Combination chemotherapy versus single‐agent chemotherapy during preoperative chemoradiation for resectable rectal cancer
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 methods
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.
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.
PICOs
Plain language summary
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
Summary of findings
| Combination chemotherapy compared with single‐agent chemotherapy for resectable rectal cancer | ||||
| Patient or population: people with resectable stage II and III rectal cancer undergoing preoperative chemoradiation followed by surgery Intervention: fluoropyrimidine plus oxaliplatin Comparison: fluoropyrimidine | ||||
| Outcomes | Relative effect | No of participants | Quality of the evidence | Comments |
| Overall survival (3 years) | HR 0.94 (0.59 to 1.48) | 598 | ⊕⊝⊝⊝ | Limited sample size with 48.8% losses at 3 years' follow‐up. ITT analysis |
| Disease‐free survival (3 years) | HR 0.88 (0.65 to 1.18) | 598 | ⊕⊝⊝⊝ | Limited sample size with 48.8% losses at 3 years' follow‐up. ITT analysis |
| Complete response rate after preoperative chemoradiation (ypCR) | OR 1.23 (1.04 to 1.46) | 3875 (4) | ⊕⊕⊕⊕ | ‐ |
| Toxicity ‐ early adverse events G3/4 | OR 2.07 (1.31 to 3.27) | 3875 | ⊕⊕⊕⊝ | Heterogeneity in the analysis |
| Metastases intra‐abdominal | OR 0.46 (0.21 to 1.01) | 2567 (3) | ⊕⊕⊕⊝ | Heterogeneity in the analysis |
| Radiotherapy compliance | OR 0.32 (0.14 to 0.75) | 2567 (3) | ⊕⊕⊕⊝ | Heterogeneity in the analysis |
| Chemotherapy compliance | OR 0.36 (0.26 to 0.52) | 1331 | ⊕⊕⊕⊕ | ‐ |
| CI: confidence interval; HR: hazard ratio; ITT: intention to treat; OR: odds ratio. GRADE Working Group grades of evidence | ||||
Background
Colorectal cancer accounts for 10% of all cancers and is the third most common cause of death among adults (Kamangar 2006). Rectal cancers represent one‐third of cancers of the large bowel and significant research effort has been invested in an attempt to achieve better treatment results. The cornerstone of the treatment is surgery with the technique of total mesorectal excision helping to improve the outcome of locally advanced rectal cancer by decreasing rates of local recurrence (Wibe 2003).
Until the late 1980s, there was high risk of local and distant recurrences after resection of rectal cancer. Since then, the addition of radiotherapy has been studied extensively in clinical trials, achieving decreases in local recurrence rates of 50% to 60% compared with surgery alone (Bosset 2006). In the early 1990s, after results of randomised trials had been presented, preoperative radiotherapy was considered in Europe as standard treatment in rectal cancer T3 and T4 (see Table 1). This was in contrast to the US National Institutes of Health recommendations, which recommended postoperative chemoradiation (NIH Consensus Conference 1990). The next phase of treatment development in this area was to explore the potential benefit of adding chemotherapy to radiation and surgery. The Fedération Francophone de Cancerologie Digestive (FFCD; France) conducted a trial comparing preoperative chemoradiation with 5‐fluorouracil and leucovorin bolus with preoperative radiotherapy alone. There were better rates of local control in the combination arm, although no improvement in overall survival (Gérard 2006). One subsequent trial by Sauer and colleagues addressed the question of whether chemoradiation should be given preoperatively or postoperatively (Sauer 2004). Once again, there was no impact on overall survival, although preoperative chemoradiation offered better rates of local control, reduced toxicity overall and better sphincter preservation in the subgroup of people (prior to randomisation) receiving abdominoperineal resection (Sauer 2004). Since then, there has been general agreement that chemoradiation should be given preoperatively.
| Primary tumour (T) | |||
| TX | Primary tumour cannot be assessed | ||
| T0 | No evidence of primary tumour | ||
| Tis | Carcinoma in situ: intraepithelial or invasion of lamina propria* | ||
| T1 | Tumour invades submucosa | ||
| T2 | Tumour invades muscularis propria | ||
| T3 | Tumour invades through the muscularis propria into pericolorectal tissues | ||
| T4a | Tumour penetrates to the surface of the visceral peritoneum• | ||
| T4b | Tumour directly invades or is adherent to other organs or structures•Δ | ||
| Regional lymph node (N)◊ | |||
| NX | Regional lymph nodes cannot be assessed | ||
| N0 | No regional lymph node metastasis | ||
| N1 | Metastasis in 1‐3 regional lymph nodes | ||
| N1a | Metastasis in 1 regional lymph node | ||
| N1b | Metastasis in 2 or 3 regional lymph nodes | ||
| N1c | Tumour deposit(s) in the subserosa, mesentery or non‐peritonealised pericolic or perirectal tissues without regional nodal metastasis | ||
| N2 | Metastasis in ≥ 4 regional lymph nodes | ||
| N2a | Metastasis in 4‐6 regional lymph nodes | ||
| N2b | Metastasis in ≥ 7 regional lymph nodes | ||
| Distant metastasis (M) | |||
| M0 | No distant metastasis | ||
| M1 | Distant metastasis | ||
| M1a | Metastasis confined to 1 organ or site (e.g. liver, lung, ovary, non‐regional node) | ||
| M1b | Metastases in ≥ 1 organ/site or the peritoneum | ||
| Anatomic stage/prognostic groups§ | |||
| Stage | T | N | M |
| I | T1 | N0 | M0 |
| T2 | N0 | M0 | |
| IIA | T3 | N0 | M0 |
| IIB | T4a | N0 | M0 |
| IIC | T4b | N0 | M0 |
| IIIA | T1‐2 | N1/N1c | M0 |
| T1 | N2a | M0 | |
| IIIB | T3‐T4a | N1/N1c | M0 |
| T2‐T3 | N2a | M0 | |
| T1‐T2 | N2b | M0 | |
| IIIC | T4a | N2a | M0 |
| T3‐T4a | N2b | M0 | |
| T4b | N1‐N2 | M0 | |
| IVA | Any T | Any N | M1a |
| IVB | Any T | Any N | M1b |
| * This includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa. • Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (e.g. invasion of the sigmoid colon by a carcinoma of the caecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e. for a retroperitoneal location, a tumour on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or for a subperitoneal location, a mid‐ or distal rectal cancer with invasion of prostate, seminal vesicles, cervix or vagina). Δ Tumour that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumour is present in the adhesion, microscopically, the classification should be pT1‐4a depending on the anatomical depth of wall invasion. The V and L classifications should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN site‐specific factor should be used for perineural invasion. ◊ A satellite peritumoural nodule in the pericolorectal adipose tissue of a primary carcinoma without histological evidence of residual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2), or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive nodes in the N category, whereas discontinuous spread or venous invasion should be classified and counted in the Site‐Specific Factor category Tumor Deposits (TD). § cTNM is the clinical classification, pTNM is the pathological classification. The y prefix is used for those cancers that are classified after neoadjuvant pretreatment (e.g. ypTNM). People who have a complete pathological response are ypT0N0cM0 that may be similar to stage group 0 or I. The r prefix is to be used for those cancers that have recurred after a disease‐free interval (rTNM). Adapted from AJCC Cancer Staging Manual 7th edition (AJCC 2010). | |||
A new question arises about what is the best chemotherapy regimen to use in the preoperative management of rectal cancer. Despite improvements in local control, through the use of optimal surgery and perioperative fluoropyrimidine‐based chemoradiation, the rates of distant metastases that represent the site of failure for up 30% of people are still unacceptably high. There is a clinical need for a more effective preoperative chemotherapy regimen.
It has been proposed that better results could be obtained with combination chemotherapy regimens as has been demonstrated in metastatic disease, with the addition of other chemotherapy drugs to the fluoropyrimidine schedule, such as oxaliplatin (de Gramont 2000), and irinotecan (Saltz 2000).
In this systematic review, we examined the effectiveness of combination chemotherapy versus single‐agent chemotherapy during preoperative chemoradiation for resectable rectal cancer. Other strategies have been studied, for example, neoadjuvant chemotherapy with oxaliplatin and capecitabine followed by preoperative chemoradiation (Chau 2006), or preoperative chemoradiation without fluoropyrimidine in the two arms (Valentini 2008). We excluded these studies, as our focus was on the preoperative combination chemotherapy versus single‐agent chemotherapy during preoperative chemoradiation using fluoropyrimidine‐based chemotherapy. Furthermore, we excluded trials using biological agents (monoclonal antibodies) such as bevacizumab, cetuximab and panitumumab, as these agents have different mechanisms of action from the chemotherapy drugs and their benefits cannot be analysed together.
Phase I trials (Freyer 2001), and phase I and II trials (Aschele 2005; Hospers 2007; Rodel 2003; Ryan 2006), tested feasibility and dose levels of oxaliplatin added to a fluoropyrimidine‐based regimen, and demonstrated that weekly oxaliplatin was active systemically and has a manageable profile toxicity.
Phase II trials have demonstrated that pathological response rates around 14% to 20.9% can be achieved by the addition of oxaliplatin to a fluoropyrimidine‐based regimen in preoperative chemoradiation (Carlomagno 2009; Gérard 2003; Machiels 2005; Rodel 2007). The studies with irinotecan have not been pursued due to overlapping toxicity of diarrhoea with radiotherapy, 5‐fluorouracil and irinotecan.
Preliminary safety results of phase III trials addressing the role of oxaliplatin in preoperative chemoradiation stage II and III rectal cancer have been presented, and their safety profiles were acceptable and allowed continuation of accrual to the studies. One of them was the ACCORD 12/0405 PRODIGE‐2 (Gérard 2008), presented at the ASCO (American Society Clinical Oncology) Annual Meeting in 2008, which compared preoperative radiotherapy (45 Gy in 25 daily fractions) plus capecitabine to radiotherapy (45 Gy in 25 daily fractions) plus oxaliplatin with optional adjuvant chemotherapy. The other trial compared infused concomitant 5‐fluorouracil chemotherapy plus preoperative radiotherapy (50.4 Gy in 28 daily fractions) to radiotherapy (50.4 Gy in 28 daily fractions) plus weekly oxaliplatin. Both arms were followed by surgery and four cycles of 5‐fluorouracil‐based adjuvant chemotherapy (Aschele 2007). Full reports of these two trials became available during the course of writing this review, and have been included along with two other phase III trials in the systematic review that have investigated the role of the addition of oxaliplatin (Aschele 2011; Gérard 2010; Gérard 2012; O'Connell 2014; Rödel 2012).
Description of the condition
Rectal cancers are lesions localised of 3 cm to 12 cm from the anal verge, with some variations accepting distances of 15 cm from the anal verge. The determination of the location of the boundary between rectum and sigmoid colon is important in defining radiotherapy, with the rectum usually being operationally defined as the area of the large bowel that is at least partially retroperitoneal (Libutti 2008). Rectal cancer represents one‐third of cancers of the large bowel and the standard treatment is preoperative treatment with chemoradiation followed by surgery. However, the incidence of distant metastases remains high for up to 30% of people.
Description of the intervention
Chemoradiation is a combination of external beam radiation given at the same time as chemotherapy (drug treatment). External beam radiation is delivered by radiation machines. Chemoradiation during preoperative treatment is the standard treatment in resectable rectal cancer (Sauer 2004). Chemotherapy can be given in oral form or intravenously in varying schedules. To date, chemotherapy has generally involved single‐agent fluoropyrimidine (e.g. 5‐fluorouracil given by infusion or bolus injection or oral capecitabine). Intravenous 5‐fluorouracil and oral capecitabine have been considered equivalents in colorectal cancer (Gérard 2010), and we considered this the control arm (single‐agent chemotherapy) in randomised controlled trials (RCTs) and compared it to the same regimens added to a second chemotherapy drug (combination chemotherapy; the intervention arm).
How the intervention might work
Chemotherapy delivered concurrently with preoperative radiation exposes the tumour immediately to an active drug and enhances the effect of radiation (radiation sensitisation). Chemotherapy circulates in the blood stream potentially treating cancer cells in other parts of the body that may have spread from the primary tumour (micrometastases). Combination chemotherapy may enhance these effects and lead to better control of the local tumour and more effective treatment of micrometastases leading to better overall survival. However, there is no evidence that combination chemotherapy actually improves complete response rate after neoadjuvant treatment (ypCR) and if improving the ypCR rate translates into better overall survival and disease‐free survival.
Why it is important to do this review
This review is important because we evaluated whether there were any improvements in patient outcomes (including overall survival rates) by the addition of another chemotherapy drug to 5‐fluorouracil. If there is no advantage in combination chemotherapy during preoperative chemoradiation, this systematic review can help by minimising the costs and adverse effects of combination chemotherapy.
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.
Methods
Criteria for considering studies for this review
Types of studies
All parallel RCTs of preoperative chemoradiation for resectable rectal cancer comparing combination regimen (fluoropyrimidine based) versus single agent (fluoropyrimidine alone). We excluded trials comparing combination chemotherapy including biological agents.
Types of participants
People with resectable stage II and III rectal cancer undergoing preoperative chemoradiation followed by surgery.
Types of interventions
Preoperative chemoradiation with single‐agent chemotherapy or combination chemotherapy.
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Combination chemotherapy: radiotherapy plus fluoropyrimidine plus an additional drug(s) (e.g. (but not limited to) oxaliplatin added to a fluoropyrimidine regimen (including, but not limited, to 5‐fluorouracil or capecitabine)).
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Single‐agent combination: radiotherapy plus fluoropyrimidine (e.g. (but not limited to) fluoropyrimidine regimen (including (but not limited to) 5‐fluorouracil or capecitabine).
The types of surgery included: surgery with curative intention. We excluded studies using local excision.
Types of outcome measures
Primary outcomes
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Overall survival.
Secondary outcomes
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Disease‐free survival.
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Toxicity.
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Local recurrence rate measured within three years.
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Pathological complete response rate (ypCR).
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Sphincter preservation rate.
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Postoperative mortality within 60 days.
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Postoperative morbidity within 60 days.
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Anastomotic leak rate.
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Treatment compliance (rate of patients that complete treatment).
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Clinical response rate (tumour down staging).
Search methods for identification of studies
We searched for studies in electronic bibliographic databases, references lists of included studies and books. We applied no language restrictions.
Electronic searches
We conducted a comprehensive literature search to identify all published and unpublished RCTs with no language or time restrictions. We searched the following electronic databases to identify possible studies:
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Cochrane Colorectal Cancer Group Specialised Register (January 2015);
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The Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 1, Appendix 1);
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Ovid MEDLINE 1950 to January 2015 (Appendix 2);
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Ovid EMBASE 1974 to January 2015 (Appendix 3);
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LILACS 1982 to January 2015 (Appendix 4).
We searched for ongoing trials in the Current Controlled Trials web site (www.controlled‐trials.com/).
Searching other resources
We searched non‐indexed publications, newsletters and abstracts presented at major meetings including ASCO (American Society of Clinical Oncology) and ESMO (European Society for Medical Oncology) from 2008 to January 2015.
Data collection and analysis
Two review authors (HMR and EMKS) selected possible RCTs, analysed and considered them for inclusion, assessed their risk of bias and graded them for their methodological quality. We resolved disagreements by consulting the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and discussing the differences in order to try to reach a consensus. If there were persistent disagreements, we consulted a third review author (DM). We also used the Cochrane Handbook for Systematic Reviews of Interventions to assess quality (Higgins 2011), and used The Cochrane Collaboration's tool for assessing risk of bias to analyse the quality of each study.
Selection of studies
Two review authors (HMR and DM) performed a non‐blinded selection of the studies (Appendix 5). In case of any disagreement, we contacted a third review author (EMKS) until we reached a consensus.
Data extraction and management
We used an electronic data collection form (Appendix 6) and two review authors (EMKS and LFPJ) independently extracted the data. A third review author (HMR) checked and entered the data into Review Manager 5 (RevMan 2014), and another review author (EMKS) checked for data entry errors.
Assessment of risk of bias in included studies
We used The Cochrane Collaboration's tool for assessing risk of bias described in Table 8.5.d of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed the risk of bias of the following domains:
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random sequence generation;
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allocation concealment;
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blinding of participants and personnel;
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blinding of outcome assessment;
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incomplete outcome data;
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selective reporting bias; and
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other bias (e.g. differences in study design).
We judged each domain as low risk, high risk or unclear risk of bias according to criteria stated in The Cochrane Collaboration's 'Risk of bias' tool (see Appendix 7) (Chapter 8.5.d, Higgins 2011).
Measures of treatment effect
For dichotomous outcomes, we used the odds ratio (OR) and for continuous data, we calculated mean differences between treatment groups if studies reported exactly the same outcomes. If similar outcomes were reported on different scales, we calculated the standardised mean difference. For time‐to‐event data, we used methods of survival analysis and expressed the intervention effect as a hazard ratio (HR). In all analyses, we calculated the 95% confidence interval (CI).
Unit of analysis issues
The unit of analysis was based on the individual participant (unit to be randomised for interventions to be compared; i.e. the number of observations in the analysis should match the number of people randomised).
Dealing with missing data
For missing or unavailable data, we had planned to contact the study authors for additional information, but for this version of the review, it was not necessary because all data were available. We reported drop‐out rates in the Characteristics of included studies table and used an intention‐to‐treat (ITT) analysis. For this, all eligible participants randomised was used as total and we considered that all missing participants did not experience the event (Higgins 2011).
Assessment of heterogeneity
We qualified inconsistency among the pooled estimates using the I2 statistic (where I2 = ((Q ‐ df)/Q) x 100% where Q was the Chi2 statistic, and df represented the degrees of freedom). This illustrated the percentage of the variability in effect estimates resulting from heterogeneity rather than sampling error (Higgins 2011).
Assessment of reporting biases
We did not evaluate reporting biases/small‐study effects by drawing a funnel plot (trial effect versus trial size), because there was an insufficient number of studies. In subsequent updates, we will perform these assessments if we included a sufficient number of studies (more than 10) in the review.
Data synthesis
We presented the results in a point estimate plot with 95% CI for each study (Forest plot). We used a fixed‐effect model in the absence of substantial heterogeneity (I2 less than 50%), otherwise we used a random‐effects model (I2 greater than 50%).
Subgroup analysis and investigation of heterogeneity
In subsequent updates of this review, we will analyse the following subgroups if further trials become available:
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stage (stage II and stage III);
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chemotherapy strategy (people receiving fluoropyrimidine plus oxaliplatin versus fluoropyrimidine plus another drug chemotherapy);
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adjuvant treatment or not; adjuvant treatment with oxaliplatin plus fluoropyrimidine versus fluoropyrimidine alone;
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doses and schedule of 5‐fluorouracil.
Sensitivity analysis
We performed a sensitivity analysis with the worst‐case scenario with all eligible randomised participants as total. We assumed that all participants with missing outcomes in the intervention group had poor outcomes, and all those with missing outcomes in the control intervention group had good outcomes. There was no significant differences in the results.
In subsequent updates of this review, if there are an adequate number of studies, we will perform a sensitivity analysis to explore the causes of any heterogeneity in the analysis and the robustness of the results.
Summary of findings
We assessed the quality of evidence of combination chemotherapy compared with single‐agent chemotherapy for resectable rectal cancer using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation) in 'Summary of findings' table(s) (Higgins 2011).
The GRADE system classifies the quality of evidence in one of four grades.
| Grade | Definition |
| High | Further research is very unlikely to change our confidence in the estimate of effect |
| Moderate | Further research is likely to have an impact on our confidence in the estimate of effect and may change the estimate |
| Low | Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate |
| Very low | Any estimate of effect is very uncertain |
Factors influencing the quality of evidence are:
| Decreases quality of evidence | Increases quality of evidence |
| Study limitation | Large magnitude of effect |
| Inconsistency of results | All plausible confounding would reduce the demonstrated effect |
| Indirectness of evidence | Dose‐response gradient |
| Imprecision | ‐ |
| Publication bias | ‐ |
Results
Description of studies
See Characteristics of included studies and Characteristics of excluded studies tables
Results of the search
We identified 1601 citations from the database searches and other sources (Figure 1). After screening by title and abstract, we obtained full paper copies for six citations that were potentially eligible for inclusion in the review. Of these six citations, five articles reporting four trials fulfilled our inclusion criteria. Therefore, we included four trials in this review (Aschele 2011; Gérard 2010; Gérard 2012; O'Connell 2014; Rödel 2012; see Characteristics of included studies). We excluded one study (Wong 2012; see Characteristics of excluded studies).
Study flow diagram.
Included studies
We included four RCTs reported in five articles with 3875 participants in this review (Aschele 2011; Gérard 2010; Gérard 2012; O'Connell 2014; Rödel 2012). Four publications reported the initial results of RCTs (Aschele 2011; Gérard 2010; O'Connell 2014; Rödel 2012), and one publication (Gérard 2012) reported subsequent clinical outcomes of one of these trials (Gérard 2010).
Types of participants
The inclusion criteria of the studies were people with histologically confirmed adenocarcinoma of the rectum, resectable without distant metastases suitable to receive preoperative chemoradiation regimens comparing single‐agent chemotherapy versus combination chemotherapy during preoperative chemoradiation. Aschele 2011 included people with resectable, locally advanced (cT3‐4 or cN1‐2, or both) adenocarcinoma of the mid‐low rectum, with tumour located within 12 cm from the anal verge, World Health Organization (WHO) performance status 0 to 2, and aged 75 years or less. Gérard 2010/Gérard 2012 included people with histologically confirmed stage T3 or resectable, T4 rectal adenocarcinoma with no evidence of distant metastases, and aged 80 years or less with WHO performance status 0 or 1. Rödel 2012 included people with histopathologically confirmed rectal carcinoma (cT3‐4 or cN+ adenocarcinoma), inferior margin no more than 12 cm above the anal verge, aged 18 years or older, and Eastern Cooperative Oncology Group (ECOG) performance status 2 or lower. O'Connell 2014 included people with clinical stage II or III rectal cancer who were undergoing preoperative chemoradiation. Participants were required to be at least 18 years old with an ECOG performance score of 0 to 1 and a life expectancy of five years. The tumour had to be confirmed to be stage II (T3‐4N0) or stage III (T1‐4N1‐2, with a positive node defined as at least 1.0 cm in diameter on imaging. There must have been no evidence of metastatic disease.
Types of intervention
The four studies randomised 3875 people to either a control group (fluoropyrimidine‐based chemotherapy) or an intervention group (fluoropyrimidine‐based chemotherapy in combination with oxaliplatin); both arms received radiotherapy. The radiotherapy schedules were similar, with some variations in doses. In one study, the fluoropyrimidine used was capecitabine; one arm received five weeks' treatment with radiotherapy (45 Gy/25 fractions) and concurrent capecitabine (800 mg/m2 twice daily, five days per week) and the other arm received radiotherapy (50 Gy/25 fractions) with capecitabine (800 mg/m2 twice daily five days per week) and oxaliplatin (50 mg/m2 once weekly) (Gérard 2010; Gérard 2012). One trial randomised people into two very similar arms, except for the inclusion of oxaliplatin in the intervention arm. The fluoropyrimidine chosen was a 5‐fluorouracil infusion (225 mg/m2/day) given throughout the period of radiotherapy, which consisted of 50.4 Gy in 28 daily fractions, over a period of approximately six weeks in both arms (Aschele 2011). In one trial, the control group received preoperative radiotherapy (50.4 Gy) plus a 5‐fluorouracil infusion (1000 mg/m2 on days one to five and 29 to 33), followed by surgery and four cycles of bolus 5‐fluorouracil (500 mg/m2 on days one to five and 29) (Rödel 2012). The intervention group received preoperative radiotherapy (50.4 Gy) plus 5‐fluorouracil infusions (250 mg/m2 on days one to 14 and 22 to 35) and oxaliplatin (50 mg/m2 on days one, eight, 22 and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m2 on days one and 15), leucovorin (400 mg/m2 on days one and 15) and 5‐fluorouracil infusions (2400 mg/m2 on days one, two, 15 and 16). In O'Connell 2014, participants were randomly assigned to one of the following chemotherapy regimens: continuous intravenous infusional fluorouracil (CVI FU; 225 mg/m2, five days per week), with or without intravenous oxaliplatin (50 mg/m2 once per week for five weeks) or oral capecitabine (825 mg/m2 twice per day, five days per week), with or without oxaliplatin (50 mg/m2 once per week for five weeks).
Types of outcome measures
All included trials analysed secondary outcomes: early toxicity, treatment compliance, intra‐abdominal metastases, postoperative mortality and morbidity, type of surgery and circumferential margin status. Only one trial reported overall survival, disease‐free survival, local and distant recurrence, bowel function and social life disturbance (Gérard 2012), and sphincter preservation rate (O'Connell 2014).
Excluded studies
We excluded one study because it was a phase II clinical trial and there was no comparator group with fluoropyrimidine alone (Wong 2012).
Risk of bias in included studies
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
All studies described randomisation by computer program and central allocation.
Blinding
Three trials did not mention blinding but were probably open studies (Aschele 2011; Gérard 2010; O'Connell 2014). One study stated that there was no blinding due to different treatment schedules (Rödel 2012).
Incomplete outcome data
Altogether, the losses were 128/3875 (3.3%). We have not contacted the authors because all studies reported the losses to follow‐up, allowing us to conduct an ITT analysis, and undertake worst‐case scenario sensitivity analyses.
Selective reporting
The four trials described outcomes planned by the authors. In three studies, the authors stated that disease‐free survival and overall survival will be report in future publications (Aschele 2011; O'Connell 2014; Rödel 2012).
Other potential sources of bias
The differences in design trial can represent a source of bias: one study used slightly different radiotherapy doses in the two arms (45 Gy in the control arm and 50 Gy in the intervention group) (Gérard 2010); one study used a different 5‐fluorouracil schedule and different adjuvant regimens in the two arms (Rödel 2012).
Effects of interventions
For the meta‐analysis, we separated the outcomes of Rödel 2012 from other trials because fluoropyrimidine doses were quite different between the two groups: 250 mg/m2 in the intervention group versus 1000 mg/m2 in the control groups. When there was significant heterogeneity between subgroups, we considered only the subtotals. If there was no heterogeneity, we pooled data in the meta‐analyses. We analysed data according to ITT (i.e. the total number of randomised participants, regardless of the losses described in Characteristics of included studies).
Primary outcomes
Overall survival
Only one study reported overall survival (Gérard 2012). There were no significant differences between the control and intervention groups in three‐year overall survival rates (87.6% with control versus 88.3% with intervention; HR 0.94, 95% CI 0.59 to 1.48).
Secondary outcomes
Disease‐free survival
One RCT reported no significant difference between control and intervention groups in three‐year disease‐free survival (67.9% with control versus 72.7% with intervention; HR 0.88, 95% CI 0.65 to 1.18) (Gérard 2012).
Toxicity
All four RCTs reported toxicity. The toxicity was graded based on the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI 2009): G1 refers mild symptoms, G2 refers to moderate, G3 refers to severe, G4 refers to life‐threatening consequences and G5 refers to death‐related adverse events. There were significantly more G3/4 adverse events in the intervention groups (with oxaliplatin) (OR 2.07, 95% CI 1.31 to 3.27; P value = 0.005; four studies; 3875 participants; Analysis 1.2; Figure 4). This analysis showed heterogeneity between studies (I2 = 87.4%). One study reported no significant differences between groups (Rödel 2012); this may have been due to the different doses of 5‐fluorouracil, as, unlike the other trials, this trial used higher fluorouracil doses in the control arm compared to the intervention arm. The main adverse events were diarrhoea and vomiting.
Forest plot of comparison: 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), outcome: 1.2 Toxicity ‐ early adverse events G3/4.
Local recurrence rate and systemic metastasis rate
One study reported no significant difference between control and intervention groups in the cumulative incidence of local recurrence (6.1% with control versus 4.4% with intervention), and in the number of distant metastasis (24.4% with control versus 22.1% with intervention) (Gérard 2012).
Pathological complete response rate
All four RCTs reported ypCR. In the meta‐analysis, there was a significant difference favouring the intervention group (OR 1.23, 95% CI 1.04 to 1.46; P value = 0.02; four studies; 3875 participants; Analysis 1.1; Figure 5). The number needed to treat for an additional beneficial outcome (NNTB) for ypCR was 35.0 (95% CI 19.2 to 188,7). There was no heterogeneity in subgroups analysis.
Forest plot of comparison: 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), outcome: 1.1 Complete response rate after preoperative chemoradiation (ypCR).
Sphincter preservation rate
Only O'Connell 2014 reported sphincter preservation rate and there was no statistically significant difference between intervention and control group in the rate of surgery with sphincter preservation (OR 0.87, 95% CI 0.70 to 1.09, P value = 0.24).
Postoperative mortality and morbidity within 60 days
Postoperative mortality was equally low in control and intervention arms of the four RCTs with no statistically significant differences (OR 1.01, 95% CI 0.47 to 2.19; Analysis 1.3). Similarly, there was no significant difference between the groups in postoperative morbidity (OR 1.07, 95% CI 0.94 to 1.23; Analysis 1.4). There was no heterogeneity between subgroups in either analysis.
Anastomotic leak rate
Only one study reported anastomotic leak rate (Rödel 2012). The rate was 5% with control and 7% with intervention.
Compliance
Three studies reported the rate of treatment compliance (Aschele 2011; Gérard 2010; Rödel 2012). Participants allocated to the control groups received more full doses of radiotherapy than participants allocated to the intervention group (OR 0.32, 95% CI 0.14 to 0.75; Analysis 1.7). However, this finding should be interpreted with caution because of the heterogeneity between studies (I2 = 74%).
Chemotherapy compliance was also significantly better in the control group when trials using the same dose of 5‐fluorouracil in both arms were combined (OR 0.36, 95% CI 0.26 to 0.52; two studies; 1331 participants). In the one study that used different 5‐fluorouracil doses in the two arms (Rödel 2012), there were no significant differences between groups (Analysis 1.8). The higher fluorouracil doses in the control arm compared to the intervention arm may be responsible for the lack of difference in the compliance between the two arms.
Clinical response rate
None of the studies reported clinical response rate.
Other outcomes
The three trials reported intra‐abdominal metastases (OR 0.46, CI 95% 0.21 to 1.01; Analysis 1.5); circumferential resection margin status (positive 1 mm or less: OR 0.76, 95% CI 0.52 to 1.09; Analysis 1.6) and rate of abdominoperineal resection and Hartmann's procedures that led to permanent stoma, with no significant differences between groups (OR 0.97, 95% CI 0.81 to 1.17; Analysis 1.9).
Discussion
Summary of main results
This review identified four RCTs that investigated the role of combination chemotherapy (which all used oxaliplatin in the intervention arms) in neoadjuvant treatment for people with resectable rectal cancer. These trials included 3875 participants and had similar designs with small differences in radiotherapy doses, fluoropyrimidine schedule and adjuvant regimens.
Only one trial provided data for the primary outcome of this review (Gérard 2010), in a second publication (Gérard 2012). According to this trial, at three years of follow‐up, there were no benefits in the cumulative incidence of local recurrence, overall survival or disease‐free survival. However, it is important to note that although survival data were calculated based on ITT, there were considerable losses to follow‐up (48.8% censured data), but these losses were equivalent in both arms of the study. Survival data from ongoing RCTs will probably help to clarify the role of oxaliplatin in preoperative chemoradiation for people with rectal cancer (Aschele 2011; O'Connell 2014; Rödel 2012;. We will update this systematic review and meta‐analyses when these survival data become available.
ypCR has been used as a surrogate for clinical outcomes, but it is not fully accepted. There are two retrospective studies that compared survival data between complete responders and incomplete responders and found benefit for the complete responders (Martin 2012; Zorcolo 2012), but there are no prospective trials that corroborate this hypothesis. The meta‐analysis found a significant difference favouring the intervention group, according to the pooled results of four RCTs (OR 1.23, 95% CI 1.04 to 1.46). This result represented a small effect of 5.5%, when compared to values proposed by Aschele 2011 (8%) and Gérard 2010 (9%), or ypCR rates as 28% according early phase trials (Aschele 2005). The effect found might have been obtained due to the increase in the sample size, and, therefore, the power to detect a difference between groups. The number needed to treat for an additional beneficial outcome (NNTB) was 35.0 (95% CI 19.2 to 188,7). Although there was a statistically significant difference on ypCR favouring intervention arm, there were significantly more G3/4 early adverse events, mainly diarrhoea and vomiting, in the trials that used the same dose of fluoropyrimidine in both groups (OR 2.53, 95% CI 1.60 to 4.00) (Aschele 2011; Gérard 2010; O'Connell 2014). These high rates of early toxicity were probably responsible for the lower treatment compliance in this group.
Oxaliplatin did not increase early mortality or the rate of postoperative complications. Postoperative mortality and morbidity were equally low in the intervention and control arms (OR 1.01, 95% CI 0.47 to 2.19 for postoperative mortality; OR 1.07, 95% CI 0.94 to 1.23 for postoperative morbidity). There are uncertainties about whether the sample sizes were suitably large to detect a difference due to oxaliplatin in these trials.
There were no significant differences in the rate of participants with intra‐abdominal metastases detected perioperatively after preoperative chemoradiation with oxaliplatin (OR 0.46, 95% CI 0.21 to 1.01; P value = 0.05). Given the upper CI was 1.00, there is also uncertainty as to whether the simple size was too small to detect a difference between groups, rather than a difference between groups not being present.
Overall completeness and applicability of evidence
The control and intervention arms were very similar in three trials in preoperative treatment except for the inclusion of oxaliplatin (Aschele 2011; Gérard 2010; O'Connell 2014). Rödel 2012 presented different doses and schedule of 5‐fluorouracil, but besides that, all four trials were comparable in neoadjuvant treatment and allowed the analysis oxaliplatin effect on ypCR.
At present, there are insufficient data on the most important clinical outcomes (overall survival and disease‐free survival). Therefore, it is not possible to establish the role of oxaliplatin in preoperative chemoradiation for people with rectal cancer. The publication of follow‐up data from three trials will help to clarify this question (Aschele 2011; O'Connell 2014; Rödel 2012).
Quality of the evidence
The studies included in this review had a very low to moderate risk of bias. Although they were not double blinded, the study outcomes were objective and unlikely to have been influenced by lack of blinding.
Potential biases in the review process
We believe that we have prevented bias in the review process by adopting a strategy where two review authors were independently involved in each step of the review and performed a comprehensive search for articles with no language restriction.
Agreements and disagreements with other studies or reviews
There is another systematic review analysing short‐term results of neoadjuvant chemoradiation with fluoropyrimidine alone or in combination with oxaliplatin in advanced rectal cancer (An 2013). This review included the same trials as our review, but analysed only short‐term outcomes, without discussing survival outcomes. In addition, An 2013 included one trial before a full report was available (O'Connell 2014). There is agreement in the findings of the two reviews related to the outcomes as yet reported; our review will be up dated when survival data become available.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), outcome: 1.2 Toxicity ‐ early adverse events G3/4.
Forest plot of comparison: 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), outcome: 1.1 Complete response rate after preoperative chemoradiation (ypCR).
Comparison 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), Outcome 1 Complete response rate after preoperative chemoradiation (ypCR).
Comparison 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), Outcome 2 Toxicity ‐ early adverse events G3/4.
Comparison 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), Outcome 3 Postoperative mortality (death within 60 days).
Comparison 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), Outcome 4 Postoperative morbidity.
Comparison 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), Outcome 5 Metastases intra‐abdominal.
Comparison 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), Outcome 6 Circumferential resection margin ‐ positive status.
Comparison 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), Outcome 7 Radiotherapy compliance.
Comparison 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), Outcome 8 Chemotherapy compliance.
Comparison 1 Combination chemotherapy (intervention) versus single‐agent chemotherapy (control), Outcome 9 Abdominoperineal resection and Hartmann's procedures.
| Combination chemotherapy compared with single‐agent chemotherapy for resectable rectal cancer | ||||
| Patient or population: people with resectable stage II and III rectal cancer undergoing preoperative chemoradiation followed by surgery Intervention: fluoropyrimidine plus oxaliplatin Comparison: fluoropyrimidine | ||||
| Outcomes | Relative effect | No of participants | Quality of the evidence | Comments |
| Overall survival (3 years) | HR 0.94 (0.59 to 1.48) | 598 | ⊕⊝⊝⊝ | Limited sample size with 48.8% losses at 3 years' follow‐up. ITT analysis |
| Disease‐free survival (3 years) | HR 0.88 (0.65 to 1.18) | 598 | ⊕⊝⊝⊝ | Limited sample size with 48.8% losses at 3 years' follow‐up. ITT analysis |
| Complete response rate after preoperative chemoradiation (ypCR) | OR 1.23 (1.04 to 1.46) | 3875 (4) | ⊕⊕⊕⊕ | ‐ |
| Toxicity ‐ early adverse events G3/4 | OR 2.07 (1.31 to 3.27) | 3875 | ⊕⊕⊕⊝ | Heterogeneity in the analysis |
| Metastases intra‐abdominal | OR 0.46 (0.21 to 1.01) | 2567 (3) | ⊕⊕⊕⊝ | Heterogeneity in the analysis |
| Radiotherapy compliance | OR 0.32 (0.14 to 0.75) | 2567 (3) | ⊕⊕⊕⊝ | Heterogeneity in the analysis |
| Chemotherapy compliance | OR 0.36 (0.26 to 0.52) | 1331 | ⊕⊕⊕⊕ | ‐ |
| CI: confidence interval; HR: hazard ratio; ITT: intention to treat; OR: odds ratio. GRADE Working Group grades of evidence | ||||
| Primary tumour (T) | |||
| TX | Primary tumour cannot be assessed | ||
| T0 | No evidence of primary tumour | ||
| Tis | Carcinoma in situ: intraepithelial or invasion of lamina propria* | ||
| T1 | Tumour invades submucosa | ||
| T2 | Tumour invades muscularis propria | ||
| T3 | Tumour invades through the muscularis propria into pericolorectal tissues | ||
| T4a | Tumour penetrates to the surface of the visceral peritoneum• | ||
| T4b | Tumour directly invades or is adherent to other organs or structures•Δ | ||
| Regional lymph node (N)◊ | |||
| NX | Regional lymph nodes cannot be assessed | ||
| N0 | No regional lymph node metastasis | ||
| N1 | Metastasis in 1‐3 regional lymph nodes | ||
| N1a | Metastasis in 1 regional lymph node | ||
| N1b | Metastasis in 2 or 3 regional lymph nodes | ||
| N1c | Tumour deposit(s) in the subserosa, mesentery or non‐peritonealised pericolic or perirectal tissues without regional nodal metastasis | ||
| N2 | Metastasis in ≥ 4 regional lymph nodes | ||
| N2a | Metastasis in 4‐6 regional lymph nodes | ||
| N2b | Metastasis in ≥ 7 regional lymph nodes | ||
| Distant metastasis (M) | |||
| M0 | No distant metastasis | ||
| M1 | Distant metastasis | ||
| M1a | Metastasis confined to 1 organ or site (e.g. liver, lung, ovary, non‐regional node) | ||
| M1b | Metastases in ≥ 1 organ/site or the peritoneum | ||
| Anatomic stage/prognostic groups§ | |||
| Stage | T | N | M |
| I | T1 | N0 | M0 |
| T2 | N0 | M0 | |
| IIA | T3 | N0 | M0 |
| IIB | T4a | N0 | M0 |
| IIC | T4b | N0 | M0 |
| IIIA | T1‐2 | N1/N1c | M0 |
| T1 | N2a | M0 | |
| IIIB | T3‐T4a | N1/N1c | M0 |
| T2‐T3 | N2a | M0 | |
| T1‐T2 | N2b | M0 | |
| IIIC | T4a | N2a | M0 |
| T3‐T4a | N2b | M0 | |
| T4b | N1‐N2 | M0 | |
| IVA | Any T | Any N | M1a |
| IVB | Any T | Any N | M1b |
| * This includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa. • Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (e.g. invasion of the sigmoid colon by a carcinoma of the caecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e. for a retroperitoneal location, a tumour on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or for a subperitoneal location, a mid‐ or distal rectal cancer with invasion of prostate, seminal vesicles, cervix or vagina). Δ Tumour that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumour is present in the adhesion, microscopically, the classification should be pT1‐4a depending on the anatomical depth of wall invasion. The V and L classifications should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN site‐specific factor should be used for perineural invasion. ◊ A satellite peritumoural nodule in the pericolorectal adipose tissue of a primary carcinoma without histological evidence of residual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2), or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive nodes in the N category, whereas discontinuous spread or venous invasion should be classified and counted in the Site‐Specific Factor category Tumor Deposits (TD). § cTNM is the clinical classification, pTNM is the pathological classification. The y prefix is used for those cancers that are classified after neoadjuvant pretreatment (e.g. ypTNM). People who have a complete pathological response are ypT0N0cM0 that may be similar to stage group 0 or I. The r prefix is to be used for those cancers that have recurred after a disease‐free interval (rTNM). Adapted from AJCC Cancer Staging Manual 7th edition (AJCC 2010). | |||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Complete response rate after preoperative chemoradiation (ypCR) Show forest plot | 4 | 3875 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.23 [1.04, 1.46] |
| 1.1 Fluoropyrimidine same dose in both group | 3 | 2639 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.97, 1.45] |
| 1.2 5‐Fluorouracil 1000 mg/m2 vs. 5‐fluorouracil 250 mg/m2 + oxaliplatin | 1 | 1236 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.35 [0.99, 1.85] |
| 2 Toxicity ‐ early adverse events G3/4 Show forest plot | 4 | 3875 | Odds Ratio (M‐H, Random, 95% CI) | 2.07 [1.31, 3.27] |
| 2.1 Fluoropyrimidine same dose in both group | 3 | 2639 | Odds Ratio (M‐H, Random, 95% CI) | 2.53 [1.60, 4.00] |
| 2.2 5‐Fluorouracil 1000 mg/m2 vs. 5‐fluorouracil 250 mg/m2 + oxaliplatin | 1 | 1236 | Odds Ratio (M‐H, Random, 95% CI) | 1.16 [0.88, 1.52] |
| 3 Postoperative mortality (death within 60 days) Show forest plot | 4 | 3875 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.47, 2.19] |
| 3.1 Fluoropyrimidine same dose in both group | 3 | 2639 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.45, 2.77] |
| 3.2 5‐Fluorouracil 1000 mg/m2 vs. 5‐fluorouracil 250 mg/m2 + oxaliplatin | 1 | 1236 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.17, 3.41] |
| 4 Postoperative morbidity Show forest plot | 4 | 3875 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.94, 1.23] |
| 4.1 Fluoropyrimidine same dose in both group | 3 | 2639 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.89, 1.24] |
| 4.2 5‐Fluorouracil 1000 mg/m2 vs. 5‐fluorouracil 250 mg/m2 + oxaliplatin | 1 | 1236 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.90, 1.40] |
| 5 Metastases intra‐abdominal Show forest plot | 3 | 2567 | Odds Ratio (M‐H, Random, 95% CI) | 0.46 [0.21, 1.01] |
| 5.1 Fluoropyrimidine same dose in both group | 2 | 1331 | Odds Ratio (M‐H, Random, 95% CI) | 0.32 [0.06, 1.68] |
| 5.2 5‐Fluorouracil 1000 mg/m2 vs. 5‐fluorouracil 250 mg/m2 + oxaliplatin | 1 | 1236 | Odds Ratio (M‐H, Random, 95% CI) | 0.61 [0.35, 1.07] |
| 6 Circumferential resection margin ‐ positive status Show forest plot | 3 | 2567 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.76 [0.52, 1.09] |
| 6.1 Fluoropyrimidine same dose in both group | 2 | 1331 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.59 [0.33, 1.03] |
| 6.2 5‐Fluorouracil 1000 mg/m2 vs. 5‐fluorouracil 250 mg/m2 + oxaliplatin | 1 | 1236 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.57, 1.51] |
| 7 Radiotherapy compliance Show forest plot | 3 | 2567 | Odds Ratio (M‐H, Random, 95% CI) | 0.32 [0.14, 0.75] |
| 7.1 Fluoropyrimidine same dose in both group | 2 | 1331 | Odds Ratio (M‐H, Random, 95% CI) | 0.09 [0.00, 3.29] |
| 7.2 5‐Fluorouracil 1000 mg/m2 vs. 5‐fluorouracil 250 mg/m2 + oxaliplatin | 1 | 1236 | Odds Ratio (M‐H, Random, 95% CI) | 0.50 [0.29, 0.84] |
| 8 Chemotherapy compliance Show forest plot | 3 | Odds Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 8.1 Fluoropyrimidine same dose in both group | 2 | 1331 | Odds Ratio (M‐H, Random, 95% CI) | 0.24 [0.07, 0.77] |
| 8.2 5‐Fluorouracil 1000 mg/m2 vs. 5‐fluorouracil 250 mg/m2 + oxaliplatin | 1 | 1236 | Odds Ratio (M‐H, Random, 95% CI) | 1.38 [1.03, 1.84] |
| 9 Abdominoperineal resection and Hartmann's procedures Show forest plot | 3 | 2567 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.81, 1.17] |
| 9.1 Fluoropyrimidine same dose in both group | 2 | 1331 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.69, 1.17] |
| 9.2 5‐Fluorouracil 1000 mg/m2 vs. 5‐fluorouracil 250 mg/m2 + oxaliplatin | 1 | 1236 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.81, 1.36] |
