Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B.

PURPOSE: To investigate the combination of docetaxel, estramustine (EM), and low-dose hydrocortisone in men with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Combinations of EM with other antimitotic agents such as docetaxel are synergistic in vitro and show significant clinical activity in patients with HRPC. We studied intravenous administration of docetaxel 70 mg/m(2), oral estramustine, and low-dose daily hydrocortisone in men with HRPC who demonstrated progression after initial hormone therapy. RESULTS: Of the 47 men enrolled onto this multicenter cooperative group study, 46 were assessable for response and/or toxicity. In the 24 patients with measurable disease, there were three complete and nine partial responses for a measurable disease response rate of 50% (12 of 24 patients; 95% confidence interval [CI], 27% to 73%). In the 44 patients in whom pretreatment prostate-specific antigen (PSA) was elevated, 30 (68%) had a 50% or greater decrease, and 25 (57%) had a 75% or greater decrease in PSA. The combined measurable disease and biochemical response rate in all 46 assessable patients was 54% (three complete responses, 22 partial responses, 95% CI, 37% to 71%). The predominant toxicity was neutropenia, with 26% of patients having grade 3 and 30% having grade 4 granulocytopenia; there were no episodes of febrile neutropenia. Other common but mild adverse effects included malaise/fatigue, peripheral edema, and hyperglycemia. The incidence of thromboembolic events during therapy was 9%. With a median follow-up of 17 months, the median survival was 20 months. The median time to disease progression was 8 months for all patients, and 10 months for those with measurable disease. CONCLUSION: This therapy is efficacious and moderately well tolerated in HRPC and should be compared in a phase III trial with mitoxantrone and prednisone.

Preoperative chemoradiation coupled with aggressive resection as needed ensures near total control in advanced head and neck cancer.

BACKGROUND: Preoperative chemotherapy or chemoradiation protocols are generally associated with high clinical response rates, but limited pathologic responses for large primary tumors. We have initiated a prospective phase II study of weekly paclitaxel 60 mg/M2, and carboplatin (AUC of 1) plus concurrent fractionated external beam radiation (45 Gy) followed by organ-preserving (or function restorative) surgery when applicable to maximize local-regional tumor control. PATIENTS AND METHODS: Operable patients staged by triple endoscopy received a percutaneous endoscopic gastrostomy and vigorous dental and nutritional support during therapy. Weekly paclitaxel 60 mg/M2, carboplatin (AUC of 1), and radiation 45 Gy were given with rebiopsy of the primary site at 5 weeks. Patients with positive biopsy had definitive surgery in 4 to 5 weeks. Patients with negative biopsy-results received 3 additional weeks of radiation, to a total dose of 72 Gy plus carboplatin and paclitaxel. RESULTS: The 35 patients were 29 men and 6 women, aged 40 to 71 years, with stage III (12) or stage IV (23) cancer. The site of the cancer was oral cavity, 10; base of tongue, 3; oropharynx, 3; hypopharynx, 4; larynx, 12 (glottic, 6; supraglottic, 6), unknown primary, 2; other, nasal cavity, 1. Of 34 evaluable patients, 16 (47%) had a complete clinical response (CR) and 18 (53%) had a partial response (PR); total clinical response rate was 100%. A pathologic CR at the primary site occurred in 23 of 34 patients (68%; 2 had an unknown primary) who went on to completion radiation at 67 to 72 Gy. After induction chemoradiation 21 patients with N1-3 nodes had neck dissection; 6 (31%) had positive nodes. Twelve patients had residual cancer at the primary site at time of rebiopsy: mandible, 4; maxilla, 1; base of tongue, 2; larynx, 4; floor of mouth, 1; and nasal cavity, 1. All were resected with function-preserving reconstruction. At median follow-up of >12 months, progression-free and overall survivals were 71% and 83%, respectively. CONCLUSION: Preoperative treatment with paclitaxel, carboplatin, and radiation is associated with high CR at the primary site and a high level of organ preservation or functional restoration if ablation is done.

Prostate-specific antigen response to withdrawal of megestrol acetate in a patient with hormone-refractory prostate cancer.

Clinically significant responses after withdrawal of flutamide in patients with hormone-refractory prostate cancer (HRPC) are well documented. Failure to recognize this syndrome of response results in potential morbidity due to salvage therapy, confusion in interpretation of disease state, and introduction of a possible source of error in clinical trials. In this case report, we describe a patient with HRPC whose prostate-specific antigen levels decreased substantially in response to withdrawal of megestrol acetate. Such a response should be considered when megestrol acetate is used in the treatment of HRPC.

Contemporary adjuvant treatment of breast cancer.

Adjuvant therapy with either chemotherapy or hormonal therapy offers statistically significant benefits for most subsets of women with breast cancer that in many cases outweigh the risks of treatment, but the potential benefit will vary from patient to patient and by modality of therapy. The absolute reduction in risk is proportional to the overall risk of relapse or death, so greater absolute benefit can be anticipated for those with a greater risk. Consensus recommendations provide a reasonable outline for initiating the discussion of adjuvant therapy, but treatment considerations must be individualized to take into account the patient's personal willingness to accept these weighed estimates of objective probabilities of benefit, toxicity, and risk. Many questions remain and will be answered only through the clinical trials process. Every patient with breast cancer should be given the opportunity to consider participation in a clinical trial when appropriate for both the sake of medical knowledge and the benefit of future patients.

Paradoxical influence of estrogenic hormones on platelet-endothelial cell interactions.

Controversies abound in the literature about the safety and efficacy of tamoxifen and estrogen. We studied the effect of these 2 hormonal agents on factors involved in in vitro thrombogenesis: platelets and endothelial cells. Endothelial cells were derived from human umbilical veins and platelets were obtained from premenopausal and postmenopausal women, women on oral contraceptives, postmenopausal women on hormone replacement therapy, men, and patients with breast cancer who had been taking adjuvant tamoxifen for more than 1 year. The interaction of platelets with endothelial cell matrix was measured in 2 systems: 1) in a flow chamber at low shear rate and, 2) with 51Cr labeled platelets in a "static" culture system. In the static system, platelets from women on tamoxifen exhibited decreased platelet adherence to endothelial cell matrix whether they were grown in tamoxifen or control conditions, when compared to platelets from premenopausal women. When flow (25 sec-1) was added these differences were negated. Neither tamoxifen nor 17 beta estradiol had an effect on endothelial cell proliferation or platelet aggregation. Adhesion of platelets at low shear was not altered when platelet rich plasma was incubated with tamoxifen nor when endothelial cells were grown in tamoxifen. In contrast, incubation of platelets in 17 beta estradiol decreased platelet adhesion at low shear rate, however, there was no effect on platelet adhesion when endothelial cells were grown in 17 beta estradiol. We conclude that in early stages of thrombus formation as measured in vitro, tamoxifen may not have a detrimental effect and estrogen may be protective.

Racial comparison of outcomes of male Department of Veterans Affairs patients with lung and colon cancer.

BACKGROUND: A study was performed to distinguish between genetic vs socioeconomic factors or artifacts inherent in retrospective studies to discover explanations for the apparent shorter survival of blacks than whites with lung and colon cancer. METHODS: Detailed biological and socioeconomic data were collected prospectively from a large cohort of patients with advanced lung and colon cancer who had not previously received chemotherapy and who consented to be entered in the clinical trial. Twelve medical centers within the Department of Veterans Affairs hospital system (Veterans Affairs Cooperative Study 188) entered patients between May 1981 and May 1986. These patients were evaluated and treated in a uniform manner within this hospital system and followed up to death. Outcome measures included time to tumor progression, tumor response, and survival. RESULTS: A total of 719 patients were entered in the study, 704 of whom were either black or white men. Blacks were found to have a significantly lower socioeconomic status than whites as measured by marital and educational status, occupation, income, housing, and number of individuals residing in household. Blacks had a significantly lower frequency of prior tumor resection and a significantly increased frequency of mediastinal lymph node involvement and of metastasis than whites. Trends existed toward a shorter time interval from original diagnosis to entry and a lower frequency of prior radiation therapy among blacks in comparison with whites at the time of entry to the study. However, no differences in intensity of treatment or follow-up, time to progression, response to treatment, or overall survival (measured from entry to the study to death) were observed for blacks vs whites. CONCLUSIONS: Lung and colon cancer are not necessarily more aggressive diseases in blacks than in whites. Based on a comparison of these data with those reported from other practice settings, we postulate that lung and colon cancer outcomes may be similar among black and white patients who receive equal access to comparable medical care in spite of socioeconomic differences. Findings suggest that future studies might focus profitably on racial factors that may exist at the time of patient entry to the health care system.

Neutrophil activation through high-affinity Fc gamma receptor using a monomeric antibody with unique properties.

The high-affinity, type I Ig Fc receptor (Fc gamma RI) for human IgG1, human IgG3, murine IgG2a, and murine IgG3 is highly expressed on monocytes, neutrophils (PMN) in certain disease states, and phagocytes treated with interferon-gamma (IFN-gamma). We studied the activation of the human PMN oxidative burst and stimulated fluid pinocytosis induced by three monoclonal antibodies (MoAbs) directed against Fc gamma RI (CD64) to study the role of this receptor in Fc-mediated cellular activation. All three MoAbs were capable of triggering PMN activation from IFN-gamma-treated PMN when cross-linked with goat antimurine Ig reagents. However, MoAb 197 alone demonstrated a concentration-dependent activation of the oxidative burst without the use of a second cross-linking antibody. The oxidative burst and stimulated fluid pinocytosis responses induced by monomeric MoAb 197 could be elicited only after the IFN-gamma induction of approximately 8,000 Fc gamma RI receptor equivalents and did not occur in freshly isolated or control-cultured PMN. Competitive blocking of Fc binding of MoAb 197 by human IgG or purified Fc fragments inhibited cellular activation. We believe the ability of MoAb 197 to activate these oxidative burst and fluid pinocytic responses was because of its murine IgG2a subclass, which allowed it to function as a trivalent anti-Fc gamma RI antibody binding through the combination of its two FAB regions and the Fc domain. This study demonstrates that the cross-linking of CD64 can activate PMN oxidative and endocytic responses and supports a role for Fc gamma RI in the human neutrophil inflammatory response.

Oral metoclopramide with or without diphenhydramine: potential for prevention of late nausea and vomiting induced by cisplatin.

Late nausea and vomiting lasting 2-7 days occurs in 20%-68% of patients receiving cisplatin. We therefore studied the effects of oral metoclopramide given at doses of 20, 50, or 100 mg four times a day for 25 doses (7 days) beginning after cisplatin to determine the maximum tolerated dose (MTD) for prophylactic oral antiemetic regimens. Patients were stratified into younger (less than or equal to 30 yr old) and older (greater than 30 yr old) groups. Dose escalation was performed without or with concomitant oral diphenhydramine. For the younger group, the MTD for metoclopramide without diphenhydramine was less than 20 mg, and the MTD with diphenhydramine was 20 mg. For the older group, the MTD without diphenhydramine was 20 mg, and the MTD with diphenhydramine was 50 mg. Extrapyramidal reactions in the younger group and agitated depression in the older group were the major dose-terminating toxic effects. Patient acceptance of these regimens was excellent.

Comparison of metoclopramide and metoclopramide plus dexamethasone for complete protection from cisplatinum-induced emesis.

Metoclopramide was compared to a metoclopramide plus dexamethasone combination in patients receiving high-dose cisplatinum. Metoclopramide 2 mg/kg intravenously was given every 2 hours for 4 doses during two consecutive chemotherapy cycles. A randomized double-blind crossover was used with placebo or dexamethasone 20 mg given intravenously before the first metoclopramide dose. Thirty-six patients completed both study arms. There was no difference in mean vomiting episodes (1.92 for metoclopramide versus 1.33 for the combination, p = 0.20). However complete protection (no vomiting episodes) was achieved in 56% receiving the combination but only 36% receiving metoclopramide alone (p less than 0.08). No significant difference in toxicity or patient preference was noted. Late nausea or vomiting lasting 2 to 7 days appeared in 26% of cycles and was associated with but not completely explained by a greater number of acute vomiting episodes. Combination antiemetic therapy can achieve a higher incidence of complete protection from cisplatinum-induced vomiting. However, late nausea and vomiting may require modification of present regimens.