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      Changes in Health Care Costs, Survival, and Time Toxicity in the Era of Immunotherapy and Targeted Systemic Therapy for Melanoma

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          Key Points

          Question

          How have health care costs, survival, and time toxicity changed after the adoption of adjuvant and palliative immunotherapies and targeted therapies for melanoma?

          Findings

          This cohort study, which evaluated matched cohorts of 731 patients with melanoma, found a substantial increase in systemic therapy costs in 2018 to 2019 compared with 2007 to 2012. Survival improved for all stages in 2018 to 2019 compared with 2007 to 2012, and time toxicity was similar between eras.

          Meaning

          These data highlight the trade-off with new effective therapies, for which there are greater health care costs and time toxicity but an associated improvement in patient survival.

          Abstract

          This cohort study compares costs, survival, and time toxicity among patients with melanoma in 2007 to 2012 vs 2018 to 2019.

          Abstract

          Importance

          Melanoma treatment has evolved during the past decade with the adoption of adjuvant and palliative immunotherapy and targeted therapies, with an unclear impact on health care costs and outcomes in routine practice.

          Objective

          To examine changes in health care costs, overall survival (OS), and time toxicity associated with primary treatment of melanoma.

          Design, Setting, and Participants

          This cohort study assessed a longitudinal, propensity score (PS)–matched, retrospective cohort of residents of Ontario, Canada, aged 20 years or older with stages II to IV cutaneous melanoma identified from the Ontario Cancer Registry from January 1, 2018, to March 31, 2019. A historical comparison cohort was identified from a population-based sample of invasive melanoma cases diagnosed from the Ontario Cancer Registry from January 1, 2007, to December 31, 2012. Data analysis was performed from October 17, 2022, to March 13, 2023.

          Exposures

          Era of melanoma diagnosis (2007-2012 vs 2018-2019).

          Main Outcomes and Measures

          The primary outcomes were mean per-capita health care and systemic therapy costs (Canadian dollars) during the first year after melanoma diagnosis, time toxicity (days with physical health care contact) within 1 year of initial treatment, and OS. Standardized differences were used to compare costs and time toxicity. Kaplan-Meier methods and Cox proportional hazards regression were used to compare OS among PS-matched cohorts.

          Results

          A PS-matched cohort of 731 patients (mean [SD] age, 67.9 [14.8] years; 437 [59.8%] male) with melanoma from 2018 to 2019 and 731 patients (mean [SD] age, 67.9 [14.4] years; 440 [60.2%] male) from 2007 to 2012 were evaluated. The 2018 to 2019 patients had greater mean (SD) health care (including systemic therapy) costs compared with the 2007 to 2012 patients ($47 886 [$55 176] vs $33 347 [$31 576]), specifically for stage III ($67 108 [$57 226] vs $46 511 [$30 622]) and stage IV disease ($117 450 [$79 272] vs $47 739 [$37 652]). Mean (SD) systemic therapy costs were greater among 2018 to 2019 patients: stage II ($40 823 [$40 621] vs $10 309 [$12 176]), III ($55 699 [$41 181] vs $9764 [$12 771]), and IV disease ($79 358 [$50 442] vs $9318 [$14 986]). Overall survival was greater for the 2018 to 2019 cohort compared with the 2007 to 2012 cohort (3-year OS: 74.2% [95% CI, 70.8%-77.2%] vs 65.8% [95% CI, 62.2%-69.1%], hazard ratio, 0.72 [95% CI, 0.61-0.85]; P < .001). Time toxicity was similar between eras. Patients with stage IV disease spent more than 1 day per week (>52 days) with physical contact with the health care system by 2018 to 2019 (mean [SD], 58.7 [43.8] vs 44.2 [26.5] days; standardized difference, 0.40; P = .20).

          Conclusions and Relevance

          This cohort study found greater health care costs in the treatment of stages II to IV melanoma and substantial time toxicity for patients with stage IV disease, with improvements in OS associated with the adoption of immunotherapy and targeted therapies. These health system–wide data highlight the trade-off with adoption of new therapies, for which there is a greater economic burden to the health care system and time burden to patients but an associated improvement in survival.

          Related collections

          Most cited references53

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          Cancer Statistics, 2021

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.
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            Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

            An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
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              Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer

              Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown.
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                Author and article information

                Journal
                JAMA Dermatol
                JAMA Dermatol
                JAMA Dermatology
                American Medical Association
                2168-6068
                2168-6084
                6 September 2023
                November 2023
                6 September 2023
                : 159
                : 11
                : 1195-1204
                Affiliations
                [1 ]Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
                [2 ]Division of General Surgery, University of Toronto, Toronto, Ontario, Canada
                [3 ]Division of Surgical Oncology, Department of Surgery, University of Alabama at Birmingham
                [4 ]ICES at Queen’s University, Kingston, Ontario, Canada
                [5 ]Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada
                [6 ]Department of Otolaryngology–Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada
                [7 ]Health Outcomes and PharmacoEconomics (HOPE) Research Centre, Sunnybrook Research Institute, Toronto, Ontario, Canada
                [8 ]Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
                [9 ]Division of Cancer Care and Epidemiology, Queen’s Cancer Research Institute, Kingston, Ontario, Canada
                [10 ]Department of Public Health Sciences, Queen’s University, Kingston, Ontario, Canada
                [11 ]Division of Hematology, Oncology, & Transplantation, University of Minnesota, Minneapolis
                [12 ]Department of Oncology, Queen’s University, Kingston, Ontario, Canada
                Author notes
                Article Information
                Accepted for Publication: June 27, 2023.
                Published Online: September 6, 2023. doi:10.1001/jamadermatol.2023.3179
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 Bateni SB et al. JAMA Dermatology.
                Corresponding Author: Timothy P. Hanna, MD, PhD, Division of Cancer Care and Epidemiology, Cancer Research Institute at Queen’s University, 10 Stuart St, Second Level, Kingston, ON K7L 3N6, Canada ( tim.hanna@ 123456kingstonhsc.ca ).
                Author Contributions: Dr Hanna had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Hanna and Look Hong contributed equally to this work as co–senior authors.
                Concept and design: Bateni, Nguyen, Mittmann, Look Hong, Hanna.
                Acquisition, analysis, or interpretation of data: Bateni, Nguyen, Eskander, Seung, Jalink, Gupta, Chan, Look Hong, Hanna.
                Drafting of the manuscript: Bateni, Nguyen, Jalink, Hanna.
                Critical review of the manuscript for important intellectual content: Bateni, Eskander, Seung, Mittmann, Jalink, Gupta, Chan, Look Hong, Hanna.
                Statistical analysis: Nguyen, Eskander, Hanna.
                Obtained funding: Hanna.
                Administrative, technical, or material support: Nguyen, Seung, Mittmann, Jalink, Hanna.
                Supervision: Look Hong, Hanna.
                Conflict of Interest Disclosures: Dr Mittmann reported being a full-time employee of the Canadian Agency for Drugs and Technologies in Health outside the submitted work. Dr Look Hong reported being a surgical consultant for Molli outside the submitted work. No other disclosures were reported.
                Funding/Support: This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. Dr Hanna holds a research chair provided by the Ontario Institute for Cancer Research through grant IA-035 provided by the Government of Ontario.
                Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Disclaimer: The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by the Canadian Institute for Health Information. However, the analyses, conclusions, opinions, and statements expressed in the material are those of the author(s) and not necessarily those of the Canadian Institute for Health Information. Parts of this material are based on data and information provided by Ontario Health (OH). The opinions, results, views, and conclusions reported in this article are those of the authors and do not necessarily reflect those of OH. No endorsement by OH is intended or should be inferred.
                Data Sharing Statement: See Supplement 2.
                Additional Contributions: We thank IQVIA Solutions Canada Inc for use of their Drug Information File.
                Article
                doi230041
                10.1001/jamadermatol.2023.3179
                10483386
                37672282
                62d2fb9b-22e5-4bdb-9f4f-b5633f8824e8
                Copyright 2023 Bateni SB et al. JAMA Dermatology.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 14 April 2023
                : 27 June 2023
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                Research
                Research
                Original Investigation
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