• Association of Disease Recurrence With Survival Outcomes in Patients With Cutaneous Squamous Cell Carcinoma of the Head and Neck Treated With Multimodality Therapy

      Sun, Lillian; Chin, Re-I; Gastman, Brian; Thorstad, Wade; Yom, Sue S; Reddy, Chandana A; Nussenbaum, Brian; Wang, Steven J; Knackstedt, Thomas; Vidimos, Allison T; et al. (AMER MEDICAL ASSOC, 2019-04-01)
      IMPORTANCE It has previously been demonstrated that immunosuppressed patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) treated with surgery and postoperative radiotherapy have significantly inferior disease-related outcomes compared with immunocompetent patients, but data on outcomes after disease recurrence are limited. OBJECTIVES To report survival outcomes in patients with cSCC-HN after disease recurrence after surgery and postoperative radiotherapy and to investigate the association of immune status with disease-related outcomes. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional study of 205 patients treated at the Cleveland Clinic, Washington University in St Louis, and the University of California, San Francisco, in which patients who underwent surgical resection and postoperative radiotherapy for primary or recurrent stage I to IV (nonmetastatic) cSCC-HN between January 1, 1995, and December 31, 2014, were identified. Patients with any disease recurrence, defined as local, regional, and/or distant failure, were included. Patients were categorized as immunosuppressed if they received a diagnosis of chronic hematologic malignant neoplasm or HIV or AIDS, or were treated with immunosuppressive therapy for organ transplantation 6 months or more before diagnosis. Statistical analysis was conducted from January 1, 1995, to December 31, 2015. MAIN OUTCOMES AND MEASURES Overall survival calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS Of the 205 patients in the original cohort, 72 patients (63 men and 9 women; median age, 71 years [range, 43-91 years]) developed disease recurrence after surgery and postoperative radiotherapy. Forty patients (55.6%) were immunosuppressed, and 32 patients (44.4%) were immunocompetent. Locoregional recurrence was the most common first pattern of failure for both groups (31 immunosuppressed patients [77.5%]; 21 immunocompetent patients [65.6%]). After any recurrence, 1-year overall survival was 43.2%(95% CI, 30.9%-55.4%), and median survival was 8.4 months. For patients for whom information on salvage treatment was available (n = 45), those not amenable to surgical salvage had significantly poorer median cumulative incidence of survival compared with those who were amenable to surgical salvage (4.7 months; 95% CI, 3.7-7.0 months vs 26.1 months; 95% CI, 6.6 months to not reached; P=.01), regardless of their immune status. CONCLUSIONS AND RELEVANCE Results of this study suggest that patients with cSCC-HN who experience disease recurrence after definitive treatment with surgery and postoperative radiotherapy have poor survival, irrespective of immune status. Survival rates are low for patients with recurrent disease that is not amenable to surgical salvage. The low rate of successful salvage underscores the importance of intensifying upfront treatment to prevent recurrence.
    • Benefits and Harms of Omalizumab Treatment in Adolescent and Adult Patients With Chronic Idiopathic (Spontaneous) Urticaria: A Meta-analysis of "Real-world" Evidence

      Tharp, Michael D; Bernstein, Jonathan A; Kavati, Abhishek; Ortiz, Benjamin; MacDonald, Karen; Denhaerynck, Kris; Abraham, Ivo; Lee, Christopher S; Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci; Univ Arizona, Dept Family & Community Med, Coll Med (AMER MEDICAL ASSOC, 2018-11-14)
      IMPORTANCE Omalizumab is indicated for the management of chronic idiopathic urticaria (CIU) (also known as chronic spontaneous urticaria) in adolescents and adults with persistent hives not controlled with antihistamines. The effectiveness of omalizumab in the real-world management of CIU is largely unknown. OBJECTIVE To quantitatively synthesize what is known about the benefits and harms of omalizumab in the real-world clinical management of CIU regarding urticaria activity, treatment response, and adverse events. DATA SOURCES Published observational studies (January 1, 2006, to January 1, 2018) and scientific abstracts on the effectiveness of omalizumab in CIU were identified using PubMed, Embase, Web of Science, and Cochrane search engines; references were searched to identify additional studies. STUDY SELECTION Included studies were observational in design and included at least 1 outcome in common with other studies and at a concurrent time point of exposure to omalizumab. A total of 67 articles (35.2% of those screened) were included in the analysis. DATA EXTRACTION AND SYNTHESIS PRISMA and MOOSE guidelines were followed; independent selection and data extraction were completed by 2 observers. Random-effects meta-analyses were performed. MAIN OUTCOMES AND MEASURES Main outcomes were change in weekly Urticaria Activity Score (UAS7; range, 0-42), change in Urticaria Activity Score (UAS; range 0-6) (higher score indicating worse outcome in both scales), complete and partial response rates (percentages), and adverse event rate (percentage). RESULTS Omalizumab therapy was associated with an improvement in UAS7 scores (-25.6 points, 95% CI, -28.2 to -23.0; P < .001; 15 studies, 294 patients), an improvement in UAS scores (-4.7 points, 95% CI, -5.0 to -4.4, P < .001; 10 studies, 1158 patients), an average complete response rate of 72.2% (95% CI, 66.1%-78.3%; P<.001; 45 studies, 1158 patients) with an additional average partial response rate of 17.8% (95% CI, 11.7%-23.9%; P <.001; 37 studies, 908 patients), and an average adverse event rate of 4.0% (95% CI, 1.0%-7.0%; P<.001; any level of severity, 47 studies, 1314 patients). CONCLUSIONS AND RELEVANCE Benefits and safety of omalizumab in the real-world treatment of CIU meet or exceed results gleaned from clinical trials. These real-world data on omalizumab in CIU may help inform both clinical treatment expectations and policy decision making.
    • Core Outcome Set for Actinic Keratosis Clinical Trials

      Reynolds, Kelly A; Schlessinger, Daniel I; Vasic, Jelena; Iyengar, Sanjana; Qaseem, Yaqoob; Behshad, Ramona; DeHoratius, Danielle M; Denes, Pablo; Drucker, Aaron M; Dzubow, Leonard M; et al. (AMER MEDICAL ASSOC, 2020-01-15)
      Question What are the most important outcomes to report in clinical trials on actinic keratosis? Findings In this survey study including physician and patient stakeholders (33 in round 1 and 29 in round 2), a consensus was reached regarding a core set of 6 of 137 outcomes and domains of actinic keratosis: complete clearance of actinic keratoses, percentage of actinic keratoses cleared, severity of adverse events, patient perspective on effectiveness, patient-reported future treatment preference, and rate of recurrence. Meaning In studies of treatment of actinic keratosis, the recommended core outcomes should be reported as a minimum to facilitate comparison of results across studies. This survey study assesses the most important outcomes to report in clinical trials on actinic keratosis based on Delphi surveys completed by physician and patient stakeholders. Importance Although various treatments have been found in clinical trials to be effective in treating actinic keratosis (AK), researchers often report different outcomes. Heterogeneous outcome reporting precludes the comparison of results across studies and impedes the synthesis of treatment effectiveness in systematic reviews. Objective To establish an international core outcome set for all clinical studies on AK treatment using systematic literature review and a Delphi consensus process. Evidence Review Survey study with a formal consensus process. The keywords actinic keratosis and treatment were searched in PubMed, Embase, CINAHL, and the Cochrane Library to identify English-language studies investigating AK treatments published between January 1, 1980, and July 13, 2015. Physician and patient stakeholders were nominated to participate in Delphi surveys by the Measurement of Priority Outcome Variables in Dermatologic Surgery Steering Committee members. All participants from the first round were invited to participate in the second round. Outcomes reported in randomized controlled clinical trials on AK treatment were rated via web-based e-Delphi consensus surveys. Stakeholders were asked to assess the relative importance of each outcome in 2 Delphi survey rounds. Outcomes were provisionally included, pending the final consensus conference, if at least 70% of patient or physician stakeholders rated the outcome as critically important in 1 or both Delphi rounds and the outcome received a mean score of 7.5 from either stakeholder group. Data analysis was performed from November 5, 2018, to February 27, 2019. Findings A total of 516 outcomes were identified by reviewing the literature and surveying key stakeholder groups. After deduplication and combination of similar outcomes, 137 of the 516 outcomes were included in the Delphi surveys. Twenty-one physicians and 12 patients participated in round 1 of the eDelphi survey, with 17 physicians (81%) retained and 12 patients (100%) retained in round 2. Of the 137 candidate outcomes, 9 met a priori Delphi consensus criteria, and 6 were included in the final outcomes set after a consensus meeting: complete clearance of AKs, percentage of AKs cleared, severity of adverse events, patient perspective on effectiveness, patient-reported future treatment preference, and recurrence rate. It was recommended that treatment response be assessed at 2 to 4 months and recurrence at 6 to 12 months, with the AK rate of progression to cutaneous squamous cell carcinoma reported whenever long-term follow-up was possible. Conclusions and Relevance Consensus was reached regarding a core outcome set for AK trials. Further research may help determine the specific outcome measures used to assess each of these outcomes.
    • Economic Evaluation of Talimogene Laherparepvec Plus Ipilimumab Combination Therapy vs Ipilimumab Monotherapy in Patients With Advanced Unresectable Melanoma

      Almutairi, Abdulaali R; Alkhatib, Nimer S; Oh, Mok; Curiel-Lewandrowski, Clara; Babiker, Hani M; Cranmer, Lee D; McBride, Ali; Abraham, Ivo; Univ Arizona, Coll Pharm, Ctr Hlth Outcomes & PharmacoEcon Res; Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci; et al. (AMER MEDICAL ASSOC, 2019-01-01)
      IMPORTANCE. A phase 2 trial comparing talimogene laherparepvec plus ipilimumab vs ipilimumab monotherapy in patients with advanced unresectable melanoma found no differential benefit in progression-free survival (PFS) but noted objective response rates (ORRs) of 38.8% (38 of 98 patients) vs 18.0% (18 of 100 patients), respectively. OBJECTIVE To perform an economic evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy. DESIGN, SETTING, AND PARTICIPANTS For PFS, cost-effectiveness and cost-utility analyses using a 2-state Markov model (PFS vs progression or death) was performed. For ORRs, cost-effectiveness analysis of the incremental cost of 1 additional patient achieving objective response was performed. In this setting based on a US payer perspective (2017 US dollars), participants were patients with advanced unresectable melanoma. MAIN OUTCOMES AND MEASURES The PFS life-years and PF5 quality-adjusted life-years were determined, and the associated incremental cost-effectiveness ratios (ICERs) and incremental cost-utility ratios (ICURs) were estimated. Also estimated was the ICER per 1 additional patient (out of 100 treated patients) achieving objective response. Base-case analyses were validated by sensitivity analyses. RESULTS In PFS analyses, the cost of talimogene laherparepvec plus ipilimumab ($494 983) exceeded the cost of ipilimumab monotherapy ($132 950) by $362 033. The ICER was $2 129 606 per PFS life-years, and the ICUR was $2 262 706 per PFS quality-adjusted life-year gained. Probabilistic sensitivity analyses yielded an ICER of $1 481 208 per PFS life-year gained and an ICUR of $1 683 191 per PFS quality-adjusted life-year gained. In 1-way sensitivity analyses, the PFS hazard ratio and the utility of response were the most influential parameters. Talimogene laherparepvec plus ipilimumab has a 50% likelihood of being cost-effective at a willingness-to-pay threshold of $1 683 191 per PFS quality-adjusted life-year gained. In ORR analyses, talimogene laherparepvec plus ipilimumab ($474 904) vs ipilimumab alone ($132 810), a $342 094 difference, yielded an ICER of $1 629 019 per additional patient achieving objective response. In subgroup analyses by disease stage and BRAF(V600E) mutation status, ICERs ranged from $1 069 044 to $17 104 700 per 1 additional patient achieving objective response. CONCLUSIONS AND RELEVANCE The cost to gain 1 additional progression-free quality-adjusted life-year, 1 additional progression-free life-year, or to have 1 additional patient attain objective response is about $1.6 million. This amount may be beyond what payers typically are willing to pay. Combination therapy of talimogene laherparepvec plus ipilimumab does not offer an economically beneficial treatment option relative to ipilimumab monotherapy at the population level. This should not preclude treatment for individual patients for whom this regimen may be indicated.