Chemo and cost of different chemotherapy with recurrences of ovarian cancer. Article update 29 december 2011
Update 13 May 2008: sources see below
For those who prefer a natural approach to ovarian cancer whether or not in combination chemotherapy or other regular treatments once read emt everything about enzyme therapy from Dr. Nicola Gonzalez on his website.
We have this complete outline article on chemotherapies as second line treatment for a relapse of ovarian cancer or metastatic in Dutch translates for you understandable. With yet alarming conclusions. Free: translates given the relatively small chance that a pegylated liposomal doxorubicin chemotherapy with Topotecan hydrochloride (PLDH), and/or paclitaxel catches, also given the small chance of a reasonable survival time with an acceptable quality of life and given the severe adverse reactions and given the very high cost versus effectiveness the researchers propose that a large group of eierstokkanker patients can do better in studies with experimental new medicines. We knew this already longer, see below under articles on ovarian cancer, so it seemed sensible that we us this great overview article would translate for you. You can also read the article under the Dutch completely and check for any translation errors and, of course, take it to your doctor-oncologist if you for the choice stands for a second lijnsbehandeling for metastatic or relapse of ovarian cancer. For an alternative once read the stories of Marjan and Deborah (see there under ovarian cancer in alphabetical list) who both a relapse of ovarian cancer with nutrition and supplementation and seem to be now heal without which wegkregen chemo whatsoever. Now here is the translated article.
Pegylated liposomal doxorubicin hydrochloride, Topotecan (PLDH) and paclitaxel as second line treatment or follow-up treatment of advanced (means a relapse and/or with uitzaaiïngen) ovarian cancer: a systematic review and economic evaluation.
C Main, 1 * L, 2 S, 2 G Bojke Griffin Norman, 1 M Barbieri, 3 L Mather, 1 D Stark, 4 S Palmer2 and R Riemsma1
1 Centre for Reviews and Dissemination, University of York, UK
2 Centre for Health Economics, University of York, UK
3 Economic and Health Research Centre, Universitat Pompeu Fabra, Barcelona, Spain
4 Department of Oncology, Bradford Royal Infirmary, UK
Background
Ovarian cancer is the most common form of gynaecological cancer with new patients on every 100,000 women in England 21.9 and 26.7 new patients in Wales (2000 figures). The prognosis is generally poor, usually caused by the advanced character of the disease at diagnosis, and in England the median lies only around 30% 5-year survival. The current primarysupports treatment by the National Institute for Health and Clinical Excellence is paclitaxel in combination with a platinum-based chemotherapy, or only a chemo with a platinum-based regime (carboplatin or cisplatin). Because the majority of patients get a second line eventually relapse is recommended if not the same as the first line treatment regime. Pegylated liposomal doxorubicin hydrocholoride, topotecan and paclitaxel (PLDH) come as second to qualify lijnsbehandeling advanced ovarian cancer. Patients who have not previously paclitaxel as a component of a first line treatment or as a second line treatment got this can get.
Goals of the outline
The goals were to examine what are the clinical effects and cost-effectiveness of intravenous treatment with topotecan, monotherapies is if (Pegylated liposomal doxorubicin hydrocholoride =) PLDH as monotherapies and paclitaxel used solo or in combination with a platinum-based chemotherapy as a second line treatment of advanced and/or metastatic or drop ovarian cancer.
Methods
Research Strategy
Randomised controlled trials were searched for databases 17 (RCTs) and systematic reviews of the clinical effectiveness of topotecan and paclitaxel and economic evaluations of PLDH, the cost-efficacy of topotecan and paclitaxel PLDH,. Previous studies were viewed going back to 2000. The recent studies were thus limited to publications from the years 2000 to 2004.
Admission and exclusion criteria.
Two researchers independently screenden all titles and/or abstract artists including economic evaluations. The full text of each study was assessed for relevance by every researcher weerd which obtained and proposed for admission as well as exclusion. Disagreements were resolved by discussion. For the assessment of clinical effectiveness were taken and assessed all RCTs which were compared with topotecan or paclitaxel monotherapy as monotherapy, PLDH administered solo or in combination with a platinum-based chemotherapy and compared with every other comparable approach, including supportive care. For the assessment of cost-effectiveness was still a greater number of studies included.
Data selection and quality of the content.
Dates of studies were examined by 1 researcher and independently verified for accuracy by the second researcher.
Methods of analysis/synthesis
The results of the gathered data and quality information from the RCTs were presented in structured tables and as a written summary. For the part of the report on the cost-effectiveness were details of each identifiedpublished economic evaluation, concurrent with a critical approach of the quality presented in structural tables.
Handling of business information.
All clinical data of effectiveness within the Bristol Myers Squibb, GlaxoSmithKline and business data of Schering-Plough Ltd were assessed. Where such equivalent to the admission criteria for the clinical effects were of this included. All economic evaluations (including accompanying models) within the corporate data were assessed and a detailed assessment of the underlying interests of the analyses used was respected. A new model was developed to cover the costs of alternative treatments, the various median lifespan and effect, to assess the impact on the quality of life. Monte-Carlo simulation was used to reflect on uncertainties in the cost-effectiveness results.
Results
A total of 2542 titles and abstracts were gescreened for admission in the overview of clinical and cost-effectiveness; 194 studies were organized as to full files and recorded in detail. Nine RCTs were identified. In five of these studies were comparisons of these trials used within the licenced indications. Of these five studies there names in three studies with platinum-resistant and platinum sensitive patients share ovarian cancer, and the other two studies with platinum-sensitive ovarian cancer patients only part names. The equations that were created within the three studies which both subtypes of patients, topotecan versus paclitaxel and topotecan versus PLDH were, PLDH versus paclitaxel. In the other two studies with patients with the disease were subtypoe of platinum sensitive comparisons between single-agent doxorubicin, paclitaxel versus a combination of cyclophosphamide and paclitaxel plus cisplatin (CAP) and to platinum-based chemotherapy versus conventional on platinum-based therapy alone.
Four other studies were identified and admitted in the overview which one of the equations was used outside the licensed indication. The comparisons made in these studies were given oxaliplatin versus paclitaxel, paclitaxel versus paclitaxel every three weeks, every week with two different doses of oral versus intravenous given and topotecan.
Clinical effectiveness
Trials with participants with relapse, resistant and platinum-sensitive disease
PLDH versus topotecan was marginally more effective than topotecan PLDH something in terms of overall survival in the total population in which both patients with platinum-sensitive trial and platinum-resistant disease. However this result was mainly achieved by higher significant effect of the treatment in the platinum-sensitive sub-group of PLDHparticipants. For participants with platinum-resistant disease, there was no statistically significant difference in overall survival between the treatment groups and PLDH topotecan. There was also no statistically significant difference between the groups in terms of progression and PLDH topotecan free survival, treatment or catch on quality of life.
In terms of toxiciteiten-side effects reported during the study, were the figures of palmar-plantar erythrodysesthesia grade 3 stomatitis, Mucosa (PPE), statistically significant higher in the problems and rashes PLDH treatment group. In the topotecan group were the figures of degree 3 and 4 toxiciteiten and haematologische grade 3 alopecia and fever significantly higher.
Topotecan versus paclitaxel
There were no statistically significant differences between the two groups in terms of overall survival, time to progression of the disease, the treatment or duration of hitting hitting the treatment. It is estimated that for all outcomes there is a preference for a treatment with topotecan above paclitaxel. However there was a statistically significant difference in establishment of treatment between the two groups in favour of paclitaxel.
In this trial became a treatment with topotecan associated with statistically significant more grade 3 and 4 adverse reactions compared with paclitaxel toxiciteiten-haematologische. In addition, grade 3 and 4 nausea, vomiting, constipation, abdominal pain, asthenia, fatigue and fever infections/significantl were hihoger in this group. Treatment with paclitaxel was associated with significantly more grade 3 and 4 alopecia, joint pain, bone pain and myalgia topotecan compared with the treatment. PLDH versus paclitaxel In relation to overall survival, there was no statistically significant difference between the treatment groups and PLDH paclitaxel. Treatment with PLDH was associated with significantly more grade 3 PPE, ascites, stomatitis and digestive problems compared with paclitaxel. Treatment with paclitaxel was only associated with a grade 3 alopecia in comparison with common PLDH. This trial was stopped prematurely so the results should be interpreted with caution.
Studies with patients with platinum-sensitive disease only
Paclitaxel versus paclitaxel CAP CAP was more effective than in terms of both overall and progression-free survival. There were no significant differences in uptake of the two static hget treatments. However the action of grade 3 and 4 adverse reactions and grade 2 haematologische toxiciteiten-nausea and vomiting was significantly higher in the CAP treatment group. Treatment with paclitaxel was associated with significantly higher figures of alopecia and allergic reactions in comparison with treatment with CAP. Paclitaxel in combination with platinumplatinum-based chemotherapy versus chemotherapy based on solo.
Paclitaxel in combination with platinum-based chemotherapy was more effective than platinum on monotherapy in relation to survival and progression free survival both overall. However there was no significant difference in efectiviteit for the combination therapy for hitting the treatment or eventual general quality of life. Treatment with paclitaxel in combination with platinum was associated with significantly higher numbers of degree 2 – 4 neurological toxicity and alopecia. The treatment with platinum monotherapy was associated with significantly higher figures of haematologische toxicity.
Studies in which one of the equations was used outside the license indications.
Paclitaxel versus oxaliplatin there was no significant difference between the paclitaxel and oxaliplatin static treatment groups in terms of overall survival, time to progression of the disease, the treatment, the duration of hitting hitting the treatment or quality of life. Treatment with paclitaxel was associated with a more frequent serious oxaliplatin was associated with neutropenia, while higher numbers of thrombosis phenomena.
Weekly Paclitaxel versus given every three weeks
There was no significant difference between the two groups in terms of overall survival, time to progression of the disease, hitting the evoke behandleing and duration of the treatment. Treatment with paclitaxel every three weeks was associated with a significant increase of degree 3 and 4 neutropenia and alopecia, while the Administration was associated with problems with the nails every week.
Paclitaxel 175 versus 250 mg/m2
There were no statistically significant differences between participants which were treated with low dosage and which were treated with the higher dosage in terms of overall survival or progression free time. There was a statistically significant difference in hitting the treatment for the higher dose. However the reported grade 3 and 4 were more frequent in the high dose toxiciteiten haematologische group.
Oral versus intravenous topotecan
Statitisch there was a significant difference in effectiveness of intravenous topotecan administered for overall survival. However, there were significant differences further static not found between the two treatment groups in terms of time to disease progression, treatment, duration of the nailing, nailing and time to the treatment was popular. Neutropenia and repeatedly came in both treatment groups leucopenia, but were higher in the intravenous treatment group. The figures of degree 3 and 4 nausea, vomiting, diarrhea and fever were all significantly higher in the treatment group received oral which the chemocompared with the group which administered intravenously administered got.
Cost-effectiveness
Four studies met the admission requirements for the cost-effectiveness overview. Additional Bristol Myers Squibb, were separate contributions received from GlaxoSmithKline and Schering-Plough Ltd. the overview of the economic evidence from the literature and business contributions identified a number of important limitations which were decisive for the cost-efficacy of topotecan and paclitaxel PLDH,. A new model was developed to the restrictions in these sources to send found in to establish a direct comparison of a full range of strategies that are relevatn for the NHS mogeljike. The model examined a range of uncertainties and variable sources which were not fully captured in existing data sources. Two separate analyses (Analysis Analysis 1 and 2) were required in order to assess the heterogeneity in several studies and to cope with the difficulties in obtaining reliable estimates and to use in a consistent approach to the methods of evidence synthesis of the relative treatment effects.
Analysis 1 explained the cost-efficacy of topotecan and paclitaxel PLDH, administered as monotherapies. Sensitivity analyses were performed to determine the influence of patient to measure/heterogeneniteit (e.g. platinum-sensitive and platinum-resistant/relapse patients), the admission of additional study data (30-57) and alternative suspicions concerning treatment and accompanying costs. In the basic results through Analysis 1, paclitaxel monotherapy came as cheapest treatment forward. When the incremental cost-effectiveness ratios (ICERs) was estimated, were dominated by PLDH topotecan. When the options of the estimation of the paclitaxel and ICERs that were included were PLDH. The PLDH compared with paclitaxel was £ 7033 ICER for quality-adjusted life years (QALY) per (Note editors: here is thus included in the provision and the quality of life not only in his life) in the overall patient population (consisting of platinum-sensitive and-resistant patients,-recidieve). The ICER was better in the platinum-sensitive group (£ 45 per QALY) and less in the platinum-recidieve/resistant Group (£ box 9555 per QALY). The cost-effectiveness results by the basic analysis were influenced by the admission of studies 30-57. When the results were taken from the trials that resulted in 30-57 for the less good estimates of ICER PLDH versus paclitaxel compared with the basic results. The ICER of PLDH compared with paclitaxel was £ 20,620 per QALY in the overall patient population, £ per QALY in the platinum-sensitive population 16,183 and £ per QALY in the platinum-resistant and 26,867-recidievepopulation.
The results from Analysis 2 examined the cost-effectiveness of a full range of comparable treatments for platinum sensitive patients. What treatment options were weighed in this model, topotecan, monotherapies PLDH paclitaxel – were, CAP, paclitaxel/platinum combination therapy and monotherapy platinum. Because there is less robust approaches were taken to the available evidence and to measure the heterogeneity between different studies, the reliability of the study results be interpreted with some caution. Topotecan, monotherapies paclitaxel and platinum all dominant relative PLDH waen monotheraie (e.g. higher costs and lower quality life years (QALYs)). After exclusion of these parameters the bleaching treatments with platinum and paclitaxel monotherapy, CAP – platinum combination therapy to get preference. Of these three alternatives to least monotherapies platinum showed costs but also the least effective. The CAP for monotherapy was £ ICER compared with 16,421 per QALY platinum. The ICER for paclitaxel – platinum combination therapy compared with CAP was £ 20,950 per QALY.
Conclusions
Clinical effectiveness
Participants with platinum-resistant disease
For participants with platinum-resistant disease there was a low ability to catch on for treatment with topotecan or paclitaxel PLDH,. There was a small difference between the three vergeljikbare treatments in relation to overall survival. The comparable treatments however gave a visible difference in toxicity-severity of the side effects. Given the low survival time and possibly catch on proves of the treatments the preservation of the quality of life and the control over symptoms and toxicity highly important in this patiëntengroep. Also because the three comparable treatments showed significant difference in terms of toxicity profiles is the choice for the patient and the doctor is also a crucial element that should be weighed in taking a final decision on which second line treatment is chosen. It can also proposed that this group of patients is included in follow-up studies with new medicines. (Note editors: in fact, said chemotherapy with topotecan here so, if second or paclitaxel lijnsbehandeling PLDH is unhelpful because the probability that the catches is small and if it catches on the survival time extends little and the side effects so serious that quality of life is greatly compromised. In short the opinion would then read: try but something else with experimental new medicines.)
Participants with platinum-sensitive disease
For participants with platinum-sensitive disease there were a number of different survival times seen during the different studies. The bestsurvival times and catch on the treatment of which was seen for paclitaxel and platinum combination therapy. This suggests that a treatment with a combination therapy makes more sense and is more effective than a single behandelinig chemotherapy regime. In terms of simple proof that chemo's suggests PLDH is more effective than topotecan. Proof of a follow-up study which compared PLDH and paclitaxel, suggests that there is no significant difference between these two similar treatments in this study. The three comparable treatments however differed in terms of toxicity profiles measured over all studies. Although treatment with topotecan, therefore seemed better than with PLDH is the choice of the patient and physician is important to the association with the toxicity profiles of each of the similar treatments and which the will of the patient to these side effects and also to daadwerkeljik.
Cost-effectiveness
The following conclusions are possible taking into consideration that the NHS is willing to pay £ 20,000 – 40,000 per patient per additional QALY qualitatively acceptable year of life =.
PLDH reveals the most cost-effective compared with topotecan and paclitaxel monotherapy, in terms of the overall patient population and the main groups be taken into account.
The cost-effectiveness results for basic analysis were influenced by the input of trial 30-57. The results of trial 30-57 factored gave a less good estimate for the PLDH versus paclitaxel monotherapy for ICER, compared with the basic results. Although the PLDH compared with paclitaxel monotherapy ICER of less well turned out, was still cost-effective PLDH compared with topotecan and paclitaxel monotherapy.
For platinum-sensitive patients, the combination of paclitaxel and platinum bljikt the most cost-effective.
Research recommendations
Participants with platinum-resistant disease
Based on the strength of this review can be collected in there proves proposed that participants with platinum-resistant disease priofiteren could participate in studies with new experimentale medications.
Participants with platinum-sensitive disease
To the effect of a combination therapy versus a single non-platinum-based chemotherapy can be proposed that a study to measure involving paclitaxel in combination with a platinum-based therapy versus single PLDH could be a reasonable option.
Doxorubicin hydrochloride pegylated liposomal paclitaxel, Topotecan and for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation C Main, 1 * L, 2 S, 2 G Bojke Griffin Norman, 1 M Barbieri, 3 L Mather, 1 D Stark, 4 S Palmer2 and R Riemsma1
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1 Centre for Reviews and Dissemination, University of York, UK
2 Centre for Health Economics, University of York, UK
3 Economic and Health Research Centre, Universitat Pompeu Fabra, Barcelona, Spain
4 Department of Oncology, Bradford Royal Infirmary, UK
* Corresponding author
Background
Ovarian cancer is the most common cancer, with an annual incidence of gynaecologische 21.9 per 100,000 women in England and 26.7 per 100,000 in Wales (2000 figures). The prognosis is generally poor, owing to the advanced stage of disease at detection in most cases, and the UK 5-year survival rate is only around 30%. The current guidance issued by the National Institute for Health and Clinical Excellence is that first-line chemotherapy should include either paclitaxel in combination with a platinum-based chemotherapy regimen, or a platinum-based regimen (carboplatin or cisplatin) stand-alone. As the majority of patients ultimately relapse and require treatment with second-line therapy, the guidance is that patients who have received recommended first-line therapy should not be treated with the same agents. Pegylated liposomal doxorubicin hydrocholoride topotecan and paclitaxel (PLDH), may therefore be considered alongside other drugs licensed for second-line therapy in advanced ovarian cancer. Participants who had not received paclitaxel as a component or first-line therapy may receive it as second-line.
Objectives of the review
Methods
Search strategy
Seventeen databases were searched for randomised controlled trials (RCTs) and systematic reviews for the clinical effectiveness of topotecan and paclitaxel and economic evaluations of PLDH, the cost-effectiveness of topotecan and paclitaxel PLDH,. Previous searches were conducted up to 2000. The current searches were therefore limited to publication years 2000 – 4.
Inclusion/exclusion criteria
Two reviewers independently screened all titles and/or abstracts including economic evaluations. The full text of any study judged to be relevant by either reviewer was obtained and assessed for inclusion or exclusion. Disagreements were resolved through discussion. For the assessment of clinical effectiveness, RCTs that compared topotecan or paclitaxel monotherapy, administered alone or in combination PLDH monotherapy with a platinum-based compound with any other comparator including usual supportive care were included. For the assessment of cost-effectiveness, a broader range of studies was considered.
Data extraction and quality assessment
Data from included studies were extracted by one reviewer and independently checked for accuracy by a second reviewer. Individual studies were assessed for quality by one reviewer and independently checked for accuracy by a second.
Methods of analysis/synthesis
The results of the data extraction and quality assessment ofthe RCTs were presented in structured tables and as a narrative summary. For the cost-effectiveness section of the report, details of each identified published economic evaluation, together with a critical appraisal of its quality, were presented in structured tables.
Handling company submissions
All the clinical effectiveness data included in the company from Bristol Myers Squibb, GlaxoSmithKline and submissions Schering-Plough Ltd were assessed. Where this with the inclusion criteria it was included in the clinical effectiveness review. All economic evaluations (including accompanying models) included in the company submissions were assessed and a detailed assessment of the assumptions underlying the submitted analyses was under tasks. A new model was developed to assess the costs of the alternative treatments, the differential mean survival duration and the impact of health-related quality of life. Monte-Carlo simulation was used to reflect uncertainty in the cost-effectiveness results.
Results
A total of 2542 titles and abstracts were screened for inclusion in the review of clinical and cost-effectiveness; 194 studies were ordered as full papers and assessed in detail. Nine RCTs were identified. In five of these trials, both the comparators were used within their licensed indications. Of these five trials, three of the trials included participants with both platinum-resistant and platinum-sensitive advanced ovarian cancer, and a further two trials only included participants with platinum-sensitive disease. The comparators that were assessed in the three trials that included both subtypes or topotecan versus paclitaxel, topotecan versus PLDH were participants and PLDH versus paclitaxel. In the further two trials that included participants with the subtype or platinum-sensitive disease, the comparators that were assessed were single-agent doxorubicin, cyclophosphamide and paclitaxel versus a combination of cisplatin and paclitaxel plus platinum (CAP)-based chemotherapy versus conventional platinum-based therapy alone.
A further four trials were identified and included in the review in which one of the comparators in the trial was used outside its licensed indication. The comparators assessed in these trials were given oxaliplatin versus paclitaxel, paclitaxel, paclitaxel weekly versus every 3 weeks at two different dose levels and oral versus intravenous topotecan.
Clinical effectiveness
Trials including participants with refractory, resistant and platinum-sensitive disease PLDH versus topotecan
Was marginally more effective than topotecan PLDH in terms of overall survival in the total trial population that included both participants with platinum-sensitive and platinum-resistant disease. However, this result appears to be driven by the more highly significant benefit or in the platinum-sensitive subgroup PLDH treatment or participants. For participants withplatinum-resistant disease there was no statistically significant difference in overall survival between the treatment groups and PLDH topotecan. There were also no statistically significant differences between the groups in terms of progression PLDH and topotecan-free survival, response or quality of life.
In terms of toxicities reported during the trial, the rates or palmar-plantar erythrodysesthesia stomatitis, grade 3 (PPE), mucous membrane disorder and rash were significantly higher in the PLDH treatment arm. In the topotecan arm the rates of grade 3 and 4 haematological toxicities and fever were significantly higher grade 3 alopecia and.
Topotecan versus paclitaxel
There were no statistically significant differences between the two treatment groups in terms of overall survival, response rate, time to progression or response duration. The point estimates for all of these outcomes favoured treatment with topotecan on paclitaxel. However, there was a significant difference between the two treatment groups in terms of time to response, favouring paclitaxel.
In this trial, treatment with topotecan was associated with significantly more grade 3 and 4 haematological toxicities compared with paclitaxel. In addition, grades 3 and 4 nausea, vomiting, constipation, abdominal pain, asthenia, fatigue and fever/infection were significantly higher in this group. Treatment with paclitaxel was associated with significantly more grade 3 and 4 myalgia arthralgia, alopecia, and skeletal pain compared with the topotecan treatment arm.
PLDH versus paclitaxel
In relation to overall survival, there was no significant difference between the treatment groups. PLDH and paclitaxel PLDH was associated with significantly more Treatment with grade 3 PPE, ascites, stomatitis and dyspnoea compared with treatment with paclitaxel. Treatment with paclitaxel was associated only with a higher incidence of grade 3 alopecia PLDH relative to. This trial was terminated prematurely, therefore the results should be interpreted with caution.
Trials including participants with platinum-sensitive disease only
Paclitaxel versus CAP
CAP was more effective than paclitaxel in terms of both overall and progression-free survival. There were no significant differences between the two treatment regi man in terms of response. However, the incidence of grade 3 and 4 nausea and vomiting haematological toxicities and grade 2 in the CAP treatment arm was significantly higher. Treatment with paclitaxel was associated with significantly higher rates of alopecia and allergic reactions relative to treatment with CAP.
Paclitaxel in combination with platinum-based chemotherapy versus platinum-based therapy alone Paclitaxel in combination with platinum-based chemotherapy was more effective than platinum monotherapy in relation to both overall survival and progression-free survival.However, there was no significant treatment benefit observed for combination therapy for response rates or overall quality of life.
Treatment with paclitaxel in combination with platinum was associated with significantly higher rates of grades 2 – 4 neurological toxicity and alopecia. Monotherapy was associated with significantly higher Treatment with platinum rates of haematological toxicity.
Trials in which one of the comparators was used outside the licensed indication
Oxaliplatin versus Paclitaxel
There were no statistically significant differences between the paclitaxel and oxaliplatin treatment groups in terms of overall survival, time to progression, response rate, response duration or quality of life. Treatment with paclitaxel was associated with a higher incidence of severe neutropenia, thrombocytopenia was associated with higher rates of oxaliplatin whereas.
Paclitaxel given weekly versus every 3 weeks
There was no significant treatment benefit for either of these man as assessed by overall survival registry, time to progression, response or response duration. Treatment with paclitaxel every 3 weeks was associated with a significantly higher incidence of grade 3 and 4 neutropenia and alopecia, whereas treatment every week was associated with problems with nail changes.
Paclitaxel 175 versus 250 mg/m2
There were no statistically significant differences between participants treated with the lower dose regimen and those treated with the higher dose regimen for overall survival or progression-free survival. There was a significant benefit in favour of the higher dose regimen for response rates. However, the reporting of grade 3 and 4 haematological toxicities was more common in the higher dose treatment group.
Oral versus intravenous topotecan
There was a significant benefit in favour of intravenous topotecan for overall survival. However, no further significant difference between the two treatment regi man was found for time to progression, response rate, response duration and time to response. Leucopenia occurred frequently in both treatment groups and Neutropenia, but were higher in the intravenous treatment group. The rates of grade 3 and 4 were all vomiting, nausea, diarrhoea and fever significantly higher in the oral treatment regimen group compared with the intravenous treatment arm.
Cost-effectiveness
Four studies met the inclusion criteria for the cost-effectiveness review. In addition, separate submissions were received from Bristol Myers Squibb, GlaxoSmithKline and Schering-Plough Ltd. The review of The economic evidence from the literature and industry submissions identified a number of significant limitations in existing studies assessing the cost-effectiveness of topotecan and paclitaxel PLDH,. A new model was developed to address the limitations identified in these sources and to providea direct comparison of the full range of possible strategies that are relevant to the NHS. The model explored a range of uncertainties and sources of variability that were not fully addressed in existing datasources. Two separate analyses (Analysis 1 and Analysis 2) were required in order to reflect the heterogeneity identified in the different trials and the difficulties encountered in obtaining robust estimates using a consistent approach for the methods of evidence synthesis or the relative treatment effects.
Analysis 1 assessed the cost-effectiveness of topotecan and paclitaxel PLDH, administered as monotherapies. Sensitivity analysis was undertaken to explore the impact of patient heterogeneity (e.g. platinum-sensitive and platinum-resistant/refractory patients), the inclusion of additional trial data (30-57) and alternative assumptions regarding treatment and monitoring costs. In the base case results for Analysis 1, paclitaxel monotherapy emerged as the cheapest treatment. When the incremental cost-effectiveness ratios (ICERs) were estimated, was dominated by PLDH topotecan. Hence the options considered in the estimation of the paclitaxel and PLDH ICERs were. The ICER for PLDH compared with paclitaxel was £ 7033 per quality-adjusted life-year (QALY) in the overall patient population (comprising platinum-sensitive and-resistant patients,-refractory). The ICER was more favourable in the platinum-sensitive group (£ 45 per QALY) and less favourable in the platinum-refractory/resistant group (£ box 9555 per QALY). The cost-effectiveness results for the base-case analysis were sensitive to the inclusion or trial 30-57. Incorporating the results of trial 30-57 resulted in less favourable estimates for the PLDH versus paclitaxel compared with the ICER for base-case results. The ICER or PLDH compared with paclitaxel was £ 20,620 per QALY in the overall patient population, £ per QALY in the platinum-sensitive 16,183 population and £ per QALY in the platinum-resistant and 26,867-refractory population.
The results from Analysis 2 explored the cost-effectiveness of the full range of treatment comparators for platinum-sensitive patients. The treatment options considered in this model, topotecan, paclitaxel monotherapy PLDH comprised –, CAP, paclitaxel monotherapy and platinum/platinum combination therapy. Owing to the less robust approaches that were employed to synthesise the available evidence and the heterogeneity between the different trials, the reliability of these results should be interpreted with some caution. Topotecan, paclitaxel monotherapy and PLDH were all dominated by platinum monotherapy (i.e. higher costs and lower QALYs). After excluding these alternatives, the treatments that remained under consideration were platinum and paclitaxel monotherapy, CAP – platinum combination therapy. Or these three alternatives, was the least costly and least monotherapy platinumeffective. The CAP compared with monotherapy was £ ICER for platinum per QALY 16,421. The ICER for paclitaxel – platinum combination therapy compared with CAP was £ 20,950 per QALY.
Conclusions
Clinical effectiveness
Participants with platinum-resistant disease
For participants with platinum-resistant disease there was a low probability of response to treatment with topotecan or paclitaxel PLDH,. Furthermore, there was little difference between the three comparators in relation to overall survival. The comparators did, however, differ considerably in their toxicity profiles. Given the low survival times and response rates, it appears that the maintenance of quality of life and the control of symptoms and toxicity are paramount in this patient group. As the three differed significantly in terms of their toxicity profiles comparators, patient and physician choice is also an important element that should be addressed when decisions are made regarding second-line therapy. It can also be suggested that this group of patients may benefit from being included in further clinical trials of new drugs.
Participants with platinum-sensitive disease
For participants with platinum-sensitive disease there was a considerable range of median survival times observed across the trials. The most favourable survival times and response rates were observed for paclitaxel and platinum combination therapy. This suggests that treatment with combination therapy may be more beneficial than treatment with a single-agent chemotherapeutic regimen. In terms of single-agent compounds, the evidence suggests that is more effective than topotecan PLDH. Evidence from a further trial that compared PLDH and paclitaxel suggests that there is no significant difference between these two comparators in this trial. The three did, however, differ significantly comparators in terms of their toxicity profiles across the trials. Although PLDH may therefore be more beneficial than treatment with that with topotecan, patient and physician choice as to the potential toxicities associated with each of the the patient's ability and willingness to tolerate comparators and these are of importance.
Cost-effectiveness
The following conclusions are possible assuming the NHS is willing to pay up to £ 20,000 – 40,000 per additional QALY:
PLDH appears to be cost-effective compared with topotecan and paclitaxel monotherapy, in terms of the overall patient population and the main subgroups considered. The cost-effectiveness results for the base-case analysis were sensitive to the inclusion or trial 30-57. Incorporating the results of trial 30-57 gift less favourable estimates for the PLDH versus paclitaxel monotherapy, ICER for compared with the base case results. Although the ICER or was less favourable compared with paclitaxel monotherapy, PLDH PLDH was still cost-effective comparedwith topotecan and paclitaxel monotherapy.
For platinum-sensitive patients, the combination of paclitaxel and platinum appears to be cost-effective. Research recommendations
Participants with platinum-resistant disease
On the strength of the evidence reviewed in this assessment, it can be suggested that participants with platinum-resistant disease may benefit from being included in further clinical trials of new drugs.
Participants with platinum-sensitive disease
To assess the effectiveness of combination therapy against a single-agent non-platinum-based compound, it can be suggested that a trial that compared paclitaxel in combination with a platinum-based therapy versus single-agent PLDH would be a reasonable option.
Publication
Main C, L, Griffin S, Norman G Bojke, Barbieri M L, et al., Mather, pegylated liposomal doxorubicin hydrochloride and Topotecan for second-line or subsequent paclitaxel treatment of advanced ovarian cancer: a systematic review and economic evaluation. Health Technol Assess 2006; 10 (9).
NHS R & D HTA Programme
The research findings from the NHS R & D Health Technology Assessment (HTA) Programme directly influence key decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC) who rely on HTA outputs to help raise standards of care. HTA findings also help to improve the quality of the service in the NHS indirectly in that they form a key component of the ' National Knowledge Service "that is being developed to improve the evidence or clinical practice throughout the NHS.
The HTA Programme was set up in 1993. Its role is to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and provide care in the NHS. Broadly defined to include ' Health technologies ' are all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care, rather than settings of care.
The HTA Programme commissions research only on topics where it has identified key gaps in the evidence needed by the NHS. Suggestions for topics are actively sought from people working in the NHS, the public, service-users groups and professional bodies such as Royal Colleges and NHS Trusts.
Research suggestions are carefully considered by panels of independent experts (including service users) whose advice results in a ranked list of recommended research priorities. The HTA Programme then commissions the research team best suited to undertake the work, in the manner most appropriate to find the relevant answers. Some projects may take only months, others need several years to answer the research questions adequately. They may involve synthesising existing evidence orconducting a trial to produce new evidence where none currently exists.
Additionally, through its Technology Assessment Report (TAR) call-off contract, the HTA Programme is able to commission bespoke reports, principally for NICE, but also for other policy customers, such as a National Clinical Director. TARs bring together evidence on key aspects of the use of specific technologies and usually have to be completed within a short time period.
Criteria for inclusion in the HTA monograph series
Reports are published in the HTA monograph series if (1) they have resulted from work commissioned for the HTA Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.
Reviews in Health Technology Assessment are termed ' systematic ' when the account or the search, appraisal and synthesis methods (to minimize biases and random errors) would, in theory, permit the replication of the review by others.
The research reported in this monograph was commissioned and funded by the HTA Programme on behalf of NICE axis project number 04/03/01. The protocol was agreed in April 2004. The assessment report began editorial review in February 2005 and was accepted for publication in June 2005. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors ' report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.
The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme, NICE or the Department of Health.
Editor-in-Chief: Professor Tom Valley
Series Editors: Dr. Peter Davidson, Dr. Chris Hyde, Dr. Riemsma and Dr. Ken Ruairidh Milne, Dr. Rob Stein Managing Editors: Sally Bailey and Sarah Llewellyn Lloyd © 2006 Crown Copyright
