Inverse probability weighting to control for censoring in a post hoc analysis of quality-adjusted survival data from a clinical trial of temsirolimus for renal cell carcinoma.

OBJECTIVE: This post hoc analysis evaluated treatment-associated quality-adjusted survival (QAS) in patients randomly assigned to temsirolimus or interferon alfa (IFN-alfa), corrected for censoring using inverse probability weighting (IPW), in the Advanced Renal Cell Carcinoma (ARCC) trial. METHODS: Follow-up was divided into 11 time intervals; Kaplan-Meier estimates for not being censored were estimated for each interval. The QAS for each interval was weighted by the inverse probability of not being censored in that interval. Overall treatment-associated QAS was calculated as the sum of the weighted QAS across all follow-up intervals. Differences in mean QAS between temsirolimus and IFN-alfa were evaluated with t-statistics at a two-sided α = 0.05. RESULTS: In total, 416 patients were randomly assigned to temsirolimus (n = 209) or IFN-alfa (n = 207); 400 patients were included in this analysis. Overall weighted mean (standard deviation) QAS during progression-free survival was 111.9 (5.3) days with temsirolimus (n = 204) and 75.7 (6.3) days with IFN-alfa (n = 196). The mean weighted QAS difference of 36.2 days in favor of temsirolimus was significant (p < 0.05). LIMITATIONS: One potential limitation is that the weights developed by the Kaplan-Meier estimates did not allow for covariates to be adjusted among treatment arms. Another possible limitation is that the ARCC trial included patients with advanced renal cell carcinoma, and thus it cannot be conclusively determined how our findings would apply to patients with less advanced disease. CONCLUSIONS: Patients with poor-prognosis advanced renal cell carcinoma treated with temsirolimus had an incremental gain of 48% (36.2 days) in QAS compared with patients treated with IFN-alfa.

Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma.

PURPOSE: Concurrent inhibition of multiple oncogenic signaling pathways might improve the efficacy of anticancer agents and abrogate resistance mechanisms. This phase I study evaluated temsirolimus in combination with sunitinib in patients with advanced RCC. PATIENTS AND METHODS: Eligibility included advanced RCC and or= 7 days) were observed in 2 of 3 patients. One patient experienced grade 3 rash during week 3, which led to treatment discontinuation. A second patient had grade 3 thrombocytopenia (platelet count, 48,000/microL), cellulitis, and gout during week 3 and was hospitalized; platelets recovered to 109,000/microL 4 days after discontinuation of protocol therapy. A third patient experienced rash, asthenia, diarrhea, stomatitis, constipation, fever, and rectal hemorrhage, all of which were mild in severity. The study was terminated because of dose-limiting toxicity observed at low starting doses of both agents. CONCLUSION: Concomitant use of I.V. temsirolimus 15 mg weekly and oral sunitinib 25 mg daily (4 weeks on, 2 weeks off) is not recommended.

The antineoplastic agent bryostatin-1 differentially regulates IFN-gamma receptor subunits in monocytic cells: transcriptional and posttranscriptional control of IFN-gamma R2.

Bryostatin-1 (Bryo-1) is a potent ligand and modulator of protein kinase C that exerts antineoplastic and immunomodulatory activities both in vitro and in vivo. We have previously reported that Bryo-1 synergized with IFN-gamma to induce NO synthase and NO by macrophages. To determine whether this effect was associated with changes in levels of IFN-gammaR, we investigated the effects of Bryo-1 on the expression and regulation of IFN-gammaR chains in monocytic cells. Northern blot analysis revealed that Bryo-1 treatment of the human monocytic cell lines MonoMac6 and THP-1 and human monocytes enhanced the expression of IFN-gammaR2 mRNA but did not affect IFN-gammaR1 mRNA expression. Bryo-1 increased IFN-gammaR2 mRNA in a dose-dependent manner as early as 3 h posttreatment. Bryo-1-induced up-regulation of IFN-gammaR2 mRNA levels is not dependent on de novo protein synthesis as shown by cell treatment with the protein-synthesis inhibitor cycloheximide. Bryo-1 treatment increased the IFN-gammaR2 mRNA half-life by 2 h. EMSA analysis from Bryo-1-treated MonoMac6 cells showed an increased nuclear protein binding to the NF-kappaB motif present in the 5' flanking region of the human IFN-gammaR2 promoter that was markedly decreased by pretreatment with the NF-kappaB inhibitor SN50. These results show for the first time that Bryo-1 up-regulates IFN-gammaR2 expression in monocytic cells. Given the pivotal role that IFN-gamma exerts on monocyte activation and in the initiation and outcome of the immune response, the induction of IFN-gammaR2 by Bryo-1 has significant implications in immunomodulation and could overcome some of the immune defects observed in cancer patients.

Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium.

PURPOSE: To assess the antitumor activity and toxicity of pemetrexed as second-line chemotherapy in patients with locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Eligible patients had a performance status of 0 or 1, adequate organ function, previous treatment with one prior chemotherapy regimen for locally advanced or metastatic TCC of the urothelium or relapsed within 1 year of adjuvant or neoadjuvant treatment. Patients received pemetrexed 500 mg/m2 intravenously on day 1 every 21 days, with vitamin B12, folic acid, and dexamethasone prophylaxis. RESULTS: Forty-seven patients were enrolled and included in the intent-to-treat efficacy analysis. Responses: 3 (6.4%) complete responses and 10 (21.3%) partial responses produced an overall response rate of 27.7%. Ten patients (21.3%) had stable disease and 22 patients (46.8%) progressed. The median time to progressive disease was 2.9 months (95% CI, 1.7 months to 4.6 months) and median overall survival was 9.6 months (95% CI, 5.1 months to 14.6 months). Median duration of response was 5.0 months (95% CI, 3.9 months to 13.8 months). Of the 47 patients assessable for safety, grade 3 or 4 hematologic events were thrombocytopenia (8.5%; 0.0%), neutropenia (4.3%; 4.3%) and anemia (2.1%; 2.1%), respectively. Nonlaboratory toxicities included grade 4 stomatitis/pharyngitis, sepsis syndrome (one patient each), and grade 3 fatigue (three patients) and diarrhea (two patients). CONCLUSION: Single-agent pemetrexed is safe and active as second-line treatment of patients with advanced TCC of the urothelium. Additional evaluation in the first- or second-line setting in TCC of the urothelium is warranted.

A randomized phase II trial using two different treatment schedules of gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer.

BACKGROUND: Gemcitabine and carboplatin combination therapy is an active and tolerable regimen in the treatment of non-small-cell lung cancer (NSCLC). Twenty-eight- and 21-day regimens without day-15 administration of gemcitabine are common; however, it remains unclear which offers the optimal therapeutic index. METHODS: This trial evaluated two schedules of the combination of gemcitabine and carboplatin: gemcitabine (1100 mg/m on days 1 and 8) plus carboplatin (area under the curve = 5 on day 8) every 28 days, or gemcitabine (1000 mg/m on days 1 and 8) plus carboplatin (area under the curve = 5 on day 1) every 21 days. Eligible patients in this trial had stage IIIB (with malignant pleural effusion) or stage IV NSCLC with no prior chemotherapy. The primary objective was to evaluate progression-free survival, with secondary objectives of overall survival, response rate, and toxicity. RESULTS: One hundred patients were randomized and enrolled from October of 2000 to January of 2002 into this multi-institutional study (48 for the 28-day regimen and 52 for the 21-day regimen). Baseline demographics were well matched, and a majority of patients (85%) enrolled with stage IV disease. Median progression-free survival and response rates were 3.8 months and 22.9%, respectively, with the 28-day regimen, and 4.9 months and 40.4%, respectively, with the 21-day regimen. Median survival was 8.7 months with the 28-day regimen and 8.0 months for the 21-day regimen. One- and 2-year survival rates were 34.7% and 8.7%, respectively, with the 28-day regimen, and 36.5% and 16.8%, respectively, with the 21-day regimen. Differences in progression-free survival (log-rank statistic, p = 0.5786), response rate (Fisher's exact test, p = 0.0859) and overall survival (log-rank statistic, p = 0.3568) were not statistically significant. Grade 3 to 4 hematologic toxicities occurred with a greater frequency in the 21-day regimen. No grade 3 to 4 nonhematologic toxicity (except nausea/vomiting with the 28-day regimen) was observed in more than 10% of patients in either treatment arm. CONCLUSION: Gemcitabine plus carboplatin is active and well tolerated in advanced NSCLC. Both regimens may be considered for further study. Although the 21-day regimen appeared to be associated with preferable outcomes, differences between treatment groups were not statistically significant.

Gemcitabine/carboplatin in patients with metastatic non-small-cell lung cancer: phase II study of 28-day and 21-day schedules.

BACKGROUND: The combination of gemcitabine/carboplatin is active and is widely used for advanced non-small-cell lung cancer (NSCLC). The optimum schedule for the administration of these agents is not currently known. This study compared 2 different combinations of carboplatin/gemcitabine to identify a schedule with a superior therapeutic index. PATIENTS AND METHODS: The 28-day schedule used gemcitabine 1,100 mg/m2 on days 1 and 8 plus carboplatin to an area under the curve (AUC) of 5 on day 8. The 21-day schedule used gemcitabine 1,000 mg/m2 on days 1 and 8 plus carboplatin to an AUC of 5 on day 1. RESULTS: Four hundred ninety-nine chemotherapy-naive patients with stage IIIB NSCLC (with malignant pleural effusion) or stage IV NSCLC were accrued. Grade 3/4 toxicities with the 28-day and 21-day schedules were anemia (4.8% and 6.9% of cycles, respectively), neutropenia (9.1% and 10.7% of cycles, respectively), and thrombocytopenia (8% and 14.4% of cycles, respectively). Thirty-four patients (13.2%) received blood transfusions with the 28-day regimen, as did 43 (20%) with the 21-day regimen, and no bleeding episodes occurred. Overall response rates were 22.8% with the 28-day schedule and 32.6% with the 21-day schedule (P=0.0338). Median survival and 1-year and 2-year survival rates were 9.8 months, 38.6%, and 15.7%, respectively, with the 28-day schedule and 12 months, 49.1%, and 15.8%, respectively, with the 21-day schedule (P=0.5098). CONCLUSION: Gemcitabine/carboplatin demonstrated efficacy comparable to other platinum agent doublets. Either schedule can be recommended, as differences in survival between groups were not significant.

Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced nonsmall cell lung cancer.

BACKGROUND: The primary objectives of this study were to determine the efficacy and tolerability of a pemetrexed-carboplatin combination as first-line therapy in patients with advanced nonsmall cell lung cancer. METHODS: Eligibility criteria included Zubrod performance status of 0 or 1, Stage IIIB (malignant effusion) or IV disease, and no prior chemotherapy. Treatment was pemetrexed 500 mg/m2 given intravenously and carboplatin area under the serum concentration-time curve = 6 given intravenously on Day 1 every 3 weeks for six cycles; patients could receive additional cycles at the discretion of the treating physician and patient. All patients received folic acid, vitamin B12, and dexamethasone prophylaxis. RESULTS: Fifty patients (31 men and 19 women) were treated. The median age was 62 years. Ninety-six percent of patients had Stage IV disease, and 88% had a performance status of 1. The median number of cycles was 6; 15 patients received 8 or more cycles. There was Grade 3/4 neutropenia in 11 (22%) and 2 (4%) patients, respectively; Grade 3/4 thrombocytopenia in 1 (2%) and 0 patients, respectively. Three patients (6%) experienced Grade 3 nonhematologic side effects (diarrhea, neutropenic pneumonia, and fatigue). No patients had sensory neuropathy or alopecia >Grade 1. The partial response rate was 24%, median time to progression 5.4 months, 1-year survival 56.0%, and median survival 13.5 months. CONCLUSIONS: This is an active, very well-tolerated regimen. Trials focused on how to integrate this doublet with novel agents are warranted.

Interleukin-12 (IL-12) ameliorates the effects of porcine respiratory and reproductive syndrome virus (PRRSV) infection.

Porcine respiratory and reproductive syndrome virus (PRRSV) disease, one of the most economically significant viral diseases in the swine industry, is characterized by miscarriages, premature farrowing, stillborn pigs, and respiratory disease associated with death and chronic poor performance of nursing and weaned pigs. Interleukin-12 (IL-12) is a key component in driving the development of cell-mediated immunity as well as stimulating interferon-gamma (IFN-gamma) production from T cells and natural killer cells. Although some studies have investigated the use of IL-12 as a vaccine adjuvant in swine, little is known about its effectiveness as a treatment against viral diseases in swine. The present study investigated whether recombinant porcine IL-12 (rpIL-12) enhances the immune response and thereby diminishes the effects of PRRSV infection in young pigs. Interestingly, in vitro experiments demonstrated that rpIL-12 is capable of inducing swine pulmonary alveolar macrophages (PAMs), the target cells of PRRSV, to produce IFN-gamma in a dose and time dependent manner. In addition, in vitro studies also revealed that rpIL-12 treatment was capable of significantly reducing PRRSV viral titers in PAMs. In vivo administration of rpIL-12 significantly decreased PRRSV titers in the lungs and blood of infected animals. Furthermore, treatment with rpIL-12 prevented significant growth retardation in PRRSV-infected animals. Finally, in response to viral antigen recall challenge, PAMs isolated from rpIL-12-treated/PRRSV-infected animals produced greater amounts of IFN-gamma and lesser amounts of interleukin-10 than PAMs isolated from non-rpIL-12-treated/PRRSV-infected animals. Taken together our data indicate that treatment with rpIL-12 may provide an effective approach to control or ameliorate PRRSV-induced disease in swine.

IL-4 synergistically enhances both IL-2- and IL-12-induced IFN-gamma expression in murine NK cells.

Interleukin-4 (IL-4) is thought to influence T and natural killer (NK) cells by down-regulating T helper 1 (Th1)-type cytokines like interferon-gamma (IFN-gamma). While investigating IL-4 regulation of IFN-gamma expression, we found that IL-4 synergized with IL-2 or IL-12 to enhance IFN-gamma production and mRNA expression in spleen-derived, IL-2-cultured NK cells, as well as negatively sorted fresh DX5+/CD3- NK cells albeit at lower levels. The positive effect of IL-4 on IL-2-induced IFN-gamma production was dependent upon signal transducer and activator of transcription 6 (Stat6) because this response was virtually abrogated in Stat6-/- mice. Notably, though, IL-12 plus IL-4 synergy on IFN-gamma expression was intact in Stat6-/- mice. In exploring possible molecular mechanisms to account for the synergistic effects of IL-4 on murine NK cells, we found that IL-2 plus IL-4 stimulation resulted in a modest increase in tyrosine phosphorylation of Stat5, while IL-12 plus IL-4 treatment resulted in a more substantial increase in tyrosine-phosphorylated Stat4. Finally, to identify regions of the IFN-gamma promoter that may be involved, NK cells from human IFN-gamma promoter/luciferase transgenic mice were treated with cytokines. NK cells from proximal (-110 to +64) promoter region mice did not respond to cytokine stimulation; however, the intact -565 to +64 IFN-gamma promoter responded synergistically to IL-2 plus IL-4 and to IL-12 plus IL-4 in NK cells. These data demonstrate a role for IL-4 in enhancing IFN-gamma expression in murine NK cells that is partially dependent on Stat6 in IL-2 costimulation and completely independent of Stat6 in IL-12 costimulations.