean age, 70.5 ± 5.6 y; 44 female and 109 male) were evaluated. The population consisted of patients who were diagnosed with colorectal (51.6%), gastric (26.8%), pancreatic (11.8%), hepatic (7.2%), biliary tract (2%), and esophageal (0.7%) cancer. Of these patients, 37.9% were malnourished, 34.6% were at risk of malnutrition, and 27.5% were well nourished. After one course of CT, the frequency of malnutrition increased to 46.4% (P = 0.001). The patient groups with the highest rates of weakness were those who were diagnosed with biliary tract, hepatic, and colorectal cancer (33.3%, 27.3%, and 20%, respectively). Weakness was significantly increased after one course of CT in patients who received CT before (P = 0.039).

Conclusions: Malnutrition and weakness were common in patients with geriatric GIS cancer, and even one course of CT worsened the nutritional status of the patients. Patients who have received CT previously should be carefully monitored for weakness.
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http://dx.doi.org/10.1016/j.nut.2017.09.013DOI Listing
March 2018

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

J Gastrointest Cancer 2019 Jun;50(2):214-220

Department of Medical Oncology, Anadolu Medical Center, Istanbul, Turkey.

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.
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http://dx.doi.org/10.1007/s12029-017-0047-2DOI Listing
June 2019

The effects of chemoradiotherapy on recurrence and survival in locally advanced rectal cancers with curative total mesorectal excision: a prospective, nonrandomized study.

World J Surg Oncol 2017 Nov 22;15(1):205. Epub 2017 Nov 22.

Department of Gastroenterology, Ege University School of Medicine, Izmir, Turkey.

Background: There are only two prospective, randomized studies comparing preoperative long-term chemoradiotherapy and postoperative chemoradiotherapy in locally advanced rectal cancer (LARC); however, conflicting results in terms of locoregional recurrence (LR) and survival rates have been reported. This prospective study aims to compare the effects of preoperative versus postoperative chemoradiotherapy on recurrence and survival rates in LARC patients.

Methods: From January 2003 to January 2016, a total of 336 eligible patients who were clinically diagnosed with LARC (T-T tm or node-positive disease) were prospectively assigned into preoperative chemoradiotherapy (n = 177) and postoperative chemoradiotherapy (n = 159) groups. The preoperative treatment consisted of 50.4 Gy total dose of radiotherapy (delivered in fractions of 1.8 Gy) and concomitant two cycles chemotherapy of 5-fluorouracil and leucovorin. The patients in the preoperative group underwent curative total mesorectal excision (TME) following long-term chemoradiotherapy. Surgery was performed 8 (range 4-12) median weeks after the completion of the chemoradiotherapy. Similar protocol was administered to the postoperative group 4 weeks after the operation. Four cycles of adjuvant chemotherapy were added to the groups. The primary end points were locoregional recurrences and 5-year cancer-specific, overall, and disease-free survivals.

Results: The mean follow-up period was 60.4 (range 12 to 168) months. Five-year cumulative incidence of locoregional recurrence (LR) was 7.4% in the preoperative group and 13.4% in the postoperative group (p = 0.021). Five-year cancer-specific survival (CSS) was 87.5% in the preoperative group and 80% in the postoperative group (p = 0.022). Overall survival (OS) was 79.8 versus 74.7% (p = 0.064), disease-free survival (DFS) was 75.2 versus 64.8% (p = 0.062), and severe late toxicity was 7.4 versus 13.2% (p = 0.002), respectively. The rate of patient compliance was higher in the preoperative group (p < 0.001).

Conclusions: Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, significantly improved local control, patient compliance, CSS, and late toxicity and suggested a trend toward improved overall and disease-free survival.
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http://dx.doi.org/10.1186/s12957-017-1275-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700528PMC
November 2017

Renal cell cancer: overview of the current therapeutic landscape.

Expert Rev Anticancer Ther 2016 Sep 24;16(9):955-68. Epub 2016 Aug 24.

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

Introduction: The last decade has witnessed dramatic improvements in the diagnosis, classification and treatment of renal cell cancer (RCC). Besides improvements in surgical techniques in early stages, introduction of novel targeted agents has resulted in improved outcomes in advanced RCC for which no effective treatment existed until recently.

Areas Covered: This article reviews epidemiology, pathology and pathogenesis, diagnosis, clinical staging, prognostic factors and treatment modalities of early stage and advanced RCC. Expert commentary: Although treatment options are expanding rapidly, practicing physicians face considerable challenges in the decision-making process. Therapeutic agents may have unique side effects and unexpected drug interactions. RCC represents one of the major success stories of clinical oncology in recent years and the progress appears to be far from having reached a plateau. We aim to present a comprehensive in-depth review of RCC in an attempt to provide evidence-based recommendations and future perspectives for practicing oncologists.
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http://dx.doi.org/10.1080/14737140.2016.1222908DOI Listing
September 2016

Benefit of Bevacizumab-Based Frontline Therapy in Patients with Metastatic Colorectal Cancer (mCRC): a Turkish Oncology Group Study.

J Gastrointest Cancer 2016 Sep;47(3):264-72

Department of Medical Oncology, Anadolu Medical Center, Istanbul, Turkey.

Background: Several chemotherapy regimens using bevacizumab have been developed. Our goal was to investigate regimens that have demonstrated significant clinical activity in patients with metastatic colorectal cancer (mCRC).

Materials And Methods: Six hundred and sixty six patients with mCRC who received first-line chemotherapy combination with bevacizumab were studied. Fluoropyrimidine (F) plus irinotecan (I)-based (FI-bev), F plus oxaliplatin (O)-based (FO-bev), and F-based (F-bev) treatment regimens were compared with respect to progression-free survival (PFS) and overall survival (OS).

Results: The median PFS of FI-bev (n = 414) was 10.9 months (95 % CI 10-11.8), of FO-bev (n = 211) was 9.4 months (95 % CI 8.3-10.4), and of F-bev (n = 41) was 9.5 months (95 % CI 5.9-13.1) (p = 0.089). The median OS of FI-bev was 26.3 months (95 % CI 21.7-30.9), of FO-bev was 27 months (95 % CI 24.3-29.7), and of F-bev was 23.3 months (95 % CI 12.7-33.9) (p = 0.102). In KRAS wild-type patients, the median PFS of FI-bev group was significantly longer than FO-bev group (10.5 vs. 9.1 months, p = 0.006). The FI-bev group had better OS than FO-bev group with borderline significance (p = 0.058). The FI-bev group had significantly longer OS than F-bev group. Patients who underwent metastasectomy or those with Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 had longer PFS and OS independent of the type of chemotherapy regimen.

Conclusion: FI-bev may be the preferred frontline regimen for patients with KRAS wild-type mCRC. Metastasectomy and performance score were the strongest positive predictors of OS and PFS regardless of backbone chemotherapy regimen.
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http://dx.doi.org/10.1007/s12029-016-9823-7DOI Listing
September 2016

Prevalence of K-Ras mutations in hepatocellular carcinoma: A Turkish Oncology Group pilot study.

Mol Clin Oncol 2015 Nov 31;3(6):1275-1279. Epub 2015 Aug 31.

Department of Medical Oncology, Necmettin Erbakan University, Meram Faculty of Medicine, 42080 Konya, Turkey.

Hepatocellular carcinoma (HCC) is the fifth most common male-predominant type of cancer worldwide. There is no effective treatment regimen available for advanced-stage disease and chemotherapy is generally ineffective in these patients. The number of studies on the prevalence of K-Ras mutations in HCC patients is currently limited. A total of 58 patients from 6 comprehensive cancer centers in 4 metropolitan cities of Turkey were enrolled in this study. Each center committed to enroll approximately 10 random patients whose formalin-fixed paraffin-embedded tumor tissues were available for K-Ras, exon 2 genotyping. Two methods were applied based on the availability of adequate amounts of tumor DNA. In the first method, the samples were processed using TheraScreen. The genomic DNA was further used to detect the 7 most frequent somatic mutations (35G>A; 35G>C; 35G>T; 34G>A; 34G>C; 34G>T and 38G>A) in codons 12 and 13 in exon 2 of the K-Ras oncogene by quantitative polymerase chain reaction (PCR). In the second method, the genomic DNA was amplified by PCR using primers specific for K-Ras exon 2 with the GML SeqFinder Sequencing System's KRAS kit. The identified DNA sequence alterations were confirmed by sequencing both DNA strands in two independent experiments with forward and reverse primers. A total of 40 samples had adequate tumor tissue for the mutation analysis. A total of 33 (82.5%) of the investigated samples harbored no mutations in exon 2. All the mutations were identified via a direct sequencing technique, whereas none were identified by TheraScreen. In conclusion, in our patients, HCC exhibited a remarkably low (<20%) K-Ras mutation rate. Patients harboring K-Ras wild-type tumors may be good candidates for treatment with epidermal growth factor inhibitors, such as cetuximab.
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http://dx.doi.org/10.3892/mco.2015.633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4665597PMC
November 2015

Octreotide in combination with AT-101 induces cytotoxicity and apoptosis through up-regulation of somatostatin receptors 2 and 5 in DU-145 prostate cancer cells.

Tumour Biol 2016 Apr 3;37(4):4939-44. Epub 2015 Nov 3.

Department of Medical Oncology, School of Medicine, Ege University, Izmir, Turkey.

Prostate cancer (PCa) is the most common type of cancer among males. Although survival rate of early-stage PCa is high, treatment options are very limited for recurrent disease. In this study, the possible synergistic cytotoxic and apoptotic effect of octreotide in combination with AT-101 was investigated in DU-145 hormone and drug refractory prostate cancer cell line. To enlighten the action mechanisms of the combination treatment, expression levels of somatostatin receptors 2 and 5 (SSTR2 and SSTR5) were also investigated. Cell viability was measured by XTT assay. Apoptosis was assessed through DNA fragmentation analysis and caspase 3/7 assay. mRNA and protein levels of SSTR2 and SSTR5 were evaluated by qRT-PCR and western blot analysis, respectively. Octreotide in combination with AT-101 inhibited cell viability and induced apoptosis synergistically in DU-145 cells as compared to any agent alone. Combination treatment increased both SSTR2 and SSTR5 mRNA and protein levels in DU-145 cells. The data suggest that this combination therapy may be a good candidate for patients with advanced metastatic PCa do not respond to androgen deprivation.
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http://dx.doi.org/10.1007/s13277-015-4331-0DOI Listing
April 2016

The Role of Body Mass Index in Triple Negative Breast Cancer.

Oncol Res Treat 2015 11;38(10):518-22. Epub 2015 Sep 11.

Division of Medical Oncology, Yunus Emre State Hospital, Eskisehir, Turkey.

Background: Triple-negative breast cancer (TNBC) has none of the targeted treatment choices due to its distinct biological property, making this subtype a unique disease. In this study, we evaluated the impact of obesity on clinical outcomes of TNBC.

Methods: The data of breast cancer patients admitted to our department were collected. TNBC was defined as lack of estrogen receptor (ER), progesterone receptor (PR) and HER-2. The body mass index (BMI) of 112 TNBC patients was calculated with weight at the time of diagnosis and height. The patients were classified into groups with a BMI of < 25 (normal/underweight), 25-29.9 (overweight) or ≥ 30 (obese). After a mean follow-up of 23.2 ± 15.5 months, there were 12 recurrences (10.71%) and 6 deaths (5.35%). Disease-free survival (DFS) and overall survival (OS) were assessed.

Results: The survival analyses of all the patients did not demonstrate any differences in OS or DFS in obese as compared to non-obese patients. However, we showed that obesity was associated with a poorer OS for postmenopausal TNBC patients (p < 0.05).

Conclusion: Obesity is related to a poorer OS in postmenopausal TNBC patients. Due to the heterogeneous disease profile of TNBC, larger randomized studies will be needed to clarify the exact role of obesity in TNBC.
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http://dx.doi.org/10.1159/000439551DOI Listing
July 2016

Docetaxel in combination with octreotide shows synergistic apoptotic effect by increasing SSTR2 and SSTR5 expression levels in prostate and breast cancer cell lines.

Cancer Chemother Pharmacol 2015 Jun 30;75(6):1273-80. Epub 2015 Apr 30.

Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, 35100, Bornova, Izmir, Turkey,

Purpose: Docetaxel (DTX) is widely used for the treatment of metastatic prostate and breast cancers. Despite the clinical success of DTX, drug-related cumulative toxicity restricts its clinical use in cancer therapy. Thus, there is an urgent need for new therapeutic options. Octreotide (OCT) is a synthetic somatostatin analog that induces apoptosis in different cancer cell lines in vitro. In this study, we investigated the possible synergistic apoptotic effects of DTX in combination with OCT in prostate and breast cancer cell lines.

Methods: The XTT cell viability assay was used to determine cytotoxicity. Apoptosis was evaluated by Cell Death Detection ELISA(Plus) Kit. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. Levels of SSTR2 and SSTR5 proteins were determined by western blot analysis.

Results: DTX and OCT combination induced apoptosis in both breast and prostate cancer cells in a concentration- and time-dependent manner. Moreover, combination treatment resulted in inhibition of anti-apoptotic proteins such as Bcl-2 and Bcl-xL and induction of pro-apoptotic proteins Bax, Cytochrome c and IAPs in all of the tested cancer cell lines. SSTR2 and SSTR5 protein levels were induced as compared to any agent alone.

Conclusions: These results indicate that this combination treatment is a significant inducer of apoptosis in a synergistic manner in breast and prostate cancer cells. This strong synergism helps to lower the dose of DTX in both types of cancers, thus letting DTX to be used for longer periods by delaying resistance development and lesser side effects.
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http://dx.doi.org/10.1007/s00280-015-2756-1DOI Listing
June 2015

Markers to predict the efficacy of bevacizumab in the treatment of metastatic colorectal cancer.

Tumori 2014 Jul-Aug;100(4):370-6

The identification of clinical, biochemical and molecular markers to predict or monitor the efficacy of bevacizumab represents a major point in the treatment of patients with metastatic colorectal cancer. Studies and genetic analyses have been conducted to identify a predictive biomarker of bevacizumab efficacy. However, genes of the angiogenic pathway and angiogenic biomarkers vary substantially, thereby causing interindividual differences that complicate the identification of predictors for anti-vascular endothelial growth factor drugs like bevacizumab. So, the current challenge in bevacizumab treatment is to find predictive markers and implement them in clinical practice. In this review we have summarized the potential candidate biomarkers that may have a role in identifying patients who benefit most from bevacizumab treatment.
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http://dx.doi.org/10.1700/1636.17888DOI Listing
December 2014

Second-line capecitabine and oxaliplatin combination for gemcitabine-resistant advanced pancreatic cancer.

Asian Pac J Cancer Prev 2014 ;15(17):7119-23

Department of Medical Oncology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey E-mail :

Background: The role of second-line therapy in metastatic pancreatic cancer is not clear. In this study, we aimed to explore the second-line efficiency of capecitabine and oxaliplatin (XELOX) in patients with advanced pancreatic cancer who have received gemcitabine-based first-line therapy.

Materials And Methods: We retrospectively evaluated 47 patients with locally advanced or metastatic pancreatic cancer previously treated with gemcitabine-based first-line regimens. Treatment consisted of oxaliplatin 130 mg/m2 and capecitabine 1000 mg/m2 twice daily with a 3 week interval, until unacceptable toxicity or disease progression.

Results: Median number of cycles was 4 (range, 2-10). The overall disease control rate was 38.3%. The median overall survival and progression-free survival from the start of second-line therapy were 23 weeks (95%CI: 16.6-29.5 weeks) and 12 weeks (95%CI: 9.8-14.4 weeks), respectively. The most common grade 3-4 toxicities were nausea, vomiting and hematologic side effects.

Conclusions: Our result suggests that the combination of capecitabine and oxaliplatin was tolerated with manageable toxicity and showed encouraging activity as second-line treatment of advanced or metastatic pancreatic cancer patients with ECOG performance status 0-2.
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http://dx.doi.org/10.7314/apjcp.2014.15.17.7119DOI Listing
June 2015

The clinical and pathological features of 133 colorectal cancer patients with brain metastasis: a multicenter retrospective analysis of the Gastrointestinal Tumors Working Committee of the Turkish Oncology Group (TOG).

Med Oncol 2014 Sep 10;31(9):152. Epub 2014 Aug 10.

Department of Medical Oncology, Faculty of Medicine, Medical School of Sitki Kocman University, Mugla, 48000, Turkey,

Brain metastasis in colorectal cancer is highly rare. In the present study, we aimed to determine the frequency of brain metastasis in colorectal cancer patients and to establish prognostic characteristics of colorectal cancer patients with brain metastasis. In this cross-sectional study, the medical files of colorectal cancer patients with brain metastases who were definitely diagnosed by histopathologically were retrospectively reviewed. Brain metastasis was detected in 2.7 % (n = 133) of 4,864 colorectal cancer patients. The majority of cases were male (53 %), older than 65 years (59 %), with rectum cancer (56 %), a poorly differentiated tumor (70 %); had adenocarcinoma histology (97 %), and metachronous metastasis (86 %); received chemotherapy at least once for metastatic disease before brain metastasis developed (72 %), had progression with lung metastasis before (51 %), and 26 % (n = 31) of patients with extracranial disease at time the diagnosis of brain metastasis had both lung and bone metastases. The mean follow-up duration was 51 months (range 5-92), and the mean survival was 25.8 months (95 % CI 20.4-29.3). Overall survival rates were 81 % in the first year, 42.3 % in the third year, and 15.7 % in the fifth year. In multiple variable analysis, the most important independent risk factor for overall survival was determined as the presence of lung metastasis (HR 1.43, 95 % CI 1.27-4.14; P = 0.012). Brain metastasis develops late in the period of colorectal cancer and prognosis in these patients is poor. However, early screening of brain metastases in patients with lung metastasis may improve survival outcomes with new treatment modalities.
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http://dx.doi.org/10.1007/s12032-014-0152-zDOI Listing
September 2014

[Case management based multidiscıplinary care protocol in the palliative care of cancer patients].

Agri 2014 ;26(2):47-56

Department of Internal Diseases Nursing, Ege University Faculty of Nursing, İzmir, Turkey.

Today, multifaceted approach is needed for the palliative care of advanced stage cancer patients. The main objective for these patients, elimination of pain and other symptoms, psychosocial and spiritual needs are met and to increase the quality of life. We are also faced with the challenge of meeting the physical and psychosocial needs of family members. The purpose of a holistic approach to patient and family who provide effective and quality care, care coordination and case management of a multidisciplinary team approach is based on cooperation. Care protocols specified patient care activities to be carried by the related disciplines to achieve results on a timeline that shows a certain, a multidisciplinary clinical management tool. A lot of care guidelines and protocols developed by a team of experts to contribute to the palliative care activities, and this is thought to be a guiding team members, working with patients.
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http://dx.doi.org/10.5505/agri.2014.93585DOI Listing
May 2016

Do high-risk features support the use of adjuvant chemotherapy in stage II colon cancer? A Turkish Oncology Group study.

Tumori 2014 Mar-Apr;100(2):143-8

Background: A high-risk group of patients with stage II colon cancer has been identified by the results of studies in Western populations. The aim of this study was to investigate the prognostic factors of adjuvant chemotherapy in Turkish patients with stage II colon cancer.

Methods: A total of 554 stage II colon cancer patients were retrospectively enrolled in the study. Three hundred fifty-three patients had received adjuvant chemotherapy (5-FU-LV, FOLFOX or FLOX) and 201 had received no adjuvant chemotherapy. T4 tumor stage, lymphovascular invasion, perineural invasion, bowel obstruction and/or perforation, <12 harvested lymph nodes, and poor differentiation were defined as high-risk factors.

Results: The median age of the patients was 62 years (range 26-88). The median disease-free survival (DFS) was 58.1 months (95% CI, 47.6 months to 68.5 months) in the non-treatment group and has not been reached in the treatment group (P <0.01). In univariate analysis, patient age >60 years and T4 tumor stage were statistically significant factors that affected DFS as poor prognostic factors. Adjuvant chemotherapy reduced the risk of recurrence with statistical significance (P <0.01). In multivariate analysis, patient age >60 years and T4 tumor stage were independent risk factors affecting DFS. In addition, adjuvant chemotherapy was an independent favorable prognostic factor for DFS (P <0.01).

Conclusions: Clinical and pathological risk factors in patients with stage II colon cancer may be different in the Turkish population compared to other populations. Further prospective studies in colon cancer are needed to understand the differences in biology and risk factors between races.
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http://dx.doi.org/10.1700/1491.16397DOI Listing
July 2014

First-line mono-chemotherapy in frail elderly patients with metastatic colorectal cancer.

Asian Pac J Cancer Prev 2014 ;15(7):3157-61

Katip Celebi University Ataturk, Izmir, Turkey E-mail :

Background: Unlike for fit elderly metastatic colorectal cancer (mCRC) patients, general approaches to initial treatment for the frail older mCRC patients are not clear. Our aim was to evaluate the efficiency and safety of first-line single-agent treatment in one such group.

Materials And Methods: We retrospectively evaluated mCRC patients aged 70 or older with an Eastern Cooperative Oncology Group performance score of 2. They had no prior treatment and underwent first-line single-agent capecitabine or other monotherapies until disease progression or unacceptable toxicity.

Results: Thirty-six patients were included. Most (n:28, 77.8%) were treated with capecitabine. One patient achieved a complete response and 5 patients had a partial response for an overall response rate of 16.6%. Twelve patients (33.3%) remained stable. Median progression free survival was 5 months (confidence interval (CI), %; 3.59-6.40) and median overall survival was 10 months (95 CI%; 8.1-11.8). Grade 3-4 toxicity was found in 6 patients (16.6%). Febrile neutropenia was not observed and there were no toxicity-associated deaths.

Conclusions: Capecitabine is a safe chemotherapeutic agent with moderate activity for first-line treatment of older metastatic colorectal cancer patients with limited performance status.
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http://dx.doi.org/10.7314/apjcp.2014.15.7.3157DOI Listing
January 2015

Tumor characteristics and metastatic sites may predict bevacizumab efficacy in the first-line treatment of metastatic colorectal cancer.

Mol Clin Oncol 2014 Jan 12;2(1):166-170. Epub 2013 Nov 12.

Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova, Izmir;

Colorectal cancer (CRC) is among the most frequently diagnosed cancers and a major cause of cancer-related mortality worldwide. The aim of the present study was to determine whether there was an improvement in the time to disease progression (TTP) in patients with metastatic colorectal cancer (mCRC) treated with first-line bevacizumab plus chemotherapy, according to tumor characteristics and metastatic sites. Tumor characteristics and tumor burden were considered to be predictive markers of the therapeutic efficacy of bevacizumab. The medical records of 705 patients with mCRC were retrospectively reviewed in three oncology centers between January, 2005 and September, 2012. A total of 101 patients completed their first-line bevacizumab-containing treatment. The median TTP was 6.93 months [interquartile range (IQR)=4.20-9.80 months] in patients treated with irinotecan, 5-fluorouracil (5-FU) and bevacizumab vs. 7.42 months (IQR=6.08-10.68 months) in those treated with oxaliplatin, 5-FU and bevacizumab (P=0.589). When we compared patients with pulmonary metastases (median TTP, 9.9000 months) or other metastatic patients without pulmonary metastasis (median TTP, 6.9000 months), we observed a statistically significant difference (P=0.046). However, when the efficacy of bevacizumab was compared in terms of other tumor characteristics (tumor grade, size and lymph node involvement) and metastatic sites, the differences were not significant (P>0.05). We concluded that bevacizumab may be effective in all subgroups of patients with mCRC. Furthermore, bevacizumab with combination chemotherapy may be superior to combination chemotherapy only as the first-line treatment of patients with mCRC and pulmonary metastasis.
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http://dx.doi.org/10.3892/mco.2013.212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915705PMC
January 2014

Examining the effect of the case management model on patient results in the palliative care of patients with cancer.

Am J Hosp Palliat Care 2014 Sep 4;31(6):655-64. Epub 2013 Oct 4.

Department of Algology, Faculty of Medicine Hospital, Ege University, Izmir, Turkey.

Purpose: We aimed to investigate the improvement in symptoms, quality of life, patient and family satisfaction with care, and direct costs resulting from a palliative care program based case management model.

Methods: The research was implemented at the Medical Oncology Clinic hospital of a University between September 2009 and September 2011. The research sample consisted of a total of 44 patients (22 control and 22 intervention group). The research tools were the Edmonton Symptom Diagnosis System, the Karnofsky Performance Scale, the EORTCQLQ-C30 Quality of Life Scale, a patient and family satisfaction form, and a patient cost record form.

Results: The difference between total symptom mean scores and the sub-dimension symptoms of pain, fatigue, nausea, depression, anxiety, lack of appetite, lethargy, well-being, dyspnea, and constipation post-hospitalization and post-discharge of patients in the control and experimental groups were found to be statistically significant (p < 0.05). The level of decrease in symptom severity in the experimental group patients was more than in the control group (p < 0.000). The satisfaction level of patients and family in the palliative care based case management service was higher than that for conventional service in the control group (p < 0.05). No statistical difference was detected between the experimental and control groups regarding health costs and duration of hospitalization (p > 0.05).

Conclusion: We provided a better symptom control, improved the patient s quality of life (excluding physical and congnitive functions), and patient and family satisfaction levels were higher in the palliative care based case management intervention group, but direct health costs were not affected.
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http://dx.doi.org/10.1177/1049909113506980DOI Listing
September 2014

Complications and toxicities after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Ann Surg Oncol 2013 Apr 2;20(4):1082-7. Epub 2013 Mar 2.

Department of Surgery, Dokuz Eylul University School of Medicine, Izmir, Turkey.

Introduction: The purpose of our study was to evaluate the perioperative complications, toxicity, mortality rates after cytoreductive surgery (CRS), and effects of hyperthermic intraperitoneal chemotherapy (HIPEC) used in the treatment of peritoneal surface malignancies.

Methods: Between September 2007 and March 2012, we performed 118 CRS and HIPEC with the closed abdominal technique on 115 patients with peritoneal carcinomatosis (PC). Systemic toxicities were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria and were analyzed from a prospectively collected database.

Results: The mean age of patients was 53.4 (range, 20-82) years; 76.3 % were female. PC was synchronous to primary cancer in 53.4 % of patients, metachronous in 41.5 %, and recurrent in 5.1 % of the patients. PCI was ≥15 in 53.4 % of the patients, and CC-0 cytoreduction was achieved in 68.5 % of the patients. Perioperative mortality was observed in 9 (7.6 %) patients. A total of 98 complications were observed in 46 (39.0 %) patients, and 4 patients underwent 6 reoperations for perioperative surgical complications. We observed toxicity in 25.4 % of the patients, nephrotoxicity in 18.6 %, and hematological toxicity in 13.6 % of patients. No significant difference was observed among age, gender, PCI and CC scores, origin of the primary tumor, and occurrence of toxicity and surgical complications. Prolonged operation times resulted in higher complication and/or toxicity rates (P < 0.01).

Conclusions: Cytoreductive surgery and HIPEC is a combined treatment strategy for peritoneal surface malignancies with acceptable complication and toxicity rates.
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http://dx.doi.org/10.1245/s10434-012-2853-xDOI Listing
April 2013

Combination of AT-101/cisplatin overcomes chemoresistance by inducing apoptosis and modulating epigenetics in human ovarian cancer cells.

Mol Biol Rep 2013 Jun 27;40(6):3925-33. Epub 2012 Dec 27.

Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, 35100, Bornova, Izmir, Turkey.

We investigated the effects of AT-101/cisplatin combination treatment on the expression levels of apoptotic proteins and epigenetic events such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzyme activities in OVCAR-3 and MDAH-2774 ovarian cancer cells. XTT cell viability assay was used to evaluate cytotoxicity. For showing apoptosis, both DNA Fragmentation and caspase 3/7 activity measurements were performed. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. DNMT and HDAC activities were evaluated by ELISA assay and mRNA levels of DNMT1 and HDAC1 genes were quantified by qRT-PCR. Combination of AT-101/cisplatin resulted in strong synergistic cytotoxicity and apoptosis in human ovarian cancer cells. Combination treatment reduced some pivotal anti-apoptotic proteins such as Bcl-2, HIF-1A, cIAP-1, XIAP in OVCAR-3 cells, whereas p21, Bcl-2, cIAP-1, HSP27, Clusterin and XIAP in MDAH-2774 cells. Among the pro-apoptotic proteins, Bad, Bax, Fas, phospho-p53 (S46), Cleaved caspase-3, SMAC/Diablo, TNFR1 and Cytochrome c were induced in OVCAR-3 cells, whereas, Bax, TRAILR2, FADD, p27, phospho-p53 (S46), Cleaved caspase-3, Cytochrome c, SMAC/Diablo and TNFR1 were induced in MDAH-2774 cells. Combination treatment also inhibited both DNMT and HDAC activities and also mRNA levels in both ovarian cancer cells. AT-101 exhibits great potential in sensitization of human ovarian cancer cells to cisplatin treatment in vitro, suggesting that the combination of AT-101 with cisplatin may hold great promise for development as a novel chemotherapeutic approach to overcome platinum-resistance in human ovarian cancer.
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http://dx.doi.org/10.1007/s11033-012-2469-zDOI Listing
June 2013

Zoledronic acid in combination with serine/threonine phosphatase inhibitors induces enhanced cytotoxicity and apoptosis in hormone-refractory prostate cancer cell lines by decreasing the activities of PP1 and PP2A.

BJU Int 2012 Dec 9;110(11 Pt C):E1147-54. Epub 2012 Aug 9.

Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Bornova, Izmir.

Unlabelled: What's known on the subject? and What does the study add? Prostate cancer is the second most common cancer diagnosed among elderly men. Current standard of care with surgery, chemotherapy or radiation in prostate cancer patients are of limited efficacy, especially in the androgen refractory state of the disease, and unfortunately metastatic disease remains incurable. Skeletal metastases are the most common site for metastases for prostate cancer and bisphosphonates have been widely used for the treatment of morbidity due to skeletal related events. Zoledronic acid (ZA) is the most potent member of the nitrogen containing new generation bisphosphonate (N-BPs) family. Okadaic acid (OA) and Calyculin A (CA) are the most commonly used inhibitors of PP1 and 2A. OA, extracted from common black sponge Halachondria okaddai is a potent inhibitor of protein phosphatases, PP1 and PP2A, and CA was isolated from another marine sponge, Discodermia calyx. Therapies based on combinations of chemotherapeutics with phosphatase inhibitors that target signaling pathways within the cell with different mechanisms of action, may be useful for increasing therapeutic effect and also diminish toxic side effects by decreasing the doses of conventional chemotherapeutics. Although clinically well known, the in vitro effects of ZA on cancer cells and the underlying mechanisms are not well elucidated. In our previous studies, we have already shown anticancer effect of ZA in hormone-and drug refractory prostate cancer cells, PC-3 and DU-145. In addition to this, we have also shown that this anticancer effect may be augmented with some cytotoxic agents in prostate cancer. Now, in our present study, we have investigated whether ZA induced growth inhibition and apoptosis in PC-3 and DU-145 may be enhanced by the combination with CA or OA, through inhibition of serine/threonine phosphatases in prostate cancer cells. Both ZA/CA and ZA/OA combinations inhibited the cell viability of hormone-and drug refractory prostate cancer cells at in vivo achievable therapeutic concentrations. Moreover, a potentiation of the apoptotic effects of the combinations was also observed in the same experimental conditions. This is the first report of a synergistic combination of ZA with phosphatase inhibitors CA and OA which inhibits cell viability and induces apoptosis in human hormone and drug refractory prostate cancer cells.

Objectives: • To investigate if the cytotoxic and apoptotic effect of zoledronic acid (ZA) can be enhanced by the addition of the serine/threonine protein phosphatase inhibitors calyculin A (CA) and okadaic acid (OA) in hormone and drug refractory prostate cancer cells, PC-3 and DU-145. • To discover the effect of these combination treatments on phosphatase 1 (PP1) and PP2A protein expression levels in prostate cancer cells.

Materials And Methods: • An XTT cell viability assay was used to determine cytotoxicity. • Apoptosis was evaluated by enzyme-linked immunosorbent assay (ELISA) using a Cell Death Detection ELISA Plus Kit and verified by measuring caspase 3/7 enzyme activity. • The PP1 and PP2A enzyme activities were evaluated by serine/threonine phosphatase ELISA and expression levels of PP1 and PP2A proteins were then re-assessed by Western blot analysis.

Results: • Combination of ZA with either CA or OA showed synergistic cytotoxicity and apoptosis compared with any agent alone in both PC-3 and DU-145 prostate cancer cells. • The combination of ZA with phosphatase inhibitors resulted in enhanced suppression of both PP1 and PP2A enzyme activity and protein levels, which was more overt with the ZA/CA combination.

Conclusion: • Results from our study increase the translational potential of our in vitro findings and offer the basic rationale for the design of new combinatory strategies with ZA and phosphatase inhibitors for the treatment of prostate cancer, which may become resistant to conventional therapy.
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http://dx.doi.org/10.1111/j.1464-410X.2012.11392.xDOI Listing
December 2012

Comparing time to disease progression of irinotecan and oxaliplatin-based chemotherapies in colorectal cancer patients with liver only metastasis.

Am J Clin Oncol 2013 Aug;36(4):388-91

Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova/Izmir, Turkey.

Objectives: The liver is the most common metastatic site in colorectal cancer (CRC). In this study, we evaluated if there is any difference between first-line irinotecan-based and oxaliplatin-based chemotherapies in the duration of time to disease progression (TTP) in CRC patients with only liver metastasis.

Methods: We retrospectively reviewed the medical records of patients with metastatic CRC referred to the Medical Oncology Department at the Faculty of Medicine of Ege University, between January 2002 and December 2010. Seventy-seven patients had only liver metastasis and completed their first-line chemotherapy. Forty-two patients had oxaliplatin-based treatments while 12 also had bevacizumab therapy, and 35 patients had irinotecan-based treatments while 16 also had bevacizumab therapy.

Results: Median TTP was 6.70 ± 0.29 months for patients treated with oxaliplatin+5-fluorouracil (5-FU) and 8.33 ± 1.15 months for patients treated with oxaliplatin+5-FU+bevacizumab. TTP was significantly improved for patients who received irinotecan+5-FU+bevacizumab (median TTP, 13.73 ± 2.10 mo) when compared with irinotecan+5-FU (median TTP, 5.13 ± 0.70 mo).

Conclusions: Although previous studies showed no survival difference between these 2 chemotherapeutic agents in metastatic CRC, there might be differences in the benefit of delaying the disease progression in subgroup populations. Irinotecan+5-FU with bevacizumab combination chemotherapy may be superior in the first-line treatment of CRC with hepatic only metastasis.
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http://dx.doi.org/10.1097/COC.0b013e318248da7cDOI Listing
August 2013

The frequency and significance of radiologically detected indeterminate pulmonary nodules in patients with colorectal cancer.

Med Princ Pract 2012 27;21(5):457-61. Epub 2012 Apr 27.

Department of Chest Diseases, Izmir M Enver Senerdem Torbalı Government Hospital, Izmir, Turkey.

Objective: To investigate the frequency and significance of pulmonary nodules in patients with colorectal cancer (CRC).

Subjects And Methods: Medical records of 1,344 patients with CRC who underwent thoracic computerized tomography scans between January 2003 and December 2009 were reviewed. Those with any distant metastatic disease or who were already known to have pulmonary malignancies were excluded. Number, size, shape and location of the nodules were evaluated. A multivariate analysis was performed to determine the predictive factors for evidence of metastases.

Results: Of the 1,344 patients, 55 (4.09%) had nodules that met the criteria of an indeterminate pulmonary nodule. The mean follow-up time was 25 ± 17.9 months and the mean time to develop pulmonary metastasis was 15.5 ± 6.4 months. The nodules of 17 (30.9%) patients showed progression at follow-up; 8 had metastasized. Multivariate analysis showed multiple indeterminate pulmonary nodules (p = 0.006) of parenchymal localization (p = 0.016) with an irregular border (p = 0.002), which is predictive of metastatic disease.

Conclusion: Our study has shown that multiple indeterminate pulmonary nodules with an irregular border in a parenchymal location were more likely to represent metastatic disease. However, the frequency of the occurrence of indeterminate pulmonary metastases of CRC was low.
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http://dx.doi.org/10.1159/000337426DOI Listing
December 2012