Feilchenfeldt, J.

Power, D. G.

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Irinotecan and mismatch repairdeficiencyWe read the recent publications of Ychou et al. [1, 2] on‘adjuvant’ irinotecan-based chemotherapy in high-risk localizedcolorectal cancer (CRC) and after resection of liver-confinedmetastatic disease with great interest. In contrast to theimproved outcome provided by oxaliplatin-based adjuvanttreatment of early-stage disease, there is now a body of evidenceshowing that the addition of irinotecan to 5-fluorouracil(5-FU)/Leucovorin does not provide a benefit in this setting[1, 3]. The authors are to be congratulated for reporting thelargest randomized trial of adjuvant treatment after resectedcolorectal liver metastases. Such trials have been historicallydifficult to accrue and it has been hard to show an overallsurvival benefit with either systemic or regional treatment in thissetting. On the basis of data, we are now pretty sure that theconclusion from the localized disease setting—onlycombination of 5-FU with oxaliplatin confers an advantage over5-FU alone—can also be applied to liver-confined resectableCRC as has already been common practice in most centers.It is a commonly uttered wish that future clinical trialsshould stratify patients according to their particular risk as wellas biomarkers predicting response to treatment. Resectablemetastatic CRC would lend itself to such a strategy as thepostoperative recovery period leaves several weeks to do the‘molecular homework’. Despite groundbreaking work in coloncancer assessing the role of topoisomerase I, thymidylatesynthase and excision repair cross-complementation group inpredicting response to irinotecan, 5-FU and oxaliplatin,respectively, practice-changing trials are still at large. DNAmismatch repair (MMR) defects, in contrast, are easily assessedby immunohistochemistry and may provide importantinformation regarding efficacy of irinotecan [4]. We areinterested to know whether Ychou et al. assessed tumor tissuefor DNA MMR defects or microsatellite instability (MSI).Patients who can undergo curative resection of liver metastaseshave an outcome that lies somewhere between that for patientswith stage IIIB–IIIC disease. MMR status may, therefore, be ofrelevance for this group. We acknowledge that MMR loss is anuncommon event in sporadic advanced CRC (<10%) [5] andrecent data from a large adjuvant trial for early-stage diseasehave shown that MSI, a surrogate for MMR protein loss, wasless common in stage III and was not independently prognosticof outcome (relapse-free survival and overall survival) [6].However, there are little data on the potential role of MMR lossas a biomarker post-liver resection and chemotherapy trials inthis setting are lacking. One of the difficulties inherent toaccrual for adjuvant trials is likely explained by the reluctanceof patients and physicians alike to consider a surgery-alone armafter liver resection. The validation of biomarkers such as MMRloss, even in small subsets of patients, may make a surgery-alone arm more attractive, improve accrual and may identifya population who will benefit most from adjuvant therapy. Inconcordance with the authors, we also feel that ‘considerationsfor tailoring combination therapies in the adjuvant treatmentof liver-limited CRC to patients who will receive most benefitwill need to be integrated into future trials’. Response tooxaliplatin-based treatment may also be different in tumorsthat harbor MMR defects [7].D. G. Power1* & J. Feilchenfeldt21Department of Medicine, Gastrointestinal Oncology Division, MemorialSloan Kettering Cancer Center, NY, USA, 2Department of Oncology,Zurich University Hospital, Zurich, Switzerland(*E-mail: drdgpower@gmail.com)disclosureThe authors have no conflict of interest to declare.references1. Ychou M, Raoul JL, Douillard JY et al. A phase III randomised trial of LV5FU2 +irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCCAccord02/FFCD9802). Ann Oncol 2009; 20: 674–680.2. Ychou M, Hohenberger W, Thezenas S et al. A randomized phase III studycomparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients followingcomplete resection of liver metastases from colorectal cancer. Ann Oncol 2009;20: 1964–1970.3. Van Cutsem E, Labianca R, Bodoky G et al. Randomized phase III trial comparingbiweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvanttreatment of stage III colon cancer: PETAAC-3. J Clin Oncol 2009; 27(19):3117–3125.letters to the editor Annals of Oncology432 | letters to the editor Volume 21 | No. 2 | February 20104. Bertagnolli MM, Niedzwiecki D, Compton CC et al. Microsatellite instabilitypredicts improved response to adjuvant therapy with irinotecan, fluorouracil, andleucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol89803. J Clin Oncol 2009; 27: 1814–1821.5. Koopman M, Kortman GA, Mekenkamp L et al. Deficient mismatch repair systemin patients with sporadic advanced colorectal cancer. Br J Cancer 2009; 100:266–273.6. Roth AD, Tejpar S, Yan P et al. Stage-specific prognostic value of molecularmarkers in colon cancer: results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial. In Proceedings of the American Society ofClinical Oncology Annual Meeting, Chicago, IL, 29 May–2 June 2009 (Abstr4002). 2009.7. Muller CI, Schulmann K, Reinacher-Schick A et al. Predictive and prognostic valueof microsatellite instability in patients with advanced colorectal cancer treated witha fluoropyrimidine and oxaliplatin containing first-line chemotherapy. A report ofthe AIO Colorectal Study Group. Int J Colorectal Dis 2008; 23: 1033–1039.doi:10.1093/annonc/mdp550Published online 25 November 2009Annals of Oncology letters to the editorVolume 21 | No. 2 | February 2010 letters to the editor | 433

Irinotecan and mismatch repair deficiency

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