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Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data
Introduction
Locally advanced rectal cancer is usually treated with preoperative chemoradiation followed by total mesorectal excision.1 Most patients show substantial downsizing of the tumour, and in 15–27% of patients no residual viable tumour cells are detected in the resected specimen.2, 3 Several studies have suggested that this pathological complete response (pCR) is associated with a favourable outcome with regard to local control, distant recurrence, disease-free survival, and overall survival.4, 5, 6, 7, 8 Such a finding is clinically relevant because it relates to whether to omit further adjuvant treatment for patients who respond well, or to intensify treatment for those who do not respond. Additionally, it can affect whether patients who respond very well to chemoradiation would benefit from less invasive strategies such as local excision, or a decision to even omit surgery and undertake intensive follow-up.9, 10
Until now published studies have reported a trend towards a favourable prognosis for patients with a pCR, but this trend was often not statistically significant, probably because of small sample sizes.3, 11 Censoring of patients in survival analyses aggravated this difficulty, since few patients could be analysed after long follow-up periods. Moreover, most studies compared responding with non-responding patients and did not make a distinction between pCR and other degrees of response.4, 7, 12 A pooled analysis of a large set of individual patient data can solve these methodological difficulties, since it allows for a large sample size. Furthermore, differences in baseline characteristics between patients with and without pCR can be adjusted with multivariate analyses, and the definition of pCR can be standardised.
For these reasons, we undertook a pooled analysis of studies, in which data were reported for the diagnosis, treatment, and prognosis of patients with and without pCR after chemoradiation. The aim was to assess whether patients who achieve a pCR have improved 5-year rates of local control, and distant-metastasis-free, disease-free, and overall survival compared with patients who did not achieve a pCR.
Section snippets
Search strategy and selection criteria
We searched PubMed, Medline, and Embase for relevant articles published from 1980, to January, 2009, with the following search terms: “rectal cancer”, “response”, “radiotherap*”, “chemotherap*”, “chemoradiation”, “radio(-)chemo*”, “chemo(-)radio*”, “chemo-radiotherapy”, “radio-chemotherapy”, “regression”, “patholog*”, “survival”, “sphincter”, “progn*”, “Dworak”, and “Mandard”. Studies were included if: they were published in English, German, or Dutch language; patients had primary rectal cancer
Results
Table 1 provides details about the 14 studies that were included in the meta-analysis. 3105 patients were included of whom 484 had a pCR. Chemoradiation consisted of 45–50·4 Gy in 25–28 fractions of 1·8 Gy with fluorouracil-based chemotherapy in most studies. The interval between chemoradiation and surgery was 6–8 weeks in almost all studies (data not shown). Table 2 provides the characteristics of the included datasets separately, and table 3 presents the baseline characteristics for all
Discussion
Findings from this pooled analysis of individual patient data from several study centres show that patients with a pCR after chemoradiation have a significantly better long-term outcome than do those with residual disease. The effect of pCR on long-term outcome was not affected or modified by clinical T or N category, administration of adjuvant chemotherapy, distance from anal verge, or type of surgery.
Chari and colleagues8 published one of the earliest studies reporting that patients with a
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