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Objectives: Nivolumab is approved as adjuvant therapy for resected stage III/IV melanoma based on the phase 3 CheckMate 238 trial. This analysis compared outcomes from CheckMate 238 with those from the real-world Flatiron Health electronic health record-derived de-identified database in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab., Materials: Outcomes included baseline characteristics, overall survival (OS) in the CheckMate 238 cohort (randomization until death or last known alive), and real-world overall survival (rwOS) in the Flatiron Health cohort (nivolumab initiation until death or data cutoff). rwOS was compared with OS using unadjusted and adjusted Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was combined with the adjusted model to reduce baseline discrepancies., Results: The CheckMate 238 and real-world cohorts included 369 and 452 patients, respectively (median age, 56.0 and 63.0 years; median follow-up, 61.4 vs. 25.5 months). rwOS was not different from OS in the unadjusted (hazard ratio [HR] 1.27; 95% CI 0.92-1.74), adjusted (HR 1.01; 95% CI 0.67-1.54), and adjusted IPTW (HR 1.07; 95% CI 0.70-1.63) analyses. In the adjusted analysis, 2-year OS and rwOS rates were 84%. Median OS and rwOS were not reached. After IPTW, OS and rwOS were not different (HR 1.07; 95% CI 0.70-1.64)., Conclusions: In this comparative analysis, OS in the CheckMate 238 trial was similar to rwOS in the Flatiron Health database after adjustments in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab, validating the trial results., (© 2024. The Author(s).)

Aim: To evaluate the cost-effectiveness of adjuvant nivolumab compared with surveillance for the treatment of patients with high-risk muscle-invasive urothelial carcinoma (MIUC) after radical resection from a US healthcare payer perspective and to investigate the impact of alternative modeling approaches on the cost-effectiveness results., Material and Methods: A four-state, semi-Markov model consisting of disease free, local recurrence, distant recurrence, and death health states was developed to investigate the cost-effectiveness of nivolumab compared with surveillance over a 30-year time horizon. The model used data from the randomized CheckMate 274 trial (NCT02632409) and published literature to inform transitions among health states, and inputs on cost, utility, adverse event, and disease management. Scenario analyses were conducted to investigate the impact of model structure and key assumptions on the results. One-way deterministic and probabilistic sensitivity analysis were conducted to investigate the robustness of the results., Results: Total expected costs were higher with nivolumab ($162,278) compared with surveillance ($63,027). Nivolumab was associated with improved survival (1.61 life-years gained compared with surveillance) and an incremental gain of 0.98 quality-adjusted life-years (QALYs). Although total treatment costs were higher for nivolumab, cost offsets were observed because of delayed or avoided recurrences and deaths experienced with nivolumab compared with observation. The incremental cost-effectiveness and cost-utility ratios were $61,462/life-year and $100,930/QALY., Limitations: At the time of analysis, CheckMate 274 had limited follow-up on disease-free survival and no overall survival data. The limited evidence necessitated assumptions on modeling survival after each type of recurrence., Conclusions: Nivolumab is estimated to be a life-extending and cost-effective option for adjuvant treatment of MIUC for patients who are at high risk of recurrence after undergoing radical resection in the United States. Using a threshold of $150,000/QALY, the cost-effectiveness conclusions remained consistent across the scenario and sensitivity analyses conducted.

Aims: To present alternative approaches related to both structural assumptions and data sources for the development of a decision analytic model for evaluating the cost-effectiveness of adjuvant nivolumab compared with surveillance in patients with high-risk muscle-invasive urothelial carcinoma (MIUC) after radical resection., Methods and Results: Alternative approaches related to both structural assumptions and data sources are presented to address challenges and data gaps, as well as discussion of strengths and limitations of each approach. Specifically, challenges and considerations related to the following are presented: (1) selection of a modeling approach (partitioned survival model or state transition model) given the available evidence, (2) choice of health state structure (three- or four-state) to model disease progression and subsequent therapy, (3) modeling of outcomes from subsequent therapy using tunnel states to account for time-dependent transition probabilities or absorbing health states with one-off costs and outcomes applied, and (4) methods for modeling health-state transitions in a setting where treatment has curative intent and available survival data are immature., Conclusions: Multiple considerations must be taken into account when developing an economic model for new, emerging oncology treatments in early lines of therapy, all of which can affect the model's overall ability to estimate (quality-adjusted) survival benefits over a lifetime horizon. This paper identifies a series of key structural and analytic considerations regarding modeling of nivolumab treatment in the adjuvant MIUC setting. Several alternative approaches with regard to structure and data have been included in a flexible cost-effectiveness model so the impact of the alternative approaches on model results can be explored. The impact of these alternative approaches on cost-effectiveness results are presented in a companion article. Our findings may also help inform the development of future models for other treatments and settings in early-stage cancer.

Background: Recurrence-free survival (RFS) and overall survival (OS) data for adjuvant nivolumab versus placebo (proxy for routine surveillance) in patients with high-risk, resected melanoma are lacking. This post hoc, indirect treatment comparison (ITC) used pooled data from the phase 3 EORTC 18,071 (ipilimumab vs. placebo) and CheckMate 238 (nivolumab vs. ipilimumab) trials to assess RFS and OS with nivolumab versus placebo and the numbers needed to treat (NNT) over 4 years., Methods: Patients with resected stage IIIB-C cutaneous melanoma (American Joint Committee on Cancer seventh edition) were included. Inverse probability treatment weighting (IPTW) was used to balance baseline characteristics. RFS NNTs were calculated for nivolumab versus ipilimumab and placebo. OS NNTs were calculated for nivolumab versus placebo. To adjust for different post-recurrence treatments, the difference in post-recurrence survival between the two ipilimumab arms was added to OS of the placebo arm., Results: This ITC included 278, 643, and 365 patients treated with nivolumab, ipilimumab, and placebo, respectively. Following IPTW, nivolumab was associated with improved RFS versus placebo (hazard ratio [HR]: 0.49; 95% confidence interval [CI] 0.39-0.61) and ipilimumab (HR: 0.69; 95% CI 0.56-0.85). RFS NNT was 4.2 for nivolumab versus placebo and 8.9 for nivolumab versus ipilimumab. After post-recurrence survival adjustment, weighted 4-year OS rates were 75.8% for nivolumab and 64.1% for placebo; OS NNT for nivolumab versus placebo was 8.5., Conclusions: In patients with resected stage IIIB-C cutaneous melanoma in this ITC, nivolumab improved RFS versus placebo and ipilimumab, and OS versus placebo after post-recurrence survival adjustment., (© 2022. The Author(s).)

The most recent successful advances in lung cancer therapy have directly and increasingly focused on personalized tumor genetic/epigenetic/immunologic profiling, and the identification and development of novel pharmacologic agents aimed at those mutations [e.g., epidermal growth factor receptor (EGFR), Kristen rat sarcoma viral oncogene homolog (KRAS), anaplastic lymphoma kinase (ALK) and immunotherapy against programmed cell death protein 1 (PD-1) and its ligands] which have extended life and provided palliation for lung cancer-patients positive for these mutations. The objective of this study is to provide a review of the large number of drugs and their efficacy as of 2022, for lung cancer, but also introduce a novel treatment that has the potential, based on one controlled murine lung cancer study and 5 anecdotal human cases, that showed marked palliative and longevity benefits in very advanced lung cancer with no other treatment options, i.e., progesterone receptor (PR) antagonists targeting the immunosuppressive protein, the progesterone induced blocking factor (PIBF). Credibility, however, will only be provided when the efficacy can be demonstrated in a large series of lung cancer cases ideally with certain controls. Thus, the ultimate objective of the review is to interest oncologists with a large population of lung cancer patients to perform a well powered study to corroborate or refute the limited experience to date with PR antagonist therapy., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Nivolumab at a dose of 480 mg every 4 weeks (Q4W) is approved for the adjuvant treatment of melanoma. However, real-world data on this regimen are limited in this setting., Methods: This retrospective observational study utilized data from the US Oncology Network iKnowMed electronic health record database and patient medical charts. Eligible patients were diagnosed with melanoma and received adjuvant nivolumab monotherapy from March to August 2018. Patients were grouped by dosing regimen: cohort 1 (C1), de novo nivolumab 480 mg Q4W; cohort 2 (C2), switched to nivolumab 480 mg Q4W after nivolumab 240 mg or 3 mg/kg every 2 weeks (Q2W); cohort 3 (C3), de novo nivolumab 3 mg/kg Q2W; or cohort 4 (C4), de novo nivolumab 240 mg Q2W. Patients were followed for up to 12 months. Duration of therapy and safety/tolerability were assessed., Results: One hundred ninety-one patients were included (C1, n = 40; C2, n = 74; C3, n = 22; C4, n = 55). Duration of therapy was relatively consistent across cohorts (median, 10.3 months; range, 8.3-10.7). Likewise, proportions of patients experiencing treatment-related adverse events (TRAEs) were similar (range, 54.5%-60.1%), as were the most common events (fatigue, rash, diarrhea, hypothyroidism, nausea, and pruritus). However, proportions experiencing 'significant' TRAEs varied between cohorts. Proportions discontinuing treatment were relatively consistent across cohorts. Propensity score matching and sensitivity analyses generally supported the unadjusted findings., Conclusions: Real-world safety profiles of nivolumab 240 mg Q2W and 480 mg Q4W were similar, and both were comparable to the well-documented safety of weight-based dosing (3 mg/kg Q2W), further supporting their approval and use in the adjuvant setting for melanoma., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Adherence to adjuvant therapy is crucial for effective disease management in patients with resected melanoma. This study assessed patient-reported adherence to adjuvant therapy and identified behavioral/belief constructs associated with adherence in patients with resected melanoma., Methods: Patients with resected stage III/IV melanoma were recruited through the Melanoma Research Foundation and a patient panel to complete an online survey. Patient characteristics, medical history, and adherence to therapy were captured. In accordance with the theory of planned behavior (TPB), the survey measured behavioral, normative, and control beliefs, and intention to adhere to therapy. Structural equation modeling (SEM) examined their relationships with adherence., Results: Among all patients who received adjuvant therapy and completed the survey (n = 184), 69% received intravenous and 31% received oral therapy; the majority (85.3%) were somewhat involved in deciding to start therapy. Mean age was 45 years, 44% of patients were female, and 83% had stage III/IV disease at diagnosis. Patients had a mean disease duration of 1.5 years, a time since complete resection of 10 months, and an adjuvant therapy duration of 8 months. Adherence to adjuvant therapy was high overall and higher with intravenous than with oral therapy (98.4% versus 91.2%, P = 0.002). All underlying TPB constructs were significant in the SEM model, which explained 60.3% of the variance in intention to adhere. Control beliefs had the strongest association with intention to adhere (standardized estimate = 0.47, P < 0.001) and intravenous therapy was associated with greater adherence than oral therapy (standardized estimate = 0.26, P < 0.001)., Conclusions: This study found that patients with resected melanoma are highly engaged in the decision to initiate systemic adjuvant therapy, with an overall high adherence rate to prescribed adjuvant treatment. Enhancing patients' view of their capability to adhere to treatments may further improve the adherence rate to melanoma adjuvant therapy., (© 2022. The Author(s).)

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a significant concern for patients with thymic epithelial tumors (TETs) due to defects in immune tolerance. An increased risk of skeletal and cardiac muscle inflammation following treatment with ICIs is well recognized in patients with advanced TETs. However, uncommon musculoskeletal and rheumatic complications can also occur. The cases presented in this report highlight the spectrum of presentation of immune-mediated, joint-predominant musculoskeletal adverse events in patients with advanced TETs treated with ICIs, including polymyalgia rheumatica-like illness and inflammatory arthritis., (Published by Oxford University Press 2022.)

Purpose: To examine the benefit of telehealth over current delivery options in oncology practices without genetic counselors., Methods: Participants meeting cancer genetic testing guidelines were recruited to this multi-center, randomized trial comparing uptake of genetic services with remote services (telephone or videoconference) to usual care in six predominantly community practices without genetic counselors. The primary outcome was the composite uptake of genetic counseling or testing. Secondary outcomes compare telephone versus videoconference services., Results: 147 participants enrolled and 119 were randomized. Eighty percent of participants in the telehealth arm had genetic services as compared to 16% in the usual care arm (OR 30.52, p < 0.001). Five genetic mutation carriers (6.7%) were identified in the telehealth arm, compared to none in the usual care arm. In secondary analyses, factors associated with uptake were lower anxiety (6.77 vs. 8.07, p = 0.04) and lower depression (3.38 vs. 5.06, p = 0.04) among those who had genetic services. There were no significant differences in change in cognitive or affective outcomes immediately post-counseling and at 6 and 12 months between telephone and videoconference arms., Conclusion: Telehealth increases uptake of genetic counseling and testing at oncology practices without genetic counselors and could significantly improve identification of genetic carriers and cancer prevention outcomes., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background/aim: It has been hypothesized that many, or even most cancers, utilize a unique immunomodulatory protein, called the progesterone induced blocking factor (PIBF) to allow spread of the cancer. Support for this concept has been provided by cancer cell line studies showing that PIBF is produced by these cancer cells and mifepristone suppresses this protein and inhibits proliferation of these cells. Furthermore, controlled murine studies with several spontaneous different types of cancer showed a clear beneficial effect of mifepristone over placebo control. Finally, there have been a variety of anecdotal reports showing efficacy of mifepristone in providing increased length and quality of life in patients with different types of advanced cancers., Case Report: Single agent mifepristone was found to provide significant palliative benefit for a 51-year-old male whose metastatic advanced fibroblastic osteosarcoma progressed despite surgery, radiotherapy, multiagent chemotherapy, and targeted therapy., Conclusion: Thus, osteosarcoma can be added to the list of cancers, not necessarily associated with the classic nuclear progesterone receptor, that seem to respond to progesterone receptor antagonist therapy., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The AMPLIFY trial found significantly lower major bleeding (MB) and similar recurrent venous thromboembolism (VTE) risks associated with apixaban vs warfarin among patients with VTE., Objectives: To compare MB, clinically-relevant non-major (CRNM) bleeding, and recurrent VTE risks among clinically-relevant subgroups of newly diagnosed elderly patients with VTE prescribed apixaban vs warfarin., Methods: US Medicare patients prescribed apixaban or warfarin within 30 days post-VTE encounter were identified. Propensity score matching (PSM) was used to control for patient characteristics. Cox models were used to assess MB, CRNM bleeding, and recurrent VTE. Subgroup analyses were conducted for index VTE encounter type, index VTE diagnosis type, index VTE etiology, sex, and frailty., Results: Post-PSM, 11,363 matched pairs of patients prescribed apixaban or warfarin were identified. Apixaban had lower MB (Hazard Ratio [HR]:0.76; 95% CI:0.64-0.91) and similar recurrent VTE risks (HR:1.04; 95% CI:0.75-1.43) vs warfarin. No significant interactions were observed between treatment and index VTE encounter type, index VTE diagnosis type, or sex for risk of MB, CRNM bleeding, or recurrent VTE. Significant interactions: frail patients prescribed apixaban had a 15% lower, while non-frail patients prescribed apixaban had 32% lower CRNM bleeding risk vs those prescribed warfarin. Patients with provoked VTE prescribed apixaban trended toward a higher, while those with unprovoked VTE trended toward a lower risk of recurrent VTE vs patients prescribed warfarin., Conclusions: Apixaban was associated with significantly lower risks of MB and CRNM bleeding, and similar risk of recurrent VTE as compared with warfarin across the overall population and most subgroups., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: There is evidence that a unique immunomodulatory protein, known as the progesterone induced blocking factor (PIBF), is utilized by a large variety of cancers to escape immune surveillance. Mifepristone, a progesterone receptor antagonist/modulator, anecdotally, has been found to increase both length and quality of life in many different types of advanced cancers., Case Report: Though there was one previous case of pancreatic cancer that showed a significant reduction in pain for the one month she took mifepristone before changing to an experimental drug, the case presented here provided much greater evidence that this drug can markedly improve both length and quality of life, in at least some patients, with very advanced pancreatic cancer., Conclusion: It is hoped that this case report will influence others to prescribe mifepristone off-label and hopefully substantiate this finding of marked palliative benefit in the majority of a larger series of patients., (Copyright © 2020 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Real-world data on recurrence and economic burden in patients with resected early-stage melanoma are limited. The objective of this study was to assess real-world recurrence rates, risk factors for recurrence, and costs of recurrence in patients with resected stage IIB, IIC, or IIIA melanoma in the USA., Methods: This retrospective analysis included patients with resected stage IIB, IIC, or IIIA melanoma (American Joint Committee on Cancer staging manual, seventh edition) in the Surveillance, Epidemiology, and End Results (SEER) program-Medicare database of the National Cancer Institute. Recurrence rates and healthcare costs (2018 USD) after recurrence were assessed., Results: Two-year recurrence rates for stages IIB, IIC, and IIIA melanoma were 29, 44, and 46%, respectively. In patients with stage IIB or IIC disease, the odds of recurrence were significantly higher in those aged > 75 years [odds ratio (OR) 1.853, 95% confidence interval (CI) 1.416, 2.425], with ulceration (OR 1.771; 95% CI 1.293, 2.425), or with a higher Charlson Comorbidity Index (OR 1.244; 95% CI 1.129, 1.372); however, the odds of recurrence were significantly lower in those with T3 staging (OR 0.522; 95% CI  0.393, 0.695). In those with stage IIIA melanoma, superficial spreading was associated with significantly lower odds of recurrence (OR 0.178; 95% CI 0.053, 0.601). Following recurrence, mean healthcare costs at 1 year were $31,870 for patients with stage IIB or IIC melanoma and $29,224 for those with stage IIIA melanoma., Conclusion: The SEER data show that a substantial proportion of adults with early-stage melanoma experience a recurrence within 2 years following resection, resulting in a significant economic burden to the US healthcare system. Dermatologists can distinguish patients with resected early-stage melanoma who are at a high risk for recurrence and consider referrals to medical oncologists for approved adjuvant therapy or enrollment in clinical trials after surgical resection to reduce the recurrence of melanoma.

Objectives: To compare the risks of 1-month all-cause, major bleeding (MB)-related and stroke-related readmissions and the associated hospital resource use and costs among patients previously hospitalized for nonvalvular atrial fibrillation (NVAF) and treated with warfarin, rivaroxaban, and dabigatran vs apixaban. Methods: Adult patients hospitalized with NVAF (any discharge diagnosis position) who received apixaban, warfarin, rivaroxaban, or dabigatran during hospitalization were identified from the Premier database (1 January 2013-30 June 2017) and grouped into respective cohorts. Propensity score matching was used to generate cohorts with similar characteristics. In regression analyses the risk of readmissions that occurred within 1 month of discharge were evaluated and the associated length of stay (LOS) and costs compared. Results: NVAF patients treated with warfarin vs apixaban had significantly greater risk of all-cause (odds ratio [OR] = 1.05; confidence interval [CI] = 1.02-1.08; p  < .001), MB-related (OR: 1.28; CI: 1.16-1.42; p  < .001), and stroke-related (OR: 1.33; CI: 1.11-1.58; p  = .002) readmissions; for all readmission categories, average LOS was significantly longer and costs significantly higher for warfarin treated patients. NVAF patients treated with rivaroxaban versus apixaban had significantly greater risk of all-cause (OR: 1.06; CI: 1.02-1.09; p  = .001) and MB-related (OR = 1.62; CI = 1.44-1.83; p  < .001) readmissions, but not stroke-related readmission; for MB-related readmissions average LOS and costs were higher for rivaroxaban treated patients. Significant differences in risks of all-cause, MB-related, and stroke-related readmissions were not observed between the apixaban and dabigatran cohorts. Conclusion: In this retrospective real-world analysis of NVAF patients, apixaban treatment was associated with better clinical outcomes than warfarin or rivaroxaban and lower hospital resource burden., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objective: To compare safety, effectiveness, and healthcare costs of major bleeding (MB), clinically relevant non-major (CRNM) bleeding, recurrent venous thromboembolism (VTE), and all-cause hospitalization among elderly Medicare VTE patients prescribed warfarin vs apixaban. Methods: Using 100% Medicare data, elderly patients prescribed apixaban or warfarin within 30 days after a VTE encounter were identified. Patients had continuous health plan enrollment and no parenteral or oral anticoagulant use ≤6 months preceding the VTE encounter. Cohorts were balanced using 1:1 propensity score matching (PSM). Cox proportional hazard models were used to assess the risk of MB, CRNM bleeding, recurrent VTE, and all-cause hospitalization. Generalized linear and two-part models were used to estimate MB-, recurrent VTE-, and all-cause related costs (per patient per month [PPPM]). Results: In the pre-matched cohort, 25,284 (66.9%) patients were prescribed warfarin and 12,515 (33.1%) apixaban. After 1:1 PSM, 11,363 matched pairs of apixaban-warfarin patients were included for a mean follow-up of 4.0 and 4.4 months, respectively. Matched cohorts had a mean age of 78 years and mean Charlson Comorbidity Index score of 2.9. Warfarin was associated with a higher risk of MB (hazard ratio [HR] = 1.31; 95% confidence interval [CI] = 1.10-1.57) and CRNM bleeding (HR = 1.31; 95% CI = 1.19-1.43) vs apixaban. The risks of recurrent VTE (HR = 0.96; 95% CI = 0.70-1.33) and all-cause hospitalization (HR = 1.05; 95% CI = 0.99-1.12) were similar among warfarin and apixaban patients. Warfarin patients had higher MB-related ($147 vs $75; p  = .003) and all-cause costs PPPM ($3,267 vs $3,033; p  < .001), but similar recurrent VTE-related medical costs PPPM ($30 vs $36; p  = .516) vs apixaban patients. Conclusions: Warfarin was associated with significantly higher risk of MB and CRNM bleeding as well as higher MB-related and all-cause costs vs apixaban patients. Recurrent VTE risk and costs were similar among warfarin and apixaban patients.

Case Report: Case 1 of an investigator-initiated study using oral single agent mifepristone to halt stage IV non-small cell lung cancer whose tumor was devoid of any targeted markers has remained ECOG zero and in good health for over 3 years. Case 2, reported here, is a 68-year-old woman with stage IV non-small cell lung cancer whose tumor was positive for the programmed death ligand-1 (PD-L1) marker. Her cancer progressed despite treatment with a check-point inhibitor (nivolumab), besides 3 rounds of multi-agent chemotherapy. After 1 ½ years of treatment with single agent mifepristone, her cancer remains stable (even some tumor regression) and her quality of life is only impaired by her pre-existing chronic obstructive lung disease, not her cancer., Conclusion: Mifepristone therapy may provide a method to halt metastatic lung cancer positive for the PD-L1 marker when check-point inhibitors are no longer effective., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)