Going Beyond Systemic Fluoropyrimidines With Radiation Therapy for Rectal Cancer: What Should Be the Priority?

OncologyONCOLOGY Vol 26 No 8
Volume 26
Issue 8

As we look forward, we suggest that the priority should be to further our understanding of the tumor’s interactions with its microenvironment and with the immune system. We think that such an understanding will be critical for advances in locally advanced rectal cancer therapy.

After over 15 years of concerted international efforts, randomized phase III trials have established preoperative chemoradiation as the current standard of care in the treatment of patients with locally advanced rectal cancer (LARC). The “German trial” established the superiority of preoperative chemoradiation over postoperative chemoradiation for LARC.[1] Advances in surgical techniques for LARC resection over the last two decades have made a substantial difference in treatment outcomes. However, even in the setting of optimal total mesorectal excision surgery for LARC, the use of preoperative radiation therapy was shown by Dutch investigators to be a necessary therapeutic modality for the enhancement of local control.[2] More recently, phase III trials from Poland and Australia have established two different but viable preoperative radiation treatment approaches. As thoroughly discussed by Drs. Cellini and Valentini, the debate has now shifted to whether to use preoperative short-course radiation therapy (25 Gy in 5 fractions) or extended-course radiation therapy (50 Gy in 25-28 fractions) with concurrent chemotherapy. This issue remains unsettled and awaits the completion of ongoing trials and the maturation of existing data. However, it is becoming clear that these regimens should not be viewed as competing approaches. The selection of short-course or extended-course plus chemotherapy should be driven by the patient’s disease and presentation rather than by the prevailing dogma of oncologists and surgeons. For example, patients with LARC advancing within the mesorectal fascia may be better served by extended-course radiation therapy and chemotherapy in an effort to facilitate an R0 resection. Similarly, patients with LARC that exhibits limited invasion into the mesorectum may be well served by short-course radiation therapy. Overall, both these approaches provide excellent local control (over 90% in most trials). More recently, there has been interest in neoadjuvant chemotherapy–only approaches for “more favorable” LARC, prompting a new US Intergroup trial comparing neoadjuvant chemotherapy and surgery vs neoadjuvant chemoradiation and surgery.

Despite the advances in cytotoxic and surgical treatments, there have also been major disappointments.

First, there have been no substantive advances in the use of systemic cytotoxics beyond a fluoropyrimidine with radiation therapy as the basic staple of neoadjuvant chemoradiation. Although phase II trial results have been promising, three phase III trials from Italy, France, and the United States have shown no clinical benefit of oxaliplatin combined with a fluoropyrimidine and radiation therapy. Whether improvements in cytotoxic therapy will lead to improvements in LARC response or patient survival beyond what is currently achieved with preoperative chemoradiation remains unclear.

Secondly, despite their proven efficacy in metastatic colorectal cancer, molecularly targeted drugs such as the anti–epidermal growth factor receptor (EGFR) antibody cetuximab (Erbitux) or the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab (Avastin) have not advanced to phase III trials in LARC. The reason for this is that neither of these drugs has demonstrated a sufficient therapeutic ratio to justify moving forward in the neoadjuvant setting in combination with cytotoxics. One current direction of research is to pursue the use of KRAS mutation status as a negative biomarker for the use of cetuximab-although this approach remains controversial in LARC.[3-4] Another is to improve our understanding of the heterogeneity of rectal cancer beyond KRAS mutations so as to determine which oncogenes drive its progression in different patients-with the aim of exploiting this knowledge therapeutically by devising more personalized treatments.[5] For strategies that target the LARC stroma, such as bevacizumab treatment, the challenge of finding a biomarker is at least equally daunting as finding biomarkers for cytotoxics.[6] In particular, a thorough understanding of the changes in the tumor vasculature that occur after radiotherapy, as well as of the impact of these changes on treatment outcomes, remains elusive.[7] Moreover, the mechanism of action of bevacizumab is still being debated. Dr. Rakesh K. Jain has proposed that antiangiogenic therapies may transiently normalize tumor vasculature, leading to better drug delivery and tumor oxygenation.[8] Indeed, we reported that bevacizumab treatment in LARC induced early changes consistent with vascular normalization.[9] The implication of these results is that future efforts should be directed to identifying the optimal use of bevacizumab to improve its synergy with cytotoxics (via vascular normalization) and its antiangiogenic effects (when used alone). Furthermore, we proposed an endogenous inhibitor of VEGF-soluble VEGF receptor 1 (sVEGFR1), a secreted factor that blocks VEGF-as a potential biomarker for bevacizumab with chemoradiation in LARC.[10] While data that support vascular normalization and the use of plasma sVEGFR1 as a biomarker have emerged from multiple clinical studies of antiangiogenic agents in other cancers,[11-13] it remains unknown whether better patient selection for a more personalized treatment (based on biomarkers) could improve the therapeutic ratio for bevacizumab in LARC.

Lastly, as we strive to improve local control in LARC, it becomes increasingly clear that the major hurdle will be preventing or treating micrometastatic disease. Phase III data from adjuvant trials of bevacizumab or cetuximab in combination with chemotherapy in colorectal cancer have been discouraging.[14,15] Similarly, early experience from phase II trials of neoadjuvant cetuximab or bevacizumab with chemoradiation in LARC did not suggest any improvements in disease-free survival.[3,16-30] The solution appears to be targeting alternative pathways to EGFR or VEGF. For example, in preclinical studies, we found that SDF1α/CXCR4 pathway activation may be responsible for metastasis in the face of VEGFR1 inhibition.[18] Of note, we also showed that both SDF1α and CXCR4 are upregulated after bevacizumab treatment, and that high plasma levels of SDF1α on treatment correlated with poor disease-free survival in LARC patients.[19] The SDF1α/CXCR4 pathway has been previously linked with metastatic progression, and it may be a target for tumor sensitization to other therapies.[20] Efforts to harness the immune system to treat cancer have finally produced results, with recent successes in immunotherapy for other cancers (melanoma, prostate cancer).[21,22] This raises the hope that immunotherapies might be used in the future-alone or in combination with other drugs[8]-to prevent or treat micrometastatic disease in LARC patients. Collectively, these results indicate that the prevention or treatment of micrometastatic disease in LARC will require a better understanding of the biology of LARC progression.

As we look forward, we suggest that the priority should be to further our understanding of the tumor’s interactions with its microenvironment (at the primary site and at metastatic sites) as well as of its interactions with the immune system. We think that such an understanding will be critical for advances in LARC therapy. Discoveries that shed light in these areas should lead to better use of the current therapeutic options, as well as to identification of novel targets for LARC therapy.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

Acknowledgements:The authors thank Drs. Rakesh K. Jain and Andrew X. Zhu for useful input. Dr. Duda’s research is supported by US National Institutes of Health (P01-CA080124, R01-CA159258, and Federal Share/National Cancer Institute Proton Beam Program Income grants) and by the American Cancer Society (grant 120733-RSG-11-073-01-TBG).



1. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731-40.

2. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345:638-46.

3. Dewdney A, Cunningham D, Tabernero J, et al. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). J Clin Oncol. 2012;30:1620-7.

4. Erben P, Strobel P, Horisberger K, et al. KRAS and BRAF mutations and PTEN expression do not predict efficacy of cetuximab-based chemoradiotherapy in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2011;81:1032-8.

5. Russo AL, Borger DR, Ryan DP, et al. Mutational analysis and clinical correlation of 185 consecutive metastatic colorectal patients: similarities and differences between colon and rectal patients. J Clin Oncol. 2011;29:(suppl; abstr 3536)/p>

6. Jain RK, Duda DG, Willett CG, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol. 2009;6:327-38.

7. Kozin SV, Duda DG, Munn LL, Jain RK. Neovascularization after irradiation: what is the source of newly formed vessels in recurring tumors? J Natl Cancer Inst. 2012;104:899-905.

8. Goel S, Duda DG, Xu L, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev. 2011;91:1071-1121.

9. Willett CG, Duda DG, di Tomaso E, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol. 2009;27:3020-6.

10. Duda DG, Willett CG, Ancukiewicz M, et al. Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer. Oncologist. 2010;15:577-83.

11. Meyerhardt JA, Ancukiewicz M, Abrams TA, et al. Phase I study of cetuximab, irinotecan, and vandetanib (ZD6474) as therapy for patients with previously treated metastastic colorectal cancer. PLoS One. 2012;7:e38231.

12. Tolaney SM, Duda DG, Boucher Y, et al. A phase II study of preoperative (preop) bevacizumab (bev) followed by dose-dense (DD) doxorubicin (A)/cyclophosphamide (C)/paclitaxel (T) in combination with bev in HER2-negative operable breast cancer (BC). J Clin Oncol. 2012;30:(suppl; abstr 1026).

13. Zhu AX, Ancukiewicz M, Supko JG, et al. Clinical, pharmacodynamic (PD), and pharmacokinetic (PK) evaluation of cediranib in advanced hepatocellular carcinoma (HCC): a phase II study (CTEP 7147). J Clin Oncol. 2012;30:(suppl; abstr 4112).

14. Allegra CJ, Yothers G, O’Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011;29:11-16.

15. De Gramont A, Van Cutsem E, Tabernero J, et al. AVANT: results from a randomized, three-arm multinational phase III study to investigate bevacizumab with either XELOX or FOLFOX4 versus FOLFOX4 alone as adjuvant treatment for colon cancer. J Clin Oncol. 2011;29:(suppl 4; abstr 362).

16. Willett CG, Duda DG, Ancukiewicz M, et al. A safety and survival analysis of neoadjuvant bevacizumab with standard chemoradiation in a phase I/II study compared with standard chemoradiation in locally advanced rectal cancer. Oncologist. 2010;15:845-51.

17. Bertolini F, Chiara S, Bengala C, et al. Neoadjuvant treatment with single-agent cetuximab followed by 5-FU, cetuximab, and pelvic radiotherapy: a phase II study in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2009;73:466-72.

18. Hiratsuka S, Duda DG, Huang Y, et al. C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase in myeloid differentiation antigen (Gr-1)-positive cells. Proc Natl Acad Sci USA. 2011;108:302-7.

19. Xu L, Duda DG, di Tomaso E, et al. Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res. 2009;69:7905-10.

20. Duda DG, Kozin SV, Kirkpatrick ND, et al. CCXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: An emerging sensitizer for anticancer therapies? Clin Cancer Res. 2011;17:2074-80.

21. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-22.

22. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-26.

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