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Surgery as primary treatment in patients with liver metastases from carcinoid tumors: A retrospective, unicentric study over 13 years
Surgery as primary treatment in patients with liver metastases from carcinoid tumors: A retrospective, unicentric study over 13 years Heike Nave, MD, Eckart Mössinger, MD, Henning Feist, MD, Hauke Lang, MD, and Hans-Rudolf Raab, MD, Hannover, Germany
Background. The heterogeneous nature of carcinoid tumors makes it difficult to develop a standardized treatment strategy for the primary tumor itself and for probable liver metastases. However, prolongation of the 5-year survival rate (5-ysr) and amelioration of the incapacitating symptoms after resection of the primary tumor and its metastases demonstrate that surgical intervention must be the treatment of choice in these tumors. Methods. The data of 31 patients (17 patients with midgut carcinoids, 10 patients with an endocrine carcinoma (carcinoid) of the pancreas, and 4 patients with carcinoids of the lung) who underwent liver operation for metastatic carcinoid tumors between 1983 and 1996 were analyzed, with special regard to factors influencing postoperative survival. Results. Ten patients underwent curative resection (5-ysr, 86%), and palliative operations were performed in 21 patients (5-ysr, 26%). The overall 5-ysr was 47%, with a mean postoperative follow-up of 3.5 years (range, 4 months to 10.8 years). Postoperative morbidity rate was 13%. Size of liver metastases, radicality of the operation and localization of the primary tumor were factors influencing postoperative survival. Conclusions. Surgery for metastatic carcinoid tumors may be curative or palliative, with a potential for cure in some cases and prolongation of survival and amelioration of symptoms in the majority of patients. (Surgery 2001;129:170-5.) From the Clinic of Visceral and Transplantation Surgery and the Department of Pathology, Hannover Medical School, Hannover, Germany
METASTATIC CARCINOID TUMORS are localized predominantly in the gastrointestinal tract.1 They are remarkably slow growing, have a low proliferation rate, but often cause severe endocrinopathy.2,3 Moreover, the impaired symptomatology may influence or even dominate the clinical course of the disease.4 It has been shown that aggressive surgical treatment of both the primary tumor itself and probable liver metastases (LM) is justified.5,6 This approach gives the patient a real chance of becoming symptom free, and survival rates are significantly improved.7,8 Alternative therapeutic approaches, such as systemic chemotherapy or hormonal therapy Accepted for publication July 22, 2000. Reprint requests: H.-R. Raab, MD, Clinic of Visceral and Transplantation Surgery, Hannover Medical School, CarlNeuberg-Str.1, 30625 Hannover, Germany. Copyright © 2001 by Mosby, Inc. 0039-6060/2001/$35.00 + 0 doi:10.1067/msy.2001.110426
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(interferon-α or somatostatin analogs) can provide effective palliation, especially in patients with advanced disease.9,10 Nevertheless, curative or cytoreductive hepatic surgery, alone or as part of a multimodal therapeutic concept, for metastatic carcinoid tumors continues to be of major importance.11-13 In this study we retrospectively evaluated our 13-year experience with hepatic surgery for metastases of carcinoid tumors. This report attempts to evaluate whether liver resection is in fact the best form of treatment for metastatic carcinoid tumors, providing most patients with the possibility of a cure. Finally, in view of the comparatively large number of patients and the long postoperative followup, another aim of the study was to identify factors with significant influence on the survival of patients after operation for LM from carcinoid tumors. PATIENTS AND METHODS The case records of 31 patients (mean age, 51 ± 15 years [SD]; range, 25 to 78 years) with LM from
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carcinoid tumors who underwent liver operation between October 1983 and September 1995 were reviewed retrospectively. The patient group comprised 15 women and 16 men (Table). The histologic type of primary tumors consisted of midgut carcinoid tumors (n = 17), carcinoids of the lung (n = 4) and according to current histopathologic criteria14 endocrine carcinomas of the pancreas (carcinoids) (n = 11) (Table). Midgut carcinoids were located in the jejunum (n = 2), in the ileum (n = 10) and in the cecum (n = 5). Statistics. Univariate survival analysis was performed separately for each possible prognostic factor from the date of surgical intervention (operation of LM) until the last follow-up attendance or until death by using the Kaplan-Meier estimation method. The log rank test was performed to detect factors with a significant influence on postoperative survival rates. A P value of .05 or less was considered statistically significant. RESULTS Clinical findings at the time of liver operation. Tumor-related symptoms were present in 22 patients (71%). Eight patients had carcinoid syndrome (flush, diarrhea and elevated 5-hydroxyindoleacetic acid [5-HIAA] urinary excretion). Elevated 5-HIAA excretion was found in 12 patients. Other clinical features included flush (n = 13), hypertension (n = 3), diarrhea (n = 13), endocardial fibrosis (n = 3) and heart failure (n = 2). Extrahepatic disease was present in 20 patients (65%), namely, lymph node involvement (n = 20), affection of the greater omentum (n = 6), peritoneal deposits (n = 5) and ovarian metastases in a single patient. Characteristics of the LM. To establish the diagnosis of LM, patients underwent various imaging procedures: preoperative ultrasound exploration in 94%, intraoperative ultrasonography in 13%, computed tomography in 87% and scintigraphy in 10%. Solitary LM were diagnosed in 10% of the patients. Two to 5 metastases were found in 19% and more than 5 metastases were present in 71% of the patients. The size of the LM was 2 cm or less in 48% and greater than 2 cm in 52% of the patients. In 77% of patients bilobar metastases were found; in 23% only 1 liver lobe was affected (right lobe in 5 and left lobe in 2 patients). The metastases were metachronous in 16% of patients, occurring a mean of 65 months (range, 11 to 182 months) after the diagnosis of the primary tumor. In 84% of the patients the LM were classed as synchronous, occurring (within 6 months) with the primary tumor. Surgical treatment. Ten patients underwent curative (R0) liver resection and 21 patients pallia-
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tive (R2) operation (Table). The designations R0 and R2 refer to the liver resection (R0, complete liver resection was performed; R2, residual tumor tissue remained in the liver). An extended hemihepatectomy (resection of segments IV to VIII) was performed in 1 patient. The other hepatic resections included right or left hemihepatectomy (n = 6), segmental resections (n = 1) and nonanatomic resections (n = 7). In 16 patients the operation remained exploratory. Simultaneous resection of LM was performed in 17 patients of the group with synchronous LM (n = 26). In 14 patients surgery for LM was performed metachronously (mean, 5 months; range, 1 to 16 months). Medical treatment. Adjuvant treatment (in patients who underwent R0 resection) was administered in 4 patients, and 12 patients (who underwent R2 operation) were treated additively. Systemic chemotherapy (n = 4) consisted of 5-fluorouracil alone or in combination with streptozocin. Chemoembolization was performed in 7 patients by using an emulsion of absorbable Gelfoam and epirubicin. Two other medical approaches were the administration of interferon-α or somatostatin analogs (eg, octreotide). Postoperative morbidity. Postoperative complications occurred in 5 patients (16%): healing of the abdominal wound by second intention (n = 4), cardiac arrhythmia (n = 1) and pneumonia (n = 1). Survival and mean postoperative follow-up. The overall postoperative survival at 5 years was 47% with a mean postoperative follow-up of 3.5 years (range, 4 months to 10.8 years). One of the 3 factors with a significant influence on postoperative survival was the resection radicality (R0 versus R2). Whereas the 5-year survival rate (5-ysr) of patients who underwent curative resection was 86%, patients operated with palliative intent had a significantly lower 5-ysr of 26% (Fig 1). It is a well-known fact that metastasizing tumors of the pancreas have a poorer prognosis than other malignant tumors of the gastrointestinal tract.15 Therefore, we compared the postoperative survival of patients with neuroendocrine pancreas tumors (carcinoids) with the survival of patients with midgut and lung carcinoids (pooled in a single group because the mean survival [53 months] of the patients with a midgut carcinoid was similar to that of the patients with a lung carcinoid [51 months]) (Fig 2). Although none of the patients with a neuroendocrine pancreas tumor survived the first 5 postoperative years, the 5-ysr of patients with other carcinoids was significantly higher (58%). Figure 3 demonstrates the survival curves in dependence on the size of LM. Two centimeters was
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Fig 1. Cumulative survival of patients after curative (R0; n = 10) or palliative (R2; n = 21) operation of LM from carcinoid tumors (P = .001).
Fig 2. Cumulative survival of patients with carcinoid of the pancreas (n = 10) in comparison with patients with midgut and lung carcinoid tumors (n = 21) (P = .03).
chosen as the size discriminator because this was the median size of LM. Patients with large LM (greater than 2 cm) had a significantly higher 5-ysr (63%) than patients with small (2 cm or less) LM (27%). To interpret this observation it is important to know that most (n = 8) of the 13 patients with large LM underwent massive resections (extended hemihepatectomy or hemihepatectomy), whereas the majority (n = 17)
of the 18 patients with small LM (often disseminated and in large numbers) had minor surgical interventions (nonanatomic resections or explorations). Factors with no significant influence on the survival of patients were the number of LM, patient age and gender, bilobar versus unilobar LM, extrahepatic spread (ie, lymph node or peritoneal metastases) and the use of adjuvant or additive therapy.
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Fig 3. Cumulative survival of patients as a function of the size of LM (> 2 cm, n = 16; ≤ 2 cm, n = 15) (P = .02).
DISCUSSION Our data are in accord with the data of other research groups, clearly demonstrating that hepatic surgery is effective and safe and does not represent an excessive (peri)operative risk for patients, provided that the preoperative examination and preparation of patients are adequate.1618 There are 2 main reasons why hepatic surgery for metastases of carcinoid tumors is particularly attractive. On the one hand, the prolonged and indolent course of most malignant carcinoid tumors gives the surgeon enough time to evaluate an appropriate therapeutic concept, to plan the surgical intervention and to conduct an elective operation.19-21 On the other hand, LM from carcinoid tumors can cause severe symptoms, either because of the incapability of the liver to cope with the large amount of metabolites produced by the tumors or because of the production of metabolites (eg, serotonin) by the LM themselves. 22 In most cases these endocrinopathies can be controlled or even eliminated by surgical intervention.8,23 Nevertheless, it must be noted that the tumor mass has to be reduced to 10% to 20% to control the symptoms.5 However, hepatic surgery done with curative intent should be the treatment of choice in patients with malignant carcinoid tumors. 24-26 The role of palliative surgery is more difficult to estimate. Nevertheless, cytoreductive hepatic surgery can create optimal conditions for additive therapeutic approaches (eg, chemotherapy) and may thus prolong patient survival.2,4
The overall survival of our patient population was 47% at 5 years. These findings are similar to those reported by other authors showing 5-ysr of 46% to 48%.2,12,25 The 5-ysr of 86% for patients who underwent R0 resection is satisfactory and compatible with previously published data.1,12 After R2 operations significantly fewer patients (26%) survived the first 5 postoperative years. In the published data the 5-ysr of patients with palliatively resected LM from carcinoid tumors varies between 25% and 50%.2,7,23 One explanation for this wide range might be the heterogeneous nature of additive therapies in palliatively operated patients, making it difficult to compare these patients. Another factor with significant influence on the postoperative survival was the size of LM. This observation is in accord with the data of McEntree et al,4 and the reason might be the extent of the resection. Whereas in 62% of the patients with large metastases, vast resections were performed, the majority (94%) of patients with small LM had minor surgical interventions. The third factor with significant influence on survival was the localization of the primary tumor. Patients with LM from neuroendocrine carcinomas of the pancreas (carcinoids) (an exceedingly rare clinical entity)27 did not survive the first 5 postoperative years, whereas the 5-ysr of patients with metastatic midgut and lung carcinoids was 58%. This interesting observation demonstrates that metastatic neuroendocrine carcinomas of the pancreas have much poorer survival rates than other carcinoids.
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Table. Resection of LM from carcinoid tumors Patient. no.
Gender
Age (y)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
M M F F F M F M F M F M M M F F M M M F F M F F M F M M M F F
44 68 61 45 28 65 43 65 53 53 60 39 78 52 41 68 53 69 69 56 29 50 29 70 63 28 56 62 34 50 31
Primary tumor Carcinoid/ileum Carcinoid/cecum Carcinoid/lung Carcinoid/jejunum Carcinoid/ileum Ec/pancreas Carcinoid/ileum Carcinoid/lung Carcinoid/lung Ec/pancreas Carcinoid/ileum Ec/pancreas Carcinoid/cecum Carcinoid/ileum Carcinoid/ileum Carcinoid/ileum Carcinoid/cecum Carcinoid/cecum Carcinoid/cecum Carcinoid/ileum Carcinoid/lung Ec/pancreas Carcinoid/jejunum Ec/pancreas Ec/pancreas Carcinoid/ileum Carcinoid/ileum Ec/pancreas Ec/pancreas Ec/pancreas Ec/pancreas
No. of LM >5 3 3 1 4 1 >5 4 2 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 1 >5 >5 >5 >5 >5 >5 5 >5 >5 >5
Operative procedure Extended hemihepatectomy Hemihepatectomy Hemihepatectomy Nonanatomic resection Hemihepatectomy Segmental resection Hemihepatectomy Nonanatomic resection Nonanatomic resection Hemihepatectomy Exploration Exploration Nonanatomic resection Exploration Exploration Exploration Exploration Exploration Exploration Exploration Hemihepatectomy Nonanatomic resection Exploration Exploration Exploration Exploration Exploration Nonanatomic resection Exploration Nonanatomic resection Exploration
R Status and classification survival (mo) R0 R0 R0 R0 R0 R0 R0 R0 R0 R0 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2
Alive, 129 Alive, 77 Alive, 67 Alive, 66 Alive, 64 Alive, 36 Alive, 25 Alive, 11 DOD, 111 DOD, 37 Alive, 81 Alive, 44 Alive, 28 DOD, 84 Dead, 75 DOD, 72 Dead, 45 DOD, 36 Dead, 28 DOD, 25 DOD, 21 DOD, 14 DOD, 14 DOD, 13 DOD, 13 DOD, 11 DOD, 11 DOD, 5 DOD, 5 DOD, 5 DOD, 4
Ec, Endocrine carcinoma; DOD, dead of disease.
Because of the protracted course of carcinoid tumors and the late onset of clinical symptoms, many patients are in an advanced stage of the disease at the time of diagnosis, with little chance of a cure. Nevertheless, for these patients it is essential to ameliorate their incapacitating symptoms and to prolong survival with palliative measures. One option for causal medical treatment is chemotherapy (4 patients in our study), preferably 5fluorouracil combined with streptozocin.10 Another palliative approach is the application of interferon-α and somatostatin analogs (5 patients in this study), either alone or in a combined treatment. With these biotherapeutic agents symptoms can be controlled and experimental studies have even shown an antitumor effect of interferon-α.28,29 Besides distinct amelioration of symptoms in 80% to 90% of the patients, chemoembolization of the hepatic artery (8 patients in this study) also decreases tumor size in 30% to 50%,30 thus providing effective palliation and mak-
ing it worthy of a place in the therapeutic management concept of LM from carcinoid tumors.31 However, palliative liver resection should, if possible, precede the above mentioned therapeutic measures, because a significant improvement in hormone-related symptoms may result after cytoreductive hepatic surgery,32,33 and tumor debulking facilitates subsequent medical treatment of the tumor. Liver transplantation in the treatment of metastatic neuroendocrine tumors might be indicated when other therapeutic strategies are ineffective.34,35 However, the rather unsatisfactory results of liver transplantation in the treatment of unresectable malignant liver tumors, together with a shortage of donor organs, makes careful patient selection mandatory.36 In conclusion, our results demonstrate that resection should be considered first-line treatment for LM from carcinoid tumors. With one of the longest post-
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Surgery Volume 129, Number 2 operative follow-ups37 and a relatively large patient group, our study shows that curative resection of LM from carcinoid tumors can reliably eliminate the incapacitating symptoms of metastatic carcinoid tumors and significantly prolong patient survival. We dedicate this article to our mentor Rudolf Pichlmayr, MD, FRCS (Hon), FACS (Hon), who died on August 19, 1997. References 1. Ihse I, Persson B, Tibblin S. Neuroendocrine metastases of the liver. World J Surg 1995;19:76-82. 2. Carty SE, Jensen RT, Norton JA. Prospective study of aggressive resection of metastatic pancreatic endocrine tumors. Surgery 1992;112:1024-31. 3. Lehnert T, Knaebel H-P. Diagnostik und Therapie von Lebermetastasen neuroendokriner Tumoren. Chirurg 1997;68:122-31. 4. McEntree GP, Nagorney DM, Kvols LK, Moertel CG, Grant CS. Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery 1990;108:1091-6. 5. Grfnbech JE, Søreide O, Bergan A. The role of resective surgery in the treatment of the carcinoid syndrome. Scand J Gastroenterol 1992;27:433-7. 6. Foster JH. Surgical treatment of metastatic liver tumors. Hepatol Gastroenterol 1990;37:182-7. 7. Søreide O, Berstad T, Bakka A, Schrumpf E, Hanssen LE, Engh V, et al. Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors. Surgery 1992;111:48-54. 8. Ahlman H, Westberg G, Wängberg B, Nilsson O, Tylén U, Scherstén T, et al. Treatment of liver metastases of carcinoid tumors. World J Surg 1996;20:196-202. 9. Arnold R. Medical treatment of metastasizing carcinoid tumors. World J Surg 1996;20:203-7. 10. Öberg K, Eriksson B, Janson ET. Interferons alone or in combination with chemotherapy or other biologicals in the treatment of neuroendocrine gut and pancreatic tumors. Digestion 1994;55(suppl 3):64-9. 11. Adam R, Akpinar E, Johann M, Kunstlinger F, Majno P, Bismuth H. Place of cryosurgery in the treatment of malignant liver tumors. Ann Surg 1997;225:39-50. 12. Dousset B, Saint-Marc O, Pitre J, Soubrane O, Houssin D, Chapuis Y. Metastatic endocrine tumors: medical treatment, surgical resection or liver transplantation. World J Surg 1996;20:908-15. 13. Loftus JP, van Heerden JA. Surgical management of gastrointestinal carcinoid tumors. Adv Surg 1995;28:317-35. 14. Solcia E, Klöppel G, Sobin LH. WHO: international histological classification of tumors—histologic typing of endocrine tumors. Berlin/Heidelberg/New York: Leipzig; 2000. 15. Fabre JM, Houry S, Manderscheid JC, Huguier M, Baumel H. Surgery for left-sided pancreatic cancer. Br J Surg 1996;83:1065-70. 16. Adson MA. Resection of liver metastases: when is it worthwhile? World J Surg 1987;11:511-20. 17. Mentha G, Morel P, Giostra E, Grossholz M, Rubbia L, Bühler L, et al. Le risque des hépatectomies majeures. Schweiz Med Wochenschr 1995;125:1820-24. 18. Paineau J, Hamy A, Savigny B, Visset J. La résection des
19. 20.
21.
22.
23.
24. 25.
26.
27.
28. 29.
30.
31.
32.
33.
34.
35.
36.
37.
métastases hépatiques des cancers non-colorectaux. J Chir (Paris) 1995;132:1-6. Mariette D, Fagniez PL. Les métastases hépatiques des cancers non colorectaux. Rev Prat (Paris) 1992;42:1271-75. Neary PC, Redmond PH, Houghton T, Watson GRK, Bouchier-Haynes D. Carcinoid disease: review of the literature. Dis Colon Rectum 1997;40:349-62. Wolf RF, Goodnight JE, Krag DE, Schneider PD. Results of resection and proposed guidelines for patient selection in instances of noncolorectal hepatic metastases. Surg Gynecol Obstet 1991;173:454-60. Norheim I, Öberg K, Theodorsson-Norheim E, Lindgren PG, Lundqvist G, Magnusson A, et al. Malignant carcinoid tumors. Ann Surg 1987;206:115-26. Norton JA. Surgical management of carcinoid tumors: role of debulking and surgery for patients with advanced disease. Digestion 1994;55(suppl 3):98-103. Delcore R, Friesen SR. Gastrointestinal neuroendocrine tumors. J Am Coll Surg 1994;178:187-211. Que FG, Nagorney DM, Batts K, Linz LJ, Kvols LK. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg 1995;169:36-43. Wängberg B, Westberg G, Tylén U, Tisell LE, Jansson S, Nilsson O, et al. Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction. World J Surg 1996;20:892-99. Maurer CA, Baer H-U, Dyong TH, Mueller-Garamvoelgyi E, Friess H, Ruchti C, et al. Carcinoid of the pancreas: clinical characteristics and morphological features. Eur J Cancer 1996;32:1109-16. Öberg K. Chemotherapy and biotherapy in neuroendocrine tumors. Curr Opin Oncol 1993;5:110-20. Arnold R, Frank M, Kajdan U. Management of gastroenteropancreatic endocrine tumors: the place of somatostatin analogues. Digestion 1994;55(suppl 3):107-13. Clouse ME, Perry L, Stuart K, Stokes KR. Hepatic arterial chemoembolisation for metastatic neuroendocrine tumors. Digestion 1994;55(suppl 3):92-7. Wallace S, Ajani JA, Charnsangavej C, DuBrow R, Yang DJ, Chuang VP, et al. Carcinoid tumors: imaging procedures and interventional radiology. World J Surg 1996;20:147-56. McDermott EWM, Guduric B, Brennan MF. Prognostic variables in patients with gastrointestinal carcinoid tumours. Br J Surg 1994;81:1007-9. Thompson GB, van Heerden JA, Martin JK, Schutt AJ, Ilstrup DM, Carney JA. Carcinoid tumors of the gastrointestinal tract: presentation, management and prognosis. Surgery 1985;98:1054-63. Lang H, Oldhafer KJ, Weimann A, Schlitt HJ, Scheumann GFR, Flemming P, et al. Liver transplantation for metastatic neuroendocrine tumors. Ann Surg 1997;225:347-54. LeTreut YP, Delpero JR, Dousset B, Cherqui D, Segol P, Mantion G, et al. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. Ann Surg 1997;225:355-64. Pichlmayr R, Weimann A, Oldhafer KJ, Schlitt HJ, Klempnauer J, Bornscheuer A. Role of liver transplantation in the treatment of unresectable liver cancer. World J Surg 1995;19:807-13. Norton JA, Doherty GM, Fraker DL, Alexander HR, Doppman JL, Venzon DJ, et al. Surgical treatment of localized gastrinoma within the liver: a prospective study. Surgery 1998;124:1145-52.
Background. The heterogeneous nature of carcinoid tumors makes it difficult to develop a standardized treatment strategy for the primary tumor itself and for probable liver metastases. However, prolongation of the 5-year survival rate (5-ysr) and amelioration of the incapacitating symptoms after resection of the primary tumor and its metastases demonstrate that surgical intervention must be the treatment of choice in these tumors. Methods. The data of 31 patients (17 patients with midgut carcinoids, 10 patients with an endocrine carcinoma (carcinoid) of the pancreas, and 4 patients with carcinoids of the lung) who underwent liver operation for metastatic carcinoid tumors between 1983 and 1996 were analyzed, with special regard to factors influencing postoperative survival. Results. Ten patients underwent curative resection (5-ysr, 86%), and palliative operations were performed in 21 patients (5-ysr, 26%). The overall 5-ysr was 47%, with a mean postoperative follow-up of 3.5 years (range, 4 months to 10.8 years). Postoperative morbidity rate was 13%. Size of liver metastases, radicality of the operation and localization of the primary tumor were factors influencing postoperative survival. Conclusions. Surgery for metastatic carcinoid tumors may be curative or palliative, with a potential for cure in some cases and prolongation of survival and amelioration of symptoms in the majority of patients. (Surgery 2001;129:170-5.) From the Clinic of Visceral and Transplantation Surgery and the Department of Pathology, Hannover Medical School, Hannover, Germany
METASTATIC CARCINOID TUMORS are localized predominantly in the gastrointestinal tract.1 They are remarkably slow growing, have a low proliferation rate, but often cause severe endocrinopathy.2,3 Moreover, the impaired symptomatology may influence or even dominate the clinical course of the disease.4 It has been shown that aggressive surgical treatment of both the primary tumor itself and probable liver metastases (LM) is justified.5,6 This approach gives the patient a real chance of becoming symptom free, and survival rates are significantly improved.7,8 Alternative therapeutic approaches, such as systemic chemotherapy or hormonal therapy Accepted for publication July 22, 2000. Reprint requests: H.-R. Raab, MD, Clinic of Visceral and Transplantation Surgery, Hannover Medical School, CarlNeuberg-Str.1, 30625 Hannover, Germany. Copyright © 2001 by Mosby, Inc. 0039-6060/2001/$35.00 + 0 doi:10.1067/msy.2001.110426
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(interferon-α or somatostatin analogs) can provide effective palliation, especially in patients with advanced disease.9,10 Nevertheless, curative or cytoreductive hepatic surgery, alone or as part of a multimodal therapeutic concept, for metastatic carcinoid tumors continues to be of major importance.11-13 In this study we retrospectively evaluated our 13-year experience with hepatic surgery for metastases of carcinoid tumors. This report attempts to evaluate whether liver resection is in fact the best form of treatment for metastatic carcinoid tumors, providing most patients with the possibility of a cure. Finally, in view of the comparatively large number of patients and the long postoperative followup, another aim of the study was to identify factors with significant influence on the survival of patients after operation for LM from carcinoid tumors. PATIENTS AND METHODS The case records of 31 patients (mean age, 51 ± 15 years [SD]; range, 25 to 78 years) with LM from
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carcinoid tumors who underwent liver operation between October 1983 and September 1995 were reviewed retrospectively. The patient group comprised 15 women and 16 men (Table). The histologic type of primary tumors consisted of midgut carcinoid tumors (n = 17), carcinoids of the lung (n = 4) and according to current histopathologic criteria14 endocrine carcinomas of the pancreas (carcinoids) (n = 11) (Table). Midgut carcinoids were located in the jejunum (n = 2), in the ileum (n = 10) and in the cecum (n = 5). Statistics. Univariate survival analysis was performed separately for each possible prognostic factor from the date of surgical intervention (operation of LM) until the last follow-up attendance or until death by using the Kaplan-Meier estimation method. The log rank test was performed to detect factors with a significant influence on postoperative survival rates. A P value of .05 or less was considered statistically significant. RESULTS Clinical findings at the time of liver operation. Tumor-related symptoms were present in 22 patients (71%). Eight patients had carcinoid syndrome (flush, diarrhea and elevated 5-hydroxyindoleacetic acid [5-HIAA] urinary excretion). Elevated 5-HIAA excretion was found in 12 patients. Other clinical features included flush (n = 13), hypertension (n = 3), diarrhea (n = 13), endocardial fibrosis (n = 3) and heart failure (n = 2). Extrahepatic disease was present in 20 patients (65%), namely, lymph node involvement (n = 20), affection of the greater omentum (n = 6), peritoneal deposits (n = 5) and ovarian metastases in a single patient. Characteristics of the LM. To establish the diagnosis of LM, patients underwent various imaging procedures: preoperative ultrasound exploration in 94%, intraoperative ultrasonography in 13%, computed tomography in 87% and scintigraphy in 10%. Solitary LM were diagnosed in 10% of the patients. Two to 5 metastases were found in 19% and more than 5 metastases were present in 71% of the patients. The size of the LM was 2 cm or less in 48% and greater than 2 cm in 52% of the patients. In 77% of patients bilobar metastases were found; in 23% only 1 liver lobe was affected (right lobe in 5 and left lobe in 2 patients). The metastases were metachronous in 16% of patients, occurring a mean of 65 months (range, 11 to 182 months) after the diagnosis of the primary tumor. In 84% of the patients the LM were classed as synchronous, occurring (within 6 months) with the primary tumor. Surgical treatment. Ten patients underwent curative (R0) liver resection and 21 patients pallia-
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tive (R2) operation (Table). The designations R0 and R2 refer to the liver resection (R0, complete liver resection was performed; R2, residual tumor tissue remained in the liver). An extended hemihepatectomy (resection of segments IV to VIII) was performed in 1 patient. The other hepatic resections included right or left hemihepatectomy (n = 6), segmental resections (n = 1) and nonanatomic resections (n = 7). In 16 patients the operation remained exploratory. Simultaneous resection of LM was performed in 17 patients of the group with synchronous LM (n = 26). In 14 patients surgery for LM was performed metachronously (mean, 5 months; range, 1 to 16 months). Medical treatment. Adjuvant treatment (in patients who underwent R0 resection) was administered in 4 patients, and 12 patients (who underwent R2 operation) were treated additively. Systemic chemotherapy (n = 4) consisted of 5-fluorouracil alone or in combination with streptozocin. Chemoembolization was performed in 7 patients by using an emulsion of absorbable Gelfoam and epirubicin. Two other medical approaches were the administration of interferon-α or somatostatin analogs (eg, octreotide). Postoperative morbidity. Postoperative complications occurred in 5 patients (16%): healing of the abdominal wound by second intention (n = 4), cardiac arrhythmia (n = 1) and pneumonia (n = 1). Survival and mean postoperative follow-up. The overall postoperative survival at 5 years was 47% with a mean postoperative follow-up of 3.5 years (range, 4 months to 10.8 years). One of the 3 factors with a significant influence on postoperative survival was the resection radicality (R0 versus R2). Whereas the 5-year survival rate (5-ysr) of patients who underwent curative resection was 86%, patients operated with palliative intent had a significantly lower 5-ysr of 26% (Fig 1). It is a well-known fact that metastasizing tumors of the pancreas have a poorer prognosis than other malignant tumors of the gastrointestinal tract.15 Therefore, we compared the postoperative survival of patients with neuroendocrine pancreas tumors (carcinoids) with the survival of patients with midgut and lung carcinoids (pooled in a single group because the mean survival [53 months] of the patients with a midgut carcinoid was similar to that of the patients with a lung carcinoid [51 months]) (Fig 2). Although none of the patients with a neuroendocrine pancreas tumor survived the first 5 postoperative years, the 5-ysr of patients with other carcinoids was significantly higher (58%). Figure 3 demonstrates the survival curves in dependence on the size of LM. Two centimeters was
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Fig 1. Cumulative survival of patients after curative (R0; n = 10) or palliative (R2; n = 21) operation of LM from carcinoid tumors (P = .001).
Fig 2. Cumulative survival of patients with carcinoid of the pancreas (n = 10) in comparison with patients with midgut and lung carcinoid tumors (n = 21) (P = .03).
chosen as the size discriminator because this was the median size of LM. Patients with large LM (greater than 2 cm) had a significantly higher 5-ysr (63%) than patients with small (2 cm or less) LM (27%). To interpret this observation it is important to know that most (n = 8) of the 13 patients with large LM underwent massive resections (extended hemihepatectomy or hemihepatectomy), whereas the majority (n = 17)
of the 18 patients with small LM (often disseminated and in large numbers) had minor surgical interventions (nonanatomic resections or explorations). Factors with no significant influence on the survival of patients were the number of LM, patient age and gender, bilobar versus unilobar LM, extrahepatic spread (ie, lymph node or peritoneal metastases) and the use of adjuvant or additive therapy.
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Fig 3. Cumulative survival of patients as a function of the size of LM (> 2 cm, n = 16; ≤ 2 cm, n = 15) (P = .02).
DISCUSSION Our data are in accord with the data of other research groups, clearly demonstrating that hepatic surgery is effective and safe and does not represent an excessive (peri)operative risk for patients, provided that the preoperative examination and preparation of patients are adequate.1618 There are 2 main reasons why hepatic surgery for metastases of carcinoid tumors is particularly attractive. On the one hand, the prolonged and indolent course of most malignant carcinoid tumors gives the surgeon enough time to evaluate an appropriate therapeutic concept, to plan the surgical intervention and to conduct an elective operation.19-21 On the other hand, LM from carcinoid tumors can cause severe symptoms, either because of the incapability of the liver to cope with the large amount of metabolites produced by the tumors or because of the production of metabolites (eg, serotonin) by the LM themselves. 22 In most cases these endocrinopathies can be controlled or even eliminated by surgical intervention.8,23 Nevertheless, it must be noted that the tumor mass has to be reduced to 10% to 20% to control the symptoms.5 However, hepatic surgery done with curative intent should be the treatment of choice in patients with malignant carcinoid tumors. 24-26 The role of palliative surgery is more difficult to estimate. Nevertheless, cytoreductive hepatic surgery can create optimal conditions for additive therapeutic approaches (eg, chemotherapy) and may thus prolong patient survival.2,4
The overall survival of our patient population was 47% at 5 years. These findings are similar to those reported by other authors showing 5-ysr of 46% to 48%.2,12,25 The 5-ysr of 86% for patients who underwent R0 resection is satisfactory and compatible with previously published data.1,12 After R2 operations significantly fewer patients (26%) survived the first 5 postoperative years. In the published data the 5-ysr of patients with palliatively resected LM from carcinoid tumors varies between 25% and 50%.2,7,23 One explanation for this wide range might be the heterogeneous nature of additive therapies in palliatively operated patients, making it difficult to compare these patients. Another factor with significant influence on the postoperative survival was the size of LM. This observation is in accord with the data of McEntree et al,4 and the reason might be the extent of the resection. Whereas in 62% of the patients with large metastases, vast resections were performed, the majority (94%) of patients with small LM had minor surgical interventions. The third factor with significant influence on survival was the localization of the primary tumor. Patients with LM from neuroendocrine carcinomas of the pancreas (carcinoids) (an exceedingly rare clinical entity)27 did not survive the first 5 postoperative years, whereas the 5-ysr of patients with metastatic midgut and lung carcinoids was 58%. This interesting observation demonstrates that metastatic neuroendocrine carcinomas of the pancreas have much poorer survival rates than other carcinoids.
174 Nave et al
Surgery February 2001
Table. Resection of LM from carcinoid tumors Patient. no.
Gender
Age (y)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
M M F F F M F M F M F M M M F F M M M F F M F F M F M M M F F
44 68 61 45 28 65 43 65 53 53 60 39 78 52 41 68 53 69 69 56 29 50 29 70 63 28 56 62 34 50 31
Primary tumor Carcinoid/ileum Carcinoid/cecum Carcinoid/lung Carcinoid/jejunum Carcinoid/ileum Ec/pancreas Carcinoid/ileum Carcinoid/lung Carcinoid/lung Ec/pancreas Carcinoid/ileum Ec/pancreas Carcinoid/cecum Carcinoid/ileum Carcinoid/ileum Carcinoid/ileum Carcinoid/cecum Carcinoid/cecum Carcinoid/cecum Carcinoid/ileum Carcinoid/lung Ec/pancreas Carcinoid/jejunum Ec/pancreas Ec/pancreas Carcinoid/ileum Carcinoid/ileum Ec/pancreas Ec/pancreas Ec/pancreas Ec/pancreas
No. of LM >5 3 3 1 4 1 >5 4 2 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 1 >5 >5 >5 >5 >5 >5 5 >5 >5 >5
Operative procedure Extended hemihepatectomy Hemihepatectomy Hemihepatectomy Nonanatomic resection Hemihepatectomy Segmental resection Hemihepatectomy Nonanatomic resection Nonanatomic resection Hemihepatectomy Exploration Exploration Nonanatomic resection Exploration Exploration Exploration Exploration Exploration Exploration Exploration Hemihepatectomy Nonanatomic resection Exploration Exploration Exploration Exploration Exploration Nonanatomic resection Exploration Nonanatomic resection Exploration
R Status and classification survival (mo) R0 R0 R0 R0 R0 R0 R0 R0 R0 R0 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2 R2
Alive, 129 Alive, 77 Alive, 67 Alive, 66 Alive, 64 Alive, 36 Alive, 25 Alive, 11 DOD, 111 DOD, 37 Alive, 81 Alive, 44 Alive, 28 DOD, 84 Dead, 75 DOD, 72 Dead, 45 DOD, 36 Dead, 28 DOD, 25 DOD, 21 DOD, 14 DOD, 14 DOD, 13 DOD, 13 DOD, 11 DOD, 11 DOD, 5 DOD, 5 DOD, 5 DOD, 4
Ec, Endocrine carcinoma; DOD, dead of disease.
Because of the protracted course of carcinoid tumors and the late onset of clinical symptoms, many patients are in an advanced stage of the disease at the time of diagnosis, with little chance of a cure. Nevertheless, for these patients it is essential to ameliorate their incapacitating symptoms and to prolong survival with palliative measures. One option for causal medical treatment is chemotherapy (4 patients in our study), preferably 5fluorouracil combined with streptozocin.10 Another palliative approach is the application of interferon-α and somatostatin analogs (5 patients in this study), either alone or in a combined treatment. With these biotherapeutic agents symptoms can be controlled and experimental studies have even shown an antitumor effect of interferon-α.28,29 Besides distinct amelioration of symptoms in 80% to 90% of the patients, chemoembolization of the hepatic artery (8 patients in this study) also decreases tumor size in 30% to 50%,30 thus providing effective palliation and mak-
ing it worthy of a place in the therapeutic management concept of LM from carcinoid tumors.31 However, palliative liver resection should, if possible, precede the above mentioned therapeutic measures, because a significant improvement in hormone-related symptoms may result after cytoreductive hepatic surgery,32,33 and tumor debulking facilitates subsequent medical treatment of the tumor. Liver transplantation in the treatment of metastatic neuroendocrine tumors might be indicated when other therapeutic strategies are ineffective.34,35 However, the rather unsatisfactory results of liver transplantation in the treatment of unresectable malignant liver tumors, together with a shortage of donor organs, makes careful patient selection mandatory.36 In conclusion, our results demonstrate that resection should be considered first-line treatment for LM from carcinoid tumors. With one of the longest post-
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Surgery Volume 129, Number 2 operative follow-ups37 and a relatively large patient group, our study shows that curative resection of LM from carcinoid tumors can reliably eliminate the incapacitating symptoms of metastatic carcinoid tumors and significantly prolong patient survival. We dedicate this article to our mentor Rudolf Pichlmayr, MD, FRCS (Hon), FACS (Hon), who died on August 19, 1997. References 1. Ihse I, Persson B, Tibblin S. Neuroendocrine metastases of the liver. World J Surg 1995;19:76-82. 2. Carty SE, Jensen RT, Norton JA. Prospective study of aggressive resection of metastatic pancreatic endocrine tumors. Surgery 1992;112:1024-31. 3. Lehnert T, Knaebel H-P. Diagnostik und Therapie von Lebermetastasen neuroendokriner Tumoren. Chirurg 1997;68:122-31. 4. McEntree GP, Nagorney DM, Kvols LK, Moertel CG, Grant CS. Cytoreductive hepatic surgery for neuroendocrine tumors. Surgery 1990;108:1091-6. 5. Grfnbech JE, Søreide O, Bergan A. The role of resective surgery in the treatment of the carcinoid syndrome. Scand J Gastroenterol 1992;27:433-7. 6. Foster JH. Surgical treatment of metastatic liver tumors. Hepatol Gastroenterol 1990;37:182-7. 7. Søreide O, Berstad T, Bakka A, Schrumpf E, Hanssen LE, Engh V, et al. Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors. Surgery 1992;111:48-54. 8. Ahlman H, Westberg G, Wängberg B, Nilsson O, Tylén U, Scherstén T, et al. Treatment of liver metastases of carcinoid tumors. World J Surg 1996;20:196-202. 9. Arnold R. Medical treatment of metastasizing carcinoid tumors. World J Surg 1996;20:203-7. 10. Öberg K, Eriksson B, Janson ET. Interferons alone or in combination with chemotherapy or other biologicals in the treatment of neuroendocrine gut and pancreatic tumors. Digestion 1994;55(suppl 3):64-9. 11. Adam R, Akpinar E, Johann M, Kunstlinger F, Majno P, Bismuth H. Place of cryosurgery in the treatment of malignant liver tumors. Ann Surg 1997;225:39-50. 12. Dousset B, Saint-Marc O, Pitre J, Soubrane O, Houssin D, Chapuis Y. Metastatic endocrine tumors: medical treatment, surgical resection or liver transplantation. World J Surg 1996;20:908-15. 13. Loftus JP, van Heerden JA. Surgical management of gastrointestinal carcinoid tumors. Adv Surg 1995;28:317-35. 14. Solcia E, Klöppel G, Sobin LH. WHO: international histological classification of tumors—histologic typing of endocrine tumors. Berlin/Heidelberg/New York: Leipzig; 2000. 15. Fabre JM, Houry S, Manderscheid JC, Huguier M, Baumel H. Surgery for left-sided pancreatic cancer. Br J Surg 1996;83:1065-70. 16. Adson MA. Resection of liver metastases: when is it worthwhile? World J Surg 1987;11:511-20. 17. Mentha G, Morel P, Giostra E, Grossholz M, Rubbia L, Bühler L, et al. Le risque des hépatectomies majeures. Schweiz Med Wochenschr 1995;125:1820-24. 18. Paineau J, Hamy A, Savigny B, Visset J. La résection des
19. 20.
21.
22.
23.
24. 25.
26.
27.
28. 29.
30.
31.
32.
33.
34.
35.
36.
37.
métastases hépatiques des cancers non-colorectaux. J Chir (Paris) 1995;132:1-6. Mariette D, Fagniez PL. Les métastases hépatiques des cancers non colorectaux. Rev Prat (Paris) 1992;42:1271-75. Neary PC, Redmond PH, Houghton T, Watson GRK, Bouchier-Haynes D. Carcinoid disease: review of the literature. Dis Colon Rectum 1997;40:349-62. Wolf RF, Goodnight JE, Krag DE, Schneider PD. Results of resection and proposed guidelines for patient selection in instances of noncolorectal hepatic metastases. Surg Gynecol Obstet 1991;173:454-60. Norheim I, Öberg K, Theodorsson-Norheim E, Lindgren PG, Lundqvist G, Magnusson A, et al. Malignant carcinoid tumors. Ann Surg 1987;206:115-26. Norton JA. Surgical management of carcinoid tumors: role of debulking and surgery for patients with advanced disease. Digestion 1994;55(suppl 3):98-103. Delcore R, Friesen SR. Gastrointestinal neuroendocrine tumors. J Am Coll Surg 1994;178:187-211. Que FG, Nagorney DM, Batts K, Linz LJ, Kvols LK. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg 1995;169:36-43. Wängberg B, Westberg G, Tylén U, Tisell LE, Jansson S, Nilsson O, et al. Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction. World J Surg 1996;20:892-99. Maurer CA, Baer H-U, Dyong TH, Mueller-Garamvoelgyi E, Friess H, Ruchti C, et al. Carcinoid of the pancreas: clinical characteristics and morphological features. Eur J Cancer 1996;32:1109-16. Öberg K. Chemotherapy and biotherapy in neuroendocrine tumors. Curr Opin Oncol 1993;5:110-20. Arnold R, Frank M, Kajdan U. Management of gastroenteropancreatic endocrine tumors: the place of somatostatin analogues. Digestion 1994;55(suppl 3):107-13. Clouse ME, Perry L, Stuart K, Stokes KR. Hepatic arterial chemoembolisation for metastatic neuroendocrine tumors. Digestion 1994;55(suppl 3):92-7. Wallace S, Ajani JA, Charnsangavej C, DuBrow R, Yang DJ, Chuang VP, et al. Carcinoid tumors: imaging procedures and interventional radiology. World J Surg 1996;20:147-56. McDermott EWM, Guduric B, Brennan MF. Prognostic variables in patients with gastrointestinal carcinoid tumours. Br J Surg 1994;81:1007-9. Thompson GB, van Heerden JA, Martin JK, Schutt AJ, Ilstrup DM, Carney JA. Carcinoid tumors of the gastrointestinal tract: presentation, management and prognosis. Surgery 1985;98:1054-63. Lang H, Oldhafer KJ, Weimann A, Schlitt HJ, Scheumann GFR, Flemming P, et al. Liver transplantation for metastatic neuroendocrine tumors. Ann Surg 1997;225:347-54. LeTreut YP, Delpero JR, Dousset B, Cherqui D, Segol P, Mantion G, et al. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. Ann Surg 1997;225:355-64. Pichlmayr R, Weimann A, Oldhafer KJ, Schlitt HJ, Klempnauer J, Bornscheuer A. Role of liver transplantation in the treatment of unresectable liver cancer. World J Surg 1995;19:807-13. Norton JA, Doherty GM, Fraker DL, Alexander HR, Doppman JL, Venzon DJ, et al. Surgical treatment of localized gastrinoma within the liver: a prospective study. Surgery 1998;124:1145-52.