Extending the Role of Hepatic Metastasectomy in Stage IV Melanoma and Breast Cancer: Patient Selection is Critical

Resection of liver metastases represents a major advance of the last few decades in the treatment of colorectal cancer. Five-year survival rates of over 50% have been reported.[1] Advances in operative techniques, perioperative care, and systemic therapy have all contributed to the success of liver resection for colorectal metastases. As our comfort with hepatic resection improves, the cost-benefit curve for liver surgery continues to shift downward, and the indications for metastasectomy for other malignancies are expanding. In their review, Zani and Clary present the existing evidence for hepatic resection of metastatic melanoma and breast cancer.

With regard to melanoma, resection of isolated metastatic disease in relatively healthy patients may improve survival and is commonly performed at many experienced cancer centers.[2-4] Isolated liver metastases are rare in melanoma, with the exception of ocular melanoma. While ocular melanoma frequently metastasizes to the liver selectively, most of these patients will have hundreds of metastases not amenable to resection. Therefore, most reported series of liver resection for melanoma are small. Zani and Clary found that most series of highly selected patients undergoing liver resection reported a high rate of recurrence within 12 months, and 5-year survival for patients with cutaneous melanomas ranged from 0% to 22%. Patients with ocular melanomas seem to fare slightly better after liver resection, with median survival times greater than those seen with cutaneous melanoma. It is worth noting that patients with ocular melanoma had a greater disease-free interval prior to resection compared with patients with cutaneous melanoma.[5] The authors conclude their discussion of liver resection for metastatic melanoma with general guidelines for patient selection, which include a long preceding disease-free interval, ability to achieve a complete resection, low tumor burden, and no extrahepatic metastatic disease burden.

In a similar fashion, the evidence for hepatic resection of breast cancer is reviewed. As with melanoma, only small series have been reported of breast cancer patients with liver metastases who have undergone resection, and these have involved highly selected patients with isolated breast liver metastases. As Zani and Clary note, the results of liver resection in breast cancer patients were slightly better than the results in melanoma patients, with median and 5-year survival rates of 32 to 34 months and 34% to 48%, respectively. Shorter preceding disease-free interval and inability to achieve a complete resection were poor prognostic factors.

The fundamental question that needs to be answered is whether the success of hepatic resection for colorectal liver metastases can be extrapolated to other malignancies. Enthusiasm for the broadening of the application of liver resection to include metastatic breast cancer or melanoma must be tempered by an understanding of the biology of the disease. Colorectal cancer in many patients metastasizes only to the liver via the portal circulation, allowing resection to be performed with curative intent. Even so, it must be acknowledged that patients in whom resection with curative intent can be performed represent the minority of patients with stage IV colorectal cancer, and they are highly selected on the basis of response to systemic therapy, lack of extrahepatic disease, limited tumor burden, and other factors.

The biology and treatment options for melanoma and breast cancer are different from each other and from colorectal cancer. These factors need to be considered when considering liver resection. It is also important to be clear about the goal of the operation. Liver resection should be performed with curative intent. While that does not mean that the majority of patients will be cured-in fact, quite the opposite is the case-patients undergoing hepatectomy should have the potential for curative resection. It makes little sense to engage in an R2 resection or resect liver metastases in the setting of significant extrahepatic disease.

The biology of melanoma differs from that of colorectal cancer in important ways. Patients with stage IV cutaneous melanoma rarely have metastasis only to the liver. If they do, they should be considered for resection. The 5-year survival rates for patients with resected stage IV melanoma are in the 25% range.[3] Our experience with liver-directed therapy (chemoembolization and radioembolization) is uninspiring to say the least. Conventional therapies such as dacarbazine (10% to 15% response rate with virtually no chance of complete response) offer little hope of cure. High-dose interleukin-2 (up to 6% durable complete response rate) is a rather toxic therapy given in the intensive care unit setting, and anecdotal experience suggests that patients with liver metastases are not likely to benefit significantly. Even with FDA approval, the two new drugs for metastatic melanoma (anti-CTLA4 agent ipilimumab [Yervoy] and BRAF inhibitor vemurafenib [Zelboraf]) have a likelihood of pathologic complete response that is in the low single digits. Therefore, all of our current systemic therapies are palliative therapies, not to be used with curative intent. While it certainly is not unreasonable to offer melanoma patients with isolated liver metastases a trial of available or investigational systemic therapy to assess response and rule out rapid development of other sites of metastatic disease, resection should be offered to patients who are appropriate candidates with acceptable operative risk. Patients with ocular melanoma have a propensity for liver-only metastasis, but miliary metastases are the rule rather than the exception. Few patients with ocular melanoma have an opportunity for resection with curative intent. However, because patients with ocular melanoma are notoriously resistant to systemic therapy, resection is the only meaningful option for prolonged survival.

Importantly, even triple-phase liver protocol computed tomography (CT) scanning may vastly underestimate the extent of disease in patients with melanoma liver metastases. Positron emission tomography (PET)/CT scanning, good in general for determining the extent of disease in patients with stage IV melanoma, is not good for detecting small liver metastases (< 1 cm). Contrast-enhanced magnetic resonance imaging (MRI) of the liver is more sensitive for detection of melanoma metastastic to the liver, and should be performed prior to surgery in addition to PET/CT or CT scans of the chest, abdomen, and pelvis to evaluate for other sites of metastatic disease. MRI of the brain should be performed preoperatively because of the significant risk of asymptomatic brain metastases.

Although breast cancer is a common disease, there are decidedly few patients with liver-only metastases. Systemic chemotherapy, hormonal therapy, and targeted therapy options are often effective at controlling the disease. The situation with breast cancer is more akin to that of colorectal cancer: most thoughtful surgeons would like to assess response to systemic therapy prior to resection because (1) the chance of response is high, (2) the chance that the liver metastases will progress to an unresectable state under observation is low, and (3) patients who progress significantly despite systemic therapy and who develop other sites of metastatic disease outside the liver are likely poor candidates for liver resection. The most common clinical scenario for resection of breast cancer metastatic to the liver is that of a relatively healthy young patient who has persistent liver disease despite extensive systemic therapy. These patients are appropriate to consider for resection; they will have demonstrated cancer biology that may result in long-term survival with liver resection.

In the absence of level I evidence (which does not exist for resection of colorectal liver metastases either), clinicians must use an abundance of clinical judgment in selecting patients with melanoma or breast cancer for liver resection. The guidelines put forth by Zani and Clary are good ones. The patient who is young, relatively healthy with a good performance status, with a long preceding disease-free interval and limited liver-only disease may very well benefit from liver resection. Pre-operative counseling of the patient is crucial, including a frank discussion of the expected risks, benefits, and likelihood of recurrence. While metastatic breast cancer and melanoma isolated to the liver are fundamentally different diseases than colorectal cancer, meticulous patient selection and careful surgical technique will yield a small but reproducible fraction of patients who will be cured of their cancer, and others who will have their life extended. In oncology, we accept the premise that toxic, expensive systemic therapy is warranted for palliation, and we offer patients the fleetingly small hope of durable complete response. Resection in selected patients offers the immediate hope of “surgical complete response,” and it should be considered in appropriate patients. As always, more evidence is needed. Zani and Clary provide a good starting point for future investigations with their review of what we already know, and they define the questions that such research needs to answer.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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REFERENCES

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2. Wood TF, DiFronzo LA, Rose DM, et al. Does complete resection of melanoma metastatic to solid intra-abdominal organs improve survival? Ann Surg Oncol. 2001;8:658-62.

3. Wasif N, Bagaria SP, Ray P, Morton DL. Does metastasectomy improve survival in patients with stage IV melanoma? A cancer registry analysis of outcomes. J Surg Oncol. 2011;104:111-5.

4. Meyer T, Merkel S, Goehl J, Hohenberger W. Surgical therapy for distant metastases of malignant melanoma. Cancer. 2000;89:1983-91.

5. Pawlik TM, Zorzi D, Abdalla EK, et al. Hepatic resection for metastatic melanoma: distinct patterns of recurrence and prognosis for ocular versus cutaneous disease. Ann Surg Oncol. 2006;13:712-20.