Clinical evaluation of MGI 209, an anesthetic, film-forming agent for relief from painful oral ulcers associated with chemotherapy.

PURPOSE: This open-label, multicenter trial evaluated the efficacy of a mucoadherent, anesthetic medication (MGI 209) for relief from painful oral ulcers associated with cytotoxic chemotherapy. PATIENTS AND METHODS: Twenty-eight eligible cancer patients who had up to five discrete oral ulcers (total area < or = 5 cm2) completed this study. Mean age was 53.5 years (range, 21 to 81). Subjective assessments of oral discomfort before and after an orange juice pain challenge (OJPC), which was measured using a visual analog scale (VAS), and visual estimates of the amount of MGI 209 that remained on treated ulcers were collected at (1) baseline (before MGI 209 treatment); and (2) 30, 60, 120, and 180 minutes posttreatment. RESULTS: Most subjects had low VAS scores (4 or less), which was indicative of oral discomfort, at baseline before and after the OJPC. At 30, 60, 120, and 180 minutes after MGI 209 treatment, most subjects had high VAS scores before and after an OJPC compared with baseline scores, which was indicative of a substantial increase in oral comfort; these differences were statistically significant (P < .0001). Mean percent of MGI 209 estimated to remain on ulcers at the previously mentioned times was 93.7%, 90.3%, 79.6%, and 71.3% of the total amount applied, respectively. CONCLUSION: Benzocaine hydrochloride in combination with the protective, mucoadherent film-coating relieved discomfort for at least 3 hours even with exposure to an irritating beverage. MGI 209 treatment should allow patients with chemotherapy-induced oral ulcers to drink and eat with significantly diminished pain or no pain.

Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: a randomized trial of the Northern California Oncology Group.

We compared the effectiveness of fluorouracil (5-FU) alone (arm A), high-dose leucovorin plus 5-FU (arm B), and sequential methotrexate, 5-FU, and leucovorin (arm C) for treatment of patients with advanced colorectal carcinomas who had not received prior chemotherapy. Arm A consisted of infusions of 5-FU at 12 mg/kg/d intravenously (IV) for 5 days followed by weekly infusions of 5-FU at 15 mg/kg; arm B consisted of leucovorin infusions at 200 mg/m2/d IV plus infusions of 5-FU at 400 mg/m2/d IV on days 1 through 5 of a 28-day cycle; arm C consisted of methotrexate at 50 mg/m2 orally every 6 hours for five doses followed by infusions of 5-FU, 500 mg/m2 IV, and leucovorin, 10 mg/m2 orally, every 6 hours for five doses every other week. A total of 265 patients were entered into the trial, of whom 249 (94%) were fully evaluable. The objective response rate (complete [CR] plus partial [PR] responses) was 17.3% on arm A, 18.8% on arm B, and 19.8% on arm C (log-rank test, P greater than .4). The median time to failure was 138 days on arm A, 166 days on arm B, and 182 days on arm C (log-rank test, P values of arm A v B = .06; arm A v arm C = .04). Median survival was 345 days on arm A, 324 days on arm B, and 356 days on arm C (log-rank test, P greater than .4). Treatment with 5-FU alone was significantly more dose intensive and more toxic than either of the experimental combinations. The rates of grade 3 or greater nonhematologic toxicity were 42.3% on arm A, 24.3% on arm B, and 14.3% on arm C. Hematologic toxicity was milder but had the same pattern. This study indicates that these regimens of high-dose leucovorin plus 5-FU and sequential methotrexate, 5-FU, and leucovorin are not more effective than is 5-FU alone for treatment of patients with colorectal carcinomas when 5-FU is administered at high-dose intensity.

Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial.

PURPOSE: To evaluate the antitumor activity and toxicity of a new steroidal aromatase inactivator, exemestane, in postmenopausal women with metastatic breast cancer who had progressive disease (PD) after treatment with a nonsteroidal aromatase inhibitor. PATIENTS AND METHODS: In this phase II trial, eligible patients were treated with exemestane 25 mg daily (n = 241) followed, at the time PD was determined, by exemestane 100 mg daily (n = 58). RESULTS: On the basis of the intent-to-treat analysis by independent review, exemestane 25 mg produced objective responses in 6.6% of patients (95% confidence interval [CI], 3.8% to 10.6%) and overall success (complete response + partial response + no change for 24 weeks or longer) in 24.3% (95% CI, 19.0% to 30.2%). The median durations of objective response and overall success were 58.4 weeks (95% CI, 49.7 to 71.1 weeks) and 37.0 weeks (95% CI, 35.0 to 39.4 weeks), respectively. Increasing the dose of exemestane to 100 mg upon the development of PD produced one partial response (1.7%; 95% CI, 0.0% to 9.2%). Both dosages were well tolerated and were discontinued because of adverse events in only 1.7% of patients. CONCLUSION: Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after multiple hormonal therapies have failed.

Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To compare the selective matrix metalloproteinase inhibitor BAY 12-9566 with the nucleoside analog gemcitabine in the treatment of advanced pancreatic cancer. METHODS: Patients with advanced pancreatic adenocarcinoma who had not previously received chemotherapy were randomly assigned to receive BAY 12-9566 800 mg orally bid continuously or gemcitabine 1,000 mg/m2 administered intravenously on days 1, 8, 15, 22, 29, 36, and 43 for the first 8 weeks, and then days 1, 8, and 15 of each subsequent 28-day cycle. The primary end point was overall survival; secondary end points were progression-free survival, tumor response, quality of life, and clinical benefit. The planned sample size of the study was 350 patients. Two formal interim analyses were planned. RESULTS: The study was closed to accrual after the second interim analysis on the basis of the recommendation of the National Cancer Institute of Canada Clinical Trials Group Data Safety Monitoring Committee. There were 277 patients enrolled onto the study, 138 in the BAY 12-9566 arm and 139 in the gemcitabine arm. The rates of serious toxicity were low in both arms. The median survival for the BAY 12-9566 arm and the gemcitabine arm was 3.74 months and 6.59 months, respectively (P <.001; stratified log-rank test). The median progression-free survival for the BAY 12-9566 and gemcitabine arms was 1.68 and 3.5 months, respectively (P <.001). Quality-of-life analysis also favored gemcitabine. CONCLUSION: Gemcitabine is significantly superior to BAY 12-9566 in advanced pancreatic cancer.

Ondansetron for nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

This multicenter, randomized, double-blind study compared the efficacy and tolerability of ondansetron 8 mg twice daily for 3 days with placebo in preventing nausea and vomiting in 81 patients receiving cyclophosphamide-doxorubicin-based chemotherapy. The first dose of study drug was administered 30 minutes before the initiation of chemotherapy. Patients received a rescue antiemetic if the investigator deemed it necessary or if the patient experienced more than two emetic episodes during the 3-day study. Sixty-one percent of patients treated with ondansetron compared with 6% of patients receiving placebo (P < 0.001) had no emetic episodes during the 3-day study. Among patients with at least one emetic episode, the mean time to emesis was 24 hours 18 minutes in the ondansetron group compared with 8 hours 1 minute in the placebo group (P < 0.001). In the intent-to-treat analysis, 78% of patients in the ondansetron group and 29% of patients in the placebo group completed the study with no need for rescue therapy. Clinical laboratory and adverse-event profiles were similar between groups. The most common adverse event was headache, occurring in 23% of ondansetron patients and 24% of placebo patients. This study is the first double-blind, placebo-controlled trial to demonstrate that ondansetron 8 mg twice daily is effective in the prevention of nausea and vomiting associated with cyclophosphamide-doxorubicin-based chemotherapy. The twice-daily regimen may encourage patient compliance and may be more cost-effective than regimens that need to be given three times daily.

Placebo-controlled trial of bexarotene, a retinoid x receptor agonist, as maintenance therapy for patients treated with chemotherapy for advanced non-small-cell lung cancer.

This study was designed as a multicenter, randomized, double-blind, placebo-controlled trial. Patients were randomized by center to placebo (16 patients, 31%), oral bexarotene 300 mg/m2/day (21 patients, 40%), or oral bexarotene 600 mg/m2/day (15 patients, 29%) following demonstration of stable or responsive disease after first-line chemotherapy. The study was prematurely terminated because of slow accrual after 54 patients enrolled. Median time to progression (TTP) from the beginning of study drug treatment was 56 days for placebo, 82 days for moderate-dose bexarotene (300 mg/m2/day), and 128 days for high-dose bexarotene (600 mg/m2/day) (P = 0.56, log-rank test). For prior chemotherapy responders only, median TTP from the beginning of study drug treatment was 56 days for placebo, 146 days for moderate-dose bexarotene, and 177 days for high-dose bexarotene. Of note, there were more chemotherapy responders randomized to the placebo group (63%) than the bexarotene treatment arms (48% and 47%), further supporting a bexarotene-related improvement in TTP. Bexarotene-related toxicity was manageable and consisted primarily of elevated serum triglycerides and asthenia, skin toxicity (dryness, peeling, flaking), thyroid dysfunction, and headache. Because this study was closed prematurely, it does not have the statistical power to detect differences among the treatment groups. This study shows that patients can tolerate bexarotene at initial doses up to 600 mg/m2/day after platinum-based chemotherapy and that bexarotene may have the potential to delay disease progression in patients with advanced non-small-cell lung cancer with previously stable or responsive disease following platinum-based chemotherapy.

A multiinstitutional evaluation of the analgesic efficacy and safety of ketorolac tromethamine, acetaminophen plus codeine, and placebo in cancer pain.

Seventy-five patients with moderate to severe cancer pain were randomly assigned in a double-blind fashion to receive first-dose ketorolac tromethamine 10 mg orally, acetaminophen 600 mg plus codeine 60 mg orally, or placebo, followed by subsequent doses of ketorolac or acetaminophen plus codeine four times daily for 7 days. Patient characteristics were similar among the treatment groups. The first-dose observation documented that both ketorolac and acetaminophen plus codeine produced an equivalent reduction in cancer pain and were superior to placebo as measured by pain intensity differences and pain relief. Multidose comparison documented a small but statistically significant advantage in mean daily pain relief favoring acetaminophen plus codeine, although there were no differences in mean daily ratings of overall effects for either study medication. Adverse symptoms were acceptable with both ketorolac and acetaminophen plus codeine. We conclude that ketorolac has significant analgesic activity in patients with cancer pain, although its precise role in the treatment regimen of these patients remains undefined.

Erythropoietic stress, macrocytosis, and hemoglobin switching in HbAA sheep.

Hemoglobin switching and macrocytosis were studied in homozygous hemoglobinAA sheep. An abrupt initiation of erythropoietic stress, accompanied by a pulsed elevation of circulating erythropoietin levels, was induced by phlebotomy. Sequential blood samples were separated according to density on Stractan gradients to isolate cells newly entering the circulation from the marrow each day. Analysis of hemoglobin phenotype and cell volume distribution in these young reticulocytes revealed a distinct temporal separation in the appearance of hemoglobin C and increased cell volume. The appearance of macrocytes within 24 hr of erythropoietin elevation suggests that macrocytosis could be the result of the action of erythropoietin during the late stages of erythroid maturation. The 72-hr delay in the appearance of hemoglobin C indicates that commitment to a particular hemoglobin phenotype occurs at an early stage of differentiation and involves immature erythroid stem cells. The results of this study show that these consequences of erythropoietic stress are initiated at two different developmental stages, resulting in the production of macrocytosis and hemoglobin switching.

A double-blind comparison of the efficacy of two dose regimens of oral granisetron in preventing acute emesis in patients receiving moderately emetogenic chemotherapy.

BACKGROUND: The purpose of this study was to define an optimal administration schedule of granisetron for patients receiving moderately emetogenic chemotherapy by comparing the antiemetic efficacy and safety of 2 mg of the drug administrated orally. METHODS: In this double-blind, randomized, parallel study, 2-dose regimens of oral granisetron were evaluated in 697 adult cancer patients. Patients were stratified by gender and randomized to receive 2 mg oral granisetron, either as a divided dose given 1 hour prior to chemotherapy and 12 hours after the start of chemotherapy, or as a single dose 1 hour prior to chemotherapy at Cycle 1. The primary efficacy endpoints assessed were the percentage of patients with complete response (no nausea, no emesis, and no additional antiemetic medication during the 24-hour post-chemotherapy interval) and the incidence of emesis and nausea. Following completion of Cycle 1, patients were given the opportunity to receive open-label granisetron (2 mg once daily) on the first day of each remaining cycle of chemotherapy. RESULTS: No statistically significant differences in any of the endpoints were observed between the two treatment groups. Approximately 50% of patients in both treatment groups achieved complete response. The proportion of patients with no episodes of emesis occurred with similar frequency in the two treatment groups. Approximately 52% of patients in either treatment group were free of nausea during the postchemotherapy period. There was no difference between treatment groups regarding the use of antiemetic rescue medication. Finally, the incidence of adverse experiences was similar for both treatment groups. CONCLUSIONS: Both dose regimens of oral granisetron were similarly effective in controlling nausea and vomiting in the 24-hour interval following chemotherapy. Granisetron was well tolerated with few adverse events attributable to the study drug.

The results of a phase II randomized trial comparing 5-fluorouracil and 5-fluorouracil plus alpha-interferon: observations on the design of clinical trials for androgen-independent prostate cancer.

The therapeutic benefit of chemotherapy in androgen independent prostate cancer is limited. 5-Fluorouracil has been reported to have modest antitumor activity in androgen independent prostate cancer. Although alpha-interferon is inactive as a single agent in prostate cancer, preclinical data indicate that it increases the in vitro cytotoxicity of 5-fluorouracil against a variety of malignant cells. We evaluated the relative antitumor activity and tolerance of 5-fluorouracil versus 5-fluorouracil plus alpha-interferon in 50 patients with histologically confirmed metastatic adenocarcinoma of the prostate. These patients had progressive disease in the presence of castrate levels of testosterone. A prospective randomized phase II open labeled trial was performed because of the difficulty in measuring responses in patients with metastatic prostate cancer. Of 23 patients treated with 5-fluorouracil alone and 28 treated with 5-fluorouracil plus alpha-interferon 17 and 23, respectively, were evaluable for response and toxicity, and 5 and 5, respectively, were evaluable for toxicity only. Only 2 of 17 (11.7%) and 4 of 23 (17%) patients, respectively, showed a greater than 50% decrease in serum prostate specific antigen (no significant difference). There was no difference in duration of response or duration of survival between the 2 groups (mean duration of response 8.64 and 6.17 weeks, respectively, and mean duration of survival 33.70 and 38.65 weeks, respectively). Both regimens caused significant morbidity (mucositis and neurotoxicity) and 3 treatment related deaths at the high 5-fluorouracil doses. 5-Fluorouracil alone and with alpha-interferon at the doses used have minimal antitumor activity against androgen independent prostate cancer and, therefore, should not be tested further in these patients. Androgen independent prostate cancer selected using our criteria is a rapidly progressive disease, and these patients are an ideal target population for phase II studies.

Treatment of recurrent malignant glioma with BCNU-fluosol and oxygen inhalation. A phase I-II study.

OBJECTIVES: To evaluate the toxicity and response rate following BCNU with oxygen inhalation and escalating dosages of fluosol administered to patients with radiographic progression of malignant glioma after definitive surgery and radiotherapy. METHOD: This single arm, phase I-II multicenter trial, enrolled 99 patients with malignant gliomas recurrent after definitive surgery and radiotherapy. All patients received a fixed dose (200 mg/m2) of BCNU along with 100% oxygen and fluosol, a perfluorochemical. Fluosol doses were escalated between patients (150, 275, 400 and 600 ml/m2). Treatment was repeated every 6 weeks for a maximum of 6 cycles. Patients were assessed for toxicity at the time of infusion and sequentially thereafter. Response was evaluated clinically and radiologically at least every 6 weeks. RESULTS: Treatment was well tolerated. Dose reductions were required at least once in 18 patients, treatment delays were necessary at least once in 33 patients. Grade 3-4 leukopenia occurred in 6 patients (12 events), grade 3-4 thrombocytopenia in 10 patients (25 events) and grade 3-4 liver enzymes elevations in 18 patients (31 events). Higher fluosol dosages did not produce increases in toxicity or responses. Response or stabilization was seen in 57% (38% were stabilizations) of the patients who entered the trial with progressive disease. The median time to progression was 45 weeks, and median survival was 66 weeks for patients who had response or stabilization. For patients with glioblastoma response/stabilization was seen in 45% with a mean duration of 24 weeks, for patients with anaplastic astrocytoma response/stabilization was seen in 68% with a mean duration of 50 weeks. CONCLUSION: This treatment regimen is well tolerated. Our results suggest fluosol may enhance the effectiveness of BCNU for the treatment of recurrent malignant gliomas. Future studies will be performed using fluosol at the dose of 400 ml/m2.