Skip to main content
NCBI home page
The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2016 Oct 5;2016(10):CD012326. doi: 10.1002/14651858.CD012326

Survival differences with immediate versus delayed chemotherapy for asymptomatic incurable metastatic colorectal cancer

Yvette Claassen 1, Anne J Breugom 1, Martine A Frouws 1, Esther Bastiaannet 1,✉, Charissa R Sabajo 1, Gerrit‐Jan Liefers 1, Cornelis JH van de Velde 1, Ellen Kapiteijn 2
PMCID: PMC6457971

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effect of immediate versus delayed chemotherapy, with or without targeted therapy, on overall survival and other relevant clinical outcomes for patients with asymptomatic metastatic incurable colorectal cancer.

Background

Description of the condition

Colorectal cancer is the third most commonly diagnosed cancer worldwide, with a total of 1.36 million new cases in 2012 (Ferlay 2015). Approximately 20% of all newly diagnosed patients with colorectal cancer have metastatic (stage IV) disease at initial presentation (Siegel 2015), and approximately 20% of all patients with stage I‐III colorectal cancer will develop recurrent disease (Elferink 2015). The only option to cure metastatic colorectal cancer is to resect the primary tumour and all synchronous metastases. Although an increasing proportion of patients can be treated with curative intent (Brouquet 2011; Kopetz 2009; Pfannschmidt 2007; Tampellini 2012; Yan 2006), the majority of these patients with metastatic colorectal cancer are diagnosed with an incurable disease. For these patients palliative systemic treatment is the only option, with or without palliative resection of the primary tumour.

Survival for patients with incurable metastatic colorectal cancer has improved significantly over the past years. Median overall survival for patients who only receive 'best supportive care' is approximately five to six months (Scheithauer 1993). With the introduction of fluoropyrimidines, median overall survival has increased to 11 to 12 months, and up to almost two years with combination chemotherapy (Grothey 2004; Khattak 2012; Tournigand 2004). Outcomes for patients with incurable metastatic colorectal cancer have improved even further with the combination of fluoropyrimidine‐based chemotherapy with targeted therapy. Targeted therapy can be either a humanised monoclonal antibody against vascular endothelial growth factor (VEGF), such as bevacizumab, or an anti‐epidermal growth factor receptor (EGFR) treatment such as cetuximab or panitumumab (Douillard 2010; Hurwitz 2004; Kabbinavar 2005; Saltz 2008; Tebbutt 2010; Van Cutsem 2011). However, a population‐based study in the Netherlands showed that only about 55% of patients with metastatic colorectal cancer diagnosed between 2005 and 2007 were treated with chemotherapy, and median overall survival of these patients was no longer than approximately one year (van der Pool 2012).

Not every patient diagnosed with colorectal cancer has disease‐related symptoms at initial presentation. In the study by Majumdar 1999, 17% of all colorectal cancer cases showed no disease‐related symptoms. Nowadays, this number is expected to increase as a result of nationwide screening programmes. Asymptomatic colorectal cancer is characterised by the absence of frequently reported disease‐related symptoms, such as pain requiring regular narcotic analgesics, weight loss over 5 kg, persistent nausea requiring medication, deterioration in performance of daily living (measured by the Eastern Cooperative Oncology Group Performance Status (ECOG; Oken 1982)), obstructive bowel symptoms, persistent fever related to metastatic disease, and other symptoms which, in the opinion of the clinician, was due to progressive metastatic cancer. Metastatic disease could be diagnosed incidentally or during routine follow‐up visits after a previous diagnosis of localised colon or rectal cancer. However, the percentage of patients with asymptomatic incurable metastatic colorectal cancer has, to our knowledge, never been described. If it turns out that patients with asymptomatic metastatic colorectal cancer are incurable, the start of palliative systemic treatment could be at initial presentation, or could be delayed until disease‐related symptoms occur. Whether the potential survival benefit of starting palliative systemic treatment immediately after diagnosis weighs up against the potential side effects is currently under debate, and will be investigated in this review.

Description of the intervention

A benefit of palliative systemic treatment in patients with metastatic colorectal cancer has been clearly demonstrated with regard to median overall survival (Douillard 2010; Grothey 2004; Hurwitz 2004; Kabbinavar 2005; Khattak 2012; Saltz 2008; Tebbutt 2010; Tournigand 2004; Van Cutsem 2011). Furthermore, in symptomatic metastatic colorectal cancer, palliative chemotherapy can diminish disease symptoms, and thereby decrease tumour burden and improve quality of life (Glimelius 1994; Sullivan 1995). However, chemotherapeutic agents often have side effects. Therefore, in patients with asymptomatic incurable metastatic colorectal cancer, the potential benefits of palliative chemotherapy must be carefully weighed against the potential side effects. Two treatment strategies can be considered: chemotherapy started immediately at diagnosis, or delayed until disease‐related symptoms occur.

How the intervention might work

Starting palliative chemotherapy immediately at diagnosis in patients with asymptomatic incurable metastatic colorectal cancer might result in a survival benefit due to the earlier initiation of treatment compared with delaying chemotherapy until disease‐related symptoms occur. However, adverse events caused by the chemotherapy can deteriorate quality of life in patients who do not yet suffer from disease symptoms. Therefore, a more favourable strategy may be to delay chemotherapy until symptoms occur.

Why it is important to do this review

Prolonging life and improving or maintaining quality of life are the main goals of palliative systemic treatment in patients with metastatic colorectal cancer. It has yet to be determined as to when to commence chemotherapy during the disease course in patients with asymptomatic incurable metastatic colorectal cancer (Ackland 2005; NGTATG 1992; Pyrhonen 1992). Since patients with incurable metastatic colorectal cancer have a limited life expectancy (Grothey 2004; Khattak 2012; Tournigand 2004; van der Pool 2012), it is important to determine the timing of when to start chemotherapy in order to optimise the benefits of chemotherapy relative to the side effects.

Objectives

To assess the effect of immediate versus delayed chemotherapy, with or without targeted therapy, on overall survival and other relevant clinical outcomes for patients with asymptomatic metastatic incurable colorectal cancer.

Methods

Criteria for considering studies for this review

Types of studies

We will include all types of randomised controlled trials (RCTs), except pseudo‐randomisation, comparing immediate with delayed chemotherapy.

Types of participants

Patients of any age with asymptomatic, incurable, metastatic colorectal cancer (including patients who are not fit for surgery), diagnosed histologically or cytologically, who did not receive previous chemotherapy for metastatic disease. Patients with and without palliative resection of the primary tumour will be eligible for inclusion.

Types of interventions

  1. The control group will receive immediate chemotherapy, defined as chemotherapy started within two weeks of diagnosis.

  2. The experimental group will receive delayed chemotherapy, defined as chemotherapy delayed until disease‐related symptoms commence.

Chemotherapy may include any agent and regimen (including different chemotherapy regimes across trial arms), with or without the addition of targeted therapy.

Types of outcome measures

Primary outcomes

  • Overall survival, which is defined as time from randomisation to death from any cause, or to the end of follow‐up.

Secondary outcomes

  • Toxicity. We will compare the percentage of grade 3 and 4 toxicities between the two groups as classified according to the World Health Organization (WHO) guidelines (Miller 1981). Grade 3 toxicity is defined as severe or medically significant, but not immediately life‐threatening; this includes hospitalisation or indication of prolongation of hospitalisation, disabling, and limiting self‐care activities of daily living. Grade 4 toxicity is defined as life‐threatening consequences, where urgent intervention is indicated.

  • Quality of life. We will take quality of life into account at one, three, and five years. If data are not reported for these time points, we will consider alternative time points reported in the trials (preferably the nearest to those they specified). All types of quality of life scales will be eligible. Where different quality of life scales are used, we will transform these into the same scale, externally advised by a Professor in Psychology at Leiden University Medical Center with great experience in the field of quality of life and combining different scales of quality of life. When appropriate, we will calculate a standardised mean difference.

  • Progression‐free survival, which is defined as time from randomisation to time on which disease 'progresses' or the date on which the patient dies, from any cause.

  • Compliance of chemotherapy. We will follow the definition of compliance in the included studies.

Search methods for identification of studies

Electronic searches

We will search the following databases to identify studies meeting the inclusion criteria.

  1. Cochrane Colorectal Cancer Group's Specialised Register.

  2. Cochrane Central Register of Controlled Trials (CENTRAL; latest issue) in the Cochrane Library).

  3. MEDLINE Ovid (from 1946 to present).

  4. Embase Ovid (from 1974 to present).

  5. PsycINFO (from 1806 to present)

For comprehensive search strategies, see Appendix 1 (CENTRAL), Appendix 2 (MEDLINE), and Appendix 3 (Embase). We will not impose any limitations based on language. We will search the databases from the date of their inception. The Information Specialist in the Cochrane Colorectal Cancer Group will conduct and verify the searches.

In addition, we will search for ongoing clinical trials on ClinicalTrials.gov, as well as the WHO International Clinical Trials Registry Platform (apps.who.int/trialsearch).

Searching other resources

We will identify additional studies by searching the bibliographies of all retrieved and relevant publications identified by the above search strategies. We will also search for additional trials through scanning reference lists in relevant papers, review articles, and conference abstracts.

Data collection and analysis

Selection of studies

Two review authors (AB and YC) will independently assess the titles and abstracts identified by the search strategy for potentially relevant studies. They will verify data from studies using Covidence software (Covidence 2013), and will obtain the full texts of all articles of possible relevance. The same two review authors will independently read the papers to ensure they meet the inclusion criteria. Disagreements between the two review authors will be resolved by discussion with a third review author (EK). In cases of more than one publication of a single trial, we will only include the publication with the most complete data unless the relevant outcomes are only published in earlier publications. We will contact study authors where clarification is necessary. We will list included studies in the 'Characteristics of included studies' table and list excluded studies and reasons for exclusion in the 'Characteristics of excluded studies' table. We will document the inclusion and exclusion of studies in a PRISMA flow chart (Figure 1; Moher 2009), and will comply to MECIR (Methodological Expectations of Cochrane Intervention Reviews) guidelines (http://editorial‐unit.cochrane.org/mecir).

Figure 1.

Figure 1

Open in a new tab

Study flow diagram.

Data extraction and management

Two review authors (AB and YC) will independently extract data from the studies using a standardised data extraction form that will be piloted. The data extraction form will include the following.

  1. General information: study title, authors, source, publication date, contact address, language.

  2. Population characteristics: number, age, gender, site of metastatic disease, whether or not patients received previous adjuvant chemotherapy (in a curative setting), site of primary tumour (colon or rectum), performance status.

  3. Intervention characteristics: method of chemotherapy administration, dosage and duration of the intervention, details of the comparison regimen, number dropped out or lost to follow‐up.

  4. Outcomes: overall survival, chemotherapy‐induced toxicities, progression‐free survival, quality of life, chemotherapy compliance.

Assessment of risk of bias in included studies

Two review authors (AB and YC) will independently assess the methodological quality of the included studies using the Cochrane tool for assessing risk of bias (Higgins 2011). Any disagreement will be resolved by a third review author (EK). Criteria for quality assessment will include the following.

  1. Selection bias: random sequence generation, allocation concealment.

  2. Performance bias: blinding of participants and personnel.

  3. Detection bias: blinding of outcome assessment.

  4. Attrition bias: incomplete outcome data.

  5. Reporting bias: selective reporting.

  6. Other bias: other sources of bias.

We will judge all criteria incorporated in the Cochrane 'Risk of bias' tool at low, high, or unclear risk of bias. See Appendix 4 for criteria for judging risk of bias (Chapter 8.5.d, Higgins 2011).

Measures of treatment effect

We will report time‐to‐event data as hazard ratios (HRs) with 95% confidence intervals (CIs). We will extract HRs and CIs from the included articles; where necessary, we will extrapolate them from Kaplan‐Meier survival curves using standardised methods (Parmar 1998). We will pool trials using a fixed‐effect meta‐analysis (and using Mantel‐Haenszel), as random‐effects models are not suitable for small numbers of studies (with a cut‐off number of 5) (Higgins 2011). We will directly insert the HRs and CIs in Review Manager 5 (RevMan 2014). A HR below 1.0 favours the experimental group (delayed chemotherapy). Preferably we will look at HRs at one year, three years, and five years; where these are not reported, we will consider measures at alternative durations of follow‐up reported in the trials. Where HRs are not available, we will use median overall survival with 95% CIs. We will interpret a P value of less than 0.05 as statistically significant. We will calculate risk ratios (RRs) with 95% CI for dichotomous variables, e.g. toxicity rate. For continuous outcomes, e.g. quality of life measurements, we will use mean differences with 95% CIs.

Unit of analysis issues

We expect only two‐arm parallel RCTs where the unit of analysis will be the individual patient. However, although unlikely to be conducted, cluster‐RCTs (e.g. groups randomised rather than individuals) will be eligible if identified (Higgins 2011). We will adjust their sample sizes using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 16.3.4 or 16.3.6, Higgins 2011) using an estimate of the intracluster correlation coefficient (ICC) derived from the trial (if possible), from a similar trial, or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs, and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely. Cross‐over RCTs are not feasible, as patients in the control group (immediate chemotherapy) cannott be switched to the experimental group (delayed chemotherapy), or vice versa.

Dealing with missing data

We will contact principal investigators or key authors of included studies for missing data (missing patients due to loss to follow‐up/dropout/withdrawal, and missing statistics). We will make every effort to minimise the amount of missing data. Our expectation is that the amount of missing data will be minimal, and that the included trials will investigate the same outcome measures. Additionally, we will perform a 'worst‐case intention‐to‐treat' analysis. We will do this by assuming that all missing patients had an event; this way we will obtain the most conservative and pessimistic estimate.

Assessment of heterogeneity

We will test for heterogeneity between study results. First, we will determine the presence or absence of overlap in the CIs. The absence of overlap in the CIs indicates heterogeneity between study results. Second, we will perform the Chi2 test for heterogeneity. If P < 0.10, we will consider data to be heterogeneous. Finally, we will calculate the I2 statistic, that should be interpreted "as the proportion of total variation in the estimates of treatment effect that is due to heterogeneity between studies" (Higgins 2002).

We will interpret the I2 as follows.

• 0% to 40%: might not be important. • 30% to 60%: may represent moderate heterogeneity. • 50% to 90%: may represent substantial heterogeneity. • 75% to 100%: considerable heterogeneity.

We will not pool data if statistical heterogeneity is classified as substantial or considerable. We will pool data even though there may be substantial clinical heterogeneity.

Assessment of reporting biases

To assess the risk of reporting bias, we will use funnel plots where possible (more than 10 included studies).

Data synthesis

As we expect the number of RCTs for this meta‐analysis to be very small, we will perform a fixed‐effect meta‐analysis. Therefore, we also remain open to the option of not doing a meta‐analysis in the face of heterogeneity, either clinical or statistical.

'Summary of findings' table

We will use GRADE to determine the quality of evidence for overall survival, toxicity, quality of life, progression‐free survival, and compliance of chemotherapy in our assessment of immediate versus delayed chemotherapy for asymptomatic metastatic colorectal cancer (Atkins 2004). We will present our findings for the quality of evidence for each of these outcomes in a 'Summary of findings' table. The classification of GRADE is presented in Figure 2.

Figure 2.

Figure 2

Open in a new tab

Atkins 2004

Subgroup analysis and investigation of heterogeneity

We will perform the following subgroup analyses.

  • Type of chemotherapy regimen: developments in chemotherapy regimens over the last few decades may impact on results. We will use date of trial as a surrogate if regimen details are not reported. In case regimens of chemotherapy in the treatment arms differ, we will compare these results with those that use the same regimen in both arms. We will conduct subgroup analyses on treatment with and without anti‐vascular endothelial growth factor (VEGF)/epidermal growth factor receptor (EGFR) and FOLFOX (a chemotherapy regimen made up of folinic acid, fluorouracil, and oxaliplatin) versus FOLFIRI (a chemotherapy regimen made up of folinic acid, fluorouracil, and irinotecan).

  • Age groups: older patients have a poorer survival prognosis relative to younger patients.

  • Gender: as women live longer, gender could play an important role.

  • Site of cancer: rectum cancer patients have a poorer survival prognosis in comparison with colon cancer patient.

Sensitivity analysis

Sensitivity analyses will assess the susceptibility of the findings of this meta‐analysis.

We will perform two sensitivity analyses.

  • We will conduct the first analysis by only including patients that received per‐protocol therapy.

  • We will perform the second analysis by including studies which we judge to be at low risk of bias. We will classify studies at low risk of bias when all the major risk of bias criteria are low (Higgins 2002); we will exclude all trials from the sensitivity analysis that cross this threshold

Acknowledgements

We would like to thank Dr. Henning Keinke Andersen, Marija Barbateskovic and the rest of the Cochrane Colorectal Cancer Group editorial board for their help and advice for composing this protocol.

Appendices

Appendix 1. CENTRAL search strategy

Cochrane Central Register of Controlled Studies (CENTRAL) (the Cochrane Library) [Latest Issue]

#1 MeSH descriptor: [Colorectal Neoplasms] explode all trees #2 ((colorect* or colon* or rect* or anal or anus or intestin* or bowel* or sigmoid*) near/3 (carcinom* or neoplas* or adenocarcinom* or cancer* or tumor* or tumour* or sarcom* or adenom*)):ti,ab,kw #3 (#1 or #2) #4 MeSH descriptor: [Neoplasm Metastasis] explode all trees #5 (metastas* or metastatic* or micrometastas* or micrometastatic* or advance* or stage IV or stage 4 or stage four or irresectable or palliati*):ti,ab,kw #6 (#4 or #5) #7 MeSH descriptor: [Antineoplastic Combined Chemotherapy Protocols] explode all trees #8 MeSH descriptor: [Antineoplastic Agents] explode all trees #9 MeSH descriptor: [Antimetabolites, Antineoplastic] explode all trees #10 MeSH descriptor: [Fluorouracil] explode all trees #11 MeSH descriptor: [Leucovorin] explode all trees #12 MeSH descriptor: [Methotrexate] explode all trees #13 MeSH descriptor: [Camptothecin] explode all trees #14 MeSH descriptor: [Thiophenes] explode all trees #15 MeSH descriptor: [Organoplatinum Compounds] explode all trees #16 (chemotherap* or antineoplastic* or capecitabin* or fluoropyrimidin* or fluorouracil* or 5‐FU* or 5‐fluorouracil* or 5FU* or 5 fluorouracil* or methothrexat* or folinic acid or Leucovorin* or oxaliplatin* or camptothecin* or thiophene* or irinotecan* or capecitabin* or panitumumab* or cetuximab* or regorafenib* or FOLFIRI* or FOLFOX* or CapeOX* or FLOX* or XELOX*):ti,ab,kw #17 (#7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16) #18 MeSH descriptor: [Time Factors] explode all trees #19 ((time or delay* or immediate or initial or expectancy or primary or early or deferred or deferral) and chemo*):ti #20 (#18 or #19) #21 (#3 or #6 and #17 and #20)

Appendix 2. MEDLINE search strategy

Ovid MEDLINE [from 1950 to date]

1. exp Colorectal Neoplasms/ 2. ((colorect* or colon* or rect* or anal or anus or intestin* or bowel* or sigmoid*) adj3 (carcinom* or neoplas* or adenocarcinom* or cancer* or tumor* or tumour* or sarcom* or adenom*)).mp. 3. 1 or 2 4. exp Neoplasm Metastasis/ 5. (metastas* or metastatic* or micrometastas* or micrometastatic* or advance* or stage IV or stage 4 or stage four or irresectable or palliati*).mp. 6. 4 or 5 7. exp Antineoplastic Combined Chemotherapy Protocols/ 8. exp Antineoplastic Agents/ 9. exp Antimetabolites, Antineoplastic/ 10. exp Fluorouracil/ 11. exp Leucovorin/ 12. exp Methotrexate/ 13. exp Camptothecin/ 14. exp Thiophenes/ 15. exp Organoplatinum Compounds/ 16. (chemotherap* or antineoplastic* or capecitabin* or fluoropyrimidin* or fluorouracil* or 5‐FU* or 5‐fluorouracil* or 5FU* or 5 fluorouracil* or methothrexat* or folinic acid or Leucovorin* or oxaliplatin* or camptothecin* or thiophene* or irinotecan* or capecitabin* or panitumumab* or cetuximab* or regorafenib* or FOLFIRI* or FOLFOX* or CapeOX* or FLOX* or XELOX*).mp. 17. 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 18. exp Time Factors/ 19. ((time or delay* or immediate or initial or expectancy or primary or early or deferred or deferral) and chemo*).m_titl. 20. 18 or 19 21. 3 or 6 and 17 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 date]

1. exp large intestine tumor/ 2. ((colorect* or colon* or rect* or anal or anus or intestin* or bowel* or sigmoid*) adj3 (carcinom* or neoplas* or adenocarcinom* or cancer* or tumor* or tumour* or sarcom* or adenom*)).mp. 3. 1 or 2 4. exp metastasis/ 5. exp advanced cancer/ 6. (metastas* or metastatic* or micrometastas* or micrometastatic* or advance* or stage IV or stage 4 or stage four or irresectable or palliati*).mp. 7. 4 or 5 or 6 8. exp antineoplastic agent/ 9. exp antineoplastic antimetabolite/ 10. exp folinic acid/ 11. exp fluorouracil/ 12. exp platinum complex/ 13. exp camptothecin/ 14. exp thiophene derivative/ 15. exp oxaliplatin/ 16. exp irinotecan/ 17. exp capecitabine/ 18. exp cancer combination chemotherapy/ 19. (chemotherap* or antineoplastic* or capecitabin* or fluoropyrimidin* or fluorouracil* or 5‐FU* or 5‐fluorouracil* or 5FU* or 5 fluorouracil* or methothrexat* or folinic acid or Leucovorin* or oxaliplatin* or camptothecin* or thiophene* or irinotecan* or capecitabin* or panitumumab* or cetuximab* or regorafenib* or FOLFIRI* or FOLFOX* or CapeOX* or FLOX* or XELOX*).mp. 20. 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 21. exp time/ 22. exp time to treatment/ 23. exp early intervention/ 24. ((time or delay* or immediate or initial or expectancy or primary or early or deferred or deferral) and chemo*).m_titl. 25. 21 or 22 or 23 or 24 26. 3 or 7 and 20 and 25 27. CROSSOVER PROCEDURE.sh. 28. DOUBLE‐BLIND PROCEDURE.sh. 29. SINGLE‐BLIND PROCEDURE.sh. 30. (crossover* or cross over*).ti,ab. 31. placebo*.ti,ab. 32. (doubl* adj blind*).ti,ab. 33. allocat*.ti,ab. 34. trial.ti. 35. RANDOMIZED CONTROLLED TRIAL.sh. 36. random*.ti,ab. 37. 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 38. (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.) 39. 37 not 38 40. 26 and 39

Appendix 4. 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 ‘low risk’ of bias. The investigators describe a random component in the sequence generation process such as:

  • 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 equivalent to being random.
Criteria for the judgement of ‘high risk’ of bias. The investigators describe a non‐random component in the sequence generation process. Usually, the description would involve some systematic, non‐random approach, for example:

  • sequence generated by odd or even date of birth;

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

  • 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 ‘unclear risk’ of bias. Insufficient information about the sequence generation process to permit judgement of ‘low risk’ 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 ‘low risk’ of bias. Participants and investigators enrolling participants could not foresee assignment because one of the 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 ‘high risk’ of bias. Participants or investigators enrolling participants could possibly foresee assignments and thus introduce 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 ‘unclear risk’ of bias. Insufficient information to permit judgement of ‘low risk’ or ‘high risk'. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement – for example, if the use of assignment envelopes is described, but it remains unclear whether envelopes 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 ‘low risk’ of bias. Any one of the following.

  • No blinding or incomplete blinding, but the review authors judge that the outcome is 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 ‘high risk’ of bias. Any one of the following.

  • No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding.

  • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Criteria for the judgement of ‘unclear risk’ of bias. Any one of the following.

  • 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.
Criteria for a judgement of ‘low risk’ of bias. Any one of the following.

  • No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding.

  • Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
Criteria for the judgement of ‘high risk’ of bias. Any one of the following.

  • No blinding of outcome assessment, and the outcome measurement is 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 is likely to be influenced by lack of blinding.
Criteria for the judgement of ‘unclear risk’ of bias. Any one of the following.

  • Insufficient information to permit judgement of ‘low risk’ or ‘high risk’.

  • The study did not address this outcome.
Incomplete outcome data
Attrition bias due to amount, nature or handling of incomplete outcome data.
Criteria for a judgement of ‘low risk’ of bias. Any one of the following.

  • No missing outcome data.

  • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring 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 standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size.

  • Missing data have been imputed using appropriate methods.
Criteria for the judgement of ‘high risk’ of bias. Any one of the following.

  • 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 standardized 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 assigned at randomisation.

  • Potentially inappropriate application of simple imputation.
Criteria for the judgement of ‘unclear risk’ of bias. Any one of the following.

  • 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).

  • The study did not address this outcome.
Selective reporting
Reporting bias due to selective outcome reporting.
Criteria for a judgement of ‘low risk’ of bias. Any of the following.

  • The study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way.

  • The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
Criteria for the judgement of ‘high risk’ of bias. Any one of the following.

  • Not all of the study’s prespecified primary outcomes have been reported.

  • One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not prespecified.

  • One or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect).

  • One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis.

  • The study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Criteria for the judgement of ‘unclear risk’ of bias. Insufficient information to permit judgement of ‘low risk’ or ‘high risk’. It is likely that the majority of studies will fall into this category.
Other bias
Bias due to problems not covered elsewhere in the table.
Criteria for a judgement of ‘low risk’ of bias. The study appears to be free of other sources of bias.
Criteria for the judgement of ‘high risk’ of bias. There is at least one important risk of bias. For example, the study:

  • had a potential source of bias related to the specific study design used; or

  • has been claimed to have been fraudulent; or

  • had some other problem.
Criteria for the judgement of ‘unclear risk’ of bias. There may be a risk of bias, but there is either:

  • insufficient information to assess whether an important risk of bias exists; or

  • insufficient rationale or evidence that an identified problem will introduce bias.
Open in a new tab

Contributions of authors

Yvette Claassen (YC): Draft of the protocol. Select which trials to include. Extract data from trials. Interpretation of data. Draft of the final review.

Anne Breugom (AB): Draft of the protocol. Select which trials to include. Extract data from trials. Interpretation of data. Draft of the final review.

Martine Frouws (MF): Select which trials to include. Extract data from trials. Interpretation of data. Co‐authoring final review.

Esther Bastiaannet (EB): Designing the review. Coordinating the review. Interpretation of data. Comments and general advice on the protocol and review.

Charissa Sabajo (CS): Interpretation of data. Co‐authoring final review. Comments on the protocol and review.

Gerrit‐Jan Liefers (GL): Comments and general advice on the review.

Cornelis van de Velde (CV): Comments and general advice on the review.

Ellen Kapiteijn (EK): Coordinating the review. Interpretation of data. Comments and general advice on the protocol and review.

Declarations of interest

None known.

New

References

Additional references

  1. Ackland SP, Jones M, Tu D, Simes J, Yuen J, Sargeant AM, et al. A meta‐analysis of two randomised trials of early chemotherapy in asymptomatic metastatic colorectal cancer. British Journal of Cancer 2005;93(11):1236‐43. [PUBMED: 16265352] [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Atkins D, Best D, Briss PA, Eccles M, Falck‐Ytter Y, Flottorp S, et al. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004;328(7454):1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brouquet A, Vauthey JN, Contreras CM, Walsh GL, Vaporciyan AA, Swisher SG, et al. Improved survival after resection of liver and lung colorectal metastases compared with liver‐only metastases: a study of 112 patients with limited lung metastatic disease. Journal of the American College of Surgeons 2011;213(1):62‐9; discussion 69‐71. [PUBMED: 21700179] [DOI] [PubMed] [Google Scholar]
  4. Veritas Health Innovation. Melbourne, Australia. Covidence systematic review software, available at www.covidence.org. Veritas Health Innovation. Melbourne, Australia, 2013.
  5. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first‐line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. Journal of Clinical Oncology 2010;28(31):4697‐705. [PUBMED: 20921465] [DOI] [PubMed] [Google Scholar]
  6. Elferink MA, Jong KP, Klaase JM, Siemerink EJ, Wilt JH. Metachronous metastases from colorectal cancer: a population‐based study in North‐East Netherlands. International Journal of Colorectal Disease 2015;30(2):205‐12. [PUBMED: 25503801] [DOI] [PubMed] [Google Scholar]
  7. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer 2015;136(5):E359‐86. [PUBMED: 25220842] [DOI] [PubMed] [Google Scholar]
  8. Glimelius B, Hoffman K, Graf W, Pahlman L, Sjoden PO. Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer. The Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Cancer 1994;73(3):556‐62. [PUBMED: 8299077] [DOI] [PubMed] [Google Scholar]
  9. Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil‐leucovorin, irinotecan, and oxaliplatin in the course of treatment. Journal of Clinical Oncology 2004;22(7):1209‐14. [PUBMED: 15051767] [DOI] [PubMed] [Google Scholar]
  10. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta‐analysis. Statistics in Medicine 2002;21(11):1539‐58. [PUBMED: 12111919] [DOI] [PubMed] [Google Scholar]
  11. Higgins JP, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
  12. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. The New England Journal of Medicine 2004;350(23):2335‐42. [PUBMED: 15175435] [DOI] [PubMed] [Google Scholar]
  13. Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. Journal of Clinical Oncology 2005;23(16):3706‐12. [PUBMED: 15867200] [DOI] [PubMed] [Google Scholar]
  14. Khattak MA, Martin HL, Beeke C, Price T, Carruthers S, Kim S, et al. Survival differences in patients with metastatic colorectal cancer and with single site metastatic disease at initial presentation: results from South Australian clinical registry for advanced colorectal cancer. Clinical Colorectal Cancer 2012;11(4):247‐54. [PUBMED: 22763194] [DOI] [PubMed] [Google Scholar]
  15. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. Journal of Clinical Oncology 2009;27(22):3677‐83. [PUBMED: 19470929] [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Majumdar SR, Fletcher RH, Evans AT. How does colorectal cancer present? Symptoms, duration, and clues to location. The American Journal of Gastroenterology 1999;94(10):3039‐45. [PUBMED: 10520866] [DOI] [PubMed] [Google Scholar]
  17. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47(1):207‐14. [PUBMED: 7459811] [DOI] [PubMed] [Google Scholar]
  18. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and meta‐analyses: The PRISMA Statement. BMJ 2009;339:2535. [PMC free article] [PubMed] [Google Scholar]
  19. Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomized trial. Journal of Clinical Oncology 1992;10(6):904‐11. [PUBMED: 1588370] [DOI] [PubMed] [Google Scholar]
  20. Oken M, Creech R, Tormey D, Horton J, Davis T. Toxicity and response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649‐55. [PUBMED: 7165009] [PubMed] [Google Scholar]
  21. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta‐analyses of the published literature for survival endpoints. Statistics in Medicine 1998;17(24):2815‐34. [DOI] [PubMed] [Google Scholar]
  22. Pfannschmidt J, Dienemann H, Hoffmann H. Surgical resection of pulmonary metastases from colorectal cancer: a systematic review of published series. The Annals of Thoracic Surgery 2007;84(1):324‐38. [PUBMED: 17588454] [DOI] [PubMed] [Google Scholar]
  23. Pyrhonen SO, Kouri MO. Phase II study of epirubicin sequential methotrexate and 5‐fluorouracil for advanced colorectal cancer. European Journal of Cancer 1992;28A(11):1828‐32. [PUBMED: 1389520] [DOI] [PubMed] [Google Scholar]
  24. Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
  25. Saltz LB, Clarke S, Diaz‐Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin‐based chemotherapy as first‐line therapy in metastatic colorectal cancer: a randomized phase III study. Journal of Clinical Oncology 2008;26(12):2013‐9. [PUBMED: 18421054] [DOI] [PubMed] [Google Scholar]
  26. Scheithauer W, Rosen H, Kornek GV, Sebesta C, Depisch D. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ (Clinical research ed.) 1993;306(6880):752‐5. [PUBMED: 7683942] [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: Cancer Journal for Clinicians 2015;65(1):5‐29. [PUBMED: 25559415] [DOI] [PubMed] [Google Scholar]
  28. Sullivan BA, McKinnis R, Laufman LR. Quality of life in patients with metastatic colorectal cancer receiving chemotherapy: a randomized, double‐blind trial comparing 5‐FU versus 5‐FU with leucovorin. Pharmacotherapy 1995;15(5):600‐7. [PUBMED: 8570432] [DOI] [PubMed] [Google Scholar]
  29. Tampellini M, Ottone A, Bellini E, Alabiso I, Baratelli C, Bitossi R, et al. The role of lung metastasis resection in improving outcome of colorectal cancer patients: results from a large retrospective study. The Oncologist 2012;17(11):1430‐8. [PUBMED: 22956535] [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Tebbutt NC, Wilson K, Gebski VJ, Cummins MM, Zannino D, Hazel GA, et al. Capecitabine, bevacizumab, and mitomycin in first‐line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. Journal of Clinical Oncology 2010;28(19):3191‐8. [PUBMED: 20516443] [DOI] [PubMed] [Google Scholar]
  31. Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery‐Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. Journal of Clinical Oncology 2004;22(2):229‐37. [PUBMED: 14657227] [DOI] [PubMed] [Google Scholar]
  32. Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first‐line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. Journal of Clinical Oncology 2011;29(15):2011‐9. [PUBMED: 21502544] [DOI] [PubMed] [Google Scholar]
  33. Pool AE, Damhuis RA, Ijzermans JN, Wilt JH, Eggermont AM, Kranse R, et al. Trends in incidence, treatment and survival of patients with stage IV colorectal cancer: a population‐based series. Colorectal Disease 2012;14(1):56‐61. [PUBMED: 21176063] [DOI] [PubMed] [Google Scholar]
  34. Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. Journal of Clinical Oncology 2006;24(24):4011‐9. [PUBMED: 16921055] [DOI] [PubMed] [Google Scholar]

Articles from The Cochrane Database of Systematic Reviews are provided here courtesy of Wiley

RESOURCES