Intervention Protocol

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Irinotecan chemotherapy combined with fluoropyrimidines versus irinotecan alone for advanced and/or metastatic colorectal cancer

  1. Wahyu Wulaningsih1,*,
  2. Ardyan Wardhana2,
  3. Naomi Yoshuantari3,
  4. Ajeng A Sekarini3,
  5. Mieke Van Hemelrijck4

Editorial Group: Cochrane Colorectal Cancer Group

Published Online: 22 AUG 2013

DOI: 10.1002/14651858.CD008593.pub2


How to Cite

Wulaningsih W, Wardhana A, Yoshuantari N, Sekarini AA, Van Hemelrijck M. Irinotecan chemotherapy combined with fluoropyrimidines versus irinotecan alone for advanced and/or metastatic colorectal cancer (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD008593. DOI: 10.1002/14651858.CD008593.pub2.

Author Information

  1. 1

    Tulip Integrated Cancer Clinic, Faculty of Medicine, Gadjah Mada University, Hematology/Oncology Division, Internal Medicine Department, Yogyakarta, Indonesia

  2. 2

    International SOS, Yogyakarta, Indonesia

  3. 3

    Faculty of Medicine, Gadjah Mada University, Tulip Integrated Cancer Clinic, Hematology/Oncology Division, Internal Medicine Department, Yogyakarta, Indonesia

  4. 4

    King?s College London, School of Medicine,, Division of Cancer Studies, Cancer Epidemiology Group, London, UK

*Wahyu Wulaningsih, Hematology/Oncology Division, Internal Medicine Department, Tulip Integrated Cancer Clinic, Faculty of Medicine, Gadjah Mada University, Jalan Kesehatan No.1 Sekip Yogyakarta, Yogyakarta, Indonesia. wahyu.wulaningsih@yahoo.com.

Publication History

  1. Publication Status: Amended to reflect a change in scope (see 'What's new')
  2. Published Online: 22 AUG 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
 

Description of the condition

Colorectal cancer (CRC) is currently the third most common cancer for men and the second most common for women, as well as a leading cause of death worldwide (Ferlay 2010). In the United States, it is estimated that 142,820 people (73,680 men and 69,140 women) will be diagnosed with CRC and 50,830 will die from it in 2013 (Siegel 2013). Despite the highest incidence and mortality rates of CRC in more developed countries, these rates has been decreasing throughout the last two decades, particularly in the United States (Jemal 2011; Siegel 2013). Conversely, both CRC incidence and mortality have increased in less developed countries, largely owing to limited resources and healthcare infrastructure (Center 2009).

Early stage of CRC is potentially curable by surgery (Kuhry 2008). However, almost 50% of CRC patients are diagnosed with an advanced stage of disease, where the tumour is either metastatic or so locally advanced that curative surgical resection is unlikely to be carried out (Rougier 2003). For these patients, systemic chemotherapy is often the palliative treatment of choice, i.e. relieving symptoms, increasing survival and improving quality of life (Simmonds 2000; Ragnhammar 2001).

 

Description of the intervention

Antimetabolite fluoropyrimidines have been the backbone of CRC chemotherapy for the past 40 years. For decades, treatment efficacy was limited with fluorouracil (FU) monotherapy. The subsequent coupling of 5-fluorouracil (5-FU) with leucovorin (LV), a reduced folate that increases thymidylate synthetase inhibition, was used in attempts to modulate effects of 5-FU and improve its efficacy (ACCMAP 1992). This combination has been confirmed to result in better response rates than 5-FU alone for advanced CRC (aCRC) (Thirion 2004) and remains the basic component of most chemotherapy regimens in CRC either as intravenous (IV) bolus injection, infusion, or both (Chau 2005; Maiello 2005).

In more recent years, a number of oral fluoropyrimidines have become available. In addition to its more convenient use as an oral agent, capecitabine has been shown in clinical trials to be superior to IV 5-FU/LV in safety profiles with similar (non-inferior) overall survival (OS), progression-free survival (PFS) and time to progression (TTP) for the treatment of aCRC (Petrelli 2012; Van Cutsem 2004). These encouraging results suggest that oral fluoropyrimidine agents may serve as a suitable replacement for IV agents  for CRC treatment. Nevertheless, when both treatment arms were combined with irinotecan, IV 5-FU/LV demonstrated longer PFS and less toxicity in metastatic CRC compared to capecitabine (Montagnani 2010).

Irinotecan (IRI) is a semisynthetic derivative of the natural alkaloid camptothecin which inhibits topoisomerase I, thus impending DNA uncoiling and leading to double-stranded DNA breaks (Hsiang 1985). This novel drug was shown to have antitumour activity against CRC when administered intravenously alone in first-line setting, or as a second-line regimen for patients with aCRC that is refractory to FU (Conti 1996; Pitot 1997; Rothenberg 1999; Rougier 1997; Rougier 1998)

 

How the intervention might work

As a first-line chemotherapeutic regimen for CRC, IV IRI alone was demonstrated to have a comparable antitumour activity to 5-FU/LV (Cao 2000, Saltz 2000). Besides a different mechanism of action from 5-FU, the lack of cross-resistance of IRI to previous 5-FU/LV treatment, as shown by its similar activity against untreated and 5-FU-pretreated CRC, is the rationale for combining it with fluoropyrimidines as first-line therapy for this disease (Rougier 1997). However, compared to oxaliplatin, IRI has weaker synergistic effects when combined with fluoropyrimidines (Fischel 2001), thus it is more commonly used as a second-line treatment (Oostendorp 2010). As second-line treatment, two phase III studies show modest benefits in survival with IRI after failure of 5-FU-based therapy for aCRC of 2.3 months and 2.7 months versus IV 5-FU and best supportive care respectively (Rougier 1998; Cunningham 1998). Until now, the superiority of IRI combined with fluoropyrimidines over fluoropyrimidines alone has been well established in many studies, and the combination regimen is now widely used for aCRC patients in clinical practice (Douillard 2000; Maiello 2000; Folprecht 2008; Giessen 2011; Muro 2010).

 

Why it is important to do this review

Several randomised controlled trials (RCTs) comparing IRI in combination with fluoropyrimidines with IRI alone suggest that the combination regimen leads to better outcomes in OS and TTP for aCRC (Saltz 2000; Seymour 2007), while the results of another trial and a meta-analysis indicate that irinotecan monotherapy has equivalent efficacy and toxicity (Graeven 2007; Clarke 2011). However, the meta-analysis comparing IRI and IV 5-FU/LV combination regimen (FOLFIRI) for second-line treatment of CRC was not specific for trials concurrently including both treatment arms (Clarke 2011). Thus the benefit of IRI and fluoropyrimidines over IRI monotherapy remains unclear. Taking their efficacy and toxicity into account, we therefore undertake this study to systematically compare the combination regimen with IRI alone to determine which regimen is more suitable for aCRC patients, either as a first-line or a second-line chemotherapeutic therapy.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support

The aim of this systematic review is to compare efficacy and safety of two chemotherapeutic regimens, irinotecan monotherapy or irinotecan in combination with fluoropyrimidines, for patients with advanced colorectal cancer when administered in the first or second-line setting.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

Randomized controlled trials (RCTs) investigating efficacy and safety of chemotherapeutic regimens which compared IRI combined with fluoropyrimidine to IRI alone for the treatment of patients with aCRC, regardless of treatment line settings, are eligible for the inclusion. If trials enrolled more than two groups, we will only extract data that related to the two regimens.

 

Types of participants

Studies involving patients who are diagnosed histologically or cytologically with locally advanced and/or metastatic CRC will be included.

 

Types of interventions

The experimental group will receive the combination regimen, namely irinotecan with any of fluoropyrimidines, intravenously or orally; the control group will have received single agent irinotecan. Other agents are acceptable as long as they are common to both treatment arms, except LV, which is specific to IV 5-FU.

 

Types of outcome measures

 

Primary outcomes

The primary outcome measures will be:

  • overall survival (OS),
  • time to progression (TTP) or progression-free survival (PFS), analysed on an intention to treat (ITT) basis.

Studies which report survival outcomes either directly or by curves will be included, if the relevant data can be obtained by using Parmar methods (Parmar 1998; Tierney 2007).

 

Secondary outcomes

The secondary outcome measures will be:

  • response rates, classified according to the RECIST criteria (see below),
  • toxicity,
  • quality of life

Response rates classified according to Response Evaluation Criteria In Solid Tumors (RECIST version 1.0) (Therasse 2000), where measurable target and non-target lesions are determined at baseline and evaluated during follow up. A complete response is defined as disappearance of full lesion, while partial response refers to a decrease of at least 30% of lesion and progressive disease an increase of at least 20% of the lesion. Those with no sufficient changes to be categorized as either partial response or progressive disease are classified as stable disease.

 

Search methods for identification of studies

 

Electronic searches

Published or unpublished trials that may be eligible for inclusion will be identified by performing searches in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index. In each database, both medical subject headings and free-text searching will be performed in order to improve the sensitivity of the searches. All above databases will be searched from the beginning of electronic records to present time and eligible studies in English will be identified without any publication date or publication status limitations.

 

Searching other resources

Published meta-analyses and relevant reviews, registers of controlled trials in progress, references cited in relevant publications and conference proceedings in related fields will also be searched (BioMed Central and Medscape's Conference). The key authors or investigators of all eligible studies, and professionals in the field will be contacted if necessary in order to obtain other relevant information on the topic. In addition, bibliographies of identified trials and relevant references will be hand-searched.

 

Data collection and analysis

 

Selection of studies

The title, abstract and keywords of every record from retrieved studies obtained by applying the above search strategies will be checked against the inclusion criteria independently by two reviewers (NY and AS). Disagreements will be resolved by discussion. Potentially eligible trials will be retrieved in full for further assessment. Where more than one publication of a single trial exists, only the publication with the most complete data will be included unless the relevant outcomes are only published in earlier versions.

 

Data extraction and management

Data will be extracted from published papers independently by two reviewers (WW and NY). Data for survival and progression will be stratified from the publications or estimated from survival curves where necessary. The following data of each study will also be requested: response rates (complete and partial), toxicity, the outcomes of quality life measurements, if any, the schedule and dosing of neither irinotecan or fluoropyrimidines, and baseline characteristics including age, sex, performance status, site of metastatic disease, whether or not patients have had previous adjuvant chemotherapy, site of primary tumor (rectum versus colon). If a study does not include one of the comparators of interest , only available results on the other interventions will be included. The investigators of included studies will be asked to supply updated data where possible.

 

Assessment of risk of bias in included studies

The methodological quality of the included studies will be evaluated independently by two reviewers (WW and AW) with disagreements resolved by a third reviewer (MVH) according to the Cochrane Handbook. For each study, the following domains will be assessed with information recorded in the Cochrane Risk of Bias tool (Higgins 2011):

  1. Selection bias: the generation of allocation schedule (truly random, quasi random, systematic) & concealment of treatment allocation
  2. Performance bias: blinding of study participants and personnel
  3. Detection bias: blinding of outcome assessors,
  4. Attrition bias: completeness of follow-up, withdrawal and drop-out rates and whether analyses were performed by ITT
  5. Selective outcome reporting: evidence that outcome data have been reported based on the nature of the results.
  6. Other bias

The methods and procedures will be judged as low, high or unclear risk of bias. Any disagreement will be resolved by discussion between the reviewers. Investigators will be contacted where this information cannot be extracted from the publication.

 

Measures of treatment effect

The absolute effects of treatment at different time points will be obtained from publication data or read from simple (non-stratified) Kaplan Meier curves of included trials. Median survival and TTP (or PFS) will be also estimated from Kaplan-Meier curves.

The information on survival and progress from each study will be summarized as a log hazard ratio and its variance and the log-rank expected number of events and variance will be used to calculate the hazard ratios (HR) for individual trials.

All time to event analyses will be performed by ITT.

 

Dealing with missing data

The key authors or the principal investigators of the trials will be contacted and asked to provide data that are missing or information which cannot be extracted from the publication.

 

Assessment of heterogeneity

The studies will be evaluated clinically and methodologically to assess if it is reasonable to consider combining data. Statistical heterogeneity will be measured by the visual inspection of the forest plots, statistically through a homogeneity test based on the Chi-square (with a P value of less than 0.10 considered to be statistically significant for heterogeneity). The I2 measurement will be calculated as an indicator of the amount of statistical variation that is not attributable to the play of chance. A value more than 50% will be considered to represent substantial heterogeneity. Further investigations will be undertaken to determine if the heterogeneity can be explained.

 

Assessment of reporting biases

Funnel plots will be used to assess the extent to which publication bias may be present .

 

Data synthesis

The statistical package Review Manager 5 (RevMan 5) provided by the Cochrane Collaboration will be used for analysing data. Pooled results on survival or progress will be expressed as HR with 95% confidence intervals (CI) by calculating the overall HR and its variance across the trials under a fixed-effects model. All Time to Event analyses will be performed by ITT. Data on toxicity and response rates will be analysed as dichotomous data and the outcomes will be reported as relative risk (RR) with 95% CI. The fixed-effect model will be used for the analysis.

 

Subgroup analysis and investigation of heterogeneity

Studies will be firstly grouped according to whether fluoropyrimidines were administered orally or intravenously. A second subgroup analysis will be performed according to the different chemotherapeutic line that individual trials were in. We will also explore possible interactions between different methods of administration of 5-FU in combination with IRI (infusion versus bolus). The chi-squared test for interaction will be also used to test for consistency of effect across these subsets of trials.

 

Sensitivity analysis

Sensitivity analyses will be performed in order to assess the robustness of our results to different assumptions or methodological approaches:

  1. Removing studies at a high risk of bias.
  2. Exclusion of studies that used other agents which may affect treatment effects of study regimen.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support

None Known.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
 

Appendix 1. MEDLINE search strategy

#1 RANDOMIZED-CONTROLLED-TRIAL in PT
#2 CONTROLLED-CLINICAL-TRIAL in PT
#3 RANDOMIZED-CONTROLLED-TRIALS
#4 RANDOM-ALLOCATION
#5 DOUBLE-BLIND-METHOD
#6 SINGLE-BLIND-METHOD
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 TG=ANIMALS not (TG=HUMANS and TG=ANIMALS)
#9 #7 not #8
#10 CLINICAL-TRIAL in PT
#11 explode CLINICAL-TRIALS
#12 (clin* near trial*) in TI
#13 (clin* near trial*) in AB
#14 (singl* or doubl* or trebl* or tripl*) near (blind* or mask*)
#15 (#14 in TI) or (#14 in AB)
#16 PLACEBOS
#17 placebo* in TI
#18 placebo* in AB
#19 random* in TI
#20 random* in AB
#21 RESEARCH-DESIGN
#22 #10 or #11 or #12 or #13 or #15 or #16 or #17 or #18 or #19 or #20 or #21
#23 TG=ANIMALS not (TG=HUMANS and TG=ANIMALS)
#24 #22 not #23
#25 #24 not #9
#26 TG=COMPARATIVE-STUDY
#27 explode EVALUATION-STUDIES
#28 FOLLOW-UP-STUDIES
#29 PROSPECTIVE-STUDIES
#30 control* or prospectiv* or volunteer*
#31 (#30 in TI) or (#30 in AB)
#32 #26 or #27 or #28 or #29 or #31
#33 TG=ANIMALS not (TG=HUMANS and TG=ANIMALS)
#34 #32 not #33
#35 #34 not (#9 or #25)
#36 #9 or #25 or #35 (to combine all 3 phases)
#37 (cancer* OR neoplas* OR carcinoma* OR malignan* OR adenocarcinoma* OR tumor*).tw
#38 (colorectal OR colon* OR rect* OR bowel*).tw
#39 #37 AND #38
#40 Colorectal Neoplasms [Mesh]
#41 #39 OR #40
#42 (fluoropyrimidine OR Fluorouracil OR 5 fluorouracil OR 5-fluorouracil OR 5 FU OR 5-FU OR Efudix OR Efudex OR S1 OR S-1 OR Fluoroplex OR Orzel OR Capecitabine OR Xeloda OR Eniluracil OR 776C85 OR UFT OR tegafur).tw
#43 (Irinotecan OR Camptosar OR camptothecin-11 OR CPT-11 OR SN-38).tw
#44 #41 AND #42 AND #43
#45 #36 AND #44

 

Appendix 2. EMBASE search strategy 

#1 "RANDOMIZED-CONTROLLED-TRIAL"/ all subheadings
#2 "RANDOMIZATION"/ all subheadings
#3 "CONTROLLED-STUDY"/ all subheadings
#4 "MULTICENTER-STUDY"/ all subheadings
#5 "PHASE-3-CLINICAL-TRIAL"/ all subheadings
#6 "PHASE-4-CLINICAL-TRIAL"/ all subheadings
#7 "DOUBLE-BLIND-PROCEDURE"/ all subheadings
#8 "SINGLE-BLIND-PROCEDURE"/ all subheadings
#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8
#10 (RANDOM* or CROSS?OVER* or FACTORIAL* or PLACEBO* or OLUNTEER*) in TI,AB
#11 (SINGL* or DOUBL* or TREBL* or TRIPL*) near (BLIND* or MASK*) in TI,AB
#12 #9 or #10 or #11
#13 HUMAN in DER
#14 (ANIMAL or NONHUMAN) in DER
#15 #13 and #14
#16 #14 not #15
#17 #12 not #16
#18 (cancer* OR neoplas* OR carcinoma* OR malignan* OR adenocarcinoma* OR tumor*).tw
#19 (colorectal OR colon* OR rect* OR bowel*).tw
#20 #18 AND #19
#21 exp Colorectal Neoplasms M
#22 #20 OR #21
#23 (fluoropyrimidine OR Fluorouracil OR 5 fluorouracil OR 5-fluorouracil OR 5 FU OR 5-FU OR Efudix OR Efudex OR S1 OR S-1 OR Fluoroplex OR Orzel OR Capecitabine OR Xeloda OR Eniluracil OR 776C85 OR UFT OR tegafur).tw
#24 (Irinotecan OR Camptosar OR camptothecin-11 OR CPT-11 OR SN-38).tw
#25 #22 AND #23 AND #24
#26 #17 AND #25

 

Appendix 3. Cochrane Library search strategy

#1 (cancer* OR neoplas* OR carcinoma* OR malignan* OR adenocarcinoma* OR tumor*).tw
#2 (colorectal OR colon* OR rect* OR bowel*).tw
#3 #1 AND #2
#4 Colorectal Neoplasms [Mesh]
#5 #3 OR #4
#6 (fluoropyrimidine OR Fluorouracil OR 5 fluorouracil OR 5-fluorouracil OR 5 FU OR 5-FU OR Efudix OR Efudex OR S1 OR S-1 OR Fluoroplex OR Orzel OR Capecitabine OR Xeloda OR Eniluracil OR 776C85 OR UFT OR tegafur).tw
#7 (Irinotecan OR Camptosar OR camptothecin-11 OR CPT-11 OR SN-38).tw
#8 #5 AND #6 AND #7

 

Appendix 4. Science Citation Index search strategy

As these databases do not have index terms a combination of the following key words were used: (colorectal or colon* or
rectum or rectal) cancer; random*; double blind; single blind; irinotecan or Camptosar or camptothecin-11 or CPT-11 or SN-28, fluoropyrimidine or fluorouracil or 5 fluorouracil or 5-fluorouracil or 5 FU or 5-FU or Efudix or Efudex or S1 or S-1 or Fluoroplex or Orzel or capecitabine or Xeloda or eniluracil or 776C85 or UFT or tegafur.

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support


DateEventDescription

24 June 2013New citation required and major changesUpdated protocol with new author team

24 June 2013AmendedAs above



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support


TASKSWHO WILL UNDERTAKE TASKS?

Draft the protocolWahyu Wulaningsih and Mieke Van Hemelrijck

Develop a search strategyWahyu Wulaningsih and Mieke Van Hemelrijck

Search for trialsNaomi Yoshuantari and Ajeng Sekarini

Select which trials to includeWahyu Wulaningsih and Ardyan Wardhana

Extract data from trialsWahyu Wulaningsih and Naomi Yoshuantari

Enter data into RevManNaomi Yoshuantari and Ajeng Sekarini

Carry out the analysisWahyu Wulaningsih and Ardyan Wardhana

Interpret the analysisWahyu Wulaningsih and Mieke Van Hemelrijck

Draft the final reviewWahyu Wulaningsih and Ardyan Wardhana



 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support

None Known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. What's new
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
 

Internal sources

  • No sources of support supplied, Not specified.

 

External sources

  • No sources of support supplied, Not specified.

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. What's new
  9. Contributions of authors
  10. Declarations of interest
  11. Sources of support
  12. Additional references
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