Melanoma and Other Skin Cancers

Treatment

Surgical Treatment of Cutaneous Melanoma

Excision of primary lesion

It was recognized over a century ago that tumor cells could extend within the skin for several centimeters beyond the visible borders of a melanoma, so that the risk of local recurrence relates to the width of normal skin excised around the primary tumor. Only much more recently was it realized that the thickness of the primary tumor influenced the likelihood of contiguous spread and that not all melanomas require the same excision margin. This realization prompted a number of randomized trials to determine the optimal excision margins for melanomas of different Breslow thicknesses.

Initially, a "one-size-fits-all" approach of taking a 5-cm margin around all invasive melanomas was adopted. With such wide margins, skin grafts were usually required for reconstruction. Modern melanoma surgical care is based on level I medical evidence, and many large, prospective randomized trials have been conducted to determine the appropriate radial margin for cutaneous melanoma based on Breslow thickness.

A randomized trial conducted by the World Health Organization found that when a 1-cm margin of normal skin was taken around a melanoma ≤ 1 mm thick, the local recurrence rate was exceedingly low (< 1%), and patient survival was just as good as when 3-cm margins were taken. For melanomas 1 to 2 mm in thickness, patient survival was the same for both margins of excision, but the local recurrence rate was higher with the 1-cm margin (3.3% after 10-year follow-up).

The Intergroup Melanoma Trial compared 2- vs 4-cm margins for all cutaneous melanomas of the trunk or proximal extremity between 1 and 4 mm in thickness. Most patients in this trial had melanomas ≤ 2 mm in thickness. In this trial both local recurrence and survival were the same regardless of whether 2- or 4-cm margins were obtained. Skin grafts were less frequent and hospital stays shorter with the narrower margin.

A trial conducted in the United Kingdom addressed patients with primary melanoma ≥ 2 mm in depth. Patients who underwent a 1-cm radial margin of excision had a higher risk of local/regional recurrence than those who underwent excision with 3-cm margins.

Current recommendations

Based on these important studies, it is possible to make rational recommendations for excision margins for melanoma patients.

• Patients with melanoma ≤ 1 mm should undergo excision of skin and subcutaneous tissue for a radial margin of 1 cm.

• Patients with melanoma between 1 and 2 mm should undergo excision of skin and subcutaneous tissue, for a radial margin of 1 to 2 cm.

• Patients with melanoma > 2 mm in depth should undergo a wide excision of skin and subcutaneous tissue of 2 to 3 cm.

• When the anatomic location of the primary tumor precludes excision of the margin (eg, on the face), at least 1 cm should be taken when feasible.

TNM Staging System

Clinically apparent lymphadenopathy

Melanoma patients with clinically enlarged nodes and no evidence of distant disease (AJCC stage IIIB) should undergo complete regional lymphadenectomy. The first step in evaluating palpable nodes is generally FNA. A negative or inadequate FNA sample may be repeated, with image guidance if necessary, or an open node biopsy performed, followed by complete lymphadenectomy in the event of a positive frozen section or touch-prep cytologic determination of metastasis.

Clinically normal nodes

The surgical management of clinically normal nodes is determined by the characteristics of the primary lesion. A direct relationship between thickness of the primary lesion and nodal involvement has long been recognized. When the depth of the primary is unknown because of the biopsy technique or other factors, consideration should be given to SLN mapping as a staging procedure.

SLNB is the primary method for regional nodal staging. All potentially involved basins should initially be examined as part of a thorough history and physical examination.

Thin melanomas. Patients with thin melanoma (< 1 mm Breslow depth) have a low risk of occult nodal involvement (< 5%). Some patients with melanomas 0.76 to 1 mm have a high enough risk of lymph node involvement to justify consideration of SLNB in addition to wide excision.

When ulceration is present, consideration should be given to SLNB. In addition, a mitotic count ≥ 1 should prompt consideration of regional nodal basin staging in the appropriate patient.

Intermediate-thickness melanomas. Risk of nodal metastasis rises significantly with increasing depth of invasion. Patients with a 1-mm thick melanoma have approximately a 10% chance of nodal involvement, whereas those with a 4-mm melanoma have a 35% to 40% risk of nodal metastases. For these reasons, wide excision of the primary tumor is generally accompanied by SLNB for staging of the nodal basin. Patients who have evidence of metastasis in the SLN are offered completion lymphadenectomy (CLND) as a "standard" approach, although nodal basin observation should also be discussed, as there is no level I medical evidence supporting CLND. Indeed, a randomized controlled trial reported by Morton et al has demonstrated no impact of SLN biopsy/CLND in node (+) patients on overall survival compared with patients undergoing wide excision alone. An prospective clinical trial evaluating the role of CLND in SLN (+) patients is ongoing (Multicenter Selective Lymphadenectomy Trial II).

Regional lymphadenectomy

The identification and management of regional nodal disease have evolved significantly over the past 20 years. Historically, regional lymph node dissections were performed on all patients with intermediate-thickness melanomas, in the belief that doing so would lead to a survival benefit. This was based on the observation that there was an approximately 20% survival advantage to patients found to have microscopic involvement of lymph nodes at "elective" lymph node dissection (ELND) when compared with patients who had clinically apparent nodal metastasis and underwent a "therapeutic" lymph node dissection (TLND). With ELND, however, most (80% to 85%) patients had pathologically negative lymph nodes. More importantly, a series of prospective randomized clinical trials failed to demonstrate a survival advantage for patients undergoing ELND over wide excision only. For this reason, the standard approach prior to the development of SLN mapping was wide excision alone and clinical observation of the nodal basin.

SLN mapping is performed by injecting radiolabeled colloid into the dermis surrounding the primary melanoma. The radiotracer migrates via the lymphatics to the regional nodal basin(s), which is visualized with a gamma camera. The patient is then taken to the operating room, where a hand-held gamma probe is used to identify the sentinel node(s). This technique, in combination with the use of vital blue dye, has led to a success rate of SLN identification exceeding 97% at experienced centers.

The hypothesis that SLN mapping and biopsy followed by CLND would result in improved survival was disproven by MSLT 1 (as discussed by Morton et al). It remains, however, an accurate predictor of outcome in patients with intermediate risk melanoma.

Thick melanomas. Deep melanomas harbor nodal metastases in up to 60% of patients. Surgical staging of the nodal basin may be performed, as most studies suggest that SLN status retains prognostic value (though less robust) in patients with deep primary melanoma. In addition, a CLND for those at high risk of local and regional recurrence may subject the patients to undue morbidity. The lymphedema associated with complete node dissection may complicate treatment of subsequent recurrences in patients with deep melanoma of the extremity. The presence of satellitosis surrounding a primary melanoma is such a poor prognostic sign for recurrence that no additional prognostic information is to be gained by SLN mapping.

Surgical Treatment of Noncutaneous Melanoma

Ocular melanomas

These lesions generally do not have access to lymphatic channels, so the surgical principles outlined previously do not apply. These lesions have a unique propensity to metastasize hematogeneously, often to the liver after a long relapse-free interval. Advances in understanding the biology of ocular melanomas may lead to adjuvant approaches different from therapies now under investigation for cutaneous primaries.

A diagnosis of ocular melanoma with no evidence of distant disease signifies that a decision must be made as to whether or not the eye can be spared. Some small melanomas situated peripherally in the retina can be excised with minimal loss of vision, but most cannot. For larger lesions, treatment options are enucleation (total removal of the eye) or implanted radiotherapy with a radioactive gold plaque fitted to the back of the eyeball immediately behind the tumor. A multi-institution, randomized trial comparing implanted radiotherapy with enucleation for local disease control and overall survival was completed by the Collaborative Ocular Melanoma Study Group; it appears that both techniques provide similar outcomes for all sizes of tumors.

Melanomas of the anus and vulva

These "mucosal" melanomas are notoriously difficult to cure and are almost always associated with a poor outcome. The surgical management of anal melanoma is controversial, but most surgeons prefer a wide excision, when possible, over an abdominoperineal resection (APR). In the past, an APR was more commonly used for patients with less-advanced disease who were viewed as potentially curable. This almost certainly explains the reported association of APR with long-term survivors. More recently, APR is reserved for patients with bulky disease or recurrent disease that is not amenable to wide excision, which is favored for patients with more localized/potentially curable disease. Not surprisingly, more recent studies demonstrate no survival advantage to APR, which appears to be equivalent to wide excision.

Radical resection is also less commonly performed for patients with vulvar melanoma, who also have a high risk of relapse and death. Function-preserving resection and nodal basin staging in the setting of relatively early disease are appropriate, but, as in patients with anal primaries, preemptive nodal staging in patients with advanced primary tumors is unlikely to impart a benefit to those whose nodal basin can be followed clinically and radiologically.

Nasal sinuses or nasopharyngeal melanomas

Melanomas arising in the nasal or nasopharyngeal mucosa should be widely excised to include adjacent bony structures, if needed. As in patients with anal or vulvar melanoma, node dissection is reserved for patients who have proven nodal involvement. Radiotherapy should be considered for patients whose primary tumor cannot be fully removed from this site with adequate margins or as adjuvant therapy in patients unlikely to be controlled with surgical resection alone.

Adjuvant Therapy for Melanoma

Interferon α-2b (IFN-α; Intron A) was approved for use in patients with deep primary melanoma or resected stage III or IV melanoma in 1995. In the Eastern Cooperative Oncology Group (ECOG) trial that led to FDA approval, interferon α-2b was administered intravenously at 20 mU/m² for 5 consecutive days every 7 days for 4 weeks, during the "induction" phase. For a subsequent 48 weeks, 10 mU/m² was administered by subcutaneous injection on alternate days for a total of three doses every 7 days in the "maintenance" phase.

This "high-dose" regimen was compared with observation. A statistically significant improvement in overall survival was demonstrated with interferon, compared with the observation arm; relapse-free survival was also improved. Three-quarters of the interferon patients experienced severe toxicities, most commonly fatigue, asthenia, fever, depression, and elevated liver transaminase levels. A quality-of-life analysis found that the toxicity associated with this regimen was largely compensated for by the prevention of disease relapse.

Due to uncertainty regarding the optimal dose and schedule of interferon, a second trial was initiated comparing the high-dose regimen and a low-dose regimen (3 mU by subcutaneous injection three times weekly for 24 months) as well as observation. No significant improvement in overall survival for either the high-dose or low-dose arm was observed compared with observation; relapse-free survival was improved by 22% in the high-dose arm compared with observation. A pooled analysis of E1684 and E1690, with longer follow-up for both trials, revealed a continued, statistically significant impact on relapse-free survival but not on overall survival.

High-dose interferon has been consistently shown to improve relapse-free survival compared with either observation or ganglioside Gm²/keyhole limpet hemocyanin (Gm²-KLH) vaccination but does not clearly confer an overall survival advantage. A recent prospective randomized trial conducted by the Hellenic Cooperative Oncology Group compared outcome in patients treated with high-dose interferon as an adjuvant for 1 month vs 1 year and found no difference in overall survival or disease-free survival; however, this trial was of insufficient size to firmly conclude that 1 month of interferon therapy is truly equivalent to the full-year regimen with regard to relapse-free survival. Due to the significant toxicity associated with 1 year of high-dose interferon and the lack of an overall survival advantage, consensus is lacking regarding the use of interferon in the adjuvant setting.

Intermediate-dose regimens with interferon have been evaluated in several trials; they have less consistently demonstrated a relapse-free survival advantage compared with observation and have never resulted in a survival advantage. A recent trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) demonstrated no survival advantage for patients undergoing 13 months or 25 months of intermediate-dose adjuvant interferon after resection of stage IIB (deep primary melanoma) or stage III nodal disease when compared with observation.

The EORTC reported the results of a prospective randomized trial of observation vs pegylated interferon-α for 5 years. Again, there was an advantage to treatment in terms of relapse-free survival but no overall survival advantage for patients with high-risk resected melanoma. Nearly one-third of the patients in the treated arm discontinued therapy due to toxicity. This regimen has received FDA approval. Induction therapy consists of 6 μg/kg weekly for 2 months, followed by 3 μg/kg weekly provided that patients can maintain good performance status. If performance is compromised, then the dose is reduced to 2 μg/kg, and again to 1 μg/kg as needed.

Adjuvant chemotherapy

Single-agent chemotherapy or combination chemotherapy regimens have not been systematically evaluated for the adjuvant treatment of melanoma because of the low response rates seen in patients with advanced disease. The largest randomized trial compared an IV administered regimen of carmustine(Drug information on carmustine) (BiCNU; 80 mg/m²) every 4 weeks, dactinomycin(Drug information on dactinomycin) (Cosmegen, 10 μg/kg), and vincristine (1 mg/m²) every 2 weeks for 6 months with observation among patients with resected stage III or IV melanoma. A significant improvement in relapse-free survival, but not overall survival, was observed in this small study. A randomized trial comparing dacarbazine(Drug information on dacarbazine) vs observation failed to demonstrate an improvement in either relapse-free survival or overall survival.

There is no widely accepted adjuvant therapy following resection of metastatic melanoma. Therefore, observation remains a standard of care for patients in this setting, and some investigational therapies are being evaluated in comparison to placebo in light of the significant percentage of patients who choose not to pursue interferon therapy.

Neoadjuvant therapy for resectable stage IIIC or IV melanoma remains an investigational approach. Neoadjuvant biochemotherapy (cisplatin, dacarbazine, vinblastine(Drug information on vinblastine), interleukin-2 [IL-2], and interferon) was evaluated in a small study of patients with stage III melanoma. In the 50 patients with measurable disease, the response rate was 26%. High-dose interferon, however, produced a 55% clinical response and 15% pathologic response when used in a neoadjuvant setting in a small group of patients with clinically apparent nodal metastasis. Currently available chemotherapy regimens for melanoma are not sufficiently active to support use in neoadjuvant therapy.

Ipilimumab (Yervoy) is a monoclonal antibody that blocks CTLA-4 mediated down regulation of T cell response. Yervoy was approved in March 2011 for use in patients with stage IV melanoma following a prospective randomized trial demonstrating an improvement in overall survival in ipilimumab-treated stage IV patients. An EORTC trial is accruing patients following lymphadenectomy for stage IIIA and B melanoma to determine whether adjuvant ipilimumab improves survival.

Radiation therapy

In vitro data from the 1970s demonstrated radiation resistance among melanoma cell lines and led to the reluctance to use radiation therapy in the treatment of melanoma. More modern data have shown that many melanomas are sensitive to radiation, but the disinclination toward use of radiation therapy for melanoma continues.

Another unanswered question is the proper fraction size to use in melanoma. In a large series of patients studied by Overgaard and colleagues, the investigators found that the response rate of metastatic melanoma lesions was dependent on the fraction size. The complete response rate was 57% when fractions greater than 4 Gy were used, compared with 24% for fractions less than 4 Gy. RTOG 83-05 is the only randomized trial that compared hypofractionated (8 Gy for 4 fractions) vs conventional (2.5 Gy for 20 fractions) schedules of radiation therapy. In this study, they noted no difference in the complete and partial responses. Though a wide spectrum of fraction sizes have been used, this does not preclude the use of radiation but emphasizes the need for more research to better understand and create an effective fractionation schedule.

Radiation therapy can provide some benefit and should be considered in the palliative treatment of melanoma metastatic to bone or other symptomatic sites, but its use in other settings remains controversial.

Adjuvant radiation treatment

Radiation treatment has been increasingly employed in the postoperative setting to improve locoregional tumor control in a select group of patients at "high risk" for local or regional recurrence. "High risk" has been variably defined but includes patients with large, matted nodes, extranodal extension of tumor, inadequate margins due to anatomic constraints, head and neck site, and multiple local/regional recurrences. The 5-year regional control has ranged from 87% to 94%, and the 5-year overall survival has ranged from 36% to 46% with the addition of radiation to surgery. Single institutions have reported that local recurrence is reduced to 6% to 11% when postoperative radiotherapy is used for high-risk lesions. Serious complication rates after radiation therapy were low, which is likely secondary to the superficial nature of the treated volumes.

A prospective randomized trial (ANZMTG 01.02/Trans-Tasman Radiation Oncology Group (TROG) 02.01) evaluated the role of adjuvant radiation treatment after therapeutic lymphadenectomy in patients with melanoma at high risk of lymph-node-field and distant recurrence. Patients were randomized to observation after surgery or to adjuvant RT (48 Gy in 20 fractions). This study showed that the use of adjuvant nodal basin radiation in these patients following surgery improved lymph-node relapse rates but had no effect on disease-free survival or overall survival. High-risk patients were those with ≥ 1 parotid, ≥ 2 cervical or axillary, or ≥ 3 groin nodes; extranodal spread of tumor; or maximum metastatic node diameter ≥ 3 cm in the neck or axilla or ≥ 4 cm in the groin. Adjuvant RT is an option for patients with isolated regional recurrence of melanoma who are considered to be at high risk of further regional recurrence after lymphadenectomy. At a median follow-up of 40 months, adjuvant RT improved regional control in melanoma patients at high risk for relapse after lymphadenectomy (hazard ratio [HR] = 0.56; 95% confidence interval [CI], 0.32–0.98; P = .041) but did not improve relapse-free survival (70 vs 73 events, HR = 0.91; 95% CI, 0.65–1.26; P = .56) or overall survival (59 vs 47 deaths, HR = 1.37; 95% CI, 0.94–2.01; P = .12). The RT compliance rate was 79%. There was a higher rate of acute toxicity (dermatitis and pain) with RT, but no grade 4 toxicity was seen.

At the Royal Prince Alfred Hospital, 143 patients with melanoma metastases to the parotid and/or cervical lymph nodes were treated with surgery alone or surgery and postoperative radiation therapy. The patients who received RT had more aggressive features such as at least two positive lymph nodes and extracapsular extension; there was a trend toward higher regional control in the group that received surgery and postoperative RT (94%) than with surgery alone (91%, P = .065).

In a retrospective study of 615 patients at Roswell Park and MD Anderson who had advanced regional nodal metastasis, adjuvant RT was associated with improved regional control when compared with surgery alone. The risk of long-term lymphedema is known to be high in patients with inguinal lymph node metastases; thus, it would be prudent to consider a higher threshold for treatment of these patients. In a review on the use of RT in malignant melanoma, Stevens and McKay offered the following recommendations for postoperative RT after regional lymph node dissection:

• Multiple involved nodes (more than one for parotid, three to four in other regions)

• Any involved node greater than 3 to 4 cm in maximum diameter

• Extranodal spread

• Incomplete dissection

• Recurrence after previous lymph node dissection (no previous RT)

Vaccines and other immunotherapy

These remain an investigational approach and are being tested among patients with resected stages II, III, and IV melanoma. The goal of this immunotherapy is to reverse immune tolerance of microscopic residual melanoma following surgery through the amplification of melanoma-specific cytolytic T cells. This approach is distinct from conventional immunization against pathogens to which the host is naive, through which long-lasting, antibody-mediated immunity is sought by induction of memory B cells.

Melanoma peptide vaccines are being intensely evaluated in clinical trials. Peptides have been selected from two classes for clinical development: melanocyte-specific proteins and so-called cancer-testis antigens. The latter are proteins that have a restricted spatiotemporal expression and are not detectable in adult tissues outside the immunologic sanctuary site of the testes. The most widely studied peptides are derived from gp-100, tyrosinase, melan-A (all melanocyte-specific), and NY-ESO-1 and melanoma antigen-encoding gene (MAGE) proteins (cancer-testis antigens). Preliminary evidence suggests that this approach may successfully engender specific and potent immunologic responses to the protein fragments being administered. Protection against disease recurrence in patients at high risk following surgery (adjuvant therapy) has not yet been demonstrated. However, a recent prospective randomized trial reported a survival advantage for patients with stage IV melanoma treated with a peptide vaccine (gp100:209-217). Patients with metastatic melanoma were randomized to receive a multivalent peptide vaccine and high-dose IL-2 vs high-dose IL-2 alone. This approach may prove promising in the adjuvant setting.

Treatment of Advanced Melanoma

Surgery

Surgical resection is a reasonable approach to treatment of the patient with isolated metastastic melanoma, or with limited sites of disease. Surgical resection is associated with better outcome than no treatment or treatment with traditional chemotherapeutic regimens, although patient selection makes conclusions about these reports difficult. All studies to date are retrospective reviews. A number of retrospective studies have shown the validity of resecting pulmonary metastases in patients with melanoma, and more recent studies have shown similar survival rates for patients undergoing resection of a limited number of lesions and sites of disease (usually up to four) for metastases to distant lymph nodes, skin and subcutaneous tissue, and lungs. Patients with isolated metastases in the liver, adrenal gland, brain, and gastrointestinal tract may undergo resection, but the survival of these patients may be less favorable.

Surgical resection may also be an important component of palliation. Bleeding or obstruction from small-intestine metastases may be managed by resection. Although palliative resection can provide short-term effective relief of patient symptoms, numerous studies have shown that incomplete resection does nothing to enhance the length of survival.

Single-agent chemotherapy

Melanoma is regarded as a relatively chemotherapy-refractory tumor. Durable objective responses have been observed in a small minority of patients with metastatic melanoma treated with single-agent chemotherapy, providing perhaps the most compelling reason to offer these agents routinely.

TABLE 4Selected chemotherapy agents–Results from phase II and phase III trials in melanoma

In a phase III trial comparing temozolomide(Drug information on temozolomide) (Temodar) and dacarbazine as first-line therapy, 3% of patients on either arm experienced complete responses. The highest response rates have been observed with alkylating agents, platinum-analog, and mictrotubule-interactive drugs (Table 4). The reference standard to which novel agents and regimens are compared is dacarbazine. In the majority of trials, dacarbazine was administered IV at daily doses of 200 mg/m² for 5 days every 3 or 4 weeks; however, 1,000 mg/m² once every 3 or 4 weeks has been given in recent trials. The most common toxicities are myelosuppression and nausea. The severity of myelosuppression rarely requires the use of growth factor support, and the advent of potent antiemetics in recent years has significantly improved the tolerability of this agent. In the largest phase III trial that included a single-agent dacarbazine arm, the objective response rate was 3.5%, and the median progression-free survival was 1.5 months. Overall survival for dacarbazine-treated patients is 6 to 9 months and does not clearly differ from the natural history of metastatic melanoma. Fotemustine(Drug information on fotemustine), a nitrosourea with modestly superior activity compared with dacarbazine, is available for clinical use in Europe but not in the United States.

Combination chemotherapy regimens

As with other types of cancer, combinations of agents with some measurable single-agent activity in melanoma have been empirically developed. Clinical trials combining chemotherapy have produced promising response rates in single-arm, single-institution studies but have never demonstrated an improvement in overall survival compared with single-agent chemotherapy in multicenter, randomized trials. Given the increased toxicity associated with such regimens, the absence of a survival advantage limits their consideration as standard therapies. These treatments include cisplatin(Drug information on cisplatin), vinblastine, and dacarbazine (CVD) and the Dartmouth regimen (cisplatin, carmustine, dacarbazine, and tamoxifen(Drug information on tamoxifen)). Inpatient treatment is standard for these regimens, and the severity of myelosuppression often requires growth factor support not needed for single-agent chemotherapies. Given that longevity is not impacted for these patients who have such a short life expectancy, the quality-of-life detriment associated with combination therapy cannot be justified.

Tamoxifen

Based on anecdotes of tumor regression associated with single-agent tamoxifen and laboratory evidence suggesting synergy with chemotherapy, clinical trials were undertaken combining tamoxifen with individual chemotherapy agents or combination regimens. As with other combination chemotherapy trials, single-arm trials of regimens containing tamoxifen appeared promising. However, in randomized trials in which the same chemotherapy regimen was administered to all patients, and tamoxifen given only to patients in the experimental arm, no evidence of clinical benefit was observed with the addition of tamoxifen.

Biologic therapies

IL-2 was approved by the FDA as a treatment for metastatic melanoma on the basis of durable complete and partial remissions associated with the "high-dose" regimen. This regimen requires patients to be in excellent overall health to tolerate the physiologic stress of 5 days of inpatient therapy. The standard dose is 200,000 U/m² repeated every 8 hours, for a maximum of 14 doses. This treatment is followed by a treatment break of 10 to 14 days and readmission for another course of therapy. Patients who demonstrate some degree of tumor regression are offered additional courses of therapy. Typical toxicities include fever, malaise, hypotension complicated by renal dysfunction, elevated levels of liver transaminases, and mood alterations. Clinical expertise among physicians and nurses is required to safely and effectively administer this therapy. As a consequence, the use of high-dose IL-2 has largely been restricted to high-volume referral centers.

Interferon-α has demonstrated single-agent activity in metastatic melanoma that is comparable to results with chemotherapy, including occasional durable responses. A randomized trial comparing interferon-α with dacarbazine in metastatic disease has never been conducted. Given the significant toxicity associated with chronic administration of interferon, its use in the metastatic setting is limited.

Biochemotherapy regimens

The distinct mechanism of action of biologic agents and evidence of single-agent activity have led investigators to combine these agents with chemotherapy for the treatment of metastatic melanoma. Given the toxicity associated with high-dose IL-2, it is not possible to safely administer chemotherapy concurrently. However, lower-dose IL-2 regimens can be safely coadministered with combination chemotherapy. Likewise, the high-dose interferon regimen that is the current standard therapy for adjuvant treatment of stages II and III melanoma cannot be easily combined with chemotherapy, whereas this is possible with modified schedules of interferon.

The first biochemotherapy regimens tested in phase II trials and then subsequently in large, randomized phase III trials combined interferon-α with dacarbazine. Despite early evidence suggesting a substantially higher response rate associated with the combination, definitive phase III trials failed to identify a survival advantage to this regimen over treatment with dacarbazine alone.

More intensive regimens combining chemotherapy with biologic agents, requiring inpatient administration, have more recently been evaluated. A regimen containing cisplatin, vinblastine, dacarbazine, with concurrent interferon and IL-2, was evaluated in several phase II trials, a small, single-institution phase III trial, and a multicenter phase III trial in comparison to multiagent chemotherapy without the biologic agents. Although progression-free survival appeared modestly superior to that of the chemotherapy backbone alone, no improvement in overall survival could be demonstrated. Likewise, a trial in which the contribution of IL-2 to a regimen of cisplatin, dacarbazine, and interferon-α was isolated failed to demonstrate a significant improvement in outcome.

CTLA-4 blockade

Ipilimumab (Yervoy) is a promising new agent for the treatment of patients with metastatic melanoma. Ipilimumab is a monoclonal antibody against CTLA-4 (cytotoxic T-lymphocyte–associated molecule-4). It has been used in patients with metastatic melanoma and renal cell carcinoma refractory to other immunotherapies. The overall response rate is 10%, with a significant percentage of patients having a durable complete response.

The efficacy of ipilimumab is due to its ability to block the normal activity of CTLA-4, a molecule that tempers the immune system's response to antigen. Although the exact antitumor activity of anti–CTLA-4 is unclear, it is thought that by inhibiting the activity of CTLA-4, the threshold for a full immune response to antigen may be lowered, and an immune response against tumor antigens is facilitated.

In 2010, investigators reported results of the first phase III trial comparing ipilimumab combined with GP-100 peptide vaccine to vaccine alone or ipilimumab alone. This trial demonstrated overall survival benefit for both of the ipilimumab-containing arms, compared with peptide vaccine alone. The rates of overall survival at 12 months for ipilimumab plus GP-100 and ipilimumab alone were 44% and 46%, compared with 25% for peptide vaccine alone. The rates of overall survival at 24 months for the ipilimumab-containing arms were 22% and 24%, compared with 14% for peptide vaccine alone. These data confirm a durable benefit associated with this novel immunotherapy in patients with metastatic melanoma who had failed to respond to one prior therapy. A second, randomized, phase III trial compared ipilimumab combined with dacarbazine vs dacarbazine alone among 502 metastatic melanoma patients. Survival rates at 1 year (47.3% vs 36.3%, respectively), 2 years (28.5% vs 17.9%), and 3 years (20.8% vs 12.2%) confirmed that ipilimumab can confer a long-term survival benefit to a subpopulation of patients treated.

In March 2011, the FDA approved ipilimumab for the treatment of patients with unresectable or metastatic melanoma. Ipilimumab is the first and only therapy for unresectable or metastatic melanoma to date that has demonstrated a significant overall survival improvement based on results from the pivotal randomized, double-blind phase III study described above.

Targeted therapy

The discovery of somatic genetic mutations in melanoma, underlying aberrant signal transduction in melanoma cells, has provided leads for the development of molecularly targeted therapy. The MAP kinase pathway, which is activated in the vast majority of melanomas due to mutations in BRAF, NRAS, and c-kit, has been the focus of most clinical investigations of signal transduction (kinase) inhibitors.

BRAF inhibition is an appealing strategy in patients with cutaneous melanoma, as 50% to 65% of patients have tumors with an activating mutation. Despite this, sorafenib(Drug information on sorafenib) (Nexavar), a first-generation BRAF targeting drug, was disappointing and ineffective. In August 2011, the BRAF kinase inhibitor vemurafenib (Zelboraf) became the first FDA-approved treatment for patients with BRAF V600E mutation–positive metastatic melanoma. Vemurafenib is a specific inhibitor of activated BRAF, and response rates in phase I, II and III clinical trials have ranged from 50% to 80%. Results of the pivotal phase III BRIM-3 trial led to approval of vemurafenib. In this study, 675 patients with BRAF-mutated metastatic melanoma that had not previously been treated in the metastatic setting were randomized to receive vemurafenib or dacarbazine. Overall survival was the primary endpoint and was reached, with an HR of 0.37 in favor of the vemurafenib group. This improvement in survival, in addition to the high early response rate, established BRAF inhibition as an additional standard therapy in the treatment of metastatic melanoma. BRAF mutation testing is now commerically available and can be conducted using paraffin(Drug information on paraffin)-embedded tumor tissue.

Activating mutations in the c-kit receptor were recently identified in patients with acral, mucosal, and lentigo maligna melanoma. The successful development of c-kit–targeted therapies in gastrointestinal carcinoma, in which c-kit mutations also are found, has provided the opportunity for immediate investigation of these oral agents in patients with metastatic melanoma harboring c-kit mutations. Early reports suggest that a subset of c-kit–mutant melanomas respond to inhibitors of the signaling portion of this receptor.

Palliative radiation therapy

Unfortunately, many patients with malignant melanoma will present with CNS metastases. These patients can be symptomatic, with complaints of headache, seizures, motor loss, or impaired mentation; these symptoms can be relieved with the use of whole-brain radiation therapy (WBRT). WBRT has been used with multiple different fractionation schemes, although none has been found to be superior to standard fractionation (300 cGy × 10). These patients have a median survival of 2.2 to 4.9 months with the addition of WBRT, with local tumor control rates in the brain in the 70% to 80% range.

Stereotactic radiosurgery (SRS) involves the use of a large, single fraction of radiation to a limited target volume and rapid dose falloff outside the target. A standard linear accelerator is used to deliver one dose, usually between 15 and 24 Gy. Most centers that perform SRS have an upper size limit for the metastatic lesion (approximately 4 cm). Proponents of this treatment have shown less cognitive decline, due to the limited area of radiation. There has been a small prospective series of patients with one to three brain metastases from melanoma, renal cell carcinoma, and sarcoma treated with SRS alone; they were found to have a 32% intracranial recurrence rate outside the SRS volume, suggesting there is a need for WBRT.

The Radiation Radiation Therapy Oncology Group (RTOG) 95-08 trial was a randomized study evaluating addition of SRS to WBRT in patients with one to three brain metastases (including those with metastatic melanoma). Both treatment modalities produced an improvement in Karnofsky Performance Status (KPS) at 6-month follow-up, with no difference in mental status or neurologic death. Patients with only one brain metastasis who underwent WBRT and SRS had a survival advantage (median survival time, 6.5 vs 4.9 months; P = .0393). There is a randomized phase III trial currently undergoing accrual for WBRT after local treatment of brain metastases in melanoma patients (trial registration Australia and New Zealand Clinic Trial Registry [ANZCTR] #ACTRN12607000512426). The primary end point is the proportion of patients with distant intracranial failure, as determined by MRI assessment at 12 months. Secondary end points include survival, quality of life, performance status, and neurocognitive function. The results of this trial should provide evidence that will aid in treatment decision making.

Patients with recurrent disease or metastasis at multiple sites may require palliative radiation therapy. Common examples include skin metastases that have bleeding and fungation, painful bony metastases or lymph node metastases that push against soft tissue, bony metastases, neurologic compromise, and spinal cord compression from vertebral metastases. These patients may experience improvement in quality of life with a short course of RT. The role of stereotactic body radiation therapy (SBRT) has been gaining favor to treat both metastatic and definitive disease sites. Recently there has been further investigation into the use of spinal SBRT (sSBRT) for spinal metastatic disease (sMET). As patients being treated for sMET with sSBRT can be widely varied, a recursive partitioning analysis (RPA) has been performed for these patients with metastatic disease. (RPA, initially described by RTOG, is a decision-making tool that can be used to divide patients into groups based on the predicted length of survival.) The investigators analyzed survival based on histologies: median overall survival for favorable, radioresistant (renal cell carcinoma, melanoma, sarcoma), and other histologies were 14 months, 11.2 months, and 7.3 months, respectively (P = .02). In the study, they performed a RPA resulting in three classes of patients. RPA Class 1 is defined as time from primary diagnosis (TPD) > 30 months and KPS > 70; Class 2 is defined as TPD > 30 months and KPS ≤ 70 or a TPD ≤ 30 months and age < 70 years; and Class 3 is TPD ≤ 30 months and age ≥ 70 years. With this RPA, the researchers found that the median overall survival for Class 1 was 21.1 months, for Class 2 was 8.7 months, and for Class 3 was 2.4 months. Use of this RPA may help to direct which metastatic patients may benefit from sSBRT.

Future Directions

In addition to the previously mentioned trials in active research, multiple studies are being performed at institutions across the United States, some of which are assessing the use of radiosensitizers. The University of Utah is performing a phase II study looking at the response rate of measurable melanoma lesions to treatment with cisplatin, a known radiomodifier, plus RT. The University of Texas MD Anderson Cancer Center is performing a phase I trial investigating the toxicity of treatment with docetaxel/temozolomide/cisplatin in patients with melanoma. There is still much to be understood about RT for patients with melanoma and how best to use it to its maximal efficacy in this setting.