ONCOLOGY. Vol. 26 No. 8

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REVIEW ARTICLE

Current Perspectives on Preoperative Integrated Treatments for Locally Advanced Rectal Cancer: A Review of Agreement and Controversies

By Francesco Cellini, MD¹, Vincenzo Valentini, MD² | August 20, 2012

¹Radioterapia Oncologica, Policlinico Universitario Campus BioMedico, Rome, Italy ²Radioterapia Oncologica, Policlinico Universitario Agostino Gemelli, Rome, Italy

How can difficulties with preoperative approaches be overcome?

Difficulties with preoperative approaches must be addressed; such difficulties include both the practical aspects of clinical trial evidence and the management of such research, the former of which is being addressed by new, ongoing studies, including the Stockholm III trial, a German study, a Dutch study, and the INTER-ACT study. The Stockholm III trial[51] is randomizing patients to LC RT (without concomitant CT) with delayed surgery, SC RT with immediate surgery, or SC RT with delayed surgery. The last arm was designed to evaluate the potential of SC therapy to produce a pCR. In the interim analysis (the first 303 patients), 12.5% of the patients who received SC RT followed by delayed surgery had a pCR, vs 0.8% of patients who received SC RT with immediate surgery.

The German study[52] is comparing SC RT followed by early surgery vs LCRTCT followed by delayed surgery. T2N+ patients will be included, adjuvant chemotherapy will be mandatory for all patients to avoid potential bias, and a large number of patients will be enrolled (760 expected). The Dutch Rectal Cancer and Pre-operative Induction Therapy Followed by Diligent Operation (RAPIDO) trial is comparing LCRTCT followed by surgery and postoperative chemotherapy (with capecitabine(Drug information on capecitabine) and oxaliplatin(Drug information on oxaliplatin) [Eloxatin]) vs SC RT followed by 6 cycles of the same chemotherapy and surgery.[53] The INTER-ACT study is determining whether intensification of the biological dose with a concomitant RT boost during LCRTCT (and reduction in the overall duration of preoperative RT) increases tumor responses.[54]

Further studies could explore the optimal association of LCRTCT with chemotherapy and new biological agents.

Oral capecitabine is safe and effective compared with a standard 5-FU–based regimen.[55]

Both of these drugs have been studied in combination with oxaliplatin, irinotecan, and biological agents (eg, cetuximab [Erbitux], panitumumab [Vectibix], and bevacizumab(Drug information on bevacizumab) [Avastin]) in phase I and II studies to determine whether combination therapy improves efficacy. Long-term results are pending from several trials of multidrug preoperative RTCT. Some results are conflicting, and recent evidence throws into question the value of oxaliplatin-based treatment: the European STAR and ACCORD trials reported similar increases in acute toxicity without a corresponding increase in pCR rates. Longer follow-up is needed to determine the impact of oxaliplatin on DFS in these studies.[56,57] The recent European CAO/ARO/AIO-04 trial showed a significant increase in pCR rates with oxaliplatin and standard treatment. The American National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 and the Pan-European Trials in Adjuvant Colon Cancer (PETACC)-6 studies are investigating this issue.

In a recent comment, Mohiuddin proposed a “switching” strategy that would involve sequential timing along with RT (START): sequential full-dose monochemotherapy cycles would be administered, switching the regimens during therapy, with goals of targeting different cell cycle pathways and potentially different cell populations to overcome resistances.[58]

Because the presentations of LARC are not homogeneous, tumor behavior should be examined to tailor treatments and improve outcomes. The inadequate biological and radiological characterization of the adverse features of tumors has necessitated the identification of other means of defining tumor behavior.[59]

With regard to research, two issues have become urgently important: the ability to use large databases (sharing data between institutions) and the availability of surrogate endpoints. Larger databases can increase statistical power and facilitate tests between datasets. Surrogate endpoints can generate results faster, as the endpoint of biochemical failure has done in prostate cancer. For rectal cancers, pCR rate is a valuable surrogate endpoint.

Recent analyses that include data from randomized trials of colon cancer patients who have undergone adjuvant chemotherapy have claimed that 2- and 3-year DFS (2-3yyDFS) is a valid surrogate endpoint for 5-year OS, and even more so for 6-year OS—a correlation that was more robust for stage III colorectal cancer patients.[60] Similarly, a pooled analysis demonstrated that rectal cancer patients who were disease free at 2 years had an OS benefit at 5 and 10 years of follow-up, compared with those who experienced early recurrence.[61]

Use of a nomogram that takes into account the main variables that influenced survival endpoints in a pooled analysis of five European clinical trials has been suggested to help with clinical decision making in rectal cancer.[31]

Longer follow-ups for current studies, the evaluation of good surrogate endpoints in a large database, results from new studies, and the increasing use of tailored treatments for LARC—for example, making wise choices of SC RT vs LCRTCT, avoiding surgery or RT, and using adjuvant postoperative CT for various tumor presentations—will translate into survival gains.

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.

Pages: 1 2 3

This article reviewed

Which Rectal Cancers Are Locally Advanced?

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

Sphincter Preservation in the Treatment of Locally Advanced Rectal Cancers

References

1. Giovannucci E, Wu K. Cancers of the colon and rectum. In: Schottenfeld D, Fraumeni J, eds. Cancer. Epidemiology and prevention. 3rd ed. Oxford University Press; 2006.

2. American Cancer Society. Cancer facts & figures, 2010. Available at http://www.cancer.org/Research/CancerFactsFigures/index. Accessed April 26, 2011.

3. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2:533-43.

4. American Cancer Society. Cancer Facts and Figures 2011. Atlanta, Ga: American Cancer Society, 2011.

5. Gunderson LL, Sosin H. Areas of failure found at reoperation (second or symptomatic look) following “curative surgery” for adenocarcinoma of the rectum: clinicopathologic correlation and implications for adjuvant therapy. Cancer. 1974;34:1278-92.

6. Rich T, Gunderson LL, Lew R, et al. Patterns of recurrence of rectal cancer after potentially curative surgery. Cancer. 1983;52:1317-29.

7 Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med. 1985;312:1465-72.

8. Douglass HO Jr, Moertel CG, Mayer RJ, et al. Survival after postoperative combination treatment of rectal cancer. N Engl J Med. 1986;315:1294-5.

9. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264:1444-50.

10. Preoperative short-term radiation therapy in operable rectal carcinoma. A prospective randomized trial. Stockholm Rectal Cancer Study Group. Cancer. 1990;66:49-55.

11. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med. 1997;336:980-7.

12. Heald RJ, Moran BJ, Ryall RD, et al. Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg. 1998;133:894-9.

13. Heald RJ. A new approach to rectal cancer. BrJ Hosp Med. 1979;22:277-81.

14. Valentini V, Aristei C, Glimelius B, et al. Multidisciplinary rectal cancer management: 2nd European Rectal Cancer Consensus Conference (EURECA-CC2). Radiother Oncol. 2009;92:148-63.

15. MacFarlane JK, Ryall RD, Heald RJ, et al. Mesorectal excision for rectal cancer. Lancet. 1993;341:457-60.

16.Quirke P, Steele R, Monson J, et al. Effect of the plane of surgery achieved on local recurrence in patients operated with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTGCO16 randomised clinical trial. Lancet. 2009;373:821-8.

17.Glimelius B, Beets-Tan R, Blomqvist L, et al. Mesorectal fascia instead of circumferential resection margin in preoperative staging of rectal cancer. J Clin Oncol. 2011;29:2142-3.

18. Blomqvist L, Rubio C, Holm T, et al. Rectal adenocarcinoma: assessment of tumour involvement of the lateral resection margin by MRI of resected specimen. Br J Radiol. 1999;72:18-23.

19. MERCURY Study Group. Extramural depth of tumor invasion at thinsection MR in patients with rectal cancer: results of the MERCURY study. Radiology. 2007; 243:132-9.

20. 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.

21. van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12:575-82.

22. Nagtegaal ID, Marijnen CA, Kranenbarg EK, et al. Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: not one millimeter but two millimeters is the limit. Am J Surg Pathol. 2002;26:350-7.

23.Sebag-Montefiore D, Stephens RJ, Steele R, et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009; 373:811-20.

24Sauer R, Becker H, Hoyhenberger W, et al. For the German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731-40.

25.Sauer R, liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30:1926-33.

26. Camma C, Giunta M, Fiorica F, et al. Preoperative radiotherapy for resectable rectal cancer: a metaanalysis. JAMA. 2000;284:1008-15.

27. Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet. 2001;358:1291-1304.

28. Glimelius B, Gronberg H, Jarnhult J, et al. A systematic overview of radiation therapy effects in rectal cancer. Acta Oncol. 2003;42:476-92.

29. Munro AJ, Bentley A. Adjuvant radiotherapy in operable rectal cancer: a systematic review. Sem Colon Rectal Surg. 2002;13:31-42.

30. Fiorica F, Cartei F, Licata A, et al. Can chemotherapy concomitantly delivered with radiotherapy improve survival of patients with resectable rectal cancer? A meta-analysis of literature data. Cancer Treat Rev. 2010;36:539-49.

31. Valentini V, van Stiphout RG, Lammering G, et al. Nomograms for predicting local recurrence, distant metastases, and overall survival for patients with locally advanced rectal cancer on the basis of European randomized clinical trials. J Clin Oncol. 2011;29:3163-72.

32. Augestad KM, Lindsetmo RO, Stulberg J, et al. International preoperative rectal cancer management: staging, neoadjuvant treatment, and impact of multidisciplinary teams. World J Surg. 2010; 34:2689-700.

33. Minsky BD. Counterpoint: long-course chemoradiation is preferable in the neoadjuvant treatment of rectal cancer. Semin Radiat Oncol. 2011;21:228-33.

34.Glimelius B, Isacsson U, Jung B, Påhlman L. Radiotherapy in addition to radical surgery in rectal cancer. Acta Oncol. 1995;34:565-70.

35. Bujko K, Nowacki MP, Nasierowska-Guttmejer A, et al. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg. 2006;93:1215-23.

36. Ngan S, Fischer R, Goldstein D, et al. A randomized trial comparing local recurrence (LR) rates between short-course (SC) and long-course (LC) radiotherapy (RT) for clinical T3 rectal cancer: an intergroup trial (TROG, AGITG, CSSANZ, RACS). J Clin Oncol. 2010;28(suppl):abstr 3509.

37. Bujko K, Bujko M. Point: short-course radiation therapy is preferable in the neoadjuvant treatment of rectal cancer. Semin Radiat Oncol. 2011;21:220-7.

38. 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;72:99-107.

39 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: 711-7.

40. 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;29:4633-40.

41.Lievens Y, Van den Bogaert W, Rijnders A, et al. Palliative radiotherapy practice within Western European countries: impact of the radiotherapy financing system? Radiother Oncol. 2000;56:289-95.

42. NCCN Clinical Practice Guidelines in Oncology – Rectal Cancer. Version 3.2012. Available from: http://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed July 13, 2012.

43. National Cancer Institute: PDQ® Rectal Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified: 10/11/2011. Available at: http://cancer.gov/cancertopics/pdq/treatment/rectal/HealthProfessional. Accessed July 13, 2012.

44. Grávalos C, García-Alfonso P, Afonso R, et al. Recommendations and expert opinion on the treatment of locally advanced rectal cancer in Spain. Clin Transl Oncol. 2011;13:862-8.

45. Glimelius B, Påhlman L, Cervantes A. Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v82-6.

46. Van Cutsem E, Dicato M, Haustermans K, et al. The diagnosis and management of rectal cancer: expert discussion and recommendations derived from the 9th World Congress on Gastrointestinal Cancer, Barcelona, 2007. Ann Oncol. 2007;19(Suppl 6):vi1–vi8.

47. DCCG Danish national guidelines for rectal cancer treatment (2009). Available from: http://www.kirurgisk-selskab.dk/dks/krc.htm#top. Accessed 15 Jan 2010.

48. Association Française de Chirurgie. French national guidelines for rectal cancer treatment. Gastroenterol Clin Biol. 2007;31:1s9–1s22.

49. Norwegian Gastrointestinal Cancer Group. Kontrollopplegg ved kolorektalcancer (Norwegian Guidelines—2007). Available from: http:// www.ngicg.no/gronnbok/gronnbok.htm. Accessed 22 Jan 2010.

50. Dutch Association of Comprehensive Cancer Centres (ACCC). Oncoline—Cancer Clinical Practice Guidelines in Rectal Cancer, 2008. Available from: http://www.oncoline.nl/rectalcancer. Accessed July 13, 2012.

51. Pettersson D, Cedermark B, Holm T, et al. Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer. Br J Surg. 2010;
97:580-7.

52. Siegel R, Burock S, Wernecke KD, et al. Preoperative short-course radiotherapy versus combined radiochemotherapy in locally advanced rectal cancer: a multi-centre prospectively randomised study of the Berlin Cancer Society. BMC Cancer. 2009;9:50.

53. Randomized multicentre phase III study of short course radiation therapy followed by prolonged pre-operative chemotherapy and surgery in patients with high risk primary rectal cancer compared to standard preoperative chemoradiotherapy, surgery and optional adjuvant chemotherapy. Available from: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3230. Accessed July 13, 2012.

54. Preoperative downstaging of extraperitoneal T3 rectal cancer: XELOXRT versus XELACRT. A multicenter, phase III study (INTERACT). ClinicalTrials.gov Identifier: NCT01653301.

55. Hofheinz R, Wenz FK, Post S, et al. Capecitabine (Cape) versus 5-fluorouracil (5-FU) based (neo)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): long-term results of a randomized, phase III trial. J Clin Oncol. 2011;29(suppl):abstr 3504.

56. 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;28:1638-44.

57. 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;29:2773-80.

58. Mohiuddin M, Mohiuddin MM. Neoadjuvant chemoradiation in rectal cancer: time to start in a new direction. J Clin Oncol. 2011;29:e350-1; author reply e352-3. Epub 2011 Mar 14.

59. Minsky BD. Progress in the treatment of locally advanced clinically resectable rectal cancer. Clin Colorectal Cancer. 2011;10:227-37.

60. Sargent D, Yothers G, van Cutsem E, et al. Use of two-year disease-free survival (DFS) as a primary endpoint in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: new data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, NSABP C-06 and C-07, and C89803. J Clin Oncol. 2009;27(suppl):4011.

61. Valentini V, van Stiphout R, Lammering G, et al. 2-Year disease free vs pathological complete response as a surrogate endpoint by using pooled data of randomized trials for locally advanced rectal cancer. In press.

Current Perspectives on Preoperative Integrated Treatments for Locally Advanced Rectal Cancer: A Review of Agreement and Controversies

How can difficulties with preoperative approaches be overcome?

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