Quality of Life Improvement in Patients Treated with Degarelix versus Leuprorelin for Advanced Prostate Cancer Dawn Lee,*,† Sandy Kildegaard Nielsen,† Marjolijn van Keep,† Fredrik Andersson‡ and Damien Greene§ From the BresMed (DL, SKN), Sheffield and Sunderland Royal Hospital (DG), Sunderland, United Kingdom, BresMed (MvK), Utrecht, The Netherlands, Ferring International PharmaScience Center (FA), Copenhagen, Denmark, and Center for Medical Technology Assessment (FA), Linko¨ping University, Linko¨ping, Sweden
Purpose: We used responses to questionnaires included in the CS21 degarelix trial and published mapping algorithms to address the paucity of evidence for health related quality of life in patients with advanced hormone dependent prostate cancer treated with degarelix. Materials and Methods: We measured health related quality of life in 610 patients enrolled in the CS21 trial using SF-12Ò and EORTC QLQ-C30. Based on responses to these questionnaires we estimated patient utility using 4 published mapping algorithms. Utility was tested for relationships with aspects of the symptom and side effect burden that may be affected by degarelix treatment, that is prostate specific antigen progression and adverse events. Results: Average utility in patients without prostate specific antigen progression or an adverse event was 0.742, similar to previously published utilities for nonprogressed prostate cancer states. Prostate specific antigen progression was associated with a utility decrement of between 0.062 and 0.134 depending on the mapping algorithm used. Of adverse events considered in our analysis musculoskeletal events were associated with the greatest effects on patient utility with a decrement of between 0.029 and 0.086. The 4 mapping algorithms generated similar utility estimates, although values derived from SF-12 were consistently lower than those derived from EORTC QLQ-C30. Conclusions: Prostate specific antigen progression status and the incidence of treatment and disease related adverse events result in significant decrements to patient health related quality of life. By slowing prostate specific antigen progression degarelix may improve patient utility and the health related quality of life burden. Key Words: prostatic neoplasms, drug therapy, quality of life, cost-benefit analysis, questionnaires
LOCALLY advanced and metastatic prostate cancer is commonly associated with a considerable symptom and treatment related burden in patients with substantial implications for quality of life.1 Available evidence indicates that HRQL decreases as patients
progress to later lines of treatment.1e5 This is attributable to disease progression, anxiety and distress about PSA levels and the side effects of current hormonal treatments, which can adversely affect patient daily function as well as the sense of well-being.
0022-5347/15/1933-0839/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2014.09.098 Vol. 193, 839-846, March 2015 Printed in U.S.A.
Abbreviations and Acronyms 8D ¼ 8 Dimensions EORTC ¼ European Organisation for Research and Treatment of Cancer EQ-5D ¼ EuroQol-5 Dimensions HRQL ¼ health related quality of life LHRH ¼ luteinizing hormone-releasing hormone PFS ¼ progression-free survival PSA ¼ prostate specific antigen QLQ-C30 ¼ Quality of Life Questionnaire-C30 UK ¼ United Kingdom Accepted for publication September 19, 2014. Study received institutional review board approval. Supported by Ferring Pharmaceuticals A/S. * Correspondence: BresMed, North Church House, 84 Queen St., Sheffield, S1 2DW, United Kingdom (telephone: þ44 (0)114 309 4372; FAX: þ44 (0)114 270 0422; e-mail: dlee@ bresmed.co.uk). † Financial interest and/or other relationship with BresMed and Ferring. ‡ Financial interest and/or other relationship with Ferring Pharmaceuticals. § Financial interest and/or other relationship with the National Health Service.
For another article on a related topic see page 1023.
www.jurology.com
j
839
840
QUALITY OF LIFE IN PATIENTS TREATED WITH DEGARELIX FOR PROSTATE CANCER
Most men with advanced prostate cancer are treated with LHRH agonists such as leuprorelin, goserelin or triptorelin. Although the aim of these treatments is to reduce testosterone to castrate levels, LHRH agonists are typically associated with an initial surge in testosterone known as a testosterone flare. This delays castration and can result in clinical symptoms affecting patient quality of life. Potential flare effects include increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression and fatal cardiovascular events due to hypercoagulation status.6,7 Therefore, LHRH agonists are often first prescribed in combination with antiandrogen therapy such as bicalutamide to reduce flare.6 However, this has not proved to decrease the incidence of testosterone flare side effects.7 Degarelix is not associated with testosterone flare and it represents an alternative to treatment with LHRH agonists in patients with advanced hormone dependent prostate cancer.8,9 Although it acts on the same receptor (gonadotropin-releasing hormone receptor) as LHRH agonists, degarelix is a receptor antagonist that blocks the receptor to achieve an immediate, sustained reduction in testosterone. The rapid effect avoids the initial testosterone surges that characterize treatment with LHRH agonists.8 Klotz et al found that degarelix significantly improved PSA PFS relative to LHRH agonists.9 Although the mechanism of action by which PSA PFS is improved is not fully established, it is likely due to short-term and long-term testosterone suppression. To our knowledge utility estimates in patients treated with degarelix have not been published previously. However, HRQL measures are required to assess the cost-effectiveness of treatment by cost utility analysis, which is used to inform reimbursement decisions. Utilities represent a valuation of HRQL on a continuum of 0 to 1, where 0 is equivalent to death and 1 represents the best possible health state.10 When utilities cannot be directly derived from HRQL instruments collected in a clinical trial such as EQ-5D, an algorithm can often be used to derive such utilities from other HRQL questionnaires. This is known as mapping. Mapping algorithms use available data from questionnaire responses to produce preference based, generic utility estimates. The CS21 trial included 2 measurements of patient HRQL, that is SF-12, version 2 and the EORTC QLQ-C30.11 Preference based utility estimates can be derived from patient responses to these instruments using mapping techniques. In this study we used various published mapping algorithms to estimate patient utility from CS21 trial observations. Using these estimates we examined
the effect of PSA progression as well as key disease and treatment related clinical adverse events on patient utility. In addition, we examined the beneficial effect of degarelix on HRQL in patients with advanced prostate cancer.
METHODS Study Population The CS21 trial recorded HRQL data on 610 patients 18 years old or older with histologically confirmed adenocarcinoma of the prostate in whom endocrine treatment was indicated (except for neoadjuvant hormonal therapy).11 Disease stage was defined as localized (T1/2, NX or N0 and M0), locally advanced (T3/4, NX or N0 and M0 or N1 and M), metastatic or not classifiable (increasing PSA after radical prostatectomy or radiotherapy). Antiandrogen flare protection was administered in 4 (6.3%), 6 (11.5%), 9 (19.1%) and 3 patients (7.7%), respectively. Table 1 lists baseline patient characteristics. Patients received degarelix at a starting dose of 240 mg followed by 12 monthly (every 28 days) maintenance doses of 80 or 160 mg (240/80 mg and 240/160 mg, respectively) or 12 monthly (every 28 days) doses of leuprorelin 7.5 mg. The degarelix 240/160 mg group was not included in this analysis of the treatment effect because this is not the licensed dosing regimen.11
HRQL Measures The SF-12 and EORTC QLQ-C30 questionnaires were administered at days 0 (baseline), 28, 84 and 168, and at the end of study visit to measure generic and cancer specific quality of life. SF-12, a 12-item generic measure of HRQL, is an abbreviated version of the SF-36Ò questionnaire.12 EORTC QLQ-C30 is a cancer specific questionnaire consisting of 30 questions that is frequently used to assess quality of life in patients in various disease states. Responses are transformed to scores on a set of 5 Table 1. Baseline patient characteristics11
No. intent to treat pts Median age (range) Median ng/ml testosterone (25the75th percentile) Median ng/ml PSA (25the75th percentile) No. disease stage (%): Localised Locally advanced Metastatic Not classifiable No. Gleason score (%): 2e4 5e6 7 8e10 No. PSA ng/ml subgroup (%): Less than 10 10e20 Greater than 20 Greater than 50
Degarelix 240/80 mg
Leuprorelin 7.5 mg/mo
207 72 (51e89) 4.11 (3.05e5.32)
201 74 (52e98) 3.84 (2.91e5.01)
19.8
(9.4e46)
17.4
(8.4e56)
69 64 37 37
(33) (31) (18) (18)
63 52 47 39
(31) (26) (23) (19)
20 68 63 56
(10) (33) (30) (27)
24 63 62 51
(12) (32) (31) (26)
55 52 52 48
(27) (25) (26) (23)
64 44 38 55
(32) (22) (19) (27)
QUALITY OF LIFE IN PATIENTS TREATED WITH DEGARELIX FOR PROSTATE CANCER
function scales and 9 symptom scales along with a scale representing global quality of life.13
Utility Calculation Neither HRQL instrument included in the CS21 trial11 can be used to directly calculate preference based utility values. Therefore, published mapping algorithms were applied to estimate patient utility. Utilities derived from the EQ-5D questionnaire are recommended as the gold standard for cost-effectiveness analysis by NICE (National Institute for Health and Care Excellence) in the UK with a preference for EQ-5D mapped values if these values are not directly available.10 Thus, our analysis featured 3 algorithms used to map available data from the CS21 trial11 to EQ-5D, including 1 with SF-12 and 2 with EORTC QLQ-C30.12,14,15 An additional algorithm was included to map trial questionnaire responses to a preference based instrument derived from EORTC-8D.16 The Appendix shows details of the mapping methods.
Measured Effects We reviewed published evidence on degarelix to identify aspects of the symptom and side effect burden that may be affected by treatment. Four key disease related effects are affected by degarelix treatment, including PSA PFS, and musculoskeletal, urinary tract and serious cardiovascular events, which were significantly decreased during 1 year of treatment with degarelix compared to LHRH agonists.9,17 Based on this review PSA progression status (progressed or not progressed) and certain adverse events were included in analysis, such as fractures, joint related signs and symptoms, musculoskeletal adverse events and cardiovascular serious adverse events. Event definitions were taken from a pooled analysis of the studies by Albertsen17 and Klotz9 et al. Urinary tract events were not separately included in analysis since too few of these events occurred during the period on which HRQL data are available. Patients were assumed to experience an adverse event if one was present at the time that they completed the questionnaires. This did not depend on previous events.
Statistical Analysis Comparisons between patient subgroups in the CS21 study11 were done with the Student t-test in STATAÒ. Additionally, multivariate regression analysis based on the generalized estimate equation was used to examine any possible dependence between PSA progression status and adverse events. Generalized estimate equation regression was done to account for the correlation between questionnaires provided by the same patient.
RESULTS In patients without PSA progression or any defined adverse event the mean utility was between 0.742 and 0.887 using the SF-12 to EQ-5D algorithm and the algorithm of Kontodimopoulos et al,15 respectively, to convert EORTC QLQ-C30 to EQ-5D utilities (table 2). Tables 2 and 3 list all utilities derived from mapping questionnaire outcomes. PSA progression was associated with a significant
841
difference in utility compared with no progression for all 4 mapping methods when considered alone. The utility decrement ranged from 0.062 for EORTC-8D to 0.134 for the algorithm of Kontodimopoulos et al (table 3).15 When controlling for the incidence of adverse events, there was also a significant utility decrement for all algorithms used. Adverse events were also associated with significant changes in utility. Patients with musculoskeletal events had a significantly lower HRQL than those without such events for all 4 mapping methods when such events were considered alone (table 3). The utility decrement ranged from 0.029 for SF-12 to 0.086 for the algorithm of McKenzie and van der Pol.14 The decrement was still significant when a covariate for PSA progression status was included (table 2). Patients with joint related signs and symptoms had significantly lower HRQL than patients without such events. The decrement ranged from 0.042 for the SF-12 to 0.086 for the algorithm of McKenzie and van der Pol (table 3).14 When combined with PSA progression status, the decrement was not significant using SF-12 but it was significant using the other 3 mapping methods (table 2). When considered alone, fracture and cardiovascular serious adverse events had no significant utility decrements except for fractures when using EORTC-8D (p ¼ 0.04, table 3). When considered together with PSA progression status (table 2), the utility decrement for fractures was significant and large for all 4 methods (range 0.118 to 0.249). The decrement for cardiovascular serious adverse events was significant when using the algorithm of McKenzie and van der Pol14 or EORTC8D. All 4 adverse events tested had a significant influence on HRQL independently using at least 2 mapping methods when accounting for PSA progression. Utility should be calculated additively, for example a patient with progression and a fracture would have a utility of 0.741 e 0.064 e 0.118 ¼ 0.559 using SF-12 mapped to EQ-5D. When utility in all patients treated with degarelix was compared to that of leuprorelin, there was a significant difference using the algorithm of McKenzie and van der Pol.14 Although we noted a general trend toward better HRQL in patients treated with degarelix, the difference was not significant when using the other 3 algorithms. When controlling for utility estimates and factors expected to be influenced by treatment (adverse events and PSA progression), there was no significant effect of treatment on HRQL regardless of the mapping algorithm used.
DISCUSSION As expected from the literature PSA progression was associated with a significant utility decrement
842
QUALITY OF LIFE IN PATIENTS TREATED WITH DEGARELIX FOR PROSTATE CANCER
Table 2. Results of generalized estimating equation multivariate regression analysis SF-12 Mapped to EQ-5D12 Health State All adverse events combined þ PSA progression: No adverse event or progression Progression Adverse event Fracture þ PSA progression: No fracture or progression Progression Fracture Joint related signs þ symptoms þ PSA progression: No joint related signs þ symptoms or progression Progression Joint related signs þ symptoms Musculoskeletal event þ PSA progression: No musculoskeletal event or progression Progression Musculoskeletal event Cardiovascular serious adverse event þ PSA progression: No cardiovascular serious adverse event or progression Progression Cardiovascular serious adverse event Treatment þ PSA progression: Degarelix, no progression Progression Leuprorelin Treatment þ adverse event: Degarelix, no adverse event Adverse event Leuprorelin Treatment, PSA progression þ adverse event: Degarelix, no PSA progression, no adverse event Progression Adverse event Leuprorelin
EQ-5D Kontodimopoulos et al15
EQ-5D McKenzie and van der Pol14
EORTC-8D16
Mean
p Value
Mean
p Value
Mean
p Value
Mean
p Value
0.742 0.061 0.029
Purpose: We used responses to questionnaires included in the CS21 degarelix trial and published mapping algorithms to address the paucity of evidence for health related quality of life in patients with advanced hormone dependent prostate cancer treated with degarelix. Materials and Methods: We measured health related quality of life in 610 patients enrolled in the CS21 trial using SF-12Ò and EORTC QLQ-C30. Based on responses to these questionnaires we estimated patient utility using 4 published mapping algorithms. Utility was tested for relationships with aspects of the symptom and side effect burden that may be affected by degarelix treatment, that is prostate specific antigen progression and adverse events. Results: Average utility in patients without prostate specific antigen progression or an adverse event was 0.742, similar to previously published utilities for nonprogressed prostate cancer states. Prostate specific antigen progression was associated with a utility decrement of between 0.062 and 0.134 depending on the mapping algorithm used. Of adverse events considered in our analysis musculoskeletal events were associated with the greatest effects on patient utility with a decrement of between 0.029 and 0.086. The 4 mapping algorithms generated similar utility estimates, although values derived from SF-12 were consistently lower than those derived from EORTC QLQ-C30. Conclusions: Prostate specific antigen progression status and the incidence of treatment and disease related adverse events result in significant decrements to patient health related quality of life. By slowing prostate specific antigen progression degarelix may improve patient utility and the health related quality of life burden. Key Words: prostatic neoplasms, drug therapy, quality of life, cost-benefit analysis, questionnaires
LOCALLY advanced and metastatic prostate cancer is commonly associated with a considerable symptom and treatment related burden in patients with substantial implications for quality of life.1 Available evidence indicates that HRQL decreases as patients
progress to later lines of treatment.1e5 This is attributable to disease progression, anxiety and distress about PSA levels and the side effects of current hormonal treatments, which can adversely affect patient daily function as well as the sense of well-being.
0022-5347/15/1933-0839/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2014.09.098 Vol. 193, 839-846, March 2015 Printed in U.S.A.
Abbreviations and Acronyms 8D ¼ 8 Dimensions EORTC ¼ European Organisation for Research and Treatment of Cancer EQ-5D ¼ EuroQol-5 Dimensions HRQL ¼ health related quality of life LHRH ¼ luteinizing hormone-releasing hormone PFS ¼ progression-free survival PSA ¼ prostate specific antigen QLQ-C30 ¼ Quality of Life Questionnaire-C30 UK ¼ United Kingdom Accepted for publication September 19, 2014. Study received institutional review board approval. Supported by Ferring Pharmaceuticals A/S. * Correspondence: BresMed, North Church House, 84 Queen St., Sheffield, S1 2DW, United Kingdom (telephone: þ44 (0)114 309 4372; FAX: þ44 (0)114 270 0422; e-mail: dlee@ bresmed.co.uk). † Financial interest and/or other relationship with BresMed and Ferring. ‡ Financial interest and/or other relationship with Ferring Pharmaceuticals. § Financial interest and/or other relationship with the National Health Service.
For another article on a related topic see page 1023.
www.jurology.com
j
839
840
QUALITY OF LIFE IN PATIENTS TREATED WITH DEGARELIX FOR PROSTATE CANCER
Most men with advanced prostate cancer are treated with LHRH agonists such as leuprorelin, goserelin or triptorelin. Although the aim of these treatments is to reduce testosterone to castrate levels, LHRH agonists are typically associated with an initial surge in testosterone known as a testosterone flare. This delays castration and can result in clinical symptoms affecting patient quality of life. Potential flare effects include increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression and fatal cardiovascular events due to hypercoagulation status.6,7 Therefore, LHRH agonists are often first prescribed in combination with antiandrogen therapy such as bicalutamide to reduce flare.6 However, this has not proved to decrease the incidence of testosterone flare side effects.7 Degarelix is not associated with testosterone flare and it represents an alternative to treatment with LHRH agonists in patients with advanced hormone dependent prostate cancer.8,9 Although it acts on the same receptor (gonadotropin-releasing hormone receptor) as LHRH agonists, degarelix is a receptor antagonist that blocks the receptor to achieve an immediate, sustained reduction in testosterone. The rapid effect avoids the initial testosterone surges that characterize treatment with LHRH agonists.8 Klotz et al found that degarelix significantly improved PSA PFS relative to LHRH agonists.9 Although the mechanism of action by which PSA PFS is improved is not fully established, it is likely due to short-term and long-term testosterone suppression. To our knowledge utility estimates in patients treated with degarelix have not been published previously. However, HRQL measures are required to assess the cost-effectiveness of treatment by cost utility analysis, which is used to inform reimbursement decisions. Utilities represent a valuation of HRQL on a continuum of 0 to 1, where 0 is equivalent to death and 1 represents the best possible health state.10 When utilities cannot be directly derived from HRQL instruments collected in a clinical trial such as EQ-5D, an algorithm can often be used to derive such utilities from other HRQL questionnaires. This is known as mapping. Mapping algorithms use available data from questionnaire responses to produce preference based, generic utility estimates. The CS21 trial included 2 measurements of patient HRQL, that is SF-12, version 2 and the EORTC QLQ-C30.11 Preference based utility estimates can be derived from patient responses to these instruments using mapping techniques. In this study we used various published mapping algorithms to estimate patient utility from CS21 trial observations. Using these estimates we examined
the effect of PSA progression as well as key disease and treatment related clinical adverse events on patient utility. In addition, we examined the beneficial effect of degarelix on HRQL in patients with advanced prostate cancer.
METHODS Study Population The CS21 trial recorded HRQL data on 610 patients 18 years old or older with histologically confirmed adenocarcinoma of the prostate in whom endocrine treatment was indicated (except for neoadjuvant hormonal therapy).11 Disease stage was defined as localized (T1/2, NX or N0 and M0), locally advanced (T3/4, NX or N0 and M0 or N1 and M), metastatic or not classifiable (increasing PSA after radical prostatectomy or radiotherapy). Antiandrogen flare protection was administered in 4 (6.3%), 6 (11.5%), 9 (19.1%) and 3 patients (7.7%), respectively. Table 1 lists baseline patient characteristics. Patients received degarelix at a starting dose of 240 mg followed by 12 monthly (every 28 days) maintenance doses of 80 or 160 mg (240/80 mg and 240/160 mg, respectively) or 12 monthly (every 28 days) doses of leuprorelin 7.5 mg. The degarelix 240/160 mg group was not included in this analysis of the treatment effect because this is not the licensed dosing regimen.11
HRQL Measures The SF-12 and EORTC QLQ-C30 questionnaires were administered at days 0 (baseline), 28, 84 and 168, and at the end of study visit to measure generic and cancer specific quality of life. SF-12, a 12-item generic measure of HRQL, is an abbreviated version of the SF-36Ò questionnaire.12 EORTC QLQ-C30 is a cancer specific questionnaire consisting of 30 questions that is frequently used to assess quality of life in patients in various disease states. Responses are transformed to scores on a set of 5 Table 1. Baseline patient characteristics11
No. intent to treat pts Median age (range) Median ng/ml testosterone (25the75th percentile) Median ng/ml PSA (25the75th percentile) No. disease stage (%): Localised Locally advanced Metastatic Not classifiable No. Gleason score (%): 2e4 5e6 7 8e10 No. PSA ng/ml subgroup (%): Less than 10 10e20 Greater than 20 Greater than 50
Degarelix 240/80 mg
Leuprorelin 7.5 mg/mo
207 72 (51e89) 4.11 (3.05e5.32)
201 74 (52e98) 3.84 (2.91e5.01)
19.8
(9.4e46)
17.4
(8.4e56)
69 64 37 37
(33) (31) (18) (18)
63 52 47 39
(31) (26) (23) (19)
20 68 63 56
(10) (33) (30) (27)
24 63 62 51
(12) (32) (31) (26)
55 52 52 48
(27) (25) (26) (23)
64 44 38 55
(32) (22) (19) (27)
QUALITY OF LIFE IN PATIENTS TREATED WITH DEGARELIX FOR PROSTATE CANCER
function scales and 9 symptom scales along with a scale representing global quality of life.13
Utility Calculation Neither HRQL instrument included in the CS21 trial11 can be used to directly calculate preference based utility values. Therefore, published mapping algorithms were applied to estimate patient utility. Utilities derived from the EQ-5D questionnaire are recommended as the gold standard for cost-effectiveness analysis by NICE (National Institute for Health and Care Excellence) in the UK with a preference for EQ-5D mapped values if these values are not directly available.10 Thus, our analysis featured 3 algorithms used to map available data from the CS21 trial11 to EQ-5D, including 1 with SF-12 and 2 with EORTC QLQ-C30.12,14,15 An additional algorithm was included to map trial questionnaire responses to a preference based instrument derived from EORTC-8D.16 The Appendix shows details of the mapping methods.
Measured Effects We reviewed published evidence on degarelix to identify aspects of the symptom and side effect burden that may be affected by treatment. Four key disease related effects are affected by degarelix treatment, including PSA PFS, and musculoskeletal, urinary tract and serious cardiovascular events, which were significantly decreased during 1 year of treatment with degarelix compared to LHRH agonists.9,17 Based on this review PSA progression status (progressed or not progressed) and certain adverse events were included in analysis, such as fractures, joint related signs and symptoms, musculoskeletal adverse events and cardiovascular serious adverse events. Event definitions were taken from a pooled analysis of the studies by Albertsen17 and Klotz9 et al. Urinary tract events were not separately included in analysis since too few of these events occurred during the period on which HRQL data are available. Patients were assumed to experience an adverse event if one was present at the time that they completed the questionnaires. This did not depend on previous events.
Statistical Analysis Comparisons between patient subgroups in the CS21 study11 were done with the Student t-test in STATAÒ. Additionally, multivariate regression analysis based on the generalized estimate equation was used to examine any possible dependence between PSA progression status and adverse events. Generalized estimate equation regression was done to account for the correlation between questionnaires provided by the same patient.
RESULTS In patients without PSA progression or any defined adverse event the mean utility was between 0.742 and 0.887 using the SF-12 to EQ-5D algorithm and the algorithm of Kontodimopoulos et al,15 respectively, to convert EORTC QLQ-C30 to EQ-5D utilities (table 2). Tables 2 and 3 list all utilities derived from mapping questionnaire outcomes. PSA progression was associated with a significant
841
difference in utility compared with no progression for all 4 mapping methods when considered alone. The utility decrement ranged from 0.062 for EORTC-8D to 0.134 for the algorithm of Kontodimopoulos et al (table 3).15 When controlling for the incidence of adverse events, there was also a significant utility decrement for all algorithms used. Adverse events were also associated with significant changes in utility. Patients with musculoskeletal events had a significantly lower HRQL than those without such events for all 4 mapping methods when such events were considered alone (table 3). The utility decrement ranged from 0.029 for SF-12 to 0.086 for the algorithm of McKenzie and van der Pol.14 The decrement was still significant when a covariate for PSA progression status was included (table 2). Patients with joint related signs and symptoms had significantly lower HRQL than patients without such events. The decrement ranged from 0.042 for the SF-12 to 0.086 for the algorithm of McKenzie and van der Pol (table 3).14 When combined with PSA progression status, the decrement was not significant using SF-12 but it was significant using the other 3 mapping methods (table 2). When considered alone, fracture and cardiovascular serious adverse events had no significant utility decrements except for fractures when using EORTC-8D (p ¼ 0.04, table 3). When considered together with PSA progression status (table 2), the utility decrement for fractures was significant and large for all 4 methods (range 0.118 to 0.249). The decrement for cardiovascular serious adverse events was significant when using the algorithm of McKenzie and van der Pol14 or EORTC8D. All 4 adverse events tested had a significant influence on HRQL independently using at least 2 mapping methods when accounting for PSA progression. Utility should be calculated additively, for example a patient with progression and a fracture would have a utility of 0.741 e 0.064 e 0.118 ¼ 0.559 using SF-12 mapped to EQ-5D. When utility in all patients treated with degarelix was compared to that of leuprorelin, there was a significant difference using the algorithm of McKenzie and van der Pol.14 Although we noted a general trend toward better HRQL in patients treated with degarelix, the difference was not significant when using the other 3 algorithms. When controlling for utility estimates and factors expected to be influenced by treatment (adverse events and PSA progression), there was no significant effect of treatment on HRQL regardless of the mapping algorithm used.
DISCUSSION As expected from the literature PSA progression was associated with a significant utility decrement
842
QUALITY OF LIFE IN PATIENTS TREATED WITH DEGARELIX FOR PROSTATE CANCER
Table 2. Results of generalized estimating equation multivariate regression analysis SF-12 Mapped to EQ-5D12 Health State All adverse events combined þ PSA progression: No adverse event or progression Progression Adverse event Fracture þ PSA progression: No fracture or progression Progression Fracture Joint related signs þ symptoms þ PSA progression: No joint related signs þ symptoms or progression Progression Joint related signs þ symptoms Musculoskeletal event þ PSA progression: No musculoskeletal event or progression Progression Musculoskeletal event Cardiovascular serious adverse event þ PSA progression: No cardiovascular serious adverse event or progression Progression Cardiovascular serious adverse event Treatment þ PSA progression: Degarelix, no progression Progression Leuprorelin Treatment þ adverse event: Degarelix, no adverse event Adverse event Leuprorelin Treatment, PSA progression þ adverse event: Degarelix, no PSA progression, no adverse event Progression Adverse event Leuprorelin
EQ-5D Kontodimopoulos et al15
EQ-5D McKenzie and van der Pol14
EORTC-8D16
Mean
p Value
Mean
p Value
Mean
p Value
Mean
p Value
0.742 0.061 0.029
