Skip to main content
Device Global Header

Subscribe
or Renew

Advanced Search

Original Article

Improving Adjuvant Therapy for Rectal Cancer by Combining Protracted-Infusion Fluorouracil with Radiation Therapy after Curative Surgery

List of authors.
  • Michael J. O'Connell,
  • James A. Martenson,
  • Harry S. Wieand,
  • James E. Krook,
  • John S. Macdonald,
  • Daniel G. Haller,
  • Robert J. Mayer,
  • Leonard L. Gunderson,
  • and Tyvin A. Rich

Abstract

Background

The combination of radiation therapy and chemotherapy with fluorouracil plus semustine after surgery has been established as an effective approach to decreasing the risk of tumor relapse and improving survival in patients with rectal cancer who are at high risk for relapse or death. We sought to determine whether the efficacy of chemotherapy could be improved by administering fluorouracil by protracted infusion throughout the duration of radiation therapy and whether the omission of semustine would reduce the toxicity and delayed complications of chemotherapy without decreasing its antitumor efficacy.

Methods

Six hundred sixty patients with TNM stage II or III rectal cancer received intermittent bolus injections or protracted venous infusions of fluorouracil during postoperative radiation to the pelvis. They also received systemic chemotherapy with semustine plus fluorouracil or with fluorouracil alone in a higher dose, both before and after the pelvic irradiation.

Results

With a median follow-up of 46 months among surviving patients, patients who received a protracted infusion of fluorouracil had a significantly increased time to relapse (P = 0.01) and improved survival (P = 0.005). There was no evidence of a beneficial effect in the patients who received semustine plus fluorouracil.

Conclusions

A protracted infusion of fluorouracil during pelvic irradiation improved the effect of combined-treatment postoperative adjuvant therapy in patients with high-risk rectal cancer. Semustine plus fluorouracil was not more effective than a higher dose of systemic fluorouracil given alone.

Introduction

Rectal cancer is a common malignant disease in the United States, with an estimated 43,000 new cases in 19931. This tumor is frequently diagnosed at a stage when complete resection is possible. However, because of local recurrence of tumor in the pelvis or distant metastasis, only half the patients who undergo surgery will be cured. The risk of relapse and death is increased if the carcinoma has penetrated through the rectal wall (TNM stage II) or has spread to regional lymph nodes (TNM stage III).

After studies conducted by the Gastrointestinal Tumor Study Group2,3 and the North Central Cancer Treatment Group,4 a National Institutes of Health Consensus Development Conference concluded that the combination of postoperative chemotherapy and radiation improved local tumor control and survival in stage II and III rectal cancer; it was recommended that this approach be followed in clinical practice5.

The current study was initiated in 1986 with the goal of developing more effective and less toxic chemotherapy to be used in conjunction with radiation after surgery for high-risk rectal cancer. A new approach that we tested was the protracted venous infusion of fluorouracil throughout the irradiation of the pelvis, which Rich et al. had shown to be tolerable6. We wished to determine whether this method of delivering fluorouracil during radiation therapy would have a better outcome than conventional2-4 bolus administration of fluorouracil. Continuous infusion was intended to prolong the exposure of noncycling tumor cells to fluorouracil; in vitro studies indicated that the cytotoxicity of radiation and fluorouracil given in combination was maximized by the constant exposure of tumor cells to fluorouracil for 24 to 48 hours after irradiation7.

Methods

Patients

All patients participating in this trial had histologically confirmed adenocarcinoma of the rectum. They had undergone a potentially curative resection, with neither gross nor microscopical evidence of residual disease, and were entered in the study 21 to 70 days after the operation. Patients were eligible if pathological examination demonstrated that the tumor had penetrated the rectal wall and involved perirectal fat or adjacent organs by direct extension (stage II) or had metastasized to regional lymph nodes (stage III). The inferior edge of the primary tumor had to be at or below the sacral promontory or within 12 cm of the anal verge. Patients were excluded if they had a history of invasive tumor within the previous five years, if their pretreatment white-cell count was less than 4000 per cubic millimeter, if their platelet count was less than 130,000 per cubic millimeter, if they had previously received chemotherapy or radiation to the pelvis, if they had any evidence of distant metastasis or regional metastasis that could not be resected en bloc with the primary lesion, if they had severe coexistent disease, or if their tumor extended to or below the dentate line. Patients who also had extrapelvic primary colon cancer could not enter the study unless the extrapelvic tumor was in stage I and was completely resected. Pregnant or lactating women were also excluded.

Randomization

Informed consent was obtained from all patients before randomization. Randomization was carried out centrally at the Operations Office of the North Central Cancer Treatment Group; treatments were balanced across strata according to the sequential-treatment-assignment method described by Pocock and Simon8. The four stratification factors were the type of resection (abdominoperineal or anterior), the degree of invasion of perirectal fat or adjacent organs by direct extension of the tumor (no invasion, microscopic invasion, gross invasion confirmed microscopically, or adherence to or invasion of surrounding structures or organs), the number of regional lymph nodes involved (0, 1 to 4, or >4), and the organization enrolling patients in the study (25 organizations).

Patients were assigned to one of the following treatments: (1) systemic chemotherapy with fluorouracil and semustine, plus radiation therapy and concomitant bolus injection of fluorouracil; (2) systemic chemotherapy with fluorouracil and semustine, plus radiation therapy and concomitant protracted venous infusion of fluorouracil; (3) systemic chemotherapy with fluorouracil, plus radiation therapy and concomitant bolus injection of fluorouracil; or (4) systemic chemotherapy with fluorouracil, plus radiation therapy and concomitant protracted venous infusion of fluorouracil.

Treatment

Figure 1. Figure 1. Schedule of Chemotherapy and Radiation Therapy for Rectal Cancer.

Bolus denotes the administration of fluorouracil by rapid intravenous injection, and PVI its administration by protracted venous infusion. Fluorouracil was given in a dose of 500 mg per square meter of body-surface area on days 1 to 5 and days 36 to 40 and 450 mg per square meter on days 134 to 138 and days 169 to 173. Semustine was given in a dose of 130 mg per square meter on day 1 and 100 mg per square meter on day 134. Radiation therapy began on day 64; the total dose was 4500 cGy. For other details of therapy, see the Methods section.

All patients received an initial nine-week cycle of systemic chemotherapy, followed by radiation therapy and concomitant fluorouracil treatment, followed in turn by a second cycle of systemic chemotherapy according to the schedule shown in Figure 1. Patients assigned to treatment with fluorouracil plus semustine received 130 mg of semustine per square meter of body-surface area on day 1 and 100 mg per square meter on day 134. The fluorouracil was administered by rapid intravenous injection at a dose of 350 mg per square meter on days 1 to 5; 400 mg per square meter on days 36 to 40; 300 mg per square meter on days 134 to 138; and 350 mg per square meter on days 169 to 173.

Patients assigned to treatment with fluorouracil as a single agent during the systemic-chemotherapy phase of the treatment received fluorouracil by rapid intravenous injection at a dose of 500 mg per square meter on days 1 to 5 and days 36 to 40, and 450 mg per square meter on days 134 to 138 and days 169 to 173. The total dose of fluorouracil per 10-week course of therapy was higher when the drug was given as a single agent than when it was given in combination with semustine.

All patients received radiation therapy beginning on day 64; radiation was delivered by a linear accelerator with a minimal photon energy of 4 MV. Multiple-field techniques9,10 were used to include the tumor bed and nodal groups (anteroposterior-posteroanterior plus lateral fields; the use of anteroposterior-posteroanterior fields only was not allowed). The superior border of the radiation field was at least 1.5 cm above the level of the sacral promontory. In patients who had undergone anterior resection, the inferior field margin was 3 to 5 cm below the anastomosis. The lateral borders of the anterior-posterior radiation field were at least 1.5 cm lateral to the widest bony margin of the true pelvic sidewalls. In patients who had undergone abdominoperineal resection, the inferior and posterior border of the radiation fields included the perineal scar. Paired lateral fields were used in combination with anteroposterior-posteroanterior fields, to decrease the dose of radiation to anteriorly located small-bowel tissue9. Techniques that displaced the small bowel out of the pelvis were also encouraged. Simulation and treatment in the prone position were recommended. A total of 4500 cGy in 180-cGy fractions given over a five-week period was directed at the initial pelvic field. All patients received a minimal boost dose of 540 cGy to the entire tumor bed, the immediately adjacent lymph nodes, and the 2 cm of adjacent tissue (in patients with abdominoperineal resection, the perineum was excluded after it had received 4500 cGy). A second boost dose of 360 cGy was allowed to a smaller field in patients with good to excellent displacement of the small bowel out of the field.

All patients received fluorouracil during pelvic irradiation therapy. Those randomly assigned to bolus fluorouracil administration received 500 mg per square meter by rapid intravenous injection for three consecutive days during weeks 1 and 5 of radiation therapy. In patients randomly assigned to protracted venous infusion of fluorouracil, access to the central venous circulation was established by means of an implanted catheter, an external catheter in a subcutaneous tunnel, or a peripheral long-line catheter. Fluorouracil was infused at a rate of 225 mg per square meter per day by an ambulatory infusion pump during the entire period of radiation therapy or until severe chemotherapy-related toxicity occurred.

Quality Control of Radiation Therapy

Radiation oncologists were required to submit simulation films for central review by a radiation-oncology coordinator before they began radiation therapy. They were notified of any needed modification of treatment. Quality-control procedures have been described in detail elsewhere11.

There were minor deviations or no deviations from protocol specifications in the treatment of 87 percent of the patients who received radiation therapy. Radiation therapy was incomplete or not administered according to protocol because of noncompliance or an intervening condition in 2 percent of patients, and the results of treatment could not be evaluated in 2 percent. There were major deviations from the protocol in 8 percent.

Follow-up

During adjuvant therapy patients were monitored for signs of toxicity, with appropriate adjustments of their chemotherapy and radiation therapy. Complete blood counts were performed weekly to detect myelosuppression. Patients were also evaluated by means of history taking and physical examination, blood-chemistry-panel testing, and chest radiography before each five-day course of chemotherapy and before radiation therapy. They were evaluated for tumor relapse and delayed toxic reactions every 3 months for the first 18 months after the completion of adjuvant treatment and then every 6 months, for a total of 5 years. It was recommended that patients with anterior resections undergo proctoscopic examination every six months for two years and then annually. Radiography of the colon was performed at one, three, and five years. It was also recommended that computed tomography of the abdomen and pelvis be performed during the six-month evaluation and at the time of tumor relapse. A clear demonstration of pulmonary or osseous metastases or demonstration of an enlarging pelvic mass by computed tomography was accepted as evidence of tumor relapse, without a biopsy. Histologic confirmation was encouraged whenever possible.

Statistical Analysis

The end points of this study were the length of time to initial tumor relapse (local recurrence or distant metastasis), rates of local recurrence and distant metastasis, and survival. A factorial (two-by-two) design was used for analysis. One primary analysis compared the combined data on the two groups of patients receiving protracted venous infusion with the combined data on the two groups receiving bolus doses, and the other analysis compared the combined data on the two groups receiving semustine plus fluorouracil with the combined data on the two groups receiving fluorouracil alone. Sample-size estimates and power calculations were based on projected rates of relapse three years after entry.

Table 1. Table 1. Distribution of Patients According to Regimen.

After 445 eligible patients had been entered, a planned interim analysis indicated that semustine treatment did not result in an improvement in relapse-free or overall survival, and the last 215 patients entered all received fluorouracil alone as systemic therapy. These 215 patients were randomly assigned to protracted venous infusion or bolus administration of fluorouracil during radiation therapy. When the rates of relapse, survival, or toxic reactions among the patients receiving semustine were compared with those among patients not receiving semustine, the analysis included only the 445 patients who were equally likely to be entered in one of the four groups (Table 1).

Statistical analyses were carried out according to SAS procedures12. The Kaplan-Meier method was used to construct curves for the relapse-free interval and overall survival13. Data on patients who died from causes other than cancer were censored in our calculations of the relapse-free interval. The log-rank statistic was used to compare distributions14. The Cox proportional-hazards model was used for all multivariate analyses15. A backward-regression analysis was used to identify significant factors; variables were kept in the model only if the standardized maximum-likelihood-estimate statistics had a P value below 0.05. To adjust for covariates when evaluating treatments, we kept treatment in the model and applied backward regression to the other covariates. All P values are two-sided.

Results

Enrollment and Follow-up

Six hundred eighty patients were entered in the study between June 1986 and August 1990. Twenty patients (3 percent) were found to be ineligible; the other 660 patients (97 percent) were included in the statistical analyses. Ninety percent of expected tumor relapses and 75 percent of expected deaths from cancer have been observed. The median length of follow-up of the 431 patients currently alive is 46 months, and all patients have been followed-up for at least 2 years.

Characteristics of the Patients

Table 2. Table 2. Characteristics of the Treatment Groups.

Selected characteristics of the treatment groups are shown in Table 2. There were no significant differences in the distributions of these characteristics among the groups.

Evaluation of the Method of Fluorouracil Administration during Radiation Therapy

Among the 328 patients who received a protracted venous infusion of fluorouracil, there was a significant decrease in the overall rate of tumor relapse (from 47 to 37 percent, P = 0.01) and distant metastasis (from 40 to 31 percent, P = 0.03), as compared with the 332 patients who received bolus injections of fluorouracil during radiation therapy. Among the 434 patients who did not receive semustine, there was also a significant decrease in the overall rate of tumor relapse and distant metastasis among patients who received a protracted infusion of fluorouracil. Individual sites of distant metastases were documented at the time of initial tumor relapse in the following numbers of patients: the liver in 105 patients, the lungs in 104, the lymph nodes in 34, the peritoneum in 19, and other sites in 30. Protracted venous infusion of fluorouracil was not associated with a significant decrease in local recurrence (P = 0.11).

Figure 2. Figure 2. Relapse-free Interval and Overall Survival among Patients with Rectal Cancer Receiving Fluorouracil by Protracted Venous Infusion (PVI) or Bolus Injection during Radiation.

The curves for relapse-free interval and overall survival are shown in Figure 2. Patients who received a protracted infusion of fluorouracil had a significant improvement in the time to relapse (P = 0.01) and survival (P = 0.005), as compared with those who received a bolus injection of fluorouracil; their tumor-relapse rate was decreased by 27 percent, and their death rate by 31 percent. When these improvements were expressed in terms of four-year rates, the time to relapse was increased from 53 percent to 63 percent and survival from 60 percent to 70 percent among patients who received a protracted venous infusion of fluorouracil.

Multivariate analyses showed that increased age, greater lymph-node involvement, a greater depth of tumor invasion, and a higher tumor grade were independent factors indicating a poor prognosis with respect to the time to relapse and survival. After adjustment for these significant prognostic variables, the method of fluorouracil administration remained significantly associated with the time to relapse (P = 0.02) and survival (P = 0.01).

Table 3. Table 3. Incidence of Severe or Life-Threatening Toxic Reactions to Treatment.

Severe or life-threatening toxic reactions associated with the two forms of adjuvant fluorouracil therapy are summarized in Table 3. Diarrhea and leukopenia were the most frequently encountered reactions during and four weeks after combined pelvic irradiation and fluorouracil therapy. The incidence of severe diarrhea was significantly higher among patients who received fluorouracil by protracted infusion, and that of severe leukopenia was significantly higher among those who received the drug by bolus injection. There was no significant difference between these two groups in the number of patients who began the full course of pelvic radiation therapy but did not complete it (protracted venous infusion, 10 patients; bolus injection, 7 patients). The average doses of fluorouracil administered were 6546 and 2499 mg per square meter when given by protracted infusion and bolus injection, respectively, during the radiation phase of the study. Small-bowel obstruction requiring surgical intervention after pelvic irradiation occurred in 10 patients who received fluorouracil by protracted venous infusion (3 percent) and 7 who received it by bolus injection (2 percent). There was a single treatment-related death during the study, due to sepsis after surgery for bowel obstruction.

Evaluation of Semustine as a Component of Systemic Chemotherapy

Figure 3. Figure 3. Relapse-free Interval and Overall Survival among Patients with Rectal Cancer Receiving Fluorouracil with or without Semustine as Systemic Chemotherapy.

No significant difference was found between the rate of local tumor recurrence among the 226 patients who received systemic chemotherapy with fluorouracil plus semustine and the rate among the 219 concurrently randomized patients who received fluorouracil alone (9 vs. 11 percent). The curves for relapse-free interval and overall survival are shown in Figure 3. After adjustment for the independent prognostic factors described above, there was no significant difference between the group who received both semustine and fluorouracil and the group who received semustine alone in relapse-free interval (P = 0.33) and overall survival (P = 0.61).

The severe or life-threatening toxic reactions to systemic chemotherapy are summarized in Table 3. The incidence of severe reactions to either of the two regimens was low. The incidence of diarrhea, stomatitis, and leukopenia was significantly higher among patients who received fluorouracil alone, and that of thrombocytopenia was significantly higher among patients who received semustine in combination with a lower dose of fluorouracil (P<0.01 for both comparisons). Acute leukemia developed in a patient who received fluorouracil alone as systemic chemotherapy. Delayed renal toxicity was not observed in any patient.

Discussion

We assessed the value of the protracted infusion of fluorouracil throughout the duration of pelvic irradiation for rectal cancer. Although we documented a decrease in local tumor recurrence with this treatment, the difference was not statistically significant, given the small number of local recurrences observed. However, the rate of distant metastasis was significantly decreased, suggesting that fluorouracil given by prolonged infusion has an improved systemic effect on micrometastases.

Theoretically, the prolonged exposure of tumor cells with low growth fractions and long doubling times to a chemotherapeutic agent with cell-cycle specificity and a short plasma half-life, such as fluorouracil, would result in enhanced cytotoxicity16. Alternatively, the beneficial effect of protracted infusion of fluorouracil in this study may simply have been the result of the much higher total doses of drug that could be safely delivered by protracted infusion as compared with bolus administration.

Controlled trials of the continuous infusion of fluorouracil in patients with advanced metastatic colorectal cancer have indicated some improvement in objective tumor-response rates but have shown no significant effect on survival17-19. Our study, however, suggests that the incorporation of protracted venous infusion of fluorouracil as a component of postoperative adjuvant therapy for patients with early-stage malignant disease can improve survival. Further follow-up will be required to determine accurately the magnitude of any long-term survival benefit.

The protracted venous infusion of fluorouracil at the dose level used in this study was generally well tolerated, although it was associated with a moderate increase in the incidence of severe diarrhea. This treatment method also requires central venous access and an ambulatory infusion pump, which increase the complexity and cost of therapy.

Although the incidence of acute side effects of adjuvant radiation combined with chemotherapy is higher than the incidence of side effects of adjuvant radiation without chemotherapy, this has not translated into an increase in chronic toxic reactions4. The relative risk of chronic small-bowel problems requiring reoperation does not exceed the risk of 5 to 10 percent associated with surgery alone. This is probably related to the use of multiple-field radiation that includes lateral fields and the imaging of the small bowel9,10,20 to reduce the volume of small-bowel tissue included within the isodose curve of 4500 to 5040 cGy.

This study has also demonstrated that semustine does not add to the therapeutic benefit of adjuvant therapy with fluorouracil and pelvic irradiation, confirming the earlier observations of the Gastrointestinal Tumor Study Group21.

Recent studies have indicated that the outcome of surgery for high-risk colon cancer is significantly improved by the use of fluorouracil given by simple bolus injection in combination with levamisole22 or leucovorin23,24. The relative efficacy of protracted venous infusion of fluorouracil as compared with bolus administration of fluorouracil modulated by leucovorin or levamisole (or both) remains to be determined in patients with rectal cancer who are at high risk for relapse or death, as does the value of administering fluorouracil by protracted venous infusion throughout all phases of adjuvant therapy (not just during radiation treatment). More effective control of occult distant metastasis remains the principal challenge in the curative treatment of rectal cancer today.

Funding and Disclosures

Supported by grants (CA-25224, CA-31224, and CA-06294) from the National Cancer Institute.

Author Affiliations

From the Mayo Clinic, Rochester, Minn. (M.J.O., J.A.M., H.S.W., L.L.G.); the Duluth Clinic, Duluth, Minn. (J.E.K.); Temple University School of Medicine (J.S.M.) and the University of Pennsylvania Cancer Center (D.G.H.), Philadelphia; the Dana-Farber Cancer Institute, Boston (R.J.M.); and the M.D. Anderson Cancer Center, Houston (T.A.R.). Coordinated by the North Central Cancer Treatment Group, Rochester, Minn. Other participants include the Southwest Oncology Group, the Eastern Cooperative Oncology Group, Cancer and Acute Leukemia Group B, the Radiation Therapy Oncology Group, and the M.D. Anderson Cancer Center.

References (24)

  1. 1. Boring CC, Squires TS, Tong T. Cancer statistics, 1993. CA Cancer J Clin 1993;43:7-26

  2. 2. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 1985;312:1465-1472

  3. 3. Douglass HO Jr, Moertel CG, Mayer RJ, et al. Survival after postoperative combination treatment of rectal cancer. N Engl J Med 1986;315:1294-1295

  4. 4. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709-715

  5. 5. Adjuvant therapy for patients with colon and rectal cancerJAMA 1990;264:1444-1450

  6. 6. Rich TA, Lokich JJ, Chaffey JT. A pilot study of protracted venous infusion of 5-fluorouracil and concomitant radiation therapy. J Clin Oncol 1985;3:402-406

  7. 7. Byfield JE, Calabro-Jones P, Klisak I, Kulhanian F. Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combine 5-Fluorouracil for ftorafur and X rays. Int J Radiat Oncol Biol Phys 1982;8:1923-1933

  8. 8. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 1975;31:103-115

  9. 9. Gunderson LL, Russell AH, Llewellyn HJ, Doppke KP, Tepper JE. Treatment planning for colorectal cancer: radiation and surgical techniques and value of small-bowel films. Int J Radiat Oncol Biol Phys 1985;11:1379-1393

  10. 10. Gunderson LL, Martenson JA. Cancers of the colon and rectum. In: Levitt SH, Khan FM, Potish RA, eds. Technological basis of radiation therapy. 2nd ed. Philadelphia: Lea & Febiger, 1992:342-50.

  11. 11. Martenson JA Jr, Urias R, Smalley SR, et al. Radiation therapy quality control in a clinical trial of adjuvant postoperative treatment for rectal cancer. Int J Radiat Oncol Biol Phys (in press).

  12. 12. SAS/STAT user's guide: version 6. 4th ed. Vol. 2. Cary, N.C.: SAS Institute, 1990.

  13. 13. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481

  14. 14. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. Natl Cancer Inst 1959;22:719-748

  15. 15. Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972;34:187-220

  16. 16. Hansen RM, Quebbeman E, Anderson T. 5-Fluorouracil by protracted venous infusion: a review of current progress. Oncology 1989;46:245-250

  17. 17. Seifert P, Baker LH, Reed ML, Vaitkevicius VK. Comparison of continuously infused 5-fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma. Cancer 1975;36:123-128

  18. 18. Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol 1989;7:425-432

  19. 19. Weinerman B, Shah A, Fields A, et al. Systemic infusion versus bolus chemotherapy with 5-fluorouracil in measurable metastatic colorectal cancer. Am J Clin Oncol 1992;15:518-523

  20. 20. Gallagher MJ, Brereton HD, Rostock RA, et al. A prospective study of treatment techniques to minimize the volume of pelvic small bowel with reduction of acute and late effects associated with pelvic irradiation. Int J Radiat Oncol Biol Phys 1986;12:1565-1573

  21. 21. Gastrointestinal Tumor Study Group. Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum. J Clin Oncol 1992;10:549-557

  22. 22. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352-358

  23. 23. O'Connell M, Mailliard J, Macdonald J, Haller D, Mayer R, Wieand H. An intergroup trial of intensive course 5FU and low dose leucovorin as surgical adjuvant therapy for high risk colon cancer. Prog/Proc Am Soc Clin Oncol 1993;12:190. abstract.

  24. 24. Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993;11:1879-1887

Citing Articles (836)

    Figures/Media

    1. Figure 1. Schedule of Chemotherapy and Radiation Therapy for Rectal Cancer.
      Figure 1. Schedule of Chemotherapy and Radiation Therapy for Rectal Cancer.

      Bolus denotes the administration of fluorouracil by rapid intravenous injection, and PVI its administration by protracted venous infusion. Fluorouracil was given in a dose of 500 mg per square meter of body-surface area on days 1 to 5 and days 36 to 40 and 450 mg per square meter on days 134 to 138 and days 169 to 173. Semustine was given in a dose of 130 mg per square meter on day 1 and 100 mg per square meter on day 134. Radiation therapy began on day 64; the total dose was 4500 cGy. For other details of therapy, see the Methods section.

    2. Table 1. Distribution of Patients According to Regimen.
      Table 1. Distribution of Patients According to Regimen.
    3. Table 2. Characteristics of the Treatment Groups.
      Table 2. Characteristics of the Treatment Groups.
    4. Figure 2. Relapse-free Interval and Overall Survival among Patients with Rectal Cancer Receiving Fluorouracil by Protracted Venous Infusion (PVI) or Bolus Injection during Radiation.
      Figure 2. Relapse-free Interval and Overall Survival among Patients with Rectal Cancer Receiving Fluorouracil by Protracted Venous Infusion (PVI) or Bolus Injection during Radiation.
    5. Table 3. Incidence of Severe or Life-Threatening Toxic Reactions to Treatment.
      Table 3. Incidence of Severe or Life-Threatening Toxic Reactions to Treatment.
    6. Figure 3. Relapse-free Interval and Overall Survival among Patients with Rectal Cancer Receiving Fluorouracil with or without Semustine as Systemic Chemotherapy.
      Figure 3. Relapse-free Interval and Overall Survival among Patients with Rectal Cancer Receiving Fluorouracil with or without Semustine as Systemic Chemotherapy.

      More Research