Adjuvant Interferon Alfa-2b Research Articles

Adjuvant interferon therapy for malignant melanoma:the debate

Based on the results of the Kirkwood high-dose interferon alpha-2b (HDI) adjuvant therapy trial of the Eastern Cooperative Oncology Group 1684, the US Food and Drug Administration (FDA) approved HDI as the postoperative adjuvant therapy for high-risk melanoma. Unfortunately, controversies continue regarding the use of interferon (IFN) as adjuvant therapy for melanoma owing to the inconsistent results of subsequent trials. Numerous trials of adjuvant interferon therapy demonstrated a benefit in terms of relapse-free survival (RFS), but without confirmed significant effect on overall survival (OS). The optimal timing, dose, and type of interferon are not yet defined. Therefore, adjuvant interferon treatment is preferentially applied in the randomized clinical trials in specialized centers. Decisions about the appropriateness of adjuvant interferon alfa-2b treatment for patients should be made on an individual basis, after discussion with the patient, including an explanation of the potential benefits and side effects of interferon therapy. Moreover, we also need to use available regimens reasonably, seek feasible and predictable prognostic factors to serve patients with individualized therapy.

Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macro-metastatic nodes: EADO trial.

LBA8506 Background: Adjuvant therapy with low-dose adjuvant interferon alfa-2b (IFN) as well as with pegylated interferon alfa-2b (PEG-IFN) were both shown to be superior to observation in melanoma (M) patients (pts) without macro-metastatic nodes. However, the two strategies have never been assessed head to head. Weekly injection of PEG-IFN facilitates a longer duration of treatment which may be critical for benefit. We thus compared adjuvant therapy of flat low-dose PEG-IFN (36 months) versus low-dose IFN (18 months) in intermediate-risk M pts without macro-metastatic nodes. Methods: In this multicenter, open-label, prospective randomized phase III trial, pts with resected M ≥ 1.5 mm in thickness and without clinically detectable nodes were randomized either to IFN (3 MU subcutaneously [sc] 3 times a week for 18 months) or to PEG-IFN (100 mcg sc once weekly for 36 months). Sentinel node procedure (SNP) was not a standard in 2003 and thus was optional. Approach was consistent by center. Randomization was stratified for centers and SNP procedure. Primary endpoint was relapse-free survival (RFS), and secondary were distant metastasis-free survival (DMFS), overall survival (OS), and grade 3-4 severe adverse events (SAE). Sample size (890 pts) was calculated to detect a 10% difference (power >80%, type I error of 5%, 2-sided) for RFS. Analysis describes 5-year probability of survival. Comparisons were done by intent-to-treat using Cox proportional models. Results: Of 898 pts enrolled, 896 (443 PEG vs 453 IFN) were eligible for evaluation after a median follow-up of 4.7 years. SLNB was performed in 68.2% of pts. Neither RFS (PEG-IFN 66.2% vs IFN 64.8%, p=0.43; HR, 0.91; 95% CI, 0.73 to 1.15) nor DMFS (71.3% vs 72.6%, p=0.86; HR, 1.02; 95% CI, 0.80 to 1.32) or OS (77.0% vs 78.4%, p=0.55; HR, 1.09; 95% CI, 0.82 to 1.45) showed statistical difference. There was an excess of SAE grade 3-4 in PEG-IFN arm (44.6% vs 26.6% in the first 18 months) which impacted on median duration of treatment (17.8 months in IFN arm; 19.2 in PEG-IFN arm, with only 28% completing 36 months treatment). Conclusions: Flat low-dose PEG-IFN did not show superiority over conventional low dose IFN. Attempts to increase benefit by prolonging treatment with PEG-IFN over 3 years were hampered by a high rate of treatment discontinuation possibly linked to SAEs with PEG-IFN. [Table: see text]

Phase III Trial Comparing Adjuvant Treatment With Pegylated Interferon Alfa-2b Versus Observation: Prognostic Significance of Autoantibodies—EORTC 18991

Conflicting data have been reported concerning the prognostic value of autoimmune antibodies in patients with melanoma treated with adjuvant interferon alfa-2b (IFN). We evaluated the prognostic significance of autoantibodies in the European Organisation for Research and Treatment of Cancer 18991 trial, comparing long-term administration of pegylated IFN (PEG-IFN) with observation. Anticardiolipin, antithyroglobulin, and antinuclear antibodies were determined by enzyme-linked immunosorbent assays in 296 patients before random assignment and every 6 months after random assignment for up to 5 years. Prognostic impact of autoantibodies on recurrence-free survival (RFS) was assessed using the following three Cox models: a model that considered autoantibody appearance as a time-independent variable (model 1); a model that considered a patient to be autoantibody positive from the first positive test (model 2); and a model in which the most recent autoantibody test was used to define the status of the patient (model 3). Patients who were autoantibody negative at baseline were analyzed (n = 220). Occurrence of autoantibodies during follow-up was higher in the PEG-IFN-treated patients (18% in the observation arm v 52% in the PEG-IFN arm). Autoantibody appearance was of prognostic importance by using model 1 (hazard ratio [HR] = 0.56; 95% CI, 0.36 to 0.87; P = .01). However, when guarantee-time bias was taken into account using model 2 (HR = 1.19; 95% CI, 0.75 to 1.88; P = .46) or method 3 (HR = 1.14; 95% CI, 0.71 to 1.83; P = .59), significance was lost. Results were similar when treatment groups were analyzed separately. Appearance of autoimmune antibodies is neither a prognostic nor a predictive factor for improved outcome in patients with melanoma treated with PEG-IFN.

Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial

Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.

Interferon alfa-induced autoimmunity and serum S100 levels as predictive and prognostic biomarkers in high-risk melanoma in the ECOG-intergroup phase II trial E2696

8506 Background: Uncontrolled evidence demonstrates that adjuvant high-dose interferon alfa-2b (HDI) benefit in high-risk melanoma patients is predicted by autoimmunity induction, and the prognosis of melanoma has been correlated with levels of S-100 protein. We have evaluated these two serological markers in the context of a completed phase II study E2696. Methods: Patients with resectable AJCC stage IIB, III, and IV melanoma were randomly assigned to receive GM2-KLH/QS-1 (GMK vaccine) plus concurrent HDI (Arm A) or GMK plus sequential HDI (Arm B), or GMK without HDI (Arm C). Sera from 103 patients were banked at baseline and 3 additional time points, and have been tested for serum protein S100, and anti-nuclear, anti-thyroid peroxidase, anti-thyroglobulin, anti-mitochondrial, and total anti-cardiolipin autoantibodies (AA) using ELISA. Results: At a median follow-up of 96.5 mo (range: 17–109), the median relapse-free survival (RFS) was 28.3 mo, 95% CI (18.4, 43.6) (64 /103 patients relapsed). Median survival has not been reached (54/103 alive). AA were induced in 17 subjects (25%; n=69) receiving HDI and GMK versus 2 (6%; n=34) receiving GMK alone (2p-value=0.031). In HDI arms induced AA were detected = 12 weeks after therapy initiation. RFS was improved among HDI recipients with AA, but with the limited numbers in this phase II trial this trend does not achieve significance. In the multivariate (Cox regression model) analysis, adjusting for treatment (HDI vs. no HDI) and baseline S-100 value for later time points, S-100 level ≥0.08 microg/l was an independent prognostic factor for RFS at baseline (HR=1.96; p=0.0273), week 4–6 (HR=1.72; p=0.073), wk 12–14 (HR=1.81; p=0.048) and wk 52 (HR=4.3; p<0.001). The hazard ratio (HR) for OS was 1.86 at wk 12–14 (p=0.061), and 5.7 at wk 52 (p<.001). In the model using wk 52 S-100 value (at completion of HDI), the HR adjusted for treatment was 7.1 p=0.009. Conclusions: Autoimmunity is a predictive biomarker of RFS with HDI in the E2696 trial compared to GMK. Serum protein S-100 level ≥0.08 microg/l is an independent prognostic marker for RFS and OS most significant at baseline and 1 year of followup. Current studies will evaluate these markers in the larger phase III trial E1694 with 880 subjects. [Table: see text]

A randomized phase III trial of 1 month versus 1 year adjuvant high-dose interferon alfa-2b in patients with resected high risk melanoma

8505 Background: High dose IFNa regimen as reported in E1684 was unique for the incorporation of an induction phase of maximally-tolerated dosages of IV therapy for the initial 4 weeks. This is the only trial that has shown prolongation of overall survival and disease-free survival in comparison to observation. Analysis of the hazard curves for DFS and OS in E1684 reveal early and durable separation of the high-dose and observation arms suggesting that the induction phase may represent a critical component of the high-dose regimen, although this has not been tested prospectively. Methods: We conducted a prospective randomized study of IV induction therapy vs a full year of high-dose IFN with primary endpoints of DFS and OS for stage IIB, IIC and III melanoma patients within 56 days of curative surgery. Patients were randomized to receive IFN alfa-2b 15×106 U/m2 IV × 5/7 days weekly × 4 weeks (arm A) versus the same regimen followed by 10×106 U(flat dose) SC 3 times a week for 48 weeks (arm B). The proposed treatment would be considered at least as good as the conventional treatment, if the relapse rate at 3 years from study entry is at most 15% higher in the former arm (power 85%, one-sided test a=0.05, required sample size: 340). Results: Between 1998 and 2004, 364 patients were enrolled (355 eligible: 178 arm A and 177 arm B). Patients′ and tumor characteristics were well balanced between the two arms. At a median follow up of 51 months (95% CI 46–55), the median DFS is 32 months vs 31 months (p=0.836) and the median OS is 61 months vs 63 months (p=0.444). Eleven patients discontinued treatment in arm A and 54 in arm B. The discontinuation rate is significantly higher in group B (p<0.001), possibly due to the longer duration. Reasons for discontinuation were disease progression (69%) and toxicity (19%). Patients in arm B had more grade 3–4 hematologic, constitutional and neurologic toxicity. Conclusions: There are no significant differences in OS and DFS between the regimen of 1 month and 1 year treatment tested. [Table: see text]

Protein S-100β serum levels predicts clinical outcome of high-risk melanoma patients treated with high-dose adjuvant interferon alfa2b

8543 Background: S-100β serum levels have been shown to be useful to monitor response to therapy in metastatic melanoma patients. We have recently reported that S-100β levels could also be useful in the adjuvant context. In this study we analyze the clinical relevance of S-100β serum levels in an homogeneuos stage IIB-III group of patients treated with high-dose interferon. Methods: Patients with melanoma diagnosis were prospectively tested for serum S-100β protein by luminoimmunometric assay (LIA) before starting interferon (baseline) and every 3 months thereafter (on.therapy), until treatment was completed. Median time to progression and overall survival were assessed. Multivariate analysis using the Cox proportional hazards model with covariable dependent on time was perfomed since S-100β under therapy changes during time. Results: Ninety-seven patients were included. Median follow-up was 62.9 months (range 32.7–87.4). Median baseline S-100β levels were 0.06μg/l (range 0.06–0.53). S-100 was considered high (=0.15 μg/l) in 20.6% of the patients. High baseline S-100β levels were associated with positive lymph-node status (p=0.02). High S-100β levels (while on therapy) showed relation with positive lymph-node status (p=0.014), number of positive lymph-nodes (p=0.01), macroscopic lymph-node involvement (p=0.002) and second melanoma diagnosis at study entry (p=0.001). By univariate analysis, high baseline S-100β levels were associated with disease free survival (DFS) (p=0.004) and overall survival (OS) (p=0.0007). Similarly, high on therapy S-100β levels were associated with DFS (p<0.0001) and OS (p<0.0001). In the multivariate analysis, high on therapy S-100β levels (HR 1.029, CI95% 1.015–1.042; p<0.0001) was an independent prognostic factor for DFS. High on therapy S-100β levels (HR 1.017, CI 95% 1.10–1.026; p<0.0001) and high baseline S-100β levels (HR 3.31, CI 95% 1.10–9.89; p=0.032) were independent prognostic factors for OS. Conclusions: These results provide novel evidence of the clinical usefulness of serum S-100β levels determination for monitoring the clinical outcome of high-risk melanoma patients treated with adjuvant therapy. No significant financial relationships to disclose.

Interferon Alfa-2b or Not 2b? Significant Differences Exist in the Decision-Making Process between Melanoma Patients Who Accept or Decline High-Dose Adjuvant Interferon Alfa-2b Treatment

Patients with thick (Breslow>4 mm) primary melanoma and/or regional nodal metastasis have a high risk of tumor recurrence. High-dose adjuvant interferon (IFN) alfa-2b offers<or=10% improvement in relapse-free survival and overall survival with significant toxicity. The objective was to determine which prognostic factors and patient characteristics are significant in the decision to undergo IFN therapy. Of 781 patients who underwent sentinel lymph node (SLN) biopsy, 135 of 781 (17.3%) had positive SLN or thick melanomas and were informed of a >/=50% risk of recurrence/disease-related mortality and offered IFN. Telephone surveys delineated reasons behind patients' decisions to accept IFN. Acceptors, 60 of 135 (45%), decided to take IFN alfa-2b whereas 75 of 135 (55%) declined. Being female (OR, 2.4; 95% CI, 1.17-5.03; p=.017) and positive SLN status (OR, 2.2; 95% CI, 1.01-4.97; p=.048) were strongly associated with patients who chose IFN. Acceptors of IFN were younger, more influenced by physicians, and less affected by depression and side effect profile (p<.05 for all). Decliners were more concerned by strained relationships with family and social life (p<.05). Gender and positive SLN were predictive of high-risk melanoma patients' acceptance of IFN treatment. Physician insight into melanoma patients' therapeutic decision-making process can guide patients through this difficult disease.

Controversies on autoimmunity and prognosis in cancer

Sir, The presence of CD4+CD25+ regulatory T cells (Treg) in cancer patients might be, in part, responsible for downregulation of antitumour immune responses. Schaefer et al (2005) have shown the importance of Treg in defining the immune profile of cancer patients, illustrating the role of these cells in downregulating functions of other T-cell subsets. Their hypothesis was that lymphocyte homeostasis disrupted by the presence of tumour fails to normalise following successful therapy. Wei et al (2005) recently assessed the possible synergy of immune reactivity to defined tumour- and self-antigens following reduction of CD4+CD25+ Treg. In a Treg-deprived environment, tumour cells primed the immune system, with consequent tumour regression. Treg-depletion enhanced autoimmunity to mouse thyroglobulin (mTg) in resistant BALB/c mice. Concurrent tumour regression and mTg immunisation resulted in further elevation of both antitumour and anti-mTg immunity. There are various inhibitory mechanisms in T cells to prevent pathological autoimmunity. Blocking CTLA4 on T cells or depleting CD25+ Treg is sufficient to break self tolerance, causing nonspecific autoimmune pathologies (Phan et al, 2003). On the other hand, an association between autoimmunity and a favourable antitumour effect has been reported. Anti-CTLA-4 Ab given to patients with metastatic melanoma induces durable objective clinical responses associated with the induction of autoimmune side effects. The autoimmune and antitumour effects seen after CTLA-4 blockade appear to act through direct activation of CD4+ and CD8+ effector cells. In addition, inhibition of a signaling inhibitor in antigen-loaded dendritic cells (DCs) can induce a tumour-associated antigen-specific pathological autoimmune response against tumour. SOCS1-silenced DCs effectively break tolerance at the host level and cause self antigen-specific autoimmune pathologies against normal tissues but also against tumours (Evel-Kabler et al, 2006). As interferon alfa-2b has the ability to induce an immune response against autoantigens with serologic and clinical manifestations of autoimmunity, it is possible that it also induces an immune response against tumours. The appearance of autoantibodies or clinical manifestations of autoimmunity during treatment with high-dose adjuvant interferon alfa-2b was associated with statistically significant improvements in relapse-free survival and overall survival (Gogas et al, 2006). By contrast, the early presence of autoantibodies in the serum has been described to correlate with an unfavourable prognosis (de Visser et al, 2006). The occurrence of autoantibodies in the serum of cancer patients, and interstitial antibody deposition in human tumours have been widely reported. As CD4+ and CD8+ T-lymphocytes are important modulators of tissue-damaging B-lymphocyte responses, considered that Ig deposition occurs in human premalignant and malignant tissues, imbalanced adaptive-immune-cell interactions could represent underlying mechanisms that regulate the onset of chronic inflammation associated with cancer development (de Visser et al, 2006). While it could be possible to use autoimmune responses as surrogate markers to evaluate new treatments (Gogas et al, 2006), it might be highlighted that individuals with progressive tumours could produce a higher antigen load, therefore triggering greater antibody deposition (de Visser et al, 2006).

Verträglichkeit und Wirksamkeit einer adjuvanten Interferon-alfa-2b-Behandlung beim Aderhautmelanom

In this manuscript, the safety and efficacy of adjuvant interferon alfa 2b treatment of uveal melanoma is described. A total of 39 patients (23 male and 16 female, mean age 56.5 years, range 35-78 years) with uveal melanoma were treated with interferon alfa 2b, 3 million units three times a week subcutaneously for 1 year after therapy of the primary tumor. In all patients age, gender, primary melanoma data, therapeutic interventions, treatment side effects and outcome were documented. Of the 39 patients, 31 (80%) finished the treatment as scheduled after 1 year. In 18 patients (46%) the initial dose had to be reduced due to leucopenia, thrombopenia, cardiac symptoms, elevated of liver function or vertigo (WHO grade I-III). In eight patients, therapy had to be withdrawn because of serious side effects (five patients) and the appearance of metastases (three patients). Neither a univariate approach nor a multivariate approach could show a protective effect of interferon treatment on survival. Adjuvant treatment of uveal melanoma with interferon alfa should be abandoned until the question of dose and administration for cutaneous melanoma is solved.

Prognostic Significance of Autoimmunity during Treatment of Melanoma with Interferon

Immunotherapy for advanced melanoma induces serologic and clinical manifestations of autoimmunity. We assessed the prognostic significance of autoimmunity in patients with stage IIB, IIC, or III melanoma who were treated with high-dose adjuvant interferon alfa-2b. We enrolled 200 patients in a substudy of a larger, ongoing randomized trial. Blood was obtained before the initiation of intravenous interferon therapy, after 1 month of therapy, and at 3, 6, 9, and 12 months. Serum was tested for antithyroid, antinuclear, anti-DNA, and anticardiolipin autoantibodies, and patients were examined for vitiligo. The median duration of follow-up was 45.6 months. Relapse occurred in 115 patients, and 82 patients died. The median relapse-free survival was 28.0 months, and the median overall survival was 58.7 months. Autoantibodies and clinical manifestations of autoimmunity were detected in 52 patients (26 percent). The median relapse-free survival was 16.0 months among patients without autoimmunity (108 of 148 had a relapse) and was not reached among patients with autoimmunity (7 of 52 had a relapse). The median survival was 37.6 months among patients without autoimmunity (80 of 148 died) and was not reached among patients with autoimmunity (2 of 52 died). In univariate and multivariate regression analyses, autoimmunity was an independent prognostic marker for improved relapse-free survival and overall survival (P<0.001). The appearance of autoantibodies or clinical manifestations of autoimmunity during treatment with interferon alfa-2b is associated with statistically significant improvements in relapse-free survival and overall survival in patients with melanoma.

Vulvar melanoma in a 10-year-old girl in association with lichen sclerosus

Vulvar melanoma in a 10-year-old girl in association with lichen sclerosus

Tyrosinase mRNA in blood of patients with melanoma treated with adjuvant interferon.

To evaluate the clinical significance of the detection of circulating melanoma cells in patients treated with adjuvant interferon and to determine their potential value as a marker of interferon response. We prospectively analyzed 616 peripheral-blood samples from 120 melanoma patients with stage IIA (n = 33), IIB (n = 22), III (n = 50), or IV (surgically resected) (n = 15) disease receiving adjuvant interferon alfa-2b therapy. Tyrosinase mRNA was assayed by reverse transcriptase polymerase chain reaction (RT-PCR) as a marker of circulating melanoma cells before the start of interferon and every 2 to 3 months thereafter. With a median follow-up time of 32.3 months (range, 7.1 to 77.5 months), 47 patients (39.8%) relapsed and 31 (26%) died. During adjuvant interferon treatment, 76 patients (64%) had undetected circulating melanoma cells and 44 patients (36%) had a positive RT-PCR result in at least one sample. Actuarial 5-year disease-free survival was 62% in patients with persistently negative RT-PCR during interferon treatment and 38% for patients with positive RT-PCR during interferon (P =.02). Actuarial 5-year overall survival was 75% and 50%, respectively (P =.03). Patients with melanoma and tyrosinase mRNA detected in the blood during adjuvant interferon therapy had a worse prognosis compared with patients with undetected tyrosinase mRNA during treatment. Further investigation into the detection of circulating melanoma cells as a surrogate marker of response to adjuvant interferon therapy is warranted.

Quality-of-Life-Adjusted Survival Analysis of High-Dose Adjuvant Interferon Alfa-2b for High-Risk Melanoma Patients Using Intergroup Clinical Trial Data

PURPOSE: High-dose adjuvant interferon alfa-2b (IFNα2b) for high-risk melanoma is a 1-year regimen that improves relapse-free and overall survival but has significant toxicity. A quality-of-life–adjusted survival (QAS) analysis analysis of two cooperative group phase III trials, E1684 and E1690/S9111/C9190, was performed, incorporating patient values (utilities) for the toxicity of IFNα2b treatment and melanoma recurrence. PATIENTS AND METHODS: Quality-Adjusted Time Without Symptoms or Toxicity methodology was used with melanoma patient utilities and trial data to estimate the effect of IFNα2b on QAS. The increase or decrease in QAS that patients could expect from treatment was estimated based on their utilities. Eleven utility predictor questions were tested to identify patients with utilities that result in decreased QAS. RESULTS: Using E1684 data, IFNα2b would result in an increase in QAS for all sets of patient utilities. This benefit was significant (P < .05) for 16% of patients. Using E1690/S9111/C9...

Developing Indications for the Use of Sentinel Lymph Node Biopsy and Adjuvant High-Dose Interferon Alfa-2b in Melanoma

To convene a multidisciplinary panel of dermatologists, surgical oncologists, and medical oncologists to formally review available data on the sentinel lymph node (SLN) biopsy procedure and high-dose adjuvant interferon alfa-2b therapy for patients with melanoma and to rate the "appropriateness," "inappropriateness," or "uncertainty" of the procedure and therapy to guide clinical decision making in practice. The panel comprised 13 specialists (4 dermatologists, 4 oncologists, and 5 surgeons) from geographically diverse areas who practiced in community-based settings (n = 8) and academic institutions (n = 5). Participants were chosen based on recommendations from the relevant specialty organizations. A formal literature review was conducted by investigators at Protocare Sciences Inc, Santa Monica, Calif, on the risks and benefits of performing an SLN biopsy in patients with stage I or II melanoma and adjuvant interferon alfa-2b therapy in patients with stage II or III disease. The MEDLINE database was searched from 1966 through July 2000, and supplemental information was obtained from various cancer societies and cancer research groups. Panel participants were queried on additional sources of relevant information. Unpublished, presented data were included in abstract form on 1 recently closed clinical trial. The RAND/UCLA Appropriateness Method was used to review and rate multiple clinical scenarios for the use of SLN biopsy and interferon alfa-2b therapy. The consensus method did not force agreement. The panel rated 104 clinical scenarios and concluded that the SLN biopsy procedure was appropriate for primary melanomas deeper than 1.0 mm and for tumors 1 mm or less when histologic ulceration was present and/or classified as Clark level 4 or higher. The SLN biopsy was deemed inappropriate for nonulcerated Clark level 2 or 3 melanomas 0.75 mm or less in depth and uncertain in tumors 0.76 to 1.0 mm deep unless they were ulcerated or Clark level 4 or higher. Interferon alfa-2b therapy was deemed appropriate for patients with regional nodal and/or in-transit metastasis and for node-negative patients with primary melanomas deeper than 4 mm. The panel considered the use of interferon alfa-2b therapy uncertain in patients with ulcerated intermediate primary tumors (2.01-4.0 mm in depth) and inappropriate for node-negative patients with nonulcerated tumors less than 4.0 mm deep. Specialty-specific ratings were conducted as well.

Patient preferences for adjuvant interferon alfa-2b treatment.

Although trials of adjuvant interferon alfa-2b (IFN alpha-2b) in high-risk melanoma patients suggest improvement in disease-free survival, it is unclear whether treatment offers improvement in overall survival. Widespread use of adjuvant IFN alpha-2b has been tempered by its significant toxicity. To quantify the trade-offs between IFN alpha-2b toxicity and survival, we assessed patient utilities for health states associated with IFN therapy. Utilities are measures of preference for a particular health state on a scale of 0 (death) to 1 (perfect health). We assessed utilities for health states associated with adjuvant IFN among 107 low-risk melanoma patients using the standard gamble technique. Health states described four IFN alpha-2b toxicity scenarios and the following three posttreatment outcomes: disease-free health and melanoma recurrence (with or without IFN alpha-2b) leading to cancer death. We also asked patients the improvement in 5-year disease-free survival they would require to tolerate IFN. Utilities for melanoma recurrence with or without IFN alpha-2b were significantly lower than utilities for all IFN alpha-2b toxicities but were not significantly different from each other. At least half of the patients were willing to tolerate mild-moderate and severe IFN alpha-2b toxicity for 4% and 10% improvements, respectively, in 5-year disease-free survival. On average, patients rate quality of life with melanoma recurrence much lower than even severe IFN alpha-2b toxicity. These results suggest that recurrence-free survival is highly valued by patients. The utilities measured in our study can be applied directly to quality-of-life determinations in clinical trials of adjuvant IFN alpha-2b to measure the net benefit of therapy.

Severe loss of vision during adjuvant interferon alfa-2b treatment for malignant melanoma

Severe loss of vision during adjuvant interferon alfa-2b treatment for malignant melanoma

Advances in melanoma therapy

This review discusses several advances in melanoma therapy that have recently occurred or are presently in a developmental stage. We discuss the history and present dogma regarding assessment of the regional lymph nodes and adjuvant therapy for melanoma. Of special interest is radiolymphatic sentinel node mapping of the lymph nodes and adjuvant interferon alfa-2b for thick primary lesions and stage III disease. We also discuss several evolving novel and innovative genetic immunotherapy approaches for patients with stage IV disease. (J Am Acad Dermatol 1998;38:731-41.)

PP34. Economic analysis of adjuvant interferon-ALFA 2B (IFN) in high risk melanoma using projections from ECOG (E) 1684

PP34. Economic analysis of adjuvant interferon-ALFA 2B (IFN) in high risk melanoma using projections from ECOG (E) 1684

Theoretical and Empirical Arguments in Relation to Elective Lymph Node Dissection for Melanoma

Nearly a century of clinical inquiry has failed to incontrovertibly resolve the question of whether elective lymph node dissection is therapeutically beneficial in the management of clinically localized melanoma. The controversy has been renewed by a recent interim update from the Intergroup Melanoma Surgical Program, sponsored by the National Cancer Institute, which has indicated a small survival benefit in a narrowly defined subgroup of patients with primary melanoma. That report stimulated this review of the data, which are presented in the historical context that originally prompted the Intergroup study. Case selection bias has intractably hindered firm conclusions from the numerous nonrandomized studies of elective lymphadenectomy. The two original randomized trials that were executed during the 1970s failed to uncover any significant effect of the procedure on survival. Definitive conclusions from the recent Intergroup report are limited by the likelihood that the observed therapeutic benefits are a chance occurrence resulting from uncorrected multiple subgroup comparisons. It remains uncertain whether elective lymphadenectomy can be therapeutically beneficial in the management of melanoma. Nevertheless, it is clear that the procedure, or preferably sentinel lymphatic mapping with selective lymphadenectomy, can provide clinically relevant prognostic information, as well as the staging data requisite to adjuvant interferon alfa-2b therapy or enrollment into other adjunctive trials for patients at high risk of clinical relapse.