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Originally published as JCO Early Release 10.1200/JCO.2008.19.2161 on October 6 2008 © 2008 American Society of Clinical Oncology.
Revisiting C.G. Moertel's Land of Small TumorsMoffitt Cancer Center, Tampa, FL Quite simply, the 1983 article by Moertel1 on the treatment of the carcinoid tumor and the malignant carcinoid syndrome in the first volume of Journal of Clinical Oncology is brilliant. It is full of clinical pearls that ring as true today as when the article was written. I had the privilege and the pleasure of working with Dr Moertel for 18 years at the Mayo Clinic. This editorial will review the continuing evolution of oncology research in the field and highlight how the science has changed in the "land of small tumors" over the last 25 years.2 HEPATIC ARTERY EMBOLIZATION AND SURGICAL UPDATE In his 1983 article, Moertel reported on 10 patients with symptomatic carcinoid syndrome who were treated with hepatic artery ligation. Eight of the nine patients showed a rapid decline in urine 5-hydroxyindole acetic acid, with prompt and usually complete relief of the carcinoid syndrome. Hepatic artery embolization or chemoembolization has largely replaced hepatic artery ligation as a palliative technique in patients with hepatic metastases who are not candidates for surgical resection. Response rates associated with embolization, as measured by either a decrease in hormonal secretion or by radiographic regressions, generally exceed 50%.3,4 Radiofrequency ablation and cryoablation, either alone or in conjunction with surgical debulking, have come of age since Moertel's 1983 article. Among 170 patients at the Mayo Clinic who underwent surgical resection for hepatic metastases, more than 90% achieved control of symptoms. Despite a high recurrence rate of 84% at 5 years, survival rates were favorable (61% and 35% at 5 and 10 years, respectively).5 In another retrospective review, patients undergoing cytoreductive hepatic surgery had a mean survival time of 43 months compared with 24 months for patients undergoing embolization.6 The lack of random assignment in this trial and the fact that embolization is commonly used for palliation in patients who are not candidates for surgery make definitive interpretation of these results difficult. ANALOGS OF SOMATOSTATIN In 1983, somatostatin could only be administered by the parenteral route and, therefore, was unsuitable for chronic therapy. In a prescient comment in the 1983 article, Moertel1 states, "It could play some role in the management of a carcinoid crisis, but effectiveness under these circumstances has not, as yet, been reported." It was only 2 years later that my colleagues and I reported rapid reversal of a carcinoid crisis with intravenous administration of a somatostatin analog, octreotide.7 A year later, in 1986, we reported our experience in 25 patients treated prospectively with octreotide administered subcutaneously at a dose of 150 µg three times a day. Symptoms of the carcinoid syndrome improved in 88% of patients.8 Two years later, the drug was approved in the United States for treating symptoms of the carcinoid syndrome. The use of a long-acting depot form of octreotide has largely eliminated the need for patients to inject themselves several times a day. After a brief trial of the short-acting formulation, the long-acting octreotide is typically initiated at a dose of 20 to 30 mg intramuscularly with gradual escalation of the dose as needed to optimize control of symptoms.9,10 Patients may use the short-acting octreotide for breakthrough symptoms. Lanreotide, another somatostatin analog, seems to be similar to octreotide in its clinical efficacy.11 More recently, pasireotide, a novel somatostatin analog with binding affinity for four of the five somatostatin receptor subtypes, has been shown to be useful in patients who are no longer responding to octreotide.12 In the two decades since octreotide was approved by the US Food and Drug Administration, the unique characteristics of the carcinoid tumor cells have been further exploited by modification of the somatostatin molecule to allow diagnostic imaging, staging, and therapy of carcinoid tumors. Krenning et al,13 in Rotterdam, were able to image tumors in vivo with a gamma-emitting isotope linked to an analog of somatostatin. The initial imaging molecule was an iodinated compound, but subsequently, an indium-labeled analog (indium-111 [111In] –labeled diethylenetriamine pentaacetic acid) octreotide became the gold standard for staging somatostatin receptor–positive neuroendocrine tumors. Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs is a promising treatment option for patients with inoperable or metastatic neuroendocrine tumors. The first therapy using this approach was performed in 1992 using high doses of 111In-labeled diethylenetriamine pentaacetic acid octreotide. This treatment relied on the Auger emission of the 111In.14 Because tumor size reduction was seldom achieved with 111In-labeled somatostatin analogs, clinical trials were developed using beta-emitting radionuclides such as 90-yttrium and 177-lutetium. Somatostatin analogs with higher receptor affinity such as octreotate labeled with 177-lutetium have yielded the most favorable results thus far. In 310 patients, Kwekkeboom et al15,16 reported a 30% objective response rate, 28% partial response rate, and 2% complete response rate. Future trials are planned to evaluate radionuclides in combination with radiosensitizing drugs.17 INTERFERON Oberg et al18 had just published their article on the use of human leukocyte interferon in patients with midgut carcinoid a few months before the 1983 article by Moertel.1 Since then, more than 500 patient cases have been reported worldwide and have been published in the literature. A typical dose range has been 3 to 5 million units administered by subcutaneous injection three times per week. Symptomatic responses are seen in more than 50% of patients, biochemical responses are seen in 44%, and objective tumor regression is seen in 11%.19 Interferon has been combined with somatostatin analogs in two randomized studies. In one study, midgut carcinoid patients who had undergone debulking by surgery and hepatic artery embolization were randomly assigned to receive octreotide or octreotide plus interferon. A significant improvement in time to progression was observed in the interferon arm.20 In the second randomized study, 80 patients who were therapy naive were treated with lanreotide, interferon, or lanreotide plus interferon. The rates of objective partial responses were low in all three groups (4%, 4%, and 7%, respectively), and the combination had no higher antiproliferative effect than that of monotherapy with either agent alone.3,21 CHEMOTHERAPY TRIALS In the 1983 report, Moertel1 laments the efficacy of chemotherapy available at the time and states "It would seem appropriate for the oncologist to restrain any urge to offer cytotoxic drugs to the patient with early stage disease who has either minor or no symptoms of tumor or syndrome." Most recently, streptozocin plus fluorouracil was compared with doxorubicin plus fluorouracil in a randomized trial of 249 patients;22 the response rates associated with the two regimens were similar (16% v 15.9%, respectively). Although there was a slight survival advantage associated with streptozocin plus fluorouracil compared with doxorubicin plus fluorouracil in this trial (24.3 v 15.7 months, respectively), more than one third of the patients treated with streptozocin developed renal toxicity. A trial of dacarbazine produced a 16% objective response rate in carcinoid patients but an 88% incidence of nausea and vomiting.23 The low response rates combined with the toxicity of these regimens continue to make them unattractive as first-line treatment for advanced carcinoid tumors. Temozolomide with thalidomide was studied by Kulke, and although the response rate for pancreatic endocrine tumors was 45%, it was a disappointing 7% for carcinoid patients.24 Ansell et al25 studied paclitaxel in 24 carcinoid patients, and only one had a nonsustained partial response. Treatment with docetaxel was associated with biochemical responses but no radiologic responses in a phase II trial of 21 carcinoid patients.26 No responses were observed in 18 neuroendocrine tumor patients (nine had carcinoid tumors) treated with gemcitabine.27 Chemotherapy remains woefully inadequate for well-differentiated carcinoid tumors. Again quoting the 1983 article by Moertel,1 "It would seem that the more mundane types of clinical trials, empirically testing drug after drug and arbitrarily concocted drug combinations, is the not the most productive road to follow." Poorly differentiated carcinoid tumors seem to be an exception to this rule. Forty-five patients with metastatic neuroendocrine tumors were treated with a regimen of etoposide plus cisplatin. Among 27 patients with well-differentiated carcinoid tumors or islet cell carcinomas, only two partial objective tumor regressions were observed (7%). Among 18 patients with poorly differentiated neuroendocrine carcinomas, however, there were nine partial regressions and three complete regressions, for an overall response rate of 67%.28 INHIBITION OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND OTHER GROWTH FACTOR SIGNALING PATHWAYS Neuroendocrine tumors are known to be highly vascular and to express vascular endothelial growth facto (VEGF). In a phase II study, 44 patients with metastatic carcinoid tumors on a stable dose of octreotide were randomly assigned to 18 weeks of treatment with either bevacizumab, a humanized monoclonal antibody targeting VEGF, or pegylated interferon alfa-2b. In the bevacizumab arm, four patients (18%) achieved partial responses compared with none in the pegylated interferon arm. Progression-free survival rates after 18 weeks were 95% in the bevacizumab arm and 68% in the pegylated interferon arm.29 A phase III randomized cooperative group trial is underway by the Southwest Oncology Group to confirm these results. Sunitinib is a multitargeted tyrosine kinase inhibitor with activity against the VEGF receptor as well as PDGFR, RET, and c-Kit. A phase II study of this agent in carcinoid patients demonstrated a partial response of only 3% but a relatively prolonged median time to progression of 44 weeks.30 At the Moffitt Cancer Center, we are evaluating this drug after hepatic artery embolization to see whether it affects time to progression. A recent phase II study investigated everolimus, a mammalian target of rapamycin inhibitor, at doses of 5 or 10 mg daily in patients with metastatic carcinoid tumors. A partial response rate of 13% and stable disease rate of 83% were reported.31 A multicenter, international study is underway to confirm this activity in a randomized double-blind trial. As Moertel1 concluded in 1983, "The patient with carcinoid tumor should not be a fascinating curio for grand rounds exhibition. He should be a focal point for research involving an experienced, multidisciplinary clinical team supported by devoted basic scientists. If our patient resources and efforts can be concentrated in this manner, the carcinoid should be a strong candidate for the next medically curable cancer." AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Moertel CG: Treatment of the carcinoid tumor and the malignant carcinoid syndrome. J Clin Oncol 1:727-740, 1983[Abstract] 2. Moertel CG: Karnofsky Memorial Lecture: An odyssey in the land of small tumors. J Clin Oncol 5:1502-1522, 1987 3. Strosberg JR, Choi J, Cantor AB, et al: Selective hepatic artery embolization for treatment of patients with metastatic carcinoid and pancreatic endocrine tumors. Cancer Control 13:72-78, 2006[Medline] 4. Moertel CG, Johnson CM, McKusick MA, et al: The management of patients with advanced carcinoid tumors and islet cell carcinomas. Ann Intern Med 120:302-309, 1994 5. Sarmiento JM, Heywood G, Rubin J, et al: Surgical treatment of neuroendocrine metastases to the liver: A plea for resection to increase survival. J Am Coll Surg 197:29-37, 2003[CrossRef][Medline] 6. Osborne DA, Zervos EE, Strosberg J, et al: Improved outcome with cytoreduction versus embolization for symptomatic hepatic metastases of carcinoid and neuroendocrine tumors. Ann Surg Oncol 13:572-581, 2006[CrossRef][Medline] 7. Kvols LK, Martin JK, Marsh HM, et al: Rapid reversal of carcinoid crisis with a somatostatin analogue. N Engl J Med 313:1229-1230, 1985[Medline] 8. Kvols LK, Moertel CG, O'Connell MJ, et al: Treatment of the malignant carcinoid syndrome: Evaluation of a long-acting somatostatin analogue. N Engl J Med 315:663-666, 1986[Abstract] 9. Rubin J, Ajani J, Schirmer W, et al: Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol 17:600-606, 1999 10. Oberg K, Kvols L, Caplin M, et al: Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol 15:966-973, 2004 11. Ruszniewski P, Ish-Shalom S, Wymenga M, et al: Rapid and sustained relief from the symptoms of carcinoid syndrome: Results from an open 6-month study of the 28-day prolonged-release formulation of lanreotide. Neuroendocrinology 80:244-251, 2004[CrossRef][Medline] 12. Schmid HA: Pasireotide (SOM230): Development, mechanism of action and potential applications. Mol Cell Endocrinol 286:69-74, 2008[CrossRef][Medline] 13. Krenning EP, Bakker WH, Breeman WA, et al: Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet 1:242-244, 1989[CrossRef][Medline] 14. Van Essen M, Krenning EP, De Jong M, et al: Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours. Acta Oncol 46:723-734, 2007[CrossRef][Medline] 15. Kwekkeboom DJ, Teunissen JJ, Bakker WH, et al: Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol 23:2754-2762, 2005 16. Kwekkeboom DJ, de Herder WW, Kam BL, et al: Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: Toxicity, efficacy, and survival. J Clin Oncol 26:2124-2130, 2008 17. van Essen M, Krenning EP, Kam BL, et al: Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging 35:743-748, 2008[CrossRef][Medline] 18. Oberg K, Funa K, Alm G: Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med 309:129-133, 1983[Abstract] 19. Oberg K: Interferon in the management of neuroendocrine GEP-tumors: A review. Digestion 62:92-97, 2000 (suppl 1)[CrossRef][Medline] 20. Kolby L, Persson G, Franzen S, et al: Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg 90:687-693, 2003[CrossRef][Medline] 21. Faiss S, Pape UF, Bohmig M, et al: Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors: The International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 21:2689-2696, 2003 22. Sun W, Lipsitz S, Catalano P, et al: Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group study E1281. J Clin Oncol 23:4897-4904, 2005 23. Bukowski RM, Tangen CM, Peterson RF, et al: Phase II trial of dimethyltriazenoimidazole carboxamide in patients with metastatic carcinoid: A Southwest Oncology Group study. Cancer 73:1505-1508, 1994[CrossRef][Medline] 24. Kulke MH, Stuart K, Enzinger PC et al: Phase II study of temozolomide and thalidimide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24:401-406, 2006 25. Ansell SM, Pitot HC, Burch PA, et al: A phase II study of high-dose paclitaxel in patients with advanced neuroendocrine tumors. Cancer 91:1543-1548, 2001[CrossRef][Medline] 26. Kulke MH, Kim H, Stuart K, et al: A phase II study of docetaxel in patients with metastatic carcinoid tumors. Cancer Invest 22:353-359, 2004[CrossRef][Medline] 27. Kulke MH, Kim H, Clark JW, et al: A phase II trial of gemcitabine for metastatic neuroendocrine tumors. Cancer 101:934-939, 2004[CrossRef][Medline] 28. Moertel CG, Kvols LK, O'Connell MJ, et al: Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin: Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 68:227-232, 1991[CrossRef][Medline] 29. Yao JC, Phan A, Hoff PM, et al: Targeting vascular endothelial growth factor in advanced carcinoid tumor: A random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol 26:1316-1323, 2008 30. Kulke MH, Lenz HJ, Meropol NJ, et al: Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26:3403-3410, 2008 31. Yao JC, Phan A, Chang DZ, et al: Phase II study of RAD001 (everolimus) and depot octreotide (sandostatin LAR) in advanced low grade neuroendocrine carcinoma (LGNET). J Clin Oncol 2007 25:198s, 2007 (suppl; abstr 4503)
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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