Review Article

Author: Ahmad A. Tarhini, MD, PhD


High-risk resected melanoma signifies a group of patients that carries a risk of melanoma recurrence and death after initial surgical resection that may be defined as 35% to 40% or higher and includes patients with American Joint Committee on Cancer (AJCC) stages IIB, IIC, III, and IV. The development of local or regional recurrence after initial surgical management portends an even poorer prognosis.1-3 In the Melanoma Surgical Trial, a local recurrence was associated with 5- and 10-year survival rates of 9% to 11% and 5%, respectively.2 Residual micrometastasis is thought to be the source of future melanoma recurrence and death. This is where systemic adjuvant therapy may alter the course of this disease, presenting an opportunity for relapse-free survival (RFS) and overall survival (OS) benefits. Various therapeutic modalities, including immunotherapy, chemotherapy, biochemotherapy, and local radiation therapy, have been tested in the adjuvant setting over the past 3 decades.

Predictors of Risk in Operable Melanoma

The AJCC TNM staging system for melanoma divides patients into 4 stages based on the pathologic characteristics of the primary tumor, the status of the regional lymphatics, and the presence or absence of distant metastases. Stages I and II define localized melanoma that is restricted to the skin. Stage III is characterized by the presence of lymph node and/or in-transit metastases, while stage IV applies to distant metastatic spread.2 The depth of the primary tumor (Breslow’s tumor thickness) is the leading prognostic factor in stages I and II (absence of lymph node involvement) where the probability of survival declines as depth (measured in millimeters) increases. The presence of primary tumor ulceration proportionately lowers patient survival rates compared with those with nonulcerated tumors of the equivalent T category; survival rates are similar to patients with a nonulcerated melanoma of the subsequent T category. Increased mitotic rate (at least 1 mitosis/mm2) is strongly correlated with diminished survival rates, and in the 7th AJCC staging edition it has replaced the Clark level of invasion as a complementary criterion to ulceration for differentiating T1a versus T1b primary tumor.4

Melanoma spread to regional lymph nodes or the presence of intralymphatic (satellite or in-transit) metastasis defines stage III. There is no minimum limit of tumor burden defining the presence of regional nodal metastases in the 7th AJCC staging edition. Lymph node tumors less than 0.2 mm that were ignored in the 2002 staging version were included. Even minute lymph node deposits (including detection by immunohistochemical staining) are felt to be relevant to melanoma recurrence and mortality and currently signify a positive lymph node. For the same T stage, the nodal subclassification N1a (micrometastasis) and N1b (macrometastasis) constitute stage IIIA and stage IIIB, respectively. In-transit lymphatic metastases without and with lymph node involvement correspond to N2c and N3, respectively.2 It is noteworthy that this population of patients without distant spread of primary melanoma who are at high risk for recurrence and death is about 3 times the size of the population with metastatic disease.

In stage IV disease with distant metastases, lactate dehydrogenase (LDH) blood levels are significantly prognostic. The 1-year survival rate of patients with M1c disease (visceral metastases or any distant metastasis with high LDH) is 33%, as compared with 62% for M1a (distant skin, subcutaneous, and lymph node metastases) and 53% for M1b melanomas (lung metastases).2 Oligometastatic melanoma metastases that are amenable to surgical removal may derive survival benefits if chosen appropriately, and these patients may be candidates for systemic adjuvant therapy.5,6


The type I interferon (IFN) family includes IFN-alfa, IFN-beta, IFN-epsilon, IFN-kappa, and IFN-omega, whereas IFN-gamma constitutes the family of type II IFN. Among the IFNs, IFN alfa- 2 has been the most widely studied clinically, and 3 commercially available subspecies exist including IFN alfa-2a (Roferon-A), IFN alfa-2b (Intron A), and IFN alfa-2c. Mechanistically, IFN-alfa has multiple effects shown in a variety of malignancies that range from potent immunomodulatory and differentiation-inducing, to antiproliferative, proapoptotic, and anti-angiogenic.7 IFN-alfa promotes tumor immunogenicity and enhances dendritic cell (DC) response to the tumor, DC polarization or maturation, survival and antigen cross-presentation.7-9 IFN-alfa promotes a Th1 shift in host immunity against tumors, enhancing cell-mediated cytotoxicity, and has a role in attracting Th1 lymphocyte traffic to the tumor.10 Host type I IFNs were reported to be critical for the innate immune recognition of a growing tumor in vivo, leading to intratumor accumulation of CD8α+ DCs that promote tumor antigen-specific CD8+ T-cell responses.11 As tested clinically in the neoadjuvant setting in melanoma, IFN-alfa has shown a significant impact on signal transducer and activator of transcription (STAT) signaling.12

IFN-Alfa in the Treatment of Stage IV Inoperable Melanoma

For stageFor stage IV inoperable melanoma, IFN-alfa was the first recombinant cytokine to be investigated clinically for the therapy of advanced metastatic melanoma. Initial phase 1 and 2 studies yielded overall response rates of about 16%, and about one-third of the responders were reported to have complete responses. Responses were observed as late as 6 months from initiation of therapy, and up to one-third of the responses were durable.13,14 As an off-label systemic therapeutic option for stage IV inoperable melanoma, IFN-alfa has been used in the community for many years and continues to be used either as monotherapy or in combination as part of the biochemotherapy regimen (consisting of IFN-alfa, interleukin-2, dacarbazine, cisplatin, vinblastine).15-18

Adjuvant IFN-Alfa Trials

Adjuvant Regimens Testing High-Dose IFN-Alfa in Melanoma Evidence of activity of IFN-alfa in metastatic disease led to its testing in the adjuvant setting. The North Central Cancer Treatment Group (NCCTG) trial19 and the Eastern Cooperative Oncology Group (ECOG) trial E168420 were the first 2 adjuvant randomized controlled trials. Both trials tested a high-dose regimen of IFN-alfa (>10 million units (MU)/dosage).

ECOG E1684: This trial was initiated in 1984 and tested a high-dose regimen of IFN-alfa (HDI). HDI was administered intravenously (IV) at 20 MU/m2 for 5 consecutive days a week for 4 weeks as the induction phase followed by subcutaneous (SC) administration at 10 MU/m2 thrice weekly for 48 weeks as maintenance.20 A total of 287 patients were randomized to either HDI or observation postoperatively. All patients underwent regional elective lymph node dissection (ELND), and the majority of patients enrolled in this study had bulky nodal or recurrent disease. At a median follow-up of 6.9 years, HDI demonstrated a statistically significant impact on RFS and OS as compared with observation. The estimated 5-year RFS in the treatment arm was 37% (95% confidence interval [CI], 30%-46%) versus 26% (95% CI, 19%-34%) in the control group. Median RFS was 1.72 versus 0.98 years (P = .0023), hazard ratio (HR) = 0.61 (P = .0013). The 5-year OS was 46% (95% CI, 39%-55%) versus 37% (95% CI, 30%-46%) in the treatment and observation arms, respectively. Median OS was 3.82 versus 2.78 years (P = .0237); HR = 0.67 (P = .01). The highest impact on survival was observed in patients with high tumor burden (node-positive disease). The outcomes of this trial led to the regulatory approval by the US Food and Drug Administration (FDA) in 1995.7 The toxicity profile of HDI as observed in E1684 included a 67% incidence for grade 3 toxicity, 9% incidence for grade 4 toxicity, and 2 early therapyrelated hepatotoxic deaths. This profile raised concerns about patient tolerance and motivated further testing of regimens that varied by dosage level, route of administration, or duration of IFN-alfa therapy.21

E1690: This ECOG and US Intergroup trial followed suit, utilizing the E1684 HDI regimen as well as a low-dose regimen of IFN alfa-2b (LDI) at 3 MU SC thrice weekly for 2 years both compared with observation.22 Patient enrollment on E1690 lasted between 1991 and 1995, and at a median follow-up of 4.3 years, the 5-year estimated RFS rates were 44% for HDI, 40% for LDI, and 35% for the observation arm, respectively.22 The effect of HDI on RFS alone was significant (P = .03). Neither HDI nor LDI was found to establish OS benefit compared with observation (52% high dose vs 53 % low dose vs 55% observation). However, improved OS in the E1690 observation arm was notable in comparison with E1684 observation arm (median, 6 years vs 2.8 years). Unlike E1684, E1690 did not require elective lymph node dissection, and a retrospective analysis showed evidence of crossover of 38 patients from the observation arm at regional nodal recurrence to IFN-alfa salvage therapy that may have impacted the survival analysis in E1690.

E1694: This trial conducted by the US Intergroup compared HDI with a ganglioside vaccine (GMK). The GMK vaccine consisted of purified ganglioside GM2 coupled to keyhole limpet hemocyanin (KLH) and combined with the QS-21 adjuvant.23 Prior studies had shown evidence of immunogenicity and clinical activity. HDI showed improvement in RFS with HDI (HR = 0.68; P = .0015) and OS (HR = 0.66; P = .009) in the eligible population. Similar benefits were seen in the intent-to-treat analysis for RFS (HR = 0.67) and OS (HR = 0.72).21,23

E2696: This was an ECOG-led randomized, phase 2 trial that enrolled 107 patients with surgically resected stage IIB, III, and IV melanoma. The trial was conducted between 1998 and 2000.6 The primary objective was to test the immunogenicity of the GMK vaccine by measuring the anti-GM2 antibody response in the presence versus absence of HDI. The study compared 3 arms: arm A (GMK plus concurrent HDI), arm B (GMK plus sequential HDI), and arm C (GMK alone). The combination arms reduced the risk of relapse when compared with GMK alone (HR = 1.96 for C vs B, and HR = 1.75 for C vs A).

A pooled analysis of the 2 observation-controlled trials (E1684 and E1690) as updated through April 2001 showed that HDI maintained significant benefits in relapse at a median follow-up of 12.6 years for E1684 and 6.6 years for E1690.24 This analysis did not include E1694 in which the GMK vaccine served as control. The pooled analysis did not show significant evidence of OS benefit, where the larger of the 2 observation-controlled trials (E1690) did not show an OS benefit for HDI. In addition, the median follow-up of 12.6 years in E1684 introduces the strong possibility that competing causes of death led to the erosion of the OS benefits originally seen in this trial at the mature median follow-up of 6.9 years.20,22-24

Trials Testing Varying Dosing Levels, Routes of Administration, and Durations of Therapy

Multiple trials have tested regimens that vary by dosing levels, routes of administration, duration of therapy, and formulation. Table 1 summarizes the completed major phase III trials of adjuvant IFN-alfa in melanoma.

Table 1. Summary of Adjuvant Phase III Studies of Interferon-Alfa in Melanoma
The studies are classified as high-dose, medium-dose, and low-dose based on the dosage levels tested in the trials.

The Sunbelt Melanoma Trial: This trial looked at lymph node dissection (LND) after a positive sentinel lymph node versus LND plus standard HDI.25 This trial failed to detect an OS or disease-free survival (DFS) benefit for HDI, but can be criticized for not reaching target enrollment, and was therefore underpowered to detect clinically significant differences.26 The Italian Melanoma Intergroup trial tested a shorter course of a more-intense IV dosing regimen versus HDI.27 No statistically significant differences in outcome were seen.

Hellenic He 13A/98 trial: The Hellenic Cooperative Oncology Group tested a modified, less-intense dosing regimen of HDI.28 Patients were randomized between 1998 and 2004 to an induction phase of 15 MU/m2 only versus the same induction phase followed by a modified maintenance phase of 10 MU flat dose (not per m2) thrice weekly for a year. At a median follow-up of 5.25 years and 182 patients per arm, there were no statistically significant differences in either RFS or OS. However, this study was also criticized for the relatively small sample size to allow the detection of clinically significant differences, in addition to the modified dosing regimen used.

E1697: The US Intergroup study E1697 targeted patients with resectable intermediate-risk melanoma (≥T3 or any thickness with microscopic nodal disease N1a-N2a).29 The study recruited 1150 patients between 1998 and 2010, and randomized them to 4 weeks of HDI (20 MU/m2/day IV for 5 days weekly) versus observation. In 2010, a third interim analysis deemed the efficacy futile, leading to study closure. A subsequent presentation at the American Society of Clinical Oncology (ASCO) meeting in 2011 reported no impact on either RFS or OS with this 4-week regimen.

Several trials investigated less-intensive dosing regimens in terms of IFN-alfa. These included the very-low-dose (1 MU SC every other day) as in the European Organization for Research and Treatment of Cancer (EORTC) 18871 study (stage IIB, IIIA).30 Low dose (≤3 MU SC thrice weekly) was tested in the WHO melanoma trial 16 (stage III),31 the low-dose arm of E1690 (T4, N1),22 the UKCCCR AIM-HIGH trial (stage IIB/III),32 the Scottish trial (stage IIB, III),33 and the 2010 German DeCOG study (T3anyN).34 Intermediate-dose regimens (5-10 MU/m2) were tested in the EORTC 18952 (T4 N1-2)35 and EORTC 18991 (TxN1)36 studies. Although these trials showed benefit in RFS for the IFN arms, this impact appeared to be lost with time. Support for this observation also comes from the French multicenter trial that indicated that the effect of IFN-alfa on RFS was lost on cessation of treatment.37

EORTC 18952: This trial enrolled 1388 patients with stage IIB/III melanoma between 1996 and 2000.35 Patients were randomized to 4 weeks of induction IFN-alfa at 10 MU IV 5 times a week, followed by 1 of 2 maintenance regimens given SC at 10 MU 3 days a week for 1 year versus SC 5 MU 3 days a week for 2 years. Both were compared with a third observation control arm. At a median follow-up of 4.65 years , the study reported a distant metastasis-free interval of 47% and 43% versus 40%, and an OS of 53% and 48% versus 48% for 2-year and 1-year regimens versus observation, respectively. Therefore, an improvement in OS was observed only in patients treated for 25 months with 5 MU IFN-alfa and not in those treated for 13 months with 10 MU IFN-alfa. These results supported the hypothesis that the duration of therapy might be more important than dosage.

DeCOG: A randomized phase III trial by the Dermatologic Cooperative Group (DeCOG) tested the combination of lowdose IFN (LDI)/dacarbazine or LDI alone versus observation, randomizing 441 patients with stage III (T, any N+, M0) melanoma.38 At a median follow-up of 4 years, the LDI group had a superior DFS (HR = 0.69) and OS (HR = 0.62). It is noteworthy that these results do not match with the earlier trials that tested LDI and showed no OS benefit, such as the Austrian (AMCG) trial22 and French (FCGM) trial.39

Pegylated Interferon

EORTC 18991: The EORTC 18991 trial tested adjuvant therapy with peg-IFN alfa-2b versus observation for AJCC stage III melanoma, recruiting 1256 patients from 2000 to 2002.36 The regimen consisted of an induction phase of peg-IFN given SC at 6 mcg/kg a week for 8 weeks followed by maintenance phase of once-weekly SC injections at 3 mcg/kg for up to 5 years. At a median follow-up of 7.6 years, the study showed an improvement in the primary endpoint of RFS (HR = 0.87; 95% CI, 0.76 -1.00; P = .05), but with no significant differences seen in OS or distant metastasis-free survival (DMFS) between observation and treatment. Subgroup analysis suggested that patients with microscopic nodal metastasis and ulcerated primary tumor derived the greatest benefit in terms of RFS, OS, and DMFS. The toxicity attrition rate during the study was 37%. Pegylated IFN-alfa was granted regulatory approval in the US as adjuvant therapy for high-risk resected melanoma with lymph node metastases.

Meta-Analyses of Adjuvant IFN-Alfa Trials

From 2002 through 2010, at least 4 different meta-analyses of melanoma adjuvant trials have been published.40-43 The largest was the 2010 meta-analysis by Mocellin et al.42 This meta-analysis included 14 randomized controlled trials (RCTs) published between 1990 and 2008 including 8122 patients, of whom 4362 subjects had received IFN-alfa. IFN-alfa was tested against observation in 12 RCTs, and 17 different comparisons were established. Four out of 14 comparators revealed a statistically significant OS benefit with IFN-alfa. The review concluded that adjuvant IFN-alfa therapy demonstrated a statistically significant 18% risk reduction for recurrence (HR = 0.82; 95% CI, 0.77- 0.87; P <.001) and 11% risk reduction for death (HR = 0.89; 95% CI, 0.83-0.96; P = .002). In this meta-analysis, no specific regimen, dosing, formulation, study design, or staging provided significant differences in overall HR estimates.

Adjuvant Biochemotherapy

S0008 was a SWOG-led intergroup phase III trial that tested a biochemotherapy (BCT) regimen administered over 9 weeks versus the standard 52-week HDI regimen.44 The BCT regimen consisted of 3 cycles of cisplatin, vinblastine, dacarbazine combined with low doses of IL-2 and IFN-alfa. At 6 years median follow-up, there was significant improvement in RFS for BCT compared with HDI (median, 4.0 years vs 1.9 years), but no improvement in OS. A higher rate of grade III/IV toxicity was observed in the BCT group than in the HDI group (76% vs 64%). It was observed that patients on the HDI arm were more frequently followed during therapy as clinically indicated with IFN-alfa, while BCT patients were seen every 3 months following completion of the 9-week BCT regimen. It is not clear whether this imbalance of early follow-up between the HDI and BCT arms may have affected the RFS outcome.

Adjuvant Trials Testing Vaccines

These trials tested peptide vaccines, ganglioside vaccines, and whole cells/cell lysates. A phase 3 trial for resected stage III/IV melanoma tested the polyvalent vaccine Canvaxin versus BCG vaccination and reported that both DFS and OS were worse in the Canvaxin group.45 The DERMA trial tested adjuvant therapy with MAGE-A3 protein in a randomized phase 3 study based on promising results from a previous study in metastatic melanoma.46 A recent press release reported that this trial did not reach its primary end point of RFS. However, it continues to be blinded in anticipation of the results of its second co-primary end point testing the vaccine’s therapeutic predictive value for a proinflammatory tumor gene expression profile. The Melacine vaccine trial conducted in the US showed some promise initially, but failed to sustain it. Similarly, an Australian study using vaccinia viral lysates in high-risk subjects following resection failed to show a statistically significant increase in RFS.47 The E1694 trial that tested GM2 with BCG and with KLH and a QS21 adjuvant (GMK) demonstrated no therapeutic impact for the vaccine.23

Adjuvant Trials Testing Immune Checkpoint Inhibitors

Two ongoing trials (EORTC 18071 and US Intergroup E1609) are testing ipilimumab in the adjuvant high-risk setting. Ipilimumab is a fully humanized immunoglobulin G1 kappa monoclonal antibody that targets CTLA-4. Phase 3 trials in advanced inoperable melanoma have demonstrated significant OS benefits at the dosage level of 3 mg/kg versus the Gp100 peptide vaccine (MDX010-20 trial),48 and at 10 mg/kg combined with dacarbazine versus dacarbazine alone (CA 184-024).49 EORTC 18071 is testing ipilimumab at 10 mg/kg versus placebo in patients with surgically resected stage III melanoma except those with in-transit metastases. The trial’s primary end point is RFS. At the 2014 ASCO Annual Meeting, Eggermont et al,50 reported the first results at a median follow-up of 2.7 years and with 951 patients randomized. Overall, 46.5% and 34.8% (P = .0013) of patients were relapse-free in the ipilimumab and placebo treatment arms, respectively. Grade 3/4 adverse events (AEs) occurred in more patients receiving ipilimumab compared with placebo and included gastrointestinal (15.9% vs 0.8%), endocrine (8.5% vs 0%), and hepatic events (10.6% vs 0.2%). It is noteworthy that the dosage level of ipilimumab used in this trial is higher than the current dosage level (3 mg/kg) approved by the FDA for inoperable metastatic melanoma. E1609 is a randomized phase 3 trial that is testing ipilimumab at 10 mg/kg or 3 mg/kg versus the current standard for adjuvant therapy in the US, HDI. When first designed, this trial was planned as a 2-arm study testing ipilimumab at 10 mg/kg versus HDI. However, upon presentation of the MDX010-20 trial results and regulatory approval of this dosage level as the standard for metastatic disease, E1609 was revised to add the 3 mg/kg-arm assessment. The study has 2 co-primary endpoints of RFS and OS and will also allow the assessment of the safety of the 2 dosage levels of ipilimumab relative to HDI. Plans are under way to develop the next generation of adjuvant trials involving PD-1/PD-L1 immune checkpoint blockers based on the highly significant clinical results with these agents in metastatic disease. S1404, which is designed to test pembrolizumab versus HDI in resected stage III and IV melanoma, is expected to begin in the last quarter of 2014.

AVAST-M Trial Testing Bevacizumab

The results of a preplanned interim analysis of the phase 3 AVAST-M trial were reported by Corrie et al51 at the 2014 ASCO Annual Meeting. This trial tested adjuvant bevacizumab versus observation in patients with stage II/III resected melanoma (N = 1343). At a median follow-up of 25 months, OS and DMFS were similar between treatment arms. An improvement in the disease-free interval (DFI) was observed (HR = 0.83; 95% CI, 0.70–0.98; P = .03). Longer follow-up is needed to better assess the modest DFI benefit seen and to evaluate the effect on the primary end point of OS at 5 years.

Adjuvant Trials of Inhibitors of BRAF/MEK

Activating mutations of BRAF are found in about 40% to 50% of melanomas, where 80% to 90% are V600E mutations in which glutamic acid has substituted for valine at the V600 locus. BRAF phosphorylates regulatory serine residues on MEK1 and MEK2; hence, mutation of BRAF activates the RAS/RAF/MEK/ERK pathway leading to tumor proliferation. The BRAF inhibitors vemurafenib and dabrafenib have achieved regulatory approval based on significant phase 3 trial impacts on RFS and OS.52 Recently, the BRAF/MEK inhibitor combination of dabrafenib and trametinib has also achieved regulatory approval based on significant phase 2 trial data.53 COMBI-AD is an ongoing phase 3 trial that, according to (NCT01682083), plans to randomize 852 patients with stage III BRAF V600E/K mutation-positive melanoma to combined adjuvant therapy with dabrafenib and trametinib versus placebo. The primary end point is RFS. In parallel, BRIM-8 plans to randomize 725 patients with stage IIC and III BRAF V600 mutation-positive melanoma to adjuvant vemurafenib versus placebo. Here too, the primary end point is DFS. Table 2 summarizes the major ongoing adjuvant trials in high-risk melanoma.

Table 2. Summary of Ongoing Adjuvant Trials in High-Risk Melanoma

Adjuvant Radiation Therapy

The risk of local or regional relapse for stage III surgically resected melanoma is 15% to 20%. A higher risk (estimated 30% to 50%) is found in the presence of high-risk features that include positive margins, involvement of 4 or more nodes, extracapsular lymph node extension, bulky disease (exceeding 3 cm in size), cervical lymph node location and recurrent disease.30 In these cases, adjuvant radiotherapy (RT) may be considered valuable for local disease control, although no OS benefit has been shown. Hypofractionation of radiation therapy appears to have a similar efficacy to standard radiation dosing regimens in melanoma.

A retrospective study from MD Anderson Cancer Center by Ballo et al54 included 160 patients who had surgery for any nodal metastasis treated with lymph node dissection followed by RT (30 Gy in 6 Gy fractions 2 times per week). The study demonstrated 10-year local, regional, and locoregional control rates of 94%, 94%, and 91%, respectively. Another study from Roswell Park Cancer Center and MD Anderson Cancer Center by Agarwal et al55 included 615 patients with clinically advanced, regional lymph node-metastatic disease. This study looked at surgery plus adjuvant radiotherapy versus surgery alone. A reduction in the regional recurrence rate was seen (10.2% vs 40.6%). Adjuvant radiotherapy was also significantly associated with 5-year regional disease control (P <.0001), DMFS (P = .0006), and disease-specific survival (P <.0001). A retrospective study by Strojan, et al56 also showed improvement in the local relapse rate at 2 years by using adjuvant radiotherapy versus surgery alone (78% vs 56%; P = .015) among patients with regionally advanced melanoma to the neck and/or parotid.

The Australia New Zealand Melanoma Trial Group/Trans-Tasman Oncology Group (ANZMTG 01.01/TRO G 02.01) recently reported results at a median follow-up of 40 months.57 This study tested adjuvant radiotherapy (48 Gy in 20 fractions) versus observation in 217 patients with nodal metastases who had lymphadenectomy. The study enrolled a high-risk population based on the number of nodes involved, extranodal spread, and maximum size of involved nodes. The risk of lymph-node field relapse was improved in the adjuvant radiotherapy group (20 relapses in RT vs 34 in observation; HR = 0.56; 95% CI, 0.32-0.98; P = .041). However, there were no statistically significant differences in RFS or OS.58-63


HDI is unique in demonstrating significant improvements in the risk of recurrence (E1684, E1690, and E1694) and death as compared with observation (E1684) and the GMK vaccine (E1694). Peg-IFN as tested in the EORTC 18991 trial met its primary end point of RFS improvement in stage III disease and received regulatory approval as adjuvant therapy. In the most recent and largest meta-analysis of 14 adjuvant IFN-alfa trials, IFN-alfa was associated with significant risk reductions in relation to both disease relapse and mortality (based on E1684 versus observation, E1694 versus the GMK vaccine and the Mocellin meta-analysis).23 Ongoing adjuvant trials are testing ipilimumab CTLA-4 blockade therapy (EORTC 18071 and US Intergroup E1609), BRAF inhibitors (BRIM-8 and COMBI-AD), and MAGE-A3 vaccine (DERMA). The RFS results of EORTC 18071 testing ipilimumab at 10 mg/kg are very encouraging, but there is a need to assess the adjuvant impact of the standard 3 mg/kg dosage level taking into account the toxicity profiles and the relative adjuvant impact of ipilimumab compared with HDI, which are being studied in E1609. The DERMA trial did not reach its primary end point of RFS but continues to be blinded relative to the therapeutic predictive value of a tumor gene expression signature. Future adjuvant trials to test anti-PD-1 antibody therapy are in the planning phases and are expected to be activated in the second half of 2014. Neoadjuvant studies with HDI and ipilimumab have added significant mechanistic insights and generated important preliminary biomarker data.64 Ongoing research nested within prior (E1697) or ongoing (E1609) adjuvant trials is focused on the development of biomarkers of disease-prognostic and therapy-predictive value, with the goals of individualizing patient therapy to those most likely to benefit, while saving others unwanted toxicities when agents are unlikely to work.

Affiliation: Ahmad A. Tarhini, MD, PhD, is associate professor of Medicine and Translational Science at the University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Clinical and Translational Science Institute, Pittsburgh, PA.

Address correspondence to: Ahmad A. Tarhini, MD, PhD, University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232; phone: 412- 648-6578; fax: 412-648-6579; e-mail:

Disclosure: Dr Tarhini has received research grant funding from Merck & Co, Inc, Bristol-Myers Squibb, Novartis, Amgen, and Prometheus (contracted with the University of Pittsburgh), and is a consultant or member of a paid advisory board for Merck & Co, Inc and Genentech Inc.


  1. Balch CM, Urist MM, Karakousis CP, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg. 1993;218:262-269; discussion 7-9.
  2. Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol. 2001;8:101-108.
  3. Karakousis CP, Balch CM, Urist MM, et al. Local recurrence in malignant melanoma: long-term results of the multiinstitutional randomized surgical trial. Ann Surg Oncol. 1996;3:446-452.
  4. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199-6206.
  5. Sosman JA, Moon J, Tuthill RJ, et al. A phase 2 trial of complete resection for stage IV melanoma: results of Southwest Oncology Group Clinical Trial S9430. Cancer. 2011;117:4740-4706.
  6. Kirkwood JM, Ibrahim J, Lawson DH, et al. High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696. J Clin Oncol. 2001;19:1430-1436.
  7. Kirkwood JM, Richards T, Zarour HM, et al. Immunomodulatory effects of high-dose and low-dose interferon alpha 2b in patients with high-risk resected melanoma: the E2690 laboratory corollary of intergroup adjuvant trial E1690. Cancer. 2002;95:1101-1112.
  8. Wang W, Edington HD, Rao UN, et al. Modulation of signal transducers and activators of transcription 1 and 3 signaling in melanoma by high-dose IFN alpha 2b. Clin Cancer Res. 2007;13:1523-1531.
  9. Paquette RL, Hsu NC, Kiertscher SM, et al. Interferon-alpha and granulocyte-macrophage colony-stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells. J Leukoc Biol. 1998;64:358-367.
  10. Tarhini AA, Gogas H, Kirkwood JM. IFN-α in the treatment of melanoma. J Immunol. 2012;189:3789-3793.
  11. Fuertes MB, Kacha AK, Kline J, et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J Exp Med. 2011;208:2005-2016.
  12. Moschos SJ, Edington HD, Land SR, et al. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol. 2006;24:3164-3171.
  13. Creagan ET, Ahmann DL, Frytak S, et al. Phase II trials of recombinant leukocyte A interferon in disseminated malignant melanoma: results in 96 patients. Cancer Treat Rep. 1986;70:619- 624.
  14. Creagan ET, Ahmann DL, Frytak S, et al. Recombinant leukocyte A interferon (rIFN-alpha A) in the treatment of disseminated malignant melanoma. Analysis of complete and long-term responding patients. Cancer. 1986;58:2576-2578.
  15. Atkins MB, Hsu J, Lee S, et al. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008;26:5748-5754.
  16. O'Day SJ, Boasberg PD, Piro L, et al. Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy. Clin Cancer Res. 2002;8:2775-2781.
  17. Eton O, Legha SS, Bedikian AY, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002;20:2045- 2052.
  18. Tarhini AA, Cherian J, Moschos SJ, et al. Safety and efficacy of combination immunotherapy with interferon alfa-2b and tremelimumab in patients with stage IV melanoma. J Clin Oncol. 2012;30:322-328.
  19. Creagan ET, Dalton RJ, Ahmann DL, et al. Randomized, surgical adjuvant clinical trial of recombinant interferon alfa- 2a in selected patients with malignant melanoma. J Clin Oncol. 1995;13:2776-2783.
  20. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7-17.
  21. Tarhini AA, Kirkwood JM. How much of a good thing? What duration for interferon alfa-2b adjuvant therapy? J Clin Oncol. 2012;30:3773-3776.
  22. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and lowdose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18:2444- 2458.
  23. 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.
  24. 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.
  25. Chao C, Wong SL, Ross MI, et al. Patterns of early recurrence after sentinel lymph node biopsy for melanoma. Am J Surg. 2002;184:520-524; discussion 5.
  26. McMasters KM, Ross MI, Reintgen DS, et al. Final results of the Sunbelt Melanoma Trial. J Clin Oncol. 2008;26(suppl 15; abstr 9003).
  27. Chiarion-Sileni V, Guida M, Romanini A, et al. Intensified high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant treatment of stage III melanoma: a randomized phase III Italian Melanoma Intergroup (IMI) trial [ISRCTN75125874]. J Clin Oncol. 2011;29(suppl; abstr 8506).
  28. Gogas H, Bafaloukos D, Ioannovich J, et al. Tolerability of adjuvant high-dose interferon alfa-2b: 1 month versus 1 year--a Hellenic Cooperative Oncology Group study. Anticancer Res. 2004;24:1947-1952.
  29. Agarwala SS, Lee SJ, Flaherty LE, et al. 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). J Clin Oncol. 2011;29(suppl; abstr 8505).
  30. Kleeberg UR, Suciu S, Bröcker EB, et al. Final results of the EORTC 18871/DKG 80-1 randomised phase III trial. rIFNalpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer. 2004;40:390-402.
  31. Cascinelli N, Bufalino R, Morabito A, Mackie R. Results of adjuvant interferon study in WHO melanoma programme. Lancet. 1994;343:913-914.
  32. Hancock BW, Wheatley K, Harris S, et al. Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon alfa-2a in high-risk resected malignant melanoma. J Clin Oncol. 2004;22:53-61.
  33. Cameron DA, Cornbleet MC, Mackie RM, et al. Adjuvant interferon alpha 2b in high risk melanoma - the Scottish study. Br J Cancer. 2001;84:1146-1149.
  34. Hauschild A, Weichenthal M, Rass K, et al. Efficacy of lowdose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >= 1.5 mm tumor thickness: results of a randomized phase III DeCOG trial. J Clin Oncol. 2010;28:841-846.
  35. Eggermont AM, Suciu S, MacKie R, et al. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005;366:1189- 1196.
  36. Eggermont AM, Suciu S, Santinami M, et al. 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. Lancet. 2008;372:117-126.
  37. Grob JJ, Dreno B, de la Salmonière P, et al. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. Lancet. 1998;351:1905-1910.
  38. Garbe C, Radny P, Linse R, et al. Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis. Ann Oncol. 2008;19:1195-1201.
  39. Pehamberger H, Soyer HP, Steiner A, et al. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. J Clin Oncol. 1998;16:1425-1429.
  40. Wheatley K, Ives N, Hancock B, et al. Does adjuvant interferon- alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treat Rev. 2003;29:241-252.
  41. Wheatley K, Ives N, Eggermont A, Kirkwood JM. Interferon-α as adjuvant therapy for melanoma: an individual patient data meta-analysis of randomised trials. J Clin Oncol.2007;25:(suppl 478; abstr 8526).
  42. Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102:493- 501.
  43. Mocellin S, Lens MB, Pasquali S, et al. Inteferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev.2013;6:CD008955. doi: 10.1002/14651858.CD008955. pub2.
  44. Flaherty LE, Moon J, Atkins MB, et al. Phase III trial of highdose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with high-risk melanoma (SWOG S0008): an intergroup study of CALGB, COG, ECOG, and SWOG. J Clin Oncol.2012;30(suppl; abstr 8504).
  45. Morton DL, Mozzillo N, Thompson JF, et al. An international, randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites. J Clin Oncol.2007;25:(suppl 18; abstr 8508).
  46. Kruit W, Suciu S, Dreno B, et al. Active immunization toward the MAGE-A3 antigen in patients with metastatic melanoma: four-year follow-up results from a randomized phase II study (EORTC16032-18031). J Clin Oncol.2011;29:(suppl; abstr 8535)
  47. Hersey P, Coates AS, McCarthy WH, et al. Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial. J Clin Oncol.2002;20:4181-4190.
  48. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
  49. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.
  50. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Ipilimumab versus placebo after complete resection of stage III melanoma: Initial efficacy and safety results from the EORTC 18071 phase III trial. J Clin Oncol. 2014;32(suppl 5s: abstr LBA9008).
  51. Corrie PG, Marshall A, Dunn JA, et al. Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study. Lancet Oncol. 2014;15(6):620-630. Erratum in: Lancet Oncol. 2014;15(7):e253 and 2014;15(9):e365.
  52. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.
  53. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694-1703.
  54. Ballo MT, Bonnen MD, Garden AS, et al. Adjuvant irradiation for cervical lymph node metastases from melanoma. Cancer. 2003;97:1789-1796.
  55. Agrawal S, Kane JM 3rd, Guadagnolo BA, et al. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer. 2009;115:5836-5844.
  56. Strojan P, Jancar B, Cemazar M, et al. Melanoma metastases to the neck nodes: role of adjuvant irradiation. Int J Radiat Oncol Biol Phys. 2010;77:1039-1045.
  57. Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol. 2012;13:589-597.
  58. Creagan ET, Cupps RE, Ivins JC, et al. Adjuvant radiation therapy for regional nodal metastases from malignant melanoma: a randomized, prospective study. Cancer. 1978;42:2206-2210.
  59. Burmeister BH, Smithers BM, Poulsen M, et al. Radiation therapy for nodal disease in malignant melanoma. World J Surg. 1995;19:369-371.
  60. Corry J, Smith JG, Bishop M, Ainslie J. Nodal radiation therapy for metastatic melanoma. Int J Radiat Oncol Biol Phys. 1999;44:1065-1069.
  61. Stevens G, Thompson JF, Firth I, et al. Locally advanced melanoma: results of postoperative hypofractionated radiation therapy. Cancer. 2000;88:88-94.
  62. Ballo MT, Ross MI, Cormier JN, et al. Combined-modality therapy for patients with regional nodal metastases from melanoma. Int J Radiat Oncol Biol Phys. 2006;64:106-113.
  63. Burmeister BH, Mark Smithers B, Burmeister E, et al. A prospective phase II study of adjuvant postoperative radiation therapy following nodal surgery in malignant melanoma-Trans Tasman Radiation Oncology Group (TRO G) Study 96.06. Radiother Oncol. 2006;81:136-142.
  64. Tarhini AA, Edington H, Butterfield LH, et al. Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PloS One. 2014;9:e87705.