Cervical cancer (recurrent) - topotecan: appraisal consultations document

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

Appraisal consultation document

Topotecan for the treatment of recurrent and stage IVB carcinoma of the cervix

Background
Key dates
Appraisal Committee's preliminary recommendations
The technology
The manufacturer's submission
Consideration of the evidence
Implementation
Related guidance
Proposed date for review of guidance
Appendix A: Appraisal Committee members and NICE project team
Appendix B: Sources of evidence considered by the Committee

Background

The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using topotecan in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation .

After consultation:

The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.

At that meeting, the Committee will also consider comments made by people who are not consultees.

After considering these comments, the Committee will prepare the final appraisal determination (FAD).

Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using topotecan in the NHS in England and Wales.

For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk)

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The key dates for this appraisal are:

Closing date for comments: 8 July 2009

Second Appraisal Committee: 23 July 2009

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.

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1 Appraisal Committee's preliminary recommendations
1.1 Topotecan in combination with cisplatin, within its licensed indication, is not recommended for the treatment of women with recurrent or stage IVB cervical cancer
1.2 Women currently receiving topotecan for the treatment of cervical cancer should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

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2 The technology
2.1 Topotecan (Hycamtin, GlaxoSmithKline) prevents DNA replication in cancer cells by inhibiting the enzyme topoisomerase I. Topotecan in combination with cisplatin has a marketing authorisation for patients with carcinoma of the cervix recurrent after radiotherapy and for patients with stage IVB disease. Patients with prior exposure to cisplatin require a sustained treatment-free interval to justify treatment with topotecan in combination with cisplatin.
2.2 The recommended dosage is 0.75 mg/m 2/day topotecan, administered as a 30-minute intravenous infusion on days 1, 2 and 3. Cisplatin is administered after topotecan as an intravenous infusion on day 1 at a dosage of 50 mg/m 2/day. Treatment should be repeated every 21 days for six courses or until disease progresses. In randomised controlled trials (RCTs) the median number of cycles given was four, with the actual number of cycles completed ranging from zero to seven. Top otecan should only be readministered if the neutrophil count is at least 1.5 × 10 9 per litre, the platelet count is at least 100 × 10 9 per litre, and the haemoglobin level is at least 9 g/100 ml (after transfusion if necessary). The summary of product characteristics (SPC) states that topotecan should only be used in units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a physician experienced in the use of chemotherapy.
2.3 Adverse effects commonly associated with topotecan include nausea, vomiting, neutropenia, leukopenia, anaemia , fatigue and alopecia. Topotecan is not recommended in patients with severe renal or hepatic impairment. Cisplatin causes nausea and vomiting in the majority of patients . Serious toxic effects of cisplatin on the kidneys, bone marrow and hearing function are common. Serum electrolyte disturbances, hyperuricaemia, allergic reactions and cardiovascular abnormalities have also been reported. For full details of adverse effects and contraindications, see the SPC.
2.4 The acquisition cost of topotecan is £97.65 for a 1-mg vial or £290.62 for a 4-mg vial (excluding VAT; ‘British national formulary’ [BNF] edition 57). The acquisition cost of cisplatin is £24.50 for a 50-mg vial or £50.22 for a 100-mg vial (excluding VAT; BNF edition 57). Assuming a body surface area of 1.7 m 2, the total dose per cycle would be 3.825 mg topotecan (that is, 1.275 mg/day). Assuming excess topotecan is wasted after each dose, a total of six 1-mg vials would be required at a cost of £585.90. For cisplatin, the cost for the required 85 mg would be £49 for two 50-mg vials. Costs may vary in different settings because of negotiated procurement discounts.

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3 The manufacturer's submission
  The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of topotecan and a review of this submission by the Evidence Review Group (ERG; appendix B).
3.1 In the submission, the manufacturer compared topotecan plus cisplatin with cisplatin alone. The manufacturer also compared topotecan plus cisplatin with paclitaxel plus cisplatin. The manufacturer justified their choice of comparator with data from the IMS Oncology Analyzer database to show that cisplatin alone is the most frequently used therapy in the group of women for whom topotecan plus cisplatin is licensed . The manufacturer indicated that paclitaxel plus cisplatin is used less frequently than cisplatin alone, but referred to clinical opinion that suggests it is being used more routinely than suggested by the IMS data. The manufacturer indicated that carboplatin is also used in the treatment of recurrent or stage IVB cervical cancer, mainly in combination with paclitaxel. However, the manufacturer did not include this in the submission because of a lack of clinical trial evidence.
3.2 The manufacturer identified one phase III, open-label RCT that compared topotecan plus cisplatin with cisplatin alone. This trial (GOG-0179; n = 293) compared women who were treated with topotecan plus cisplatin with women who were treated with cisplatin alone. These women were followed up for 36 months. The trial reported increased median overall survival for topotecan plus cisplatin compared with cisplatin alone: 9.4 versus 6.5 months, respectively (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.59 to 0.98; p = 0.033), and increased median progression-free survival for topotecan plus cisplatin compared with cisplatin alone: 4.6 versus 2.9 months, respectively (HR 0.76; 95% CI 0.60 to 0.97; p = 0.027).
3.3 The manufacturer reported that the safety profile for topotecan plus cisplatin was predictable and manageable. However, there were four treatment-related deaths in the topotecan plus cisplatin group compared with none in the cisplatin group. Febrile neutropenia occurred in 17.7% of women treated with topotecan plus cisplatin and in 7.5% of women treated with cisplatin alone. Serious adverse events occurred in 10% of women treated with cisplatin alone compared with 14% of women treated with topotecan plus cisplatin.
3.4 Seventy-one women in GOG-0179 were not included in the licensed population for topotecan (32 with persistent disease and 39 for whom the sustained cisplatin-free interval was less than 180 days) and data from these women were subsequently excluded from the analysis. The median overall survival estimates for the licensed population in the topotecan plus cisplatin group (n = 107) and the cisplatin alone group (n = 115) were 11.9 and 7.3 months, respectively (HR 0.65; 95% CI 0.49 to 0.88; p = 0.0041).
3.5 The manufacturer completed further subgroup analyses of the licensed population to consider the benefits of topotecan in women who had never had cisplatin (cisplatin naive; n = 120) and those with a sustained cisplatin-free interval longer than 180 days (n = 102). The median overall survival in the cisplatin-naive group was 14.5 and 8.5 months for the topotecan plus cisplatin and cisplatin alone groups, respectively (HR 0.59; 95% CI 0.39 to 0.88; p = 0.0098). The median overall survival in the sustained cisplatin-free interval group was 9.9 and 6.3 months for topotecan plus cisplatin and cisplatin alone, respectively (HR 0.75; 95% CI 0.49 to 1.16; p = 0.1912).
3.6 The manufacturer identified a trial (GOG-0204) that was not formally included in the clinical-effectiveness review. An abstract reported on this trial, which included a head-to-head comparison of four cisplatin-containing combinations: paclitaxel (n = 103), vinorelbine (n = 108), gemcitabine (n = 112) and topotecan (n = 111). Women who had received prior chemotherapy were only included in the trial if this was concurrent with radiotherapy. Approximately 70% of women included in the trial had previously received cisplatin as a radiosensitiser. A planned interim analysis recommended early closure of GOG-0204 because the comparator groups were unlikely to demonstrate a statistically significant benefit compared with paclitaxel plus cisplatin. For the comparison of cisplatin plus topotecan and cisplatin plus paclitaxel, the trial reported a hazard ratio for progression-free survival of 1.268, in favour of the paclitaxel combination. The hazard ratio for overall survival for the same comparison was 1.255, again favouring the paclitaxel combination.
3.7 The manufacturer identified another trial (GOG-0169) which was used in a model-based comparison of topotecan plus cisplatin and paclitaxel plus cisplatin. This phase III study compared paclitaxel plus cisplatin (n = 130) with cisplatin alone (n = 134) in women with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix. The trial duration was 24 months. The median overall survival was 9.7 months for paclitaxel plus cisplatin and 8.8 months for cisplatin alone. The median progression-free survival was 4.8 months for paclitaxel plus cisplatin and 2.8 months for cisplatin alone. GOG-0169 had a similar design to GOG-0179, although GOG-0169 excluded women who had previously received chemotherapy (except as radiosensitisation).

3.8

 

The manufacturer submitted two separate cost-effectiveness analyses:

  • A trial-based direct comparison between topotecan plus cisplatin and cisplatin alone using a time horizon of 36 months and patient-level data from the GOG-0179 trial.
  • A model-based comparison of topotecan plus cisplatin and paclitaxel plus cisplatin, using a time horizon of 24 months and data from the GOG-0179 and GOG-0169 trials.

In the submission the results of the trial-based comparison were reported as cost per quality-adjusted life year gained (QALY) and in the model-based comparison as cost per life year gained (LYG). In response to a request from the ERG, an additional model-based comparison was presented expressing outcomes in terms of both LYGs and QALYs gained.

3.9 For the trial-based comparison the manufacturer performed separate analyses for the main licensed population and subgroups of this population. The subgroups were women who were cisplatin naive and women who had had a sustained cisplatin-free period. The manufacturer stated that the least potentially biased analysis in the model-based comparison would be between the cisplatin-naive population of GOG-0179, including women with persistent disease, and the overall intention-to-treat (ITT) population of GOG-0169. The manufacturer considered the trial-based comparison to be the primary analysis within their submission. The model-based comparison was presented as a secondary analysis to include alternative comparators used in England and Wales.
3.10 In the trial-based comparison, the manufacturer included patient-level data for clinical efficacy, safety and quality of life from the GOG-0179 trial. Data on resource use were based on clinical events occurring in the trial supplemented by data from external sources, including expert opinion. Costs were obtained from published sources, including NHS Reference Costs 2006/07. The manufacturer did not give a breakdown of the costs for the trial-based comparison. It was assumed that the cost of topotecan was £488.25 per cycle and the cost of cisplatin was £50.74 per cycle. The cost of topotecan was varied in a sensitivity analysis from £390.60 to £585.90 to reflect minimum (where vials were reused over the 3-day dosing schedule) and maximum wastage (where vials were discarded immediately after use) of unused topotecan. The cost of administering topotecan was assumed to be £277 for the first dose of each cycle and £51 for each subsequent dose.
3.11 The manufacturer incorporated quality-of-life benefits into the trial-based comparison using an algorithm linking a disease-specific measure of quality of life ( Functional Assessment of Cancer Therapy – General [ FACT-G]) to utility. Utility values differed depending on whether a woman was assigned to the cisplatin alone or topotecan plus cisplatin group. Values also differed according to the treatment phase: prior to randomisation, prior to cycle 2, prior to cycle 5 and 9 months after randomisation. The values for the cisplatin alone group were 0.79, 0.73, 0.58 and 0.33, for these four treatment phases, respectively. The corresponding values for the topotecan plus cisplatin group were 0.79, 0.72, 0.66 and 0.45. The manufacturer also included a sensitivity analysis that used alternative utility data from a review of the literature on cervical cancer and other gynaecological cancers (including breast cancer). The utility values used in the sensitivity analysis were identified from a study of breast cancer and were 0.64 at the start of treatment, 0.81 to reflect response to treatment, 0.39 following progression of disease and 0.16 during the last week of life.
3.12 In the model-based comparison the manufacturer based the key analysis on aggregate data from indirectly comparing the GOG-0179 and GOG-0169 trials. GOG-0169 did not report the hazard ratio for overall survival, therefore the manufacturer estimated the hazard ratio from the survival curves (HR = 0.87; 95% CI 0.68 to 1.11). The estimated hazard ratio was then applied to the observed overall survival for the cisplatin group of GOG-0179 to estimate the overall survival for paclitaxel plus cisplatin in the model-based comparison. The hazard ratio for the compared trials was 0.72 (95% CI 0.46 to 1.15). An additional sensitivity analysis included direct data on this comparison from the GOG-0204 trial. Resource use in the model-based comparison was based on the costing algorithms developed for the trial-based comparison. The utility values from the literature review were included in the cost per QALY analyses.
3.13 In the trial-based comparison, the base-case results for the main licensed population were an incremental QALY gain of 0.23 at an incremental cost of £4122, giving an incremental cost-effectiveness ratio (ICER) of £17,974 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of topotecan being cost effective at £20,000 and £30,000 was 50% and 88%, respectively. For the cisplatin-naive population (including women with stage IVB cancer) the incremental QALY gain was 0.32 at an incremental cost of £3521, giving an ICER of £10,928 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of topotecan being cost effective at £20,000 and £30,000 was 89% and 98%, respectively. For the sustained cisplatin-free interval population the incremental QALY gain was 0.13 at an incremental cost of £4145, giving an ICER of £32,463 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of topotecan being cost effective at £20,000 and £30,000 was 31% and 55%, respectively.
3.14 In the model-based comparison, the manufacturer only presented results for the cisplatin-naive population (including women with persistent disease). In the base-case results topotecan plus cisplatin dominated paclitaxel plus cisplatin, and had an ICER of £19,964 per LYG compared with cisplatin alone. Using the hazard ratio from GOG-0204 (rather than from GOG-0169), paclitaxel plus cisplatin had an ICER of £982 per LYG compared with topotecan plus cisplatin. In response to a request for clarification from the ERG, the manufacturer submitted a revised model-based comparison incorporating health-related quality of life and a time horizon of 36 months. When the hazard ratio from GOG-0169 was used, topotecan plus cisplatin dominated paclitaxel plus cisplatin; when the hazard ratio from GOG-0204 was used, paclitaxel plus cisplatin had an ICER of £13,260 per QALY gained compared with topotecan plus cisplatin.
3.15 The ERG identified a number of differences between the inclusion criteria of the clinical trials. Women who had previously received chemotherapy were eligible for inclusion in GOG-0179 but not in GOG-0169. In addition, it was unclear how many women received cisplatin as a radiosensitiser in GOG-0169. GOG-0204 also excluded women who had previously received chemotherapy, unless this was given at the same time as radiotherapy. However, the proportion of women who had previously received cisplatin as a radiosensitiser was approximately 70%. The ERG considered this study may be more representative of the UK population than GOG-0169, given the increasing number of women in the UK receiving cisplatin as first line treatment. The ERG stated that th e manufacturer had included treatments currently used in the UK, but had not explained why other potentially relevant comparators were not included such as cisplatin plus 5-fluorouracil and cisplatin plus mitoxantrone.
3.16 The ERG stated that it was unclear from the manufacturer’s submission whether a complete network of evidence had been identified and investigated. GOG-0179 was a generally well-conducted RCT and it was reasonable for the manufacturer to use this as the direct comparison. However, head-to-head comparisons were also available from GOG-0204. The ERG considered such a direct comparison of topotecan plus cisplatin and paclitaxel plus cisplatin would have been preferable to the indirect comparison used, particularly given the differences in populations between GOG-0169 and GOG-0179. The inclusion of trial GOG-0204 would also have increased the number of potential comparators and expanded the network of indirect evidence.
3.17 The ERG stated that a complete validation of the trial-based comparison was not possible because complete datasets and coding had not been provided within the timelines of the ERG critique. In addition, the ERG raised concerns about the external validity of this comparison. When comparing the two economic analyses, the ERG noted a difference in the mean costs obtained from the direct comparison and the model-based comparison. The ERG was unable to fully investigate the difference because a breakdown of the costs was not provided for the trial-based comparison. The ERG noted that the utility estimates did not appear to have been derived accurately from the trial because of incorrect mapping of FACT-G data to utility values. In addition, there were concerns about the imputation methods and that the impact of mortality may have been double counted. Furthermore, the ERG questioned the appropriateness of the utility values used in the model-based comparison and sensitivity analysis because they were from a study on metastatic breast cancer and not cervical cancer. The ERG raised concerns about the costing in both analyses, particularly costs relating to administration and adverse events.
3.18 The ERG undertook a number of exploratory analyses for both the cisplatin-naive and the main licensed populations using the model-based comparison. The ERG amended the utility values, the costs of administering topotecan and the assumed number of vials of topotecan used per treatment cycle. The ERG also performed exploratory analyses that considered dose reduction.
3.19 In order to address the limitations in the utility values available, the ERG considered three scenarios. The first used the manufacturer’s submission Brown 1998 utility values (0.64) adopted in the manufacturer’s submission for the model-based comparison. The second used a slightly higher starting utility of 0.67 taken from literature estimates of mean utility associated with cervical cancer, weighted to health states according to the decrements used in the manufacturer submission from the Brown 1998 utilities. This second scenario assumed that utility remained constant from starting treatment to disease progression. The third scenario was the same as the second but used a starting utility of 0.72 derived from the FACT-G data collected in GOG-0179. The ICERs for topotecan plus cisplatin compared with cisplatin alone for the cisplatin-naive population for the three utility scenarios were £25,309, £26,156 and £24,513 per QALY gained, respectively. The ICERs for the main licensed population were £55,926, £59,406 and £54,352 per QALY gained, respectively. The ERG used the third scenario in all subsequent exploratory analyses because they considered it the most appropriate.
3.20 The ERG considered that the costs of administering topotecan may have been underestimated. The ERG stated that more appropriate estimates of the administration costs for each treatment could be taken from the health resource group (HRG) code SB14Z for the d elivery of complex chemotherapy, including prolonged infusional treatment at first attendance, and code SB15Z for the delivery of subsequent elements of a chemotherapy cycle, given in NHS Reference Costs 2006/07 . The cost code SB14Z (£289, inflated to £299 at 2007/08 prices) was assumed to reflect the administration of cisplatin, paclitaxel plus cisplatin, or the first infusion of topotecan plus cisplatin. The cost code SB15Z (£189, inflated to £195 at 2007/08 prices) was assumed to reflect the second and third infusion of topotecan. The total cost of administering topotecan plus cisplatin was £689 per cycle, while the cost of administering cisplatin alone or paclitaxel plus cisplatin was £299 per cycle. The ICER for topotecan plus cisplatin compared with cisplatin alone (including the amended utilities) was £31,831 per QALY gained in the cisplatin-naive population and £68,885 per QALY gained in the main licensed population. The revised administration costs were used in subsequent exploratory analyses.
3.21 The ERG had concerns about the number of topotecan vials used and the amount of wastage in the manufacturer’s analysis. In the cisplatin-naive population the ICERs for topotecan plus cisplatin compared with cisplatin alone (including the amended utilities and administration costs) were £26,778 and £34,327 per QALY gained, for minimum and maximum wastage, respectively. For the main licensed population the ICERs were £58,872 and £73,833 per QALY gained, respectively.
3.22 The ERG considered that the differences in costs between the trial-based comparison and the model-based comparison may have been because of dose reduction. The ERG therefore calculated the difference in costs between the manufacturer’s model-based comparison and the ERG’s revised cost estimates. The differences were then applied to the absolute estimates of costs in the trial-based analysis. Both minimum and maximum wastage of vials was considered. When wastage was minimised, the ICER for topotecan plus cisplatin compared with cisplatin alone was £19,815 per QALY gained in the cisplatin-naive population and £53,868 per QALY gained in the main licensed population. When maximum wastage of topotecan was assumed, the ICERs were £27,362 and £68,826 per QALY gained, respectively.
3.23 The manufacturer’s model-based comparison did not report an ICER for any treatment in comparison with cisplatin. The ERG integrated the cost and QALY values for cisplatin into the manufacturer’s model-based comparison so that cisplatin could be considered as a comparator alongside topotecan plus cisplatin and paclitaxel plus cisplatin. This allowed for a simultaneous incremental analysis to be carried out between the three comparators. The ERG presented two separate scenarios, one using the hazard ratio from the indirect comparison of GOG-0169 and GOG-0179 and another using the hazard ratio from GOG-0204. Both included the amended utility values and administration costs, but neither included dose reduction. When the GOG-0169 hazard ratio was used and minimum wastage assumed, the ICER was £26,778 per QALY gained for topotecan plus cisplatin compared with cisplatin alone in the cisplatin-naive population and £58,872 per QALY gained in the main licensed population. When maximum wastage was assumed, the ICER was £34,327 per QALY gained for topotecan plus cisplatin compared with cisplatin alone for the cisplatin-naive population. In this scenario paclitaxel plus cisplatin was extendedly dominated. However, for the main licensed population the ICER for topotecan plus cisplatin compared with paclitaxel plus cisplatin was £116,788 per QALY gained, and the ICER for paclitaxel plus cisplatin in comparison with cisplatin alone was £64,865 per QALY gained. When the GOG-0204 hazard ratio was used, topotecan plus cisplatin was dominated by paclitaxel plus cisplatin regardless of the assumption about topotecan wastage. The ICER for paclitaxel plus cisplatin compared with cisplatin alone was £17,021 per QALY gained for the cisplatin-naive population and £21,926 per QALY gained for the main licensed population.
3.24 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/TAxxx

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4 Consideration of the evidence
4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of topotecan, having considered evidence on the nature of recurrent and stage IVB cervical cancer and the value placed on the benefits of topotecan by women with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
  Clinical effectiveness
4.2 The Committee considered current clinical practice for treating recurrent and stage IVB cervical cancer. The Committee heard from clinical specialists that there is currently no standard treatment for women with this condition. Treatment may consist of topotecan plus cisplatin, cisplatin alone, or paclitaxel plus either carboplatin or cisplatin. The clinical specialists considered that combination therapies were generally more effective than single agent therapies. They also stated that the main reason for why there is no single established treatment regimen is because clinical trials had in the past not shown clinically significant gains in response rates or overall survival for any single regimen in this patient group. The Committee heard from patient experts that they considered it was important to have a number of treatment options because one may be more suitable than others for the individual patient. For example, the choice of treatment may be influenced by comorbidities such as renal dysfunction. Patient experts also highlighted that for some women topotecan plus cisplatin may be considered a final treatment option.
4.3 The Committee specifically considered the use of cisplatin to treat recurrent and stage IVB cervical cancer. It heard from clinical specialists that approximately 90–95% of women within the licensed population will have previously received cisplatin because it is standard UK clinical practice to use cisplatin either with radiotherapy or as chemotherapy alone as first-line treatment for cervical cancer. It heard how cervical screening in the UK enables early identification of disease and so initial presentation with stage IVB disease is unusual. The Committee also heard that the dose of cisplatin used in chemotherapy and in chemoradiotherapy is the same.
4.4 The Committee heard from clinical specialists that previous cisplatin use has a significant effect on response rates to subsequent cisplatin-containing chemotherapy regimens. In cisplatin-naive women, response rates to cisplatin were approximately 45%, which could be higher if combination therapy were used. However, for women who had previously received cisplatin, response rates could be as low as 10%. In addition, the response rates were found to increase as the duration of remission after initial cisplatin treatment increases.
4.5 The Committee discussed the clinical effectiveness of topotecan plus cisplatin compared with cisplatin alone presented in the main trial. The Committee considered that combination therapy was shown to be more effective than cisplatin alone in the GOG-0179 trial population. The Committee noted the results from the subgroup analyses suggesting that topotecan plus cisplatin was more clinically effective in women who had not previously received cisplatin (the cisplatin-naive group) than in women who had previously received cisplatin. The Committee considered that the reduced response to cisplatin was evident even when the sustained cisplatin-free interval was longer than 180 days.
4.6 The Committee examined the trial comparing four combination treatments, including topotecan plus cisplatin, which had been included in the manufacturer’s submission only as additional evidence. The Committee was aware that the trial had closed early because none of the other treatment combinations were likely to show a significant benefit over paclitaxel plus cisplatin. The Committee noted that hazard ratios from this trial suggested that paclitaxel plus cisplatin was more effective than the other cisplatin combination therapies, but this difference did not reach statistical significance. The Committee heard from clinical specialists that they did not consider there to be any differences in effectiveness between the different combinations that had been used in this trial. The Committee noted that the manufacturer had also included an indirect comparison of topotecan plus cisplatin with paclitaxel plus cisplatin. The Committee recognised that this comparison suggested that topotecan plus cisplatin was more effective than paclitaxel plus cisplatin, but again the difference did not reach statistical significance. The Committee concluded that there was considerable uncertainty about the differences in effectiveness between combination chemotherapy regimens.
4.7 When considering the indirect comparative evidence the Committee was mindful that there were differences in the trial populations including factors such as performance status and prior cisplatin exposure. The Committee recognised that this may affect the robustness of the comparisons between the trials. The Committee considered that the direct trial of combination therapies may more appropriately reflect the clinical population in England and Wales than the trial used to determine the indirect estimate. The Committee also noticed the large numbers of censored observations in the main clinical trial and noted that it was not clear why these patients were censored. The Committee considered that this introduced further uncertainty into the likely treatment effect of topotecan plus cisplatin relative to other treatments.
4.8 The C ommittee considered the adverse event profile of topotecan and recognised that women receiving topotecan plus cisplatin may have more adverse events compared with those receiving cisplatin alone. The Committee heard from clinical specialists specifically about neutropenia and febrile neutropenia. It heard how febrile neutropenia may lead to hospital admission, and may be a more frequent occurrence than for other regimens such as paclitaxel plus cisplatin. However, patient experts mentioned that they considered the safety profile of topotecan plus cisplatin to be manageable, although they were concerned about reported deaths following chemotherapy. They also indicated that quality of life may not be worse for women receiving combination therapy than for women receiving monotherapy, although they were specifically concerned about fatigue.
  Cost effectiveness
4.9 The Committee considered the evidence on the cost effectiveness of topotecan plus cisplatin presented in the manufacturer’s submission. The Committee recognised that the manufacturer considered their main analysis to be the trial based comparison and not the model-based comparison. The Committee noted that the ERG could not completely validate the trial based comparison. The ERG considered the manufacturer’s model-based comparison to have greater external validity. The ERG had therefore used the model-based comparison as the basis for their exploratory analyses.
4.10 The Committee noted that in the trial based comparison the base-case ICER provided by the manufacturer for topotecan plus cisplatin compared with cisplatin alone was £18,000 per QALY gained in the main licensed population, £11,000 per QALY gained in the cisplatin-naive population and £32,500 per QALY gained in the sustained cisplatin-free interval population. The Committee noted that the results of the model-based comparison using the hazard ratio derived from the indirect comparison suggested that topotecan plus cisplatin had greater efficacy and lower costs than paclitaxel plus cisplatin. However, when the hazard ratio from the trial comparing different combination therapies directly was used, paclitaxel plus cisplatin was more effective and less costly than topotecan plus cisplatin.
4.11 The Committee considered the utility estimates provided by the manufacturer. The Committee heard from the ERG that the manufacturer had incorrectly mapped disease-specific quality of life to utility and that correcting this led to a lower starting utility of 0.72 instead of 0.79. The ERG also expressed concerns about the mapping equation used in the base-case analysis, including the transparency of the analysis and imputation methods. The ERG suggested that combining their amended starting utility from the main clinical trial with data identified by the manufacturer from a study of breast cancer could be more appropriate. The Committee recognised that neither approach to estimating utilities reflected the reference case and considered that both sets of utility estimates were associated with uncertainty. However, on balance the Committee considered that utility values suggested by the ERG, which led to more favourable ICERs, may be more appropriate than those provided by the manufacturer.
4.12 The Committee considered the manufacturer’s assumptions about the number of topotecan vials required in clinical practice and the administration costs. The Committee heard that the manufacturer may have underestimated the administration costs for topotecan on days 2 and 3 because they had used an assessment report from a previous appraisal that had built up the costs without the appropriate HRG codes being available. The ERG stated that these codes were now available and that the cost for administering the second and third infusion of topotecan would be £195 rather than £51. The Committee considered that the revised administration costs proposed by the ERG were appropriate. The Committee also heard from the ERG that the manufacturer had not assumed minimum or maximum wastage of excess topotecan, but used a midpoint. The ERG considered that an assumption of maximum wastage may be more consistent with the SPC. The Committee heard from clinical specialists that although women were grouped so that drug wastage could be reduced, there was less opportunity to group women receiving topotecan because fewer women receive the drug. The Committee considered that although there was uncertainty about the manufacturer’s estimate of topotecan wastage, assumptions of either minimum or maximum wastage may also not be accurate.
4.13 The Committee noted that there appeared to be inconsistencies between the mean cost estimates in the trial based comparison and the model-based comparison. The Committee heard from the ERG that this may be because dose reduction related to adverse events was included in the trial based comparison but not in the model-based comparison. However, without a breakdown of costs, the ERG was unable to confirm this. In addition, there were no data on how the use of paclitaxel may be affected by dose reduction. The Committee considered that dose reduction could be important and the ERG’s exploratory analyses showed that dose reduction could reduce the ICER. However, the Committee was not persuaded that the data were sufficiently robust for this to be taken into consideration when examining the cost-effectiveness estimates.
4.14 The Committee considered how adverse events had been included in the model-based comparison. The Committee heard from clinical specialists that the manufacturer’s assumption that an adverse event lasted only a week was appropriate. The Committee noted that only the most severe adverse event was taken into account in the manufacturer’s analysis even if two or more adverse events were experienced concurrently. The clinical specialists agreed that there may be a further negative impact on quality of life for women who have two concurrent adverse events. Overall the Committee considered that the manufacturer may have underestimated the reduction in quality of life associated with multiple adverse events.
4.15 The Committee considered the fully incremental exploratory analysis undertaken by the ERG that incorporated amended administration costs and utility values. The Committee noted that, for the main licensed population, using the hazard ratio from the model-based comparison, the ICER for topotecan plus cisplatin compared with cisplatin alone was £59,000 per QALY gained when minimum wastage was assumed, and the ICER for topotecan plus cisplatin compared with paclitaxel plus cisplatin was £117,000 per QALY gained when maximum wastage was assumed. The Committee was also aware that when the hazard ratio derived from the trial based comparison of different combination therapies was used, topotecan plus cisplatin was less effective and more costly than paclitaxel plus cisplatin. The Committee concluded that topotecan in combination with cisplatin could not be recommended as treatment for the licensed population as an efficient use of NHS resources.
4.16 The Committee considered the subgroup of women who had not previously received cisplatin. The Committee noted that the manufacturer’s estimates suggested topotecan plus cisplatin may be cost effective in this group. The Committee considered the ERG’s exploratory analyses for this subgroup. When the hazard ratios from the model-based comparison were used the ICER for topotecan plus cisplatin compared with cisplatin alone was £26,800 per QALY gained assuming minimum wastage, and £34,000 per QALY gained assuming maximum wastage. However, the Committee noted that when the hazard ratios from the trial based comparison of different combination therapies were used, topotecan plus cisplatin appeared more costly and less effective than paclitaxel plus cisplatin. The Committee noted that these estimates did not fully capture the uncertainty in the analyses. Taking into account all evidence from GOG 0179, GOG-0169 and GOG 204, the Committee was not persuaded that topotecan was more effective than paclitaxel. Although the Committee took into account the nature of the condition and the severity of the disease, it concluded that topotecan in combination with cisplatin would not be an appropriate use of NHS resources for the treatment of women who had not previously received cisplatin and could therefore not be recommended.
4.17 The Committee discussed the higher prevalence of cervical carcinoma amongst women living in the most socio-economically deprived areas, as outlined by the patient expert statements, in light of the duty to have due regard to the need to eliminate unlawful discrimination and promote equality. The Committee noted that a negative recommendation for topotecan in combination with cisplatin does not impact particularly on any group protected by the equalities legislation. Moreover, given the uncertainty as to whether topotecan in combination with cisplatin is clinically more effective than other combination therapies for the treatment of cervical cancer, and the availability of alternative treatment options, the Committee was satisfied that its recommendation was consistent with NICEs obligations under the equalities legislation and the requirement for fairness.

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5 Implementation
5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2

 

NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]

  • Slides highlighting key messages for local discussion.
  • Costing report and costing template to estimate the savings and costs associated with implementation.
  • Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
  • A costing statement explaining the resource impact of this guidance.
  • Audit support for monitoring local practice.

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6 Related guidance
 

Published

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7 Proposed date for review of guidance

7.1

 

NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in June 2012. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

David Barnett
Chair, Appraisal Committee
May 2009

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Appendix A. Appraisal Committee members and NICE project team
A. Appraisal Committee members

The Appraisal Committee is one of NICE’s standing advisory committees. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester

Professor Philip Home (Vice Chair)
Professor of Diabetes Medicine, Newcastle University

Dr Amanda Adler
Consultant Physician, Cambridge University Hospitals Trust

Professor A E Ades
MRC Senior Scientist, MRC Health Services Research Collaboration, Department of Social Medicine, University of Bristol

Dr Tom Aslan
General Practitioner, Stockwell, London

Mrs Fiona Duncan
Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool

Dr Paul Ewings
Statistician, Taunton & Somerset NHS Trust, Taunton

Mr Adrian Griffin
VP Strategic Affairs, LifeScan, Johnson & Johnson

Dr Alec Miners
Lecturer in Health Economics, London School of Hygiene and Tropical Medicine

Dr Ann Richardson
Lay Member

Mrs Angela Schofield
Chairman, Bournemouth and Poole Teaching PCT

Mr David Thomson
Lay Member

Mr William Turner
Consultant Urologist, Addenbrooke 's Hospital

Mr Mike Spencer
General Manager, Cardiff and Vale NHS Trust – Facilities and Clinical Support Services

Dr Jane Adam
Department of Diagnostic Radiology, St George’s Hospital

Professor Karl Claxton
Professor of Health Economics, University of York

Dr David Newsham
Lecturer (Orthoptics), University of Liverpool

Professor Iain Squire
Consultant Physician, University Hospitals of Leicester

Dr James Moon
Consultant Cardiologist and Senior Lecturer, University College London Hospital (UCLH) and UCL

Dr Ian Lewin
Consultant Endocrinologist, North Devon District Hospital

Mr Christopher Earl
Nurse Advisor, Medicines and Healthcare Products Regulatory Agency

Dr Simon Dixon
Reader in Health Economics, University of Sheffield

B. NICE Project Team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Andres Roman
Technical Lead

Zoe Garrett
Technical Adviser

Bijal Chandarana
Project Manager

 

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Appendix B. Sources of evidence considered by the Committee

A

 

The Evidence Review Group (ERG) report for this appraisal was prepared by the Centre for Reviews and Dissemination (CRD), Centre for Health Economics (CHE) , University of York:

  • Paton F et al, Topotecan for the treatment of recurrent and stage IVB carcinoma of the cervix , April 2009

B

 

The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I II and III also have the opportunity to appeal against the final appraisal determination.

I. Manufacturer/sponsor:

  • GlaxoSmithKline

II. Professional/specialist and patient/carer groups:

  • Cancer Research UK
  • Jo’s Trust
  • Rarer Cancers Forum
  • Royal College of Nursing
  • Royal College of Pathologists
  • Royal College of Physicians
  • Royal College of Radiologists
  • United Kingdom Oncology Nursing Society

III. Other consultees

  • Department of Health
  • Welsh Assembly Government

IV. Commentator organisations (did not provide written evidence and without the right of appeal)

  • Centre for Reviews and Dissemination (CRD), Centre for Health Economics (CHE) , University of York
  • Department of Health , Social Services and Public Safety for Northern Ireland
  • National Collaborating Centre for Cancer
  • National Institute for Health Research (NIHR) Health Technology Assessment Programme (HTA Programme)
  • NHS Quality Improvement Scotland
  • Pfizer

C

 

The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on topotecan by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

  • Dr Lynn Hirschowitz, Consultant Gynaecological Pathologist, nominated by t he Royal College of Pathologists – clinical specialist
  • Dr Paul Symonds, Reader in Oncology/Consultant Oncologist , nominated by t he Royal College of Physicians – clinical specialist
  • Ms Catherine Oakley, Chemotherapy Nurse Consultant , nominated by United Kingdom Oncology Nursing Society – clinical specialist
  • Ms Stella Pendleton, Executive Director , nominated by Rarer Cancers Forum – patient expert

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Selected, reliable information for health and social care in one place

Accessibility | Cymraeg | Freedom of information | Vision Impaired | Contact Us | Glossary | Data protection | Copyright | Disclaimer | Terms and conditions

Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.