Prolonged pemetrexed infusion plus gemcitabine in refractory metastatic colorectal cancer: Preclinical rationale and phase II study results

Background. We investigated the cytotoxic activity of pemetrexed in combination with several drugs (gemcitabine, carboplatin, vinorelbine, and mitomycin C) using different exposure schedules in three colon cancer cell lines. The best results were obtained with the following schedule: a prolonged pemetrexed exposure followed by a 48-hour wash-out and then gemcitabine. This combination was then advanced to a phase II clinical trial. Methods. Patients with metastatic colorectal cancer in progression after standard treatment were included in the study. Adequate bonemarrow reserve, normal hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were required. Treatment consisted of an 8-hour intravenous infusion of pemetrexed 150 mg/m 2 on day 1 and a 30-minute intravenous infusion of gemcitabine 1,000 mg/m 2 on day 3 of each cycle, repeated every 14 days. Results. Fourteen patients were enrolled onto the study (first step). No objective responses were seen, and evidence of stable disease was observed in only one of the 12 evaluable patients. The most important grade 3-4 side effects were hematological toxicity (neutropenia 64.2%, thrombocytopenia 71.4%, anemia 28.7%), fatigue (50.0%), and stomatitis (21.5%). Median overall survival and time to progression were 5.8 months (95% confidence interval [CI]: 3.9-7.1) and 2.1 months (95% CI: 1.7-2.8), respectively. Conclusion. The experimental pemetrexed-gemcitabine combination proved to be inactive and moderately toxic

Peritoneal carcinomatosis from ovarian cancer: chemosensitivity test and tissue markers as predictors of response to chemotherapy

<p>Abstract</p> <p>Background</p> <p>Platinum-based regimens are the treatments of choice in ovarian cancer, which remains the leading cause of death from gynecological malignancies in the Western world. The aim of the present study was to compare the advantages and limits of a conventional chemosensitivity test with those of new biomolecular markers in predicting response to platinum regimens in a series of patients with peritoneal carcinomatosis from ovarian cancer.</p> <p>Methods</p> <p>Fresh surgical biopsy specimens were obtained from 30 patients with primary or recurrent peritoneal carcinomatosis from ovarian cancer. <it>ERCC1, GSTP1, MGMT, XPD</it>, and <it>BRCA1 </it>gene expression levels were determined by Real-Time RT-PCR. An <it>in vitro </it>chemosensitivity test was used to define a sensitivity or resistance profile to the drugs used to treat each patient.</p> <p>Results</p> <p><it>MGMT </it>and <it>XPD </it>expression was directly and significantly related to resistance to platinum-containing treatment (p = 0.036 and p = 0.043, respectively). Significant predictivity in terms of sensitivity and resistance was observed for <it>MGMT </it>expression (75.0% and 72.5%, respectively; p = 0.03), while high predictivity of resistance (90.9%) but very low predictivity of sensitivity (37.5%) (p = 0.06) were observed for <it>XPD</it>. The best overall and significant predictivity was observed for chemosensitivity test results (85.7% sensitivity and 91.3% resistance; p = 0.0003).</p> <p>Conclusions</p> <p>The in vitro assay showed a consistency with results observed in vivo in 27 out of the 30 patients analyzed. Sensitivity and resistance profiles of different drugs used in vivo would therefore seem to be better defined by the in vitro chemosensitivity test than by expression levels of markers.</p