Carbonic anhydrase IX expression is associated with improved outcome of high-dose interleukin-2 therapy for metastatic renal cell carcinoma.

AIM: The objectives of this study were to evaluate treatment responses to high-dose interleukin-2 (HD IL-2) in patients with metastatic renal cell carcinoma (mRCC) and assess correlation between responses and prognostic factors, such as histology, site of metastatic disease, prior treatment, prior nephrectomy, and carbonic anhydrase IX (CAIX) expression. PATIENTS AND METHODS: A retrospective analysis was performed on all mRCC patients treated with HD IL-2 between 1996 and 2006 at the University of Minnesota Medical Center in Minneapolis, Minnesota, USA. A cycle of HD IL-2 consisted of 600,000 U/kg given once every 8 hours for 14 doses. Cycles were repeated until disease progression or intolerable toxicities developed. CAIX expression and staining intensity were evaluated on available primary tumor tissue. RESULTS: Forty-seven patients with mRCC were identified. Of the 107 cycles of therapy that were given, 97.1% of patients received only two cycles of therapy. Complete response and partial response were seen in 3 (6%) and 15 (32%) patients, respectively. The overall disease control rate was 42.6%. The longest durable CR was 72 months and the shortest was 45 months. The median time to disease progression in patients with a CR or PR was 12 months. Patients with a Memorial Sloan-Kettering Cancer Center prognostic score of '1' were two times more likely to progress after two cycles than patients with a score of '0'. No response was observed in patients whose tumors were negative for CAIX by immunoperoxidase staining. CONCLUSION: HD IL-2 is a reasonable option for first-line therapy for selected patients with mRCC. Patients with tumors negative for CAIX may not benefit from HD IL-2 therapy. Further research is necessary to define patients with a higher likelihood of disease response to this therapy.

Phase II trial of neoadjuvant therapy with carboplatin, gemcitabine plus thalidomide for stages IIB and III non-small cell lung cancer.

INTRODUCTION: This phase II study assessed the clinical activity of neoadjuvant therapy with carboplatin, gemcitabine, and thalidomide in patients with stage IIB to IIIA non-small cell lung cancer (NSCLC). A secondary goal was to assay a panel of candidate serum biomarkers before and after neoadjuvant therapy. METHODS: Patients received three 21-day cycles consisting of gemcitabine (1000 mg/m) on days 1 and 8, carboplatin (area under the curve, 5.5) on day 1, and thalidomide (200 mg) daily after a gradual dose escalation. RESULTS: A total of 22 patients (12 women, 10 men) were enrolled with inoperable stage IIB NSCLC (32%) or III NSCLC (68%). Median age was 53 years (range: 32-78). Sixty-six cycles of neoadjuvant therapy were administered with 10 cycles requiring dose reductions (21.28%). Response rates were 70% for partial response (n = 14), 20% for disease stability (n = 4), and 10% for disease progression (n = 2). Disease in 14 patients (70%) was downstaged, allowing for 10 lobectomies (45.5%), one bilobectomy (4.5%), and 3 pneumonectomies (13.64%). Grades 3/4 hematologic events included neutropenia (55%), thrombocytopenia (14%), and anemia (14%). Grade 3 skin toxicity was reported in one patient due to thalidomide. Posttreatment increases from baseline in serum levels of angiopoietin (100 pg/ml), platelet/endothelial cell adhesion molecule 1 (100 pg/ml), hepatocyte growth factor (100 pg/ml), vascular endothelial growth factor (10 pg/ml), and interleukin-8 (10 pg/ml) corresponded to a reduction in the probability of death (p = 0.09, 0.055, 0.097, 0.052, and 0.095, respectively). Overall survival was 3.6 years (95% CI: 1.938-infinity). CONCLUSION: This neoadjuvant regimen was well tolerated and effective in inoperable NSCLC and warrants additional investigation.

Continuous antiretroviral therapy decreases bone mineral density.

OBJECTIVES: To assess the effects of antiretroviral therapy (ART) on bone mineral density (BMD) DESIGN: Randomized comparison of continuous ART (viral suppression group; VS) with intermittent ART (drug conservation group; DC) SETTING: Outpatient clinics in the United States, Australia, and Spain. PARTICIPANTS: Participants in the Strategies for Management of Antiretroviral Therapy (SMART) Body Composition substudy. MAIN OUTCOME MEASURES: Annual hip and spine BMD by dual-energy radiographic absorptiometry (DXA) and spine BMD by quantitative computed tomography (qCT). METHODS: Comparisons were by intention-to-treat analysis, using longitudinal models for change in BMD. Risk factors for BMD loss were evaluated. RESULTS: The 214 participants (median 44 years, 19% female participants, 73% on ART; median T-scores -0.5 total hip, -0.7 spine DXA, -0.9 spine qCT; 98 randomized to VS and 116 to DC) were followed for a mean 2.4 years. With continuous ART, BMD declined per year by 0.8% (hip), 0.4% (spine DXA), and 2.4% (spine qCT). BMD declined significantly less with intermittent ART. Estimated DC minus VS group differences in mean BMD change through follow-up were 1.4% [hip; 95% confidence interval (CI) 0.6-2.3; P = 0.002], 1.3% (spine DXA; 95% CI 0.1-2.4, P = 0.03), and 3.0% (spine qCT; 95% CI 0.8-5.2, P = 0.007). No consistent drug-specific association with BMD decline was found. In the parent study, 10 of 2753 participants in the VS group and two of 2720 in the DC group reported serious fractures (hazard ratio 4.9; 95% CI 1.1-22.5; P = 0.04). CONCLUSION: Continuous ART is associated with decline in BMD and possibly more fractures relative to intermittent, CD4 cell count-guided ART.