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A systematic review and economic evaluation of pegylated liposomal doxorubicin hydrochloride for ovarian cancer |
Forbes C, Wilby J, Richardson G, Sculpher M, Mather L, Riemsma R |
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Authors' objectives To examine the clinical effectiveness and cost-effectiveness of intravenous pegylated liposomal doxorubicin hydrochloride (PLDH) for second-line treatment of advanced ovarian cancer, after the failure of platinum-based regimes.
Searching BIOSIS Previews (1985 to May 2001), Cancerlit (1966 to May 2001), the Cochrane Controlled Trials Register (Issue 2, 2001), the Cochrane Database of Systematic Reviews (Issue 2, 2001), CINAHL (1982 to February 2001), PubMed (January 2001 to May 2001), DARE (May 2001), EMBASE (1980 to February 2001), HTA (May 2001), HealthSTAR (1981 to December 2000), Index to Scientific and Technical Proceedings (1990 to May 2001), MEDLINE (1966 to December 2000), NHS EED (May 2001), the Science Citation Index (1981 to May 2001) and HEED (May 2001) were searched for published studies. The National Research Register, UK co-ordinating Committee on Cancer Research Register, National Cancer Institute, National Institute of Health, CenterWatch Clinical Trials Listing Service, Current Controlled Trials, American Society of Clinical Oncology and the National Cancer Institute of Canada were contacted for ongoing trials. Internet searches were also conducted, using Google, Metaeureka, Altavista, Schering-Plough Ltd., RxList and the BNF. The search strategies were provided. Bibliographies of retrieved articles and industry submissions made to the National Institute of Clinical Excellence were also searched.
Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs), full economic evaluations, and non-comparative phase II studies were eligible for inclusion.
Specific interventions included in the reviewStudies of PLDH-containing regimens, either alone or in combination with other chemotherapeutic agents, were eligible for inclusion. Second-line treatments were defined as a second chemotherapy regimen administered either following on from first-line platinum-based therapy, or as a result of relapse after this treatment. Salvage therapy was defined as therapy given in the hope of getting a response when platinum-based therapy failed. The one comparative included study compared PLDH with topotecan.
Participants included in the reviewStudies of women with ovarian cancer, at any stage of the disease, were eligible for inclusion.
Outcomes assessed in the reviewStudies reporting progression-free survival, overall survival, response, quality of life, adverse events, or cost were eligible for inclusion.
How were decisions on the relevance of primary studies made?Two reviewers independently screened the results of the searches for potentially relevant studies. Any discrepancies were resolved by consensus, or with a third reviewer if consensus could not be reached. It was unclear how many reviewers assessed the full papers retrieved for inclusion.
Assessment of study quality RCTs were assessed on the basis of: method of randomisation; allocation concealment; sample size; comparability of the groups at baseline; reporting of selection criteria; identification of cointerventions; blinding of assessors, participants and carers and its success; attrition; explanation for withdrawals; and whether an intention-to-treat analysis was performed.
Phase II studies were assessed on the basis of: adequacy of the description of the participants; whether the study aims were clear; if a control group was used or should have been used; study design; follow-up; sample size; validity and relevance of outcome measures; monitoring of compliance; description, appropriateness and reporting of statistical analyses; reporting of unforeseen events that might have affected the results; identification of confounding factors; and appropriate interpretation of the results.
Economic evaluations were assessed on the basis of: clarity of the research question; adequate description of the competing alternatives; establishment of the effectiveness of the programmes; identification, measurement and value of relevant costs and consequences; adjustment for differential timing and allowance for uncertainty in the estimates of costs and consequences; analyses performed; and whether all issues were discussed adequately.
Two reviewers independently assessed the quality of the included studies. Any disagreements were resolved by consensus, or with a third reviewer if consensus could not be reached.
Data extraction One reviewer extracted the data and a second reviewer checked the data extracted. Data were extracted on study design, population characteristics, and intervention and comparator characteristics. Relative risks (RRs) or hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted, or calculated, where possible.
Methods of synthesis How were the studies combined?The studies were combined in a narrative.
How were differences between studies investigated?As the studies were not combined in a meta-analysis, heterogeneity was not investigated statistically. Differences between the studies were discussed in the text.
Results of the review Ten studies were included in the review. Two of these were RCTs, although one was an abstract with no outcome data available from the company. Therefore, the review included results from one RCT (n=474), six phase II studies (n=336) and two economic evaluations (n=474 as both publications were based on the same included RCT).
Survival.
The RCT reported that, overall, there was no statistically significant difference in survival between women treated with PLDH and those treated with topotecan in this study. One subgroup analysis in women with platinum-sensitive disease showed a statistically significant increase in survival when treated with PLDH (HR 1.72, 95% CI: 1.145, 2.585). Five phase II studies reported on survival: the median progression-free survival varied between 13 and 44.9 weeks, while median overall survival varied between 25.1 and 47.6 weeks.
Response.
The RCT reported no statistically significant difference in response rate, time to response, or duration of response, between women receiving PLDH and those receiving topotecan, whether the baseline response to platinum therapy was taken into consideration or not. All six Phase II studies reported total response rates (complete and partial), which varied between 5.5 and 25.7%.
Time to progression.
The RCT reported no statistically significant difference in time to progression between women receiving PLDH and those receiving topotecan.
Quality of life.
The RCT reported no statistically significant difference in global quality of life scores, physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning, fatigue, or nausea and vomiting, between women receiving PLDH and those receiving topotecan. There was a statistically significant difference in pain scores, with women receiving topotecan experiencing less pain than those receiving PLDH (RR 1.264, 95% CI: 1.076, 1.500). This was also true in women with platinum-sensitive disease (RR 1.542, 95% CI: 1.211, 2.023).
Adverse events.
The RCT reported that 16% of women treated with PLDH discontinued treatment due to adverse events, compared with 12% receiving topotecan. There were no reported deaths in women receiving PLDH, whereas two women receiving topotecan died as a result of treatment-related adverse events. The incidence of palmer-plantar erythrodysesthesia, stomatitis, mucus membrane disorders and skin rashes were statistically significantly higher in women receiving PLDH than in those receiving topotecan. The incidence of neutropenia, anaemia, thrombocytopenia, leukopenia, nausea, vomiting and alopecia were statistically significantly higher in women receiving topotecan than in those receiving PLDH.
All six phase II studies reported adverse events. One study reported three deaths in women receiving PLDH. Withdrawals due to drug-related adverse events varied from 2 to 10.7%. The overall proportion of women experiencing adverse events varied from 91.4 to 95.2%. The most common adverse events were palmer-plantar erythrodysesthesia and stomatitis, with nausea, asthenia, leukopenia and neutropenia frequently reported.
Cost information Two studies provided information on cost, both based on the same RCT. The mean cost per person was estimated to be £9,970 and £9,998 for treatment with PLDH, and £12,627 and £12,076 for treatment with topotecan. The cost per patient of treating adverse events was estimated at £3,362 and £2,799, with the difference between the two studies primarily due to the reduction in the cost of treating neutropenia from £893 to £540. Possible differences in health-related quality of life between the two treatments means that the overall cost-effectiveness of PLDH is not clear. Authors' conclusions There was little RCT evidence with which to assess the use of PLDH as second-line therapy for advanced ovarian cancer. The evidence available suggests that there are no differences between PLDH and topotecan in the main clinical outcomes.
CRD commentary The review question and the inclusion criteria were clearly stated. The authors conducted an extensive search, with attempts to locate published and unpublished data. Each stage of the review was carried out in duplicate (although this is less clear for the screening of full articles), thus minimising the potential of error or bias. Full details of the studies and an appropriate quality assessment were presented. The main analysis and evaluation were based on a single RCT. Data from the uncontrolled trials were described in a narrative. The decision not to pool the studies in a meta-analysis seemed appropriate. Overall, this was a well-conducted systematic review, and the conclusions drawn by the authors are likely to be limited only by the lack of data.
Implications of the review for practice and research Practice: The authors stated that it would be difficult to make any choices about PLDH and other drugs for second-line therapy for advanced ovarian cancer, owing to the lack of available evidence.
Research: The authors recommended good-quality RCTs comparing PLDH with other licensed and potentially useful second-line chemotherapy agents for ovarian cancer, which also evaluate the cost-effectiveness of each alternative.
Funding NHS R&D Health Technology Assessment (HTA) Programme, project number 01/20/01.
Bibliographic details Forbes C, Wilby J, Richardson G, Sculpher M, Mather L, Riemsma R. A systematic review and economic evaluation of pegylated liposomal doxorubicin hydrochloride for ovarian cancer. Health Technology Assessment 2002; 6(23): 1-130 Indexing Status Subject indexing assigned by NLM MeSH Aged; Antineoplastic Agents /adverse effects /economics /therapeutic use; Cost-Benefit Analysis; Doxorubicin /adverse effects /economics /therapeutic use; Female; Great Britain; Middle Aged; Outcome Assessment (Health Care); Ovarian Neoplasms /drug therapy; Quality of Life; Randomized Controlled Trials as Topic; State Medicine; Survival AccessionNumber 12003008014 Date bibliographic record published 30/06/2005 Date abstract record published 30/06/2005 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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