1. 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

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

3. 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

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
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

5. 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

6. HIPPA Compliant IRB approved Prospective Study
Study Design
HIPPA Compliant IRB approved Prospective Study
Pre operative staging
19 patients ( )
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 16 patients 9M:6F Mean-55yrs 3 patients 3M Mean-57yrs
2 weeks
6 weeks
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

8. Scanning Technique CT perfusion 18 FDG PET
IV contrast (370mgI/ml) – 70 7cc/sec
Delay = 7-10 sec
First pass - Cine acquisition for 45 sec
Delayed phase
Limited acquisition (15)
kVp and mA
Fasting 6 hrs
10-20 mCi of 18-FDG, delay 45 min
Static and emission scans
Section thickness of mm. 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

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. 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

11. 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

12. 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

13. 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

14. 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

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. 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

18. 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