Publications by authors named "Mehmet A N Sendur"

29 Publications

  • Page 1 of 1

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

Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study.

J Clin Oncol 2021 Jan 29:JCO2003579. Epub 2021 Jan 29.

LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.

Purpose: Pembrolizumab monotherapy is standard first-line therapy for metastatic non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50% without actionable driver mutations. It is not known whether adding ipilimumab to pembrolizumab improves efficacy over pembrolizumab alone in this population.

Methods: In the randomized, double-blind, phase III KEYNOTE-598 trial (ClinicalTrials.gov identifier: NCT03302234), eligible patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing or aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6 weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3 weeks for up to 35 doses. Primary end points were overall survival and progression-free survival.

Results: Of the 568 participants, 284 were randomly allocated to each group. Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9 months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; = .74). Median progression-free survival was 8.2 months for pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard ratio, 1.06; 95% CI, 0.86 to 1.30; = .72). Grade 3-5 adverse events occurred in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The external data and safety monitoring committee recommended that the study be stopped for futility and that participants discontinue ipilimumab and placebo.

Conclusion: Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab monotherapy as first-line treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable or aberrations. These data do not support use of pembrolizumab-ipilimumab in place of pembrolizumab monotherapy in this population.
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http://dx.doi.org/10.1200/JCO.20.03579DOI Listing
January 2021

Atezolizumab and Bevacizumab in Hepatocellular Carcinoma.

N Engl J Med 2020 08;383(7):694

Yildirim Beyazit University, Ankara, Turkey.

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http://dx.doi.org/10.1056/NEJMc2021840DOI Listing
August 2020

A historical turning point for the treatment of advanced renal cell carcinoma: inhibition of immune checkpoint.

Curr Med Res Opin 2020 04 23;36(4):625-635. Epub 2020 Jan 23.

Faculty of Medicine, Department of Medical Oncology, Ankara Yildirim Beyazit University, Ankara, Turkey.

Renal cell carcinoma (RCC) is the most common type of renal malignancy with 87% frequency. As a global health problem, kidney cancer is responsible for 2.2% of new cancer cases. One of the highly effective mechanisms that renal cancer cells avoid in the immune system is PD-1 and PD-L1 interaction. Literature search is made from PubMed, Medline, and ASCO and ESMO Annual Meeting abstracts using the following search keywords: "nivolumab," "pembrolizumab," "atezolizumab," "avelumab," "durvalumab," and "renal cell cancer." The last search was on November 1, 2019. The combination of nivolumab and ipilimumab have better survival results than sunitinib for intermediate and poor risk patients but not for favorable risk groups. In 2019, two combination regimens with pembrolizumab plus axitinib and avelumab plus axitinib demonstrated efficacy over sunitinib for every risk group. The overall survival data of these trials are still immature. Advanced RCC has high morbidity and mortality with an increasing prevalence. Following tyrosine kinase inhibitors, checkpoint inhibitors have a great influence on treatment of advanced RCC, especially the combination of these two strategies. In 2019 these combined strategies demonstrated 5% complete remission with up to 60% objective response rate. While not immediately, but perhaps in the near future, advanced RCC will become a manageable chronic disease, even if a cure is not possible.
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http://dx.doi.org/10.1080/03007995.2020.1716705DOI Listing
April 2020

An update on immunotherapy options for urothelial cancer.

Expert Opin Biol Ther 2019 12 17;19(12):1265-1274. Epub 2019 Sep 17.

Faculty of Medicine, Department of Medical Oncology, Ankara Yıldırım Beyazıt University, Ankara, Turkey.

: The efficacy of immune checkpoint inhibitors has been shown in many malignancies. Urothelial cancers have a high mutational load and also express a high level of PD-L1. Therefore, the use of immune checkpoint inhibitors (ICIs) in various treatment lines is being intensively investigated in urothelial cancers.: In this review article, we aimed to summarize the development of immune checkpoint inhibition in urothelial cancers. We also provide updated and comprehensive data about the use of ICIs in the second-line and first-line treatment of patients who are ineligible for cisplatin. We also summarize ongoing trials and the results of published trials. A literature search was made using PubMed, Medline, and ASCO and ESMO Annual Meetings abstracts by using the following search terms: nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and urothelial cancer.: ICIs as a monotherapy are effective for the first-line treatment of the patients with advanced urothelial carcinoma who are ineligible for cisplatin, and also patients who are pre-treated with platinum-based chemotherapy. The results of trials investigating the efficacy of the combination of ICIs and chemotherapy in the first-line setting are awaited; it remains unclear as to whether this combination may become the standard first-line treatment in advanced urothelial cancer.
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http://dx.doi.org/10.1080/14712598.2019.1667975DOI Listing
December 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

Adjuvant Capecitabine for Breast Cancer.

N Engl J Med 2017 08;377(8):791

Ankara Yildirim Beyazit University, Ankara, Turkey

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http://dx.doi.org/10.1056/NEJMc1708487DOI Listing
August 2017

A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer.

Curr Med Res Opin 2017 09 25;33(9):1559-1569. Epub 2017 Jul 25.

a Ankara Yıldırım Beyazıt University , Faculty of Medicine, Department of Medical Oncology , Ankara , Turkey.

Background: Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinase (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates.

Scope: A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; "palbociclib", "abemaciclib", "ribociclib", "cyclin-dependent kinase inhibitors" and "CDK 4/6" in metastatic breast cancer (MBC). The last search was on 10 June 2017.

Findings: CDKs and cyclins are two molecules that have a key role in cell cycle progression. Today, there are three highly selective CDK4/6 inhibitors in clinical development - palbociclib, ribociclib and abemaciclib. Palbociclib and ribociclib were recently approved by the US FDA in combination with letrozole for the treatment of MBC in a first-line setting, as well as palbociclib in combination with fulvestrant for hormone-receptor (HR)-positive MBC that had progressed while on previous endocrine therapy according to the PALOMA-1, MONALEESA-2 and PALOMA-3 trials, respectively. In the recently published randomized phase III MONARCH 2 trial, abemaciclib plus letrozole had longer progression-free survival and higher objective response rates with less serious adverse events in advanced HR-positive breast cancer previously treated with hormonal treatment.

Conclusion: CDK4/6 inhibition is a new and promising target for patients with hormone-receptor-positive MBC. Both palbociclib and ribociclib showed significant additive benefit for patients receiving first-line treatment for HR-positive, epidermal growth factor receptor-2-negative advanced breast cancer. Palbociclib and abemaciclib also had significant activity in combination with fulvestrant for patients with MBC that progressed on previous endocrine therapy.
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http://dx.doi.org/10.1080/03007995.2017.1348344DOI Listing
September 2017

Targeting the PD-1 pathway: a new hope for gastrointestinal cancers.

Curr Med Res Opin 2017 04 31;33(4):749-759. Epub 2017 Jan 31.

a Yıldırım Beyazıt University , Faculty of Medicine, Department of Medical Oncology , Ankara , Turkey.

Background: VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most gastrointestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. In this review article, we aim to discuss the efficacy and safety of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in published or reported recent studies.

Scope: A literature search was made from PubMed and ASCO Annual Meeting abstracts by using the following search keywords: "nivolumab", "pembrolizumab", "avelumab", "GI cancers" "anti-PD1 therapy" and "anti-PD-L1 therapy". The last search was on 2 November 2016. The most important limitation of our review is that most of the data on anti-PD-1/PD-L1 therapies in GI cancers relies on phase 1 and 2 trials.

Findings: Currently, there are two anti-PD-1 (nivolumab and pembrolizumab) and one anti-PDL1 (atezolizumab) agents approved by FDA. After the treatment efficacy of immune checkpoint blockade was shown in melanoma, renal cell cancer and non-squamous lung cancer, trials which evaluate immune checkpoint blockade in GI cancers are ongoing. Early results of trials have been promising and encouraging for patients with advanced stage gastroesophageal cancer. According to early results of published trials, response to anti-PD1/PD-L1 agents appears to be associated with tumor PD-L1 levels. According to two recently published phase 2 trials, the clinical benefits of immune checkpoint blockade with both nivolumab and pembrolizumab were limited in patients with microsatellite instability (MSI) positive advanced colorectal cancer. However, several phase 2/3 trials are still ongoing.

Conclusion: Both pembrolizumab and nivolumab show promising efficacy with acceptable safety data in published trials in GI cancers, especially in refractory MSI positive metastatic colorectal cancer.
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http://dx.doi.org/10.1080/03007995.2017.1279132DOI Listing
April 2017

Effect of body mass index on the efficacy of adjuvant tamoxifen in premenopausal patients with hormone receptor-positive breast cancer.

J BUON 2016 Jan-Feb;21(1):27-34

Yildirim Beyazit University, Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey.

Purpose: Obesity has been confirmed to be an adverse prognostic factor in patients who were treated with aromatase inhibitors; however, such relationship has never been thoroughly investigated in patients treated with tamoxifen. The purpose of this study was to examine the effect of body mass index (BMI) on the efficacy of adjuvant tamoxifen in premenopausal patients with hormone receptor-positive breast cancer.

Methods: Newly diagnosed premenopausal and non-metastatic hormone receptor-positive breast cancer patients were enrolled in the study. Patients with BMI ranging between 18.5 and 24.9 kg/m(2) were considered as normal weight patients (Arm A, n = 408), and/patients with a BMI ≥ 25 kg/m(2) were considered as overweight and obese patients (Arm B, n = 418).

Results: In both normal weight and overweight patients, the baseline clinicopathologic properties and the treatment history with radiotherapy and chemotherapy were similar and no statistical significant difference could be detected. Tamoxifen in combination with luteinizing hormone-releasing hormone (LHRH) agonist was used in 33% (136/408) of the patients in Arm A and in 22% (91/418) of patients in Arm B (p<0.001). Three-year disease free survival (DFS) rates were 89% and 87% in arm A and arm B, respectively (p=0.39). Three-year overall survival (OS) rates were 99% in arm A and 94% in arm B which appeared to be of significance (p=0.028). In univariate analysis no statistical significant effect of LHRH agonist usage on DFS (p=0.58) and OS (p=0.96) was found.

Conclusion: Although BMI had no negative effect on recurrence risk, poor OS was observed in overweight and obese premenopausal breast cancer patients with hormone-receptor positive tumors who were treated with tamoxifen.
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May 2016

A comprehensive review of denosumab for bone metastasis in patients with solid tumors.

Curr Med Res Opin 2016 25;32(1):133-45. Epub 2015 Nov 25.

b b Yıldırım Beyazıt University, Faculty of Medicine , Department of Medical Oncology , Ankara , Turkey.

Background: Denosumab is fully human monoclonal antibody that specifically binds and inactivates receptor activator of NF-kB ligand (RANKL), an important ligand that regulates bone remodeling. In this review, we aimed to show the clinical data about denosumab treatment and discuss its advantages for the management of patients with solid tumors and bone metastasis.

Scope: Denosumab showed positive results in clinical studies of solid tumors with bone metastasis. PubMed database and ASCO Symposium Meeting abstracts were searched until August 2015 by using the terms 'denosumab', 'RANKL inhibitor' and 'bone metastasis'. The last search was on 21 August 2015. All resulting studies were retrieved and were also checked for related publications. Clinical trials in this review fulfilled the following criterion: inclusion of sufficient data to allow estimation of the efficacy and safety of denosumab.

Findings: The effects of denosumab on skeletal-related events (SREs) were investigated in three large randomized trials: one in patients with breast cancer, one in patients with prostate cancer, and one in patients with multiple myeloma or solid tumors other than breast or prostate cancer. In the breast cancer and prostate cancer studies denosumab was non-inferior and also superior to zoledronic acid in terms of the primary outcome time to first on-study SRE. In the third study denosumab was non-inferior to zoledronic acid but was not superior to zoledronic acid in solid tumors excluding breast and prostate cancer with bone metastases. In the three studies median overall survival and disease progression rates were similar between zoledronic acid and denosumab. Denosumab has also been studied in bone loss associated with hormonal therapy in both breast and prostate cancer. Adjuvant denosumab significantly reduced the risk of clinical fracture risk by 50% in breast cancer patients and by 62% in non-metastatic prostate cancer patients treated with adjuvant aromatase inhibitors or androgen deprivation therapy. In addition, biochemical markers of bone turnover and fractures were significantly reduced in patients under denosumab treatment.

Conclusion: The promising outcomes in the initial trials with denosumab have shown clinical activity and a favorable safety profile in patients with solid tumors and bone metastasis. Denosumab significantly reduced treatment-related osteoporosis associated with breast and prostate cancer and was superior to zoledronic acid in prevention or delaying of SRE.
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http://dx.doi.org/10.1185/03007995.2015.1105795DOI Listing
September 2016

Actual benefit of chemo-hormonal therapy in non-castrate metastatic prostate cancer.

Future Oncol 2015 ;11(8):1141-3

Yıldırım Beyazıt University, Faculty of Medicine, Department of Medical Oncology, 06800 Bilkent, Ankara, Turkey.

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http://dx.doi.org/10.2217/fon.15.36DOI Listing
February 2016

Which sequence best protects the heart against trastuzumab and anthracycline toxicity? An electron microscopy study in rats.

Anticancer Res 2015 Feb;35(2):857-64

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

Background/aim: Two effective cytotoxic agents, doxorubicin and trastuzumab, are associated with potentially life-threatening cardiotoxicity. The present study was designed to investigate cardiotoxicity aggravated by the timing of administration of trastuzumab and doxorubicin in rats.

Materials And Methods: Twenty-four rats were randomly assigned to one of four groups. These received one of the following treatment drug regimens administered via intraperitoneal injection: (i) 0.9% saline control (n=6); (ii) doxorubicin (5 mg/kg) on day 1 then trastuzumab 10 mg/kg on day 15 (n=6); (iii) trastuzumab 10 mg/ kg on day 1 then doxorubicin (5 mg/kg) on day 15 (n=6) or (iv) doxorubicin (5 mg/kg) on day 1 and trastuzumab 10 mg/ kg on day 1 (n=6). On the 30th day, the hearts were processed for pathological analysis by electron microscopy.

Results: Electron microscopy revealed an ultrastructurally normal heart tissue in the control group. At electron microscopic examination of the tissue samples in the second and fourth group, a mild degree of dilation was observed in the peri-nuclear cisternae of some heart muscle cells. In the third group, pathological changes were detected in mitochondria. These exhibited prominent cristae, which also showed a mild degree of ultrastructural pathology in mitochondria.

Conclusion: Based on electron microscopy findings, sequential administration of anthracycline first, followed by trastuzumab is safer in terms of cardiotoxicity, while the most toxic schedule for the rat heart was trastuzumab first, followed by anthracycline.
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February 2015

Pertuzumab-induced cardiotoxicity: safety compared with trastuzumab.

Future Oncol 2015 ;11(1):13-5

Yıldırım Beyazıt University, Faculty of Medicine, Department of Medical Oncology, 06800, Ankara, Turkey.

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http://dx.doi.org/10.2217/fon.14.184DOI Listing
September 2015

Impact of acetylsalicylic Acid on the clinicopathological characteristics and prognosis of patients with invasive breast cancer.

Breast Care (Basel) 2014 Apr;9(4):261-6

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

Background: The impact of acetylsalicylic acid (ASA) on the clinicopathological characteristics of breast cancer has not yet been elucidated in detail; we therefore aimed to investigate the effects of ASA on the clinicopathological characteristics of patients with breast cancer.

Patients And Methods: Patients diagnosed with breast cancer were retrospectively analyzed. Breast cancer patients who were taking ASA at the time of breast cancer diagnosis were enrolled as ASA users (n = 84); matching patients with the same age who were not taking ASA were included as control group (n = 890).

Results: The median age was 56 (range 34-82) years in both groups. ASA users had a significantly lower incidence of grade II-III tumors compared to non-users (P = 0.02). The other clinicopathological characteristics and treatment histories were similar in both groups. In patients using ASA, the disease-free survival (DFS) rate was 97.3%, 89.4%, and 79.9% and in non-users it was 94.1%, 81.8%, and 70.9% in the 1rst, 3rd, and 5th year, respectively (P = 0.01). In aspirin users, the overall survival rate was 95.0%, 90.6%, and 87.6% and in non-users it was 98.1%, 91.2%, and 85.5% in the 1rst, 3rd, and 5th year, respectively (P = 0.50).

Conclusion: Using ASA at the time of breast cancer diagnosis was associated with significantly improved DFS in breast cancer patients.
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http://dx.doi.org/10.1159/000365952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209281PMC
April 2014

Recurrent parathyroid carcinoma with spinal metastases unresponsive to cinacalcet therapy.

J BUON 2014 Jul-Sep;19(3):863-4

Ankara Numune Education and Research Hospital, Department of Medical Oncology, Ankara; Hacettepe University Faculty of Medicine, Ankara, Turkey.

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November 2014

The efficacy of adjuvant trastuzumab in HER-2 positive breast cancer with axillary lymph node metastases according to the treatment duration.

Curr Med Res Opin 2014 Dec 29;30(12):2535-42. Epub 2014 Sep 29.

Yildirim Beyazit University, Department of Medical Oncology , Ankara , Turkey.

Introduction: Trastuzumab is the first anti-HER-2 humanized monoclonal antibody. The benefit of adjuvant trastuzumab has been shown in randomized phase III trials. Despite trastuzumab being recommended for 52 weeks in the adjuvant treatment of HER-2 positive breast cancer according to the current breast cancer guidelines, there is still no consensus on the optimal duration of adjuvant trastuzumab. The aim of our study is to investigate the efficacy and safety of adjuvant trastuzumab for 9 weeks and 52 weeks in axillary lymph node positive HER-2 positive breast cancer patients.

Patients And Methods: A total of 271 HER-2 and axillary node positive breast cancer patients who received trastuzumab in adjuvant treatment between the years 2005 and 2013 were retrospectively analyzed. Patients with axillary node positive HER-2 positive breast cancer who were non-metastatic were enrolled to the study. Patients were allocated to the 9 week trastuzumab group (n = 155) or the 52 week trastuzumab group (n = 116). Kaplan-Meier survival analysis was carried out for disease free survival (DFS) and overall survival (OS). Two-sided p values of <0.05 were considered statistically significant. The most important limitation of our manuscript is the retrospective design.

Results: The median follow-up time for this analysis was 34 (4-95) months. Patients' clinical and pathological characteristics were well balanced between the two treatment arms. In the 9 week trastuzumab treatment group, the DFS rate was 96.7%, 84.8% and 74.9% in the first, third and fifth years respectively, whereas in the 52 week trastuzumab treatment group it was 94.3%, 80.0% and 80.0% (P = 0.76). In the 9 week trastuzumab treatment group, the OS rate was 99.3%, 92.2% and 88.3% in the first, third and fifth years respectively, whereas in the 52 week trastuzumab treatment group it was 99.0%, 94.7% and 78.6% (P = 0.99). In both groups, symptomatic heart failure was not reported but asymptomatic left ventricular ejection fraction (LVEF) decline was observed 3 (1.9%) and 18 (15.5%) patients in the 9 week and 52 week trastuzumab treatment groups, respectively (P < 0.001).

Conclusion: In our study, the efficacy of trastuzumab for 52 weeks and 9 weeks was similar in node-positive HER-2 positive breast cancer. Cardiotoxicity was significantly increased in the 52 week trastuzumab arm compared to the 9 week trastuzumab arm.
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http://dx.doi.org/10.1185/03007995.2014.965775DOI Listing
December 2014

Can targeted programmed death-1 antibody be a new treatment approach in breast cancer.

J BUON 2014 Apr-Jun;19(2):584

Ankara Numune Education and Research Hospital, Department of Medical Oncology, Ankara, Turkey.

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September 2014

Is programmed cell death ligand-1 expression required for optimal response to anti-PD-1 antibody in cancer.

J BUON 2014 Apr-Jun;19(2):577-8

Ankara Numune Education and Research Hospital, Department of Medical Oncology, Ankara, Turkey.

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September 2014

Evaluation of erectile dysfunction risk factors in young male survivors of colorectal cancer.

J BUON 2014 Jan-Mar;19(1):115-23

Ankara Numune Education and Research Hospital, Department of Medical Oncology, Ankara, Turkey.

Purpose: Improved long-term survival of colorectal cancer patients (CRC) treated with surgery and/or chemotherapy ± radiotherapy (RT) has led to increased awareness of long-term side effects, including effecting sexual life, which can ultimately affect the quality of life in these patients. Because the absolute risk factors of erectile dysfunction (ED) have not been defined in CRC patients, the aim of this research was to identify the severity and the absolute risk factors of ED in male CRC survivors.

Methods: The medical records of 61 male survivors of CRC treated with surgery and/or chemotherapy ± RT were retrieved from the medical oncology outpatient clinics during routine follow-up visits in 2011-2012. Patients older than 55 years and those with ED history before diagnosis were excluded. International Index of Erectile Function (IIEF) questionnaire was filled in by the patients.

Results: The patient mean age was 47.6±6.7 years (range 18-55) at the time of filling in the questionnaire. According to the International Index of Erectile Function (IIEF) score, 83.6% of the patients had some degree of ED. The risk factors of erectile dysfunction were advancing age (p=0.01), tumor location (p=0.01), type of surgery (p=0.02), presence of stoma (p=0.03)) and RT (p=0.005). Chemotherapy didn't impact ED (p=0.46). Also, there was no significant correlation between smoking status, hypertension, diabetes mellitus, cardiovascular disease, stage of the tumor and ED. Also hormonal disturbances such as serum FSH, LH and testesterone levels did not affect the presence of ED.

Conclusion: Overall, 83.6% of the male CRC survivors had some degree of ED according to the IIEF. The risk factors of ED were advancing age, tumor location, type of operation, presence of stoma and RT. Clinicians should be aware of these risk factors to offer their patients adequate treatment options and also come up with new treatment strategies necessary to reduce further ED in CRC survivors.
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May 2014

Current approaches for prophylactic cranial irradiation in extrapulmonary small cell carcinoma.

Curr Med Res Opin 2014 Jul 4;30(7):1327-36. Epub 2014 Apr 4.

Ankara Numune Education and Research Hospital , Ankara , Turkey.

Background: Small cell lung cancer (SCLC) patients, who have achieved complete or partial response after chemotherapy, should be followed with prophylactic cranial irradiation (PCI). PCI for extrapulmonary small cell carcinoma (EPSCC) is not routinely recommended. The purpose of this review is to discuss all aspects of PCI in management of EPSCC.

Scope: The PubMed database and the database of online abstracts of the American Society of Oncology (ASCO), ASCO Genitourinary (GU) Cancers meetings and clinical trials were searched up to 15 October 2013 using the following search keywords: 'SCC or EPSCC of each organ site and prophylactic cranial radiotherapy'. The language of screened abstracts and manuscripts was limited to English. The papers which included the largest case series and data of cases about prophylactic cranial radiotherapy and/or were published in the last 10 years were selected.

Findings: Many single center studies showed low incidence of brain metastasis in patients with esophageal small cell carcinoma (SCC). Due to the low incidence of brain metastasis, PCI is not recommended for esophageal SCC. Genitourinary, colorectal, small bowel and appendix cranial metastatic SCCs are extremely rare. Therefore, PCI is not recommended. The frequency of brain metastasis of prostate small cell carcinoma is much higher (16-19%) compared to other counterparts of EPSCC. PCI can be performed in selected cases of prostate SCC. High rates (41%) of brain metastasis develop in head and neck SCC. PCI should be considered for patients with head neck SCC.

Conclusion: In the literature, the brain metastasis incidence of EPSCC might vary from 1.7% up to 40%. In many patients with ESPCC, PCI is not recommended. However, we have to keep in mind that primary head and neck and prostate SCC are exceptions due to the high incidence of cranial metastasis; PCI should be recommended for these patients on an individual basis.
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http://dx.doi.org/10.1185/03007995.2014.904771DOI Listing
July 2014

Necrotizing fasciitis secondary to bevacizumab treatment for metastatic rectal adenocarcinoma.

Indian J Pharmacol 2014 Jan-Feb;46(1):125-6

Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara, Turkey.

Bevacizumab is a recombinant humanized monoclonal antibody that selectively blocks the activity of vascular endothelial growth factor (VEGF) receptor and it is used in metastatic colorectal patients. We present here a case of fatal necrotizing fasciitis in a patient during bevacizumab treatment for colorectal cancer. In our review of the literature, necrotizing fasciitis was not reported before or during bevacizumab treatment.
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http://dx.doi.org/10.4103/0253-7613.125195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912798PMC
October 2014

Everolimus: a new hope for patients with breast cancer.

Curr Med Res Opin 2014 Jan 14;30(1):75-87. Epub 2013 Oct 14.

Ankara Numune Education and Research Hospital, Department of Medical Oncology , Ankara , Turkey.

Background: Breast cancer cells can develop resistance to standard hormonal treatment and chemotherapy with the activation of the mTOR pathway; this is supported by results of preclinical and clinical studies. In clinical trials, the addition of everolimus to hormonal treatment or anti-HER2 treatment improved the outcomes of breast cancer patients. The aim of this review is to discuss the efficacy and safety data of everolimus in all categories of breast cancer in recent published studies.

Scope: Everolimus showed positive results in clinical studies. A literature search was made from PubMed, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts by using the following search key words: 'everolimus', 'RAD001', 'mTOR inhibitor', 'breast cancer' 'endocrine therapy resistance' and 'HER-2 targeted therapies'. The last search was on June 10, 2013. The most important limitation of our review is that most of the data on everolimus rely on phase I and II trials.

Findings: Preclinical studies showed that mTOR activation can be the responsible mechanism in all subgroups of breast cancer. Results of both the TAMRAD and BOLERO-2 studies have showed that mTOR inhibition in combination with endocrine therapy can be a new treatment strategy for MBC patients who are resistant to aromatase inhibitors. In the BOLERO-2 study, time to deterioration in health-related quality of life was also significantly higher in the everolimus and exemestane arm compared to the exemestane plus placebo arm. The recently completed BOLERO-3 study showed that mTOR inhibition in combination with trastuzumab plus vinorelbine treatment significantly improved PFS compared to trastuzumab plus vinorelbine alone in trastuzumab-resistant MBC patients.

Conclusion: Recent trials have shown that everolimus has produced promising anti-tumor activity in combination with trastuzumab in HER2-positive metastatic breast cancer and in combination with exemestane in patients with hormone-receptor-positive metastatic breast cancer who had recurrence or progression while receiving a nonsteroidal aromatase inhibitor. Results of ongoing studies with everolimus show evidence that using everolimus in earlier stages of the disease, namely in the adjuvant and neoadjuvant settings, could be benefical.
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http://dx.doi.org/10.1185/03007995.2013.846253DOI Listing
January 2014

Cardiotoxicity of novel HER2-targeted therapies.

Curr Med Res Opin 2013 Aug 7;29(8):1015-24. Epub 2013 Jun 7.

Ankara Numune Education and Research Hospital, Department of Medical Oncology, Ankara, Turkey.

Background: Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab.

Scope: Novel HER2-targeted therapies showed favorable results in HER2 positive metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched until January 2013 using the following search keywords; 'trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and neratinib'; papers which were considered relevant for the aim of this review were selected by the authors. Lapatinib, pertuzumab, T-DM1, neratinib and afatinib molecules are evaluated in the study.

Findings: In a comprehensive analysis, 3689 lapatinib treated patients enrolled in 49 trials; asymptomatic cardiac events were reported in 53 patients (1.4%) and symptomatic grade III and IV systolic dysfunction was observed only in 7 patients (0.2%) treated with lapatinib. In phase I-III trials of pertuzumab, cardiac dysfunction was seen in 4.5-14.5% of patients with pertuzumab treatment and cardiac dysfunction was usually grade I and II. Cardiotoxicity of pertuzumab was usually reported with the trastuzumab combination and no additive cardiotoxicity was reported with addition of pertuzumab to trastuzumab. T-DM1 had a better safety profile compared to trastuzumab, no significant cardiotoxicity was observed with T-DM1 in heavily pre-treated patients. In the EMILIA study, only in 1.7% of patients in the T-DM1 group experienced reduction of left ventricular ejection fraction (LVEF) and grade III LVEF reduction developed only in one patient (0.2%) in the T-DM1 group compared to the lapatinib plus capacitabine group. In phase I-II trials with neratinib no cardiotoxicity was reported whereas cardiotoxicity was seen between 0-5.3% with afatinib treatment.

Conclusion: Although cardiac toxicity has been reported as an adverse event for novel HER2-targeted therapies, cardiac dysfunction rate of the novel HER2-targeted therapies is significantly lower than the trastuzumab and combination of these agents with trastuzumab did not significantly increase the cardiac adverse events.
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http://dx.doi.org/10.1185/03007995.2013.807232DOI Listing
August 2013

Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer.

Curr Med Res Opin 2013 Apr 1;29(4):405-14. Epub 2013 Mar 1.

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

Background: Trastuzumab emtansine (T-DM1), a novel drug developed for the treatment of HER2-positive breast cancer, is a human epidermal growth factor receptor (HER2) targeted antibody drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). It has been shown that, in preclinical studies, it has anti-tumor activity in trastuzumab refractory cancer cells. In this review, we aim to show the clinical data about trastuzumab-DM1 (T-DM1) therapy and to discuss the therapy advantages for the management of patients with HER2-positive breast cancer.

Scope: T-DM1 showed positive results in clinical studies of HER2-positive metastatic breast cancer. PubMed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched up to September 2012 by using the terms 'trastuzumab emtansine (T-DM1) and anti-HER2 treatment'; papers which were considered relevant for the aim of this review were selected by the authors.

Findings: The phase III randomized trial EMILIA has shown that T-DM1 provided objective tumor responses and significantly improved progression free survival and overall survival compared to lapatinib and capacitabine combination in HER2-positive metastatic breast cancer patients treated with a prior taxane and trastuzumab regimen. It is believed that T-DM1 will play a role in the management of patients with advanced and early stage HER2-positive breast cancer, but this awaits further study. In particular, the ongoing phase III trials MARIANNE and TH3RESA will further give information about the place of T-DM1 in the treatment algorithms for HER2-positive disease.

Conclusion: The trials of T-DM1 as a single agent and in combination with other chemotherapies have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. There are ongoing studies of T-DM1 showing an increasing tendency towards moving the study of these agents to earlier stages of HER2-positive breast cancer.
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http://dx.doi.org/10.1185/03007995.2013.775113DOI Listing
April 2013

Pertuzumab in HER2-positive breast cancer.

Curr Med Res Opin 2012 Oct 11;28(10):1709-16. Epub 2012 Oct 11.

Ankara Numune Education and Research Hospital, Department of Medical Oncology, Ankara, Turkey.

Background: Lack of response in some patients and relapse during the course of therapy in the treatment of HER2-positive early breast cancer and metastatic breast cancer continue to challenge researchers and clinicians towards a better understanding of the fundamental mechanisms of trastuzumab action and new therapies for HER2. The aim of this review is to discuss current and future treatment options with pertuzumab in the light of new insights into HER2-positive breast cancer.

Scope: Pertuzumab showed positive results in clinical studies and agents in routine clinical usage are updated. The PubMed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched up to June 2012 by using the terms 'pertuzumab' and 'anti-HER2 treatment'; papers which were considered relevant for the aim of this review were selected by the authors.

Findings: The presented trials of phase II and phase III randomized trials of CLEOPATRA, NEOSPHERE and TRYPHAENA have showed pertuzumab action to be complementary to trastuzumab without increasing adverse events. Adding pertuzumab to trastuzumab in the first line of HER2-positive metastatic breast cancer and in the neoadjuvant treatment of locally advanced HER2-positive breast cancer is usually well tolerated. The evaluation of health-related quality of life showed that combining pertuzumab with docetaxel and trastuzumab compared to placebo have no detrimental effect with adding pertuzumab.

Conclusion: Pertuzumab is the first HER dimerization inhibitor with a mechanism of action complementary to trastuzumab. Studies with anti-HER2 combination treatments indicate that the use of more than one HER2-targeted therapy was superior to one of these agents alone. Pertuzumab has produced impressive anti-tumor activity in combination with trastuzumab. There are ongoing studies with pertuzumab with an increasing tendency towards moving the study of these agents to earlier stages of the disease, namely in the adjuvant and neoadjuvant setting.
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http://dx.doi.org/10.1185/03007995.2012.728132DOI Listing
October 2012

Pertuzumab plus trastuzumab in metastatic breast cancer.

N Engl J Med 2012 04;366(14):1348; author reply 1349-50

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http://dx.doi.org/10.1056/NEJMc1201462DOI Listing
April 2012