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34 Results TABLE 15 Grade 3 or 4 adverse events for mitoxantrone plus prednisone plus clodronate versus mitoxantrone plus prednisone plus placebo Adverse event Clodronate Placebo Granulocytopenia 14 14 Anaemia 8 5 Thrombocytopenia 2 4 Cardiovascular 0 3 Nausea/vomiting 9 7 Headache 4 1 Shortness of breath 4 7 Infection 7 3 Adverse effects of treatment Adverse events were measured using the NCI CTC. There were no treatment-related deaths. Three patients in the clodronate group and two patients in the placebo group discontinued treatment due to adverse events. Table 15 shows the numbers of patients experiencing grade 3 or 4 adverse events. Summary results are presented in Table 16. Evidence synthesis This section first describes the combined results of the three studies evaluating the relative effectiveness of mitoxantrone plus a corticosteroid in comparison with a corticosteroid alone. Next it presents the results of each intervention described in the included trials using mitoxantrone plus a corticosteroid as the common comparator. Finally, the results of any indirect pairwise comparisons that may be of interest are presented. Pooled estimate of effectiveness of mitoxantrone plus a corticosteroid versus a corticosteroid In order to assess the overall effectiveness of mitoxantrone plus a corticosteroid compared with a corticosteroid alone, it is possible to estimate a pooled treatment effect in a meta-analysis. However, there are a number of differences between the three studies that may limit the interpretation of the estimate of the pooled treatment effect. Outcomes were measured differently in the three trials The primary outcomes in the three studies were all different: Berry and colleagues 30 designed the trial to investigate the median time to treatment failure, CCI-NOV22 31 was designed to examine the effects on the palliation of symptoms and CALGB 9182 32 was designed to determine the survival duration. Although these differences in objectives are unlikely to affect the results of any meta-analyses, it may mean that the trials will have been designed differently, which could affect the appropriateness of using pooling techniques. The definitions and the measurements of outcomes varied across the three trials. Overall survival was the only outcome that was measured in a sufficiently similar manner to allow a pooled estimate. It is only appropriate to estimate a pooled treatment effect if the outcomes were measured and defined in a sufficiently similar manner across all trials. Crossovers were permitted in CCI-NOV22 The CCI-NOV22 trial allowed patients originally randomised to receive prednisone alone to cross TABLE 16 Summary results table for mitoxantrone plus prednisone plus clodronate versus mitoxantrone plus prednisone plus placebo Clodronate group Placebo group Comparison Mortality 87/104 (84%) 89/105 (85%) HR = 0.95a (95% CI: 0.71 to 1.28) Progression-free survival 95/104 (91%) 101/105 (96%) HR = 1.24 (95% CI: 0.93 to 1.64) Response rate 43/101 (43%) 39/104 (38%) RR = 1.14 (95% CI: 0.81 to 1.59) QoL response 39/104 (38%) 44/105 (42%) RR = 0.89 (95% CI: 0.64 to 1.25) Pain response 34/104 (33%) 27/105 (26%) RR = 1.27 (95% CI: 0.83 to 1.95) PSA decline (≥ 50% over trial) Adverse events: 30/101 (30%) 30/105 (29%) RR = 1.04 (95% CI: 0.68 to 1.59) Discontinued Grade 3/4 3 2 Died: 0 0 a HR < 1 favours placebo group.
over to receive additional mitoxantrone after they had progressed or remained stable for at least 6 weeks on prednisone therapy. However, crossovers were not permitted in either the CALGB 9182 trial or in the trial by Berry and colleagues. Including crossovers in intention-to-treat (ITT) analyses can result in ‘dilution’ of the true effects of a treatment, as patients are analysed as randomised. For example, if mitoxantrone plus prednisone is more effective than prednisone alone, then any analyses would be less conclusive. This is because in that situation, it is likely that there would be a number of patients randomised to receive prednisone alone crossing over and receiving mitoxantrone also later in the trial. If any of these patients who crossed over then responded to the mitoxantrone therapy, they would still be analysed as randomised, i.e. to prednisone alone. This therefore would attribute an effect to prednisone rather than mitoxantrone, thus diluting the true estimate of the treatment effect of mitoxantrone. However, in this case the study that allowed crossovers had a stronger treatment effect in favour of mitoxantrone plus prednisone than the two studies that did not allow crossovers. Hydrocortisone was used in CALGB 9182 The CALGB 9182 trial used hydrocortisone, whereas both CCI-NOV22 and the trial by Berry and colleagues used prednisone. However, both hydrocortisone and prednisone are forms of corticosteroid, both similar to a natural hormone produced by the adrenal glands. They both relieve inflammation and are used to treat certain types of cancer. Both hydrocortisone and prednisone cause similar side-effects such as stomach irritations, headaches and insomnia. In all three trials, the dosages of hydrocortisone and prednisone were equivalent and administered in the recommended manner. 18 Therefore, given these similarities, hydrocortisone and prednisone will be classed as equivalent corticosteroids. Differences in the populations In any meta-analysis and estimation of a pooled treatment effect, differences in the populations of the individual studies must be carefully considered. Trials can differ significantly especially with respect to patient selection and baseline characteristics. These differences may mean that combining the results from one trial conducted in a specific set of patients and the results from another trial conducted in a completely different patient population is inappropriate. © Queen’s Printer and Controller of HMSO 2007. All rights reserved. Health Technology Assessment 2007; Vol. 11: No. 2 One of the key factors causing differences in the populations between trials is the varying inclusion criteria for each trial. The inclusion criteria for the trial by Berry and colleagues restricted eligibility to men with asymptomatic disease, CCI-NOV22 required patients to be symptomatic with symptoms including pain and disease progression, whereas CALGB 9182 required patients only to have metastatic disease – no restrictions on symptoms were imposed, meaning that this trial included a varied population – with both symptomatic and asymptomatic patients. The impact of this means that the baseline characteristics and prognosis for patients in each of the trials may not be comparable and therefore combining the results from each trial may be inappropriate. In particular, looking at the overall median survival of the patients in each trial, it appears that the patients in the trial by Berry and colleagues had longer life expectancies at baseline than the patients in CALGB 9182 and CCI- NOV22. All of the patients included in the trial by Berry and colleagues were asymptomatic and 38% of patients included in CALGB 9182 had no analgesic requirement at baseline; however, patients without pain and analgesic requirements were ineligible for inclusion in the CCI-NOV22 trial. Patients included in the trial by Berry and colleagues had better performance status scores than those in CALGB 9182 and CCI-NOV22 at baseline; 99% of patients in the trial by Berry and colleagues 87% of patients in CALGB 9182 and 63% of patients in CCI-NOV22 had a performance status score of 0 or 1. Patients had lower PSA levels at baseline in the trial by Berry and colleagues compared with CALGB 9182 and CCI-NOV22. The median baseline PSA levels for those receiving mitoxantrone were 56.7, 209 and 150 ng/ml, respectively, and for those receiving a corticosteroid the median baseline PSA levels were 71.0, 158 and 141 ng/ml, respectively. The number of prior treatments also varied between the studies; for example, patients in CALGB 9182 had a greater prior exposure to antiandrogens compared with those in CCI-NOV22 (72% compared with 42%). However, as all of the trials administered chemotherapy, all had to include men with mHRPC who were fit and healthy enough to receive chemotherapy. This means that the trials were conducted in a restricted subset of men with 35
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A systematic review and economic mo
Page 3 and 4: A systematic review and economic mo
Page 5 and 6: Objectives: A systematic review was
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Page 18 and 19: xvi Executive summary of study desi
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Page 25 and 26: ● Patients with severe fluid rete
Page 27 and 28: Search strategy As stated in Chapte
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Page 71 and 72: TABLE 27 Cost-effectiveness results
Page 73 and 74: Introduction The review of cost-eff
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Page 98 and 99: 78 Discussion subsequent chemothera
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84 References Compendium; 2004. URL
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86 References (D) in patients (pts)
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88 References 100. Aventis Pharma.
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90 References low-dose prednisone i
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92 References 180. Kozloff M, Robin
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94 References locally advanced pros
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96 References 251. Scholz MC, Guess
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Clinical effectiveness Searching fo
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1. Prostatic Intraepithelial Neopla
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19. donataxel 20. doxetal 21. doxmi
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6. Mitozantrone.ti,ab. 7. Mitoxantr
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Texot or Trazoteva or Trixotene or
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1. (docetaxel OR asodecel OR doxeta
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10. (index of wellbeing or quality
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Appendix 2 Excluded studies Study d
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Study details Reason for exclusion
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Meeting: 2004 ASCO Annual Meeting C
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Studies of clinical effectiveness w
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Using the method outlined by Parmar
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Appendix 6 Data extraction tables
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Study details and Participant detai
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158 Appendix 7 Ernst et al. 33 Qual
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Appendix 9 © Queen’s Printer and
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Sanofi-Aventis 61 Bloomfield et al.
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Sanofi-Aventis 61 Bloomfield et al.
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168 Appendix 10 TABLE 51 Mean (SD)
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170 Appendix 10 TABLE 54 Distributi
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172 Appendix 10 TABLE 57 Mean stand
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174 Appendix 11 TABLE 63 Drug and a
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176 Appendix 12 Scenario: moderate
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178 Appendix 13 ● You occasionall
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Members Chair, Professor Tom Walley
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Members Chair, Professor Bruce Camp
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Feedback The HTA Programme and the
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