Elsevier

The Lancet Oncology

Volume 11, Issue 9, September 2010, Pages 835-844
The Lancet Oncology

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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

https://doi.org/10.1016/S1470-2045(10)70172-8 Get rights and content

Summary

Background

Locally advanced rectal cancer is usually treated with preoperative chemoradiation. After chemoradiation and surgery, 15–27% of the patients have no residual viable tumour at pathological examination, a pathological complete response (pCR). This study established whether patients with pCR have better long-term outcome than do those without pCR.

Methods

In PubMed, Medline, and Embase we identified 27 articles, based on 17 different datasets, for long-term outcome of patients with and without pCR. 14 investigators agreed to provide individual patient data. All patients underwent chemoradiation and total mesorectal excision. Primary outcome was 5-year disease-free survival. Kaplan-Meier survival functions were computed and hazard ratios (HRs) calculated, with the Cox proportional hazards model. Subgroup analyses were done to test for effect modification by other predicting factors. Interstudy heterogeneity was assessed for disease-free survival and overall survival with forest plots and the Q test.

Findings

484 of 3105 included patients had a pCR. Median follow-up for all patients was 48 months (range 0–277). 5-year crude disease-free survival was 83·3% (95% CI 78·8–87·0) for patients with pCR (61/419 patients had disease recurrence) and 65·6% (63·6–68·0) for those without pCR (747/2263; HR 0·44, 95% CI 0·34–0·57; p<0·0001). The Q test and forest plots did not suggest significant interstudy variation. The adjusted HR for pCR for failure was 0·54 (95% CI 0·40–0·73), indicating that patients with pCR had a significantly increased probability of disease-free survival. The adjusted HR for disease-free survival for administration of adjuvant chemotherapy was 0·91 (95% CI 0·73–1·12). The effect of pCR on disease-free survival was not modified by other prognostic factors.

Interpretation

Patients with pCR after chemoradiation have better long-term outcome than do those without pCR. pCR might be indicative of a prognostically favourable biological tumour profile with less propensity for local or distant recurrence and improved survival.

Funding

None.

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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