Immunomodulation in colorectal cancer: disappointment or promise?

G. Pentheroudakis and N. Pavlidis*

Department of Medical Oncology, Ioannina University Hospital, 45110 Ioannina, Greece

*E-mail: npavlid@cc.uoi.gr

The treatment of patients with localised rectal carcinoma is a field of continuing debate as failure rates of 30–60% for Dukes’ B2 and C disease [1] indicate the need for optimal adjuvant therapy. Postoperative 5-FU-based chemoradiation is the standard of care [2] in the USA whereas the European approach ranges from adoption of the NIH Consensus Conference recommendations to focus on preoperative radiation or total mesorectal excision. Ongoing studies are likely to enlighten us with the optimal multimodality strategy. With the recent resurgence of interest in the interactions of the immune system and colorectal cancer, immunomodulation may well become part of such a therapy.

At the end of the 19th century William B. Coley, a New York surgeon, intentionally infected patients with metastatic solid tumours with heat-killed streptococci after he observed tumour regression in a patient with recurrent erysipelas. Surprisingly, he did obtain a few complete responses. More than a century later, have we managed to develop more specific forms of immunomodulation and improve its efficacy?

Levamisole, an antiparasitic agent with stimulatory immune effects, re-inaugurated the exploration of immunomodulation in the modern era. Combined with 5-FU, it was shown to be an effective adjuvant treatment for patients with Dukes’ C or B2 colorectal cancer [3, 4]. It took the scientific community four large randomised studies [58] and several years to realise that levamisole is not needed on top of leucovorin-modulated 5-FU therapy, and that the benefit initially seen was due to the high dose-intensity of weekly 5-FU. Futile attempts to establish some benefit for cimetidine, BCG, OK432 or Corynobacterium parvum vaccines followed until preclinical studies suggested synergism between the interferons (IFNs) and 5-FU.

Interferon-a enhances 5-FU conversion to FdUMP, the active cytotoxic metabolite that binds thymidylate synthase, and reduces cellular levels of the target enzyme. It also reduces thymidine incorporation into DNA, thus ablating one of the salvage pathways of malignant cells to 5-FU-induced cytotoxicity. Interferons augment FdUMP incorporation into tumour DNA, a secondary mechanism of 5-FU cell kill. Anti-angiogenesis effects have been shown, whereas pharmacologic studies suggested a reduction in 5-FU elimination caused by IFN-a leading to an increased AUC of the drug [9]. These preclinical data generated enthusiasm as soon as Wadler et al. reported a 76% response rate to 5-FU–IFN in patients with advanced colorectal cancer [10], an optimism that was sustained by confirmatory phase II studies.

In this issue of Annals of Oncology, Gennatas et al. report on the first published prospective, randomised trial that could answer several interesting questions in the field of rectal cancer management: is there a relapse-free or overall survival benefit when IFN is added on top of postoperative chemoradiotherapy after curative resection of Dukes’ B2 or C rectal carcinoma? If not, is the toxicity profile improved, due to a possible IFN-induced sparing of normal tissues from radiation injury?

In this multicentre study, patients were balanced for prognostic variables and received Mayo Clinic type chemotherapy before, during and after standard four-field pelvic radiotherapy. The schedule was chosen in view of the adundance of data on bolus 5-FU–leucovorin–IFN biochemical and pharmacological interactions [11, 12]. The 5-year overall and disease-free survival rates were 70% and 55%, respectively, in both treatment arms. Neither relapses nor deaths were significantly different in the two cohorts. Does this mean absence of additional benefit from IFN? Probably, although some points have to be highlighted: a trial with a sample size of 204 patients can only detect a 15–20% absolute survival difference, assuming a type I error of 5%, a power of 80% and a baseline survival function of 40–60%. Obviously such differences are unrealistic in oncology. Consequently, even if a 5–10% absolute survival benefit was present, it would probably have been missed by the trial. Moreover, data on cancer-specific deaths are not available. In other studies, survival gains from radiation were offset by radiation-induced vascular and septic deaths in elderly patients; this is theoretically possible in our case for IFN. Finally, no data on the percentage of patients who underwent total mesorectal excision, an optimal surgical technique that may obviate the need for additional locoregional therapy, or on local relapses was given. Interferon effects on the local relapse rate could have been ‘diluted’ by optimal surgery, as locoregional recurrence rates <10% are difficult to improve.

Interferon may protect from radiation toxicity by inhibiting nuclear effects of TGF-b [13], a known mediator of radiation-induced fibrosis, or by inducing cell cycle arrest in normal tissues [14]. In this study, the toxicity profile in the two patient groups was identical apart from flu-like symptoms that were present in all of the IFN-treated patients and none of the rest. Accordingly, despite lack of data on radiation treatment breaks and delays, it is safe to say that toxic effects were more pronounced in the presence of the cytokine.

In conclusion, this randomised study exludes the presence of a large survival gain from the addition of IFN-a and depicts a non-useful compromise of treatment tolerance in patients with resected Dukes’ B2 or C rectal cancer. This is in agreement with evidence reported to date for colon cancer. In advanced disease patients, nine randomised studies evaluated unmodulated 5-FU with or without IFN, 5-FU schedules modulated by either leucovorin or IFN and leucovorin-modulated 5-FU with or without IFN [15]. All studies failed to show any activity or survival benefit for the IFN arms, at the cost of increased treatment-related toxicity. To build further on the evidence of lack of benefit, the National Surgical Adjuvant Breast and Bowel Project C-05 protocol could not identify any survival benefit for IFN in 2176 patients with resected Dukes’ B2 or C colon carcinoma who received adjuvant 5-FU–leucovorin with or without the cytokine [16]. As side-effects were worse for the IFN arm, this trial is, for most clinicians, the ‘end of story’ for IFN immunomodulation in colorectal cancer.

Despite the ineffectiveness of combined immunochemotherapy, what is a dead end for IFN is not necessarily so for new, more sophisticated immunomodulatory concepts. The latter are likely to be ineffective against large tumour cell aggregates but may work better in a ‘minimal residual disease’ state against micrometastases. Autologous or allogeneic tumour cell vaccines with immunogenic adjuvants elicit a specific antitumour cell-mediated immune response in the host with negligible toxicity. Three randomised studies and a meta-analysis [1719] were published, suggesting a disease-free and overall survival benefit in patients with resected stage II colonic primaries and patients with a good delayed hypersensitivity cellular reaction, notably without the use of adjuvant chemotherapy.

As the technical difficulty of vaccine manufacture represents a major barrier, specific monoclonal antibodies have been developed. Edrecolomab, a murine antibody targeting the 17-1A glycoprotein on the surface of colonic epithelial cells, was shown to be promising as adjuvant therapy by inducing complementary- and antibody-dependent cellular cytotoxic effects as well as an anti-idiotypic network. Following a German trial that showed a significant relapse and death risk reduction in resected Dukes’ C colorectal cancer patients [20], five multinational randomised studies have begun assessing monotherapy or the antibody–5-FU–FA combination in the adjuvant setting. To the disappointment of the medical community, a large trial with >2700 stage III colon cancer patients recently showed no evidence of benefit from combined therapy compared with chemotherapy, and inferiority of antibody monotherapy [21]. Still, a new generation of less immunogenic anti-17-1A antibodies are being developed (GA733, 323/A3) in the hope that suppressed human anti-mouse antibody formation and enhanced immunomodulatory effects will contribute towards a clinical benefit.

Anti-idiotypic antibody vaccines (3H1, 105AD7) [22, 23] that mimic tumour antigens (CEA, gp72) have been shown to elicit idiotype-specific T-cell responses and are being evaluated in phase II and III trials. Cetuximab (C225), an epidermal growth factor receptor-inhibitor, has been shown to possess activity in patients with both chemoresistant and chemosensitive colon cancer overexpressing EGFR [24], and is likely to be assessed in phase III trials combined with chemotherapy. Potential new avenues for exploration include: radioisotope-labelled monoclonal antibodies; antibodies against MHC-restricted Her2/neu or VEGF; naked DNA or RNA polynucleotides encoding for tumour antigens; MUC1 peptides; and modified dendritic cells acting as tumour peptide carriers. As the feasibility and safety of combining modern immunotherapeutic approaches with chemotherapy is being established, large randomised trials assessing such therapies in a ‘minimal residual disease’, adjuvant setting will be needed. Only these will show whether an effective, targeted, non-toxic therapy for eradication of micrometastatic disease in colorectal cancer will be available for combination with cytotoxic treatment. If this happens, we shall be able to definitely expel William B. Coley in the history books and face the future with additional optimism.

G. Pentheroudakis & N. Pavlidis*

Department of Medical Oncology, Ioannina University Hospital, 45110 Ioannina, Greece (*E-mail: npavlid@cc.uoi.gr)

References

1. Glynne-Jones R, Debus J. Improving chemoradiotherapy in rectal cancer. Oncologist 2001; 6: 29–34.[Abstract/Free Full Text]

2. National Institutes of Health Consensus Conference. Adjuvant therapy for patients with colon and rectum cancer. J Am Med Assoc 1990; 264: 1444–1450.[CrossRef][ISI][Medline]

3. Moertel CG, Fleming TR, McDonald JS et al. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Int Med 1995; 122: 321–326.[Abstract/Free Full Text]

4. Zoetmulder F, Taal B, Van Tinteren H. Adjuvant 5-FU plus levamisole improves survival in stage II and III colonic cancer, but not in rectal cancer. Interim analysis of the NACCP. Proc Am Soc Clin Oncol 1999; 18: 266a (Abstr).

5. Wolmark N, Rockette H, Mamounas EP et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, levamisole in patients with Dukes’ B and C carcinoma of the colon: results from NSABP C-04. J Clin Oncol 1999; 17: 3553–3559.[Abstract/Free Full Text]

6. O Connell MJ, Laurie JA, Kahn M et al. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998; 16: 295–300.[Abstract]

7. Haller DG, Catalano PJ, MacDonald JS, Mayer RJ. Fluorouracil, leucovorin and levamisole adjuvant therapy for colon cancer: four-year results of INT-0089. Proc Am Soc Clin Oncol 1997; 16: 265a (Abstr).

8. Gray R, Kerr D, McConkey C, Williams N. QUASAR: a UKCCCR study of adjuvant chemotherapy for colorectal cancer. Eur J Cancer 1999; 35 (Suppl 2): S82.

9. Grem JL, van Groeningen CJ, Ismail AA et al. The role of interferon-a as a modulator of fluorouracil and leucovorin. Eur J Cancer 1995; 31: 1316–1320.[CrossRef]

10. Wadler S, Schwartz EL, Goldman M et al. Fluorouracil and recombinant alfa-2a-interferon: an active regimen against advanced colorectal carcinoma. J Clin Oncol 1989; 7: 1769–1775.[Abstract]

11. Houghton JA, Cheshire PJ, Morton CL, Stewart CF. Potentiation of 5-fluorouracil–leucovorin activity by alpha-2a-interferon in colon adenocarcinoma xenografts. Clin Cancer Res 1995; 1: 33–40.[Abstract]

12. Raderer M, Scheithauer W. Treatment of advanced colorectal cancer with 5-fluorouracil and interferon-a: an overview of clinical trials. Eur J Cancer 1995; 6: 1002–1008.[CrossRef]

13. Nguyen NP, Antoine JE, Dutta S et al. Current concepts in radiation enteritis and implications for future clinical trials. Cancer 2002; 95: 1151–1163.[CrossRef][ISI][Medline]

14. Stolfi RL, Martin DS, Sawyer RC, Spiegelman S. Modulation of 5-fluorouracil-induced toxicity in mice with interferon or with the interferon inducer, polyinosinic-polycytidylic acid. Cancer Res 1983; 43: 561–566.[Abstract]

15. Yip D, Strickland AH, Karapetis CS et al. Immunomodulation therapy in colorectal carcinoma. Cancer Treat Rev 2000; 26: 169–190.[CrossRef][ISI][Medline]

16. Wolmark N, Bryant J, Smith R et al. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 1998; 90: 1810–1816.[Abstract/Free Full Text]

17. Hoover H, Ransom J, Pinedo H et al. Meta-analysis of three randomized adjuvant trials of active specific immunotherapy of colon cancer. Proc Am Soc Clin Oncol 1999; 18: 437a (Abstr).

18. Vermorken JB, Claessen AM, van Tinteren H et al. Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet 1999; 353: 345–350.[CrossRef][ISI][Medline]

19. Harris JE, Ryan L, Hoover HC et al. Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Oncol 2000; 18: 148–157.[Abstract/Free Full Text]

20. Riethmuller G, Holz E, Schlimok G et al. Monoclonal antibody therapy for resected Dukes’ C colorectal cancer: seven-year outcome of a multicenter randomized trial. J Clin Oncol 1998; 16: 1788–1794.[Abstract]

21. Punt CJ, Nagy A, Douillard JY et al. Edrecolomab alone or in combination with 5-fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet 2002; 360: 671–677.[CrossRef][ISI][Medline]

22. Foon KA, John WJ, Chakraborty M et al. Clinical and immune responses in resected colon cancer patients treated with an anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen. J Clin Oncol 1999; 17: 2889–2895.[Abstract/Free Full Text]

23. Maxwell-Armstrong C. Studies using the anti-idiotypic monoclonal antibody 105AD7 in patients with primary and advanced colorectal cancer. Ann R Coll Surg Engl 2002; 84: 314–318.[ISI][Medline]

24. Rosenberg AH, Loehrer PJ, Needle MN et al. Erbitux (IMC-C225) plus weekly irinotecan, fluorouracil and leucovorin in colorectal cancer that expresses the epidermal growth factor receptor. Proc Am Soc Clin Oncol 2002; 21: 135a (Abstr 536).





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