Lessons Learned.O_LIThe combination of irinotecan and etoposide showed modest efficacy in terms of response rate in the refractory setting for patients with metastatic breast cancer.
C_LIO_LIThe studied dose and schedule of irinotecan and etoposide is very toxic, with >70% grade 3 or 4 treatment-related adverse events.
Background.As single agents, both irinotecan and etoposide have documented activity against breast cancer among patients who have received multiple lines of prior chemotherapy. Irinotecan interacts with topoisomerase I (Topo I) to stabilize its cleavable complex, and etoposide has an analogous interaction with topoisomerase II (Topo II). This stabilization without rapid resealing of the cleavage point results in apoptotic cell death and accounts for the antitumor activity of these agents. Topo II levels may increase after administration of a Topo I inhibitor, thus providing a rationale for combining these agents in practice. Based on preclinical data, we conducted a phase II trial of the Topo I inhibitor irinotecan combined with the Topo II inhibitor etoposide in patients with metastatic breast cancer (MBC).
Methods.This was a single-arm phase II clinical trial in patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1-14 and intravenous irinotecan at 100mg/m2 on days 1 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was median time to progression. Secondary end points included overall clinical response rate using RECIST criteria and assessing the toxicity and safety profile associated with this combination regimen.
Results.We enrolled 31 women with refractory MBC to our trial. Median age was 54 (range, 36-84), with the majority (64%) having hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2 neg) MBC. Median number of prior therapies was five (range, 3-14). Efficacy was evaluated in 24 patients. Seventeen percent had a partial response, and 38% had stable disease as best response. Median progression-free survival was 9 weeks (range, 3-59). All 31 patients were evaluable for toxicity assessment, and 22 patients (71 %) experienced treatment-related grade 3 or 4 adverse events (AEs; Table 1). The most common grade 3-4 AE was neutropenia. The study was terminated early based on interim analysis assessment that suggested toxicities outweighed the efficacy.
Conclusion.Irinotecan and etoposide demonstrated only modest clinical activity and poor tolerability in patients with MBC refractory to anthracycline, taxane, and capecitabine therapy. Further studies testing a lower dose and/or different schedule could be considered given ease of administration and responses seen.
Lessons Learned.O_LIThis is the first human interventional study in patients with Cowden syndrome that is driven by inactivation of germline PTEN gene.
C_LIO_LISingle-agent sirolimus, a mTOR inhibitor, suppressed mTOR signaling in surrogate human tissues without significant toxicity.
Background.Cowden syndrome is characterized by inactivating germline PTEN mutations, which can lead to activation of the PI3K-Akt-mTOR pathway.
Methods.Adult subjects with germline PTEN mutation who met international diagnostic criteria for Cowden syndrome and who had Eastern Cooperative Oncology Group (ECOG) performance status 0-2 and adequate organ function were enrolled. Subjects were treated with a 56-day course of daily oral sirolimus. In addition to symptom assessment and physical examination, dermatologic, endoscopic, neurologic (cerebellar), and radiographic assessments were conducted. Inhibition of the mTOR pathway in benign skin and gastrointestinal (GI) lesion was assessed by immunohistochemistry.
Results.A total of 18 patients and 16 families were enrolled. PTEN mutations were located at exons 1-8. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Neurological evaluation showed improvement in cerebellar function score at 1 month. Immunohistochemistry (IHC) analysis in skin and GI benign lesions showed a decrease in the ratio of phosphorylated (p)S6 to total S6 in response to sirolimus. Ratios of pS6K to total S6 at days 14 and 56 were significantly lower than at baseline (p = .0026, p = .00391, respectively). A 56-day course of sirolimus was well tolerated.
Conclusion.A 56-day course of sirolimus was well tolerated in subjects with Cowden syndrome and was associated with some evidence of improvement in symptoms, skin and GI lesions, cerebellar function, and decreased mTOR signaling.
Lesson Learned.O_LICirculating tumor cells, microRNA markers, or other biomarkers merit examination as part of correlative scientific analyses in prospective clinical trials.
Background.Platinum chemotherapy resistance occurs in approximately 25% of patients with ovarian carcinoma; however, no biomarkers of ovarian carcinoma chemoresistance have been validated. We performed a prospective trial designed to identify tumor-based predictive biomarkers of platinum resistance.
Methods.Tumor specimens were collected from 29 women with newly diagnosed histopathologically proven primary ovarian carcinoma. Of these, 23 women had specimens accessible for assessment and outcome data available regarding chemosensitive versus chemoresistance status via review of the medical record. Tumor slices were stained with antibodies against two microRNAs (miRNAs 29b and 199a) differentially expressed in chemoresistant ovarian cancer cell lines. Additionally, blood samples obtained at the time of diagnosis were analyzed for the presence of circulating tumor cells (CTCs).
Results.The average age of the patients was 64 years, and 82.6% had high-grade epithelial carcinomas. The baseline median CA-125 was 464 (range 32-2,782). No statistically significant differences were observed in miR29b or 199a expression in platinum-resistant/refractory versus platinum-sensitive tumors. Furthermore, the presence of CTCs was not found to be statistically significantly predictive of eventual platinum resistance.
Conclusion.Our analysis showed no differences in miR29b and 199a expression, and differences in baseline CTCs in women with newly diagnosed ovarian tumors were not statistically significant.
Lessons Learned.O_LIThis clinical trial, evaluating the efficacy and safety of a carboplatin plus paclitaxel regimen in a biweekly or weekly schedule instead of the more toxic 3-weekly administration, showed that the weekly regimen was better in efficacy than the biweekly regimen, with mild toxicities, for patients with non-small cell lung cancer (NSCLC).
C_LIO_LIThe weekly carboplatin plus paclitaxel regimen could be considered as an alternative to the 3-weekly regimen in Japanese patients with NSCLC.
Background.Combination therapy comprising carboplatin (C) and paclitaxel (P) is the most commonly used regimen for the treatment of advanced non-small cell lung cancer (NSCLC). Common toxicities associated with the regimen, such as neuropathy and myelosuppression, cause its discontinuation. In the present study, we conducted a clinical trial evaluating the efficacy of biweekly (B) and weekly (W) PC therapy to identify the appropriate chemotherapy schedule for Asian patients.
Methods.Chemonaive patients with IIIB/IV NSCLC and a performance status of 0-1 were randomly assigned to a biweekly regimen (paclitaxel 135 mg/m2 with carboplatin area under the curve [AUC] 3 on days 1 and 15 of every 4 weeks) or to a weekly regimen (paclitaxel 90 mg/m2 on days 1, 8, and 15 with carboplatin AUC 6 on day 1 of every 4 weeks).
Results.A total of 140 patients were enrolled in the study. The objective response rates (ORRs) were 28.1% (B) and 38.0% (W). The most common toxicity was neutropenia, with incidence rates of 62.0% (B) and 57.8% (W). Progression-free survivals (PFSs) were 4.3 months (B) and 5.1 months (W), and overall survival durations were 14.2 months (B) and 13.3 months (W).
Conclusion.The ORR and PFS in the weekly regimen were better than those in the biweekly schedule, although a statistical difference was not observed. The toxicity profile was generally mild for both regimens. The weekly CP regimen was suitable to be considered as an alternative to the current 3-weekly regimen in NSCLC treatment.
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