Surgical Management of Distant Organ Metastases
Swathi B. Reddy and Dale Han
Melanoma is an aggressive form of skin cancer, but it is most often found in its early stages. In these cases, complete surgical excision may be curative with a 5-year survival of over 90% in patients with thin melanoma (1). However, prognosis worsens with increasing thickness or with the presence of ulceration, nodal metastasis, in-transit lesions, or distant disease. For melanoma, the most common sites of distant metastases are lung, skin, lymph nodes, brain, liver, and bowel (2). As shown in Table 9.1, the presence of distant organ metastasis (stage IV) has historically conferred a very poor prognosis of approximately 5% survival at 5 years and a median survival of 6 to 10 months (3).
This chapter begins with a brief overview of systemic therapy options and then will discuss the types of surgical options for patients with distant metastatic melanoma. In particular, surgery for stage IV melanoma patients may be performed for palliative or curative intent. Surgery for curative intent is done in order to remove all malignant disease. In contrast, surgery for palliation is done in order to relieve symptoms or to improve quality of life in patients who have incurable disease. This chapter discusses the surgical treatment of specific sites of distant metastatic melanoma, particularly in light of these new systemic therapies that have dramatically improved the outlook for patients with stage IV melanoma.
Patients with distant metastatic melanoma are at high risk for occult micrometastases in other organs, and the primary mode of treatment for stage IV patients usually consists of systemic therapy to control not only the clinically evident disease but also other sites of microscopic disease. Historically, the treatment for distant metastatic melanoma was chemotherapy, with surgical therapy offering benefit in a very limited number of cases. Unfortunately, chemotherapy when used for melanoma patients has often proven to have limited efficacy in improving prognosis, and there are no clinical trials that have shown a survival benefit over placebo or supportive/palliative care (12). Newer treatment options include both targeted therapies and immune-modulating therapies.
The Food and Drug Administration (FDA)-approved targeted therapies for melanoma primarily involve inhibition of the MAP kinase pathway, and include BRAF and MEK inhibitors (see Chapter 14). Use of single-agent targeted therapy is associated with relatively high response rates, although treatment resistance develops in most of these patients. Combination targeted therapy is associated with an even higher response rate of approximately 70% and longer duration of response, which potentially allows for more patients with distant metastatic disease to become potential surgical candidates. In recent years, immunotherapy has taken on a prominent role in the systemic treatment of metastatic melanoma given the relatively high response rates, durable responses, and efficacy in tumors regardless of mutational status (13). Many of these responses are sustained, thereby allowing more stage IV patients to become potential surgical candidates.
SURGERY FOR PALLIATION
Prior to the development of more effective systemic therapies, which have made more patients who are potential candidates for curative procedures, the role of surgery for distant metastatic disease was primarily palliative, and few patients with stage IV disease were candidates for surgery to remove all sites of metastatic disease. Palliative surgery is performed to relieve symptoms or to improve quality of life in patients who would continue to have residual and incurable disease after surgery. Palliative surgery may be indicated to control pain or bleeding caused by specific metastatic lesions. Surgery may also be a means to control a site of infection, such as an infected metastatic mass, or to allow for hygiene in cases of large fungating tumors. In patients with metastases in the gastrointestinal (GI) tract, the most common indications for surgery are bleeding or intestinal obstruction.
In the palliative setting, extensive attempts at tumor debulking should generally be avoided, and in this population of patients who have a limited life span, the benefit of surgical intervention needs to be weighed against the risk of complications or mortality from the procedure. Rather, there should be a clear understanding of the goals of the procedure, and if surgery is pursued, it should be directed at specific symptoms with the goal of improving a patient’s quality of life. Depending on the clinical situation, surgery may be favored when the proposed procedure would be straightforward or is reasonably likely to alleviate symptoms and there is a low risk for complications, low risk for a reduced quality of life, limited time in the hospital, and minimal risk for mortality (3). This discussion should involve the patient and his or her family, and the goals of providing relief of symptoms or preventing future symptoms, in the setting of incurable disease, should be clearly delineated (14). Indeed, when these guidelines are followed, palliative surgery can be very effective. Ollila et al. reported that 97% of patients with GI tract metastases experienced relief of their presenting symptoms (15).
SURGERY FOR POTENTIAL CURATIVE INTENT
The presence of overt distant metastatic disease implies the presence of disseminated occult micrometastases in other organs. Therefore, the role of surgical metastasectomy has been relatively limited due to the inability to control all disease, the potential for rapid development of additional metastases soon after surgery, and the need for systemic therapy, which may be delayed by postsurgical complications. Because of this, careful selection of patients for metastasectomy is required, and surgery for distant disease is often confined to patients that have had good responses to systemic therapy, to patients with a single or a limited number of metastatic lesions, or to patients who have been progression free for a relatively long period of time.
Nevertheless, more recent studies demonstrate that in highly selected patients with stage IV melanoma, a significant survival benefit can be seen after distant metastasectomy (see Table 9.2). A number of prospective studies have looked at metastasectomy in patients, including a randomized phase III clinical trial evaluating an adjuvant vaccine, the Malignant Melanoma Active Immunotherapy Trial (MMAIT) (16). This trial enrolled only patients who underwent a complete resection of all metastatic disease and were then found to be disease free on follow-up imaging. Patients were randomized to receive either Bacillus Calmette–Guerin (BCG) vaccine and Canvaxin (a polyvalent vaccine developed from melanoma cells) or BCG and a placebo. The authors hypothesized that the immune response triggered by Canvaxin would affect disease progression, and therefore prolong survival. Although the results did not show a survival benefit with Canvaxin, the key finding in this study was a remarkably high overall 5-year survival rate of 40% to 45% in both groups, indicating that resection of distant metastatic disease could produce a previously unexpected improvement in survival (8,17). Similarly, a smaller phase II trial from the Southwest Oncology Group (SWOG) demonstrated an overall survival (OS) of 21 months for patients with stage IV melanoma and completely resected disease. Furthermore, 4-year survival was 31% (18), which is greater than that reported for any combination of cytotoxic or biologic agents (19). This study was notable for prospectively enrolling patients regardless of prior treatment modalities.
Based on the results of these studies and the development of more powerful systemic therapies, aggressive surgical management of distant disease for curative intent in appropriately selected patients is becoming more common. Additional reasons for increased use of metastasectomy include lower potential morbidity relative to highly toxic systemic agents, the potential for repeat excisions in the face of recurrence (27), and the decrease in perioperative morbidity due to improvements in surgical technique and perioperative care, especially in the treatment of lung and liver lesions (28). Furthermore, multiple new systemic therapies for treating distant metastatic melanoma are available and associated with impressive response rates and durable responses. Thus, a larger number of patients with distant metastatic melanoma are becoming potential candidates for metastasectomy to consolidate disease in those who have a good response to systemic treatment, and to remove treatment-resistant foci of disease. The availability of these effective systemic agents also allows for control of other occult microscopic distant sites of disease before and after surgery.
PATIENT SELECTION AND EVALUATION
Appropriate patient selection for metastasectomy is crucial to maximizing outcomes. Indeed, the stringent patient selection criteria of the MMAIT and SWOG studies were considered partly responsible for their high survival rates. When metastatic disease is identified, the extent of disease should be evaluated. Imaging, such as MRI of the brain, CT scans of the chest/abdomen/pelvis, and PET scans, should be performed (10). If metastasectomy is being considered, special attention must be paid to determine whether lesions are anatomically amenable to resection.
Certain disease characteristics can also be used to select patients for metastasectomy. Of these, the pattern of spread—whether the disease exhibits an oligometastatic pattern (a few discrete lesions in a limited number of locations) or a widely disseminated pattern—is the most agreed upon determinant of the applicability of surgical therapy (3). This pattern of spread may be a sign of the biologic characteristics of the tumor, and one potentially important prognostic marker is the tumor volume doubling time (TDT). Studies from John Wayne Cancer Institute confirm that behavior and amenability to resection of a metastatic lesion is proportional to the TDT, specifically in pulmonary lesions where a TDT of at least 60 days was prognostic (29).
In addition to pattern of spread, control of primary site, pace of disease progression, patient age and comorbidities, performance status, and anticipated survival without surgery are all factors that previous multi-institutional studies have considered when selecting patients to undergo metastasectomy. Reviews of prior retrospective studies also imply that metastases that involve a fewer number of organs (regardless of number of total lesions), nonvisceral sites of disease, and longer intervals of time between primary diagnosis and the development of metastases are all indicators of a favorable response to surgery (2). In particular, patients with a single metastatic site that is amenable to resection with low risk may be recommended for early metastasectomy, as opposed to surgery followed by systemic therapy. However, the majority of patients with distant metastases will be initially treated with systemic therapy, and response to systemic therapy has also been considered as an important factor to consider in selecting patients for metastasectomy.
SURGICAL MANAGEMENT OF SPECIFIC METASTATIC SITES