Weekly versus tri-weekly paclitaxel with carboplatin for first-line treatment in women with ovarian cancer
This is the protocol for a review and there is no abstract. The objectives are as follows:
To compare the effectiveness and safety of weekly paclitaxel with that of three-weekly paclitaxel, in combination with carboplatin, as first-line chemotherapy treatment for ovarian cancer.
Description of the condition
Ovarian cancer is the seventh most common cancer in women worldwide - 239,000 new cases were diagnosed in 2012 and the five-year prevalence is 22.6 per 100,000 population (Bray 2013; Ferlay 2012; Ferlay 2013). A woman’s risk of developing ovarian cancer before the age of 75 is estimated to range from 0.5% in developing countries to 1% in developed countries (Jemal 2011). It is also the most lethal gynaecological malignancy, with a five-year survival rate ranging from approximately 30% to 50% (Ferlay 2012). This is because most women are diagnosed when the cancer is already at an advanced stage (Jemal 2008). In Europe, just over a third of women with ovarian cancer are alive five years after diagnosis (Sant 2003). Therefore, there is an urgent need to establish interventions which may enhance the survival of women with ovarian cancer (primary objective) or reduce adverse events (secondary objective), or both.
Epithelial ovarian cancer (EOC) is shown to be most amenable to a taxane-platinum combination compared with other treatment modalities (Kyrgiou 2006). The taxane compound may be paclitaxel or docetaxel. This review focuses on paclitaxel as it is in wider clinical usage, and has a different side effects profile and biological mode of action compared to docetaxel.
Description of the intervention
Combination treatment with paclitaxel and carboplatin, given on a three-weekly basis, is the most common first line chemotherapeutic approach for women with advanced epithelial ovarian cancer (Baird 2010). Cisplatin may be administered instead of carboplatin, but may be associated with increased toxicity with no significant additional survival benefit (Neijt 2000; Ozols 2003). Paclitaxel and docetaxel are equally efficacious taxanes, but with different side effects profiles: paclitaxel is associated with a higher risk of neuropathy (e.g. weakness, numbness and pain due to nerve dysfunction); docetaxel is associated with a higher risk of myelosuppression (e.g. reduction of white blood cells, red blood cells and platelets) (Katsumata 2003; Pertusini 2001; Vasey 2004).
The most recent National Comprehensive Cancer Network (NCCN) clinical guidelines for intravenous (IV) chemotherapy regimens (National Comprehensive Cancer Network 2015) include:
paclitaxel 175 mg/m2 IV over three hours followed by carboplatin AUC 5 to 6 IV over one hour on day 1, repeated every three weeks for six cycles;
dose-dense paclitaxel 80 mg/m2 IV over one hour on days 1, 8, and 15 followed by carboplatin AUC 5-6 IV over one hour on day 1, repeat every three weeks for six cycles;
paclitaxel 60 mg/m2 IV over one hour followed by carboplatin AUC 2 IV over 30 minutes weekly for 18 weeks;
docetaxel 60 mg/m2 to 75 mg/m2 IV over one hour followed by carboplatin AUC 5 to 6 IV over one hour on day 1, repeat every three weeks for six cycles.
How the intervention might work
Paclitaxel works by binding to tubulin, which causes defects in chromosome segregation and consequently cell division (Jordan 2004). Additionally, at lower concentrations, it may be anti-angiogenic, that is it disrupts the formation of new blood vessels which help the cancer to spread and grow (Schwartz 2009).
Importantly, the efficacy and safety of paclitaxel is dependent on dosing schedule and infusion duration, likely because of differences in the pharmacokinetic and pharmacodynamic profile of paclitaxel under different circumstances. For example, it was previously observed that a 96-hour infusion leads to more frequent grade 3 or 4 anaemia compared to a 24-hour infusion (Spriggs 2007), which in turn results in more neutropenia, but similar response rates, compared to a 3-hour infusion (Eisenhauer 1994). Weekly paclitaxel is administered at 60 mg/m2 to 80 mg/m2 over a one-hour infusion, with possibly greater efficacy at higher doses.
According to Baird 2010, the pharmacologic rationale for weekly paclitaxel is: first, at 60 mg/m2/week to 80 mg/m2/week, it is more dose-dense and potentially more dose-intense (if the cumulative dose is higher than the three-weekly dose e.g. 175 mg/m2) compared to the three-weekly schedule. The shortened interval between doses provides more sustained paclitaxel exposure and could potentiate tumour cell-kill. Second, it could be less myelosuppressive, as it is administered over a shorter infusion duration (one hour versus three hours), which has been found in pharmacokinetic studies to reduce the time wherein plasma paclitaxel is above the haemotoxic concentration of 50 nM (Gianni 1995; Marchetti 2002). Third, paclitaxel also exerts anti-angiogenic effects at lower plasma concentrations, such as those observed with the weekly schedule (Thomas 2002).
Cisplatin and carboplatin are both platinum agents that exert antitumour activity by promoting DNA damage (Siddik 2003). The difference between them is how they interact with DNA (Knox 1986).
Why it is important to do this review
Interest in a three-weekly paclitaxel regimen was inspired by the JGOG 3016 trial, which found that weekly paclitaxel was associated with an improvement in progression-free survival (28.2 months versus 17.5 months, hazard ratio (HR) = 0.76, P value < 0.01) and overall survival (100.5 months versus 62.2 months, HR = 0.79, P value = 0.04), even at long-term follow-up (Katsumata 2009, Katsumata 2013). In this study, 631 women with Stage II to IV ovarian cancer were randomised to treatment with carboplatin and paclitaxel (every three weeks) or to carboplatin (every three weeks) with dose-dense weekly paclitaxel. The regimen in both arms was repeated every three weeks for up to nine cycles.
However, the survival benefit in more recent and ongoing studies has been less remarkable:
The GOG 262 trial randomised 692 women with Stage I to IV ovarian cancer to a three-weekly carboplatin and paclitaxel regimen versus a three-weekly carboplatin and weekly paclitaxel regimen, and bevacizumab was allowed in both arms. An interim analysis found that there was no difference in progression-free survival between the two regimens, but subgroup analysis showed that, in women not treated with bevacizumab, a weekly paclitaxel regimen improved progression-free survival compared with a three-weekly regimen (Chan 2013). A single-arm phase II study evaluating front-line bevacizumab, carboplatin and weekly paclitaxel demonstrated median progression-free survival of approximately two years (Gonzalez-Martin 2013).
The MITO-7 trial randomised 822 women with Stage IC to IV ovarian cancer to three-weekly carboplatin and paclitaxel versus weekly carboplatin and paclitaxel. Both treatment regimens were given a total of six cycles. They found that there was no difference in progression-free survival or overall survival between the two arms. The toxicity rates were lower in the weekly treatment arm (Pignata 2014).
As the optimal dose schedule of carboplatin and paclitaxel in the first-line treatment for ovarian cancer is unclear, it is necessary to conduct this review to clarify the effectiveness and safety of a weekly paclitaxel regimen when compared to a three-weekly paclitaxel regimen as first-line IV chemotherapy treatment for ovarian cancer. However, the review will only be conducted when results of the ICON8 trial (ClinicalTrials.gov Identifier: NCT01654146) is published either as an abstract (if sufficient details are provided) or as a full paper.
To compare the effectiveness and safety of weekly paclitaxel with that of three-weekly paclitaxel, in combination with carboplatin, as first-line chemotherapy treatment for ovarian cancer.
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs)
Types of participants
Adult women, 18 years or older, newly diagnosed with epithelial ovarian cancer, FIGO Stage I to IV
Types of interventions
Intervention: weekly paclitaxel, including metronomic (similar cumulative dosage) or dose-dense (increased cumulative dosage) in combination with carboplatin.
Comparison: three-weekly paclitaxel in combination with carboplatin.
Other chemotherapeutic agents, including platinum agents, molecular therapies such as those which target the epidermal growth factor receptor (i.e. anti-EGFR), and immunotherapy are allowed, but must be given in both groups which are being compared.
Types of outcome measures
Overall survival: time from randomisation to death from any cause.
Progression-free survival: time from randomisation to disease progression or death from any cause.
Risk of severe (grade 3 and 4) neutropenia.
Quality of life (QoL), measured using a scale that has been validated through reporting of norms in a peer-reviewed publication.
Adverse events, classified according to Common Terminology Criteria for Adverse Events (CTCAE) version 2.0, 3.0 and 4.0. (CTCAE 2010).
Grades of toxicity will be extracted and grouped as:
haematological: anaemia, thrombocytopenia, leucopenia, haemorrhage;
cardiac: bradycardia, atrial fibrillation;
neurological: peripheral and central;
skin: nail disorders, alopecia, stomatitis, mucositis, allergy;
gastrointestinal: diarrhoea, anorexia, nausea, vomiting, liver dysfunction, proctitis.
Search methods for identification of studies
There will be no language or date restrictions. We will search for papers in all languages and have them translated as necessary.
We will search the following electronic databases:
The Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group’s Trial Register
Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue)
MEDLINE Ovid (1946 to present date);
EMBASE (1980 to present date);
The MEDLINE search strategy is presented in Appendix 1. We will adapt the search strategy accordingly for the databases listed above other than MEDLINE.
Searching other resources
We will identify all relevant articles on PubMed and carry out a further search for newly published articles using the ‘related articles’ feature. We will search references of retrieved articles for relevant articles.
Unpublished and Grey Literature
We will search the following for ongoing trials:
If these searches identify any ongoing trials that have not been published, we will contact the principal investigators to request the relevant data.
We will handsearch the citation lists of included studies, key textbooks and previous systematic reviews to identify further reports of trials. We will also handsearch the reports of conferences in the following sources:
Gynecologic Oncology (Annual Meeting of the American Society of Gynaecologic Oncologists)
International Journal of Gynaecologic Cancer (Annual Meeting of the International Gynaecologic Cancer Society)
Annual Meeting of European Society of Medical Oncology (ESMO)
Annual Meeting of the American Society of Clinical Oncology (ASCO)
European Society of Gynaecological Oncology (ESGO)
Data collection and analysis
Selection of studies
We will download all titles and abstracts retrieved by electronic searching to the Mendeley reference management database and remove duplicates. Two review authors (NLS, RMG) will examine the remaining references independently. We will exclude those studies which clearly do not meet the inclusion criteria and obtain copies of the full text of potentially relevant references. Two review authors (YYS, DST) will independently assess the eligibility of the retrieved papers and resolve any disagreements through discussion, and if necessary by consulting a third review author (BCG). We will document reasons for exclusion.
Data extraction and management
Two review authors (NLS, RMG) will independently extract study characteristics and outcome data from included studies on to a pre-piloted data collection form. We will note in the ‘Characteristics of included studies’ table if outcome data was not reported in a usable way. We will resolve disagreements by consensus or by appeal to a third review author (DST). One review author (NLS) will transfer data into the Cochrane Review Manager Software (RevMan) (RevMan 2014). A second review author (BCG) will double-check that data has been entered correctly by comparing the data presented in the systematic review with the study reports.
For included studies, we will extract the following data:
Author, year of publication and journal citation (including language)
Inclusion and exclusion criteria
Study design, methodology
Choice, dose intensity and frequency of platinum agent
Dose and frequency of paclitaxel
Route of paclitaxel administration
Details of radiotherapy and debulking surgery if applicable
Details of targeted therapy if applicable
Risk of bias in study (see below)
Duration of follow-up
Outcomes: For each outcome, we will extract the outcome definition and unit of measurement (if relevant). For adjusted estimates, we will record variables adjusted for in analyses.
Results: We will extract the number of participants allocated to each intervention group, the total number analysed for each outcome, and the missing participants.
Notes: Funding for trial, and notable conflicts of interest of trial authors
For results we will extract the following data:
For time-to-event data (survival and disease progression), we will extract the log of the hazard ratio [log(HR)] and its standard error from trial reports. If these are not reported, we will attempt to estimate the log (HR) and its standard error using the methods of (Parmar 1998).
For dichotomous outcomes (e.g. adverse events), we will extract the number of patients in each treatment arm who experienced the outcome of interest and the number of patients assessed at endpoint, in order to estimate a risk ratio.
For continuous outcomes (e.g. QoL measures), we will extract the final value and standard deviation of the outcome of interest and the number of patients assessed at endpoint in each treatment arm at the end of follow-up, in order to estimate the mean difference between treatment arms and its standard error.
Assessment of risk of bias in included studies
We will assess and report on the methodological risk of bias of included studies using the Cochrane risk of bias tool, which assesses the explicit reporting of the following individual elements for RCTs (Higgins 2011).
Selection bias: random sequence generation and allocation concealment
Performance bias: blinding of participants and personnel (patients and treatment providers)
Detection bias: blinding of outcome assessment
Attrition bias: incomplete outcome data
Reporting bias: selective reporting of outcomes
Two review authors (NLS, RMG) will apply the risk of bias tool independently and will resolve any differences by discussion or by appeal to a third review author (DST). We will judge each item as being at high, low or unclear risk of bias as set out in the criteria provided by Higgins 2011, and provide a quote from the study report or a statement, or both as justification for the judgement for each item in the 'Risk of bias' table. We will summarise results in both a 'Risk of bias' graph and a 'Risk of bias' summary. When interpreting treatment effects and meta-analyses, we will take into account the risk of bias for the studies that contribute to that outcome. Where information on risk of bias relates to unpublished data or correspondence with a study author, we will note this in the 'Risk of bias' table. Please see Appendix 2 for the full risk of bias criteria.
Measures of treatment effect
We will use the following measures of the effect of treatment.
For time-to-event data, we will use the hazard ratio (HR), if possible
For dichotomous outcomes, we will analyse data based on the number of events and the number of people assessed in the intervention and comparison groups. We will use these to calculate the risk ratio (RR) and 95% confidence interval (CI)
For continuous outcomes, we will analyse data based on the mean, standard deviation (SD) and number of people assessed for both the intervention and comparison groups to calculate mean difference (MD) between treatment arms with a 95% CI. If the MD is reported without individual group data, we will use this to report the study results. If more than one study measures the same outcome using different tools, we will calculate the standardised mean difference (SMD) and 95% CI using the inverse variance method in RevMan (RevMan 2014)
Dealing with missing data
We will attempt to contact study authors to obtain missing data (participant, outcome, or summary data). We will report on the levels of loss to follow-up and assess this as a source of potential bias.
Assessment of heterogeneity
Where studies are considered similar enough (in terms of participants, settings, intervention and outcome measures) to allow pooling of data using meta-analysis, we will assess the degree of heterogeneity by visual inspection of forest plots, by estimation of the percentage heterogeneity (I² statistic) between trials which cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Chi²) (Deeks 2001) and, if possible, by sub-group analyses. We will regard heterogeneity to be substantial if I² is greater than 50% or there is a low P-value (< 0.10) in the Chi² test for heterogeneity.
If there is evidence of substantial clinical, methodological or statistical heterogeneity across included studies we will not report pooled results from meta-analysis but will instead use a narrative approach to data synthesis. In this event we will investigate and report the possible clinical or methodological reasons for this.
Assessment of reporting biases
We will examine funnel plots corresponding to meta-analysis of the primary outcome to assess the potential for small study effects such as publication bias if more than ten studies are identified. We will assess funnel plot asymmetry visually, and if asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it (Sterne 2011).
As sources of variation are likely between studies, we will pool their results in meta-analyses using the random-effects model in RevMan 2014 with inverse variance for meta-analysis DerSimonian 1986.
For time-to-event data, we will pool hazard ratios using the generic inverse variance facility of RevMan 2014
For any dichotomous outcomes, we will calculate the risk ratio (RR) as appropriate for each study and these will then be pooled.
For continuous outcomes, will pool the mean differences (MD) between the treatment arms at the end of follow-up, if all trials measure the outcome on the same scale; otherwise we will pool standardised mean differences (SMD).
We will undertake meta-analyses only where this is meaningful, that is if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense. We will describe skewed data reported as medians and interquartile ranges. Where multiple trial arms are reported in a single trial, we will include only the relevant arms.
If any trials have multiple treatment groups, we will divide the ‘shared’ comparison group into the number of treatment groups and comparisons between each treatment group and treat the split comparison group as independent comparisons.
'Summary of findings' table
We will use the GRADEprofiler (GRADEpro) software to assist with the preparation of the 'Summary of findings' table (GRADEproGDT 2015). 'Summary of findings' tables present the review’s main findings in a table format, and provide key information about the best estimate of the magnitude of the effect, in relative terms, and absolute differences for each relevant comparison of alternative management strategies, numbers of participants and studies addressing each important outcome and the rating of the overall confidence in effect estimates for the comparisons in an outcome-specific manner. The outcomes we will include in the 'Summary of findings' table are:
haematological adverse events
neurological adverse events
We acknowledge that it may not be possible to address all important outcomes within the constraints of results reported in randomized controlled trials only.
Quality of evidence
We will assess the quality of evidence as 'High', 'Moderate', 'Low' or 'Very Low' using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach (GRADE Working Group 2004, Schünemann 2011), which evaluates studies on five domains: study limitations (risk of bias), consistency, imprecision, indirectness and publication bias. Two review authors (NLS, RMG) will independently rate the quality for each outcome. We will resolve any disagreements by appeal to a third (DST) or fourth review author (BCG) if necessary.
Subgroup analysis and investigation of heterogeneity
If possible, we will perform subgroup analyses for the following factors:
studies conducted in Asia or with a majority of Asian patients versus studies conducted in Western countries or with a majority of Caucasian patients
metronomic (similar cumulative dosage) versus dose-dense (increased cumulative dosage) dosing schedule
intraperitoneal route (injection into the peritoneum (body cavity)) of administration versus non-intraperitoneal
targeted therapy versus no targeted therapy
cytoreductive (or debulking) surgery to remove malignant tissue versus no cytoreductive surgery
We will consider factors such as age, stage, type of intervention, length of follow-up and risk-of-bias status in interpretation of any heterogeneity.
We will perform sensitivity analyses excluding studies with unclear or high risk of bias, and imputed data.
Ensuring relevance to decision in healthcare
This review aims to inform clinical decisions regarding the choice of paclitaxel schedule by reporting pooled estimates for the treatment effect of weekly paclitaxel compared to tri-weekly paclitaxel, using outcomes that matter to physicians and patients with ovarian cancer (survival and adverse events) (Baird 2010). Another pertinent issue is whether it is possible to select patients for treatment with weekly paclitaxel (Baird 2010), which we will attempt to address through subgroup analysis.
The results of the review, once published, will be disseminated to major organisations and groups with an interest in clinical oncology, especially in the field of gynaecological malignancies and those with the ability to influence healthcare policy making, for example American Society for Clinical Oncology (ASCO), American Association for Cancer Research (AACR), National Comprehensive Cancer Network (NCCN), Cancer Research UK, Gynaecologic Oncology Group (COG), International Gynaecologic Cancer Society (IGCS), National Cancer Institute (NCI), World Health Organization (WHO) Cancer Control Programme. We will work with Cochrane to issue a press release, as well as coverage on Cochrane social media platforms, and relevant PLoS blogs. We will also update relevant Wikipedia pages.
We thank Jane Hayes for designing the search strategy; Jo Morrison for her clinical expertise; Clare Jess and Tracey Bishop for their contribution to the editorial process.
This project was supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.
Appendix 1. MEDLINE OVID
1 exp Ovarian Neoplasms/
2 (ovar* adj5 (cancer* or tumor* or tumour* or neoplas* or carcinoma* or adenocarcinoma* or malignan*)).mp.
3 1 or 2
5 (paclitaxel or taxol or praxel or anzatax or nsc125973 or nsc 125973 or paxene or onxol or abraxane).mp.
6 4 or 5
7 exp Drug Administration Schedule/
9 (dose or dosage or dosing or dose-dense or PcW or Pc3W or week or weekly or schedule*).mp.
10 7 or 8 or 9
11 randomised controlled trial.pt.
12 controlled clinical trial.pt.
15 drug therapy.fs.
19 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18
20 3 and 6 and 10 and 19
mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier
Appendix 2. Risk of bias criteria
The following criteria will also be used to assess risk of bias.
Low risk of bias e.g. where the allocation sequence could not be foretold
High risk of bias e.g. allocation sequence could be foretold by patients, investigators or treatment providers
Unclear risk of bias e.g. not reported
Low risk of bias - if review authors do not suspect any other source of bias and the trial appears to be methodologically sound
High risk of bias - if review authors suspect that the trial was prone to an additional bias
Unclear risk of bias - if review authors are uncertain whether an additional bias may have been present
|21 September 2016||Amended||Contact details updated.|
Contributions of authors
Draft the protocol : Nicholas Syn, Yu Yang Soon, David Tan, Boon Cher Goh
Obtain copies of trials : Yu Yang Soon
Select which trials to include : David Tan, Yu Yang Soon, Nicholas Syn, Robby Goh, Boon Cher Goh
Extract data from trials : Nicholas Syn, Robby Goh
Enter data into RevMan : Nicholas Syn, Robby Goh
Carry out the analysis : Nicholas Syn, Robby Goh, Yu Yang Soon
Interpret the analysis : Nicholas Syn, David Tan, Yu Yang Soon, Robby Goh, Boon Cher Goh
Draft the final review : Nicholas Syn, David Tan, Yu Yang Soon, Robby Goh, Boon Cher Goh
Update the review : Nicholas Syn, Robby Goh, David Tan, Yu Yang Soon
Declarations of interest
Nicholas Li-Xun Syn : nothing to declare
Robby M Goh: nothing to declare
Boon Cher Goh : nothing to declare
Yu Yang Soon : nothing to declare
David Shao Peng Tan : nothing to declare