Adjuvant Chemotherapy in Colorectal Cancer Patients with Microsatellite Instability
Authors: Toshiaki Watanabe, Takamitsu Kanazawa, Yoshihiro Kazama, Junichiro Tanaka, Toshiaki Tanaka, Soichiro Ishihara, Hirokazu Nagawa
Journal: Clinical Cancer Research (2006)

To the Editor: In a recent issue of Clinical Cancer Research (1), we read Benatti et al.'s article with interest, therein they showed significantly better survival in microsatellite instability high (MSI-H) patients than microsatellite stable patients, and concluded that the type of genomic instability could influence the prognosis of colorectal cancer, in particular, in stages II and III. Furthermore, in relation to adjuvant treatment, they concluded that fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients. Although Benatti et al. introduced our results, our research on the similar topic came to a different conclusion (2). There are major issues to be discussed as to how Benatti et al. drew their conclusions.The first point is the total number of MSI-H patients who received chemotherapy. In Benatti et al.'s study, only 65 MSI-H patients received fluorouracil-based chemotherapy; among these 65 patients, 31 patients had stage IV disease. Considering that most of the patients who had stage IV disease would have received postoperative chemotherapy, the total number of MSI-H patients, in stages II and III, who received chemotherapy seems to be much fewer than 65.The second point is how they examined the survival rate. Benatti et al. examined the survival in stage II and stage III patients separately. Therefore, the number of MSI-H patients who received chemotherapy in either stage II or III should be ∼20 at most. This number of patients seems to be too small to find any difference in survival. In fact, MSI-H patients who underwent chemotherapy showed higher survival rates than those who did not, although it did not reach statistical significance. Furthermore, according to the survival curve of stage II cancers, there seems to be no cancer-related death in MSI-H patients who had undergone chemotherapy.Considering all these points, the small number of MSI-H patients who underwent chemotherapy seems to be the main reason why they could not find significant differences in survival between MSI-H patients who did or did not undergo chemotherapy. All of these points are also true in an analysis of MSI-H patients in stage III. In Benatti et al.'s study, the number of MSI-H patients with chemotherapy in stage II or III seems to be too small to draw any conclusion. In our previous study, we examined 73 MSI-H patients who received chemotherapy and showed a significant difference in survival between MSI-H patients and microsatellite stable patients (2). Taken together, Benatti et al.'s study may potentially bias the significance of MSI-H as a predictor of survival in patients with adjuvant-treated colon cancer.In response: The major criticism raised by Watanabe in his letter about our recently published article (1) concerns the number of patients with stage II and III MSI-H colorectal cancer (CRC) who received chemotherapy, that “should be around 20 at most” and thus “seems too small to draw any conclusions.”The assumption of Watanabe on the small number of patients in our study is based on his interpretation that among those 65 MSI-H who received chemotherapy, 31 were in stage IV. This assumption is not correct. In fact, we considered as patients receiving adjuvant chemotherapy only those who underwent surgical intervention with curative intent (i.e., radical surgery), thus excluding most of stage IV patients who received only palliative chemotherapy. We apologize for the fact that this explanation was not present in the text leading to the misinterpretation of the data. On this basis, among the 65 MSI-H patients considered as treated with adjuvant chemotherapy, only 2 were in stage IV whereas 25 were in stage II and the remaining 38 were in stage III, which is almost double of what was hypothesized.Furthermore, Watanabe states that the results of our study “could potentially bias the significance of MSI-H as predictor of survival in adjuvant-treated colon cancer patients” as shown by the results of his study (2), which compared the survival of MSI-H and MSS patients in stage II and III who received chemotherapy.We think that our results are not completely comparable with those of Watanabe, mainly for the reason that our study had a different design. In his work, Watanabe compared, among patients who received chemotherapy, those affected by MSI-H CRC versus those with stable tumors and found a survival advantage in the first group; this study design could not clearly establish whether this prognostic advantage is conferred by the better sensitivity of MSI-H CRC to chemotherapeutic agents or is due to the presence of instability by itself.On the contrary, our study was designed to investigate the sensitivity of MSI-H CRC to chemotherapy. For this reason, we compared among MSI-H CRC patients the outcome of those who underwent 5-fluorouracil-based chemotherapy versus those who were not treated. The results showed that chemotherapy did not confer any survival advantage in MSI-H CRC patients, confirming the report of another study with larger sample size (3). In addition, the results of multivariate analysis in stage II and III CRC cases showed the presence of MSI-H as an independent prognostic factor: this means that even in our study, in accordance with Watanabe's study, among patients who received chemotherapy, MSI-H patients have a better outcome than MSS patients.Finally, another difference between the two studies involved the definition of MSI. To define MSI, in our study, we used the reference marker panel, as established in Bethesda guidelines. Watanabe used eight dinucleotide and two polyadenine markers in most cases, or two mononucleotide markers in those cases without normal DNA available. This could have important implications leading to heterogeneity in the population defined as MSI in the two investigations.