Bulent Yalcin

Cisplatin plus oral etoposide (EoP) combination is more effective than paclitaxel in patients with advanced breast cancer pretreated with anthracyclines: a randomised phase III trial of Turkish Oncology Group

Our objective was to determine whether oral etoposide and cisplatin combination (EoP) is superior to paclitaxel in the treatment of advanced breast cancer (ABC) patients pretreated with anthracyclines. From December 1997 to August 2003, 201 patients were randomised, 100 to EoP and 101 to paclitaxel arms. Four patients in each arm were ineligible. The doses of etoposide and cisplatin were 50 mg p.o. twice a day for 7 days and 70 mg m−2 intravenously (i.v.) on day 1, respectively, and it was 175 mg m−2 on day 1 for paclitaxel. Both treatments were repeated every 3 weeks. A median of four cycles of study treatment was given in both arms. The response rate obtained in the EoP arm was significantly higher (36.3 vs 22.2%; P=0.038). Median response duration was longer for the EoP arm (7 vs 4 months) (P=0.132). Also, time to progression was significantly in favour of the EoP arm (5.5 vs 3.9 months; P=0.003). Median overall survival was again significantly longer in the EoP arm (14 vs 9.5 months; P=0.039). Toxicity profile of both groups was similar. Two patients in each arm were lost due to febrile neutropenia. The observed activity and acceptable toxicity of EoP endorses the employment of this combination in the treatment of ABC following anthracyclines.

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

Abstract 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.

The effect of venous thromboembolism on survival of cancer patients and its relationship with serum levels of factor VIII and vascular endothelial growth factor: a prospective matched-paired study.

BACKGROUND Venous thromboembolism (VT) increases mortality and morbidity in cancer patients. The primary aim of this study was to evaluate the effect of VT on the survival of cancer patients and its relationship with serum vascu-lar endothelial growth factor (VEGF) and plasma factor VIII levels. PATIENTS AND METHODS Eighty-two patients with locally advanced or metastatic cancer were included in this study between September 2001 and March 2004, and 31 of them had VT. Fifty-one matched-paired cancer patients without VT were prospectively selected as a control group in the same period. Criteria for the selection of control group patients were hav-ing the same malignancy, stage, metastatic site, performance status and age (5 years) as patients in the VT group. RESULTS Plasma factor VIII and serum D-dimer levels in the VT group were significantly higher than those in the control group (p=0.030 and p=0.016, respectively). However, mean serum VEGF levels were similar in both groups (p=0.199). In the VT group, the median survival of patients who had higher serum VEGF levels (>150 pg/mL) was significantly shorter than that of patients in the same group with lower serum VEGF levels (p=0.005). The median survival of the VT group was 14 months, whereas it was 25 months in the control group (p=0.199). CONCLUSION There was a worse prognostic trend for cancer patients with VT. Nevertheless, the difference in survival was not statistically significant between the groups. Plasma factor VIII and serum D-dimer levels might have prognostic value in cancer patients with VT. Cancer patients with VT and higher serum VEGF levels had a significantly poorer prognosis.

Medication Errors in Chemotherapy Preparation and Administration: a Survey Conducted among Oncology Nurses in Turkey

BACKGROUND Medication errors in oncology may cause severe clinical problems due to low therapeutic indices and high toxicity of chemotherapeutic agents. We aimed to investigate unintentional medication errors and underlying factors during chemotherapy preparation and administration based on a systematic survey conducted to reflect oncology nurses experience. MATERIALS AND METHODS This study was conducted in 18 adult chemotherapy units with volunteer participation of 206 nurses. A survey developed by primary investigators and medication errors (MAEs) defined preventable errors during prescription of medication, ordering, preparation or administration. The survey consisted of 4 parts: demographic features of nurses; workload of chemotherapy units; errors and their estimated monthly number during chemotherapy preparation and administration; and evaluation of the possible factors responsible from ME. The survey was conducted by face to face interview and data analyses were performed with descriptive statistics. Chi-square or Fisher exact tests were used for a comparative analysis of categorical data. RESULTS Some 83.4% of the 210 nurses reported one or more than one error during chemotherapy preparation and administration. Prescribing or ordering wrong doses by physicians (65.7%) and noncompliance with administration sequences during chemotherapy administration (50.5%) were the most common errors. The most common estimated average monthly error was not following the administration sequence of the chemotherapeutic agents (4.1 times/month, range 1-20). The most important underlying reasons for medication errors were heavy workload (49.7%) and insufficient number of staff (36.5%). CONCLUSIONS Our findings suggest that the probability of medication error is very high during chemotherapy preparation and administration, the most common involving prescribing and ordering errors. Further studies must address the strategies to minimize medication error in chemotherapy receiving patients, determine sufficient protective measures and establishing multistep control mechanisms.

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

Abstract 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.

The symptomatic benefit (the clinical benefit response) from the second-line chemotherapy in patients with advanced gastric adenocarcinoma

There are few reports on use of symptomatic benefits as an alternative or adjunctive for the assessment of objective response in chemotherapy of the advanced cancer. This study is performed to assess the symptomatic benefits (the clinical benefit response), in addition to the efficacy and toxicity of cisplatin plus infusional 5-fluorouracil (5-FU) combination as second-line therapy in patients with advanced gastric cancer. Fifty-eight advanced gastric cancer patients with previous chemotherapy were enrolled into the study. Cisplatin 20 mg/m(2) was given for 5 days, and 5-FU was given 1000 mg/m(2) as 20 h continuous infusion for 5 days, repeated every 28 days. The overall objective response rate was 11.3%, and overall tumour control rate was 33.9%. The clinical benefit response, in terms of weight gain, reduction in analgesic consumption and the improvement in performance status observed in 12 patients [six patients with partial response (PR) and six patients with stable disease (SD)] (22.6%), while the rates of the clinical benefit response in patients with PR and with SD were 100% and 50% respectively. Cisplatin plus infusional 5-FU combination seems to improve disease-related symptoms (clinical benefit response) of patients with advanced gastric cancer, even in patients without objective response.

Comparison of Clinicopathologic Parameters and Survivals Between Epstein-barr Virus–positive and Her2-positive Gastric Cancers

Gastric carcinomas are highly mortal neoplasms for which new therapeutic options are being searched. The molecular subtyping of gastric adenocarcinomas was proposed recently, and the relationship between etiopathogenetic types is still under investigation. Here we compared histopathologic, prognostic, and survival differences between Epstein-Barr virus (EBV)-positive and Her2-positive gastric adenocarcinomas. In a retrospective design, we searched the EBV status with Epstein Barr Virus encoded small RNA (EBER) in situ hybridization, and the Her2 status both by immunohistochemistry and by chromogenic in situ hybridization of 106 gastrectomized gastric carcinomas. Histologic and clinical prognostic parameters and survival information were determined, and retrieved from archival tissues and clinical notes. The Her2 positivity rate was 12.3% and the EBV positivity rate was 7.6%. Among EBER-positive cases, Her2 positivity was not detected. Her2 positivity was detected more in intestinal differentiated tumors, whereas EBER positivity was detected in undifferentiated tumors (P=0.003). There was no correlation of Her2 or EBER positivity with the tumor stage. Median survivals of EBER-positive, Her2-positive, and both negative cases were 11.5, 18, and 20.5 months, respectively. The tumor stage and distant metastasis were found to be significant for survival in the multivariate analysis. In our 106 gastrectomized gastric carcinoma cases, EBV-positive and Her2-positive groups were found to be unrelated as proposed in the upcoming classification of gastric carcinomas.

Neoadjuvant Chemotherapy Followed by Extrapleural Pneumonectomy in Malignant Pleural Mesothelioma: Is It Safe?

TO THE EDITOR: We read with interest the article by Weder et al. They conducted a pilot study with neoadjuvant gemcitabine and cisplatin followed by extrapleural pneumonectomy in patients with malignant pleural mesothelioma. The response rate to neoadjuvant chemotherapy was 32% and extrapleural pneumonectomy was performed in 16 of 19 patients. Thirteen patients received postoperative radiotherapy. Weder et al concluded that extrapleural pneumonectomy can be performed safely after neoadjuvant chemotherapy in an experienced center. Unfortunately, this conclusion is somewhat incorrect. Although Weder et al reported no perioperative death, the perioperative morbidity rate was quite high. Perioperative morbidity was observed in seven of the 16 patients (43.75%) on whom extrapleural pneumonectomy was performed: pulmonary embolism in one patient, chylothorax in three patients, thrombosis of the brachiocephalic vein in one patient, bronchopleural fistula in one patient, and pyothorax in one patient. Two patients were operated on for the treatment of these operative complications. Two patients were hospitalized for bleeding intrathoracically and retroperitoneally. It is unclear whether neoadjuvant chemotherapy is responsible for this high rate of perioperative morbidity. Therefore, the safety of this treatment modality should be questioned before further studies on uncured malignant pleural mesothelioma. Quality of life related to the treatment becomes more important in this group of patients because of the high rate of perioperative morbidity, and Weder et al should have assessed this in their study. On the other hand, although Weder et al reported in the abstract of their article that the major toxicity of neoadjuvant gemcitabine and cisplatin was thrombocytopenia, if we consider their Table 2, it is seen that grade 3 and 4 leukopenia and neutropenia are more frequent than thrombocytopenia. Gungor Utkan, Bulent Yalcin, and Abdullah Buyukcelik Department of Medical Oncology, Ankara University School of Medicine, Ibni Sina Hospital, Sihhiye, Ankara, Turkey.

Overdose of lomustine: report of two cases.

Two male patients with high-grade gliomas were treated with subtotal or total resection and radiotherapy followed by a lomustine-containing chemotherapy regimen. Both patients took lomustine at an oral dose of 800 mg over five days instead of their regular doses of 200 and 240 mg. Grade 4 neutropenia and thrombocytopenia developed in both patients within two weeks of the last lomustine dose. One of them was admitted to hospital because of febrile neutropenia. Neutropenia and thrombocytopenia were detected in the other patient when he was examined in the emergency room following a generalized convulsion. Both patients recovered from the severe myelosuppression caused by lomustine. No other organ toxicities were observed.

Hospitalization Risk According to Geriatric Assessment and Laboratory Parameters in Elderly Hematologic Cancer Patients

BACKGROUND Utilizing geriatric screening tools for the identification of vulnerable older patients with cancer is important. The aim of this study is to evaluate the hospitalization risk of elderly hematologic cancer patients based on geriatric assessment and laboratory parameters. MATERIALS AND METHODS In this cross sectional study 61 patients with hematologic malignancies, age 65 years and older, were assessed at a hematology outpatient clinic. Standard geriatric screening tests; activities of daily living (ADL), instrumental activities of daily living (IADL), Mini Nutritional Assessment (MNA), Mini Mental State Examination (MMSE), timed up and go test (TUG), geriatrics depression scale (GDS) were administered. Demographic and medical data were obtained from patient medical records. The number of hospitalizations in the following six months was then recorded to allow analysis of associations with geriatric assessment tools and laboratory parameters. RESULTS The median age of the patients, 37 being males, was 66 years. Positive TUG test and declined ADL was found as significant risk factors for hospitalization (p=0.028 and p=0.015 respectively). Correlations of hospitalization with thrombocytopenia, vitamin B12 and folic acid deficiency were statistically significant (p=0.004, p=0.011 and p=0.05 respectively). CONCLUSIONS In this study, geriatric conditions which are usually unrecognized in a regular oncology office visit were identified. Our study indicates TUG and ADL might be use as predictive tests for hospitalization in elderly oncology populations. Also thrombocytopenia, and vitamin B12 and folic acid deficiencies are among the risk factors for hospitalization. The importance of vitamin B12 and folic acid vitamin replacement should not be underestimated in this population.