Perfusion MDCT enables early detection of therapeutic response to antiangiogenic therapy.
OBJECTIVE
The objective of our study was to determine whether perfusion CT can be used to detect early changes in therapeutic response to antiangiogenic therapy in an animal tumor model.


METHODS
Twenty-five rats implanted with R3230 mammary adenocarcinoma (diameter, 1.2-2.0 cm) randomly received 7.5 or 30 mg/kg of an antiangiogenic agent, sorafenib, by daily gavage for 4 (n = 4), 9 (n = 9), or 14 (n = 5) days. Seven untreated animals served as a control group. Perfusion MDCT was performed at days 0, 4, 9, and 14 with 0.4 mL of ioversol (350 mg/mL) and included four 5-mm slices covering the entire tumor volume. Changes in tumor growth were determined by volumetric analysis of CT data. Serial changes in tumor volume and blood flow were assessed and correlated with pathology findings.


RESULTS
All control tumors grew larger (from 2.0 +/- 0.7 cm(3) at day 0 to 5.9 +/- 1.0 cm(3) at day 14), whereas all treated tumors shrank (from 2.5 +/- 1.1 to 2.1 +/- 1.0 cm(3)), with a statistically significant rate of growth or shrinkage in both groups (p < 0.05). Although perfusion in the control tumors changed little from day 0 to day 14 (day 0, 18.1 +/- 9.2 mL/min/100 g; day 4, 15.8 +/- 5.6; day 9, 21.7 +/- 12.2; day 14, 27.7 +/- 34), in the sorafenib group, the mean blood flow was significantly lower at day 4 (5.2 +/- 3.2 mL/min/100 g, 77% decrease), day 9 (6.4 +/- 4.0 mL/min/100 g, 66% decrease), and day 14 (6.3 +/- 5.2 mL/min/100 g, 83% decrease) compared with day 0 (23.8 +/- 11.6 mL/min/100 g) (p < 0.05). Poor correlation was seen between changes in blood flow and tumor volume for days 0-9 (r(2) = 0.34), 4-9 (r(2) = 0.0004), and 9-14 (r(2) = 0.16). However, when comparing day 4 images with days 9 and 14 images, seven of 14 (50%) sorafenib-treated tumors had focal areas of new perfusion that correlated with areas of histopathologic viability despite the fact that these tumors were shrinking in size from day 4 onward (day 4, 2.18 +/- 0.8 cm(3); day 9, 1.98 +/- 0.8 cm(3)).


CONCLUSIONS
Perfusion MDCT can detect focal blood flow changes even when the tumor is shrinking, possibly indicating early reversal of tumor responsiveness to antiangiogenic therapy. Given that changes in tumor volume after antiangiogenic therapy do not necessarily correlate with true treatment response, physiologic imaging of tumor perfusion may be necessary.
Sabir
Adeel
A
Minimally Invasive Tumor Therapy Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Schor-Bardach
Rachel
R
Wilcox
Carol J
CJ
Rahmanuddin
Syed
S
Atkins
Michael B
MB
Kruskal
Jonathan B
JB
Signoretti
Sabina
S
Raptopoulos
Vassilios D
VD
Goldberg
S Nahum
SN
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001557:Benzenesulfonates / Q000008:administration & dosage*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D017063:Outcome Assessment, Health Care / Q000379:methods*; D010477:Perfusion / Q000379:methods; D010671:Phenylurea Compounds; D011379:Prognosis; D011725:Pyridines / Q000008:administration & dosage*; D051381:Rats; D000077157:Sorafenib; D014057:Tomography, X-Ray Computed / Q000379:methods*; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib