Andrew S. Kennedy1,14; David Ball2; Steven J. Cohen2; Michael Cohn3; Douglas M. Coldwell4; Alain Drooz5; Edward Ehrenwald6; Samir Kanani7; Charles W. Nutting8; Fred M. Moeslein9; Samuel G. Putnam III2; Steven C. Rose10; Michael A. Savin11; Sabine Schirm1; Navesh K. Sharma12; and Eric A. Wang13

1Cancer Centers of North Carolina, Cary, NC; 2Fox Chase Cancer Center, Philadelphia, PA; 3Radiology Associates of Hollywood, Pembroke Pines, FL; 4James Graham Brown Cancer Center, University of Louisville, Louisville, KY; 5Fairfax Radiological Consultants, Fairfax, VA; 6Abbott Northwestern Hospital, Minneapolis, MN; 7Inova Fairfax Hospital, Annandale, VA; 8Radiology Imaging Associates, Englewood, CO; 9University of Maryland Medical Center, Baltimore, MD;

10University of California, San Diego Moores Cancer Center, La Jolla, CA; 11Beaumont Hospital, Royal Oak, Royal Oak, MI; 12University of Maryland School of Medicine, Baltimore, MD; 13Charlotte Radiology, Charlotte, NC; 14Sarah Cannon Research Institute, Nashville, TN

Hepatic Imaging Response to 90Y-microsphere Therapy Administered for Tumor Progression During Systemic Chemotherapy in Patients with Colorectal Liver Metastases

•  90Y-microsphere therapy is a form of brachytherapy (Radioembolization) which destroys tumors via radiation damage from locally implanted microspheres

•Radioactive microspheres (30 microns diameter) are administered via the hepatic vasculature and permanently implant in the terminal arterioles inside hepatic tumors

•Because the depth of penetration of radiation (beta) is only a mean of 2.5 mm, normal liver parenchyma adjacent to the tumor is spared injury. There are two commercially available microsphere products: resin (reported in this study) and glass (not included in this report) based

•Phase III trials have demonstrated a significant improvement in time to liver progression in chemotherapy refractory metastatic colorectal liver tumors

•Numerous retrospective and small prospective studies in liver-dominant mCRC patients no longer responding to chemotherapy have suggested improvements in overall survival and minimal acute or delayed toxicity

•Frequent questions arise during consultation and tumor board discussions as to the expected imaging response rate in typically presenting patients vs. those in prospective studies

• It is important to understand the likely effect in the liver of resin 90Y microsphere radioembolization for unselected patients treated in both community and academic cancer centers in the USA

BACKGROUND AND RATIONALE

•A retrospective review of consecutively treated patients with liver-dominant mCRC from July 2002 to December 2011 at 11 US institutions was conducted

•An independent imaging review following resin-only 90Y microsphere treated cases of mCRC from July 2002 to December 2011 at 9 US institutions was conducted. A board certified radiologist systematically reviewed hepatic Computed Tomography (CT) images (portal-venous phase) at baseline and 3 months after 90Y treatment

•Tumor response was assessed using RECIST 1.0, and 1.1 criteria, based on a maximum of 5 and 2 target lesions respectively

•Peri-tumoral edema and necrosis; known artifacts which can affect the interpretation of RECIST response, were documented for each lesion

•Kaplan Meier analysis compared survival for responders [Partial Response (PR)] vs. non-responders [Stable Disease (SD) or Progressive Disease (PD)]

MATERIALS AND METHODS • A total of 195 patients were studied; male (60%) and Caucasians (67%) most common, mean age 62 years received a median of 2 (range 0–6) lines of chemotherapy prior to 90Y therapy. Median tumor/liver ratio at 90Y therapy was 15% (IQR 24%). Median 90Y activity administered was 1.18 GBq (IQR 0.59)

• RECIST 1.0 response based on best response observed (n=195) was PR=10.3%, SD= 51.8% and PD=37.9%; Disease Control Rate=62.0%. Corresponding values for RECIST 1.1 response were PR=10.3%, SD=52.8% and PD=36.9%; Disease Control Rate=63.1%. Tumor response rates as determined by RECIST 1.0 and RECIST 1.1 exhibited excellent agreement [Kappa = 0.906 (95% CI 0.855-0.956)]

• RECIST 1.0 response for 131 patients with 3 month follow-up imaging was PR=7.6%, SD=47.3% and PD=45.0%; Disease Control Rate=55.0%. Corresponding values for RECIST 1.1 response were PR=6.9%, SD=48.1% and PD=45.0%; Disease Control Rate=55.0%. Tumor response rates for RECIST 1.0 and RECIST 1.1 also showed excellent agreement for 3 month follow-up [Kappa = 0.915 (95% CI 0.856-0.975)]

• In the 3 month follow-up cohort evaluated via RECIST 1.0, necrosis was documented in 48.1%; peri-tumoral edema in 32.8% and both in 57.3% of cases. For RECIST 1.1 necrosis=41.2%, peri-tumoral edema=29.8% and both=50.4% respectively

• No significant differences in background characteristics between responders and non-responders were evident (p>0.05)

• RECIST response at 3 months predicted survival; RECIST 1.0: PR median 25.2 months (95% CI 9.2–49.4) vs. SD 15.8 (9.3–21.1) vs. PD 7.1 (6.0–9.5) [p<0.0001]. Corresponding survivals using RECIST 1.1 response criteria were PR 20.0 months (4.4-49.4) vs. SD 14.3 (9.2-21.4) vs. PD 7.1 (6.0-10.1 [p<0.0001]

RESULTS

Parameter Patients, n (%) Gender

- Male 117 (60.0%) - Female 78 (40.0%)

Age, years - mean + SD (range) 62 + 12.61 (33.6 - 90.0) - > 70 years 57 (29.2%)Race - White or Caucasian 130 (66.7%) - Unknown 44 (22.6%) - Black or African American 14 (7.2%) - Other 3 (1.5%) - Asian 2 (1.0%) Ethnicity - Hispanic or Latino 2 (1.0%) Primary Tumor Site - Colon : rectum 149 (77.2%) : 35 (18.1%) - Colorectal 9 (4.7%)ECOG Performance Status

- 0 82 (66.7%) - 1 36 (29.3%) - 2 5 (4.1%) Ascites

- None 187 (96.9%) - Controlled : Uncontrolled 2 (1.0%) : 4 (2.1%)Primary Tumor in situ 28 (14.5%)Extra-hepatic metastases at radioembolization: (any site, including lung, lymph node(s), peritoneum, bone and other) 67 (34.9%)Prior liver-directed surgery and/or ablation 42 (21.5%)Prior vascular/percutaneous procedure 8 (4.1%) Previous radiotherapy procedure to upper abdomen 3 (1.5%) Any prior procedure 46 (23.6%)Prior chemotherapy lines, median (range) 2 (0 - 6)

mCRC diagnosis to radioembolization, median (range) 13.7 months (0.6 - 69.3)

BASELINE CHARACTERISTICS (n=195)

Imaging Response at 3 months N Median Survival (95% CI)1 00

Stable Disease by RECIST 1.0 62 15.8 months (9.3 – 21.1)

Progressive Disease by RECIST 1.0 59 7.1 months (6.0 – 9.5)

Partial Response by RECIST 1.0 10 25.2 months ( 9.2 – 49.4)g g p ( )

p<0.0001

n

1.00

Censored Observations n

Func

tion 0.75

istr

ibut

ion

0.50

Surv

ival

D

0.25

S

0 00

Time from Radioembolization (months)

0.000 10 20 30 40 7050 60

OVERALL SURVIVAL BY RESPONSE AT 3 MONTHS USING RECIST 1.0

548 (100%)

Best Response (n=195)1 3 Month Follow-up (n=131)2

Tumor Response (RECIST 1.0) n % n %Partial Response (PR) 20 10.3 10 7.6Stable Disease (SD) 101 51.8 62 47.3Disease Control Rate (SD + PR) 121 62.1 72 55.0Progressive Disease (PD) 74 37.9 59 45.0

Tumor Response (RECIST 1.1)Partial Response (PR) 20 10.3 9 6.9Stable Disease (SD) 103 52.8 63 48.1Disease Control Rate (SD + PR) 123 63.1 72 55.0Progressive Disease (PD) 72 36.9 59 45.0

TUMOR RESPONSES

1Median time to best response=70 days (IQR=55 days)2Median time to 3 month FU= 82 days (IQR=34 days)

548 (100%)

n Necrosis Peri-tumoral Edema Necrosis or Peri-tumoral Edema

Tumor Response (RECIST 1.0) n % n % n %Partial Response (PR) 10 6 60.0 7 70.0 9 90.0Stable Disease (SD) 62 29 46.8 16 25.8 33 53.2Progressive Disease (PD) 59 28 47.5 20 33.9 33 55.9TOTAL 131 63 48.1 43 32.8 75 57.3

Tumor Response (RECIST 1.1)Partial Response (PR) 9 4 44.4 5 55.6 7 77.8Stable Disease (SD) 63 26 41.3 15 23.8 29 46.0Progressive Disease (PD) 59 24 40.7 19 32.2 30 50.8TOTAL 131 54 41.2 39 29.8 66 50.4

IMAGING ARTIFACTS OBSERVED AT 3 MO. FU1 (n=131)

1Median time to 3 month FU= 82 days (IQR=34 days)

•RECIST 1.0 and 1.1 imaging response criteria provide equivalent interpretations in the assessment of hepatic tumors following treatment with 90Y therapy

•Radiological lesion response to 90Y therapy at 3 months must be interpreted with caution due to the significant proportions of necrosis and peri-tumoral edema encountered

•Both of these artifacts may lead to either the under estimation of PR/SD or the overestimation of PD, respectively

•Given these caveats, early (3 month) hepatic radiological response to 90Y therapy appears to predict longer term prognosis

CONCLUSIONS

Imaging Response at 3 months N Median Survival (95% CI)1 00

Stable Disease by RECIST 1.1 63 14.3 months (9.2 – 21.4)

Progressive Disease by RECIST 1.1 59 7.1 months (6.0 – 10.1)

Partial Response by RECIST 1.1 9 20.0 months (4.4 – 49.4)g g p ( )

p<0.0001

n

1.00

Censored Observations

n Fu

ncti

on 0.75

istr

ibut

ion

0.50

Surv

ival

D

0.25

S

0 00

Time from Radioembolization (months)

0.000 10 20 30 40 7050 60

OVERALL SURVIVAL BY RESPONSE AT 3 MONTHS USING RECIST 1.1

RECIST 1.0 AND ARTIFACT

Peritumoral Edema with SD (RECIST 1.0)Peritumoral Edema with SD (RECIST 1.0)

Pre Treatment Day 64 post treatment

Index lesion decreased 19.1% from baselineClinical improvement and drop in CEA noted

Partial Response (RECIST 1.0)Partial Response (RECIST 1.0)

Pre Treatment Day 48 post treatment Day 76 post treatment

Index lesion decreased 49.5% from baseline

Partial Response (RECIST 1.0)Partial Response (RECIST 1.0)

Pre Treatment                                                      Day 76 Post Treatment

Partial Response (RECIST 1.0)Partial Response (RECIST 1.0)

Pre Treatment Day 90 post treatment Day 255 post treatment

Index lesion decreased 73.7% from baselineNadir response occurred at day 104