Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients

Abstract

BackgroundCyclooxygenase-2 overexpression is associated with poor outcome and resistance to platinum-based chemotherapy in ovarian cancer. We evaluated the antitumor activity and safety of the combination carboplatin plus the COX-2 inhibitor celecoxib in recurrent heavily-treated OC patients.MethodsPatients were administered oral celecoxib (400 mg/day) in combination with intravenous carboplatin (AUC5, q28). A Simon's two-stage design was employed.Results45 patients were enrolled: 23 (51.1%) presented platinum-resistance, and 27 (60%) had received at least 3 prior regimens for recurrence. The response rate was 28.9% with 3 complete and 10 partial responses (median duration of response = 6 months). Only one (0.4%) G4 non-febrile neutropenia was observed; G3 neutropenia, anemia, or thrombocytopenia, were observed in 2.5%, 1.7%, and 1.7% of the cycles, respectively. G3-4 vomiting was reported in only 1.7%, and 0.4% of the cycles were associated with G3 dyspepsia or diarrhea or constipation. Only one patient experienced G3 hypertension associated to G2 hypersensitivity reaction. No differences in baseline versus post-treatment Quality of Life scores were observed. Median progression free survival and overall survival were 5 and 13 months, respectively.ConclusionsCelecoxib combined with carboplatin showed promising activity and it is well tolerated in heavily-treated recurrent ovarian cancer patients.Trial registration numberNCT01124435 (ClinicalTrials.gov Identifier) and 935/03 (study ID numbers).

NSAIDs induce apoptosis in nonproliferating ovarian cancer cells and inhibit tumor growth in vivo

“…Moreover, Celecoxib, a COX-2 inhibitor, has been shown to increase the cytotoxicity of docetaxel in lung cancer (31) and has been approved for use in familial adenomatous polyposis by the FDA (21). Phase II trials have also been conducted to test Celecoxib and carboplatin in patients with pretreated recurrent OC, and this approach is yielding promising results (32). In combination with oxaliplatin, Celecoxib has also been shown to inhibit proliferation and tumor growth in colon carcinoma and breast cancer cells (22,33).…”

“…NSAIDs have been evaluated as therapies in different types of cancer (23,34,35) and have been shown to have a synergistic effect with known chemotherapeutic agents (31)(32)(33)(36)(37)(38). However, none of these studies have looked specifically at NSAIDs effects on nonproliferating cells.…”

Potency of non-steroidal anti-inflammatory drugs in chemotherapy

“…In the case of non-small-cell lung carcinoma (NSCLC), the combination of celecoxib and chemotherapy was associated with increased overall survival (152,153). In the case of heavily pretreated recurrent ovarian cancer, the administration of celecoxib in combination with carboplatin-based chemotherapy also yielded promising results (154). The discrepancy in various results may be due to multiple factors, such as complex pharmacodynamic interactions between NSAIDs and the cytotoxic drugs and the varying levels of intratumoural COX-2 and ABC transporters (155)(156)(157)(158)(159).…”

Co-treatment with Celecoxib or NS398 Strongly Sensitizes Resistant Cancer Cells to Antimitotic Drugs Independent of P-gp Inhibition

“…The importance of COX-2 inhibitors in cancer treatment has been previously demonstrated (6,7,18,19). There are two well-known inhibitors, NS398 and celecoxib, that have been investigated in various cancer models, including drugresistant cancer cells, as potential cancer treatments (11,12,14).…”

“…In addition, co-treatment with COX-2 inhibitors showed increased sensitization to anti-cancer drugs in various models (14-17). Adverse effects, such as cardiovascular events, have been reported in clinical trials involving celecoxib-treated cancer patients (18,19). Better understanding of the mechanism governing the sensitization effect of COX-2 inhibitors in cancer patients could facilitate their safe therapeutic use.…”