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Abstract Background Adjuvant ipilimumab was found to improve the overall survival and reduce toxicity compared to high‐dose interferon (HDI) in patients with resected, high‐risk melanoma. However, the cost of ipilimumab is substantially higher than HDI. This study evaluates the cost‐effectiveness of ipilimumab as an adjuvant treatment in melanoma from a healthcare perspective. Methods We designed a Markov model simulating resected, high‐risk melanoma patients receiving either ipilimumab or HDI. Transition probabilities, including risks of survival, disease progression, and toxicity, were ascertained from clinical trial data. Costs and quality of life measurements (health utilities) were extracted from the literature. Incremental cost‐effectiveness ratios (ICERs), defined as incremental costs divided by incremental quality‐adjusted life‐years (QALYs), assessed cost‐effectiveness. ICERs

Background: Adjuvant ipilimumab was found to improve the overall survival and reduce toxicity compared to high‐dose interferon (HDI) in patients with resected, high‐risk melanoma. However, the cost of ipilimumab is substantially higher than HDI. This study evaluates the cost‐effectiveness of ipilimumab as an adjuvant treatment in melanoma from a healthcare perspective. Methods: We designed a Markov model simulating resected, high‐risk melanoma patients receiving either ipilimumab or HDI. Transition probabilities, including risks of survival, disease progression, and toxicity, were ascertained from clinical trial data. Costs and quality of life measurements (health utilities) were extracted from the literature. Incremental cost‐effectiveness ratios (ICERs), defined as incremental costs divided by incremental quality‐adjusted life‐years (QALYs), assessed cost‐effectiveness. ICERs <$100,000/QALY were deemed cost‐effective. We measured model uncertainty with one‐way and probabilistic sensitivity analyses. Results: In our base case model, ipilimumab increased costs by $107,100 and increased effectiveness by 0.43 QALY, yielding an ICER of $392,600/QALY. Our model was moderately sensitive to the costs of ipilimumab, though the cost of ipilimumab would need to decrease by 44% for ipilimumab to become cost‐effective compared to HDI. The model was not sensitive to survival, toxicity, or other costs. Probabilistic sensitivity analysis showed that HDI would remain the cost‐effective treatment option 96.2% of the time at a willingness‐to‐pay threshold of $100,000/QALY. Conclusions: Adjuvant ipilimumab increases the survival and decreases the toxicity compared to HDI in resected, high‐risk melanoma patients, though this would not be considered cost‐effective due to the high price of ipilimumab. [ABSTRACT FROM AUTHOR]

Background: The pivotal E1684, E1690, E1694, and E2696 trials of adjuvant high-dose interferon-α (HDI) enrolled nearly 2000 patients, and established HDI as the standard of care in adjuvant therapy for patients with resected high-risk melanoma. Herein, the authors present an updated analysis of these 4 trials.Methods: Survival and disease status were updated in September 2016. These data represent a median follow-up of 17.9 years for the E1684 trial, 12.2 years for the E1690 trial, 16.0 years for the E1694 trial, and 16.5 years for the E2696 trial.Results: The current analysis confirmed the benefit to recurrence-free survival (RFS) of HDI in the E1684 trial at a median follow-up of 17.9 years. The RFS benefit in the E1694 trial remained evident at a median follow-up of 16 years. Furthermore, the results of the current study confirmed the RFS benefit of adjuvant HDI compared with observation in a pooled analysis of the E1684 and E1690 trials. No overall survival benefit was apparent in this pooled analysis. Updated results for the E1690 and E2696 trials did not differ from those previously reported. In addition, to the authors' knowledge, the current study is the first to report a significant difference in melanoma-specific survival (MSS) between patients treated with HDI compared with the ganglioside GM2/keyhole limpet hemocyanin (GMK) vaccine in the E1694 trial.Conclusions: In patients with resected high-risk melanoma, adjuvant HDI demonstrated improved RFS in the E1684 and E1694 trials, and improved MSS in a pooled analysis of HDI in the E1694 trial. To the authors' knowledge, these findings represent the most mature level of evidence for the benefit of HDI with respect to RFS and MSS. HDI is the only approved adjuvant treatment for which there are data available in patients with resected stage IIB/IIC melanoma, and remains a reasonable treatment option in this population. [ABSTRACT FROM AUTHOR]

Background Although high-dose interferon (hd-ifn) is the sole approved adjuvant systemic treatment for melanoma in many jurisdictions, it is toxic. We sought to assess the population-level effects of hd-ifn toxicity, particularly neuropsychiatric toxicity, hypothesizing that such toxicity would have the greatest effect on mental health services use in advanced resected melanoma. Methods This retrospective population-based registry study considered all melanoma patients receiving adjuvant hd-ifn in Ontario during 2008-2012. Toxicity was investigated through health services use compatible with hd-ifn toxicity (for example, mental health physician billings). Using stage data reported from cancer centres about a subset of patients (stages iib-iiic), a propensity-matched analysis compared such service use in patients who did and did not receive hd-ifn. Associations between early hd-ifn discontinuation and health services use were examined. Results Of 718 melanoma patients who received hd-ifn, 12% were 65 years of age and older, and 83% had few or no comorbidities. One third of the patients experienced 1 or more toxicity-associated health care utilization events within 1 year of starting hd-ifn. Of 420 utilization events, 364 (87%) were mental health-related, with 54% being family practitioner visits, and 39% being psychiatrist visits. In the propensity-matched analysis, patients receiving hd-ifn were more likely than untreated matched controls to use a mental health service (p = 0.01), with 42% of the control group and 51% of the hd-ifn group using a mental health service in the period spanning the 12 months before to the 24 months after diagnosis. In the multivariable analysis, early drug discontinuation was more likely in the presence of pre-existing mental health issues (odds ratio: 2.0; 95% confidence limits: 1.1, 3.4). Conclusions Stage iib-iiic melanoma patients carry a substantial burden of mental health services use whether or not receiving hd-ifn, highlighting an important survivorship issue for these patients. High-dose interferon is associated with more use of mental health services, and pre-treatment use of mental health services is associated with treatment discontinuation. That association should be kept in mind when hd-ifn is being considered. [ABSTRACT FROM AUTHOR]

Since the pivotal cooperative group trials in the 1980's-90's,, high-dose interferon (HDI) has been the standard of adjuvant therapy. Despite multiple other trials evaluating potential new therapies in melanoma, HDI remains the only FDA-approved therapy for stage IIB and III melanoma. Initial reports from the more recent phase III international trials of modifications of the original HDI regimen linked the appearance of autoimmunity with improved outcomes of disease. Trials of high-dose interleukin-2, many years earlier, reported anecdotal observations that were consistent with the hypothesis that autoimmunity and clinical benefit of immunotherapies of melanoma are linked with one another. The only prospectively conducted study examining the appearance of clinical and laboratory evidence of autoimmunity during HDI therapy was published by Gogas and colleagues, demonstrating statistically significant impact on relapse-free survival and overall survival. Retrospectively conducted studies of different intermediate dosage regimens of interferon (IFN) have not fully confirmed the linkage of serological evidence of autoimmunity and improved survival outcomes. With the emergence of new immunotherapies in treatment of melanoma, this review highlights the importance of autoimmunity for future applications in melanoma and reviews significant differences of past studies evaluating the appearance of autoimmunity during IFN therapy in high-risk melanoma. [ABSTRACT FROM AUTHOR]

Background: Evidence from randomized trials in the pre-sentinel lymph node biopsy era indicate that adjuvant treatment with high-dose interferon-alpha (IFN) increases recurrence-free survival (RFS) in patients with high-risk melanoma. However, to the authors' knowledge, the role of this treatment in selected patients with early stage III disease has not been well studied.Methods: The clinical and pathologic characteristics of 486 patients undergoing surgical treatment for stage III melanoma were evaluated and the authors compared outcomes for those given adjuvant treatment with IFN with those patients who had surgery alone. A particular focus was on the effect of IFN therapy on RFS and overall survival (OS) among those patients with stage IIIA disease.Results: The median follow-up for the entire cohort was 5.2 years; the 5-year RFS and OS rates for the entire group were 41% and 53%, respectively. Adjuvant IFN was given to 141 patients (29%). On multivariate analysis, IFN was found to be the only independent predictor for RFS in patients with stage IIIA disease (hazards ratio of 0.4; 95% confidence interval, 0.2-0.9 [P = .02]). IFN was not found to be associated with increased RFS in patients with more advanced lymph node disease (stage IIIB and stage IIIC). IFN appeared to have no effect on OS in any patient with stage III disease.Conclusions: Adjuvant treatment with IFN improves RFS in melanoma patients with early stage III disease. The results of the current study should help guide management when considering adjuvant treatment for these patients. [ABSTRACT FROM AUTHOR]

Efficacy and safety of interferon induction therapy alone or in combination with ribavirin or ribavirin plus amantadine were evaluated in chronic hepatitis C patients who were nonresponders to primary antiviral treatment. The study was designed to have 225 HCV nonresponder patients, but at an interim analysis the response rate difference between groups was lower than expected and the enrollment was stopped when 75 patients had been randomized to receive interferon-α2a (group A, n = 26), interferon-α2a plus 15 mg/kg per day of ribavirin (group B, n = 24), or interferon-α2a plus ribavirin plus 200 mg/day of amantadine hydrochloride (group C, n = 25). Treatment duration was 48 weeks. The dose of interferon was 6 MU/day for 4 weeks followed by 3 MU/day for the remaining 44 weeks. On intention-to-treat, the sustained virological response at 24 weeks of follow-up was 11.5% in group A, 12.5% in group B, and 12% in group C. Therapy was discontinued because of adverse effects in three patients in group A (11.5%), three in group B (12.5%), and two in group C (8%). Nonresponders with chronic hepatitis C may achieve a sustained virological response rate of approximately 12% if retreated with interferon induction treatment followed by administration of a daily dose. The addition of ribavirin or amantadine did not seem to improve the response rates. [ABSTRACT FROM AUTHOR]

Background: In chronic hepatitis C virus (HCV) infection, interferon (IFN) monotherapy usually is carried out at doses of 3 to 6 million units (MU) 3 times per week, but treatment efficacy is low.Objective: The aim of our study was to assess the efficacy and tolerability of IFN-alfa2b in combination with ribavirin in relapsers and nonresponders to high-dose IFN treatment (5 to 6 MU 3 times per week). We measured the biochemical and virologic responses to treatment and the risk for relapse during the 24 weeks following the end of treatment.Methods: Patients with chronic HCV infection (relapsers and nonresponders to a previous treatment with high-dose IFN) received IFN-alfa2b, 3 MU 3 times per week, and ribavirin, 1000 or 1200 mg/d for 24 or 48 weeks. The patients were then followed up for an additional 24 weeks. Sustained response was defined as normal serum alanine aminotransferase (ALT) level and undetectable HCV RNA 24 weeks after treatment was stopped.Results: Forty-three patients (32 men, 11 women; mean [SD] age, 45 [2] years; 10 relapsers, 33 nonresponders) were included in the study. Four patients were withdrawn from the study at week 4 of treatment because of treatment-related adverse events, and 1 dropped out. At the end of the treatment period, normalization of serum ALT levels and undetectable HCV RNA levels were seen in 58.1% and 30.2% of patients, respectively. No significant difference in virologic response at the end of treatment was found between nonresponders (10/33 [30.3%]) to previous IFN therapy and relapsers (3/10 [30.0%]). At the end of follow-up, 3 (7.0%) treated patients had sustained response (2 nonresponders to the first IFN course and 1 relapser). All of the patients with sustained response were treated for 24 weeks.Conclusion: Based on the results of our study, combination therapy with IFN-alfa and ribavirin may be of value in a limited number of patients with chronic HCV infection who do not respond to, or relapse after, a first course of treatment with high-dose IFN monotherapy. [Copyright &y& Elsevier]

Abstract Background High-dose Interferon (HDI) therapy produces a clinical response and achieves relapse-free survival in 20-33% of patients with operable high risk or metastatic melanoma. However, patients may develop significant side effects frequently necessitating dose reduction or discontinuation of therapy. We recently showed that peripheral blood lymphocytes (PBL) from some melanoma patients have impaired interferon (IFN) signaling which could be restored with high concentrations of IFN. This exploratory study evaluated IFN signaling in PBL of melanoma patients to assess whether the restoration of PBL IFN signaling may predict a beneficial effect for HDI in melanoma patients. Methods PBL from 14 melanoma patients harvested on Day 0 and Day 29 of neoadjuvant HDI induction therapy were analyzed using phosflow to assess their interferon signaling patterns through IFN-α induced phosphorylation of STAT1-Y701. Results Patients who had a clinical response to HDI showed a lower PBL interferon signaling capacity than non-responders at baseline (Day 0). Additionally, clinical responders and patients with good long-term outcome showed a significant increase in their PBL interferon signaling from Day 0 to Day 29 compared to clinical non-responders and patients that developed metastatic disease. The differences in STAT1 activation from pre- to post- HDI treatment could distinguish between patients who were inclined to have a favorable or unfavorable outcome. Conclusion While the sample size is small, these results suggest that interferon signaling patterns in PBL correlate with clinical responses and may predict clinical outcome after HDI in patients with melanoma. A larger confirmatory study is warranted, which may yield a novel approach to select patients for HDI therapy.