Metastatic melanoma: Surgical management

INTRODUCTION — The treatment landscape for patients with advanced melanoma has changed dramatically with the introduction of effective systemic therapies such as molecularly targeted agents and immune checkpoint blockade in the adjuvant, neoadjuvant, and metastatic settings, leading to marked improvements in melanoma-specific survival.

Surgery continues to have a role in treatment in the face of these more effective systemic therapies for advanced melanoma and may be associated with improved long-term survival for carefully selected patients with distant metastatic disease. As effective treatment options for patients with advanced melanoma continue to evolve, the role of surgery for stage IV disease will also likely continue to evolve and should always be considered in the context of a multidisciplinary team discussion and engagement.

The role of surgery in the treatment of distant metastatic disease is discussed in this topic [1-4]. An overview of the management of advanced melanoma is presented separately, including discussions regarding systemic therapy. (See "Overview of the management of advanced cutaneous melanoma", section on 'Targeted therapy' and "Cytotoxic chemotherapy for metastatic melanoma" and "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)

DIAGNOSTIC EVALUATION PRIOR TO SURGERY FOR METASTATIC DISEASE — Metastatic melanoma can affect any major organ, and metastases are often synchronous. The lung, liver, and central nervous system are common sites of metastatic melanoma. Other sites include the gastrointestinal tract, adrenal gland, bone, distant skin and/or lymph nodes, and less commonly, pancreas and spleen. Patients suspected to have distant metastatic disease during follow-up surveillance should undergo a comprehensive evaluation to assess sites and burden of disease prior to multidisciplinary discussion and treatment planning. (See "Staging work-up and surveillance of cutaneous melanoma", section on 'Symptomatic disease or suspected metastases' and "Imaging studies in melanoma", section on 'Approach to patient imaging based on disease site'.)

The evaluation should include a careful history and examination of the skin, soft tissues, and all lymph node basins, serum lactate dehydrogenase (which has prognostic significance for patients with distant metastasis) (table 1A-B), brain imaging (magnetic resonance imaging), and body imaging (computed tomography [CT] or positron emission tomography/CT scans).

CONSIDERATIONS FOR SURGERY — Overall, the decision to perform surgery in patients with stage IV melanoma is a complex and often difficult, whether for curative or palliative intent. In this rapidly evolving contemporary era of effective systemic therapy, surgery alone is generally not indicated, except for isolated metastases that can be completely resected, or for complications of metastatic disease (eg, ulceration/bleeding, bowel obstruction). For other presentations, surgery may be indicated following systemic therapy as part of a multidisciplinary care plan.

Patient selection and multidisciplinary treatment planning with input from surgery, medical oncology, radiation oncology, and radiology, among others, is critical and should consider functional status; patient symptoms; goals for surgery (curative, palliation); tumor biology including number of sites of disease; disease-free interval between completion of primary melanoma treatment and diagnosis of metastatic disease; tumor growth rate and/or response to systemic therapy; options for first-, second- or subsequent-line systemic therapy; and resectability. Ideal candidates have limited sites of disease, a longer disease free-interval, slower tumor growth, and good response to systemic therapy. In addition, resection should provide a benefit at an acceptable level of surgical risk.

Curative intent — Several multicenter trials and other observational studies conducted largely prior to the era of more effective systemic therapy reported improved survival following complete curative resection of stage IV melanoma metastases in carefully selected patients [5-7]. In general, patients with longer disease-free interval, indolent disease, fewer metastatic sites, and metastatic disease that can be completely resected have the best outcomes.

●The prospective Southwest Oncology Group 9430 phase II study evaluated the role of complete resection of distant melanoma metastases. Sixty-four patients underwent complete resection of their metastases with a median overall survival of 21 months and four-year overall survival of 31 percent [5].

●The prospective Multicenter Selective Lymphadenectomy Trial (MSLT-I) phase III randomized trial, which enrolled clinical stage I and II patients to examine the role of sentinel lymph node biopsy, reported outcomes of a subset of patients who developed distant recurrence (n = 291) [6]. Among patients who underwent surgery for stage IV disease (n = 151, 55 percent) with or without systemic therapy (mostly prior to contemporary era of targeted and immune checkpoint blockade therapies), median survival was 15.8 months and four-year OS was 20.8 percent, compared with 6.9 months and 7 percent for patients who received systemic therapy alone. Patients who had surgery were more likely to have <2 involved organ sites and <3 metastatic lesions compared with those who did not undergo surgery for stage IV disease.

●The prospective randomized phase III trial Malignant Melanoma Active Immunotherapy Trial for Stage IV disease (MMAIT-IV) evaluated the efficacy of an allogenic melanoma vaccine (canvaxin) with Bacille Calmette-Guerin (BCG) compared with placebo with BCG [7]. Prior to treatment randomization, all patients underwent complete resection of distant metastatic disease followed by repeat staging to confirm no evidence of recurrence. At the time of publication, patients in this trial had the highest overall survival rates reported among patients with stage IV melanoma (5-year overall survival >40 percent, 10-year overall survival >30 percent in both study arms).

In the contemporary era of more effective targeted and immune checkpoint blockade therapies, response to systemic therapy has also proven to be prognostically useful in selecting appropriate patients for metastasectomy [8-12]. (See "Overview of the management of advanced cutaneous melanoma" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations" and "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

Neoadjuvant approaches, ideally as part of a clinical trial, using targeted therapies (BRAF/MEK inhibitors may be considered for patients with BRAF V600 tumor mutations) and immune checkpoint inhibitors (table 2) should also be considered and may help to downstage tumor, improve resectability, improve patient selection, help guide subsequent therapy selection, and improve outcomes for those with M1a disease undergoing curative resection.

A study from Memorial Sloan-Kettering Cancer Center evaluated outcomes after metastasectomy in 237 highly selected patients with stage III and IV melanoma who received immune checkpoint therapy [10]. The estimated five-year survival was 75 percent for all patients, among whom 88 percent had stage IV disease. Factors associated with improved survival included complete resection of disease (median OS not reached compared with 10.8 months for incomplete resection) and response to therapy prior to resection (median overall survival not reached for patients with responding disease or an isolated site of progression compared with 7.8 months for patients with multiple progressing lesions).

Furthermore, patients with stage IV melanoma who undergo complete curative resection of their disease may benefit from adjuvant systemic therapy. A multicenter phase II study from Germany (adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease [IMMUNED]) evaluated outcomes after metastasectomy in 167 patients randomized to receive placebo, nivolumab, or nivolumab plus ipilimumab [13]. Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival compared with placebo in patients with stage IV melanoma with no evidence of disease.

Palliation — Surgery can also be considered in the multidisciplinary setting for the palliation of symptoms associated with melanoma metastases, such as pain, bleeding, bowel obstruction, tumor ulceration, or infection.

SURGERY BY DISTANT METASTATIC DISEASE SITE

Skin, subcutaneous tissue, and lymph nodes — Skin, subcutaneous tissue, and lymph nodes (M1a) disease in the American Joint Committee on Cancer 8th edition staging system includes distant melanoma metastases to the skin, soft tissue, and/or nonregional lymph nodes [14]. Surgery for M1a disease should always be discussed with multidisciplinary team input. Curative intent resection of M1a disease can be associated with improved survival outcomes in carefully selected patients [6], while surgery may also be considered in select circumstances for palliation of symptoms such as pain, bleeding, infection, and ulceration. Microscopically negative resection margins should be the goal in resection of distant soft tissue and cutaneous metastases and are sufficient in this setting as opposed to the wider, 1 to 2 cm evidence-based excision margins recommended for the management of primary cutaneous melanoma based on primary tumor thickness. (See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites", section on 'Resection margins'.)

Complete lymphadenectomy may be appropriate and may be considered in select circumstances for management of distant nodal disease. (See "Evaluation and management of regional nodes in primary cutaneous melanoma".)

In the Multicenter Selective Lymphadenectomy Trial (MSLT-1), 32 of 291 (10 percent) patients who underwent treatment of distant metastases had M1a disease. Those with M1a disease who underwent complete resection with or without systemic therapy had superior median overall survival compared with those who received systemic therapy alone (60 versus 12.4 months).

Lung — The lungs (M1b) are the most common site of distant melanoma metastasis, comprising up to 40 percent of stage IV disease. Most pulmonary metastases are asymptomatic and are found on chest imaging for staging or surveillance. (See "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques" and "Surgical resection of pulmonary metastases: Outcomes by histology", section on 'Melanoma'.)

Preoperative pulmonary status must be carefully evaluated in patients being considered for pulmonary metastasectomy. Surgery should achieve complete resection of the pulmonary metastases while preserving normal lung parenchyma. Patient selection for pulmonary metastasectomy should involve multidisciplinary team discussion.

Pulmonary metastasectomy may improve survival. Patients most likely to benefit are those with limited lung nodules, no extrapulmonary metastasis, longer disease-free interval before development of pulmonary metastasis, and those in whom complete resection can be achieved [15-20]. In the contemporary era of targeted and immune checkpoint blockade therapies, selection for pulmonary metastasectomy should also include the patient's response to systemic therapy [9,10,21].

The results from two large series [15,16], which included patients treated prior to the contemporary era of targeted and immune checkpoint blockade therapies, illustrated outcomes for patients undergoing resection of lung metastases with outcomes that are consistent with later reports from smaller cohorts [17,18].

●Data from the International Registry of Lung Metastases defined parameters associated with a better prognosis following resection [15]. Among 328 patients who underwent pulmonary metastasectomy, 282 underwent complete resection. Five- and 10-year survival rates were 22 and 16 percent, respectively. There were no long-term survivors after incomplete resection. Poor prognostic factors included a metastasis-free interval less than 36 months and multiple lung metastases. Patients without these risk factors had the best five-year survival, followed by those with one and two risk factors (29, 20, and 7 percent, respectively).

●In a single-institution series of 318 patients who underwent metastasectomy for lung metastases, factors affecting prognosis were evaluated over a 34-year period [16]. In multivariate analysis, risk factors associated with a poorer prognosis included the presence of two or more metastases, a disease-free interval less than five years, extrathoracic disease, or nodular histology. For patients with none of these risk factors, the median survival was 14 months, and the five-year survival was 26 percent. By contrast, patients with three or more risk factors had a median survival of five months and five-year survival of 2 percent.

For patients who are poor candidates for pulmonary metastasectomy, stereotactic body radiotherapy (SBRT) for pulmonary oligometastatic disease is a treatment option [22].

Non-central nervous system visceral sites — Non-central nervous system visceral sites (M1c) disease includes distant metastases to any visceral organ excluding the central nervous system and thus represents a diverse group of patients. Melanoma metastases within the abdominal cavity most commonly affects the gastrointestinal tract, liver, and less commonly the adrenal glands, spleen, and pancreas.

Selection of patients with M1c disease for metastasectomy must involve multidisciplinary team discussion, with considerations including disease response to initial systemic therapy, indication for surgery (palliation of symptoms versus complete resection of metastatic disease for potential survival benefit), patient's ability to undergo proposed surgery, and alternative local tumor-directed treatment options (such as ablation), as well as options for other systemic therapy.

Numerous studies, comprised of patients largely treated prior to the era of contemporary targeted and immune checkpoint blockade therapies, have shown that with careful patient selection, complete resection of intra-abdominal metastases has been associated with improved overall survival compared with nonsurgical treatment [6-8,23,24]. Given the improved overall survival for patients with visceral metastases treated in this continually evolving era of more effective systemic therapy, these data, combined with associated decisions to consider metastasectomy, must also be integrated with ongoing advances in the multidisciplinary management of these patients.

Gastrointestinal tract — The most common site of gastrointestinal metastases is the small bowel followed by the colon, stomach, and rectum [25]. Metastases are often symptomatic, with patients presenting with pain (29 to 55 percent), obstruction (27 percent), bleeding (27 percent), palpable mass (12 percent), or weight loss (9 percent). Palliative resection is often considered even if curative resection is not possible, as surgery can provide symptom relief in many patients [26,27]. However, surgery should only be offered to good-risk candidates who have limited disease within the gastrointestinal tract and for whom the potential benefit of metastasectomy has been carefully weighed against the risks and potential complications of surgery. In carefully selected patients, palliative surgery may offer patients an opportunity to improve their overall clinical status and ability to tolerate and benefit from systemic therapy.

In cohorts treated largely in the era prior to targeted and immune checkpoint blockade therapies, patients selected for and who underwent curative resection of gastrointestinal metastases generally experienced longer overall survival compared with those who underwent palliative resection or medical therapy (48.9 versus 5.4 and 5.7 months, respectively) [26,28].

Liver — Hepatic metastases are the predominant site of metastases in patients with ocular melanoma but are also commonly observed in patients with metastatic cutaneous melanoma. Similar to other sites, hepatic metastasectomy (often nonanatomic resection) should only be considered if complete resection can be achieved, with appropriate patient selection, and only after multidisciplinary team input. (See "Overview of hepatic resection" and "Open hepatic resection techniques".)

In a retrospective review of 1078 patients with melanoma liver metastases treated between 1991 and 2010 (ie, prior to the era of contemporary targeted and immune checkpoint blockade therapies), a highly selected group of 58 (5.4 percent) patients received surgical therapy with or without ablation [8]. Median overall survival was 24.8 months for patients who underwent complete metastasectomy compared with eight months for those receiving systemic therapy alone. Patients selected for surgery who achieved stabilization of their melanoma on therapy prior to surgery and who underwent complete surgical resection of melanoma hepatic metastases experienced longer median overall survival compared with patients who underwent incomplete resection or who were not selected to receive surgery.

Adrenal — Melanoma metastasis to the adrenal gland(s) in isolation is uncommon; most patients have synchronous metastases to other sites. In patients selected for resection of adrenal metastases, surgery involves complete removal of the involved gland. (See "Adrenalectomy techniques".)

The largest series of patients with melanoma adrenal metastases included 154 patients treated at MD Anderson Cancer Center (Texas, United States). Of 5638 patients treated for melanoma between 1993 and 2006 (prior to the era of contemporary targeted and immune checkpoint blockade therapies), 1180 developed distant metastatic disease with a median follow-up of 5.2 years. Adrenal metastasis presented in 154 patients (13 percent), the majority (95 percent) of whom had prior and/or synchronous metastasis to other sites. Of 22 patients selected for adrenalectomy, the adrenal gland was the only site of disease at the time of adrenalectomy in 15 patients. Adrenalectomy was performed by open (n = 13) and laparoscopic/retroperitoneoscopic (n = 9) approach and for various indications, including to render the patient disease free (n = 20), for palliation of symptoms (n = 5), and for tissue harvest for clinical trial/protocol (n = 6). Similar to other sites of disease, adrenal metastasectomy was associated with improved median overall survival for patients selected for surgery compared with those who received systemic therapy alone (20.7 versus 6.8 months) [24]. Both nonselection for adrenal metastasectomy and poorer overall survival were associated with elevated serum lactate dehydrogenase level and presence of synchronous metastasis [29]. In a later series of 91 patients with adrenal metastasis treated between 2000 and 2014, 24 patients were selected for adrenalectomy [30]. Patients selected for surgery had longer median overall survival from the time of the diagnosis of adrenal metastasis compared with those who received nonoperative treatment (29.2 versus 9.4 months).

Selective application of adrenal metastasectomy in an updated cohort of 74 consecutive patients treated with adrenalectomy between 2007 and 2019 was associated with median survival of 117 months after diagnosis of adrenal metastasis, compared with 11 months in 69 patients with adrenal metastasis treated with systemic therapy alone.

Rare sites

●Pancreas, spleen – Melanoma metastases to the pancreas and splenic are uncommon. There is a paucity of literature regarding surgery for melanoma metastasis to the pancreas and spleen [2,31,32].

●Bone – There is a paucity of literature regarding surgery for melanoma metastasis to the bone, as osseous metastases are uncommon and prognosis has historically been poor [2,33]. Curative intent surgery is almost never indicated. Palliative surgery may be considered for the management of pathologic fractures.

Central nervous system — Central nervous system (M1d) disease includes distant metastases to the brain or spinal cord. (See "Management of brain metastases in melanoma".)

More than 50 percent of patients with stage IV melanoma will develop brain metastasis, which can be asymptomatic or present with headache, seizure, neurological deficits, or behavior changes [1,25]. Prognosis has historically been poor, with a median overall survival of three to seven months with systemic treatment alone in the era prior to contemporary targeted and immune checkpoint blockade therapies [34,35], although surgical resection, whole-brain radiation, and stereotactic body radiotherapy (SBRT) can improve neurologic symptoms and improve survival [2,25,34,35].

Metastasectomy appears to have the greatest benefit in patients with isolated brain metastases, without neurologic deficits, and in the absence of progressing extracranial disease [36,37]. Although local treatment approaches with radiotherapy and surgery remain important in the management of melanoma brain metastases, recent studies suggest that targeted therapies and immune checkpoint inhibitors therapies may offer significant survival benefit for patients with brain metastases and represent an area of intense clinical investigation [38-40]. (See "Management of brain metastases in melanoma" and "Overview of the treatment of brain metastases".)

Melanoma metastasis to the spinal cord (leptomeningeal disease [LMD]) is rare and has been associated with a dismal prognosis, with survival on the order of weeks to a few months [41], although initial results of an ongoing single-arm phase 1/1b study of concurrent intrathecal and intravenous nivolumab suggests potential efficacy in patients with LMD [42]. Surgical intervention is rarely indicated but may include placement of an Ommaya reservoir for the delivery of intrathecal therapy [41].

REPEAT METASTASECTOMY — Patients who successfully undergo complete resection of metastatic disease remain at high risk for recurrent metastatic disease. For those that recur after a disease-free interval following complete resection of distant metastatic disease, a second metastasectomy may offer a survival benefit in carefully selected patients.

In a single-institution series of 211 patients who were disease-free after surgical resection of distant metastases treated prior to the era of contemporary targeted and immune checkpoint blockade therapies, 131 patients (62 percent) developed recurrent distant metastases at a median recurrence-free interval of eight months [43]. Patients who were able to undergo another metastasectomy had a median overall survival of 18.2 months compared with 5.9 months for patients managed nonoperatively.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)" and "Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)")

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

SUMMARY AND RECOMMENDATIONS

●Diagnostic evaluation – Patients with suspected distant metastatic disease should undergo a comprehensive evaluation to assess sites and burden of disease prior to considering surgery. The liver and CNS are common sites and frequently the cause of death from metastatic melanoma. Other sites include the skin, lung, lymph nodes, gastrointestinal tract, adrenal gland, pancreas, spleen, and bone. (See 'Diagnostic evaluation prior to surgery for metastatic disease' above.)

●Consideration for surgery – Patients with advanced melanoma have historically had a poor prognosis, but the introduction of molecularly targeted agents and immune checkpoint blockade has markedly improved survival outcomes for these patients. Optimal management of patients with metastatic melanoma who are being considered for metastasectomy consists of a multidisciplinary approach that integrates both surgical and nonsurgical treatment strategies into the clinical decision-making process. (See 'Considerations for surgery' above.)

•As medical treatments continue to evolve, surgery for advanced melanoma will undoubtedly also continue evolve. However, the optimal role, timing, and outcome of surgery in the contemporary era of targeted and immune checkpoint blockade therapies remains to be determined. Neoadjuvant therapy may help to downstage tumor, improve resectability, and improve patient selection and outcomes for those with M1a undergoing resection with curative intent. (See 'Curative intent' above.)

•Metastasectomy will continue to have a role for palliation of symptoms in some patients, and it may be associated with improved long-term survival following complete curative resection in carefully selected patients. (See 'Palliation' above.)

•Whether for curative or palliative intent, the decision to perform surgery in patients with metastatic melanoma is complex and often difficult. Factors to consider during multidisciplinary discussion and treatment planning, which is critical, include:

-Patient comorbidities and functional status

-Presence and type of symptoms

-The goals of surgery (curative, palliation)

-Tumor resectability (ie, to microscopically negative margins)

-Tumor biology including number of disease sites

-Disease-free interval between completion of primary melanoma treatment and diagnosis of metastatic disease

-Tumor growth rate

-Tumor response to systemic therapy, and available options for subsequent systemic therapy

•In general, the best outcomes have been achieved in patients with longer disease-free interval, indolent disease, fewer metastatic sites, and metastatic disease that can be completely resected. In select patients who experience major responses to systemic therapy, complete resection of residual metastatic disease may contribute to improved disease-free interval and a potential for cure.

●Recurrence – For patients who have recurrence after a disease-free interval following complete resection of metastatic disease, a second metastasectomy may offer a survival benefit in carefully selected patients. (See 'Repeat metastasectomy' above.)