Daniel R. Budman

c-erbB-2 Expression and Response to Adjuvant Therapy in Women with Node-Positive Early Breast Cancer

BACKGROUND The role of molecular markers in predicting the response to treatment of breast cancer is poorly defined. The Cancer and Leukemia Group B (CALGB) conducted a randomized adjuvant-chemotherapy trial (CALGB 8541) comparing three doses (high, moderate, and low) of cyclophosphamide, doxorubicin, and fluorouracil in 1572 women with node-positive breast cancer. This study (CALGB 8869) was designed to determine whether the DNA index, the S-phase fraction, c-erbB-2 expression, or p53 accumulation could be used as a marker to identify a subgroup of patients more likely than others to benefit from high doses of chemotherapy. METHODS Tissue blocks were obtained from 442 patients randomly selected from the larger CALGB trial. Paraffin sections from the primary lesions were analyzed for DNA content, S-phase fraction, c-erbB-2 expression, and p53 accumulation. RESULTS Patients randomly assigned to the high-dose regimen of adjuvant chemotherapy had significantly longer disease-free and overall survival if their tumors had c-erbB-2 overexpression. No further information was gained by adding the data on S-phase fraction or p53 accumulation to the analysis. There was no clear evidence of a dose-response effect in patients with minimal or no c-erbB-2 expression. CONCLUSIONS There is a significant dose-response effect of adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil in patients with overexpression of c-erbB-2 but not in patients with no c-erbB-2 expression or minimal c-erbB-2 expression. Overexpression of c-erbB-2 may be a useful marker to identify the patients who are most likely to benefit from high doses of adjuvant chemotherapy.

Dose and Dose Intensity of Adjuvant Chemotherapy for Stage II, Node-Positive Breast Carcinoma

BACKGROUND Adjuvant chemotherapy is widely used for breast cancer and is known to extend survival. Some clinicians seek a greater survival benefit by increasing the intensity of the dose, whereas others lower it to diminish toxicity. METHODS The Cancer and Leukemia Group B (CALGB) conducted a randomized trial of different levels of doses and dose intensity (dose per unit of time) of adjuvant chemotherapy in 1572 women with node-positive, stage II breast cancer who were assigned to three treatment groups. One group received 400 mg of cyclophosphamide per square meter of body-surface area and 40 mg of doxorubicin per square meter once every 28 days and 400 mg of fluorouracil per square meter twice every 28 days, for six cycles. Another group received 50 percent higher doses of the three drugs (600 mg, 60 mg, and 600 mg, respectively) but for only four cycles, so that the total dose was identical in these two groups but the dose intensity was higher in the first. The third group of women received half the total dose used in the other two groups and at half the dose intensity used in the second group. RESULTS After a median of 3.4 years of follow-up, the women treated with a high or moderate dose intensity had significantly longer disease-free survival (P < 0.001) and overall survival (P = 0.004) than those treated with a low dose intensity, in three-way log-rank comparisons. However, the difference in survival between the two groups treated with a moderate or high dose intensity was not significant. These results are consistent with either a dose-response effect or a threshold level of the dose or dose intensity. CONCLUSIONS The doses of chemotherapy used to treat breast cancer, especially early breast cancer, should not be reduced if the maximal benefit is to be achieved.

The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review.

Purpose: Microtubules are important cytoskeletal components involved in many cellular events. Antimicrotubule agents including polymerizing agents (paclitaxel and docetaxel) and depolymerizing drugs (vincristine, vinorelbine, and estramustine phosphate) are widely used either alone or in combination with other anticancer drugs. These antimicrotubule agents are promoters of apoptosis in cancer cells. In this review, we discuss the role of bcl-2 family genes in the regulation of apoptosis, and summarize effects of microtubule targeting agents on apoptotic signal transduction pathways. Conclusion: Disruption of microtubule structure by antimicrotubule drugs results in induction of tumor suppressor gene p53 and inhibitor of cyclin-dependent kinases, p21WAF1/CIP1 (p21), and activation/inactivation of several protein kinases including Ras/Raf, PKC/PKA I/II, MAP kinases, and p34cdc2. These protein kinases are associated directly or indirectly with phosphorylation of bcl-2. Phosphorylation of bcl-2 and the elevations of p53 and p21 lead to apoptosis. New pathways of antitumor agents could be directed at this p53, p21 and bcl-2/bax function, and may enhance the effect of existing agents.

Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine.

PURPOSE To evaluate the toxicology and pharmacology of an orally active fluoropyrimidine given as a continuous daily dose divided into two portions for 6 weeks, and to determine the maximal-tolerated daily dose (MTD) and the suggested phase II daily dose. PATIENTS AND METHODS Solid-tumor patients with a Karnofsky performance status greater than 70 who had normal organ function and resolution of the effects of prior therapy, and who gave informed written consent, were enrolled. Oral capecitabine, as a divided morning and evening dose, was administered to cohorts of a minimum of 3 patients starting at 110 mg/m2 and escalating by means of a modified Fibonacci scheme to 1,657 mg/m2/d. Pharmacologic samples were obtained on days 1 and 15. Toxicity evaluations were performed approximately every 3 days for the first 43 days. Antitumor effect was evaluated at day 42 of therapy. RESULTS Thirty-three patients entered the study. Few side effects occurred at or below 1,331 mg/m2/d. The MTD was 1,657 mg/m2/d with limiting toxicities of palmar-plantar erythrodysesthesia, nausea, vomiting, vertigo, abdominal pain, diarrhea, and thrombocytopenia. All toxicities were reversible. A mixed response was seen in one breast cancer patient. Pharmacologic studies showed rapid and extensive metabolism of the parent drug into cytotoxic metabolites with a maximum plasma concentration (Cmax) 1 hour after ingestion. Linear increases in the area under the concentration-time curve (AUC) and Cmax were seen with linear increases in administered dose. CONCLUSION The suggested phase II dose on a continuous 42-day dosing schedule is 1,331 mg/m2/d. Linear pharmacologic parameters of the parent compound and metabolites are demonstrated.

Review: Tubulin Function, Action of Antitubulin Drugs, and New Drug Development

Anticancer agents that interfere with microtubulin function are in widespread use in man and have a broad spectrum of activity against both hematological malignancies and solid tumors. The mechanisms of actions of these agents have been better defined during the past decade, indicating that there are distinct binding sites for these agents and that they interfere with microtubulin dynamics (growth and shortening of tubules) at low concentrations and only evoke microtubulin aggregation or dissociation at high concentrations. Tubulin has been recently described in the nucleus of cells and in mitochondria. Downstream events from tubulin binding are believed to be critical events for the generation of apoptosis in the malignant cell. The effects of vinca alkaloids and taxanes are distinct, suggesting that the interference with the tubulin cap by high-affinity binding of effective agents is not the only mechanism of cytotoxic effect, and the low-affinity binding of drug, which distorts microtubulin function, may also be important. The epothilones share some of the binding characteristics of the taxanes and are in clinical trials because of cytoxic activity in taxane resistant cells. Tubulin has additional target sites for anticancer drugs including interference with the binding and function of microtubule associated proteins and interference with motor proteins which are essential for the transport of substances within the cell. Because many of these microtubule associated proteins have an ATP binding site, both computer-aided design and combinatorial chemistry techniques can be used to make agents to interfere with their function analogous to imatinib mesylate (Gleevec™). Agents that interfere with the motor protein kinesin are entering clinical trials.

International Society of Geriatric Oncology Chemotherapy Taskforce: Evaluation of Chemotherapy in Older Patients—An Analysis of the Medical Literature

The elderly comprise the majority of patients with cancer and are the recipients of the greatest amount of chemotherapy. Unfortunately, there is a lack of data to make evidence-based decisions with regard to chemotherapy. This is due to the minimal participation of older patients in clinical trials and that trials have not systematically evaluated chemotherapy. This article reviews the available information with regard to chemotherapy and aging provided by a task force of the International Society of Geriatric Oncology (SIOG). Due to the lack of prospective data, the conclusions and recommendations made are a consensus of the participants. Extrapolation of data from younger to older patients is necessary, particularly to those patients older than 80 years, for which data is almost entirely lacking. The classes of drugs reviewed include alkylators, antimetabolites, anthracyclines, taxanes, camptothecins, and epipodophyllotoxins. Clinical trials need to incorporate an analysis of chemotherapy in terms of the pharmacokinetic and pharmacodynamic effects of aging. In addition, data already accumulated need to be reanalyzed by age to aid in the management of the older cancer patient.

Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer.

PURPOSE This prospective multicenter randomized trial was performed to compare the effectiveness and safety of intravenous (i.v.) vinorelbine tartrate (Navelbine [NVB]; Burroughs Wellcome Co, Research Triangle Park, NC) with i.v. melphalan (Alkeran [ALK]; Burroughs Wellcome Co) in a heavily pretreated population of patients with anthracycline-refractory advanced breast cancer (ABC). Efficacy end points included time to disease progression (TDP), time to treatment failure (TTF), survival, tumor response rates, and quality of life (QL) and relief of cancer-related symptoms. PATIENTS AND METHODS Between August 24, 1990, and December 1, 1992, 183 patients were randomized (2:1) to treatment with NVB (30 mg/m2 weekly) or ALK (25 mg/m2 every 4 weeks) i.v. Patients were stratified by measurable or nonmeasurable-assessable disease and by treatment center. RESULTS Time to disease progression was significantly longer with NVB than with ALK, with a median 12 weeks versus 8 weeks, respectively (P < .001). NVB patients also had significantly longer time to treatment failure than ALK patients, with a median 12 weeks versus 8 weeks, respectively (P < .001). The effect of NVB on survival was also statistically significant (P = .034): 1-year survival rates were 35.7% with NVB and 21.7% with ALK and the median survival rate was 35 weeks and 31 weeks, respectively. In total, 46.5% of NVB patients and 28.2% of ALK patients achieved an objective response or stabilization of disease (P = .06). No intergroup differences were noted in patient-assessed QL and cancer-related symptoms. The most common toxicities were hematologic, including granulocytopenia with NVB and thrombocytopenia and granulocytopenia with ALK. Both drugs were generally well tolerated, and no septic deaths were reported. CONCLUSION This randomized trial demonstrates a survival benefit in anthracycline-refractory ABC. NVB was well tolerated and demonstrated activity superior to ALK in anthracycline-refractory ABC, without compromising QL. Based on activity of single-agent NVB in this difficult-to-treat patient population, investigations of NVB in combination with other anticancer drugs are warranted.

Toxicity of Older and Younger Patients Treated With Adjuvant Chemotherapy for Node-Positive Breast Cancer: The Cancer and Leukemia Group B Experience

PURPOSE Older node-positive patients treated with newer adjuvant chemotherapy regimens have improvements in relapse-free and overall survival similar to younger patients. We compared toxicity of older and younger patients in three randomized trials of adjuvant chemotherapy. PATIENTS AND METHODS Toxicity data were available for 93% of 6,642 patients enrolled. The three trials included: Cancer and Leukemia Group B (CALGB) 8541, a comparison of cyclophosphamide, doxorubicin, and fluorouracil in three dose schedules; CALGB 9344: cyclophosphamide and doxorubicin with or without paclitaxel; and CALGB 9741: cyclophosphamide, doxorubicin, and paclitaxel every 2 versus every 3 weeks. National Cancer Institute grade 3 to 5 toxicities were compared among age groups. RESULTS Seven percent of patients (n = 458) were age 65 or older, 3% were 70 or older, 38% were 51 to 64, and 55% were 50 or younger. Twenty-four deaths (0.4%) were attributed to treatment; seven (1.5%) of 486 in patients 65 or older, 10 (0.40%) of 2,480 in patients who were 51 to 64 years, and seven (0.19%) of 3,676 occurred in patients younger than 50. In multivariate analysis, older patients were significantly more likely to have grade 4 hematologic toxicity, to have discontinued treatment for toxicity, or to have died of acute myeloid leukemia/myelodysplastic syndrome. There were no significant differences in grade 3 to 4 nonhematologic toxicity. CONCLUSION Healthy older patients who met the strict eligibility criteria for these trials had a higher rate of hematologic toxicity and treatment-related deaths than younger patients, but no increase in nonhematologic toxicity. Elderly patients treated with newer adjuvant chemotherapy regimens derive the same benefits from newer chemotherapy regimens as younger patients but should be cautioned about the increased risk of toxicity and treatment-related death.

Phase I trial of the combination of daily estramustine phosphate and intermittent docetaxel in patients with metastatic hormone refractory prostate carcinoma

BACKGROUND To apply our preclinical findings of cytotoxic synergy with the combination of estramustine phosphate (EP) and docetaxel as the basis of treatment of hormone refractory metastatic prostate cancer in man. To determine the optimal dosage and the toxicities of these two agents for future trials. PATIENTS AND METHODS Seventeen patients with hormone refractory metastatic prostate cancer who were ambulatory with performance status < or = 2, normal marrow, renal and hepatic function were entered. Prior exposure to EP or a taxane were exclusion factors. EP was given orally at a dose of 14 mg/kg of body weight daily with concurrent docetaxel administered every 21 days as an intravenous infusion over 1 hour with dexamethasone 8 mg. PO BID for five days. EP dosages were kept static; docetaxel dosages were explored in a minimum of three patients per level for dosages of 40, 60, 70, and 80 mg/m2. Patients were evaluated weekly. Prostate specific antigen (PSA) was measured every three weeks. RESULTS Five patients were entered at a docetaxel dose of 40 mg/m2, three at 60 mg/m2, six at 70 mg/m2, and three at 80 mg/m2. Only one patient had received prior chemotherapy. Grades 1 or 2 hypocalcemia and hypophosphatemia were seen at all dosage levels. Other grade 2 or less toxicities not related to dosage included alopecia, anorexia, stomatitis, diarrhea, and epigastric pain. Dose limiting toxicities (DLT) as grade 4 leukopenia and grade 4 fatigue were seen at 80 mg/m2. The phase II dose was defined at 70 mg/m2 with rapidly reversible leukopenia and minor liver function abnormalities. At this dosing level, dose intensity was 88% and 86% over consecutive cycles for docetaxel and EP, respectively. Two vascular events occurred at this dose level (70 mg/m2): one arterial and the other venous. PSA decreases greater than 50% from baseline were seen in 14 of 17 patients at all dosage levels. Four of the 17 patients demonstrated a complete biochemical response (PSA < or = 4 ng/ml). One patient had a partial response with measurable lung and liver lesions. CONCLUSION EP given continuously with every three-week docetaxel at a dose of 70 mg/m2 is tolerable with evidence of antitumor activity based upon significant declines in PSA in the majority of patients and improvement of lung metastasis in one patient. Larger phase II studies of this combination in a homogenous population are warranted.

Phase I and Pharmacokinetic Trial of Gemcitabine in Patients With Hepatic or Renal Dysfunction: Cancer and Leukemia Group B 9565

PURPOSE To ascertain if hepatic or renal dysfunction leads to increased toxicity at a given dose of gemcitabine and to characterize the pharmacokinetics of gemcitabine and its major metabolite in patients with such dysfunction. PATIENTS AND METHODS Adults with tumors appropriate for gemcitabine therapy and who had abnormal liver or renal function tests were eligible. Patients were assigned to one of three treatment cohorts: I-AST level less than or equal to two times normal and bilirubin level less than 1.6 mg/dL; II-bilirubin level 1.6 to 7.0 mg/dL; and III-creatinine level 1.6 to 5.0 mg/dL with normal liver function. Doses were explored in at least three patients within each cohort. Gemcitabine and its metabolite were to be measured in the blood in all patients. RESULTS Forty patients were assessable for toxicity. Transient transaminase elevations were observed in many patients but were not dose limiting. Patients with AST elevations tolerated gemcitabine without increased toxicity, but patients with elevated bilirubin levels had significant deterioration in liver function after gemcitabine therapy. Patients with elevated creatinine levels had significant toxicity even at reduced doses of gemcitabine, including two instances of severe skin toxicity. There were no apparent pharmacokinetic differences among the three groups or compared with historical controls. CONCLUSION If gemcitabine is used for patients with elevations in AST level, no dose reduction is necessary. Patients with elevated bilirubin levels have an increased risk of hepatic toxicity, and a dose reduction is recommended. Patients with elevated creatinine levels seem to have increased sensitivity to gemcitabine, but the data are not adequate to support a specific dosing recommendation.