A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of adjuvant radiation therapy and chemotherapy for resectable rectal cancer.

BACKGROUND: Combined radiation therapy and chemotherapy after surgery, compared with postsurgical radiation therapy alone, has been shown to improve disease-free survival and overall survival significantly among patients with poor-prognosis (i.e., advanced stage disease or metastasis to regional lymph nodes) resectable rectal cancer. However, the combined therapy is associated with more toxic effects, raising the question of whether the benefits of the treatment justify its quality-of-life costs for the individual patient. PURPOSE: To assess the trade-offs between improved survival and increased treatment toxicity, we reanalyzed data from a randomized clinical trial that compared the efficacy of combined adjuvant chemotherapy and radiation therapy with adjuvant radiation therapy alone in the treatment of patients with poor-prognosis resectable rectal cancer. METHODS: The data were from a North Central Cancer Treatment Group trial in which 204 patients with poor-prognosis rectal cancer were randomly assigned to receive either postoperative radiation therapy alone or radiation therapy plus fluorouracil-based chemotherapy. A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis was used to account for freedom from symptomatic disease and from early and late side effects of treatment. All reported P values are two-sided. RESULTS: As reported previously, the combined therapy reduced the risk of relapse by 34% (95% confidence interval [CI] = 12%-50%; P = .0016) and reduced the overall death rate by 29% (95% CI = 7%-45%; P = .025) in comparison with adjuvant radiation therapy alone. In the 5 years following assignment to treatment, patients who received the combined therapy had more time with toxicity (3.1 months; 95% CI = 2.0-4.1 months), shorter survival after relapse (3.6 months less; 95% CI = 0.9-6.3 months less), and more TWiST (6.1 months; 95% CI = 0.2-12.0 months) than patients who received adjuvant radiation therapy alone. Despite an increase in the amount of time that individuals spent with early and late toxic effects, the Q-TWiST analysis indicated that the combined therapy conferred significantly greater benefit for a wide range of patient preferences about living with the toxicity of treatment or the symptoms of overt disease. CONCLUSIONS AND IMPLICATIONS: Use of combined chemotherapy and radiation therapy as an adjuvant to surgery for patients with poor-prognosis resectable rectal cancer is justified, since the improved outcome in terms of delayed recurrence and increased survival balances the time spent with early and late toxic effects. The Q-TWiST method is an excellent way to compare treatment outcomes that include quality-of-life considerations.

Phase II evaluation of carboplatin in advanced endometrial carcinoma.

Carboplatin was administered by iv bolus every 28 days to 26 patients who had extensive metastatic or recurrent endometrial adenocarcinoma and no prior chemotherapy exposure. The dose level was 400 mg/m2 in 5 patients with and 4 patients without prior irradiation and 300 mg/m2 in 16 patients with prior pelvic irradiation. Partial disease regressions were seen in 28% of patients (95% confidence interval, 12%-50%), with a median response duration of 129 days. Median survival of all patients was 215 days; median time to disease progression for all patients was 117 days. We conclude that carboplatin is an active agent in advanced endometrial carcinoma and is worthy of further investigation in single-agent and combination chemotherapy.

Validation studies for models projecting the risk of invasive and total breast cancer incidence.

BACKGROUND: In 1989, Gail and colleagues developed a model for estimating the risk of breast cancer in women participating in a program of annual mammographic screening (designated herein as model 1). A modification of this model to project the absolute risk of developing only invasive breast cancer is referred to herein as model 2. We assessed the validity of both models by employing data from women enrolled in the Breast Cancer Prevention Trial. METHODS: We used data from 5969 white women who were at least 35 years of age and without a history of breast cancer. These women were in the placebo arm of the trial and were screened annually. The average follow-up period was 48.4 months. We compared the observed number of breast cancers with the predicted numbers from the models. RESULTS: In terms of absolute risk, the ratios of total expected to observed numbers of cancers (95% confidence intervals [CIs]) were 0.84 (0. 73-0.97) for model 1 and 1.03 (0.88-1.21) for model 2, respectively. Within the age groups of 49 years or less, 50-59 years, and 60 years or more, the ratios of expected to observed numbers of breast cancers (95% CIs) for model 1 were 0.91 (0.73-1.14), 0.96 (0.73-1. 28), and 0.66 (0.52-0.86), respectively. Thus, model 1 underestimated breast cancer risk in women more than 59 years of age. For model 2, the risk ratios (95% CIs) were 0.93 (0.72-1.22), 1.13 (0.83-1.55), and 1.05 (0.80-1.41), respectively. Both models exhibited a tendency to overestimate risk for women classified in the higher quintiles of predicted 5-year risk and to underestimate risk for those in the lower quintiles of the same. CONCLUSION: Despite some limitations, these methods provide useful information on breast cancer risk for women who plan to participate in an annual mammographic screening program.

Cyclophosphamide-cisplatin versus cyclophosphamide-carboplatin in stage III-IV ovarian carcinoma: a comparison of equally myelosuppressive regimens.

Between March 1985 and January 1987, 103 women with histologically proven stage III-IV ovarian carcinoma were randomly allocated to groups receiving monthly intravenous regimens of 1 g of cyclophosphamide/m2 plus either 60 mg of cisplatin (CDDP)/m2 or 150 mg of carboplatin (CBDCA)/m2 for 1 year unless disease progressed earlier. The groups were well balanced according to the stratification factors (age, histologic differentiation, extent of residual disease, and performance score), and both treatments were well tolerated and produced similar median first-course leukopenia (2,200 and 2,000 cells/microL) and thrombocytopenia (220,000 and 202,500 cells/microL). The CBDCA regimen was less emetogenic. After an interim analysis in January 1987 revealed superior progression-free survival for the group of 53 patients receiving CDDP (P = .005), the study was closed to further accrual. Those 24 patients still receiving CBDCA were encouraged to cross over to the CDDP-based regimen and 21 of them did. Following treatment crossover, the relative risk of death associated with original allocation to CBDCA receded from 1.79 to 0.97, indicating success of the salvage treatment using the CDDP-based regimen. This aborted study demonstrated the superiority of CDDP over CBDCA when the two platinum compounds were compared at equally myelosuppressive low doses in combination with 1 g of cyclophosphamide/m2. If CDDP is to be supplanted by CBDCA, larger, more myelosuppressive doses of CBDCA will be required. The platinum drug antitumor effect is a critically important therapeutic feature of this combination.

Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02.

BACKGROUND: The conviction that postoperative radiotherapy and chemotherapy represent an acceptable standard of care for patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the rectum evolved in the absence of data from clinical trials designed to determine whether the addition of radiotherapy results in improved disease-free survival and overall survival. This study was carried out to address this issue. An additional aim was to determine whether leucovorin (LV)-modulated 5-fluorouracil (5-FU) is superior to the combination of 5-FU, semustine, and vincristine (MOF) in men. PATIENTS AND METHODS: Eligible patients (n = 694) with Dukes' B or C carcinoma of the rectum were enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol R-02 from September 1987 through December 1992 and were followed. They were randomly assigned to receive either postoperative adjuvant chemotherapy alone (n = 348) or chemotherapy with postoperative radiotherapy (n = 346). All female patients (n = 287) received 5-FU plus LV chemotherapy; male patients received either MOF (n = 207) or 5-FU plus LV (n = 200). Primary analyses were carried out by use of a stratified log-rank statistic; P values are two-sided. RESULTS: The average time on study for surviving patients is 93 months as of September 30, 1998. Postoperative radiotherapy resulted in no beneficial effect on disease-free survival (P =.90) or overall survival (P =.89), regardless of which chemotherapy was utilized, although it reduced the cumulative incidence of locoregional relapse from 13% to 8% at 5-year follow-up (P =.02). Male patients who received 5-FU plus LV demonstrated a statistically significant benefit in disease-free survival at 5 years compared with those who received MOF (55% versus 47%; P =.009) but not in 5-year overall survival (65% versus 62%; P =.17). CONCLUSIONS: The addition of postoperative radiation therapy to chemotherapy in Dukes' B and C rectal cancer did not alter the subsequent incidence of distant disease, although there was a reduction in locoregional relapse when compared with chemotherapy alone.

Comparison of portal and peripheral blood levels of carcinoembryonic antigen, CA 19-9, and CA 125 tumor-associated antigens in patients with colorectal and pancreatic cancer.

Synchronous serum specimens from the systemic and portal circulations of 43 patients with gastrointestinal cancer were assayed for levels of carcinoembryonic antigen, CA 19-9, and CA 125 tumor-associated antigens. The number of patients having a mean ratio of portal to systemic levels greater than 1 and the observed quantity of tumor-associated antigens were significant for carcinoembryonic antigen and CA 125 only in patients with colorectal cancer. No correlations were noted with the surgical stage of disease or with high or low (normal) levels of the three tumor-associated antigens. These findings suggest that peripheral concentrations of these antigens are in equilibrium with shedding from tumors and that hepatic clearance of a single pass does not significantly alter peripheral concentrations.

Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors.

The development of multidrug resistance in MCF-7 human breast cancer cells and the acquisition of broad resistance to xenobiotics in rat hyperplastic nodules are both associated with increased P-glycoprotein (mdr) gene expression as well as changes in activities of intracellular detoxication enzymes; among these changes is a significant increase in the activity of the anionic isozyme of glutathione-S-transferase (GST). We have isolated a cDNA encoding the human anionic glutathione-S-transferase, GST pi-1, from a cDNA library constructed from multidrug-resistant MCF-7 cells. The deduced amino acid sequence of GST pi-1 shows that while the human anionic GST displays 85% nucleotide and amino acid sequence homology to the rat anionic isozyme, it is markedly less related to human basic GST isozymes. We have examined the expression of GST pi and P-glycoprotein in 170 specimens of human tissues and tumors. P-Glycoprotein RNA expression was positive in eight of 23 lymphomas and two of 12 colon tumors; however, many other normal and malignant tissues, including lung, bladder, and breast tumors, had low or undetectable levels of P-glycoprotein RNA expression. In contrast, GST pi was readily detected in a wide variety of normal and malignant tissues. The level of GST pi mRNA expression in normal tissues was heterogeneous, with lowest levels found in liver and the highest levels found in lung, esophagus, and placenta. GST pi was also variably expressed in human tumors, with the lowest relative levels occurring in lymphoma and breast cancer and the highest levels found in lung cancer and head and neck tumors. In addition, comparison of paired specimens from the same patient indicated that GST pi expression was increased in many tumors relative to matched normal tissue.

A phase II study of combined 5-fluorouracil, doxorubicin, and cisplatin in the treatment of advanced upper gastrointestinal adenocarcinomas.

In a phase II study of 67 patients with upper gastrointestinal carcinomas and measurable disease without previous chemotherapy, we have evaluated the combination of intensive course 5-fluorouracil (5-FU) (300 mg/m2/d for five days) doxorubicin (40 mg/m2 on day 1), and cisplatin (60 mg/m2 on day 1). Courses were repeated every 5 weeks. Among 26 patients with gastric carcinoma, a 50% regression rate was obtained with a median survival for all patients of 9 months. Among 29 patients with pancreatic carcinoma, the regression rate was 21% and the median survival was 4 months. Regressions were also observed in smaller numbers of patients with carcinomas of the gallbladder and ampulla of Vater, as well as in cholangiocellular carcinoma of the liver. Toxic reactions were usually clinically tolerable and consisted primarily of nausea, vomiting, stomatitis, diarrhea, leukopenia, and alopecia. Phase III studies are in progress to place the value of this experimental regimen into clinical perspective.

Prostate-specific antigen as a pretherapy prognostic factor in patients treated with radiation therapy for clinically localized prostate cancer.

PURPOSE: This study was conducted to determine the value of prostate-specific antigen (PSA) as a pretherapy prognostic factor for localized prostate cancer treated with primary irradiation (RT). PATIENTS AND METHODS: Between March 1987 and December 1990, 254 patients with pretherapy PSA determinations were treated for clinical stage A2 to C prostate adenocarcinoma. In conjunction with other prognostic factors, pretherapy PSA was evaluated to determine whether it had independent predictive value for disease outcome. RESULTS: Pretherapy PSA was highly and directly correlated with clinical stage, tumor grade, and acid phosphatase level. With a median follow-up duration of 24 months, 241 patients (95%) were fully assessable for disease outcome. In these patients, PSA and tumor grade were the sole independent predictive factors for tumor relapse (ie, clinically determined and/or increasing PSA level). The combination of pretherapy PSA and tumor grade information defined groups of patients with distinctly different outcome. For patients in low- (favorable PSA and tumor grade), intermediate- (favorable PSA or tumor grade), and high- (adverse PSA and tumor grade) risk categories, the actuarial rates of survival free of tumor relapse or increasing PSA level were 94%, 77%, and 42% at 3 years, respectively (P < .0001). CONCLUSION: Pretherapy PSA is a strongly independent prognostic factor for disease outcome following primary RT. The combination of adverse pretherapy PSA and unfavorable tumor grade identified a cohort of patients with a high risk of early treatment failure in whom combined modality therapy may be appropriately investigated.

Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer.

PURPOSE: The goal of this study was to determine the efficacy of intensive-course fluorouracil (5FU) plus low-dose leucovorin given for 6 months following potentially curative resection of colon cancer. PATIENTS AND METHODS: Three hundred seventeen patients with high-risk stage II or stage III colon cancer were randomly assigned 3 to 4 weeks following surgery to receive either (1) chemotherapy with six cycles of 5FU (425 mg/m2) plus leucovorin (20 mg/m2) by rapid intravenous injection daily for 5 consecutive days every 4 to 5 weeks, or (2) observation. RESULTS: The median follow-up duration is 72 months for patients still alive. Patients who received postoperative 5FU plus leucovorin experienced significant improvement in time to relapse (P < .01) and survival (P = .02) compared with control patients treated with surgery alone. Stomatitis, diarrhea, and leukopenia were the predominant chemotherapy toxicities. There were no treatment-related deaths. CONCLUSION: These results indicate that intensive-course 5FU plus low-dose leucovorin is effective in preventing tumor relapse and improving survival in patients with high-risk colon cancer. These benefits were seen with only six cycles of treatment, using low-dose leucovorin in combination with 5FU on a schedule convenient for outpatient administration.

Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer.

In a previous study (J Clin Oncol 7:1407-1417, 1989), we identified two dosage administration schedules of fluorouracil (5FU) combined with leucovorin that were superior to single-agent 5FU for the treatment of advanced colorectal cancer. In this same study, a regimen of 5FU plus high-dose methotrexate (MTX) demonstrated a suggestive advantage over 5FU alone. To permit a more definitive comparison, we have extended our evaluation of these three regimens to involve an additional 259 patients. In all, 457 patients with advanced colorectal cancer were randomly assigned to one of the following regimens: 5FU plus low-dose leucovorin, 5FU plus high-dose leucovorin, or 5FU plus high-dose MTX with leucovorin rescue. We have found that each of the 5FU/leucovorin regimens demonstrates a significant (P less than or equal to .01) advantage over 5FU plus high-dose MTX for objective tumor response and interval to tumor progression. Moreover, 5FU plus low-dose leucovorin confers a significant survival benefit (P less than or equal to .01) compared with 5FU plus high-dose MTX. The 5FU plus high-dose leucovorin regimen shows a survival benefit only in unadjusted analyses (P = .04), but this difference is not significant when adjusted for imbalances in prognostic variables (P = .44). Evaluation of the two 5FU/leucovorin regimens rules out a 10% decrease in death rate for the high-dose leucovorin regimen compared with the low-dose leucovorin regimen (P less than .05). The regimen of 5FU plus low-dose leucovorin has now been shown to offer a statistically significant survival advantage versus 5FU alone and versus 5FU plus high-dose MTX, a regimen that had shown promise in earlier trials. These data confirm the efficacy of leucovorin combined with 5FU in patients with advanced colorectal cancer and establish that it is not necessary to use high doses of leucovorin to achieve these results.

Prospective evaluation of prognostic variables from patient-completed questionnaires. North Central Cancer Treatment Group.

PURPOSE: This study was developed to determine whether descriptive information from a patient-completed questionnaire could provide prognostic information that was independent from that already obtained by the patient's physician. PATIENTS AND METHODS: An initial detailed questionnaire was administered to approximately 150 patients with advanced cancer. This questionnaire was subsequently revised and given to a total of 1,115 patients with advanced colorectal or lung cancer. Univariate and multivariate analyses were performed to evaluate the data from these questionnaires. RESULTS: A total of 36 variables showed statistically significant prognostic information for survival in univariate analyses, even though many of these variables were associated with only a minimal increase in risk. A multivariate analysis demonstrated that there was a high correlation between many variables. Three major groups of variables became apparent as providing strong prognostic information. These included the following: (1) a physician's assessment of performance status (PS); (2) a patient's assessment of their own PS; and (3) a nutritional factor such as appetite, caloric intake, or overall food intake. CONCLUSION: Data generated by a patient-completed questionnaire can provide important prognostic information independent from that obtained by other physician-determined prognostic factors.

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.

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.

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.

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.

Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic.

A total of 401 eligible patients with resected stages B and C colorectal carcinoma were randomly assigned to no-further therapy or to adjuvant treatment with either levamisole alone, 150 mg/d for 3 days every 2 weeks for 1 year, or levamisole plus fluorouracil (5-FU), 450 mg/m2/d intravenously (IV) for 5 days and beginning at 28 days, 450 mg/m2 weekly for 1 year. Levamisole plus 5-FU, and to a lesser extent levamisole alone, reduced cancer recurrence in comparison with no adjuvant therapy. These differences, after correction for imbalances in prognostic variables, were only suggestive for levamisole alone (P = .05) but quite significant for levamisole plus 5-FU (P = .003). Whereas both treatment regimens were associated with overall improvements in survival, these improvements reached borderline significance only for stage C patients treated with levamisole plus 5-FU (P = .03). Therapy was clinically tolerable with either regimen and severe toxicity was uncommon. These promising results have led to a large national intergroup confirmatory trial currently in progress.

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.

Controlled clinical trial of interferon-gamma as postoperative surgical adjuvant therapy for colon cancer.

PURPOSE: The primary goal of this study was to assess the effectiveness of interferon gamma (IFN-gamma) to prevent tumor relapse following potentially curative surgery in patients with high-risk colon cancer. A secondary goal was to determine the effect of IFN-gamma on immune function and to correlate alterations in immune parameters with survival. PATIENTS AND METHODS: Three to 4 weeks after undergoing resection of all known malignant disease, 99 patients with stage II, III, or IV colon cancer were randomly assigned to receive IFN-gamma 0.2 mg total dose by subcutaneous injection daily for 6 months or observation. Serial assessment of human leukocyte antigen (HLA)-DR expression and Fc receptors on peripheral-blood monocytes was conducted in 24 patients who received IFN-gamma and 27 control patients. RESULTS: With a median follow-up duration of 59 months in patients still alive, there was evidence of a detrimental effect on time to relapse (P = .03) among patients who received IFN-gamma. There was no significant difference in patient survival (P = .12). This study has sufficient power to rule out a 25% reduction in death rate for patients who received IFN-gamma (P < .05). Significant enhancement of immune function was observed in patients treated with IFN-gamma as measured by HLA-DR expression (P < .01) and Fc receptors (P < .001) on peripheral-blood monocytes. CONCLUSION: This study effectively rules out any clinically meaningful benefit for IFN-gamma as surgical adjuvant treatment for patients with high-risk colon cancer. Although significant enhancement of nonspecific immune function was seen with this dosage administration schedule of IFN-gamma, this was not associated with any demonstrable antitumor effect.

Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer.

PURPOSE: This study had two major goals: (1) to assess the effectiveness of a regimen of fluorouracil (5-FU) plus levamisole plus leucovorin as postoperative surgical adjuvant therapy for patients with high-risk colon cancer, and (2) to evaluate 6 months versus 12 months of chemotherapy. PATIENTS AND METHODS: Patients with poor-prognosis stage II or III colon cancer were randomly assigned to receive adjuvant chemotherapy with either intensive-course 5-FU and leucovorin combined with levamisole, or a standard regimen of 5-FU plus levamisole. Patients were also randomly assigned to receive either 12 months or 6 months of chemotherapy, which resulted in four treatment groups. RESULTS: Eight hundred ninety-one of 915 patients entered (97.4%) were eligible. The median follow-up duration is 5.1 years for patients still alive. There was a difference among the four treatment groups with respect to patient survival, and a significant duration-by-regimen interaction was observed. Specifically, standard 5-FU plus levamisole was inferior to 5-FU plus leucovorin plus levamisole when treatment was given for 6 months (5-year survival rate, 60% v 70%; P < .01). CONCLUSION: There was no significant improvement in patient survival when chemotherapy was given for 12 months compared with 6 months. When chemotherapy was given for 6 months, standard 5-FU plus levamisole was associated with inferior patient survival compared with intensive-course 5-FU plus leucovorin plus levamisole. These data suggest that 5-FU plus levamisole for 6 months should not be used in clinical practice, whereas 6 months of treatment with 5-FU plus leucovorin plus levamisole is effective.