Phase III trial of adjuvant 5-fluorouracil and adriamycin versus 5-fluorouracil, adriamycin, and polyadenylic-polyuridylic acid (poly A:U) for locally advanced gastric cancer after curative surgery: final results of 15-year follow-up.

BACKGROUND: This phase III trial was to compare 5-fluorouracil (5-FU), adriamycin, and polyadenylic-polyuridylic acid (poly A:U) against 5-fluorouracil plus adriamycin (FA) for operable gastric cancer. PATIENTS AND METHODS: From 1984 to 1989, patients who had D(2-3) curative resection were randomly assigned to receive chemotherapy or chemoimmunotherapy. Chemotherapy consisted of 12 mg/kg 5-FU every week for 18 months and 40 mg/m2 adriamycin every 3 weeks for 12 cycles. Chemoimmunotherapy consisted of FA plus 100 mg of poly A:U weekly for six cycles and was followed 6 months later by six weekly 50-mg booster injections. RESULTS: A total of 292 patients were enrolled. After excluding 12 ineligible patients, 142 and 138 patients were allocated to each treatment. Patients were balanced with prognostic variables: age, sex, tumor location, differentiation, degree of tumor invasion (T2-T4a), and lymph node status (N0-N2). During the 15-year follow-up, chemoimmunotherapy significantly prolonged overall (P = 0.013) and recurrence-free (P = 0.005) survivals compared with chemotherapy alone. The survival benefits were prominent in the subset of patients with T3/T4a, N2, or stage III. Treatments were generally well tolerated in both arms. CONCLUSIONS: These results indicate a survival advantage of chemoimmunotherapy with a regimen of FA and poly A:U in curatively resected gastric adenocarcinoma.

Adjuvant 5-fluorouracil plus doxorubicin in D2-3 resected gastric carcinoma: 15-year experience at a single institute.

BACKGROUND: The authors evaluated the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) plus doxorubicin in gastric carcinoma after D2-3 curative resection. They also evaluated the effect of dose-related factors (delivered total dose/m(2), actual dose intensity [ADI], relative dose intensity [RDI]) of this regimen on patient survival. METHODS: A total of 301 patients with Stage II to IV (en bloc resected T4b; 1984 American Joint Committee on Cancer staging) were accrued between 1984 and 1996. Chemotherapy was started within 4 weeks of surgery according to the following schedule: intravenous bolus injection of doxorubicin 40 mg/m2 every 3 weeks for 12 cycles and 5-FU 400 mg/m2 weekly for 60 weeks. The toxicity and survival were evaluated. RESULTS: The median follow-up duration was 58 months. Sixty-four percent of the total patients and 71.7% of the patients who did not experience recurrence during the chemotherapy finished the protocol completely with acceptable toxicities. The 5- and 10-year disease free survival rates of total 301 patients were 58.4% and 46.5%, and the overall survival rates were 62.1% and 50.5%, respectively. Treatment completion group showed survival benefit over the early termination group in 5-year survival (75.2% vs. 52.9%; P = 0.0005). The median ADI of 5-FU and doxorubicin were 349 and 11 mg/m2/week, and the median RDIs of 5-FU and doxorubicin were 0.87 and 0.83, respectively. Multivariate analysis demonstrated that completion of chemotherapy is an independent prognostic factor of both disease free and overall survival. However, ADI and RDI did now show any effect on survival. CONCLUSIONS: Adjuvant chemotherapy with 5-FU plus doxorubicin for 60 weeks after D2-3 dissection induced promising survival duration with acceptable toxicities. Full administration of the planned dosage of the combined drugs is recommendable as opposed to early termination of the chemotherapy in gastric carcinoma.

Monthly 5-days 5-fluorouracil and low-dose leucovorin for adjuvant chemotherapy in colon cancer.

We investigated the dose-related effect of the 5-fluorouracil (5-FU)/leucovorin regimen on survival in 139 colon cancer patients with Dukes' B2 and C2 stage disease. Chemotherapy consisted of 400 mg/m(2) of 5-FU and 20 mg/m(2) of leucovorin injected daily for 5 days in every 4 weeks for a maximum of 12 cycles. The total dose of 5-FU administered per body surface area had a significant effect on the 5-year disease-free survival and 5-year overall survival in stage B2 and C2 colon cancer patients (P=0.0018, P=0.0011). Analysis with reference to the median DSDI demonstrated that there was a significant difference in 5-year survival in Dukes' C2 (P=0.0016), but survival was not affected by the dose intensity. Multivariate analysis demonstrated that only the total dose of 5-FU administered per surface area affected the 5-year disease-free survival and 5-year overall survival (P=0.0016, P=0.0007, respectively). It can be concluded that the total dose of 5-FU administered is important in planned dosage schedule of adjuvant chemotherapy in colon cancer.

Early postoperative intraperitoneal chemotherapy with mitomycin C, 5-fluorouracil and cisplatin for advanced gastric cancer.

OBJECTIVE: The long-term survival of patients who undergo surgery for stage IV gastric cancer is poor, due to metastatic spread of the tumor. Intraperitoneal chemotherapy (IPT) as a possible treatment for peritoneal dissemination has been investigated in a number of different tumors. The aim of this study was to investigate the toxicity and impact of early postoperative IPT on the survival of patients with advanced gastric cancer. METHODS: Between 1993 and 1997, a total of 91 patients with stage IV gastric cancer who underwent potentially curative or palliative resection received intraperitoneal mitomycin C before closure of the abdominal wound. 5-Fluorouracil and cisplatin were administered intraperitoneally on postoperative days 1-4, and this was repeated at 4-week intervals. RESULTS: All patients received a median of 3 IPT perfusions. There were 24 (26.4%) postoperative complications and 1 (1.1%) mortality. The most frequent hematologic toxicity (grade 3-4) was leukopenia. The major nonhematologic toxicities (grade 3-4) were emesis and nephrotoxicity. After a median follow-up period of 26 months, 14 patients remain alive without evidence of recurrence, whereas 75 patients died due to recurrence or progression of disease. The median survival period for all 91 patients was 15.4 months. When survival according to the residual tumor was analyzed, median survival was 36.0 months in the R0 (curative resection) group, 20.6 months in the R1 group (margins of resected specimens showing microscopic residual tumor or diameter of each residual tumor less than 3 mm) and 9.0 months in the R2 group (macroscopic residual tumor larger than 3 mm) (p < 0.001). CONCLUSIONS: IPT was found to be safe, and it appears to improve the prognosis in patients with minimal residual tumors. However, complete cytoreductive surgery is mandatory for achieving the beneficial effect of IPT.

A prospective randomized trial comparing intravenous 5-fluorouracil and oral doxifluridine as postoperative adjuvant treatment for advanced rectal cancer.

BACKGROUND: Postoperative adjuvant chemoradiation treatment after curative resection for rectal cancer was needed to reduce recurrence and improve a survival rate. Intravenous 5-fluorouracil (5-FU) and leucovorin has been a mainstay of chemotherapy, but oral 5-FU derivatives have been shown a comparable antitumor activity. Intravenous 5-FU and oral doxifluridine were compared with respect to therapeutic efficacy, drug toxicity, and quality of life. METHODS: A total of 166 patients were randomized to receive intravenous 5-FU (450 mg/m2/day) or oral doxifluridine (900 mg/m2/day) in combination with leucovorin (20 mg/m2/day) for depth of invasion, nodal status, metastasis (TNM) stage II and III patients between October 1997 and February 1999. Consecutive daily intravenous infusion for 5 days per every month for a total of 12 cycles (IV arm, n = 74) and oral doxifluridine daily for 3 weeks and 1 week rest for a total of 12 cycles (oral arm, n = 92). Drug toxicity and quality of life were observed. Quality of life was scored according to 22 daily activity items (good, > or =71; fair, < 70; poor, < 52). RESULTS: There was no difference of sex between two groups (IV arm: male/female = 45/29, oral arm: male/female = 59/33). The mean age was 52.3 vs. 59.5, respectively. There was also no difference of TNM stage distribution and type of operation between groups (P>.05). Mean numbers of chemotherapy cycles were 6.5+/-3.7 (IV arm) vs. 7.2+/-4.3 (oral arm), respectively. The rate of recurrence was 9/74 (12.1%) in the IV arm and 6/92 (6.5 %) in the oral arm, respectively (P = .937). Local recurrence was 2/74 (stage III; 2.7%) in the IV arm and 1/92 (stage II; 1.1%) in the oral arm, respectively. Systemic recurrence was 7/74 (stage III; 9.4%) in the IV arm and 5/92 (stage III; 5.4%) in the oral arm, respectively. The most common site of systemic recurrence was the liver. Toxicity profile was as follows: leukopenia (30/74 vs. 17/92) and alopecia (21/74 vs. 13/92) were statistically more common in the IV arm. Diarrhea was more common in the oral arm. Poor quality of life score between two groups was observed at 1 month (23.9% vs. 13%) and 2 months (15.8% vs. 3.7%) after chemotherapy. Good quality of life score was observed at 1 month (19.5% vs. 49%) and 2 months (47% vs. 72%), respectively (P<.05). CONCLUSIONS: Oral doxifluridine with leucovorin shows a comparable therapeutic efficacy to intravenous 5-FU regimen with high quality of life as postoperative adjuvant therapy. The oral regimen also can be safely given with appropriate toxicity and tolerability.

P-glycoprotein: the intermediate end point of drug response to induction chemotherapy in locally advanced breast cancer.

Expression and clinical relevance of p-glycoprotein (p-gp) were evaluated in 31 cases of locally advanced breast cancer and 9 cases involving inflammatory breast cancer after induction chemotherapy. The de novo p-gp expression rate was 26% and increased up to 58% (p = 0.03) with the FAC (5-fluorouracil, adriamycin, cyclophosphamide) regimen. Although more clinically complete responders were found in the secondary p-gp negative group (p = 0.02), this difference was not found in pathological tumor response. Moreover, as the grade of the secondary p-gp expression increased, the chemotherapeutic effect decreased, suggesting an inverse relationship between p-gp expression and drug effect (p = 0.04). When we subgrouped the patients into 4 groups using these two parameters, p-gp negative patients presenting with a high drug effect showed a low recurrence rate (p = 0.05) and marginal survival benefits (p = 0.09) as opposed to patients with a low drug effect. But in p-gp positive groups, the recurrence rate was the same between the two groups regardless of the drug effect. Thus, in the p-gp negative patient with a high drug effect, adjuvant chemotherapy with the same regimen as induction chemotherapy may induce more prognostically favorable results. Therefore, clinical application of the secondary p-gp detection can be used as an intermediate endpoint in evaluating drug response for an induction regimen.

Overexpression of erbB-2 protein in gastric adenocarcinoma--a potential role in therapeutic response to adjuvant 5-FU-doxorubicin regimen.

In order to study the influence of erbB-2 protein overexpression on outcome of patients with gastric cancer after attempted curative resection with or without adjuvant chemotherapy, paraffin embedded sections from 109 cases of primary gastric cancer with defined treatments have been immunostained for erbB-2 protein in a retrospective study. Thirty four cases (31%) showed strong membrane staining of tumor cells. erbB-2 overexpression did not show significant effect on outcome when all patients were considered. However, erbB-2 overexpression was an indicator for poor disease free survival (p = 0.0474), local relapse free survival (p = 0.0293), and overall survival (p = 0.0310) of the patients treated with surgery only (N = 51), while it did not show any effect on outcome of patients treated with 5-FU plus Doxorubicin (FA) as adjuvant chemotherapy (N = 58). Furthermore, the apparent therapeutic benefit from FA regimen was restricted to patients with erbB-2 positive tumors. Combined predictive value of erbB-2 and FA regimen was found to be significant in predicting local relapse in multivariate analysis (p = 0.0439). The data suggests that erbB-2 may be associated with an improved response to FA regimen and that erbB-2 should be included as a potential confounding variable in the analysis of the data from the clinical trials for gastric cancer.

Adjuvant treatment of operable stomach cancer with polyadenylic.polyuridylic acid in addition to chemotherapeutic agents: a preliminary report.

A randomized trial of polyadenylic.polyuridylic acid [poly(A).poly(U)] in addition to chemotherapy was undertaken in patients with stomach cancer following curative gastrectomy. They were randomized into a group of 108 patients receiving chemotherapy plus poly(A).poly(U) and a control group of 116 patients receiving chemotherapy alone. Chemotherapy consisted of injections of 5-fluorouracil, 12 mg/kg once weekly and adriamycin, 40 mg/m2 once every 3 weeks, continuously after operation. Poly(A).poly(U) was infused in a 100 mg dose, once a week six times from 5 days after the first injection of chemotherapeutic agents and 6 months later in a half dose similarly. At 55 months after initiation of the trial, the mean follow-up periods were 24 months for both groups. It has been revealed that patients who received the combined treatment postoperatively showed a lesser mortality and lower rate of recurrence, both reflecting significant increases in overall (P less than 0.05) and relapse-free (P less than 0.02) survivals as compared to those who received chemotherapy alone. This effect is more pronounced in patients having moderately advanced lymphnode involvement (N1) than in patients without (N0) or more advanced (N2) involvement. Thus, poly(A).poly(U) appears to be an effective agent when used postoperatively with chemotherapy in stomach cancers.

Adjuvant treatment of operable stomach cancer with polyadenylic.polyuridylic acid in addition to chemotherapeutic agents. Differential effect on natural killer cell and antibody-dependent cellular cytotoxicity.

Peripheral blood lymphocytes of operable stomach cancer patients were evaluated sequentially for their natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) activities before and after chemotherapy in association with polyadenylic.polyuridylic acid [poly(A).poly(U)]. Their cytotoxicity was measured by 4 h-chromium release assays, using human K562 and sensitized murine L1210 cells as targets for assays of NK and ADCC respectively. The mean NK cytotoxicity of 89 patients before treatment was significantly lower than that of the 18 sex- and age-matched healthy controls, whereas assays of ADCC showed similar levels of cytotoxicity in both groups. Patients who had received postoperative chemotherapy (5 fluorouracil, 12 mg/kg and adriamycin, 40 mg/M2) once, had, 5 days after injection, NK cytotoxicity levels similar to those before treatment. For these patients, an additional administration of poly(A).poly(U) (100 mg) resulted, 2 days later, in a significant increase in the levels of NK cytotoxicity without affecting the levels of ADCC. Repeated injections of poly(A).poly(U) alternated with chemotherapy induced, consistently, exclusive enhancement of NK activity after each injection. These results suggest that the effector cells for NK and ADCC activities are of functionally different cell populations.