Resectable rectal cancer: Is radiotherapy still an option?

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Resectable rectal cancer: Is radiotherapy still an option?

David P Edwards ChM FRCSEd, Consultant Colorectal

Surgeon, Frimley Park Hospital, Frimley, Surrey GU16 7UJ, United Kingdom

david.edwards@doctors.org.uk Brendan J Moran MCh FRCSI, Consultant Colorectal Surgeon, Colorectal Research Unit, North Hampshire Hospital, Basingstoke, Hants RG249NA, United Kingdom,

moranbj@tmesurgery.demon.co.uk


Local recurrence is common, disabling and almost inevitably fatal complication following rectal cancer surgery. Local recurrence rates as high as 50%, even after a “curative” resection, were not uncommon in the 1970-80s1. Two strategies have evolved to reduce local recurrence, namely refinement of surgical techniques, in particular Total Mesorectal Excision (TME) and the use of adjuvant radiotherapy (RT).

TME, popularised by Heald2, involves the complete excision of the lymphovascular package of the rectum surrounded by an intact mesorectal fascia. Using this technique local recurrence rates of less than 5% have been achieved3. However, very low rectal cancers, and anterior tumours (particularly in a narrow, inaccessible male pelvis) have a higher risk of recurrence compared to mid rectal, upper rectal and posterior cancers. This has led most TME surgeons to select high-risk patients for pre-operative RT4.

The second major strategy has been the use of adjuvant RT. In Europe, this is generally given pre-operatively, whereas in the USA, post-operative treatment has been the standard, following the NIHCC 1990 statement5. The only randomised trial to compare pre- and post-operative RT found that pre-operative treatment (given in fractions of 5Gy for 5 days) was associated with fewer local recurrences (13% versus 22%)6. This RT regime has been used in the two Stockholm trials7,8 and the Swedish Rectal Cancer Study Group trial9 and demonstrated a reduction in local recurrence rates from 30%, 21% and 27% to 15%, 10% and 11% respectively. The high rates of early morbidity of RT in the earlier trials has been reduced by refinement of delivery to a 4-field technique, with sphincter protection in those patients planned to have a restorative surgical procedure. However, the late effects of RT are not fully known. As a result of RT associated morbidity and the published benefits of TME, the Stockholm surgeons adopted TME, by surgical workshop training programmes in the early 1900s in addition to RT. A significant reduction in local recurrence rates with TME led to a policy of selecting low risk patients not to receive pre-operative RT. The results of this population study were compared to the Stockholm trials10. Local recurrence was reduced by 50% and the number of abdomino-perineal was also reduced by 50% in the whole population of 1.9 million people. In the population study 56% had preoperative radiotherapy and there appeared to be additional benefits when patients had both RT and TME.

The Dutch Colorectal Cancer Group has endeavoured to answer this question in a randomised trial in patients with resectable rectal cancer11. All participating surgeons were trained in the technique of TME. Patients were randomised to pre-operative RT (5 x 5Gy) or no RT and all patients underwent major surgical excision (anterior resection of the rectum, abdomino-perineal excision, or Hartmann’s procedure) with TME. A total of 1861 patients were included in the study, of which 1759 were eligible for analysis. The rate of local recurrence at two years was 2.4% in the RT plus surgery group and 8.2% in the surgery alone group (p<0.001). The report concluded “short-term pre-operative radiotherapy reduces the risk of local recurrence in patients with (operable) rectal cancer who undergo a standardised TME”. The size and statistical power of this study suggests that radiotherapy is not an option but a requisite for resectable rectal cancer.

A detailed analysis of the data11 suggests that a measure of caution and refection is called for. The study was designed to only include resectable rectal cancers, but 23% (408 of 1759) had tumour-involved margins and/or tumour spillage. The nature of pre-operative radiological assessment of patients in the study was not detailed, and must be considered to be less than optimal. It is likely that with modern MR imaging, some of these patients would have been deemed locally advanced and excluded from the trial, with a reduction in local recurrence in both arms of the study.

Local recurrence rates at two years are the principal data supporting RT, however the authors detail the follow-up for patients without local recurrence as a median of 24.9 (range 1.1 to 56) months, and admit that only 54% of patients had 2 year follow-up. Such short follow-up biases in favour of RT as RT delays presentation with local recurrence. In Stockholm, after 2 years follow-up, local recurrence without RT was evident in 80% of those destined to recur, but when pre-operative RT was used 64% (Stockholm I)7 and 72% (Stockholm II)8 of recurrences had presented by 2 years.

Whilst local recurrence is important there are other equally important endpoints. Local recurrence identified in patients with distant metastases often requires no intervention, as death often intervenes before local recurrence becomes symptomatic. Overall survival at 2 years in this study was about 82% for each group, with no difference in the survival curves until nearly 4 years when those in the surgery alone group seemed to fair better. This is hard to understand, as overall recurrence (local and distant) was greater in the surgery-only group. One possible explanation could be late RT related morbidity. Although the late effects of high dose RT are not known, RT in this study was associated with early morbidity, including a greater operative blood loss and more perineal wound complications in patients who had an abdomino-perineal excision (26% versus 18%; p=0.05)11. Acute toxicity from RT occurred in up to 19%, and lumbosacral plexopathy in 10% of patients, with some experiencing chronic pain12.

A major change of practice to the universal use of RT in rectal cancer management cannot be justified on the immature data of the Dutch trial11,12, as the adverse effects of RT in all patients, and the benefits with regard to prevention of symptomatic local recurrence and survival in truly resectable patients are not yet known. An important documented factor has been omitted, in that the local recurrence in Holland prior to the widespread use of TME was over 30% compared to approximately 5% in the current report. As subgroup analysis of 2-year rates of local recurrence failed to show a significant benefit for RT in Stage I and IV disease and cancers with a distal margin more than 10cm from the anal verge, the current report11, already being hailed as a landmark, is likely to be mis-interpreted. The conclusion of this important study should say that TME dramatically reduces local recurrence and selective use of short-course pre-operative RT, in addition to TME, reduces local recurrence in patients with a threatened margin. Surgical precision, sometimes with adjunctive pre-operative RT, optimises outcomes in rectal cancer surgery.

References

1. Pahlman L, Glimelius B. Local recurrences after surgical treatment of rectal carcinoma. Acta Chir Scand 1984; 150: 331-335.

2. MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet 1993; 341: 457-460.

3. Heald RJ, Moran BJ, Ryall RD, Sexton R, Marfarlane JK. Rectal cancer: The Basingstoke experience of total mesorectal excision, 1978-1997. Ann Surg 1998; 133: 894-899.

4. Edwards DP, Mortensen NJM. Is radiotherapy for rectal cancer indicated if surgery is optimised? Eur J Surg Oncol 2001; 27: 442-445.

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

6. Pahlman L, Glimelius B, Graffman S. Pre- versus postoperative radiotherapy in rectal carcinoma: an interim report from a randomized multicentre trial. Brit J Surg 1985; 72: 961-6.

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

8. Randomized study on preoperative radiotherapy in rectal carcinoma. Stockholm Colorectal Cancer Study Group. Ann Surg Oncol 1996; 3: 423-30.

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

10. Lehander Martling A, Holm T, Rutqvist L-E, Moran BJ, Heald RJ, Cedermark B. Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Lancet 2000; 256: 93-96.

11. Kapiteijn E, Marijnen CAM, Nagtegaal ID et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345: 638-646.

12. Kapiteijn E, Klein Kranenbarg E, Steup WH et al. Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer. Eur J Surg 1999; 165: 410-420.

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