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In Reply

Baylor University Medical Center, Dallas, TX

It would appear we all agree that retrospective analyses have inherent biases, and I would add that there is no substitute for prospective randomization. The problem with the National Surgical Adjuvant Breast and Bowel Project analyses¹ and the Australian study² is that patients were selected for treatment from larger groups of colorectal cancer (CRC) patients, and since the treatments were new and untested at the time, the patients selected were likely to be younger, more robust, and to live longer.² Despite Kim et al's contrary statement, this was not the case in the Ribic study, in which the patients were prospectively randomized, and this study showed no benefit, and possible harm, when treating microsatellite instability (MSI) CRC patients with fluorouracil (FU)-based chemotherapy. The relative risk for death in stage II CRC patients was 3.28, which must be taken seriously. We know that we provide clinical benefit to just a subset of CRC patients treated with adjuvant FU; we need to identify those subsets most likely to respond, avoid treating those who would receive no benefit, and above all, do no harm. Preclinical studies had already demonstrated that CRC cells with MSI have in vitro resistance to FU.³ The suggestion that the prospective Ribic study was flawed because of differences in the treatment protocols should be dismissed as disingenuous; the doses of FU used in these five studies all provide blood levels predicted to be associated with drug resistance,³ and there is no experimental evidence to suggest that leucovorin or levamisole would be differentially affected by the presence or absence of MSI. The reality is that several prospectively designed studies have drawn attention to this issue, and it is imperative that we have impeachable evidence for benefit before we treat our patients, rather than the absence of evidence for harm.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Kim GP, Colangelo LH, Wieand HS, et al: Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: A National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol 25:767-772, 2007[Abstract/Free Full Text]

2. Elsaleh H, Joseph D, Grieu F, et al: Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 355:1745-1750, 2000[CrossRef][Medline]

3. Carethers JM, Chauhan DP, Fink D, et al: Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology 117:123-131, 1999[CrossRef][Medline]

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Related Correspondence

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