Characterization of tumor dose heterogeneity for 90Y microsphere therapies using voxel- based dosimetry

Purpose: Dosimetry for 90Y microsphere therapies (YMT) with Standard (SM) and Partition (PM) models provide only uniform dose estimates to tumor and liver. Our objective is to calculate tumor dose heterogeneity, known to effect response, using voxel-based dosimetry and investigate the limitations of SM and PM.Methods: Voxel-based dosimetry was performed on 17 YMT patients using Monte Carlo DOSXYZnrc. 90Y activity and tissue/density distributions were based on quantitative 90Y bremsstrahlung SPECT/CT. Tumors (n=31), liver, and treatment lobe/segments were segmented on diagnostic CT or MR. Dose volume histograms (DVH) were created for tumors and normal liver. Bland-Altman analysis compared voxel-based mean absorbed doses to tumor and liver with SM and PM. Tumor and normal liver absorbed dose heterogeneity were investigated through metrics: integral uniformity (IU), D10/D90, COV. Correlations of heterogeneity with voxel-based mean doses and volumes were evaluated.Results: Heterogeneity metrics (mean ± 1σ) for tumor dose were COV = 0.48 ± 0.28, D10/D90 = 4.7 ± 3.9, and IU = 0.8 ± 0.18. Heterogeneity metrics correlated with tumor volume (r > 0.58) but not tumor mean doses (r < 0.20). Voxel-based tumor mean doses correlated with PM (r = 0.84) but not SM (r = 0.08). Both yielded poor limits of agreement with of 83 ± 174 and -28 ± 181 Gy, respectively. Normal liver heterogeneity metrics (mean ± 1σ) were COV = 0.83 ± 0.29, D10/D90 = 12 ± 15, and IU = 0.97 ± 0.03. Only D10/D90 (r = 0.49) correlated with mean normal liver absorbed dose. Voxel-based normal liver/lobe mean doses correlated with PM (r = 0.96), but had poor limits of agreement (26 ± 29 Gy).Conclusion: Tumor doses have high levels of heterogeneity that increase with volume but are independent of dose. Voxel-based DVH and dose heterogeneity metrics will promote accurate characterization of tumor response following YMT.--------------------------------------Cite this article as: Mikell J, Mourtada F, Mahvash A, Kappadath SC. Characterization of tumor dose heterogeneity for 90Y microsphere therapies using voxel- based dosimetry. Int J Cancer Ther Oncol 2014; 2(2):020228. DOI: 10.14319/ijcto.0202.2

Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

Background The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation. Methods The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed. Results Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders. Conclusions MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection. Trial registration ClinicalTrials.gov, NCT01277757 . Registered 13 January 2011

Characterization of tumor dose heterogeneity for 90Y microsphere therapies using voxel- based dosimetry

Purpose: Dosimetry for 90Y microsphere therapies (YMT) with Standard (SM) and Partition (PM) models provide only uniform dose estimates to tumor and liver. Our objective is to calculate tumor dose heterogeneity, known to effect response, using voxel-based dosimetry and investigate the limitations of SM and PM.Methods: Voxel-based dosimetry was performed on 17 YMT patients using Monte Carlo DOSXYZnrc. 90Y activity and tissue/density distributions were based on quantitative 90Y bremsstrahlung SPECT/CT. Tumors (n=31), liver, and treatment lobe/segments were segmented on diagnostic CT or MR. Dose volume histograms (DVH) were created for tumors and normal liver. Bland-Altman analysis compared voxel-based mean absorbed doses to tumor and liver with SM and PM. Tumor and normal liver absorbed dose heterogeneity were investigated through metrics: integral uniformity (IU), D10/D90, COV. Correlations of heterogeneity with voxel-based mean doses and volumes were evaluated.Results: Heterogeneity metrics (mean ± 1σ) for tumor dose were COV = 0.48 ± 0.28, D10/D90 = 4.7 ± 3.9, and IU = 0.8 ± 0.18. Heterogeneity metrics correlated with tumor volume (r &gt; 0.58) but not tumor mean doses (r &lt; 0.20). Voxel-based tumor mean doses correlated with PM (r = 0.84) but not SM (r = 0.08). Both yielded poor limits of agreement with of 83 ± 174 and -28 ± 181 Gy, respectively. Normal liver heterogeneity metrics (mean ± 1σ) were COV = 0.83 ± 0.29, D10/D90 = 12 ± 15, and IU = 0.97 ± 0.03. Only D10/D90 (r = 0.49) correlated with mean normal liver absorbed dose. Voxel-based normal liver/lobe mean doses correlated with PM (r = 0.96), but had poor limits of agreement (26 ± 29 Gy).Conclusion: Tumor doses have high levels of heterogeneity that increase with volume but are independent of dose. Voxel-based DVH and dose heterogeneity metrics will promote accurate characterization of tumor response following YMT.--------------------------------------Cite this article as: Mikell J, Mourtada F, Mahvash A, Kappadath SC. Characterization of tumor dose heterogeneity for 90Y microsphere therapies using voxel- based dosimetry. Int J Cancer Ther Oncol 2014; 2(2):020228. DOI: 10.14319/ijcto.0202.28</p

Calculation of lung mean dose and quantification of error for Y-90-microsphere radioembolization using Tc-99m-MAA SPECT/CT and diagnostic chest CT

Purpose: Current treatment planning for 90Y radioembolization estimates lung mean dose (LMD) by measuring the lung shunt fraction (LSF) from 99mTc-macroaggregated albumin (MAA) planar imaging and assuming a 1-kg lung mass. This methodology, however, overestimates LSF and LMD and could therefore unnecessarily limit the dose to target volume(s). We propose an improved LMD calculation that derives LSF from 99mTc-MAA SPECT/CT and the patient-specific lung mass from diagnostic chest CT. Furthermore, we investigated the errors in lung mass, LSF, and LMD arising from contour variability in patient data in order to estimate the precision of our proposed methodology. Methods: Our proposed LMD (LMDnew) calculation consisted of the following steps: (a) estimate liver counts from the MAA SPECT/CT liver contour; (b) estimate total lung counts by multiplying density (counts/g) from the MAA SPECT/CT left-lung contour by the total lung mass (g) from the diagnostic CT lung contours; (c) compute LSFnew from liver and lung counts; (d) calculate LMDnew using LSFnew and the total lung mass from the diagnostic CT (Mnew). LMDnew, LSFnew, and Mnew estimates were compared to standard model values (LMDclin, LSFclin, and 1 kg, respectively) in 52 consecutive patients with hepatocellular carcinoma who underwent radioembolization using 90Y glass microspheres. The precision of our methodology was quantified by varying lung and liver contours in the same patient population and calculating the resulting relative errors in the liver count, lung count, and lung mass measurements. Results: The median Mnew was 839 g (range, 550–1178 g) for men and 731 g (range, 548–869 g) for women. The median LSFnew was 0.02 (range, 0.01–0.11), while the median LMDnew was 4.9 Gy (range, 0.3–25.5 Gy). Mnew, LSFnew, and LMDnew were significantly lower than Mclin, LSFclin, and LMDclin, with respective relative mean (±SD) differences of −20% (±16%) for Mnew, −63% (±15%) for LSFnew, and −53% (±23%) for LMDnew. The estimated 1-sigma uncertainties in Mnew, LSFnew, and LMDnew were 9%, 10%, and 13%, respectively. Conclusions: We derived a method to calculate lung mass and LSF using routinely available diagnostic chest CT and 99mTc-MAA SPECT/CT. More importantly, we systematically quantified the errors in our measurements to establish the precision of the estimated lung dose (13%). The proposed methodology provides a more accurate LMD and an estimate of its precision, which will improve treatment and retreatment planning for 90Y radioembolizations

Temporary Balloon Occlusion of the Common Hepatic Artery for Yttrium-90 Glass Microspheres Administration in a Patient with Hepatocellular Cancer and Renal Insufficiency

The most severe complication of yttrium-90 therapy is gastrointestinal ulceration caused by extrahepatic dispersion of microspheres. Standard pretreatment planning requires extensive angiographic evaluation of the hepatic circulation and embolization of hepatoenteric collaterals; however, in patients with severe renal insufficiency, this evaluation may lead to acute renal failure. In order to minimize iodinated contrast utilization in a patient with preexisting severe renal insufficiency, the authors describe the use of a balloon catheter for temporary occlusion of the common hepatic artery to induce transient redirection of flow of the hepatoenteric arteries towards the liver, in lieu of conventional coil embolization

Selective Internal Radiation Therapy with Yttrium-90 for Intrahepatic Cholangiocarcinoma: A Systematic Review on Post-Treatment Dosimetry and Concomitant Chemotherapy

Selective internal radiation therapy (SIRT) with yttrium-90 (90Y)-loaded microspheres is increasingly used for the treatment of Intrahepatic Cholangiocarcinoma (ICC). Dosimetry verifications post-treatment are required for a valid assessment of any dose-response relationship. We performed a systematic review of the literature to determine how often clinics conducted post-treatment dosimetry verification to measure the actual radiation doses delivered to the tumor and to the normal liver in patients who underwent SIRT for ICC, and also to explore the corresponding dose-response relationship. We also investigated other factors that potentially affect treatment outcomes, including the type of microspheres used and concomitant chemotherapy. Out of the final 47 studies that entered our study, only four papers included post-treatment dosimetry studies after SIRT to quantitatively assess the radiation doses delivered. No study showed that one microsphere type provided a benefit over another, one study demonstrated better imaging-based response rates associated with the use of glass-based TheraSpheres, and two studies found similar toxicity profiles for different types of microspheres. Gemcitabine and cisplatin were the most common chemotherapeutic drugs for concomitant administration with SIRT. Future studies of SIRT for ICC should include dosimetry to optimize treatment planning and post-treatment radiation dosage measurements in order to reliably predict patient responses and liver toxicity

Temporary Reversal of Hepatoenteric Collaterals during ⁹⁰Y Radioembolization Planning and Administration

Purpose: This paper aims to evaluate the safety and efficacy of the temporary redirection of blood flow of hepatoenteric collaterals using a balloon catheter in the common hepatic artery (CHA) to prevent the nontarget deposition of 90Y microspheres. Materials and Methods: In this retrospective single-center study of patients who received 90Y radioembolization (RE) from September 2010 to September 2015, diagnostic (67 patients) or treatment (72 patients) angiograms with the attempted use of a balloon catheter in the CHA to temporarily direct blood flow away from the hepatoenteric arteries were analyzed. SPECT/CT nuclear scintigraphy was performed after both diagnosis and treatment. Results: Overall, only 12 hepatoenteric arteries in 11 patients required embolization due to persistent hepatoenteric flow despite the use of the balloon occlusion technique in a total of 86 patients. Physicians performed the 90Y RE using balloon occlusion with glass (n = 22) or resin (n = 50) microspheres. Over 80% administration of the prescribed 90Y dose was accomplished in 34 (67%) resin and 20 (95%) glass microsphere patients. Post-treatment 90Y RE scintigraphy confirmed the absence of extrahepatic activity in all patients. One grade 2 gastrointestinal ulcer was present after 90 days of follow-up. Conclusion: Temporary CHA occlusion with a balloon catheter is a reliable and reproducible alternative to the conventional coil embolization of hepatoenteric arteries during diagnostic Tc-99m macroaggregated albumin and therapeutic 90Y RE delivery

Baseline Apparent Diffusion Coefficient as a Predictor of Response to Liver-Directed Therapies in Hepatocellular Carcinoma

Predicting outcomes in patients with hepatocellular carcinoma (HCC) who undergo locoregional therapies remains a substantial clinical challenge. The purpose of this study was to investigate pre-procedure diffusion weighted magnetic resonance imaging (DW-MRI) as an imaging biomarker for tumoral response to therapy for patients with HCC undergoing drug eluting embolic (DEE) chemoembolization and radioembolization. A retrospective review of HCC patients who underwent DEE chemoembolization or radioembolization was performed. Of the 58 patients who comprised the study population, 32 underwent DEE chemoembolization and 26 underwent radioembolization. There was no significant difference in median apparent diffusion coefficient (ADC) values across the two treatment groups (1.01 × 10−3 mm2/s, P = 0.25). The immediate objective response (OR) rate was 71% (40/56). Tumors with high ADC values were found to have a higher probability of OR within 90 days (odds ratio 4.4, P = 0.03). Moreover, index lesion specific progression free survival (PFS) was greater for high ADC tumors, independent of conventional predictors of treatment response (hazard ratio 0.44, P = 0.01). Low ADC was associated with poorer PFS (P = 0.02). Pre-procedure ADC &lt; 1.01 × 10−3 mm2/s is an independent predictor of poorer immediate OR and index lesion specific PFS in patients with HCC undergoing DEE chemoembolization or radioembolization