Citations

Abstract Purpose: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG). Experimental Design: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m2/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy. Results: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+, 7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in α-fetoprotein and stable disease over three cycles. At 270 mg/m2/dose, the Cmax and areas under the plasma concentration-time curves of 17-AAG were 5,303 ± 1,591 ng/mL and 13,656 ± 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 ± 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m2 dose level. Conclusions: Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360 mg/m2/d. Non-DMSO–containing formulations may improve acceptance of this drug by children and their families.

Purpose We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A → C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC). Patients and Methods High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A → C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cyles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A → C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy. Results Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor–positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A → C. Grade 4 hematologic toxicity was greater on A → C, but nonhematological grade 4 was similar. Conclusion The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.

Purpose Treatment with aromatase inhibitors decreases bone mineral density (BMD) and may increase the risk of fractures in postmenopausal women with early-stage breast cancer. The addition of zoledronic acid to adjuvant letrozole therapy may protect against bone loss. Patients and Methods Patients receiving adjuvant letrozole were randomly assigned to receive either upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months). The delayed group received zoledronic acid when lumbar spine (LS) or total hip (TH) T score decreased to less than −2.0 or when a nontraumatic fracture occurred. The primary end point of this study was to compare the change in LS BMD at month 12 between the groups. Secondary end points included change in TH BMD and changes in serum bone turnover markers at month 12. Results The upfront and delayed groups each included 301 patients. At month 12, LS BMD was 4.4% higher in the upfront group than in the delayed group (95% CI, 3.7% to 5.0%; P < .0001), and TH BMD was 3.3% higher (95% CI, 2.8% to 3.8%; P < .0001). In the upfront group, mean serum N-telopeptide and bone-specific alkaline phosphatase concentrations decreased by 15.1% (P < .0001) and 8.8% (P = .0006), respectively, at month 12, whereas concentrations increased significantly in the delayed group by 19.9% (P = .013) and 24.3% (P < .0001), respectively. Conclusion With 1 year of follow-up, results of the primary end point of the Zometa-Femara Adjuvant Synergy Trial (Z-FAST) indicate that upfront zoledronic acid therapy prevents bone loss in the LS in postmenopausal women receiving adjuvant letrozole for early-stage breast cancer.

Abstract Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of 17-allylamino-demethoxy-geldanamycin (17-AAG) administered on days 1, 4, 8, and 11 every 21 days and to examine the effect of 17-AAG on the levels of chaperone and client proteins. Experimental Design: A phase I dose escalating trial in patients with advanced solid tumors was done. Toxicity and tumor responses were evaluated by standard criteria. Pharmacokinetics were done and level of target proteins was measured at various points during cycle one. Results: Thirteen patients were enrolled in the study. MTD was defined as 220 mg/m2. Dose-limiting toxicities were as follows: dehydration, diarrhea, hyperglycemia, and liver toxicity. At the MTD, the mean clearance of 17-AAG was 18.7 L/h/m2. There was a significant decrease in integrin-linked kinase at 6 hours after infusion on day 1 but not at 25 hours in peripheral blood mononuclear cells. Treatment with 17-AAG on day 1 significantly increased pretreatment levels of heat shock protein (HSP) 70 on day 4, which is consistent with the induction of a stress response. In vitro induction of a stress response and up-regulation of HSP70 resulted in an increased resistance to HSP90-targeted therapy in A549 cells. Conclusions: The MTD of 17-AAG on a twice-weekly schedule was 220 mg/m2. Treatment at this dose level resulted in significant changes of target proteins and also resulted in a prolonged increase in HSP70. This raises the possibility that HSP70 induction as part of the stress response may contribute to resistance to 17-AAG.

Purpose Retrospective studies suggest cytogenetic abnormalities detected by interphase fluorescent in situ hybridization (FISH) can identify patients with chronic lymphocytic leukemia (CLL) who will experience a more aggressive disease course. Other studies suggest that patients may acquire chromosome abnormalities during the course of their disease. There are minimal prospective data on the clinical utility of the widely used hierarchical FISH prognostic categories in patients with newly diagnosed early-stage CLL or the frequency of clonal evolution as determined by interphase FISH. Patients and Methods Between 1994 and 2002, we enrolled 159 patients with previously untreated CLL (83% Rai stage 0/I) on a prospective trial evaluating clonal evolution by FISH. Patients provided baseline and follow-up specimens for FISH testing during 2 to 12 years. Results Chromosomal abnormalities detected by FISH at study entry predicted overall survival. Eighteen patients experienced clonal evolution during follow-up. The rate of clonal evolution increased with duration of follow-up with only one occurrence in the first 2 years (n = 71; 1.4%) but 17 occurrences (n = 63; 27%) among patients tested after 5+ years. Clonal evolution occurred among 10% of ZAP-70–negative and 42% of ZAP-70–positive patients at 5+ years (P = .008). Conclusion This clinical trial confirms prospectively that cytogenetic abnormalities detected by FISH can predict overall survival for CLL patients at the time of diagnosis, but also suggests that many patients acquire new abnormalities during the course of their disease. Patients with higher ZAP-70 expression may be more likely to experience such clonal evolution. These findings have important implications for both clinical management and trials of early treatment for patients with high-risk, early-stage CLL.

Abstract Tumor-associated eosinophilia has been observed in numerous human cancers and several tumor models in animals; however, the details surrounding this eosinophilia remain largely undefined and anecdotal. We used a B16-F10 melanoma cell injection model to demonstrate that eosinophil infiltration of tumors occurred from the earliest palpable stages with significant accumulations only in the necrotic and capsule regions. Furthermore, the presence of diffuse extracellular matrix staining for eosinophil major basic protein was restricted to the necrotic areas of tumors, indicating that eosinophil degranulation was limited to this region. Antibody-mediated depletion of CD4+ T cells and adoptive transfer of eosinophils suggested, respectively, that the accumulation of eosinophils is not associated with T helper cell type 2-dependent immune responses and that recruitment is a dynamic, ongoing process, occurring throughout tumor growth. Ex vivo migration studies have identified what appears to be a novel chemotactic factor(s) released by stressed/dying melanoma cells, suggesting that the accumulation of eosinophils in tumors occurs, in part, through a unique mechanism dependent on a signal(s) released from areas of necrosis. Collectively, these studies demonstrate that the infiltration of tumors by eosinophils is an early and persistent response that is spatial-restricted. It is more important that these data also show that the mechanism(s) that elicit this host response occur, independent of immune surveillance, suggesting that eosinophils are part of an early inflammatory reaction at the site of tumorigenesis.

Abstract Intervention trials with supplemental β-carotene have observed either no effect or a harmful effect on lung cancer risk. Because food composition databases for specific carotenoids have only become available recently, epidemiological evidence relating usual dietary levels of these carotenoids with lung cancer risk is limited. We analyzed the association between lung cancer risk and intakes of specific carotenoids using the primary data from seven cohort studies in North America and Europe. Carotenoid intakes were estimated from dietary questionnaires administered at baseline in each study. We calculated study-specific multivariate relative risks (RRs) and combined these using a random-effects model. The multivariate models included smoking history and other potential risk factors. During follow-up of up to 7–16 years across studies, 3,155 incident lung cancer cases were diagnosed among 399,765 participants. β-Carotene intake was not associated with lung cancer risk (pooled multivariate RR = 0.98; 95% confidence interval, 0.87–1.11; highest versus lowest quintile). The RRs for α-carotene, lutein/zeaxanthin, and lycopene were also close to unity. β-Cryptoxanthin intake was inversely associated with lung cancer risk (RR = 0.76; 95% confidence interval, 0.67–0.86; highest versus lowest quintile). These results did not change after adjustment for intakes of vitamin C (with or without supplements), folate (with or without supplements), and other carotenoids and multivitamin use. The associations generally were similar among never, past, or current smokers and by histological type. Although smoking is the strongest risk factor for lung cancer, greater intake of foods high in β-cryptoxanthin, such as citrus fruit, may modestly lower the risk.