Tumor Perfusion or Metabolism for Predicting Early and Late Treatment Response in Advanced Rectal Cancer?

1. Tumor Perfusion or Metabolism for Predicting Early and Late Treatment Response in Advanced Rectal Cancer? AvinashKambadakone Ramesh1 Anna Galluzzo1 Onofrio Catalano1 Lawrence Blaszkowsky2 C G Willett3 Dushyant Sahani*1 1Department of Abdominal Imaging and Intervention, 2Department of Oncology, Massachusetts General Hospital 3 Department of Radiology, Duke University

2. Disclosures • Dushyant Sahani MD has received Research Grants from GE healthcare • NCI grants (R21 CA099237 to CGW and PO1 CA80124 to RKJ)"

3. Advanced stage Rectal Cancer (T3>) conventionally treated preoperative chemo-radiation followed by curative resection Targeted therapies (anti-angiogenic drug) in a neo-adjuvant setting (+C-XRT) have shown to improve the patient outcome in rectal cancer. Background Howe et al J Natl Cancer Inst 2001, Lindmark et al Dis Colon Rectum 1994, Willett et al Nat Med 2004 Introduction • Objectives • Materials and Methods • Results • Conclusion

4. Background • Evaluation of treatment response to targeted therapies by measuring changes in tumor burden using morphological assessment is not reliable • Perfusion CT (CTp) has shown to be a validated surrogate to measure early treatment changes • 18 FDG-PET/CT - effective modality to measure metabolic response following chemo-radiation in rectal cancer RECIST WHO 540 mm 598mm 350 mm 180mm Sahani et al Radiology 2005, Bellomi et al Radiology 2007, Sahani et al Radiology 2008 Zhu et al The Oncologist 2008, Rosenberg et al Int J Colorect 2009 Introduction • Objectives • Materials and Methods • Results • Conclusion

5. Locally advanced rectal cancer To EVALUATE and COMPARE treatment effects with CTp and 18FDG-PET EARLY changes after Bevacizumab therapy LATE changes following chemoradiation (C-XRT) To assess if the baseline tumor perfusion and SUV values can PREDICT treatment response and long term outcome To CORRELATE the baseline tumor perfusion and SUV values with nodal stages and tumor volume Aims and Objectives Introduction • Objectives • Materials and Methods • Results • Conclusion

6. Study Design HIPPA Compliant IRB approved Prospective Study Pre operative staging 19 patients (2003 - 2008) 13M:6F (Mean age 56 yrs, range 38-69yrs) Locally advanced Rectal cancer (Stage T3 or above) and no distant metastases MRI (n=17) and EUS (n=2) 18 patients - T3 1 patient - T4 Introduction • Objectives • Materials and Methods • Results • Conclusion

7. Study Design 6-10 weeks 2 weeks 6 weeks 16 patients 9M:6F Mean-55yrs CTp1 CTp2 CTp3 4-6 weeks after treatment completion 10-14 days after start of BVZ Baseline PET1 PET 3 PET 2 3 patients 3M Mean-57yrs Introduction • Objectives • Materials and Methods • Results • Conclusion

8. Scanning Technique BV MTT PS CT perfusion 18 FDG PET BF • Fasting 6 hrs • 10-20 mCi of 18-FDG, delay 45 min • Static and emission scans • Section thickness of 2.5-3.5mm. • IV contrast (370mgI/ml) – 70 ml @ 7cc/sec • Delay = 7-10 sec • First pass - Cine acquisition for 45 sec • Delayed phase • Limited acquisition (15) • kVp 80-100 and mA 200-240 • Metabolic quantification • Standardized uptake value (SUV) • GE deconvolution method • Advantage Windows 4.0, CT perfusion 3.0 Introduction • Objectives • Materials and Methods • Results • Conclusion

9. Data Analysis • Response Assessment • Responders – Tumor downstaging at surgery • Non responders – Tumor staging unchanged at surgery • Long term outcome (follow up of 24 months) • - Evaluation of recurrence and metastases • Nodal staging • N0- No Nodal metastases • N1- Metastasis to 1-3 regional nodes • N2- 4 or more regional nodes • Tumor L-T product Introduction • Objectives •Materials and Methods • Results • Conclusion

10. Results Early CTp vs SUV changes 2 weeks following start of therapy 32% 5% 21% 10% 16% (p=0.5) (p=0.01) (p=0.4) (p=0.07) (p=0.05) No change in SUV Drop in BF and PS Introduction • Objectives • Materials and Methods • Results • Conclusion

11. Results Late CTp vs SUV changes following completion of treatment 77% 59% 87% 37% 54% (p<0.01) (p<0.01) Substantial drop in tumor perfusion and metabolism Introduction • Objectives • Materials and Methods • Results • Conclusion

12. BVZ Post CXRT Baseline Sag Sag Sag 18FDG PET 2.5 12.4 12.5 Ax Ax Ax CTP 26 ml/100g/min 117 ml/100g/min 63 ml/100g/min Introduction • Objectives • Materials and Methods • Results • Conclusion

13. Results Responders (n=10) vs Non-responders (n=9) • No significant difference in baseline tumor CTp and tumor SUV between R & NR • After C-XRT, higher drop in perfusion values and SUV values in R than NR Baseline 18 FDG PET Baseline CTp Introduction • Objectives • Materials and Methods • Results • Conclusion

14. Results Long Term Outcome (Mean Follow up -32 months) Favorable LT outcome - Lower baseline perfusion (BF, PS) values - Higher baseline SUV values Introduction • Objectives • Materials and Methods • Results • Conclusion

15. Results Nodal Stage Tumor L-T product N2- 12 patients, N1- 5 patients, N0- 2 patients L-T product >10 (18.8)= 11 patients L-T product <10 (6.5) = 8 patients • No significant association between • the perfusion parameters, SUV values and tumor L-T product at baseline Advanced nodal disease - higher perfusion Introduction • Objectives • Materials and Methods • Results • Conclusion

16. Conclusion CT perfusion is a more robust surrogate to evaluate early antiangiogenic activity in advanced rectal cancer Both CT perfusion and FDG PET can be used as reliable indicators to measure late tumor response following completion of treatment. Responders show substantially greater drop in perfusion and metabolic activity compared to non responders. Introduction • Objectives • Materials and Methods • Results • Conclusion

17. Patients with favorable LT outcome show lower baseline perfusion (BF, PS) values and higher baseline SUV values Tumors with advanced nodal stage have higher perfusion values There is no significant association between tumor L-T product, perfusion parameters and tumor metabolic activity Conclusion Introduction • Objectives • Materials and Methods • Results • Conclusion

18. CT perfusion – Ongoing projects