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Cochrane Database of Systematic Reviews Protocol - Intervention

Taxane‐platinum combination chemotherapy versus single agent platinum for the first‐line treatment of epithelial ovarian cancer

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the benefit and harms of adding a taxane to platinum therapy compared to platinum chemotherapy alone for the primary management of epithelial ovarian, fallopian tube or peritoneal epithelial adenocarcinoma.

Background

Description of the condition

Ovarian cancer describes many different tumours that develop from diverse tissues contained within the ovary. Ovarian epithelial cancer (adenocarcinoma) is the commonest and these cells come from the surface of the ovary, peritoneum or fallopian tube. Ovarian cancer is similar to peritoneal and fallopian tube adenocarcinoma.

Ovarian cancer is often hard to detect in early stages and women usually present for the first time when their cancer has spread beyond the ovary (beyond Stage 1). It is unusual for the tumour to remain close to the ovary (Stage 2) because it usually spreads throughout all of the abdominal cavity (Stage 3). It becomes a Stage 4 disease once it metastases to the liver or beyond the abdomen (Shepherd 1989).

A woman's risk of developing ovarian cancer by age 65 years ranges from 0.36% in developing countries to 0.64% in developed countries (Ferlay 2008). The presenting symptoms of ovarian cancer are often vague and may mimic other conditions. Currently three‐quarters of women with ovarian cancer are diagnosed when the disease has spread throughout the abdomen and the five‐year survival rate is 20 to 30% (Jemal 2008). In Europe, just over a third of women with ovarian cancer are alive five years after diagnosis (Quinn 2001; Sant 2003), largely because the majority of women with ovarian cancer are diagnosed when the cancer is already at an advanced stage (Jemal 2008).

Description of the intervention

The usual initial treatment of ovarian cancer is surgical removal and chemotherapy. One of the most popular drugs is platinum based chemotherapy (cisplatin [Platinol®] or carboplatin [Paraplatin®]) and this is commonly combined with paclitaxel (Taxol®).

The first trial to examine the survival advantages attributable to paclitaxel was GOG 111 (McGuire 1996). Three hundred and eighty‐six women with advanced ovary cancer and suboptimal debulking surgery received cisplatin (75 mg/m2) combined with either paclitaxel (135 mg/m2 over 24 hours) or cyclophosphamide (750 mg/m2). The median overall survival was significantly longer in women given cisplatin‐paclitaxel (38 versus 24 months).

Subsequently, Piccart 2000 studied 680 women with ovary cancer. All had cisplatin at a dose of 75 mg/m2 and either paclitaxel (175 mg/m2 infused over 3 hours) or cyclophosphamide (750 mg/m2). The survival difference was most pronounced in the subgroup of women who had suboptimal debulking surgery with a median overall survival of 30 months for the women allocated initial treatment with cisplatin‐paclitaxel compared to 20 months if cisplatin‐cyclophosphamide was used.

The third trial (GOG 132; Muggia 2000) measured survival in 648 women with suboptimally debulked ovary cancer after treatment with either cisplatin (100 mg/m2), paclitaxel (200 mg/m2 over 24 hours), or combination therapy (paclitaxel 135 mg/m2 over 24 hours followed by a lower dose of cisplatin 75 mg/m2). In this trial, 100 mg/m2 cisplatin alone was associated with an overall survival of 30 months compared to 26 months for the combination of paclitaxel and lower dose of cisplatin.

The ICON 3 trial recruited 2074 women with advanced ovary cancer (ICON Group 2002). Paclitaxel (175 mg/m2 3‐hour infusion) plus carboplatin (AUC 5) was associated with the same median overall survival as single‐agent carboplatin and CAP (500 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, and 50 mg/m2 cisplatin) (36 to 35 months). Subgroup analysis hinted that there may be a trend (pt = 0·22) towards a survival advantage with the addition of paclitaxel in the group of women who have residual disease greater than 2 to 0 cm after surgery .

Mouratidou 2007 measured survival in 120 women with ovary cancer. Half had suboptimal debulking surgery. All had cisplatin (75 mg/m2) and either paclitaxel (175 mg/m2 over 3 hours) or cyclophosphamide (700 mg/m2). The median survival was 24 and 20 months, respectively.

How the intervention might work

Advanced and disseminated epithelial ovarian cancer is an unusual solid tissue malignancy because it often regresses with chemotherapy. Despite this, of the 75% of women who present with advanced disease (stage III or IV), eventually develop drug resistance and suffer from tumour recurrence (Hennessy 2009). Randomised trials have failed to show any clear advantage to single, doublet or triplet regimens (Bookman 2010), to dosing density or maintenance chemotherapy (Makatsoris 1997; Ozols 2003; Tuma 2009; Vasey 2005; van der Burg 2011). As a result, patients and their physicians are faced with a choice. They could maximise initial exposure to the most active drugs (e.g. platinum and paclitaxel) with concomitant therapy in the hope of delivering greater initial responses and less drug resistance in the tumour. The alternative is to adopt a policy of sequential therapy giving platinum as primary treatment and using paclitaxel in the face of primary platinum resistance or at relapse.

Some women could achieve tumour regression, even if they received a relatively low dose of a single agent platinum, and some women will not respond well, irrespective of dose of type of treatment. Other women may have a better tumour response, if they are given a high dose of chemotherapy, and if multiple agents are used. This group may benefit from a policy of intense and prolonged courses of multimodal chemotherapy. Additional drugs may increase the progression‐free survival (PFS) interval and overall survival (OS) when compared to single agent carboplatin but the disadvantage is that entire treatment population are exposed to a reduction in QoL due to the additional treatment toxicity (Goldie 1994).

Why it is important to do this review

Informed consent to treatment occurs when a patient understands the benefits and side effects of a health intervention. Some women with ovary cancer will want treatment that offers the greatest chance of prolonging life. However, cure is unlikely and some women will feel that their quality of life may be a significant decider.  An up‐to‐date systematic assessment of randomised trials may be the best way to help patients decide if any potential additional survival value is worth the added toxicity from paclitaxel.

Objectives

To evaluate the benefit and harms of adding a taxane to platinum therapy compared to platinum chemotherapy alone for the primary management of epithelial ovarian, fallopian tube or peritoneal epithelial adenocarcinoma.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

Adult women newly diagnosed with epithelial adenocarcinoma of the ovary, peritoneum or fallopian tube of any stage who receive first line chemotherapy. This excludes women with recurrent disease.

Types of interventions

RCTs involving platinum plus any taxane chemotherapy by any route versus single agent platinum chemotherapy.

Types of outcome measures

Primary outcomes

Overall survival (OS): survival until death from all causes. Survival will be assessed from the time when women are enrolled in the study.

Secondary outcomes

  • Progression‐free survival (PFS) or disease progression

  • Quality of life (QoL), measured using a scale that has been validated through reporting of norms in a peer‐reviewed publication

  • Serious adverse events

    • haematological (leucopenia, anaemia, thrombocytopenia, neutropenia, haemorrhage, transfusion rates)

    • gastrointestinal (nausea, vomiting, anorexia, diarrhoea, liver, proctitis

    • skin (stomatitis, mucositis, alopecia, allergy)

    • neurological (peripheral and central)

Data on other serious/severe adverse events will be recorded but not subjected to formal statistical comparative analysis.

Search methods for identification of studies

Papers in all languages will be sought and translations carried out if necessary.

Electronic searches

We will follow methods as set out by the Cochrane Gynaecological Cancer Group methods with support from the Gynaecological Cancer Review Group Information manager, Jane Hayes. The following electronic databases will be searched:

  • The Cochrane Gynaecological Cancer Group's Specialised Trial Register

  • Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library)

  • MEDLINE

  • EMBASE

  • Google Scholar

The MEDLINE (Ovid) search strategy is presented in Appendix 1.

For databases other than MEDLINE, the search strategy will be adapted accordingly. Google strategy will be limited to Medicine pharmacology and use "randomised trial" and taxol and ovary and "health technology"

All relevant articles will be identified on PubMed and using the 'related articles' feature a further search will be carried out for newly published articles.

Searching other resources

Unpublished and grey literature

Metaregister (http://www.controlled‐trials.com/rct), Physicians Data Query (http://www.nci.nih.gov), ClinicalTrials.gov (http://www.clinicaltrials.gov) and the National Cancer Institute's List of Cancer Clinical Trials (http://www.cancer.gov/clinicaltrials) will be searched for ongoing trials.  If ongoing trials which have not been published are identified through these searches, the principal investigators will be approached to ask if for relevant data. The major co‐operative trials groups active in this area will also be approached.

We will also search conference proceedings and abstracts from year 2000:

  • Gynecologic Oncology (Annual Meeting of the American Society of Gynecologic Oncologist)

  • International Journal of Gynecological Cancer (Annual Meeting of the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology )

  • Annual Meeting of European Society of Medical Oncology (ESMO)

  • Annual Meeting of the American Society of Clinical Oncology (ASCO).

Authors will be contacted for additional data when necessary.

Data collection and analysis

Selection of studies

All titles and abstracts retrieved by electronic searching will be downloaded to a reference management database, duplicates will be removed and the remaining references will be examined by two review authors independently.  Those studies which clearly do not meet the inclusion criteria will be excluded and copies of the full text of potentially relevant references will be obtained and read in full.  The eligibility of retrieved papers will be assessed independently by two authors (NJ and TM), and disagreements will be resolved by discussion with a third author (PC). Reasons for exclusion will be documented.  

Data extraction and management

For included studies, the following data will be extracted:

  • author, year of publication and journal citation (including language);

  • country;

  • setting;

  • inclusion and exclusion criteria;

  • study design, methodology;

  • study population and any reference to breast cancer susceptibility gene 1 and breast cancer susceptibility gene 2 (BRCA1 and 2)

  • total number enrolled;

  • patient characteristics;

  • age;

  • timing and effectiveness of surgery;

  • stage of disease;

  • intervention details

    • type of platinum (carbo or cisplatin)

    • dose of platinum

    • type of taxane

    • dose of Taxol

    • number of cycles

    • timing of cycles

    • timing of surgery

    • crossover;

  • comparison

    • the outcomes will be compared for women treated with added taxane and for women where the intention is to add a taxane (by treatment and by intention to treat);

  • risk of bias in study (Assessment of risk of bias in included studies);

  • 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;

  • duration of follow‐up.

We will extract the number of participants allocated to each intervention group, the total number analysed for each outcome, and the missing participants. The outcomes will be compared for women treated with added taxane and for women where the intention as to add a taxane (by treatment and by intention to treat). For time to event data (survival and progression free survival), 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 and digitisation of survival curves. This will involve enlarging the published curve and calculating the survival times using the pixels and calculated HR estimates in the standard spreadsheet.

For dichotomous outcomes (e.g. adverse events or deaths) 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.

Both unadjusted and adjusted statistics will be extracted, if reported. All data extracted will be those relevant to an intention‐to‐treat analysis, in which participants will be analysed in groups to which they were assigned. In addition, trials that permitted cross over treatment will be managed by extracting data according to treatment received.

The time points at which outcomes were collected and reported will be noted.

Data will be extracted independently by two authors (TM and NJ) onto a data abstraction form specially designed for the review. Differences between review authors will be resolved by discussion or by appeal to a third author (PC) if necessary.

Assessment of risk of bias in included studies

The risk of bias in included studies will be assessed using the Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011). This will include assessment of:

  1. selection bias: random sequence generation and  allocation concealment;

  2. performance bias: blinding of participants and personnel (patients and treatment providers);

  3. detection bias: blinding of outcome assessment;

  4. attrition bias: incomplete outcome data (we will code a satisfactory level of loss to follow‐up for each outcome as: 'Low risk of bias', if fewer than 20% of patients were lost to follow‐up and 'high risk of bias' if more than 20% of patients were lost to follow‐up);

  5. reporting bias: selective reporting of outcomes;

  6. other possible sources of bias.

The risk of bias tool will be applied independently by two review authors (NJ, TM) and differences resolved by discussion or by appeal to a third review author (PC). Results will be summarised in both a 'Risk of bias graph' and a 'Risk of bias summary'.  Results of meta‐analyses will be interpreted in light of the findings with respect to risk of bias.

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, if possible;

  • for dichotomous outcomes, we will use the risk ratio;

  • for continuous outcomes, we will use the mean difference between treatment arms.

Dealing with missing data

We will not impute missing outcome data for the primary outcome. If data are missing or only imputed data are reported we will contact trial authors to request data on the outcomes only among participants who were assessed.

Assessment of heterogeneity

Heterogeneity between studies will be assessed by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Deeks 2001) and if possible, by subgroup analyses.

Substantial heterogeneity will be defined by I2 greater than 30%. If there is evidence of substantial heterogeneity, trial outcome data will be grouped by common features to see if there is a theme that separates trials with differing apparent outcomes. Sensitivity analysis will be used to investigate heterogeneity.

Assessment of reporting biases

Egers plot of the intercept will be used to analyse funnel plots corresponding to meta‐analysis of the primary outcome to assess the potential for small study effects such as publication bias.

If there is substantial heterogeneity, as defined by I2 greater than 30%, the fixed effects model meta‐analyses will be performed.

Data synthesis

  • If sufficient, clinically similar studies are available their results will be pooled in meta‐analyses. For time‐to‐event data, hazard ratios will be pooled using the generic inverse variance facility of the Cochrane Collaboration's statistical software, Review Manager 2011.

  • For any dichotomous outcomes, the risk ratio will be calculated for each study and these will then be pooled.   

  • For continuous outcomes, the mean differences between the treatment arms at the end of follow‐up will be pooled if all trials measured the outcome on the same scale, otherwise standardised mean differences will be pooled. 

Funnel plots corresponding to meta‐analysis of the primary outcome will be examined to assess the potential for small study effects such as publication bias. If these plots suggest that treatment effects may not be sampled from a symmetric distribution, as assumed by the random effects model, further meta‐analyses will be performed using fixed effects models.The random effects model will be used when heterogeneity between studies is excluded.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses will stratify the trials to interpret any heterogeneity. If very different treatment allocations have been amalgamated in a trial report, we will separate the data and use meta‐analysis to analyse each part separately. Deviding a trial onto separate sub‐trials may weaken the overall power of any trial and consequently, this separation will take place before any meta‐analysis begins. If the authors disagree on the need to divide a trial, the summary data will be presented using data from any disputed trial with and without separation. The proposed strata will be selected by both oncology experts from the following list once the forest plots for OS and PFS are available:

  • type of platinum (carbo or cisplatin);

  • dose of platinum;

  • dose of paclitaxel;

  • number of cycles;

  • stage of disease (early/Stage 1 and 2 versus advanced/Stage3 and 4);

  • volume of residual disease after surgery;

  • use of any Taxol in the control arm;

  • crossover versus no crossover;

  • type of trial (factorial, crossover or simple design);

  • performance of the control group using Egger regression method;

  • length of follow‐up;

  • age;

  • performance status.

Sensitivity analysis

Sensitivity analyses will be performed by excluding studies at high risk of bias.