Treating cisplatin-resistant cancer: a systematic analysis of oxaliplatin or paclitaxel salvage chemotherapy

Objective: To examine the pre-clinical and clinical evidence for the use of oxaliplatin or paclitaxel salvage chemotherapy in patients with cisplatin-resistant cancer. Methods: Medline was searched for 1) Cell models of acquired resistance reporting cisplatin, oxaliplatin and paclitaxel sensitivities and 2) Clinical trials of single agent oxaliplatin or paclitaxel salvage therapy for cisplatin/carboplatin-resistant ovarian cancer. Results: Oxaliplatin - Oxaliplatin is widely regarded as being active in cisplatin-resistant cancer. In contrast, data in cell models suggests that there is cross-resistance between cisplatin and oxaliplatin in cellular models with resistance levels which reflect clinical resistance (<10 fold). Oxaliplatin as a single agent had a poor response rate in patients with cisplatin-resistant ovarian cancer (8%, n=91). Oxaliplatin performed better in combination with other agents for the treatment of platinum-resistant cancer suggesting that the benefit of oxaliplatin may lie in its more favourable toxicity and ability to be combined with other drugs rather than an underlying activity in cisplatin resistance. Oxaliplatin therefore should not be considered broadly active in cisplatin-resistant cancer. Paclitaxel – Cellular data suggests that paclitaxel is active in cisplatin-resistant cancer. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel. Paclitaxel as a single agent had a response rate of 22% in patients with platinum-resistant ovarian cancer (n = 1918), a significant increase from the response of oxaliplatin (p<0.01). Paclitaxel-resistant cells were also sensitive to cisplatin, suggesting that alternating between agents may be beneficial. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously received paclitaxel had an improved response rate of 35.3% n=232 (p<0.01), suggesting that pre-treatment with paclitaxel improves the response of salvage paclitaxel therapy. Conclusions: Cellular models reflect the resistance observed in the clinic as the cross resistant agent oxaliplatin has a lower response rate compared to the non-cross resistant agent paclitaxel in cisplatin-resistant ovarian cancer. Alternating therapy with cisplatin and paclitaxel may therefore lead to an improved response rate in ovarian cancer

The Competitive Dynamics of Entrepreneurial Market Entry

Research on general market entry usually focuses on large enterprises, often, however, small entrants can alter the competitive dynamic of an industry. This volume brings together the most prominent thought leaders and the best research on the asymmetric entrant-incumbent dynamics. This ideas presented offer a more nuanced perpective on how, when, where and with whar consequence small, single-product firms enter market that are dominated by large, multiproduct and multimarket incumbents. Sholars and student in entrepreneurship, strategy, international business and related fields will find this excellent collection of key published and original material illuminating

Probing F-theory With Multiple Branes

We study multiple 3-branes on an F theory orientifold. The world-volume theory of the 3-branes is d=4, N=2 Sp(2k) gauge theory with an antisymmetric tensor and four flavors of matter in the fundamental. The solution of this gauge theory is found for vanishing bare mass of the antisymmetric tensor matter, and massive fundamental matter. The integrable system underlying this theory is constructed.Comment: 9 pages, harvma

Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma

BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centre

Integrability and Seiberg-Witten Theory: Curves and Periods

Interpretation of exact results on the low-energy limit of $4d$ $N=2$ SUSY YM in the language of $1d$ integrability theory is reviewed. The case of elliptic Calogero system, associated with the flow between $N=4$ and $N=2$ SUSY in $4d$, is considered in some detail.Comment: 26 page

Are Three Additional Cycles of Chemotherapy Useful in Patients with Advanced-stage Epithelial Ovarian Cancer After a Complete Response to Six Cycles of Intravenous Adjuvant Paclitaxel and Carboplatin?†

BACKGROUND: To evaluate the efficacy of three additional cycles of chemotherapy in patients with the International Federation of Gynecology and Obstetrics Stage III or IV, who achieved a complete response after six cycles of intravenous adjuvant paclitaxel/carboplatin after surgery. METHODS: The clinical data of 94 patients with complete response after six cycles of adjuvant paclitaxel/carboplatin after surgery between January 1997 and March 2007 were reviewed retrospectively. Three additional cycles using the same chemotherapy were administered to 57 patients as consolidation chemotherapy (Group 1). Thirty-seven patients without the additional cycles served as controls (Group 2). Disease-free survival (DFS) and overall survival (OS) were evaluated using the Kaplan-Meier method with the log-rank test. The importance of consolidation chemotherapy as a prognostic factor affecting survival was examined using the Cox's proportional hazard analysis. The incidence of chemotherapy-induced hematological toxicities was compared between the two groups using chi-square test. RESULTS: Median DFS and mean OS were not significantly different between the two groups (15 versus 22 months, P = 0.703; 69 versus 73 months, P = 0.891, respectively). Consolidation chemotherapy was not a prognostic factor of survival although optimal debulking surgery and lower value of serum CA-125 levels after six cycles of the chemotherapy were prognostic factors improving DFS (P < 0.01). Grade 3 or 4 leukopenia was more common in patients treated with consolidation chemotherapy than in those not treated (50.9 versus 21.6%, P = 0.004). CONCLUSION: Consolidation chemotherapy using paclitaxel/carboplatin may be inefficient and relatively toxic to advanced-stage epithelial ovarian cancer patients with complete response to six cycles of the same chemotherapy after surgery