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EDITORIALS |
From the Department of Surgery, University of Illinois at Chicago, Chicago Illinois.
Correspondence: Address correspondence to: Scott Helton, MD, Department of Surgery, University of Illinois at Chicago, MC/958, 840 South Wood St., Chicago, IL 60612; Fax: 312-355-1987; E-mail: scoth{at}uic.edu
In this issue of the Annals of Surgical Oncology, Feldman and colleagues1 from the Surgical Branch of the National Cancer Institute present a nice overview of locoregional treatment options for ocular melanoma (OM) metastatic to the liver. The authors’ review demonstrates that this disease remains largely incurable, although some long-term survivors exist. Surgical resection is rarely possible, given the rare incidence of isolated, resectable disease. Chemotherapy, immunotherapy, chemoembolization, and immunoembolization are the more commonly used treatment options because most patients have more extensive liver metastases. These treatments, however, have marginally improved overall median survival. Isolated hepatic chemoperfusion has increased the response rate for this disease but is costly, morbid, and had little impact on extending survival beyond 2 years. The authors rightfully conclude that current treatment modalities are inadequate and new ones need to be developed to improve the outlook for patients with this disease. This editorial focuses on the potential value of surgical management for patients with metastatic OM to the liver and discusses how it can be included in future multimodality therapies for this lethal disease.
Metastasectomy for metastatic melanoma is not widely practiced for American Joint Committee on Cancer (AJCC) patients with stage IV disease because surgery is considered a local therapy and, therefore, of little value for the management of disseminated disease. Unlike cutaneous melanoma, which metastasizes to numerous sites, OM more commonly metastasizes only to the liver. This fact underscores the importance of developing effective forms of "liver-directed therapy" for patients with this notoriously chemoresistant tumor. This is an important issue because liver-directed therapy for any metastatic cancer to the liver is indicated only when extrahepatic cancer is absent or at least excluded by a thorough evaluation. An exception to this common practice would be if liver-directed therapy were offered to a patient with extrahepatic disease as part of a cytoreduction strategy when the patient receives adjunctive therapy and all known extrahepatic disease is extirpated.2
Although Feldman et al. state that "surgery is not considered a first-line approach secondary to the diffuse, multifocal nature of the hepatic disease" several reasons exist why patients with OM metastatic to the liver should first be evaluated for resection and, if found to have limited disease, offered this option. First, and most importantly, experience has shown that patients with OM liver metastases rendered NED (no evidence of disease) by resection will experience improved overall survival when compared with all other forms of treatment.3–5 Second, most patients with good performance status will recover from a major liver resection and be able to resume their preoperative level of activity within 6 weeks of surgery. This is in contrast to patients having had ineffective chemotherapy, chemoperfusion, or immunobiotherapy where return to full activity is more prolonged. Third, rendering a patient NED, if possible, can act as a form of immunotherapy in that tumor burden is reduced, increasing the chance that a patient’s immunity can be more capable of controlling subclinical micrometastases. Patients rendered NED by hepatic resection are also ideal candidates to enroll in adjunctive clinical trials investigating the utility of multimodality therapies.
Patients with isolated hepatic metastasis from OM are indeed rare. In the largest prospective data base on melanoma in the world (the combined experience of The John Wayne Cancer Institute and Sydney Melanoma Unit) only 24 of 1750 patients (1.3%) with hepatic metastasis were found to have disease that was resectable4; of these, only 2 of the 1750 patients (0.1%) had OM and an R0 resection. These two patients had a median survival of 24 months and disease-free survival of 14 months (personal communication, Anton Bilchik, MD, PhD, John Wayne Cancer Institute, Santa Monica California). Memorial Sloan Kettering Cancer Institute probably performs more liver resections for metastatic cancer than any other center in North America and yet only 4 of 1642 patients (0.2%) having liver resection over the past decade had OM.6
Cytoreduction combined with chemotherapy has been explored in patients with metastatic OM to the liver. The largest reported trial of cytoreductive surgery combined with chemotherapy for this disease enrolled 75 patients.5 Disseminated disease in both lobes was present in all but one patient. An R0 resection was obtainable in only 27% of patients, whereas tumor reduction was achieved in 49%. Postoperatively, patients received intrahepatic arterial fotemustine, DTIC-platinum, or both for four to nine cycles. In the 61 patients receiving both surgery and chemotherapy, median survival was 10 months—a figure that is similar to historic controls not having surgery. In the subset of patients with a R0 resection, median survival significantly increased to 22 months. This study demonstrated that surgical resection, when combined with postoperative adjunctive therapy, resulted in improved survival only if an R0 resection was performed. On the other hand, the benefit of the adjunctive therapy used was not demonstrated because similar outcomes have been achieved in patients having an R0 resection without such chemotherapy.
Even when patients have an R0 resection for metastatic OM, recurrence both in and outside the liver is common. This observation supports the need for evaluating multimodality, adjunctive therapies. Physicians from The Deshands Cancer Center at The University of Florida recently reported a patient with OM metastatic to liver and pancreas treated by cytoreductive surgery consisting of mesohepatic resection, distal pancreatectomy, and portal node dissection, followed by biochemotherapy with dacarbazine and interferon alpha.2 The patient had a disease-free survival of 32 months and is currently alive with recurrent disease at 38 months (personal communication, Al Hemming MD, Gainesville, Florida). Patients whose tumor can be resected can also be enrolled in melanoma vaccine studies. Such trials are ongoing at Thomas Jefferson University Hospital (Philadelphia, PA) and The University of Southern California (Los Angeles, CA).
In managing any patient with metastatic cancer to the liver, several principles are important to keep in mind. First, patients should not be subjected to a nontherapeutic laparotomy to minimize impairments in physical activity and the quality of their remaining limited life. This objective can occur only by operating on patients who are found to have liver-only metastases after a comprehensive evaluation by sophisticated imaging techniques and diagnostic laparoscopy. Surgeons at John Wayne Cancer Institute recommend that preoperative staging include computed tomography (CT) scan of the chest, abdomen, and pelvis, magnetic resonance imaging (MRI) of the brain, bone scans, and whole body 18-fluorodeoxyglucose (18FDG)-positron emission tomography (PET) scanning.4 The utility of this extensive diagnostic workup is based predominantly on an experience with metastatic cutaneous melanoma. Others have reported that whole body PET is insensitive to detect ocular melanoma.7
Although the probability of having limited, resectable OM of the liver is extremely low (<1%), surgery as a therapeutic option or component of multimodality therapy should be discussed with patients. Because most patients will harbor extensive metastatic OM that is not detected by abdominal CT or MRI (Fig. 1), it is imperative that all patients being considered for liver resection have diagnostic laparoscopy and laparoscopic liver ultrasound, as part of any type of therapy, before laparotomy because the detection of more extensive hepatic or extrahepatic disease would spare patients from what would otherwise turn out to be a nontherapeutic laparotomy.8,9 Almost one third of patients explored for possible liver resection for metastatic melanoma to the liver have been found to have unresectable disease.4 In another study in which 195 patients with melanoma were staged with laparoscopy, 34% of patients with metastasis to the liver and peritoneum had lesions that were <1 cm in diameter and undetectable by abdominal imaging.8
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Experimental phase I and II clinical trials are under investigation for metastatic OM. The interested reader is referred to (http://www.lafn.org/~bc534/OcularMelMets.htm) as a source of information regarding such studies. Ocular melanoma is highly vascular and for this reason a number of antiangiogenic drug trials are being investigated (e.g., angiostatin, anti-vascular endothelial growth factor, and thalidomide).
In summary, surgical resection will rarely benefit patients with OM. Despite this, resection should be discussed as an option for the appropriately selected patient because survival beyond 2 years is possible. Hepatic resection of OM can also provide the only source of tumor for enrollment in a vaccine trial. Finally, surgical resection can be of benefit to patients when used as a cytoreduction treatment strategy.
Received for publication November 21, 2003. Accepted for publication December 16, 2003.
REFERENCES
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  S. L. Chen, D. M. Iddings, R. P. Scheri, and A. J. Bilchik Lymphatic Mapping and Sentinel Node Analysis: Current Concepts and Applications CA Cancer J Clin, September 1, 2006; 56(5): 292 - 309. [Abstract] [Full Text] [PDF]
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