1. Dynamic Contrast Enhanced (DCE)-MRI as a Predictor of Response in Head & Neck Squamous Cell Carcinoma (HNSCC) : Initial Analysis A.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 Departments of Medical Physics 1, Radiology 2, Radiation Oncology 3, Surgery 4, Medicine 5 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. 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) DCE-MRI

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. 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/m 2 IV; weeks 1, 4, and 7 –Carboplatin (70 mg/m 2 IV x 4 days +5FU (600/mg/m 2 x 3-4 days) –Paclitaxel (50mg/m 2 ) + Carboplatin (AUC=1) IV weekly Methods

9. 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 mm 3 –Total time ~1hr (DCE-MRI part of the clinical study) Methods

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

11. 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 Methods

12. 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 Results

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

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

15. Histogram Analysis (Ak ep, Slope) Clinical Response Ak ep Amplitude Slope Amplitude Ak ep Median Slope Median NED 0.17 ±0.03 0.09 ±0.01 6.12 ±1.30 359.2 ±76.6 NR 0.41 ±0.18 0.17 ±0.07 2.11 ±0.94 177.8 ±79.5 P value 0.030.0080.004

16. Histogram Analysis (Ak ep, Slope) P=0.004

17. 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 Limitations of Study

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