Adjuvant Interferon Alfa-2b Research Articles

Abstract 3641: Use of adjuvant interferon alfa-2b or ipilimumab 10 mg/kg for high-risk patients with melanoma, and associated adverse events and duration of therapy

Abstract OBJECTIVE: Adjuvant systemic therapy with interferon alfa-2b (IFN) or ipilimumab 10 mg/kg (IPI10) has been the standard for high-risk patients with melanoma who have undergone surgery; however, a high proportion of patients remain untreated. This analysis examines the adverse events (AEs) and duration of therapy (DoT) associated with IFN or IPI10. METHODS: A retrospective cohort study was conducted among each of the four US healthcare databases: OptumInsight, IMS PharMetrics, Truven Commercial, and Truven Medicare Supplemental. Patients receiving melanoma-related surgery (lymph node dissection) from July 1, 2006, to September 30, 2016, were identified. The study estimated the incidence rate (IR) per patient per year of AEs that commonly occur with IFN or IPI10 across different DoT levels among patients with melanoma following surgery. RESULTS: Of 46,401 eligible patients with melanoma surgery claims, 2423 (5%) were treated: 2316 with IFN and 107 with IPI10. Mean age was 51.7 years (60.5% male), and mean (standard deviation) Charlson comorbidity index score was 6.6 (2.8) and 7.5 (2.5) for patients prescribed IFN or IPI10, respectively. The DoT (median, mean (SD)) for IFN was 142, 182 (162) days and for IPI10 was 84, 73 (26) days. Similarly, the number of prescriptions (median, mean (SD)) for IFN were 20, 26 (28) and for IPI10 were 4, 3 (1). The overall AE IR per year was 4.4 in patients receiving IFN and 4.9 for those receiving IPI10. Among patients receiving IFN, the most common AEs were hepatitis, nausea, and fatigue (IRs: 0.92, 0.67, and 0.66, respectively). The most common AEs among IPI10-treated patients were fatigue, rash, nausea, and diarrhea (IRs of 0.95, 0.71, 0.66, and 0.63, respectively). AE rates were greater in patients with low DoT compared with those with a high DoT for most AEs in both IFN and IPI10 cohorts. CONCLUSION: Only 5% of high-risk patients with melanoma following lymph node dissection surgery were treated with adjuvant IPI10 or IFN, while the remaining were untreated. Patients treated with IPI10 or IFN had high AE rates impacting their ability to remain on therapy. Newer adjuvant treatments with more favorable AEs and DoT profiles are urgently needed for high-risk patients with melanoma. Disclosure: This research was funded by Bristol-Myers Squibb. Citation Format: Ahmad Tarhini, Komal Gupte-Singh, Min You, Amit Gupta, Le Trong Kim, Sumati Rao. Use of adjuvant interferon alfa-2b or ipilimumab 10 mg/kg for high-risk patients with melanoma, and associated adverse events and duration of therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3641.

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.

Intravenous high‐dose interferon with or without maintenance treatment in melanoma at high risk of recurrence: meta‐analysis of three trials

Resected stage IIB-IIIC malignant melanoma has a poor prognosis with a high risk of relapse and death. Treatment with adjuvant interferon alfa-2b (IFN-α-2b) is associated with improved relapse-free and overall survivals (OS), but the most appropriate dose and duration of treatment are unknown. In this article, we present an individual patient data random effects meta-analysis of melanoma patients from the U.K., Greek, and Chinese randomized trials. All patients were randomized either to IFN-α-2b 15-20 MIU/m(2) IV daily 5 days per week for 4 weeks (IV) or to the same regimen followed by IFN-α-2b 9-10 MIU/m(2) administered three times per week for 48 weeks (IV and SC). Allowing for dose interruptions and reductions, an equivalent total dose of IFN-α-2b was delivered in all three studies. We assessed whether IV was noninferior to IV and SC in terms of relapse-free survival (RFS) and investigated tumor and patient characteristics that impacted on outcomes. Median follow-up of 716 stage IIB-IIIC patients was 5.4 years. Noninferiority of IV compared to IV and SC could not be conferred for RFS (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.89-1.52; noninferior P = 0.17). Stage (P < 0.0001), site (acral vs. other, P < 0.0001), and Breslow thickness (P = 0.02) were significant predictors of RFS. The HR for death was 1.13 for IV compared to IV and SC, (95% CI 0.91-1.39). Stage (P < 0.0001) and Breslow thickness (P = 0.001) were significant independent predictors of OS. The available data suggest that where adjuvant high-dose interferon is being considered there is no evidence to deviate from the year long regimen described in the Eastern Cooperative Oncology Group and Intergroup studies.

The GERMELATOX DeCOG-trial: Attitude of German melanoma patients towards toxicity during adjuvant interferon treatment—Differences between the patient's and the physician's perspective.

e20099 Background: Although trials of adjuvant interferon alfa-2b (IFNa-2b) in high-risk melanoma patients suggest improvement in disease-free survival (DFS), metaanalyses showed only a marginal ov...

Benefit of adjuvant interferon alfa-2b (IFN-α) therapy in melanoma patients with high serum MMP-8 levels.

Matrix metalloproteinases (MMPs) are important enzymes in tissue turnover and various inflammatory processes. In this study, it was evaluated whether serum MMP-8 can predict the response to adjuvant interferon alfa-2b (IFN-α) therapy in patients with operated high-risk cutaneous melanoma. Pre-treatment sera from 460 patients with stage IIB-IIIC melanoma were analyzed for MMP-8. The patients were randomized after surgery to adjuvant IFN-α for 12 or 24 months (n = 313) or observation only (n = 147). The median serum MMP-8 level was used to classify the patients into a low MMP-8 (n = 232) and a high MMP-8 (n = 228) group. In the high MMP-8 subgroup, IFN-α therapy significantly improved relapse-free survival (RFS). RFS was 36.8 months in patients with high MMP-8 levels receiving IFN-α therapy, whereas RFS for those with high MMP-8 levels with observation only was 10.6 months (P = 0.027). Median overall survival for patients with high MMP-8 and observation only was 36.7 versus 71.7 months in those receiving IFN-α (P = 0.13). In a multivariate model, IFN-α therapy was a significant predictor of favorable RFS (HR 0.74; 95 % CI 0.55-0.99; P = 0.048), after adjustment for pre-treatment MMP-8 (HR 1.17; 95 % CI 0.88-1.55; P = 0.28), gender (HR 1.16; 95 % CI 0.86-1.56; P = 0.32), age (HR 1.00; 95 % CI 1.00-1.02; P = 0.12), ulceration (HR 1.09; 95 % CI 0.81-1.46; P = 0.58), and the presence of node metastases (HR 1.36; 95 % CI 1.17-1.58; P < 0.0001). In conclusion, patients with high serum MMP-8 levels may benefit from adjuvant IFN-α therapy, but this observation should be further investigated.

Treatment Patterns of Adjuvant Interferon Alfa-2B (Ifn-&amp;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.

The GERMELATOX DeCOG-trial: German melanoma patients and their attitude toward toxicity during adjuvant interferon treatment.

TPS9113^ Background: Although trials of adjuvant interferon alfa-2b (IFN alpha-2b) in high-risk melanoma patients suggest improvement in disease-free survival (DFS), a metaanalysis could only show ...

Adjuvant Interferon in Melanoma: Is Duration of Therapy Important?

Adjuvant Interferon in Melanoma: Is Duration of Therapy Important?

Conjunctival Papilloma

Conjunctival papilloma is a benign epithelial tumor occurring in both children and adults with varying clinical features and outcomes. In this article, we describe our experience regarding the difference in the clinical features and outcomes of conjunctival papilloma based on age at initial examination. To evaluate the clinical features, treatment, and outcomes in patients with conjunctival papilloma based on age at initial examination. Retrospective study. Ocular Oncology Service, Wills Eye Hospital, Philadelphia, Pennsylvania. Ten children and adolescents (aged ≤20 years) and 63 adults (aged >20 years) with conjunctival papilloma. Excisional biopsy, cryotherapy, oral cimetidine, topical or injection interferon alfa-2b, and photodynamic therapy. Tumor response. A comparison of conjunctival papillomas between age groups revealed significant differences in the mean number of tumors per eye (children and adolescents vs adults, 2 vs 1; P = .05), tumor basal dimension (8 vs 6 mm; P = .05), and associated feeder vessels (20% vs 47%; P = .05). Primary treatment included sole treatment with oral cimetidine (15% vs 5%), topical interferon alfa-2b (0% vs 1%), cryotherapy (0% vs 3%), photodynamic therapy (0% vs 1%), excisional biopsy and cryotherapy (38% vs 65%), excisional biopsy and cryotherapy with adjuvant oral cimetidine (8% vs 9%), and excisional biopsy and cryotherapy with adjuvant topical or injection interferon alfa-2b (38% vs 15%). Significant differences in age groups in treatment outcome during the follow-up period (mean, 24 vs 38 months) included complete regression with single treatment (38% vs 95%; P < .01) and tumor recurrence (15% vs 1%; P = .05). Conjunctival papillomas are larger and more likely to be multiple in children and adolescents than in adults. Excisional biopsy and cryotherapy with or without adjuvant oral cimetidine and/or topical interferon alfa-2b provide satisfactory tumor control. Papilloma recurrence is more common in children and adolescents than in adults.

Retrospective US database analysis of drug utilization patterns, health care resource use, and costs associated with adjuvant interferon alfa-2b therapy for treatment of malignant melanoma following surgery

BackgroundThe purpose of this study was to identify a real-world US population having undergone surgery for malignant melanoma and describe treatment patterns, health care resource utilization, and costs for patients who subsequently received interferon alfa-2b (IFN) therapy or other standard of care chemotherapies.MethodsA retrospective cohort study was conducted using administrative claims from MarketScan® databases among melanoma patients diagnosed between 2004 and 2008 who had surgery and were subsequently treated with IFN or other chemotherapies. Health care resource utilization and costs of services (converted to 2009 dollars) were evaluated. Cost refers to the amount paid to providers associated with the health service.ResultsOf 18,075 subjects with melanoma surgery claims, 1525 (8.4%) were treated with IFN and 1194 (6.6%) with other chemotherapies. Median duration (days) and number of doses of IFN therapy were 29 and 20, respectively. Approximately half of patients who received IFN discontinued therapy within or after the one-month induction phase. For IFN therapy patients, average total cost per patient for the last melanoma-related surgery prior to start of therapy, including costs of the surgery itself, pathology, anesthesia, and hospital care, was $2219. The average total cost per patient related to IFN therapy was $1188; this included costs for drug, office visits, blood work, and infusions. Other chemotherapy costs ranged from $146 to $2678.ConclusionThere is an unmet treatment need, considering that this study observed that melanoma patients on IFN therapy post-surgery do not complete the recommended one-year course of treatment which may compromise its full therapeutic benefits. Further study to investigate reasons for discontinuation may be warranted. In addition, costs associated with adjuvant IFN therapy in post-surgical treatment of disease are likely acceptable.

Phase II randomized study of high-dose interferon alfa-2b (HDI) versus chemotherapy as adjuvant therapy in patients with resected mucosal melanoma.

8506 Background: High-dose interferon alfa-2b regimen has been demonstrated as the standard of adjuvant therapy for resected melanoma. But the subgroup of mucosal melanoma seems more aggressive and insensitive to immunotherapy. So we conducted a phase II study (ChiCTR-TRC-11001798) to compare Interferon regimen with chemotherapy as adjuvant therapy for this particular subgroup pts. Methods: Resected mucosal melanoma pts were randomized to observation (Group A) or receive postoperative adjuvant Interferon (IFN) alfa2b 15 MU/m2/day for 5 days/week X 4 weeks followed by 9 MU/m2 three times each week for 48 weeks (Group B), or chemotherapy with temozolomide 200 mg/m2 d1-5 + cisplatin 25 mg/m2 d1-3, repeated every 3 Weeks X 6 cycles (Group C). Results: 189 patients were enrolled and 184 patients were eligible for survival analysis. With a median follow-up of 26.8 months, the median RFS for Group A, B and C were 5.4, 9.4 and 20.8 months, respectively (P&lt;0.001). Estimated median OS for Group A, B and C were 21.2, 41.1 and 49.6 months (P&lt;0.001), respectively. Toxicities were generally mild to moderate. Conclusions: Chemotherapy significantly improved RFS and OS as adjuvant therapy for mucosal melanoma pts over HDI regimen or observation. This trial suggests that different subgroup of melanoma may need different adjuvant therapy.

Side effects in melanoma patients receiving adjuvant interferon alfa-2b therapy: a nurse’s perspective

The aim of this review was to examine the toxicity profile of adjuvant interferon (IFN) alfa-2b in melanoma patients from a nursing perspective and to summarize practical information to guide the effective management of common IFN toxicities to improve patient comfort. This is a narrative summary of both research and review articles identified by searching PubMed, National Cancer Institute, and American Cancer Society websites. It also assesses recognized guidelines on the management of adjuvant IFN toxicity relevant to nurses who are caring for patients receiving adjuvant IFN therapy. Adjuvant high-dose IFN alfa-2b (HDI) as compared with observation significantly prolongs relapse-free survival in patients with melanoma at high risk for recurrence after surgical resection; however, treatment compliance and patient quality of life can be compromised by its toxicity profile. HDI toxicities affect a number of organ systems and the majority of patients will experience some side effects. Common toxicities such as flu-like symptoms, fatigue, anorexia, neuropsychiatric symptoms, and laboratory abnormalities are discussed, along with both pharmacological and nonpharmacological management strategies. The considerable side effects of HDI can be managed using established strategies. Oncology nurses play a significant role in the management of patients with melanoma receiving adjuvant HDI, and their prompt recognition of side effects, together with an understanding of effective pharmacological and nonpharmacological interventions, will improve patient comfort; this has the potential to positively influence treatment adherence and completion of the recommended treatment course.

Long-Term Results of a Randomized, Observation-Controlled, Phase III Trial of Adjuvant Interferon Alfa-2b in Hepatocellular Carcinoma After Curative Resection

To investigate the clinical efficacy of adjuvant interferon alfa-2b (IFNα-2b) therapy on recurrence-free survival (RFS) of patients with postoperative viral hepatitis-related hepatocellular carcinoma (HCC). Despite most individual trials have failed to meet their primary endpoint, recent pooled-data meta-analyses suggest that adjuvant IFN therapy may significantly reduce the incidence of recurrence in curatively ablated HCC. Patients with curative resection of viral hepatitis-related HCC were eligible, and were stratified by underlying viral etiology and randomly allocated to receive either 53 weeks of adjuvant IFNα-2b treatment or observation alone. The primary endpoint of this study was RFS. A total of 268 patients were enrolled with 133 in the IFNα-2b arm and 135 in the control arm. Eighty percent of them were hepatitis B surface antigen seropositive. At a median follow-up of 63.8 months, 154 (57.5%) patients had tumor recurrence and 84 (31.3%) were deceased. The cumulative 5-year recurrence-free and overall survival rates of intent-to-treat cohort were 44.2% and 73.9%, respectively. The median RFS in the IFNα-2b and control arms were 42.2 (95% confidence interval [CI], 28.1-87.1) and 48.6 (95% CI, 25.5 to infinity) months, respectively (P = 0.828, log-rank test). Adjuvant IFNα-2b treatment was associated with a significantly higher incidence of leucopenia and thrombocytopenia. Thirty-four (24.8%) of treated patients required dose reduction, and 5 (3.8%) of these patients subsequently withdrew from therapy because of excessive toxicity. Adjuvant IFNα-2b only temporarily suppressed viral replication during treatment period. In this study, adjuvant IFNα-2b did not reduce the postoperative recurrence of viral hepatitis-related HCC. More potent antiviral therapy deserves to be explored for this patient population. This study is registered at ClinicalTrials.gov and carries the identifier NCT00149565.

Health-related quality of life in patients with high-risk melanoma randomised in the Nordic phase 3 trial with adjuvant intermediate-dose interferon alfa-2b

PurposeTo compare health-related quality of life (HRQoL) and side-effects in patients with high-risk melanoma participating in a randomised phase III trial of adjuvant interferon alfa-2b (IFN). Patients and methodsA total of 855 patients with histologically verified resected cutaneous melanoma in AJCC stage IIb (T4 N0 M0) or stage III (Tx N1-3 M0) were randomised to: Arm A: observation only (n=284); Arm B: 1-year treatment: induction: IFN alfa-2b, 10 MU (flat dose), SC, 5days/week, 4weeks, maintenance: IFN alfa-2b, 10 MU (flat dose), SC, 3days/week for 12months (n=285); or Arm C: 2years of same treatment as Arm B. HRQoL was assessed using The European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) before randomisation and at 8 pre-defined time-points during 2years. IFN-related side-effects were assessed by a study-specific questionnaire. Results>80% of eligible patients returned questionnaires at the different assessment points. Statistically significant interactions between randomisation arm and time after randomisation were found for almost all EORTC QLQ-30 variables. While patients in Arm A improved or remained at baseline levels; patients in Arms B and C reported decreased functioning and quality of life, and an increase in side-effects during their treatment. Patients in Arm B improved after the 12th month assessment, when IFN treatment was scheduled to end, to the 16th month assessment (p<0.001). The same pattern of improvement was found for 5 of 7 interferon-related side-effects. ConclusionA significant negative impact on HRQoL of IFN treatment was demonstrated, however the impact were reversible when treatment was stopped.

Current approaches to adjuvant therapy of melanoma

The incidence of malignant melanoma is rising faster than any other solid tumour and in young adults melanoma is the most common tumour type. In spite of improved early recognition and early treatment melanoma mortality rates are increasing. The therapeutic management of melanoma is challenging and the tumour remains among the most resistant tumour types to medical treatment. Surgical removal of the primary tumour is virtually the only curative approach presently available. To prevent disease recurrence in high-risk patients, stage IIB–IIC disease without lymph-node metastases or stage III, who have a 5-year survival of 24−67% [1] different adjuvant treatments have been tested. Up to now interferon alfa-2b has been the most frequently investigated. The Eastern Cooperative Oncology Group (ECOG) E1684 Trial demonstrated prolonged relapsefree survival (RFS) and prolonged overall survival in patients treated with adjuvant high-dose interferon alfa-2b [2]. In the confirmatory Trial E1690, however, this survival benefit could not be reproduced. The E1690 Trial showed improved RFS, but did not show a benefit in overall survival with the high-dose interferon alfa-2b regimen [3]. Since the toxic effects of the high-dose interferon regimen has been of concern the question was raised whether lower doses of interferon alfa-2b would be a less toxic alternative to high doses. The EORTC 18952 Trial explored intermediate-dose interferon alfa-2b and showed significant improvement in RFS, but no effect on overall survival [4]. Similarly, the recent Nordic Melanoma Collaborative Group Trial [5] also demonstrated a significant improvement in RFS compared with untreated controls, but no survival benefit. In the 18991 EORTC Trial with pegylated interferon alfa-2b (PEG-IFN-alfa-2b), a drug preparation allowing more convenient drug administration, i.e. once-weekly injection, demonstrated significant prolongation of RFS, but no significant improvement in overall survival [6]. Meta-analysis

Health-related quality of life (HRQOL) in the Nordic randomized trial of adjuvant intermediate-dose interferon alfa-2b in high-risk melanoma.

8547 Background: A total of 855 patients with histologically verified resected cutaneous melanoma in AJCC stage IIb (T4 N0 M0) or stage III (Tx N1-3 M0) were randomized to: Arm A: Observation only (n=284), to Arm B: One year treatment - Induction: IFN-α2b, 10 MU (flat dose), SC, 5 days/w, 4 weeks, Maintenance: IFN-α2b, 10 MU (flat dose), SC, 3 days/w for 12 months (n=285), or to Arm C: Two years treatment - Induction: Same as arm B Maintenance: IFN- α2b, 10 MU (flat dose), SC, 3 days/w for 24 months (n=286). Adjuvant intermediate-dose IFN-a2b was delivered with moderate and expected toxicities in both 1- and 2 year treatment arms. No significant effect of adjuvant IFN treatment on overall survival was observed (J Hansson et al. Lancet Oncol, 12: 144-152, 2011). Aim: To compare HRQOL between the three randomization arms during two years from inclusion in the study. Methods: HRQOL was assessed by the EORTC-QLQ C30 questionnaire before randomization, and at 3, 6, 9, 12, 16, 20 and 24 months after inclusion. Questionnaire completion rate was high at all points of assessment (>80%). Results: Overall, Arm A improved or remained at the same level as at inclusion, while functioning and quality of life decreased and symptoms increased during treatment in Arms B and C. Arm B improved, reaching levels comparable to Arm A, between months’ 12 and 16 assessments when IFN alfa-2b treatment was stopped. In the longitudinal analyses, statistical significant interactions between randomization arm and time were found for all the HRQOL scales, indicating that treatment effect differed over time (p<0.001). Conclusions: The results of this study revealed significant effects of IFN alfa-2b treatment on HRQOL. The impact on HRQOL is important to consider as part of the decision process on whether or not to use adjuvant Interferon.

A randomized phase II trial of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in high-risk acral melanoma patients.

8544 Background: Acral melanoma (AM) is the predominant subtype of cutaneous melanoma in the Chinese population. Clinical trials on adjuvant therapy have not previously been reported in this subgroup. Therefore, we conducted this exploratory study in order to observe potential optimal dose intensity and duration of high-dose interferon (HD-IFN) in Chinese postoperative high-risk AM patients. Methods: Patients with resected high-risk (stages IIb-IIIc) AM were randomly assigned to a regimen of 4-week (arm A: 15×106 U/m2 d1-5/w×4w) or 1-year adjuvant HD-IFN (arm B: 15×106 U/m2 d1-5/w×4w, 9×106 U tiw×48w), respectively. The endpoints were relapse-free survival (RFS), overall survival (OS) and toxicities. Results: 158 postoperative patients with AM of stage IIb-IIIc were enrolled in this study, of whom 147 patients were eligible for survival analysis. With a median follow-up of 36.1 months, median RFS for arm A (4 weeks) and arm B (1 year) were 17.9 months and 22.5 months, respectively (P=0.72). There was a trend towards longer RFS with arm B (1 year) although not statistically significant. Stratified analysis demonstrated that RFS of very-high-risk patients (IIIb-IIIc) was statistically shorter in arm A compared with arm B (7.6 months and 12.0 months, respectively; P=0.02). The median RFS of patients with more nodal metastases (n ≥3) was shorter in arm A compared with arm B (3.3 months and 11.9 months, respectively; P=0.004). In addition, there were no statistical differences between groups stratified by age, gender and primary ulceration. Safety analysis showed the most common adverse effects to be Grade 1/2 flu-like symptoms, fatigue, hepatotoxicity, hematologic toxicity and anorexia in both arms; patients in arm B had higher incidence of Grade 3/4 hepatotoxicity (P=0.03), but these were reversible. Conclusions: The preliminary results of this study demonstrated no statistically significance were detected in RFS between the 4 weeks and 1 year regimen for all the high-risk population, while a 1-year regimen showed a significant clinical benefit in patients with stage IIIb-IIIc AM or nodal metastases ≥3. Further survival data are needed for long-term follow-up.

Randomized phase III trial of high-dose interferon alfa-2b (HDI) for 4 weeks induction only in patients with intermediate- and high-risk melanoma (Intergroup trial E 1697) .

8505 Background: To assess the benefit of 4 weeks of HDI compared with observation (obs) in relation to the relapse free survival (RFS) and overall survival (OS) of patients (pts) with resectable intermediate and high-risk melanoma Methods: Pts with intermediate and high-risk melanoma defined as T3 (AJCC 6th ed. >Breslow thickness 1.5mm (AJCC 7th ed. >2.0mm) or any thickness with microscopically positive node disease (N1a-N2a) were randomized to receive postoperative adjuvant Interferon (IFN) alfa2b 20 MU/m2/day for 5 days/week X 4 weeks or observation. Primary endpoints of the trial were RFS and OS. A sample size of 1420 pts was chosen to detect a 15% relative increase in the median time-to-event for those not cured and a 7.5% absolute increase in the cure rate with 88% power at a 5% level of significance, using a two-sided log-rank test. Results: Between December 1998 and October 2010, 1150 pts were enrolled – 581 assigned to HDI and 596 to obs. The breakdown of stage at entry was as follows: T2N0: 22%, T3N0: 45%, T4N0: 14%, T1-4, N1a-2a:19%. Primary ulceration was present in 36% of pts. A third interim analysis of this trial was carried out in August 2010 with RFS data in 838 and OS data in 1091 pts. The 234 RFS events correspond to 69.0% information time, while the 134 OS events correspond to 74% information time. Median RFS for Obs was 7.3 years (95% CI 5.3, 9.8; n=413) while for IFN, RFS was 6.8 years (95% CI 5.1, 9.0; n=425). The 5-year survival rate for OBS was 0.85 (95% CI .81, .89; n=535) while for IFN induction-only the 5-year survival rate was 0.82 with (95% CI .78, .86; n=556). Accrual to the trial has therefore been terminated. Conclusions: Adjuvant HDI induction with only 4 weeks therapy neither improved RFS nor OS over observation for pts with intermediate and high-risk melanoma. This trial supports the importance of HDI treatment duration and argues that the approved 1 year Interferon regimen of induction followed by maintenance remains the standard of care for pts with T4N0 or node positive disease.

Adjuvant interferon: extended follow-up times needed?

1 presented results from the Nordic IFN trial. Their fi ndings support results from earlier studies, showing a clear eff ect of adjuvant high-dose interferon alfa-2b on relapse-free survival in patients with high-risk melanoma, but no or a small eff ect on overall survival. In past investigations, this discrepancy might be partly explained by in suffi cient follow-up time because many studies have been prematurely fi nalised before most of the expected deaths had occurred. 2,3 Therefore, an important merit of the Nordic IFN trial is its long length of follow-up; however, this time might still not be long enough. Stadler and colleagues' study 4

Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial

Adjuvant high-dose interferon alfa-2b improves relapse-free survival (RFS) in patients with high-risk melanoma, although benefits in overall survival are uncertain. Because of the toxic effects of high-dose regimens, intermediate doses are being explored. We investigated whether adjuvant therapy with intermediate-dose interferon alfa-2b for 1 or 2 years would improve outcomes in patients with stage IIB-IIC or III resected cutaneous melanoma. This randomised, open-label, phase 3, parallel-group trial was undertaken between 1996 and 2004. 855 patients were randomly assigned at 35 centres in the Nordic countries by block randomisation to three groups: observation only (group A); 4 weeks of induction (interferon alfa-2b 10 million units flat dose subcutaneously 5 days per week) followed by 12 months of maintenance therapy (interferon alfa-2b 10 million units flat dose subcutaneously 3 days per week; group B); or 1 month of induction and 24 months of maintenance (group C). Neither investigators nor patients were masked to treatment assignment. Patients were stratified for country and tumour stage; patients with stage III disease were further stratified for presence of metastatic lymph nodes at primary diagnosis versus at relapse, palpable versus non-palpable lymph-node metastases, and number of metastatic lymph nodes. The primary endpoint was overall survival in the two interferon alfa-2b groups combined. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01259934. 284 patients were assigned to group A, 285 to group B, and 286 to group C; all patients were analysed. The median follow-up time was 72·4 months (IQR 46·9-98·0). We recorded no significant improvement in overall survival in patients given interferon alfa-2b compared with observation: median overall survival was 56·1 months (IQR 22·3 to >120·0) in group A, 72·1 months (25·8 to >120) in group B, and 64·3 months (24·7 to >120) in group C (p=0·600). Hazard ratios (HR) for overall survival were 0·91 (95% CI 0·74-1·10; p=0·642) for groups B and C combined versus observation; 0·91 (0·72-1·14; p=0·652) for group B versus observation; and 0·91 (0·72-1·15; p=0·858) for group C versus observation. Median RFS was 23·2 months (IQR 5·6 to <120) in group A, 37·8 months (10·8 to >120) in group B, and 28·6 months (8·6 to >120) in group C (p=0·034). HRs for RFS were 0·80 (0·67-0·96; p=0·030) for groups B and C combined versus observation, 0·77 (0·63-0·96; p=0·034) for group B versus observation, and 0·83 (0·68-1·03; p=0·178) for group C versus observation. The most common grade 3 and 4 adverse events were fatigue (five in group A [1·8%], 28 in group B [9·8%], and 32 in group C [11·2%]), myalgia (three [1·1%], 15 [5·3%], 14 [4·9%], respectively), and thrombocytopenia (15 [5·3%], 23 [8·1%], eight [2·8%], respectively). Adjuvant therapy with intermediate-dose interferon alfa-2b did not significantly improve overall survival. Interferon alfa-2b with 1-year maintenance therapy significantly improved RFS, but we recorded no significant effect for 2-year maintenance therapy. Further research is in progress to define the subgroup of patients who benefit from adjuvant interferon alfa-2b. Schering-Plough (now Merck); the Radiumhemmet Research Funds, Stockholm; the Stockholm County Council; and the Swedish Cancer Society.