Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1998 Apr;77(8):1349–1354. doi: 10.1038/bjc.1998.225

Combined intravenous and intraperitoneal chemotherapy with fluorouracil + leucovorin vs fluorouracil + levamisole for adjuvant therapy of resected colon carcinoma.

W Scheithauer 1, G V Kornek 1, A Marczell 1, J Karner 1, G Salem 1, R Greiner 1, D Burger 1, F Stöger 1, J Ritschel 1, E Kovats 1, H M Vischer 1, B Schneeweiss 1, D Depisch 1
PMCID: PMC2150168  PMID: 9579845

Abstract

Adjuvant chemotherapy with fluorouracil (FU) and levamisole or FU/leucovorin (LV) has been established as effective adjuvant treatment for patients with stage III colon cancer. Among several other promising treatment strategies in resected colon cancer, intraperitoneal anti-cancer drug administration with its appealing rationale of counteracting microscopic residual disease on peritoneal surfaces and occult metachronous liver metastases by achieving high intraportal drug concentrations has not yet undergone sufficient clinical evaluation. To determine whether a combination of this locoregional therapeutic concept with systemic intravenous administration of FU/LV would yield better results than conventional adjuvant chemoimmunotherapy with FU/levamisole, the present randomized study was initiated. A total of 241 patients with resected stage III or high-risk stage II (T4N0M0) colon cancer were randomly assigned to 'standard therapy' with FU and levamisole, given for a duration of 6 months, or to an investigational arm, consisting of LV 200 mg m(-2) plus FU 350 mg m(-2), both administered intravenously (days 1-4) and intraperitoneally (days 1 and 3) every 4 weeks for a total of six courses. In patients with stage II disease, no significant difference was noted between the two arms after a median follow-up time of 4 years (range 2.5-6 years). Among 196 eligible patients with stage III disease, however, a comparative analysis of the two treatment groups suggested both an improvement in disease-free survival (P = 0.0014) and a survival advantage (P = 0.0005), with an estimated 43% reduction in mortality rate (95% confidence interval 26-70%) in favour of the investigational arm. In agreement with its theoretical rationale, combined intraperitoneal and intravenous FU/LV was particularly effective in reducing locoregional tumour recurrences with or without liver or other organ site involvement (9 vs 25 patients in the FU/levamisole arm; P = 0.005). Treatment-associated side-effects were infrequent and generally mild in both arms, although a lower rate of severe (WHO grade 3) adverse reactions was noted in patients receiving locoregional plus intravenous chemotherapy (3% vs 12%; P = 0.01). The results of this trial suggest that combined intraperitoneal plus systemic intravenous chemotherapy with FU/LV is a promising adjuvant treatment strategy in patients with surgically resected stage III colon carcinoma.

Full text

PDF
1352

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Buroker T. R., Moertel C. G., Fleming T. R., Everson L. K., Cullinan S. A., Krook J. E., Mailliard J. A., Marschke R. F., Klaassen D. J., Laurie J. A. A controlled evaluation of recent approaches to biochemical modulation or enhancement of 5-fluorouracil therapy in colorectal carcinoma. J Clin Oncol. 1985 Dec;3(12):1624–1631. doi: 10.1200/JCO.1985.3.12.1624. [DOI] [PubMed] [Google Scholar]
  2. Cunliffe W. J., Sugarbaker P. H. Gastrointestinal malignancy: rationale for adjuvant therapy using early postoperative intraperitoneal chemotherapy. Br J Surg. 1989 Oct;76(10):1082–1090. doi: 10.1002/bjs.1800761030. [DOI] [PubMed] [Google Scholar]
  3. DeLorenzo L., Stewart J. A. Levamisole toxicity. J Clin Oncol. 1990 Feb;8(2):365–365. doi: 10.1200/JCO.1990.8.2.365. [DOI] [PubMed] [Google Scholar]
  4. Francini G., Petrioli R., Lorenzini L., Mancini S., Armenio S., Tanzini G., Marsili S., Aquino A., Marzocca G., Civitelli S. Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenterology. 1994 Apr;106(4):899–906. doi: 10.1016/0016-5085(94)90748-x. [DOI] [PubMed] [Google Scholar]
  5. Köhne-Wömpner C. H., Schöffski P., Schmoll H. J. Adjuvant therapy for colon adenocarcinoma: current status of clinical investigation. Ann Oncol. 1994;5 (Suppl 3):97–104. [PubMed] [Google Scholar]
  6. Laffer U. T., Metzger U. Intraportal chemotherapy for colorectal hepatic metastases. World J Surg. 1995 Mar-Apr;19(2):246–251. doi: 10.1007/BF00308634. [DOI] [PubMed] [Google Scholar]
  7. Laurie J. A., Moertel C. G., Fleming T. R., Wieand H. S., Leigh J. E., Rubin J., McCormack G. W., Gerstner J. B., Krook J. E., Malliard J. 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. J Clin Oncol. 1989 Oct;7(10):1447–1456. doi: 10.1200/JCO.1989.7.10.1447. [DOI] [PubMed] [Google Scholar]
  8. MANTEL N., HAENSZEL W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959 Apr;22(4):719–748. [PubMed] [Google Scholar]
  9. Miller A. B., Hoogstraten B., Staquet M., Winkler A. Reporting results of cancer treatment. Cancer. 1981 Jan 1;47(1):207–214. doi: 10.1002/1097-0142(19810101)47:1<207::aid-cncr2820470134>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  10. Moertel C. G., Fleming T. R., Macdonald J. S., Haller D. G., Laurie J. A., Goodman P. J., Ungerleider J. S., Emerson W. A., Tormey D. C., Glick J. H. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990 Feb 8;322(6):352–358. doi: 10.1056/NEJM199002083220602. [DOI] [PubMed] [Google Scholar]
  11. Moertel C. G., Fleming T. R., Macdonald J. S., Haller D. G., Laurie J. A., Tangen C. M., Ungerleider J. S., Emerson W. A., Tormey D. C., Glick J. H. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med. 1995 Mar 1;122(5):321–326. doi: 10.7326/0003-4819-122-5-199503010-00001. [DOI] [PubMed] [Google Scholar]
  12. O'Connell M. J., Mailliard J. A., Kahn M. J., Macdonald J. S., Haller D. G., Mayer R. J., Wieand H. S. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997 Jan;15(1):246–250. doi: 10.1200/JCO.1997.15.1.246. [DOI] [PubMed] [Google Scholar]
  13. Reynolds T. Dutch trial casts doubt on colorectal adjuvant therapy. J Natl Cancer Inst. 1995 Apr 5;87(7):476–479. doi: 10.1093/jnci/87.7.476. [DOI] [PubMed] [Google Scholar]
  14. Rougier P., Nordlinger B. Large scale trial for adjuvant treatment in high risk resected colorectal cancers. Rationale to test the combination of loco-regional and systemic chemotherapy and to compare l-leucovorin + 5-FU to levamisole + 5-FU. Ann Oncol. 1993;4 (Suppl 2):21–28. doi: 10.1093/annonc/4.suppl_2.s21. [DOI] [PubMed] [Google Scholar]
  15. Scheithauer W., Kornek G., Rosen H., Sebesta C., Marcell A., Kwasny W., Karall M., Depisch D. Combined intraperitoneal plus intravenous chemotherapy after curative resection for colonic adenocarcinoma. Eur J Cancer. 1995 Nov;31A(12):1981–1986. doi: 10.1016/0959-8049(95)00426-2. [DOI] [PubMed] [Google Scholar]
  16. Speyer J. L. The rationale behind intraperitoneal chemotherapy in gastrointestinal malignancies. Semin Oncol. 1985 Sep;12(3 Suppl 4):23–28. [PubMed] [Google Scholar]
  17. Sugarbaker P. H., Gianola F. J., Speyer J. C., Wesley R., Barofsky I., Meyers C. E. Prospective, randomized trial of intravenous versus intraperitoneal 5-fluorouracil in patients with advanced primary colon or rectal cancer. Surgery. 1985 Sep;98(3):414–422. [PubMed] [Google Scholar]
  18. Sugarbaker P. H., Schellinx M. E., Chang D., Koslowe P., von Meyerfeldt M. Peritoneal carcinomatosis from adenocarcinoma of the colon. World J Surg. 1996 Jun;20(5):585–592. doi: 10.1007/s002689900091. [DOI] [PubMed] [Google Scholar]
  19. Wolmark N., Rockette H., Fisher B., Wickerham D. L., Redmond C., Fisher E. R., Jones J., Mamounas E. P., Ore L., Petrelli N. J. 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 Oct;11(10):1879–1887. doi: 10.1200/JCO.1993.11.10.1879. [DOI] [PubMed] [Google Scholar]
  20. Zelen M. A new design for randomized clinical trials. N Engl J Med. 1979 May 31;300(22):1242–1245. doi: 10.1056/NEJM197905313002203. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES