Addition of curcuminoids to treatment with docetaxel was well tolerated and showed promise in improving the response rate to docetaxel “in terms of both PSA decrease and objective response” in a phase II trial in patients with castration-resistant prostate cancer.
CHICAGO-Addition of curcuminoids to treatment with docetaxel was well tolerated and showed promise in improving the response rate to docetaxel “in terms of both PSA decrease and objective response” in a phase II trial in patients with castration-resistant prostate cancer (CRPC). Findings were reported by Hakim Mahammedi, MD, of Centre Jean Perrin, Clermont-Ferrand, France (abstract e10621). Mahammedi and colleagues will formally present the findings during the annual meeting of the European Society for Medical Oncology in Amsterdam, September 27–October 1.
Chemical structure of curcuminoids demethoxycurcumin (top) and bisdemethoxycurcumin (bottom)
Curcumin is derived from Curcuma longa Linn, the rhizome root of turmeric. Curcuminoids include curcumin and its derivatives, demethoxycurcumin and bisdemethoxycurcumin. “Preclinical studies suggested that curcuminoids inhibit tumor metastasis, invasion, and angiogenesis, and reverse drug resistance,” said Mahammedi. “We wanted to potentiate docetaxel by curcuminoids in CRPC first line.” In a previous phase I trial he and colleagues evaluated the safety and tolerability of the addition of curcuminoids to docetaxel for treatment of advanced breast cancers.
In this phase II trial, patients (n = 30) with progressing CRPC and rising PSA were enrolled to receive the investigational treatment. Docetaxel was administered according to standard protocols (75 mg/m2, 1 hour intravenous infusion every 3 weeks for 6 cycles plus prednisolone) with curcuminoids given orally at the dose of 6 g/day (7 days by cycle: beginning 4 days prior to docetaxel infusion through 2 days after).
The primary endpoint was response rate assessed by biological and paraclinical examinations. Secondary endpoints included safety, time to progression, and compliance. Twenty-nine of the 30 patients were evaluable on PSA assessment and 15 on RECIST criteria. Twenty-six patients completed the trial and received all treatments. Four patients withdrew prematurely, none due to toxicity attributable to medication (two deaths and two PSA progressions).
Four complete PSA responses and 13 partial responses were observed in 17 of 29 patients (59%). Responses occurred rapidly, before the third cycle in 15 patients, reported Mahammedi. Median time to subsequent PSA progression (TTP) was 5.8 months. Six patients (40%) had a partial objective response and 9 (60%) had stable disease. The median TTP was 7.85 months (n = 13/15). The regimen was well tolerated, with little grade 3/4 toxicity. No adverse event was attributed to curcuminoids.
“Of 169 cycles, 150 (89%) were completed with perfect compliance,” said Mahammedi. “Overall survival was 19 months (mean) and 24 months (median) with 17 events as of December 2012.” The investigators concluded that a randomized trial is necessary to confirm the results.
“We have started new clinical studies with curcuminoids in metastatic prostate cancer and breast cancer,” Mahammedi said in an interview with Cancer Network. “The studies are randomized with placebo to demonstrate clinical benefit.” He said the source for the curcuminoids used in the studies is a French pharmaceutical company that provides purified curcuminoids according to requested specifications.
The formulation is not available commercially but Mahammedi believes, “after extensive research,” a curcuminoid formulation may be developed by a pharmaceutical company in the future.
“I think that the combination of curcuminoids and docetaxel has the potential in the future to enhance the efficacy of chemotherapy with no additional toxicity,” he concluded. “If the studies are positive we can expect to take purified curcuminoid for a long time to neutralize the spread of cancer.”
Commenting on the findings, Derek Raghavan, MD, president of the Levine Cancer Institute, Carolinas HealthCare System, cautioned that the information provided in the abstract is insufficient “to assess the utility of this novel compound.” And, he added, “The patient population is poorly characterized, the definition of progression is unclear, and there appears to be an absence of strong preclinical modeling data.”
Matthew Cooperberg, MD, PhD, of the Helen Diller Comprehensive Cancer Center at the University of California San Francisco, agrees that “it's very hard to draw any conclusions given these numbers.” Nevertheless, he said, “I think the unfolding curcuminoids story is an interesting one. I'm glad a phase III study is planned, and that these candidate agents are being studied rigorously.”