Randomized phase II trial of sorafenib alone or in combination with carboplatin/paclitaxel in women with recurrent platinum sensitive epithelial ovarian, peritoneal, or fallopian tube cancer.

BACKGROUND/PURPOSE: This study was designed to evaluate the response and toxicity of sorafenib alone or when combined with carboplatin and paclitaxel in patients with platinum-sensitive, recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (EOC). METHODS: Patients with recurrent platinum-sensitive EOC with no more than 2 prior courses of chemotherapy were randomized to single-agent sorafenib 400 mg twice daily or combination sorafenib 400 mg bid (days 2-19) with IV carboplatin (AUC 6) and IV paclitaxel 175 mg/m(2) (S+C/T) every 3 weeks. Single agent sorafenib could cross over to combination upon progression. RESULTS: Patients were initially randomized to either arm, however, due to poor accrual, sorafenib arm was prematurely closed. A total of 13 patients were evaluable for response to sorafenib and 23 patients were evaluable for response to S+C/T. Objective response rate (RR) was 15 % for patients on sorafenib vs. 61 % for patients on S+C/T (p = 0.014); stable disease was seen in 62 % and 35 %, respectively. Clinical benefit rate (CBR) at 4 months (mos.) was 69 % for S and 65 % for S+C/T. The median progression free survival was 5.6 months on sorafenib vs. 16.8 months on S+C/T (p = 0.012) and there was no significant difference of overall survival between two arms (p = 0.974) with median overall survival 25.6 months under sorafenib vs. 25.9 months on S+C/T. Patients remained on trial for a median of 7.8 cycles on sorafenib and 5.4 cycles on S+C/T. CONCLUSION: Sorafenib, alone or in combination with carboplatin and paclitaxel, has activity in patients with platinum-sensitive EOC. Sorafenib in combination with carboplatin and paclitaxel improved RR and PFS; however, there were increased grade and frequencies of toxicities.

Clinical and immunomodulatory effects of celecoxib plus interferon-alpha in metastatic renal cell carcinoma patients with COX-2 tumor immunostaining.

INTRODUCTION: Cycloxygenase-2 (COX-2) is an enzyme involved in prostaglandin E2 (PGE(2)) synthesis associated with higher renal cell carcinoma stage. COX-2 inhibition enhances interferon (IFN-α) anti-tumor immune effects in pre-clinical models. A phase II trial of celecoxib and IFN-α in a targeted population of metastatic renal cell carcinoma patients with maximal COX-2 expression was conducted. METHODS: Cytokine-naive metastatic renal cell carcinoma patients with tumors expressing ≥10% maximal COX-2 staining by immunohistochemistry received IFN-α 5 million units daily and celecoxib 400 mg orally twice daily in an open-label, single-arm phase II trial. RESULTS: There were 3 partial responses among 17 patients (objective response rate 18%; 95% confidence interval, 4-43%). Time to progression was 5.6 months. Increased tumor staining 3+ for COX-2 was associated with increased baseline peripheral blood PGE(2) levels, and these patients demonstrated less PGE(2) decrease with therapy. Patients with more 3+ COX-2 staining had significantly more CD3(+) (p = 0.004) and CD4(+) (p = 0.002) IFN-γ T cells at baseline and a significantly greater decrease in these cells with therapy. DISCUSSION: Celecoxib plus IFN-α in renal cell carcinoma (RCC) patients with maximally staining COX-2 tumors does not significantly enhance overall response rates over IFN monotherapy. CONCLUSION: COX-2-expressing RCC demonstrates inherent immunosuppression. COX-2 inhibition with IFN results in minimal immunomodulation and no augmented clinical activity in RCC.

Chemotherapy plus radiation in advanced-stage endometrial cancer.

HYPOTHESIS: We hypothesize that adjuvant radiation and chemotherapy improve the clinical benefit from treatment of advanced-stage endometrial adenocarcinoma. METHODS: We conducted a retrospective review of 125 patient with stage III or IVA endometrial adenocarcinoma who received adjuvant chemotherapy (n = 60) or chemoradiation (n = 65). Primary end points were rate of clinical benefit (ie, the percentage of patients who were alive and disease-free for at least 6 months after the last day of adjuvant treatment) and progression-free and overall survival. RESULTS: The addition of radiation to chemotherapy improved the rate of clinical benefit from 55% to 77%. Differences in clinical benefit were attributed to a reduction in the number of pelvic relapses after chemoradiation. There were no substantial differences in the rate of extrapelvic relapse events seen between the chemotherapy alone and chemoradiation groups. Patients receiving radiation had prolonged median progression-free survival (36 vs 17 months in chemotherapy alone) and median overall survival (70 vs 64 months in chemotherapy alone). CONCLUSIONS: The addition of radiation to chemotherapy improved the clinical benefit of patients with stage III or IVA endometrial adenocarcinoma. A clinical trial powered to evaluate clinical benefit and survival outcomes of chemotherapy and radiation is under way.

Complications of androgen deprivation therapy in prostate cancer.

PURPOSE OF REVIEW: To review the current data on adverse effects of androgen deprivation therapy for prostate cancer and to discuss some considerations when choosing therapy and managing side-effects. RECENT FINDINGS: Despite the existing data supporting the use of androgen deprivation therapy in prostate cancer patients, several questions regarding timing, survival benefit and impact in quality of life remain quite controversial. Although androgen deprivation therapy appears to increase overall survival in select populations with locally advanced and symptomatic metastatic prostate cancer, their side-effects often lead to secondary short and long-term toxicities that negatively impact patient's quality of life and ultimately affect their survival. In addition to the most common side-effects of low testosterone levels such as hot flushes, lack of libido, erectile dysfunction, gynecomastia and bone mineral density loss, recent studies have confirmed the detrimental effects of low testosterone states on patient's cardiac risk profile and development of metabolic syndrome ultimately leading to an increase risk of diabetes, hyperlipidemia and heart disease. SUMMARY: Long-term use of androgen deprivation in prostate cancer patients continues to increase. Timing of therapy should be optimized based on each individual's prostate cancer natural history and medical risk profile. Emphasis should be placed on quality of life concerns, with adequate pretreatment education of anticipated side-effects, individualization of therapy, and review of strategies for prevention of side-effects.

Perinatal transmission of Trichomonas vaginalis: a case report.

BACKGROUND: Trichomonas vaginalis infection is associated with increased risks of adverse pregnancy outcome. Perinatal transmission of T vaginalis from an infected, untreated, pregnant woman to her female neonate can occur. CASE: A 22-year-old woman, gravida 3, para 2, with untreated trichomoniasis had an uncomplicated spontaneous vaginal delivery of a healthy female infant. At day of life 19 the newborn was diagnosed and treated for trichomoniasis. No evidence was found consistent with child sexual abuse. CONCLUSION: Perinatal transmission of T vaginalis occurs rarely. Neonatal infection has medical and psychosocial implications. This outcome, albeit rare, should be a consideration in the decision regarding antenatal treatment of T vaginalis infection.

Phase-II trial of rebeccamycin analog, a dual topoisomerase-I and -II inhibitor, in relapsed "sensitive" small cell lung cancer.

Relapsed small cell lung cancer (SCLC) carries a poor prognosis. Topoisomerase I and II inhibitors and DNA-damaging agents are considered among the most active agents against SCLC. Rebeccamycin analog (RA, Becatecarin) is an antitumor antibiotic with inhibitory activity against both topoisomerase I and II, and DNA-intercalating properties. We performed a phase-II trial of RA in relapsed, sensitive SCLC with the primary end point of response rate. Patients with previously treated SCLC who relapsed more than 60 days after the completion of first-line chemotherapy were treated with RA-administered intravenously at a dose of 140 mg/m on days 1 to 5 of 21-day cycles for a maximum of six cycles. Eligibility included Eastern Cooperative Oncology Group performance status 0 to 2 and adequate organ function. A two-stage design was employed. Twenty evaluable patients were enrolled. Median age was 61 years. Two patients (10%) had a partial response and six had stable disease. The clinical benefit rate was 40% (95% confidence interval [CI], 23-64%). The median progression-free survival was 2 months (95% CI, 1.2-5.2 months). The median survival was 6.7 months (95% CI, 3.3-8.0 months). No treatment-related deaths occurred. Grade-4 neutropenia and thrombocytopenia occurred in 23% and 14% of the patients, respectively. In conclusion, RA has single-agent activity in relapsed, sensitive SCLC with manageable toxicities but is unlikely to provide any superiority compared to existing agents for this disease.

Updates in cytogenetics and molecular markers in MDS.

Myelodysplastic syndromes (MDS) are clonal hematologic neoplasms that can result in cytopenias and increase the risk of leukemic transformation. The disease is characterized by several recurrent cytogenetic defects, which can affect diagnosis, prognosis, and treatment. Metaphase cytogenetics (MC) is the gold standard in karyotypic analysis in hematology. Progress in molecular analysis, including additional karyotypic tools exemplified by fluorescence in situ hybridization, comparative genomic hybridization, and more importantly, single nucleotide polymorphism array (SNP-A) analysis, has led to increased detection of chromosomal abnormalities in myeloid malignancies and improved prognostic risk stratification. SNP-A, together with MC, has also been instrumental in the discovery of genes that have improved our understanding of the biology of MDS. Newly elucidated molecular abnormalities in MDS include mutations in CBL, TET2, ASXL1, IDH1/IDH2, EZH2, DNMT3A, and UTX. This review provides an update on the changing landscape of molecular and cytogenetic characterization in MDS and its significance in disease biology and clinical practice.

Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma.

Advances in the understanding of the biology of renal cell carcinoma have led to recent approval of several new agents including drugs that target vascular endothelial growth factor. Sunitinib is an oral tyrosine kinase inhibitor which interferes with multiple intracellular tumorogenic pathways, and has demonstrated impressive antitumor activity in phase II and subsequently improvement in progression free survival in phase III renal cancer trials. We review the unique side effects of sunitinib therapy with emphasis on establishing effective patient education for anticipation and early management of therapy-related side effects.