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Malignant Melanoma Treatment & Management

  • Author: Winston W Tan, MD, FACP; Chief Editor: Dirk M Elston, MD  more...
 
Updated: Feb 11, 2016
 

Approach Considerations

Surgery is the definitive treatment for early-stage melanoma. Wide local excision with sentinel lymph node biopsy and/or elective lymph node dissection (LND) is considered the mainstay of treatment for patients with primary melanoma. In patients with solitary or acutely symptomatic brain metastases, surgical management may alleviate symptoms and provide local control of disease.[24]

Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy of patients with advanced melanoma. Less than one half of patients with deep primaries (>4 mm) or regional lymph node involvement have long-term disease-free survival; consequently, these patients are classified as high risk and should be considered for adjuvant therapy.

Interferon alfa is approved for adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence. Currently, there are no standard systemic therapeutic regimens that offer significant prolongation of survival for most patients with metastatic melanoma without significant risk of toxicities.In patients with BRAF V600 wild-type unresectable or metastatic melanoma, however, the introduction of immune-based therapy has resulted in improved survival.

Also see Lentigo Maligna Melanoma, Oral Malignant Melanoma, and Head and Neck Mucosal Melanomas.

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Adjuvant Therapy

Gould Rothberg et al developed and validated a multimarker prognostic assay for determining survival in stage II melanoma, which these researchers suggest might be beneficial in improving the selection of patients for adjuvant therapy.[25] Multiple iterations of a genetic algorithm using the automated quantitative analysis (AQUA) method for immunofluorescence-based immunohistochemistry on 246 serial primary melanomas yielded a consistent five-marker solution. A favorable prognosis was predicted by the following criteria:

  • ATF2 ln(non-nuclear/nuclear AQUA score ratio) greater than -0.052
  • p21(WAF1) nuclear compartment AQUA score greater than 12.98
  • p16(INK4A) ln(non-nuclear/nuclear AQUA score ratio) -0.083 or less
  • Beta-catenin total AQUA score greater than 38.68
  • Fibronectin total AQUA score 57.93 or less

Primary tumors that met at least four of these five conditions were considered low risk. Validation of the score showed that tumors in the high-risk group (those that met three or fewer conditions) were associated with significantly reduced survival (hazard ratio, 2.72; 95% confidence interval, 1.12-6.58; P = 0.027).

Interferon alfa

A large multicenter study using high-dose interferon (IFN) alfa-2b, Eastern Cooperative Group (ECOG) 1684, showed improvement in disease-free survival and survival benefit (time to progression improvement of 8 months, with a 1-year survival benefit).[26] On the basis of ECOG-1684, the US Food and Drug Administration (FDA) approved IFN as adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence.

A pooled analysis of 1016 patients and 716 observational controls from all ECOG trials showed a significant increase in relapse-free survival (P = 0.006) but not overall survival (P = 0.42).[27]

Concerns about toxicity associated with high-dose adjuvant interferon alfa have prompted several investigators to test lower doses of the drug. Lower-dose adjuvant interferon alfa has demonstrated less toxicity than high-dose interferon alfa but also less efficacy in delaying progression, with no survival advantage.

To investigate the possibility that the survival benefit seen in ECOG-1684 had to do with its incorporation of an induction phase of maximally tolerated dosages of IFN given intravenously for the initial 4 weeks, Pectasides et al conducted a prospective, randomized study in 364 patients with stage IIB, IIC, or III melanoma who had undergone curative surgery. Patients were randomly assigned to receive IFN-alpha-2b IV for 5/7 days weekly for 4 weeks (arm A) versus the same induction regimen followed by IFN-alpha-2b administered subcutaneously 3 times a week for 48 weeks (arm B). At a median follow-up of 63 months, there were no significant differences in overall survival and relapse-free survival between the 2 arms, and patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity.[28]

On the other hand, Hauschild et al found that the addition of a 4-week modified high-dose IFN-alpha induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome. In their prospective, randomized, multicenter trial in 674 lymph node–negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness, there was no significant difference in 5-year relapse-free survival and overall survival between patients who received an induction phase (IFN-alpha-2b 5 times weekly IV for 2 wk and 5 times weekly subcutaneously for another 2 wk) followed by 23 months of low-dose IFN-alpha-2b, and patients who received low-dose subcutaneous treatment 3 times a week for 24 months.[29]

Hauschild et al also studied optimal duration of treatment of malignant melanoma with low-dose IFN alfa-2a and concluded that prolonging treatment with conventional low-dose IFN alfa-2a from 18 to 60 months showed no clinical benefit in patients with intermediate- and high-risk primary melanoma. Patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness and lymph node negative were included in this prospective, randomized, multicenter trial (n=850). Patients were randomly assigned to receive 3 MU IFN alfa-2a SC 3 times/wk for either 18 or 60 months. Median follow-up was 4.3 years. Relapse-free survival and distant-metastasis-free survival did not differ between the 2 groups.[30]

Meta-analysis data shows that ulceration and tumor stage are important predictors of response to interferon alfa/pegylated-interferon.[31]

Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. It was approved by the FDA in March 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy.

The drug’s approval was based on a 5-year, open-label, multicenter trial in which cancer recurrence was delayed about 9 months longer in patients who took peginterferon alfa-2b than it was in patients who did not take the drug.[3]

Granulocyte-macrophage colony-stimulating factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in the adjuvant setting to treat high-risk melanoma. In a study of 46 patients with resected stage III or IV melanoma treated with a subcutaneous dose of 125 mg/m2 for 2 weeks on and 2 weeks off for a year, progression-free survival was 37 months, vs 12 months in historical controls.[32]

However, a subsequent double-blind, placebo-controlled trial that compared the effect of GM-CSF and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in 815 patients with resected high-risk melanoma (locally advanced and/or stage 4) found that neither adjuvant GM-CSF nor PV significantly improved RFS or OS. Exploratory analyses did show a trend toward improved OS in GM-CSF-treated patients with resected visceral metastases.[33]

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Treatment of Advanced-Stage Melanoma (Stage IV)

Treatment of patients with advanced-stage melanoma (stage IV) has continued to improve despite the challenges.

No combination chemotherapy regimen has proven to be significantly better than single-agent dacarbazine (DTIC), which yields only a 10-15% response rate.[34]

Two combination regimens commonly are used in the treatment of patients with advanced-stage melanoma. The first regimen is the cisplatin, vinblastine, and DTIC (CVD) regimen. The second commonly used regimen is the Dartmouth regimen, which is a combination of cisplatin, DTIC, carmustine, and tamoxifen. However, a meta-analysis found that the strength of evidence does not support the addition of tamoxifen to combined chemotherapy regimens.[35]

Biologic therapies now are being used alone and with chemotherapy regimens in the treatment of patients with advanced-stage melanoma. To date, studies do not show that interferon and interleukin 2 (IL-2) added to DTIC is better than DTIC alone.

Dacarbazine

DTIC was the first drug approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma. In the initial studies with dacarbazine, the overall response rate was 22%, with no impact on survival. In a phase III study of dacarbazine compared with temozolomide, the response rate was 12% versus 13%.[36] On the basis of this trial, and the greater ease of administration of temozolomide versus dacarbazine (oral versus intravenous), most oncologists currently use temozolomide as their first-line drug for melanoma.

Interleukin 2

The second drug approved by the FDA for the treatment of metastatic melanoma was IL-2, a recombinant hormone of the immune system originally described as a T-cell derived growth factor and used as a lymphokine-activated cell killer therapy.

A pooled analysis of 270 patients treated with a high-dose IL-2 bolus (600,000-720,000 units/kg every 8 hours for 5 days) resulted in an objective response rate of 16% (complete response of 6%) with the best response in patients with soft tissue and lung metastases. The overall median survival was 11.4 months.[37]

The treatment was quite toxic, with some patients requiring intensive care unit support. The more common toxicities included hypotension (45%), vomiting (37%), diarrhea (32%), and oliguria (39%). Consequently, this therapy is offered only in centers that have adequately trained staff and facilities. To qualify for this type of treatment, patients must have normal results on pulmonary function testing, brain MRI, and cardiac stress testing, plus adequate renal and hepatic function.

Carboplatin and paclitaxel

Carboplatin and paclitaxel have been tested in two small phase II studies, and when used in combination with sorafenib, the response rate was 11-17%. This regimen sometimes is being used by clinicians in clinical practice because of lesser toxicity than dacarbazine and also as a second- or third-line regimen.

However, a randomized, placebo-controlled phase III study by Hauschild et al found that the addition of sorafenib to carboplatin and paclitaxel did not improve outcome in patients with unresectable stage III or IV melanoma; these investigators recommend against this combination in the second-line setting for patients with advanced melanoma.[38, 39]

Treatment of melanoma with BRAF mutations

BRAF mutations are present in 60% of melanomas. Detection of this mutation is important prior to starting treatment in any melanoma patient. In a multicenter, phase I, dose-escalation trial, 32 patients with metastatic melanoma who had a BRAF mutation were treated with vemurafenib (PLX4032).[40] Two patients had a complete response, and 24 had a partial response.

First-line treatment of patients with BRAF V600 wild-type or mutation-positive, unresectable or metastatic melanoma is with nivolumab as a monotherapy or in combination with the immunotherapy ipilimumab.[73]

Vemurafenib (Zelboraf) was approved by the FDA in August 2011. It is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF -V600E. This agent is indicated for the treatment of unresectable or metastatic melanoma with BRAF -V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.

In May 2013 the FDA approved dabrafenib (Taflinar), a BRAF inhibitor in the same class as vemurafenib, for patients with unresectable or metastatic melanoma with BRAF V600E mutation confirmed by the THxID BRAF mutation test.[41] In a multicenter, open-label, phase III randomized controlled trial, treatment with dabrafenib significantly improved progression-free survival in patients with BRAF-mutated metastatic melanoma, compared with dacarbazine (5.1 vs 2.7 mo).[42]

Phase III trial results for the investigational BRAF inhibitor vemurafenib included a 63% relative reduction in the risk of death as well as a 74% relative reduction in the risk of tumor progression in patients with previously untreated metastatic melanoma with the BRAF V600E mutation compared with dacarbazine, the only chemotherapeutic drug currently approved by the US Food and Drug Administration (FDA) for this disease.[43]

In addition, the overall survival rate at 6 months in the vemurafenib group was 84%, versus 64% in the dacarbazine group.[43] Despite the short follow-up period, these results have significant clinical implications, as, of the previously mentioned 40-60% of cutaneous melanomas with BRAF mutations, about 90% involve the BRAF V600E mutation. Moreover, a response to vemurafenib in four of 10 patients with the BRAF V600K mutation was noted, suggesting sensitivity of this mutation variant to vemurafenib.[43]

Vemurafenib was generally well tolerated, with cutaneous events (squamous cell carcinoma, keratoacanthoma, or both; all were treated with simple excision), arthralgia, fatigue, and photosensitivity the most common adverse events; such events led to dose modification or interruption in 38% of patients.[43] Adverse events seen with dacarbazine were primarily fatigue, nausea, vomiting, and neutropenia and led to dose modification or interruption in 16% of patients.

Dabrafenib was shown to significantly improve progression-free survival compared with dacarbazine (5.1 vs 2.7 mo) in patients with BRAF -mutated metastatic melanoma in a multicenter, open-label, phase III randomized controlled trial.[44]

Trametinib (Mekinist) is a mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that was approved by the FDA in May 2013 for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by the THxID BRAF mutation test.[41] Approval was based on a phase III open-label trial that compared trametinib with either dacarbazine or paclitaxel. Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group. At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% confidence interval [CI], 0.32 to 0.92).[45]

In January 2014, the FDA approved trametinib for use in combination with dabrafenib for treating patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Approval was based on the demonstration of response rate and median duration of response in a phase I/II study. Median progression-free survival in the combination full-dose 150 mg/2 mg group was 9.4 months compared with 5.8 months in the dabrafenib monotherapy group (hazard ratio for progression or death, 0.39; 95% CI, 0.25 to 0.62). The rate of complete or partial response with combination therapy was 76% compared with 54% with monotherapy. Improvement in disease-related symptoms or overall survival has not been demonstrated for this combination.[46, 47, 48]

In November 2015, the FDA approved cobimetinib, an MEK1 and MEK2 inhibitor, for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafenib. Approval was based on results in 495 patients with advance melanoma from the phase 3 coBRIM study, in which median progression-free survival was longer with cobimetinib plua vemiurafenib than with vemurafenib monotherapy (12.3 vs 7.2 months; hazard ratio, 0.58; 95% confidence interval, 0.46 - 0.72). Additionally, the objective response rate was higher with the combination than with vemurafenib alone (70% vs 50%; P <0.0001).[49]

Treatment of BRAF V600 wild-type melanoma

First-line treatment of patients with BRAF V600 wild-type or mutation-positive, unresectable or metastatic melanoma is with nivolumab as a monotherapy or in combination with the immunotherapy ipilimumab.

The November 2015 approval for nivolumab monotherapy is based on data from the randomized phase 3 CheckMate-066 trial, which compared nivolumab monotherapy with dacarbazine in the first-line treatment of 418 patients with advanced BRAF wild-type melanoma. In an interim analysis, nivolumab demonstrated superior overall survival, which was the primary outcome. The overall survival rate at 1 year was 72.9% (95% CI, 65.5 to 78.9) in the nivolumab group and 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group. A significant benefit with respect to overall survival was observed in the nivolumab group, as compared with the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). Median progression-free survival was also improved in the nivolumab-treated patients compared with dacarbazine (5.1 vs 2.2 months; HR, 0.43; P <0.001).[50]

The FDA approved the combination regimen of nivolumab plus ipilimumab on September 30, 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma. Approval was based on results from the phase 2 CheckMate-069 study Of the 142 patients enrolled, 109 had both BRAF wild-type and BRAF mutation-positive melanoma. The primary endpoint was objective response rate (ORR) in patients. In patients with BRAF wild-type melanoma treated with the combination regimen, the overall response rate was 61% (95% CI: 48-71) compared to 11% (95% CI: 3-25) in patients given ipilimumab monotherapy (P <0.001).

Additional analysis showed that complete responses were seen in 22% of patients. Partial responses were seen in 43% of the combination group and 11% of the ipilimumab monotherapy group. The combination group had a 60% reduction in the risk of progression compared with ipilimumab alone (HR=0.40; 95% CI: 0.22-0.71; P <0.002). Median PFS was 8.9 months with the combination (95% CI: 7.0, NA) and 4.7 months with ipilimumab alone (95% CI: 2.8-5.3).[51]

In January 2016, this indication was expanded to include mutation-positive melanoma, making nivolumab effective across BRAF status.[73]

Vaccines

Melanoma vaccines and gene therapy are two additional treatment options that may become available.[52]

A 2007 review found no clear evidence that the addition of immunotherapy to chemotherapy increases survival in metastatic melanoma and recommended that combined immunotherapy and chemotherapy be limited to clinical trials.[53] Because numerous protocols for patients with advanced-stage melanoma exist, eligible patients should be referred to an oncology center participating in these studies. Vaccines have not been successful as a treatment for metastatic melanoma but are still a reasonable area of research in the adjuvant setting.[33]

External-beam radiation

The brain is a common site of metastasis in malignant melanoma. Brain metastases are associated with a poor prognosis. Management of brain metastases can be difficult due to rapid progression of disease and resistance to conventional therapies. Stereotactic radiosurgery is used increasingly in patients with a limited number of metastases; it is less invasive than craniotomy. External-beam radiation alone appears effective in palliating symptoms. Chemotherapy alone is relatively ineffective, although the combination of chemotherapy with external-beam radiation is being investigated.[24]

Future therapies

In a multicenter phase II trial, targeted therapy with imatinib was an effective treatment option in patients with advanced melanoma harboring mutations or amplification of the KIT proto-oncogene.[54, 55, 56] Of 50 patients with melanomas arising from acral, mucosal, or chronically sun-damaged sites with KIT alterations, 24 evaluable patients with KIT -mutant (n = 8), KIT -amplified melanoma (n = 11), or both (n = 5) were treated with imatinib. Seven of these 24 patients achieved a partial response to therapy, with five patients' responses confirmed on subsequent imaging studies, for an overall confirmed response rate of 21%.[54, 55]

These findings reinforce similar findings in two earlier studies.[1, 57]

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Ipilimumab

Anti–cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a humanized antibody directed at a down-regulatory receptor on activated T-cells.[58] The proposed mechanism of action is inhibition of T-cell inactivation, allowing expansion of naturally developed melanoma-specific cytotoxic T-cells.

Ipilimumab, a CTLA-4 blocker, has demonstrated remarkable promise in patients with metastatic melanoma. Clinical trials for monotherapy and in combination with other immunotherapies and vaccines have been concluded or are currently under way.[59] Ipilimumab was approved by the FDA in March 2011 for unresectable or metastatic melanoma.

Hodi et al reported improved survival with ipilimumab in patients with metastatic melanoma. Ipilimumab blocks CTLA-4 to a potentiate T-cell response. In a phase 3 study, 676 patients with HLA2-positive patients with unresectable stage III or IV melanoma who disease progressed while receiving therapy for metastatic disease were randomly assigned in a 3:1:1 ratio to ipilimumab plus gp100, ipilimumab, or gp100 alone. Ipilimumab was given at a dose of 3 mg/kg and was administered with or without gp100 every 3 weeks for up to 4 treatments; subsequently, patients would receive reinduction therapy. The median overall survival was 10 months among patients receiving ipilimumab plus gp100, compared with 6.4 months in those receiving gp100 alone. There was no difference in survival in the other ipilimumab arm compared with the ipilimumab-plus-gp100 arm. Because of these findings, ipilimumab has been approved as a treatment for metastatic melanoma.[59]

In a phase 3 study of ipilimumab and dacarbazine compared with dacarbazine and placebo, survival among patients with metastatic melanoma was improved by 2 months (11 mo vs 9 mo) in the ipilimumab arm; however, they had more grade 3 and 4 toxicity.[60]

In the MDX010-20 trial, researchers evaluated immune-related adverse events (AEs) in 676 patients previously treated for metastatic melanoma who were randomly assigned to receive 1 of the following 3 treatment regimens (in a 3:1:1 ratio): (1) ipilimumab plus glycoprotein 100 melanoma antigen vaccine (gp100); (2) ipilimumab plus placebo; or (3) gp100 plus placebo.[61, 62] Most of the immune-related AEs developed within 12 weeks of initial dosing, typically resolving in 6-8 weeks. Fewer than 10% of patients receiving any ipilimumab treatment experienced an immune-related AE more than 70 days after their last drug dose, and all of these AEs were grade 1 or 2 in severity. Most immune-related AEs, even grade 3/4 events, were readily managed with monitoring and early corticosteroid therapy; only 5 patients needed infliximab for gastrointestinal AEs, and all 5 subsequently improved.[61, 62]

The FDA approved the combination regimen of nivolumab plus ipilimumab on September 30, 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma.[51]  Additionally, it is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy.[63]

The use of immune checkpoint inhibitors for the treatment of advanced melanoma has evolved beyond monotherapies to combination strategies. This combination approach results in response rates around 60% and superior progression-free survival compared with ipilimumab monotherapy (median 11.5 versus 2.9 months).[74]

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Immune-Based Therapy

PD-1 inhibitors

Programmed cell death–1 protein (PD-1) and the related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. The PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells.

In September 2014, the FDA granted accelerated approval for pembrolizumab (Keytruda). Pembrolizumab is the first monoclonal antibody for inhibition of PD-1.[64] It was initially indicated for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on data including a study in which approximately 24% of patients experienced tumor shrinkage.[2]  In December 2015, the FDA approved pembrolizumab as first-line treatment for unresectable or metastatic melanoma. Approval was based on the phase 3 KEYNOTE-006 trial. Patients with advanced melanoma were randomized to receive either pembrolizumab 10 mg/kg every 2wk or every 3wk, or 4 doses of ipilimumab (3 mg/kg every 3wk). Progression-free survival for the pembrolizumab groups were 47.3% and 46.4% respectively and 26.5% for ipilimumab. Note that the trial used a higher dose of pembrolizumab than the dose that is approved by the FDA, which is 2 mg/kg every 3 wk.[72]

Nivolumab (Opdivo), another PD-1 inhibitor, was granted accelerated approval in December 2014 for unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on interim results of a randomized clinical trial in patients with unresectable or metastatic melanoma that had progressed after ipilimumab. Interim analysis confirmed objective responses in 38 of the first 120 patients treated with nivolumab (31.7%; 95% confidence interval [CI] 23.5-40.8) versus five of 47 patients who received investigator's choice of chemotherapy (10.6%; CI, 3.5-23.1).[4]

Nivolumab and ipilimumab combination

The FDA approved the combination regimen of nivolumab plus ipilimumab on September 30, 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma. Approval was based on results from the phase 2 CheckMate-069 study Of the 142 patients enrolled, 109 had both BRAF wild-type and BRAF mutation-positive melanoma. In patients with BRAF wild-type melanoma, the overall response rate was 61% (95% CI: 48-71) with the combination regimen, compared with 11% (95% CI: 3-25) with ipilimumab monotherapy (P <0.001). Additional analysis showed that complete responses were seen in 22% of patients. Partial responses were seen in 43% of the combination group and 11% of the ipilimumab monotherapy group. The combination group had a 60% reduction in the risk of progression compared with ipilimumab alone (HR=0.40; 95% CI: 0.22-0.71; P <0.002). Median PFS was 8.9 months with the combination (95% CI: 7.0, NA) and 4.7 months with ipilimumab alone (95% CI: 2.8-5.3).[51]

Talimogene laherparepvec

In October 2015, the FDA approved the oncolytic immunotherapeutic vaccine talimogene laherparepvec (Imlygic). It is a genetically modified, live attenuated herpes simplex type I virus programmed to replicate within tumors and produce the immune stimulatory protein granulocyte-macrophage colony-stimulating factor (GM-CSF). In this process, the gene ICP 34.5 is deleted and replaced with the coding sequence for GM-CSF. It is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery. It is administer by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.[65]

The study enrolled 436 patients, of which 295 patients treated with talimogene laherparepvec were compared with 141 patients treated with GM-CSF. The primary endpoint was the durable response rate (DRR), defined as the rate of complete response plus partial response continuously lasting ≥6 months and beginning within the first 12 months. Secondary endpoints included overall survival (OR) and the overall response rate (ORR).

The DRR was significantly higher among patients who received talimogene laherparepvec compared with those given GM-CSF (16.3% vs 2.1%; odds ratio, 8.9; P < 0.001). Of the patients who experienced a durable response, 29.1% had a durable complete response and 70.8% had a durable partial response. The median time to response was 4.1 (range: 1.2 to 16.7) months in the arm receiving talimogene laherparepvec.

ORR rate was also higher with talimogene laherparepvec (26.4% vs 5.7%; P <0.001). In all, 32 (10.8%) patients receiving talimogene laherparepvec experienced a complete response, compared with just one (<1%) patient receiving GM-CSF. The median time to treatment failure was 8.2 months with talimogene laherparepvec and 2.9 months with GM-CSF (hazard ratio [HR], 0.42). Median OS was 23.3 months and 18.9 months, respectively (HR, 0.79; P = 0.051), which just missed being statistically significant.[66]

 

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Prevention of Malignant Melanoma

The focus of melanoma prevention is avoidance of sun exposure. Everyone, especially those individuals at high risk of developing a melanoma, should wear protective clothing, avoid peak sun hours, protect children against exposure to ultraviolet radiation, avoid tanning booths, and wear sunscreen with a sun protection factor (SPF) of at least 15. This last recommendation is considered somewhat controversial, because no study has shown sunscreen to reduce the incidence of melanoma.[67] Moreover, a systematic review found that sunscreen use leads to longer duration of intentional sun exposure, and sunburns tend to be more frequent among sunscreen users.[68]

First-degree relatives of a patient diagnosed with familial melanoma should be encouraged to have annual skin examinations.

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Consultations

A patient with a suggestive lesion should be referred to a dermatologist or surgical oncologist for excisional biopsy.

If the diagnosis of melanoma is made, the patient should be referred to an oncologist after definitive surgery is performed.

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Long-Term Monitoring

Follow-up care of a patient with melanoma is based on the stage of the primary. The follow-up examination should be performed with the knowledge that the patient has an increased risk for a second primary and that, of all solitary sites of visceral recurrence, the lungs are the most frequent.

Follow-up guidelines from the National Comprehensive Cancer Network are listed below.[18]

Follow-up for stage 0 in situ is as follows:

  • At least annual skin examination for life
  • Educate patient in monthly self-examination of skin

Follow-up for stage IA is as follows:

  • History and physical examination (H&P) (with emphasis on nodes and skin) every 3-12 mo for 5 y, then annually as clinically indicated
  • At least annual skin examination for life
  • Educate patient in monthly self-examination of skin and lymph nodes

Follow-up for stage IB-IV (patients with no evidence of disease) is as follows:

  • H&P (with emphasis on nodes and skin) every 3-6 mo for 2 y, then every 3-12 mo for 2 y, then annually as clinically indicated
  • Chest radiography, lactate dehydrogenase (LDH) level, and complete blood cell count (CBC) every 6-12 mo (optional)
  • Routine imaging is not recommended for stage IB or IIA disease
  • CT scans to follow up for specific signs and symptoms
  • Consider CT scans to screen stage IIB and higher for recurrent/metastatic disease
  • At least annual skin examination for life
  • Educate patient in monthly self-examination of skin and lymph nodes
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Contributor Information and Disclosures
Author

Winston W Tan, MD, FACP Associate Professor of Medicine, Mayo Medical School; Consultant and Person-in-Charge of Genitourinary Oncology-Medical Oncology, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Jacksonville; Vice Chairman of Education, Division of Hematology/Oncology, Mayo Clinic Florida

Winston W Tan, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Hematology, Texas Medical Association, American Society of Clinical Oncology, Philippine Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Philip Schulman, MD Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center

Philip Schulman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.

References
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  2. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Jul 14. [Medline].

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A 1.5-cm melanoma with characteristic asymmetry, irregular borders, and color variation.
Malignant melanoma. Image courtesy of Hon Pak, MD.
Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ). Image courtesy of Susan M. Swetter, MD.
 
 
 
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