A phase II study for metabolic in vivo response monitoring with sequential 18FDG-PET-CT during treatment with the EGFR-monoclonal-antibody cetuximab in metastatic colorectal cancer: the Heidelberg REMOTUX trial

BMC Cancer

Dirk Jäger⁴  Florian Lordick⁵  Uwe Haberkorn⁷  Georg Martin Haag⁴  Annika Stange⁴  Tim Frederik Weber²  Jennifer Ose⁴  Matthias Kloor³  Stefan Delorme⁶  Ulrich Abel¹  Carl von Gall⁸  Anne Katrin Berger⁴ 

[1]Institute of Medical Biometry and Informatics, University Medical Center of Heidelberg, Heidelberg, Germany

[2]Department of Diagnostic and Interventional Radiology, University Medical Center Heidelberg, Heidelberg, Germany

[3]Department of Applied Tumor Biology, University Medical Center Heidelberg, Heidelberg, Germany

[4]National Center for Tumor Diseases (NCT), University Medical Center Heidelberg, Heidelberg, Germany

[5]Department of Oncology and Hematology, Hospital of Braunschweig, Braunschweig, Germany

[6]Department of Radiology, German Cancer Research Center, Heidelberg, Germany

[7]Department of Nuclear Medicine, University Medical Center Heidelberg, Heidelberg, Germany

[8]Department of Nuclear Medicine, University Hospital Erlangen, Erlangen, Germany

关键词: ¹⁸F-FDG PET CT;    Metabolic imaging;    Cetuximab;    Metastases;    Colorectal cancer;   

Others  :  1080499
DOI  :  10.1186/1471-2407-12-108

 received in 2012-01-23, accepted in 2012-03-22,  发布年份 2012

【 摘 要 】

Background

The epidermal growth factor receptor monoclonal antibody cetuximab has proven activity in metastatic colorectal cancer. To date, the mechanisms of action are not completely understood. Especially the impact on tumor glucose metabolism, or tumor vascularization remains largely unclear. The understanding of mechanisms such as early changes in tumor metabolism is of clinical importance since there may be a substantial influence on choice and sequence of drug combinations. Early signals of response to cetuximab may prove useful to identify patients having a relevant clinical treatment benefit. The objective of this trial is to evaluate the predictive relevance of the relative change in ¹⁸ F-Fluorodeoxyglucose tumor uptake for early clinical response during short-term single agent treatment with cetuximab. Early clinical response will be routinely measured according to the response evaluation criteria in solid tumors. Accompanying research includes cytokine immune monitoring and analysis of tumor proteins and tumor genes.

Methods/design

The REMOTUX trial is an investigator-initiated, prospective, open-label, single-arm, single-center early exploratory predictive study. The first ¹⁸ F-FDG PET-CT is conducted at baseline followed by the run-in phase with cetuximab at days 1 and 8. At day 14, the second ¹⁸ F-FDG PET-CT is performed. Subsequently, patients are treated according to the Folfiri-cetuximab regimen as an active and approved first-line regimen for metastatic colorectal carcinoma. At day 56, clinical response is evaluated with a CT-scan compared to the baseline analysis. Tracer uptake is assessed using standardized uptake values (SUVs). The main hypothesis to be tested in the primary analysis is whether or not the relative change in the SUV from baseline to day 14 has any predictive relevance for early clinical response determined at day 56. Patients are followed until death from any cause or until 24 months after the last patient has ended trial treatment.

Discussion

The aim of this trial is to evaluate metabolic changes in metastatic colorectal cancer during short-term single agent treatment with cetuximab and to analyse their potential of predicting early clinical response. This could be helpful to answer the question if early identification of patients not responding to cetuximab is possible.

Trial registration

ClinicalTrials.gov NCT200811021020; EudraCT 200901327923

【 授权许可】

   
2012 Berger et al; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global Cancer statistics. CA Cancer J Clin 2011, 61:69-90.
• [2]Sanoff HK, Sargent DJ, Campbell ME, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Goldberg RM: Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol 2008, 26:5721-5727.
• [3]Van Cutsem EM, Nowacki I, Lang S, Cascinu I, Shchepotin J, Maurel P, Rougier D, Cunningham J, Nippgen C: Köhn KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol 2007. ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement)
• [4]Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ: Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007, 357:2040-2204.
• [5]Linardou H, Dahabreh IJ, Kanaloupiti D, Siannis F, Bafaloukos D, Kosmidis P, Papadimitriou CA, Murray S: Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008, 9:962-972.
• [6]Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008, 359:1757-1765.
• [7]Folprecht G, Grothey A, Alberts S, Raab HR, Köhne CH: Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005, 16:1311-1319.
• [8]Lordick F, Ruers T, Aust DE, Collette L, Downey RJ, El Hajjam M, Flamen P, Haustermans K, Ilson D, Julié C, Krause BJ, Newiger H, Ott K, Roth A, Van Cutsem E, Weber WA, Lutz MP: European Organisation of Research and Treatment of Cancer (EORTC) Gastrointestinal Group: Workshop on the role of metabolic imaging in the neoadjuvant treatment of gastrointestinal cancer. Eur J Cancer 2008, 44:1807-1819.
• [9]Lordick F, Ott K, Krause BJ, Weber WA, Becker K, Stein HJ, Lorenzen S, Schuster T, Wieder H, Herrmann K, Bredenkamp R, Höfler H, Fink U, Peschel C, Schwaiger M, Siewert JR: PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol 2007, 8:797-805.
• [10]Lorenzen S, von Gall C, Stange A, Haag GM, Weitz J, Haberkorn U, Lordick F, Weichert W, Abel U, Debus J, Jäger D, Münter MW: Sequential FDG-PET and induction chemotherapy in locally advanced adenocarcinoma of the Oesophago-gastric junction (AEG): the Heidelberg Imaging program in Cancer of the oesophago-gastric junction during Neoadjuvant treatment: HICON trial. BMC Cancer 2011, 11:266. BioMed Central Full Text
• [11]Weber WA, Figlin RE: Monitoring cancer treatment with PET/CT: does it make a difference? J Nucl Med 2007, 48(Suppl 1):36S-44S.
• [12]Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45:228-247.
• [13]Noether GE: Sample size determination for some common nonparametric statistics. JASA 1987, 82:645-647.
• [14]Zhou XH: Statistical methods in diagnostic medicine. New York: Wiley Interscience; 2002:157ff.
• [15]Meropol NJ, Schrag D, Smith TJ, Mulvey TM, Langdon RM Jr, Blum D, Ubel PA, Schnipper LE, American Society of Clinical Oncology: American Society of Clinical Oncology guidance statement: the cost of cancer care. J Clin Oncol 2009, 27:3868-3874.
• [16]Di Fabio F, Pinto C, Rojas Llimpe FL, Fanti S, Castellucci P, Longobardi C, Mutri V, Funaioli C, Sperandi F, Giaquinta S, Martoni A: The predictive value of 18F-FDG-PET early evaluation in patients with metastatic gastric adenocarcinoma treated with chemotherapy plus cetuximab. Gastric Cancer 2007, 10:221-227.