Metastatic carcinoid: Don’t forget the surgical consultation Rachel R. Kelz, MD, MSCE and Douglas L. Fraker, MD, Philadelphia, PA
From the Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
NEUROENDOCRINE TUMORS (NETs), considered among the most interesting tumors to diagnose and treat, are more common than historically appreciated. The incidence of neuroendocrine tumors, including carcinoids, is estimated at 1.9–5.7 per 100,000.1 At the time of diagnosis, 40–45% of carcinoid tumors have metastasized to the liver. For patients with malignant NET, it is the liver metastases that often determine the disease prognosis. Multimodality care can be used in the treatment of the NET metastases to the liver; however, operation offers the only potential for cure. Surgery is considered the recommended approach for grade 1 or 2 liver lesions when complete liver resection is possible, regardless of the resectability of any extra-hepatic disease.1 Operation typically is able to offer the patient relief from pain, hormonal symptoms and, in many cases, has been associated with prolonged survival. Surgery also is an acceptable option for certain patients who are not candidates for complete resection. Determining the appropriateness of liver resection in the management of NET liver metastases involves a detailed understanding of the goals of therapy. The timing and extent of resection must be considered when recommending operative debulking in patients who are not likely to be candidates for complete resection. In patients without evidence of extra-hepatic disease, liver transplantation may be considered for unresectable liver metastasis. The relative value of incomplete liver debulking for metastatic carcinoid tumors is controversial. Cochrane reviews have not shown a benefit to liver Accepted for publication August 22, 2014. Reprint requests: Rachel R. Kelz, MD, MSCE, Department of Surgery, Hospital of the University of Pennsylvania, 3400 Spruce Street, 4 Silverstein, Philadelphia, PA 19104. E-mail: Rachel. [email protected]. Surgery 2014;156:1367-8. 0039-6060/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.08.086
resection over nonoperative treatment options; however, the utility of the evidence is limited by the quality of the available data. As shown in the recent study ‘‘Expanded Criteria for Carcinoid Liver Debulking: Maintaining Survival and Increasing the Number of Eligible Patients,’’2 surgical debulking, even when only 70% of the tumor can be removed, is safe and can be effective in providing symptomatic relief and possibly impacting on the natural history of the disease. Resectability often is based on imaging that includes both structural and functional components. Ultrasound frequently underestimates the extent of liver disease. Therefore, magnetic resonance imaging and/or 3-dimensional computed tomography (CT) should be used to assess the burden of disease, to help with complex operative management, and to estimate the size of the functional liver remnant. 68Ga-somatostatin receptor positron emission tomography (PET)/CT, although not widely available, and 18F-fluorodeoxyglucose positron emission tomography/CT can be very helpful functional studies to estimate the burden of extrahepatic disease and to estimate the likelihood of resection for cure. These imaging modalities also are integral to the planning of nonoperative management. Differences in the criteria used to select patients for debulking procedures across providers and institutions make the comparison of outcomes reported in individual case series challenging. In addition to the disease burden, patient-related comorbidities may influence case selection and consequent outcomes, thereby representing a source of unmeasured bias. Moreover, the distinction between 70% and 90% debulking may be difficult to objectively measure with current intraoperative tools. The technical aspects of hepatic resection for carcinoid differ from the approaches used for resection of metastatic colorectal adenocarcinoma. For colon cancer, lobar or segmental resection to achieve negative margins is of primary importance to the operating surgeon because most studies SURGERY 1367
1368 Kelz and Fraker
have shown negative resection margins to be a very important variable in disease free survival for this histology. For carcinoid tumors metastatic to the liver, enucleation of lesions right on the tumor margin often is performed with excellent disease control. Any lesion near the surface can be dissected rapidly right on the capsule with minimal blood loss. By using individual tumor enucleation in combination with wedge resections, the pool of patients who are eligible for a substantial if not complete operative debulking for carcinoid is expanded greatly compared with colorectal patients. Importantly, medical oncologists who are unfamiliar with this technical difference may review films on patients with bilateral hepatic carcinoid metastases and, inappropriately, deem them unresectable. In such a situation, the failure to consult with a surgical oncologist experienced in treating this histology would result in the denial of appropriate care. Control of the liver disease in metastatic carcinoid is of paramount importance because many of these patients ultimately succumb to liver failure as the cause of their death. Unfortunately, when historical selection criteria are used, it is estimated that less than 20% of patients with metastatic NET are eligible for complete liver resection.3 Locally ablative techniques and angiographic liver-directed therapy should be considered when operative debulking is no longer feasible either because of the distribution or extent of disease or because of other contraindications to operative management. These nonresective but effective options can both be performed in isolation or in combination with open or laparoscopic surgery. The use of radiofrequency ablation, microwave, or laser ablation may be performed percutaneously by interventional radiologists or in combination with operative resection/enucleation. Transarterial embolization is preferred for unresectable liver disease over transarterial chemoembolization in the management of hepatic metastases secondary to carcinoid. These liver directed therapies can result in symptomatic responses and delay disease progression but, seldom lead to cure. When liver directed treatment options are possible, systemic chemotherapy and biologic
Surgery December 2014
agents have not been shown to achieve sufficient benefit in the management of metastatic NETs to warrant use. Comparative studies of individual regimens are difficult because of the difference in patient selection criteria for each intervention; however, ongoing clinical trials of these agents should be considered for patients without options for liver directed therapy. The efficacy of individual agents appears to vary by tumor grade and primary site. Somatotstatin is widely used in the management of metastatic NETs. It has been found to provide symptomatic relief to patients with the carcinoid syndrome. Arrested tumor progression has been observed in patients with metastatic midgut NETs with limited (
From the Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
NEUROENDOCRINE TUMORS (NETs), considered among the most interesting tumors to diagnose and treat, are more common than historically appreciated. The incidence of neuroendocrine tumors, including carcinoids, is estimated at 1.9–5.7 per 100,000.1 At the time of diagnosis, 40–45% of carcinoid tumors have metastasized to the liver. For patients with malignant NET, it is the liver metastases that often determine the disease prognosis. Multimodality care can be used in the treatment of the NET metastases to the liver; however, operation offers the only potential for cure. Surgery is considered the recommended approach for grade 1 or 2 liver lesions when complete liver resection is possible, regardless of the resectability of any extra-hepatic disease.1 Operation typically is able to offer the patient relief from pain, hormonal symptoms and, in many cases, has been associated with prolonged survival. Surgery also is an acceptable option for certain patients who are not candidates for complete resection. Determining the appropriateness of liver resection in the management of NET liver metastases involves a detailed understanding of the goals of therapy. The timing and extent of resection must be considered when recommending operative debulking in patients who are not likely to be candidates for complete resection. In patients without evidence of extra-hepatic disease, liver transplantation may be considered for unresectable liver metastasis. The relative value of incomplete liver debulking for metastatic carcinoid tumors is controversial. Cochrane reviews have not shown a benefit to liver Accepted for publication August 22, 2014. Reprint requests: Rachel R. Kelz, MD, MSCE, Department of Surgery, Hospital of the University of Pennsylvania, 3400 Spruce Street, 4 Silverstein, Philadelphia, PA 19104. E-mail: Rachel. [email protected]. Surgery 2014;156:1367-8. 0039-6060/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2014.08.086
resection over nonoperative treatment options; however, the utility of the evidence is limited by the quality of the available data. As shown in the recent study ‘‘Expanded Criteria for Carcinoid Liver Debulking: Maintaining Survival and Increasing the Number of Eligible Patients,’’2 surgical debulking, even when only 70% of the tumor can be removed, is safe and can be effective in providing symptomatic relief and possibly impacting on the natural history of the disease. Resectability often is based on imaging that includes both structural and functional components. Ultrasound frequently underestimates the extent of liver disease. Therefore, magnetic resonance imaging and/or 3-dimensional computed tomography (CT) should be used to assess the burden of disease, to help with complex operative management, and to estimate the size of the functional liver remnant. 68Ga-somatostatin receptor positron emission tomography (PET)/CT, although not widely available, and 18F-fluorodeoxyglucose positron emission tomography/CT can be very helpful functional studies to estimate the burden of extrahepatic disease and to estimate the likelihood of resection for cure. These imaging modalities also are integral to the planning of nonoperative management. Differences in the criteria used to select patients for debulking procedures across providers and institutions make the comparison of outcomes reported in individual case series challenging. In addition to the disease burden, patient-related comorbidities may influence case selection and consequent outcomes, thereby representing a source of unmeasured bias. Moreover, the distinction between 70% and 90% debulking may be difficult to objectively measure with current intraoperative tools. The technical aspects of hepatic resection for carcinoid differ from the approaches used for resection of metastatic colorectal adenocarcinoma. For colon cancer, lobar or segmental resection to achieve negative margins is of primary importance to the operating surgeon because most studies SURGERY 1367
1368 Kelz and Fraker
have shown negative resection margins to be a very important variable in disease free survival for this histology. For carcinoid tumors metastatic to the liver, enucleation of lesions right on the tumor margin often is performed with excellent disease control. Any lesion near the surface can be dissected rapidly right on the capsule with minimal blood loss. By using individual tumor enucleation in combination with wedge resections, the pool of patients who are eligible for a substantial if not complete operative debulking for carcinoid is expanded greatly compared with colorectal patients. Importantly, medical oncologists who are unfamiliar with this technical difference may review films on patients with bilateral hepatic carcinoid metastases and, inappropriately, deem them unresectable. In such a situation, the failure to consult with a surgical oncologist experienced in treating this histology would result in the denial of appropriate care. Control of the liver disease in metastatic carcinoid is of paramount importance because many of these patients ultimately succumb to liver failure as the cause of their death. Unfortunately, when historical selection criteria are used, it is estimated that less than 20% of patients with metastatic NET are eligible for complete liver resection.3 Locally ablative techniques and angiographic liver-directed therapy should be considered when operative debulking is no longer feasible either because of the distribution or extent of disease or because of other contraindications to operative management. These nonresective but effective options can both be performed in isolation or in combination with open or laparoscopic surgery. The use of radiofrequency ablation, microwave, or laser ablation may be performed percutaneously by interventional radiologists or in combination with operative resection/enucleation. Transarterial embolization is preferred for unresectable liver disease over transarterial chemoembolization in the management of hepatic metastases secondary to carcinoid. These liver directed therapies can result in symptomatic responses and delay disease progression but, seldom lead to cure. When liver directed treatment options are possible, systemic chemotherapy and biologic
Surgery December 2014
agents have not been shown to achieve sufficient benefit in the management of metastatic NETs to warrant use. Comparative studies of individual regimens are difficult because of the difference in patient selection criteria for each intervention; however, ongoing clinical trials of these agents should be considered for patients without options for liver directed therapy. The efficacy of individual agents appears to vary by tumor grade and primary site. Somatotstatin is widely used in the management of metastatic NETs. It has been found to provide symptomatic relief to patients with the carcinoid syndrome. Arrested tumor progression has been observed in patients with metastatic midgut NETs with limited (
