Maintenance chemotherapy for ovarian cancer

  • Review
  • Intervention

Authors

  • Ling Mei,

    1. West China Second University Hospital, West China Women's and Children's Hospital, Department of Obstetrics and Gynecology, Chengdu, Sichuan, China
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  • Hui Chen,

    1. West China Second University Hospital, West China Women's and Children's Hospital, Department of Obstetrics and Gynecology, Chengdu, Sichuan, China
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  • Dong Mei Wei,

    1. West China Second University Hospital, West China Women's and Children's Hospital, Department of Obstetrics and Gynecology, Chengdu, Sichuan, China
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  • Fang Fang,

    Corresponding author
    1. West China Second University Hospital, West China Women's and Children's Hospital, Department of Obstetrics and Gynecology, Chengdu, Sichuan, China
    • Fang Fang, Department of Obstetrics and Gynecology, West China Second University Hospital, West China Women's and Children's Hospital, No. 17, Section Three, Ren Min Nan Lu Avenue, Chengdu, Sichuan, 610041, China. ffmn59@163.com.

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  • Guan J Liu,

    1. West China Hospital, Sichuan University, Chinese Cochrane Centre, Chinese Evidence-Based Medicine Centre, Chengdu, Sichuan, China
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  • Huan Yu Xie,

    1. People's Hospital of Deyang City, Department of Obstetrics and Gynecology, Deyang, Sichuan, China
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  • Xun Wang,

    1. West China Second University Hospital, West China Women's and Children's Hospital, Department of Obstetrics and Gynecology, Chengdu, Sichuan, China
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  • Juan Zou,

    1. West China Second University Hospital, West China Women's and Children's Hospital, Department of Obstetrics and Gynecology, Chengdu, Sichuan, China
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  • Xu Han,

    1. West China Second University Hospital, West China Women's and Children's Hospital, Department of Obstetrics and Gynecology, Chengdu, Sichuan, China
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  • Dan Feng

    1. Cheng du Women & Children’s Central Hospital, Department of Obstetrics and Gynecology, Chengdu, Sichuan, China
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Abstract

Background

Epithelial ovarian cancer accounts for about 90% of all cases of ovarian cancer. Debulking surgery and six courses of platinum-based chemotherapy results in complete clinical remission (CCR) in up to 75% of cases. However, 75% of the responders will relapse within a median time of 18 to 28 months and only 20% to 40% of women will survive beyond five years. It has been suggested that maintenance chemotherapy could assist in prolonging remission. To date, there has not been a systematic review on the impact of maintenance chemotherapy for epithelial ovarian cancer.

Objectives

To assess the effectiveness and toxicity of maintenance chemotherapy for epithelial ovarian cancer and to evaluate the impact on quality of life (QoL).

Search methods

In the original review we searched the Cochrane Gynaecological Cancer Review Group Specialised Register, The Cochrane Central Register of Controlled Trails (CENTRAL, The Cochrane Library 2009, Issue 1), MEDLINE, EMBASE, PubMed, CBMdisc, CNKI and VIP (to May 2009). We collected information from ongoing trials, checked reference lists of published articles and consulted experts in the field. For this update, the searches were extended to October 2012.

Selection criteria

Randomised controlled trials (RCTs) comparing maintenance chemotherapy with no further intervention, maintenance radiotherapy or other maintenance therapy.

Data collection and analysis

Two review authors independently assessed trials for eligibility and quality and extracted data. We analysed overall survival (OS) and progression-free survival (PFS) rates as dichotomous variables. Toxicity and QoL data were extracted where present. All analyses were based on intention-to-treat (ITT) on the endpoint of survival. We also analysed data by subgroups of drugs.

Main results

We included eight trials (1644 women). When all chemotherapy regimens were combined, meta-analysis indicated no significant difference in three-, five- and 10-year OS or PFS. For five-year OS, the combined risk ratio (RR) was 1.03 (95% confidence interval (CI) 0.96 to 1.10) and for the five-year PFS, the combined RR was 1.06 (95% CI 0.97 to 1.17). Results were very similar when trials of different regimens were analysed. Comparing chemotherapy with radiotherapy, only the RR for 10-year PFS in pathological complete remission (PCR) was in favour of whole abdominal radiotherapy 0.51 (95% CI 0.27 to 1.00), while three- and five-year OS rates have no significant difference between the two groups.

Authors' conclusions

There is no evidence to suggest that the use of platinum agents, doxorubicin or paclitaxel used as maintenance chemotherapy is more effective than observation alone. Further investigations regarding the effect of paclitaxel used as maintenance chemotherapy are required.

Résumé scientifique

Chimiothérapie d'entretien pour le cancer de l'ovaire

Contexte

Le cancer épithélial de l'ovaire représente près de 90 % de tous les cas de cancer ovarien. La chirurgie de réduction tumorale et six cycles de chimiothérapie à base de platine conduisent à la rémission clinique complète (RCC) chez jusqu'à 75 % des cas. Cependant, 75 % des répondeurs rechutent après 18 à 28 mois en moyenne, et seulement 20 à 40 % des femmes survivent au-delà de cinq ans. Il a été suggéré que la chimiothérapie d'entretien peut aider à prolonger la rémission. À ce jour, il n'existe aucune revue systématique portant sur les effets de la chimiothérapie d'entretien pour le cancer épithélial de l'ovaire.

Objectifs

Évaluer l'efficacité et la toxicité de la chimiothérapie d'entretien pour le cancer épithélial de l'ovaire, ainsi que les effets sur la qualité de vie.

Stratégie de recherche documentaire

Dans la revue d'origine, nous avons effectué des recherches dans le registre spécialisé du Groupe Cochrane sur les cancers gynécologiques et le registre Cochrane des essais contrôlés (CENTRAL, The Cochrane Library, numéro 1, 2009), ainsi que dans MEDLINE, EMBASE, PubMed, CBMdisc, CNKI et VIP (jusqu'à mai 2009). Nous avons recueilli des informations provenant d'essais en cours, examiné les références bibliographiques des articles publiés et consulté les spécialistes du domaine. Pour cette mise à jour, nous avons étendu les recherches jusqu'en octobre 2012.

Critères de sélection

Les essais contrôlés randomisés (ECR) comparant la chimiothérapie d'entretien sans autre intervention, la radiothérapie d'entretien ou une autre thérapie d'entretien.

Recueil et analyse des données

Deux auteurs de revue ont évalué la qualité et l'éligibilité des essais et extrait les données de manière indépendante. La survie globale et la survie sans progression ont été analysées en tant que variables dichotomiques. Les données relatives à la toxicité et à la qualité de vie ont été extraites lorsqu'elles étaient présentes. Toutes les analyses étaient faites sur l'intention de traiter (ITT) à partir du critère de jugement de survie. Les données ont aussi été analysées par sous-groupes de médicaments.
 

Résultats principaux

Huit essais ont été inclus (1644 femmes). Lorsque tous les schémas chimiothérapeutiques étaient combinés, la méta-analyse n'indiquait aucune différence significative concernant la survie globale et la survie sans progression à 3, 5 et 10 ans. Pour la survie globale à 5 ans, le risque relatif (RR) combiné était de 1,03 (intervalle de confiance (IC) à 95 % entre 0,96 et 1,10) et de 1,06 pour la survie sans progression à 5 ans (IC à 95 % entre 0,97 et 1,17). Les résultats étaient très similaires quand les essais portant sur différents schémas étaient analysés. En comparant la chimiothérapie avec la radiothérapie, seul le RR de survie sans progression à 10 ans en rémission pathologique complète était favorable à la radiothérapie abdominale intégrale 0,51 (IC à 95 % entre 0,27 et 1,00), tandis que les taux de survie globale à 3 et 5 ans n'affichaient aucune différence significative entre les deux groupes.

Conclusions des auteurs

Aucune preuve n'indique que l'utilisation d'agents à base de platine, de paclitaxel ou de doxorubicine en tant que chimiothérapie d'entretien est plus efficace que l'observation seule. D'autres recherches portant sur l'effet du paclitaxel utilisé en tant que chimiothérapie d'entretien sont nécessaires.

Notes de traduction

Translated by: French Cochrane Centre

Translation supported by: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Plain language summary

Maintenance chemotherapy for ovarian cancer

Of all the gynaecological cancers, ovarian cancer has the highest death rate and epithelial ovarian cancer accounts for about 90% of all cases. Surgery and six courses of platinum-based chemotherapy is the standard treatment and 75% of the women may not have any evidence of disease at the end of this treatment. However, 75% of the women who respond to initial treatment will relapse within 18 to 28 months and only 20% to 40% of all women will survive beyond five years.

Some doctors suggest giving maintenance chemotherapy for epithelial ovarian cancer. Maintenance chemotherapy refers to the chemotherapy given to women who have achieved remission after initial surgery and induction chemotherapy.The aim of maintenance chemotherapy is to prolong the duration of remission and improve the overall length of survival. Some studies indicate that maintenance chemotherapy can improve the time without cancer progression, while others do not show any effect. The aim of this review was to establish whether using maintenance chemotherapy is better than observation alone for women with epithelial ovarian cancer. We identified eight trials that used different types of chemotherapy (e.g. platinum agents, doxorubicin, topotecan or paclitaxel) but there was not sufficient evidence to prove any of the drugs were better than observation alone.

An important consideration for women with advanced disease is the balance between the benefit of treatment and the harms or adverse effects that these treatments may cause. There were insufficient data to comment on the overall impact of the maintenance chemotherapy on clinical benefit from the women's perspective.

Résumé simplifié

Chimiothérapie d'entretien pour le cancer de l'ovaire

De tous les cancers gynécologiques, le cancer de l'ovaire est celui qui présente le taux de mortalité le plus élevé. En outre, le cancer épithélial de l'ovaire représente près de 90 % de tous les cas de cancer ovarien. La chirurgie et six cycles de chimiothérapie à base de platine constituent le traitement classique. À la suite de ce traitement, 75 % des femmes peuvent ne plus avoir aucune trace de la maladie. Cependant, 75 % des femmes répondant au traitement initial rechutent dans les 18 à 28 mois, et seulement 20 à 40 % de toutes les femmes survivent au-delà de cinq ans.

Certains médecins proposent l'administration d'une chimiothérapie d'entretien pour le cancer épithélial de l'ovaire. La chimiothérapie d'entretien fait référence à la chimiothérapie administrée aux femmes en phase de rémission après la chirurgie initiale et la chimiothérapie d'induction. Le but de ce type de chimiothérapie est de prolonger la durée de rémission et d'améliorer la durée de survie globale. Certaines études indiquent que la chimiothérapie d'entretien peut accroître le laps de temps sans progression du cancer, tandis que d'autres ne signalent aucun effet. L'objectif de cette revue était de déterminer si l'utilisation d'une chimiothérapie d'entretien est préférable à l'observation seule des femmes atteintes d'un cancer épithélial de l'ovaire. Huit essais ont été identifiés. Ils avaient recours à différents types de chimiothérapie (par exemple, des agents à base de platine, doxorubicine,  paclitaxel ou topotécane), mais l'insuffisance de preuves ne permettait pas de démontrer que l'un des médicaments l'emportait sur l'observation seule.

L'équilibre entre le bénéfice du traitement et les effets délétères ou indésirables que ces médicaments peuvent provoquer constitue une considération importante pour les femmes souffrant de la maladie à un stade avancé. Les données étaient trop peu nombreuses pour formuler des observations à l'égard des effets de la chimiothérapie d'entretien sur le bénéfice clinique, du point de vue des patientes.

Notes de traduction

Translated by: French Cochrane Centre

Translation supported by: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Background

Description of the condition

Worldwide, approximately 200,000 women are diagnosed with ovarian cancer and about 115,000 die from this disease each year (Ozols 2006). Ovarian cancer is the sixth most common cancer among women. A woman's cumulative risk of developing ovarian cancer by age 65 years is 0.5%: 0.4% in less developed countries and 0.7% in more developed countries. It is less common in women under the age of 35 years, and its incidence increases with age (GLOBOCAN 2002).

Of all the malignant gynaecological tumours, ovarian cancer has the highest mortality rate because ovarian cancer often does not cause symptoms until it has become widespread (Poveda 2003). Despite, however, good responses to chemotherapy, there is a high recurrence rate (Ozols 2006). Epithelial ovarian cancer accounts for about 90% of all cases of ovarian cancer (Thigpen 2004). Debulking surgery and six courses of platinum-based chemotherapy results in complete clinical remission (CCR) in up to 75% of cases (Thigpen 2004). However, 75% of the responders will relapse within the median time of 18 to 28 months (Stuart 2003) and only 20% to 40% women will survive beyond five years (Kikuchi 2005). Studies have shown that more than six courses of induction chemotherapy does not improve progression-free survival (PFS) or overall survival (OS) but increases toxicity (Bertelsen 1993; Hakes 1992; Lambert 1997). Women receiving prolonged courses of chemotherapy therefore may gain little survival benefit while suffering from more adverse effects.

Description of the intervention

It has been suggested that maintenance or consolidation chemotherapy may be administered for epithelial ovarian cancer. Maintenance chemotherapy refers to chemotherapy given after women have achieved CCR or pathological complete remission (PCR), after initial surgery and induction chemotherapy.

How the intervention might work

The aim of the intervention is to prolong the interval of remission and improve the OS. Some clinicians differentiate maintenance chemotherapy from consolidation chemotherapy, as high-dose or relatively short-term chemotherapy given after CCR or PCR (Ozols 2004). The aim in this setting is to prevent recurrence rather than delay recurrence. Currently there are no specific definitions for these concepts, so we will consider consolidation and maintenance chemotherapy as the same, as long as it is applied after the women have achieved CCR or PCR and it will be referred to as maintenance chemotherapy in this review.

CCR is defined as a patient with a normal CA-125 blood test according to the local laboratory parameters, having no cancer-related symptoms, a normal physical examination and a negative CT scan of the abdomen and/or pelvis and chest x-ray (Markman 2003). PCR is defined as a patient with CCR confirmed as tumour-negative by the second-look surgery (Varia 2003).

Why it is important to do this review

Some studies have indicated that maintenance chemotherapy can improve PFS (Markman 2003), while others did not show any effect. To date, there have not been any published systematic reviews on the impact of maintenance chemotherapy for epithelial ovarian cancer.

Objectives

To assess the effectiveness and toxicity of maintenance chemotherapy for epithelial ovarian cancer and to evaluate the impact on quality of life (QoL) of maintenance chemotherapy.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

Women with epithelial ovarian cancer who have achieved CCR or PCR after initial surgery and chemotherapy.

Types of interventions

  • Maintenance chemotherapy versus no further intervention

  • Maintenance chemotherapy versus maintenance radiotherapy

  • Maintenance chemotherapy versus other maintenance therapy except chemotherapy and radiotherapy (e.g. biotherapy, immunotherapy)

Types of outcome measures

Primary outcomes
  • PFS and OS rates

Secondary outcomes
  • Adverse effect events (nausea-vomiting, diarrhoea, ileus, bone marrow toxicity, neurotoxicity, mucositis, renal toxicity, hepatic toxicity, bladder toxicity etc) and

  • QoL (if a validated scale had been used)

Search methods for identification of studies

Electronic searches

For the original review we searched the following databases, The Cochrane Gynaecological Cancer Review Group Specialised Register, The Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, 2009, Issue 1, MEDLINE (from 1950 to May 2009), EMBASE (from 1966 to May 2009), PubMed (May 2009), CBMdisc (1978 to May 2009), CNKI (1979 to May 2009) and VIP (1989 to May 2009).

For this update we extended the search to: The Cochrane Gynaecological Cancer Review Group Specialised Register (October 2012), CENTRAL 2012, Issue 10, MEDLINE (to October week 2, 2012), EMBASE (to week 42, 2012), PubMed (October 2012), CBMdisc (to October 2012), CNKI (to October 2012) and VIP (to October 2012).

For MEDLINE, the subject search used a combination of vocabulary (MeSH terms) and free text terms (Appendix 1). We adapted the search strategy accordingly for CENTRAL, EMBASE, PubMed, CBMdisc,CNKI and VIP. The search strategies can be found in Appendix 2, Appendix 3, Appendix 4.

For MEDLINE, EMBASE and PubMed, there were no language restrictions placed on the search.

The search strategies used were developed and executed by the author team.

Searching other resources

  1. We checked the reference lists of obtained articles to check for other related published and unpublished studies.

  2. We searched relevant web sites for ongoing trials:

    1. http://www.nccn.org

    2. http://www.clinicaltrials.gov/ct

    3. http://www.gog.org

    4. http://www.cancer.gov/clinicaltrials

    5. http://www.eortc.be/

    6. http://www.swog.org/

  3. Personal communication: In addition, we contacted authors of included RCTs to identify any additional published and unpublished materials.

Data collection and analysis

Selection of studies

Two review authors (ML and WDM) scanned the titles and abstracts from the initial search in order to exclude those that did not meet the inclusion criteria. The full text of potentially relevant studies were obtained for independent assessment of eligibility by two review authors (ML and CH). Any disagreements were resolved through discussion with a third review author (FF) if necessary.

Data extraction and management

Two review authors (XHY and WX) independently extracted data using a previously specified form listing the following:

  • study characteristics (randomisation process, allocation concealment, blinding, attrition bias and intention-to-treat (ITT) analysis);

  • basic information of the participants (number of the women, mean age, age range);

  • base-line data of the participants (FIGO stages, histological type, pathological grade and response to the first-line treatment);

  • intervention (drug, dose and courses); and

  • outcome (OS after three, five and 10 years, PFS after three, five and 10 years, the incidence and severity of toxicity such as nausea-vomiting, mucositis, leucopenia, thrombocytopenia, neutropenia, neurotoxicity, hepatic toxicity and renal toxicity and QoL score).

We resolved any disagreements by referring to the trial report or by consulting a third review author (FF). We contacted the trial authors for additional information if data from the trial reports were insufficient or missing.

Assessment of risk of bias in included studies

We assessed the methodological quality of each trial in terms of randomisation process, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other possible sources of bias and classified them as yes, no, or unclear according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions 5.0.2 (Higgins 2009).

Randomisation process
  • Yes: allocation sequence was generated by computer or by a random number table.

  • No: quasi-randomisation, participants were allocated by date of birth, code of hospital admission, etc.

  • Unclear: randomisation stated to have been done but no method reported.

Concealment of allocation

Allocation concealment was regarded as particularly important in protecting against bias and was graded as follows:

  • Yes: clearly adequate concealment.

  • No: participants or investigators enrolling participants could possibly foresee assignments.

  • Unclear: insufficient information to permit judgement.

Blinding

Blinding was very unlikely in this setting and is less important as the end points were OS and PFS.

Incomplete outcome data
  • Yes: reasons for missing outcome data unlikely to be related to true outcome. 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.

  • No: 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. As-treated analysis done with substantial departure of the intervention received from that assigned at randomisation.

  • Unclear: insufficient reporting of attrition/exclusions to permit judgement or the study did not address this outcome.

Selective outcome reporting
  • Yes: if the study protocol is available and all of the study's primary and secondary outcomes that are of interest in the review have been reported in the pre-specified way. If the study protocol is not available but it is clear that the published reports include all expected outcomes.

  • No: not all of the study's pre-specified primary outcomes have been reported. One or more primary outcomes is reported using measurements, analysis methods or subsets of the data that were not pre-specified. 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.

  • Unclear: insufficient information to permit judgement.

Other possible sources of bias
  • Yes: the study appears to be free of other sources of bias.

  • No: there is at least one important risk of bias such as extreme baseline imbalance.

  • Unclear: insufficient information to assess.

Based on these criteria, studies were broadly subdivided into the following three categories:
A - All quality criteria met: low risk of bias
B - Unclear risk of bias for one or more quality criteria
C - High risk of bias for one or more quality criteria

Measures of treatment effect

When sufficient, clinically similar trials were available, we pooled the results in meta-analyses. For dichotomous outcomes, we calculated the risk ratio (RR) for each study and pooled them. For continuous outcomes, we planned to pool the mean differences (or standardised mean differences) between the treatment arms at the end of follow-up.

Dealing with missing data

Whenever possible, we contacted the original investigators to request missing data.

Data synthesis

When sufficient, clinically similar trials were available, we pooled their results in meta-analyses. We analysed the data using Review Manager 5. We used RR and its 95% confidence interval (CI) to estimate the combined effect of OS, PFS and certain adverse effect rate. If the effect could not be combined, we described the outcome separately. If QoL had been reported by continuous data, we would have pooled the mean differences between the treatment arms.

Subgroup analysis and investigation of heterogeneity

We performed subgroup analysis by type of regimen, such as platinum-based chemotherapy and doxorubicin-based chemotherapy. We tested heterogeneity using both the Chi2 test and the I2 test. A significance level of less than 0.10 of Chi2 was interpreted as evidence of heterogeneity. I2 was used to estimate total variation across studies, where less than 30% is considered as low level of heterogeneity and higher than 50% as high level (Higgins 2002).  If there was evidence of substantial heterogeneity, we investigated and reported the possible reasons for this.

Sensitivity analysis

We intended that if the eligibility of some studies in the meta-analysis had been dubious, sensitivity analysis might involve undertaking the meta-analysis twice: firstly including all studies and secondly only excluding studies that were of high risk of bias and had unadjusted results. We planned to report the sensitivity analyses in a summary table.

Results

Description of studies

Results of the search

The search identified 718 trials and initially 559 were excluded. We then obtained full text articles for the remaining 159 trials for further scrutiny. The flow chart on how the selection of studies was made can be found in Figure 1.

Figure 1.

Studies Selection

Included studies

We identified two additional studies for inclusion (Mannel 2011; Pecorelli 2009) and therefore have included data from a total of eight RCTs and 1644 women in this review. Seven trials compared maintenance chemotherapy with no further treatment (Bolis 2006; Cheng 2006; Mannel 2011; Nicoletto 2004; Pecorelli 2009; Piccart 2003; Placido 2004).

One study (Sorbe 2003) was a three-arm study comparing maintenance chemotherapy, maintenance radiotherapy and no further treatment. A total of 172 women were included, 98 with PCR and 74 with CCR. The included women had endometrial ovarian cancer ranging from stage ⅠC to stage Ⅳ. Women with stage Ⅲ to Ⅳ accounted for 89.9% of the total number of women included.

In addition, Piccart 2003 included women with non-epithelial cancer, but we included it because the percentage of participants with non-epithelial cancer was very small and there was no significant heterogeneity when compared with the other studies.

Excluded studies

We excluded 140 ineligible trials and four ongoing trials after the authors read the full original texts. Seven trials were initially identified as potentially eligible for inclusion but were subsequently found to be ineligible and therefore excluded (Abaid 2010; Cure 2001; Lesnock 2011; Mannel 2010; Markman 2003; Markman 2009; Scarfone 2002). Reasons for exclusions are listed in the table of Characteristics of excluded studies.

Risk of bias in included studies

We summarised the risk of bias in included studies in Figure 2 and Figure 3.

Figure 2.

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

Figure 3.

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

Allocation

All eight studies used randomised allocation, but only four described the randomisation method (Bolis 2006; Mannel 2011; Pecorelli 2009; Placido 2004) and two (Bolis 2006; Mannel 2011) had adequate allocation concealment. According to the assessment criteria, all could be judged with low risk of bias for sequence generation and unclear risk of bias for allocation concealment.

Blinding

None of the included studies used blinding, but this is not likely to have influenced the results as the outcomes were OS and PFS. We therefore judged the studies as having low risk of bias for blinding.

Incomplete outcome data

Two studies lost one patient to follow-up (Nicoletto 2004; Piccart 2003), but both used ITT analysis and for OS and PFS the proportion of missing outcomes compared with observed event risk was not enough to have a clinically relevant impact on the intervention effect. One study had 32 patients who withdrew during the follow-up (Mannel 2011), but it was balanced between the treatment and the control arms, therefore, they were graded with low risk of bias.

Selective reporting

All expected outcomes were reported. There was no selective reporting identified for any of the studies.

Other potential sources of bias

Piccart 2003 had a high risk of bias as "the study was closed prematurely in view of a disappointing recruitment rate. …". The remaining studies appeared to be free of other sources of bias.

Effects of interventions

Maintenance chemotherapy versus observation

Data were available on 1221 women from six of the included trials (Bolis 2006; Mannel 2011; Nicoletto 2004; Pecorelli 2009; Piccart 2003; Sorbe 2003). One trial used cisplatin alone (Piccart 2003), another studied epidoxorubicin (Bolis 2006), a third cisplatin-based combination chemotherapy (Nicoletto 2004), another trial used the regimen of cisplatin and doxorubicin (Sorbe 2003) and another two studies used paclitaxel (Mannel 2011; Pecorelli 2009). The intended number of courses ranged from three to six. Except for Mannel 2011, the other included studies had maintenance chemotherapy scheduled to start after the women had achieved PCR or CCR. There was no significant heterogeneity within each category of drugs. In addition, there was no statistically significant difference in the three-, five- and ten-year PFS or OS. For the five-year PFS the combined risk ratio (RR) was 1.06 (95% confidence interval (CI) 0.97 to 1.17) (Analysis 1.2) and for five-year OS, the combined RR was 1.03 (95% CI, 0.96 to 1.10) (Analysis 1.5)

Two trials (Mannel 2011; Pecorelli 2009) that used paclitaxel were not combined in the analysis because there was significant heterogeneity between the stage of disease. Mannel 2011 included high risk early-staged disease (stage I-A or B (grade 3 or clear cell), all I-C or II epithelial ovarian cancer) whereas, Pecorelli 2009 mainly included advanced staged disease. In addition, the regimens used in each study were different; Mannel 2011 used weekly low dose paclitaxel (40mg/m²) and Pecorelli 2009 used six courses of paclitaxel (175mg/m²) at three-week intervals. Neither study indicated if paclitaxel could decrease the recurrence rate or increase the OS rate.

One trial (Cheng 2006) used a regimen of cisplatin and cyclophosphamide or taxol was also not included in the meta-analysis as it used different outcomes. The results indicated maintenance chemotherapy could prolong the time of progression-free interval (P = 0.033), while it had little effect on prolonging survival time (P = 0.22).

Another trial (Placido 2004) used topotecan and was not included in the meta-analysis because the follow-up duration was shorter and the outcomes could not be combined with other studies. It indicated that the one-year PFS was 60.4% and 65.4% in the topotecan and control arms respectively and there was no significant difference between the arms.

Trials using cisplatin-based regimens

We analysed three studies including 341 women (Nicoletto 2004; Piccart 2003; Sorbe 2003) comparing cisplatin alone or combined with other drugs with no further treatment. Results were not conclusive and the 95% CI for absolute difference in OS was consistent with a 12% detriment to a 31% benefit of chemotherapy at five years. Similarly, the 95% CI for absolute difference in PFS is consistent with a 12% detriment to a 58% benefit at five years.

Trials using doxorubicin-based regimens

We undertook a subgroup analysis of two studies including 204 women (Bolis 2006; Sorbe 2003) comparing doxorubicin-based maintenance chemotherapy with observation. Overall survival for three and five years was RR 1.00 (95% CI 0.86 to 1.15 and 0.79 to 1.27 respectively) (Analysis 3.1; Analysis 3.2).

Maintenance chemotherapy versus maintenance radiotherapy

One trial (Sorbe 2003) randomised 141 women into the chemotherapy and whole abdominal radiotherapy group. Sixty-seven women achieved PCR and the other 74 women CCR. There was considerable diversity of results across the two sub-groups. The test for heterogeneity was significant for the combined RR for three- and ten-year PFS and ten-year OS. Ten-year PFS in the PCR group was in favour of whole abdominal radiotherapy (RR 0.51, 95% CI 0.27 to 1.00) (Analysis 4.3). The other results showed no statistical difference between chemotherapy and radiotherapy in either group.

Maintenance chemotherapy versus other maintenance therapy

We found no eligible RCTs for this comparison.

Toxicity of maintenance chemotherapy

Seven trials described the toxicities of maintenance chemotherapy (Bolis 2006; Mannel 2011; Nicoletto 2004; Pecorelli 2009; Piccart 2003; Placido 2004; Sorbe 2003) but only one (Mannel 2011) made comparison between intervention and control groups. It reported that the incidence of grade 2 or worse peripheral neuropathy, infection or fever, and dermatologic events were significantly higher among patients treated on the maintenance weekly paclitaxel regimen (P < 0.001). There was also a slight incidence of grade 2 or worse cardiovascular events (P = 0.044) among those on the maintenance regimen. Grade 3 or 4 peripheral neuropathy was reported in 0.7% of the observation group compared to 4.4% of the maintenance paclitaxel group (P = 0.012).

One trial (Piccart 2003) used intraperitoneal cisplatin and reported that the main side effect was bowel obstruction due to intraperitoneal catheters. The most common toxicities of cisplatin were vomiting (82% grade 2) and renal toxicity (45% grade 2).

Another trial (Bolis 2006) using epidoxorubicin reported neutropenia, anaemia and thrombocytopenia and 41.9% of women had severe grade 4 neutropenia .

In the trial that used topotecan (Placido 2004), data were available for 112 out of 117 women in the experimental arm. Grade 3 to 4 neutropenia was recorded in 58% of women and 21% had grade 3 thrombocytopenia. Nausea and vomiting were the most frequent non-haematologic toxicities.

When comparing chemotherapy with radiotherapy, more side effects were recorded in the radiotherapy group, notably adverse gastro-intestinal effects. In the radiotherapy arm,14.5% of women had severe diarrhoea, bloody stools or bowel obstruction compared to 4.2% of women in the chemotherapy arm (P = 0.034).

Discussion

Summary of main results

To date, there are no data which adequately support the use of platinum, doxorubicin or paclitaxel as maintenance chemotherapy for ovarian cancer.

When comparing maintenance chemotherapy with maintenance radiotherapy, the number of included women was too small to give an accurate results. However, from the subgroup analysis we may speculate that maintenance chemotherapy is more appropriate for women in CCR, while women in PCR will benefit from maintenance radiotherapy.

The toxicity from platin was tolerable but the clinical application of doxorubicin and topotecan may be limited due to the severe bone marrow toxicity induced.

Overall completeness and applicability of evidence

This review was unable to address the issue of impact on QoL of maintenance chemotherapy due to a lack of trials reporting data relating to QoL. Therefore, it could not be addressed in the meta-analysis.

This review was unable to report on the results of meta-analysis of toxicity of maintenance chemotherapy as only one of the included trials (Mannel 2011) made comparison between the chemotherapy and observed groups. It was only possible to describe the observed toxicities during treatment.

This review was also unable to address the issue of whether maintenance chemotherapy is more effective than other maintenance therapy, especially biologic therapy because so far no RCT has focused on this topic.

Quality of the evidence

This meta-analysis is based on data from 1644 women, from eight RCTs that compared platinum-, doxorubicin- or paclitaxel-based maintenance chemotherapy with no further treatment in epithelial ovarian cancer. We employed a number of methods to try to identify all trials and included both published and unpublished data in this review; thereby minimising the influence of publication bias. Although the number of included women is small, this meta-analysis currently provides a reliable assessment of the average treatment effect of platinum and doxorubicin among women with advanced epithelial ovarian cancer.

Potential biases in the review process

Current practice prescribes that maintenance therapy begins after a woman achieves PCR or CCR but does not define how long the woman must be in remission before maintenance therapy is commenced. None of the trials included in this review described the exact start time of maintenance chemotherapy. It is widely accepted that the remission phase of platin-sensitive cases usually lasts more than six months. Therefore, if maintenance chemotherapy was started earlier than this, some platin non-sensitive cases may be included, which may introduce bias into the review.

Agreements and disagreements with other studies or reviews

The meta-analysis indicated that there has not been sufficient evidence to prove that maintenance chemotherapy using platin or doxorubicin for advanced epithelial ovarian cancer can improve the PFS or OS. According to Markman 2003 12 courses of paclitaxel can significantly prolong PFS rather than three courses. However, the control arm used three courses of maintenance chemotherapy but not observation and the trial was closed prematurely. So far, only one trial (Pecorelli 2009), studied paclitaxel as maintenance chemotherapy for advanced epithelial ovarian cancer but the results showed no survival benefit. One ongoing trial using paclitaxel as maintenance chemotherapy may provide new evidence (NCT00108745).

Authors' conclusions

Implications for practice

There is insufficient evidence to prove that platin, doxorubicin or paclitaxel used as maintenance chemotherapy are more effective than observation alone.

Implications for research

Considering the wide use of paclitaxel and its effectiveness during the induction phase of chemotherapy for advanced epithelial ovarian cancer, further studies on the effect of paclitaxel as maintenance chemotherapy should be investigated.

Larger treatment effects are needed before there is convincing evidence that maintenance chemotherapy is beneficial. Any future high-quality trials should include QoL as this is an important consideration when prescribing maintenance chemotherapy.

Acknowledgements

We would like to thank Chris Williams and Clare Jess of the Editoral base of the Cochanre Gynaecological Cancer Group for there contribution to the editorial process.

Data and analyses

Download statistical data

Comparison 1. Maintenance chemotherapy versus observation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 3-year PFS4541Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.91, 1.25]
2 5-year PFS3761Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.97, 1.17]
3 10-year PFS2219Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.65, 1.41]
4 3-year OS5679Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.92, 1.08]
5 5-year OS4899Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.96, 1.10]
6 10-year OS2219Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.78, 1.49]
Analysis 1.1.

Comparison 1 Maintenance chemotherapy versus observation, Outcome 1 3-year PFS.

Analysis 1.2.

Comparison 1 Maintenance chemotherapy versus observation, Outcome 2 5-year PFS.

Analysis 1.3.

Comparison 1 Maintenance chemotherapy versus observation, Outcome 3 10-year PFS.

Analysis 1.4.

Comparison 1 Maintenance chemotherapy versus observation, Outcome 4 3-year OS.

Analysis 1.5.

Comparison 1 Maintenance chemotherapy versus observation, Outcome 5 5-year OS.

Analysis 1.6.

Comparison 1 Maintenance chemotherapy versus observation, Outcome 6 10-year OS.

Comparison 2. Platin-based maintenance chemotherapy versus observation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 3-year PFS3341Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.86, 1.24]
2 5-year PFS2219Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.88, 1.58]
3 10-year PFS2219Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.65, 1.41]
4 3-year OS3341Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.94, 1.18]
5 5-year OS2219Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.88, 1.31]
6 10-year OS2219Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.78, 1.49]
Analysis 2.1.

Comparison 2 Platin-based maintenance chemotherapy versus observation, Outcome 1 3-year PFS.

Analysis 2.2.

Comparison 2 Platin-based maintenance chemotherapy versus observation, Outcome 2 5-year PFS.

Analysis 2.3.

Comparison 2 Platin-based maintenance chemotherapy versus observation, Outcome 3 10-year PFS.

Analysis 2.4.

Comparison 2 Platin-based maintenance chemotherapy versus observation, Outcome 4 3-year OS.

Analysis 2.5.

Comparison 2 Platin-based maintenance chemotherapy versus observation, Outcome 5 5-year OS.

Analysis 2.6.

Comparison 2 Platin-based maintenance chemotherapy versus observation, Outcome 6 10-year OS.

Comparison 3. Doxorubicin-based maintenance chemotherapy versus observation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 3-year OS2204Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.86, 1.15]
2 5-year OS2204Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.79, 1.27]
Analysis 3.1.

Comparison 3 Doxorubicin-based maintenance chemotherapy versus observation, Outcome 1 3-year OS.

Analysis 3.2.

Comparison 3 Doxorubicin-based maintenance chemotherapy versus observation, Outcome 2 5-year OS.

Comparison 4. Maintenance chemotherapy versus maintenance radiotherapy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 3-year PFS1141Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.75, 1.54]
1.1 PCR167Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.50, 1.11]
1.2 CCR174Risk Ratio (M-H, Fixed, 95% CI)2.14 [0.99, 4.64]
2 5-year PFS1141Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.55, 1.37]
2.1 PCR167Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.39, 1.12]
2.2 CCR174Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.59, 3.79]
3 10-year PFS1141Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.51, 1.55]
3.1 PCR167Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.27, 1.00]
3.2 CCR174Risk Ratio (M-H, Fixed, 95% CI)4.0 [0.91, 17.59]
4 3-year OS1141Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.85, 1.32]
4.1 PCR167Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.72, 1.16]
4.2 CCR174Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.84, 1.94]
5 5-year OS1141Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.70, 1.35]
5.1 PCR167Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.57, 1.20]
5.2 CCR174Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.68, 2.29]
6 10-year OS1141Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.58, 1.52]
6.1 PCR167Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.41, 1.20]
6.2 CCR174Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.66, 6.07]
Analysis 4.1.

Comparison 4 Maintenance chemotherapy versus maintenance radiotherapy, Outcome 1 3-year PFS.

Analysis 4.2.

Comparison 4 Maintenance chemotherapy versus maintenance radiotherapy, Outcome 2 5-year PFS.

Analysis 4.3.

Comparison 4 Maintenance chemotherapy versus maintenance radiotherapy, Outcome 3 10-year PFS.

Analysis 4.4.

Comparison 4 Maintenance chemotherapy versus maintenance radiotherapy, Outcome 4 3-year OS.

Analysis 4.5.

Comparison 4 Maintenance chemotherapy versus maintenance radiotherapy, Outcome 5 5-year OS.

Analysis 4.6.

Comparison 4 Maintenance chemotherapy versus maintenance radiotherapy, Outcome 6 10-year OS.

Appendices

Appendix 1. MEDLINE search strategy

#1   exp Ovarian Neoplasms/
#2   (ovar* adj5 (cancer* or tumor* or tumour* or malignan* or neoplas* or carcinoma*)).mp.
#3   1 or 2
#4   drug therapy.fs.
#5   exp Antineoplastic Agents/
#6   Antineoplastic Combined Chemotherapy Protocols/
#7   chemotherap*.mp.
#8   4 or 5 or 6 or 7
#9   (maintain or maintenance or consolidat*).mp.
#10 3 and 8 and 9
#11 randomized controlled trial.pt.
#12 controlled clinical trial.pt.
#13 randomized.ab.
#14 placebo.ab.
#15 drug therapy.fs.
#16 randomly.ab.
#17 trial.ab.
#18 groups.ab.
#19 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18
#20 10 and 19

key:
mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier
pt=publication type
fs=floating subheading
ab=abstract

Appendix 2. CENTRAL search strategy

#1 MeSH descriptor: [Ovarian Neoplasms] explode all trees
#2 ovar* near/5 (cancer* or tumor* or tumour* or malignan* or neoplas* or carcinoma*)
#3 #1 or #2
#4 Any MeSH descriptor with qualifier(s): [Drug therapy - DT] in all MeSH products
#5 MeSH descriptor: [Antineoplastic Agents] explode all trees
#6 MeSH descriptor: [Antineoplastic Combined Chemotherapy Protocols] this term only
#7 chemotherap*
#8 #4 or #5 or #6
#9 maintain or maintenance or consolidat*
#10 #3 and #8 and #9

Appendix 3. EMBASE search strategy

#1   exp ovary tumor/
#2   (ovar* adj5 (cancer* or tumor* or tumour* or malignan* or neoplas* or carcinoma*)).mp.
#3   1 or 2
#4   dt.fs.
#5   exp antineoplastic agent/
#6   chemotherap*.mp.
#7   4 or 5 or 6
#8   (maintain or maintenance or consolidat*).mp.
#9   3 and 7 and 8
#10 crossover procedure/
#11 double-blind procedure/
#12 randomized controlled trial/
#13 single-blind procedure/
#14 random*.mp.
#15 factorial*.mp.
#16 (crossover* or cross over* or cross-over*).mp.
#17 placebo*.mp.
#18 (double* adj blind*).mp.
#19 (singl* adj blind*).mp.
#20 assign*.mp.
#21 allocat*.mp.
#22 volunteer*.mp.
#23 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22
#24 9 and 23

key:
mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword

Appendix 4. CNKI,VIP, CBMdis

#1 ovarian cancer
#2 ovarian tumor
#3 maintenance therapy
#4 maintenance chemotherapy
#5 maintenance radiotherapy
#6 consolidation therapy
#7 consolidation chemotherapy
#8 consolidation radiotherapy
#9 or/1 2
#10 or/3 8
#11 9 and 10

What's new

DateEventDescription
21 September 2016AmendedContact details updated.

History

Protocol first published: Issue 4, 2008
Review first published: Issue 9, 2010

DateEventDescription
27 March 2014AmendedContact details updated.
5 June 2013AmendedMinor amendment to PLS
29 May 2013New citation required but conclusions have not changedTwo studies added but conclusions remain unchanged.
5 May 2013New search has been performedReview updated, new searches run and text revised.
5 August 2010AmendedEMBASE search strategy added.

Contributions of authors

Mei Ling and Chen Hui were responsible for searching for studies, quality assessment, data extraction, data analysis and review development. Fang Fang offered clinical expertise and took part in the development of this review. Wei Dongmei, Zou Juan and Han Xu undertook searching for studies and quality assessment. Feng Dan, Xie Huanyu, Wang Xun and Chen Fuxia participated in data extraction and analysis. Liu Guan Jian offered methodological expertise. For the update, Mei Ling and Wei Dongmei were responsible for searching for studies, quality assessment, data extraction and data analysis. Mei Ling was in charge of revising the text.

Declarations of interest

None known.

Sources of support

Internal sources

  • West China Second Hospital, China.

External sources

  • No sources of support supplied

Differences between protocol and review

For the assessment of risk of bias in included studies, we changed the original five criteria to six criteria according to the guidelines of Cochrane Handbook for Systematic Reviews of Interventions 5.1.0.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bolis 2006

MethodsRCT
Participants

138 women with epithelial ovarian cancer achieved PCR or CCR

Stage 2c, 3 and 4

Mean age was 55.6 years old

Median follow-up time was 40 months

InterventionsEpidoxorubicin versus observation
Outcomes3-year overall survival and 5-year overall survival; toxic events
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated list
Allocation concealment (selection bias)Low riskQuote: "..according to a computer-generated list, by phone at the coordinating center"
Comment: Probably done.
Blinding (performance bias and detection bias)
All outcomes
Low riskNo blinding, but the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Cheng 2006

MethodsRCT
Participants

44 women with epithelial ovarian cancer achieved CCR

Stage 3 and 4

Mean age was 53.8 years old in maintenance chemotherapy group and 53.7 in observation group

Mean follow-up time was 39.6 months in maintenance chemotherapy group and 33.2 months in observation group

InterventionsPlatin + CTX/Taxel versus observation
OutcomesRecurrence rate, disease-free survival
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: " patients were randomly allocated"

Comment: Probably done

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding (performance bias and detection bias)
All outcomes
Low riskNo blinding, but the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Mannel 2011

MethodsRCT
Participants

542 women with early stage of epithelial ovarian cancer.

stage ⅠA or B grade 3 or clear cell subtype, or any stage IC, or stage II disease.

Mean age was 55.1 years old in maintenance chemotherapy group and 56 in observation group

Mean follow-up time was 6.7 years

InterventionsWeekly paclitaxel 40mg/m² × 24 weeks versus observation
OutcomesOverall survival, progression-free survival
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "treatment was randomly assigned through the GOG Statistical and Data Center prior to receiving any chemotherapy."

Comment: Probably done

Allocation concealment (selection bias)Low risk

Quote: "The treatment assignment was not revealed until after the patient was successfully registered onto the study"

Comment: Probably done

Blinding (performance bias and detection bias)
All outcomes
Low riskNo blinding, but the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "18 patients randomized to the additional 24 weeks of paclitaxel withdrew during the follow-up,14 patients of the control group withdrew during the follow-up."

Comment: It is balanced between the two groups

Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Nicoletto 2004

MethodsRCT
Participants

122 women with epithelial ovarian cancer achieved PCR

Stage 1c, 2b, 2c, 3 and 4

Mean age was 55 years old

Median follow-up time was not reported

Interventions5-Fu + cisplatin versus observation
Outcomes3-year overall survival and 3-year progression-free survival; toxic events
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "…at time of randomization"

Comment: Probably done

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding (performance bias and detection bias)
All outcomes
Low riskNo blinding, but the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "one patient refused treatment entirely after randomization and is therefore not evaluable"

Comment: For OS and PFS, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate.

Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Pecorelli 2009

MethodsRCT
Participants

200 women with epithelial ovarian cancer

Stage ⅡB-Ⅳ with PCR or CCR

Mean age was 59 years old in maintenance chemotherapy group and 58 in observation group

Median follow-up time was 43.5 months

Interventions6 cycles of paclitaxel 175mg/m² every 3 weeks versus observation
OutcomesOverall survival and progression-free survival
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "A system of random permuted blocks within strata was used."

Comment: Comment: Probably done

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding (performance bias and detection bias)
All outcomes
Low riskNo blinding, but the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "6% never started treatment, and a total of 17% stopped treatment early because of toxicity (9%), progression/death (3%), patient refusal (3%), or other reasons (2%)."

Comment: For OS and PFS, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate.

Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Piccart 2003

MethodsRCT
Participants

153 women with ovarian cancer achieved PCR

Stage 2b, 2c, 3 and 4

Mean age was 55 years old

Median follow-up time was 96.7 months

InterventionsCisplatin versus observation
Outcomes3, 5, 8, 10-year OS and PFS; toxic events
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "randomization took place…"

Comment: Probably done

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding (performance bias and detection bias)
All outcomes
Low riskNo blinding, but the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "one patient no follow-up forms. No statistically significant difference between the two groups"
Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasHigh riskQuote: "the study was closed prematurely in view of a disappointing recruitment rate…"

Placido 2004

MethodsRCT
Participants

273 women with epithelial ovarian cancer achieved CCR or partial clinical remission

Stage 1c, 2, 3 and 4

Mean age was 55 years old in maintenance chemotherapy group and 56 in observation group

Median follow-up time was 28 months

InterventionsTopotecan versus observation; toxic events
Outcomes1-year PFS
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "…by means of a computer-driven minimization procedure"

Comment: Probably done

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding (performance bias and detection bias)
All outcomes
Low riskNo blinding, but the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Sorbe 2003

  1. a

    CCR: complete clinical remission
    GOG: Gynecologic Oncology Group
    OS: overall survival
    PCR: pathological complete remission
    PFS: progression-free survival
    RCT: randomised controlled trial

MethodsRCT
Participants

172 women with epithelial ovarian cancer achieved PCR and CCR

Stage 3 and 4

Mean age was 55 years old

Median follow-up time was not reported

InterventionsCisplatin + doxorubicin/epidoxorubicin versus observation
Outcomes3, 5, 10-year OS and PFS; toxic events
NotesThis study is a 3-arm study comparing maintenance chemotherapy, maintenance radiotherapy and no further treatment. The total partIcipants are 172 women with 98 of PCR and 74 of CCR. The women with PCR were divided into chemotherapy, radiotherapy and observation groups while the women with CCR were divided into chemotherapy and radiotherapy groups.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "Patients…were entered in a prospective, randomized, multicenter trial"

Comment: Probably done

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding (performance bias and detection bias)
All outcomes
Low riskNo blinding, but the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    GOG: Gynecologic Oncology Group
    PBSC: peripheral blood stem cell

Abaid 2010The follow-up of Markman 2003 and the results were of high potential bias
Cure 2001It compared high dose chemotherapy combined with PBSC versus normal dose maintenance chemotherapy
Lesnock 2011A cost-effect analysis of three GOG studies
Mannel 2010The same trial with the Mannel 2011 but not the final result
Markman 2003It compared short- versus long-duration maintenance chemotherapy
Markman 2009The follow-up of Markman 2003 and the results were of high potential bias
Scarfone 2002The original article or data are unavailable

Characteristics of ongoing studies [ordered by study ID]

NCT00108745

  1. a

    IV: intravenous
    RCT: randomised controlled trial

Trial name or titlePaclitaxel or polyglutamate paclitaxel or observation in treating women with stage III or stage IV ovarian epithelial or peritoneal cancer
MethodsRCT
ParticipantsWomen with advanced ovarian or primary peritoneal cancer who achieve a complete clinical response to primary platinum/taxane chemotherapy
Interventions
  • Arm I: women receive polyglutamate paclitaxel IV over 10-20 minutes on day 1.

  • Arm II: women receive paclitaxel IV over 3 hours on day 1.

  • Arm III: women receive no further anticancer treatment until evidence of disease progression.

In arms I and II, treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity

OutcomesPrimary outcome measures: overall survival

Secondary outcome measures: Peripheral neuropathy by Gynecologic Oncology Group (GOG) NTX4 at 6 months after study enrolment
General quality of life by Functional Assessment of Cancer Therapy-Ovarian-Trial Outcome Index (FACT-O-TOI) at 6 months after study enrolment
Exploratory assessment of several tissue and serum angiogenic markers for prognosis by immunohistochemistry and antibody array prior to treatment in courses 1 and 2
Exploratory time-dependent assessment of quality of life and peripheral neuropathy by FACT-O-TOI and GOG-NTX4 monthly during year 1 and then every 3 months for 2 years
Starting dateMarch 2005
Contact informationStudy Chair: Maurie Markman, MD; M.D. Anderson Cancer Center
Notes 

Ancillary