Single or combination chemotherapy during preoperative treatment for rectal cancer

Background

Rectal cancer accounts for one-third of all cancers of the large intestine and is an important cause of death worldwide. Radiotherapy and surgery have improved results, but there is still a high proportion of people where the cancer spreads to other parts of the body (distal metastases). In the period before surgery (preoperative period), anti-cancer drugs (chemotherapy) are given to help destroy smaller tumours and enhance the effects of radiotherapy (high-energy radiation that targets the cancer). Chemotherapy also has benefits on organs other than the rectum, making the use of these drugs highly desirable in the preoperative period. Therefore, it is possible that adding a second drug to the chemotherapy regimen (e.g. oxaliplatin) may increase these benefits further.

Study characteristics

We searched scientific databases for randomised controlled trials (RCTs; clinical trials where people were randomly allocated to one of two or more treatment groups) reviewing the benefit of two types of chemotherapy regimens, combined with radiotherapy, given before surgical treatment for rectal cancer. We considered a regimen with a single drug (e.g. fluoropyrimidine) compared with a regimen with two drugs (e.g. fluoropyrimidine plus oxaliplatin). The searches were conducted in January 2015.

Key results

We included four RCTs with 3875 people with operable rectal cancer, who were treated preoperatively either one or two chemotherapy drugs along with radiotherapy. People received either fluoropyrimidine alone (the control group) or fluoropyrimidine plus oxaliplatin (the intervention, or experimental, group).

Only one trial reported the time people were alive with or without cancer (overall survival) and the time people were alive and free of cancer (disease-free survival). This trial found no differences between the two chemotherapy regimens. All four trials reported on whether there were still signs of cancer at the surgery site (no signs means complete pathological response, and, therefore, removal of all the cancer) and there was evidence that this was better with the two-drug regimen. However, the two-drug regimen was associated with more side effects (early toxicity). These side effects were manageable in most people but they were probably the reason why more people carried on taking the treatment in the one-drug control group than in the two-drug intervention group. There were no differences between groups in the number of deaths within 60 days of surgery or illness after the operation.

Quality of the evidence

There evidence that people with operable rectal cancer who receive a combination chemotherapy before surgery have no improvements in overall survival or disease-free survival, but the quality of this evidence was very low, and, therefore, may not be reliable. There is better evidence to suggest that the two-drug combination chemotherapy with oxaliplatin improved local tumour control, but that it also caused more side effects that could make the treatment unacceptable to those receiving treatment. Given the lack of evidence on survival, we cannot draw robust conclusions, and, therefore, cannot make any recommendations as to the use of these regimens in clinical practice. Further research on the impact on survival is needed before such conclusions can be drawn.

Authors' conclusions: 

There was very low quality evidence that people with resectable rectal cancer who receive combination preoperative chemotherapy have no improvements in overall survival or disease-free survival. There was high quality evidence that suggested that combination chemotherapy with oxaliplatin may improve local tumour control in people with resectable rectal cancer, but this regimen also caused more toxicity. The review included four RCTs but only one reported survival; therefore, we cannot make robust conclusions or useful clinical recommendations. The publication of more survival data from these studies will contribute to future analyses.

Read the full abstract...
Background: 

Colorectal cancer represents 10% of all cancers and is the third most common cause of death in women and men. Almost two-thirds of all bowel cancers are cancers of the colon and over one-third (34%) are cancers of the rectum, including the anus. Surgery is the cornerstone for curative treatment of rectal cancer. Mesorectal excision decreases the rate of local recurrences; however, it does not improve the overall survival of people with locally advanced rectal cancer. There have been significant research efforts since the mid-1990s to optimise the treatment of rectal cancer. Based on the findings of clinical trials, people with T3/T4 or N+ rectal tumours are now being treated preoperatively with radiation and chemotherapy, mainly fluoropyrimidine. However, the incidence of distant metastases remains as high as 30%. Combination chemotherapy regimens, similar to those used in metastatic disease with the addition of oxaliplatin and irinotecan, have been tested to improve the prognosis of people with rectal cancer.

Objectives: 

To compare outcomes (including overall survival, disease-free survival and toxicity) between two 5-fluorouracil-containing chemotherapy regimens in people with stage II and III rectal cancer who are receiving preoperative chemoradiation.

Search strategy: 

We searched the Cochrane Colorectal Cancer Group Specialised Register (January 2015), the Cochrane Central Register of Controlled Trials (2015, Issue 1), Ovid MEDLINE (1950 to January 2015), Ovid EMBASE (1974 to January 2015) and LILACS (1982 to January 2015). We reviewed the reference lists of included studies, checked clinical trials registers and handsearched relevant journal proceedings. We applied no language or publication restrictions.

Selection criteria: 

Randomised controlled trials (RCTs) comparing single-agent chemotherapy (fluoropyrimidine) versus combination chemotherapy (fluoropyrimidine plus another agent including, but not limited to, oxaliplatin) during preoperative radiochemotherapy in people with resectable rectal cancer.

Data collection and analysis: 

Two review authors (HMR, EMKS) independently extracted data and assessed trial quality. When necessary, we requested additional information and clarification of published data from the authors of individual trials.

Main results: 

We included four RCTs involving 3875 people with resectable rectal cancer. In the preoperative period, the participants of these studies were randomised to receive chemoradiation either with a single fluoropyrimidine agent (capecitabine or 5-fluorouracil) or with a combination of drugs (fluoropyrimidine plus oxaliplatin). The only study that reported overall survival and disease-free survival found no significant differences between the intervention and control groups; we considered this evidence very low quality.

For pathological complete response after preoperative treatment (ypCR) there was high quality evidence favouring the intervention group (odds ratio (OR) 1.23, 95% confidence interval (CI) 1.04 to 1.46), but there was also moderate quality evidence suggesting a higher risk for early toxicity in the intervention group (OR 2.07, 95% CI 1.31 to 3.27). Moderate to high quality evidence suggested that the control group had better compliance to radiotherapy (OR 0.32, 95% CI 0.14 to 0.75). There were no significant differences between groups in postoperative mortality within 60 days, postoperative morbidity, resection margins, abdominoperineal resection and Hartmann procedures.

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