Samuel G. Putnam

Multicenter evaluation of the safety and efficacy of radioembolization in patients with unresectable colorectal liver metastases selected as candidates for (90)Y resin microspheres.

BACKGROUND Metastatic colorectal cancer liver metastases Outcomes after RadioEmbolization (MORE) was an investigator-initiated case-control study to assess the experience of 11 US centers who treated liver-dominant metastases from colorectal cancer (mCRC) using radioembolization [selective internal radiation therapy (SIRT)] with yttrium-90-((90)Y)-labeled resin microspheres. METHODS Data from 606 consecutive patients who received radioembolization between July 2002 and December 2011 were collected by an independent research organization. Adverse events (AEs) and survival were compared across lines of treatment using Fishers exact test and Kaplan-Meier estimates, respectively. RESULTS Patients received a median of 2 (range, 0-6) lines of prior chemotherapy; 35.1% had limited extrahepatic metastases. Median tumor-to-liver ratio and -activity administered at first procedure were 15% and 1.17 GBq, respectively. Hospital stay was <24 hours in 97.8% cases. Common grade ≥3 AEs over 184 days follow-up were: abdominal pain (6.1%), fatigue (5.5%), hyperbilirubinemia (5.4%), ascites (3.6%) and gastrointestinal ulceration (1.7%). There was no statistical difference in AEs across treatment lines (P>0.05). Median survivals [95% confidence interval (CI)] following radioembolization as a 2(nd)-line, 3(rd)-line, or 4(th)-plus line were 13.0 (range, 10.5-14.6), 9.0 (range, 7.8-11.0), and 8.1 (range, 6.4-9.3) months, respectively; and significantly prolonged in patients with ECOG 0 vs. ≥1 (P=0.009). Statistically significant independent variables for survival at radioembolization were: disease stage [extrahepatic metastases, extent of liver involvement (tumor-to-treated-liver ratio)], liver function (uncontrolled ascites, albumin, alkaline phosphatase, aspartate transaminase), leukocytes, and prior chemotherapy. CONCLUSIONS Radioembolization appears to have a favorable risk/benefit profile, even among mCRC patients who had received ≥3 prior lines of chemotherapy.

Thermal ablation of the small renal mass: Case selection using the R.E.N.A.L.-Nephrometry Score

OBJECTIVES Treatment decision-making for localized renal lesions remains overly subjective. While the AUA Guidelines list thermal ablation (TA) as a treatment option for the clinical T1 renal mass, few data exist regarding the relationship between TA and tumor complexity. The R.E.N.A.L.-Nephrometry Scoring System (NS) was introduced to objectify salient renal mass anatomy and standardize academic reporting. Here we correlate the salient anatomical attributes of renal masses undergoing TA with technical and oncologic outcomes. MATERIALS AND METHODS We queried our prospectively maintained kidney cancer database of 2,312 patients and identified 39 patients who underwent TA with available nephrometry scores. Patient clinical, technical, functional, and oncologic characteristics were reviewed. RESULTS Median patient age, serum creatinine, estimated glomerular filtration rate, and Charlson Comorbidity Index were 71 (range = 57-86) years, 1.37 (range = 0.7-3.5) mg/dl, 57.1 (range = 23.3-93.8) ml/min, and 2 (range = 0-5), respectively. Median Nephrometry Score for patients undergoing tumor ablation was 6 (4-10). Low (NS = 4-6), moderate (NS = 7-9), and high (NS = 10-12) complexity tumors were identified in 20 (51.3%), 17 (43.6%), and 2 (5.1%) patients. Six (15%) patients experienced a tumor recurrence. Of those with a recurrence, 5/6 (83.3%) had moderate complexity tumors with the remaining tumor being low complexity. Minor and major Clavien complications occurred in 4 (10%) and 1 (3%) patients, all of whom had moderate complexity tumors. CONCLUSIONS At our institution, 95% of tumors undergoing TA were anatomically low or moderate complexity lesions as measured by the R.E.N.A.L.-Nephrometry Scoring System. Nephrometry may help predict disease recurrence and peri-procedural complications, yet multi-institutional analysis is needed to further validate these findings.

Transhepatic Dialysis Catheter Tract Embolization to Close a Venous-Biliary-Peritoneal Fistula

O SCVIR, 1998 THE use of transhepatic venous catheters in patients with extremely limited venous access has been described (1-4). Transhepatic placement of large-bore hemodialysis catheters also has been reported (5,6). These limited studies describe techniques for insertion and maintenance of these catheters; however, none describe techniques to limit complications secondary to removal of these catheters. Potential complications include hemorrhage, biliary fistulas, and peritonitis. At our institution, we had a case of near fatal intraperitoneal hemorrhage that developed after inadvertent removal of a transhepatic hemodialysis catheter. Several investigators have described techniques to limit hemorrhage after percutaneous liver biopsy (7-9) and biliary or gallbladder drainage (10-12). Applying similar techniques to those previously described, we present a case of catheter tract embolization after transhepatic hemodialysis catheter removal to isolate a catheter tract-biliary fistula and to prevent potential intraperitoneal hemorrhage.

Phase I study of capecitabine combined with radioembolization using yttrium-90 resin microspheres (SIR-Spheres) in patients with advanced cancer

Background:This was a prospective single-centre, phase I study to document the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended phase II dose for future study of capecitabine in combination with radioembolization.Methods:Patients with advanced unresectable liver-dominant cancer were enrolled in a 3+3 design with escalating doses of capecitabine (375–1000 mg/m2 b.i.d.) for 14 days every 21 days. Radioembolization with 90Y-resin microspheres was administered using a sequential lobar approach with two cycles of capecitabine.Results:Twenty-four patients (17 colorectal) were enrolled. The MTD was not reached. Haematologic events were generally mild. Common grade 1/2 non-haematologic toxicities included transient transaminitis/alkaline phosphatase elevation (9 (37.5%) patients), nausea (9 (37.5%)), abdominal pain (7 (29.0%)), fatigue (7 (29.0%)), and hand-foot syndrome or rash/desquamation (7 (29.0%)). One patient experienced a partial gastric antral perforation with a capecitabine dose of 750 mg/m2. The best response was partial response in four (16.7%) patients, stable disease in 17 (70.8%) and progression in three (12.5%). Median time to progression and overall survival of the metastatic colorectal cancer cohort was 6.4 and 8.1 months, respectively.Conclusions:This combined modality treatment was generally well tolerated with encouraging clinical activity. Capecitabine 1000 mg/m2 b.i.d. is recommended for phase II study with sequential lobar radioembolization.

Hepatic imaging response to radioembolization with yttrium-90-labeled resin microspheres for tumor progression during systemic chemotherapy in patients with colorectal liver metastases

BACKGROUND To assess response and the impact of imaging artifacts following radioembolization with yttrium-90-labeled resin microspheres ((90)Y-RE) based on the findings from a central independent review of patients with liver-dominant metastatic colorectal cancer (mCRC). METHODS Patients with mCRC who received (90)Y-RE (SIR-Spheres(®); Sirtex Medical, Sydney, Australia) at nine US institutions between July 2002 and December 2011 were included in the analysis. Tumor response was assessed at baseline and 3 months using either the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 or 1.1. For each lesion, known artifacts affecting the interpretation of response (peri-tumoral edema and necrosis) were documented. Survivals (Kaplan-Meier analyses) were compared in responders [partial response (PR)] and non-responders [stable (SD) or progressive disease (PD)]. RESULTS Overall, 195 patients (mean age 62 years) received (90)Y-RE after a median of 2 (range, 1-6) lines of prior chemotherapy. Using RECIST 1.0 and RECIST 1.1, 7.6% and 6.9% of patients were partial responders, 47.3% and 48.1% had SD, and 55.0% and 55.0% PD, respectively. RECIST 1.0 and RECIST 1.1 showed excellent agreement {Kappa =0.915 [95% confidence interval (CI): 0.856-0.975]}. Peri-tumoral edema was documented in 32.8%, necrosis in 48.1% and both in 57.3% of cases (using RECIST 1.0). Although baseline characteristics were similar in responders and non-responders (P>0.05), responders survived significantly longer in an analysis according to RECIST 1.0: PR median (95% CI) 25.2 (range, 9.2-49.4) months vs. SD 15.8 (range, 9.3-21.1) months vs. PD 7.1 (range, 6.0-9.5) months (P<0.0001). CONCLUSIONS RECIST 1.0 and RECIST 1.1 imaging responses provide equivalent interpretations in the assessment of hepatic tumors following (90)Y-RE. Radiologic lesion responses at 3 months must be interpreted with caution due to the significant proportion of patients with peri-tumoral edema and necrosis, which may lead to an under-estimation of PR/SD. Nevertheless, 3-month radiologic responses were predictive of prolonged survival.

Hepatopulmonary Shunting: A Prognostic Indicator of Survival in Patients with Metastatic Colorectal Adenocarcinoma Treated with 90Y Radioembolization

Purpose To determine if high lung shunt fraction (LSF) is an independent prognostic indicator of poor survival in patients who undergo yttrium 90 radioembolization for unresectable liver-dominant metastatic colorectal cancer. Materials and Methods Retrospective data were analyzed from 606 patients (62% men; mean age, 62 years) who underwent radioembolization to treat liver metastases from colorectal adenocarcinoma between July 2002 and December 2011 at 11 U.S. centers. Institutional review board exemptions were granted prior to the collection of data at each site. Overall survival was estimated by using Kaplan-Meier survival and univariate Cox proportional hazards models to examine the effect of LSF on survival and to compare this to other potential prognostic indicators. Multivariate analysis was also performed to determine whether LSF is an independent risk factor for poor survival. Results LSF higher than 10% was predictive of significantly decreased survival (median, 6.9 months vs 10.0 months; hazard ratio, 1.60; P < .001) and demonstrated a mild but significant correlation to serum carcinoembryonic antigen levels and tumor-to-liver volume ratio (Pearson correlation coefficients, 0.105 and 0.113, respectively; P < .05). A progressive decrease in survival was observed as LSF increased from less than 5% to more than 20% (P < .05). LSF did not correlate with the presence of extrahepatic metastases or prior administration of bevacizumab. Conclusion Increased LSF is an independent prognostic indicator of worse survival in patients undergoing radioembolization for liver-dominant metastatic colorectal adenocarcinoma. High LSF correlates poorly to other potential markers of tumor size, such as tumor-to-liver volume ratio or serum carcinoembryonic antigen level, and does not correlate to the presence of extrahepatic metastases.

Baseline hemoglobin and liver function predict tolerability and overall survival of patients receiving radioembolization for chemotherapy-refractory metastatic colorectal cancer

BACKGROUND Patients with liver metastatic colorectal cancer (mCRC) often benefit from receiving 90Y-microsphere radioembolization (RE) administered via the hepatic arteries. Prior to delivery of liver-directed radiation, standard laboratory tests may assist in improving outcome by identifying correctable pre-radiation abnormalities. METHODS A database containing retrospective review of consecutively treated patients of mCRC from July 2002 to December 2011 at 11 US institutions was used. Data collected included background characteristics, prior chemotherapy, surgery/ablation, radiotherapy, vascular procedures, 90Y treatment, subsequent adverse events and survival. Kaplan-Meier estimates compared the survival of patients across lines of chemotherapy. The following values were obtained within 10 days prior to each RE treatment: haemoglobin (HGB), albumin, alkaline phosphatase (Alk phosph), aspartate aminotransferase (AST), alanine transaminase (ALT), total bilirubin and creatinine. Common Terminology Criteria Adverse Events (CTCAEs) 3.0 grade was assigned to each parameter and analysed for impact on survival by line of chemotherapy. Consensus Guidelines were used to categorize the parameter grades as either within or outside guidelines for treatment. RESULTS A total of 606 patients (370 male; 236 female) were studied with a median follow-up was 8.5 mo. (IQR 4.3-15.6) after RE. Fewer than 11% of patients were treated outside recommended RE guidelines, with albumin being the most common, 10.5% grade 2 (<3-2.0 g/dL) at time of RE. All seven parameters showed statistically significant decreased median survivals with any grade >0 (P<0.001) across all lines of prior chemotherapy. Compared to grade 0, grade 2 albumin decreased overall survival 67%; for grade 2 total bilirubin a 63% drop occurred, and grade 1 HGB resulted in 66% lower median survival. CONCLUSIONS Review of pre-RE laboratory parameters may aid in improving median survivals if correctable grade >0 values are addressed prior to radiation delivery. HGB <10 g/dL is a well-known negative factor in radiation response and is easily corrected. Improving other parameters is more challenging. These efforts are important in optimizing treatment response to liver radiotherapy.