Borbath, Ivan

Ceratti, Antonio

Delaunois, Thierry

Deleporte, Amélie

Demols, Anne

Laurent, Stéphanie

Van Cutsem, Eric

Van Laethem, Jean-Luc

Vergauwe, Philippe

Verslype, Chris

English

Ghent University Academic Bibliography

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma : a phase II studyIvan Borbath1*, Antonino Ceratti1*, Chris Verslype2, Anne Demols3, Thierry Delaunoit4, Stéphanie Laurent5, Amélie Deleporte6, Philippe Vergauwe7, Eric Van Cutsem2, Jean-Luc Van Laethem31Cliniques universitaires Saint-Luc Bruxelles, 2University Hospital Leuven, 3Hopital Erasme Bruxelles, 4Centre Hospitalier de Jolimont, 5University Hospital Gent, 6Institut Bordet Bruxelles, 7Groeninge Hopital, on behalf of the BGDO.* These authors contrubuted equally to this workBackground Results 8060100Probability of Progression Free Survival (%)Table 2 : Adverse events during treatment (N=44)Grades 1-2 (%)Grades 3-4 (%)Hematologic Neutropenia 13 (29.5) 12 (27.3)Thrombocytopenia 29 (65.9) 4 (9.1) Cholangiocarcinomas are uncommon tumors arising as a result ofneoplastic transformation of epithelial cells covering bile ducts (1). Although rare, cholangiocarcinoma remains the second most commonhepatobiliary cancer (approximately 9000 new cases per year in theUnited States) (2) and its incidence is increasing due to a betterknowledge of the disease and an improvement of diagnosis (3). Theonly curative treatment of cholangiocarcinoma is surgical resection withnegative resection margins. At the time of diagnosis, more than two-thirds of cholangiocarcinoma patients have unresectable disease (4).PATIENTS CHARACTERISTICS A total of 44 patients from nine Belgian institutions affiliated to theBelgian Group of Digestive Oncology (BGDO) were enrolled over 18months (September 2008 to January 2010). Patients' characteristicsare summarized in table 1.402000 3 6 9 12 15 18Probability of Progression Free Survival (%)Time to progression (months)------806040200100Probability of Progression Free Survival (%)Grade ≥ 2 Skin toxicityGrade ≤ 1 Skin toxicityFigure 1 : Kaplan-Meier curve for PFSTable 1 : Baseline characteristics of the patients (N=44)Anemia 33 (75.0) 5 (11.3)NonhematologicNausea 16 (36.4) 2 (4.5)Vomiting 14 (31.8) 1 (2.3)Diarrhea 13 (29.5) 0Anorexia 6 (13.6) 1 (2.3)Stomatitis 2 (4.5) 0Fatigue 25 (56.8) 5 (11.3)Liver dysfunction 1 (2.3) 2 (4.5)InfectionBiliary tract 0 6 (13.6)Other 2 (4.5) 1 (2.3)Furthermore, patients who undergo curative surgery experience a hightumor relapse rate (5). Recently, a randomized phase III trial has shown that the addition ofcisplatin to gemcitabine alone led to a significant improvement in overallsurvival (median 11.7 vs 8.1 months) and in progression-free survival(median 8.0 vs 5.0 months) (6). To improve anti-tumoral treatments, targeted therapies are alsoexplored. Epidermal growth factor-Receptor (EGFR or HER1) expression andactivation are particularly involved in tumor growth. It has beenRESPONSE ASSESSMENT AND PATIENT’S OUTCOME- - - -0 6 12 18Probability of Progression Free Survival (%)Time to progression (months)Figure 3 : Kaplan-Meier curve for PFS stratified by skin toxicity		Figure 2 : Kaplan-Meier curve for OSAge, yearsMedian (range) 61.5 (40-86)Gender – No. (%)Male 26 (59.1)Female 18 (40.9)ECOG performance status – No. (%)0 30 (68.2)1 14 (31.8)Site of primary disease – No. (%)Edema 3 (6.8) 0Allergic reaction 2 (4.5) 0Deep venous    thrombosis1 (2.3) 1 (2.3)Hemolytic uremic syndrome0 2 (4.5)Nephrotic syndrome 0 1 (2.3)Other 9 (20.5) 3 (6.8)Skin toxicity 31 (70.5) 6 (13.6)demonstrated that cholangiocarcinomas express mutated EGFR (7) butalso that EGFR can be overexpressed (8) (9). Cetuximab is achimerized IgG1 monoclonal antibody which blocks binding of EGF andTGF-α to the EGFR. Based on early results, we designed a phase II study combiningcetuximab and gemcitabine in front line treatment of advancedunresectable cholangiocarcinoma. Forty-three patients (98%) were assessable for response. Table 3summarizes the response assessment parameters. Forty-six percent of the patients were progression-free at 6 months.The median PFS time was 5.8 months (95%CI, 4.3 to 7.4 months).Figure 1 shows the Kaplan-Meier curve for PFS.The median OS time was 11.6 months (95% CI, 8.7 to 14.6 months)with 46.6% of patients alive one year after study entry. At the time ofanalysis, 24 patients (54.5%) are still alive. Figure 2 shows the Kaplan-Meier curve for OS.   		Summary and conclusions The toxicity profile of the combination of gemcitabine andIntrahepatic location 27 (61.4)Distal  location 5 (11.4)Perihilar location 12 (27.3)Extent of disease – No. (%)Locally advanced 18 (40.9)Metastatic 26 (59.1)Prior surgery – No. (%)Yes 19 (43.2)No 25 (56.8)Patients and methodsKEY ELIGIBILITY CRITERIA AND STUDY DESIGNGEMCITABINE AND CETUXIMAB ADMINISTRATIONS Patients received a total of 251 cycles of treatment (mean: 5.7cycles per patient, range: 1 to 14 cycles per patient). Fifty-sevenpercent of patients received between 2 and 6 cycles of studytreatment. At the cut-off date of analysis (31 July 2010), 7 patientswere still ongoing (mean duration of follow-up: 10.4± 3.1 months).Nine patients achieved partial response (20.9%) with a medianduration of 5 months (range: 2 to 10 months). At the time of thisanalysis, four of these nine patients were still ongoing on the trial.Among these responders, 5 patients experienced a grade 2 skin toxicityand 3 patients a grade 3 skin toxicity. Twenty-six patients (60.4%) achieved stable disease with a medianduration of 6 months (range: 6 to 12 months). The estimated overall response rate was 20.9% and disease controlrate was 81.4%.The median PFS time was 7.2 months (95%CI, 4.8 to 9.6 months) incetuximab is manageable; no unexpected adverse events wereobserved from adding cetuximab to gemcitabine. Progression-free survival rate at 6 months was 46%, which metour predefined hypothesis. Median PFS was better for subjectswith a skin toxicity above or equal to grade 2. Overall responserate was 20.9% and 1-year overall survival was 46.6%. This combination is promising and further investigations,probably combining the cisplatine – gemcitabine doublet withcetuximab, are warranted.•Histologically or cytologicallyconfirmed cholangiocarcinoma, excluding gallbladder cancer, thatwas surgically unresectable or CETUXIMABInitial dose of 400 mg/m² in a 120 min IV infusion ECOG = Eastern Cooperative Oncology GroupReferences The median duration of treatment was 19 weeks (range: 2 to 65weeks).TOXICITY All patients were assessable for toxicity. Table 2 summarizes alladverse reactions reported during the trial according to NCI-CTC(version 3.0). Most frequent grades 3-4 side effects were hematologicalabnormalities (47.7%), biliary tract infections (13.6%), skinpatients with a skin toxicity above or equal to grade 2 and 3.2 months(95%CI, 1.6 to 4.7 months) in patients with a skin toxicity below or equalto grade 1, p = 0.012. Figure 3 shows Kaplan-Meier curve for PFSstratified by skin toxicity. Additional study exploring relationship between K-Rasmutational status, EGFR mutations, skin rash as predictive factorfor response and clinical outcome would be interesting.metastatic•Measurable disease, according to RECIST•ECOG 0 or 1•No prior systemic treatment•Adequate hematological and biochemical parameters•Age ≥ 18 years oldFurther injections of 250 mg/m² in a 60 min IV infusionEvery 7 days+GEMCITABINE1000 mg/m² in a 30 min IV infusionD1, D8 and D15 every 4 weeksTreatment until disease progression, consent withdrawn, investigator’sTable 3 : Response assessmentN=43Partial response (PR)No. (%) 9 (20.9)OBJECTIVESThe primary endpoint of this trial was to evaluate progression-freesurvival (PFS) at 6 months; secondary endpoints were to assessresponse rate, safety and overall survival (OS). The statistical designtoxicity (13.6%) and fatigue (11.3%). Biliary tract infections wereconsidered to be related to study disease. There were no treatmentrelated deaths. Six patients (13.6%) discontinued study treatment because oftoxicity : two patients for prolonged grade 3 skin toxicity, one patientfor grade 4 skin toxicity, two patients for hemolytic-uremic syndromeand one patient for nephrotic syndrome. Fourteen patients had a gemcitabine dose reduction (with onepatient at two dose levels) and 25 patients a dose interruption(median : 1.1 week, range : 1 to 3 weeks) both mostly due to (1) Gores GJ. Cholangiocarcinoma: Current concepts and insights. Hepatology 2003; 37(5):961-969. (2) Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 2001; 33(6):1353-1357. (3) Shaib YH, Davila JA, McGlynn K, El Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? Journal of Hepatology 2004; 40(3):472-477. (4) Khan SA, Davidson BR, Goldin R, Pereira SP, Rosenberg WMC, Taylor-Robinson SD et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 2002; 51:1-9. (5) Jarnagin WR, Fong Y, Dematteo RP, Gonen M, Burke EC, Bodniewicz J et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Annals of Surgery 2001; 234(4):507-517. (6) Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A et al. Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. New England Journal of Medicine 2010; 362(14):1273-1281. (7) Leone F, Cavalloni G, Pignochino Y, Sarotto I, Ferraris R, Piacibello W et al. Somatic mutations of decision or unacceptable toxicityTumor assessements (CT or MRI) performed every 8 weeksDuration (months) : Median (range) 5.0 (2-10)Stable disease (SD)No. (%) 26 (60.4)Duration (months) : Median (range) 6 (2-12)Disease control rate (%) 81.4 Duration (months) : Median (range) 6 (2-12)Progression-free survival (PFS) Median, 95%CI (months) 5.8 [4.3 – 7.4]3-month PFS 76.7%6-month PFS 46.0%1-year PFS 19.8%Printed bywas a Simon 2-stage design, built to improve 6-month PFS from 20% to40%. After 3 patients within the first 13 met the criterion of 6-monthPFS, a total of 43 patients was needed in the study.hematological toxicities. Regarding cetuximab, 3 patients had a dosereduction (with one patient at two dose levels) and 9 patients a doseinterruption (median : 1.2 weeks, range : 1 to 3 weeks), both mostlydue to dermatological eventsepidermal growth factor receptor in bile duct and gallbladder carcinoma. Clinical Cancer Research 2006; 12(6):1680-1685. (8) Lee CS, Pirdas A. Epidermal growth factor receptor immunoreactivity in gallbladder and extrahepatic biliary tract tumours. Pathology Research and Practice 1995; 191(11):1087-1091. (9) Ogo Y, Nio Y, Yano S, Toga T, Koike M, Hashimoto K et al. Immunohistochemical expression of HER-1 and HER-2 in extrahepatic biliary carcinoma. Anticancer Research 2006; 26(1B):763-770.  N=44Overall survival (OS) Median, 95%CI (months) 11.6 [8.7 – 14.6]6-month OS 84.0%1-year OS 46.6%

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study

https://biblio.ugent.be/publication/2047787/file/2047824

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study

Abstract

Similar works

Full text

Available Versions

Ghent University Academic Bibliography