High-dose Interferon Alfa-2b Research Articles

Granulomatous and Sarcoid-like Immune-Related Adverse Events following CTLA4 and PD1 Blockade Adjuvant Therapy of Melanoma: A Combined Analysis of ECOG-ACRIN E1609 and SWOG S1404 Phase III Trials and a Literature Review.

Treatment with immune checkpoint inhibitors (ICIs) has been linked to granulomatous and sarcoid-like lesions (GSLs) affecting different organs. This study sought to evaluate GSL incidence in patients with high-risk melanoma treated with cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death 1 (PD1) blockade adjuvant therapy in two clinical trials: ECOG-ACRIN E1609 and SWOG S1404. Descriptions and GSL severity ratings were recorded. Data were collected from ECOG-ACRIN E1609 and SWOG S1404. Descriptive statistics along with GSL severity grades were reported. Additionally, a literature review for such cases was summarized. A total of 11 GSL cases were reported among 2878 patients treated with either ICI or with High-Dose Interferon Alfa-2b (HDI) in ECOG-ACRIN E1609 and SWOG S1404 trials. Cases were numerically more commonly reported with ipi10, followed by pembrolizumab, ipi3, and HDI, respectively. Most of the cases were grade III. Further, organs involved included lung, mediastinal lymph nodes, skin and subcutaneous tissue, and eye. Furthermore, a summary of 62 reports in the literature was described. GSLs following anti-CTLA4 and anti-PD1 antibody therapy in patients with melanoma were reported unusually. Reported cases ranged in grade from I to III and appeared manageable. Careful attention to these events and their reporting will be essential to better guide practice and management guidelines.

1073P Quality of life (QOL) endpoints from the phase III intergroup S1404 adjuvant melanoma trial

A key issue for adjuvant melanoma patients is how they weigh the potential benefits of treatment and QOL. We assessed QOL in S1404, a trial of adjuvant pembrolizumab versus either high-dose interferon-alfa 2b (HDI) or ipilimumab.

The current state of adjuvant therapy of melanoma.

Melanoma adjuvant therapy targets residual micrometastatic disease destined for future recurrence. In patients with resected stage III or IV melanoma, adjuvant therapy was shown to reduce the risk of recurrence, death, or both, leading to the regulatory approval of several agents since 1995: IFNα, pegylated-IFNα, checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab, and BRAF and MEK inhibitors dabrafenib and trametinib. 1 Kirkwood JM Manola J Ibrahim J et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004; 10: 1670-1677 Crossref PubMed Scopus (456) Google Scholar , 2 Kirkwood JM Ibrahim JG Sosman JA et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001; 19: 2370-2380 Crossref PubMed Scopus (783) Google Scholar , 3 Eggermont AM Suciu S Testori A et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012; 30: 3810-3818 Crossref PubMed Scopus (208) Google Scholar , 4 Eggermont AM Chiarion-Sileni V Grob JJ et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015; 16: 522-530 Summary Full Text Full Text PDF PubMed Scopus (856) Google Scholar , 5 Tarhini AA Lee SJ Hodi FS et al. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American Intergroup E1609. J Clin Oncol. 2020; 38: 567-575 Crossref PubMed Scopus (51) Google Scholar , 6 Eggermont AMM Blank CU Mandala M et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018; 378: 1789-1801 Crossref PubMed Scopus (929) Google Scholar , 7 Long GV Hauschild A Santinami M et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017; 377: 1813-1823 Crossref PubMed Scopus (799) Google Scholar Key adjuvant trials, their outcomes, and current standard of care status are summarised in the appendix. Adjuvant nivolumab versus ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trialAt a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB–C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab. Full-Text PDF

Patient-reported outcomes among patients with resected high-risk melanoma (AJCC7 IIIB, IIIC, M1a, M1b) randomized to low- or high-dose adjuvant Ipilimumab (ipi) versus high-dose interferon alfa-2b (HDI): Health-related quality of life (HRQL) analysis of ECOG-ACRIN E1609.

e22078 Background: The primary objective of the patient-reported outcomes (PRO) study of E1609 patients (pts) was to compare overall HRQL among pts receiving ipi (ipi10, ipi3) or HDI. We hypothesized that ipi would be superior to HDI in HRQL. Secondary analyses compared HRQL and GI distress between ipi10 and ipi3. Methods: PROs were administered among pts enrolled from NCI Community Oncology Research Program (NCORP) sites at baseline, every 12 weeks (wks) during treatment, and every 24 wks off-treatment for one year. Differences between ipi arms and HDI in overall HRQL at 12 wks (completion of ipi induction) was defined a priori as the primary outcome. HRQL was assessed using the 27-item Functional Assessment of Cancer Therapy –General (FACT-G) total score. GI toxicity was a secondary outcome measured by the 11-item FACIT-Diarrhea (FACIT-D) scale. Two sample t-test was used to compare scores between arms. Results: 548 pts completed PROs at baseline and 334 at 12 wks. Among 322 (59%) pts with PRO data at both time points, mean FACT-G total change scores from baseline to 12 wks were significantly lower (indicating less decline in HRQL) among pts randomized to ipi10 (-4.9,SD:14.1) or ipi3 (-3.4 points,SD:13.2) vs. HDI (-12.9, SD:14.1), p < 0.05 for both ipi10 vs. HDI and ipi3 vs. HDI. Mean FACIT-D change scores indicated higher GI distress from baseline to 12 wks among pts randomized to ipi10 (-3.7, SD:6.9) or ipi3 (-2.2, SD:5.1) vs HDI (-0.7, SD:2.7), p < 0.05 for both comparisons. In comparing ipi10 to ipi3, FACT-G total and FACIT-D total change scores from baseline to wk 12 were comparable. Conclusions: Overall decline in HRQL from baseline to completion of ipi induction was less among pts receiving ipi compared to HDI. Pts randomized to ipi reported a greater increase in diarrhea compared to HDI. HRQL and diarrhea were comparable between ipi3 and ipi10. Our findings are based on PRO data, thus increase our confidence in capturing pts’ experience with treatment from the pt’s perspective. Clinical trial information: NCT01274338. [Table: see text]

Systemic adjuvant therapy for adult patients at high risk for recurrent cutaneous or mucosal melanoma: an Ontario Health (Cancer Care Ontario) clinical practice guideline.

Previous versions of the guideline from the Program in Evidence-Based Care (pebc) at Ontario Health (Cancer Care Ontario) recommended that the use of high-dose interferon alfa 2b therapy be discussed and offered to patients with resected cutaneous melanoma with a high risk of recurrence. Subsequently, several clinical trials in patients with resected or metastatic melanoma found that immune checkpoint inhibitors and targeted therapies have a benefit greater than that with interferon. It was therefore considered timely for an update to the guideline about adjuvant systemic therapy in melanoma. The present guideline was developed by the pebc and the Melanoma Disease Site Group (dsg). Based on a systematic review from a literature search conducted using medline, embase, and the Evidence Based Medicine Reviews databases for the period 1996 to 28 May 2019, the Working Group drafted recommendations. The systematic review and recommendations were then circulated to the Melanoma dsg and the pebc Report Approval Panel for internal review; the revised document underwent external review. For patients with completely resected cutaneous or mucosal melanoma with a high risk of recurrence, the recommended adjuvant therapies are nivolumab, pembrolizumab, or dabrafenib-trametinib for patients with BRAF V600E or V600K mutations; nivolumab or pembrolizumab are recommend for patients with BRAF wild-type disease. Use of ipilimumab is not recommended. Molecular testing should be conducted to help guide treatment decisions. Interferon alfa, chemotherapy regimens, vaccines, levamisole, bevacizumab, bacillus Calmette-Guérin, and isolated limb perfusion are not recommended for adjuvant treatment of cutaneous melanoma except as part of a clinical trial.

The Sunbelt Melanoma Trial.

The Sunbelt Melanoma Trial, a multicenter, prospective randomized clinical study, evaluated the role of high-dose interferon alfa-2b (HDI) therapy for patients with a single positive sentinel lymph node (SLN) metastasis treated with a completion lymph node dissection (CLND). A second protocol in the trial evaluated the prognostic significance of using molecular markers to identify submicroscopic metastases in sentinel lymph nodes that were negative by routine pathologic analysis. The role of CLND with or without adjuvant HDI was evaluated in this group of patients. The results of the study demonstrated that adjuvant HDI offered no survival benefit for patients with a single positive SLN in terms of disease-free or overall survival. Molecular staging using polymerase chain reaction (PCR) for melanoma markers did not identify a high-risk group of patients at increased risk of melanoma recurrence. Additional treatment of these patients who were PCR-positive with either CLND alone or CLND plus HDI did not improve their survival. Additional studies from the Sunbelt Melanoma Trial helped to validate the operational standards of the SLN biopsy procedure and defined the complication rates for both SLN biopsy and CLND. A prognostic risk calculator has been developed from trial data, and the importance of different micrometastatic tumor burden measurements was reported. Although the Sunbelt Melanoma Trial did not demonstrate an improvement in survival with HDI, it is an important trial that highlights the significance of surgeon-initiated randomized clinical trials that incorporate surgical techniques, molecular biomarkers, and adjuvant therapy.

Duration of Anti-Programmed Death-1 Therapy in Advanced Melanoma: How Much of a Good Thing Is Enough?

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 53-year-old healthy man presented with recurrent in-transit melanoma of the right lower extremity. Eight years prior he had undergone wide local excision and sentinel lymph node biopsy for invasive melanoma of the anteromedial aspect of the distal right thigh. Pathology revealed an ulcerated melanoma, Breslow depth 3.5 mm, and with one involved micrometastatic inguinal lymph node. Staging studies did not demonstrate distant metastases. Superficial inguinal node dissection was performed and did not identify any additional metastatic nodes of 14 retrieved for a final pathologic staging of T3bN1aM0 (stage IIIB) cutaneous melanoma. He received 12 months of adjuvant high-dose interferon alfa-2b. Two years later, he developed a 1.2-cm subcutaneous focus of in-transit recurrence approximately 4 cm proximal to the original melanoma site in the right thigh, which was treated with surgical resection followed by adjuvant radiotherapy. Over the next 4 years, he underwent six additional surgeries for isolated in-transit recurrences affecting the same limb. He was referred for therapeutic options at the time of his latest in-transit recurrence. Examination revealed three palpable subcutaneous nodules in the right thigh in the setting of lymphedema. A core biopsy confirmed recurrent melanoma (Fig 1). Whole-body fluorodeoxyglucose positron emission tomography imaging revealed at least 17 hypermetabolic cutaneous and subcutaneous nodules in the right thigh, four fluorodeoxyglucose-avid nodules below the right knee, but no distant metastases (Fig 2A). Brain magnetic resonance imaging was normal. His serum chemistry profile, including lactate dehydrogenase, was normal. Molecular analysis demonstrated presence of BRAF V600E mutation in the tumor. After multidisciplinary evaluation, an isolated limb infusion procedure of the right lower extremity was not believed to be feasible, secondary to the proximal extent of the recurrence. Therapy was initiated with pembrolizumab at 2 mg/kg intravenously every 3 weeks.

Systemic Immune-Inflammation Index and Circulating T-Cell Immune Index Predict Outcomes in High-Risk Acral Melanoma Patients Treated with High-Dose Interferon

High-dose interferon alfa-2b (IFN-α-2b) improves the survival of patients with high-risk melanoma. We aimed to identify baseline peripheral blood biomarkers to predict the outcome of acral melanoma patients treated with IFN-α-2b. Pretreatment baseline parameters and clinical data were assessed in 226 patients with acral melanoma. Relapse-free survival (RFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox regression analyses were applied after adjusting for stage, lactate dehydrogenase (LDH), and ulceration. Univariate analysis showed that neutrophil-to-lymphocyte ratio ≥2.35, platelet-to-lymphocyte ratio ≥129, systemic immune-inflammation index (SII) ≥615 × 109/l, and elevated LDH were significantly associated with poor RFS and OS. The SII is calculated as follows: platelet count × neutrophil count/lymphocyte count. On multivariate analysis, the SII was associated with RFS [hazard ratio (HR)=1.661, 95% confidence interval (CI): 1.066-2.586, P=.025] and OS (HR=2.071, 95% CI: 1.204-3.564, P=.009). Additionally, we developed a novel circulating T-cell immune index (CTII) calculated as follows: cytotoxic T lymphocytes/(CD4+ regulatory T cells × CD8+ regulatory T cells). On univariate analysis, the CTII was associated with OS (HR=1.73, 95% CI: 1.01-2.94, P=.044). The SII and CTII might serve as prognostic indicators in acral melanoma patients treated with IFN-α-2b. The indexes are easily obtainable via routine tests in clinical practice.

A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): Preliminary safety and efficacy of the ipilimumab arms.

9500 Background: In the U.S., 3 regimens have regulatory approval as adjuvant therapy for high-risk melanoma, including high-dose interferon-alfa (HDI) and ipilimumab 10 mg/kg (ipi10). Ipilimumab 3 mg/kg (ipi3) has regulatory approval for metastatic inoperable melanoma. The toxicity of ipi is dose- dependent, and following the recent approval of adjuvant ipi10, it has become urgent to evaluate the relative safety and efficacy of adjuvant ipi at the 2 dose levels that have been tested in E1609. Methods: E1609 randomized patients (pts) with resected high-risk melanoma (stratified by stages IIIB, IIIC, M1a, M1b) to ipi10 or ipi3 versus HDI. Co-primary endpoints were RFS and OS. The current analysis investigates the relative safety and preliminary, non-comparative RFS of the ipi arms as of 3/2/17. Results: E1609 was activated on 5/25/11 and completed adult pt accrual on 8/15/14. Accrual to ipi10 was suspended due to toxicity between 9/23-11/16/2013. Final adult pt accrual was 1670 including 511 ipi10, 636 HDI and 523 ipi3 pts. Treatment related adverse events (AEs) were reported among 503 ipi10 and 516 ipi3 pts. Worst degree (Gr 3+) AEs were experienced by 57% ipi10 and 36.4% ipi3 pts and were mostly immune related (Table 1). AEs led to discontinuation of treatment in 271 (53.8 %) of 503 ipi10 and in 180 (35.2 %) of 512 ipi3 pts during the initial 4 dose induction phase. Gr5 AEs considered at least possibly related were 8 with ipi10 and 2 with ipi3. At a median follow-up of 3.1 years, an unplanned RFS analysis of ipi3 and ipi10 on concurrently randomized pts showed no difference between the 2 arms. Three-year RFS rate was 54% (95% CI: 49, 60) with ipi10 and 56% (50, 61) with ipi3. Conclusions: Adjuvant therapy of pts with high-risk melanoma is associated with significantly more toxicity at ipi10 compared to ipi3. An unplanned RFS analysis of concurrently randomized pts on the 2 ipi arms showed no difference in RFS. Clinical trial information: NCT01274338. [Table: see text]

Association of immune-inflammation index with outcome of high-risk acral melanoma patients treated with adjuvant high-dose interferon.

e21070Background: High-dose interferon alfa-2b(IFN-α-2b) improves the survival of high-risk melanoma patients, especially acral melanoma patient. However, there is a significant number of patients fails to benefit from treatment because of the toxicities. In this study, we aimed to identify baseline peripheral blood biomarkers to predict the outcome of acral melanoma patients with adjuvant high-dose interferon treatment. Methods: Pretreatment full blood counts, CD4+CD25+ regulatory T cells (CD4+Tregs),CD8+CD28-regulatory T cells(CD8+Tregs), CD8+CD28+cytotoxic T lymphocyte(CTL),serum lactate dehydrogenase (LDH), and clinical date were assessed in 113acral melanoma patients. 76 patients treated with 4-week IFN-α-2b (15*106 U/m2d1–5/w*4w) and 37 patients treated with1-year IFN-α-2b (15*106 U/m2 d1–5/w*4w + 9*106 U tiw*48w). Relapse free survival (RFS) and overall survival (OS) were assessed using the Kaplan–Meier method, and multivariate Cox regression analysis were applied, adjusting for other prognostic fa...

The role of BRAF mutation in patients with high-risk malignant melanoma treated with high-dose adjuvant interferon therapy.

Data regarding the prognostic importance of BRAFV600 tumor mutations in high-risk, non-metastatic, stage 2 and 3 malignant melanoma (MM) patients are controversial. There is not sufficient information in the medical literature regarding the reliability of BRAF mutations as a predictive factor in prognosis and adjuvant treatment decision issues in this patient group. The data of 50 operated high-risk, non-metastatic, stage 2B/2C and 3 MM patients who received high-dose interferon alfa-2b therapy were evaluated retrospectively. BRAF mutations were analyzed by using microarray-based molecular methods. The associations between BRAF mutations and both clinicopathological characteristics and survival were assessed. Of the 50 patients, 52% was female and 48% was male, and the median age was 51.5years. Twenty-three (46%) and 27 (54%) patients had stage 2B/2C and stage 3 disease, respectively. BRAF mutation was detected in 21 patients. The median overall survival (OS) was 58.1months, whereas the median disease-free survival (DFS) was 22.7months. When the OS and DFS were compared according to the BRAF mutation status, no difference was detected between the two groups. BRAF mutations were detected more frequently in tumors with mitosis and ulceration; however, no statistically significant difference was observed in other clinicopathological parameters. In conclusion, it is not appropriate to use BRAF mutations as a prognostic and predictive marker for selecting the treatment and assessing its outcomes in patients with early stage, high-risk MM.

Treatment Patterns of Adjuvant Interferon Alfa-2B (Ifn-&Agr;2B) for High-Risk Melanoma. a Retrospective Study of the Grupo Español Multidisciplinar De Melanoma (Gem)

ABSTRACT Aim: To describe patterns of use of adjuvant Interferon alfa-2b (IFN-a2b): dose, schedule, duration, adherence to therapy as well as others factors, in an unselected cohort of patients with high-risk melanoma, treated in different hospitals of Spain between January 2000 and December 2009. Methods: A multi-institutional retrospective clinical trial, including a statistically predefined sample of 325 melanoma patients with stage IIB, IIC or III and treated with adjuvant IFN-a2b was considered feasible to fulfill the study objective. Eligibility criteria include: 1) Pathologically confirmed diagnosis of cutaneous melanoma in the established period; 2) Complete resection of disease; 3) Adjuvant therapy with at least one dose of IFN-a2b; 4) Complete treatment details and follow-up data available; 5) Written informed consent in all patients that were alive at the time of review. Results: From June 2013 to January 2014, a total of 347 patients were included. As of April 2014, data analysis has been performed for 126 patients. Preliminary results in this cohort are presented: Median age: 59 years, male/female: 58%/42%. Pathological stage (AJCC 2009): IIB 15%, IIC 7%, IIIA 30%, IIIB 33% and IIIC 15%. Breslow thickness: 4mm 39%. Ulceration: 51.4%. 90% of patients received high-dose IFN-a2b and 10% either low or intermediate doses. High-dose IFN-a2b induction phase was completed by 88% of patients, and 70% completed the maintenance phase, although dose delay and dose reduction due to toxicity were common in both periods. Sixty percent of patients have relapsed as per investigator's review. Final analysis including disease-free and overall survival will be completed in July 2014. Conclusions: Most patients included in this preliminary analysis receive both, high dose IFN-a2b induction and maintenance phases, although dose delay and dose reduction are common. The complete analysis of this study will provide relevant and detailed information about the feasibility of IFN-a2b adjuvant treatment programs used for high-risk melanoma in Spain. These results will be relevant for the design and interpretation of future trials of adjuvant therapy. Disclosure: S. Martin-Algarra: In the past 36 months I have participated in Advisory Boards of MSD, BMS, Roche, GSK and Novartis. In the past 36 months have given lectures in events organized/sponsorized by BMS, Roche and GSK; G. Nocea: Employee of Merck Sharp and Dohme Spain; K. Stevinson: Employee of Merck US; P. Del Barrio: Employee of Merck Sharp and Dohme Spain; M.V. Tornamira: Employee of Merck Sharp and Dohme Spain; E. Espinosa: I am participated in the Advisory Board of MSD (Merck Sharp and Dohme). All other authors have declared no conflicts of interest.

Impact of health care professional interventions on completion of therapy in patients receiving high-dose interferon-alfa 2b adjuvant therapy for high-risk melanoma.

e20038^ Background: Melanoma incidence increased dramatically in the last decades. Intron A is the only adjuvant therapy shown to significantly increase progression-free and overall survival in hig...

Adjuvant Interferon in Melanoma: Is Duration of Therapy Important?

Adjuvant Interferon in Melanoma: Is Duration of Therapy Important?

Phase II Pilot Study of Intravenous High-Dose Interferon With or Without Maintenance Treatment in Melanoma at High Risk of Recurrence

High-dose interferon alfa-2b (HDI) has emerged as a potentially effective adjuvant therapy in patients with resected melanoma at high risk of recurrence. Evidence suggests it may be the early, very-high-dose part of the regimen that is critical. This pilot study sought to provide an early indication of whether the same effects can be achieved with the intravenous component of HDI alone and inform the feasibility and design of a phase III trial. Patients with stage 2B, 2C, 3B, and 3C melanoma were randomly assigned to receive interferon alfa-2b (IFN-α-2b) 20 MIU/m(2) intravenously (IV) daily 5 days per week for 4 weeks (arm A) versus the same regimen followed by IFN-α-2b 10 MIU/m(2) administered subcutaneously three times per week for 48 weeks (arm B) and observed for relapse-free survival (RFS) and overall survival. Between 2003 and 2009, 194 patients were enrolled (arm A, 96; arm B, 98). After median follow-up of 39.5 months, RFS was 22.7 months (95% CI, 14.1 to 38.1 months) in arm A versus 33.3 months (95% CI, 18.2 to not reached) in arm B (P = .28). The proportions of patients free of relapse at 2 years were 50% and 54.1% (P = .569; hazard ratio, 0.89), respectively. Overall survival favored arm B (median, 41.5 months v not reached; P = .05). Clinical outcomes were better in patients who had the longer regimen. Our results do not support either the use of a month of IV HDI alone in place of the year-long regimen or the initiation of a larger trial on this question.

Trends and variations in the use of adjuvant immunotherapy for stage III melanoma in the U.S. population.

9077 Background: High dose Interferon alfa-2b (IFN), an adjuvant immunotherapy for patients (pts) with stage III melanoma, was the only approved treatment option in the US from 1995-2011. There is limited information on how high dose IFN has been disseminated to eligible pts in general clinical practice, and whether variations exist in its adoption according to non-clinical factors. Methods: We obtained data on 34,208 pts diagnosed between 1998-2010 with stage III melanoma from the National Cancer Data Base (NCDB). IFN treatment was abstracted as immunotherapy. We investigated the use of immunotherapy according to pt demographic, socioeconomic, and clinical variables. We conducted multiple logistic regression analysis to examine the effect of these variables on the receipt of immunotherapy. Results: 62% of pts in our study population were male, 88% were Caucasian and 31% were over age 65. Overall, 27% of the pts received immunotherapy. There was no significant trend in its adoption between year 1998 and 2010. After adjustment for clinical variables, age at diagnosis, facility type, and geographic region are predictors strongly associated with use of immunotherapy. Only 16% of pts aged 65-74 and 3% over 75 received immunotherapy compared to 42% of those ages less than 45 (adjusted ORs 0.44 [0.32-0.59], 0.05 [0.04-0.14), respectively). Also 24% of pts treated at a comprehensive community cancer program received immunotherapy compared to 30% of those treated at an academic/research program (OR, 0.71 [0.51-0.99]). The frequency of immunotherapy was 25% in the Atlantic region and 17% in the Western region compared to 33% in Northeast (ORs 0.42 [0.18-0.99], 0.31 [0.13-0.74], respectively). Median household income, insurance type and comorbidity were not associated with adoption of immunotherapy after adjustment for all other variables. Conclusions: Less than one-third of all eligible patients received adjuvant immunotherapy in US general practice over the past decade. There is significant variation in its adoption according to non-clinical factors. Further exploration of the reasons for these variations and whether they are linked to important patient outcomes is needed.

Overwhelming response to Dabrafenib in a patient with double BRAF mutation (V600E; V600M) metastatic malignant melanoma

The recent findings brought the necessity of testing the mutational status of a series of genes which had been already identified as responsible for melanomas development and progression, such as BRAF, CKIT and PTEN: the consequent results are, in fact, essential to guide the assessment of the novel treatment protocols based on tailored targeted therapies. We present here the case of a 66 year-old male patient, diagnosed with an advanced melanoma in June 2011, and treated with Dabrafenib for double mutant metastatic disease. The patient was referred to our attention for a large exophytic malignant melanoma on the left shoulder. After complete surgical excision and elective lymph node dissection for presence of metastatic sentinel lymph node, the patient has started high-dose interferon alfa-2b injections as adjuvant therapy for a complete negative staging. The treatment was interrupted in August 2011 due to the appearance of metastatic lymph nodes. Tumor burden was rapidly growing reaching in few months the size of a tennis ball for the tumor mass located in the shoulder. Mutational study of the tumor revealed a double BRAF mutation on V-600E and V600M. This finding incited us to enroll the patient in compassionate Dabrafenib clinical trial. The therapy was started on may 2012 at 150 mg bid dosage. Almost surprisingly for the rapidity of the effect, one week later the lesion on the shoulder has reduced its size by 60% and one month later it has completely disappeared from sight. CT scan of June 2012 documented the astonishing clinical response.

How Much of a Good Thing? What Duration for Interferon Alfa-2b Adjuvant Therapy?

How Much of a Good Thing? What Duration for Interferon Alfa-2b Adjuvant Therapy?

Reduction of circulating regulatory T cells by intravenous high-dose interferon alfa-2b treatment in melanoma patients

High-dose interferon alfa-2b (IFNα-2b) is the only approved adjuvant systemic therapy for resected, high risk melanoma in the United States (Fecher and Flaherty, in Natl Compr Cancer Netw 7:295-304, 2009). Recently, two important meta-analyses of randomized trials (Wheatley et al., in J Clin Oncol, 2007; Mocellin et al. in J Natl Cancer Inst, 2010) investigating IFNα-2b versus observation in high risk melanoma patients, showed that adjuvant IFNα-2b has an impact both on relapse-free survival (RFS) and overall survival (OS) independently by dosage, duration and route compared with observation in high risk melanoma patients. Despite of an absolute benefits of 3 % (Wheatley et al., in J Clin Oncol, 2007), this treatment is associated with significant toxicity, which impacts on patient quality of life. A better understanding of the mechanism of action may help to potentiate the clinical efficacy and reduce the toxicity of IFNα-2b/Peg-IFNα-2b. Numerous studies suggest that interferon's mechanism of action in melanoma is primarily immunomodulatory (Table 1) (de La Salmoniere, in Clin Cancer Res 6:4713-4718, 2000; Stuckert, in J Clin Oncol 25:8506, 2007; Gogas et al., in N Engl J Med 354:709-718, 2006; Moschos et al., in J Clin Oncol 24:3164-3171, 2006; Ascierto and Kirkwood, in J Transl Med 6:62, 2008) Recent efforts to elucidate the mechanism of action for interferon have focused upon signal transducers and activators of transcription (STAT) (Simons et al., in J Transl Med 9:52, 2011) signaling and immunoregulatory responses mediated by regulatory T cells (Tregs) (Wang et al., in Clin Cancer Res 13:1523-1531, 2007; Clin Cancer Res 14:8314-8320, 2008). Tregs are a suppressive CD4+ T cell population that is present, along with primed effector T cells, in tumor and tumor-draining lymph nodes (Hiura et al. in J Immunol 175:5058-5066, 2005). Tregs express high levels of surface antigens such as CD25, cytotoxic T lymphocyte associated antigen 4 (CTLA-4), and glucocorticoid-induced tumor necrosis factor receptor (GITR) (Takahashi et al., in J Exp Med 192:303-310, 2000; Shimizu et al., in Nat Immunol 3:135-142, 2002). Moreover, Tregs express a characteristic nuclear transcription regulator, forkhead box P3 (FoxP3) (Hori et al., in Science 299:1057-1061, 2003; Gabriel and Lattime, in Clin Cancer Res 13:785-788, 2007). The presence of Tregs in tumor-draining lymph nodes and tumors provides a potential inhibitory population that may block or balance effector cell function. Thus, depletion of Tregs or blockade of Treg function using targeted antibodies or other strategies might be able to remove Treg suppression and enhance antitumor immunity (Viguier et al., in J Immunol 173:1444-1453, 2004). We conducted an observational study to examine whether the induction phase of the FDA-approved HDI regimen administered iv in patients with stage 3-4 melanoma (20 MU/m(2) intravenously (IV) five times per week for 4 weeks) reduced the number of Treg cells in the peripheral blood.

The National Cancer Data Base report on the utilization of an adjuvant immunotherapy in stage III melanoma in relation to age.

e19000 Background: The 5-year survival of Stage III melanoma ranges from 30-70%. High dose interferon alfa-2b (IFN) is an adjuvant immunotherapy approved in 1995 for stage III melanoma, however, its use has been limited by its significant toxicity and modest benefit. We hypothesized the utilization of adjuvant immunotherapy is less in older age group compared to younger patients. Methods: Using the National Cancer Data Base (NCDB) aggregate data, demographic, socioeconomic, insurance information, and treatment data were analyzed. Proportions were compared using Pearson Chi squared tests. Results: From 2000-2008, 27,365 cases of stage III melanoma were reported to NCDB. Most patients were male (63%) and Caucasian (94.2%). Twenty-nine percent were over the age of 70. Educational and socioeconomic factors across all age groups were not significantly different. The primary insurer for patients younger than 60 was a managed care plan (54.3%) as compared to Medicare with supplemental insurance for patients older than 60 (47.4%). In terms of systemic therapy, 23% received immunotherapy alone, 6% received chemotherapy alone, 2% received both, and 66% received no therapy. When compared to patients under age 39, older age groups were significantly less likely to receive adjuvant immunotherapy as shown in the table below. Conclusions: There is an inverse relationship between age and the use of adjuvant immunotherapy. Further study is planned to adjust for comorbidity, socioeconomic status using patient-level data. [Table: see text]