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10.1245/ASO.2006.03.071
Annals of Surgical Oncology 13:572-581 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Improved Outcome With Cytoreduction Versus Embolization for Symptomatic Hepatic Metastases of Carcinoid and Neuroendocrine Tumors

Dana A. Osborne, MD1, Emmanuel E. Zervos, MD1,2, Jonathon Strosberg, MD2, Brian A. Boe, BS1, Mokenge Malafa, MD2, Alexander S. Rosemurgy, MD1, Timothy J. Yeatman, MD2, Larry Carey, MD1, Lisa Duhaine, MD2 and Larry K. Kvols, MD2

1 Digestive Disorders Center, Tampa General Hospital, 1 Davis Island, Tampa, Florida 33601
2 Department of Clinical Investigation, GI Tumor Section, H. Lee Moffitt Cancer Center and Research Institute, 12901 Bruce B. Downs Boulevard, SRB 22134, Tampa, Florida 33612

Correspondence: Address correspondence and reprint requests to: Emmanuel E. Zervos, MD, Department of Clinical Investigation, GI Tumor Section, H. Lee Moffitt Cancer Center and Research Institute, 12901 Bruce B. Downs Boulevard, SRB 22134, Tampa, FL 33612; E-mail: zervosee{at}moffitt.usf.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Few data exist regarding outcomes after resection versus embolic treatment of symptomatic metastatic carcinoid and neuroendocrine tumors. The purpose of this study was to determine whether cytoreduction provides any benefit over embolic management of diffuse neuroendocrine tumors.

Methods: A prospective database of 734 patients treated at our institution was retrospectively queried for symptomatic metastatic tumors treated with embolization or cytoreduction. Patients were compared with regard to pretreatment performance status, relief of symptoms, and survival.

Results: A total of 120 patients were identified: 59 undergoing embolization and 61 undergoing cytoreduction. Twenty-three patients had palliative cytoreduction (gross residual disease). Pretreatment performance status (Eastern Cooperative Oncology Group) was similar for both groups: .7 ± .70 (embolization) versus .8 ± .72 (cytoreduction; P = .27). Complete symptomatic relief was observed in 59% and partial relief in 32% of patients who underwent embolization, with a mean symptom-free interval of 22 ± 13.6 months. A total of 69% of patients who underwent cytoreduction had complete symptomatic relief, and 23% had partial relief (P = .08 vs. embolization). The mean duration of relief was 35 ± 22.0 months (P < .001 vs. embolization). The mean survival for the patients who underwent embolization was 24 ± 15.8 months versus 43 ± 26.1 months for those who underwent cytoreduction (P < .001). Survival in patients who underwent palliative cytoreduction was 32 ± 18.9 months (P < .001 vs. embolization), whereas it was 50 ± 27.6 months in patients who underwent curative resection (P < .001 vs. embolization; P < .001 vs. palliative).

Conclusions: Cytoreduction for metastatic neuroendocrine tumors resulted in improved symptomatic relief and survival when compared with embolic therapy in this nonrandomized study. Cytoreduction should be pursued whenever possible even if complete resection may not be achievable.

Key Words: Neuroendocrine tumors • Cytoreduction • Embolization • Outcomes


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Neuroendocrine tumors are a rare clinical entity, occurring with a reported incidence of 1 to 2 cases per 100,000 people per year in the United States.1,2 These tumors are characteristically slow growing and metastasize primarily to the liver.3 Although most neuroendocrine tumors are nonfunctioning and are found incidentally at autopsy, most patients who develop symptoms (either as a result of excess hormone production or a mass effect) will have metastatic disease at the time of presentation.4,5 In many patients, these tumors are associated with clinical endocrinopathies in which increased serum hormone levels have been detected, and clinical signs and symptoms common to a particular hormonal excess are noted.6 The main prognostic indicators for survival in patients with neuroendocrine tumors have been assessed by several authors and included the location of the primary tumor, tumor bulk, histological subtype, and adequacy of resection in patients deemed acceptable candidates for resection.5,7,8 Treatment can be medical (chemotherapy/embolization) or surgical.

Medical management of symptomatic neuroendocrine tumors includes systemic or regional chemotherapy. Although several chemotherapeutic regimens are used in these patients, the response rates are variable, and regression rates for systemic chemotherapy for metastatic cancers rarely exceed 30% and are short lasting.6 Somatostatin analogues (Sandostatin; Novartis Pharmaceutical Corp., East Hanover, NJ) are used frequently, because they are highly effective in controlling symptoms related to hormonal excess and may slow tumor growth; however, their use rarely leads to tumor regression.9 In the rare case in which some tumor response is noted, it is often brief, with median response times of 12 months in patients with carcinoid tumors and 3 months in patients with islet cell tumors.6

Regional therapy is achieved through hepatic artery embolization, which induces ischemic injury in tumor cells, thus rendering them more susceptible to other chemotherapeutic options. Some series have reported palliation in as many as 90% of patients with hormonal symptoms.10 Major complications at a rate of 3% to 4% have been reported with common hepatic artery embolization and include fulminant hepatic failure, tumor rupture, and nontargeted embolization to the gut.11 Embolizations have recently been undertaken in multistage procedures in which there are sequential embolizations of the right and left hepatic arteries. This has decreased the complication rate of these procedures; however, data are still lacking as to long-term survival in these patients.12

Recently, many authors have advocated aggressive surgical resection for metastatic neuroendocrine tumors even when complete extirpation of disease cannot be achieved.13–19 Unfortunately, prospective randomized data on such treatment options are lacking because of the rarity of these tumors. Historically, patients with metastatic neuroendocrine tumors and untreated liver metastasis have a 5-year survival rate of 35%, with a median survival of 2 to 4 years.20,21 As demonstrated in several series, many patients with symptomatic tumors can have resolution of their endocrinopathies after resection of all gross disease.16,22–25

To date, no study has attempted to report outcomes of different modes of therapeutic intervention in patients with metastatic symptomatic neuroendocrine tumors treated at the same institution. Because of the volume of patients seen at our institution and the diversity of our surgical experience, a nonrandomized, retrospective review of these patients was undertaken. By using an ongoing, continuously updated database of 734 patients, a historical review comparing embolization versus cytoreductive therapy was undertaken. Our hypothesis in doing so was that patients who underwent cytoreductive therapy for metastatic neuroendocrine tumors would enjoy improved symptomatic relief and longer survival than those who received other forms of therapy, even when complete tumor resection could not be achieved.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All patients who presented to our institutions from 2000 to 2004 were entered into a continuously updated database. Data contained in the database included presentation, age at diagnosis, serum hormone levels at the initial visit (if available), and the site of origin of the neuroendocrine tumor. Patients in whom clinical endocrinopathies were present were further stratified for inclusion onto this investigation. Only patients with symptomatic neuroendocrine tumors and evidence of metastatic liver disease (based on computed tomographic or octreotide scanning) were further divided into those receiving either embolization or cytoreductive surgical therapy. Patients with evidence of extra-abdominal disease were not included, because bone or distant metastases were a contraindication to regional hepatic therapy.

Before any intervention, patients underwent thorough evaluation, including comprehensive history and physical and complete laboratory interrogation, including liver function tests, complete blood counts, and coagulation studies. Tumors were classified according to hormonal products and clinical presentation. Any suspicion of carcinoid heart disease was thoroughly evaluated with echocardiography, and patients were referred for possible valve replacement when clinically significant disease was noted. The patient’s Eastern Cooperative Oncology Group performance status was also assessed before the procedure and after each therapeutic intervention, as well as during routine follow-up visits with both the oncologist and the surgeon.

Surgical exploration and cytoreductive therapy were undertaken on the basis of preoperative imaging studies suggesting that 100% of the primary and regional disease was resectable and that resection of at least 90% of the hepatic disease was feasible and safe. The goal of cytoreduction was palliation of symptoms. The type of hepatic resection undertaken was based on the extent of disease. To illustrate the extent of hepatic disease and tumor burden in the patient populations, Fig. 1Go shows computed tomographic scans of representative patients who underwent cytoreductive hepatic surgery and representative scans of patients who underwent embolization. The resections were characterized as curative if all disease was removed or as palliative if there was evidence of gross residual disease after resection; microscopic margins were not taken into consideration. Tumors that were ablated with radiofrequency were considered curative when all gross disease was addressed. Embolizations were undertaken if preoperative imaging suggested that complete extirpation of disease was not feasible because of extent or location, when patients refused, or when functional status suggested prohibitive surgical risk. In some instances, patients were referred for embolization in hopes of reducing the hepatic disease to resectability.


Figure 1
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  		FIG. 1. Representative computed tomographic scans from patients who were candidates for surgical cytoreduction (left) and embolization (right). All patients shown in the column on the left were referred for and eventually underwent cytoreductive hepatic surgery. All patients in the column on the right received embolization because of the presence of scattered bilobar disease.

 
Follow-up data were obtained from initial and routine postoperative visits with the medical oncologists, surgeons, or both, and the database was updated regularly. Symptoms of the initial clinical endocrinopathy were assessed, and performance status was graded at each postoperative visit. Clinical and hormonal responses were classified as complete, partial, or none. The symptom-free interval was calculated as the time from the completion of the intervention (surgery or last embolization) to recrudescence of symptoms. Serum hormone levels were evaluated after surgery only if the patient developed symptoms consistent with the preoperative endocrinopathy. Survival was calculated as the time from the last intervention; Kaplan-Meier survival curves were generated by using SPSS for Windows (SPSS Inc., Chicago, IL). All other statistical calculations were performed with Tru EpiStat (EpiStat Services, Richardson, TX).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Demographics
With institutional review board approval, a prospectively collected database was reviewed retrospectively. Of 734 patients in the database, 120 were identified who had both metastatic and symptomatic disease and also underwent some form of liver-directed therapy. Of the 120 patients, 61 underwent surgical cytoreduction, and 59 underwent embolization. All patients had symptoms due to hormone overproduction by the tumor, although some patients had additional symptoms relating to mechanical factors of either their primary tumor or metastatic disease (pain, intermittent obstruction, and so on). Almost all primary tumors were confined to the pancreas or small bowel, and several arose from unknown primary sites. Detailed demographic data are listed in Table 1Go.


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  		TABLE 1. Patient demographics
 
Symptoms
Most patients in this series (73%) had carcinoid tumors. Thirty-nine percent of these patients presented with only symptoms attributed to a clinical endocrinopathy: these included flushing and diarrhea. Two patients presented with carcinoid heart disease. The remaining patients with carcinoid tumors presented with symptoms due to hormonal excess in addition to mechanical symptoms such as pain and obstruction. Of the 21 patients with islet cell carcinomas, 38% presented solely with hormonal symptoms such as diarrhea, headache, and weight loss; the remaining patients (62%) had a combination of symptoms. For patients with glucagonomas, 67% presented with symptoms such as diabetes and necrolytic migratory erythema, and the remaining patients had symptoms of both hormone excess and mechanical factors. Of the three patients with gastrinomas, all presented with ulcer disease, dyspepsia, or upper gastrointestinal hemorrhage. The same was true for the patients with insulinomas; all presented after episodes of profound hypoglycemia. Table 2Go lists the number of patients in each group who presented with hormonal or combined symptoms and the number of patients who had either a complete or partial response to liver-directed therapy.


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  		TABLE 2. Presenting symptoms and symptom response after liver-directed therapy
 
Hormone Profile
Of the 87 patients with carcinoid tumors, most had increased urinary 5-hydroxyindole acetic acid. There were 35 patients with polyfunctioning tumors who had serum increases of chromogranin A, serotonin, and/or substance P, as shown in Table 3Go. Eleven patients had no hormone levels recorded before any intervention. A total of 33 patients had islet cell carcinomas. Of those patients, 12 received a diagnosis of glucagonoma (n = 6), insulinoma (n = 3), or gastrinoma (n = 3) due to prevailing hormone production and resultant clinical endocrinopathy. Fourteen patients had symptoms that could not be attributed to isolated hormone production and were characterized as having polyfunctional tumors. Table 3Go shows the constellation of hormones found to be increased in these 14 patients. The remaining 7 patients had no recorded assessment of hormone levels.


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  		TABLE 3. Hormone production by tumor type
 
Embolization
A total of 59 patients underwent embolization as their primary mode of treatment. The embolizations were performed as multistage procedures. All embolizations performed before 2002 used polyvinyl alcohol particles. After that, Micro Embosphere beads (Biosphere Medical, Rockland, MA), which are porous acrylic polymer particles, were used exclusively. Patients were observed in the hospital per protocol until their liver enzymes peaked and began trending down toward baseline. Patients underwent an average of 2.5 embolizations over the course of their treatment, with a range of 1 to 6 procedures.

Cytoreduction
Operative resections were undertaken in 61 patients. Of those patients, 38 (62%) were able to undergo curative resections in which all evidence of gross disease was removed. Three of these patients had prior embolizations performed at an outside institution. The remaining 23 patients had palliative resections; 1 patient in this group underwent embolization before resection. The type of resection undertaken was at the discretion of the operating surgeon according to intraoperative findings and the extent of disease. In addition to resections, many patients underwent intraoperative radiofrequency ablations (RFA) when scattered, bilobar lesions were present. In many cases, the primary tumor was also resected at the time of cytoreduction by performing a pancreatic resection (distal pancreatectomy or Whipple procedure) or bowel resection in conjunction with the hepatic cytoreduction. The remaining patients with a known primary tumor had resection at an earlier operation. Of the 26 patients who had their primary tumor resected before liver-directed therapy, 12 had evidence of liver disease at their initial operation. The distribution of the various operative strategies applied is listed in Table 4Go.


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  		TABLE 4. Operative strategies
 
Periprocedural Morbidity and Mortality
Of the patients who underwent embolization, there were no immediate deaths related to the procedure. The only complications noted were as follows: bilateral lower extremity edema in one patient immediately after the procedure requiring compression stockings, abscess in the liver requiring percutaneous drain placement in one patient, and intractable ascites requiring maximal medical therapy in addition to multiple paracenteses in another. More than half of the patients who underwent embolization reported complete a symptom response after the completion of their treatment series.

Complications in patients who underwent surgery were limited to two patients, both of whom experienced intra-abdominal abscess formation necessitating percutaneous drainage. One perioperative death occurred in the palliative group; this patient had a glucagonoma and underwent a distal pancreatectomy and splenectomy with RFA of multiple liver nodules. The patient developed a perforated viscus that necessitated re-exploration on postoperative day 8 and later died from multisystem organ failure related to fulminant sepsis.

Symptomatic Relief
The symptom response based on the type of intervention performed is listed in Table 5Go. In most cases, patients reported a complete symptom response to either embolization or cytoreductive therapy; however, the average symptom response was significantly longer in patients who underwent cytoreductive surgical therapy. The frequency of complete symptomatic relief was greater (69% vs. 59%) in the cytoreduction group, but not significantly. Figure 2Go shows symptom-free survival. With use of log-rank analysis, there was no difference in overall symptom-free survival, but the median symptom-free interval (95% confidence interval) for patients who underwent cytoreductive hepatic surgery was 56 months (44–71 months) versus 37 months (29–45 months) for patients who underwent embolization, and this approached statistical significance (P = .08).


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  		TABLE 5. Symptom response
 

Figure 2
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  		FIG. 2. Kaplan-Meier analysis of symptom-free survival.

 
Performance Status
The Eastern Cooperative Oncology Group performance status was graded both before surgery and at each postoperative visit. Although most patients who underwent embolization had more diffuse hepatic disease, this did not equate to a difference in pre-treatment performance status. Posttreatment performance status was calculated by including only patients who were still alive at the conclusion of this study. Patient condition at the last recorded follow-up was used to calculate the performance status for this investigation. Patients who underwent embolization had a significant decrease in performance status at the completion of this study, not only as compared with patients who underwent cytoreductive surgery, but also as compared with their own pretreatment functional status. These comparisons are listed in Table 6Go.


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  		TABLE 6. Eastern Cooperative Oncology Group performance statusa
 
Survival
To date, 16 of the 61 patients in the cytoreduction group have died: 1 as a result of complications surrounding the operation and the rest because of disease progression. Thirty-three of 59 patients from the embolization group have died. Figure 3Go shows comparative survival data between patients who underwent embolization and patients who underwent palliative and curative cytoreductive hepatic surgery. A significant difference in survival was noted when all forms of cytoreduction were compared with embolization; however, it should be noted that the survival difference when comparing palliative cytoreduction with embolization was also significant. Curative cytoreduction imparted the greatest mean (±SD) survival benefit (50 ± 27.6 months), which was significantly longer than that after embolization (24 ± 15.8 months; P < .01) or palliative cytoreduction (32 ± 18.9 months; P < .01 by Student’s t-test).


Figure 3
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  		FIG. 3. Kaplan-Meier survival analysis. Survival for patients who underwent embolization was significantly shorter by log-rank test than survival not only for patients who underwent curative resections (P < .01), but also for those who underwent palliative cytoreduction (P = .03).

 
Repeat Interventions
Ten patients evaluated in this series underwent additional interventions as disease or symptoms progressed. Six patients who underwent curative resections at our institution developed disease progression that was treated with embolization therapy. Of those six patients, four are still alive and free of any evidence of clinical endocrinopathy. For patients who were initially treated with embolization, three have undergone surgical resection of residual hepatic disease, and one patient received an additional series of embolizations. One patient in this group was able to undergo a curative resection, and all four patients are alive and enjoying improvements in symptoms. Table 7Go summarizes the clinical courses of all patients who underwent repeat interventions.


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  		TABLE 7. Patients with repeat interventions
 
Adjuvant Therapy
Most patients in all groups received adjuvant therapy (Table 8Go). Many patients were treated with somatostatin analogues (either Sandostatin or Sandostatin LAR depot injections) for their antiproliferative effects. In addition, patients who still had symptoms related to a clinical endocrinopathy after their cytoreduction or embolization were maintained on this therapy. If there was disease progression or if symptoms reappeared or worsened, patients were referred for additional therapy, which included radiation, inteferon, 5-fluorouracil/streptozocin, or several experimental protocols in Europe, which included peptide receptor radiotherapy. Several patients in each group received somatostatin analogues in addition to other forms of chemotherapy.


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  		TABLE 8. Adjuvant therapy (number of patients)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Neuroendocrine tumors are typically slow growing, indolent entities that can cause significant impingement on quality of life when they are associated with a clinical endocrinopathy. As such, treatment of these tumors is directed towards relief of symptoms rather than improvement in survival, especially when symptomatic tumors are diffuse and cannot be completely eradicated. Improvements in symptoms and subsequent beneficial effects on quality of life have recently been used as justification for a more aggressive surgical approach. This may include cytoreductive strategies even when it is apparent that all gross disease cannot be removed. Alternative therapies include systemic chemotherapy or embolization. Each of these treatments is known to improve symptoms and, in some cases, prolong life. Comparisons of such treatments are difficult because of the relatively low incidence of symptomatic tumors and the lack of concentration of such patients at any one institution. In this study, we investigated patients with symptomatic metastatic neuroendocrine tumors who underwent each type of therapy at our institution. In doing so, we had hoped not to demonstrate the superiority of one approach, but rather to better define their appropriate use in select patients.

In this study, we have shown that patients who undergo surgical cytoreduction of symptomatic neuroendocrine hepatic metastases enjoy more frequent and lasting improvements in symptoms and prolonged survival when compared with their medically treated counterparts. It can be argued that surgical therapy was applied whenever possible, thus imparting an inherent selection bias favoring that group with regard to tumor burden, although accurate objective assessment of tumor burden was impossible because of the limitations of current imaging modalities. Nonetheless, accepting some intrinsic selection bias in this group of patients, we believe that several important conclusions can still be gleaned from the data.

The complication rate for patients who underwent cytoreductive therapy in this study does not make the risk for operative resection prohibitive, because the perioperative risk does not differ from that of hepatic resection for other malignancies.26–30 Embolization was also shown to be safe in this study, with very limited complications, all of which were addressed nonsurgically. Given these observations, we conclude that aggressive surgical therapy (including RFA) should not be denied to any patient because of a perceived risk of morbidity or mortality. Patients undergoing surgical therapy in this study enjoyed improved symptomatic relief and survival even when gross residual disease remained at the conclusion of surgery. These findings underscore the importance of strict guidelines regarding the appropriate application of surgical treatment in this group of patients. Currently, at our institution, patients deemed surgical candidates undergo aggressive resections of both primary and metastatic lesions, as well as the application of RFA for scattered bilobar lesions.

Current recommendations by various authors for patients with metastatic neuroendocrine tumors support resection if preoperative evaluation shows that 100% of the primary/regional disease and at least 90% of the metastatic disease can be removed.6,16 This seems to be true for both symptomatic and asymptomatic tumors. As Sarmiento et al.26 described in 2003, a survival benefit can be achieved with cytoreduction, even in asymptomatic patients. Our results support these recommendations, because even patients who underwent palliative resection enjoyed symptomatic relief and prolonged survival.

There is clearly a role for embolization in patients with metastatic neuroendocrine tumors. Some authors have advocated its use to reduce tumor bulk and facilitate resection, whereas others recommend its use in patients who cannot withstand major abdominal surgery.31–33 In this series, four patients had undergone prior embolizations at another institution, and three of these patients were able to undergo curative resections. These indications for the use of embolization are reasonable and intuitive. In this study, a handful of patients did come to resection after first being treated with embolization. As with cytoreduction, embolization must be used with caution, because it can result in mortality as high at 6% in some early series and similarly high rates of major morbidity.5,34,35 Even so, in patients deemed inappropriate for surgical therapy, embolization provided symptomatic relief in more than half of the patients treated, albeit of shorter duration, and some survival benefit over nontreated historical controls.

Received for publication March 10, 2005. Accepted for publication October 12, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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