Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer.

PURPOSE: To compare two commonly used schedules of fluorouracil (5FU) and leucovorin in the treatment of patients with advanced metastatic colorectal cancer. Each of these dosage administration schedules has been demonstrated to be superior to single-agent bolus 5FU in previous controlled trials. PATIENTS AND METHODS: Three hundred seventy-two ambulatory patients with metastatic colorectal cancer were stratified according to performance status, and presence and location of any measurable indicator lesion(s). They were then randomized to receive chemotherapy with one of the following regimens: (1) intensive-course 5FU plus low-dose leucovorin (5FU 425 mg/m2 plus leucovorin 20 mg/m2 intravenous [IV] push daily for 5 days with courses repeated at 4- to 5-week intervals); (2) weekly 5FU plus high-dose leucovorin (5FU 600 mg/m2 IV push plus leucovorin 500 mg/m2 as a 2-hour infusion weekly for 6 weeks with courses repeated every 8 weeks). RESULTS: Three hundred sixty-two of 372 patients randomized (97.3%) were eligible and included in the analysis. Three hundred forty-six patients (95.6%) have died. There were no significant differences in therapeutic efficacy between the two 5FU/leucovorin regimens tested with respect to the following parameters: objective tumor response (35% v 31%), survival (median, 9.3 v 10.7 months), and palliative effects (as assessed by relief of symptoms, improved performance status, and weight gain). There were significant (P < .05) differences in toxicity, with more leukopenia and stomatitis seen with the intensive-course regimen, and more diarrhea and requirement for hospitalization to manage toxicity with the weekly regimen. Financial cost was also higher with the weekly regimen. CONCLUSION: Intensive-course 5FU plus low-dose leucovorin appears to have a superior therapeutic index compared with weekly 5FU plus high-dose leucovorin using the dosage administration schedules applied in this study based on similar therapeutic effectiveness, but lower financial cost, and less need for hospitalization to manage chemotherapy toxicity.

A randomized prospective assessment of recombinant leukocyte A human interferon with or without aspirin in advanced renal adenocarcinoma.

We performed a prospective, controlled trial of recombinant leukocyte A interferon (IFN-alpha 2A) with or without aspirin (ASA) in 176 patients with assessable advanced renal cell cancer in light of a 34% response rate (10 of 29 patients) from the two-agent regimen in an earlier nonrandomized trial. This encouraging result was substantially higher than the 15% response rate typically achieved with IFN therapy alone. Eighty-seven patients received IFN-alpha 2A 20 x 10(6) U/m2 intramuscularly three times a week, and 89 received the same IFN therapy with ASA 600 mg orally four times each day. Each group was balanced as to relevant prognostic discriminants. Response rates were 8% for the group receiving ASA in addition to IFN, and 13% for the group receiving IFN alone (P = .30). The median times to progression were 1.9 months for the group receiving IFN with ASA and 2.7 months for the group receiving IFN alone (log-rank P = .36). The median survival durations were 8.8 months for the IFN and ASA group and 8.0 months for the IFN-only group (log-rank P = .60). These figures are also inferior to those typically reported from other studies. Our findings reemphasize the crucial role of randomized trials, admittedly cumbersome and time-consuming, to determine accurately the value of apparently promising therapies. Although some patients may derive benefit from IFN therapy, our findings raise disturbing questions regarding the potential IFN-alpha 2A according to the dose and schedule used in this trial to have any substantive impact on the ultimate outcome of disseminated renal cell cancer.

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.

Pharmacokinetics of 5-fluorouracil administered orally, by rapid intravenous and by slow infusion.

Pharmacokinetic studies of 5-fluorouracil (5-FUra) were performed on 18 patients divided into three groups: seven patients were given 5-FUra i.v. by rapid injection; five patients received the drug p.o.; and six patients were treated by continuous i.v. infusion for 96 hr. The results showed rapid i.v. injection to be manifested by high early levels of drug achieved both in plasma and bone marrow with a rapid fall afterwards. Administration of 5-FUra p.o. gave rise to erratic plasma values due to greater variability in absorption, whereas 96-hr i.v. infusions showed constant levels of the drug in plasma and significantly (50- to 1000-fold) less 5-FUra in bone marrow. The main difference observed between rapid injection and slow infusion in the kinetics of the drug was the very high level of 5-FUra reached by rapid injection in plasma and bone marrow, which was of short duration (min) when compared to the low sustained levels observed during infusion. This route-dependent pharmacokinetic profile is consistent with the reported absence of myelosuppression in prolonged infusion and may be related to the resultant lower levels of 5-FUra achieved in bone marrow.

Clinical trial of rubidazone in advanced squamous cell carcinoma of the lung and adenocarcinoma of the large intestine.

Sixteen patients with disseminated squamous cell carcinoma of the lung and 26 patients with adenocarcinoma of the colon and rectum were given rubidazone. Only one partial remission was observed in a previously untreated patient who had local recurrence of a rectal adenocarcinoma. The main toxic effects observed in previously treated patients consisted of leukopenia and thrombocytopenia. Also observed were anorexia, nausea, vomiting, alopecia, fever, and chills. Cardiotoxicity was observed in one patient after a total dose of 720 mg/m2 of rubidazone. It is concluded that rubidazone is a relatively inactive compound in the management of these two diseases.

Mitomycin-C alone and in combination with infused 5-fluorouracil to the treatment of disseminated gastrointestinal carcinomas.

One hundred and thirty-two previously untreated patients with metastatic adenocarcinoma of the gastrointestinal (GI) tract were randomized to receive either a 120-hr infusion of 5-fluorouracil (5FU) with mitomycin-C or mitomycin-C alone. Superiority of the combination treatment was demonstrated with remissions in 30 out of 82 (37%) patients versus 9 out of 50 (18%) with the single drug treatment (P = 0.02). The median survial with 5FU--mitomycin-C was 29 weeks, as opposed to 20 weeks with mitomycin-C alone (P = 0.03). The combination produced significantly more severe myelotoxicity than the single drug, and jaundiced patients experienced more myelosuppression than non-jaundiced patients with both treatments.

Combined therapy for cancer of the anal canal: a follow-up report.

We believe this preoperative combined therapy is highly effective in treating squamous-cell carcinoma of the anal canal, and that a subsequent larger cooperative study with controls is indicated. This pilot study suggests that some individuals may be spared abdominoperineal resection when treated in the manner described.

Phase I clinical trial of combined therapy with vinblastine (NSC-49842), bleomycin (NSC-125066), and cisdichlorodiammineplatinum(II)( NSC-119875).

Seventeen patients with various histologic types of incurable malignant disease were treated with a combination of vinblastine, bleomycin, and cis-dichlorodiammineplatinum(II). Creatinine and blood urea nitrogen elevations were noted but were not of a severe degree. White blood cell and platelet count depressions were seen and appeared to be cumulative, though not life-threatening. Tinnitus and high-frequency hearing loss were noted. Tumor regression was seen in one patient with adenocarcinoma of the lung and in one patient with a testicular tumor. This appears to be a manageable drug combination with frequent monitoring of renal, hematopoietic, pulmonary, and auditory function. A phase II study establishing the therapeutic efficacy of this combination in advanced testicular neoplasms now appears to be indicated.

Estrogen receptor and natural course of breast cancer.

The tumors from approximately 50% of patients with breast cancer contained estrogen receptor (ER). ER appeared more often and at higher levels in the tumors of postmenopausal women. Eleven out of 12 patients who had multiple ER assays from various metastatic sites showed no significant discrepancies in ER values. ER level appears to decrease as the duration of metastatic cancer increase. Patients with ER in the tumor more frequently have bone metastases than those without ER. Visceral metastases occurred more often with ER negative patients and appeared to have a more malignant course with significant shorter survival.

Acquired hypertrichosis languiginosa. Report of two new cases and a review of the literature.

Hypertrichosis lanuginosa is a pathologic state characterized by an excessive, new growth of fine, fetal hair. Two cases of hypertrichosis languinosa with malignancy (lymphoma and uterine cancer) are presented and added to the 9 in the literature. Lymphoma and uterine cancer are previously unreported as associated with hypertrichosis osis lanuginosa. Review of the 11 cases of hypertrichosis lanuginosa revealed the following characteristics: females were predominant; none was below the 4th decade; all had advanced neoplastic disease; all malignancies except one were of epithelial origin; and there were no demonstrable endocrine abnormalities. Despite an attempt to find etiologic factors in our patients and in the literature, none could be elicited.

Response of patients with carcinoma of the breast to hormonal therapy and combination chemotherapy.

Of the 89 patients with disseminated carcinoma of the breast treated with combination or sequential cyclophosphamide, fluorouracil and vincristine, 63 had received evaluable course of endocrine therapy and chemotherapy. The response to endocrine therapy, regardless of its nature or duration, failed to predict response to subsequent chemotherapy. Selection of the patients on the basis of pretreatment disease free interval, menopausal status or metastatic pattern showed the groups of patients to be homogeneous in distribution. In addition, evaluation for a disease free interval greater or less than two years, menopausal status and visceral or nonvisceral metastasis did not allow identification of groups predicting responsiveness to combination chemotherapy.