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Shukla-Dave 1,2 , N. Lee 3 , Y. Wang 1 , H. Stambuk 2 , S. Karimi 2 ,

Dynamic Contrast Enhanced (DCE)-MRI as a Predictor of Response in Head & Neck Squamous Cell Carcinoma (HNSCC) : Initial Analysis. Shukla-Dave 1,2 , N. Lee 3 , Y. Wang 1 , H. Stambuk 2 , S. Karimi 2 , J.P. Shah 4 , D.G. Pfister 5 , J.A. Koutcher 1,2,5

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Shukla-Dave 1,2 , N. Lee 3 , Y. Wang 1 , H. Stambuk 2 , S. Karimi 2 ,

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  1. Dynamic Contrast Enhanced (DCE)-MRI as a Predictor of Response in Head & Neck Squamous Cell Carcinoma (HNSCC) : Initial Analysis • Shukla-Dave1,2, N. Lee3, Y. Wang1, H. Stambuk2, S. Karimi2, • J.P. Shah4, D.G. Pfister5, J.A. Koutcher1,2,5 • Departments of Medical Physics1, Radiology2, Radiation Oncology3 , Surgery4, Medicine5 • Memorial Sloan-Kettering Cancer Center, New York, USA

  2. Introduction • Concomitant chemoradiation is a cornerstone of standard treatment for advanced HNSCC • However, a significant minority of patients will have local or regional failure despite this approach • There is a need for an a priori or early biomarker of response, particularly patients treated with organ preservation intent AIM: To assess whether pretreatment Dynamic Contrast Enhanced MRI (DCE-MRI) can reliably predict response to chemoradiation in HNSCC

  3. Possible Predictors of Outcome Clinical parameter Stage, site, tumor volume, nodal status • TALK score (T stage, albumin, EtOH history, KPS) • HPV status Molecular markers • P53 mutation, EGFR overexpression, cyclin D1, TGF-α, HIF1-α Hypoxia Treatment Related Factors • Fraction size, response at 5 weeks, XRT dose Imaging • PET; DCE-MRI

  4. Dynamic Contrast Enhanced MRI (DCE-MRI)1-5 • Possible Surrogate Marker • correlated with pO2 (measured by Eppendorf probes; cervical Ca) • evaluate changes in angiogenesis (cervical Ca) • Prediction of Tumor Response • may predict tumor response to treatment (rectal, H&N Ca) • correlates with tumor necrosis in bone sarcomas 1. Z. Wang et al Technol Cancer Res Treat, 1, 29, 2002; 2. H. Konouchi et al Oral Oncol, 30, 290, 2003; 3. P.J. Hoskin et al Br J Radiol, 72, 1093, 1999; 4. N.J. Fischbein et al Am J Neuroradiol, 24, 301, 2003; 5. R.A. Cooper et al Radiother Oncol, 57, 53, 2000

  5. DCE-MRI • IV Injection of contrast agent (Gd-DTPA) • Gd-DTPA  from intravascular space to interstitial space • Rate of diffusion depends on perfusion, permeability, vascularity • Rapid imaging (~3-6 seconds/time point) • Data Analysis: • Slope or maximum change in signal • Compartmental Model  derive microenvironment • parameters (permeability, interstitial compartment)

  6. Objectives • A priori marker of long term disease free survival • For this study 1 year freedom from loco-regional relapse was measured • Early marker of long term relapse free survival • Correlation with hypoxia (18F-Miso study) • Correlation with molecular markers, proliferation, and gene array analysis

  7. Methods Eligibility Criteria • Histologically proven, regionally advanced, HNSCC; • Node +; Node > 1 cm • Previously untreated • TX plan = Concomitant chemoradiation with definitive intent • No contraindications to MRI

  8. Methods Planned Treatment Schema Concomitant XRT and chemotherapy • Dose painting IMRT • Gross disease = 70 Gy • High risk subclinical disease = 59.4 Gy • Lower risk subclinical disease = 54 Gy • Chemotherapy • CDDP 100 mg/m2 IV; weeks 1, 4, and 7 • Carboplatin (70 mg/m2 IV x 4 days +5FU (600/mg/m2 x 3-4 days) • Paclitaxel (50mg/m2) + Carboplatin (AUC=1) IV weekly

  9. Methods Pretreatment MR Imaging (1.5T) • Localizer images Pre-contrast multiplanar T1 & T2w MRI DCE-MRI Methods • Contrast agent (Gd-DTPA; 0.1mmol/kg at 2ml/sec) • DCE-MRI scan  FMSPGR sequence • temporal resolution 3-6 sec/time point • Pixel size = 0.7 x 1.4 x 3-6 mm3 • Total time ~1hr (DCE-MRI part of the clinical study)

  10. Methods DCE-MRI Data Analysis • Performed using Brix and Hoffman’s two compartment model6,7 • Parameters studied • A=Amplitude, kep= rate constant • Slope 6. U. Hoffman et al Magn Reson Med, 33, 506, 1995 7. G. Brix et al J Comput Assit Tomog, 15, 621, 1991

  11. Methods Patient Response Evaluation • Patients evaluated at one year after finishing treatment • Assessment by involved oncologist supplemented by imaging (CT or MRI, and PET) • Response dichotomized at 1 year: • No Response = progression or salvage surgery by 1 year; • Response = NED at one year • 2 patients had neck dissection within one year of treatment One = NED; One = 1 mm focus of viable tumor

  12. Results Patient Population • N= 27 patients; all with SCC • 24 M, 3 F • Median age = 57 yrs (37-82) • Primary tumor location • base of tongue 12; tonsil 12; larynx 1;nasopharynx 2 • Stage distribution • Stage III – 7 patients; Stage IV – 20 patients

  13. Tumor Muscle Time intensity curves for tumor & muscle Time intensity curves for Internal Carotid Artery DCE-MR image DCE-MRI Results

  14. Data from a typical complete responder Data from a typical non-responder DCE-MRI (Akep) - Histogram Analysis

  15. Histogram Analysis (Akep, Slope)

  16. Histogram Analysis (Akep, Slope) P=0.004 P=0.004

  17. Limitations of Study • Small study (27 patients) • Short followup (1 year) • Variability of data needs to be determined • Does not take into account perfusion (arterial input function) • Results appear to be predictive for patients with high values - low values not predictive

  18. Conclusion • Pretreatment DCE-MRI data shows a significant effect for predicting response • Effort is underway to incorporate Arterial Input Function (AIF) and effect of water exchange on analysis of DCE-MRI data Research supported by NIH R01 CA115895

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