4 Evidence and interpretation
4.1.1 One randomised controlled trial (RCT) that investigated docetaxel within its licensed indications was identified (TAX327). In TAX327, docetaxel plus prednisone or prednisolone was compared with mitoxantrone plus prednisone or prednisolone.
4.1.2 TAX327 was an international, multicentre, open-label, phase III RCT. The trial enrolled 1006 men with metastatic prostate cancer with disease progression during hormonal therapy. The men were randomised to three chemotherapy arms, all of which received prednisone or prednisolone 5 mg orally twice daily. The chemotherapy regimens were: docetaxel at 75 mg/m2 administered every 3 weeks (335 patients); docetaxel at 30 mg/m2 administered weekly for the first 5 weeks in a 6-week cycle (334 patients); and mitoxantrone 12 mg/m2 administered every 3 weeks (337 patients). Up to 10 cycles of treatment were planned for the 3-weekly docetaxel group and the mitoxantrone group, and up to five cycles (of 6 weeks each) in the weekly docetaxel group. Patients in the docetaxel groups also received premedication with dexamethasone.
4.1.3 Patients were required to have a Karnofsky performance-status score (see appendix D) of at least 60%, and stable levels of pain for at least 7 days before randomisation. The median length of follow-up was 20.8 months for the 3-weekly docetaxel group and 20.7 months for the other two groups. The planned treatment was delivered to 98% of patients in the 3-weekly docetaxel group, 96% of patients in the weekly docetaxel group and 99% in the mitoxantrone group. There was a high level of crossover between groups; 27% of patients randomised to the 3‑weekly docetaxel group received mitoxantrone and 20% of patients randomised to the mitoxantrone group received docetaxel.
4.1.4 Overall survival was the primary end point for the trial and was defined as the time from the date of randomisation to the date of death from any cause, or censored at the date of last contact. There was a statistically significant benefit in terms of overall survival for the 3-weekly docetaxel group compared with the mitoxantrone group, with a hazard ratio for death of 0.76 (95% confidence interval [CI] 0.62 to 0.94, p = 0.009). At the time of analysis 166/335 (50%) patients receiving 3-weekly docetaxel and 201/337 (60%) of patients receiving mitoxantrone had died. The median survival was 18.9 months (95% CI 17.0 to 21.2) in the 3-weekly docetaxel group compared with 16.5 months (95% CI 14.4 to 18.6) in the mitoxantrone group. There was no statistically significant difference in overall survival between the weekly docetaxel group and the mitoxantrone group, with a hazard ratio for death of 0.91 (95% CI 0.75 to 1.11).
4.1.5 Quality of life response was defined as a 16-point improvement in score on the Functional Assessment of Cancer Therapy – Prostate (FACT-P) questionnaire, compared with baseline, on two measures at least 3 weeks apart. There was a statistically significant benefit in terms of quality of life response observed for both the 3-weekly docetaxel group (22% [61/278] response; 95% CI 17 to 27%) and the weekly docetaxel group (23% [62/270] response; 95% CI 18 to 28%) compared with the mitoxantrone group (13% [35/267] response; 95% CI 9 to 18%), giving a relative risk of 1.67 (95% CI 1.14 to 2.45, p = 0.009) for the 3-weekly docetaxel group, and 1.75 (95% CI 1.20 to 2.56, p= 0.005) for the weekly docetaxel group. The responses to the FACT-P questionnaire were not mapped to utility values.
4.1.6 In TAX327 there was a statistically significant benefit in terms of pain response observed for the 3-weekly docetaxel group (35% [54/153] response; 95% CI 27 to 43%) compared with the mitoxantrone group (22% [35/157] response, 95% CI 16 to 29%), giving a relative risk of 1.58 (95% CI 1.1 to 2.27).
4.1.7 In TAX327 a statistically significant benefit in terms of PSA response was observed for the 3-weekly docetaxel group (45% [131/291] response; 95% CI 40 to 51%) compared with the mitoxantrone group (32% [96/300] response; 95% CI 26 to 37%), giving a relative risk of 1.41 (95% CI 1.14 to 1.73).
4.1.8 In TAX327 a higher proportion of grade 3 or 4 adverse events was reported in the 3-weekly docetaxel group (45.8%) than in the mitoxantrone group (34.6%). Adverse events were measured using the Common Toxicity Criteria of the US National Cancer Institute, version 2, and were reported for all 997 patients who received their planned treatment.
4.1.9 To allow for a comparison between docetaxel and relevant comparators other than mitoxantrone plus corticosteroid (for example, other chemotherapy regimens and best supportive care), the Assessment Group searched for RCTs in which other treatments were compared with mitoxantrone plus a corticosteroid, which could then be used as the common comparator. The Assessment Group performed a meta-analysis of the results from three RCTs comparing mitoxantrone plus a corticosteroid with corticosteroid alone. Although various health outcomes other than mortality were measured in those studies (including health-related quality of life and pain response in two of them), the only outcome suitable for the pooling of results was overall survival. The pooled estimate of the hazard ratio for death for mitoxantrone plus corticosteroid versus corticosteroid was 0.99 (95% CI 0.82 to 1.20). This was then compared indirectly, using appropriate statistical analysis, with that from the TAX327 study, giving an indirect hazard ratio for death for docetaxel plus a corticosteroid (prednisone or prednisolone) versus corticosteroid alone (prednisone, prednisolone or hydrocortisone), of 0.752 (95% CI 0.567 to 0.999). The Assessment Report notes that results of the adjusted indirect comparison should be interpreted with caution because the underlying trials differed in patient population and methodology.
4.1.10 Two other RCTs that investigated the effects of docetaxel in combination with estramustine in patients with hormone-refractory metastatic prostate cancer were submitted in support of the efficacy of docetaxel and included in the Assessment Report. SWOG 9916 compared docetaxel plus estramustine versus mitoxantrone plus prednisone. A statistically significant benefit, in terms of overall survival, was observed for the docetaxel plus estramustine group compared with the mitoxantrone plus prednisone group, with a hazard ratio for death of 0.80 (95% CI 0.67 to 0.97). Oudard and coworkers investigated two different regimens of docetaxel plus prednisone plus estramustine versus mitoxantrone plus prednisone. There was a non-statistically significant reduction in the relative risk of death for patients in the docetaxel groups. The median survival was longer in the docetaxel groups than in the mitoxantrone group, but the difference was not statistically significant.
4.2.1 The manufacturer (Sanofi-Aventis) and the Assessment Group provided estimates of cost effectiveness. Some consultees commented on economic issues. The Assessment Group developed its own economic model and critiqued the model submitted by Sanofi-Aventis.
4.2.2 The Assessment Group's literature search did not yield any suitable cost-effectiveness studies of docetaxel-based treatment regimens. One study was found that compared mitoxantrone and prednisone with prednisone alone and was based on the CCI-NOV-22 RCT. That study was used to inform the follow-up costs of the Assessment Group's economic model.
4.2.3 The Sanofi-Aventis model estimates the incremental cost per life-year gained (LYG) from docetaxel plus prednisone or prednisolone compared with mitoxantrone plus prednisone or prednisolone. No adjustment is made for quality of life. The evaluation is based on an analysis of patient-level data derived from prospective collection of resource use and patient outcome data from the TAX327 trial. Only the 3-weekly regimen of docetaxel is considered in the analysis, in keeping with the licensed recommended dose. Two analyses are presented: the preliminary analysis uses the difference in median survival within the TAX327 trial as the measure of clinical benefit, and the base case uses an estimate of the mean difference in survival extrapolated beyond the trial period; data extrapolation is used to characterise the survival of patients beyond the period of follow-up in the trial. The sponsor submission states that in economic valuation, mean survival times are preferred to medians to provide the best estimate of relative cost effectiveness between two competing interventions. Uncertainty is considered using two different one-way sensitivity analyses, one related to the estimate of survival, and the other to that of costs per patient.
4.2.4 The base-case result of the Sanofi-Aventis model was £19,483 as the incremental cost per life year gained from docetaxel plus prednisone or prednisolone over mitoxantrone plus prednisone or prednisolone. In the preliminary analysis, the incremental cost per life year gained was £30,280.
4.2.5 The Assessment Group model estimates the incremental cost per quality-adjusted life year (QALY) gained by using docetaxel plus prednisone or prednisolone compared with the least expensive of a number of treatment comparators not excluded by dominance or extended dominance. It is a probabilistic model that was run for a time horizon of 15 years. A Markov model was used to estimate mean survival and incorporate discounting. Resource utilisation and cost data were estimated from the perspective of the NHS, based on the drug acquisition and administration costs for each intervention and subsequent follow-up costs including the management of side effects, further chemotherapies and palliative care. The Assessment Group undertook a systematic review of literature on measurement of the utility associated with the health-related quality of life of patients with hormone-refractory metastatic prostate cancer, and used this review to inform inputs to the model.
4.2.6 Two analyses were reported. Analysis 1 compares 3-weekly docetaxel plus prednisone or prednisolone, mitoxantrone plus prednisone or prednisolone, and best supportive care in the form of prednisone or prednisolone alone. Analysis 2 extends this comparison to include the full range of potential comparators identified in the clinical effectiveness review. In both base cases, and all reported sensitivity analyses, the relevant resulting incremental cost-effectiveness ratio (ICER) is that of 3-weekly docetaxel plus prednisone or prednisolone (the licensed regimen) compared with mitoxantrone plus prednisone or prednisolone (the cheapest non-dominated strategy). Uncertainty is characterised using probabilistic sensitivity analysis, as well as three different one-way sensitivity analyses.
4.2.7 In the base-case results of the Assessment Group model the ICER of 3-weekly docetaxel plus prednisone or prednisolone compared with mitoxantrone plus prednisone or prednisolone is estimated to be £32,700 per QALY, with all other strategies compared in both analyses dominated by mitoxantrone plus prednisone or prednisolone. Three one-way sensitivity analyses were undertaken to test the robustness of the model to alternative assumptions about discount rates, utility associated with health-related quality of life and the impact of adverse effects on quality of life. The ICER associated with 3-weekly docetaxel plus prednisone or prednisolone remained fairly robust to these variations, with estimates ranging from £28,000 to £33,000 per QALY.
4.3.1 The Committee reviewed the data available on the clinical and cost effectiveness of docetaxel for hormone-refractory metastatic prostate cancer, having considered evidence on the nature of the condition and the value placed on the benefits of docetaxel by people with hormone-refractory metastatic prostate cancer, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.
4.3.2 The Committee noted that prednisone was used as an alternative to prednisolone in the RCTs. It was aware that prednisone is a pro-drug of prednisolone, and that in the UK prednisolone has historically been preferred to prednisone on the grounds that it does not require conversion to the active substance. The Committee concluded that in practice the difference between prednisone and prednisolone was not clinically significant, and it therefore accepted the relevance of the results of international studies to the appraisal.
4.3.3 The Committee understood from the testimony of the clinical experts that docetaxel is the first treatment to show survival benefit in men with hormone-refractory metastatic prostate cancer. The Committee was persuaded that there was a significant survival advantage for the 3-weekly docetaxel regimen over treatment with mitoxantrone, as opposed to the weekly regimen, for which there was no statistically significant difference. It also considered that this differential effect between the two docetaxel regimens was biologically plausible. The Committee considered evidence from the SWOG 9916 trial and noted that although the regimen was not licensed, its results added weight to the evidence of the effect on overall survival of a 3-weekly regimen of docetaxel compared with treatment with mitoxantrone.
4.3.4 The Committee carefully considered the adverse events related to docetaxel, and the differential adverse events associated with a 3-weekly docetaxel regimen as opposed to a weekly regimen were discussed. The clinical experts indicated that patients receiving weekly docetaxel are more likely to experience painful and debilitating nail dystrophia, whereas this is less common in those receiving the drug 3-weekly. However the 3-weekly regimen was associated with a higher incidence of neutropenia. Additionally the Committee heard from both the clinical experts and the patient representatives that many patients feel that the benefits of treatment with docetaxel outweigh the side effects. The Committee concluded that the adverse events related to docetaxel, when weighed against the potential for beneficial effects, should not preclude recommendation of the use of docetaxel in patients with hormone-refractory metastatic prostate cancer.
4.3.5 The Committee considered the economic models put forward by the manufacturer and the Assessment Group. The structure of the Assessment Group model was discussed and it was accepted as suitable and adequate for this appraisal. The Committee discussed the base-case assumptions in the Assessment Group model for patients' extrapolated mean survival, drug and administration costs per cycle, follow-up costs, terminal care costs and the number of cycles received per patient. The Committee accepted these as reasonable assumptions and noted that they were similar to those used in the manufacturer's economic model.
4.3.6 The Committee discussed the way in which life years survived were adjusted for health-related quality of life in the Assessment Group model, noting that this had not been done in the manufacturer's model. The Committee noted that no information on utilities had been collected in TAX327 and that, in order to adjust life years survived for health-related quality of life, the Assessment Group had used an assumption based on a study found through a systematic literature review. The Committee further noted that the same utility assumption had been used for all treatment strategies and concurred that it was likely to be a reasonable estimate because it had been derived from a study in a large sample using appropriate methodology. Furthermore, the Committee noted that an ICER of £28,000 had resulted from a one-way sensitivity analysis using a utility assumption derived from the elicitation of preferences of the NHS Value in Health Panel.
4.3.7 The Committee considered the potential for quality of life benefits associated with docetaxel treatment over and above mitoxantrone treatment. The Committee discussed the results observed for quality of life response in TAX327 based on the FACT-P questionnaire, and noted that this was the only evidence available and it had not been possible to relate those results to utility values. The Committee agreed with the Assessment Group's conclusion that indirect comparisons of quality of life and pain responses could not have been undertaken because of differences in the definitions and measurements. The Committee concluded that although there is potentially a quality of life benefit of docetaxel over mitoxantrone treatment, it was appropriate not to include it in the base-case assumptions of the economic model because the evidence was insufficient to support doing so. However, the Committee recognised that this approach was conservative and was satisfied by the additional analyses that indicated the inclusion of any quality of life benefit results in an ICER lower than £32,700. Furthermore, the Committee noted that the base-case ICER in the Assessment Group model was robust to a sensitivity analysis in which the reductions in quality of life of the different adverse effects associated with docetaxel and mitoxantrone were modelled.
4.3.8 In summary of the Committee's considerations of the cost-effectiveness evidence, it considered the methodology used in Assessment Group's model to be sound, and the base-case assumptions to be either reasonable or conservative. It noted that the base-case ICER of £32,700 had been robust to the one-way sensitivity analyses presented. The Committee therefore concluded that docetaxel within its licensed indications was acceptably cost-effective based on the evidence available at the time of this appraisal.
4.3.9 The Committee discussed the uncertainty surrounding the generalisability of the evidence from the RCT to everyday clinical practice. It was aware that the patients enrolled into the pivotal trial (TAX327) generally were younger and had a higher performance status than those who typically present for treatment in the UK. The Committee heard from the clinical experts that performance status, as defined by the Karnofsky score, was an important predictor of the likelihood of benefit from treatment for individual patients, irrespective of age. The Committee therefore decided that the recommendation on the use of docetaxel for patients with hormone-refractory metastatic prostate cancer should be limited to patients who have a Karnofsky score of 60% or more, an entry requirement of the TAX327 RCT. The experts agreed that such an approach would be appropriate. Additionally the Committee considered the potential for the Karnofsky performance-status score to be interpreted in such a way as to potentially discriminate against men who were disabled in a manner unrelated to their likelihood of benefit or harm from docetaxel treatment for prostate cancer. The Committee concluded that for disabled men the restriction in the guidance to a minimum Karnofsky performance-status score should be interpreted on an individual basis at the discretion of the clinician.
4.3.10 The Committee also discussed the lack of evidence and the uncertainty surrounding the generalisability of the results of the TAX327 RCT with regard to duration of treatment. The Committee heard testimony from the experts that in clinical practice the duration of treatment is determined by the balance of clinical benefit against the occurrence of adverse events, and in practice it is rare for patients to receive more than six cycles of 3-weekly docetaxel therapy. The Committee therefore concluded, in agreement with the experts and in accordance with the stopping rules of the TAX327 RCT, that treatment should be stopped either in the presence of progression of disease (as evidenced by clinical or laboratory criteria, or by imaging studies) or the presence of severe adverse events, and that patients should not receive more than a maximum of 10 cycles of treatment. Further, the Committee discussed repeat cycles in the event of disease recurrence after completion of the planned course of docetaxel treatment. It considered that there was no evidence to support a recommendation for further cycles of docetaxel therapy if the disease recurs (as evidenced by clinical or laboratory criteria, or by imaging studies) after completion of the planned course of chemotherapy.
4.3.11 The Committee heard testimony from clinical experts that the diagnosis of hormone-refractory metastatic prostate cancer may vary in clinical practice in terms of the number and type of hormonal treatments the patient has previously received. The Committee was therefore satisfied that it was not appropriate to limit the recommendation to patients who had received a particular number of hormonal manipulations.
4.3.12 In summary, the Committee considered that the use of docetaxel in hormone-refractory metastatic prostate cancer was both clinically and cost effective on the basis of the above considerations and where the treatment protocol was that which was shown to be clinically effective in the pivotal RCT (TAX327), namely the 3-weekly docetaxel regimen administered for a maximum of 10 cycles only.