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.

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 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.

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.

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.

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.

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.

Chemotherapy for hormonally refractory advanced prostate carcinoma. A comparison of combined versus sequential treatment with mitomycin C, doxorubicin, and 5-fluorouracil.

One hundred forty-two patients with progressive, hormonally refractory advanced prostate carcinoma who had not received prior chemotherapy were randomized to receive either combination chemotherapy with 5-fluorouracil (5-FU), doxorubicin, and mitomycin C (FAM) or sequential chemotherapy with the same agents, i.e., mitomycin C, followed by doxorubicin on disease progression, followed by 5-FU. Objective tumor regressions were observed in 10 of 70 (14%) patients receiving the FAM treatment arm and 10 of 72 (14%) patients initially receiving mitomycin C. Of the 24 patients who received secondary therapy with doxorubicin alone, 3 (12.5%) achieved objective tumor regression. There were no responses among five patients who received tertiary therapy with 5-FU alone. The median survival time for all patients treated with the combination arm was 8.7 months, compared with 7.1 months for patients who received the FAM arm (P = 0.025). However, this modest survival advantage in favor of the FAM treatment arm must be weighed against significantly more myelosuppression experienced by these patients. The chemotherapeutic regimens used in this study have only minor clinical value in the treatment of hormonally refractory advanced prostate cancer.

A double-blind trial of tamoxifen plus prednisolone versus tamoxifen plus placebo in postmenopausal women with metastatic breast cancer. A collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic.

This trial was conducted to determine if the reported superiority of tamoxifen (TAM) plus prednisolone (PRDLN) over TAM alone in postmenopausal women with metastatic breast cancer could be corroborated. A total of 326 patients were randomized on a double-blind trial to TAM (10 mg twice daily) plus placebo or TAM plus PRDLN (5 mg twice daily). Six patients (2%) were disqualified. Considering 256 patients with measurable or evaluable disease, objective responses were seen in 48 (38%) of 126 TAM patients and 61 (47%) of 130 TAM plus PRDLN patients (chi-square, P = 0.15). Considering all 320 evaluated patients, median time to disease progression was 11 months for TAM and 10 months for TAM plus PRDLN (log rank, P = 0.81), and median survival time was 35 and 32 months, respectively (P = 0.40). Covariate analyses showed no significant association between treatment and outcome. Weight gain and edema were significantly greater with TAM plus PRDLN. The addition of PRDLN to TAM is not advocated for the management of postmenopausal women with metastatic breast cancer.

Combination hormonal therapy with tamoxifen plus fluoxymesterone versus tamoxifen alone in postmenopausal women with metastatic breast cancer. An updated analysis.

A randomized trial was performed to determine if therapy with tamoxifen (TAM) plus fluoxymesterone (FLU) was more efficacious than TAM alone for 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 (42%) TAM patients and 64 of 119 (54%) TAM plus FLU patients (two-sided P = 0.07). Time to disease progression was better for TAM plus FLU (medians: 11.6 versus 6.5 months; Cox model, P = 0.03). Duration of response and survival were similar in the two treatment arms. Among 97 patients with estrogen receptor (ER) of 10 or greater and 65 years of age or older, there were highly significant advantages for treatment with TAM plus FLU in both response rate and time to progression. Of particular note is that in this patient group TAM plus FLU showed a survival advantage (Cox model, P = 0.05). Although these data require confirmation in a prospective randomized trial, they suggest that there is a substantive therapeutic advantage for TAM plus FLU over TAM alone in elderly women with ER of 10 fmol or greater.

A clinical trial of biochemical modulation of 5-fluorouracil with N-phosphonoacetyl-L-aspartate and thymidine in advanced gastric and anaplastic colorectal cancer.

A novel sequential administration schedule of PALA (N-phosphonoacetyl-L-aspartate) and thymidine to enhance the cytotoxic effect of 5-fluorouracil (5FU) was tested in 36 patients with advanced gastric cancer and 21 patients with advanced poorly differentiated (anaplastic) colorectal cancer. The potency of 5FU was dramatically increased as indicated by the observation of dose-limiting leukopenia at less than one tenth the maximum tolerated dose of 5FU when given as a single agent by intravenous bolus technique. Twenty-five percent of gastric cancer patients and 33% of colorectal cancer patients experienced an objective tumor response, including three patients with complete response. However, response duration was brief (median, 6 months), and there were four treatment-related fatalities due to severe and unpredictable leukopenia leading to sepsis. Survival was short with a median of 6 months for gastric cancer patients and 3 1/2 months for colorectal cancer patients. We conclude that therapeutic index of 5FU was not improved by the addition of PALA and thymidine in this patient population based on considerations of objective tumor response rate, patient survival, and toxicity.

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.

Randomized clinical trial of CFP versus CMFP in women with metastatic breast cancer.

A randomized trial was performed to determine relative efficacy and toxicity of two first-line combination chemotherapy regimens in women with metastatic breast cancer: CFP (cyclophosphamide, 5-fluorouracil, prednisone) and CMFP (cyclophosphamide, 5-fluorouracil, methotrexate, prednisone). Both regimens have reported efficacy in this setting but differ in dosages and scheduling of the agents they have in common. Three hundred thirty-six women with no prior chemotherapy for metastatic disease were eligible and evaluable, and 309 had either measurable or evaluable disease and were assessable for objective response. Responses were seen in 65 of 153 (42%) on CFP and 83 of 156 (53%) on CMFP (two-sided P = 0.06). Median durations of response were 7.1 months for CFP and 8.5 months for CMFP (log-rank, two-sided P = 0.67). Considering all 336 patients, the median times to disease progression were 4.7 months for CFP and 6.2 months for CMFP (log-rank P = 0.31) and median survivals were 15.2 and 14.9 months, respectively (log-rank P = 0.88). Covariate analysis did not alter these findings. Median leukocyte nadirs were 1800 for CFP and 1500 for CMFP, with 22% and 21%, respectively, having nadirs less than 1000/microliters. Emesis was more frequent on CFP (49%) than on CMFP (26%) but was severe in only 7% and 5%, respectively. It is concluded that despite a higher response rate on CMFP and some differences in toxicities including a higher reported incidence of emesis on CFP, there was no substantial difference in efficacy or tolerability between the two regimens.

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.

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.

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.

A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin.

Three hundred five patients with advanced pancreatic and gastric carcinoma were randomly assigned to treatment with fluorouracil, fluorouracil plus doxorubicin (Adriamycin) (FA), or fluorouracil plus doxorubicin plus mitomycin (mitomycin C) (FAM). All regimens were equivalent with regard to patient survival. There is no reasonable likelihood that either the FA or FAM regimen could produce a meaningful survival advantage over fluorouracil alone. Interval to disease progression, objective response rates, and palliative effects (improved performance, body weight, or symptoms) were essentially equivalent among the three regimens. With regard to toxicity, the FAM regimen produced more anorexia, nausea, vomiting, leukopenia, thrombocytopenia, and cumulative bone marrow suppression. Fluorouracil alone produced more stomatitis and diarrhea. Because of a failure to produce improved survival or palliation, unrewarded toxicity, and excessive cost, neither the FA nor FAM regimen can be recommended for the treatment of advanced pancreatic or gastric cancer.