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Phase III Trial of Chemotherapy Using 5-Fluorouracil and Streptozotocin

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Phase III Trial of Chemotherapy Using 5-Fluorouracil and Streptozotocin Endocrine-Related Cancer (2009) 16 1351–1361 Phase III trial of chemotherapy using 5-fluorouracil and streptozotocin compared with interferon a for advanced carcinoid tumors: FNCLCC–FFCD 9710 Laetitia Dahan1*, Frank Bonnetain2*, Philippe Rougier 3, Jean-Luc Raoul 4, Eric Gamelin5, Pierre-Luc Etienne6, Guillaume Cadiot 7, Emmanuel Mitry4, Denis Smith8, Fre´de´rique Cvitkovic9, Bruno Coudert 10, Floriane Ricard1, Laurent Bedenne1, Jean-Franc¸ois Seitz1 for the Fe´de´ration Francophone de Cance´rologie Digestive (FFCD) and the Digestive Tumors Group of the Fe´de´ration Nationale des Centres de Lutte Contre le Cancer (FNCLCC) 1Assistance Publique, Hoˆpitaux de Marseille, Hoˆpital Timone, Universite´ de la Me´diterrane´e, CHU Timone, 264 rue Saint Pierre, 13385 Marseille Cedex 5, France 2FFCD, Dijon, France 3AP-HP, Hoˆpital Ambroise Pare´, Boulogne, France 4Centre Euge`ne Marquis, Rennes, France 5Centre Paul Papin, Angers, France 6Clinique Armoricaine, Saint Brieuc, France 7Hopital Robert Debre´, Reims, France 8CHU Haut Leveque, Pessac, France 9Centre Rene´ Huguenin, Saint Cloud, France 10Centre Franc¸ois Leclerc, Dijon, France (Correspondence should be addressed to L Dahan; Email: [email protected]) *(L Dahan and F Bonnetain contributed equally to this work) Abstract The aim of this randomized multicenter phase III trial was to compare chemotherapy and interferon (IFN) in patients with metastatic carcinoid tumors. Patients with documented progressive, unresectable, metastatic carcinoid tumors were randomized between 5-fluorouracil plus streptozotocin (day 1–5) and recombinant IFN-a-2a (3 MU!3 per week). Primary endpoint was progression-free survival (PFS). From February 1998 to June 2004, 64 patients were included. The two arms were well matched for median age, sex ratio, PS 0–1, previous chemotherapy, surgery, or radiotherapy. The median PFS for chemotherapy was 5.5 months versus 14.1 for IFN (hazard ratioZ0.75 (0.41–1.36)). Overall survival (OS), tolerance, and effects on carcinoid symptoms were not significantly different. Despite a trend in favor of IFN, there was no difference in PFS and OS in advanced metastatic carcinoid tumors and therapeutic effect of both treatments was mild. Endocrine-Related Cancer (2009) 16 1351–1361 Introduction resection of the primary tumor and metastases is the Metastatic midgut endocrine carcinomas (formerly best treatment for metastatic disease (Nave et al. 2001). called ‘carcinoid tumor’) are an uncommon neoplasm, Transarterial hepatic chemoembolization is used only accounting for 1% of digestive cancers. It is often for nonresectable liver metastases. However, for diagnosed late when it has become metastatic (Lepage most patients, only a palliative systemic treatment is et al.2004). Surgery including, when possible, appropriate. Somatostatin analogs are useful to control Endocrine-Related Cancer (2009) 16 1351–1361 Downloaded from Bioscientifica.comDOI: 10.1677/ERC-09-0104 at 10/02/2021 02:14:14PM 1351–0088/09/016–001351 q 2009 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.orgvia free access L Dahan, F Bonnetain et al.: Chemotherapy in advanced carcinoid tumors hormonal symptoms and have a potential effect on immunochemistry; documented tumor progression tumor growth. Many chemotherapeutic agents have according to WHO criteria as judged by computed been evaluated but their effect on survival is unclear. tomography (CT), and/or biochemical progression Only four randomized studies have been conducted, according to levels of urinary 5-hydroxyindoleacetic and these showed that the best combination acid (5-HIAA; increase in levels of 5-HIAA of more (5-fluorouracil (5-FU)–streptozotocin (STZ)) gener- than 25%) documented during the 12 months before the ated response rates from 16 to 33% (Moertel & Hanley enrollment; prior chemotherapy O6 weeks; WHO PS of 1979, Engstrom et al. 1984, Haller et al. 1990, Sun 0–2; age O18 years and %75 years; white blood cells et al. 2005). Biological therapy using human leukocyte (WBC) O4000/mm3, neutrophils R2000/mm3, and interferon (IFN) was investigated in the 1980s by hemoglobin R10 g/dl; platelets R100 000/mm3, Oberg et al. (1983).IFN-a primary stabilizes serum bilirubin %twice the upper limit of normal symptoms in functional tumor disease and, in some (ULN), aspartate aminotransferase (AST) %4 times patients, an antiproliferative effect has been reported. ULN, alkaline phosphatase %4 times ULN, and serum The antitumoral effect is attributed to the inhibition of creatinine !130 mmol/l; proteinuria !0.5 g/24 h, gly- angiogenesis, induction of apoptosis, and interruption cemia %1.25 times ULN, and life expectancy of the cell cycle (Oberg 2000). IFN-a and somatostatin R12 weeks. analogs are the main antisecretory drugs used in the Exclusion criteria were: prior immunotherapy by treatment of these tumors. In a large study of patients IFN or other cytokines; prior chemotherapy !6 weeks with malignant carcinoid tumors and hepatic metas- before enrollment; prior radiotherapy to the primary tases receiving IFN-a, a biochemical response was area of measurable disease; myocardial infarction; obtained in 42%, and stabilization of tumor growth was history of major psychiatric disease; history of reported in 39% (Oberg & Eriksson 1991). A recent epilepsy, brain metastases, and pregnancy. phase II study has suggested that IFN-g was well Written informed consent was obtained from all tolerated, but had no significant antiproliferative patients. The protocol was approved by the Regional effects (Stuart et al. 2004). In contrast, a randomized Ethics Committee (Marseille). trial showed that the addition of IFN-a to octreotide may delay tumor growth in patients with midgut carcinoid tumors compared with octreotide alone Design of the study and randomization (Kolby et al. 2003). Only one trial compared the Clinical and biochemical work up 5-FU–STZ combination with recombinant IFN-a; it showed tumor response rates as high as 50% in the Pre-treatment evaluation included a full medical immunotherapy group. However, this was a limited history, physical examination, hematologic, and series that included only 20 patients and no tumor biochemical analysis. Radiological (CT) evaluation response in the chemotherapy arm was observed of the tumor and 24 h collection of urine for 5-HIAA (Oberg et al. 1989). were also performed. Therefore, because of the potential therapeutic After confirming the eligibility criteria, all registered effects of IFN in this disease, a randomized multicenter patients were randomized 1:1 through a minimization phase III trial was conducted by the Fe´de´ration program at the FFCD center (Dijon, France) by fax or Nationale des Centres de Lutte Contre le Cancer phone: in arm A, 5-FU plus STZ, or in arm B recombinant (FNCLCC) and Fe´de´ration Francophone de Cancer- IFN-a-2a (IFN; ROFERON supplied by Roche). ologie Digestive (FFCD) among patients with a Patients were stratified by WHO PS (0, 1, or 2), prior progressive metastatic endocrine tumor to compare chemotherapy and/or immunotherapy (yes or no), and IFN-a to a combination of STZ and 5-FU. participating institutions. Treatment plan Patients and methods In arm A, chemotherapy was administered i.v. using a central catheter. Every 6-week cycle consisted of five Patient selection administrations of 5-FU (400 mg/m2 per day) by 2 h Eligibility criteria were: histologically or cytologically i.v. infusion (day 1–5), in combination with five confirmed unresectable malignant carcinoid tumor, administrations of STZ (500 mg/m2 per day) by 2 h i.e. well-differentiated endocrine carcinoma on i.v. infusion (day 1–5). In arm B, IFN-a (ROFERON) hematoxylin–eosin staining, with positive Grimelius was administered continuously at doses of 3!106 staining and with chromogranine A expression by three times a week by s.c. injection (6-week cycle). Downloaded from Bioscientifica.com at 10/02/2021 02:14:14PM via free access 1352 www.endocrinology-journals.org Endocrine-Related Cancer (2009) 16 1351–1361 In each arm, treatment was planned for at least 12 metastases. The biochemical response was defined as weeks (two cycles) and for a maximum of eight cycles. more than a 50% reduction in the initial 5-HIAA After eight cycles, patients experiencing stabilization level (mean value in two urine samples collected in a of the disease or an objective response pursued the 24 h period) lasting for 1 month. Biochemical allocated therapy. Treatment was stopped in case of progression was defined as more than a 25% increase disease progression (tumoral or biochemical), limiting in 5-HIAA level. toxicities, or patient request. Then further treatments All toxicities were graded according to WHO were chosen by the referent clinician including the criteria every 6 weeks. Serious adverse events were possibility of cross over. Surgical or radiotherapy also recorded within 24 h. treatments were allowed after an objective response After ending the treatment, follow up information and evaluation of the toxicity. was available for all patients every 12 weeks until Concomitant treatments with somatostatin analogs progression or death. were allowed in patients suffering from significant carcinoid symptoms. In arm A, corticoids and setron Statistical methods were advised to prevent nausea. In arm B, paracetamol This phase III study was designed to evaluate 1-year was advised to treat flu-like syndrome if necessary. progression-free survival (PFS) as the primary end- point. It was planned to include 120 patients, to Dose adjustment observe 38 progressions or deaths, in order to detect an At the first occurrence of grade 3 or 4 toxicity, expected improvement in 1-year PFS from 55% treatment was interrupted until recovery to grade 2 (Engstrom et al. 1984) to 80% (bilateral aZ5% and toxicity or less. Then treatment was pursued with a bZ20%) in the IFN arm. The trial was closed early, 50% reduction in the original dose. A second after enrollment of 64 patients, due to insufficient occurrence of any grade 3 or 4 toxicity led to a further recruitment.
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