Controlled evaluation of three drug combination regimens versus fluorouracil alone for the therapy of advanced gastric cancer. North Central Cancer Treatment Group.

PURPOSE: The purpose of this study was to evaluate the therapeutic effectiveness of fluorouracil (5-FU), doxorubicin, and methyl lomustine (CCNU) (FAMe), 5-FU, doxorubicin, and cisplatin (FAP), and FAMe alternating with triazinate (TZT) when compared with a standard therapy of 5-FU alone in patients with advanced gastric cancer. PATIENTS AND METHODS: Two hundred fifty-two eligible patients selected for study had proven locally unresectable and/or metastatic gastric adenocarcinoma. The majority had nonmeasureable disease. They were randomly assigned to receive one of the three drug combination regimens or to 5-FU alone administered by rapid injection in 5-day course. Survival was the primary study end point. RESULTS: None of the three drug combinations showed a significant advantage over 5-FU alone in improved performance score, weight gain, or patient survival. Each of the three combinations was more toxic than 5-FU alone. CONCLUSION: FAMe, FAP, or FAMe alternating with TZT cannot be recommended for the therapy of advanced gastric carcinoma. Therapy of this disease should remain an experimental endeavor. It would seem reasonable to prove the value of any new treatment approach by a randomized comparison to simple therapy with 5-FU alone.

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.

Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.

The purpose of this study was to evaluate the effectiveness of several new approaches designed to enhance the activity of fluorouracil (5-FU) in the management of advanced colorectal cancer. A total of 429 patients were randomized to one of the following regimens: single-agent 5-FU, given by standard 5-day, intensive-course intravenous bolus technique; 5-FU plus high-dose folinic acid (leucovorin) or 5-FU plus low-dose leucovorin; 5-FU plus high-dose methotrexate (MTX) with oral leucovorin rescue; 5-FU plus low-dose MTX; and 5-FU plus cisplatin (CDDP). The median survival for patients receiving 5-FU alone was 7.7 months. The high- and low-dose leucovorin plus 5-FU regimens had median survivals of 12.2 and 12.0 months, respectively, and offered a significant survival advantage over 5-FU alone with one-sided P values of .037 and .050, respectively (P = .051 for each treatment after correction for prognostic variables). The only other regimen possibly associated with improved survival was high-dose MTX plus 5-FU, with a median survival of 10.5 months (P = .21, P = .076 corrected). In addition, both high- and low-dose leucovorin plus 5-FU regimens were associated with significantly improved tumor response rates (P = .04 and .001) and significantly improved interval-to-tumor-progression rates (P = .015 and .007) when compared with 5-FU alone. Only the low-dose leucovorin plus 5-FU regimen was associated with significant (P less than .05) superiority in each of the following parameters of quality of life: performance status, weight gain, and symptomatic relief. The overall most therapeutically favorable regimen in this trial was 5-FU given with low-dose leucovorin; fortuitously, this regimen is associated with very low drug cost. Whereas this is the first study to demonstrate both improved palliation and survival for any regimen compared with 5-FU given by rapid intravenous (IV) injection for 5 consecutive days at a dose of 500 mg/m2/d in patients with advanced colorectal cancer, the magnitude of the gain is still relatively small. Our low-dose leucovorin plus 5-FU regimen is currently being studied in a national trial with the hope that this increased advanced disease activity may produce more substantive gains in the surgical adjuvant setting.

Alternating chemotherapy with or without VP-16 in extensive-stage small-cell lung cancer.

In this study, we evaluated the role of alternating chemotherapy with or without etoposide (VP-16) in patients with extensive-stage small-cell carcinoma (SCC) of the lung. All patients received initial treatment with CMC [cyclophosphamide, methotrexate, and chloroethyl-cyclohexyl-nitrosourea (CCNU)]. Four weeks after initial treatment, patients were stratified by performance score, central nervous system (CNS) metastasis, age, and response to initial CMC therapy and randomized to receive AO (doxorubicin and vincristine) or AVO (doxorubicin, VP-16, and vincristine) alternating with CMC. One hundred eighty-two eligible patients were treated with the initial cycle of CMC and 98 responded (54%). One hundred fifty-four patients were randomized to either AO/CMC or AVO/CMC. The response rates to AO/CMC and AVO/CMC were similar (72 vs. 68%). The time to progression and survival were not significantly different on the two treatment regimens. Toxicity was significantly greater for patients receiving AVO/CMC with six treatment-related deaths. Etoposide as used in this regimen did not significantly influence response rates, time to progression, or survival of patients with extensive small-cell lung cancer.

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 trial to evaluate the addition of tamoxifen to cyclophosphamide, 5-fluorouracil, prednisone adjuvant therapy in premenopausal women with node-positive breast cancer.

A randomized clinical trial was performed to determine if the addition of hormonal therapy with tamoxifen to a combination chemotherapy regimen was superior to the chemotherapy alone for adjuvant treatment of premenopausal women after mastectomy for node-positive breast cancer. The chemotherapy regimen utilized consisted of cyclophosphamide (C), 5-fluorouracil (F), and prednisone (P), and the doses employed were: C, 150 mg/m2 IV days 1 to 5; F, 300 mg/m2 IV days 1 to 5; and P, 10 mg orally three times daily on days 1 to 7. A total of ten courses of therapy, given every 6 weeks, was planned. Tamoxifen (T) was given at a dose of 10 mg twice daily and was stopped 6 weeks after the last course of CFP. Four hundred patients are fully eligible and evaluable. With a median observation time of 5.3 years, the proportion of recurrences on each arm were: CFP, 95 of 202 (47%); CFPT, 77 of 198 (39%). The relapse-free survival distribution for CFPT was superior to that for CFP, at a borderline level of significance (two-sided P = 0.06). When significant prognostic factors were considered in covariate analysis, CFPT was not significantly better than CFP (P = 0.43). This marked change in level was due to imbalance in several factors not considered in stratification. Currently, 31% of CFP and 25% of CFPT patients have died, and although there is a slight separation of the survival curves in favor of CFPT, the difference is not significant (P = 0.21). Analysis within receptor subsets also showed no significant advantage for the addition of tamoxifen. This study does not establish a significant advantage for the concurrent administration of tamoxifen with the CFP regimen. It does, however, clearly demonstrate the importance of examination of clinically important prognostic factors, even those not utilized in stratification, and consideration of these factors in covariate analysis if imbalances are present.

Results of salvage hormonal therapy and salvage chemotherapy in women failing adjuvant chemotherapy after mastectomy for breast cancer.

We have evaluated the results of salvage systemic therapy in 257 patients with breast cancer recurrent after surgical adjuvant treatment with cyclophosphamide, fluorouracil, and prednisone (CFP) with or without tamoxifen. The overall objective response rate to salvage hormonal therapy was 29% (47 responses in 161 patients) and to salvage chemotherapy was 28% (43 responses in 156 patients). Response rates to salvage chemotherapy were similar whether or not prior salvage hormonal therapy or local modalities had been administered. Retreatment with CFP as a salvage chemotherapy yielded responses in 11 of 44 patients (25%). Response rates were similar for patients who began salvage CFP less than or equal to 12 months or greater than 12 months after completion of adjuvant CFP. We conclude that when this unselected population of patients failing adjuvant CFP is considered, 1) response rates to salvage chemotherapy were low regardless of whether or not prior salvage hormonal or local therapies were given, 2) repeating adjuvant chemotherapy (CFP) following relapse produced a low response rate, and 3) response rates to salvage hormonal therapy were low, but on the order of those observed in patients with advanced disease unselected by estrogen receptor status who are treated with first line hormonal maneuvers.

Randomized trial of observation versus adjuvant therapy with cyclophosphamide, fluorouracil, prednisone with or without tamoxifen following mastectomy in postmenopausal women with node-positive breast cancer.

Following mastectomy for node-positive breast cancer, 261 postmenopausal women were randomized to observation or adjuvant treatment with cyclophosphamide, fluorouracil, prednisone (CFP) alone or combined with tamoxifen (T). Doses used were: C, 150 mg/m2 intravenously (IV) days 1 to 5; F, 300 mg/m2 IV days 1 to 5; P, 10 mg by mouth 3 times daily on days 1 to 7; and T, 10 mg by mouth 2 times daily. A total of ten courses of treatment, administered every 6 weeks, was planned and T was stopped 6 weeks after the last course of CFP. Two hundred thirty-four patients were fully eligible and evaluable. With a median observation time slightly in excess of 5 years, the proportion of recurrences on each arm were: CFP, 29 of 75 (39%); CFPT, 29 of 71 (41%); and observation, 50 of 88 (57%). Relapse-free survival distributions for both CFP and CFPT were superior to observation (both two-sided P = .01). Considering prognostic factors in covariate analysis revealed two-sided P = .0006 for CFP v observation and P = .0003 for CFPT v observation. No substantial difference was identified between CFP and CFPT. Survival data are not yet mature with 31% dead; and, although slight separations of the curves exist in favor of the treatment arms, no significant differences in survival have been seen. Both adjuvant therapy programs are well tolerated and there were no treatment-related deaths. Further maturation of the data is required to determine if the advantages in relapse-free survival will be translated into any overall survival benefit which must be considered the goal of primary interest.

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.

Phase II studies of bleomycin, cyclophosphamide, doxorubicin and cisplatin, and bleomycin and cisplatin in advanced cervical carcinoma.

In a randomized phase II trial of two cisplatin-based chemotherapy regimens, 45 patients with advanced cervical carcinoma received a combination of bleomycin, cyclophosphamide, doxorubicin, and cisplatin (BCAP), and 45 others received bleomycin plus cisplatin (BP). BCAP was repeated every 4 weeks, and BP was given at 3-week intervals. Although 19 of 43 (44%) evaluable patients receiving BCAP and 16 of 42 (38%) evaluable patients receiving BP experienced tumor regression, only 22% of those receiving BCAP and 21% of those on BP survived 1 year after beginning treatment. Among bidimensionally measurable patients, 15 of 27 (56%) and 8 of 25 (32%) receiving BCAP and BP, respectively, achieved tumor regression. One patient died of bleeding resulting from severe myelosuppression on BCAP, and two others succumbed to pulmonary toxicity of bleomycin on the BP regimen. Although active against cervical carcinoma, these regimens have limited therapeutic value at this advanced stage of the disease.

Phase II study of bisantrene administered by continuous 72-hour infusion for advanced pancreatic adenocarcinoma.

Eighteen ambulatory patients who had proven metastatic adenocarcinoma of the pancreas and measurable disease but no previous chemotherapy were treated with bisantrene given by constant central intravenous infusion over 72 hours at a total dose of 300 mg/m2 repeated every 3 to 4 weeks. No objective regression was seen. The median interval to progression was 6 weeks; the median survival was 14 weeks. Primary toxic reactions were nausea, vomiting, and leukopenia. In no instance were these life-threatening. When administered by the method we used, bisantrene cannot be recommended for treatment of advanced pancreatic adenocarcinoma.

Phase II studies of single-agent cimetidine and the combination N-phosphonacetyl-L-aspartate (NSC-224131) plus L-alanosine (NSC-153353) in advanced malignant melanoma.

We conducted parallel phase II trials of cimetidine as a single agent and the combination N-phosphonacetyl-L-aspartate (PALA) plus L-alanosine among 40 previously untreated patients with biopsy-proven, measurable disseminated malignant melanoma. We did not design the trial to be a comparative assessment of the two regimens. Among 19 patients treated with cimetidine, 300 mg orally four times daily, there was one complete response of extensive pleural and pulmonary metastases for 16+ months and two partial regressions of soft tissue lesions for 7 and 21+ months, respectively. Among 21 patients treated with the combination regimen, there was only one partial response in soft tissue for 1 month. The median times to progression and death were 1.4 and 6 months, respectively, for cimetidine, and 1.3 and 4 months, respectively, from the combination of PALA plus L-alanosine. Among patients who progressed on initial treatment, there were no responses in 12 who received crossover therapy with cimetidine and 11 with the combination regimen. Two patients treated with the combination program had severe stomatitis, two developed renal failure, and one had severe leukopenia and thrombocytopenia. Recognizing the limitations of small sample size, these early observations suggest that cimetidine may have intriguing implications in the management of disseminated malignant melanoma.

Ineffectiveness of tamoxifen in advanced endometrial carcinoma after failure of progestin treatment.

Between May 1980 and November 1983, 46 eligible patients with advanced, objectively evaluable endometrial carcinoma were treated with tamoxifen, 10 mg twice daily. Twenty-two of the patients had previously received progestational agents. None of the progestin-refractory patients experienced tumor regression on tamoxifen treatment, while five of the 24 previously untreated with progestins did experience tamoxifen-induced tumor regression. Of the five patients previously treated with cytotoxic drugs, only one experienced objective tumor regression on tamoxifen. Although 28 of these 46 patients were completely ambulatory at the beginning of tamoxifen treatment, only 26% were alive 1 year later; median survival for the entire group was only 120 days. Tamoxifen in this dose cannot be recommended routinely as effective secondary treatment for patients with progestin-refractory advanced endometrial carcinoma.

A controlled evaluation of recent approaches to biochemical modulation or enhancement of 5-fluorouracil therapy in colorectal carcinoma.

Three hundred thirty-five previously untreated patients with advanced colorectal carcinoma were randomly assigned to treatment with 5-fluorouracil (5-FU) alone, 5-FU plus N-(phosphonacetyl)-L-aspartic acid (PALA), 5-FU plus high-dose thymidine, 5-FU plus levamisole, or 5-FU plus methyl CCNU, vincristine, and streptozotocin (MOF-Strept). Dosages were designed to produce definite toxicity in the majority of patients, although the nature of dose-limiting reactions varied considerably among regimens. 5-FU alone and 5-FU plus levamisole produced mucocutaneous reactions, diarrhea, and leukopenia; 5-FU plus PALA produced primarily mucocutaneous reactions and diarrhea; 5-FU plus thymidine produced leukopenia with occasional neurotoxicity and hypotension; and MOF-Strept produced substantial nausea and vomiting with both thrombocytopenia and leukopenia. Objective response rates among patients with measurable disease varied from 12% (5-FU plus PALA) to 34% (MOF-Strept), but none of the regimens were significantly superior to 5-FU alone. Both interval to progression and survival were comparable among the five regimens with no reasonable chance that any combination regimen could produce as much as a 50% improvement when compared with 5-FU alone. Whereas we observed definite modulation of 5-FU dose--toxicity relationships, particularly with the thymidine and PALA combinations, this did not result in a detectable improvement in therapeutic effect. None of the combination regimens, administered in the dosages and schedules we used, can be recommended as standard therapy of advanced colorectal carcinoma.

Comparison of cyclophosphamide plus cisplatin versus hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin in combination as initial chemotherapy for stage III and IV ovarian carcinomas.

Among 187 women with stage III and IV ovarian carcinoma who participated in this comparative clinical trial, 181 were eligible for analysis. Of these patients, 89 received monthly treatment with CP [cyclophosphamide (1 g/m2) plus cisplatin (60 mg/m2)] and 92 received monthly treatment with HCAP [hexamethylmelamine (150 mg/m2/day X 7), cyclophosphamide (400 mg/m2), doxorubicin (30 mg/m2), and cisplatin (60 mg/m2)]. All treatments were administered iv on Day 1 of each monthly treatment cycle, except for hexamethylmelamine, which was administered orally on Days 2-8. With a median follow-up time of 30 months, survival curves for the two treatment groups were almost identical, as were their times to progression [estimated median survival, 24.6 months (Kaplan-Meier)]. Patient characteristics which significantly influenced survival were age, degree of histologic differentiation, extent of residual disease, stage of disease, and histologic type. Results of posttreatment laparotomies have been equal for the two treatment groups. Toxic effects of the two regimens have been similar, except for more frequent, more severe, and earlier neurotoxicity among patients treated with HCAP. Of the two regimens, CP has the better therapeutic index.

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.

Randomized clinical trial of cyclophosphamide, 5-FU, and prednisone with or without tamoxifen in postmenopausal women with advanced breast cancer.

The purpose of this study was to determine if tamoxifen added to the efficacy of a CFP (cyclophosphamide, 5-FU, and prednisone) regimen. One hundred thirty-one postmenopausal women with advanced breast cancer without prior chemotherapy exposure were randomized to receive CFP alone or combined with tamoxifen; six were disqualified because of ineligibility. Objective responses were seen in 68% of the eligible patients receiving CFP and in 61% of those receiving CFP plus tamoxifen. Median times to progression were 287 days for CFP and 158 days for CFP plus tamoxifen (two-sided log-rank test of equality of progression distributions, P = 0.07). Median survival times were 544 days for CFP and 394 days for CFP plus tamoxifen (two-sided log-rank test of equality of survival distributions, P = 0.14). The addition of tamoxifen to CFP was not associated with longer time to progression or survival in any Cox covariate model. On the basis of our data, it can be concluded that the addition of tamoxifen to CFP does not substantially improve either the time to disease progression or survival in women with metastatic breast cancer.

Neuromyopathy of cyanide intoxication due to "laetrile" (amygdalin). A clinicopathologic study.

A 67-year-old woman with lymphoma presented with a neuromyopathy following "laetrile" (amygdalin) treatment. She had significant elevation of blood and urinary thiocyanate and cyanide levels. Sural nerve biopsy specimen revealed a mixed pattern of demyelination and axonal degeneration, the latter being prominent. Gastrocnemius muscle biopsy specimen showed histochemically a mixed pattern of denervation and myopathy with Type II atrophy. It is concluded that cyanide toxicity secondary to laetrile therapy and nutritional deficiency caused the neuromyopathy, as the changes in peripheral nerve are similar to changes described in ataxic polyneuropathy occurring in Nigeria attributed to high cyanide content in the diet and nutritional deficiency. Although this patient received vincristine initially, the development of the neuromyopathy had no temporal relationship to its administration. The clinical profile, as well as peripheral nerve and muscle changes were not similar to either vincristine neuromyopathy or neuromyopathy due to paraneoplastic manifestation of lymphoma. Clinical improvement following discontinuation of "laetrile" by the patient further supports the toxic etiologic results for the neuromyopathy in this patient.