miércoles, 8 de mayo de 2019

Melanoma Treatment (PDQ®) 2/3 —Health Professional Version - National Cancer Institute

Melanoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Melanoma Treatment (PDQ®)–Health Professional Version

Stage 0 Melanoma Treatment

Standard Treatment Options for Stage 0 Melanoma

Standard treatment options for stage 0 melanoma include the following:
  1. Excision.

Excision

Patients with stage 0 disease may be treated by excision with minimal, but microscopically free, margins.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Stage I Melanoma Treatment

Standard Treatment Options for Stage I Melanoma

Standard treatment options for stage I melanoma include the following:
  1. Excision with or without lymph node management.

Excision

Evidence suggests that lesions no thicker than 2 mm may be treated conservatively with radial excision margins of 1 cm.
Depending on the location of the melanoma, most patients can now have the excision performed on an outpatient basis.
Evidence (excision):
  1. A randomized trial compared narrow margins (1 cm) with wide margins (≥3 cm) in patients with melanomas no thicker than 2 mm.[1,2][Level of evidence: 1iiA]
    • No difference was observed between the two groups in the development of metastatic disease, disease-free survival (DFS), or overall survival (OS).
  2. Two other randomized trials compared 2-cm margins with wider margins (4 cm or 5 cm).[3,4][Level of evidence:1iiA]
    • No statistically significant difference in local recurrence, distant metastasis, or OS was found; the median follow-up was at least 10 years for both trials.
  3. In the Intergroup Melanoma Surgical Trial, the reduction in margins from 4 cm to 2 cm was associated with both of the following:[5][Level of evidence: 1iiA]
    • A statistically significant reduction in the need for skin grafting (from 46% to 11%; P < .001).
    • A reduction in the length of hospital stay.
  4. A multicenter, phase III randomized trial (SWOG-8593) of patients with high-risk stage I primary limb melanoma did not show a DFS or OS benefit from isolated limb perfusion with melphalan, when compared with surgery alone.[6,7]
Lymph node management
Elective regional lymph node dissection is of no proven benefit for patients with stage I melanoma.[8]
Lymphatic mapping and sentinel lymph node biopsy (SLNB) for patients who have tumors of intermediate thickness and/or ulcerated tumors may identify individuals with occult nodal disease. These patients may benefit from regional lymphadenectomy and adjuvant therapy.[6,9-11]
Evidence (immediate lymphadenectomy vs. observation with delayed lymphadenectomy):
  1. The International Multicenter Selective Lymphadenectomy Trial (MSLT-1 [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm–3.5 mm in this study) primary melanomas.[12][Level of evidence: 1iiB]
    • There was no melanoma-specific survival advantage (primary endpoint) for patients randomly assigned to undergo wide excision plus SLNB, followed by immediate complete lymphadenectomy for node positivity versus nodal observation and delayed lymphadenectomy for subsequent nodal recurrence at a median of 59.8 months.
    • This trial was not designed to detect a difference in the impact of lymphadenectomy in patients with microscopic lymph node involvement.
  2. The Sunbelt Melanoma Trial (UAB-9735 [NCT00004196]) was a phase III trial to determine the effects of lymphadenectomy with or without adjuvant high-dose interferon alpha-2b versus observation on DFS and OS in patients with submicroscopic sentinel lymph node (SLN) metastasis detected only by the polymerase chain reaction assay (i.e., SLN negative by histology and immunohistochemistry).
    • No survival data have been reported from this study.

Treatment Options Under Clinical Evaluation for Stage I Melanoma

Treatment options under clinical evaluation for patients with stage I melanoma include the following:
  1. Clinical trials evaluating new techniques to detect submicroscopic SLN metastasis. Because of the higher rate of treatment failure in the subset of clinical stage I patients with occult nodal disease, clinical trials have evaluated new techniques to detect submicroscopic SLN metastasis to identify patients who may benefit from regional lymphadenectomy with or without adjuvant therapy.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991. [PUBMED Abstract]
  2. Veronesi U, Cascinelli N, Adamus J, et al.: Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 318 (18): 1159-62, 1988. [PUBMED Abstract]
  3. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al.: Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer 89 (7): 1495-501, 2000. [PUBMED Abstract]
  4. 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 8 (2): 101-8, 2001. [PUBMED Abstract]
  5. 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 218 (3): 262-7; discussion 267-9, 1993. [PUBMED Abstract]
  6. Essner R, Conforti A, Kelley MC, et al.: Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early-stage melanoma. Ann Surg Oncol 6 (5): 442-9, 1999 Jul-Aug. [PUBMED Abstract]
  7. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998. [PUBMED Abstract]
  8. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998. [PUBMED Abstract]
  9. Gershenwald JE, Thompson W, Mansfield PF, et al.: Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17 (3): 976-83, 1999. [PUBMED Abstract]
  10. Mraz-Gernhard S, Sagebiel RW, Kashani-Sabet M, et al.: Prediction of sentinel lymph node micrometastasis by histological features in primary cutaneous malignant melanoma. Arch Dermatol 134 (8): 983-7, 1998. [PUBMED Abstract]
  11. Morton DL, Thompson JF, Cochran AJ, et al.: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355 (13): 1307-17, 2006. [PUBMED Abstract]
  12. Morton DL, Thompson JF, Cochran AJ, et al.: Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 370 (7): 599-609, 2014. [PUBMED Abstract]

Stage II Melanoma Treatment

Standard Treatment Options for Stage II Melanoma

Standard treatment options for stage II melanoma include the following:
  1. Excision with or without lymph node management.

Excision

For melanomas with a thickness between 2 mm and 4 mm, surgical margins need to be 2 cm to 3 cm or smaller.
Few data are available to guide treatment in patients with melanomas thicker than 4 mm; however, most guidelines recommend margins of 3 cm whenever anatomically possible.
Depending on the location of the melanoma, most patients can have the excision performed on an outpatient basis.
Evidence (excision):
  1. The Intergroup Melanoma Surgical Trial Task 2b compared 2-cm versus 4-cm margins for patients with melanomas that were 1 mm to 4 mm thick.[1]
    • With a median follow-up of more than 10 years, no significant difference in local recurrence or survival was observed between the two groups.
    • The reduction in margins from 4 cm to 2 cm was associated with the following:
      • A statistically significant reduction in the need for skin grafting (from 46% to 11%; P < .001).
      • A reduction in the length of the hospital stay.
  2. A study conducted in the United Kingdom randomly assigned patients with melanomas thicker than 2 mm to undergo excision with either 1-cm or 3-cm margins.[2]
    • Patients treated with excision with 1-cm margins had higher rates of local regional recurrence (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.00–1.59; P = .05).
    • No difference in survival was seen (HR, 1.24; 95% CI, 0.96–1.61; P = .1).
    • This study suggests that 1-cm margins may not be adequate for patients with melanomas thicker than 2 mm.
Lymph node management
Lymphatic mapping and sentinel lymph node biopsy (SLNB)
Lymphatic mapping and SLNB have been used to assess the presence of occult metastasis in the regional lymph nodes of patients with stage II disease, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections (LNDs) and individuals who may benefit from adjuvant therapy.[3-7]
To ensure accurate identification of the sentinel lymph node, lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.
With the use of a vital blue dye and a radiopharmaceutical agent injected at the site of the primary tumor, the first lymph node in the lymphatic basin that drains the lesion can be identified, removed, and examined microscopically. Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[3,8-12] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.
Regional lymphadenectomy
No published data on the clinical significance of micrometastatic melanoma in regional lymph nodes are available from prospective trials. Some evidence suggests that for patients with tumors of intermediate thickness and occult metastasis, survival is better among patients who undergo immediate regional lymphadenectomy than it is among those who delay lymphadenectomy until the clinical appearance of nodal metastasis.[13] This finding should be viewed with caution because it arose from a post hoc subset analysis of data from a randomized trial.
Evidence (regional lymphadenectomy):
  1. The International Multicenter Selective Lymphadenectomy Trial (MSLT-1 [JWCI-MORD-MSLT-1193]) included 1,269 patients with intermediate-thickness (defined as 1.2 mm–3.5 mm in this study) primary melanomas.[14][Level of evidence: 1iiB]
    • There was no melanoma-specific survival advantage (primary endpoint) for patients randomly assigned to undergo wide excision plus SLNB, followed by immediate complete lymphadenectomy for node positivity versus nodal observation and delayed lymphadenectomy for subsequent nodal recurrence at a median of 59.8 months.
    • This trial was not designed to detect a difference in the impact of lymphadenectomy in patients with microscopic lymph node involvement.
  2. Three other prospective randomized trials have failed to show a survival benefit for prophylactic regional LNDs.[15-17]

Adjuvant therapy

High-dose interferon
High-dose interferon alpha-2b was approved in 1995 for the adjuvant treatment of patients with melanoma who have undergone a complete surgical resection but are at a high risk of relapse. Evidence was based on a significantly improved relapse-free survival (RFS) and marginally improved overall survival (OS) that were seen in EST-1684.
Subsequent large, randomized trials have not been able to reproduce a benefit in OS. Ongoing trials are testing therapies that have demonstrated improved OS in patients with stage IV disease.
Clinicians should be aware that the high-dose regimens have significant toxic effects.
Evidence (high-dose interferon alpha-2b):
  1. A multicenter, randomized, controlled study (EST-1684) compared a high-dose regimen of interferon alpha-2b (20 mU/m2 of body surface qd given intravenously 5 days a week for 4 weeks, then 10 mU/m2 of body surface qd given subcutaneously 3 times a week for 48 weeks) with observation.[8][Level of evidence: 1iiA]
    • This study included 287 patients at high risk of recurrence after potentially curative surgery for melanoma (patients with melanomas thicker than 4 mm without involved lymph nodes or patients with melanomas of any thickness with positive lymph nodes).
    • Patients who had recurrent melanoma involving only the regional lymph nodes were also eligible.
    • At a median follow-up of 7 years, this trial demonstrated a significant prolongation of RFS (P = .002) and OS (P = .024) for patients who received high-dose interferon.
    • The median OS for patients who received the high-dose regimen of interferon alpha-2b was 3.8 years, compared with 2.8 years for those in the observation group.
    • A subset analysis of the stage II patients failed to show any RFS or OS benefit from high-dose interferon. Because the number of stage II patients was small in this subset analysis, it is difficult to draw meaningful conclusions from this study for this specific group.
  2. A multicenter, randomized, controlled study (EST-1690) conducted by the same investigators compared the same high-dose interferon alpha regimen with either a low-dose regimen of interferon alpha-2b (3 mU/m2 of body surface qd given subcutaneously three times per week for 104 weeks) or observation. The stage entry criteria for this trial included patients with stage II and III melanoma. This three-arm trial enrolled 642 patients.[9][Level of evidence: 1iiA]
    • At a median follow-up of 52 months, a statistically significant RFS advantage was shown for all patients who received high-dose interferon (including the clinical stage II patients) when compared with the observation group (P = .03).
    • No statistically significant RFS advantage was seen for patients who received low-dose interferon when compared with the observation group.
    • The 5-year estimated RFS rate was 44% for the high-dose interferon group, 40% for the low-dose interferon group, and 35% for the observation group.
    • Neither high-dose nor low-dose interferon yielded an OS benefit when compared with observation (HR, 1.0; P = .995).

Treatment Options Under Clinical Evaluation for Stage II Melanoma

Postsurgical adjuvant treatment (e.g., with interferons) has not been shown to affect survival.
Treatment options under clinical evaluation for patients with stage II melanoma include the following:
  1. Clinical trials are testing therapies of postsurgical adjuvant treatment that have improved OS in patients with stage IV disease, including NCT01274338, NCT01667419, and NCT01682083. Postsurgical adjuvant treatment (e.g., with interferons) has not been shown to affect survival; therefore, clinical trials are an important therapeutic option for patients at high risk for relapse.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  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 218 (3): 262-7; discussion 267-9, 1993. [PUBMED Abstract]
  2. Thomas JM, Newton-Bishop J, A'Hern R, et al.: Excision margins in high-risk malignant melanoma. N Engl J Med 350 (8): 757-66, 2004. [PUBMED Abstract]
  3. Gershenwald JE, Thompson W, Mansfield PF, et al.: Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17 (3): 976-83, 1999. [PUBMED Abstract]
  4. McMasters KM, Reintgen DS, Ross MI, et al.: Sentinel lymph node biopsy for melanoma: controversy despite widespread agreement. J Clin Oncol 19 (11): 2851-5, 2001. [PUBMED Abstract]
  5. Cherpelis BS, Haddad F, Messina J, et al.: Sentinel lymph node micrometastasis and other histologic factors that predict outcome in patients with thicker melanomas. J Am Acad Dermatol 44 (5): 762-6, 2001. [PUBMED Abstract]
  6. Essner R: The role of lymphoscintigraphy and sentinel node mapping in assessing patient risk in melanoma. Semin Oncol 24 (1 Suppl 4): S8-10, 1997. [PUBMED Abstract]
  7. Chan AD, Morton DL: Sentinel node detection in malignant melanoma. Recent Results Cancer Res 157: 161-77, 2000. [PUBMED Abstract]
  8. Morton DL, Wen DR, Wong JH, et al.: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127 (4): 392-9, 1992. [PUBMED Abstract]
  9. Reintgen D, Cruse CW, Wells K, et al.: The orderly progression of melanoma nodal metastases. Ann Surg 220 (6): 759-67, 1994. [PUBMED Abstract]
  10. Thompson JF, McCarthy WH, Bosch CM, et al.: Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res 5 (4): 255-60, 1995. [PUBMED Abstract]
  11. Uren RF, Howman-Giles R, Thompson JF, et al.: Lymphoscintigraphy to identify sentinel lymph nodes in patients with melanoma. Melanoma Res 4 (6): 395-9, 1994. [PUBMED Abstract]
  12. Bostick P, Essner R, Glass E, et al.: Comparison of blue dye and probe-assisted intraoperative lymphatic mapping in melanoma to identify sentinel nodes in 100 lymphatic basins. Arch Surg 134 (1): 43-9, 1999. [PUBMED Abstract]
  13. Cascinelli N, Morabito A, Santinami M, et al.: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351 (9105): 793-6, 1998. [PUBMED Abstract]
  14. Morton DL, Thompson JF, Cochran AJ, et al.: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355 (13): 1307-17, 2006. [PUBMED Abstract]
  15. Veronesi U, Adamus J, Bandiera DC, et al.: Delayed regional lymph node dissection in stage I melanoma of the skin of the lower extremities. Cancer 49 (11): 2420-30, 1982. [PUBMED Abstract]
  16. Sim FH, Taylor WF, Ivins JC, et al.: A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results. Cancer 41 (3): 948-56, 1978. [PUBMED Abstract]
  17. Balch CM, Soong SJ, Bartolucci AA, et al.: Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 224 (3): 255-63; discussion 263-6, 1996. [PUBMED Abstract]

Resectable Stage III Melanoma Treatment

Standard Treatment Options for Resectable Stage III Melanoma

Standard treatment options for resectable stage III melanoma include the following:
  1. Excision with or without lymph node management.
  2. Adjuvant therapy.
    1. Immunotherapy.
    2. Combination signal transduction inhibitors.

Excision

The primary tumor may be treated with wide local excision with 1-cm to 3-cm margins, depending on tumor thickness and location.[1-7] Skin grafting may be necessary to close the resulting defect.
Lymph node management
Sentinel lymph node biopsy (SLNB)
Lymphatic mapping and SLNB can be considered to assess the presence of occult metastases in the regional lymph nodes of patients with primary tumors larger than 1 mm to 4 mm, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections and individuals who may benefit from adjuvant therapy.[3,8-12]
To ensure accurate identification of the sentinel lymph node (SNL), lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.
Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[8,12-17] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.
Complete lymph node dissection (CLND)
Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive for regional control or considered for entry into the Multicenter Selective Lymphadenectomy Trial II (NCT00297895) to determine whether CLND affects survival. SLNB should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping.

Adjuvant Therapy

Adjuvant therapeutic options for patients at high risk of recurrence after complete resection are expanding, building on advances seen with both immunotherapy and targeted therapies in the metastatic setting. Prospective, randomized, multicenter treatment trials have demonstrated a clinically significant impact on relapse-free survival (RFS) with checkpoint inhibitors (ipilimumab, nivolumab, and pembrolizumab) and combination signal transduction inhibitor therapy (dabrafenib plus trametinib).
Data on the results of adjuvant therapies are early, but ipilimumab, which has a median follow-up of 5.3 years, shows an improved overall survival (OS) when compared with placebo.[18] Treatment takes longer than a year, however, and toxicity is significant (grade 3 and 4 adverse events [AEs], death, and discontinuation of therapy due to AEs). Other completed adjuvant trials have also used placebo as a control arm, except for trials of nivolumab, which used an active control, ipilimumab, with 1-year treatment for both arms or until disease recurrence or unacceptable toxicity. Nivolumab demonstrated a statistically significant improved RFS, with less toxicity than ipilimumab. The benefit of immunotherapy with ipilimumab, nivolumab, and pembrolizumab has been seen regardless of programmed death-ligand 1 (PD-L1) expression or BRAF mutations. Combination signal transduction inhibitor therapy is an additional option for patients with BRAF mutations.
Although some trials of interferon alpha-2b have demonstrated an effect on RFS, both adjuvant high-dose and pegylated interferon have been shown to not improve OS in randomized trials.
Participation in clinical trials to identify treatments that will further extend RFS and OS with less toxicity is an important option for all patients.
Immunotherapy
Checkpoint inhibitors
Nivolumab
Evidence (nivolumab):
  1. In a multinational, randomized, double-blind trial (CheckMate 238 [NCT02388906]), patients with stage IIIB, IIIC, or IV melanoma who underwent complete resection were randomly assigned (1:1) to receive nivolumab or ipilimumab.[19][Level of evidence: 1iDii] The primary endpoint was RFS and was defined as time from randomization until the date of the first recurrence, new primary melanoma, or death from any cause. Patients who were excluded included those with resection occurring more than 12 weeks before randomization, autoimmune disease, use of systemic glucocorticoids, previous systemic therapy for melanoma, and an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score higher than 1. Nivolumab was administered at the dose of 3 mg/kg intravenously (IV) every 2 weeks and ipilimumab was administered at the dose of 10 mg/kg every 3 weeks for four doses, then every 3 months for up to 1 year or until disease recurrence, along with corresponding placebo.
    A total of 906 patients were randomly assigned: 453 patients to nivolumab and 453 patients to ipilimumab. Baseline characteristics were balanced. Approximately 81% of patients had stage III disease, 32% had ulcerated primary melanoma, 48% had macroscopic lymph node involvement, 62% had less than a 5% PD-L1 expression, and 42% harbored BRAF mutations.
    • The European Organisation for Research and Treatment of Cancer (EORTC) Independent Data Monitoring Committee stopped the study at the protocol-specified interim analysis, when all patients had a minimum follow-up of 18 months, at which time there were 360 events of recurrence-free survival. The median RFS has not been reached in either treatment group. At 12 months, the rate of RFS for patients treated with nivolumab was 70.5% (95% confidence interval [CI], 66.1–74.0) versus 60.8% (95% CI, 56.0–65.2) in patients treated with ipilimumab. There were 154 (34%) recurrences or deaths in 453 patients treated with nivolumab versus 206 (45.5%) recurrences or deaths in 453 patients treated with ipilimumab (hazard ratio (HR) recurrence or death, 0.65; 97.56% CI, 0.51–0.83; P < .001). Subgroup analyses of RFS favored nivolumab regardless of PD-L1 expression or BRAF V600 mutation.
    • Patients treated with nivolumab had fewer AEs, including grade 3 to 4 serious AEs and death. Nivolumab was discontinued in 9.7% of patients, and ipilimumab was discontinued in 42.6% of patients because of AEs. Two treatment-related deaths occurred with ipilimumab (e.g., marrow aplasia and colitis) and none in the nivolumab-treated patients. The AE profile was like the type of checkpoint inhibitor toxicities seen in the metastatic setting, with immune-related events most commonly seen in the gastrointestinal system, hepatic system, and skin. Grade 3 or 4 AEs occurred in 14% of patients treated with nivolumab and in 46% of patients treated with ipilimumab.
Pembrolizumab
Evidence (pembrolizumab):
  1. In a multinational, randomized, double-blind trial (MK-3475-054/KEYNOTE-054[NCT02362594]), patients with completely resected stage IIIA, IIIB, or IIIC melanoma were randomly assigned (1:1) to receive pembrolizumab or placebo.[20][Level of evidence: 1iDii] The primary endpoint was RFS, defined as time from randomization until the date of first recurrence or death from any cause. If recurrence was documented, patients could cross over or repeat treatment with pembrolizumab. Pembrolizumab was given as an IV infusion of 200 mg every 3 weeks, for a total of 18 doses (approximately 1 year).
    A total of 1,019 patients were randomly assigned: 514 to pembrolizumab and 505 to placebo. Baseline characteristics were balanced. Approximately 40% had ulcerated primary melanoma, 66% had macroscopic lymph node involvement, 84% had positive PD-L1 expression (melanoma score >2 by 22C3 antibody assay), and 44% harbored BRAF mutations.
    • The EORTC Independent Data Monitoring Committee reviewed the unblinded results at an amended interim analysis when 351 events (recurrences or deaths) had occurred. The results were positive, and the interim analysis of RFS became the final analysis. Patients will continue to be monitored for OS and other secondary efficacy endpoints.
    • At a median follow up of 15 months, the 12-month rate of RFS was 75.4% (95% CI, 71.3–78.9) in the pembrolizumab group vs. 61.0% (95% CI, 56.5–65.1) in the placebo group. Pembrolizumab maintained its effect regardless of PD-L1 positive or negative expression or BRAF mutation status.
    • Approximately 14% of patients discontinued pembrolizumab due to an AE. Grade 3, 4, or 5 AEs considered to be related to pembrolizumab occurred in 15% of patients. There was one death due to treatment (myositis).
Ipilimumab
Evidence (ipilimumab):
  1. In a multinational, randomized, double-blind trial, patients with stage III melanoma, who had complete resection, were randomly assigned (1:1) to receive ipilimumab or placebo.[21][Level of evidence: 1iiDii] Patients with lymph node metastasis larger than 1 mm, in-transit metastasis, resection occurring more than 12 weeks before randomization, autoimmune disease, previous or concurrent immunosuppressive therapy, previous systemic therapy for melanoma, and an ECOG PS score of greater than 1 were excluded. The ipilimumab dose was 10 mg/kg every 3 weeks for four doses, then every 3 months for up to 3 years. The primary endpoint was RFS, defined as recurrence or death (regardless of cause), whichever came first, as assessed by an independent review committee.
    • A total of 951 patients were enrolled (475 patients to the ipilimumab arm and 476 patients to the placebo arm). The median age was 51 years, and 94% of the patients had a PS of 0.
    • At a median follow-up of 2.7 years, there were 528 RFS events: 234 in the ipilimumab group (49%; 220 recurrences, 14 deaths) and 294 in the placebo group (62%; 289 recurrences, 5 deaths). Median RFS was 26 months for the ipilimumab group (95% CI, 19–39) versus 17 months for the placebo group (95% CI, 13–22). The HR was 0.75 (95% CI, 0.64–0.90); P < .002. The effect of ipilimumab was consistent across subgroups.
    • Ipilimumab was discontinued for AEs in 52% of the patients. Patients received ipilimumab for a median of four doses; 36% of patients in the ipilimumab group stayed on treatment for more than 6 months, and 26% stayed on treatment for more than 1 year. Five patients died from drug-related events: three secondary to colitis, one with myocarditis, and one of multiorgan failure with Guillain-Barré syndrome. The most common AEs were gastrointestinal, hepatic, and endocrine in nature and included rash, fatigue, and headache.
  2. An updated analysis was performed at a median follow-up of 5.3 years.[18]
    • The 5-year rate of RFS was 40.8% in patients treated with ipilimumab and 30.3% in patients who received the placebo (HR recurrence or death, 0.76; 95% CI, 0.64–0.89; P < .001) and the median RFS was 27.6% in patients treated with ipilimumab and 17.1% in patients who received the placebo.
    • The rate of OS, a secondary endpoint, at 5 years was 65.4% in patients treated with ipilimumab versus 54.4% in patients who received the placebo (HRdeath, 0.72; 95.1% CI, 0.58–0.88; P = .001).
The optimal dose of ipilimumab in the adjuvant setting is unknown. Patients are fully accrued and data are pending from an intergroup trial, E1609 (NCT01274338), testing high-dose (10 mg) versus low-dose (3 mg) ipilimumab versus interferon. For patients with metastatic disease, the recommended dose is 3 mg/kg.
Interferon alpha-2b
Evidence (high-dose interferon alpha):
  1. A multicenter, randomized, controlled study (EST-1690) compared a high-dose interferon alpha regimen with either a low-dose regimen of interferon alpha-2b (3 mU/m2 of body surface qd given subcutaneously three times per week for 104 weeks) or observation. The stage entry criteria for this trial included patients with stage II and III melanoma. This three-arm trial enrolled 642 patients.[14][Level of evidence: 1iiA]
    • At a median follow-up of 52 months, a statistically significant RFS advantage was shown for all patients who received high-dose interferon (including the clinical stage II patients) when compared with the observation group (P = .03).
    • No statistically significant RFS advantage was seen for patients who received low-dose interferon when compared with the observation group.
    • The 5-year estimated RFS rate was 44% for the high-dose interferon group, 40% for the low-dose interferon group, and 35% for the observation group.
    • Neither high-dose nor low-dose interferon yielded an OS benefit when compared with observation (HR, 1.0; P = .995).
    • Pooled analyses (EST-1684 and EST-1690) of the high-dose arms versus the observation arms suggest that treatment confers a significant RFS advantage but not a significant benefit for survival.
  2. A randomized, multicenter, national trial ECOG-1697 [NCT00003641] evaluated high-dose IV interferon for a short duration (1 month) versus observation in patients with node-negative melanoma at least 2 mm thick or with any thickness and positive sentinel nodes. This trial was closed at interim analysis because of the lack of benefit from treatment with interferon.
  3. In 2011, pegylated interferon alpha-2b, which is characterized by a longer half-life and can be administered subcutaneously, was approved by the U.S. Food and Drug Administration for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of complete surgical resection, including complete lymphadenectomy.
    Approval of pegylated interferon alpha-2b was based on EORTC-18991 (NCT00006249), which randomly assigned 1,256 patients with resected stage III melanoma to observation or weekly subcutaneous pegylated interferon alpha-2b for up to 5 years.[15][Level of evidence: 1iiDii]
    • RFS, as determined by an independent review committee, was improved for patients receiving interferon (34.8 months vs. 25.5 months in the observation arm; HR, 0.82; 95% CI, 0.71–0.96; P = .011).
    • No difference in median OS between the arms was observed (HR, 0.98; 95% CI, 0.82–1.16).
    • One-third of the patients receiving pegylated interferon discontinued treatment because of toxicity.
Combination signal transduction inhibitors
Dabrafenib plus trametinib
Evidence (dabrafenib plus trametinib):
  1. In a multinational, randomized, double-blind trial (COMBI-AD [NCT01682083]), patients with stage IIIA, IIIB, or IIIC melanoma with BRAF V600E or V600K mutations who underwent completion lymphadenectomy were randomly assigned (1:1) to receive dabrafenib plus trametinib or two matched placebo tablets.[22][Level of evidence: 1iDii] The primary endpoint was RFS and was defined as time from randomization until the date of the first recurrence or death from any cause. Patients with resection occurring more than 12 weeks before random assignment and an ECOG PS score of greater than 1 were excluded. Dabrafenib was given at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy) for 12 months in the absence of disease recurrence, unacceptable toxic effects, or death. A total of 870 patients were randomly assigned (438 patients to combination therapy and 432 patients to placebo). Baseline characteristics were balanced. Most patients (91%) harbored the V600E mutation compared with 9% who harbored the V600K mutation. Most patients (92%) had an ECOG PS of 0.
    • At the data cutoff date for the primary analysis, the minimum follow-up was 2.5 years (median, 2.8 years), and all patients had completed trial treatment. Disease recurrence was reported in 163 of 438 patients (37%) receiving combination therapy and in 247 of 432 patients (57%) receiving placebo (HR for RFS, 0.47; 95% CI, 0.39–0.59; P < .001). Median RFS had not been reached in the combination arm (95% CI, 44.5–not reached) and was 16.6 months (95% CI, 12.7–22.1) in the placebo group. HRdeath was 0.57; 95% CI, 0.42– 0.79; P = .0006. This result did not meet the protocol-specified interim boundary for statistical significance (P = .000019).
    • In the combination therapy arm, 26% of the patients had an AE leading to the discontinuation of therapy, 38% of the patients required dose reduction, and 66% of the patients required dose interruption. In the placebo arm, 3% of the patients had an AE leading to discontinuation of therapy, 3% of the patients required dose reduction, and 15% of the patients required dose interruption. Serious AEs occurred in 36% of the patients receiving the combination therapy versus 10% of the patients in the placebo group. One death, which resulted from pneumonia, was reported in the combination therapy arm.

Treatment Options Under Clinical Evaluation for Resectable Stage III Melanoma

Treatment options under clinical evaluation for patients with resectable stage III melanoma include the following:
  1. Trials of combination immunotherapies, including vaccines.
  2. Trials of adjuvant therapies that target a known mutation, e.g., c-KIT.
  3. Intralesional therapies.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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  2. Veronesi U, Cascinelli N, Adamus J, et al.: Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 318 (18): 1159-62, 1988. [PUBMED Abstract]
  3. Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000. [PUBMED Abstract]
  4. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al.: Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer 89 (7): 1495-501, 2000. [PUBMED Abstract]
  5. 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 8 (2): 101-8, 2001. [PUBMED Abstract]
  6. Heaton KM, Sussman JJ, Gershenwald JE, et al.: Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma. Ann Surg Oncol 5 (4): 322-8, 1998. [PUBMED Abstract]
  7. 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 218 (3): 262-7; discussion 267-9, 1993. [PUBMED Abstract]
  8. Shen P, Wanek LA, Morton DL: Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol 7 (8): 554-9; discussion 560-1, 2000. [PUBMED Abstract]
  9. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998. [PUBMED Abstract]
  10. Cascinelli N, Morabito A, Santinami M, et al.: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351 (9105): 793-6, 1998. [PUBMED Abstract]
  11. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998. [PUBMED Abstract]
  12. Wong SL, Balch CM, Hurley P, et al.: Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 30 (23): 2912-8, 2012. [PUBMED Abstract]
  13. 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 14 (1): 7-17, 1996. [PUBMED Abstract]
  14. Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12): 2444-58, 2000. [PUBMED Abstract]
  15. 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 372 (9633): 117-26, 2008. [PUBMED Abstract]
  16. 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 22 (1): 53-61, 2004. [PUBMED Abstract]
  17. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011. [PUBMED Abstract]
  18. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al.: Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med 375 (19): 1845-1855, 2016. [PUBMED Abstract]
  19. Weber J, Mandala M, Del Vecchio M, et al.: Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med 377 (19): 1824-1835, 2017. [PUBMED Abstract]
  20. Eggermont AMM, Blank CU, Mandala M, et al.: Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med 378 (19): 1789-1801, 2018. [PUBMED Abstract]
  21. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al.: Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 16 (5): 522-30, 2015. [PUBMED Abstract]
  22. Long GV, Hauschild A, Santinami M, et al.: Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med 377 (19): 1813-1823, 2017. [PUBMED Abstract]
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