EBM: Trials on trial

Cancer
Volume 177 - Issue 10

Does preoperative radiotherapy improve outcome in patients with resectable rectal cancer?

Author:  Michael J Veness

Med J Aust 2002; 177 (10): 563-564. || doi: 10.5694/j.1326-5377.2002.tb04954.x
Published online: 18 November 2002
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Question

Should patients with resectable rectal cancer receive preoperative pelvic radiotherapy?

Trial details

Design:

Multicentre international randomised controlled trial.

Setting:

108 hospitals, with a predominance of hospitals in Holland.

Patients:

1805 eligible patients with histologically proven adenocarcinoma of the rectum. Patients with fixed tumours were excluded. All patients had either a low anterior resection or an abdominoperineal resection using the standardised surgical approach of total mesorectal excision (TME).

Intervention:

After stratification for treatment centre and anticipated type of operation, 897 patients were assigned to receive, or not receive, preoperative short course pelvic radiotherapy (25 Gy in five daily fractions).

Main outcome measures:

Overall survival and local recurrence at 2 years; overall and distant recurrence at 2 years; and postoperative mortality and morbidity (operative blood loss and perineal complications). Overall survival was analysed on an intention-to-treat basis and included all eligible patients. The rate of local recurrence was calculated for patients in whom macroscopically complete resection had been achieved. The rate of distant recurrence was calculated for patients who did not have distant disease at the time of surgery.

Main results:

Median follow-up in surviving eligible patients without local recurrence was 24.9 months (range, 1.1–56 months). There was no difference in overall survival between the two groups (82.0% radiotherapy and surgery v 81.8% surgery alone; P = 0.84). However, local recurrence was significantly lower in patients who had received radiotherapy compared with those who had not (2.4% v 8.2%; P < 0.001). There was no difference in the rate of distant recurrence (P = 0.87). Median operative blood loss was marginally increased in the combined arm (1000 v 900 mL; P < 0.001), as were perineal complications after abdominoperineal resection (26% v 18%; P = 0.05).

Conclusion:

A short course of preoperative pelvic radiotherapy reduces pelvic recurrence after total mesorectal excision. Despite this, overall survival was not improved.

Commentary
Rationale for the trial

The primary treatment for rectal cancer is surgery. The rationale for also irradiating the pelvis is to prevent the suffering associated with local recurrence, even if survival is not improved. Pelvic recurrence after surgery occurs in 20%–50% of patients with poor pathological features, such as transmural spread and nodal involvement.1 Adjuvant treatment may be delivered either before or after surgery and may also include chemotherapy. The risk of serious late bowel complications after postoperative adjuvant treatment is reported to be higher when compared with preoperative treatment.2 It is this finding that has, in part, prompted interest in delivering radiotherapy before surgery. The optimal scheduling for preoperative radiotherapy remains unclear. Radiation oncologists in Europe favour a short preoperative approach (25 Gy in five daily fractions), while those in North America and Australia favour a more protracted preoperative regimen (45–50.4 Gy in 25–28 daily fractions, with infusional chemotherapy) given to a more select subgroup of patients with unfavourable clinical features such as tethering and fixation,3 with the aim of "downstaging" the cancer and enhancing operability. While the approach to pelvic radiotherapy may differ, many surgeons advocate that surgery alone, using a total mesorectal excision (TME) technique, could negate the need for pelvic radiotherapy as a result of relatively low pelvic recurrence rates (< 10%).4

Trial methods

This was a large and well-constructed multicentre trial with an adequate sample size and an equal balance of important variables, especially disease stage. The random allocation was simple, and the surgery was standardised by training and supervision of surgeons. Pathological findings were independently reviewed. Importantly, the authors detailed all patients deemed ineligible after randomisation with an acceptable figure of 3% in both arms. All protocol violations were listed. A limited subgroup analysis failed to show a differing treatment effect based on TNM stage or tumour location. The results (overall survival and recurrence) are presented at two years, which is appropriate considering the median follow-up time was only 24.9 months and the number of patients reaching three and four years of follow-up limited at the time of analysis. Short-term toxicity data are presented without any significant difference between the two groups, except for perineal complications. In a subsequent report, the authors showed no difference in postoperative mortality (4% v 3.3%; P = 0.49).5 This is an important finding, as previous studies in which a suboptimal radiotherapy technique was used showed an increased mortality rate.

New information

This is one of the largest studies examining the potential benefits of a short course of preoperative pelvic radiotherapy. Unlike a previous Swedish study,6 this trial failed to show any overall survival benefit (at least at two years), despite a significant reduction in local recurrence from 8.2% to 2.4%. This reduction was seen despite standardised TME. The question remains whether the morbidity (acute and late) of radiotherapy justifies the reduction in local recurrence and its associated morbidity (intractable pain, bleeding, discharge).

Longer-term toxicity data are not yet available from this trial. Nor are data on the late effect of bowel function and quality of life from the addition of radiotherapy. Despite what many would consider an excellent pelvic control rate with TME alone, the local recurrence rate after surgery only in those diagnosed with tumour–node–metastases (TNM) stage III disease was 15%. Pelvic radiotherapy reduced this to 4.3% (P < 0.001). Those with TNM stage II disease also benefited from radiotherapy, although not as much in absolute terms (5.7% v 1%; P = 0.01). Notably, this study included over 500 patients with TNM stage I disease, so it is not surprising that the local recurrence rate in both arms was less than 1%. Patients with TNM stage I disease are not routinely given adjuvant treatment (see TNM classification of malignant tumours7).

Implications for clinical practice

The optimal approach to adjuvant treatment in rectal cancer remains unclear. The National Health and Medical Research Council (NHMRC) guidelines on the prevention, early detection and management of colorectal cancer currently recommend that any adjuvant treatment should include both chemotherapy and radiotherapy,8 as this combination has been consistently shown to give a survival advantage.9 To date, there are insufficient data to recommend preoperative radiotherapy alone as the standard approach. The NHMRC guidelines recommend combined treatment be given to patients with high-risk rectal cancer (transmural spread and/or nodal involvement). The Trans Tasman Radiation Oncology Group (TROG) is currently comparing long-course preoperative radiotherapy (50.4 Gy in 28 daily fractions) and chemotherapy (infusional fluorouracil) with short-course radiotherapy (25 Gy in five daily fractions), and early surgery in patients with T3 resectable rectal cancer. TROG is also comparing combination preoperative treatment (50.4 Gy and infusional fluorouracil) with surgery plus optional combined adjuvant treatment. The results from this trial will be important in clarifying many unanswered questions.

The Dutch Colorectal Cancer Trial raises the not uncommon scenario of a small but potentially clinically meaningful benefit (ie, in this case, decreased pelvic recurrence after total mesorectal excision) from a treatment. But who should benefit? Those at higher risk will obviously benefit the most in absolute terms and perhaps be more willing to accept the toxicity associated with treatment. Ultimately, it is the patient who must decide if the benefits outweigh the inconvenience and potential toxicities of treatment.

Author

  • Michael J Veness MB BS, MMed(ClinEpi),FRANZCR1
  • 1. Department of Radiation Oncology, Westmead Hospital, Westmead, NSW.

Correspondence: michael@radonc.wsahs.nsw.gov.au

References

View this article on Wiley Online Library