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Lymph Node Status and TS Gene Expression Are Prognostic Markers in Stage II/III Rectal Cancer After Neoadjuvant Fluorouracil-Based Chemoradiotherapy

Torsten Liersch, Claus Langer, B. Michael Ghadimi, Bettina Kulle, Daniela E. Aust, Gustavo B. Baretton, Wolfgang Schwabe, Peter Häusler, Heinz Becker, Christiane Jakob

From the Department of General Surgery, University Medical Center, Göttingen; Institute for Pathology, University of Technology, Dresden; Oncoscreen GmbH, Jena, Germany; and the Department of Biostatistics, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway.

Address reprint requests to Torsten Liersch, MD, Department of General Surgery University Medical Center, Göttingen, Robert-Koch-Str 40, D-37075 Göttingen, Germany; e-mail: tliersc{at}gwdg.de

Purpose: According to the CAO/ARO/AIO-94 trial of the German Rectal Cancer Study Group, preoperative combined fluorouracil (FU) -based long-term chemoradiotherapy (CT/RT) is recommended for patients with International Union Against Cancer (UICC) stage II/III rectal cancer. However, despite the local benefit of neoadjuvant treatment, the overall prognostic value remains uncertain in comparison with adjuvant CT/RT. Furthermore, the prognostic value of molecular biomarkers, such as thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), all of which are involved in the FU metabolism, is unknown in neoadjuvant settings. We assessed the impact of standardized preoperative CT/RT and intratumoral TS, TP, and DPD levels on patient outcome.

Patients and Methods: Forty patients with rectal cancer pretherapeutic UICC stage II/III, receiving preoperative FU-based CT/RT (CAO/ARO/AIO-94 trial) followed by standardized surgery, including total mesorectal excision, were investigated. Downsizing, downstaging, tumor regression, as well as TS, TP, and DPD gene expression of post-treatment surgical specimens were correlated with disease-free survival (DFS) and overall survival (OS).

Results: Significant downsizing (P < .001) and downstaging (P = .001) were achieved with preoperative CT/RT. During a median follow-up of 49 months (95% CI, 43 to 58 months), the cancer recurrence rate was 28.2%. DFS and OS were significantly increased in patients with downstaging (P < .001 and P = .003, respectively), compared with patients without downstaging. All patients who developed cancer recurrence had a persistent positive lymph node status after preoperative CT/RT (P < .001) and a significantly higher TS gene expression (P = .035) compared with those patients without recurrence.

Conclusion: Persistent positive lymph node status and high intratumoral TS expression after preoperative CT/RT are predictive of an unfavorable prognosis in rectal cancer UICC stage II/III.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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