Radiotherapy for colorectal cancer

Introduction
Radiotherapy as a definitive or adjuvant modality for colon cancer lying above peritoneal reflection never gained popularity. Radiotherapy has two major limitations when applied to colon cancer: a poorly defined target, since colon is mobile, and the fact that dose-limiting structures surround the colon (i.e., large amount of small bowel, kidney, and liver). An exception is occasionally given to carcinoma of the cecum with extension into the abdominal wall, where it is possible to define the area at risk, particularly if it is marked with clips. Radiotherapy is used, however, for palliation in colon cancer. To date, no randomized study results are available to substantiate the use of adjuvant radiotherapy for colon cancer. Chemotherapy remains the most important adjuvant treatment for colon cancer.

The role of radiotherapy in rectal cancer is more justified anatomically. The rectum is a relatively fixed structure in the pelvis and it is situated below the organs of limited tolerance to radiotherapy. It is feasible to deliver reasonably high doses of radiotherapy without severe toxicity. Of the 296 patients with rectal cancer and rectosigmoid cancer referred to the BC Cancer Agency in 1996, 204 (69%) of them were treated with radiotherapy.

Radical radiotherapy
Radical surgery such as low anterior resection with anastomosis or abdominoperineal resection with permanent stoma remains the definitive modality for rectal cancer. Because of the relatively narrow difference between the curative and toxic doses, radiotherapy has a limited application as a solo modality. However, in some clinical situations—such as high surgical risk, or a patient’s refusal to undergo surgery—it may be considered as the primary therapy.

External beam radiotherapy
This usually consists of 4 to 6 weeks (20 to 30 sessions) of treatments given 5 days a week. Radiotherapy is delivered by a linear accelerator.

A tumor control of 39% and a 37% 5-year survival were achieved at Princess Margaret Hospital.[1] One important observation was the slow pace of response of rectal cancer to radiotherapy: it took 6 to 7 months to achieve complete regression.

Intracavitary radiotherapy
This form of radiotherapy was pioneered by Dr J. Papillon.[2] Only a small fraction of patients with rectal cancer are suitable for this treatment (10% in the institutions where it is practised). There are strict criteria for selection of the patients:

• Tumor confined to rectal wall 
• Tumor accessible by treatment proctoscope (<12 cm from anal verge) 
• Optimal size ≤3 cm 
• No extension to anal canal

With intracavity radiotherapy, a 74% 5-year survival was achieved for a select group of patients. Because conditions are rarely optimal for this treatment, it is not practised in BC. Similar tumors might be successfully managed with transanal local excision and postoperative radiotherapy. A rate of 81% recurrence-free survival at 5 years was achieved among 23 patients treated with this approach at the BC Cancer Agency.[3]

Preoperative radiotherapy

Preoperative radiotherapy for clinically resectable tumors
Preoperative radiotherapy in these circumstances may have theoretical advantages:

• It may be more effective in killing tumor cells, since better vascularized and oxygenated cells are more sensitive to radiotherapy. 
• Radiotherapy has a better defined target when the tumor is in place.
• Preoperative radiotherapy usually utilizes short regimens and therefore is more convenient for patients and more cost effective (1 week of treatment).

A number of randomized studies have tested this theory. The results of the Swedish Rectal Cancer Trial[4] are impressive. Preoperative radiotherapy (five treatments over 1 week) followed by radical surgery 2 weeks later was compared with surgery alone. With median follow up of 75 months, the recurrence rate was significantly lower in the radiotherapy group (11% versus 27%). In addition, more patients in the radiotherapy group had early stages of the disease pathologically, which may indicate a downstaging effect of radiotherapy. Overall survival was also better in the radiotherapy group (58% versus 48% over 5 years). It is of interest that similar 5-year survival was achieved by combined postoperative treatment (chemotherapy plus radiotherapy) in a major North Central Cancer Treatment Group (NCCTG) trial.[5] The Swedish trial did not use postoperative chemotherapy for the pathologically high-risk group, which theoretically might have achieved even better results. A multicentre study comparing pre- and postoperative radiotherapy showed no difference in survival rate, but the local recurrence rate was lower in the preoperative radiotherapy group (12% versus 21%).[6]

Preoperative radiotherapy is currently recommended by the BC Cancer Agency as the standard modality for managing rectal cancer.

The role of preoperative radiotherapy in conjunction with so-called total mesorectal excision remains uncertain. A trial is proposed to answer this question.[7]

Preoperative radiotherapy for unresectable tumors
For most surgeons and oncologists, the term “unresectable” indicates that the tumor is fixed to adjacent pelvic structures. The goal of radiotherapy here is to shrink the tumor and to make it surgically resectable. A substantial dose of radiotherapy should be delivered for two reasons:

• Radiotherapy should affect gross macroscopic disease (unlike adjuvant radiotherapy, which is dealing with microscopic disease only). 
• In the case of a failure to facilitate resectability, radiotherapy will be the principal treatment modality, which can at least delay the progression of the disease.

Therefore, the regimens recommended for preoperative radiotherapy for unresectable disease will be similar to radical radiotherapy. The Memorial Sloan-Kettering Cancer Center reported a 52% 3-year survival rate using this approach.[8] Among the 70 patients, only 12 underwent surgical excision. In seven of them, the resection margin was negative, microscopically positive in one patient, and grossly positive in one patient. The approach of the University of Florida[9] included external beam radiotherapy in combination with 5-fluorouracil infusion. In a series of 18 patients, 5 had no residual disease in a surgical specimen, 1 had stage PT1 (pathological T1), 3 had PT2 and 8 had PT3 tumor in the resected specimen.

The BC Cancer Agency advocates a similarly aggressive approach for patients in good general condition. The protocol includes 5-fluorouracil and folinic acid with two cycles given over the first and last week of a 5-week course of radiotherapy. There is a plan to introduce 24 hour continuous 5-fluorouracil infusion throughout the entire course of radiotherapy.

Postoperative radiotherapy
In 1990, the National Institute of Health Consensus Conference on Adjuvant Therapy of Large Bowel Cancer evaluated the effectiveness of adjuvant treatment for rectal cancer. Their conclusion was that “combined postoperative chemotherapy and radiation improves local control and survival in Stage II and III patients and is recommended.”[10] In North America, it has become customary to offer postoperative adjuvant treatment, radiotherapy plus chemotherapy to patients with high-risk rectal cancer. These are patients with stage T3 or B2 disease and those with positive nodes.

Several randomized trials have established the benefit of postoperative adjuvant treatment in decreasing the risk of local recurrence and improving survival following surgical resection in patients with rectal cancer.[11-13] Two of these trials allow direct measurement of the impact of radiotherapy on the rate of local control.[5,11] In the NSABP R-01 study, 555 patients with Duke’s B and C rectal cancer treated with curative resection were randomly assigned to receive no further treatment, postoperative chemotherapy, or postoperative radiotherapy. The rates of locoregional recurrence were 24.5% in the surgery alone group and 16.3% in the surgery with postoperative radiation group. The difference reached borderline statistical significance (P=0,06). Similar results were obtained from the Gastrointestinal Study Group (GITSG) 7175 study. Table 1 presents a comparison of the BC Cancer Agency results with those of the GITSG and NCCTG.

Although postoperative radiation is still currently administered to high-risk patients with rectal cancer, preoperative radiotherapy as pioneered by the Swedish Group[4] is gaining popularity in North America and is currently recommended by the BC Cancer Agency.

Technically, radiotherapy is administered to the area where the tumor was initially located and includes a margin to account for microscopic extension, immediate nodal drainage areas, site of the anastomosis, and any other areas considered at risk (presacral space, perineum, etc.). Patient and organ motion, as well as variation in the daily setup, also have to be taken into consideration. A high to moderate dose of radiotherapy is administered daily 5 days per week over 5 to 5½ weeks. Toxicity from the treatment may include cramps, diarrhea, local discomfort, dysuria, tenesmus, rectal discharge, proctitis, skin reaction, and fatigue. These transient symptoms usually resolve during the few weeks following treatment. The long-term toxicity, although much less common, is somewhat more serious. It stems mainly from scar-tissue formation and vascular injury. This may include chronic cystitis and proctitis, bowel obstruction, and bleeding.

Palliative radiotherapy

Palliation of symptoms from primary lesion
Local recurrence of rectal cancer can be accompanied by signs and symptoms that can greatly affect patients’ quality of life. Intractable pain from recurrence in the presacral space and sacral nerve root entrapment often causes a great deal of distress. Continuous bleeding from a rectal tumor can require frequent blood transfusions. The decision to treat a local recurrence is based on several criteria and guided by an evaluation of the patient’s benefit in terms of improved quality of life. Factors to consider include:

• Previous radiotherapy and time between treatment and recurrence 
• Tolerance of normal tissues 
• Volume of tissue to irradiate 
• Performance status of the patient

Palliation of symptoms caused by distant metastases
Frequent sites of treatment include bones, lungs, and brain. Usually a short course of radiotherapy is sufficient (from a single treatment to 2 weeks of treatment).

Radiotherapy is not advised, however, in situations where the patient has partial or complete obstruction related to tumor. Instead, surgical correction in the form of colostomy should be a priority and radiation can be added later.

Dr Agranovich is a radiation oncologist at the BC Cancer Agency, Fraser Valley Cancer Clinic, and a clinical assistant professor in the Department of Surgery at UBC. Dr Berthelet is a radiation oncologist at the BC Cancer Agency, Fraser Valley Cancer Clinic, and a clinical instructor in the Department of Surgery at UBC.