Quality of Clinical Trials in Gastroenteropancreatic Neuroendocrine TumoursWalter T. · Krzyzanowska M.K.
aDepartment of Medical Oncology and Hematology, Princess Margaret Hospital, and bDepartment of Medicine, University of Toronto, Toronto, Ont., Canada; cHospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, Lyon, France
Background: The heterogeneity of neuroendocrine tumours (NETs) makes interpretation of clinical trials in this disease challenging. Our aim was to review the quality of treatment trials in NETs in order to inform the design and reporting of future studies. Methods: We identified studies by searching MEDLINE. We considered all phase II and III trials of systemic antineoplastic treatments published between 2000 and 2011. Information on trial design, study population, end points, statistical considerations and results was abstracted from each article using a standardized form. Results: Seven phase III and 39 phase II trials were identified. The make-up of the study population was variable: only 24% of trials included patients with one type of tumour (pancreatic NET or carcinoid tumour), 41% included patients with both tumour types, and 35% of trials included other endocrine cancers. Disease progression at baseline was often not reported and was documented for all patients in 22% of the trials. The functional status of the tumour, tumour differentiation, and Ki67 index were reported in 35, 43, and 15% of trials, respectively. The primary end point was clearly defined in 72% of trials. Identifiable statistical design, and predefined sample size were reported in 74 and 61% of trials, respectively. Conflicts of interest and study sponsorship were reported in 46 and 85% of trials. Conclusions: The quality of the design and reporting of phase II/III NET trials, as described in other cancers, is poor. Future trials should include more homogenous patient populations while adhering to rigorous selection, reporting and interpretation of population and trial parameters.
List of the 46 identified trials
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2 Ansell SM, Mahoney MR, Green EM, Rubin J: Topotecan in patients with advanced neuroendocrine tumors: a phase II study with significant hematologic toxicity. Am J Clin Oncol 2004;27:232–235.
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6 Brixi-Benmansour H, Jouve JL, Mitry E, Bonnetain F, Landi B, Hentic O, et al: Phase II study of first-line FOLFIRI for progressive metastatic well-differentiated pancreatic endocrine carcinoma. Dig Liver Dis 2011;43:912–916.
7 Brizzi MP, Berruti A, Ferrero A, Milanesi E, Volante M, Castiglione F, et al: Continuous 5-fluorouracil infusion plus long acting octreotide in advanced well-differentiated neuroendocrine carcinomas. A phase II trial of the Piemonte Oncology Network. BMC Cancer 2009;9:388.
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9 Chan JA, Zhu AX, Stuart K, Bhargava P, Earle CC, Clark JW, et al: Phase II study of pemetrexed in patients with advanced neuroendocrine tumors. Cancer Chemother Pharmacol 2010;66:961–968.
10 Cwikla JB, Sankowski A, Seklecka N, Buscombe JR, Nasierowska-Guttmejer A, Jeziorski KG, et al: Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): a phase II study. Ann Oncol 2010;21:787–794.
11 Dahan L, Bonnetain F, Rougier P, Raoul JL, Gamelin E, Etienne PL, et al: Phase III trial of chemotherapy using 5-fluorouracil and streptozotocin compared with interferon-α for advanced carcinoid tumors: FNCLCC-FFCD 9710. Endocr Relat Cancer 2009;16:1351–1361.
12 Ducreux M, Ruszniewski P, Chayvialle JA, Blumberg J, Cloarec D, Michel H, et al: The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors. Am J Gastroenterol 2000;95:3276–3281.
13 Ducreux M, Boige V, Leboulleux S, Malka D, Kergoat P, Dromain C, et al: A phase II study of irinotecan with 5-flurouracil and leucovorin in patients with pretreated gastroenteropancreatic well-differentiated endocrine carcinomas. Oncology 2006;70:134–140.
14 Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G, et al: A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 2006;95:1148–1154.
15 Faiss S, Pape UF, Bohmig M, Dorffel Y, Mansmann U, Golder W, et al: Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon-α, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors – the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 2003;21:2689–2696.
16 Gross DJ, Munter G, Bitan M, Siegal T, Gabizon A, Weitzen R, et al: The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer 2006;13:535–540.
17 Hainsworth JD, Spigel DR, Litchy S, Greco FA: Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research Network Study. J Clin Oncol 2006;24:3548–3554.
18 Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, et al: Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA] -TOC in metastasized neuroendocrine cancers. J Clin Oncol 2011;29:2416–2423.
19 Kolby L, Persson G, Franzen S, Ahren B: Randomized clinical trial of the effect of interferon-α on survival in patients with disseminated midgut carcinoid tumours. Br J Surg 2003;90:687–693.
20 Krzyzanowska MK, Tsao MS, Oza AM, Haider M, Feld R, Knox J, et al: Capecitabine plus rofecoxib show no activity in patients with metastatic neuroendocrine tumours. Clin Oncol (R Coll Radiol) 2006;18:88–89.
21 Kulke MH, Bergsland EK, Ryan DP, Enzinger PC, Lynch TJ, Zhu AX, et al: Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol 2006;24:3555–3561.
22 Kulke MH, Chan JA, Meyerhardt JA, Zhu AX, Abrams TA, Blaszkowsky LS, et al: A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors. Cancer Chemother Pharmacol 2011;68:293–300.
23 Kulke MH, Kim H, Clark JW, Enzinger PC, Lynch TJ, Morgan JA, et al: A phase II trial of gemcitabine for metastatic neuroendocrine tumors. Cancer 2004;101:934–939.
24 Kulke MH, Kim H, Stuart K, Clark JW, Ryan DP, Vincitore M, et al: A phase II study of docetaxel in patients with metastatic carcinoid tumors. Cancer Invest 2004;22:353–359.
25 Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, et al: Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26:3403–3410.
26 Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, et al: Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 2006;24:401–406.
27 Kulke MH, Wu B, Ryan DP, Enzinger PC, Zhu AX, Clark JW, et al: A phase II trial of irinotecan and cisplatin in patients with metastatic neuroendocrine tumors. Dig Dis Sci 2006;51:1033–1038.
28 Lubner SJ, Kunnimalaiyaan M, Holen KD, Ning L, Ndiaye M, Loconte NK, et al: A preclinical and clinical study of lithium in low-grade neuroendocrine tumors. Oncologist 2011;16:452–457.
29 Medley L, Morel AN, Farrugia D, Reed N, Hayward N, Davies JM, et al: Phase II study of single agent capecitabine in the treatment of metastatic non-pancreatic neuroendocrine tumours. Br J Cancer 2011;104:1067–1070.
30 Mohammed TA, Holen KD, Jaskula-Sztul R, Mulkerin D, Lubner SJ, Schelman WR, et al: A pilot phase II study of valproic acid for treatment of low-grade neuroendocrine carcinoma. Oncologist 2011;16:835–843.
31 Pavel ME, Hainsworth JD, Baudin E, Peeters M, Horsch D, Winkler RE, et al: Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomized study, placebo-controlled, phase 3 study. Lancet 2011;378:2005–2012.
32 Ramanathan RK, Cnaan A, Hahn RG, Carbone PP, Haller DG: Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Ann Oncol 2001;12:1139–1143.
33 Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al: Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501–513.
34 Ricci S, Antonuzzo A, Galli L, Ferdeghini M, Bodei L, Orlandini C, et al: Octreotide acetate long-acting release in patients with metastatic neuroendocrine tumors pretreated with lanreotide. Ann Oncol 2000;11:1127–1130.
35 Ricci S, Antonuzzo A, Galli L, Orlandini C, Ferdeghini M, Boni G, et al: Long-acting depot lanreotide in the treatment of patients with advanced neuroendocrine tumors. Am J Clin Oncol 2000;23:412–415.
36 Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al: Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009;27:4656–4663.
37 Shah MH, Young D, Kindler HL, Webb I, Kleiber B, Wright J, et al: Phase II study of the proteasome inhibitor bortezomib (PS-341) in patients with metastatic neuroendocrine tumors. Clin Cancer Res 2004;10:6111–6118.
38 Stuart K, Levy DE, Anderson T, Axiotis CA, Dutcher JP, Eisenberg A, et al: Phase II study of interferon-γ in malignant carcinoid tumors (E9292): a trial of the Eastern Cooperative Oncology Group. Invest New Drugs 2004;22:75–81.
39 Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG: 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 2005;23:4897–4904.
40 Varker KA, Campbell J, Shah MH: Phase II study of thalidomide in patients with metastatic carcinoid and islet cell tumors. Cancer Chemother Pharmacol 2008;61:661–668.
41 Waldherr C, Pless M, Maecke HR, Haldemann A, Mueller-Brand J: The clinical value of [90Y-DOTA] -d-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol 2001;12:941–945.
42 Yao JC, Zhang JX, Rashid A, Yeung SC, Szklaruk J, Hess K, et al: Clinical and in vitro studies of imatinib in advanced carcinoid tumors. Clin Cancer Res 2007;13:234–240.
43 Yao JC, Phan A, Hoff PM, Chen HX, Charnsangavej C, Yeung SC, 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-α2b. J Clin Oncol 2008;26:1316–1323.
44 Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, et al: Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008;26:4311–4318.
45 Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, et al: Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010;28:69–76.
46 Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al: Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011;364:514–523.
Monika K. Krzyzanowska
Department of Medical Oncology and Hematology
Princess Margaret Hospital, 610 University Ave, Suite 5-206
Toronto, ON M5G 2M9 (Canada)
Tel. +1 416 946 6542, E-Mail email@example.com
Received: November 2, 2011
Accepted after revision: February 28, 2012
Published online: August 28, 2012
Number of Print Pages : 11
Number of Figures : 1, Number of Tables : 5, Number of References : 29
Neuroendocrinology (International Journal for Basic and Clinical Studies on Neuroendocrine Relationships)
Vol. 96, No. 3, Year 2012 (Cover Date: November 2012)
Journal Editor: Millar R.P. (Edinburgh)
ISSN: 0028-3835 (Print), eISSN: 1423-0194 (Online)
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