N0332 phase 2 trial of weekly irinotecan hydrochloride and docetaxel in refractory metastatic breast cancer: a North Central Cancer Treatment Group (NCCTG) Trial.

BACKGROUND: Because of the single-agent activity of irinotecan hydrochloride, combination of irinotecan and docetaxel treatment against metastatic breast cancer (MBC) should be evaluated. PATIENTS AND METHODS: Single-stage phase 2 study of irinotecan and docetaxel to evaluate tumor response, toxicity, time to progression, and overall survival was carried out. Regimen of docetaxel (25 mg/m(2)) and irinotecan (70 mg/m(2)) was administered on days 1 and 8 of each 3-week cycle. Patients had histologically confirmed breast adenocarcinoma and metastatic cancer measurable with RECIST. RESULTS: Of 70 patients enrolled, 64 were assessable. Prior treatment with an anthracycline and a taxane was required. Eighteen (28%) patients [95% confidence interval (CI) 15% to 31%] had tumor response, plus four patients had stable disease (less than 30% decrease in sum of longest diameter and less than 20% increase) for >6 months. The clinical benefit rate was 34% overall. Median duration of tumor response was 6.7 months (95% CI 4.2-37.7 months); median follow-up was 18.6 months (range 8.5-37.7 months). The most common severe adverse events included fatigue [n = 16 (25%)] and neutropenia [n = 13 (20%)]. CONCLUSIONS: Weekly dosing of combination of irinotecan and docetaxel is active against MBC. However, the response rate to our regimen was not significantly better than single-agent docetaxel. Other schedules of irinotecan plus docetaxel should be considered for future studies.

Phase II trial of oral vinorelbine for the treatment of metastatic breast cancer in patients > or = 65 years of age: an NCCTG study.

BACKGROUND: A one-stage phase II trial was conducted to assess the tumor response rate and toxicity profile of single agent oral vinorelbine as first or second-line chemotherapy for women at least 65 years of age with metastatic breast cancer. PATIENTS AND METHODS: Twenty-five patients with metastatic breast cancer aged > or = 65 years of age were enrolled to receive oral vinorelbine on a weekly basis. The oral vinorelbine was given at 60 mg/m2 weekly for the first four doses and was increased to 70 mg/m2 for the subsequent administrations if there was no grade 4 neutropenia or no more than one episode of grade 3 neutropenia. Therapy was continued until progression or intolerable toxicity. RESULTS: Twenty-five patients were included and evaluable for analysis. One patient (4%) achieved a partial response (PR) that lasted for more than 13 months. Two additional patients remained stable for at least 6 months for a clinical benefit rate (PR + stable disease) of 12%. The 1-year survival rate was estimated to be 48% (95% CI 30% to 74.5%). Median time to progression was estimated to be 4.7 months (95% CI 2.0-5.5 months) and the 9-month disease progression-free rate was estimated to be 8% (95% CI 30.9% to 74.5%). The treatment was fairly well tolerated with grade 3 neutropenia in 12.5%, fatigue in 12.5% of the patients, and grade 2 neuromotor and neurosensory toxicities in 12.5% and 8.3%, respectively. CONCLUSION: Oral vinorelbine as a single agent at these dose and schedule in this population of women > or = 65 years is well tolerated but has a low level of objective efficacy for the treatment of metastatic breast cancer.

A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma.

BACKGROUND: The current study was conducted to determine whether the addition of interferon-alpha (IFN-alpha) to treatment with radiation therapy and carmustine (BCNU) improves time to disease progression or overall survival in patients with high-grade glioma. METHODS: Patients with anaplastic astrocytoma, anaplastic oligoastrocytoma, glioblastoma multiforme, or gliosarcoma received radiation therapy plus BCNU as initial therapy. Subsequently, patients without tumor progression at the completion of radiation therapy were stratified by age, extent of surgery, tumor grade and histology, Eastern Cooperative Oncology Group performance status, and treating institution, and then were randomly assigned to receive either BCNU alone (200 mg/m(2) on Day 1) or BCNU (150 mg/m(2) on Day 3) plus IFN--alpha (12 million U/m(2) on Days 1-3, Weeks 1, 3, and 5) every 7 weeks for a maximum of 6 cycles. RESULTS: Of the 383 patients enrolled in the study, 275 eligible patients were randomized. There was no significant difference with regard to time to disease progression or overall survival between the two groups. Patients receiving IFN-alpha experienced more fever, chills, myalgias, and neurocortical symptoms including somnolence, confusion, and exacerbation of neurologic deficits. Cox multivariate regression models confirmed known favorable prognostic variables including younger age, Grade 3 tumor (according to World Health Organization criteria), and greater extent of surgery. Cox and classification and regression tree analysis models also demonstrated that a normal baseline Folstein mini-mental status examination (MMSE) score was associated with better prognosis. CONCLUSIONS: IFN-alpha does not appear to improve time to disease progression or overall survival in patients with high-grade glioma and appears to add significantly to toxicity. The baseline MMSE score may serve as an independent prognostic factor and warrants further investigation.

Phase II evaluation of continuous-infusion 5-fluorouracil, leucovorin, mitomycin-C, and oral dipyridamole in advanced measurable pancreatic cancer: a North Central Cancer Treatment Group Trial.

At present there remains a need for more effective systemic therapy in advanced pancreatic cancer. Some studies have suggested that infusional chemotherapy schedules and biomodulation of 5-fluorouracil (5-FU) may improve the therapeutic outcome in advanced colon cancer. One such regimen that uses continuous infusion 5-FU, weekly leucovorin, daily dipyridamole, and intermittent mitomycin-C has activity in both colon and unresectable pancreatic carcinoma. The intent of this trial was to test the effectiveness of this four-drug regimen in advanced pancreatic cancer. Patients received 5-FU 200 mg/m2 daily by continuous infusion, leucovorin 30 mg/m2 IV weekly, mitomycin-C 10 mg/m2 day 1, and dipyridamole 75 mg orally four times daily for 5 weeks. After a 1-week break, treatment cycles were repeated every 6 weeks. Eligibility included biopsy-proven advanced measurable pancreatic cancer, Eastern Cooperative Oncology Group performance status 0 and 2, and no prior systemic chemotherapy. Of 46 evaluable patients, 9 partial responses and 1 complete tumor response were seen, for an overall response rate of 22% (95% confidence interval 11-36%). The median survival in the group of 50 patients registered to this trial was 4.6 months, with a range of 0.33 to 40.2 months. Toxicity was manageable, with the most common toxicities (> or =grade III National Cancer Institute Common Toxicity Criteria) being anorexia (13%), stomatitis (17%), and hand-foot syndrome (13%). Of note, little severe hematologic toxicity and no significant headaches were reported. Although some patients did respond, the therapeutic results are not encouraging enough to take this regimen to phase III testing.

HER-2/neu protein-receptor-positive breast carcinoma: an immunologic perspective.

Immunotherapy using a monoclonal antibody against the human epidermal growth factor receptor 2 protein, HER-2/neu, has proven to be clinically efficacious in about one-half of breast cancer patients who exhibit strong (3+) plasmalemmal immunoreactivity for this protein. The tumoricidal effect of this antibody relies in part upon antibody-dependent cell-mediated cytotoxicity. This report provides observations on certain factors or circumstances which could have an impact on this aspect of the therapeutic approach. These include: (1) concurrent medications; (2) the composition (immunophenotype) of peritumoral lymphocytes and the generally limited numbers of intratumoral T-lymphocytes/natural killer (NK) cells, monocytes, and neutrophilic granulocytes; (3) the presence of circulating HER-2/neu antigens which might bind the exogenous antibody and lead to immune complex formation; (4) the variable co-expression in the tumor of cytokines known to downregulate NK cell function (ie, transforming growth factor-beta1 [TGF-beta1] and platelet-derived growth factor [PDGF]-AB); and (5) the tumoral and/or stromal immunoreactivity for angiotensin-converting enzyme, which forms a part of one of the pathways for the activation of latent TGF-beta1 and for the biosynthesis of PDGF-AB. These observations provide an immunologic perspective for the use of monoclonal antibody therapy in HER-2/neu protein-receptor-positive breast carcinoma and suggest a role for the clinical laboratory in identifying potential avenues for additional manipulations of the immune system in individual cases in order to enhance the therapeutic response.

A North Central Cancer Treatment Group phase II trial of topotecan in relapsed gliomas.

Current systemic treatment options for patients with relapsed gliomas are limited. The topoisomerase I inhibitor topotecan has demonstrated broad antitumor activity in both preclinical studies as well as a number of phase I and II trials in humans. Studies in primates have shown good cerebrospinal fluid levels of topotecan following systemic administration. We therefore performed this phase II trial in patients who developed evidence of progressive glioma after definitive radiation therapy. Patients were treated with 1.5 mg/m2 intravenously daily for 5 consecutive days repeated every three weeks. For patients who had received prior nitrosourea-containing chemotherapy, the starting dose was 1.25 mg/m2. Thirty-three patients were entered on this study. All patients were eligible and evaluable for both response and toxicity. Seven patients experienced grade 4 leukopenia with 2 of these patients dying of infection-related complications. Six of these seven patients were not taking anticonvulsants during treatment. Nine patients developed grade 3-4 thrombocytopenia, seven of whom were not taking anticonvulsants. Nonhematologic side effects were infrequent and manageable. One patient experienced a partial response to this treatment for an overall response rate of 3% (95% binomial confidence interval 0.3%-20.4%). The median time to progression was 14.9 weeks and median survival 19.9 weeks. Topotecan at this dose and schedule showed no substantial activity in relapsed gliomas.

Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver.

PURPOSE: Extrahepatic metastasis represents a frequent pattern of disease progression when fluorodeoxyuridine (FUDR) is given by the intraarterial route for the treatment of unresectable colorectal liver metastases. Systemic fluorouracil (5-FU) plus leucovorin was added to intrahepatic FUDR to prolong the duration of disease control. METHODS: Only patients with colorectal cancer who had evidence of unresectable metastases confined to the liver were eligible. Laparotomy was performed to establish arterial perfusion of the liver. Cycles of intrahepatic FUDR followed by a 1-week rest period then intravenous chemotherapy with 5-FU plus leucovorin were administered until maximal regression of hepatic metastases. Maintenance chemotherapy with 5-FU plus leucovorin was then given until disease progression. RESULTS: Fifty-seven patients entered this trial; four patients (7%) were ineligible and 13 (23%) did not receive any chemotherapy on study because of findings at laparotomy. The 40 eligible patients who began chemotherapy are included in the statistical analyses. Twenty-five patients (62% of those who received chemotherapy) experienced regression of liver metastases. The median time to tumor progression was 9 months, but only 3% remained progression-free at 24 months. The median survival duration was 18 months. Toxicity was tolerable with no cases of biliary sclerosis. One treatment-related fatality due to sepsis was observed. CONCLUSION: Although short-term treatment results appear to be somewhat better than we have previously observed with intrahepatic FUDR alone, the sequential regimen did not have an impact on long-term, progression-free survival in patients with unresectable liver metastases. We are now investigating this regimen as surgical adjuvant therapy in selected patients following hepatic metastasectomy where this aggressive approach might have a greater therapeutic effect in the minimal residual disease setting.

Phase III evaluation of 4 doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia.

Several randomized, placebo-controlled clinical trials have demonstrated that megestrol acetate therapy can result in appetite stimulation and nonfluid weight gain in patients with cancer anorexia/cachexia. The present trial was designed to compare megestrol acetate doses ranging from 160 to 1,280 mg/day. day. This trial randomly assigned 342 evaluable patients with cancer anorexia/cachexia to receive oral megestrol acetate at doses of 160, 480, 800 and 1,280 mg/day. Patients were evaluated monthly by history, examination and patient-completed questionnaires, as well as by serum albumin levels. The data demonstrate a positive dose-response effect for megestrol acetate on appetite stimulation (p = 0.02). there was a trend for more nonfluid weight gain with higher drug doses. Megestrol acetate was well tolerated in this group of patients with advanced malignant disease. The positive dose-response effect observed for megestrol acetate on appetite stimulation supports both the prestudy hypothesis and findings in the literature. The optimal dose in this study seemed to be 800 mg/day; no further benefit was derived from using the higher dose. Nonetheless, it may be reasonable to start with lower initial doses in routine clinical practice, taking into account dosage form, availability and cost of therapy.

Apramycin: minimal inhibitory concentrations for avian Escherichia coli and serum levels after intramuscular injection in turkeys.

The minimal inhibitory concentrations (MIC) of apramycin, a unique aminocyclitol antibiotic, for 100 Escherichia coli isolates recovered from clinical cases of avian colibacillosis were determined using the agar dilution method. All isolates were inhibited at apramycin concentration of 8.0 micrograms/ml; 90 and 50% of the isolates were inhibited at 6.6 and 3.4 micrograms/ml, respectively. A commercial injectable product containing 200 mg apramycin/ml was administered intramuscularly (i.m.) to groups of 6- and 12-week-old turkeys at 10, 15 and 20 mg/kg. Apramycin was quickly absorbed from the i.m. injection site. Mean peak serum drug concentrations were reached 1 h after treatment and were 19.5, 27.5 and 36.0 micrograms/ml, respectively. The serum elimination half-life (t 1/2) of the drug ranged between 1.75 h for the 10 mg/kg dose and 2.5 h for the 20 mg/kg dose. Very low concentrations of the drug were found 24 h after treatment. Duration of serum apramycin concentrations in relation to the MIC, dose, and age of birds was determined.

Double-blind crossover trial of droperidol, metoclopramide, and prochlorperazine as antiemetics in cisplatin therapy.

Droperidol, metoclopramide, and prochlorperazine were compared in a double-blind crossover trial to determine their relative effectiveness in preventing and controlling the nausea and vomiting caused by cisplatin-containing chemotherapy. Twenty-five patients receiving cisplatin-containing chemotherapy for various malignancies were entered into this trial with 14 patients completing the three-drug randomization sequence. This was the patient's first exposure to cisplatin. Each antiemetic was administered in a diluted 50 ml i.v. injection over 15 minutes beginning 0.5 hour before cisplatin and 1.5, 3.5, 5.5, and 8.5 hours after cisplatin. Dosages of antiemetics for doses of cisplatin greater than or equal to 100 mg/sq m were droperidol 2.5 mg, metoclopramide 2 mg/kg, or prochlorperazine 5 mg in each infusion. For doses of cisplatin less than 100 mg/sq m, the dosages were droperidol 2.5 mg for the first two doses and 1.25 mg for subsequent doses, metoclopramide 1 mg/kg, or prochlorperazine 5 mg for each dose. The median number of emetic episodes for the first 24 hours were as follows: droperidol 3.2; metoclopramide 1.8; prochlorperazine 3.7. There was a significant difference in number of emetic episodes demonstrating antiemetic superiority of metoclopramide over both droperidol and prochlorperazine. For these 14 patients completing the trial, eight preferred metoclopramide, two preferred prochlorperazine, one preferred droperidol, and three had no preference. At the doses used in this study, the antiemetic efficacy of metoclopramide was superior to either droperidol or prochlorperazine.

Iliac artery-bladder fistulization ten years post-renal transplantation.

We report the first known case of arteriovesical fistulization arising from the iliac artery and presenting ten years post-renal transplantation.

Stab wounds of the kidney: conservative management in flank penetration.

Between April 1976 and December 1980, 373 patients with stab wounds of the abdomen were seen in our emergency room. Of 47 cases (12.6 per cent) in which renal penetration was confirmed nonoperative management was selected in 34 (70.2 per cent), with no further sequelae in 28 (82 per cent). The site of abdominal penetration was posterior to the anterior axillary line in 30 successful conservatively managed patients (88 per cent). The site of abdominal wound penetration in conjunction with clinical stability may avoid unnecessary renal explorations.

Randomized trial of aminoglutethimide versus tamoxifen in metastatic breast cancer.

We compared antiestrogen therapy (tamoxifen) with an estrogen suppression regimen (aminoglutethimide-hydrocortisone) in postmenopausal women with metastatic breast carcinoma. Fifteen of 39 patients (38%) who received tamoxifen experienced an objective tumor regression (3 complete, 12 partial remissions), whereas 13 of 36 women (36%) receiving aminoglutethimide responded (one complete remission, 12 partial remissions). The median duration of response was similar. The site of tumor involvement appears to be important in choosing between these hormonal treatments. Aminoglutethimide appears to offer a greater chance of response in patients with bone involvement.

Renal venography in diagnosis of infiltrating transitional cell carcinoma of renal pelvis.

Urologic evaluation of a ninety-two-year-old man with hematuria suggested lower segmental renal infarction on selective renal angiogram. Nonvisualization of the lower segmental venous tributaries and capillaries on renal venogram was consistent with the operative findings of microscopic infiltrating transitional cell carcinoma. The use of renal venography in these tumors is suggested.

Ureteral diverticulosis in a case of dermatomyositis.

We present the third case of ureteral diverticulosis discovered by excretory urography alone and the twenty-sixth case reported in the world literature. Unlike previously reported cases our patient had dermatomyositis and is urologically asymptomatic.