Combination Chemotherapy Versus Single-Agent Chemotherapy During Preoperative Chemoradiation For Resectable Rectal Cancer (Review)

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Cochrane Database of Systematic Reviews

Combination chemotherapy versus single-agent chemotherapy
during preoperative chemoradiation for resectable rectal cancer
(Review)
Resende HM, Jacob LFP, Quinellato LV, Matos D, da Silva EMK
Resende HM, Jacob LFP, Quinellato LV, Matos D, da Silva EMK.

Combination chemotherapy versus single-agent chemotherapy during preoperative chemoradiation for resectable rectal
cancer.
Cochrane Database of Systematic Reviews 2015, Issue 10. Art. No.: CD008531.
DOI: 10.1002/14651858.CD008531.pub2.
www.cochranelibrary.com

Combination chemotherapy versus single-agent chemotherapy during preoperative chemoradiation for
resectable rectal cancer (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.

Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 5
OBJECTIVES.................................................................................................................................................................................................. 6
METHODS..................................................................................................................................................................................................... 6
RESULTS........................................................................................................................................................................................................ 8
Figure 1.................................................................................................................................................................................................. 9
Figure 2.................................................................................................................................................................................................. 11
Figure 3.................................................................................................................................................................................................. 12
Figure 4.................................................................................................................................................................................................. 13
Figure 5.................................................................................................................................................................................................. 14
DISCUSSION.................................................................................................................................................................................................. 14
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 15
ACKNOWLEDGEMENTS................................................................................................................................................................................ 15
REFERENCES................................................................................................................................................................................................ 16
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 18
DATA AND ANALYSES.................................................................................................................................................................................... 22
Analysis 1.1. Comparison 1 Combination chemotherapy (intervention) versus single-agent chemotherapy (control), Outcome 24
1 Complete response rate after preoperative chemoradiation (ypCR)..............................................................................................
2 Toxicity - early adverse events G3/4.................................................................................................................................................
3 Postoperative mortality (death within 60 days)..............................................................................................................................
4 Postoperative morbidity....................................................................................................................................................................
5 Metastases intra-abdominal..............................................................................................................................................................
6 Circumferential resection margin - positive status..........................................................................................................................
7 Radiotherapy compliance..................................................................................................................................................................
8 Chemotherapy compliance...............................................................................................................................................................
9 Abdominoperineal resection and Hartmann's procedures.............................................................................................................
ADDITIONAL TABLES.................................................................................................................................................................................... 29
APPENDICES................................................................................................................................................................................................. 31
WHAT'S NEW................................................................................................................................................................................................. 37
HISTORY........................................................................................................................................................................................................ 38
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 38
DECLARATIONS OF INTEREST..................................................................................................................................................................... 38
SOURCES OF SUPPORT............................................................................................................................................................................... 38
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 38
Combination chemotherapy versus single-agent chemotherapy during preoperative chemoradiation for resectable rectal cancer (Review) i
Informed decisions.

[Intervention Review]
Combination chemotherapy versus single-agent chemotherapy during

preoperative chemoradiation for resectable rectal cancer
Heloisa M Resende1, Luiz Felipe Pitzer Jacob2, Luciano Vasconcellos Quinellato2, Delcio Matos3, Edina MK da Silva4
1Post-Graduation Program Emergency Medicine and Evidence Based Medicine of the Federal University of São Paulo (UNIFESP), Escola
Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil. 2Medicine School, Centro Universitário de Volta Redonda,
Volta Redonda, Brazil. 3Department of Gastroenterological Surgery, Escola Paulista de Medicina, Universidade Federal de São Paulo, São
Paulo, Brazil. 4Emergency Medicine and Evidence Based Medicine, Universidade Federal de São Paulo, São Paulo, Brazil
Contact address: Heloisa M Resende, Post-Graduation Program Emergency Medicine and Evidence Based Medicine of the Federal
University of São Paulo (UNIFESP), Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Borges Lagoa 564 cj 64, Vl.
Clementino, São Paulo, 04038-000, Brazil. heloisa.resende@terra.com.br.
Editorial group: Cochrane Colorectal Cancer Group.

Publication status and date: Edited (no change to conclusions), published in Issue 10, 2015.
Citation: Resende HM, Jacob LFP, Quinellato LV, Matos D, da Silva EMK. Combination chemotherapy versus single-agent chemotherapy
during preoperative chemoradiation for resectable rectal cancer. Cochrane Database of Systematic Reviews 2015, Issue 10. Art. No.:
CD008531. DOI: 10.1002/14651858.CD008531.pub2.
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.
Combination chemotherapy versus single-agent chemotherapy during preoperative chemoradiation for resectable rectal cancer (Review) 1
Informed decisions.

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.
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
Informed decisions.

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.
Informed decisions.

SUMMARY OF FINDINGS

Summary of findings for the main comparison. Combination chemotherapy compared with single-agent
chemotherapy for resectable rectal cancer
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 par- Quality of the Comments

(95% CI) ticipants evidence
(studies) (GRADE)
Overall survival HR 0.94 (0.59 to 1.48) 598 ⊕⊝⊝⊝ Limited sample size with 48.8%
(1) very low losses at 3 years' follow-up. ITT
(3 years) analysis
Disease-free survival HR 0.88 (0.65 to 1.18) 598 ⊕⊝⊝⊝ Limited sample size with 48.8%
(1) very low losses at 3 years' follow-up. ITT
(3 years) analysis
Complete response rate after OR 1.23 (1.04 to 1.46) 3875 ⊕⊕⊕⊕ -

preoperative chemoradiation high
(ypCR) (4)
Toxicity - early adverse events OR 2.07 (1.31 to 3.27) 3875 ⊕⊕⊕⊝ Heterogeneity in the analysis
G3/4 (4) moderate
Metastases intra-abdominal OR 0.46 (0.21 to 1.01) 2567 ⊕⊕⊕⊝ Heterogeneity in the analysis
moderate
(3)
Radiotherapy compliance OR 0.32 (0.14 to 0.75) 2567 ⊕⊕⊕⊝ Heterogeneity in the analysis
moderate
(3)
Chemotherapy compliance OR 0.36 (0.26 to 0.52) 1331 ⊕⊕⊕⊕ -

(2) high
CI: confidence interval; HR: hazard ratio; ITT: intention to treat; OR: odds ratio.
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change
the estimate.
Low quality: 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 quality: We are very uncertain about the estimate.
Informed decisions.

BACKGROUND agent chemotherapy during preoperative chemoradiation using

fluoropyrimidine-based chemotherapy. Furthermore, we excluded
Colorectal cancer accounts for 10% of all cancers and is the third trials using biological agents (monoclonal antibodies) such as
most common cause of death among adults (Kamangar 2006). bevacizumab, cetuximab and panitumumab, as these agents have
Rectal cancers represent one-third of cancers of the large bowel different mechanisms of action from the chemotherapy drugs and
and significant research effort has been invested in an attempt to their benefits cannot be analysed together.
achieve better treatment results. The cornerstone of the treatment
is surgery with the technique of total mesorectal excision helping Phase I trials (Freyer 2001), and phase I and II trials (Aschele 2005;
to improve the outcome of locally advanced rectal cancer by Hospers 2007; Rodel 2003; Ryan 2006), tested feasibility and dose
decreasing rates of local recurrence (Wibe 2003). levels of oxaliplatin added to a fluoropyrimidine-based regimen,
and demonstrated that weekly oxaliplatin was active systemically
Until the late 1980s, there was high risk of local and distant and has a manageable profile toxicity.
recurrences after resection of rectal cancer. Since then, the addition
of radiotherapy has been studied extensively in clinical trials, Phase II trials have demonstrated that pathological response
achieving decreases in local recurrence rates of 50% to 60% rates around 14% to 20.9% can be achieved by the addition of
compared with surgery alone (Bosset 2006). In the early 1990s, oxaliplatin to a fluoropyrimidine-based regimen in preoperative
after results of randomised trials had been presented, preoperative chemoradiation (Carlomagno 2009; Gérard 2003; Machiels 2005;
radiotherapy was considered in Europe as standard treatment Rodel 2007). The studies with irinotecan have not been pursued
in rectal cancer T3 and T4 (see Table 1). This was in contrast due to overlapping toxicity of diarrhoea with radiotherapy, 5-
to the US National Institutes of Health recommendations, which fluorouracil and irinotecan.
recommended postoperative chemoradiation (NIH Consensus
Conference 1990). The next phase of treatment development in this Preliminary safety results of phase III trials addressing the role
area was to explore the potential benefit of adding chemotherapy of oxaliplatin in preoperative chemoradiation stage II and III
to radiation and surgery. The Fedération Francophone de rectal cancer have been presented, and their safety profiles were
Cancerologie Digestive (FFCD; France) conducted a trial comparing acceptable and allowed continuation of accrual to the studies.
preoperative chemoradiation with 5-fluorouracil and leucovorin One of them was the ACCORD 12/0405 PRODIGE-2 (Gérard 2008),
bolus with preoperative radiotherapy alone. There were better presented at the ASCO (American Society Clinical Oncology) Annual
rates of local control in the combination arm, although no Meeting in 2008, which compared preoperative radiotherapy (45
improvement in overall survival (Gérard 2006). One subsequent Gy in 25 daily fractions) plus capecitabine to radiotherapy (45
trial by Sauer and colleagues addressed the question of whether Gy in 25 daily fractions) plus oxaliplatin with optional adjuvant
chemoradiation should be given preoperatively or postoperatively chemotherapy. The other trial compared infused concomitant 5-
(Sauer 2004). Once again, there was no impact on overall survival, fluorouracil chemotherapy plus preoperative radiotherapy (50.4 Gy
although preoperative chemoradiation offered better rates of local in 28 daily fractions) to radiotherapy (50.4 Gy in 28 daily fractions)
control, reduced toxicity overall and better sphincter preservation plus weekly oxaliplatin. Both arms were followed by surgery
in the subgroup of people (prior to randomisation) receiving and four cycles of 5-fluorouracil-based adjuvant chemotherapy
abdominoperineal resection (Sauer 2004). Since then, there has (Aschele 2007). Full reports of these two trials became available
been general agreement that chemoradiation should be given during the course of writing this review, and have been included
preoperatively. along with two other phase III trials in the systematic review that
have investigated the role of the addition of oxaliplatin (Aschele
A new question arises about what is the best chemotherapy 2011; Gérard 2010; Gérard 2012; O'Connell 2014; Rödel 2012).
regimen to use in the preoperative management of rectal
cancer. Despite improvements in local control, through the use Description of the condition
of optimal surgery and perioperative fluoropyrimidine-based Rectal cancers are lesions localised of 3 cm to 12 cm from the
chemoradiation, the rates of distant metastases that represent the anal verge, with some variations accepting distances of 15 cm
site of failure for up 30% of people are still unacceptably high. There from the anal verge. The determination of the location of the
is a clinical need for a more effective preoperative chemotherapy boundary between rectum and sigmoid colon is important in
regimen. defining radiotherapy, with the rectum usually being operationally
defined as the area of the large bowel that is at least partially
It has been proposed that better results could be obtained with
retroperitoneal (Libutti 2008). Rectal cancer represents one-third
combination chemotherapy regimens as has been demonstrated in
of cancers of the large bowel and the standard treatment is
metastatic disease, with the addition of other chemotherapy drugs
preoperative treatment with chemoradiation followed by surgery.
to the fluoropyrimidine schedule, such as oxaliplatin (de Gramont
However, the incidence of distant metastases remains high for up
2000), and irinotecan (Saltz 2000).
to 30% of people.
In this systematic review, we examined the effectiveness of
combination chemotherapy versus single-agent chemotherapy Description of the intervention
during preoperative chemoradiation for resectable rectal cancer. Chemoradiation is a combination of external beam radiation
Other strategies have been studied, for example, neoadjuvant given at the same time as chemotherapy (drug treatment).
chemotherapy with oxaliplatin and capecitabine followed by External beam radiation is delivered by radiation machines.
preoperative chemoradiation (Chau 2006), or preoperative Chemoradiation during preoperative treatment is the standard
chemoradiation without fluoropyrimidine in the two arms treatment in resectable rectal cancer (Sauer 2004). Chemotherapy
(Valentini 2008). We excluded these studies, as our focus was can be given in oral form or intravenously in varying schedules.
on the preoperative combination chemotherapy versus single-
Informed decisions.

To date, chemotherapy has generally involved single-agent to) oxaliplatin added to a fluoropyrimidine regimen (including,
fluoropyrimidine (e.g. 5-fluorouracil given by infusion or bolus but not limited, to 5-fluorouracil or capecitabine)).
injection or oral capecitabine). Intravenous 5-fluorouracil and 2. Single-agent combination: radiotherapy plus fluoropyrimidine
oral capecitabine have been considered equivalents in colorectal (e.g. (but not limited to) fluoropyrimidine regimen (including
cancer (Gérard 2010), and we considered this the control arm (but not limited to) 5-fluorouracil or capecitabine).
(single-agent chemotherapy) in randomised controlled trials (RCTs)
and compared it to the same regimens added to a second The types of surgery included: surgery with curative intention. We
chemotherapy drug (combination chemotherapy; the intervention excluded studies using local excision.
arm).
Types of outcome measures
How the intervention might work Primary outcomes
Chemotherapy delivered concurrently with preoperative radiation 1. Overall survival.
exposes the tumour immediately to an active drug and enhances
the effect of radiation (radiation sensitisation). Chemotherapy Secondary outcomes
circulates in the blood stream potentially treating cancer cells
in other parts of the body that may have spread from the 1. Disease-free survival.
primary tumour (micrometastases). Combination chemotherapy 2. Toxicity.
may enhance these effects and lead to better control of the local 3. Local recurrence rate measured within three years.
tumour and more effective treatment of micrometastases leading 4. Pathological complete response rate (ypCR).
to better overall survival. However, there is no evidence that
5. Sphincter preservation rate.
combination chemotherapy actually improves complete response
rate after neoadjuvant treatment (ypCR) and if improving the ypCR 6. Postoperative mortality within 60 days.
rate translates into better overall survival and disease-free survival. 7. Postoperative morbidity within 60 days.
8. Anastomotic leak rate.
Why it is important to do this review 9. Treatment compliance (rate of patients that complete
This review is important because we evaluated whether there treatment).
were any improvements in patient outcomes (including overall 10.Clinical response rate (tumour down staging).
survival rates) by the addition of another chemotherapy drug to 5-
fluorouracil. If there is no advantage in combination chemotherapy Search methods for identification of studies
during preoperative chemoradiation, this systematic review can We searched for studies in electronic bibliographic databases,
help by minimising the costs and adverse effects of combination references lists of included studies and books. We applied no
chemotherapy. language restrictions.
OBJECTIVES Electronic searches
To compare outcomes (including overall survival, disease-free We conducted a comprehensive literature search to identify
survival and toxicity) between two 5-fluorouracil-containing all published and unpublished RCTs with no language or time
chemotherapy regimens in people with stage II and III rectal cancer restrictions. We searched the following electronic databases to
who are receiving preoperative chemoradiation. identify possible studies:
METHODS 1. Cochrane Colorectal Cancer Group Specialised Register

(January 2015);
Criteria for considering studies for this review 2. The Cochrane Central Register of Controlled Trials (CENTRAL;
Types of studies 2015, Issue 1, Appendix 1);
3. Ovid MEDLINE 1950 to January 2015 (Appendix 2);
All parallel RCTs of preoperative chemoradiation for resectable
4. Ovid EMBASE 1974 to January 2015 (Appendix 3);
rectal cancer comparing combination regimen (fluoropyrimidine
based) versus single agent (fluoropyrimidine alone). We excluded 5. LILACS 1982 to January 2015 (Appendix 4).
trials comparing combination chemotherapy including biological
We searched for ongoing trials in the Current Controlled Trials web
agents.
site (www.controlled-trials.com/).
Types of participants
Searching other resources
People with resectable stage II and III rectal cancer undergoing
We searched non-indexed publications, newsletters and abstracts
preoperative chemoradiation followed by surgery.
presented at major meetings including ASCO (American Society
Types of interventions of Clinical Oncology) and ESMO (European Society for Medical
Oncology) from 2008 to January 2015.
Preoperative chemoradiation with single-agent chemotherapy or
combination chemotherapy. Data collection and analysis
1. Combination chemotherapy: radiotherapy plus Two review authors (HMR and EMKS) selected possible RCTs,
fluoropyrimidine plus an additional drug(s) (e.g. (but not limited analysed and considered them for inclusion, assessed their risk
Informed decisions.

of bias and graded them for their methodological quality. We Dealing with missing data
resolved disagreements by consulting the Cochrane Handbook for
For missing or unavailable data, we had planned to contact the
Systematic Reviews of Interventions (Higgins 2011), and discussing
study authors for additional information, but for this version of
the differences in order to try to reach a consensus. If there
the review, it was not necessary because all data were available.
were persistent disagreements, we consulted a third review author
We reported drop-out rates in the Characteristics of included
(DM). We also used the Cochrane Handbook for Systematic Reviews
studies table and used an intention-to-treat (ITT) analysis. For
of Interventions to assess quality (Higgins 2011), and used The
this, all eligible participants randomised was used as total and
Cochrane Collaboration's tool for assessing risk of bias to analyse
we considered that all missing participants did not experience the
the quality of each study.
event (Higgins 2011).
Selection of studies
Assessment of heterogeneity
Two review authors (HMR and DM) performed a non-blinded
We qualified inconsistency among the pooled estimates using
selection of the studies (Appendix 5). In case of any disagreement,
we contacted a third review author (EMKS) until we reached a the I2 statistic (where I2 = ((Q - df)/Q) x 100% where Q was the
consensus. Chi2 statistic, and df represented the degrees of freedom). This
illustrated the percentage of the variability in effect estimates
Data extraction and management resulting from heterogeneity rather than sampling error (Higgins
2011).
We used an electronic data collection form (Appendix 6) and two
review authors (EMKS and LFPJ) independently extracted the data. Assessment of reporting biases
A third review author (HMR) checked and entered the data into
Review Manager 5 (RevMan 2014), and another review author We did not evaluate reporting biases/small-study effects by
(EMKS) checked for data entry errors. drawing a funnel plot (trial effect versus trial size), because there
was an insufficient number of studies. In subsequent updates, we
Assessment of risk of bias in included studies will perform these assessments if we included a sufficient number
of studies (more than 10) in the review.
We used The Cochrane Collaboration's tool for assessing risk of bias
described in Table 8.5.d of the Cochrane Handbook for Systematic Data synthesis
Reviews of Interventions (Higgins 2011). We assessed the risk of bias
of the following domains: 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
1. random sequence generation; absence of substantial heterogeneity (I2 less than 50%), otherwise
2. allocation concealment; we used a random-effects model (I2 greater than 50%).
3. blinding of participants and personnel;
Subgroup analysis and investigation of heterogeneity
4. blinding of outcome assessment;
5. incomplete outcome data; In subsequent updates of this review, we will analyse the following
subgroups if further trials become available:
6. selective reporting bias; and
7. other bias (e.g. differences in study design). 1. stage (stage II and stage III);
2. chemotherapy strategy (people receiving fluoropyrimidine
We judged each domain as low risk, high risk or unclear risk of bias
plus oxaliplatin versus fluoropyrimidine plus another drug
according to criteria stated in The Cochrane Collaboration's 'Risk of
chemotherapy);
bias' tool (see Appendix 7) (Chapter 8.5.d, Higgins 2011).
3. adjuvant treatment or not; adjuvant treatment with oxaliplatin
Measures of treatment effect plus fluoropyrimidine versus fluoropyrimidine alone;
4. doses and schedule of 5-fluorouracil.
For dichotomous outcomes, we used the odds ratio (OR) and
for continuous data, we calculated mean differences between Sensitivity analysis
treatment groups if studies reported exactly the same outcomes. If
similar outcomes were reported on different scales, we calculated We performed a sensitivity analysis with the worst-case scenario
the standardised mean difference. For time-to-event data, we used with all eligible randomised participants as total. We assumed
methods of survival analysis and expressed the intervention effect that all participants with missing outcomes in the intervention
as a hazard ratio (HR). In all analyses, we calculated the 95% group had poor outcomes, and all those with missing outcomes in
confidence interval (CI). the control intervention group had good outcomes. There was no
significant differences in the results.
Unit of analysis issues
In subsequent updates of this review, if there are an adequate
The unit of analysis was based on the individual participant (unit to number of studies, we will perform a sensitivity analysis to explore
be randomised for interventions to be compared; i.e. the number the causes of any heterogeneity in the analysis and the robustness
of observations in the analysis should match the number of people of the results.
randomised).
Summary of findings
We assessed the quality of evidence of combination chemotherapy
compared with single-agent chemotherapy for resectable rectal
Informed decisions.

cancer using the GRADE approach (Grading of Recommendations The GRADE system classifies the quality of evidence in one of four
Assessment, Development and Evaluation) in 'Summary of grades.
findings' table(s) (Higgins 2011).

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 ef-
fect 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 full paper copies for six citations that were potentially eligible for
inclusion in the review. Of these six citations, five articles reporting
Description of studies four trials fulfilled our inclusion criteria. Therefore, we included
four trials in this review (Aschele 2011; Gérard 2010; Gérard
See Characteristics of included studies and Characteristics of
2012; O'Connell 2014; Rödel 2012; see Characteristics of included
excluded studies tables
studies). We excluded one study (Wong 2012; see Characteristics of
Results of the search excluded studies).
We identified 1601 citations from the database searches and other

sources (Figure 1). After screening by title and abstract, we obtained

Informed decisions.

Figure 1. Study flow diagram.

Included studies 2012), and one publication (Gérard 2012) reported subsequent
clinical outcomes of one of these trials (Gérard 2010).
We included four RCTs reported in five articles with 3875
participants in this review (Aschele 2011; Gérard 2010; Gérard 2012; Types of participants
O'Connell 2014; Rödel 2012). Four publications reported the initial
results of RCTs (Aschele 2011; Gérard 2010; O'Connell 2014; Rödel The inclusion criteria of the studies were people with
histologically confirmed adenocarcinoma of the rectum,
Informed decisions.

resectable without distant metastases suitable to receive day) given throughout the period of radiotherapy, which consisted
preoperative chemoradiation regimens comparing single- of 50.4 Gy in 28 daily fractions, over a period of approximately six
agent chemotherapy versus combination chemotherapy during weeks in both arms (Aschele 2011). In one trial, the control group
preoperative chemoradiation. Aschele 2011 included people received preoperative radiotherapy (50.4 Gy) plus a 5-fluorouracil
with resectable, locally advanced (cT3-4 or cN1-2, or both) infusion (1000 mg/m2 on days one to five and 29 to 33), followed by
adenocarcinoma of the mid-low rectum, with tumour located surgery and four cycles of bolus 5-fluorouracil (500 mg/m2 on days
within 12 cm from the anal verge, World Health Organization one to five and 29) (Rödel 2012). The intervention group received
(WHO) performance status 0 to 2, and aged 75 years or less. preoperative radiotherapy (50.4 Gy) plus 5-fluorouracil infusions
Gérard 2010/Gérard 2012 included people with histologically (250 mg/m2 on days one to 14 and 22 to 35) and oxaliplatin (50
confirmed stage T3 or resectable, T4 rectal adenocarcinoma with mg/m2 on days one, eight, 22 and 29), followed by surgery and
no evidence of distant metastases, and aged 80 years or less
eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m2
with WHO performance status 0 or 1. Rödel 2012 included people
on days one and 15), leucovorin (400 mg/m2 on days one and 15)
with histopathologically confirmed rectal carcinoma (cT3-4 or cN
+ adenocarcinoma), inferior margin no more than 12 cm above and 5-fluorouracil infusions (2400 mg/m2 on days one, two, 15 and
the anal verge, aged 18 years or older, and Eastern Cooperative 16). In O'Connell 2014, participants were randomly assigned to one
Oncology Group (ECOG) performance status 2 or lower. O'Connell of the following chemotherapy regimens: continuous intravenous
2014 included people with clinical stage II or III rectal cancer who infusional fluorouracil (CVI FU; 225 mg/m2, five days per week), with
were undergoing preoperative chemoradiation. Participants were or without intravenous oxaliplatin (50 mg/m2 once per week for five
required to be at least 18 years old with an ECOG performance score weeks) or oral capecitabine (825 mg/m2 twice per day, five days per
of 0 to 1 and a life expectancy of five years. The tumour had to week), with or without oxaliplatin (50 mg/m2 once per week for five
be confirmed to be stage II (T3-4N0) or stage III (T1-4N1-2, with a weeks).
positive node defined as at least 1.0 cm in diameter on imaging.
There must have been no evidence of metastatic disease. Types of outcome measures
All included trials analysed secondary outcomes: early toxicity,
Types of intervention
treatment compliance, intra-abdominal metastases, postoperative
The four studies randomised 3875 people to either a control mortality and morbidity, type of surgery and circumferential
group (fluoropyrimidine-based chemotherapy) or an intervention margin status. Only one trial reported overall survival, disease-
group (fluoropyrimidine-based chemotherapy in combination with free survival, local and distant recurrence, bowel function and
oxaliplatin); both arms received radiotherapy. The radiotherapy social life disturbance (Gérard 2012), and sphincter preservation
schedules were similar, with some variations in doses. In one study, rate (O'Connell 2014).
the fluoropyrimidine used was capecitabine; one arm received
five weeks' treatment with radiotherapy (45 Gy/25 fractions) and Excluded studies
concurrent capecitabine (800 mg/m2 twice daily, five days per We excluded one study because it was a phase II clinical trial and
week) and the other arm received radiotherapy (50 Gy/25 fractions) there was no comparator group with fluoropyrimidine alone (Wong
with capecitabine (800 mg/m2 twice daily five days per week) 2012).
and oxaliplatin (50 mg/m2 once weekly) (Gérard 2010; Gérard
2012). One trial randomised people into two very similar arms, Risk of bias in included studies
except for the inclusion of oxaliplatin in the intervention arm. The
See Figure 2 and Figure 3.
fluoropyrimidine chosen was a 5-fluorouracil infusion (225 mg/m2/

Informed decisions.

Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.

Informed decisions.

Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation Incomplete outcome data
All studies described randomisation by computer program and Altogether, the losses were 128/3875 (3.3%). We have not contacted
central allocation. the authors because all studies reported the losses to follow-up,
allowing us to conduct an ITT analysis, and undertake worst-case
Blinding scenario sensitivity analyses.
Three trials did not mention blinding but were probably open
Selective reporting
studies (Aschele 2011; Gérard 2010; O'Connell 2014). One study
stated that there was no blinding due to different treatment The four trials described outcomes planned by the authors. In
schedules (Rödel 2012). 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).
Informed decisions.

Other potential sources of bias 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).
The differences in design trial can represent a source of bias: one
study used slightly different radiotherapy doses in the two arms Secondary outcomes
(45 Gy in the control arm and 50 Gy in the intervention group)
(Gérard 2010); one study used a different 5-fluorouracil schedule Disease-free survival
and different adjuvant regimens in the two arms (Rödel 2012). One RCT reported no significant difference between control and
intervention groups in three-year disease-free survival (67.9% with
Effects of interventions control versus 72.7% with intervention; HR 0.88, 95% CI 0.65 to 1.18)
See: Summary of findings for the main comparison Combination (Gérard 2012).
chemotherapy compared with single-agent chemotherapy for
resectable rectal cancer Toxicity
All four RCTs reported toxicity. The toxicity was graded based on
For the meta-analysis, we separated the outcomes of Rödel the National Cancer Institute's Common Terminology Criteria for
2012 from other trials because fluoropyrimidine doses were quite Adverse Events (NCI 2009): G1 refers mild symptoms, G2 refers
different between the two groups: 250 mg/m2 in the intervention to moderate, G3 refers to severe, G4 refers to life-threatening
group versus 1000 mg/m2 in the control groups. When there was consequences and G5 refers to death-related adverse events. There
significant heterogeneity between subgroups, we considered only were significantly more G3/4 adverse events in the intervention
the subtotals. If there was no heterogeneity, we pooled data in groups (with oxaliplatin) (OR 2.07, 95% CI 1.31 to 3.27; P value
the meta-analyses. We analysed data according to ITT (i.e. the = 0.005; four studies; 3875 participants; Analysis 1.2; Figure 4).
total number of randomised participants, regardless of the losses This analysis showed heterogeneity between studies (I2 = 87.4%).
described in Characteristics of included studies). One study reported no significant differences between groups
(Rödel 2012); this may have been due to the different doses of
Primary outcomes
5-fluorouracil, as, unlike the other trials, this trial used higher
Overall survival fluorouracil doses in the control arm compared to the intervention
arm. The main adverse events were diarrhoea and vomiting.
Only one study reported overall survival (Gérard 2012). There were
no significant differences between the control and intervention

Figure 4. 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 Pathological complete response rate
One study reported no significant difference between control and All four RCTs reported ypCR. In the meta-analysis, there was a
intervention groups in the cumulative incidence of local recurrence significant difference favouring the intervention group (OR 1.23,
(6.1% with control versus 4.4% with intervention), and in the 95% CI 1.04 to 1.46; P value = 0.02; four studies; 3875 participants;
number of distant metastasis (24.4% with control versus 22.1% with Analysis 1.1; Figure 5). The number needed to treat for an additional
intervention) (Gérard 2012). beneficial outcome (NNTB) for ypCR was 35.0 (95% CI 19.2 to 188,7).
There was no heterogeneity in subgroups analysis.
Informed decisions.


Figure 5. 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 Clinical response rate
Only O'Connell 2014 reported sphincter preservation rate and there None of the studies reported clinical response rate.
was no statistically significant difference between intervention and
control group in the rate of surgery with sphincter preservation (OR Other outcomes
0.87, 95% CI 0.70 to 1.09, P value = 0.24). The three trials reported intra-abdominal metastases (OR 0.46, CI
95% 0.21 to 1.01; Analysis 1.5); circumferential resection margin
Postoperative mortality and morbidity within 60 days
status (positive 1 mm or less: OR 0.76, 95% CI 0.52 to 1.09; Analysis
Postoperative mortality was equally low in control and intervention 1.6) and rate of abdominoperineal resection and Hartmann's
arms of the four RCTs with no statistically significant differences procedures that led to permanent stoma, with no significant
(OR 1.01, 95% CI 0.47 to 2.19; Analysis 1.3). Similarly, there was differences between groups (OR 0.97, 95% CI 0.81 to 1.17; Analysis
no significant difference between the groups in postoperative 1.9).
morbidity (OR 1.07, 95% CI 0.94 to 1.23; Analysis 1.4). There was no
heterogeneity between subgroups in either analysis. DISCUSSION
Anastomotic leak rate Summary of main results

Only one study reported anastomotic leak rate (Rödel 2012). The This review identified four RCTs that investigated the role of
rate was 5% with control and 7% with intervention. combination chemotherapy (which all used oxaliplatin in the
intervention arms) in neoadjuvant treatment for people with
Compliance resectable rectal cancer. These trials included 3875 participants
Three studies reported the rate of treatment compliance (Aschele and had similar designs with small differences in radiotherapy
2011; Gérard 2010; Rödel 2012). Participants allocated to the doses, fluoropyrimidine schedule and adjuvant regimens.
control groups received more full doses of radiotherapy than
Only one trial provided data for the primary outcome of this review
participants allocated to the intervention group (OR 0.32, 95%
(Gérard 2010), in a second publication (Gérard 2012). According
CI 0.14 to 0.75; Analysis 1.7). However, this finding should be
to this trial, at three years of follow-up, there were no benefits
interpreted with caution because of the heterogeneity between
in the cumulative incidence of local recurrence, overall survival
studies (I2 = 74%). or disease-free survival. However, it is important to note that
Chemotherapy compliance was also significantly better in the although survival data were calculated based on ITT, there were
control group when trials using the same dose of 5-fluorouracil considerable losses to follow-up (48.8% censured data), but these
in both arms were combined (OR 0.36, 95% CI 0.26 to 0.52; two losses were equivalent in both arms of the study. Survival data from
studies; 1331 participants). In the one study that used different ongoing RCTs will probably help to clarify the role of oxaliplatin
5-fluorouracil doses in the two arms (Rödel 2012), there were no in preoperative chemoradiation for people with rectal cancer
significant differences between groups (Analysis 1.8). The higher (Aschele 2011; O'Connell 2014; Rödel 2012;. We will update this
fluorouracil doses in the control arm compared to the intervention systematic review and meta-analyses when these survival data
arm may be responsible for the lack of difference in the compliance become available.
between the two arms.
Informed decisions.

ypCR has been used as a surrogate for clinical outcomes, but it is not Quality of the evidence
fully accepted. There are two retrospective studies that compared
survival data between complete responders and incomplete The studies included in this review had a very low to moderate risk
responders and found benefit for the complete responders (Martin of bias. Although they were not double blinded, the study outcomes
2012; Zorcolo 2012), but there are no prospective trials that were objective and unlikely to have been influenced by lack of
corroborate this hypothesis. The meta-analysis found a significant blinding.
difference favouring the intervention group, according to the
Potential biases in the review process
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 We believe that we have prevented bias in the review process by
proposed by Aschele 2011 (8%) and Gérard 2010 (9%), or ypCR rates adopting a strategy where two review authors were independently
as 28% according early phase trials (Aschele 2005). The effect found involved in each step of the review and performed a comprehensive
might have been obtained due to the increase in the sample size, search for articles with no language restriction.
and, therefore, the power to detect a difference between groups.
The number needed to treat for an additional beneficial outcome Agreements and disagreements with other studies or
(NNTB) was 35.0 (95% CI 19.2 to 188,7). Although there was a reviews
statistically significant difference on ypCR favouring intervention
arm, there were significantly more G3/4 early adverse events, There is another systematic review analysing short-term results
mainly diarrhoea and vomiting, in the trials that used the same of neoadjuvant chemoradiation with fluoropyrimidine alone or in
dose of fluoropyrimidine in both groups (OR 2.53, 95% CI 1.60 to combination with oxaliplatin in advanced rectal cancer (An 2013).
4.00) (Aschele 2011; Gérard 2010; O'Connell 2014). These high rates This review included the same trials as our review, but analysed
of early toxicity were probably responsible for the lower treatment only short-term outcomes, without discussing survival outcomes.
compliance in this group. In addition, An 2013 included one trial before a full report was
available (O'Connell 2014). There is agreement in the findings of the
Oxaliplatin did not increase early mortality or the rate two reviews related to the outcomes as yet reported; our review will
of postoperative complications. Postoperative mortality and be up dated when survival data become available.
morbidity were equally low in the intervention and control arms
(OR 1.01, 95% CI 0.47 to 2.19 for postoperative mortality; OR AUTHORS' CONCLUSIONS
1.07, 95% CI 0.94 to 1.23 for postoperative morbidity). There are
uncertainties about whether the sample sizes were suitably large to
Implications for practice
detect a difference due to oxaliplatin in these trials. There was very low quality evidence that people with
resectable rectal cancer who received combination preoperative
There were no significant differences in the rate of participants chemotherapy had no improvements in overall survival or disease-
with intra-abdominal metastases detected perioperatively after free survival. There was high quality evidence that combination
preoperative chemoradiation with oxaliplatin (OR 0.46, 95% CI 0.21 chemotherapy with oxaliplatin may improve local tumour control
to 1.01; P value = 0.05). Given the upper CI was 1.00, there is also in people with resectable rectal cancer but it also caused more
uncertainty as to whether the simple size was too small to detect toxicity. The review included four randomised controlled trials but
a difference between groups, rather than a difference between only one reported on survival; therefore, we could not draw robust
groups not being present. conclusions or useful clinical recommendations. The publication of
more survival data from ongoing studies will contribute to future
Overall completeness and applicability of evidence
analyses.
The control and intervention arms were very similar in three trials
in preoperative treatment except for the inclusion of oxaliplatin Implications for research
(Aschele 2011; Gérard 2010; O'Connell 2014). Rödel 2012 presented The full results of three studies will help to clarify the role
different doses and schedule of 5-fluorouracil, but besides that, all of oxaliplatin in preoperative chemoradiation for people with
four trials were comparable in neoadjuvant treatment and allowed resectable rectal cancer (Aschele 2011; O'Connell 2014; Rödel
the analysis oxaliplatin effect on ypCR. 2012).
At present, there are insufficient data on the most important clinical
ACKNOWLEDGEMENTS
outcomes (overall survival and disease-free survival). Therefore, it
is not possible to establish the role of oxaliplatin in preoperative We would like to thank The Cochrane Collaboration, in particular
chemoradiation for people with rectal cancer. The publication of the Managing Editor, Henning Keinke Andersen, for the opportunity
follow-up data from three trials will help to clarify this question to undertake this research.
(Aschele 2011; O'Connell 2014; Rödel 2012).
Informed decisions.

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Informed decisions.


CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Aschele 2011
Methods Randomised phase III trial, multicentric
Participants People with resectable, locally advanced (cT3-4 or cN1-2, or both) adenocarcinoma of the mid-low rec-
tum (with tumour located within 12 cm from the anal verge), WHO performance status 0-2, and aged ≤
75 years
Interventions Control: 377 participants assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and con-
comitant infused 5-fluorouracil (225 mg/m2/day)
Intervention: 362 participants assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and
concomitant infused 5-fluorouracil (225 mg/m2/day) plus oxaliplatin (60 mg/m2 weekly for 6 weeks)
All participants underwent total mesorectal excision 6-8 weeks after the end of chemoradiation
Outcomes Treatment compliance, acute toxicity, type of surgery, macroscopic residual disease, intra-abdominal
metastases, intraoperative complications, postoperative complications, mortality within 60 days, tu-
mour diameter, ypT-stage, examined lymph nodes, ypN-stage, tumour regression grade (0-1-2 or 3 or 4
= ypCR), resection status, circumferential resection margin
Notes Total losses at endpoint: 38 (5.1%) participants: 19 control and 19 intervention
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk Use of permuted blocks of variable size. Stratification was done by centre and
tion (selection bias) cancer stage (T4 or N1-2 (or both) vs. T3N0)
Allocation concealment Low risk Random assignment was centrally performed

(selection bias)
Blinding of participants High risk Comment: no information provided. Probably open study
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk Comment: no information provided. Probably open study
sessment (detection bias)
All outcomes
Incomplete outcome data Low risk Losses of 38 (5.1%). ITT analysis

(attrition bias)
All outcomes
Selective reporting (re- Low risk All outcomes were reported

porting bias)
Other bias Low risk Comment: the study appeared to be free of other source of bias

Gérard 2010
Informed decisions.

Gérard 2010 (Continued)
Participants People with histologically confirmed stage T3 or resectable, T4 rectal adenocarcinoma accessible to
digital rectal examination and with no evidence of distant metastases, and aged ≤ 80 years with WHO
performance status 0 or 1
Interventions Control: 293 participants underwent radiotherapy (45 Gy) once daily 5 days/week concurrent with oral
capecitabine (800 mg/m2) twice daily 5 days/week in weeks 1-5
Intervention: 291 participants underwent radiotherapy (50 Gy) and concurrent with oral capecitabine
(800 mg/m2) twice daily 5 days/week in weeks 1-5 plus oxaliplatin (50 mg/m2) once weekly in weeks 1-5
All participants underwent total mesorectal excision 6 weeks after completion of chemoradiation
Outcomes Compliance treatment, early adverse events, type of surgery, blood loss, metastases found at surgery,
second surgery for toxicity, medical postoperative toxicity, median hospital stay, postoperative mortal-
ity within 60 days, operative total mesorectal excision specimen, gross incomplete R2 resection, medi-
an gross tumour diameter, ypT-stage, median number of sampled lymph nodes, ypN-stage, circumfer-
ential rectal margin, Dworak score (0 = no response, 1 = partial response, 2 = major response, 3 = com-
plete response = ypCR)
Notes Total losses at endpoint: 19 participants (3.2%): 11 control and 8 intervention
Risk of bias
Random sequence genera- Low risk Randomisation done centrally with stratification performed by centre, sex,
tion (selection bias) stage (cT2, cT3, cT4) and distance from anal verge (< 6 vs. > 6 cm)
Allocation concealment Low risk Random assignment was performed centrally

(selection bias)
mance bias)
All outcomes
All outcomes

(attrition bias)
All outcomes
Selective reporting (re- Low risk All outcomes are recorded

porting bias)
Other bias Low risk Different radiotherapy doses in control (45 Gy) and intervention (50 Gy) arms

Gérard 2012
Methods See Gérard 2010
Participants See Gérard 2010
Interventions See Gérard 2010
Informed decisions.

Gérard 2012 (Continued)
Outcomes Local recurrence, distant metastasis, 3-year overall survival and disease-free survival, toxicity, bowel
continence, erectile dysfunction, social life disturbance
Notes
Risk of bias
Random sequence genera- Low risk See Gérard 2010

tion (selection bias)
Allocation concealment Low risk See Gérard 2010

(selection bias)
Blinding of participants High risk See Gérard 2010

mance bias)
All outcomes
Blinding of outcome as- High risk See Gérard 2010

All outcomes
Incomplete outcome data High risk Losses of 292 (48.8%) at endpoint (3 years of follow-up), 153 participants in
(attrition bias) each arm. ITT analysis
All outcomes
Selective reporting (re- Low risk See Gérard 2010

porting bias)
Other bias Low risk See Gérard 2010

O'Connell 2014
Participants People with clinical stage II or III rectal cancer who were undergoing preoperative chemoradiation.
Participants aged ≥ 18 years old with an Eastern Cooperative Oncology Group performance score of
0-1 and a life expectancy of 5 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
Interventions Participants were randomly assigned to 1 of the following chemotherapy regimens: continuous intra-
venous infusional fluorouracil (225 mg/m2, 5 days per week), with or without intravenous oxaliplatin
(50 mg/m2 once per week for 5 weeks) or oral capecitabine (825 mg/m2 twice per day, 5 days per week),
with or without oxaliplatin (50 mg/m2 once per week for 5 weeks). Participants received 45 Gy in 25
fractions over 5 weeks plus a boost of 5.4 Gy to 10.8 Gy in 3-6 daily fractions
Intervention group: 655 participants
Control group: 653 participants
Outcomes ypCR, sphincter-sparing surgery, and surgical down staging (conversion to sphincter-sparing surgery)
Informed decisions.

O'Connell 2014 (Continued)
Notes NSABPR-04 trial began in July 2004, and participants were randomly assigned to receive either radio-
therapy plus fluorouracil (group 1) or radiotherapy plus capecitabine (group 2). In October 2005, the
protocol was amended to add oxaliplatin during radiotherapy, creating a 2 x 2 factorial design with 4
treatment groups. We included only the after amendment participants
Risk of bias
Random sequence genera- Low risk Participants were stratified by institution, sex, intended operative procedure
tion (selection bias) (sphincter-saving surgery or non-sphincter-saving surgery), and clinical tu-
mour stage (stage II (T3-4N0) or stage III (T1-4N1-2)). Participants were ran-
domly assigned to treatment groups using the NSABP biased-coin minimisa-
tion algorithm
Allocation concealment Low risk Random assignment was performed centrally

(selection bias)
mance bias)
All outcomes
All outcomes
Incomplete outcome data Low risk Losses 32/1308 (2.4%)

(attrition bias)
All outcomes
Selective reporting (re- Low risk All outcomes were reported

porting bias)
Other bias Low risk Comment: the study appeared to be free of other source of bias

Rödel 2012
Participants People with histopathologically confirmed rectal carcinoma (cT3-4 or cN+ adenocarcinoma), inferior
margin no more than 12 cm above the anal verge, accessible by rigid proctoscopy, aged ≥ 18 years, and
Eastern Cooperative Oncology Group performance status ≤ 2
Interventions Control: 623 participants underwent preoperative radiotherapy 50.4 Gy plus infusional 5-fluorouracil
(1000 mg/m2 days 1-5 and 29-33) followed by total mesorectal excision and 4 cycles of bolus 5-fluo-
rouracil (500 mg/m2 days 1-5 and 29)
Intervention: 613 participants underwent preoperative radiotherapy of 50.4 Gy plus infusional 5-fluo-
rouracil (250 mg/m2 days 1-14 and 22-35) and oxaliplatin (50 mg/m2 days 1, 8, 22 and 29), followed by
total mesorectal excision and 8 cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m2 days 1
and 15), leucovorin (400 mg/m2 days 1 and 15) and infusional 5-fluorouracil (2400 mg/m2 days 1-2 and
15-16)
Outcomes Adverse events, treatment compliance, type of surgery, postoperative morbidity (overall complica-
tions, second surgery for complications and postoperative mortality), grading of operative specimen,
completeness of local tumour resection, circumferential resection margin, pathological stage; num-
Informed decisions.

Rödel 2012 (Continued)
ber of lymph nodes examined, tumour regression grade (0 = no regression, 1 = minimal regression, 2 =
moderate regression, 3 = major regression, 4 = total regression = ypCR)
Notes Total losses at endpoint: 68 participants (3.1%): 17 control and 22 intervention
Risk of bias
Random sequence genera- Low risk Randomisation was done centrally using computer-generated randomisation
tion (selection bias) codes (sequential permuted clocks)
Allocation concealment Low risk Participants assignment implemented through a fax interface and web inter-
(selection bias) face hosted by the Department of Medical Informatics, Biometry and Epidemi-
ology, University of Erlangen (Erlangen, Germany), ensuring that the next as-
signment in the sequence was masked
Blinding of participants High risk Open study

mance bias)
All outcomes
Blinding of outcome as- High risk Open study

All outcomes

(attrition bias)
All outcomes
Selective reporting (re- Low risk All outcomes were recorded

porting bias)
Other bias High risk Different 5-fluorouracil schedule between the intervention and control group.
Intervention group: 1000 mg /m2 on days 1-5 and 29-33 of radiotherapy; con-
trol group: 250 mg/m2 on days 1-14 and 22-35 and a 2-hour infusion of oxali-
platin 50 mg/m2 on days 1, 8, 22 and 29
ITT: intention to treat; WHO: World Health Organization; ypCR: pathological response; ypN:pathological nodal stage ; ypT: pathological
tumour stage.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Wong 2012 Phase II study, absence of comparator arm (radiotherapy vs. fluoropyrimidine alone)

DATA AND ANALYSES

Informed decisions.

Comparison 1. Combination chemotherapy (intervention) versus single-agent chemotherapy (control)
Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
1 Complete response rate after preoperative 4 3875 Odds Ratio (M-H, Fixed, 95% CI) 1.23 [1.04, 1.46]
chemoradiation (ypCR)
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-fluo- 1 1236 Odds Ratio (M-H, Fixed, 95% CI) 1.35 [0.99, 1.85]
rouracil 250 mg/m2 + oxaliplatin
2 Toxicity - early adverse events G3/4 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-fluo- 1 1236 Odds Ratio (M-H, Random, 95% CI) 1.16 [0.88, 1.52]
3 Postoperative mortality (death within 60 4 3875 Odds Ratio (M-H, Fixed, 95% CI) 1.01 [0.47, 2.19]
days)
4 Postoperative morbidity 4 3875 Odds Ratio (M-H, Fixed, 95% CI) 1.07 [0.94, 1.23]
5 Metastases intra-abdominal 3 2567 Odds Ratio (M-H, Random, 95% CI) 0.46 [0.21, 1.01]
6 Circumferential resection margin - positive 3 2567 Odds Ratio (M-H, Fixed, 95% CI) 0.76 [0.52, 1.09]
status
7 Radiotherapy compliance 3 2567 Odds Ratio (M-H, Random, 95% CI) 0.32 [0.14, 0.75]
Informed decisions.

Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
8 Chemotherapy compliance 3 Odds Ratio (M-H, Random, 95% CI) Subtotals only
9 Abdominoperineal resection and Hartmann's 3 2567 Odds Ratio (M-H, Fixed, 95% CI) 0.97 [0.81, 1.17]
procedures

Analysis 1.1. Comparison 1 Combination chemotherapy (intervention) versus single-agent
chemotherapy (control), Outcome 1 Complete response rate after preoperative chemoradiation (ypCR).
Study or subgroup Intervention Control Odds Ratio Weight Odds Ratio
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
1.1.1 Fluoropyrimidine same dose in both group
Gérard 2010 55/291 40/293 13.52% 1.47[0.95,2.3]
Aschele 2011 62/368 59/379 20.22% 1.1[0.74,1.62]
O'Connell 2014 125/655 113/653 38.3% 1.13[0.85,1.49]
Subtotal (95% CI) 1314 1325 72.04% 1.18[0.97,1.45]
Total events: 242 (Intervention), 212 (Control)
Heterogeneity: Tau2=0; Chi2=1.19, df=2(P=0.55); I2=0%
Test for overall effect: Z=1.64(P=0.1)

1.1.2 5-Fluorouracil 1000 mg/m2 vs. 5-fluorouracil 250 mg/m2 + oxali-
platin
Rödel 2012 103/613 81/623 27.96% 1.35[0.99,1.85]
Subtotal (95% CI) 613 623 27.96% 1.35[0.99,1.85]
Heterogeneity: Not applicable

Total (95% CI) 1927 1948 100% 1.23[1.04,1.46]
Test for subgroup differences: Chi2=0.48, df=1 (P=0.49), I2=0%
Favours control 0.01 0.1 1 10 100 Favours intervention

Informed decisions.

Analysis 1.2. Comparison 1 Combination chemotherapy (intervention) versus single-

agent chemotherapy (control), Outcome 2 Toxicity - early adverse events G3/4.
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
Aschele 2011 85/368 29/379 22.97% 3.62[2.31,5.68]
Gérard 2010 74/291 32/293 22.92% 2.78[1.77,4.37]
O'Connell 2014 258/655 175/653 27.38% 1.78[1.41,2.24]
Subtotal (95% CI) 1314 1325 73.28% 2.53[1.6,4]
Heterogeneity: Tau2=0.13; Chi2=9.01, df=2(P=0.01); I2=77.81%
Test for overall effect: Z=3.98(P<0.0001)

platin
Rödel 2012 140/613 127/623 26.72% 1.16[0.88,1.52]
Subtotal (95% CI) 613 623 26.72% 1.16[0.88,1.52]

Total (95% CI) 1927 1948 100% 2.07[1.31,3.27]
Heterogeneity: Tau2=0.19; Chi2=23.11, df=3(P<0.0001); I2=87.02%
Test for overall effect: Z=3.1(P=0)
Test for subgroup differences: Chi2=8.34, df=1 (P=0), I2=88.01%
Favours intervention 0.01 0.1 1 10 100 Favours control

agent chemotherapy (control), Outcome 3 Postoperative mortality (death within 60 days).
Gérard 2010 1/291 1/293 7.74% 1.01[0.06,16.17]
Aschele 2011 3/368 3/379 22.84% 1.03[0.21,5.14]
O'Connell 2014 6/655 5/653 38.66% 1.2[0.36,3.95]
Subtotal (95% CI) 1314 1325 69.24% 1.12[0.45,2.77]

platin
Rödel 2012 3/613 4/623 30.76% 0.76[0.17,3.41]
Subtotal (95% CI) 613 623 30.76% 0.76[0.17,3.41]

Total (95% CI) 1927 1948 100% 1.01[0.47,2.19]
Informed decisions.



Analysis 1.4. Comparison 1 Combination chemotherapy (intervention) versus
single-agent chemotherapy (control), Outcome 4 Postoperative morbidity.
Gérard 2010 88/291 96/293 16.13% 0.89[0.63,1.26]
Aschele 2011 83/368 80/379 14.75% 1.09[0.77,1.54]
O'Connell 2014 241/655 225/653 34.41% 1.11[0.88,1.39]
Subtotal (95% CI) 1314 1325 65.29% 1.05[0.89,1.24]

platin
Rödel 2012 278/613 265/623 34.71% 1.12[0.9,1.4]
Subtotal (95% CI) 613 623 34.71% 1.12[0.9,1.4]
Test for overall effect: Z=1(P=0.32)

Total (95% CI) 1927 1948 100% 1.07[0.94,1.23]

single-agent chemotherapy (control), Outcome 5 Metastases intra-abdominal.
Aschele 2011 2/368 16/379 19.15% 0.12[0.03,0.54]
Gérard 2010 8/291 12/293 33.6% 0.66[0.27,1.64]
Subtotal (95% CI) 659 672 52.75% 0.32[0.06,1.68]
Informed decisions.



platin
Rödel 2012 21/613 34/623 47.25% 0.61[0.35,1.07]
Subtotal (95% CI) 613 623 47.25% 0.61[0.35,1.07]

Total (95% CI) 1272 1295 100% 0.46[0.21,1.01]

agent chemotherapy (control), Outcome 6 Circumferential resection margin - positive status.
Aschele 2011 9/368 15/379 22% 0.61[0.26,1.41]
Gérard 2010 11/291 19/293 27.8% 0.57[0.26,1.21]
Subtotal (95% CI) 659 672 49.8% 0.59[0.33,1.03]

platin
Rödel 2012 32/613 35/623 50.2% 0.93[0.57,1.51]
Subtotal (95% CI) 613 623 50.2% 0.93[0.57,1.51]

Total (95% CI) 1272 1295 100% 0.76[0.52,1.09]
Test for subgroup differences: Chi2=1.44, df=1 (P=0.23), I2=30.56%

Informed decisions.


single-agent chemotherapy (control), Outcome 7 Radiotherapy compliance.
Aschele 2011 295/368 348/379 47.31% 0.36[0.23,0.56]
Gérard 2010 260/291 293/293 7.74% 0.01[0,0.23]
Subtotal (95% CI) 659 672 55.05% 0.09[0,3.29]

platin
Rödel 2012 571/613 601/623 44.95% 0.5[0.29,0.84]
Subtotal (95% CI) 613 623 44.95% 0.5[0.29,0.84]

Total (95% CI) 1272 1295 100% 0.32[0.14,0.75]

single-agent chemotherapy (control), Outcome 8 Chemotherapy compliance.
Aschele 2011 244/368 320/379 66.7% 0.36[0.26,0.52]
Gérard 2010 273/291 291/293 33.3% 0.1[0.02,0.45]
Subtotal (95% CI) 659 672 100% 0.24[0.07,0.77]

platin
Rödel 2012 516/613 495/623 100% 1.38[1.03,1.84]
Subtotal (95% CI) 613 623 100% 1.38[1.03,1.84]
Test for subgroup differences: Chi2=8.15, df=1 (P=0), I2=87.73%

Informed decisions.

Analysis 1.9. Comparison 1 Combination chemotherapy (intervention) versus single-agent

chemotherapy (control), Outcome 9 Abdominoperineal resection and Hartmann's procedures.
Aschele 2011 68/368 76/379 27.06% 0.9[0.63,1.3]
Gérard 2010 65/291 71/293 24.36% 0.9[0.61,1.32]
Subtotal (95% CI) 659 672 51.41% 0.9[0.69,1.17]
Heterogeneity: Tau2=0; Chi2=0, df=1(P=0.99); I2=0%

platin
Rödel 2012 149/613 146/623 48.59% 1.05[0.81,1.36]
Subtotal (95% CI) 613 623 48.59% 1.05[0.81,1.36]

Total (95% CI) 1272 1295 100% 0.97[0.81,1.17]

ADDITIONAL TABLES

Table 1. TNM staging for colorectal cancer
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
Informed decisions.

Table 1. TNM staging for colorectal cancer (Continued)

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 re-
gional 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
Informed decisions.

Table 1. TNM staging for colorectal cancer (Continued)

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 (intramu-
cosal) 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 can-
cers 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 resid-
ual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2), or a totally re-
placed 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 af-
ter 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).

APPENDICES
Appendix 1. CENTRAL search strategy

Cochrane Central Register of Controlled Trials (CENTRAL), 2015, Issue 1
#1 MeSH descriptor: [Rectal Neoplasms] explode all trees
#2 ((rectum or rectal or recti or retrorectal or pararectal or anal* or anus*) near/3 (carcinom* or neoplas* or adenocarcinom* or cancer*
or tumor* or tumour*)):ti,ab,kw
#3 (#1 or #2)
#4 MeSH descriptor: [Radiotherapy] explode all trees
#5 (radiation or irratiation or radio* or rontgen or roentgen or x-ray or x ray or bioradiant or bucky):ti,ab,kw
#6 (#4 or #5)
#7 MeSH descriptor: [Antineoplastic Agents] explode all trees
#8 MeSH descriptor: [Organoplatinum Compounds] explode all trees
#9 MeSH descriptor: [Antineoplastic Combined Chemotherapy Protocols] explode all trees
#10 MeSH descriptor: [Fluorouracil] explode all trees
#11 MeSH descriptor: [Camptothecin] explode all trees
#12 MeSH descriptor: [Chemoradiotherapy] explode all trees
#13 (crisapla or dacotin or dacplat or eloxatin or eloxatine or heloxatin or oplat or oxalip or oxaltic or transplastin or xaliplat or
oxalatoplatinum9 or oxalatoplatin or L-OHP or diaminocyclohexane oxalatoplatinum or oxaliplatin) or (campto* or camptosar or cpt 11 or
cpt11 or irinotecan or irinotel or topotecin) or (5-Fluoracil or 5-Fluoropyrimidine-2,4-dione or 5-Fluorouracil or 5-Fluracil or 5-FU or Fluoro
Uracil or Fluorouracil or Fluorouracilo or Fluorouracilum or Fluouracil) or (chemo*):ti,ab,kw
#14 (#7 or #8 or #9 or #10 or #11 or #12 or #13)
#15 MeSH descriptor: [Neoadjuvant Therapy] explode all trees
#16 MeSH descriptor: [Chemotherapy, Adjuvant] explode all trees
#17 MeSH descriptor: [Radiotherapy, Adjuvant] explode all trees
#18 MeSH descriptor: [Chemoradiotherapy, Adjuvant] explode all trees
#19 (adjuvant or neoadjuvant):ti,ab,kw
Informed decisions.

#20 (#15 or #16 or #17 or #19)

#21 (#3 and #6 and #14 and #20)
Appendix 2. MEDLINE search strategy

Ovid MEDLINE - 1950 to 16 January 2015
1. exp Rectal Neoplasms/
2. ((rectum or rectal or recti or retrorectal or pararectal or anal or anus) adj3 (carcinom* or neoplas* or adenocarcinom* or cancer* or
tumor* or tumour*)).mp.
3. 1 or 2
4. exp Radiotherapy/
5. (radiation or irratiation or radio* or rontgen or roentgen or x-ray or x ray or bioradiant or bucky).mp.
6. 4 or 5
7. exp Antineoplastic Agents/
8. exp Organoplatinum Compounds/
9. exp Antineoplastic Combined Chemotherapy Protocols/
10. exp Fluorouracil/
11. exp Camptothecin/
12. exp Chemoradiotherapy/
13. (crisapla or dacotin or dacplat or eloxatin or eloxatine or heloxatin or oplat or oxalip or oxaltic or transplastin or xaliplat or
oxalatoplatinum9 or oxalatoplatin or L-OHP or diaminocyclohexane oxalatoplatinum or oxaliplatin or (campto* or camptosar or cpt 11 or
Uracil or Fluorouracil or Fluorouracilo or Fluorouracilum or Fluouracil) or chemo*).mp.
14. 7 or 8 or 9 or 10 or 11 or 12 or 13
15. exp Neoadjuvant Therapy/
16. exp Chemotherapy, Adjuvant/
17. exp Radiotherapy, Adjuvant/
18. exp Chemoradiotherapy, Adjuvant/
19. (adjuvant or neoadjuvant).mp.
20. 15 or 16 or 17 or 18 or 19
21. 3 and 6 and 14 and 20
22. randomized controlled trial.pt.
23. controlled clinical trial.pt.
24. randomized.ab.
25. placebo.ab.
26. clinical trial.sh.
27. randomly.ab.
28. trial.ti.
29. 22 or 23 or 24 or 25 or 26 or 27 or 28
30. humans.sh.
31. 29 and 30
32. 21 and 31
Appendix 3. EMBASE search strategy

Ovid EMBASE - 1974 to 16 January 2015
1. *rectum cancer/
2. ((rectum or rectal or recti or retrorectal or pararectal or anal or anus) and (carcinom* or neoplas* or adenocarcinom* or cancer* or
tumor* or tumour*)).m_titl.
3. 1 or 2
4. exp radiotherapy/
5. (radiation or irratiation or radio* or rontgen or roentgen or chemoradio* or x-ray or x ray or bioradiant or bucky).mp.
6. 4 or 5
7. exp platinum complex/
8. exp fluorouracil/
9. exp oxaliplatin/
10. exp cancer chemotherapy/
11. exp chemoradiotherapy/
12. (crisapla or dacotin or dacplat or eloxatin or eloxatine or heloxatin or oplat or oxalip or oxaltic or transplastin or xaliplat or
oxalatoplatinum9 or oxalatoplatin or L-OHP or diaminocyclohexane oxalatoplatinum or oxaliplatin or (campto* or camptosar or cpt 11 or
Uracil or Fluorouracil or Fluorouracilo or Fluorouracilum or Fluouracil) or chemo*).mp.
13. 7 or 8 or 9 or 10 or 11 or 12
Informed decisions.

14. exp adjuvant therapy/

15. (adjuvant or neoadjuvant).mp.
16. 14 or 15
17. 3 and 6 and 13 and 16
18. CROSSOVER PROCEDURE.sh.
19. DOUBLE-BLIND PROCEDURE.sh.
20. SINGLE-BLIND PROCEDURE.sh.
21. (crossover* or cross over*).ti,ab.
22. placebo*.ti,ab.
23. (doubl* adj blind*).ti,ab.
24. allocat*.ti,ab.
25. trial.ti.
26. RANDOMIZED CONTROLLED TRIAL.sh.
27. random*.ti,ab.
28. 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27
29. (exp animal/ or exp invertebrate/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans or man or men
or wom?n).ti.)
30. 28 not 29
31. 17 and 30
Appendix 4. LILACS search strategy

Descritor Inglês: Rectal Neoplasms
Descritor Espanhol: Neoplasias del Recto
Descritor Português: Neoplasias Retais
Sinônimos Português: Câncer do Reto

Câncer Retal
Tumores Retais
Categoria: C04.588.274.476.411.307.790
C06.301.371.411.307.790
C06.405.249.411.307.790
C06.405.469.491.307.790
C06.405.469.860.180.500
Definição Português: Tumores ou câncer do reto

(NEOPLASIAS RETAIS) AND ((oxaliplatin) OR (1,2-diamminocyclohexane(trans-1)oxolatoplatinum(II)) OR (platinum(II)-1,2-
cyclohexanediamine oxalate) OR (L-OHP cpd) OR (oxalato-(1,2-cyclohexanediamine)platinum II) OR (oxaliplatine) OR (1,2-
diaminocyclohexane platinum oxalate) OR (1-OHP) OR (cisoxalato-(trans-l)-1,2-diaminocyclohexane-platinum(II)) OR (oxaliplatin, (SP-4-3-
(cis))-isomer) OR (oxaliplatin, (SP-4-2-(1Rtrans))-isomer) OR (oxaliplatin, (SP-4-2-(1S-trans))-isomer) OR (ACT 078) OR (ACT-078) OR
(eloxatine) OR (sanofi brand of oxaliplatin) OR (sanofi synthelabo brand of oxaliplatin) OR (eloxatin))
Appendix 5. Study selection form

Randomised Relevant participants Relevant interventions Relevant outcomes
controlled trial
- People with resectable Combination chemotherapy ypCR, early toxicity, intra-abdominal metastases,
rectal cancer vs. single-agent chemotherapy postoperative mortality, conservative surgery, over-
all and disease-free survival
Informed decisions.

(Continued)
Yes/No/Unclear Yes/No/Unclear Yes/No/Unclear Yes/No/Unclear

Appendix 6. Data extraction form

Code of the paper: N= N=
Outcome Reported in paper (circle) Intervention Control
ypCR Yes / No
Early toxicity G3/4 Yes / No
intra abdominal metastases Yes / No
postoperative mortality Yes / No
postoperative morbidity Yes / No
radiotherapy compliance Yes / No
chemotherapy compliance Yes / No
abdominoperineal and Hartman's procedure Yes / No
circumferential resection margin positive status Yes / No

Appendix 7. Criteria for judging risk of bias in the 'Risk of bias' assessment tool

RANDOM SEQUENCE GENERATION
Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
Criteria for a judgement of The investigators described a random component in the sequence generation process such as:
'low risk' of bias
• referring to a random number table;
• using a computer random number generator;
• coin tossing;
• shuffling cards or envelopes;
• throwing dice;
• drawing of lots;
• minimisation*
*Minimisation may be implemented without a random element, and this is considered to be equiv-
alent to being random
Criteria for the judgement of The investigators described a non-random component in the sequence generation process. Usual-
'high risk' of bias ly, the description would involve some systematic, non-random approach, e.g.:
• sequence generated by odd or even date of birth;

• sequence generated by some rule based on date (or day) of admission;
Informed decisions.

(Continued)
• sequence generated by some rule based on hospital or clinic record number;
• other non-random approaches happen much less frequently than the systematic approaches
mentioned above and tend to be obvious. They usually involve judgement or some method of
non-random categorisation of participants, for example:
* allocation by judgement of the clinician;
* allocation by preference of the participant;
* allocation based on the results of a laboratory test or a series of tests;
* allocation by availability of the intervention
Criteria for the judgement of Insufficient information about the sequence generation process to permit judgement of 'low risk'
'unclear risk' of bias or 'high risk'
ALLOCATION CONCEALMENT
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
Criteria for a judgement of Participants and investigators enrolling participants could not foresee assignment because 1 of the
'low risk' of bias following, or an equivalent method, was used to conceal allocation:
• central allocation (including telephone, web-based and pharmacy-controlled randomisation);

• sequentially numbered drug containers of identical appearance;
• sequentially numbered, opaque, sealed envelopes
Criteria for the judgement of Participants or investigators enrolling participants could possibly foresee assignments and thus in-
'high risk' of bias troduce selection bias, such as allocation based on:
• using an open random allocation schedule (e.g. a list of random numbers);

• assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed
or nonopaque or not sequentially numbered);
• alternation or rotation;
• date of birth;
• case record number;
• any other explicitly unconcealed procedure
Criteria for the judgement of Insufficient information to permit judgement of 'low risk' or 'high risk'. This is usually the case if
'unclear risk' of bias the method of concealment is not described or not described in sufficient detail to allow a definite
judgement, e.g. if the use of assignment envelopes is described, but it remains unclear whether en-
velopes were sequentially numbered, opaque and sealed
BLINDING OF PARTICIPANTS AND PERSONNEL
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
Criteria for a judgement of Any 1 of the following:

'low risk' of bias
• no blinding or incomplete blinding, but the review authors judged that the outcome was not likely
to be influenced by lack of blinding;
• blinding of participants and key study personnel ensured, and unlikely that the blinding could
have been broken
Criteria for the judgement of Any 1 of the following:

'high risk' of bias
• no blinding or incomplete blinding, and the outcome was likely to be influenced by lack of blind-
ing;
• blinding of key study participants and personnel attempted, but likely that the blinding could
have been broken, and the outcome was likely to be influenced by lack of blinding
Informed decisions.

(Continued)
'unclear risk' of bias
• insufficient information to permit judgement of 'low risk' or 'high risk';
• the study did not address this outcome
BLINDING OF OUTCOME ASSESSMENT
Detection bias due to knowledge of the allocated interventions by outcome assessors

'low risk' of bias
• no blinding of outcome assessment, but the review authors judged that the outcome measure-
ment is not likely to be influenced by lack of blinding;
• blinding of outcome assessment ensured, and unlikely that the blinding could have been broken

'high risk' of bias
• no blinding of outcome assessment, and the outcome measurement was likely to be influenced
by lack of blinding;
• blinding of outcome assessment, but likely that the blinding could have been broken, and the
outcome measurement was likely to be influenced by lack of blinding

• insufficient information to permit judgement of 'ow risk' or 'high risk';
INCOMPLETE OUTCOME DATA
Attrition bias due to amount, nature or handling of incomplete outcome data

'low risk' of bias
• no missing outcome data;
• reasons for missing outcome data unlikely to be related to true outcome (for survival data, cen-
soring unlikely to be introducing bias);
• missing outcome data balanced in numbers across intervention groups, with similar reasons for
missing data across groups;
• for dichotomous outcome data, the proportion of missing outcomes compared with observed
event risk not enough to have a clinically relevant impact on the intervention effect estimate;
• for continuous outcome data, plausible effect size (difference in means or standardised difference
in means) among missing outcomes not enough to have a clinically relevant impact on observed
effect size;
• missing data were imputed using appropriate methods

'high risk' of bias
• reason for missing outcome data likely to be related to true outcome, with either imbalance in
numbers or reasons for missing data across intervention groups;
• for dichotomous outcome data, the proportion of missing outcomes compared with observed
event risk enough to induce clinically relevant bias in intervention effect estimate;
• for continuous outcome data, plausible effect size (difference in means or standardised difference
in means) among missing outcomes enough to induce clinically relevant bias in observed effect
size;
• 'as-treated' analysis done with substantial departure of the intervention received from that as-
signed at randomisation;
• potentially inappropriate application of simple imputation
Informed decisions.

(Continued)
• insufficient reporting of attrition/exclusions to permit judgement of 'low risk' or 'high risk' (e.g.
number randomised not stated, no reasons for missing data provided);
SELECTIVE REPORTING
Reporting bias due to selective outcome reporting
Criteria for a judgement of Any of the following:

'low risk' of bias.
• the study protocol was available and all of the study's pre-specified (primary and secondary) out-
comes that were of interest in the review were reported in the pre-specified way;
• the study protocol was not available but it was clear that the published reports included all ex-
pected outcomes, including those that were pre-specified (convincing text of this nature may be
uncommon)

'high risk' of bias
• not all of the study's pre-specified primary outcomes were reported;
• ≥ 1 primary outcomes was reported using measurements, analysis methods or subsets of the data
(e.g. subscales) that were not pre-specified;
• ≥ 1 reported primary outcomes were not pre-specified (unless clear justification for their reporting
was provided, such as an unexpected adverse effect);
• ≥ 1 outcomes of interest in the review were reported incompletely so that they could not be en-
tered in a meta-analysis;
• the study report did not include results for a key outcome that would be expected to have been
reported for such a study
Criteria for the judgement of Insufficient information to permit judgement of 'low riskl or lhigh risk'. It is likely that the majority
'unclear risk' of bias of studies will fall into this category
OTHER BIAS
Bias due to problems not covered elsewhere in the table
Criteria for a judgement of The study appeared to be free of other sources of bias
'low risk' of bias
Criteria for the judgement of There is at least 1 important risk of bias. For example, the study:
'high risk' of bias
• had a potential source of bias related to the specific study design used; or
• had been claimed to have been fraudulent; or
• had some other problem
Criteria for the judgement of There may be a risk of bias, but there was either:
• insufficient information to assess whether an important risk of bias existed; or
• insufficient rationale or evidence that an identified problem will introduce bias

WHAT'S NEW

Informed decisions.

Date Event Description
21 October 2015 Amended Analysis 1.1 is now reported as OR

HISTORY
Protocol first published: Issue 6, 2010
Review first published: Issue 10, 2015

Date Event Description
16 February 2015 New search has been performed Searches updated and one new RCT included
18 September 2014 New search has been performed Searches updated.
27 May 2010 Amended 2nd author address updated

CONTRIBUTIONS OF AUTHORS
Draft the protocol: HMR, DM.
Develop a search strategy: HMR, LFPJ, LVQ.
Search for trials: LFPJ, LVQ.
Select which trials to include: HMR, DM.
Extract data from trials: HMR, EMKS.
Enter data into Review Manager 5 (RevMan 2014): HMR, EMKS.
Conduct the analysis: HMR, EMKS.
Interpret the analysis: DM, HMR, EMKS.
Draft the final review: DM, EMKS, HMR.
DECLARATIONS OF INTEREST
There were no conflicts of interest.
SOURCES OF SUPPORT
Internal sources
• We received support from the Evidence Based Medicine Department, Universidade Federal de São Paulo, Brazil.
Technological support
External sources
• We did not receive any external support, Other.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
We included the intra-abdominal metastases, treatment compliance, circumferential resection margin status and type of surgery (number
of abdominoperineal resection and Hartmann's procedure) outcomes in the review. We included subgroup analysis according to doses
and schedule of 5-fluorouracil. We also changed our work team, and excluded three review authors (Suzana Angelica Silva Lustosa, Vinicius
Informed decisions.

Menandro and Juliana Novaes). We included three other review authors (Edina Mariko Koga da Silva, Luiz Felipe Pitzer Jacob and Luciano
Vasconcellos Quinellato). Edina Mariko Koga da Silva was the new co-ordinator team.
We excluded the outcome 'time to response clinical rate' because pCR overlapped it.

Combination Chemotherapy Versus Single-Agent Chemotherapy During Preoperative Chemoradiation For Resectable Rectal Cancer (Review)

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Combination Chemotherapy Versus Single-Agent Chemotherapy During Preoperative Chemoradiation For Resectable Rectal Cancer (Review)

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Resende HM, Jacob LFP, Quinellato LV, Matos D, da Silva EMK

Resende HM, Jacob LFP, Quinellato LV, Matos D, da Silva EMK.

Combination chemotherapy versus single-agent chemotherapy during

Editorial group: Cochrane Colorectal Cancer Group.

Data collection and analysis

Single or combination chemotherapy during preoperative treatment for rectal cancer

Quality of the evidence

Intervention: fluoropyrimidine plus oxaliplatin

Outcomes Relative effect No of par- Quality of the Comments

Complete response rate after OR 1.23 (1.04 to 1.46) 3875 ⊕⊕⊕⊕ -

Chemotherapy compliance OR 0.36 (0.26 to 0.52) 1331 ⊕⊕⊕⊕ -

GRADE Working Group grades of evidence

BACKGROUND agent chemotherapy during preoperative chemoradiation using

METHODS 1. Cochrane Colorectal Cancer Group Specialised Register

Very low Any estimate of effect is very uncertain

Study limitation Large magnitude of effect

Indirectness of evidence Dose-response gradient

We identified 1601 citations from the database searches and other

Figure 1. Study flow diagram.

Anastomotic leak rate Summary of main results

Roh MS, Yothers GA, O'Connell MJ, Beart RW, Pitot HC, Carlomagno 2009

Characteristics of included studies [ordered by study ID]

Notes Total losses at endpoint: 38 (5.1%) participants: 19 control and 19 intervention

Bias Authors' judgement Support for judgement

Allocation concealment Low risk Random assignment was centrally performed

Incomplete outcome data Low risk Losses of 38 (5.1%). ITT analysis

Selective reporting (re- Low risk All outcomes were reported

Notes Total losses at endpoint: 19 participants (3.2%): 11 control and 8 intervention

Bias Authors' judgement Support for judgement

Allocation concealment Low risk Random assignment was performed centrally

Incomplete outcome data Low risk Losses of 33 (5.5%). ITT analysis

Selective reporting (re- Low risk All outcomes are recorded

Participants See Gérard 2010

Interventions See Gérard 2010

Bias Authors' judgement Support for judgement

Random sequence genera- Low risk See Gérard 2010

Allocation concealment Low risk See Gérard 2010

Blinding of participants High risk See Gérard 2010

Blinding of outcome as- High risk See Gérard 2010

Selective reporting (re- Low risk See Gérard 2010

Other bias Low risk See Gérard 2010

Intervention group: 655 participants

Control group: 653 participants

Bias Authors' judgement Support for judgement

Allocation concealment Low risk Random assignment was performed centrally

Incomplete outcome data Low risk Losses 32/1308 (2.4%)

Selective reporting (re- Low risk All outcomes were reported

Notes Total losses at endpoint: 68 participants (3.1%): 17 control and 22 intervention

Bias Authors' judgement Support for judgement

Blinding of participants High risk Open study

Blinding of outcome as- High risk Open study

Incomplete outcome data Low risk Losses of 68 (5.4%). ITT analysis

Selective reporting (re- Low risk All outcomes were recorded

Comparison 1. Combination chemotherapy (intervention) versus single-agent chemotherapy (control)

Outcome or subgroup title No. of No. of Statistical method Effect size

Outcome or subgroup title No. of No. of Statistical method Effect size

Favours control 0.01 0.1 1 10 100 Favours intervention

Analysis 1.2. Comparison 1 Combination chemotherapy (intervention) versus single-

Favours intervention 0.01 0.1 1 10 100 Favours control

Favours intervention 0.01 0.1 1 10 100 Favours control

Study or subgroup Intervention Control Odds Ratio Weight Odds Ratio

Favours intervention 0.01 0.1 1 10 100 Favours control

Favours intervention 0.01 0.1 1 10 100 Favours control