N. J. Meropol, S. J. Cohen, N. Iannotti, B. H. Saidman, K. D. Sabbath, M. C. Miller, G. V. Doyle, H. Tissing, L. W.M.M. Terstappen, C.J.A. Punt Fox Chase Cancer Center, Philadelphia, PA; Hematology Oncology Associates, Port St. Lucie, FL; Medical Oncology Associates, Kingston, PA; Medical Oncology and Hematology, PC, Waterbury, CT; Immunicon Corporation, Huntingdon Valley, PA; Radboud University Medical Center, Nijmegen, The Netherlands Circulating tumor cells (CTC) predict progression free (PFS) and overall survival (OS) in patients with metastatic colorectal cancer
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N. J. Meropol, S. J. Cohen, N. Iannotti, B. H. Saidman, K. D. Sabbath, M. C. Miller, G. V. Doyle, H. Tissing, L. W.M.M. Terstappen, C.J.A. Punt Fox Chase.
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N. J. Meropol, S. J. Cohen, N. Iannotti, B. H. Saidman, K. D. Sabbath, M. C. Miller, G. V. Doyle, H. Tissing, L. W.M.M. Terstappen, C.J.A. Punt
Fox Chase Cancer Center, Philadelphia, PA; Hematology Oncology Associates, Port St. Lucie, FL; Medical Oncology Associates, Kingston, PA;
Medical Oncology and Hematology, PC, Waterbury, CT; Immunicon Corporation, Huntingdon Valley, PA; Radboud University Medical Center,
Nijmegen, The Netherlands
Circulating tumor cells (CTC) predict progression free (PFS) and overall survival (OS) in patients
with metastatic colorectal cancer
Background
• There are approximately 1,000,000 new cases of colorectal cancer and 500,000 deaths worldwide each year
• Multiple therapeutic options render the management of patients with metastatic disease complicated and nuanced
• A noninvasive prognostic and predictive marker could guide therapeutic decisions
• Circulating tumor cells can be isolated from the blood of patients with metastatic colorectal cancer (SJ Cohen et al, Clin Colorectal Cancer 2006)
Hypothesis: Circulating tumor cells can be used to guide therapy
• Baseline– prognostic
• During treatment– early indication of treatment effect– complementary to radiographic imaging– prognostic– Non-invasive source of tumor for in vivo
pharmacodynamic monitoring
Objectives
Primary Objective
To measure agreement between circulating tumor cell number and objective antitumor response defined by imaging
Secondary Objective
To determine the association between circulating tumor cell number and progression-free and overall survival
Eligibility
• Adults with measurable metastatic colorectal cancer
• Initiating first-, second-, or third-line therapy (if EGFR inhibitor)
• ECOG performance status 0-2
• Hemoglobin >8 g/dL
• Written informed consent
Methods
• Multicenter international study• Radiographic tumor measurement at baseline
and every 6-12 weeks after treatment initiation (RECIST criteria)
• Peripheral blood was collected for CTC enumeration at baseline and subsequently at 1-2, 3-5, 6-12, and 13-20 weeks after treatment initiation
• Blood mailed overnight at room temperature, and processed at 1 of 4 laboratories within 96 hours
CTC Sample Preparation (1)
Magnetic Incubations
-
7.5 ml Blood + 6.5mL Buffer
PlasmaAspiration & Addition of
EPCAM Ferrofluid
Station 1 Stations2 & 3
Primary Magnetic
Separation & Resuspension
Station 4
-
Addition of Cytokeratin-PECD45-APC, &
DAPI
Station 5
Centrifuge
Place on Instrument
Described in: WJ Allard et al, Clin Cancer Res 10: 6897-6904, 2004
CTC Sample Preparation (2)
Stations 6,7, & 8 Station 9b
Staining Incubation, Magnetic Wash &
Free Particle Removal
Final Resuspension
Station 9a Image Gallery
Automatic Transfer of Sample for Fluorescent
Image Analysis
Training and Validation Sets
• Preplanned analysis after 100 patients to select cutoff for “favorable” vs. “unfavorable” CTC at 3-5 weeks
• Criteria for selection of cutoff:– CTC threshold must be above normal
background– Percent accuracy for agreement of CTC with
imaging and median PFS and OS must reach a plateau
– Frequency of CTC unfavorable patients must be at least 10%
• Based upon these criteria, > 3 CTC per 7.5 ml of blood was defined as “unfavorable”
Statistical Considerations for Primary Endpoint
• >99% power
• one-sided type I error () = 0.025
• Ho of <60% overall agreement between CTC (“favorable” vs. “unfavorable”) and radiographic response
• Ha of >75% agreement
• N = 400
Patient CharacteristicsTraining
Set (N=109)Validation
Set (N=321)p All Patients
(N=430)
Median Age (Range) 65 (25-86) 63 (22-92) 0.29 64 (22-92)
• In patients with metastatic colorectal cancer, CTC number before and after initiation of treatment is a significant independent predictor of progression free survival and overall survival
• Elevated CTC number at 3-5 weeks has high specificity but low sensitivity for early disease progression
• CTC enumeration is complementary to imaging, and may provide early evidence of treatment success or failure
• Further research is required to determine whether change in therapy based upon elevated CTC number at early followup will improve patient outcomes
Participating Clinical Investigators
N. Iannotti, Hematology Oncology Associates of the Treasure Coast, Port Saint Lucie, FL; B.H. Saidman, Medical Oncology Associates, Kingston, PA; T.M. Fynan, Medical Oncology and Hematology, P.C., New Haven, CT; J. Picus, Washington University School of Medicine, St. Louis, MO; N. Gabrail, Canton, OH; M. Morse, Duke University Medical Center, Durham, NC; S.J. Cohen and N.J. Meropol, Fox Chase Cancer Center, Philadelphia, PA; M. Schwartz, Richmond VA; E. Mitchell, Thomas Jefferson University, Philadelphia, PA; F. Swan, Cancer Outreach Associates, Abingdon, VA; H.S. Jhangiani, Compassionate Cancer Care Medical Group, Inc, Corona, CA; K. Patel, Little Rock Hematology Oncology Associates, Little Rock, AR; R. Pelley, Cleveland Clinic Foundation, Cleveland, OH; C. Farber, Hematology-Oncology Associates of Northern New Jersey, Morristown, NJ; R.L. Robles, Bay Area Cancer Research Group, Concord, CA; V. Jones, Yakima Valley Memorial Hospital/North Star Lodge Cancer Center, Yakima, WA; H. Ghazal, Kentucky Cancer Center, Hazard, KY; P. Ross, St. Thomas Hospital, London, UK; G.A. Fisher, Stanford University Medical Center, Stanford, CA; R. Rangineni, St. Joseph Oncology, Inc, St. Joseph, MO; L. Bertoli, Clinical Research Consultations; Birmingham, AL; R.O. Giudice, New Mexico Oncology Hematology Consultants, Ltd., Alruquerque, NM; A. Khojasteh, Columbia Comprehensive Cancer Care Clinic, Jefferson City, MO; M.V. Pillai, Virginia Oncology Care, P.C., Richlands, VA; A. Pippas, John B. Amos Cancer Center, Columbus, GA; S. Berk, Hematology Oncology Associates of South Jersey, P.A., Mount Holly, NJ; A. Rakkar, Palo Verde Hematology Oncology, Inc, Glendale, AZ; M.B. Wax, Summit Medical Group/Overlook Oncology Center, Summit, NJ; K. Nahum, Oncology Physicians Network, Howell, NJ; A. Gonzalez, Cancer Specialists of South Texas, P.A., Corpus Christi, TX; R.K. Gamble, Cancer Care Specialists, Houma, LA; J.W. Jakub, Lakeland Regional Cancer Center, Lakeland, FL; R.J. Jacobson, Palm Beach Cancer Institute, Palm Beach, FL; J. Fleagle, Rocky Mountain Cancer Center – Thornton, Thornton, CO; G. E. Newman, Knoxville, TN; M. Woodson, Hematology Oncology Consultants, Inc., St. Louis, MO; P. Cobb, Hematology/Oncology Centers of the Northern Rockies, Billings, MT; D. Mukhopadhyay and R. Prabhu, Redrock Medical Group, Las Vegas, NV; A.M. Wierman, Nevada Cancer Center, Las Vegas, NV; W. Ho, St. Joseph Hospital, Orange, CA; A. Cohn, Rocky Mountain Cancer Center – Lone Tree, Lone Tree, CO.
Dutch Colorectal Cancer Group (DCCG):C.J.A. Punt, Radboud University Medical Center, Nijmegen; G.J. Creemers, Catharina Ziekenhuis, Eindhoven; P. Deprest, F.A. Valster and T.J. Roding, Ziekenhuis de Lievensberg, Bergen op Zoom; M.B. Polee, Medisch Centrum Leeuwarden, Leeuwarden; A.J. ten Tije, Ziekenhuis Gooi-Noord, Blaricum; D.J. Richel, University of Amsterdam, Amsterdam; M. Legdeur, Medisch Spectrum Twente, Enschede, J.J.M. van her Hoeven, Amstelveen, A. Honkoop, Isala Klinieken, Zwolle; Z. Erjavec, Delfzicht Ziekenhuis, Delfzijl; R.S. de Jong, Martini Ziekenhuis, Groningen, P. Slee, St. Antonius Ziekenhuis, Nieuwegein; J. Douma, Ziekenhuis Rijnstate, Arnhem; J. Sleeboom, Ziekenhuis Leyenburg, Den Haag.