CR07 - Evidence into Clinical Practice

David Sebag-Montefiore

Powerpoint File

The first results of the Medical Research Council / National Cancer Research Institute CR07 trial were presented at the American Society of Clinical Oncology Meeting in June 2006. The trial compared two policies of adjuvant radiotherapy in patients with resectable rectal cancer. Patients were randomised between a policy of short course pre-operative radiotherapy using 25Gy over one week (PRE) and initial surgery with post-operative chemoradiation used for patients with involvement of the circumferential resection margin (POST).

The trial recruited 1350 patients between 1998 and 2005 and there was a median follow up of 3 years at the time of initial analysis. The 3 year and 5 year rates of local recurrence are 5 vs 11% and 5 vs 17% and the for the PRE and POST arms respectively (p<0.001) . The 3 yr disease free survival is improved from 75 to 80% in favour of the PRE policy (p=0.03).

There is clear evidence of a reduction in favour of PRE across TNM stages I-III with an increasing absolute difference in LR rates with increasing stage. There is also a substantial LR rate of >20% at 5 years for patients in whom surgery alone was used (and because they were CRM-ve, did not receive post-operative CRT according to the POST policy).

The results of the MRC CR07 trial are likely to result in an increasing use of pre-operative radiotherapy. The presentation will focus on how SCPRT might be incorporated into our current adjuvant radiotherapy policy. How might things change? My personal view is that we should still try and identify patients at the end of the early stage disease spectrum in whom initial surgery is the preferred option. The question that follows is how to determine the threshold for selecting SCPRT rather than initial surgery (possible approaches will be discussed). It is important to recognise that the CR07 data suggests that patients who undergo initial surgery and have involved lymph nodes and are CRM-ve should be considered for post-operative CRT. The increased use of and balance between pre-operative and post operative treatment will be influenced by the threshold used to select for SCPRT.

Whenever adjuvant therapy is considered, the balance between benefit and toxicity must be considered as well as the likely success of salvage therapy. The CR07 trial data (and the results of other similar trials) all suggest that the risk of local recurrence is at least halved by the addition of radiation. We also know that the majority of patients who develop local recurrence are not cured and the morbidity and complexity of treatment of symptomatic local recurrence is considerable.

The data on late toxicity is less easy to simply quantify. In part, this is because there is a combined contribution to later toxicity from both the surgical procedure as well as the radiotherapy. Two examples of this are bowel and sexual dysfunction. Certain complications are operation dependent (for example delayed perineal wound healing if an APER is performed and bowel dysfunction if an anterior resection is performed). Other complications are both gender and age dependent. For example, sterility induced by radiotherapy is an important late toxicity that applies to post menopausal women and men who wish to father children (sperm banking is available for patients if their sexual function is adequate prior to treatment).

How should we approach the individual patient? It is important that MDT’s define their policy with respect to adjuvant radiotherapy. When adjuvant radiotherapy is considered patients should have the opportunity to discuss the potential benefits and late toxicity of treatment with a clinical oncologist. It is important wherever possible to determine the type of operation that is intended to facilitate this discussion. The individual discussion will focus on the potential late complications that are relevant to that patient.

Examples of the late complications are summarised below:-

Future research is required to refine the radiation volume that is treated as improvements in radiation technique are likely to reduce the risk of late toxicity. There is clear evidence that small bowel and pelvic bony complications have significantly reduced with successive trials that have used increasingly smaller radiation volumes.

References

Sebag-Montefiore D, Steele R, Quirke P, Grieve R, Khanna S, Monson J, Holliday A, . Thompson L, Griffiths G, Stephens R. Routine short course pre-op radiotherapy or selective post-op chemoradiotherapy for resectable rectal cancer? Preliminary results of the MRC CR07 randomised trial. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 3511,2006

Quirke P, Sebag-Montefiore D, Steele R, Khanna S, Monson J, Holliday A, Thompson L, Griffiths G, Stephens R. Local recurrence after rectal cancer resection is strongly related to the plane of surgical dissection and is further reduced by pre-operative short course radiotherapy. Preliminary results of the Medical Research Council (MRC) CR07 trial. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 3512, 2006

Anonymous Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet 2001;358(9290):1291-304.

Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 1997;336(14):980-7.

H. Birgisson, L. Pahlman, U. Gunnarsson, and B. Glimelius
Adverse Effects of Preoperative Radiation Therapy for Rectal Cancer: Long-Term Follow-Up of the Swedish Rectal Cancer Trial J. Clin. Oncol. 2005 23: 8697-8705

Dahlberg M,Glimelius B, Pahlman L.Improved survival and reduction in local failure rates after preoperative radiotherapy: evidence for the generalizability of the results of Swedish Rectal Cancer Trial.
Ann Surg. 1999 Apr;229(4):493-7.

Dahlberg M, Glimelius B, Graf W, Pahlman L. Preoperative irradiation affects functional results after surgery for rectal cancer: results from a randomized study Dis Colon Rectum. 1998 May;41(5):543-9; discussion 549-51

Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative
radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med
2001;345(9):638-46.

J. Folkesson, H. Birgisson, L. Pahlman, B. Cedermark, B. Glimelius, and U. Gunnarsson Swedish Rectal Cancer Trial: Long Lasting Benefits From Radiotherapy on Survival and Local Recurrence Rate J. Clin. Oncol. 2005 23: 5644-5650

Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345(9):638-46

Kollmorgen CF, Meagher AP, Wolff BG, Pemberton JH, Martenson JA, Illstrup DM. The long-term effect of adjuvant postoperative chemoradiotherapy for rectal carcinoma on bowel function. Ann Surg. 1994 Nov;220(5):676-82

Peeters KC, van de Velde CJ, Leer JW, Martijn H, Junggeburt JM, Kranenbarg EK, Steup WH, Wiggers T, Rutten HJ, Marijnen CA. Related Articles, Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients--a Dutch colorectal cancer group study.J Clin Oncol. 2005 Sep 1;23(25):6199-206.

van den Brink, Mandy, Stiggelbout, Anne M., van den Hout, Wilbert B., Kievit, Job, Klein Kranenbarg, Elma, Marijnen, Corrie A.M., Nagtegaal, Iris D., Rutten, Harm J.T., Wiggers, Theo, van de Velde, Cornelis J.H.Clinical Nature and Prognosis of Locally Recurrent Rectal Cancer After Total Mesorectal Excision With or Without Preoperative Radiotherapy J Clin Oncol 2004 22: 3958-396