Skip to main content

Advertisement

SpringerLink
Log in

Adjuvant therapy for colorectal cancer

Present and future perspectives

  • Current Status
  • Published:
Diseases of the Colon & Rectum

Abstract

In recent years, adjuvant therapy for colorectal cancer has advanced considerably. This article reviews these advances and provides an update of the most recent and ongoing trials. In 1990, adjuvant therapy became the “standard of care” for patients with Stage III colon cancer (Dukes C) in the United States. Recent clinical trial data indicate that adjuvant treatment may also be effective in patients with Stage II (Dukes B2) colon cancer. The combination of 5-fluorouracil plus leucovorin may slightly improve survival (5–10 percent) compared with the standard 5-fluorouracil plus levamisole combination. The three-drug regimen (5-fluorouracil plus levamisole plus leucovorin) is more toxic, with no superior effect on survival. Intraportal chemotherapy, although it may significantly improve patient survival, does not decrease the frequency of liver metastases. However, it is still a promising form of adjuvant therapy owing to its short treatment period and relatively equivalent effects in survival compared with that of systemic therapy. For patients with Stage II or Stage III rectal cancer, postoperative systemic 5-fluorouracil plus radiation therapy plus protracted venous 5-fluorouracil infusion is the most effective postoperative adjuvant regimen. However, results from several studies show that preoperative radiation alone or chemoradiation for advanced local rectal cancers might also be effective while also improving resectability, decreasing morbidity, and increasing the chance that a sphincter-sparing procedure may be performed. The role of leucovorin in rectal cancer remains to be determined. Immune therapies with agents such as interferon-α-2a, monoclonal antibody 17-1A, and autologous tumor vaccines are being assessed and could further improve survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics 1997. CA Cancer J Clin 1997;47:5–27.

    PubMed  CAS  Google Scholar 

  2. Abulafi AM, Williams NS. Local recurrence of colorectal cancer: the problem, mechanisms, management and adjuvant therapy. Br J Surg 1994;81:7–19.

    PubMed  CAS  Google Scholar 

  3. Quirke P, Durdey P, Dixon MF, Williams NS. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: histopathological study of lateral tumor spread and surgical excision. Lancet 1986;2:996–8.

    CAS  PubMed  Google Scholar 

  4. Buyse M, Zeleniuch-Jacquotte A, Chalmers TC. Adjuvant therapy for colorectal cancer, why we still don't know. JAMA 1988;259:3571–8.

    Article  PubMed  CAS  Google Scholar 

  5. Gastrointestinal Tumor Study Group. Adjuvant therapy of colon cancer-results of a prospectively randomized trial. N Engl J Med 1984;310:737–43.

    Article  Google Scholar 

  6. Moertel CG, Fleming TR, Macdonald JS,et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352–8.

    Article  PubMed  CAS  Google Scholar 

  7. Steele GD, Augenlicht LH, Begg CB,et al. National Institutes of Health consensus development conference statement: adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264:1444–50.

    Article  PubMed  Google Scholar 

  8. Reynolds T. Dutch trials casts doubt on colorectal adjuvant therapy. J Natl Cancer Inst 1995;87:476–80.

    PubMed  CAS  Google Scholar 

  9. Mamounas EP, Rockette H, Jones J,et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes' Bversus Dukes' C colon cancer: results from four NSABP Adjuvant Studies (C-01, C-02, C-03, C-04) [abstract]. Proc Am Soc Clin Oncol 1996;15:205.

    Google Scholar 

  10. Wolmark N, Rockette H, Manounas EP,et al. The relative efficacy of 5-FU + leucovorin (FU-LV), 5-FU + levamisole (FU-Lev), and 5-FU + leucovorin + levamisole (FU-LV-Lev) in patients with Dukes'B and C carcinoma of the colon: first report of NSABP C-04 [abstract].Proc Am Soc Clin Oncol 1996;15:205.

    Google Scholar 

  11. Crucitti F, Sofo L, Doglietto GB,et al. Prognostic factors in colorectal cancer: current status and new trends. J Surg Oncol Suppl 1991;2:76–82.

    PubMed  CAS  Google Scholar 

  12. Rognum TO, Thorud E, Lund E. Survival of large-bowel carcinoma patients with different DNA ploidy pattern. Br J Cancer 1987;5:633–6.

    Google Scholar 

  13. Takanishi D, Hart J, Covarelli P, Chappell R, Michelassi F. Ploidy as a prognostic feature in colonic adenocarcinoma. Arch Surg 1996;131:587–92.

    PubMed  Google Scholar 

  14. Nori D, Merimsky O, Samala E,et al. Tumor ploidy as a risk factor for disease recurrence and short survival in surgically-treated Dukes' B2 colon cancer patients.J Surg Oncol 1995;59:239–42.

    PubMed  CAS  Google Scholar 

  15. Cunningham C, Dunlop MG. Molecular genetic basis of colorectal cancer susceptibility. Br J Surg 1996;83:321–9.

    PubMed  CAS  Google Scholar 

  16. Jen J, Kim H, Piantadosi S,et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 1994;331:213–21.

    Article  PubMed  CAS  Google Scholar 

  17. Bardi G, Johansson B, Pandis N,et al. Cytogenetic analysis of 52 colorectal carcinomas non-random aberration pattern and correlation with pathologic parameters. Int J Cancer 1993;55:422–8.

    PubMed  CAS  Google Scholar 

  18. Pricolo VE, Finkelstein SD, Wu TT,et al. Prognostic value of Tp53 and K-ras-2 mutational analysis in stage III carcinoma of the colon. Am J Surg 1996;171:41–6.

    Article  PubMed  CAS  Google Scholar 

  19. Auvinen A, Isola J, Visakorpi T, Koivula T, Virtanen S, Hakama M. Overexpression of p53 and long-term survival in colon carcinoma. Br J Cancer 1994;70:293–6.

    PubMed  CAS  Google Scholar 

  20. Tomoda H, Kakeji Y. Immunohistochemical analysis of p53 in colorectal cancer regarding clinicopathological correlation and prognostic significance. J Surg Oncol 1995;58:125–8.

    PubMed  CAS  Google Scholar 

  21. Mulder J, Baas I, Polak M,et al. Evaluation of p53 protein expression as a marker for long-term prognosis in colorectal carcinoma.BrJ Cancer 1995;71:1257–62.

    CAS  Google Scholar 

  22. Benhattar J, Losi L, Chaubert P,et al. Prognostic significance of K-ras mutations in colorectal carcinoma. Gastroenterology 1993;104:1044–8.

    PubMed  CAS  Google Scholar 

  23. Finkelstein SD, Sayegh R, Baker A, Swalsky P. Determination of tumor aggressiveness in colorectal cancer by K-ras-2 analysis. Arch Surg 1993;128:526–32.

    PubMed  CAS  Google Scholar 

  24. Sinicrope F, Hart J, Brasitus T,et al. Relationship of P-glycoprotein and carcinoembryonic antigen expression in human colon carcinoma to local invasion, DNA ploidy, and disease relapse. Cancer 1994;74:2908–17.

    PubMed  CAS  Google Scholar 

  25. Leichman L, Lenz HJ, Leichman CG,et al. Quantitation of intratumoral thymidylate synthase expression predicts for resistance to protracted infusion of 5-FU and weekly leucovorin in disseminated colorectal cancers: preliminary report from an ongoing trial. Eur J Cancer 1995;31A:1306–10.

    Article  PubMed  CAS  Google Scholar 

  26. Moertel CG, Fleming TR, Macdonald JS,et al. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med 1995;122:321–6.

    PubMed  CAS  Google Scholar 

  27. MacFarlane JK, Ryall RD, Heald RG. Mesorectal excision for rectal cancer. Lancet 1993;341:457–60.

    Article  PubMed  CAS  Google Scholar 

  28. Wiggers T. Total mesorectal excision: a new standard for the surgical treatment of rectal carcinoma [letter]. Ned Tijdschr Geneeskd 1996;140:17.

    Google Scholar 

  29. Gastrointestinal Tumor Study Group. Prolongation of disease-free interval in surgically treated rectal carcinoma. N Engl J Med 1985;312:1465–72.

    Article  Google Scholar 

  30. Grem JL, Allegra CJ. Toxicity of levamisole and 5-fluorouracil in human colon carcinoma cells. J Natl Cancer Inst 1989;81:1413–6.

    PubMed  CAS  Google Scholar 

  31. Chlebowski RT, Lillington L, Nystrom JS, Sayre J. Late mortality and levamisole adjuvant therapy in colorectal cancer. Br J Cancer 1994;69:1094–7.

    PubMed  CAS  Google Scholar 

  32. O'Connell MJ, Laurie L, Sheperd MJ,et al. A prospective evaluation of chemotherapy duration and regimen as surgical adjuvant treatment for high-risk colon cancer: a collaborative trial of the North Central Cancer Treatment Group and the National Cancer Institute of Canada Clinical Trials Group [abstract]. Proc Am Soc Clin Oncol 1996;15:209.

    Google Scholar 

  33. Haller DG, Catalina PJ, Macdonald JS, Macer R. Fluorouracil, leucovorin, and levamisole adjuvant therapy for colon cancer: preliminary results of INT-0089 [abstract]. Proc Am Soc Clin Oncol 1996;15:211.

    Google Scholar 

  34. Slevin M. Adjuvant treatment for colorectal cancer: no more room for nihilism. BMJ 1996;312:392–3.

    PubMed  CAS  Google Scholar 

  35. Wolmark N, Rockette H, Wickerham DL,et al. Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project protocol C-02. J Clin Oncol 1990;8:1466–75.

    PubMed  CAS  Google Scholar 

  36. Keyman HD, Robertson SH, Bloom TS,et al. Rectal carcinoma: long-term experience with moderately high-dose preoperative radiation and low-anterior resection. Cancer 1992;69:2813–9.

    PubMed  Google Scholar 

  37. Minsky BD, Cohen AM, Enker WE, Kelsen DP, Kemeny N, Frankel J. Efficacy of postoperative 5-FU, high-dose leucovorin, and sequential radiation therapy for clinically resectable rectal cancer. Cancer Invest 1995;13:1–7.

    CAS  PubMed  Google Scholar 

  38. Sause WT, Pajak TF, Noyes RD,et al. Evaluation of preoperative radiation therapy in operable colorectal cancer. Ann Surg 1994;220:668–75.

    PubMed  CAS  Google Scholar 

  39. Goldberg P, Nicholls R, Porter N,et al. Long-term results of a randomised trial of short-course low-dose adjuvant pre-operative radiotherapy for rectal cancer: reduction in local treatment failure. Eur J Cancer 1994;30A:1602–6.

    Article  PubMed  CAS  Google Scholar 

  40. Marsh PJ, James RD, Schofield PF. Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma: results of a prospective randomized trial. Dis Colon Rectum 1994;37:1205–14.

    PubMed  CAS  Google Scholar 

  41. Cedermark B, Johansson H, Rutqvist L, Wilking N. The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. Cancer 1995;75:2269–75.

    PubMed  CAS  Google Scholar 

  42. Gerard A, Buyse M, Nordlinger M,et al. Preoperative radiotherapy as adjuvant treatment in rectal cancer: final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg 1988;208:606–14.

    PubMed  CAS  Google Scholar 

  43. Pahlman L, Glimelius B. Pre-or postoperative radiotherapy in rectal and rectosigmoid carcinoma: report from a randomized multicenter trial. Ann Surg 1990;211:187–95.

    Article  PubMed  CAS  Google Scholar 

  44. Swedish Rectal Cancer Trial. Five-year survival after preoperative radiation in rectal cancer [abstract]. Int J Colorectal Dis 1996;11:198.

    Google Scholar 

  45. Stockholm Colorectal Cancer Study Group. Randomized study on preoperative radiotherapy in rectal carcinoma. Ann Surg Oncol 1996;3:423–30.

    Google Scholar 

  46. Krook JE, Moertel CG, Gunderson LL,et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709–15.

    Article  PubMed  CAS  Google Scholar 

  47. 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;10:549–57.

    Google Scholar 

  48. O'Connell MJ, Martenson JA, Wieand HS,et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502–7.

    Article  PubMed  Google Scholar 

  49. Tepper I, O'Connell M, Petroni G,et al. Toxicity in the adjuvant therapy of rectal cancer: a preliminary report of Intergroup 0114 [abstract], Proc Am Soc Clin Oncol 1996;15:210.

    Google Scholar 

  50. Minsky B, Cohen A, Enker W,et al. Preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for rectal cancer. Cancer 1994;73:273–80.

    PubMed  CAS  Google Scholar 

  51. Minsky BD, Cohen AM, Kemeny N,et al. Enhancement of radiation-induced downstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy. J Clin Oncol 1992;10:79–84.

    PubMed  CAS  Google Scholar 

  52. Boulis-Wassif S, Gerard A, Loygue J,et al. Final results of a randomized trial on the treatment of rectal cancer with preoperative radiotherapy alone or in combination with 5-FU, followed by radical surgery. Trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Cancer 1984;53:1811–8.

    PubMed  CAS  Google Scholar 

  53. Landry JC, Koretz M, Wood WC,et al. Preoperative irradiation and fluorouracil chemotherapy for locally advanced rectosigmoid carcinoma: phase I-II study. Radiology 1993;188:423–6.

    PubMed  CAS  Google Scholar 

  54. Meterissian S, Skibber J, Rich T,et al. Patterns of residual disease after preoperative chemoradiation in ultrasound T3 rectal carcinoma. Ann Surg Oncol 1994;1:111–6.

    PubMed  CAS  Google Scholar 

  55. Minsky BD, Conti JA, Huang Y, Knopf K. Relationship of acute gastrointestinal toxicity and the volume of irradiated small bowel in patients receiving combined modality therapy for rectal cancer. J Clin Oncol 1995;13:1409–16.

    PubMed  CAS  Google Scholar 

  56. Minsky BD, Cohen AM, Kemeny N,et al. Combined modality therapy of rectal cancer: decreased acute toxicity with the preoperative approach. J Clin Oncol 1992;10:1218–24.

    PubMed  CAS  Google Scholar 

  57. Hyams DM, Mamounas EP, Petrelli N,et al. A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum. Dis Colon Rectum 1997;40:131–9.

    Article  PubMed  CAS  Google Scholar 

  58. Beart RW, Moertel C, Wieand H,et al. Adjuvant therapy for resectable colorectal carcinoma with fluorouracil administered by portal vein infusion. Arch Surg 1990;125:897–901.

    PubMed  Google Scholar 

  59. Swiss Group for Clinical Research. Long-term results of single course of adjuvant intraportal chemotherapy for colorectal cancer. Lancet 1995;345:349–53.

    Google Scholar 

  60. Fielding LP, Hittinger R, Grace RH, Fry J. Randomized controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma. Lancet 1992;340:502–6.

    Article  PubMed  CAS  Google Scholar 

  61. Taylor I, Rowling J, West C,et al. A randomized controlled trial of adjuvant portal vein cytotoxic perfusion in colorectal cancer. Br J Surg 1985;72:359–63.

    PubMed  CAS  Google Scholar 

  62. Wereldsma JC, Bruggink ED, Meijer WS, Roukema JA, van Putten WL. Adjuvant portal liver infusion in colorectal cancer with 5-fluorouracil/heparinversus urokinaseversus control: results of a prospective randomized clinical trial (colorectal adenocarcinoma trial). Cancer 1990;65:425–32.

    PubMed  CAS  Google Scholar 

  63. Laffer UT, Metzger U. Intraportal chemotherapy for colorectal hepatic metastases. World J Surg 1995;19:246–51.

    Article  PubMed  CAS  Google Scholar 

  64. Garten L, Stenning S, Gray R. Intraportal 5-FU for colorectal cancer: the AXIS trial [letter]. Lancet 1992;340:985.

    Article  CAS  PubMed  Google Scholar 

  65. Sugarbaker PH, Graves T, DeBruijn EA,et al. Early postoperative intraperitoneal chemotherapy as an adjuvant therapy for peritoneal carcinomatosis from gastrointestinal cancer: pharmacological studies. Cancer Res 1990;50:5790–4.

    PubMed  CAS  Google Scholar 

  66. Speyer JL, Sugarbaker PH, Collins JM, Dedrick RL, Klecker RW, Myers CE. Portal levels and hepatic clearance of 5-fluorouracil after intraperitoneal administration in humans. Cancer Res 1981;41:1916–22.

    PubMed  CAS  Google Scholar 

  67. Graf W, Westlin JE, Pahlman L, Glimelius B. Adjuvant intraperitoneal 5-fluorouracil and intravenous leucovorin after colorectal cancer surgery: a randomized phase II placebo-controlled study. Int J Colorectal Dis 1994;9:35–9.

    Article  PubMed  CAS  Google Scholar 

  68. Kelsen DP, Saltz L, Cohen AM,et al. A phase I trial of immediate postoperative intraperitoneal floxuridine and leucovorin plus systemic 5-fluorouracil and levamisole after resection of high-risk colon cancer. Cancer 1994;74:2224–33.

    PubMed  CAS  Google Scholar 

  69. Scheithauer W, Kornek G, Rosen H,et al. Combined intraperitoneal plus intravenous chemotherapy after curative resection for colonic adenocarcinoma. Eur J Cancer 1995;31A:1981–6.

    Article  PubMed  CAS  Google Scholar 

  70. Wadler S, Lembersky B, Atkins M, Kirkwood J, Petrelli N. Phase II trial of fluorouracil and recombinant interferon alpha-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 1991;9:1806–10.

    PubMed  CAS  Google Scholar 

  71. Grem JL, Jordan E, Robson ME,et al. Phase II study of fluorouracil, leucovorin, and interferon alfa-2a in metastatic colorectal carcinoma. J Clin Oncol 1993;11:1737–45.

    PubMed  CAS  Google Scholar 

  72. Pazdur R, Ajani JA, Patt YZ,et al. Phase II study of fluorouracil and recombinant interferon alpha-2a in previously untreated advanced colorectal carcinoma. J Clin Oncol 1990;8:2027–31.

    PubMed  CAS  Google Scholar 

  73. Wadler S, Schwartz EL, Goldman M,et al. Fluorouracil and recombinant alpha-2a interferon: an active regimen against advanced colorectal carcinoma. J Clin Oncol 1989;7:1769–75.

    PubMed  CAS  Google Scholar 

  74. Seymour MT, Slevin ML, Cunningham D,et al. Randomized trial assessing the addition of interferon-a2a to 5-fluorouracil and leucovorin in advanced colorectal cancer: colorectal cancer working party of the United Kindom Medical Reserach Council. J Clin Oncol 1996;14:2280–8.

    PubMed  CAS  Google Scholar 

  75. Reithmüller G, Schneider-Gädicke E, Schlimok G,et al. Randomized trial of monoclonal antibody for adjuvant therapy of resected Dukes C colorectal carcinoma. Lancet 1994;343:1177–83.

    Article  PubMed  Google Scholar 

  76. Wolmark N, Fisher B, Rockette H,et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP Protocol C01. J Natl Cancer Inst 1988;80:30–6.

    PubMed  CAS  Google Scholar 

  77. Hoover HS, Brandhorst JS, Peters LC,et al. Adjuvant active specific immunotherapy for human colorectal cancer: 6.5-year median follow-up of a phase III prospectively randomized trial. J Clin Oncol 1993;11:390–9.

    PubMed  Google Scholar 

  78. Moertel C. Vaccine adjuvant therapy for colorectal cancer: “very dramatic” or ho-hum. J Clin Oncol 1993;11:385–6.

    PubMed  CAS  Google Scholar 

  79. Hoover HC. Dr. Hoover responds to Dr. Moertel [letter]. J Clin Oncol 1993;11:586–95.

    PubMed  Google Scholar 

  80. Brown ML, Nayfield SG, Shibley LM. Adjuvant therapy for stage III colon cancer: economics returns to research and cost-effectiveness of treatment. J Natl Cancer Inst 1994;86:424–30.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Colorectal Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio

    Sergio Casillas M.D. & Jeffrey W. Milsom M.D.

  2. Departments of Hematology and Medical Oncology, The Cleveland Clinic Foundation, Cleveland, Ohio

    Robert J. Pelley M.D.

Authors
  1. Sergio Casillas M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert J. Pelley M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffrey W. Milsom M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Casillas, S., Pelley, R.J. & Milsom, J.W. Adjuvant therapy for colorectal cancer. Dis Colon Rectum 40, 977–992 (1997). https://doi.org/10.1007/BF02051209

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02051209

Key words

Search

Navigation