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Background: Letrozole after 5 years of adjuvant tamoxifen results in a significant reduction in risk of recurrence from estrogen receptor (ER) positive breast cancer. An individualized estimate of the risk of relapse and death after 5 years of tamoxifen could improve decisions regarding extended hormonal therapy., Methods: The British Columbia Breast Cancer Outcomes database was used to identify women aged 45 years or older at the time of diagnosis with early-stage (I-IIIA) breast cancer who received tamoxifen and were disease free 5 years after diagnosis. Ten-year breast cancer event rates and mortality were calculated as well as annualized hazard rates of recurrence., Results: A total of 1086 women were identified with a median age of 64 years and follow-up of 10.5 years. The relative risk (RR) of death was 3.1 (P=0.003) and for recurrence was 1.7 (P=0.037) for N1 (one to three positive nodes) versus N0 (zero nodes positive) disease. N2 (four to nine nodes positive) had a RR of 5.8 (P<0.001) for death and 3.0 (P=0.002) for recurrence. Low tumor grade and high ER level subgroups had a more favorable prognosis. Annual breast cancer risk between years 6 and 10 was, respectively, 2.2%, 3.5% and 7.6% for N0, N1 and N2 disease and 2.6% and 4.5% for T1 and T2 breast cancer., Conclusion: T and N stages predicted late relapse and death from breast cancer in a population-based cohort of postmenopausal women. Risk estimates reported herein may be used to optimize decision making regarding adjuvant therapy after 5 years of tamoxifen.

Purpose: To determine if time to start of adjuvant chemotherapy after curative surgery influences survival in early-stage breast cancer., Patients and Methods: A retrospective review was conducted of 2,594 patients receiving adjuvant chemotherapy for stage I and II breast cancer between 1989 and 1998 at the British Columbia Cancer Agency. Relapse-free survival (RFS) and overall survival (OS) were compared among patients grouped by time from definitive curative surgery to start of adjuvant chemotherapy (< or = 4 weeks, > 4 to 8 weeks, > 8 to 12 weeks, and >12 to 24 weeks)., Results: RFS and OS were similar for women starting chemotherapy up to 12 weeks after surgery. OS hazard ratio (univariate) for initiation of chemotherapy more than 12 weeks compared with 12 weeks or less after surgery was 1.5 (95% CI, 1.07 to 2.10; P = .017). Five-year OS rates were 84%, 85%, 89%, and 78%, (log-rank P = .013); RFS rates were 74%, 79%, 82%, and 69% (log-rank P = .004) for patients starting chemotherapy 4 weeks or fewer, more than 4 to 8 weeks, more than 8 to 12 weeks, and more than 12 to 24 weeks after surgery, respectively. In multivariate analysis, independent prognostic factors were grade, size, nodal status, estrogen receptor, age, and lymphatic and/or vascular invasion. Initiation of adjuvant chemotherapy more than 12 weeks from surgery remained significantly associated with inferior survival, with a hazard ratio of 1.6 (95% CI, 1.2 to 2.3; P = .005)., Conclusion: This retrospective analysis suggests that adjuvant chemotherapy is equally effective up to 12 weeks after definitive surgery but that RFS and OS appear to be compromised by delays of more than 12 weeks after definitive surgery.

Background: Trastuzumab-based chemotherapy can improve median survival in the metastatic setting when used in patients with cancer that overexpresses HER2/neu. In addition to HER2 expression, other molecular markers are needed to better predict outcomes after the initiation of trastuzumab-based chemotherapy and to elucidate potential mechanisms of resistance to trastuzumab., Patients and Methods: Patients with clinical documentation of HER2/neu-overexpressing metastatic breast cancer treated with trastuzumab between 1998 and 2004 were identified from the British Columbia Provincial Pharmacy Database. Tissues were obtained for microarray analysis of 153 of 306 patients who fit our clinical criteria. Tissue microarrays were constructed for the analysis of multiple molecular factors, and results were correlated to clinical outcomes. Immunohistochemistry was performed on the microarray specimens, and results were correlated with survival and time to progression., Results: Factors commonly associated with poor prognosis in the metastatic setting in general, including short disease-free intervals, high tumor grade, and low estrogen receptor status, were all associated with poor survival in this population with HER2 overexpression. Overexpression of HER3 was observed in 9% of specimens and was associated with a trend toward worse overall survival (P = 0.1). HER3 expression was not correlated with a significant difference in time to progression but did trend to predict for worse survival after progression (P = 0.06). In multivariate analysis, tumor grade and HER3 expression were significantly predictive of overall survival. Phosphatase and tensin homologue status did not appear to correlate with response or survival., Conclusion: Our findings suggest that prognosis after initiation of trastuzumab-based chemotherapy depends, in part, on coexpression of HER3.

Purpose: Cardiotoxicity precludes the concurrent use of doxorubicin and trastuzumab. Because pegylated liposomal doxorubicin (PLD) has equal efficacy but significantly less cardiotoxicity than conventional doxorubicin, this phase II study assessed the rate of cardiotoxicity and efficacy of first-line PLD plus trastuzumab in HER-2-positive metastatic breast cancer (MBC)., Patients and Methods: Women with HER-2-positive, measurable MBC, and a baseline left ventricular ejection fraction (LVEF) > or = 55% were treated with PLD 50 mg/m2 every 4 weeks for six cycles and weekly trastuzumab (4 mg/kg loading dose then 2 mg/kg thereafter). Cardiotoxicity was defined as symptomatic congestive heart failure (CHF) with > or = 10% decline in LVEF to below lower limits of normal, > or = 15% decline in LVEF without symptomatic CHF, or less than 10% LVEF decline to less than 45%., Results: Thirty women were enrolled, 13 had received prior adjuvant anthracyclines. A median 5.5 cycles of PLD were administered. Mean baseline LVEF was 62.8%, 59.5% after cycle four, and 58.3% after cycle six. Three patients (10%) developed protocol-defined cardiotoxicity. No patients developed symptomatic CHF. Response rate was 52%, with an additional 38% stable disease rate. At a median follow-up of 13.9 months, the median progression-free survival was 12.0 months; median overall survival has not yet been reached. The most common adverse events were grade 3 hand-foot syndrome (30%) and grade 3/4 neutropenia (27%)., Conclusion: The combination of PLD and trastuzumab is a well tolerated and active regimen in HER-2-positive MBC. Cardiotoxicity was observed, but limited to asymptomatic declines in LVEF. Further evaluation of this combination is warranted.

Capecitabine is an important drug in the therapeutic armamentarium for metastatic breast cancer. A comprehensive worldwide clinical trial program involving >10,000 patients with locally advanced and metastatic breast cancer has provided evidence for the current treatment strategies. On the basis of data demonstrating consistent activity across several trials in patients with heavily pretreated breast cancer, capecitabine was approved in the U.S. in 1998 for the treatment of patients with metastatic disease resistant to paclitaxel and anthracycline-containing therapy, with later European Union approval for single-agent capecitabine in the metastatic setting. Capecitabine plus docetaxel (XT) was approved by the U.S. Food and Drug Administration for the treatment of metastatic breast cancer in 2001 on the basis of the large phase III trial comparing XT with docetaxel alone, which showed a survival advantage for combination therapy compared with single-agent therapy. This was shortly followed by European approval for the combination in metastatic breast cancer. The clinical utility of capecitabine in the management of breast cancer is supported by its convenient oral dosing schedule and favorable safety profile, as well as its excellent clinical activity in primary and metastatic breast cancer. Recently, clinical trials have studied single-agent capecitabine as first-line treatment and evaluated other capecitabine-containing combinations with cytotoxic and novel targeted agents.

Background: The clinical significance of coexpression of type 1 growth factor receptor (T1GFR) family members remains largely unknown. The objective of the current study was to determine the frequency and the possible prognostic effect of coexpression of HER-1, HER-2, HER-3, and HER-4 by breast carcinoma., Methods: Tissue microarrays were constructed using clinically annotated formalin-fixed, paraffin-embedded tumor samples from 242 patients with invasive breast carcinomas with a median 15-year follow-up. The levels of TIGFR family members (HER-1-HER-4) were measured by immunohistochemistry. K-means clustering algorithm, as well as univariate (Kaplan-Meier, log-rank test) and multivariate (Cox regression) survival analyses were applied to the data set., Results: Using univariate analysis, expression of HER-1, HER-2, and HER-3, but not HER-4, was significantly associated with decreased patient disease-specific survival (P < 0.05). Kaplan-Meier survival analysis showed that coexpression of >/= 2 of HER-1, HER-2, and HER-3 in any combination was associated with reduced patient disease-specific survival compared with single marker expression or no expression (35% vs. 65% vs. 78% 10-year survival rates, P = 0.001). Using multivariate analysis, expression of >/= 2 of HER-1, HER-2, and HER-3 was independent of lymph node status and tumor size., Conclusions: In a cohort of patients with breast carcinoma, the authors observed T1GFR family member coexpression (HER-1, HER-2, and HER-3) to have a negative synergistic effect on patient outcome, independent of tumor size or lymph node status. Thus, coexpression of T1GFR family members identified a subset of patients with a poor disease prognosis who may potentially benefit from therapy simultaneously targeting several T1GFR family members., ((c) 2005 American Cancer Society.)

Background: The British Columbia randomized radiation trial was designed to determine the survival impact of locoregional radiation therapy in premenopausal patients with lymph node-positive breast cancer treated by modified radical mastectomy and adjuvant chemotherapy. Three hundred eighteen patients were assigned to receive no further therapy or radiation therapy (37.5 Gy in 16 fractions). Previous analysis at the 15-year follow-up showed that radiation therapy was associated with a statistically significant improvement in breast cancer survival but that improvement in overall survival was of only borderline statistical significance. We report the analysis of data from the 20-year follow-up., Methods: Survival was analyzed by the Kaplan-Meier method. Relative risk estimates were calculated by the Wald test from the proportional hazards regression model. All statistical tests were two-sided., Results: At the 20 year follow up (median follow up for live patients: 249 months) chemotherapy and radiation therapy, compared with chemotherapy alone, were associated with a statistically significant improvement in all end points analyzed, including survival free of isolated locoregional recurrences (74% versus 90%, respectively; relative risk [RR] = 0.36, 95% confidence interval [CI] = 0.18 to 0.71; P = .002), systemic relapse-free survival (31% versus 48%; RR = 0.66, 95% CI = 0.49 to 0.88; P = .004), breast cancer-free survival (48% versus 30%; RR = 0.63, 95% CI = 0.47 to 0.83; P = .001), event-free survival (35% versus 25%; RR = 0.70, 95% CI = 0.54 to 0.92; P = .009), breast cancer-specific survival (53% versus 38%; RR = 0.67, 95% CI = 0.49 to 0.90; P = .008), and, in contrast to the 15-year follow-up results, overall survival (47% versus 37%; RR = 0.73, 95% CI = 0.55 to 0.98; P = .03). Long-term toxicities, including cardiac deaths (1.8% versus 0.6%), were minimal for both arms., Conclusion: For patients with high-risk breast cancer treated with modified radical mastectomy, treatment with radiation therapy (schedule of 16 fractions) and adjuvant chemotherapy leads to better survival outcomes than chemotherapy alone, and it is well tolerated, with acceptable long-term toxicity.

The effects of HER-2/neu overexpression on the tumor microenvironment in an aggressive breast cancer xenograft model were investigated. These studies focused on tumors derived following the subcutaneous injection of MDA-MB-435/LCC6 cells transfected with human c-erbB2 (LCC6(HER-2)) into SCID-Rag2M mice. LCC6(HER-2) tumors were more viable (H&E-stained tumor sections) than isogenic vector control tumors (LCC6(Vector)). Correspondingly, a 2.7-fold increase in trypan blue-excluding cells (P = 0.00056) and a 4.8-fold increase in clonogenic cells (P = 0.00146) were noted in cell suspensions derived from disaggregated LCC6(HER-2) versus LCC6(Vector) tumors. Tumor sections stained with the antibody detecting 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5), a marker of hypoxia, showed a greater fraction of hypoxic tissue in LCC6(HER-2) tumors compared with control tumors. Flow cytometric analyses based on viable tumor cells (DNA content >/= 2N) in cell suspensions from disaggregated tumors confirmed that there were significantly more EF5-positive cells (i.e., hypoxic) in LCC6(HER-2) than in LCC6(Vector) tumors (16.41 +/- 8.1% and 5.96 +/- 4.1%, respectively; P = 0.0015). Protein levels of phosphorylated (Ser(536)) nuclear factor-kappaB p65 were significantly elevated in LCC6(HER-2) tumors (P = 0.00048), and a trend in increased hypoxia-inducible factor-1alpha protein levels was observed in LCC6(HER-2) compared with LCC6(Vector) tumors. Despite the substantial viable hypoxic cell fraction and a 1.7-fold increase of vascular endothelial growth factor protein (P = 0.05) in LCC6(HER-2) tumors, no significant differences were found (P > 0.05) between LCC6(HER-2) and LCC6(Vector) vasculature (CD31 staining and Hoechst 33342 perfusion). These results suggest that HER-2/neu overexpression may be linked with overall increased tumor viability and a significant increase in the population of viable hypoxic cells, which is not due to differences in tumor vascularization.

Purpose: To define the maximum tolerated dose (MTD), recommended phase II dose (RD) and dose limiting toxicity (DLT) of liposomal lurtotecan, OSI-211 (formerly known as NX211), given as a short intravenous infusion on days 1, 2, and 3 every three weeks., Experimental Design: Thirty-seven patients were enrolled and treated in a dose escalation study from a starting dose of 0.15 mg/m(2) daily x 3 to 2.1 mg/m(2) daily x 3. Detailed pharmacokinetic analyses of blood were done on both days 1 and 3 of the first cycle and toxicity was monitored., Results: Two MTDs were defined; one for patients defined as minimally pretreated and one for those heavily pretreated. Dose limiting toxicity was myelosuppression: primarily thrombocytopenia although neutropenia was also noted. The MTD was 2.1 mg/m(2)/d (total dose of 6.3 mg/m(2)) in minimally pretreated patients and 1.8 mg/m(2)/d (5.4 mg/m(2) total dose) in heavily pretreated patients. Pharmacokinetics revealed that AUC and C (max) increased with dose and were significantly higher than that of free lurtotecan (AUC approx. 100 fold higher). The half life and duration of the active lactone form were also significantly longer than historical data on free drug. Two partial responses were seen, one each in a patient with breast and ovarian cancer., Conclusions: Two Phase II recommended doses were established for OSI-211 given as a daily x 3 schedule every three weeks. The recommended phase II dose is 1.8 mg/m(2) daily x 3 for minimally pretreated patients and 1.5 mg/m(2) for those heavily pretreated. Phase II studies should be initiated in sensitive tumours.

Background: AMD473 (previously ZD0473) is a new-generation platinum compound with activity against a wide range of human tumour cell lines and xenografts, including carboplatin- and cisplatin-resistant lines. To assess its potential combined with a taxane, a phase I study of AMD473 and docetaxel in advanced cancer was initiated by the National Cancer Institute of Canada-Clinical Trials Group., Patients and Methods: Patients with advanced cancer, measurable disease, performance status Eastern Cooperative Oncology Group 0-2, no major organ dysfunction, and one or no previous taxane regimen received escalating doses of AMD473 and docetaxel every 3 weeks, with a starting dose of AMD473 80 mg/m(2) and docetaxel 60 mg/m(2)., Results: Thirty-three patients enrolled on four dose levels were evaluable for toxicity and 25 patients were evaluable for response. The maximum tolerated dose was dose level 4 (AMD473 120 mg/m(2) and docetaxel 75 mg/m(2)), with grade 4 neutropenia in both minimally and heavily pretreated patients causing dose-limiting toxicity. As well at dose level 4, one patient had grade 3 vomiting despite premedication. Dose level three was expanded for both groups of patients and was defined as the recommended phase II dose at AMD473 100 mg/m(2) and docetaxel 75 mg/m(2). Non-hematologic toxicities included fatigue, diarrhoea and other mild toxicities. There was one partial response in a patient with prostate cancer and stable disease in 15 patients. No apparent pharmacokinetic interaction was noted., Conclusion: AMD473 and docetaxel can be combined with a recommended phase II dose level of 100 mg/m(2) and 75 mg/m(2), respectively, given intravenously every 3 weeks. The combination has activity and should be explored in responsive tumour types.

Tissue microarrays containing 348 cases of invasive breast carcinoma were studied by immunohistochemical staining for CD-117, CD-3, CD-20, CD-68, Her2, estrogen receptor protein, and progesterone receptor protein, and results were correlated with patient outcome. Hormone receptor status (both estrogen receptor and progesterone receptor) correlated with a good outcome while Her2 overexpression was associated with a poor outcome. The presence of mast cells in the stroma, as demonstrated by positive c-kit (CD-117) staining, correlated with a good prognosis (P=0.0036). On subset analysis, this association between the presence of mast cells and favorable prognosis was present in the node-negative patients (P=0.018). The presence of mast cells showed an inverse correlation with the presence of CD-68 positive macrophages. No correlation was observed between the presence of mast cells and either B-cells (CD20-positive) or T-cells (CD3-positive). The presence of stromal mast cells was of prognostic significance independent of nodal status and tumor size (P=0.02). When the multivariate analysis was expanded to include tumor grade, estrogen receptor status and Her2 status, as well as tumor size and nodal status, the presence of stromal mast cells approached significance as an independent prognostic indicator.

Background: OSI-211 (also known as NX211) is a liposomal preparation of the topoisomerase I inhibitor, lurtotecan, which has shown antitumor activity in phase I and II clinical trials. Cisplatin is a widely used antineoplastic agent with activity in a broad range of tumor types. This phase I trial was conducted to determine the recommended doses of these agents, and their pharmacokinetic properties and toxicities in patients with advanced solid malignancies., Patients and Methods: Fourteen patients with advanced and/or metastatic solid malignancies were enrolled in this trial. The first planned dose level was OSI-211 0.9 mg/m(2) with cisplatin 25 mg/m(2) administered intravenously daily for the first three consecutive days of a 21-day cycle. Patients were evaluated for hematological and non-hematological toxicities, and pharmacokinetic studies were performed on both agents., Results: The recommended phase II dose was determined to be 0.7 mg/m(2) OSI-211 given with 25 mg/m(2) cisplatin. Dose-limiting neutropenia was seen in two of three patients at the starting dose level. Three of 11 patients at the second (lower) dose level experienced dose-limiting thrombocytopenia; febrile neutropenia was also seen in one patient. Non-hematological toxicities were generally manageable and included fatigue, nausea and vomiting. Considerable variability was seen in both hematological toxicities and pharmacokinetics. One complete response and three partial responses were seen., Conclusions: The recommended phase II dose for this combination is 0.7 mg/m(2) OSI-211 with 25 mg/m(2) cisplatin given as an intravenous infusion on days 1, 2 and 3 of a 21-day cycle. The main toxicity was myelosuppression. Preliminary evidence of antitumor activity was seen.

Purpose: The purpose of this research was to assess the effects of single agent and combination treatment with trastuzumab and gefitinib on tumor growth and tumor microenvironment in two HER-2/neu overexpressing breast xenograft models, MDA-MB-435/LCC6(HER-2) (LCC6(HER-2); estrogen receptor negative) and MCF-7(HER-2) (estrogen receptor positive)., Experimental Design: LCC6(HER-2) and MCF-7(HER-2) cells, both in tissue culture and xenografts grown in SCID-Rag 2M mice, were treated with trastuzumab and gefitinib, alone or in combination. The rate of tumor growth was determined. In addition, tumor HER-2/neu and epidermal growth factor receptor expression, cell viability, cell cycle distribution, and proportion of viable hypoxic cells were determined by flow cytometric analyses of single tumor cell suspensions., Results: Both tumor models were very sensitive to trastuzumab and moderately sensitive to gefitinib in vivo. The combination resulted in therapeutic effects, as judged by inhibition of tumor growth, which was greater (albeit not statistically significant) than that observed with trastuzumab administered as a single agent. Trastuzumab was effective in down-regulating HER-2/neu, and gefitinib mediated a reduction in epidermal growth factor receptor expression on tumor cells. In LCC6(HER-2) tumors, trastuzumab significantly reduced tumor cell viability, which was not improved by the addition of gefitinib. Gefitinib dramatically reduced the proportion of viable hypoxic cells in LCC6(HER-2) and MCF-7(HER-2) tumors. This effect was abrogated by the addition of trastuzumab., Conclusions: Although in vivo efficacy studies in two HER-2/neu overexpressing breast xenograft models showed that the combination of trastuzumab and gefitinib was effective, analyses of various cellular parameters failed to reveal beneficial effects and argue that this drug combination may not be favorable.

Purpose: N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is a novel agent that augments chemotherapy cytotoxicity in vitro and in vivo. A phase II trial combining DPPE and doxorubicin (DOX) in metastatic breast carcinoma showed increased response over that expected with DOX. We report a phase III trial comparing DOX with DPPE plus DOX in metastatic or recurrent breast cancer., Patients and Methods: Anthracycline-naive women with measurable metastatic disease were randomly assigned to receive, every 21 days, either DOX 60 mg/m(2) intravenously or DOX during the last 20 minutes of an 80-minute infusion of DPPE (5.3 mg/kg), in both cases to cumulative DOX doses of 450 mg/m(2). Patients receiving DPPE were aggressively premedicated to ameliorate toxicity. End points included progression-free survival (PFS), response rate (RR), and response duration (RD), quality of life (QOL), toxicity, and overall survival (OS)., Results: A planned interim analysis failed to detect an RR difference more than 5%. The study was closed to additional accrual and all DPPE was discontinued. The final analysis was conducted as planned after 256 progression events (median follow-up, 20.5 months). There was no significant difference in RR, RD, or PFS between arms. DPPE plus DOX was statistically superior to DOX in OS (hazard ratio, 0.66; 95% CI, 0.48 to 0.91; P =.021). DPPE plus DOX was associated with more gastrointestinal and CNS toxicity. No consistent influence on QOL was detected., Conclusion: This study demonstrated no advantage in RR, RD, or PFS but significantly superior OS for DPPE plus DOX. Additional studies of DPPE are warranted.

Purpose: This phase II study evaluated the pharmacokinetics and safety of trastuzumab and paclitaxel given every 3 weeks to women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer., Patients and Methods: Thirty-two patients received a loading dose of trastuzumab 8 mg/kg intravenously (day 1) and paclitaxel 175 mg/m2 (day 0). Thereafter, trastuzumab 6 mg/kg was administered on the same day as paclitaxel 175 mg/m2 every 3 weeks for seven cycles. In responding patients, trastuzumab monotherapy every 3 weeks was then continued until disease progression or patient withdrawal., Results: Trastuzumab trough levels were more than 20 mug/mL by the end of cycle 1. The half-life of trastuzumab was estimated to be 18 to 27 days, although this may be an underestimate. The combination of paclitaxel and trastuzumab was generally well tolerated, with no unexpected toxicities and no pharmacokinetic interaction. The most common adverse events were myalgia, paresthesias, alopecia, arthralgia, and fatigue. Events associated with trastuzumab included infusion-related reactions and cardiac dysfunction. Ten patients had a > or = 15% decrease in ejection fraction, but only one had symptomatic heart failure. The investigator-assessed objective response rate was 59% (four complete and 15 partial responses) and seven patients (22%) had stable disease. The median duration of response was 10.5 months and median time to progression was 12.2 months., Conclusion: Additional investigation of trastuzumab administered every 3 weeks is warranted. In combination with paclitaxel, it is generally well tolerated. Plasma trastuzumab trough levels and clinical response rates compare favorably with those achieved with the standard weekly trastuzumab regimen plus chemotherapy. The presence of trastuzumab does not alter exposure to paclitaxel.

Background: ZD0473 is a new generation platinum compound with activity against a wide range of human tumor cell lines and xenografts, including carboplatin- and cisplatin-resistant lines. A phase II study of ZD0473 in advanced breast cancer was initiated by the National Cancer Institute of Canada Clinical Trials Group., Patients and Methods: Women with metastatic breast cancer, measurable disease, an Eastern Cooperative Oncology Group performance status of up to two, and a maximum of one prior cytotoxic agent for recurrent disease were enrolled and treated at 120 mg/m(2) every 3 weeks. After 13 patients were enrolled, the dose was increased to 150 mg/m(2) on the basis of emergent data from studies ongoing at the time., Results: Thirty-three women were evaluable for toxicity and 26 patients for response. Toxicity was mainly hematological with grade 3/4 thrombocytopenia in 12 of 20 patients (60%) treated at 150 mg/m(2) and grade 3 thrombocytopenia in three of 13 patients (23%) at 120 mg/m(2). Grade 3/4 neutropenia occurred in 15 patients (75%) at 150 mg/m(2) and two patients (10%) at 120 mg/m(2). Non-hematological toxicities were generally mild or moderate. There was one partial response seen for a response rate of 3.8% (95% confidence interval 0.1% to 19.5%) and stable disease in 15 patients., Conclusion: ZD0473 has minor activity as a single agent in metastatic breast cancer. Combinations with other drugs including docetaxel are ongoing and may be of interest.

A combination of factors has been responsible for improvements in cancer survival and cure rates. In addition to new therapies with novel/genetic targets, these include improvements in drug delivery, new schedules/sequencing of drug administration and the identification of combination therapies with greater activity/dose density than existing regimens. The recognition that such criteria can affect treatment outcome has led to their incorporation into clinical trials of new drugs. Furthermore, pharmacokinetic and pharmacodynamic parameters have become increasingly important for the rational selection of dose, administration route and schedule. The humanized monoclonal antibody trastuzumab (Herceptin) has been rationally developed to target the human epidermal growth factor receptor-2 (HER2), which is overexpressed in 20%-30% of breast cancers and is associated with poor prognosis. Trastuzumab when administered i.v. on a weekly schedule either alone or in combination with taxanes, improves survival of women with HER2-positive metastatic breast cancer. Based upon pharmacokinetic considerations, current studies are examining whether trastuzumab can be administered i.v. every three weeks or by the s.c. route. These regimens would have advantages for patients and medical staff in terms of acceptability, ease of administration and, potentially, cost effectiveness. Furthermore, various combinations of trastuzumab and chemotherapeutic agents are being explored with the aim of identifying the optimal combination regimen for clinical use. The rationale for these various studies and the studies themselves are described.

Purpose: To define the maximum-tolerated dose, recommended phase II dose (RD), dose-limiting toxicity (DLT), and pharmacokinetics of a novel taxane, RPR 109881A, administered on days 1 and 8 of a 21-day cycle., Patients and Methods: Twenty-nine patients were enrolled and treated according to a modified continual reassessment method from a starting dose of 7.5 mg/m(2) to 52.5 mg/m(2). Detailed pharmacokinetic analyses of blood and urine were performed on days 1 and 8 of the first cycle. Toxicity was monitored weekly., Results: DLT consisting of grade 3 or 4 diarrhea was seen in three of six patients at 52.5 mg/m(2). Grade 3 or 4 granulocytopenia was also seen in five of six patients treated at this dose (four of six in the first cycle). At the next lower dose level, 45 mg/m(2) toxicity was moderate, with only one of 12 patients experiencing severe diarrhea and grade 4 granulocytopenia with associated infection. Drug concentrations were consistent with a three-compartment open model. The total-body clearance suggests a linear dose-concentration relationship. RPR 109881A has a high clearance (mean, 42.6 L/h/m(2)), a large volume of distribution (mean, 952 L/m(2)), and a long terminal half-life (mean, 24 hours). There was no drug accumulation between days 1 and 8. One partial response was seen in a patient with renal cell carcinoma., Conclusion: The RD of RPR 109881A given as a 1-hour infusion on days 1 and 8 of a 21-day cycle is 45 mg/m(2). At this dose the drug is well tolerated and should be further studied.

Cationic amphipathic peptides, such as the defensins and cecropins, induce cell death in prokaryotic and eukaryotic cells by increasing membrane permeability. Increased permeability may lead to cell lysis or, alternatively, may produce subtle changes in the membrane's barrier function that promote cell death. The in vitro cytotoxic and lytic activity of short mammalian-derived extended-helical cationic peptides and insect-derived alpha-helical peptides was measured in this study with the objective of establishing the anticancer potential of these agents. Two specific aims were addressed: (i) to assess the activity of peptides against non-malignant cells (sheep erythrocytes and human umbilical vein endothelial cells) versus tumor cells; and (ii) to characterize the cytotoxic activity using multidrug-resistant tumor cell lines in the presence and absence of the anthracycline doxorubicin. Cell lysis assays demonstrated that the lytic activity of the peptides tested was 2->50 times more cytotoxic to tumor cells than to non-malignant cells. Further, the cytotoxic activity of these peptides was equivalent when tested against sensitive and multidrug-resistant cell lines. In addition to their inherent cytotoxic activity, these membrane-active peptides can also augment the in vitro cytotoxic activity of doxorubicin against multidrug-resistant tumor cells.

Several studies have been conducted to assess the safety and efficacy of paclitaxel plus radiation therapy in patients with non-small cell lung cancer (NSCLC) and to assess whether the radiosensitization demonstrated by paclitaxel in vivo can translate into clinical benefit. The National Cancer Institute of Canada Clinical Trials Group conducted a phase I/II trial in patients with inoperable stage IIIA or IIIB NSCLC to determine the maximum tolerated dose and efficacy of paclitaxel, given as a 3-hour infusion every 2 weeks during radical radiotherapy. The paclitaxel maximum tolerated dose using this schedule was 135 mg/m2; the recommended phase II dose was 120 mg/m2. The dose-limiting toxicity was grade 3 neutropenia, which prevented paclitaxel re-treatment. The overall response to all paclitaxel doses was 59% (n = 17); the overall response to the recommended phase II dose was 78% (n = 9). Median survival for all patients was 1.31 years; the 1-year survival rate was 64%. Lymphocytopenia was observed in all 17 patients; four patients had associated pneumonia or other febrile episodes during treatment. Grade 3 skin toxicity within the radiation field was reported in three patients receiving paclitaxel 120 mg/m2. This combination can be safely delivered to patients with NSCLC and has demonstrated activity in this setting. This combination has been used in Canada outside of clinical trials, and its use may be expanded as additional data from ongoing clinical trials further define the role of paclitaxel-based combined modality therapy in NSCLC.

Purpose: BMS-182248-1 (BR96-doxorubicin immunoconjugate) is a chimeric human/mouse monoclonal antibody linked to approximately eight doxorubicin molecules. The antibody is directed against the Lewis-Y antigen, which is expressed on 75% of all breast cancers but is limited in expression on normal tissues. Preclinical xenograft models demonstrated significant antitumor activity, including cures. A randomized phase II design was chosen to estimate the activity of the BR96-doxorubicin conjugate in metastatic breast cancer in a study population with confirmed sensitivity to single-agent doxorubicin., Patients and Methods: Patients with measurable metastatic breast cancer and immunohistochemical evidence of Lewis-Y expression on their tumor received either BR96-doxorubicin conjugate 700 mg/m2 IV over 24 hours or doxorubicin 60 mg/m2 every 3 weeks. Patients were stratified on the basis of prior doxorubicin exposure, visceral disease, and institution. Cross-over to the opposite treatment arm was allowed with progressive or persistently stable disease., Results: Twenty-three patients who had received a median of one prior chemotherapy regimen were assessable. There was one partial response (7%) in 14 patients receiving the BR96-doxorubicin conjugate and one complete response and three partial responses (44%) in nine assessable patients receiving doxorubicin. No patient experienced a clinically significant hypersensitivity reaction. The toxicities were significantly different between the two treatment groups, with the BR96-doxorubicin conjugate group having limited hematologic toxicity, whereas gastrointestinal toxicities, including marked serum amylase and lipase elevations, nausea, and vomiting with gastritis, were prominent., Conclusion: The BR96-doxorubicin immunoconjugate has limited clinical antitumor activity in metastatic breast cancer. The gastrointestinal toxicities likely represent binding of the agent to normal tissues expressing the target antigen and may have compromised the delivery of the immunoconjugate to the tumor sites.

Background: Single-agent bi-weekly paclitaxel was studied as first-line metastatic treatment for breast cancer in a phase I-II trial., Patients and Methods: Thirty-eight women with metastatic breast cancer were enrolled. Thirty-seven are evaluable for toxicity, 35 for response., Results: The MTD was defined at 160 mg/m2 q two weeks with dose limiting toxicity in two patients consisting of hematological toxicity (1) and neurotoxicity (2). Twenty patients were treated at 150 mg/m2, the recommended dose. Response rates were two CRs and nine PRs (overall 61%) at the RD of 150 mg/m2 and three CRs and 11 PRs for an overall RR of 67% for the two top doses., Conclusions: The good drug tolerance, response rates, and convenience over weekly treatment suggest this may be a worthwhile regimen.

We performed a Phase II trial to evaluate the activity and tolerability of docetaxel as a single agent in the treatment of advanced non-small cell lung cancer (NSCLC). Forty-four patients with metastatic and/or locally advanced NSCLC received i.v. docetaxel 100 mg/m2 every 3 weeks for a median of 4 (range 1-11) cycles. All patients received premedication with oral dexamethasone 8 mg twice daily for 5 days starting the day before chemotherapy. Seven partial responses were observed among 35 evaluable patients, and the overall response rate was 20% (95% CI 8-37). The median response duration was 5 months, median survival time was 10 months and the estimated 1-year survival rate was 42%. Treatment was generally well tolerated. Febrile neutropenia occurred in 10 patients (23%); neutropenic infection occurred in 4 patients, and led to 2 toxic deaths (both patients had borderline exclusion criteria). The corticosteroid premedication effectively reduced the overall incidence (34%) and severity (4% severe) of fluid retention, and delayed the median time to onset from cycle 4 to cycle 7. This study shows the promising efficacy of docetaxel as monotherapy in advanced NSCLC, and combination chemotherapy regimens incorporating docetaxel are now being evaluated in this clinical setting.

The pharmacokinetic behavior of vincristine sulfate (VINC) following administration of vincristine sulfate liposome injection (VSLI), 0.16 mg/ml, as an intravenous infusion over 60 min in 24 of 25 patients enrolled in a phase I clinical study of this drug is described. Plasma samples for determination of the pharmacokinetic behavior of VINC were collected during the infusion at 15, 30 and 60 min as well as at 2, 4, 8, 12, 48 and 72 h postinfusion. Total VINC concentration was determined using a validated high-performance liquid chromatographic (HPLC) assay. Patients receiving doses of 0.5 to 1.5 mg/m2 VSLI did not provide useful pharmacokinetic data at late time-points owing to the limit of quantitation of the HPLC assay (28.6 ng/ml). Sufficient concentration-time data were available for seven of the patients receiving doses of VSLI from 2.0 to 2.8 mg/m2 for compartmental modelling. A two-compartment open model (PCNONLIN Model 10) was the best fit for the observed VINC plasma data for these patients. The mean maximum observed concentration values were significantly greater for patients receiving VSLI at 2.8 mg/m2 (2260 +/- 212 ng/ml, n = 2) than for those receiving 2.0 mg/m2 and 2.4 mg/m2 (891 +/- 671 ng/ml, n = 6; 679 +/- 634 ng/ml, n = 6, respectively). No significant differences were observed in maximum concentration values between patients at 2.0 mg/m2 and those at 2.4 mg/m2. A trend towards higher parametric AUC (0 to infinity) values with increasing dose (on a milligram per meter squared basis) was observed but statistical significance was not reached. Comparison of the pharmacokinetic behavior of VSLI observed in this study with nonencapsulated VINC demonstrated that (1) the variability observed for VSLI pharmacokinetic parameters was similar to nonencapsulated VINC, (2) although variability in absolute concentration was observed between patients, the behavior of VSLI in individual patients followed a two- rather than a three-compartment open model, and (3) VINC plasma concentrations were significantly greater following administration of VSLI than described for nonencapsulated VINC. Overall, the results for patients treated with VSLI from 2.0 to 2.8 mg/m2 suggest that this formulation protects VINC from the early phase of rapid elimination seen with nonencapsulated drug, resulting in significantly elevated VINC plasma concentrations over extended periods of time.

Purpose: The Breast Cancer Site Group of the National Cancer Institute of Canada - Clinical Trials Group (NCIC-CTG) undertook two parallel phase I studies to determine the maximum tolerated dose (MTD) and recommended phase II dose of vinorelbine in combination with doxorubicin and fluorouracil (with or without folinic acid) in metastatic breast cancer., Methods: Cohorts of five patients were to receive: (a) fluorouracil 500 mg/m2 and doxorubicin 50 mg/m2 on day 1 only and escalating doses of vinorelbine (15, 20, 25, 30 mg/m2) on days 1, 8 and 15 every 3 weeks (FAN regimen), or (b) fluorouracil 340 mg/m2 and folinic acid 200 mg/m2 on days 1, 2, 3, 4 and 5, doxorubicin 40 mg/m2 on day 1 only and escalating doses of vinorelbine (15, 20, 25, 30 mg/m2) on day 1 and again on day 5 every 4 weeks (SUPERFAN regimen). Eligibility included measurable or evaluable metastatic breast cancer and having received neither previous chemotherapy for metastatic disease nor anthracycline-containing adjuvant therapy., Results: Of 26 and 12 patients enrolled in the FAN and SUPERFAN regimens, 26 and 12 were evaluable for toxicity and 21 and 9 for response, respectively. Median ages were 60.3 years (41-71 years) and 64.2 years (51-73 years). Both regimens required amendment after the first cohort with an original day- 15 vinorelbine dose omitted from the FAN regimen and more prolonged nadir granulocyte counts allowed. Myelosuppression was dose limiting. MTDs in the FAN and SUPERFAN regimens were vinorelbine 25 mg/m2 and 20 mg/m2. Other toxicities included mucositis, septicemia and febrile neutropenia. Peripheral neuropathy and constipation were mild. Of the 21 FAN patients evaluable for response, 3 (14%) had complete responses and 7 (33%) had partial responses, for an overall response rate of 48%; 9 (43%) had stable disease and 2 (9%) had progressive disease as their best response. Of the nine SUPERFAN patients evaluable for response, none had a complete response. There were two (22%) with partial responses, and six (67%) had stable disease and one (11%) had progressive disease as their best response., Conclusions: The SUPERFAN regimen was too toxic to pursue even at the lowest dose. The recommended phase II starting dose for the FAN regimen was vinorelbine 20 mg/m2. Although these were phase I studies response rates in evaluable patients were less than expected and toxicity did not allow the use of as much vinorelbine in the combinations as had been anticipated. The limited response data from our study would imply that combining vinorelbine with more toxic agents may not enhance response rates and may defeat the advantage of tolerability, especially in elderly patients.

The usual occurrence of Kaposi's sarcoma in otherwise healthy gay men in North America in the early 1980s was one of the first hints of the HIV epidemic. Kaposi's sarcoma remains a vexing problem. Existing treatments are not wholly satisfactory, but they can control the disease's unsightly appearance and the complications of visceral involvement.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered by a 3-hour infusion causes a rapid decline to and recovery from the hematologic white blood cell nadir. This suggests that biweekly administration of paclitaxel alone or in combination with drugs that have limited hematologic toxicity may be possible. The first study discussed in this report tried to determine the tolerability and activity of biweekly paclitaxel administered in combination with cisplatin in patients with metastatic breast cancer. Subsequently, after an impressive response rate, a second study of biweekly paclitaxel alone was initiated to attempt to discern which activity spectrum and which toxicities were due to paclitaxel and which were due to cisplatin. Patients with metastatic breast cancer who received up to one prior adjuvant chemotherapy regimen were eligible for both studies. Paclitaxel was administered intravenously by a 3-hour infusion followed by intravenous cisplatin biweekly in the ambulatory setting. In the second study, paclitaxel was administered alone. Twenty-nine patients have been entered in the combination study, of whom 27 had received prior adjuvant therapy and 23 had received prior anthracyclines. Dose-limiting toxicity for the phase I study of paclitaxel and cisplatin proved to be a failure to recover neutrophil counts greater than 750 cells/microL by day 14. The maximum tolerated dose was paclitaxel 90 mg/m2 and cisplatin 60 mg/m2 every 2 weeks. Nonhematologic toxicities were mild and included fatigue, arthralgias, and nausea and vomiting. At this time, the 27 patients evaluable for response have achieved an 85% response rate and an 11% complete response rate. Complete responses have been seen in soft tissue, lung, and nodal disease. All patients with complete responses have had previous anthracyclines. The biweekly paclitaxel-alone study is still accruing patients. The current paclitaxel dose level is 150 mg/m2. It is still too early to evaluate response; however, response rates appear to be less impressive than those seen with combined paclitaxel/cisplatin. The final results of these studies are pending.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered in a 3-hour infusion exhibits both a rapid decline to, and recovery from, the hematologic nadir. This suggests that a biweekly administration schedule of this agent either alone or in combination with agents that have limited hematologic toxicity may be possible. The objective of this study was to determine the tolerability and activity of biweekly administered paclitaxel in combination with cisplatin in patients with metastatic breast cancer. Patients with metastatic breast cancer who may have received up to one prior chemotherapy regimen in the adjuvant setting were eligible. Paclitaxel was administered intravenously by a 3-hour infusion followed by intravenous cisplatin every 2 weeks in the ambulatory setting. Twenty-nine patients have been entered in the study, of whom 27 had received prior adjuvant chemotherapy. Dose-limiting toxicity for the phase I study proved to be failure to recover the neutrophil count to more than 750 cells/microL by day 15; the maximum tolerated dose was therefore paclitaxel 90 mg/m2 and cisplatin 60 mg/m2 every 2 weeks. Nonhematologic toxicities were mild and included fatigue, arthralgias, peripheral neuropathy, and nausea and vomiting. At the present analysis, 234 cycles of treatment have been given. Among 27 patients evaluable for response (four of whom are still receiving therapy), three have had complete remissions and 18 partial responses, for an interim overall response rate of 78%. In summary, weekly paclitaxel and cisplatin is a safe and active combination in the treatment of metastatic breast cancer. Final determination of toxicity and activity will be published at the conclusion of this study.

An ongoing phase I/II trial in patients with chemotherapy-naive metastatic breast cancer (one adjuvant chemotherapy regimen is allowed) uses a 3-hour infusion of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 90 mg/m2 followed by a 3-hour infusion of cisplatin 60 mg/m2 every 2 weeks given with standard premedications. The protocol called for the escalation of paclitaxel in 10 mg/m2 increments to as much as 130 mg/m2 combined with a fixed 60 mg/m2 cisplatin dose without granulocyte colony-stimulating support in the phase I portion of the trial, but dose-limiting neutropenia identified the initial 90 mg/m2 paclitaxel dose as the maximum tolerated in this biweekly schedule. The phase II portion is continuing to accrue patients and results are preliminary. Twenty-two patients have been enrolled thus far. Of the 16 evaluable for response, four (25%) have had a complete and II (69%) a partial response, for an overall response rate of 94%. Eighteen patients are evaluable for toxicity. Significant neutropenia has been dose limiting, but the mean duration of the absolute neutrophil nadir (< 0.5 x 10(9)/L) is only 2 days. Nonhematologic toxicity has been generally mild, with no grade 4 and few grade 3 toxicities occurring. Nausea, most likely attributable to cisplatin, has occurred frequently, as have mild hypersensitivity reactions. Other nonhematologic toxicity (arthralgias, fatigue, neurologic symptoms) also has been mild.

We describe here investigations into the ability of a tiapamil derivative, Ro44-5912 to overcome multidrug resistance (MDR) in doxorubicin (ADR)-resistant murine leukemic P388 cells. This compound has the formula: C27H39NO4S2.1:2C6H8O6, a M. W. of 858 and is structurally similar to verapamil, an established inhibitor of P-glycoprotein (PGP). We have compared the MDR modulating properties of Ro44-5912 with verapamil in P388ADR cells. Doxorubicin concentration required to achieve 50% inhibition of growth (IC50) for P388ADR cells was found to be 24 microM. In contrast, treatment of P388ADR cells with Doxorubicin and 3 microM verapamil decreased the IC50 value to 2.5 microM. A further decrease was observed with 3 microM Ro44-5912 treatment, where an IC50 value of 1.1 microM was obtained. Doxorubicin accumulation was also determined by flow cytometry in order to determine whether the increased levels of chemosensitivity observed for Ro44-5912 were reflected by increased cellular drug uptake. The results revealed that Ro44-5912, at equivalent concentration, increased doxorubicin accumulation in P388ADR cells beyond that obtained with verapamil whereas no effects were seen with the parental P388 cells. The effect of Ro44-5912 on the binding of C219 monoclonal antibody to PGP in MDR cells was also studied and found not to decrease C219 expression on P388ADR cells.

Two trials are being conducted to evaluate paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with cisplatin in previously treated and untreated breast and ovarian cancer. Preliminary results are presented. The objectives of these nonrandomized trials are (1) to determine the toxicity of paclitaxel/cisplatin in a biweekly schedule, (2) to establish the maximum tolerated dose of paclitaxel in combination with a fixed dose of cisplatin (60 mg/m2), (3) to determine the feasibility of repeated biweekly administrations, and (4) to evaluate the efficacy of the combination in these diseases. In the breast cancer study, 22 patients have been enrolled to date and eight patients have completed treatment. Dose-limiting neutropenia, which occurred with the starting dose of paclitaxel (90 mg/m2) followed by 60 mg/m2 cisplatin, has precluded any attempts to escalate the paclitaxel dose. Overall, the regimen has been well tolerated at the doses just described. There has been little grade III and no grade IV nonhematologic toxicity. Among 16 patients currently evaluable for response, four had a complete response and II had a partial response, for an overall response rate of 94%. In the ovarian cancer study, 14 patients have been enrolled thus far. Paclitaxel/cisplatin appears to be well tolerated, although it is still too early to assess response rates or to define the MTD. Patients continue to be accrued in both trials.

Quality of life was assessed by self-report questionnaires in 30 patients receiving dose-intensive chemotherapy for either non-small-cell lung cancer (20 patients) or recurrent head and neck cancer (10 patients). Megestrol acetate was given daily to try to improve appetite and prevent the weight loss usually associated with this chemotherapy. Appetite did not change significantly overall during the first 4 weeks of chemotherapy, but it did improve in those patients still receiving chemotherapy at 8 weeks. Changes in global quality of life were significantly correlated with changes in appetite, fatigue, energy level, and physical function. Thus, these parameters may have more relevance to patients' perceptions of quality of life than does weight change, and should be used more frequently as endpoints in studies of supportive care and palliative treatment of patients with cancer.

Background and Methods: We examined the effect of adjuvant systemic therapy on survival after breast cancer among the residents of the Canadian province of British Columbia. Data on survival were collected for all women in whom breast cancer was diagnosed in British Columbia during each of three calendar years chosen to represent different province-wide treatment recommendations: 1974, when no adjuvant systemic therapy was recommended; 1980, when adjuvant chemotherapy was recommended only for premenopausal women with node-positive disease; and 1984, when adjuvant chemotherapy was also recommended for premenopausal women with node-negative disease and lymphatic, vascular, or neural invasion and tamoxifen was recommended for postmenopausal women with involved lymph nodes or lymphatic, vascular, or neural invasion unless their tumors were negative for estrogen receptors., Results: For women less than 50 years of age, disease-specific survival at seven years (i.e., with censoring of data on women who died from causes other than breast cancer) improved from 65.2 to 76.3 percent between 1974 and 1984 (P = 0.008), and overall survival improved from 64.8 to 74.6 percent (P = 0.02). For women from 50 through 89 years of age, disease-specific survival at seven years improved from 62.5 to 70.4 percent between 1980 and 1984 (P = 0.001), and overall survival improved from 53.9 to 58.3 percent (P = 0.05). The timing of the improvements in survival correlated with the introduction of adjuvant systemic therapy in each group., Conclusions: Survival among women with breast cancer improved significantly in a geographically defined population during the period when adjuvant systemic therapy became widely used.

Megestrol acetate was given daily to lung cancer patients undergoing therapy with CODE and to recurrent head and neck cancer patients receiving DEB/M in an attempt to prevent weight loss. The outcomes in this study were compared with the same outcomes in similar groups of patients treated with the same chemotherapy regimens, but in which prednisone was used as the main supportive drug along with co-trimoxazole, ketoconazole, and either cimetidine or sucralfate. Weight loss was less pronounced in the current patients than in the previous ones. Nevertheless, there were several factors that led us to conclude that megestrol is not an adequate substitute for prednisone in patients receiving this kind of chemotherapy.

Purpose: To establish the optimum biologic dose and maximal-tolerated dose (MTD) of once-daily, subcutaneous recombinant human granulocyte-macrophage colony-stimulating factor derived from yeast (RhuGM-CSF) in patients with breast cancer., Patients and Methods: Seventeen patients with either newly diagnosed breast cancer with more than four involved axillary nodes (five patients) or metastatic breast cancer (12 patients) were treated with cyclophosphamide 1 g/m2, doxorubicin 50 mg/m2, and fluorouracil 500 mg/m2 (CAF) intravenously (IV) once every 3 weeks. RhuGM-CSF was administered subcutaneously once daily for 14 days after the second and third CAF cycles, at one of three dose levels., Results: The 125-micrograms/m2/d RhuGM-CSF dose level shortened the duration of neutropenia in only one of three patients. The 250-micrograms/m2/d level was effective in shortening the duration of the neutropenic nadir (< .5 x 10(9)/dL) by 2 or more days in five of six patients. The 500-micrograms/m2/d level caused severe toxicity (chest pain, two patients; deep vein thrombosis, one patient) in three of eight patients., Conclusion: RhuGM-CSF administered once daily at the 250-micrograms/m2/d level is well tolerated and effective in shortening the duration of the neutrophil nadir by 2 or more days after CAF therapy.

A sensitive and specific quantitative assay for total doxorubicin concentrations in plasma containing liposome-encapsulated doxorubicin hydrochloride (TLC D-99) was developed, with solvent extraction and reversed-phase high-performance liquid chromatography (HPLC). Separation of doxorubicin from its metabolites was accomplished with a 15 cm x 3.9 mm i.d., microBondapak phenyl analytical HPLC column. Optimum chromatographic conditions, obtained with a mobile phase gradient from 85 to 50% (v/v) 16 mM ammonium formate buffer in tetrahydrofuran at a flow rate of 2 mL/min, gave a detection limit of 0.3 pmol/injection. Eleven-point standard curves with from 0.00595 to 29.8 microM TLC D-99 and 0.1 microM internal standard in plasma were analyzed on three separate occasions to formally validate this assay. An overall correlation coefficient of 0.9985 was found for the logarithmic transformed data. The pharmacokinetic characteristics of doxorubicin were investigated after administration of TLC D-99 to 12 non-small-cell lung cancer patients as an intravenous infusion at doses of 60 and 75 mg/m2. The data are best described by a three-compartment model with alpha, beta, and gamma elimination half-lives of 0.0721, 2.84, and 25.2 h for the 60-mg/m2 group and 0.103, 2.56, and 14.9 h for the 75-mg/m2 patients. A mean plasma clearance of 9.89 L/h (range: 1.95 to 23.4 L/h) was found for the 60-mg/m2 patients, with that from the 75-mg/m2 group being within these values. Mean area under the plasma concentration versus time curve estimates of 37.1 and 47.9 microM/h were observed for the patients receiving 60 and 75 mg/m2, respectively. The plasma concentration-time course for total doxorubicin following administration of TLC D-99 suggests that the disposition of the liposomal formulation is determined more by the pharmacokinetics of the liposome than the encapsulated drug.

The belief that HIV-1 infection causes AIDs has been questioned, and the suggestion made that to know the correct cause of AIDS the incidence of disease in patients with and without risk behaviours and with and without antibody to HIV-1 must be known. We describe findings in such a cohort. In 715 homosexual men followed for a median of 8.6 years, all 136 AIDS cases occurred in the 365 individuals with pre-existing HIV-1 antibody. Most men negative for HIV-1 antibody reported risk behaviours but none developed any AIDS illnesses. CD4 counts fell in anti-HIV-1-positive men but remained stable in antibody-negative men, whether or not risk behaviours were present. The hypothesis that AIDS in homosexual men is caused not by HIV-1 infection but by drugs and sexual activity is rejected by these data. HIV-1 has an integral role in the pathogenesis of AIDS.

Seventy-four HIV-infected homosexual males belonging to CDC groups IIB, III, and IVC2 were treated with increasing doses of zidovudine within the Multicentre Canadian AZT Trial. Following a 3 week observation period, consenting volunteers received 600 mg/day for 18 weeks, 900 mg/day for 9 weeks, and 1,200 mg/day for 9 weeks. This was followed by a 6 week washout period after which zidovudine was restarted at 1,200 mg/day for 18 weeks. Patients were followed for a total of 63 weeks. Every 3 weeks they underwent a full clinical and laboratory assessment. For the purpose of this analysis, subjects were divided according to the mean initial platelet value (greater than or equal to 150,000 or less than 150,000/L) into normals (n = 57) and thrombocytopenics (n = 12), respectively. Analysis of variance was used to compare the mean platelet values at each zidovudine dose. All comparisons were made against baseline values. Zidovudine increased platelet counts in normal and thrombocytopenic subjects. The magnitude of this effect varied depending on the baseline platelet count. Among normals, the platelet count increased from 241,000 +/- 45,000/L at baseline to 261,000 +/- 51,000/L (p less than 0.01). while receiving 600 mg/day of zidovudine. This effect was self-limited, reaching a peak by week 3. The platelet count decreased to baseline values despite increasing the dose of zidovudine to 900 or 1,200 mg/day. The platelet count further decreased to 218,000 +/- 43,000/L during the washout phase (washout vs. 1,200 mg, p less than 0.01).2+ not found to be dose related. The platelet count decreased to 101,000 +/- 34,000/L during the washout phase (washout vs. 1,200 mg/day, p less than 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

We determined whether drug-resistant variants of HIV-1 could be isolated from the peripheral blood mononuclear cells of 20 individuals with HIV infection (Centers for Disease Control groups II and III) on long-term zidovudine (AZT) therapy. Toward this end, zidovudine (10 microM) has been included in the tissue culture medium used to isolate HIV-1. Under these circumstances, virus with a zidovudine-resistant phenotype was successfully obtained in five out of 20 cases. This property of drug resistance appeared to be stable, and did not disappear upon extended replication of such virus in the absence of drug pressure. Drug-resistant virus could also be isolated from these subjects on subsequent occasions, but was not present in samples obtained prior to therapy. Replication of these zidovudine-resistant isolates in tissue culture was inhibited by each of four other nucleoside analogues. Thus, other drugs may be useful in controlling selective zidovudine-resistant variants of HIV-1.

To characterize the nature, time course and dose dependency of zidovudine-related side effects, we undertook a multicenter, prospective, dose-range finding study. Our study group consisted of 74 HIV-positive homosexual men belonging to groups II B, III and IV C2 from the Centers for Disease Control (CDC) classification of HIV disease. Following a 3-week observation period, volunteers were treated with zidovudine 600 mg/day for 18 weeks, 900 mg/day for 9 weeks and 1200 mg/day for 9 weeks, followed by a washout period of 6 weeks after which they were re-started on 1200 mg/day or the highest tolerated dose at 8-hourly intervals. Subjects were randomly assigned to 4-hourly or 8-hourly regimens within CDC groups while taking 600 and 1200 mg/day. Clinical and laboratory evaluations were performed at 3-week intervals. Symptomatic adverse effects were present in 96% of subjects, most commonly nausea (64%), fatigue (55%) and headache (49%). These were generally self-limited, reappearing briefly at each dose increment. A decrease in hemoglobin occurred shortly after initiation of therapy. This was not dose dependent and reversed rapidly upon discontinuation of treatment. A red blood cell count decrease, a mean cell volume increase and a granulocyte count decrease developed early in a dose-independent fashion, reverting at least partially during the washout phase. The decrease in reticulocyte count was dose related between 600 and 900 mg/day with no further change when the dose was escalated to 1200 mg/day. Bone marrow changes occurred rapidly as demonstrated by megaloblastosis in 95% of 65 specimens at week 18.(ABSTRACT TRUNCATED AT 250 WORDS)