Patrick McNeillie

Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: Early results in 148 patients

Purpose:The use of 90Y-microspheres to treat unresectable liver metastases originating from a variety of neuroendocrine tumors was reviewed. Materials and Methods:This is a retrospective review from 10 institutions of patients given 90Y-microsphere therapy for neuroendocrine hepatic metastases. Physical, radiographic, biochemical, and clinical factors associated with treatment and response were examined. All patients were followed with laboratory and imaging studies at regular intervals until death, or censured whether other therapy was given after brachytherapy. Toxicities (acute and late) were recorded, and survival of the group determined. Results:A total of 148 patients were treated with 185 separate procedures. The median age was 58 years (26–95 years) at treatment with median performance status of Eastern Cooperative Oncology Group (0). The median activity delivered was 1.14 GBq (0.33–3.30 GBq) with a median of 99% of the planned activity able to be given (38.1%–147.4%). There were no acute or delayed toxicity of Common Terminology Criteria for Adverse Events v3.0 grade 3 in 67% of patients, with fatigue (6.5%) the most common side effect. Imaging response was stable in 22.7%, partial response in 60.5%, complete in 2.7% and progressive disease in 4.9%. No radiation liver failure occurred. The median survival is 70 months. Conclusion:Radioembolization with 90Y-microspheres to the whole liver, or lobe with single or multiple fractions are safe and produce high response rates, even with extensive tumor replacement of normal liver and/or heavy pretreatment. The acute and delayed toxicity was very low without a treatment related grade 4 acute event or radiation induced liver disease in this modest-sized cohort. The significant objective response suggests that further investigation of this approach is warranted.

Treatment Parameters and Outcome in 680 Treatments of Internal Radiation With Resin 90Y-Microspheres for Unresectable Hepatic Tumors

PURPOSE Radioembolization (RE) using (90)Y-microspheres is an effective and safe treatment for patients with unresectable liver malignancies. Radiation-induced liver disease (RILD) is rare after RE; however, greater understanding of radiation-related factors leading to serious liver toxicity is needed. METHODS AND MATERIALS Retrospective review of radiation parameters was performed. All data pertaining to demographics, tumor, radiation, and outcomes were analyzed for significance and dependencies to develop a predictive model for RILD. Toxicity was scored using the National Cancer Institute Common Toxicity Criteria Adverse Events Version 3.0 scale. RESULTS A total of 515 patients (287 men; 228 women) from 14 US and 2 EU centers underwent 680 separate RE treatments with resin (90)Y-microspheres in 2003-2006. Multifactorial analyses identified factors related to toxicity, including activity (GBq) Selective Internal Radiation Therapy delivered (p < 0.0001), prescribed (GBq) activity (p < 0.0001), percentage of empiric activity (GBq) delivered (p < 0.0001), number of prior liver treatments (p < 0.0008), and medical center (p < 0.0001). The RILD was diagnosed in 28 of 680 treatments (4%), with 21 of 28 cases (75%) from one center, which used the empiric method. CONCLUSIONS There was an association between the empiric method, percentage of calculated activity delivered to the patient, and the most severe toxicity, RILD. A predictive model for RILD is not yet possible given the large variance in these data.

Safety and efficacy of Y-90 microsphere treatment in patients with primary and metastatic liver cancer: The tumor selectivity of the treatment as a function of tumor to liver flow ratio

BackgroundTreatment records and follow-up data on 40 patients with primary and metastatic liver malignancies who underwent a single whole-liver treatment with Y-90 resin microspheres (SIR-Spheres® Sirtex Medical, Lake Forest, IL) were retrospectively reviewed. The objective of the study was to evaluate the anatomic and physiologic determinants of radiation dose distribution, and the dose response of tumor and liver toxicity in patients with liver malignancies who underwent hepatic arterial Y-90 resin microsphere treatment.MethodsLiver and tumor volume calculations were performed on pre-treatment CT scans. Fractional tumor and liver flow characteristics and lung shunt fractions were determined using hepatic arterial Tc-99m MAA imaging. Absorbed dose calculations were performed using the MIRD equations. Liver toxicity was assessed clinically and by liver function tests. Tumor response to therapy was assessed by CT and/or tumor markers.ResultsOf the 40 patients, 5 had hepatocellular cancer (HCC), and 35 had metastatic liver tumors (15 colorectal cancer, 10 neuroendocrine tumors, 4 breast cancer, 2 lung cancer, 1 ovarian cancer, 1 endometrial cancer, and 2 unknown primary adenocarcinoma). All patients were treated in a salvage setting with a 3 to 80 week follow-up (mean: 19 weeks). Tumor volumes ranged from 15.0 to 984.2 cc (mean: 294.9 cc) and tumor to normal liver uptake ratios ranged from 2.8 to 15.4 (mean: 5.4). Average administered activity was 1.2 GBq (0.4 to 2.4 GBq). Liver absorbed doses ranged from 0.7 to 99.5 Gy (mean: 17.2 Gy). Tumor absorbed doses ranged from 40.1 to 494.8 Gy (mean: 121.5 Gy). None of the patients had clinical venoocclusive disease or therapy-induced liver failure. Seven patients (17.5 %) had transient and 7 patients (17.5 %) had persistent LFT abnormalities. There were 27 (67.5%) responders (complete response, partial response, and stable disease). Tumor response correlated with higher tumor flow ratio as measured by Tc-99m MAA imaging.ConclusionDoses up to 99.5 Gy to uninvolved liver are tolerated with no clinical venoocclusive disease or liver failure. The lowest tumor dose producing a detectable response is 40.1 Gy. The utilization of MAA-based imaging techniques to determine tumor and liver blood flow for clinical treatment planning and the calculation of administered activity may improve clinical outcomes.

Post-transplantation Lymphoproliferative Disease Epstein-Barr Virus DNA Levels, HLA-A3, and Survival

RATIONALE Elevation in Epstein-Barr virus (EBV) circulating DNA has been proposed as a marker for development of post-transplant lymphoproliferative disease (PTLD), but few published data exist in the study of lung-transplant recipients. OBJECTIVES To determine if elevated EBV DNA levels, in combination with other risk factors, were predictive of PTLD. METHODS We conducted a retrospective, single-center study examining all lung transplant recipients (n = 296) and EBV DNA levels (n = 612) using real-time TaqMan polymerase chain reaction. There were 13 cases of PTLD overall, of which 5 occurred in the era of EBV DNA monitoring. MEASUREMENTS AND MAIN RESULTS EBV DNA levels were distributed differently among seropositive and seronegative patients, with the latter having higher values (P < 0.0001). Among the cohort of pretransplantation seropositive patients, there was one diagnosed with PTLD. The EBV DNA level in this patient was elevated at the time of PTLD diagnosis (sensitivity = 100%, specificity = 100% for PTLD). Among the cohort of pretransplantation seronegative patients, there were four with a diagnosis of PTLD. In all four patients, the EBV DNA level was detectable (sensitivity = 100%, specificity = 24%), but in only two was it elevated (sensitivity = 50%, specificity = 22%). HLA-A3 expression in the recipient and/or donor conferred additional risk for PTLD among the seronegative patients (P = 0.026 to 0.003). No other PTLD risk factor was found. CONCLUSIONS EBV DNA levels are a useful but imperfect predictor of PTLD in patients with lung transplants. Pretransplant EBV status affected the results of the assay and should be considered when interpreting test results. HLA-A3 was strongly linked to PTLD and may be a novel marker of PTLD risk.

Combined donor specific transfusion and anti‐CD154 therapy achieves airway allograft tolerance

Background: The state of tolerance allows long term graft survival without immunosuppressants. Lung transplantation tolerance has not been consistently achieved in either small or large animal models. Methods: The mechanisms and effectiveness of a tolerance induction protocol consisting of donor specific transfusion (DST; day 0) and a short course of co-stimulatory blockade (anti-CD154 antibody; days −7, −4, 0 and +4) were studied in the mouse heterotopic tracheal transplant model of chronic lung rejection. C57BL/6 mice received BALB/c tracheal grafts (day 0) and were treated with DST alone, anti-CD154 alone, the combination (DST/anti-CD154), or no treatment. No non-specific immunosuppressants were used. Results: DST/anti-CD154 in combination, but neither treatment alone, markedly prolonged the lumen patency and survival (>100 days) of fully histo-incompatible allografts (p<0.05 versus control allografts at every time point studied up to 16 weeks) without immunosuppression. This protocol was donor antigen specific as third party grafts (C3H) were promptly rejected. In addition, DST/anti-CD154 did not result in mixed chimerism but induced transplantation tolerance via a peripheral mechanism(s), which included significantly reduced cytotoxic T cell activity (p<0.001) and a significantly increased percentage of CD4+CD25+ cells (p = 0.03). Conclusions: The DST/anti-CD154 protocol successfully induced and maintained long term, donor specific tolerance in the mouse heterotopic airway graft model of chronic lung rejection. This finding may lead us closer to successful tolerance induction in lung transplantation.

90 Y Microspheres: Concepts and Principles

Why use radiation in the liver at all since it is known to be much more sensitive to radiation damage than the tumors growing in it? This is an excellent and oft-stated question by many in oncology. With the development of internal brachytherapy, the delivery of tumoricidal doses of radiation to tumors of all origins and in all segments of the liver became a reality. Recent advances in medical oncology (anti-angiogenic agents, new systemic chemotherapy agents) have produced encouraging response rates and increased median survivals for many solid tumors. However, despite clearance of disease elsewhere in the body, the liver is usually the site of tumor resistance and ultimately the patient’s death. Moreover, with increased skill and more sophisticated and specialized catheters, today’s interventional radiologists are able to help oncology patients more than ever before. Precise access to the particular artery feeding a chemoinsensitive or unresectable tumor is now a widely available service in most medical centers that treat cancer patients.

Dosimetry and Dose Calculation

Two components relate to the topic of dosimetry in microsphere therapy. Dose (Gy) that is desired to be delivered to tumor tissue in the liver; and the activity (GBq) of yttrium-90 (90Y) delivered to the target organ. Classically, dosimetry is a Radiation Oncology term for the estimation of the absorbed dose expressed in units of Gy of radiation in tissue that will be or has been delivered. For microsphere treatment, it is more appropriate to describe an activity of radiation that will be implanted into the liver tumors, as there is not yet a proven way of preplan or post-plan confirmation of the absorbed dose in the target tissue. In other brachytherapy sites, seeds measuring several millimeters in size can be readily identified on CT scan or plain film and the resultant absorbed dose in the tissue calculated by hand or software solution. Microsphere implantation is a hybrid of interstitial brachytherapy and radioactive liquid therapy which at the present time is more accurately characterized by Nuclear Medicine conventions (Medical Internal Radiation Dose, MIRD) Committee of the Society of Nuclear Medicine [1] MIRD [2-5] and Partition Model [6, 7] than current or historical brachytherapy dose calculation methods (Patterson Parker, Point Source, and Volume Implant Rules).

Development of a tissue-equivalent human liver phantom for 90Y-microsphere dosimetry studies and testing of other local ablation therapies.

244 Background: 90Y-microsphere brachytherapy for unresectable hepatic cancers is an increasingly popular therapy. The beta radiation dosimetry involved is not well understood and there is lack of pre and post treatment planning capabilities. METHODS A phantom was developed with tissue equivalent electron density, accurate anthropomorphic size, shape and volume to an adult human liver, with similar properties in response to heat, cold, radiation and diagnostic imaging as human liver tissue. Space-occupying masses were created to accommodate implantation of microspheres to simulate a human treatment. Imaging included MRI, CT and SPECT gamma scans pre and post implantation of 90Y-microspheres. RESULTS A phantom was produced that was shaped from a mold of an adult human liver. A mass with a different density than the liver was created in the right lobe that had a 3mm - 6mm rim for microsphere implantation. A known quantity of 99mTc was implanted into the left lobe. 90Y-microspheres of known activity were implanted in the periphery of the right lobe tumor. CT contrast was mixed with the microspheres to improve localization on subsequent CT scans. The electron density of the phantom was identical to human liver. Microsphere implantation was limited to the outer 6 mm of the right lobe tumor and 99mTc limited to the left lobe. Spatial resolution in 3D was excellent on all three modalities (MRI, CT and SPECT gamma). CONCLUSIONS A human liver phantom as described will be a useful tool in future studies of beta radiation dosimetry, cross sectional and nuclear imaging and tissue responses. The next generation phantom is being developed with blood vessel-like branching channels to allow fluids to pass into and through the phantom similar in scale and diameter to hepatic vessels and tumors.

Results in Liver Metastatic Colorectal Cancer

Patients with metastatic colorectal cancer (mCRC) involving the liver present several therapeutic challenges for the oncology team. The majority of patients will not be candidates for potentially curative surgical resection and therefore must rely on other local therapies to augment systemic cheotherapy. Unlike some other solid tumors with liver metastases, mCRC patients now have access to a plethora of new biologic agents and cytotoxic drugs that did not exist a decade ago. Changes in liver arterial caliber and tolerance of liver lobules to radiation are both negatively effected by these new systemic therapies and have had an impact on aspects of microsphere therapy.

Liver Tolerance to Repeat 90Y-Microsphere Radioembolization

Purpose: Liver tolerance to multiple doses of Y90-microspheres is not known. Many patients (pts) are surviving long enough to be considered for a second and third liver treatments with internal radiation. Materials and Methods: The experience of a single center treating liver tumors with resin Y90-microspheres. Pts that received liver radiation prior to or after resin microsphere therapy were studied. Endpoints were toxicity, tumor response, shunting to lung, and effects on liver volume and function. The delivery activity of microspheres selected was not reduced below BSA dose calculation for patients without prior treatment. All patients received bilobar single session delivery. Results: A total of 38 pts; 14 women, 24 men, treated 6∕2003 to 9∕2006, with 33 pts receiving 2 courses and 5 pts with 3 courses of liver radiation. Retreatment with resin microspheres 26 pts, prior external beam radiation in 7 pts, prior glass microspheres in 2 pts, prior systemic radiotherapy in 2 pts, and prior stereotactic liver radiation in 1 pt. Liver function was stable and adequate in all patients after additional liver radiation, and no pts developed radiation-induced liver dysfunction (RILD) or veno-occlusive disease (VOD). The percentage of shunting to the lung decreased with retreatment. Conclusions: Repeated implantation in the liver with Y90-microspheres is safe in patients that have sufficient liver function and reserve based on known and accepted laboratory parameters already used for selection of microsphere therapy. No acute life-threatening, fatal, or late liver damage was observed, RILD or VOD. No specific dose reduction is recommended for retreatment of the liver.