Safety and Efficacy of Resin Y90-microspheres in 548 Patients with Colorectal Liver Metastases Progressing on Systemic Chemotherapy

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The results of a large multi-center clinical study re-affirming the safety and efficacy of Selective Internal Radiation Therapy (SIRT) with SIR-Spheres® microspheres in patients with metastatic colorectal cancer were presented at the American Society of Clinical Oncology’s 2013 Gastrointestinal Cancers Symposium.(1,2) The data were presented by lead investigator Andrew S. Kennedy, M.D., F.A.C.R.O., Director, Radiation Oncology Research Sarah Cannon Research Institute, Nashville, TN.

Multi-Institutional U.S. Study Overview:
This investigator initiated study was a retrospective analysis of the outcomes in 548 patients with metastatic colorectal cancer treated with SIR-Spheres microspheres from July 2002 to December 2011at 11 U.S. institutions.1 All patients had received prior chemotherapy, with more than 30% having also received prior liver surgery or ablation.

The authors reported median survivals of 13.0, 9.0 and 8.1 months, respectively, in patients who had received 1, 2 or 3+ prior lines of chemotherapy. There were no significant differences in the adverse event profiles between the three groups. Most patients (97.8%) spent less than 24 hours in the hospital with the most common Grade 3 side effects being abdominal pain (7%) and fatigue (6%). The authors concluded that SIRT with SIR-Spheres microspheres appears to have a favorable risk/benefit ratio in patients with metastatic colorectal cancer who have failed chemotherapy. These data show a clinically relevant survival benefit in patients not responding to chemotherapy, including those who have been heavily pre-treated.
Sources:
1. Kennedy AS, Ball D, Steven J. Cohen SJ et al. Safety and efficacy of resin 90Y-microspheres in 548 patients with colorectal liver metastases progressing on systemic chemotherapy. ASCO Gastrointestinal Cancers Symposium 2013; Abs. 264.
2. Kennedy AS, Ball D, Steven J. Cohen SJ et al. Hepatic imaging response to 90Y-microsphere therapy administered for tumor progression during systemic chemotherapy in patients with colorectal liver metastases. ASCO Gastrointestinal Cancers Symposium 2013; Abs. 270.

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Safety and Efficacy of Resin Y90-microspheres in 548 Patients with Colorectal Liver Metastases Progressing on Systemic Chemotherapy

  1. 1. Hepatic Imaging Response to Y-microsphere Therapy Administered for Tumor Progression 90 During Systemic Chemotherapy in Patients with Colorectal Liver Metastases Andrew S. Kennedy ; David Ball ; Steven J. Cohen ; Michael Cohn ; Douglas M. Coldwell ; Alain Drooz ; Edward Ehrenwald ; Samir Kanani ; Charles W. Nutting ; 1,14 2 2 3 4 5 6 7 8 Fred M. Moeslein ; Samuel G. Putnam III ; Steven C. Rose ; Michael A. Savin ; Sabine Schirm ; Navesh K. Sharma ; and Eric A. Wang 9 2 10 11 1 12 13 Cancer 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; 1 5 Fairfax 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; 10 University 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 BACKGROUND AND BASELINE CHARACTERISTICS (n=195) 548 (100%) TUMOR RESPONSES RECIST 1.0 AND ARTIFACT RATIONALE Parameter Patients, n (%) Best Response (n=195)1 3 Month Follow-up (n=131)2 Gender Tumor Response (RECIST 1.0) n % n % Peritumoral Edema with SD (RECIST 1.0) Edema with SD (RECIST 1.0) Partial Response (RECIST 1.0) Partial Response (RECIST 1.0)•  90Y-microsphere therapy is a form of brachytherapy - Male 117 (60.0%) Partial Response (PR) 20 10.3 10 7.6 (Radioembolization) which destroys tumors via radiation - Female 78 (40.0%) Stable Disease (SD) 101 51.8 62 47.3 damage from locally implanted microspheres Age, years Disease Control Rate (SD + PR) 121 62.1 72 55.0 - mean + SD (range) 62 + 12.61 (33.6 - 90.0) Progressive Disease (PD) 74 37.9 59 45.0• Radioactive microspheres (30 microns diameter) - > 70 years 57 (29.2%) Tumor Response (RECIST 1.1) are administered via the hepatic vasculature and Race Partial Response (PR) 20 10.3 9 6.9 permanently implant in the terminal arterioles inside - White or Caucasian 130 (66.7%) Stable Disease (SD) 103 52.8 63 48.1 - Unknown 44 (22.6%) hepatic tumors - Black or African American 14 (7.2%) Disease Control Rate (SD + PR) 123 63.1 72 55.0 - Other 3 (1.5%) Progressive Disease (PD) 72 36.9 59 45.0• Because the depth of penetration of radiation (beta) is - Asian 2 (1.0%) 1 Median time to best response=70 days (IQR=55 days) Pre Treatment Day 64 post treatment only a mean of 2.5 mm, normal liver parenchyma adjacent Median time to 3 month FU= 82 days (IQR=34 days) 2 Ethnicity Index lesion decreased 19.1% from baseline to the tumor is spared injury. There are two commercially - Hispanic or Latino 2 (1.0%) Clinical improvement and drop in CEA noted Pre Treatment                                                      Day 76 Post Treatment available microsphere products: resin (reported in this Primary Tumor Site study) and glass (not included in this report) based - Colon : rectum 149 (77.2%) : 35 (18.1%) IMAGING ARTIFACTS OBSERVED AT 3 MO. FU (n=131) 1 - Colorectal 9 (4.7%) 548 (100%) Partial Response (RECIST 1.0) Partial Response (RECIST 1.0) Partial Response (RECIST 1.0) Partial Response (RECIST 1.0)• Phase III trials have demonstrated a significant Necrosis or Peri-tumoral ECOG Performance Status n Necrosis Peri-tumoral Edema improvement in time to liver progression in - 0 82 (66.7%) Edema chemotherapy refractory metastatic colorectal liver - 1 36 (29.3%) Tumor Response (RECIST 1.0) n % n % n % tumors - 2 5 (4.1%) Partial Response (PR) 10 6 60.0 7 70.0 9 90.0 Ascites Stable Disease (SD) 62 29 46.8 16 25.8 33 53.2• Numerous retrospective and small prospective studies in - None 187 (96.9%) Progressive Disease (PD) 59 28 47.5 20 33.9 33 55.9 liver-dominant mCRC patients no longer responding to - Controlled : Uncontrolled 2 (1.0%) : 4 (2.1%) TOTAL 131 63 48.1 43 32.8 75 57.3 chemotherapy have suggested improvements in overall Primary Tumor in situ 28 (14.5%) Tumor Response (RECIST 1.1) survival and minimal acute or delayed toxicity Partial Response (PR) 9 4 44.4 5 55.6 7 77.8 Extra-hepatic metastases at radioembolization: (any site, Stable Disease (SD) 63 26 41.3 15 23.8 29 46.0 Pre Treatment Day 48 post treatment Day 76 post treatment Pre Treatment Day 90 post treatment Day 255 post treatment• Frequent questions arise during consultation and including lung, lymph node(s), peritoneum, bone and other) 67 (34.9%) Progressive Disease (PD) 59 24 40.7 19 32.2 30 50.8 Index lesion decreased 49.5% from baseline Index lesion decreased 73.7% from baseline tumor board discussions as to the expected imaging Prior liver-directed surgery and/or ablation 42 (21.5%) TOTAL 131 54 41.2 39 29.8 66 50.4 Nadir response occurred at day 104 response rate in typically presenting patients vs. those in Prior vascular/percutaneous procedure 8 (4.1%) 1 Median time to 3 month FU= 82 days (IQR=34 days) prospective studies Previous radiotherapy procedure to upper abdomen 3 (1.5%)• It is important to understand the likely effect in the liver Any prior procedure 46 (23.6%) of resin 90Y microsphere radioembolization for unselected Prior chemotherapy lines, median (range) 2 (0 - 6) OVERALL SURVIVAL BY RESPONSE OVERALL SURVIVAL BY RESPONSE CONCLUSIONS patients treated in both community and academic cancer centers in the USA mCRC diagnosis to radioembolization, median (range) 13.7 months (0.6 - 69.3) AT 3 MONTHS USING RECIST 1.0 AT 3 MONTHS USING RECIST 1.1 • RECIST 1.0 and 1.1 imaging response criteria provide equivalent RESULTS interpretations in the assessment of hepatic tumors following treatment MATERIALS AND METHODS • A total of 195 patients were studied; male (60%) and Caucasians (67%) most common, mean age 62 1.00 1 00 Imaging Response at 3 months g g p Partial Response by RECIST 1.0 N 10 Median Survival (95% CI) ( 25.2 months ( 9.2 – 49.4) ) 1.00 1 00 Imaging Response at 3 months g g p N Median Survival (95% CI) ( ) years received a median of 2 (range 0–6) lines of chemotherapy prior to 90Y therapy. Median tumor/liver p<0.0001 Partial Response by RECIST 1.1 9 20.0 months (4.4 – 49.4) with 90Y therapy ratio at 90Y therapy was 15% (IQR 24%). Median 90Y activity administered was 1.18 GBq (IQR 0.59) Stable Disease by RECIST 1.0 62 15.8 months (9.3 – 21.1) Stable Disease by RECIST 1.1 63 14.3 months (9.2 – 21.4) p<0.0001• A retrospective review of consecutively treated patients Progressive Disease by RECIST 1.0 59 7.1 months (6.0 – 9.5) with liver-dominant mCRC from July 2002 to December • RECIST 1.0 response based on best response observed (n=195) was PR=10.3%, SD= 51.8% and Progressive Disease by RECIST 1.1 59 7.1 months (6.0 – 10.1) • Radiological lesion response to Survival Distribution Function n Censored Observations Survival Distribution Function n Censored Observations 2011 at 11 US institutions was conducted PD=37.9%; Disease Control Rate=62.0%. Corresponding values for RECIST 1.1 response were PR=10.3%, 0.75 0.75 90 Y therapy at 3 months must be• An independent imaging review following resin-only 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)] interpreted with caution due to the 90 Y microsphere treated cases of mCRC from July 2002 significant proportions of necrosis and n n to December 2011 at 9 US institutions was conducted. • RECIST 1.0 response for 131 patients with 3 month follow-up imaging was PR=7.6%, SD=47.3% and A board certified radiologist systematically reviewed PD=45.0%; Disease Control Rate=55.0%. Corresponding values for RECIST 1.1 response were PR=6.9%, 0.50 0.50 peri-tumoral edema encountered hepatic Computed Tomography (CT) images (portal- SD=48.1% and PD=45.0%; Disease Control Rate=55.0%. Tumor response rates for RECIST 1.0 and RECIST venous phase) at baseline and 3 months after 90Y 1.1 also showed excellent agreement for 3 month follow-up [Kappa = 0.915 (95% CI 0.856-0.975)] • Both of these artifacts may lead to treatment• Tumor response was assessed using RECIST 1.0, and 1.1 • In the 3 month follow-up cohort evaluated via RECIST 1.0, necrosis was documented in 48.1%; peri- either the under estimation of PR/SD or criteria, based on a maximum of 5 and 2 target lesions tumoral edema in 32.8% and both in 57.3% of cases. For RECIST 1.1 necrosis=41.2%, peri-tumoral 0.25 0.25 the overestimation of PD, respectively S respectively S edema=29.8% and both=50.4% respectively• Peri-tumoral edema and necrosis; known artifacts which • No significant differences in background characteristics between responders and non-responders were • Given these caveats, early (3 month) can affect the interpretation of RECIST response, were documented for each lesion evident (p>0.05) hepatic radiological response to 90Y 0.00 0 00 0.00 0 00• Kaplan Meier analysis compared survival for responders • RECIST response at 3 months predicted survival; RECIST 1.0: PR median 25.2 months (95% CI 9.2–49.4) 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 therapy appears to predict longer term [Partial Response (PR)] vs. non-responders [Stable Disease 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 Time from Radioembolization (months) Time from Radioembolization (months) prognosis (SD) or Progressive Disease (PD)] 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]

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