Advanced melanoma has become a different entity in the era of immunotherapy and targeted agents. Considering the potential for good outcomes from systemic therapy in advanced disease, has the role of surgery changed? Should it be offered up front or limited to patients with oligometastatic disease?
Michael Lowe, MD, MA
Discussing this issue at the 2019 Debates and Didactics in Hematology and Oncology conference in Sea Island, Georgia, were Michael Lowe, MD, MA, Assistant Professor of Surgery, and Ragini Kudchadkar, MD, Associate Professor of Medicine, both at Emory University’s Winship Cancer Institute, which sponsors the conference every year.1
Dr. Lowe reviewed the history of surgery in melanoma and then put it into modern context. He speculated that today many patients may gain a survival advantage when surgery is added to contemporary systemic therapy for patients with metastatic melanoma. Their combined use facilitates the elimination of all sites of disease, he said.
Dr. Kudchadkar, on the other hand, doubted that surgery adds much—at least in the upfront setting—considering the impressive survival benefit achieved with new systemic agents. “Surgery can still be part of our multidisciplinary care. I just don’t think it should necessarily be done upfront,” she commented.
Rationale for Surgery
Metastatic melanoma presents in a variety of ways, from “explosive, widespread” disease with rapid progression to slow-growing oligometastatic disease. An ever-growing list of drugs has improved long-term survival for patients with stage IV melanoma, but surgical resection is still appropriate for many patients, the speakers agreed.
To choose to perform surgery or not in a given patient is often difficult, Dr. Lowe, a surgeon, acknowledged. “Effective systemic therapy has dramatically altered the role that surgery
“Surgery can still be part of our multidisciplinary care [for patients with stage IV melanoma]. I just don’t think it should necessarily be done upfront.”— Ragini Kudchadkar, MD
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should play, but we can also agree that any patient who responds to systemic therapy should be evaluated by a surgical oncologist and be considered for metastasectomy,” he said.
As far back as 20 years ago, dramatic differences in overall survival were shown for patients with metastatic melanoma who underwent surgery (although selection bias is an issue), Dr. Lowe noted. In the 2011 observational SWOG S9430 trial, patients who underwent resection had a 4-year survival of 31%.2 “This was considered a home run for metastatic melanoma,” he said, although that outcome is clearly inferior to that achieved with systemic agents today.
Definitive support for surgery came from the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1). In this study, patients with M1a disease who underwent surgery plus medical therapy had a median survival of 5 years, compared with just over 1 year (P = .0106) for patients who received systemic therapy alone.3 This study showed that “aggressive metastasectomy results in good outcomes,” and it highlighted the role of surgery, especially in low-volume disease, Dr. Lowe said.
Recently, researchers at the Angeles Clinic and Cedars Sinai Medical Center presented “the most definitive proof to date” of the benefit of upfront surgery in stage IV resectable melanoma.4 In the study of 2,353 patients with stage IV disease, surgery followed by modern systemic therapy in 47 matched pairs was associated with higher 5-year melanoma-specific survival than modern therapy alone (58.8% vs 38.9%; P = .049). Independent predictors were single-organ involvement (hazard ratio [HR] = 0.43; P = .02), first-line surgery (HR = 0.47; P = .04), and use of modern agents (HR = 0.29; P < .001).
Defining ‘Oligometastatic’ Disease
Although the role of upfront surgery may be debated, it is less controversial in the patient with oligometastatic disease, the speakers agreed. “Certainly, in the setting of oligometastatic resectable asymptomatic disease, I would argue that surgery followed by systemic therapy should be recommended, based on the plethora of data we have,” Dr. Lowe said.
However, this also is not a straightforward decision, because the meaning of “oligometastatic disease” can vary by surgeon, the speakers said. Is it defined as a patient with three liver
“In the setting of oligometastatic resectable asymptomatic disease, I would argue that surgery followed by systemic therapy should be recommended, based on the plethora of data we have.”— Michael Lowe, MD, MA
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lesions, a patient with one solitary lung nodule, or a patient with two 1-cm lung lesions in separate lobes? Is it defined by stage—M1a vs M1b vs M1c vs M1d? Most clinicians would not, for instance, view multiple liver metastases as oligometastatic disease, but some surgeons believe they can resect them all, Dr. Kudchadkar commented.
Being able to define oligometastatic disease helps to determine whether surgery is needed upfront, she said. “Regardless of how you define it, I think the vast majority of patients who undergo surgery [alone] will have worse outcomes. Surgery needs to be moved to the salvage setting or into treatment of residual disease, rather than in the upfront setting.”
Recommendations for Surgery
The decision to perform surgery should be made via a multidisciplinary discussion, the speakers said, agreeing enrollment in a clinical trial is always the first choice. A good option is SWOG 1801 in patients with resectable stage IV (M1a, M1b, and M1c) disease, which is comparing neoadjuvant and adjuvant pembrolizumab (and surgery).
Otherwise, Dr. Lowe said, clinicians “should seriously consider upfront surgery followed by adjuvant therapy in patients with small-volume disease.” For a single metastatic lesion, he recommends upfront surgery followed by adjuvant therapy. For resectable oligometastases, surgery either before or after systemic therapy is a reasonable option.
According to Dr. Lowe, patients with unresectable disease should go straight to systemic therapy, with surgery considered for those with a good response or oligoprogression after treatment. In patients with widespread disease, surgery should be reserved for palliation.
Source: Nelson DW, et al.4
Dr. Kudchadkar said that outside of a trial, she considers surgery for patients with stage III disease and for those who have comorbidities that limit their ability to receive systemic therapy or who have no other good systemic therapy options. “The majority of patients are not in this group, however,” she maintained. “Even if they have oligometastatic disease, they have good outcomes from targeted agents and immunotherapy and will be considered for upfront systemic therapy.”
Other issues to consider are the ability to achieve R0 resection, the potential for surgical morbidity, and the disease-free interval. If the disease-free interval is short, the patient is not likely to fare well and needs systemic therapy upfront, added Dr. Kudchadkar.
Role of Surgery in Salvage Setting
Dr. Kudchadkar emphasized the role of surgery in other settings, such as in treating residual disease after immunotherapy and locoregional disease progression after systemic therapy. “Keep in mind that we don’t do many complete lymph node dissections now, and more patients will have local or regional recurrence,” she added.
In a recent “real-world” study of patients who discontinued treatment with pembrolizumab or nivolumab after 12 months, 78% remained free of disease progression. However, of the 40 patients who experienced disease progression, 30% were salvaged with locoregional surgery.5
DISCLOSURE: Dr. Lowe reported no conflicts of interest. Dr. Kudchadkar has served on the advisory boards of Bristol-Myers Squibb, Array, Novartis, and ImClone and has received research support from Bristol-Myers Squibb, Merck, and Regeneron.
1. Lowe MC, Kudchadkar R: Role of surgery in oligometastatic stage IV melanoma. 2019 Debates and Didactics in Hematology and Oncology. Debate 2. Presented July 28, 2019.
2. Sosman JA, Moon J, Tuthill RJ, et al: A phase II trial of complete resection for stage IV melanoma: Results of Southwest Oncology Group clinical trial S9430. Cancer 117:4740-4746, 2011.
3. Howard JH, Thompson JF, Mozzillo N, et al: Metastasectomy for distant metastatic melanoma: Analysis of data from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I). Ann Surg Oncol 19:2547-2555, 2012.
4. Nelson DW, Fischer TD, Graff-Baker A, et al: Impact of effective systemic therapy on metastasectomy in stage IV melanoma: A matched-pair analysis. Ann Surg Oncol. June 10, 2019 (early release online).
5. Jansen YJL, Rozeman EA, Mason R, et al: Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: Clinical outcomes in advanced melanoma. Ann Oncol. March 28, 2019 (early release online).