Randomized phase II study of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatin-induced emesis.

PURPOSE: To determine the efficacy and safety of the neurokinin type 1 receptor antagonist CJ-11,974 for the control of high-dose cisplatin-induced emesis. PATIENTS AND METHODS: A double-blind, randomized, phase II design with a group sequential stopping rule was used in this study. Sixty-one patients with cancer who were receiving cisplatin at a dose of at least 100 mg/m2 for the first time were enrolled. All patients received granisetron 10 microg/kg and dexamethasone 20 mg intravenously 30 minutes before they were given cisplatin. Patients were randomly assigned to two groups: group 1 received CJ-11,974 100 mg, and group 2 received placebo orally 30 minutes before and 12 hours after cisplatin and then twice daily on days 2 through 5 after cisplatin. The primary end point was the percentage of patients who developed delayed emesis (emesis on the second to fifth days after cisplatin). RESULTS: Thirty patients were enrolled in group 1, and 31 patients were enrolled in group 2. Fifty-eight patients were assessable for efficacy. Complete control of emesis (expressed as the percentage of patients who had no emesis) was as follows: day 1, 85.7% (group 1) and 66.7% (group 2) (P = .090); days 2 through 5, 67.8% (group 1) and 36.6% (group 2) (P = .0425, adjusted); days 1 through 5, 64.3% (group 1) and 30% (group 2) (P = .009). Patients in group 1 experienced significantly less nausea than patients in group 2 on day 1 (P = .024). Treatment was well tolerated in both groups. CONCLUSION: We conclude from this exploratory phase II trial that CJ-11,974 is superior to placebo in controlling cisplatin-induced delayed emesis and may provide additive benefit in acute emesis and nausea control when combined with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. Additional larger trials are indicated to confirm the clinical value of CJ-11,974.

Randomized trial comparing the tolerability of sargramostim (yeast-derived RhuGM-CSF) and filgrastim (bacteria-derived RhuG-CSF) in cancer patients receiving myelosuppressive chemotherapy.

A prospective, randomized, double-blind, multicenter study in cancer patients receiving myelosuppressive chemotherapy was undertaken to evaluate and compare the tolerability of sargramostim (yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor, RhuGM-CSF) and filgrastim (bacteria-derived recombinant human granulocyte colony-stimulating factor, RhuG-CSF) in the prophylaxis or treatment of chemotherapy-induced neutropenia. In all, 137 evaluable patients received sargramostim (300 micrograms; 193 mg/m2) or filgrastim (481 mg; 7 mg/kg) once daily by self-administered s.c. injection, usually beginning within 48 h after completion of chemotherapy. With the exception of a slightly higher incidence of grade 1 fever (< 38.1 degrees C) with sargramostim, there were no statistically significant differences in the incidence or severity of local or systemic adverse events possibly related to the growth factors. Although the study was not designed to evaluate efficacy directly, there also were no statistically significant differences between treatment groups in total days of growth factor therapy, days of hospitalization, or days of i.v. antibiotic therapy during the treatment period. Both sargramostim and filgrastim were comparably well tolerated when given by s.c. injection in this group of patients, and no clinically significant differences between the growth factors were demonstrated.

Hormonal palliation of chemoresistant ovarian cancer: three consecutive phase II trials of the Mid-Atlantic Oncology Program.

PURPOSE: To evaluate the efficacy of three hormonal manipulations in the palliation of chemoresistant ovarian cancer, and to analyze the results in the light of other clinical trials. PATIENTS AND METHODS: Three sequential phase II trials were performed in patients with refractory epithelial ovarian carcinoma, using high-dose megestrol acetate (800 mg/d for 30 days, then 400 mg/d), high-dose tamoxifen (80 mg/d for 30 days, then 40 mg/d), and aminoglutethimide (1 g/d plus tapering doses of hydrocortisone). Results were compared with those described in the world literature from trials of the same or similar agents. RESULTS: No responses were seen among 30 assessable patients treated with megestrol acetate, and most (but not all) similar trials have reported low response rates. Five responses (17%) were seen among 29 patients treated with tamoxifen. Two responses exceeded 5 years in duration. No responses were seen among 15 patients treated with aminoglutethimide. CONCLUSION: Antiestrogen therapy may offer the possibility of useful and, occasionally, long-term palliation of refractory epithelial ovarian carcinoma, with little toxicity. There may be a trend toward a dose-response effect, which represents a suitable topic for a future prospective trial.

Efficacy and tolerability of imipenem-cilastatin versus ceftazidime plus tobramycin as empiric therapy of presumed bacterial infection in neutropenic cancer patients.

The efficacy and tolerability of monotherapy with imipenem-cilastatin (I-C) were compared with that of ceftazidime plus full-course therapy with an aminoglycoside (tobramycin) (C&T) in the treatment of presumed bacterial infection in neutropenic cancer patients. A total of 106 adult patients diagnosed with presumed bacterial infection and an underlying malignancy with an absolute neutrophil count (ANC) < 500/mm3 were enrolled in this open-label study. A total of 131 febrile episodes occurred. Forty-five patients in the I-C group and 41 in the C&T group, who were well matched on demographic and baseline characteristics, were evaluable for efficacy and safety. Seventy-two hours after the start of therapy, no significant between-group differences in treatment outcomes, including withdrawals or deaths, were seen. Thirty-five (78%) of 45 patients in the I-C group and 29 (71%) of the 41 in the C&T group had successful outcomes at the final evaluation. Superinfection occurred in 8 (18%) I-C patients and 3 (7%) C&T patients. Within the subgroup of patients with an initial ANC < 100/mm3, the final evaluation showed no significant differences in treatment outcome between groups. Of the 131 in the safety population 30 (46%) I-C patients and 28 (42%) C&T patients had one or more adverse experiences; drug-related adverse events occurred in 25 (38%) patients in the I-C group and 11 (17%) patients in the C&T group. The data suggest that imipenem-cilastatin should be considered for initial empiric therapy of presumed bacterial infection in neutropenic cancer patients.

Continuous infusion 5-fluorouracil with bolus adriamycin and mitomycin and low-dose cisplatin (FAMP) in the treatment of metastatic gastric carcinoma: an evaluation of efficacy and toxicity.

A pilot study was performed to evaluate the feasibility of administering prolonged continuous infusion 5-fluorouracil with multiple bolus chemotherapeutic agents. Twelve patients with advanced measurable gastric carcinoma were treated with a combination chemotherapy program of continuous infusion 5-fluorouracil, bolus Adriamycin, mitomycin C, and low-dose cisplatin (FAMP). Responses were observed in 5 patients (2 complete and 3 partial). Observed toxicities included leukopenia, thrombocytopenia, mucositis, and hand-foot syndrome. Although the FAMP regimen has activity in advanced gastric carcinoma, the number of patients evaluated was small and significant improvement over currently available regimens could not be demonstrated. Evaluation of toxicities indicates that bolus administration of multiple agents (specifically, Adriamycin, mitomycin C, and cisplatin) can be used in conjunction with continuously infused 5-fluorouracil without excessive toxicity.

5-fluorouracil, adriamycin, and mitomycin in the treatment of adenocarcinoma of unknown primary.

The combination of 5-fluorouracil (5-FU), doxorubicin, and mitomycin (FAM) is often recommended for empiric management of patients with adenocarcinoma of unknown primary. This recommendation is based on the activity of FAM for adenocarcinomas of specific known sites of origin. A literature search disclosed no reports of the efficacy of FAM in this clinical entity. We report on 45 patients with biopsy-proven adenocarcinoma in whom investigation revealed no primary site and who were treated in a phase II trial with FAM. Of 43 evaluable patients, four achieved a complete tumor response, and nine obtained a partial response for an overall response rate of 30%. The median survival for all patients was greater than 10 months. The median survival for patients whose tumors were unresponsive to FAM was 6 months, and median survival was greater than or equal to 14 months in patients with stable disease or FAM-responsive tumors. A phase III trial comparing no therapy or 5-FU with FAM is warranted. For patients not treated in an investigative setting, FAM compares favorably with reported series using other regimens.

Local-regional failure in patients treated with adjuvant chemotherapy for breast cancer.

Risk factors for local-regional recurrence of breast cancer were analyzed in a retrospective review of 117 patients treated with adjuvant CMF (Cytoxan [Mead Johnson & Co, Evansville, Ind], methotrexate, 5-fluorouracil) after radical or modified radical mastectomy at the Vincent T. Lombardi Comprehensive Cancer Center (Washington, DC). The median follow-up time was 50 months after mastectomy. The median time to recurrence was 23 months. The actuarial local-regional failure rate was 19% at five years. Risk of local failure correlated with size of primary (27% for T3 v 15% for T1) and axillary node status (36% for four or more positive nodes v 9% for three or fewer positive nodes). These findings suggest a rationale for the addition of postoperative radiation therapy in high-risk patients treated with adjuvant chemotherapy.

Treatment of advanced breast cancer with two doxorubicin-containing regimens.

The Georgetown University Hospital experience in the treatment of advanced breast cancer using either a combination of doxorubicin (adriamycin) and vincristine (AV) or adriamycin and mitomycin-C (AM) is presented. Of 74 previously treated patients with advanced breast cancer, 50 patients were given AV and 24 patients were given AM. Both groups were comparable in regard to number of disease sites, age, prior radiation therapy, disease-free interval after mastectomy, duration of treatment, and estrogen-receptor status. The response rates were 32% and 25% with AV and AM combinations, respectively. Achievement of response was not related to menopausal or estrogen-receptor status. Median time to disease progression was 7.0 and 9.6 months for AV and AM, respectively. Median survivals were not statistically different (9.7 months for AV and 11.1 months for AM). Life-table analysis for responders versus nonresponders within each regimen and between responders in either regimen revealed no statistical differences. Duration of response for each regimen was also equivalent. Toxicity was mild and similar to previous reports using these drugs. However, myelosuppression was significantly greater for premenopausal than postmenopausal patients in the AV group. The possible reasons for this are discussed. Both AM and AV are well-tolerated regimens which provide equivalent but limited response rates, duration of response, and median survival in previously treated women with advanced breast cancer.

Phase II trial of thymosin fraction 5 in advanced renal cancer.

Partially purified thymosin fraction 5 ( TF5 ) was administered to 21 patients with advanced renal cancer. Two different loading dose schedules and doses (60 and 120 mg/m2) of SQ TF5 were employed in 10 patients each. Of 20 evaluable patients, three exhibited partial responses and two exhibited stable disease. All five of these patients had had prior nephrectomies and lung metastases as the dominant site of disease. Toxicity was minimal but included one probable systemic allergic reaction. We could not identify any specific relationship between TF5 dose/schedule or pretreatment immune abnormalities and tumor responsiveness. Our results indicate that the administration of TF5 alone can induce regressions of renal cancer. Additional trials with larger numbers of patients appear to be justified.

Phase-II study of cis-diammine-dichloro platinum (cis-platinum), bleomycin and methotrexate for advanced squamous cell carcinoma of head and neck.

Twenty-one patients with head and neck carcinomas relapsing after radiotherapy were treated with a combination of cis-platinum, bleomycin, and methotrexate. Four patients (19%) achieved a partial response. Toxicity was significant in selected cases; three patients developed WBC counts less than 1,000/mm3 and one of these patients died with sepsis. Severe mucositis was present in three of the twenty-one patients. Considering the toxicity of this combination and the limited therapeutic activity with the dose and schedule used in this study, this regimen is not recommended for the treatment of squamous head and neck carcinomas relapsing after radiotherapy.

5-Fluorouracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer.

Sixty-two patients with advanced measurable gastric cancer were treated with a combination chemotherapy program of 5-fluorouracil, doxorubicin, and mitomycin (FAM). Forty-two percent of patients achieved an objective partial response. The median duration of remission was 9 months and the median survival for responding patients, 12.5 months. The median survival for nonresponding patients was 3.5 months; all patients were dead by 8 months after initiation of therapy. The median survival of all 62 patients treated with FAM was 5.5 months. An analysis of possible prognostic variables including initial performance status, resectability of the primary gastric tumor, and histologic differentiation of the neoplasm failed to account for differences in patient response and survival. The FAM regimen was well tolerated, producing only moderate bone marrow suppression. These results show that patients with metastatic gastric cancer can be effectively palliated with FAM chemotherapy. The efficacy of this regimen should now be tested in patients with less advanced stages of this disease.

5-fluorouracil, adriamycin, and mitomycin-C (FAM) combination chemotherapy in the treatment of advanced gastric cancer.

Thirty-six patients with advanced measurable gastric cancer were treated with a new combination chemotherapy program consisting of 5-fluorouracil, Adriamycin and mitomycin-C (FAM). Fifty percent of patients achieved an objective partial response. The median duration of remission was 9.5 months and the median survival for responding patients was 13.5 months, with 2 remaining alive at 14 and 26 months. The median survival for nonresponding patients was 3.0 months and all were dead by 6 months after initiation of therapy. The median survival of all 36 patients treated with FAM was 5.5 months. An analysis of possible prognostic variables including initial performance status, resectability of the primary gastric tumor and histologic differentiation of the neoplasm failed to account for differences in patient response and survival. The FAM regimen was well tolerated, and produced only moderate bone marrow suppression. These results demonstrate that some patients with advanced gastric cancer can be effectively palliated with FAM chemotherapy. Phase III trials are warranted to assess the effect of the FAM regimen on the survival of patients with advanced gastric cancer.

Phase II trial of streptozotocin, mitomycin-C and 5-fluorouracil (SMF) in the treatment of advanced pancreatic cancer.

Ten of 23 patients with advanced measureable adenocarcinoma of the pancreas achieved an objective response after treatment with a regimen consisting of streptozotocin, mitomycin-C and 5-fluorouracil (SMF). The median duration of response is in excess of 7 months and responding patients have lived significantly longer than patients with progressive disease (7.5 + months vs. 3 months). The SMF regimen was adequately tolerated. Principal toxicities included myelosuppression, which was generally mild, nausea and vomiting. There was reversible nephrotoxicity in the form of proteinuria in 30% of patients and persistent axotemia in 9% of patients.