- Email: [email protected]
Health-related quality of life in patients with malignant melanoma by stage and treatment status
Accepted Manuscript Health-related quality of life in patients with malignant melanoma by stage and treatment status Abby R. Rosenberg, MPHS, Sara J. Weston, PhD, Teresa Deshields, PhD, Ryan C. Fields, MD, Gerald P. Linette, MD, PhD, Lynn A. Cornelius, MD, Yevgeniy R. Semenov, MD, MA PII:
S0190-9622(18)32068-1
DOI:
10.1016/j.jaad.2018.06.007
Reference:
YMJD 12585
To appear in:
Journal of the American Academy of Dermatology
Received Date: 16 March 2018 Revised Date:
22 May 2018
Accepted Date: 4 June 2018
Please cite this article as: Rosenberg AR, Weston SJ, Deshields T, Fields RC, Linette GP, Cornelius LA, Semenov YR, Health-related quality of life in patients with malignant melanoma by stage and treatment status, Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2018.06.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Article type: Research Letter Title: Health-related quality of life in patients with malignant melanoma by stage and treatment status
25 26 27 28 29
Funding sources: This study was supported in part by the Washington University School of Medicine Dean’s Fellowship. Study data were collected and managed using REDCap electronic data capture tools hosted at Washington University School of Medicine in St. Louis. The WUSM REDCap installation is supported by Clinical and Translational Science Award (CTSA) Grant [UL1 TR000448] and Siteman Comprehensive Cancer Center and NCI Cancer Center Support Grant P30 CA091842.
30 31 32 33
IRB approval status: Reviewed and approved by The Washington University in St. Louis Institutional Review Board; approval # 201409103
34 35 36 37 38 39 40 41 42
Reprint requests: Yevgeniy Semenov
Abby R. Rosenberg, MPHS1, Sara J. Weston, PhD2,3, Teresa Deshields, PhD4, Ryan C. Fields, MD5, Gerald P. Linette, MD, PhD6,7, Lynn A. Cornelius, MD1; Yevgeniy R. Semenov, MD, MA1 1
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Washington University School of Medicine in St. Louis, Division of Dermatology. Washington University in St. Louis, Department of Psychological and Brain Sciences. 3 Northwestern University, Department of Medical Social Sciences. 4 Washington University School of Medicine in St. Louis, Siteman Cancer Center Counseling Services. 5 Washington University School of Medicine in St. Louis, Department of Surgery. 6 Washington University School of Medicine in St. Louis, Division of Oncology. 7 Perelman School of Medicine, University of Pennsylvania, Division of Hematology and Oncology.
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Corresponding author: Yevgeniy Semenov, MD, MA Division of Dermatology Washington University School of Medicine 660 S. Euclid Ave Campus Box 8123 St. Louis, MO 63110 Phone: 443-791-3311 Fax: 314-362-8159 Email: [email protected]
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Conflicts of Interest: The authors have no conflict of interest to declare.
Manuscript word count: 481 words References: 5 Figures: 0 Tables: 2 Attachments: Functional Assessment of Cancer Therapy – Melanoma (survey)
43
Melanoma QoL
ACCEPTED MANUSCRIPT 2 To the Editor: While the introduction of numerous immunotherapy and targeted therapy agents has led
45
to improved survival in advanced-stage melanoma over the past decade, these therapies have been
46
associated with severe adverse effects. Further, the overall impact of these therapies on quality of life
47
(QoL) is yet unknown, and few studies have investigated differences in QoL attainment of melanoma
48
patients by stage and treatment status.
RI PT
44
49
A consecutive sample of adults diagnosed with melanoma within the past 24 months was recruited from
51
Washington University School of Medicine clinics between June 2015 and June 2016. Eighty-seven
52
patients completed the Functional Assessment of Cancer Therapy – Melanoma (FACT-M), a validated
53
disease-specific QoL instrument.1 Using a validated mapping function, FACT-M scores were converted to
54
European Quality of Life-5 Dimensions (EQ-5D) scores, a generic health utility measure useful in
55
comparing to other populations.2 Patients were stratified by localized (stages 0-II) versus advanced
56
(stages III-IV) melanoma. Baseline comparisons were tested using ANOVA for continuous variables and
57
χ2 for categorical variables. Multivariate regression models, adjusted for demographic and clinical
58
variables, were used to estimate the association between melanoma stage and QoL outcomes. A series
59
of structural equation models were constructed to explore the extent to which systemic therapy status
60
mediated the relationship between melanoma stage and QoL. STATA version 14 (StataCorp, College
61
Station, Texas) was used for analyses.
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62
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50
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Our melanoma patient population achieved a lower mean EQ-5D score than their peers in the U.S.
64
general population (0.76 vs. 0.87, respectively).3 Melanoma patients achieved similar scores to patients
65
with coronary artery disease (0.73), diabetes mellitus (0.76), hypertension (0.79), arthritis (0.79), lung
66
cancer (0.80), and breast cancer (0.82).3,4
67
Melanoma QoL
ACCEPTED MANUSCRIPT 3 Localized melanoma patients had significantly higher overall FACT-M scores than advanced-stage
69
patients and performed better on all subscales except those corresponding to social and emotional well-
70
being (Table 1). Thus, the QoL disparity between localized and advanced melanoma patients was
71
primarily a consequence of physical rather than psychological factors.
72
RI PT
68
In sequential multivariable regression models (Table 2), advanced stage and systemic therapy were
74
significant predictors of lower QoL. Mediation analyses demonstrated that systemic therapy is
75
responsible for 75.5% of the association between stage and FACT-M score. Further, patients on targeted
76
therapy had overall the lowest QoL attainment in comparison to other systemic therapies and those not
77
on systemic therapy. In contrast, patients receiving single-agent immunotherapy had similar QoL to
78
those not receiving systemic therapy. These results suggest immunotherapy may be better tolerated
79
than targeted therapy.
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While statistically significant, the magnitude of the EQ-5D disparity between advanced and localized
82
melanoma patients (0.04) was smaller than the minimally important difference of the instrument (0.07-
83
0.09).5 This suggests that the therapy-mediated QoL decline in advanced relative to localized melanoma
84
was below the threshold for concluding that two scores yield clinically disparate QoL outcomes. Thus,
85
we propose that the overall QoL impact of modern systemic therapies is minimal and is likely to be
86
outweighed by their proven survival benefit.
88
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87
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81
89 90 91 Melanoma QoL
ACCEPTED MANUSCRIPT 4 92
References
93
1.
Cormier JN, Ross MI, Gershenwald JE, et al. Prospective assessment of the reliability, validity, and sensitivity to change of the functional assessment of cancer therapy-melanoma
95
questionnaire. Cancer. 2008;112:2249-2257. 2.
97
health utility weights. Value Heal. 2011;14:900-906. 3.
99 100
Chronic Conditions in the United States. Med Care Care. 2005;43:736-749. 4.
101 102 103
Sullivan PW, Lawrence WF, Ghushchyan V. A National Catalog of Preference-Based Scores for
SC
98
Askew RL, Swartz RJ, Xing Y, et al. Mapping FACT-melanoma quality-of-life scores to EQ-5D
Naik H, Howell D, Su S, et al. EQ-5D Health Utility Scores: Data from a Comprehensive Canadian
M AN U
96
Cancer Centre. Patient. 2017;10:105-115. 5.
Askew RL, Xing Y, Palmer JL, Cella D, Moye LA, Cormier JN. Evaluating minimal important differences for the FACT-melanoma quality of life questionnaire. Value Heal. 2009;12:1144-1150.
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108 109
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111 112 113 114
Melanoma QoL
ACCEPTED MANUSCRIPT 5 Table 1. Baseline characteristics and univariate analyses stratified by stage. Early stage (N=44) 53.4 (15.8)
Advanced stage (N=43) 57.2 (15.5)
48 (55.2) 39 (44.8)
20 (45.4) 24 (54.6)
28 (65.1) 15 (34.9)
0.07
84 (96.6) 1 (1.1) 2 (2.3)
44 (100) 0 (0) 0 (0)
40 (93.0) 1 (2.3) 2 (4.7)
0.20
27 (31.0) 36 (41.4) 44 (27.6)
10 (22.7) 19 (43.2) 15 (34.1)
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Melanoma QoL
SC
RI PT
P Value 0.27
17 (39.5) 17 (39.5) 9 (20.9)
0.18
10.4 (7.5)
9.1 (7.8)
11.8 (7.1)
0.09
64 (73.6) 23 (26.4)
43 (97.7) 1 (2.3)
22 (50.0) 22 (50.0)
<0.001
9 (10.3) 78 (89.7)
41 (93.2) 3 (6.8)
37 (86.1) 6 (13.9)
0.28
39 (44.8) 48 (55.2)
29 (65.9) 15 (34.1)
19 (44.2) 24 (55.8)
0.04
7 (8.1) 80 (91.9)
1 (2.3) 43 (97.7)
6 (13.9) 37 (86.1)
0.05
23 (26.4) 64 (73.6)
10 (22.7) 34 (77.3)
13 (30.2) 30 (69.8)
0.43
24 (27.6) 63 (72.4)
11 (25.0) 33 (75.0)
13 (30.2) 30 (69.8)
0.59
24.4 (4.3) 23.7 (4.4) 18.5 (4.4) 22.4 (4.8) 55.2 (7.6) 28.2 (4.4) 143.9 (19.4) 0.76 (0.07)
25.8 (2.9) 23.3 (4.0) 18.9 (3.9) 23.6 (3.7) 57.1 (5.7) 29.6 (2.7) 148.5 (13.5) 0.77 (0.05)
23.0 (5.0) 24.3 (4.8) 18.0 (4.9) 21.1 (5.5) 53.3 (8.7) 26.7 (5.3) 139.1 (23.2) 0.74 (0.09)
0.002 0.29 0.35 0.02 0.02 0.002 0.02 0.02
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Characteristic Age, mean (SD), years Gender, N (%) Male Female Race, N (%) Non-Hispanic White Non-Hispanic Black Hispanic Estimated annual income, N (%) $25,000 - $50,000 $50,000 - $75,000 >$75,000 Time since diagnosis, mean (SD), months Treatment modality, N (%) No current systemic therapy Current systemic therapy Diabetes mellitus, N (%) Yes No Hypertension, N (%) Yes No Cardiovascular disease, N (%) Yes No Arthritis, N (%) Yes No Psychiatric disease, N (%) Yes No QoL, mean (SD) Physical well-being Social well-being Emotional well-being Functional well-being Melanoma-specific subscale Melanoma surgery subscale FACT-M EQ-5D
Total (N=87) 55.3 (15.7)
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ACCEPTED MANUSCRIPT 6
Table 2. Multivariate regression models of EQ5D scores by melanoma stage and systemic therapy status. Model Variable Coefficient 95% CI P Value Stage 1 Localized (N=44) ref1 ref1 ref1 -0.703, -0.007
0.016
No (N=64) Yes (N=23) Systemic therapy type2
ref1 -0.058
ref1 -0.092, -0.023
ref1 0.001
ref1
ref1
ref1
No systemic therapy (N=64) 3
Immunotherapy3 (N=11)
-0.036
4
RI PT
-0.039
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2
Advanced (N=43) Systemic therapy2
-0.084, 0.019
0.138
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117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132
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Targeted therapy (N=7) -0.076 -0.133, -0.020 0.009 5 Combination or other (N=5) -0.072 -0.136, -0.009 0.026 1 Reference group 2 Most recently received within 12 months prior to questionnaire completion. 3 Modern immunotherapies included ipilimumab, pembrolizumab, nivolumab, durvalumab, seviprotimut-L, and T-Vec. 4 BRAF/MEK targeted therapies included dabrafenib, trametinib, vemurafenib, cobimetinib, and selumetinib. 5 Other systemic therapies included interferon-alpha, dacarbazine, and imatinib. All models adjusted for age, sex, estimated income, time since diagnosis, and history of diabetes mellitus, hypertension, cardiovascular disease, arthritis, and psychiatric disease.
Melanoma QoL
S0190-9622(18)32068-1
DOI:
10.1016/j.jaad.2018.06.007
Reference:
YMJD 12585
To appear in:
Journal of the American Academy of Dermatology
Received Date: 16 March 2018 Revised Date:
22 May 2018
Accepted Date: 4 June 2018
Please cite this article as: Rosenberg AR, Weston SJ, Deshields T, Fields RC, Linette GP, Cornelius LA, Semenov YR, Health-related quality of life in patients with malignant melanoma by stage and treatment status, Journal of the American Academy of Dermatology (2018), doi: 10.1016/j.jaad.2018.06.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Article type: Research Letter Title: Health-related quality of life in patients with malignant melanoma by stage and treatment status
25 26 27 28 29
Funding sources: This study was supported in part by the Washington University School of Medicine Dean’s Fellowship. Study data were collected and managed using REDCap electronic data capture tools hosted at Washington University School of Medicine in St. Louis. The WUSM REDCap installation is supported by Clinical and Translational Science Award (CTSA) Grant [UL1 TR000448] and Siteman Comprehensive Cancer Center and NCI Cancer Center Support Grant P30 CA091842.
30 31 32 33
IRB approval status: Reviewed and approved by The Washington University in St. Louis Institutional Review Board; approval # 201409103
34 35 36 37 38 39 40 41 42
Reprint requests: Yevgeniy Semenov
Abby R. Rosenberg, MPHS1, Sara J. Weston, PhD2,3, Teresa Deshields, PhD4, Ryan C. Fields, MD5, Gerald P. Linette, MD, PhD6,7, Lynn A. Cornelius, MD1; Yevgeniy R. Semenov, MD, MA1 1
RI PT
Washington University School of Medicine in St. Louis, Division of Dermatology. Washington University in St. Louis, Department of Psychological and Brain Sciences. 3 Northwestern University, Department of Medical Social Sciences. 4 Washington University School of Medicine in St. Louis, Siteman Cancer Center Counseling Services. 5 Washington University School of Medicine in St. Louis, Department of Surgery. 6 Washington University School of Medicine in St. Louis, Division of Oncology. 7 Perelman School of Medicine, University of Pennsylvania, Division of Hematology and Oncology.
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Corresponding author: Yevgeniy Semenov, MD, MA Division of Dermatology Washington University School of Medicine 660 S. Euclid Ave Campus Box 8123 St. Louis, MO 63110 Phone: 443-791-3311 Fax: 314-362-8159 Email: [email protected]
SC
2
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Conflicts of Interest: The authors have no conflict of interest to declare.
Manuscript word count: 481 words References: 5 Figures: 0 Tables: 2 Attachments: Functional Assessment of Cancer Therapy – Melanoma (survey)
43
Melanoma QoL
ACCEPTED MANUSCRIPT 2 To the Editor: While the introduction of numerous immunotherapy and targeted therapy agents has led
45
to improved survival in advanced-stage melanoma over the past decade, these therapies have been
46
associated with severe adverse effects. Further, the overall impact of these therapies on quality of life
47
(QoL) is yet unknown, and few studies have investigated differences in QoL attainment of melanoma
48
patients by stage and treatment status.
RI PT
44
49
A consecutive sample of adults diagnosed with melanoma within the past 24 months was recruited from
51
Washington University School of Medicine clinics between June 2015 and June 2016. Eighty-seven
52
patients completed the Functional Assessment of Cancer Therapy – Melanoma (FACT-M), a validated
53
disease-specific QoL instrument.1 Using a validated mapping function, FACT-M scores were converted to
54
European Quality of Life-5 Dimensions (EQ-5D) scores, a generic health utility measure useful in
55
comparing to other populations.2 Patients were stratified by localized (stages 0-II) versus advanced
56
(stages III-IV) melanoma. Baseline comparisons were tested using ANOVA for continuous variables and
57
χ2 for categorical variables. Multivariate regression models, adjusted for demographic and clinical
58
variables, were used to estimate the association between melanoma stage and QoL outcomes. A series
59
of structural equation models were constructed to explore the extent to which systemic therapy status
60
mediated the relationship between melanoma stage and QoL. STATA version 14 (StataCorp, College
61
Station, Texas) was used for analyses.
M AN U
TE D
EP
AC C
62
SC
50
63
Our melanoma patient population achieved a lower mean EQ-5D score than their peers in the U.S.
64
general population (0.76 vs. 0.87, respectively).3 Melanoma patients achieved similar scores to patients
65
with coronary artery disease (0.73), diabetes mellitus (0.76), hypertension (0.79), arthritis (0.79), lung
66
cancer (0.80), and breast cancer (0.82).3,4
67
Melanoma QoL
ACCEPTED MANUSCRIPT 3 Localized melanoma patients had significantly higher overall FACT-M scores than advanced-stage
69
patients and performed better on all subscales except those corresponding to social and emotional well-
70
being (Table 1). Thus, the QoL disparity between localized and advanced melanoma patients was
71
primarily a consequence of physical rather than psychological factors.
72
RI PT
68
In sequential multivariable regression models (Table 2), advanced stage and systemic therapy were
74
significant predictors of lower QoL. Mediation analyses demonstrated that systemic therapy is
75
responsible for 75.5% of the association between stage and FACT-M score. Further, patients on targeted
76
therapy had overall the lowest QoL attainment in comparison to other systemic therapies and those not
77
on systemic therapy. In contrast, patients receiving single-agent immunotherapy had similar QoL to
78
those not receiving systemic therapy. These results suggest immunotherapy may be better tolerated
79
than targeted therapy.
M AN U
SC
73
TE D
80
While statistically significant, the magnitude of the EQ-5D disparity between advanced and localized
82
melanoma patients (0.04) was smaller than the minimally important difference of the instrument (0.07-
83
0.09).5 This suggests that the therapy-mediated QoL decline in advanced relative to localized melanoma
84
was below the threshold for concluding that two scores yield clinically disparate QoL outcomes. Thus,
85
we propose that the overall QoL impact of modern systemic therapies is minimal and is likely to be
86
outweighed by their proven survival benefit.
88
AC C
87
EP
81
89 90 91 Melanoma QoL
ACCEPTED MANUSCRIPT 4 92
References
93
1.
Cormier JN, Ross MI, Gershenwald JE, et al. Prospective assessment of the reliability, validity, and sensitivity to change of the functional assessment of cancer therapy-melanoma
95
questionnaire. Cancer. 2008;112:2249-2257. 2.
97
health utility weights. Value Heal. 2011;14:900-906. 3.
99 100
Chronic Conditions in the United States. Med Care Care. 2005;43:736-749. 4.
101 102 103
Sullivan PW, Lawrence WF, Ghushchyan V. A National Catalog of Preference-Based Scores for
SC
98
Askew RL, Swartz RJ, Xing Y, et al. Mapping FACT-melanoma quality-of-life scores to EQ-5D
Naik H, Howell D, Su S, et al. EQ-5D Health Utility Scores: Data from a Comprehensive Canadian
M AN U
96
Cancer Centre. Patient. 2017;10:105-115. 5.
Askew RL, Xing Y, Palmer JL, Cella D, Moye LA, Cormier JN. Evaluating minimal important differences for the FACT-melanoma quality of life questionnaire. Value Heal. 2009;12:1144-1150.
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105
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107
110
AC C
108 109
RI PT
94
111 112 113 114
Melanoma QoL
ACCEPTED MANUSCRIPT 5 Table 1. Baseline characteristics and univariate analyses stratified by stage. Early stage (N=44) 53.4 (15.8)
Advanced stage (N=43) 57.2 (15.5)
48 (55.2) 39 (44.8)
20 (45.4) 24 (54.6)
28 (65.1) 15 (34.9)
0.07
84 (96.6) 1 (1.1) 2 (2.3)
44 (100) 0 (0) 0 (0)
40 (93.0) 1 (2.3) 2 (4.7)
0.20
27 (31.0) 36 (41.4) 44 (27.6)
10 (22.7) 19 (43.2) 15 (34.1)
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Melanoma QoL
SC
RI PT
P Value 0.27
17 (39.5) 17 (39.5) 9 (20.9)
0.18
10.4 (7.5)
9.1 (7.8)
11.8 (7.1)
0.09
64 (73.6) 23 (26.4)
43 (97.7) 1 (2.3)
22 (50.0) 22 (50.0)
<0.001
9 (10.3) 78 (89.7)
41 (93.2) 3 (6.8)
37 (86.1) 6 (13.9)
0.28
39 (44.8) 48 (55.2)
29 (65.9) 15 (34.1)
19 (44.2) 24 (55.8)
0.04
7 (8.1) 80 (91.9)
1 (2.3) 43 (97.7)
6 (13.9) 37 (86.1)
0.05
23 (26.4) 64 (73.6)
10 (22.7) 34 (77.3)
13 (30.2) 30 (69.8)
0.43
24 (27.6) 63 (72.4)
11 (25.0) 33 (75.0)
13 (30.2) 30 (69.8)
0.59
24.4 (4.3) 23.7 (4.4) 18.5 (4.4) 22.4 (4.8) 55.2 (7.6) 28.2 (4.4) 143.9 (19.4) 0.76 (0.07)
25.8 (2.9) 23.3 (4.0) 18.9 (3.9) 23.6 (3.7) 57.1 (5.7) 29.6 (2.7) 148.5 (13.5) 0.77 (0.05)
23.0 (5.0) 24.3 (4.8) 18.0 (4.9) 21.1 (5.5) 53.3 (8.7) 26.7 (5.3) 139.1 (23.2) 0.74 (0.09)
0.002 0.29 0.35 0.02 0.02 0.002 0.02 0.02
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Characteristic Age, mean (SD), years Gender, N (%) Male Female Race, N (%) Non-Hispanic White Non-Hispanic Black Hispanic Estimated annual income, N (%) $25,000 - $50,000 $50,000 - $75,000 >$75,000 Time since diagnosis, mean (SD), months Treatment modality, N (%) No current systemic therapy Current systemic therapy Diabetes mellitus, N (%) Yes No Hypertension, N (%) Yes No Cardiovascular disease, N (%) Yes No Arthritis, N (%) Yes No Psychiatric disease, N (%) Yes No QoL, mean (SD) Physical well-being Social well-being Emotional well-being Functional well-being Melanoma-specific subscale Melanoma surgery subscale FACT-M EQ-5D
Total (N=87) 55.3 (15.7)
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ACCEPTED MANUSCRIPT 6
Table 2. Multivariate regression models of EQ5D scores by melanoma stage and systemic therapy status. Model Variable Coefficient 95% CI P Value Stage 1 Localized (N=44) ref1 ref1 ref1 -0.703, -0.007
0.016
No (N=64) Yes (N=23) Systemic therapy type2
ref1 -0.058
ref1 -0.092, -0.023
ref1 0.001
ref1
ref1
ref1
No systemic therapy (N=64) 3
Immunotherapy3 (N=11)
-0.036
4
RI PT
-0.039
SC
2
Advanced (N=43) Systemic therapy2
-0.084, 0.019
0.138
EP AC C
117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132
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Targeted therapy (N=7) -0.076 -0.133, -0.020 0.009 5 Combination or other (N=5) -0.072 -0.136, -0.009 0.026 1 Reference group 2 Most recently received within 12 months prior to questionnaire completion. 3 Modern immunotherapies included ipilimumab, pembrolizumab, nivolumab, durvalumab, seviprotimut-L, and T-Vec. 4 BRAF/MEK targeted therapies included dabrafenib, trametinib, vemurafenib, cobimetinib, and selumetinib. 5 Other systemic therapies included interferon-alpha, dacarbazine, and imatinib. All models adjusted for age, sex, estimated income, time since diagnosis, and history of diabetes mellitus, hypertension, cardiovascular disease, arthritis, and psychiatric disease.
Melanoma QoL