Cost–Utility Analysis of Paclitaxel in Combination with Cisplatin for Patients with Advanced Ovarian Cancer

The standard treatment for patients with advanced ovarian cancer (AOC) has been cyclophosphamide and cisplatin (CP). Recently, the results of a large randomized comparative trial demonstrated that the combination of paclitaxel and cisplatin (TP) provided a progression-free survival benefit of 5 months. In this study, a cost–utility analysis was performed from a Canadian health care system perspective to estimate the incremental cost-effectiveness of the TP combination. Twelve AOC patients who received treatment with TP were matched for age and disease stage on a 1-to-2 basis with a CP control. Total hospital resource consumption was then collected for all patients. Treatment preferences were estimated from a cohort of 20 patients and 40 healthy female volunteers using the time trade-off technique. The outcomes were then generated through a decision-analytic model. First-line treatment costs with TP were approximately fourfold greater on a per-cycle basis than the CP alternative (Can$1911 vs Can$459). When progression-free survival benefit and patient treatment preferences were incorporated into the analysis, the results of the decision model revealed an incremental cost between Can$12,000 and Can$24,000 per quality-adjusted progression-free year with the TP protocol. Even though the TP combination has a considerably higher drug acquisition cost, the results of the current analysis suggest that this new chemotherapy regimen does provide patients with substantial quality-adjusted progression-free survival benefit at a reasonable cost to the Canadian health care system.     

2'-Chlorodeoxyadenosine: evaluation of a novel predominantly lymphocyte selective agent in lymphoid malignancies.

2''-Chlorodeoxyadenosine (2CDA) is a purine analogue selectively active against both resting and dividing lymphoid cells. Twenty-one patients with a variety of previously treated lymphoid malignancies received a total of 41 courses of 2CDA (0.1-0.15 mg/kg/day over 7 days continuous intravenous infusion) on compassionate grounds. The profile of the patient population was as follows: low grade non-Hodgkin''s lymphoma (NHL) = 8, intermediate grade NHL = 2, transformed (intermediate grade NHL) = 6, Hodgkin''s disease = 1, lymphoplasmacytoid NHL = 3 and lymphoblastic NHL = 1. The overall response rate was 53%, with three patients attaining complete remission (CR) and eight partial remission (PR). Three of 16 patients with primary resistant or resistant recurrent disease entered either CR (1) or PR (2). Ten patients had no response or progressive disease. The latter group was comprised of patients who had extensively pre-treated lymphoplasmacytoid tumours and/or poor performance status (WHO grades 2-4). The median duration of response is 6 months (range 1 to 12 months). Treatment was well tolerated and the chief toxicities were leucopenia and thrombocytopenia which were most pronounced when there was bone marrow involvement. As a result of dose limiting myelotoxicity, a dose escalation to 0.15 mg/kg/day was possible on just three occasions. These data confirm other reports of the activity of 2CDA in low grade NHL and indicate it may have activity in Hodgkin''s disease. There was no demonstrable activity in poor performance status patients or those with extensively pre-treated lymphoplasmacytoid tumours.     

The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers – a study of the National Cancer Institute of Canada Clinical Trials Group

A multicenter phase II trial was conducted to define the activity of letrozole in postmenopausal women with recurrent or advanced endometrial carcinoma, who had no more than one prior line of progestins and never had chemotherapy (except adjuvant). Archival paraffin-embedded tumor samples were retrieved to determine the expression level of estrogen (ER) and progesterone receptor (PgR), p53, HER-2, bcl-2 and PTEN protein, and phosphorylation status of protein kinase B (PKB/Akt). Thirty-two eligible patients were treated with letrozole at 2.5 mg daily continuously, of whom 10 (31%) had prior progestins. Of the 28 patients evaluated for response, one complete and two partial responses were noted; overall response was 9.4% (95% confidence interval 2-25%). Eleven patients had stable disease for a median duration of 6.7 months (range 3.7-19.3 months). Amongst 22 patients who had tumor blocks available, the proportion showing positive expression of the following markers includes: PgR (86%), ER (86%), PTEN (82%), phosphorylated PKB/Akt (59%), bcl-2 (45%), p53 (32%), and HER-2 (0%). None of these markers correlated with response to letrozole or disease progression. In conclusion, letrozole is well tolerated but has little overall activity in this cohort of women with endometrial cancer.     

Detection of heat-stable antigens of Campylobacter jejuni and C. coli by direct agglutination and passive hemagglutination

The two serotyping schemes for the detection of heat-stable antigens of Campylobacter jejuni and Campylobacter coli use the same strains for antiserum production but differ in the detection systems used for identifying agglutination. The Penner method uses passive hemagglutination (PHA) while the Laboratory of Enteric Pathogens method uses the same antisera but in a whole-bacterial-cell direct agglutination (DA) protocol. C. jejuni produces a polysaccharide capsule, which is antigenic, and is the main component detected by the PHA method. The DA method will detect both capsule antigens and lipopolysaccharide (LPS) or lipooligosaccharide (LOS) surface antigens. Comparison of both methods by using a selection of isolates from human infection has shown a range of variation in agglutination specificity, reflecting the differences in antigens detected by the two methods. While 27.4% of the 416 C. jejuni isolates reacted with the antisera raised against the same type strains by either method, the majority showed a range of more complex relationships. None of the 37 C. coli isolates reacted with the same antiserum by both methods. Together the two schemes gave a total of 102 distinct combined serogroups for C. jejuni and 16 for C. coli. Thus, while some clonally related isolates share the same capsule and LOS or LPS antigens, other strains appear to have a common capsule antigen but differ in their LPS or LOS structures or vice versa.     

Antitumor effect of i.p. dopamine in mice bearing Ehrlich ascites carcinoma

Summary The cancer chemotherapeutic efficacy of dopamine (DA) was evaluated in female strain A mice bearing transplantable Ehrlich ascites carcinoma. The results demonstrated significant inhibition of tumor growth with appreciable increase in the host survival time following DA treatment. Diminished activity of the growth-related respiratory enzyme succinate dehydrogenase along with stimulated activity of the lysosomal enzyme, -glucuronidase in DA-treated tumor cells indicated inhibition of tumor growth as well as active lysis of the tumor cells. The direct effect of this compound on tumor proliferation was demonstrated by marked inhibition of DNA synthesis. RNA synthesis was only marginally inhibited.Abbreviations DA Dopamine - EAC Ehrlich ascites carcinoma - SDH Succinate dehydrogenase - -Glu -glueuronidase - ILS Increase of life span     

The statins as anticancer agents.

3-Hydroxy-3-methylgutaryl CoA reductase inhibitors, commonly referred to as the statins, have proven therapeutic and preventative effects in cardiovascular diseases. Recently, there are emerging interests in their use as anticancer agents based on preclinical evidence of their antiproliferative, proapoptotic, anti-invasive, and radiosensitizing properties. Inhibition of 3-hydroxy-3-methylgutaryl CoA reductase by the statins interferes with the rate-limiting step of the mevalonate pathway, leading to reduced levels of mevalonate and its downstream products, many of which play important roles in critical cellular functions such as membrane integrity, cell signaling, protein synthesis, and cell cycle progression. Perturbations of these processes in neoplastic cells by the statins may therefore result in control of tumor initiation, growth, and metastasis. The statins have demonstrated growth inhibitory activity in cancer cell lines and preclinical tumor models in animals. Phase I trials of statins in humans have demonstrated myotoxicity as their main dose-limiting toxicity, and Phase II trials in various tumor types are ongoing to evaluate their efficacy. Potential future directions in the development of the statins as anticancer agents include combinations with chemotherapeutic or other molecular-targeted agents, combinations with radiotherapy, maintenance therapy in minimal disease status, and as chemopreventive therapy.     

Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial.

PURPOSE: Biliary cancer has a poor prognosis, and chemotherapy has had little impact. The objectives of this trial were to determine the response rate, time to disease progression, survival, and safety profile of the combination of gemcitabine and capecitabine (GemCap) in patients with advanced biliary cancer. PATIENTS AND METHODS: Eligible patients had pathologically proven, locally advanced or metastatic adenocarcinoma arising from the intra- and extrahepatic bile ducts or gallbladder with no prior chemotherapy. Patients were treated on a 3-week cycle consisting of capecitabine at 650 mg/m(2) orally twice a day for 14 days and gemcitabine at a fixed dose of 1,000 mg/m(2) intravenously over 30 minutes on days 1 and 8. RESULTS: Forty-five patients were enrolled between July 2001 and January 2004. Fifty-three percent of patients had cholangiocarcinoma, 47% had gallbladder cancer, and 89% had metastatic disease. The overall objective response rate was 31%, with an additional 42% of patients with stable disease, for a disease control rate of 73%. The median overall survival time was 14 months (95% CI, 7.3 months to not available), and the median progression-free survival time was 7 months (95% CI, 4.6 to 11.8 months). This chemotherapy combination was generally well tolerated. Transient neutropenia, thrombocytopenia, fatigue, and hand-foot syndrome were commonly observed but were easily managed without discontinuing further treatment. CONCLUSION: The significant antitumor activity combined with a mild toxicity profile seen in this study argue that GemCap chemotherapy may benefit patients with advanced biliary cancer. This regimen warrants further evaluation in a randomized study with survival and quality of life end points.     

Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors.

BACKGROUND: BAY 43--9006, an oral multi-kinase inhibitor, targets serine-threonine kinases and receptor tyrosine kinases, and affects the tumor and vasculature in preclinical models. Based on its pharmacologic effect, it may be a useful cancer treatment. This study determined the maximum tolerated dose (MTD) of BAY 43-9006 in 42 patients with advanced, refractory metastatic or recurrent solid tumors. Dose-limiting toxicities (DLTs), safety, pharmacokinetics and tumor response were also evaluated. PATIENTS AND METHODS: In this open-label, phase I, dose-escalation study, BAY 43--9,006 was administered orally in repeated cycles of 35 days (28 days on/7 days off). Eight doses were investigated: from 50 mg every fourth day to 600 mg twice daily. Treatment continued until unacceptable toxicity, tumor progression or death. RESULTS: The MTD was 400 mg twice daily. BAY 43-9006 was well tolerated, with mild to moderate toxicities; only six patients discontinued study therapy due to adverse events. DLTs consisted of hand-foot skin reaction in three of seven patients receiving 600 mg twice daily. Stable disease was achieved in 22% of patients; median duration of stable disease was 7.2 months. Consistent with its observed half-life of approximately 27 h, BAY 43-9, 006 accumulated on multiple dosing. Increases in exposure were less than proportional to the increases in dose. CONCLUSIONS: Results indicate that further clinical investigation of BAY 43--9006 is warranted, and suggest it could be a promising future therapy for patients with cancer.     

Neutrophilic urticarial dermatosis as a presenting feature of systemic juvenile idiopathic arthritis

This report describes a case of chronic neutrophilic urticarial dermatosis as a presenting feature of systemic juvenile idiopathic arthritis. When encountered in children, neutrophilic urticarial dermatosis should raise suspicion of autoimmune or autoinflammatory disease.