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Contemporary Surgical Treatment of Advanced-Stage Melanoma
Richard Essner, MD;
Jonathan H. Lee, MD;
Leslie A. Wanek, DrPH;
Hitoe Itakura, MD;
Donald L. Morton, MD
Arch Surg. 2004;139:961-967.
ABSTRACT
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Hypothesis The clinical treatment of patients with stage IV melanoma according to criteria of the American Joint Committee on Cancer (AJCC) is controversial because the 5-year survival rate is approximately 5%. Specific clinicopathologic factors are predictive of survival following curative surgery.
Design Cohort analysis of 1574 successive patients undergoing surgical resection of metastatic melanoma for a 29-year period. Patients received follow-up on a routine basis with serial examinations and radiographic studies. The median follow-up time was 19 months (range, 1-382 months).
Setting Tertiary cancer center.
Patients Surgical resection was performed in 1574 patients. The decision to perform surgery was individualized for each patient.
Intervention The technique of surgical resection was based on the site of metastasis.
Main Outcome Measure Computer-assisted database with statistical analyses using log-rank tests and Cox regression models.
Results Of the 4426 patients with AJCC stage IV melanoma, 1574 (35%) underwent surgical resection; 970 (62%) were men, with a median age of 50 years. Of the primary melanomas, 46% arose on the trunk, and 56% were Clark level IV or V with a median thickness of 2.2 mm. We found 697 patients (44%) to have AJCC stage III melanoma (lymph node) prior to the development of stage IV metastases. The most common site for resection was the lung (42%), followed by the skin or lymph node (19%) and the alimentary tract (16%). Of our patients, 877 (56%) had melanoma at a single site. The 5-year survival rate was significantly (P<.001) better for patients with a solitary melanoma (mean ± SD, 29% ± 2%) than those with 4 or more metastases (n = 147; mean ± SD, 11% ± 3%). Skin and lymph node metastases had the most favorable survival rate (median, 35.1 months). Multivariate analyses identified an earlier primary tumor stage (I vs II) (P<.001), an absence of intervening stage III metastases (P = .02), solitary metastasis (P<.001), and a long (>36 months) disease-free interval from AJCC stage I or II to stage IV (P = .005) as predictive of survival.
Conclusions Our results demonstrate the benefit of surgical resection for advanced-stage melanoma. Patients with limited sites and numbers of metastases should be considered for curative resection regardless of the location of the disease.
INTRODUCTION
Once an uncommon malignancy, cutaneous melanoma is rapidly becoming a major health concern in the United States. It is estimated that 55 100 Americans will develop melanoma in 2004 and that 7910 will ultimately die.1 Melanoma is the fifth most common cancer in men and the sixth most common in women, representing 4.5% of all cancer cases in the United States. Although most cases of cutaneous melanoma are cured by excision of the primary tumor, about 30% of patients will develop metastases. The treatment of advanced-stage melanoma is controversial. During the last 30 years, chemotherapy, immunotherapy, and biologics have had no effect on overall survival. The results from many studies raise the question of whether surgery should be incorporated into the care of patients with advanced-stage disease.2-5
Surgery is not a new treatment modality for metastatic melanoma, but it has evolved during the last 150 years as the biology and natural history of the disease have been better understood. In 1857, Norris6 first described the concept of wide excision of the primary melanoma to prevent melanoma recurrence. In 1892, Snow7 advocated elective removal of the regional lymph nodes at the time of excising the primary melanoma and raised the debate about elective lymph node dissection, a controversy that persists more than 100 years later. In 1907, Handley8 demonstrated anatomic pathways of the lymphatic vessels from the primary tumor with local permeation of tumor cells along these pathways. On the basis of relatively few patients, Handley advocated wide excision for each case of melanoma. The first case of surgery for melanoma metastases to the lymph nodes was reported in 1851.9 The development of surgery for metastatic melanoma has evolved with increased operative experience at specialized centers. Advancements in surgical technique, anesthesia, and intensive care unit treatment have made the morbidity and mortality rates for extensive surgical resection acceptable. Whereas surgery for palliative purposes has relatively clear indications, resection for potentially curative intent is less well defined.10-11 The rationale for this study is to evaluate the outcome of patients with advanced-stage melanoma treated during the past 29 years at our institute in whom surgical resection was considered part of the curative intent.
METHODS
In the last 29 years, more than 4426 patients have come to our institute for treatment for stage IV melanoma according to criteria of the American Joint Committee on Cancer (AJCC).12 During that time, 1574 patients (35%) underwent surgical resection with curative intent. Our computer-assisted database was used to identify patient sex, age, primary melanoma site, and histologic features along with details of subsequent sites of metastasis and methods of treatment.
During the last 3 decades, the staging methods for patients considered for surgical resection have evolved from chest x-ray and radionuclide imaging (bone and gallium scans) to ultrafast computed tomographic (CT) scans, magnetic resonance imaging (MRI), and whole-body positron emission tomography (PET).13-16 The imaging modalities used for our patients were directed by the individual surgeon and varied according to the patient's disease state and symptoms. Patients underwent surgical resection with curative intent (n = 1574) with a variety of operative techniques. Patients with skin or subcutaneous metastases limited to nonlocal and regional sites underwent resection of the lesions using wide surgical margins. Resection of distant lymph node metastases was performed according to the individual lymph node basin (axilla, inguinal/iliac, or cervical) being dissected.17-18 Patients with lung metastases typically underwent posterolateral thoracotomy, median sternotomy, or thoracoscopic-assisted resection; many had the hilar and mediastinal lymph nodes resected with removal of the lung parenchyma.19 Gastrointestinal, adrenal, and liver metastases were removed using open laparotomy techniques.20-22 In each case, resection of all visible disease was the surgeon's goal. Follow-up ranged from 1 to 382 months, with a median of 19 months. Survival curves were constructed using Kaplan-Meier estimates.23 Differences in survival distributions were tested with the log-rank method.24 Differences in frequency distributions and proportions were evaluated using  2 analysis or the Fisher exact test. P<.05 was considered significant. Survival time was determined from the diagnosis of stage IV melanoma until death or the last follow-up visit.
RESULTS
Of the 4426 patients with AJCC stage IV melanoma, 1574 (35%) underwent curative resection. The decision to perform surgical resection in these cases was based on the individual surgeons. Most procedures were performed by only a few physicians, and the faculty has remained relatively stable in our institute during the last 29 years. Most (62%) of the patients were men, with a median age of 50 years (Table 1). Most patients undergoing resection of metastatic melanoma had primary tumors on the trunk, and most of these were Clark level IV or V with a median thickness of 2.2 mm. We found that 697 patients (44%) had stage III (regional lymph node) metastases prior to developing stage IV disease. The median time to develop stage IV melanoma was 13.5 months for patients with regional lymph node metastases (stage III) and 44 months for patients progressing from stage I or II to stage IV. Most (56%) of the patients had a single site or organ with metastatic disease; 9% had 4 or more metastases. The most common first site of metastatic disease was the lung (42%), followed by the skin and subcutaneous sites (18%) and the brain (14%). Less common first sites included the gastrointestinal tract, adrenal glands, bone, and other sites (eg, spleen, breast, or ovaries). The 5-year survival rate of the 1574 patients who underwent surgical resection (mean ± SD, 23% ± 2%) was significantly (P<.001) better than for the 2852 patients treated with nonsurgical approaches (mean ± SD, 6% ± 5%) (Table 2).
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Table 1. Clinicopathologic Features of 1574 Patients Undergoing Resection for Advanced-Stage Melanoma
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Table 2. Comparison of Risk Factors for 1574 Surgically Treated and 2852 Nonsurgically Treated Patients With Stage IV Melanoma
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Most patients had resection of metastases to the distant skin, subcutaneous tissue, lymph nodes, gastrointestinal tract, and lungs. Patients with skin and subcutaneous metastases had the most favorable outcome, with a median survival rate of 48 months. We combined the survival data of patients with skin and subcutaneous metastases with those generated for patients with lymph node metastases because it is often difficult to clinically differentiate the 2 scenarios. When combined, the mean ± SD 5-year survival rate for these 260 patients was 25% ± 6% (Figure 1). The mean ± SD 5-year survival rates of patients with gastrointestinal and lung metastases were similar: 28% ± 8% and 21% ± 4%, respectively.
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Figure 1. Five-year survival estimates for patients with gastrointestinal tract, lung, and skin/subcutaneous/lymph node metastases. Although median survival is slightly higher for patients with skin or subcutaneous sites (alone) than for lymph node, gastrointestinal tract, or lung sites, the 5-year estimates demonstrate no significant differences (P = .29) in survival rate.
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In general, patients with metastases to the adrenal gland, brain, and liver are not considered candidates for surgery because many of them have multiple sites of metastasis. However, long-term survival is achievable in these patients (Figure 2). The median survival rate was 27.4 months for patients with adrenal metastases, 21.9 months for those with brain metastases, and 18.2 months for patients with liver metastases. The mean ± SD 5-year survival rates for these 3 sites were 0% (22% ± 18% for 4 years), 23% ± 5%, and 22% ± 9%, respectively.
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Figure 2. Five-year survival estimates for patients with adrenal, brain, and liver metastases. Five-year survival estimates demonstrate no significant difference (P = .53) in survival rates for these 3 patient groups.
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On the basis of statistical analysis, we were able to categorize the patients according to favorable and unfavorable outcome sites (Figure 3). Patients with favorable sites had significantly (P = .004) better survival rates than those with unfavorable sites. Patients who underwent surgery primarily were men older than 50 years, had early-stage primary melanoma, and had short disease-free intervals from primary to metastatic disease. Most patients had a solitary metastasis and disease in a favorable site.
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Figure 3. Five-year survival estimates for the combined favorable (skin/subcutaneous/lymph node, lung, and gastrointestinal) and unfavorable (brain, adrenal, and liver) sites. Mean ± SD 5-year survival rates were 30% ± 4% for favorable sites and 24% ± 6% for unfavorable sites. The survival rate was significantly (P = .004) better for the favorable sites of metastases.
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We performed univariate and multivariate analyses to determine the interactions of risk factors for metastatic disease and overall survival. Patients with early-stage primary melanoma (AJCC stage I), no intervening regional lymph node metastases, a long disease-free interval, and a low-risk site of metastasis achieved statistical significance (P<.05) in the multivariate analysis. The first site of metastasis interacted closely with the number of metastases (ie, patients with low-risk sites tended to have fewer metastases than those with high-risk sites). When the first site of metastasis is removed from the stepwise analysis, the number of metastases becomes statistically significant (P = .001) in the analysis (Table 3).
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Table 3. Univariate and Multivariate Analyses of Factors Predicting Overall Survival of 1574 Patients Undergoing Surgical Resection of Metastatic Melanoma*
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COMMENT
When melanoma has spread to a distant site, the median survival rate is only 7 to 8 months, and the 5-year survival rate is about 5%.10-11 This grim prognosis, which has remained relatively unchanged for 30 years, reflects the continued inadequacy of systemic therapy for metastatic melanoma. The response to conventional chemotherapy is rarely complete, and 5-year survival rates are generally less than 5%.2-3 The results of biologic therapy with interleukin 2 are also disappointing; survival prolonged by either a complete or partial response is uncommon (20%).4-5 The toxicity associated with this therapy can be considerable. Complete responses to combination biochemotherapy are higher (20%-30%),25 but the long-term durability is questionable.
In general, prognosis depends on the initial site of metastasis.26-27 Median and 5-year survival rates decrease progressively for surgically resected sites of the skin and subcutaneous tissue, distant lymph nodes, gastrointestinal tract, lung, bone, liver, and brain (Figure 1 and Figure 2).28-32 Median survival rates range from 48 to 18 months. The number of organ and tissue sites containing metastasis is also an important prognostic factor; the median survival rate is 29 months for patients with metastasis to 1 site, 16 months for those with metastasis to 2 or 3 sites, and only 14 months for those with metastasis to 4 or more sites. The disease-free interval before distant metastasis and the stage of the disease preceding distant metastasis also have prognostic significance.29 The 5-year survival rate is 17% if the disease-free interval is less than 36 months and 30% if it is greater than 36 months (Figure 4). In addition, the median survival rate for patients who progress from regional to distant metastasis is 18 months, whereas it is 24 months for patients without prior lymph node metastases (Figure 5).
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Figure 4. Overall survival of patients based on disease-free interval. Patients with a disease-free interval greater than 36 months demonstrated a significantly (P<.001) better survival rate.
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Figure 5. Overall survival of patients based on prior lymph node disease. The 5-year survival rate was significantly (P<.001) better for patients with no prior lymph node disease.
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Although surgical excision is the treatment of choice for melanoma confined to the primary site and regional nodes, it is infrequently the initial intervention in patients with 1 or more distant metastases. This reflects the prevailing assumption that distant metastases are beyond the reach of local therapy. It is true that most patients who die of metastatic melanoma have multiple tumor-involved organ sites, but 86% of patients initially have only 1 metastatic organ site.29-30 This site is most commonly the lung, followed by the skin, lymph nodes, brain, liver, and gastrointestinal tract.
Although surgical resection is technically possible in most patients who have only 1 or 2 metastatic organ sites, the surgeon's role is usually limited to occasional complete resection of a solitary visceral metastasis or for palliative resection for symptomatic metastases causing bowel obstruction or a bleeding brain lesion, resulting in neurologic symptoms. Many of these patients become the sole responsibility of the medical oncologist and are treated primarily with chemotherapy or biochemotherapy. However, the last few decades have brought numerous reports of long-term survival following resection of multiple distant metastases.10, 17, 31-32 In the absence of more active biologic and chemotherapeutic agents for the systemic treatment of metastatic melanoma, surgery should be reconsidered in the treatment paradigm.
In essence, the cancer cell either produces or induces the surrounding tissue to manufacture specific and nonspecific immunosuppressive factors that turn off the host's antitumor immune response.33-37 Complete surgical resection removes the tumor microenvironment. By mechanical reduction of the immunosuppressive factors of the tumor, surgery can restore immune function to a level that controls the progression of residual occult metastases and ensures a durable clinical response.38-39 Recent studies have shown a strong prognostic correlation with the development of an endogenous immune response to a melanoma-associated tumor antigen after the resection of melanoma metastatic to distant sites.40 These findings suggest that the patient's immune response is an important determinant of long-term survival.41-44 The presence of a favorable immune response may explain why the 5-year survival rate following resection of multiple metastases is 15% to 20% even though a vast majority of these patients would be expected to have residual occult metastases and die of their disease.45
Surgery for advanced melanoma is most effective when the disease is limited to a few sites and a small number of metastases. Surgical excision of isolated metastatic melanoma lesions can provide effective and quick palliation and, in some instances, survival rates exceeding 5 or 10 years.46-48 The favorable outcome resulting from surgical resection of distant metastases in selected patients has been shown at multiple major centers.43-46
AUTHOR INFORMATION
Correspondence: Richard Essner, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Suite 123, Santa Monica, CA 90404 (essner{at}jwci.org).
Accepted for publication May 21, 2004.
This study was supported by grants CA 12582 and CA 29605 from the National Institutes of Health, Bethesda, Md; the California Cancer Research Fund, Sacramento, Calif; and the Saban Family Foundation and George Hoag Foundation, Los Angeles, Calif.
This paper was presented at the 75th Annual Meeting of the Pacific Coast Surgical Association; February 17, 2004; Maui, Hawaii; and is published after peer review and revision. The discussions that follow this article are based on the originally submitted manuscript and not the revised manuscript.
Dr Wanek was the validating statistician for this study.
From the Roy E. Coats Research Laboratories, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, Calif.
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Discussion
Jan H. Wong, MD, Honolulu, Hawaii: The management of patients with nonregional metastatic melanoma remains highly problematic. It is apparent that novel approaches to advanced melanoma are needed. The John Wayne Cancer Institute group has hypothesized that me |
