Early stopping of a clinical trial when there is evidence of no treatment benefit: protocol B-14 of the National Surgical Adjuvant Breast and Bowel Project

In patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), risk score models that reflect disease severity have been developed and can serve as an objective measurement to assess and evaluate the effect of the severity of liver disease on the outcome of liver transplantation. Thus, using the established Mayo risk scores for PBC and PSC, one not only can estimate survival for the individual patient but can measure disease activity as well. Indeed, several studies have suggested that the optimal timing of liver transplantation with use of the Mayo PBC model may be an important tool to improve survival, decrease morbidity, and decrease overall related costs. Likewise, studies in patients with PSC have yielded similar results. This review explores how prognostic mathematical survival models for PBC and PSC might be applied to individual patients in need of liver transplantation. The following question is addressed: How can the timing of liver transplantation be optimized to increase survival, decrease postoperative morbidity, and ultimately, decrease the overall resource utilization involved in this procedure?     

Compliance with quality of life data collection in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial

This paper describes compliance with the completion of a quality of life questionnaire in the Breast Cancer Prevention Trial, a large multi-centre randomized trial that is studying the efficacy of Tamoxifen in preventing breast cancer. In the first 4875 women enrolled in the control arm of the study, there was a very high rate of questionnaire completion at baseline, 3 months, 6 months and 12 months of follow-up (89.8 per cent completed forms at 12 months). The sample was examined according to demographic and risk factors, as well as by recruitment cohort. There was a significantly poorer compliance rate for the most recently recruited cohort that was followed-up during a time of substantial external negative publicity related to clinical trial research. Nevertheless, the overall compliance with completion of quality of life data in this trial is very high, which is probably attributable to the high educational status of the trial participants.     

Fluorouracil and leucovorin with or without interferon alfa-2b in advanced colorectal cancer: analysis of a prospective randomized phase III trial. Hellenic Cooperative Oncology Group

PURPOSE: To investigate if double modulation of fluorouracil (5-FU) with leucovorin (folinic acid [FA]) and interferon alfa-2b (IFN 2b) improves responses and survival in comparison to single modulation of 5-FU with FA. PATIENTS AND METHODS: One hundred six patients with histologically confirmed advanced colorectal cancer, measurable disease, and without previous chemotherapy were prospectively randomized into two groups. Patients in group A received 5-FU 450 mg/m2 as an intravenous bolus in the midinfusion of FA weekly. FA was given at a dose of 200 mg/m2 in 500 mL 0.9% normal saline solution in 2-hour infusion. Patients in group B received exactly the same regimen plus IFN 2b 5 million units subcutaneously three times weekly. RESULTS: All patients were well balanced in both groups regarding age, sex, performance status, number, and site of metastasis. One hundred two patients were assessable. All patients have died. There was no difference in response between the two groups (7.8% v 9.8%). Median survival was 10.1 months in group A, and 7.2 months in group B (P = .00189). Median time to progression was 8.4 and 5.2 months, respectively (P = .00196). Overall, better performance status and older age had a positive impact on survival. Toxicity was the most important and catastrophic aspect of this study. Patients who received IFN 2b had significantly worse anemia, neutropenia, diarrhea, anorexia, weight loss, flu-like syndrome, and psychological reactions. CONCLUSION: Based on this final analysis, the addition of IFN 2b to the combination of 5-FU and FA enhances toxicity and contributes to decreased survival.     

Phase II trials of 5-fluorouracil and leucovorin in patients with metastatic gastric or pancreatic carcinoma

BACKGROUND: Previous trials in patients with colorectal carcinoma have indicated that enhancement of 5-fluorouracil (5-FU) by leucovorin (LV) can result in an improved response rate and increased survival. METHODS: Phase II trials were performed with patients who had either gastric or papcreatic adenocarcinoma with inetastases. Forty-one gastric carcinoma patients and 31 pancreatic carcinoma patients with measurable disease were treated with 5-FU, 425 mg/m2 intraveneosly (i.v.) on Days 1-5 plus LV, 20 mg/m2 i.v., on Days 1-5, reported at 4 and 8 weeks, and then every 5 weeks thereafter. RESULTS: The patients with metastatic gastric carcinoma had a median survival of 4.8 months. There was a 22% objective response rate, including a 4.9% complete response rate and a 17.1% partial response rate. Among the 31 patients with pancreatic carcinoma, there was a median survival of 5.7 months. No patients in this group showed a response. CONCLUSIONS: The response rate for patients with metastatic gastric adenocarcinoma was modest and this regimen may provide temporary palliation for some patients. However, 5-FU and LV treatment is ineffective against metastatic pancreatic carcinoma.     

Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17

PURPOSE: In 1993, findings from a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial to evaluate the worth of radiation therapy after lumpectomy concluded that the combination was more beneficial than lumpectomy alone for localized intraductal carcinoma-in-situ (DCIS). This report extends those findings. PATIENTS AND METHODS: Women (N = 818) with localized DCIS were randomly assigned to lumpectomy or lumpectomy plus radiation (50 Gy). Tissue was removed so that resected specimen margins were histologically tumor-free. Mean follow-up time was 90 months (range, 67 to 130). Size and method of tumor detection were determined by central clinical, mammographic, and pathologic assessment. Life-table estimates of event-free survival and survival, average annual rates of occurrence for specific events, relative risks for event-specific end points, and cumulative probability of specific events comprising event-free survival are presented. RESULTS: The benefit of lumpectomy plus radiation was virtually unchanged between 5 and 8 years of follow-up and was due to a reduction in invasive and noninvasive ipsilateral breast tumors (IBTs). Incidence of locoregional and distant events remained similar in both treatment groups; deaths were only infrequently related to breast cancer. Incidence of noninvasive IBT was reduced from 13.4% to 8.2% (P = .007), and of invasive IBT, from 13.4% to 3.9% (P < .0001). All cohorts benefited from radiation regardless of clinical or mammographic tumor characteristics. CONCLUSION: Through 8 years of follow-up, our findings continue to indicate that lumpectomy plus radiation is more beneficial than lumpectomy alone for women with localized, mammographically detected DCIS. When evaluated according to the mammographic characteristics of their DCIS, all groups benefited from radiation.     

5-Fluorouracil plus interferon alpha-2a compared to 5-fluorouracil alone in the treatment of advanced colon carcinoma: a multicentric randomized study

Biochemical modulation is one of the most interesting fields in cancer chemotherapy. Interferon-alpha (IFNalpha) is a cytokine that is able to influence the pharmacodynamics of 5-fluorouracil (5FU) through a number of mechanisms. With the aim of confirming some data emerging from the literature, we initiated a multicentric randomized study comparing the combination of 5FU and IFNalpha-2a with 5FU alone in the treatment of advanced or metastatic colon cancer. A group of 205 colon cancer patients (104 in the 5FU arm and 101 in the 5FU + IFNapha-2a arm) were included in the final intention-to-treat analysis. Rectal cancers were not considered eligible. All patients had measurable disease, were aged 75 years or less, had a Karnofsky index of at least 60 and had good bone marrow, renal, liver and cardiac functions. No previous chemo-immunotherapy was allowed. The treatment was 750 mg/m2 5FU (4 h i.v. infusion) on days 1 5 and then i.v. bolus weekly, starting from day 12, with or without IFNalpha-2a given s.c. three times weekly (starting dose 3 x 10(6) IU rising to 9 x 10(6) IU, if tolerated). Patients were treated until progression or, if responsive, for a maximum of 48 weeks and then observed for a period of 2 years. The primary end-point of the study was objective clinical response (OR); secondary parameters were time to progression, overall survival, and time to death after progression. WHO criteria were used for both clinical response and toxicity measurements. Dose reduction was planned a priori in the event of significant toxicity due to 5FU, IFNalpha-2a or both. Association between primary and secondary end-points and treatment was studied by univariate and multivariate analysis. Altogether, 47 patients achieved a documented response. A 25% OR was observed in the combination arm while a 21% OR was seen in the 5FU arm; this difference is not statistically significant (P = 0.6). Patients with a small tumour burden (below 5 cm2) showed a higher probability of response in both arms. Patients in the experimental arm had a higher but not statistically significant cumulative progression-free probability. Median survival was 47.1 weeks overall, while it was 43.7 and 48.5 weeks in the control and experimental arms, respectively. The combination was clearly more toxic than 5FU alone, leukopenia being the most frequent side-effect in the experimental arm and nausea and vomiting in the control arm. In conclusion these results are quite disappointing and 5FU + IFNalpha-2a can not be considered a standard treatment for advanced colon cancer.     

In vitro synergism between 5-fluorouracil and natural beta interferon in human colon carcinoma cells

The combination of 5-fluorouracil (FUra) plus IFN-beta was studied in vitro using a human colon carcinoma cell line, HCT-8. Continuous exposure to high concentrations of IFN-beta is cytotoxic to these cells (ED50, 600 +/- 50 IU/ml). A strong synergism (P < 0.002) was observed when a short-term (1-h), high-concentration exposure to fluoropyrimidine (300 or 1000 microM) was followed by IFN-beta given continuously. In fact, the mean ratio between the expected (product of the survival of each agent alone) and the observed clonogenic cell survival rates of the combination was 3.4 (range, 2.4-4.9). Longer exposures to the fluoropyrimidine (24 h, 7 days) produced less than additive effects with IFN-beta, indicating strong schedule dependency for this synergism. The mechanism of interaction was studied at four levels. First, thymidylate synthase (TS) activity, inhibition, and recovery were measured by an in situ assay in cells treated with FUra, IFN-beta, and their combination. When the prolonged infusion of IFN-beta followed a 1-h exposure to FUra, the observed TS inhibition and recovery, at each time point, were very similar to the expected values, indicating that the interactions between these drugs at the level of TS are not the determinant of the synergism. Second, cell cycle analysis was done. During the continuous exposure to IFN-beta, a significant accumulation of HCT-8 cells in S-phase was observed at 24, 48, and 72 h compared to untreated controls (P = 0.003); however, under the same experimental conditions producing synergy in the clonogenic assay, no significant cell cycle perturbations were produced by the combination of FUra followed by IFN-beta compared to those caused by each agent alone. Third, using the alkaline elution test, we also demonstrated that the synergism is not due to enhanced FUra-induced DNA single-strand break frequency in high molecular weight DNA. Finally, nucleic acid incorporation experiments, using tritiated FUra, showed that the cytokine, given continuously (300 IU/ml), enhanced the amount of FUra incorporated into nucleic acids 24 h after a 1-h exposure to 300 and 1000 microM of FUra. The median percentage of enhancement values were 31.6 +/- 11.5%,m for the lower drug concentration and 18. 4 +/- 8.1% for the higher drug concentration tested. These results suggest that the mechanism of this synergism may be related to the ability of IFN-beta to promote the incorporation of intracellular FUra metabolites into nucleic acids and/or to inhibit the cleavage of FUra nucleotides from RNA/DNA.     

Intensive regimen of cytokines with interleukin-2 and interferon alfa-2b in selected patients with metastatic renal carcinoma

We conducted a Phase II trial using an intensive regimen combining interleukin-2 (IL2), interferon-alfa-2b (IFN), and lymphokine-activated killer (LAK) cells. The aim of this study was to evaluate the toxicity and the efficacy of this combination in selected patients with metastatic renal cell carcinoma. Thirty-one assessable patients were treated with at least one cycle of a regimen consisting of 20 x 10(6) IU/day s.c. IFN for 5 days, followed 2 days later by i.v. injections of 24 x 10(6) IU/m2/day IL2 every 8 h together with i.v. bolus of 5 x 10(6) IU/m2/day IFN every 8 h during 5 days. After a 6-day break, during which four leukophereses were performed, this i.v. combination was administered along with the LAK cell reinjections for a maximum of 5 days. Twenty-seven patients underwent the two parts of the first course of treatment; respectively, 42% and 46% of the planned dose of IL2 and IFN were administered. Several severe toxicities were observed including two treatment-related deaths. Significant tumor responses were observed in seven patients, including two complete remissions. Two of these patients remain alive without evidence of disease 36 and 40 months after treatment, respectively. This intensive regimen of IL2 together with IFN and LAK cells cannot be recommended even in selected patients with metastatic renal cell carcinoma. In addition, our results argue against the concept of a dose-response relationship in this setting.     

The cellular interaction of 5-fluorouracil and cisplatin in a human colon carcinoma cell line

The combination of 5-fluorouracil (5-FU) and cisplatin (CDDP) has been shown to have synergistic cytotoxicity in human tumours, but the biochemical mechanism for this interaction remains unclear. Therefore, the aim of this study was to investigate the interaction of 5-FU and CDDP in a human colon carcinoma cell line, NCI H548. A 24 h exposure to 5-FU resulted in a 5-FU IC50 value of 24.2 +/- 4.5 microM, Dm 22.6 microM; exposure to CDDP for 2 h resulted in a IC50 value of 20.8 +/- 8.0 microM, Dm 21.9 microM. When cells were exposed simultaneously to 5-FU for 24 h and CDDP for the initial 2 h, or when cells were treated with CDDP for 2 h followed by various concentrations of 5-FU for 24 h, no greater than additive cytotoxicity was observed. In contrast, when cells were treated with 5-FU for 24 h prior to CDDP for 2 h, a greater than additive interaction was noted (5-FU IC50 1.2 +/- 0.6 microM, Dm 1.3 microM, CI 0.45). Thymidine 10 microM partially reversed the growth inhibitory effects of the 5-FU/ CDDP combination. Using both immunological and biochemical assays, no notable differences in the total amount of TS enzyme or the fraction of bound TS enzyme could be detected in the absence or presence of CDDP. No notable differences could be detected in intracellular reduced folate pools, FdUMP or FUTP pools, or 5-FU incorporation into RNA or DNA with the addition of CDDP to 5-FU. DNA fragmentation studies revealed that the combination of 5-FU followed by CDDP demonstrated a greater degree of single-stranded DNA fragments in parental (P = 0.024) and newly synthesised DNA (P = 0.025) compared with the administration of CDDP prior to 5-FU or either drug alone. The increase in smaller DNA fragment size was reversed with the addition of thymidine (10 microM). These findings suggest that the interaction of 5-FU and CDDP is associated with a greater degree of fragmentation of both nascent and parental DNA.     

A phase II trial of 5-fluorouracil, leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma

BACKGROUND: Unresectable adenocarcinoma of the biliary tree are associated with a very poor prognosis. 5-fluorouracil (5-FU) combination regimens have produced objective response rates in approximately 10-20% of patients. Leucovorin increases the selective cytotoxicity of 5-FU. There also are encouraging reports of carboplatin in combination with 5-FU in other gastrointestinal tract malignancies. METHODS: Fourteen consecutive eligible patients were treated with a combination of carboplatin, 300 mg/m2, intravenously (i.v.) on Day 1 only and 5-FU, 400 mg/m2, i.v. with leucovorin, 25 mg/m2, i.v. on Days 1-4. All patients were required to have a histologically confirmed diagnosis and measurable disease. Patients were evaluated for response, survival, and toxicity. RESULTS: A total of 48 cycles of therapy were delivered. The median survival was 5 months. One patient achieved complete remission and two others partial remission, for a total response rate of 21.4%. Four additional patients had stable disease for a median duration of 4 months. The therapy was well tolerated, with moderate myelosuppression as the main dose-limiting toxicity. CONCLUSIONS: The current combination regimen of leucovorin-modulated 5-FU with carboplatin is well tolerated with appropriate supportive care, produces significant objective responses in 21% of patients with biliary tree carcinoma, and should be considered for the treatment of this disease.     

Successful treatment of recurrent multiple lung metastasis from colon cancer with combination chemotherapy using methotrexate, 5-fluorouracil, and high-dose leucovorin: a case report

A 66-year-old man, who had received sigmoidectomy for sigmoid cancer in 1985, was diagnosed as having multiple lung and liver tumors in September 1988. When celiac-angiography was performed, recurrent liver metastases from sigmoid cancer were suspected and he received a transarterial embolism with ADM 30 mg and MMC 20 mg. In addition, he was treated with a sequential chemotherapy with methotrexate (MTX), 1,200 mg intravenously (6 h-infusion) followed by 5-fluorouracil (5-FU), 600 mg/m2/day and leucovorin, 300 mg/body/day in continuous infusion for 5 days from day 2 with concomitant oral administration of dipyridamole (300 mg/day) over 14 days. Treatment was repeated every 28 days for two courses. For the third course, administration of only 5-FU, leucovorin and dipyridamole was performed. As a result, the size of pulmonary lesions was prominently reduced on computed tomography. Although mucositis, anal erosion, diarrhea and thrombocytopenia were noted, no severe side effects were observed. This sequential chemotherapy appears useful for metastatic lesions from colon cancer.     

Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Fran?ais d'Immunothérapie

BACKGROUND: Recombinant human interleukin-2 (aldesleukin) and recombinant human interferon alfa can induce notable tumor regression in a limited number of patients with metastatic renal-cell carcinoma. We conducted a multicenter, randomized trial to determine the effect of each cytokine independently and in combination, and to identify patients who are best suited for this treatment. METHODS: Four hundred twenty-five patients with metastatic renal-cell carcinoma were randomly assigned to receive either a continuous intravenous infusion of interleukin-2, subcutaneous injections of interferon alfa-2a, or both. The main outcome measure was the response rate; secondary outcomes were the rates of event-free and overall survival. Predictive factors for response and rapid progression were identified by multivariate analysis. RESULTS: Response rates were 6.5 percent, 7.5 percent, and 18.6 percent (P<0.01) for the groups receiving interleukin-2, interferon alfa-2a, and interleukin-2 plus interferon alfa-2a, respectively. At one year, the event-free survival rates were 15 percent, 12 percent, and 20 percent, respectively (P=0.01). There was no significant difference in overall survival among the three groups. Toxic effects of therapy were more common in patients receiving interleukin-2 than in those receiving interferon alfa-2a. Response to treatment was associated with having metastasis to a single organ and with receiving the combined treatment. The probability of rapid progression of disease was at least 70 percent for patients with at least two metastatic sites, liver metastases, and a period of less than one year between the diagnosis of the primary tumor and the appearance of metastases. CONCLUSIONS: Cytokines are active in a few patients with metastatic renal-cell carcinoma. The higher response rate and longer event-free survival obtained with a combination of cytokines must be balanced against the toxicity of such treatment.     

Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial

PURPOSE: To compare progression-free survival (PFS), overall survival (OS), and toxicity of a doxorubicin-containing regimen administered alone or in combination with interferon alfa-2b (IFNalpha) in patients with low-grade follicular lymphoma (FL) and poor prognostic factors. PATIENTS AND METHODS: Two hundred sixty-eight patients with advanced-stage FL received cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP) monthly for 6 months, then every 2 months for 12 months. After randomization, 242 patients were evaluated for efficacy: 119 received CHVP alone, and 123 also received IFNalpha at a dose of 5 million units three times weekly for 18 months. RESULTS: After a 6-year median follow-up, the patients treated with CHVP + IFNalpha showed significantly longer median PFS than those who received CHVP alone (2.9 years v 1.5 years, respectively; P = .0002) and significantly longer median OS (not reached v 5.6 years, respectively; P = .008). Although some side effects, which included neutropenia, asthenia, fever, elevated serum transaminase levels, flu-like symptoms, and thrombocytopenia, were more frequently observed in patients who received the combination regimen, these reactions were moderate. IFNalpha was withdrawn because of toxicity in 10% of the patients, and a dosage reduction or temporary suspension was required in 28%. CONCLUSION: With long-term follow-up of 6 years, these results confirm that the addition of IFNalpha to a doxorubicin-containing regimen for patients with advanced-stage and clinically aggressive FL not only increased PFS, as in most other similar trials, but also prolonged OS. Toxicity was moderate. The beneficial effects of this combined chemotherapy and IFNalpha regimen on OS probably reflect the selection of FL patients with poor prognostic factors.     

Interleukin 2 and interferon alpha-2a do not improve anti-tumour activity of 5-fluorouracil in advanced colorectal cancer

Treatment using a combination of 5-fluorouracil (5-FU), interferon-alpha (IFN alpha-2a) and interleukin 2 (IL-2) has been shown to mediate disease regression in selected patients with advanced colorectal cancer. This phase II study was designed to evaluate the anti-tumour activity and toxicity of the combination of IL-2, IFN alpha-2a and 5-FU in patients with advanced colorectal cancer. Forty-four patients with metastatic colorectal cancer were treated, predominantly on an outpatient basis, with subcutaneous IFN alpha-2a and IL-2 three times per week followed by once a week bolus intravenous 5-FU injections. There were six (14%) partial responses among the 43 evaluable patients [95% confidence interval (CI) 5-28%]. Twenty-four patients had stable disease (56%) and 13 patients (30%) showed progressive disease. The median time to progressive disease in 43 patients was 19 weeks (range 2-72 weeks) and in responders 34 weeks (range 24-30 weeks). The median overall survival was 47 weeks (range 2-85 weeks) and in responders 60 weeks (range 35-71 weeks). Treatment-related toxic effects included fatigue, nausea and vomiting. Granulocytopenia was the main reason for the dose reductions or treatment interruptions in 32 out of 44 patients. One patient died of toxicity due to renal failure. Serial assessments of immunophenotyping and cytolytic activities of peripheral blood lymphocytes did not show changes in the numbers of circulating natural killer (NK) cells or in the levels of NK and lymphokine-activated killer (LAK) cytolytic activities. This regimen of IL-2 and IFN alpha-2a with 5-FU has only modest anti-tumour activity in advanced colorectal cancer.     

Pharmacokinetics of recombinant human interferon-alpha 2a combined with 5-fluorouracil in patients with advanced colorectal carcinoma

A cohort study was conducted to estimate the risk of breast cancer recurrence among women diagnosed with ductal carcinoma in situ (DCIS) and to identify tumor or patient characteristics that influence that risk. A population-based cancer registry was used to identify a cohort of 709 female residents of western Washington who were diagnosed with DCIS between January 1980 and June 1992 and were treated with breast-conserving surgery. Information about breast cancer recurrences, treatment, and several patient characteristics and exposures was obtained from postal questionnaires. Recurrences were confirmed using information from the cancer registry or hospital pathology reports. Approximately 15% of women experienced a recurrence within the first 5 years after diagnosis [95% confidence interval (CI), 12-18%]; 31% had a recurrence within 10 years (95% CI, 24-38%). There was a suggestion that risk was slightly elevated for women with larger tumors (> or =1.5 cm) and tumors of comedo subtype. Relative risks (RRs) were elevated for women who were premenopausal at diagnosis of DCIS (RR = 2.3; 95% CI, 1.1-5.0). Women in the upper decile of body mass index were at twice the risk of a recurrence as those women in the lower four deciles (RR = 2.3; 95% CI, 1.1-4.8). There was also a suggestion that women who used menopausal hormones for at least 2 years after their diagnosis of DCIS were at increased risk of recurrence compared to nonusers of menopausal hormones (RR = 1.8; 95% CI, 0.7-5.0). Our results suggest that the risk of recurrence may be related to some tumor characteristics as well as the hormonal milieu of the patient at or after her diagnosis of DCIS. However, larger studies are needed to more clearly document predictors of disease recurrence after DCIS.     

Comparison of the effects of intralesional interferon alfa-2a, 2b and the combination of 2a and 2b in the treatment of basal cell carcinoma

Interferons (IFN), especially alfa-2a and 2b, are potent inhibitors of normal and malignant cell growth and effective choices in the treatment of basal cell carcinoma (BCC). The aim of the study was to evaluate the effectiveness of the IFN alfa-2a and 2b, and whether this effect may be increased by their combination. A total of 45 patients with histopathologically confirmed BCC were divided into three groups, equally. Groups 1,2 and 3 were treated with intralesional IFN alfa-2a, 2b, and the combination of 2a and 2b, respectively. Lesions were injected three times weekly in Groups 1 and 2 (total ten injections). IFN alfa-2a and 2b were injected alternately in Group 3 (5 IFN alfa-2a and 5 IFN alfa-2b). Eight weeks after completion of therapy, cytologic specimens were taken, and all cases were evaluated clinically and cytologically. Ten (66.6%) patients had a complete response (CR) and 5 (33.3%) had a partial response (PR) in Group 1. Patients in Group 2 showed 10 (66.6%) CR, 4 (26.6%) PR, and 1 (6.6%) non response. In Group 3, 11 (73.3%) patients had CR and 4 (26.6%) had PR. Follow-up periods ranged from 6-24 months, and no recurrences have been observed. These results suggest that IFN alfa-2a, 2b, and the combination of 2a and 2b appear to be effective choices for the treatment of BCC; the effectiveness is not increased by their combination.     

Comparison between short or long exposure to 5-fluorouracil in human gastric and colon cancer cell lines: biochemical mechanism of resistance

Recent preclinical and clinical data indicate that the main mechanisms of 5-fluorouracil (5-FU) cytotoxicity depend on the mode of administration. To gather further insight into the major causes of acquired 5-FU resistance, drug-sensitive human gastric (M2), colon (HT29) and breast (MCF7) cancer cell lines were repeatedly exposed to a fixed concentration of 5-FU given either for 1 or 24 h. Although equieffective doses (IC50) of 5-FU were used, resistance to a 1 h exposure of 5-FU developed faster in all models than to a 24 h exposure. Cell lines with acquired resistance to a 1 h application of 5-FU were only partly cross-resistant to a 24 h exposure, whereas lines with resistance to protracted application of 5-FU displayed significant cross-resistance to the 1 h schedule. Resistance to methotrexate was only seen in cell lines with acquired resistance to 24 h of 5-FU. All 5-FU-resistant cell lines showed reduced incorporation of 5-FU into cellular RNA. Furthermore, elevations of thymidylate synthase were seen in all cell lines with resistance to 24 h of 5-FU but also in one cell line with resistance to a bolus schedule. No alterations in folylpolyglutamate synthase developed in the resistant cell lines. These data support the concept that the main mechanisms of 5-FU cytotoxicity depend on the mode of application. Incorporation of fluorouridine triphosphate into RNA appears to be the most important mechanism of action for 5-FU bolus schedules, whereas inhibition of thymidylate synthase becomes more important as the infusion time is prolonged. These data could have implications on the interaction of 5-FU given at different schedules with various other cytostatic agents.     

Subcutaneous interleukin-2, interferon alfa-2a, and continuous infusion of fluorouracil in metastatic renal cell carcinoma: a multicenter phase II trial. Groupe Fran?ais d'Immunothérapie

PURPOSE: A phase II trial was designed to determine the efficacy and the tolerance of interleukin-2 (IL-2), interferon alfa-2a (IFNalpha), and fluorouracil (5-FU) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: One hundred eleven patients were included. Patients received subcutaneous IL-2 9 x 10(6) IU daily for 6 days and IFNalpha 6 x 10(6) IU on days 1, 3, and 5 every other week for 8 weeks. 5-FU was administered through a continuous infusion at 600 mg/m2 for 5 consecutive days for 1 week every 4 weeks. RESULTS: The response rate was 1.8% (95% confidence interval [CI], 0% to 4.3%) with only two partial responses (PRs). Toxicity was moderate with 3.6% grade 4 events and two deaths related to treatment. CONCLUSION: This regimen of IL-2, IFNalpha, and 5-FU in patients with metastatic renal cell carcinoma was ineffective. The results raise the question of the dose and schedule of subcutaneous cytokines that must be used in metastatic renal carcinoma.