Effect Of Cisplatin-based Chemotherapy Research Articles

Vascular aging long-term effect of cisplatin-based chemotherapy

Vascular aging long-term effect of cisplatin-based chemotherapy

Abstract NTOC-101: INTRAPERITONEAL (IP) THERAPY FOR ADVANCED STAGE EPITHELIAL OVARIAN CANCER (EOC): THE CURRENT SPOTLIGHT IS ON CARBOPLATIN AND QUALITY OF LIFE

Abstract PURPOSE: First-line treatments for (EOC) have been platinum-based for more than three decades; 16 years ago the landmark Gynecologic Oncology Group (GOG158) non-inferiority trial for optimal stage III patients led to the universal adoption of IV carboplatin/paclitaxel as the standard systemic regimen. However, IV cisplatin-based doublets were the comparators in the first 3 GOG studies assessing IP cisplatin-based regimens. Our purpose is to describe recent randomized trials that have assessed IP carboplatin and highlight quality of life (QOL) findings. METHODS: Gynecology Oncology Group (GOG) studies comparing IP to IV cisplatin regimens formed the basis of the National Cancer Institute (NCI) 2005 Clinical Announcement that considered IP cisplatin-based therapy as a new standard for optimally debulked EOC. Recently, randomized trials with IV carboplatin/paclitaxel-based regimens as comparators have been part of preliminary reports: 1) GOG252 on March 2016 at the Society of Gynecologic Oncology (SGO), completing accrual in 2015, and 2) OV21/PETROC neoadjuvant randomized ‘pick the winner’ study at the June 2016 American Society of Clinical Oncology (ASCO). Beyond 2016, additional data is expected from the ongoing randomized study by the Japan GOG of IP versus IV carboplatin, --both with IV paclitaxel. RESULTS: GOG252, the largest Phase III study of IV versus IP platinum-based therapy for the first line treatment of ovarian cancer, is the first IP GOG trial with a IV carboplatin-based control arm. None of the 3 arms differed in median progression-free survival. However, the companion QOL study, --contrary to prior GOG studies utilizing IV cisplatin-based controls—showed a clear advantage for the two non-cisplatin arms (not different whether IV or IP). In the OV21/PETROC trial, adverse toxicities coupled with no obvious therapeutic advantage led to dropping the IP cisplatin arm. With additional accrual in the two remaining arms, IP carboplatin was superior to IV carboplatin in time to progression. CONCLUSIONS: Cisplatin has an unfavorable impact on QOL in women with ovarian cancer whether given IP or IV relative to carboplatin. With IV carboplatin as part of the comparator, unfavorable effects of cisplatin-based chemotherapy are further highlighted. IP carboplatin randomized studies and their final publications are awaited. On the other hand, revisiting the role of IP cisplatin at this time is not warranted. Citation Format: Franco Muggia MD, Lari Wenzel, PhD. INTRAPERITONEAL (IP) THERAPY FOR ADVANCED STAGE EPITHELIAL OVARIAN CANCER (EOC): THE CURRENT SPOTLIGHT IS ON CARBOPLATIN AND QUALITY OF LIFE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-101.

Characterization of Aurora A and Its Impact on the Effect of Cisplatin-Based Chemotherapy in Patients with Non–Small Cell Lung Cancer

BACKGROUND AND OBJECTIVE: Aurora A, as a member of serine/threonine kinase family and a common characteristic of epithelial cancers, plays a critical role in cell mitosis. However, the clinical significance of Aurora A in non–small cell lung cancer (NSCLC) remains undetermined. METHODS: The expression of Aurora A in NSCLC and paired normal adjacent lung tissues was determined by immunohistochemistry, Western blot, and reverse transcriptase polymerase chain reaction. Receiver operating characteristic (ROC) curve analysis was employed to determine a cutoff score for Aurora A expression in a training set (n=135). For validation, the ROC-derived cutoff score was subjected to analysis of the association of Aurora A expression with patient outcome and clinicopathological characteristics in a testing set (n=128) and overall patients (n=263). The correlation of Aurora A with cisplatin resistance and epithelial-mesenchymal transition (EMT) was examined in vitro in NSCLC cells by overexpression or knockdown of Aurora A. RESULTS: Aurora A expression was significantly upregulated in tumor tissues compared with paired normal tissues (P<.01). The expression of Aurora A was closely associated with clinical stage, lymph node metastasis, and recurrence and was an independent prognostic parameter in multivariate analysis. High level of Aurora A expression predicted poorer overall survival and disease-free survival in NSCLC patients treated with cisplatin-based adjuvant chemotherapy. In vitro data showed that overexpression or knockdown of Aurora A resulted in increased or decreased cellular resistance to cisplatin. Furthermore, inhibition of Aurora A reversed the EMT process. CONCLUSIONS: Aurora A was identified as an inferior prognostic and cisplatin-resistant biomarker in NSCLC patients, which provided potential evidences for therapeutic target and reversing drug resistance.

Pretreatment with 5-FU enhances cisplatin cytotoxicity in head and neck squamous cell carcinoma cells

In the treatment of head and neck malignancy, cisplatin and 5-FU have been used the most as chemotherapeutic agents. The difference in efficacies of these is unclear and controversial. To investigate more effective schedule, we analyzed the cytotoxicity in different treatment sequence with two agents in vitro and the mechanism for different effectiveness. UM-SCC-23 and UM-SCC-81B, head and neck squamous cell carcinoma cell lines, were analyzed for cellular killing in alternative sequence treatment with cisplatin and 5-FU. The treatment schedule was designed based on the clinical regimen. To determine the mechanism for the difference of cytotoxicity with each schedule, cell cycle distributions of both cells after 5-FU treatment with various durations were analyzed by flow-cytometry and immunostaining with anti-PCNA and anti-BrdU. 5-FU pretreatment followed by cisplatin treatment showed higher cell killing in both types of cells than the reverse treatment schedule. In the cell cycle analysis and immunostaining after the treatment of 5-FU, the rate of PCNA-positive cells was increased from 24 to 144 h in both cells. The rate of BrdU-positive cells of UM-SCC-81B in flow-cytometry was also increased, while that of UM-SCC-23 was gradually decreased. These data suggested that the cells treated with 5-FU for more than 144 h were still in the S-phase with or without DNA synthesis. In head and neck carcinoma cells, we showed 5-FU pretreatment enhanced cisplatin cytotoxicity. The result of cell cycle analysis and immunostaining showed S-phase arrest by treatment of prolonged 5-FU treatment. The very long arrest in S-phase might be a mechanism to enhance cisplatin cytotoxicity by 5-FU pretreatment. We thus suggest pretreatment with 5-FU to enhance the effectiveness of cisplatin-based chemotherapy.

Increased late toxicity in 12–20 year survivors of germ cell tumors (GCT)

4509 Background: There is extensive literature on occurrence of late effects of cisplatin-based chemotherapy, but it comes from centers of excellence and may reflect case selection or ascertainment biases. Funded by the NIH SEER Program and the Lance Armstrong Foundation, we studied community-based late outcomes via identification of cases from the Los Angeles SEER Tumor Registry and comparison with a control group. Methods: We identified 951 patients treated in Los Angeles County through the records of the L.A. SEER Cancer Registry/Cancer Surveillance Program (CSP) for 1983–1987, giving a minimum follow-up of 12 years. Consent was obtained from physician of record and forms sent to the patients, requesting information about a broad range of demographic, treatment-related and psycho-social issues. In addition, patients were asked to provide a “control”, a friend of approximately the same age at time of diagnosis, known to the patient before diagnosis and known not to have a history of testis cancer. Questionnaires were also sent to controls, to allow data comparison with patients. Anticipated initial difficulties included mobility of young males and invalid addresses. This occurred in &gt; 50% of cases, and we used a planned strategy for acquisition through State agencies, Department of Motor Vehicles, etc. Results: Surveys were returned by 298 cases and 67 control subjects, and 35 patients refused. In 1983–87, success rates were lower, and 142 patients had died. An unexpected problem was reluctance or inability of subjects to identify friends of comparable age to provide a control population. Differences in groups are summarized in the Table. Conclusions: Long term survivors with GCT have an excess of late toxicity, including cardiovascular, neurological, hematologic, musculoskeletal and neoplastic problems, which increase with time. These data should assist in design of surveillance protocols. [Table: see text] No significant financial relationships to disclose.

Neurocognitive function (NCF) in long-term survivors of testicular cancer (TC)

8034 Background: Cisplatin-based chemotherapy (CBCT) regimens are standard treatment for TC, delivering long-term survival and cure rates. However, cisplatin is a neurotoxin with documented iatrogenic nervous system effects, including neuronal degeneration and myelin thinning. TC occurs primarily in men aged 15 to 35, coinciding with maturation of the frontal lobes and the continuing myelination extending through middle adulthood. Thus, CBCT occurs at a time of increased neurocognitive vulnerabilty and may impact NCF. Despite recent interest in the neurocognitive sequelae of chemotherapy, little is known about the effects of CBCT on NCF in TC survivors. Method: This study compared NCF between TC survivors who had completed either CBCT (n = 16) or localized treatment (LT; n = 7). NCF was assessed with a standard neuropsychological battery. Participants also completed measures of psychological distress, fatigue, and quality of life (QOL). Results: Men ranged in age from 23–64 years (M = 41), were at least 2.5 years post-diagnosis (M = 7.4), and were primarily college educated (78%). Demographics, psychological distress, fatigue, and QOL did not differ between treatment groups (all ps > .3). Compared to men who received LT, men treated with CBCT demonstrated poorer performance on two executive function measures, Stroop Interference (p = .028), and the Penn Conditional Exclusion Test (PCET: p = .008). Increased PCET errors were associated with poorer Functional QOL (p = .007). Psychological distress and fatigue were unrelated to NCF (all ps ≥ .2). Conclusions: Although preliminary, these data suggest that TC survivors treated with CBCT have mild deficits in NCF that impact QOL. Given the similarity of the treatment groups, and that NCF was unrelated to psychological distress or fatigue, the most likely mechanism is cisplatin associated neurotoxicity. Larger scale studies are needed to elucidate the mechanisms underlying NCF deficits in TC survivors and to explore the real-life impact of these deficits on QOL. No significant financial relationships to disclose.

O-60 The big lung trial quality of life study: Determining the effect of cisplatin-based chemotherapy for supportive care patients with non-small cell lung cancer (NSCLC)

O-60 The big lung trial quality of life study: Determining the effect of cisplatin-based chemotherapy for supportive care patients with non-small cell lung cancer (NSCLC)

Effect of cisplatin-based chemotherapy on emergence of cisplatin resistance, and its correlation with intracellular glutathione levels and accumulation of p53 protein in human ovarian cancer.

Forty-seven ovarian cancer cases in which 20 were previously treated with cisplatin (cisPt) based chemotherapy, were checked for in vitro chemosensitivity using MTT assay. The drugs included in the study were cisPt, adriamycin (ADR), epirubicin (EPR) and etoposide (ETO). The logarithemic concentrations (0.1, 1.0, 10.0 and 100.0 micrograms/ml) of these drugs were used in the MTT assay. The IC50 values for these drugs in the above tumor samples were calculated. The effect of pretreatment with cisPt based chemotherapy on the emergence of drug resistance, expression of p53 protein (detected using immunohistochemical method by employing monoclonal antibody to p53) and intracellular glutathione (GSH) levels was also studied. Our results demonstrated the superiority of EPR in terms of its efficacy as compared to the other drugs used in the study. EPR was effective in both, previously cisPt-exposed and cisPt-unexposed ovarian cancer cases indicating its importance as a second line chemotherapy in the refractory ovarian carcinoma cases. Pre-exposure to cisPt based chemotherapy appears to result in the emergence of cisPt resistance, elevated intracellular GSH levels as well as p53 positivity. A statistically significant correlation was also observed between ADR and EPR resistance and p53 positivity (P < 0.01 and 0.05 respectively).

Comparison of Granisetron, Ondansetron and Tropisetron for Control of Vomiting and Nausea Induced by Cisplatin

Severe nausea and vomiting are common and one of the most feared side effects of cisplatin-based chemotherapy. A total of 106 patients were randomized to receive a single dose of 8 mg ondansetron or 3 mg granisetron or 5 mg tropisetron intravenously as prevention of cisplatin-induced acute nausea and vomiting. Antiemetic therapy was done within 30 minutes before initiating chemotherapy. A questionnaire evaluating nausea, vomiting and retches was administered to patients and the responses were categorized as complete, partial or failure. The response determination was repeated in the first 24 hours, and within 24-72 hours following cisplatin administration.The complete response rates for ondansetron, granisetron and tropisetron in the first 24 hours were 51.4%, 65.7% and 61.1% respectively. All three agents were highly effective against cisplatin-induced acute and late vomiting and the results were statistically significant. This study demonstrated no significant difference in effectiveness of these three antiemetics. 5-HT3 (5-hydrox-ytryptamine 3) receptor antagonists have similar efficacy in the prevention of nausea and vomiting due to cisplatin. Thus, we recommend that drug choice be based on cost-benefit and patient tolerance.

Acute and Late Vascular Complications Following Chemotherapy for Germ Cell Tumors

Side effects of cisplatin-based chemotherapy for germ cell tumors include myelosup-pression, nephro-, neuro- and ototoxicity. These side effects as well as the pulmonary toxicity of bleomycin are dose-dependent. On the contrary, chemotherapy-associated vascular complications are unpredictable. Whereas Raynaud’s phenomenon is observed in a considerable proportion of patients, myocardial infarction, stroke, and pulmonary embolism appear to occur infrequently. The fact that some patients have been in complete remission at the time of myocardial infarction or cerebrovascular accident argues against a tumor-induced complication and is an argument in favor of a possible causative role of chemotherapy. An alteration of the clotting system and vascular smooth muscle tone as well as an endothelial cell damage are discussed to be pathogenetic mechanisms. Pulmonary embolism, on the contrary, seems to be more frequently associated with inferior vena caval obstruction by tumor masses. Presently there is a debate whether, apart from rare acute vascular events, chemotherapy for testicular cancer leads to a long-term alteration of lipid profile and thereby eventually increases cardiovascular risk.