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"An organoplatinum compound that possesses antineoplastic activity." (MeSH 2013)

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Li J, Yi W, Jiang P, et al.
Effects of ambroxol hydrochloride on concentrations of paclitaxel and carboplatin in lung cancer patients at different administration times.
Cell Mol Biol (Noisy-le-grand). 2016; 62(13):85-89 [PubMed] Related Publications
Our previous preliminary study revealed a synergistic effect of ambroxol hydrochloride with chemotherapeutic agents such as paclitaxel and carboplatin in lung cancer. However, the optimal conditions such as administration time and drug concentration of ambroxol hydrochloride to achieve the maximum synergistic effect remained unclear. Therefore, concentration changes of the chemotherapy drugs paclitaxel and carboplatin in the sputum were observed after ambroxol hydrochloride administration at different times in order to determine the most effective time frame of ambroxol hydrochloride administration. In this study, 470 cases of non-small cell lung cancer (NSCLC) were divided into different groups with ambroxol hydrochloride administered at different time points prior to chemotherapy, while another 171 cases received no ambroxol hydrochloride prior to chemotherapy. The results showed the concentrations of paclitaxel and carboplatin in sputum of patients treated with ambroxol hydrochloride were significantly higher than those of the control group, suggesting that ambroxol hydrochloride significantly increased the local concentrations of chemotherapeutic agents in lung tissues of NSCLC. Furthermore, the intravenous administration of ambroxol hydrochloride more than 48 hours before chemotherapy showed an optimized schedule and much greater efficacy in increasing drug concentrations than that of the control group. No statistical differences were found in the rates of grade 2 or above myelosuppression between the ambroxol intervention and control groups. Taken together, these results demonstrate that ambroxol hydrochloride administered intravenously more than 48 hours prior to chemotherapy optimally increased the concentrations of paclitaxel and carboplatin in lung tissue without significantly increasing hematologic toxicity.

Isaka T, Nakayama H, Yokose T, et al.
Platinum-Based Adjuvant Chemotherapy for Stage II and Stage III Squamous Cell Carcinoma of the Lung.
Ann Thorac Cardiovasc Surg. 2017; 23(1):19-25 [PubMed] Related Publications
INTRODUCTION: The efficacy of platinum-based adjuvant chemotherapy (PBAC) for pathological stage II and stage III squamous cell carcinoma (SCC) of the lung was analyzed retrospectively.
MATERIALS AND METHODS: The prognoses of 94 patients with stage II and stage III SCC with or without PBAC (more than three courses of cisplatin-, carboplatin-, and nedaplatin-based adjuvant chemotherapy) were compared.
RESULTS: The mean observation period was 46.1 months. PBAC was not administered for the following reasons: 39 (55.7%) patients had comorbidities, 25 (35.7%) were older than 75 years, 19 (27.1%) patients underwent surgery before the approval of PBAC, and 3 (4.3%) patients could not continue PBAC (≤2 cycles) because of adverse events. PBAC patients (n = 24) were significantly younger than non-PBAC patients (n = 70; 66.3 vs 69.6 years old, respectively; p = 0.043). Disease-free survival (DFS) did not differ between PBAC and non-PBAC patients (55.0% and 67.1%, respectively; p = 0.266). PBAC patients tended to have worse overall survival (OS) than non-PBAC patients (56.1% and 70.2%, respectively; p = 0.138). PBAC was not prognostic for OS (hazard ratio (HR), 2.11; 95% confidence interval (CI), 0.82%-5.40%; p = 0.120).
CONCLUSION: PBAC did not improve the prognoses of patients with pathological stage II or stage III SCC in the single institution experience.

Wang F, Du X, Li X, et al.
Effects of sequential paclitaxel-carboplatin followed by gemcitabine-based chemotherapy compared with paclitaxel-carboplatin therapy administered to patients with advanced epithelial ovarian cancer: A retrospective, STROBE-compliant study.
Medicine (Baltimore). 2016; 95(51):e5696 [PubMed] Free Access to Full Article Related Publications
We aimed to compare the efficacy of paclitaxel and carboplatin followed by gemcitabine-based combination chemotherapy with paclitaxel-carboplatin for treating advanced epithelial ovarian cancer in this retrospective, STROBE-compliant study. Patients' tolerance to treatment was also assessed.We retrospectively analyzed the records of 178 women who underwent initial optimal debulking surgery between January 2003 and December 2011 to treat FIGO stage IIIc epithelial ovarian cancer. Patients in arm 1 (n = 88) received 4 cycles of paclitaxel and carboplatin followed by 2 to 4 cycles of gemcitabine-based combination chemotherapy. Patients in arm 2 (n = 90) received 6 to 8 cycles of paclitaxel and carboplatin. The granulocyte-colony stimulating factor was administered prophylactically to all patients.The median follow-up for both arms was 62 months. Medianprogression-free survival (PFS) between arms 1 and 2 (28 and 19 months [P = 0.003]) as well as 5-year OS (34.1% and 18.9% [P = 0.021]) differed significantly. The neurotoxicity rate was significantly higher in arm 2 than in arm 1 (45.2% vs 27.1%, P = 0.026). There was no significant difference between study arms in hematological toxicity.The sequential regimen significantly improved PFS and 5-year OS with tolerable toxicity compared with the single regimen, and offers an alternative for treating patients with advanced epithelial ovarian cancer.

Takeda K, Matsushita H, Kubozono M, et al.
Definitive Chemoradiotherapy for Advanced Pulmonary Sarcomatoid Carcinoma.
Intern Med. 2016; 55(22):3325-3330 [PubMed] Free Access to Full Article Related Publications
Pulmonary sarcomatoid carcinoma is a rare subtype of non-small cell lung cancer with a poor prognosis. We herein report on a case of pulmonary sarcomatoid carcinoma that was treated successfully by concurrent chemoradiotherapy. A 65-year-old man was diagnosed to have pulmonary pleomorphic carcinoma (clinical T4N2M0 stage IIIB). He received concurrent chemoradiotherapy (60 Gy of radiotherapy in 30 fractionations and two courses of chemotherapy with carboplatin and paclitaxel). After chemoradiotherapy, a significant reduction of the tumor size was observed. Two courses of adjuvant chemotherapy were performed. He is currently alive at 15 months after the first treatment without any recurrence or metastasis.

Dermitzakis EV, Kimiskidis VK, Lazaridis G, et al.
The impact of paclitaxel and carboplatin chemotherapy on the autonomous nervous system of patients with ovarian cancer.
BMC Neurol. 2016; 16(1):190 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Paclitaxel-based regimens are frequently associated with the development of peripheral neuropathy. The autonomous nervous system (ANS) effects, however, of this chemotherapeutic agent remain unexplored.
METHODS: We investigated a group of 31 female patients with ovarian cancer receiving treatment with paclitaxel and carboplatin, as well as a group of 16 healthy age- and gender-matched healthy volunteers. All study participants completed a questionnaire and were assessed neurophysiologically at three time points (baseline, 3-4 months and 6-8 months following the onset of chemotherapy). The evaluation of the ANS included assessment of the adrenergic cardiovascular function (orthostatic hypotension-OH), parasympathetic heart innervation (30/15 ratio) and sympathetic skin response (SSR).
RESULTS: At the 3-4 months ANS assessment, 19.2 % of the patients had systolic OH and the same percentage had diastolic OH, but at the 6-8 months evaluation no patient had systolic OH and only 13.8 % had diastolic OH. The values of the 30/15 ratio were significantly reduced at both time points, whereas the SSR was not affected.
CONCLUSIONS: Combined paclitaxel and carboplatin chemotherapy is associated with significant effects on the parasympathetic heart innervation and occasionally with effects on the adrenergic cardiovascular reaction. The SSR remained unaffected. Physicians should be alert to the possibility of these treatment-emergent side effects, so as to monitor ANS parameters and introduce treatment modifications accordingly. Our findings however, should be validated in larger cohorts.

Mao W, Sun Y, Zhang H, et al.
A combined modality of carboplatin and photodynamic therapy suppresses epithelial-mesenchymal transition and matrix metalloproteinase-2 (MMP-2)/MMP-9 expression in HEp-2 human laryngeal cancer cells via ROS-mediated inhibition of MEK/ERK signalling pathway.
Lasers Med Sci. 2016; 31(8):1697-1705 [PubMed] Related Publications
Photodynamic therapy (PDT) has been developed as a promising treatment modality for laryngeal cancer. 9-Hydroxypheophorbide α (9-HPbD), a novel chlorophyll-derived photosensitizer, has a longer absorption wavelength, which increases the penetration of light to malignant tissues. Carboplatin (CBDCA), a second-generation platinum derivative, also has gained more popularity for the treatment of laryngeal cancer. Our previous studies have elucidated that 9-HPbD-PDT could inhibit the migration and invasion of HEp-2 cells. The objective of this study is to investigate the change of migration and invasion of HEp-2 cells induced by a combined modality of CBDCA and 9-HPbD-PDT in vitro. A wound healing assay, cell migration assay and Matrigel invasion assay were used to evaluate the cellular migration and invasion. Reactive oxygen species (ROS) and Western blots for epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and vimentin), MMPs (MMP-2 and MMP-9) and MEK/ERK signalling pathway were performed to investigate the possible mechanisms that may be involved. We observed that CBDCA and 9-HPbD-PDT administration synergistically inhibited the migration and invasion of HEp-2 cells. Moreover, the combined modality cooperatively repressed the EMT process and down-regulated expressions of MMP-2 and MMP-9 via ROS-mediated inhibition of phosphorylation in the MEK/ERK signalling pathway. Our results suggested that the combination of CBDCA and 9-HPbD-PDT might be a promising therapeutic strategy for laryngeal cancer metastasis.

Rugo HS, Olopade OI, DeMichele A, et al.
Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer.
N Engl J Med. 2016; 375(1):23-34 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin.
METHODS: In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well.
RESULTS: With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control.
CONCLUSIONS: The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

Shimada M, Nagao S, Fujiwara K, et al.
Neoadjuvant chemotherapy with docetaxel and carboplatin followed by radical hysterectomy for stage IB2, IIA2, and IIB patients with non-squamous cell carcinoma of the uterine cervix.
Int J Clin Oncol. 2016; 21(6):1128-1135 [PubMed] Related Publications
BACKGROUND: We conducted a phase II study to evaluate the efficacy of neoadjuvant chemotherapy with docetaxel and carboplatin followed by radical hysterectomy for patients with non-squamous cell carcinoma of the uterine cervix.
METHODS: Sixty-one patients with International Federation of Gynecology and Obstetrics stage IB2, IIA2, or IIB non-squamous cell carcinoma of the uterine cervix were enrolled. The patients were administered docetaxel at a dose of 60 mg/m(2), followed by carboplatin at a dose based on an area under the curve of 6. The treatments were repeated every 21 days for one to three cycles. Fifty-two patients were eligible to evaluate the efficacy of neoadjuvant chemotherapy followed by radical hysterectomy. Adverse events were evaluated in 59 patients.
RESULTS: The response rate was 69 % (95 % CI, 57-82 %), with 5 patients achieving complete response, 31 partial response, 15 stable disease, and 1 progressive disease. Median follow-up duration was 1913 days with a range of 145-2632 days. Of 52 patients, 50 underwent radical hysterectomy after neoadjuvant chemotherapy. The 2-year overall survival rate was 81.8 % for stage IB2, 85.7 % for stage IIA2, and 92.6 % for stage IIB. The most frequent grade 3 and 4 hematological toxicity was neutropenia, with 43 patients experiencing grade 4 and 11 with grade 3. The nonhematological toxicities were mainly grade 1 or 2 in severity.
CONCLUSION: Neoadjuvant chemotherapy with docetaxel and carboplatin followed by radical hysterectomy may be a useful strategy for patients with non-squamous cell carcinoma of uterine cervix.

Stope MB, Wiegank L, Weiss M, et al.
Drug-induced Modulation of Heat Shock Protein HSPB1 in an Ovarian Cancer Cell Model.
Anticancer Res. 2016; 36(7):3321-7 [PubMed] Related Publications
BACKGROUND: Heat-shock protein HSPB1 (alternative name HSP27) plays a pivotal role in cell survival pathways, apoptosis, metastasis and has been frequently linked to treatment resistance in ovarian cancer (OC) and other malignancies. Characteristic HSPB1 induction in different solid tumors is often caused by cytotoxic agents.
MATERIALS AND METHODS: An in vitro OC cell model system was established to characterize resistance mechanisms during chemotherapy. Human OC cell lines OVCAR-3, SK-OV-3 and TOV-21G were treated with paclitaxel or carboplatin. Cellular growth was analyzed by cell counting. Intra- and extracellular HSPB1 concentrations were assessed by western blot and enzyme-linked immunosorbent assays.
RESULTS: Incubation with paclitaxel, and with carboplatin significantly reduced cell growth without a definitive increase of intracellular HSPB1 expression. HSPB1 demonstrated drug-inducible secretion into the extracellular compartment.
CONCLUSION: Despite its current lack of analysis in patient samples, serum soluble HSPB1 may function as a specific biomarker for monitoring response to chemotherapy in patients with OC.

Gutierrez F, Gonzalez-de-la-Fuente GA, Nazco GJ, et al.
Hematological toxicity of carboplatin for gynecological cancer according to body mass index.
Eur J Clin Pharmacol. 2016; 72(9):1083-9 [PubMed] Related Publications
PURPOSE: The aim of the present study was to analyze how patient weight affects the hematological toxicity of carboplatin and whether this toxicity is more prevalent in overweight patients.
METHODS: We performed a retrospective 2-year study of patients diagnosed with a gynecological cancer and whose treatment regimen contained carboplatin (AUC dose = 5 or 6) and paclitaxel (dose = 175 mg/m(2)) every 3 weeks (CP scheme). We recorded all severe hematological events (thrombocytopenia, neutropenia, and/or anemia grade III/IV) according to the CTCAE v4.03, as well as treatment modifications and the need for granulocyte colony-stimulating factors (G-CSF) and/or erythropoietin (EPO) or packed red blood cells (PRBC). Patients with a body mass index (BMI) ≥27 kg/m(2) were considered as overweight (OW) and those with a BMI <27 kg/m(2) were considered as normal weight (NW).
RESULTS: Fifty-two patients met the inclusion criteria (21 patients in the OW group, 31 patients in the NW group). The OW group showed a higher incidence of thrombocytopenia (95% confidence intervals (CI) 1.51-27.72; p < 0.02) and anemia (95% CI 1.06-33.63; p < 0.05). Moreover, this was reflected in a greater number of changes in the usual CP regimen (95% CI 2.19-44.32; p < 0.01). The need for G-CSF and/or EPO/PRBC was also significantly higher in the OW group (95% CI 1.08-12.16; p < 0.04).
CONCLUSIONS: Carboplatin dosing based on real weight in obese patients resulted in increased hematologic toxicity, mainly thrombocytopenia. Dose adjustment based on other descriptors of weight, such as adjusted weight, may be better tolerated by patients. However, future studies are needed to demonstrate not only better safety of carboplatin but also improved survival rates.

Lin L, Tu HB, Wu L, et al.
MicroRNA-21 Regulates Non-Small Cell Lung Cancer Cell Invasion and Chemo-Sensitivity through SMAD7.
Cell Physiol Biochem. 2016; 38(6):2152-62 [PubMed] Related Publications
BACKGROUND/AIMS: SMAD7 is a key inhibitor of transforming growth factor β (TGFβ) receptor signaling, which regulates the alteration of cancer cell invasiveness through epithelial-mesenchymal cell conversion. Carboplatin is a commonly used drug in the chemotherapy for non-small cell lung cancer (NSCLC). Nevertheless, the molecular mechanisms underlying its suppressive effects on the NSCLC cell invasion are not completely understood. In the current study, we addressed this question by analyzing the effects of Carboplatin on microRNA-regulated SMAD7.
METHODS: We used Carboplatin to treat NSCLC cell lines. We performed bioinformatics analyses on the binding of microRNA-21 (miR-21) to the 3'-UTR of SMAD7 mRNA, and verified the biological effects of this binding using promoter luciferase reporter assay. The effects of Carboplatin or miR-21-modification on NSCLC cell invasion were evaluated in either a transwell cell invasion assay, or a scratch wound healing assay.
RESULTS: We found that Carboplatin inhibited the NSCLC cell invasion, in either a transwell cell invasion assay, or a scratch wound healing assay. Moreover, Carboplatin increased the levels of SMAD7 protein, but not mRNA, in NSCLC cells, suggesting presence of post-transcriptional control of SMAD7 by Carboplatin. Furthermore, expression of miR-21 was found to be inhibited by Carboplatin, and bioinformatics analyses showed that miR-21 targeted the 3'-UTR of SMAD7 mRNA to inhibit its translation, which was confirmed by luciferase reporter assay.
CONCLUSION: Carboplatin may upregulate SMAD7 through suppression of miR-21 to inhibit TGFβ receptor signaling mediated NSCLC cell invasion.

Chen C, Ma FW, Du CY, Wang P
Multiple Differential Networks Strategy Reveals Carboplatin and Melphalan-Induced Dynamic Module Changes in Retinoblastoma.
Med Sci Monit. 2016; 22:1508-15 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Retinoblastoma (RB) is the most common malignant tumor of the eye in childhood. The objective of this paper was to investigate carboplatin (CAR)- and melphalan (MEL)-induced dynamic module changes in RB based on multiple (M) differential networks, and to generate systems-level insights into RB progression. MATERIAL AND METHODS To achieve this goal, we constructed M-differential co-expression networks (DCNs), assigned a weight to each edge, and identified seed genes in M DCNs by ranking genes based on their topological features. Starting with seed genes, a module search was performed to explore candidate modules in CAR and MEL condition. M-DMs were detected according to significance evaluations of M-modules, which originated from refinement of candidate modules. Further, we revealed dynamic changes in M-DM activity and connectivity on the basis of significance of Module Connectivity Dynamic Score (MCDS). RESULTS In the present study, M=2, a total of 21 seed genes were obtained. By assessing module search, refinement, and evaluation, we gained 18 2-DMs. Moreover, 3 significant 2-DMs (Module 1, Module 2, and Module 3) with dynamic changes across CAR and MEL condition were determined, and we denoted them as dynamic modules. Module 1 had 27 nodes of which 6 were seed genes and 56 edges. Module 2 was composed of 28 nodes and 54 edges. A total of 28 nodes interacted with 45 edges presented in Module 3. CONCLUSIONS We have identified 3 dynamic modules with changes induced by CAR and MEL in RB, which might give insights in revealing molecular mechanism for RB therapy.

Waqar SN, Mann J, Baggstrom MQ, et al.
Delayed nausea and vomiting from carboplatin doublet chemotherapy.
Acta Oncol. 2016; 55(6):700-4 [PubMed] Article available free on PMC after 01/06/2017 Related Publications
BACKGROUND: Delayed nausea and vomiting following administration of carboplatin containing chemotherapy regimen remains a clinically significant problem for patients with cancer despite administration of standard antiemetic prophylaxis comprising of a 5-HT3 antagonist and dexamethasone. We performed a prospective study to define the incidence and risk factors for delayed chemotherapy-induced nausea and vomiting (CINV).
METHODS: Previously untreated patients with newly diagnosed cancer scheduled to receive carboplatin containing chemotherapy (AUC 5 or above), but no prophylactic aprepitant were enrolled in the study. The primary endpoint was the incidence of delayed CINV after Cycle 1 of chemotherapy. Secondary endpoints included the incidence of CINV with the third chemotherapy cycle and gender differences in incidence of CINV. Patients completed the Functional Living Index Emesis (FLIE) questionnaires 24, 48, 72 and 96 hours after receiving chemotherapy. Telephone interviews were conducted 24-48 hours following chemotherapy to assess the severity and need for breakthrough medications for CINV.
RESULTS: Between December 2006 and July 2009, 105 patients were enrolled onto this study. Delayed emesis following Cycle 1 of carboplatin was observed in 30% of patients. Of these, 14.1%, 22.4% and 23.5% of patients described CINV at 48, 72, and 96 hours, respectively. The incidence of delayed CINV following Cycle 3 dropped to 12.8%, 14.6% and 16% of patients at 48, 72 and 96 hours, respectively. No differences were observed in the incidence of CINV between men and women. A total of 20% of patients required use of breakthrough antiemetics with Cycle 1.
CONCLUSIONS: Without prophylactic aprepitant administration, 30% of patients receiving carboplatin containing regimen had moderate to severe delayed CINV.

Sekine A, Satoh H, Baba T, et al.
Safety and efficacy of S-1 in combination with carboplatin in non-small cell lung cancer patients with interstitial lung disease: a pilot study.
Cancer Chemother Pharmacol. 2016; 77(6):1245-52 [PubMed] Related Publications
PURPOSE: There is no established standard regimen for non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD). For them, we performed a pilot study to evaluate the feasibility of chemotherapy with carboplatin and S-1, which are known as cytotoxic drug with rare development of ILD as adverse event.
METHODS: A total of 21 chemotherapy-naive NSCLC patients with ILD were prospectively enrolled between March 2009 and September 2011. Every 3 weeks, carboplatin at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m2 daily for 14 days were administered.
RESULTS: The median age at initiating chemotherapy was 67. Histological examination revealed 10 patients (48 %) with adenocarcinoma. Before chemotherapy, partial pressure of arterial O2 (PaO2) was low with a median of 71 Torr on room air. The median number of cycles administered was four, and the overall response rate and disease control rate were 33 and 67 %, respectively. At the time of data cut-off, all patients were deceased. The median progression-free survival (PFS) and median overall survival (OS) periods were 4.2 and 9.7 months. There was no significant difference of PFS and OS according to tumor histology. Acute exacerbation (AE) of ILD following S-1 plus carboplatin occurred in two patients (10 %, 2/21) within first course treatment. However, they were successfully managed with steroid therapy and survived for 7.0 and 8.8 months, respectively, after AE-ILD development.
CONCLUSIONS: This is the first prospective study to evaluate the safety and efficacy of S-1 plus carboplatin treatment for NSCLC patients with ILD. This regimen could be a feasible option for NSCLC patients with ILD, regardless of tumor histology. Our results would support to carry out a large-scale clinical trial to confirm the feasibility of this regimen.

Ho GY, Woodward N, Coward JI
Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies.
Crit Rev Oncol Hematol. 2016; 102:37-46 [PubMed] Related Publications
The platinum analogues, cisplatin and carboplatin, are among the most widely used chemotherapeutic agents in oncology. Both agents have a broad spectrum of clinical activity in numerous malignancies including gynaecological cancers, germ cell tumours, head and neck cancer, thoracic cancers and bladder cancer. Although the final mechanism of inducing tumour cell apoptosis is similar for both compounds, cisplatin has been shown to be more effective in treating specific tumour types. Whilst more favourable toxicity profiles are often associated with carboplatin, this can frequently translate to inferior response in certain malignancies. This review succinctly collates the evidence for the preferential use of these platinum analogues in particular settings in addition to the long-standing dilemma surrounding the paucity of biomarkers predicting response to these agents.

Nakano K, Sato Y, Sasaki T, et al.
Combination chemotherapy of carboplatin and paclitaxel for advanced/metastatic salivary gland carcinoma patients: differences in responses by different pathological diagnoses.
Acta Otolaryngol. 2016; 136(9):948-51 [PubMed] Related Publications
BACKGROUND: A standard chemotherapy for recurrent/metastatic salivary gland cancers has not been established. Combination chemotherapy of carboplatin and paclitaxel should be evaluated as a treatment option.
METHODS: This study retrospectively reviewed salivary gland cancer patients who received combination chemotherapy of carboplatin and paclitaxel. The differences in objective responses and in the prognoses according to the different pathological diagnoses were evaluated.
RESULTS: A total of 38 patients were enrolled in the study; of them, 18 had salivary duct carcinomas (SDCs), nine had adenoid cystic carcinomas (ACCs), and 11 had other pathological diagnoses. Objective responses were observed in 15 (39%) patients. The median progression-free survival (PFS) was 6.5 months, and the median overall survival (OS) was 26.5 months. ACC patients had relatively low response rates (9%), but there were no significant differences in PFS or OS compared to other sub-types. The treatment was well tolerated, with few adverse events.
CONCLUSION: Salivary gland cancer patients showed a moderate clinical response to the combination chemotherapy of carboplatin and paclitaxel. The objective response rates differed according to the pathological diagnoses, but there were no significant differences in prognoses.

Abed MN, Abdullah MI, Richardson A
Antagonism of Bcl-XL is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells.
J Ovarian Res. 2016; 9:25 [PubMed] Article available free on PMC after 01/06/2017 Related Publications
BACKGROUND: BH3 mimetics are a class of drugs that antagonize the Bcl-2 family of apoptosis inhibitors. We have previously shown that these compounds can potentiate the activity of carboplatin against several ovarian cancer cell lines. However, recent clinical studies have highlighted that BH3 mimetics which antagonise Bcl-XL are associated with significant thrombocytopenia. This has led to the development of ABT-199 which specifically inhibits Bcl-2. Unfortunately, Bcl-XL appears to be more frequently deregulated in ovarian cancer than Bcl-2. We therefore compared the ability of ABT-199, and the Bcl-XL selective compound WEHI-539, to potentiate the activity of carboplatin in ovarian cancer cell lines.
METHODS: WEHI-539, ABT-737 and ABT-199 were tested in combination with carboplatin using a panel of 6 ovarian cancer cell lines. The activity of the drugs was evaluated using cell growth assays, staining with trypan bue and measurement of apoptosis by measuring caspase 3/7 activity, PARP cleavage and annexin-V/propidium iodide staining.
RESULTS: We found that WEHI-539 and ABT-737, but not ABT-199, were synergistic with carboplatin in cell growth assays and potentiated cell death when assessed by trypan blue staining. Furthermore, WEHI-539 and ABT-737 augmented carboplatin induced caspase 3/7 activity, PARP cleavage and annexin V labelling, but ABT-199 failed to do so.
CONCLUSIONS: These observations suggest that compounds which target Bcl-XL are necessary if BH3 mimetics are to be successfully used to treat patients with ovarian cancer and this highlights the need to develop strategies to minimize thrombocytopenia induced by such compounds.

Frielink LM, Pijlman BM, Ezendam NP, Pijnenborg JM
Clinical Practice of Adjuvant Chemotherapy in Patients with Early-Stage Epithelial Ovarian Cancer.
Chemotherapy. 2016; 61(6):287-94 [PubMed] Related Publications
BACKGROUND: Adjuvant platinum-based chemotherapy improves survival in women with early-stage epithelial ovarian cancer (EOC). Yet, there is a wide variety in clinical practice.
METHODS: All patients diagnosed with FIGO I and IIa EOC (2006-2010) in the south of the Netherlands were analyzed. The percentage of patients that received adjuvant chemotherapy was determined as well as the comprehensiveness of staging and outcome.
RESULTS: Forty percent (54/135) of the patients with early-stage EOC received adjuvant chemotherapy. Treatment with adjuvant chemotherapy was associated with FIGO stage, clear-cell histology and nonoptimal staging. Optimal staging was achieved in 50%, and nonoptimal staging was associated with advanced age, comorbidity and treatment in a non-referral hospital. Overall, there was no difference in outcome between patients with and without adjuvant chemotherapy. Yet, in grade 3 tumors, adjuvant chemotherapy seems beneficial.
CONCLUSIONS: Selective treatment of patients with early-stage EOC might reduce adjuvant chemotherapy without compromising outcome.

Sun XJ, Deng QH, Yu XM, et al.
A phase II study of Endostatin in combination with paclitaxel, carboplatin, and radiotherapy in patients with unresectable locally advanced non-small cell lung cancer.
BMC Cancer. 2016; 16:266 [PubMed] Article available free on PMC after 01/06/2017 Related Publications
BACKGROUND: Endostatin inhibits the pro-angiogenic action of basic fibroblast growth factor and vascular endothelial growth factor in different human cancers. This study assessed the efficacy of endostatin combined with concurrent chemoradiotherapy of non-small cell lung cancer (NSCLC).
METHODS: Nineteen patients with unresectable stage III NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status 0-l, and adequate organ function were treated with 60-66 Gy thoracic radiation therapy over 30-33 fractions concurrent with weekly 7.5 mg/m(2) endostatin for 14 days, 50 mg/m(2) paclitaxel, and 2 mg/mL/min carboplatin over 30 min. Patients were then treated with 7.5 mg/m(2) endostatin for 14 days, 150 mg/m(2) paclitaxel, and 5 mg/mL/min carboplatin every 3 weeks for 2 cycles as the consolidation treatment. The objective response rate was recorded according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and the toxicity was evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria.
RESULTS: Six patients were unable to complete the consolidation treatment (4 pulmonary toxicity, 1 tracheoesophageal fistulae, and 1 progressive disease). Seventeen patients were included for data analysis. Specifically, one (5.9%) patient had a complete response and 12 (70.6%) had a partial response, whereas two patients had stable disease and the other two had disease progression. The overall response rate was 76% (95% confidence interval [CI], 51%-97%). The median progression-free survival was 10 months (95% CI, 7.6-12.3 months), and the median overall survival was 14 months (95% CI, 10.7-17.2 months). Early 10 patients who completed the treatment regimen showed that four patients experienced grade III pulmonary toxicity a few months after chemoradiotherapy, leading to the early closure of the trial according to the study design.
CONCLUSIONS: The result of concurrent endostatin treatment with chemoradiotherapy in locally advanced unresectable NSCLC did not meet the goal per study design with unacceptable toxicity. The real impact of endostatin as the first-line treatment combined with chemoradiotherapy on the survival of NSCLC patients remains to be determined. (NCT 01158144).

Murakami R, Matsumura N, Brown JB, et al.
Prediction of taxane and platinum sensitivity in ovarian cancer based on gene expression profiles.
Gynecol Oncol. 2016; 141(1):49-56 [PubMed] Related Publications
OBJECTIVE: Prognoses of ovarian cancer (OC) have improved with the paclitaxel-carboplatin regimen. However, it remains unclear which cases exhibit a genuine benefit from taxane or from platinum. We aimed to predict taxane and platinum sensitivity in OC via gene expression.
METHODS: We identified differentially expressed genes in responsive and resistant cases from advanced OC biopsy expression dataset GSE15622, containing responses to paclitaxel or carboplatin monotherapy. These genes generated a scoring system for prediction of drug response by applying single-sample gene set enrichment analysis. Discriminative metrics termed the T-score and C-score were derived.
RESULTS: High C-score levels were significant in responders compared to non-responders in a separate cisplatin treatment dataset (GSE18864, p=0.043). High C-score groups also had significantly better progression-free survival in three OC datasets (The Cancer Genome Atlas, TCGA: p=0.02; GSE9891: p=0.03; GSE30161: p=0.001). In two additional datasets of advanced OC, high T-scores could associate taxane and platinum regimens with better survival than non-taxane and platinum regimens (GSE9891: p<0.0001; GSE3149: p=0.045), whereas in cases with low T-scores, different chemotherapeutic regimens did not result in a significant difference. Assessing TCGA and GSE9891, T-scores were elevated in the C1/Mesenchymal subtype, whereas C-scores were elevated in the C5/Proliferative subtype and were lower in the C1/Mesenchymal subtype (p<0.0001, respectively). C- and T-scores negatively correlated with each other, suggesting complementary roles of taxane and platinum.
CONCLUSIONS: Our proposal and finding of a scoring system that could predict platinum or taxane response could be useful to develop individualized treatments to ovarian cancer.

Wang ZY, Zhang JA, Wu XJ, et al.
IL-6 Inhibition Reduces STAT3 Activation and Enhances the Antitumor Effect of Carboplatin.
Mediators Inflamm. 2016; 2016:8026494 [PubMed] Article available free on PMC after 01/06/2017 Related Publications
Recent studies suggest that tumor-associated macrophage-produced IL-6 is an important mediator within the tumor microenvironment that promotes tumor growth. The activation of IL-6/STAT3 axis has been associated with chemoresistance and poor prognosis of a variety of cancers including colorectal carcinoma and thus serves as a potential immunotherapeutic target for cancer treatment. However, it is not fully understood whether anticytokine therapy could reverse chemosensitivity and enhance the suppressive effect of chemotherapy on tumor growth. In this study, we aimed to investigate the effect of IL-6 inhibition therapy on the antitumor effect of carboplatin. Enhanced expression of IL-6 and activation of STAT3 were observed in human colorectal carcinoma samples compared to normal colorectal tissue, with higher levels of IL-6/STAT3 in low grade carcinomas. Treatment of carboplatin (CBP) dose-dependently increased IL-6 production and STAT3 activation in human colorectal LoVo cells. Blockade of IL-6 with neutralizing antibody enhanced chemosensitivity of LoVo cells to carboplatin as evidenced by increased cell apoptosis. IL-6 blockade abolished carboplatin-induced STAT3 activation. IL-6 blockade and carboplatin synergistically reduced cyclin D1 expression and enhanced caspase-3 activity in LoVo cells. Our results suggest that inhibition of IL-6 may enhance chemosensitivity of colon cancers with overactive STAT3 to platinum agents.

Unni SK, Schauerhamer MB, Deka R, et al.
BRCA testing, treatment patterns and survival in platinum-sensitive recurrent ovarian cancer - an observational cohort study.
J Ovarian Res. 2016; 9:18 [PubMed] Article available free on PMC after 01/06/2017 Related Publications
BACKGROUND: Breast cancer associated (BRCA) genes are critical for DNA repair. Mutations in BRCA1 and BRCA2 (BRCAm) result in loss of these repair mechanisms and potential carcinogenesis. Germline BRCAm are common in ovarian carcinomas, particularly in platinum-sensitive disease. The increased prevalence of BRCAm in platinum-sensitive disease is likely due to enhanced responsiveness to platinum chemotherapy from homologous recombination repair deficiency. The purpose of this study was to explore BRCA testing, treatment patterns and survival in platinum-sensitive recurrent (PSR) ovarian cancer.
METHODS: This was an observational cohort analysis of PSR ovarian cancer treated at the Huntsman Cancer Institute from 1995 to 2012. Germline BRCA status was ascertained through chart review and categorized as BRCAm (BRCA1/2 positive), BRCAwt (BRCA wild type or variant of uncertain significance), and untested. Treatment patterns and survival were assessed from recurrence until death or last follow-up. The Kaplan-Meier method was used to evaluate survival from recurrence by BRCA status. Logistic regression and COX proportional hazard model was used to estimate predictors of BRCA testing and survival, respectively.
RESULTS: Of the 168 PSR patients, 15 (9 %) were BRCAm, 25 (15 %) were BRCAwt, and 128 (76 %) were untested. Median age at PSR was 56 years for BRCAm and BRCAwt (p = 0.90) and 63 years for those untested (p = 0.033 vs BRCAm). Overall survival was similar between BRCAm and BRCAwt (median 50.4 vs 67.5 months, p = 0.86) and was 24.9 months in untested patients. Significant predictors for the likelihood of BRCA testing were age (OR = 0.93, 95 % CI 0.89, 0.97, p = 0.002), family history of breast or ovarian cancer (OR = 8.33, 95 % CI: 3.08, 22.59, p < 0.001), and cancer diagnosis year (OR = 10.02, 95 % CI: 3.22, 31.21, p < 0.001). BRCA-tested patients had a lower risk of death versus untested (HR 0.35, 95 % CI 0.17, 0.68, p = 0.001).
CONCLUSIONS: BRCAwt patients had similar outcomes to BRCAm patients, potentially owing to similar age at diagnosis, representing a BRCA testing channeling bias. Younger patients, those with a family history of breast or ovarian cancer, and those diagnosed more recently were more likely to be BRCA tested. BRCA tested patients had a lower risk of death.

Liu Z, Yang W, Long G, Wei C
Trace Elements and Chemotherapy Sensitivity.
Biol Trace Elem Res. 2016; 173(2):283-90 [PubMed] Related Publications
Trace elements might be associated with the development of hepatocellular carcinoma (HCC) and the efficacy of chemotherapy against HCC. Therefore, this study aimed to explore the association between trace elements and efficacy of chemotherapy in patients with HCC. Cancer, cancer-adjacent, and cancer-free tissues were collected intraoperatively from 55 patients with HCC between January 2001 and April 2004 at the Affiliated Tumor Hospital of Guangxi Medical University in Guangxi (China), a high HCC incidence area in the world. Trace element levels were analyzed by atomic absorption spectrophotometry. In vitro sensitivity of cancer cells to five chemotherapeutic drugs (5-fluorouracil, doxorubicin, cisplatin, carboplatin, and mitomycin) was tested using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in cancer cells from 32 patients. Zinc, copper, manganese, and selenium levels had the same gradient distribution in different liver tissues: cancer < cancer-adjacent < cancer-free tissues. Copper levels of cancer tissues were negatively correlated with body weight (r = -0.278, P = 0.027), while manganese and selenium levels were negatively correlated with age (r = -0.297, P = 0.015; r = -0.285, P = 0.018, respectively). Simple correlation analyses revealed that the carboplatin sensitivity was negatively correlated with selenium levels of cancer tissues, while doxorubicin sensitivity was negatively correlated with manganese levels (r = -0.497, P = 0.004). Partial correlation analyses showed that doxorubicin sensitivity only was negatively correlated with manganese levels (r = -0.450, P = 0.014). These results suggest that the selenium and manganese content in primary HCC tissues could influence the response of the HCC cells to carboplatin and doxorubicin. These preliminary results provide a basis for future studies.

Zhu T, Liu CL, Zhang YF, et al.
A phase II trial of dose-dense (biweekly) paclitaxel plus carboplatin as neoadjuvant chemotherapy for operable breast cancer.
Breast Cancer Res Treat. 2016; 156(1):117-24 [PubMed] Related Publications
The aim of the present study is to investigate the efficacy and safety of dose-dense (biweekly) carboplatin and paclitaxel as a neoadjuvant treatment for operable breast cancer. Patients with previously untreated breast cancer (stages Ic-III) were treated with four cycles of paclitaxel (175 mg/m(2), intravenous drip, D1) and carboplatin (area under the curve of 5, D1). Patients with HER2+ disease simultaneously received trastuzumab (6 mg/kg initial dose with subsequent doses of 4 mg/kg biweekly). The primary endpoint was a pathologically complete response (pCR). Between January 2012 and February 2014, 110 patients were enrolled. The overall pCR rate was 35.45 % (39 of 110). The pCR rates for the different cancer subtypes were as follows: 10.53 % (2 of 19) among the patients with the luminal A subtype, 12.50 % (5 of 40) among the patients with the luminal B (HER2-) subtype, 58.33 % (14 of 24) among the patients with the luminal B (HER2+) subtype, 57.14 % (8 of 14) among the patients with the triple-negative subtype, and 76.92 % (10 of 13) among the patients with the HER2+ subtype. The patients experienced the following toxicity side effects: grade 3/4 neutropenia (N = 27, 24.55 %), grade 3/4 anemia (N = 6, 5.45 %), grade 3/4 thrombocytopenia (N = 2, 1.82 %), grade 3 alanine aminotransferase (ALT) elevation (N = 1, 0.91 %), grade 3 neuropathy (N = 3, 2.73 %), grade 3 pain (N = 2, 1.82 %), and grade 3 fatigue (N = 1, 0.91 %). In total, 19.09 % of the patients experienced treatment delay or discontinuation due to hematological toxicity, and one patient discontinued treatment due to non-hematological toxicity. Neoadjuvant biweekly paclitaxel plus carboplatin is a feasible therapy that achieved high pCR rates in patients with the HER2+, triple-negative, and luminal B (HER2+) cancer subtypes (NCT0205986).

Chan JK, Brady MF, Penson RT, et al.
Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer.
N Engl J Med. 2016; 374(8):738-48 [PubMed] Article available free on PMC after 01/06/2017 Related Publications
BACKGROUND: A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab.
METHODS: We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival.
RESULTS: A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%).
CONCLUSIONS: Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.).

Karayama M, Inui N, Fujisawa T, et al.
Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non small cell lung cancer.
Eur J Cancer. 2016; 58:30-7 [PubMed] Related Publications
OBJECTIVES: Single agent maintenance therapy is widely accepted for advanced non-squamous non small cell lung cancer (NSCLC). However, there is no consensus on the initial and maintenance phase regimens, and the clinical benefit of adding bevacizumab to cytotoxic drugs in the maintenance phase remains unclear.
METHODS: Chemotherapy-naïve patients with non-squamous NSCLC were randomly assigned to maintenance therapy with pemetrexed and bevacizumab or pemetrexed alone, after achieving disease control after four cycles of induction therapy with carboplatin (area under the curve = 6), pemetrexed (500 mg/m(2)), and bevacizumab (15 mg/kg). The primary end-point was 1-year progression-free survival (PFS) rate.
RESULTS: One hundred ten patients were enrolled in the study, with 55 patients assigned to the two groups. The mean 1-year PFS rate was 43.9% (95% confidence interval [CI]: 29.6-59.2%) in the combination maintenance group and 35.2% (95% CI: 22.1-51.0%) in the pemetrexed maintenance group, and the difference was not significant (p = 0.433). Median PFS measured from enrolment was 11.5 months (95% CI: 7.1-19.0) in the combination maintenance group and 7.3 months (95% CI: 5.7-14.1, hazard ratio: 0.73, 95% CI: 0.44-1.19, log-rank p = 0.198) in the pemetrexed maintenance group. Nasal haemorrhage, hypertension, and proteinuria were significantly more frequent in the combination maintenance group, but they were mild and tolerable.
CONCLUSION: Both maintenance therapy with pemetrexed alone and pemetrexed and bevacizumab in combination were feasible in patients with non-squamous NSCLC who have achieved disease control after induction therapy with carboplatin, pemetrexed, and bevacizumab. According to the selection design, differences in the superiority between these maintenance therapies were not demonstrated.

Petanidis S, Kioseoglou E, Domvri K, et al.
In vitro and ex vivo vanadium antitumor activity in (TGF-β)-induced EMT. Synergistic activity with carboplatin and correlation with tumor metastasis in cancer patients.
Int J Biochem Cell Biol. 2016; 74:121-34 [PubMed] Related Publications
Epithelial to mesenchymal transition (EMT) plays a key role in tumor progression and metastasis as a crucial event for cancer cells to trigger the metastatic niche. Transforming growth factor-β (TGF-β) has been shown to play an important role as an EMT inducer in various stages of carcinogenesis. Previous reports had shown that antitumor vanadium inhibits the metastatic potential of tumor cells by reducing MMP-2 expression and inducing ROS-dependent apoptosis. However, the role of vanadium in (TGF-β)-induced EMT remains unclear. In the present study, we report for the first time on the inhibitory effects of vanadium on (TGF-β)-mediated EMT followed by down-regulation of ex vivo cancer stem cell markers. The results demonstrate blockage of (TGF-β)-mediated EMT by vanadium and reduction in the mitochondrial potential of tumor cells linked to EMT and cancer metabolism. Furthermore, combination of vanadium and carboplatin (a) resulted in synergistic antitumor activity in ex vivo cell cultures, and (b) prompted G0/G1 cell cycle arrest and sensitization of tumor cells to carboplatin-induced apoptosis. Overall, the findings highlight the multifaceted antitumor action of vanadium and its synergistic antitumor efficacy with current chemotherapy drugs, knowledge that could be valuable for targeting cancer cell metabolism and cancer stem cell-mediated metastasis in aggressive chemoresistant tumors.

Dziegielewska B, Casarez EV, Yang WZ, et al.
T-Type Ca2+ Channel Inhibition Sensitizes Ovarian Cancer to Carboplatin.
Mol Cancer Ther. 2016; 15(3):460-70 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer is the deadliest gynecologic cancer, due in large part to the diagnosis of advanced stage disease, the development of platinum resistance, and inadequate treatment alternatives. Recent studies by our group and others have shown that T-type calcium (Ca(2+)) channels play a reinforcing role in cancer cell proliferation, cell-cycle progression, and apoptosis evasion. Therefore, we investigated whether T-type Ca(2+) channels affect ovarian tumor growth and response to platinum agents. Inhibition of T-type Ca(2+) channels with mibefradil or by silencing expression resulted in growth suppression in ovarian cancer cells with a simultaneous increase in apoptosis, which was accompanied by decreased expression of the antiapoptotic gene survivin (BIRC5). Analysis of intracellular signaling revealed mibefradil reduced AKT phosphorylation, increased the levels and nuclear retention of FOXO transcription factors that repress BIRC5 expression, and decreased the expression of FOXM1, which promotes BIRC5 expression. Combining carboplatin with mibefradil synergistically increased apoptosis in vitro. Importantly, mibefradil rendered platinum-resistant ovarian tumors sensitive to carboplatin in a mouse model of peritoneal metastasis. Together, the data provide rationale for future use of T-type channel antagonists together with platinum agents for the treatment of ovarian cancer.

Diminutto A, Basso U, Maruzzo M, et al.
Adjuvant Carboplatin Treatment in 115 Patients With Stage I Seminoma: Retrospective Multicenter Survey.
Clin Genitourin Cancer. 2016; 14(2):e161-9 [PubMed] Related Publications
BACKGROUND: The administration of carboplatin AUC 7 has become a standard adjuvant option for patients undergoing orchiectomy for stage I seminoma, in alternative to radiotherapy on retroperitoneal lymphnodes or surveillance. The toxicity of AUC 7 carboplatin appeared manageable in the pivotal trial of Oliver et al, but dose ranges were not reported. Fear of toxicity may induce arbitrary dose reductions, which may potentially compromise patients' outcome.
PATIENTS AND METHODS: We reviewed adjuvant carboplatin administration in 115 stage I seminoma patients followed in 11 Italian medical oncology centers since 2005. Clinical and pathological data, modality of carboplatin dose calculation, dose reductions, toxicities, and relapses were recorded.
RESULTS: Median age was 35 years (range, 18-65 years), adverse prognostic factors were either T ≥ 4 cm (17.4%) or rete testis invasion (28.7%), both of them (35.7%), none or unspecified (18.3%). GFR was estimated mainly by Cockroft-Gault formula (55.7%) or Jeliffe formula (26.1%), with a median of 105 mL/min (range, 75-209 mL/min). The median dose of carboplatin was 900 mg (range, 690-1535 mg). A dose reduction > 10% was applied to 14 patients. Toxicities were mild fatigue, moderate nausea/vomiting, 5.2% of grade 3 to 4 thrombocytopenia. After a median follow-up of 22.1 months, 5.2% of patients have relapsed in the retroperitoneal lymph nodes. None of the patients that relapsed were treated with reduced dose. All but one achieved complete remission with salvage chemotherapy.
CONCLUSIONS: Adjuvant AUC 7 carboplatin reduce relapses of stage I seminoma patients to 5.2%, with manageable toxicities. Dose reductions should be proscribed.

Kubota T, Okano Y, Sakai M, et al.
Carboplatin plus Weekly Paclitaxel with Bevacizumab for First-line Treatment of Non-small Cell Lung Cancer.
Anticancer Res. 2016; 36(1):307-12 [PubMed] Related Publications
AIM: The present study aimed to evaluate the effectiveness and safety of weekly paclitaxel (PTX) combined with carboplatin (CBDCA) plus bevacizumab (BEV), followed by maintenance BEV in patients with advanced NSCLC.
PATIENTS AND METHODS: Patients with unresectable stage IIIB and IV NSCLC (n=43) were treated with CBDCA (AUC 6, day 1), BEV (15 mg/kg, day 1), and PTX (70 mg/m(2), days 1, 8, 15) intravenously every 4 weeks, for 3 to 6 cycles, followed by maintenance BEV (15 mg/kg) every 3 weeks.
RESULTS: The objective response rate and disease control rate were 67.4% and 90.7%, respectively. The median progression-free survival was 7.6 months. The median overall survival was 17.7 months. Common adverse events were tolerable bone marrow suppression, fatigue, hypertension, and nasal bleeding.
CONCLUSION: Weekly administration of PTX combined with CBDCA plus BEV therapy was effective, and well-tolerated by advanced NSCLC patients.

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