Avinash Kambadakone Ramesh1 Tumor Perfusion or Metabolism for Predicting Early and Late Treatment Response in Advanced Rectal Cancer? Avinash Kambadakone 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

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

Background 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. 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 3

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 598mm 540 mm 180mm 350 mm Traditionally, the tumor response to treatment have been evaluated by studying morphological changes depicted by change in tumor dimensions. Cannot be used for response evaluation of non-measurable lesions (Cystic lesions, lesions with ill-defined margins and tumors with irregular shape) Cannot assess treatment response if there is no change in tumor size. Inability to detect functional changes like metabolic and physiological responses which occur before morphological change Inability to depict early treatment response to noncytotoxic drugs which help in predicting clinical outcome 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

Aims and Objectives 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 Introduction • Objectives • Materials and Methods • Results • Conclusion

HIPPA Compliant IRB approved Prospective Study 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

Study Design 16 patients 9M:6F Mean-55yrs 3 patients 3M Mean-57yrs 2 weeks 6 weeks 6-10 weeks 16 patients 9M:6F Mean-55yrs Bevacizumab (BVZ) Bevacizumab + 5-Flurouracil Radiation Surgery with HPE Follow up (CT/CEA) 6 monthly-3yrs Yearly- 4-5yrs CTp1 CTp2 CTp3 10-14 days after start of BVZ 4-6 weeks after treatment completion Baseline PET 2 PET 3 Total 16 patients enrolled so far PET1 Bevacizumab + Erlotinib(ERT) + 5-Flurouracil Radiation + Erlotinib(ERT) Surgery with HPE Follow up (CT/CEA) 6 monthly-3yrs Yearly- 4-5yrs 3 patients 3M Mean-57yrs Introduction • Objectives • Materials and Methods • Results • Conclusion

Scanning Technique CT perfusion 18 FDG PET 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 Fasting 6 hrs 10-20 mCi of 18-FDG, delay 45 min Static and emission scans Section thickness of 2.5-3.5mm. BF BV PS MTT Metabolic quantification Standardized uptake value (SUV) GE deconvolution method Advantage Windows 4.0, CT perfusion 3.0 Introduction • Objectives • Materials and Methods • Results • Conclusion

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

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

Late CTp vs SUV changes following completion of treatment 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

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

Results Responders (n=10) vs Non-responders (n=9) Baseline 18 FDG PET Baseline CTp Baseline 18 FDG PET 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 Introduction • Objectives • Materials and Methods • Results • Conclusion

Results Long Term Outcome (Mean Follow up -32 months) Favorable (n=15) Unfavorable (n=4) p value BF 68.6±23 88.8±6.7 0.1 MTT 9.8±4.4 6.7±1.5 0.5 PS 16.8±7 19.4±8.5 SUV 6.6±3.9 5.9±1.6 0.7 Favorable LT outcome - Lower baseline perfusion (BF, PS) values - Higher baseline SUV values Introduction • Objectives • Materials and Methods • Results • Conclusion

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

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

Conclusion 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 Introduction • Objectives • Materials and Methods • Results • Conclusion

CT perfusion – Ongoing projects Pre Post Organ Tumor Drugs / Tx Retroperitoneum/ Extremities Sarcoma Bevacizumab Chemoradiation Liver HCC Bevacizumab Gemcitabine Oxaliplatin Pancreas Pancreatic Adeno Ca 5Fluorouracil Oxaliplatin Bevacizumab Chest Lung cancer Carboplatin Abraxane Neck Squamous cell cancer AZD2171 Monotherapy