Skip to main content

Advertisement

Log in

Pathological Complete Response After Neoadjuvant Therapy for Rectal Cancer and the Role of Adjuvant Therapy

  • Gastrointestinal Cancers (BG Czito, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Both the addition of neoadjuvant chemoradiation therapy and improvements in surgical techniques have improved local control and overall survival for locally advanced rectal cancer patients over the past few decades. The addition of adjuvant chemotherapy has likely improved outcomes as well, though the contribution has been more difficult to quantify. At present, the majority of resected locally advanced rectal cancer patients receive adjuvant chemotherapy, though there is great variability in this practice based on both patient and institution characteristics. Recently, questions have been raised regarding which sub-groups of patients benefit most from adjuvant chemotherapy. As pathologic complete response (pCR) is increasingly found to be a reasonable surrogate for long-term favorable outcomes, some have questioned the need for adjuvant therapy in this select group of patients. Multiple retrospective analyses have shown minimal to no benefit for adjuvant chemotherapy in this group. Indeed, the patients most consistently shown to benefit from adjuvant therapy both in terms of disease free survival (DFS) and overall survival (OS) are those who achieve an intermediate pathologic response to neoadjuvant treatment. Tumors that have high expression of thymidylate synthetase have also shown to benefit from adjuvant therapy. More study is needed into clinical and molecular features that predict patient benefit from adjuvant therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics. CA: Cancer J Clin. 2012;62(1):10–29.

    Article  Google Scholar 

  2. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Canc Inst. 1988;80(1):21–9.

    Article  CAS  Google Scholar 

  3. Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24(28):4620–5.

    Article  PubMed  Google Scholar 

  4. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. New Engl J Med. 2004;351(17):1731–40.

    Article  PubMed  CAS  Google Scholar 

  5. •• Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. New Engl J Med. 2006;355(11):1114–23. EORTC 22921 was the largest prospective, randomized study to date investigating the benefit of adjuvant chemotherapy in locally advanced rectal cancer patients after neoadjuvant chemoradiation and surgical resection. They found a trend toward improvement in OS after adjuvant chemotherapy.

    Article  PubMed  CAS  Google Scholar 

  6. Quirke P, Steele R, Monson J, et al. Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial. Lancet. 2009;373(9666):821–8.

    Article  PubMed  Google Scholar 

  7. Minsky BD. Adjuvant management of rectal cancer: the more we learn, the less we know. J Clin Oncol. 2007;25(28):4339–40.

    Article  PubMed  Google Scholar 

  8. National Comprehensive Cancer Network. Rectal Cancer. Accessed at http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf on October 21, 2012. 2012;v2.2013.

  9. Khrizman P NJ, ter Veer A et al. Postoperative adjuvant chemotherapy use in stage II/III rectal cancer patients treated with neoadjuvant therapy: a National Comphrehensive Cancer Network (NCCN) Analaysis. J Clin Oncol, 2013;31(1):30–8.

    Google Scholar 

  10. Khrizman P JN, A ter Veer et al. Postoperative adjuvant chemotherapy use in stage II/III rectal cancer patients (Pts) treated with neoadjuvant therapy: a National Comphrehensive Cancer Network (NCCN) Analysis. Presented at the American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, 2011. 2011.

  11. Romanus D, Weiser MR, Skibber JM, et al. Concordance with NCCN Colorectal Cancer Guidelines and ASCO/NCCN Quality Measures: an NCCN institutional analysis. J Natl Compr Canc Netw. 2009;7(8):895–904.

    PubMed  Google Scholar 

  12. • Collette L, Bosset JF, den Dulk M, et al. Patients with curative resection of cT3-4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J Clin Oncol. 2007;25(28):4379–86. This unplanned retrospective study analyzed data from EORTC 22921 to see if specific sub-groups gained benefit from adjuvant chemotherapy. They found that those who had pathologic downstaging to ypT0-2 disease had improved DFS and OS after adjuvant chemotherapy but those with ypT3-4 disease did not.

    Article  PubMed  CAS  Google Scholar 

  13. Ayanian JZ, Zaslavsky AM, Fuchs CS, et al. Use of adjuvant chemotherapy and radiation therapy for colorectal cancer in a population-based cohort. J Clin Oncol. 2003;21(7):1293–300.

    Article  PubMed  Google Scholar 

  14. Abraham NS, Gossey JT, Davila JA, Al-Oudat S, Kramer JK. Receipt of recommended therapy by patients with advanced colorectal cancer. Am J Gastroenterol. 2006;101(6):1320–8.

    Article  PubMed  Google Scholar 

  15. Das P, Skibber JM, Rodriguez-Bigas MA, et al. Clinical and pathologic predictors of locoregional recurrence, distant metastasis, and overall survival in patients treated with chemoradiation and mesorectal excision for rectal cancer. Am J Clin Oncol. 2006;29(3):219–24.

    Article  PubMed  Google Scholar 

  16. Park IJ, You YN, Agarwal A, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol. 2012;30(15):1770–6.

    Article  PubMed  CAS  Google Scholar 

  17. Capirci C, Valentini V, Cionini L, et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys. 2008;72(1):99–107.

    Article  PubMed  Google Scholar 

  18. Una E, Alonso P, and Perea C. Rectal cancer: the relevance of the interval between chemoradiation and surgery. J Clin Oncol. 2011;29 (suppl: abstr e14029).

  19. Francois Y, Nemoz CJ, Baulieux J, et al. Influence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01 randomized trial. J Clin Oncol. 1999;17(8):2396.

    PubMed  CAS  Google Scholar 

  20. Glehen O, Chapet O, Adham M, Nemoz JC, Gerard JP. Long-term results of the Lyons R90-01 randomized trial of preoperative radiotherapy with delayed surgery and its effect on sphincter-saving surgery in rectal cancer. Br J Surg. 2003;90(8):996–8.

    Article  PubMed  CAS  Google Scholar 

  21. How P, Shihab O, Tekkis P, et al. A systematic review of cancer related patient outcomes after anterior resection and abdominoperineal excision for rectal cancer in the total mesorectal excision era. Surg Oncol. 2011;20(4):e149–55.

    Article  PubMed  CAS  Google Scholar 

  22. Das P, Skibber JM, Rodriguez-Bigas MA, et al. Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer. Cancer. 2007;109(9):1750–5.

    Article  PubMed  CAS  Google Scholar 

  23. Silberfein EJ, Kattepogu KM, Hu CY, et al. Long-term survival and recurrence outcomes following surgery for distal rectal cancer. Ann Surg Oncol. 2010;17(11):2863–9.

    Article  PubMed  Google Scholar 

  24. Aschele C, Cionini L, Lonardi S, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol. 2011;29(20):2773–80.

    Article  PubMed  CAS  Google Scholar 

  25. Gerard JP, Azria D, Gourgou-Bourgade S, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol. 2010;28(10):1638–44.

    Article  PubMed  CAS  Google Scholar 

  26. Valentini V, Coco C, Picciocchi A, et al. Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients. Int J Radiat Oncol Biol Phys. 2002;53(3):664–74.

    Article  PubMed  Google Scholar 

  27. Janjan NA, Crane C, Feig BW, et al. Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol. 2001;24(2):107–12.

    Article  PubMed  CAS  Google Scholar 

  28. Roh MS YG, O'Connell MJ, et al. The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patinets with carcinoma of the rectum: NSABP R-04. Proc Am Soc Clin Oncol. 2011;29 (suppl): abstract 3503.

    Google Scholar 

  29. Hofheinz RD, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012;13(6):579–88.

    Article  PubMed  CAS  Google Scholar 

  30. Rodel C, Liersch T, Becker H, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012;13(7):679–87.

    Article  PubMed  Google Scholar 

  31. Martijnse IS, Dudink RL, Kusters M, et al. T3+ and T4 rectal cancer patients seem to benefit from the addition of oxaliplatin to the neoadjuvant chemoradiation regimen. Ann Surg Oncol. 2012;19(2):392–401.

    Article  PubMed  Google Scholar 

  32. Cohen SJ FY, Landry JC et al. Phase II study of preoperative radiation with concurrent capecitabine, oxaliplatin, and bevacizumab followed by surgery and postoperative 5-FU, leucovorin, oxaliplatin (FOLFOX), and bevacizumab in patients with locally advanced rectal cancer: a trial of the Eastern Cooperative Oncology Group (E3204). J Clin Oncol. 2012;suppl: abstr 3605 Presented at the American Society of Clincal Oncology annual meeting, June 2012.

  33. Landry JC FY, Cohen SJ. Phase II study of preoperative radiation with concurrent capecitabine, oxaliplation and bevacizumab followed by surgery and postoperative 5-FU, Leucovorin, Oxaliplation (FOLOFX) and Bevacizumab in Patients with Locally Advnaced Rectal Cancer: ECOG 3204. 2012;Presented at ASTRO Annual Meeting, October 2012.

  34. Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27(19):3109–16.

    Article  PubMed  CAS  Google Scholar 

  35. Chan AK, Wong AO, Langevin J, et al. Preoperative chemotherapy and pelvic radiation for tethered or fixed rectal cancer: a phase II dose escalation study. Int J Radiat Oncol Biol Phys. 2000;48(3):843–56.

    Article  PubMed  CAS  Google Scholar 

  36. Fietkau R, Barten M, Klautke G, et al. Postoperative chemotherapy may not be necessary for patients with ypN0-category after neoadjuvant chemoradiotherapy of rectal cancer. Dis Colon Rectum. 2006;49(9):1284–92.

    Article  PubMed  Google Scholar 

  37. Pereira VSA, Reig O et al. Do we need adjuvant therapy in rectal cancer with complete pathologic response (ypT0N0) after induction chemoradiation and laparoscopic mesorectal excision? J Clin Oncol. Presented at the 2012 ASCO Annual Meeting, June 2012. 2012;suppl: abstr 3536.

  38. • Chang GJ PI, Eng C et al. Exploratory analysis of adjuvant chemotherapy benefits after preoperative chemoradiotherapy and radical resection for rectal cancer. J Clin Oncol. 2012;suppl; abstr 3556. Presented at 2012 ASCO Annual Meeting, Chicago, IL June 2012.

  39. • Beets GL MM, Neleman PJ et al. Evaluation of response after chemoradiation for rectal cancer as a predictive factor for the benefit of adjuvant chemotherapy: a pooled analysis of 2,724 individual patients. J Clin Oncol. 2011;29 (suppl 4; abstr 361). Presented at the American Society of Clinical Oncology Annual Meeting, June 2012.

  40. O'Neill BD, Brown G, Heald RJ, Cunningham D, Tait DM. Non-operative treatment after neoadjuvant chemoradiotherapy for rectal cancer. Lancet Oncol. 2007;8(7):625–33.

    Article  PubMed  Google Scholar 

  41. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004;240(4):711–7. discussion 717–718.

    PubMed  Google Scholar 

  42. Habr-Gama A, Perez RO, Nadalin W, et al. Long-term results of preoperative chemoradiation for distal rectal cancer correlation between final stage and survival. J Gastrointest Surg. 2005;9(1):90–9. discussion 99–101.

    Article  PubMed  Google Scholar 

  43. Habr-Gama A. Assessment and management of the complete clinical response of rectal cancer to chemoradiotherapy. Colorectal Dis. 2006;8 Suppl 3:21–4.

    Article  PubMed  Google Scholar 

  44. Maas M, Beets-Tan RG, Lambregts DM, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011;29(35):4633–40.

    Article  PubMed  Google Scholar 

  45. Suppiah A, Hunter IA, Cowley J, et al. Magnetic resonance imaging accuracy in assessing tumour down-staging following chemoradiation in rectal cancer. Colorectal Dis. 2009;11(3):249–53.

    Article  PubMed  CAS  Google Scholar 

  46. Bipat S, Glas AS, Slors FJ, Zwinderman AH, Bossuyt PM, Stoker J. Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging—a meta-analysis. Radiology. 2004;232(3):773–83.

    Article  PubMed  Google Scholar 

  47. Shihab OC, Taylor F, Salerno G, et al. MRI predictive factors for long-term outcomes of low rectal tumours. Ann Surg Oncol. 2011;18(12):3278–84.

    Article  PubMed  Google Scholar 

  48. de Geus-Oei LF, Vriens D, van Laarhoven HW, van der Graaf WT, Oyen WJ. Monitoring and predicting response to therapy with 18F-FDG PET in colorectal cancer: a systematic review. J Nucl Med. 2009;50 Suppl 1:43S–54.

    Article  PubMed  Google Scholar 

  49. Zhang C, Tong J, Sun X, Liu J, Wang Y, Huang G. (18) F-FDG-PET evaluation of treatment response to neo-adjuvant therapy in patients with locally advanced rectal cancer: a meta-analysis. Int J Cancer. 2012;131(11):2604–11.

    Article  PubMed  CAS  Google Scholar 

  50. Janssen MH, Ollers MC, van Stiphout RG, et al. PET-based treatment response evaluation in rectal cancer: prediction and validation. Int J Radiat Oncol Biol Phys. 2012;82(2):871–6.

    Article  PubMed  Google Scholar 

  51. Calvo FA, Domper M, Matute R, et al. 18F-FDG positron emission tomography staging and restaging in rectal cancer treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys. 2004;58(2):528–35.

    Article  PubMed  Google Scholar 

  52. Yeung JM, Kalff V, Hicks RJ, et al. Metabolic response of rectal cancer assessed by 18-FDG PET following chemoradiotherapy is prognostic for patient outcome. Dis Colon Rectum. 2011;54(5):518–25.

    Article  PubMed  CAS  Google Scholar 

  53. Martoni AA, Di Fabio F, Pinto C, et al. Prospective study on the FDG-PET/CT predictive and prognostic values in patients treated with neoadjuvant chemoradiation therapy and radical surgery for locally advanced rectal cancer. Ann Oncol. 2011;22(3):650–6.

    Article  PubMed  CAS  Google Scholar 

  54. Taylor FG, Quirke P, Heald RJ, et al. Preoperative high-resolution magnetic resonance imaging can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multicenter, European study. Ann Surg. 2011;253(4):711–9.

    Article  PubMed  Google Scholar 

  55. Danenberg PV. Thymidylate synthetase - a target enzyme in cancer chemotherapy. Biochim Biophys Acta. 1977;473(2):73–92.

    PubMed  CAS  Google Scholar 

  56. Santi DV, McHenry CS, Sommer H. Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry. 1974;13(3):471–81.

    Article  PubMed  CAS  Google Scholar 

  57. Chu E, Koeller DM, Johnston PG, Zinn S, Allegra CJ. Regulation of thymidylate synthase in human colon cancer cells treated with 5-fluorouracil and interferon-gamma. Mol Pharmacol. 1993;43(4):527–33.

    PubMed  CAS  Google Scholar 

  58. Clark JL, Berger SH, Mittelman A, Berger FG. Thymidylate synthase gene amplification in a colon tumor resistant to fluoropyrimidine chemotherapy. Canc Treat Rep. 1987;71(3):261–5.

    CAS  Google Scholar 

  59. Spears CP, Shahinian AH, Moran RG, Heidelberger C, Corbett TH. In vivo kinetics of thymidylate synthetase inhibition of 5-fluorouracil-sensitive and -resistant murine colon adenocarcinomas. Canc Res. 1982;42(2):450–6.

    CAS  Google Scholar 

  60. Johnston PG, Fisher ER, Rockette HE, et al. The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol. 1994;12(12):2640–7.

    PubMed  CAS  Google Scholar 

  61. Liersch T, Langer C, Ghadimi BM, et al. Lymph node status and TS gene expression are prognostic markers in stage II/III rectal cancer after neoadjuvant fluorouracil-based chemoradiotherapy. J Clin Oncol. 2006;24(25):4062–8.

    Article  PubMed  CAS  Google Scholar 

  62. Sebio A PD, Pare L et al. A pharmacogenetic study in rectal cancer patients treated with preoperative chemoradiotherapy based on capecitabine: polymorphisms in thymidilyate synthase and DNA repair genes. J Clin Oncol. 2011;29 (suppl: abstr e14009).

  63. Ghadimi BM, Grade M, Difilippantonio MJ, et al. Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol. 2005;23(9):1826–38.

    Article  PubMed  CAS  Google Scholar 

  64. National Cancer Institute. NCT00303628. Accessed at http://clinicaltrials.gov/ct2/show/NCT00303628 on November 4, 2012.

  65. National Cancer Institute. NCT01515787. Accessed at http://www.cancer.gov/clinicaltrials/search/view?cdrid=715321&version=HealthProfessional on November 7, 2012. 2012.

Download references

Disclosure

V. M. Nelson: none; A. B. Benson: consultant for Sanofi, Genentech, and Roche.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Al B. Benson III.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nelson, V.M., Benson, A.B. Pathological Complete Response After Neoadjuvant Therapy for Rectal Cancer and the Role of Adjuvant Therapy. Curr Oncol Rep 15, 152–161 (2013). https://doi.org/10.1007/s11912-013-0297-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-013-0297-5

Keywords

Navigation