Safety and Efficacy of Resin Y-microspheres in 548 Patients with                                                          ...
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Hepatic Imaging Response to 90Y-microsphere Therapy Administered for Tumor Progression During Systemic Chemotherapy in Patients with Colorectal Liver Metastases

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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.

Independent Imaging Study Confirms Efficacy with SIRT
The second presentation from this study illustrated the response to SIRT therapy with SIR-Spheres microspheres from an imaging perspective.2 The study presented the results of an independent central review by a board-certified radiologist of 195 patients with metastatic colorectal cancer that were treated with SIR-Spheres microspheres and had measureable lesions at baseline and follow-up imaging. Tumor RECIST response at three months showed a Partial Response in 7.6% of patients, 47.3% experienced Stable Disease and 45.0% had Progressive Disease resulting in a Disease Control Rate of 55.0%. RECIST response at three months predicted median survival of 25.2 months in Partial Responders compared to 15.8 months in those with Stable Disease and 7.1 months with Progressive Disease.

Researchers noted that response to SIRT therapy at three months must be interpreted with caution due to the significant proportions of peri-tumoral edema and necrosis encountered. Both imaging findings may lead to either the underestimation of Partial Response/Stable Disease or the overestimation of Progressive Disease, respectively. Given these caveats, early hepatic radiological response to SIRT therapy appears to predict longer-term prognosis.

“These studies add to the growing body of scientific data further supporting the role of SIRT in treating metastatic colorectal cancer. In this specific patient population, the results compare favorably to many of recently approved chemotherapy and biologic agents, and provide another option to patients who may have stopped responding to systemic therapy,” said Mike Mangano, president of Sirtex Medical Inc. “It is our intention to continue to study SIR Spheres microspheres in various patient populations, with the goal of adding this treatment to conventional chemotherapy even earlier in the treatment algorithm. The SIRFLOX study, which is expected to complete enrollment in the first quarter of 2013, will test this hypothesis with the hope that controlling liver tumors will allow patients to live longer and experience an improved quality of life. We look forward to those results.”

References:
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.

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

  1. 1. Safety and Efficacy of Resin Y-microspheres in 548 Patients with 90 Colorectal Liver Metastases Progressing on Systemic Chemotherapy Andrew S. Kennedy ; David Ball ; Steven J. Cohen ; Michael Cohn ; Douglas M. Coldwell ; Alain Drooz ; Edward Ehrenwald ; Samir Kanani ; Steven C. Rose ; 1,14 2 2 3 4 5 6 7 8 Charles W. Nutting ; Fred M. Moeslein ; Michael A. Savin ; Sabine Schirm ; Samuel G. Putnam III ; Navesh K. Sharma ; and Eric A. Wang 9 10 11 1 2 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; 8University of California, San Diego Moores Cancer Center, La Jolla, CA; 9Radiology Imaging Associates, Englewood, CO; 10 University of Maryland Medical Center, Baltimore, MD; 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=548) 548 (100%) 90 Y TREATMENTS AND TARGET APPROACH RESULTS RATIONALE Parameter Patients, n (%) Treated Target Treatment Design Number of Radioembolization Treatments, n (%) Total • Median follow-up was 8.5 months (IQR 4.3–15.6) 1 2 3 4 5 Patients Gender•  90Y-microsphere is a form of brachytherapy Whole Liver Whole-liver, single session + retreatment (partial or whole) 121 (44.5%) 38 (16.0%) 1 (3.7%) 1 (11.1%) 1 (50.0%) 162 (29.6%) • A total of 548 patients were included; majority were male (61%), Caucasian (66%), mean age 61 years; received - Male 336 (61.3%) - Female 212 (38.7%) Right lobe > left lobe sequential† (<10 weeks) - 131 (55.0%) 15 (55.5%) 5 (55.5%) 1 (50.0%) 152 (27.7%) (Radioembolization) which destroys tumors via radiation median of 2 (range 1–6) lines of chemotherapy prior to 90Y therapy Left lobe > right lobe sequential† (<10 weeks) - 17 (7.1%) 3 (11.1%) 1 (11.1%) - 21 (3.8%) damage from locally implanted microspheres Age, years Right lobe initially > left lobe or whole liver (>10 weeks) - 16 (6.7%) 3 (11.1%) - - 19 (3.5%) - mean + SD (range) 61 + 12.22 (30.0 - 89.2) Left lobe initially > right lobe or whole liver (>10 weeks) - 4 (1.7%) 2 (7.4%) 1 (11.1%) - 7 (1.3%) • Median tumor/liver ratio at 90Y therapy was 15% (IQR 23%). Median 90Y activity administered was 1.18 GBq (IQR• Radioactive microspheres (30 microns diameter) - > 70 years 133 (24.3%) 0.48). Hospital stay duration was <24 hours for most cases (97.8%) Whole Liver Sub-Total 121 (44.5%) 206 (86.6%) 24 (88.9%) 8 (88.9%) 2 (100%) 361 (65.9%) are administered via the hepatic vasculature and Race Partial Liver Right lobe + segmental 126 (46.3%) 23 (9.7%) 3 (11.1%) - - 152 (27.7%) permanently implant in the terminal arterioles inside - White or Caucasian 362 (66.1%) Left lobe + segmental 22 (8.1%) 5 (2.1%) - 1 (11.1%) - 28 (5.1%) • The most common adverse events (grade 3+) following 90Y therapy included: abdominal pain 6.6% (n=36), GI hepatic tumors - Unknown 81 (14.8%) Segmental 3 (1.1%) 1 (0.4%) - - - 4 (0.7%) - Black or African American 60 (10.9%) ulceration 1.8% (10), nausea 1.5% (8), vomiting 1.6% (9), fatigue 6.0% (33), ascites 3.5% (19), hyperbilirubinemia Unknown Right lobe + left or unknown target segment - 3 (1.3%) - - - 3 (0.5%)• Phase III trials have demonstrated a significant - Other 17 (3.1%) 5.7% (31) and anorexia 1.1% (6). A comparison of 1, 2 and 3+ lines of prior chemotherapy versus grade 3+ TOTAL 272 (49.6%) 238 (43.4%) 27 (4.9%) 9 (1.6%) 2 (0.4%) 548 (100%) improvement in time to liver progression in - Asian 12 (2.2%) † adverse events to 3 months post-90Y therapy revealed no significant difference (p>0.05) Sequential treatment defined as first and second radioembolization to contralateral lobe within a 10-week interval chemotherapy refractory metastatic colorectal liver Ethnicity - Hispanic or Latino 16 (2.9%) • Corresponding median survivals (95% CI) were 13.0 months (10.5–14.6) for patients treated with RE at 2nd-line, tumors Primary Tumor Site 9.0 months (7.8–11.0) for 3rd-line and 8.1 months (6.4–9.3) for 4th-line+ (p<0.0001)• Numerous retrospective and small prospective studies in - Colon : rectum 400 (73.0%) : 121 (22.1%) RADIOEMBOLIZATION TREATMENTS liver-dominant mCRC patients no longer responding to - Colorectal 26 (4.7%) 548 (100%) chemotherapy have suggested improvements in overall ECOG Performance Status Radioembolization Treatment survival and minimal acute or delayed toxicity - 0 161 (29.4%) - 1 69 (12.6%) Parameter 1 2 3 4 5 OVERALL SURVIVAL BY LINE OF THERAPY• Frequent questions arise during consultation and tumor - 2 11 (2.0%) Number of patients treated, n 548 276 38 11 2 - 3 3 (0.5%) board discussions as to the expected safety and efficacy - Unknown 304 (55.5%) Lung Shunt %, mean (range) 5.8% (0.02–31.0%) 4.7% (0.02–22.5%) 5.9% (1.1–19.0%) 7.8% (2.0–11.4%) 7.75% (5.9–9.6%) in the typically presenting patient vs. those in prospective Activity calculation: BSA formula 506 (97.1%) 248 (95.0%) 36 (100%) 11 (100%) 2 (100%) Ascites Activity calculation: Empiric method 15 (2.9%) 13 (5.0%) 0 0 0 studies - None 508 (92.7%) Activity planned (GBq), median (range) 1.27 (0.32–3.00) 0.72 (0.2–2.0) 1.01 (0.4–1.81) 0.71 (0.31–1.45) 0.84 (0.63–1.04) - Controlled : Uncontrolled 4 (0.7%) : 23 (4.2%) Radioembolization N Median Survival (95% CI)• It is important to understand the safety and efficacy of Activity delivered (GBq), median (range) 1.18 (0.11–2.29) 0.66 (0.1–1.81) 0.93 (0.33–1.79) 0.62 (0.11–1.45) 0.81 (0.62–0.99) 1.00 1 00 Primary Tumor in situ 72 (13.1%) Hospital stay duration <24 hours, n (%) 532 (97.6%) 265 (97.8%) 37 (97.4%) 11 (100%) 2 (100%) at 2nd-line [1 prior line chemo] 206 13.0 months (10.5 – 14.6) resin 90Y-microsphere radioembolization in unselected patients treated in both community and academic cancer Extra-hepatic metastases at radioembolization: (any site, Total liver volume (mL), median (range) 1765.4 (664–5844) 1825.6 (842–4528) 1677 (1070–4304.3) 2046.6 (1279.5–2664.1) 2141.6 (2139.4–2143.8) at 3rd-line [2 prior lines chemo] 184 9.0 months (7.8 – 11.0) p<0.0001 including lung, lymph node(s), peritoneum, bone and other) 201 (36.7%) Tumor volume (mL), median (range) 151.50 (2.8–3329) 82.10 (2.14–1978) 120.3 (4.7–753.9) 249.30 (3.6–500.3) 133.45 (18–248.9) centers in the USA at >4th-line [3+ prior lines chemo] 158 8.1 months (6.4 – 9.3) Prior liver-directed surgery and/or ablation 162 (29.6%) - Surgery 113 (20.6%) Survival Distribution Function n Censored Observations - Ablation 98 (17.9%) 0.75 Previous liver-directed vascular procedure 37 (6.8%) 548 (100%) ADVERSE EVENTS BY TIME INTERVAL FROM FIRST RADIOEMBOLIZATION - HAI 18 (3.3%) - TAC 17 (3.1%) All Timepoints Day of Days 1–7 Days 8–90 Days 90–184 n MATERIALS AND METHODS Post 1st Treatment 1st Treatment Post 1st Treatment Post 1st Treatment Post 1st Treatment - TAE 3 (0.5%) CTCAE v3 System Organ Class Grade 1-2 Grade > 3 Grade 1-2 Grade > 3 Grade 1-2 Grade > 3 Grade 1-2 Grade > 3 Grade 1-2 Grade > 3 Previous radiotherapy procedure to upper abdomen 7 (1.3%) GASTROINTESTINAL DISORDERS 311 (56.8%) 54 (9.9%) 152 (27.7%) 183 (33.4%) 43 (7.8%) 0.50• A retrospective review of consecutively treated patients Any prior procedure 177 (32.3%) Abdominal Pain 198 (36.1%) 36 (6.6%) 19 (3.5%) 6 (1.1%) 92 (16.8%) 10 (1.8%) 108 (19.7%) 21 (3.8%) 23 (4.2%) 5 (0.9%) with liver-dominant mCRC from July 2002 to December Prior chemotherapy lines, median (range) 2 (1- 6) Constipation 19 (3.5%) - - - 11 (2.0% - 8 (1.5%) - - - Duodenitis 1 (0.2%) 1 (0.2%) - - - - - 1 (0.2%) 1 (0.2%) - 2011 at 11 US institutions was conducted mCRC diagnosis to radioembolization, median (range) 17.5 months (0.7 - 95.0) Gastritis 3 (0.5%) 3 (0.5%) - - - 1 (0.2%) 3 (0.5%) 1 (0.2%) - 1 (0.2%) Gastrointestinal Perforation 1 (0.2%) - - - - - - - 1 (0.2%) -• The most experienced 15 centers in the US for Gastrointestinal Ulcer 11 (2.0%) 10 (1.8%) - - 1 (0.2%) - 6 (1.1%) 7 (1.3%) 4 (0.7%) 2 (0.4%) radioembolization were invited to participate, with 11 Intestinal Obtruction 2 (0.4%) 4 (0.7%) - - 1 (0.2%) 1 (0.2%) - 3 (0.5%) 1 (0.2%) - 0.25 S Nausea 155 (28.3%) 8 (1.5%) 28 (5.1%) 2 (0.4%) 74 (13.5%) 3 (05%) 61 (11.1%) 3 (0.5%) 10 (1.8%) 1 (0.2%) centers accepting. All patients with a diagnosis of mCRC were included from each site since the start of their PRIOR CHEMOTHERAPY HISTORY Vomiting CONSTITUTIONAL 58 (10.6%) 280 (51.1%) 9 (1.6%) 7 (1.3%) 31 (5.7%) - 19 (3.5%) 119 (21.7%) 5 (0.9%) 30 (5.5%) 185 (33.8%) 3 (0.5%) 1 (0.2%) 33 (6.0%) 1 (0.2%) program Fatigue 221 (40.3%) 33 (6.0%) 23 (4.2%) 3 (0.5%) 92 (16.8%) 6 (1.1%) 147 (26.8%) 22 (4.0%) 20 (3.6%) 3 (0.5%) Peripheral Edema 4 (0.7%) 5 (0.9%) - - - - 1 (0.2%) 2 (0.4%) 2 (0.4%) 2 (0.4%)• Institutional Review Board approval for exemption Prior Agents Exposure Across Prior Lines of Therapy, n (%) Pyrexia 42 (7.7%) 2 (0.4%) 3 (0.5%) 1 (0.2%) 26 (4.7%) - 17 (3.1%) 1 (0.2%) 2 (0.4%) - 0.00 0 00 was obtained for each site prior to data collection. All PSYCHIATRIC DISORDERS 50 (9.1%) 1 (0.2%) 22 (4.0%) 31 (5.7%) 3 (0.5%) 1 line 2 lines 3+ lines 0 10 20 30 40 50 identifiers were replaced with a study number Chemotherapy Agent (n = 206) (n = 184) (n = 158) Anorexia Nervosa 40 (7.3%) 6 (1.1%) 1 (0.2%) - 17 (3.1%) 3 (0.5%) 25 (4.6%) 3 (0.5%) 3 (0.5%) - HEPATOBILIARY DISORDERS 127 (23.2%) - 5 (0.9%) 75 (13.7%) 52 (9.5%) Time from Radioembolization (months)• Data was collected by an independent CRO at each fluoropyrimidine 185 (89.8%) 177 (96.2%) 155 (98.1%) Ascities 12 (2.2%) 19 (3.5%) - - - - 9 (1.6%) 10 (1.8%) 3 (0.5%) 6 (1.1%) Cholecystitis 5 (0.9%) 3 (0.5%) - - 2 (0.4%) - 3 (0.5%) 1 (0.2%) 1 (0.2%) 1 (0.2%) site using only original documents which included: oxaliplatin 148 (71.8%) 152 (82.6%) 150 (94.9%) Hepatic Failure 2 (0.4%) 2 (0.4%) - - 1 (0.2%) - 2 (0.4%) 2 (0.4%) - - background characteristics, prior chemotherapy, surgery/ Hyperbilirubinemia 62 (11.3%) 31 (5.7%) - - 1 (0.2%) - 35 (6.4%) 17 (3.1%) 29 (5.3%) 16 (2.9%) ablation, radiotherapy, vascular procedures, resin 90Y irinotecan 27 (13.1%) 124 (67.4%) 145 (91.8%) Radiation Hepatitis (RILD) 2 (0.4%) 3 (0.5%) - - - - 2 (0.4%) 3 (0.5%) 1 (0.2%) - treatment, subsequent adverse events (CTCAE 3.0) and Any biologic agent 141 (68.4%) 151 (82.1%) 148 (93.7%) CARDIAC DISORDERS 3 (0.5%) - 1 (0.2%) 3 (0.5%) - 3 (0.5%) - 1 (0.2%) 3 (0.5%) - survival bevacizumab 132 (64.1%) 139 (75.5%) 133 (84.2%) Cardiac Arrest Cardiac Failure Congestive - - 1 (0.2%) 1 (0.2%) - - - - - - 1 (0.2%) - - - - 1 (0.2%) - - - - CONCLUSIONS Coronary Artery Disease - 1 (0.2%) - - - - - 1 (0.2%) - -• Trends in the occurrence of adverse events for patients EGFR inhibitor 12 (5.8%) 44 (23.9%) 109 (69.0%) VASCULAR DISORDERS 16 (2.9%) 1 (0.2%) 6 (1.1%) 8 (1.5%) 1 (0.2%) receiving 1, 2 or 3+ lines of systemic chemotherapy were •  90Y-microsphere therapy appears to have a favorable risk/benefit ratio in patients with mCRC who have failed TKI inhibitors 0 1 (0.5%) 7 (4.4%) Hemodynamic Instabillity - 1 (0.2%) - - - 1 (0.2%) - - - - prior systemic chemotherapy evaluated by Fisher’s Exact Hypertension 2 (0.4%) - 1 (0.2%) - - - 1 (0.2%) - - - Unspecified agent(s) 16 (7.8%) 21 (11.4%) 14 (8.9%) Hypotension - 1 (0.2%) - - - 1 (0.2%) - - - -• Kaplan-Meier estimates compared the overall survival of Pulmonary Embolism - 1 (0.2%) - - - - - 1 (0.2%) - - • These data show a potentially clinically relevant survival benefit for 90Y therapy in patients not responding to patients across lines of chemotherapy Other agent(s) 3 (1.5%) 5 (2.7%) 13 (8.2%) Shock - 1 (0.2%) - - - - - 1 (0.2%) - - chemotherapy, including those heavily pre-treated (3+ lines)

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