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Review
. 2012 Apr;397(4):543-55.
doi: 10.1007/s00423-012-0929-5. Epub 2012 Mar 2.

The molecular basis of chemoradiosensitivity in rectal cancer: implications for personalized therapies

Marian Grade  1 , Hendrik A Wolff, Jochen Gaedcke, B Michael Ghadimi
Affiliations
Review

The molecular basis of chemoradiosensitivity in rectal cancer: implications for personalized therapies

Marian Grade et al. Langenbecks Arch Surg. 2012 Apr.

Abstract

Introduction: Preoperative chemoradiotherapy represents the standard treatment for patients with locally advanced rectal cancer. Unfortunately, the response of individual tumors to multimodal treatment is not uniform and ranges from complete response to complete resistance. This poses a particular problem for patients with a priori resistant tumors because they may be exposed to irradiation and chemotherapy, treatment regimens that are both expensive and at times toxic, without benefit. Accordingly, there is a strong need to establish molecular biomarkers that predict the response of an individual patient's tumor to multimodal treatment and that indicate treatment-associated toxicities prior to therapy. Such biomarkers may guide clinicians in choosing the best possible treatment for each individual patient. In addition, these biomarkers could be used to identify novel molecular targets and thereby assist in implementing novel strategies to sensitize a priori resistant tumors to multimodal treatment regimens.

Objective: The aim of this review is to summarize recent findings about the molecular basis of treatment resistance and treatment toxicity in patients with rectal cancer. Whole-genome, as well as single-biomarker or multibiomarker, analyses and their potential implications will be highlighted. At the end, we will outline a future vision of rectal cancer treatment in the era of personalized medicine.

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Figures

Fig. 1
Fig. 1
RNAi-mediated silencing of TCF4 results in radiosensitization. TCF4 was silenced in SW837 and SW480 cells using shRNA constructs, and stable single-cell clones were subsequently established. A standard colony-forming assay demonstrated that silencing of TCF4 significantly increased the sensitivity of SW480 and SW837 cells to clinically relevant doses of X-rays
Fig. 2
Fig. 2
Potential pathways and proteins regulating and mediating resistance of rectal cancer cells to chemoradiotherapy
Fig. 3
Fig. 3
Outline of the TransValid-KFO179/GRCSG-Trials (TransValid A, TransValid B). TransValid A (validation study): 200 patients will be treated with 5-FU-based (1,000 mg/m2, 120 h continuous i.v. on days 1–5 and 29–33) chemoradiotherapy (radiation, 28 × 1.8 Gy) followed by radical surgery. Adjuvant therapy consists of either four cycles of 5-FU (500 mg/m2, bolus i.v. on days 1–5, repeat on day 29) or, in selected cases based on the clinicians’ discretion, six applications of a shortened FOLFOX regimen (folinic acid 400 mg/m2, 2 h continuous i.v.; oxaliplatin 100 mg/m2, 2 h continuous i.v.; 5-FU 2,400 mg/m2, 46 h continuous i.v.; on days 1, 15, 30, 45, 60, and 75). TransValid B (feasibility study, phase I/II): 50 patients will be treated with chemoradiotherapy (radiation, 28 × 1.8 Gy; 5-FU 250 mg/m2, continuous i.v. on days 1–14 and 22–35; oxaliplatin, 50 mg/m2, 2 h continuous i.v. on days 1, 8, 22, and 29), followed by three applications of a shortened FOLFOX regimen on days 1, 15, and 30 and radical surgery
Fig. 4
Fig. 4
Future vision for the treatment of patients with locally advanced rectal cancers. Pretherapeutic patient material (tumor and normal tissue) will be subjected to multilayer genomic analyses. Based on the results of these analyses, patients will be stratified into different (preoperative) treatment concepts (personalized medicine)
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