Prognostic effect of activated EGFR expression in human colon carcinomas: comparison with EGFR status.

BACKGROUND: Evidence suggests that epidermal growth factor receptor (EGFR)-activation status may better predict the clinical behaviour of colon cancers than does EGFR expression. However, the prognostic effect of phospho-EGFR in primary colon cancer remains undefined. METHODS: Phospho-EGFR (Tyr-1173) and EGFR expression were analysed by immunohistochemistry (IHC) in tissue microarrays of TNM stage II and III colon cancers from completed adjuvant therapy trials (n=388). Staining intensity was scored and correlated with clinicopathological variables, DNA mismatch repair (MMR) status, rates of cell proliferation (Ki-67), apoptosis (caspase-3), and patient survival. RESULTS: Phospho-EGFR expression was detected in 157 of 388 (40%) tumours, whereas EGFR was found in 214 of 361 (59%). Although phospho-EGFR was unrelated to clinicopathological variables, strong EGFR intensity was associated with higher tumour stage (P=0.03). Tumours overexpressing EGFR (P=0.0002) or phospho-EGFR (P=0.015) showed increased Ki-67, but not caspase-3 expression. Phospho-EGFR was not prognostic. EGFR intensity was associated with worse disease-free survival (DFS) (hazard ratio (HR): 1.21 (1.03, 1.41); P=0.019) and overall survival (OS) (HR: 1.19 (1.02, 1.39); P=0.028). Tumours expressing both EGFR and phospho-EGFR had similar survival as EGFR alone. Stage and lymph node number were prognostic for DFS and OS, and histological grade for OS. EGFR was an independent predictor of DFS (P=0.042) after adjustment for stage, histological grade, age, and MMR status. CONCLUSION: Phospho-EGFR and EGFR expression were associated with tumour cell hyperproliferation. Phospho-EGFR was not prognostic, whereas increased EGFR intensity was independently associated with poor DFS.

Methodologic lessons learned from hot flash studies.

PURPOSE: In the course of conducting a series of prospective clinical trials devoted to defining new treatment opportunities for hot flashes in cancer survivors, considerable experience has been acquired with related methodologic issues. This article has been written in response to many queries regarding this methodology. PATIENTS AND METHODS: A series of seven different clinical trials that involved 968 patients was used for this work. Reliable and valid definitions of hot flash intensity were developed from patient-reported descriptions. Concomitant validity and reliability assessment of patient-completed diaries was undertaken to compare hot flash data with toxicity and quality-of-life (QOL) end points and to examine consistency across patient groups using variability analysis and correlation procedures. Parametric data from this meta-analysis was used to examine relative power considerations for the design of phase II and phase III clinical trials. RESULTS: Daily diaries used in these studies exhibited consistency and reliability and had few missing data. Hot flash frequency and hot flash score (frequency multiplied by average severity) variables produced almost identical end point results. For phase III placebo-controlled studies, 50 patients per treatment arm seem appropriate to provide sufficient power specifications to detect a clinically meaningful change in hot flash activity. For phase II trials, 25 patients per trial seem to provide reasonable estimates of eventual hot flash efficacy to screen potential agents for more definitive testing. CONCLUSION: Given the data gained from these experiences, we can plan and carry out more efficient trials to identify efficacious agents for the reduction of hot flash activity.

Evaluation of a somatostatin analog in the treatment of lymphoproliferative disorders: results of a phase II North Central Cancer Treatment Group trial.

PURPOSE: Malignant cells from non-Hodgkin's lymphomas (NHL) have been shown to express the somatostatin receptor on their cell surface and most NHL are visible on somatostatin radioscintigraphy scans. This provided the rationale to conduct a phase II trial of a somatostatin analog in patients with B- and T-cell lymphoproliferative disorders. PATIENTS AND METHODS: Sixty-one patients with measurable or assessable lymphoproliferative disorders (31 stage III or IV low-grade NHL; 21 chronic lymphocytic leukemia [CLL]; and nine cutaneous T-cell NHL [CTCL]) were enrolled. Patients were treated with somatostatin 150 micrograms subcutaneously (SQ) every 8 hours for 1 month. Patients with stable or responding disease received 2 additional months of therapy; those who responded after 3 months were treated for an additional > or = 3 months. RESULTS: Sixty patients were assessable for toxicity and 56 for response. There were no complete remissions. In the low-grade NHL group, 36% (10 of 28 patients; 95% confidence interval [CI], 19% to 56%) had a partial remission. Forty-four percent (four of nine; 95% CI, 14% to 79%) of patients with CTCL had a partial response. No patients with CLL had a partial remission. Among 45 patients with stable disease or a partial remission, the mean time to progression (TTP) was 10.9 months (median, 6.2; range, 1.6 to 48.5). The drug was well tolerated, with the most common side effects being diarrhea and hyperglycemia. CONCLUSION: Somatostatin at a dose of 150 micrograms every 8 hours is well tolerated and has activity in low-grade NHL.

Perioperative blood transfusions do not affect disease recurrence of patients undergoing curative resection of colorectal carcinoma: a Mayo/North Central Cancer Treatment Group study.

PURPOSE: To evaluate the effect of perioperative blood transfusions on colorectal cancer recurrence and patient survival. PATIENTS AND METHODS: A total of 1,051 patients treated with curative surgery for stage II or III colorectal adenocarcinoma were retrospectively studied for the effect of perioperative blood transfusions on disease recurrence and patient survival. Forty-two percent of patients received perioperative blood components. RESULTS: Perioperative transfusions had no effect on disease progression in univariate or multivariate analysis. Tumor stage (P = .0001), locally advanced tumor characteristics (adherence, involvement of adjacent structure, or perforation; P = .0001), location (rectal v colon; P = .0002), grade (P < .001), and cell kinetic profile (nondiploid or high percent synthetic phase [%S]+ percent gap 2 mitosis phase [%G2M]; P = .0003) were the most powerful independent predictors of tumor recurrence. Use of transfusions was associated with an adverse effect on overall survival (P < .004) using multivariate analysis, as well as tumor stage (P = .0001), location (P = .004), grade (P = .001), patient age (P = .0001), sex (P < .04), and cell kinetic profile (P = .0001). In further evaluation of the prognostic effects of transfusions, there was no increased risk of disease recurrence after whole-blood transfusion (P = .14) as compared with packed RBC or no transfusions, although the disease-specific survival for patients who received whole blood was lower than for nontransfused patients (P < .0005) patients who received other blood components (P < .03). CONCLUSION: With transfusion practices that use blood components, most commonly RBCs, medically indicated transfusions to patients with colorectal carcinoma seem to have no impact on disease recurrence. The adverse impact of transfusions on cancer patient survival is more likely due to other unevaluated tumor variables or underlying illness rather than tumor recurrence enhancement by immunosuppression induced by transfusion of blood components.

Randomized clinical trial of tamoxifen alone or combined with fluoxymesterone in postmenopausal women with metastatic breast cancer.

A randomized clinical trial was performed to determine if combination hormonal therapy with tamoxifen (TAM) and fluoxymesterone (FLU) was more efficacious than TAM alone for the treatment of postmenopausal women with metastatic breast cancer. Patients failing TAM could subsequently receive FLU. The dose of both drugs was 10 mg orally twice daily. Objective responses were seen in 50 of 119 TAM patients (42%) and 63 of 119 TAM plus FLU patients (53%) (one-sided P = .05). Time to disease progression distributions were better for TAM plus FLU (median, 350 days v 199 days), but the log rank test only approached statistical significance (one-sided P = .07). Duration of response and survival distributions were similar between the two treatment arms. Toxicities, in terms of androgenic side effects, were greater on the TAM plus FLU regimen. Fifty-two patients are evaluable for response with FLU following TAM and 21 (40%) have achieved a response. We conclude that the advantages in terms of response rate and time to progression observed with TAM plus FLU probably represent a biological effect, but are not of sufficient magnitude to justify the routine clinical use of this combination given the lack of survival advantage and side effects encountered.

A controlled evaluation of combined 5-fluorouracil, doxorubicin, and mitomycin C (FAM) for the treatment of advanced non-small-cell lung cancer.

One hundred eighty-six patients with advanced non-small-cell lung cancer were randomly assigned to treatment with combined 5-fluorouracil, doxorubicin, and mitomycin C (FAM) or combined methotrexate, doxorubicin, cyclophosphamide, and lomustine (MACC). Respective objective regression rates were comparable at 20% and 16%. Distribution of intervals to progression (overall median, 2.8 months) and survival times (overall median, 5.0 months) were essentially identical between the two regimens. The comparability of therapeutic effect was also evident within the subset of 81 patients who had adenocarcinoma cell type, although MACC showed a small advantage in survival after covariate analysis. In large-cell carcinoma, MACC showed a higher regression rate than that of FAM as well as a small advantage in survival. In squamous-cell carcinoma, however, FAM was superior to MACC in regression rates (32% v 4%) and also provided somewhat longer survival. With regard to toxicity, MACC produced a higher incidence of nausea and vomiting, whereas FAM produced more frequent and severe thrombocytopenia. From an overall standpoint, the therapeutic accomplishments of both regimens were disappointing. Our study does, however, provide additional evidence that mitomycin C-containing regimens may be selectively effective for squamous-cell carcinoma of the lung.

Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer.

A randomized clinical trial was performed to compare the efficacy of bilateral oophorectomy with that of tamoxifen at a dose of 10 mg twice daily in premenopausal women with metastatic breast cancer, and to examine the efficacy of each as a crossover treatment. Initial treatment responses were seen in ten of 27 patients (37%) treated with oophorectomy and seven of 26 patients (27%) treated with tamoxifen. The difference was not statistically significant. Crossover responses were seen in five of 15 patients (33%) treated with oophorectomy, including three responses in ten prior tamoxifen nonresponders; and two of 18 patients (11%) treated with tamoxifen. Time to progression distributions were not significantly different during initial treatment, and no significant differences in survival were noted. Thus, there was no overall disadvantage to the use of tamoxifen as opposed to oophorectomy as initial hormonal therapy, and a failure to respond to tamoxifen did not preclude a response to subsequent oophorectomy. Exploratory data analysis within subsets indicated consistent differential treatment effects in the visceral dominant patients. Of the 16 such patients treated with oophorectomy, eight (50%) experienced objective responses but there were no responses in the 14 patients treated with tamoxifen. In the nine visceral dominant crossover patients who had not responded to initial tamoxifen, three (33%) subsequently responded to oophorectomy. Time to progression distributions within the visceral dominant subset appeared to be better for the patients treated initially with oophorectomy. However, one must be very cautious in drawing conclusions from exploratory subset analyses, especially with the small sample size. Further studies would be required to test any hypothesis of differential organ site responsiveness.

Phase III randomized double-blind study to evaluate the efficacy of a polycarbophil-based vaginal moisturizer in women with breast cancer.

PURPOSE: Vaginal dryness and dyspareunia are significant estrogen-depletion symptoms that affect many breast cancer survivors. The present trial was developed to evaluate the nonhormonal vaginal lubricating preparation, Replens, for alleviating these symptoms. MATERIALS AND METHODS: A double-blind, crossover, randomized clinical trial was developed. Patients received 4 weeks of Replens (Columbia Research Laboratories, Rockville Centre, NY) followed by a 1-week washout period followed by 4 weeks of a placebo lubricating product, or vice versa. Weekly patient-completed diaries were used for measuring efficacies and toxicities of therapy. RESULTS: The 45 assessable patients provided well-balanced treatment groups. During the first 4 weeks, average vaginal dryness decreased by 62% and 64% in the placebo and Replens groups, respectively (P = .3). Average dyspareunia scores also improved by 41% and 60%, respectively (P = .05). Crossover analysis indicated that the bulk of the beneficial effects appeared within the first 2 weeks of the first treatment and remained constant thereafter. Both treatments were relatively well tolerated. CONCLUSION: Both Replens and the placebo appear to substantially ameliorate vaginal dryness and dyspareunia in breast cancer survivors.

Phase II trial of irinotecan in patients with metastatic colorectal carcinoma.

PURPOSE: To evaluate the objective tumor response rate and toxicities of patients with metastatic colorectal carcinoma treated with irinotecan hydrochloride (CPT-11). PATIENTS AND METHODS: A total of 121 patients with advanced colorectal carcinoma--90 with prior fluorouracil (5-FU) exposure and 31 chemotherapeutically naive patients--were enrolled between May 1993 and June 1994. Patients were treated with CPT-11 at 125 mg/m2 intravenously weekly for 4 weeks followed by a 2-week rest. RESULTS: Among 90 patients with prior 5-FU chemotherapy, 12 partial responses were observed (response rate, 13.3%; 95% confidence interval [CI], 7.1% to 22.1%). Among 31 chemotherapy-naive patients, eight had partial responses (response rate, 25.8%; 95% CI, 11.9% to 44.6%). The median response duration as measured from time of initial treatment for the two groups was 7.7 months and 7.6 months, respectively. The major adverse reactions were gastrointestinal and hematologic. The incidence of grade 3 or 4 diarrhea was 36.4%, while the overall incidence of grade 3 or 4 leukopenia was 21.5% of patients. Only four of 121 patients (3.3%) developed neutropenic fever (grade 4 neutropenia with > or = grade 2 fever). The incidence of grade 4 leukopenia was higher in patients with prior pelvic radiotherapy (chi2 test P = .04), while the incidence of grade 3 or 4 diarrhea demonstrated no association with previous pelvic irradiation. CONCLUSION: According to the study design, CPT-11 showed promising activity in chemotherapy-naive patients with advanced colorectal carcinoma and modest activity in patients with prior 5-FU exposure. The toxicity with this schedule appears manageable with appropriate dose modification for individual patient tolerance and an intensive loperamide regimen for the management of diarrhea. Care should be taken when treating patients with prior pelvic radiotherapy because of the increased risk of neutropenia.

Adjuvant therapy for resectable colorectal carcinoma with fluorouracil administered by portal vein infusion. A study of the Mayo Clinic and the North Central Cancer Treatment Group.

We randomized 224 patients with resected Dukes' stage B2 or C colorectal cancer to either an untreated control group or to a group receiving 7 days of fluorouracil therapy (500 mg/m2 per day) by portal vein infusion. Randomization was accomplished during surgery after staging by frozen section. Only 5 (2.2%) of our 224 patients were ineligible, but an additional 10 patients assigned to portal vein infusion could not be treated because of technical problems with catheter placement. Toxic reactions were mild. There was only 1 postoperative death on each study arm. At present, the median follow-up for all patients is 5.5 years (range, 1.5 to 9.5 years). Interval to progression and survival curves essentially overlap. The same lack of treatment effect is seen in both the stage B and C subsets.

Evaluation of intravenous 6-thioguanine as first-line chemotherapy in women with metastatic breast cancer.

6-Thioguanine (6-TG) is a purine analog that has marked variability in plasma concentration after oral administration. Following the development of a multiple-day i.v. regimen, we performed a phase II trial of this agent as first-line chemotherapy in women with metastatic breast cancer. Forty-one patients with measurable (31 patients) or evaluable (10 patients) disease were entered into this trial. 6-TG was administered i.v. over a 10 min period daily for 5 consecutive days, with a planned cycle length of 35 days. The daily dosage level was 55 mg/m2 in the first 15 patients, but this was increased to 65 mg/m2 in the remaining patients due to inadequate myelosuppression at the lower dose. Six patients, all with measurable disease, achieved a complete response (CR) (two patients) or a partial response (PR) (four patients). Three responses occurred at the 55 mg/m2 level and three at the 65 mg/m2 level. The 95% confidence interval (CI) for the true response rate among patients with measurable disease was 6-39%. The median time to progression was 140 days and median survival time was 460 days. The regimen was well tolerated. We conclude that 6-TG, as given in this study, has limited activity as first-line chemotherapy for women with metastatic breast cancer.

A phase II trial of edatrexate, vinblastine, adriamycin, cisplastin, and filgrastim (EVAC/G-CSF) in patients with non-small-cell carcinoma of the lungs: a North Central Cancer Treatment Group Trial.

Edatrexate is an antifolate agent with improved in vitro antineoplastic activity as compared with methotrexate. A Mayo phase I trial of edatrexate (E), vinblastine (V), doxorubicin (Adriamycin) (A), cisplatin (C), and filgrastim (GCSF), (EVAC-GCSF) showed promising antineoplastic activity in non-small-cell lung cancer (NSCLC) (Colon-Otero G, et al. Cancer J Sci Am 1997;3:297-302) leading to a phase II trial of this regimen, the results of which are reported here. A total of 34 patients with stage IIIB or IV measurable or evaluable NSCLC were entered in this North Central Cancer Treatment Group phase II study. Treatment consisted of edatrexate 100 mg/m2 intravenously on day 1 and cisplatin 30 mg/m2/d on day 1 and day 2 followed by vinblastine 3 mg/m2 intravenously and doxorubicin 30 mg/m2 intravenously on day 2. Filgrastim was given at 300 microg subcutaneously daily from day 4 to day 18 or until an absolute neutrophil count of 2,000/mm3 or more was obtained. Cycles were repeated every 21 days until either progression or the development of intolerable toxicity. Sixteen of 34 evaluable patients responded to therapy, for a response rate of 47.1% with a 95% CI of 30.3% to 63.8%. Median time to disease progression was 132 days, median survival time was 219 days, and the estimated 1-year survival was 41.2% (95% CI of 27.6-61.5%). The EVAC/G-CSF regimen has significant antineoplastic activity as seen by the response rates for patients with NSCLC. However, this study had significant myelosuppressive toxicity; 56% patients had grade III or higher leukopenia with three treatment-related deaths observed. In addition, Quality of Life assessments indicate that patients experienced an overall decline in quality of life during the course of treatment. These mitigating factors need to be considered regarding further evaluation of this regimen in this patient population.

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.

Paclitaxel and G-CSF in previously untreated patients with extensive stage small-cell lung cancer: a phase II study of the North Central Cancer Treatment Group.

Paclitaxel is an antimicrotubule agent that interferes with cell division. It has demonstrated promising single-agent activity against non-small-cell lung cancer. The purpose of this study was to evaluate the therapeutic effectiveness of paclitaxel in previously untreated patients with extensive stage small-cell lung cancer (SCLC). The study was designed as a two-stage phase II trial. All patients who entered received paclitaxel by intravenous infusion at a dose of 250 mg/m2 during 24 hours. Granulocyte colony stimulating factor was also provided to ameliorate neutropenia. Cycles were repeated at 21-day intervals. Patients who achieved a complete response received a maximum of 10 cycles of treatment, whereas those who achieved a partial response/regression continued treatment until progression or undue toxicity developed. Patients who progressed or maintained stable disease for six cycles were crossed over to cisplatin and etoposide. Forty-three patients entered the study and all were evaluable for analysis. Responses were observed in 23 (53%) of the patients. There was no significant difference in the response rates in patients with measurable or evaluable disease (13/23 versus 10/20, p = 0.76). At the time of analysis, 39 patients had progressed with a median time to progression of 95 days, and 39 patients had died with a median survival of 278 days. The 1-year achieved survival rate was 24%. Significant neutropenia (absolute neutrophil count <1,000/microl) occurred in 24 (56%) of the patients, but only 2 patients experienced severe infection (grade > or = 3), and there were no septic deaths. The results indicate that paclitaxel is active against SCLC. Myelosuppression was the main side effect in this patient population. Response duration was short (median = 3.4 months), which suggests that paclitaxel is not sufficient as a single agent. Further studies of paclitaxel in combination with other agents against SCLC are currently in progress within the North Central Cancer Treatment Group and other cancer treatment groups. Key Words: Paclitaxel-G-CSF-Small-cell lung cancer-North Central Cancer Treatment Group.

Neuropeptide Y, leptin, and cholecystokinin 8 in patients with advanced cancer and anorexia: a North Central Cancer Treatment Group exploratory investigation.

BACKGROUND: Anorexia is a noxious symptom, and over half of patients with advanced cancer experience it. Neuropeptide Y (NPY), leptin, and cholecystokinin 8 (CCK8) have been implicated. METHODS: This exploratory study 1) compared circulating concentrations of NPY and leptin between anorectic cancer patients and historic controls and 2) explored whether NPY, leptin, or CCK8 may serve as correlates of anorexia severity. Cancer patients met predefined eligibility criteria: 1) weight loss > or = 2.3 kg over the preceding 2 months and/or a physician-estimated caloric intake of < 20 calories per kilogram of body weight per day and 2) patient acknowledgment that appetite or weight loss was an ongoing problem. RESULTS: Seventy-three cancer patients were studied, and > 90% reported a > or = 50% decline in appetite from baseline in the preceding 2 months. NPY levels were lower than control values: mean +/- standard deviation, 466 pg/mL +/- 161 pg/mL versus 560 pg/mL +/- 151 pg/mL, respectively (P = 0.004). Because a few (but not all) earlier studies suggested an age-related decline in NPY levels, a subgroup analysis was performed and found no age-adjusted difference in NPY levels between groups. Similarly, leptin concentrations were not different between groups. Significant correlations were not observed between anorexia severity and NPY, leptin, or CCK8 levels. CONCLUSIONS: There were no differences in leptin and CCK8 levels between anorectic cancer patients and historic controls. Circulating concentrations of NPY, leptin, and CCK8 did not correlate with anorexia severity. However, the current results suggest a need for further examination of NPY in cancer-associated anorexia.

A phase II randomized trial of megestrol acetate or dexamethasone in the treatment of hormonally refractory advanced carcinoma of the prostate.

The results of a randomized, multicenter, cooperative group trial evaluating hormonal therapy with either megestrol acetate or dexamethasone in advanced, hormonally refractory prostate cancer are reported. Three of 29 patients (approximately 10%) on the megestrol acetate arm experienced an objective response lasting 41, 84, and 202 days, respectively, whereas two of 29 patients (approximately 7%) on the dexamethasone arm achieved an objective response lasting 359 and 512 days, respectively. Twenty of 29 patients (approximately 69%) on the megestrol acetate arm had stable disease lasting for a median duration of 117 days, whereas 21 of 29 patients (72%) on the dexamethasone arm had stable disease for a median duration of 86 days. Median survival of all patients was 9 months from initiation of treatment. The median survival of all patients on the megestrol acetate arm was 268 days compared to 246 days for patients on the dexamethasone arm (P = 0.2). Neither dexamethasone nor megestrol acetate would seem to be of substantive value in altering the progression of advanced, hormonally refractory prostate cancer.

A Phase II trial of cisplatin plus WR-2721 (amifostine) for metastatic breast carcinoma: an Eastern Cooperative Oncology Group Study (E8188).

BACKGROUND: Cisplatin has minimal antitumor activity when used as second- or third-line treatment of metastatic breast carcinoma. Older reports suggest an objective response rate of 8% when 60-120 mg/m2 of cisplatin is administered every 3-4 weeks. Although a dose-response effect has been observed with cisplatin, the dose-limiting toxicities associated with cisplatin (e.g., nephrotoxicity, ototoxicity, and neurotoxicity) have limited its use as a treatment for breast carcinoma. WR-2721 or amifostine initially was developed to protect military personnel in the event of nuclear war. Amifostine subsequently was shown to protect normal tissues from the toxic effects of alkylating agents and cisplatin without decreasing the antitumor effect of the chemotherapy. Early trials of cisplatin and amifostine also suggested that the incidence and severity of cisplatin-induced nephrotoxicity, ototoxicity, and neuropathy were reduced. METHODS: A Phase II study of the combination of cisplatin plus amifostine was conducted in patients with progressive metastatic breast carcinoma who had received one, but not more than one, chemotherapy regimen for metastatic disease. Patients received amifostine, 910 mg/m2 intravenously over 15 minutes. After completion of the amifostine infusion, cisplatin 120 mg/m2 was administered over 30 minutes. Intravenous hydration and mannitol was administered before and after cisplatin. Treatment was administered every 3 weeks until disease progression. RESULTS: Forty-four patients were enrolled in the study of which 7 (16%) were ineligible. A median of 2 cycles of therapy was administered to the 37 eligible patients. Six partial responses were observed for an overall response rate of 16%. Most patients (57%) stopped treatment because of disease progression. Neurologic toxicity was reported in 52% of patients. Seven different life-threatening toxicities were observed in patients while receiving treatment. CONCLUSIONS: The combination of cisplatin and amifostine in this study resulted in an overall response rate of 16%. Neither a tumor-protective effect nor reduced toxicity to normal tissues was observed with the addition of amifostine to cisplatin in this trial.