Molecular Perspectives in Radioactive Iodine Theranostics: Current Redifferentiation Protocols for Mis-Differentiated Thyroid Cancer.

Thyroid cancer molecular oncogenesis involves functional dedifferentiation. The initiating genomic alterations primarily affect the MAPK pathway signal transduction and generate an enhanced ERK output, which in turn results in suppression of the expression of transcription of the molecules of iodine metabolomics. The clinical end result of these molecular alterations is an attenuation in theranostic power of radioactive iodine (RAI). The utilization of RAI in systemic therapy of metastatic disease requires restoration of the functional differentiation. This concept has been accomplished by modulation of MAPK signaling. Objective responses have been demonstrated in metastatic disease settings. RAI-refractoriness in "differentiated thyroid cancers" remains a clinical problem despite optimized RAI administration protocols. Functional mis-differentiation and associated RAI-indifference are the underlying primary obstacles. MAPK pathway modulation offers a potential for reversal of RAI-indifference and combat refractoriness. This review presents the latest clinical experience and protocols for the redifferentiation of radioiodine-refractory mis-differentiated thyroid cancer, providing a comprehensive overview of the current protocols and intervention strategies used by leading institutions. Timing and techniques of imaging, thyrotropin (TSH) stimulation methods, and redifferentiation agents are presented. The efficacy and limitations of various approaches are discussed, providing an overview of the advantages and disadvantages associated with each of the protocols.

Theranostic Risk Stratification for Thyroid Cancer in the Genomic Paradigm.

Theranostics define diagnostic evaluations directing patient-specific therapeutic decisions. Molecular theranostics involves genomic, transcriptomic, proteomic, metabolomic and finally phenonic definitions thyroid cancer differentiation. It is the functional differentiation that determines the sensitivity and accuracy of RAI imaging as well as the effectiveness of RAI treatment. Total thyroidectomy is performed to empower an anticipated RAI treatment. A preoperative determination of the genomic and transcriptomic profile of the tumor is a strong predictor of response to therapeutic interventions. This article discusses the oncopathophysiologic basis of the theranostic risk stratification approach.

Molecular Profiling of 50 734 Bethesda III-VI Thyroid Nodules by ThyroSeq v3: Implications for Personalized Management.

CONTEXT: Comprehensive genomic analysis of thyroid nodules for multiple classes of molecular alterations detected in a large series of fine needle aspiration (FNA) samples has not been reported. OBJECTIVE: To determine the prevalence of clinically relevant molecular alterations in Bethesda categories III-VI (BCIII-VI) thyroid nodules. METHODS: This retrospective analysis of FNA samples, tested by ThyroSeq v3 using Genomic Classifier and Cancer Risk Classifier at UPMC Molecular and Genomic Pathology laboratory, analyzed the prevalence of diagnostic, prognostic, and targetable genetic alterations in a total of 50 734 BCIII-VI nodules from 48 225 patients. RESULTS: Among 50 734 informative FNA samples, 65.3% were test-negative, 33.9% positive, 0.2% positive for medullary carcinoma, and 0.6% positive for parathyroid. The benign call rate in BCIII-IV nodules was 68%. Among test-positive samples, 73.3% had mutations, 11.3% gene fusions, and 10.8% isolated copy number alterations. Comparing BCIII-IV nodules with BCV-VI nodules revealed a shift from predominantly RAS-like alterations to BRAF V600E-like alterations and fusions involving receptor tyrosine kinases (RTK). Using ThyroSeq Cancer Risk Classifier, a high-risk profile, which typically included TERT or TP53 mutations, was found in 6% of samples, more frequently BCV-VI. RNA-Seq confirmed ThyroSeq detection of novel RTK fusions in 98.9% of cases. CONCLUSION: In this series, 68% of BCIII-IV nodules were classified as negative by ThyroSeq, potentially preventing diagnostic surgery in this subset of patients. Specific genetic alterations were detected in most BCV-VI nodules, with a higher prevalence of BRAF and TERT mutations and targetable gene fusions compared to BCIII-IV nodules, offering prognostic and therapeutic information for patient management.

Birth of the Beta-knife Thyroidectomy: The Radiance of Saul Hertz.

This is the story of how one man's life's work allowed for Iodine-131 (I-131) to become a therapy for hyperthyroidism and thyroid cancer. What is now a standard in our times arose from Saul Hertz's rather challenging and humble beginnings. Thyroid lobectomy and total thyroidectomy were therapeutic mainstays for thyroid disease until Hertz treated his first patient with radioactive iodine (RAI) ablation therapy at Massachusetts General Hospital (MGH) on March 31, 1941. His concepts for using beta particle emission from RAI to ablate thyroid tissue were revolutionary. Hertz's RAI therapy translated to research with thyroid cancer by the mid-1940s. The high-energy beta particles produced cytolethal effects on remnant thyroid tissue left behind by total thyroidectomy, thereby accomplishing completion thyroidectomy in some patients. Progressive surgeons from the Hertz era incorporated RAI into their practice. MGH surgery resident Francis Moore took sabbatical from clinical training to do translational research with RAI and other radioisotopes. Irving Ariel of New York became known as a nuclear surgeon in the wake of Hertz's work. George Crile Jr of Cleveland became an RAI advocate for the surgical community, implementing several paradigm-changing concepts in thyroid disease along the way. Hertz was a visionary who sparked this movement, predicting many of the molecular dilemmas with RAI-tumor avidity that clinical researchers continue to navigate today. This timely history for surgical oncologists and endocrine surgeons traces the development of RAI therapy through the life of Saul Hertz, a biographical window influenced by social stigma, political controversy, and mainstream media.

Radiomicrosphere Dosimetry: Principles and Current State of the Art.

Radiomicrosphere Therapy (RMT) refers to a liver-directed therapeutic modality based on the intrahepatic arterial administration of radiolabeled microspheres. There is a need for standardization of the terminology of RMT. A descriptive identifier should first name the radioisotope, then the chemical formulation of the microsphere, and lastly add the term RMT that indicates the therapeutic modality. At present, clinically available options include |Y-90| |Resin| |RMT|, |Y-90| |Glass| |RMT| and |Ho-166| |PLLA| |RMT|. The latter is available in Europe and is being considered for clearance by the FDA in the United States. Preclinical studies with |Re-188| |PLLA| |RMT| are underway. Dosimetric considerations are strongly tied to both the type of the radioisotope and the chemical composition of the microsphere type. This review will focus on Y-90 resin and glass RMT, the history, dosimetry, clinical use, and controversies.

A Joint Statement from the American Thyroid Association, the European Association of Nuclear Medicine, the European Thyroid Association, the Society of Nuclear Medicine and Molecular Imaging on Current Diagnostic and Theranostic Approaches in the Management of Thyroid Cancer.

Background: The American Thyroid Association (ATA), the European Association of Nuclear Medicine, the European Thyroid Association, and the Society of Nuclear Medicine and Molecular Imaging have established an intersocietal working group to address the current controversies and evolving concepts in thyroid cancer management and therapy. The working group annually identifies topics that may significantly impact clinical practice and publishes expert opinion articles reflecting intersocietal collaboration, consensus, and suggestions for further research to address these important management issues. Summary: In 2019, the intersocietal working group identified the following topics for review and interdisciplinary discussion: (i) perioperative risk stratification, (ii) the role of diagnostic radioactive iodine (RAI) imaging in initial staging, and (iii) indicators of response to RAI therapy. Conclusions: The intersocietal working group agreed that (i) initial patient management decisions should be guided by perioperative risk stratification that should include the eighth edition American Joint Committee on Cancer staging system to predict disease specific mortality, the modified 2009 ATA risk stratification system to estimate structural disease recurrence, with judicious incorporation of molecular theranostics to further refine management recommendations; (ii) diagnostic RAI scanning in ATA intermediate risk patients should be utilized selectively rather than being considered mandatory or not necessary for all patients in this category; and (iii) a consistent semiquantitative reporting system should be used for response evaluations after RAI therapy until a reproducible and clinically practical quantitative system is validated.

A Case of Papillary Thyroid Carcinoma and Kostmann Syndrome: A Genomic Theranostic Approach for Comprehensive Treatment.

BACKGROUND Theranostics is a combined diagnostic and treatment approach to individualized patient care. Kostmann syndrome, or severe congenital neutropenia, is an autosomal recessive disease that affects the production of neutrophils. Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy associated with gene alterations, including in the mitogen-activated protein kinase (MAPK) signaling pathway gene. Translocation of the ETS variant 6/neurotrophic receptor tyrosine kinase 3 (ETV6/NTRK3) gene has been implicated in radiation-induced and pediatric forms of thyroid carcinoma but has rarely been described in sporadic PTC. This report is of a case of PTC in a patient with Kostmann syndrome associated with ETV6/NTRK3 gene translocation. CASE REPORT A 32-year-old woman with a history of Kostmann syndrome, acute myeloid leukemia (AML), and chronic graft versus host disease (GVHD) was diagnosed with PTC with cervical lymph node metastases and soft tissue invasion following total thyroidectomy and bilateral modified radical neck dissection. Her postoperative radioactive iodine (RAI) scan confirmed lymph node metastasis. Gene expression studies identified increased expression of iodine-handling genes and ETV6/NTRK3 gene fusion. Because of the bone marrow compromise due to Kostmann syndrome and AML, a careful genomic and molecular analysis was performed to guide therapy. CONCLUSIONS This is the first reported case of the association between PTC, Kostmann syndrome, and ETV6/NTRK3 gene translocation in which multimodality treatment planning was optimized by genomic profiling.

90 Y SPECT/CT quantitative study and comparison of uptake with pretreatment 99 m Tc-MAA SPECT/CT in radiomicrosphere therapy.

INTRODUCTION: Yttrium-90 (90 Y) microsphere post-treatment imaging reflects the true distribution characteristics of microspheres in the tumor and liver compartments. However, due to its decay spectra profile lacking a pronounced photopeak, the bremsstrahlung imaging for 90 Y has inherent limitations. The absorbed dose calculations for 90 Y microspheres radiomicrosphere therapy (RMT) sustain a limitation due to the poor quality of 90 Y imaging. The aim of this study was to develop quantitative methods to improve the post-treatment 90 Y bremsstrahlung single photon emission tomography (SPECT)/computed tomography (CT) image analysis for dosimetric purposes and to perform a quantitative comparison with the 99m Tc-MAA SPECT/CT images, which is used for theranostics purposes for liver and tumor dosimetry. METHODS: Pre and post-treatment SPECT/CT data of patients who underwent RMT for primary or metastatic liver cancer were acquired. A Jasczak phantom with eight spherical inserts of various sizes was used to obtain optimal iteration number for the contrast recovery algorithm for improving 90 Y bremsstrahlung SPECT/CT images. Comparison of uptake on 99m Tc-MAA and 90 Y microsphere SPECT/CT images was assessed using tumor to healthy liver ratios (TLRs). The voxel dosimetry technique was used to estimate absorbed doses. Absorbed doses within the tumor and healthy part of the liver were also investigated for correlation with administered activity. RESULTS: Improvement in CNR and contrast recovery coefficients on patient and phantom 90 Y bremsstrahlung SPECT/CT images respectively were achieved. The 99m Tc-MAA and 90 Y microspheres SPECT/CT images showed significant uptake correlation (r = 0.9, P = 0.05) with mean TLR of 9.4 ± 9.2 and 5.0 ± 2.2, respectively. The correlation between the administered activity and tumor absorbed dose was weak (r = 0.5, P > 0.05), however, healthy liver absorbed dose increased with administered activity (r = 0.8, P = 0.0). CONCLUSIONS: This study demonstrated correlation in mean TLR between 99m Tc-MAA and 90 Y microsphere SPECT/CT.

18F-FLT Positron Emission Tomography/Computed Tomography Imaging in Pancreatic Cancer: Determination of Tumor Proliferative Activity and Comparison with Glycolytic Activity as Measured by 18F-FDG Positron Emission Tomography/Computed Tomography Imaging.

OBJECTIVE: This phase-I imaging study examined the imaging characteristic of 3'-deoxy-3'-(18F)-fluorothymidine (18F-FLT) positron emission tomography (PET) in patients with pancreatic cancer and comparisons were made with (18F)-fluorodeoxyglucose (18F-FDG). The ultimate aim was to develop a molecular imaging tool that could better define the biologic characteristics of pancreas cancer, and to identify the patients who could potentially benefit from surgical resection who were deemed inoperable by conventional means of staging. METHODS: Six patients with newly diagnosed pancreatic cancer underwent a combined FLT and FDG computed tomography (CT) PET/CT imaging protocol. The FLT PET/CT scan was performed within 1 week of FDG PET/CT imaging. Tumor uptake of a tracer was determined and compared using various techniques; statistical thresholding (z score=2.5), and fixed standardized uptake value (SUV) thresholds of 1.4 and 2.5, and applying a threshold of 40% of maximum SUV (SUVmax) and mean SUV (SUVmean). The correlation of functional tumor volumes (FTV) between 18F-FDG and 18F-FLT was assessed using linear regression analysis. RESULTS: It was found that there is a correlation in FTV due to metabolic and proliferation activity when using a threshold of SUV 2.5 for FDG and 1.4 for FLT (r=0.698, p=ns), but a better correlation was obtained when using SUV of 2.5 for both tracers (r=0.698, p=ns). The z score thresholding (z=2.5) method showed lower correlation between the FTVs (r=0.698, p=ns) of FDG and FLT PET. CONCLUSION: Different tumor segmentation techniques yielded varying degrees of correlation in FTV between FLT and FDG-PET images. FLT imaging may have a different meaning in determining tumor biology and prognosis.

(124)I PET/CT in Patients with Differentiated Thyroid Cancer: Clinical and Quantitative Image Analysis.

BACKGROUND: Although radioactive iodine (RAI) imaging/therapy is one of the earliest applications of theranostics, there remain a number of unresolved clinical questions as to the optimization of diagnostic techniques/protocols and improvements in patient-specific treatment planning strategies. The objectives of this study were to determine the imaging characteristics and clinical feasibility of (124)I positron emission tomography/computed tomography (PET/CT) for the determination of extent of disease and evaluation of RAI kinetics in its physiologic and neoplastic distribution in patients with differentiated thyroid cancer (DTC). METHODS: The study was designed as a prospective phase II diagnostic trial of patients with confirmed DTC. Following adequate preparation, patients received 2 mCi (124)I in liquid form and sequential whole-body PET/CT imaging was performed at five time points (2-4 h, 24 ± 6 h, 48 ± 6 h, 72 ± 6 h, and 96 ± 6 h post-administration). All patients who had (124)I imaging subsequently underwent RAI treatment with (131)I, with administered activities ranging from 100 to 300 mCi. Post-treatment scans were obtained 5-7 days after RAI treatment. A by-patient and by-lesion analysis of the (124)I images was performed and compared with the post-treatment (131)I scans as well as F-18 FDG PET/CT images. Quantitative image analysis was also performed to determine the total functional volume (mL), activity per functional volume (µCi/mL), and cumulated activity (µCi/h) for remnants, salivary glands, and nodal metastases. RESULTS: Fifteen patients (6 women; Mage = 57 years; range 29-91 years) were enrolled into the study. Forty-six distinct lesions were identified in these 15 patients on (124)I PET/CT images, with a sensitivity of 92.5%. In addition, (124)I identified 22.5% more foci of RAI-avid lesions compared with the planar (131)I post-treatment scans. This study demonstrates different kinetic profiles for normal thyroid remnants (peaked at 24 h with mono-exponential clearance), salivary glands (peaked at 4 h with bi-exponential clearance), and metastatic lesions (protracted retention), as well as individual variations in functional volumes and thus cumulated activities. CONCLUSIONS: (124)I PET/CT is a valuable clinical imaging tool/agent, both in determining the extent of disease in the setting of metastatic DTC and in the functional volumetric and kinetic evaluation of target lesions.

Y-90 Radiomicrosphere Therapy for Colorectal Cancer Liver Metastases.

At present, the systemic treatment of unresectable colorectal cancer liver metastases involves oxaliplatin and irinotecan-based chemotherapy regimens combined with targeted therapies such as bevacizumab (Avastin) and cetuximab (Erbitux). Radiation therapy, traditionally, is not considered a viable treatment modality owing to its unacceptably high hepatic toxicity, and still steering traditional wisdom or dogma that chemoradiation cannot be an oncological strategy for a stage IV disease. Selective internal radiation treatment with yttrium-90 (Y-90) radiomicrospheres has emerged as an effective liver-directed therapy with a favorable therapeutic ratio. Since its early clinical trials, it has demonstrated improved response rates when used in conjunction with systemic or regional chemotherapy. This article reviews the clinical role for Y-90 radiomicrosphere therapy in the contemporary management of colorectal cancer liver metastases. All the structured clinical trials, to date, are summarized, including those that studied the value of combined Y-90 radiomicrosphere therapy and current chemotherapy protocols.

PET-Probe: Evaluation of Technical Performance and Clinical Utility of a Handheld High-Energy Gamma Probe in Oncologic Surgery.

BACKGROUND: Positron emission tomography (PET) has become an invaluable part of patient evaluation in surgical oncology. PET is less than optimal for detecting lesions <1 cm, and the intraoperative localization of small PET-positive lesions can be challenging as a result of difficulties in surgical exposure. We undertook this investigation to assess the utility of a handheld high-energy gamma probe (PET-Probe) for intraoperative identification of 18F-deoxyglucose (FDG)-avid tumors. METHODS: Forty patients underwent a diagnostic whole-body FDG-PET scan for consideration for surgical exploration and resection. Before surgery, all patients received an intravenous injection of 7 to 10 mCi of FDG. At surgery, the PET-Probe was used to determine absolute counts per second at the known tumor site(s) demonstrated by whole-body PET and at adjacent normal tissue (at least 4 cm away from tumor-bearing sites). Tumor-to-background ratios were calculated. RESULTS: Thirty-two patients (80%) underwent PET-Probe-guided surgery with therapeutic intent in a recurrent or metastatic disease setting. Eight patients underwent surgery for diagnostic exploration. Anatomical locations of the PET-identified lesions were neck and supraclavicular (n = 8), axilla (n = 5), groin and deep iliac (n = 4), trunk and extremity soft tissue (n = 3), abdominal and retroperitoneal (n = 19), and lung (n = 2). PET-Probe detected all PET-positive lesions. The PET-Probe was instrumental in localization of lesions in 15 patients that were not immediately apparent by surgical exploration. CONCLUSIONS: The PET-Probe identified all lesions demonstrated by PET scanning and, in selected cases, was useful in localizing FDG-avid disease not seen with conventional PET scanning.

Non-pigmented melanoma with nodal metastases masquerading as pyogenic granuloma in a 1-year old.

Malignant melanomas are the most common skin cancer in the pediatric population. Melanoma incidence is extremely low in infants, and metastatic disease is even less common. We present the case of an 11-month-old girl who presented with a non-pigmented lesion that progressed to an ulcerated lesion. Pathology was found to be Spitzoid melanoma of 7.6-mm thickness. Micrometastases were found on examination of the sentinel lymph node. The family chose expectant observation following the excision procedure. A pediatric melanoma registry may be helpful in developing future analyses of incidence in survival in this specialized population.

Yttrium-90 microsphere-selective internal radiation therapy with chemotherapy (chemo-SIRT) for colorectal cancer liver metastases: an in vivo double-arm-controlled phase II trial.

OBJECTIVES: Selective internal radiation therapy (SIRT) with yttrium-90 (Y) microspheres has emerged as an effective liver-directed therapy with a favorable therapeutic ratio for treatment of colorectal cancer liver metastases. The aim of this study was to investigate the objective responses obtained by Y microsphere treatment when combined with contemporary chemotherapy in the front-line (first or second line) setting in patients with CRCLM. METHODS: This study used an in vivo comparison between the right and left liver lobes; systemic chemotherapy was supplied to both liver lobes by virtue of systemic administration, whereas SIRT was administered selectively to the target liver lobe only. Response to treatment was evaluated by serial fludeoxyglucose positron emission tomography computed tomography performed at 4 weeks, 2 to 4 months, and 6 to 8 months. Standard uptake value, anatomic volume, functional tumor volume, and total lesion glycolysis (TLG) calculations were obtained at each time point. RESULTS: A decrease in TLG on fludeoxyglucose positron emission tomography computed tomography imaging was seen in 19 of the 20 patients. The mean decrease in TLG values in the tumors receiving chemo-SIRT and chemo-only treatment were 86.26%±18.57% and 31.74%±80.99% (P<0.01), 93.13%±11.81% and 40.80%±73.32% (P=0.01), and 90.55%±19.75% and 54.91%±38.55% (P<0.01) at 4 weeks, 2 to 4 months, 6 to 8 months posttreatment, respectively. Functional and anatomic tumor volume changes were in concordance with the TLG changes. CONCLUSIONS: The study demonstrated that, under near identical conditions in terms of patient and tumor characteristics, the chemo-SIRT combination produced superior objective responses compared with chemo-only treatment in a front-line treatment setting in patients with colorectal cancer liver metastases.

An algorithm for PET tumor volume and activity quantification: without specifying camera's point spread function (PSF).

PURPOSE: The authors have developed an algorithm for segmentation and removal of the partial volume effect (PVE) of tumors in positron emission tomography (PET) images. The algorithm accurately measures functional volume (FV) and activity concentration (AC) of tumors independent of the camera's full width half maximum (FWHM). METHODS: A novel iterative histogram thresholding (HT) algorithm is developed to segment the tumors in PET images, which have low resolution and suffer from inherent noise in the image. The algorithm is initiated by manually drawing a region of interest (ROI). The segmented tumors are subjected to the iterative deconvolution thresholding segmentation (IDTS) algorithm, where the Van-Cittert's method of deconvolution is used for correcting PVE. The IDTS algorithm is fully automated and accurately measures the FV and AC, and stops once it reaches convergence. The convergence criteria or stopping conditions are developed in such a way that the algorithm does not rely on estimating the FWHM of the point spread function (PSF) to perform the deconvolution process. The algorithm described here was tested in phantom studies, where hollow spheres (0.5-16 ml) were used to represent tumors with a homogeneous activity distribution, and an irregular shaped volume was used to represent a tumor with a heterogeneous activity distribution. The phantom studies were performed with different signal to background ratios (SBR) and with different acquisition times (1 min, 3 min, and 5 min). The parameters in the algorithm were also changed (FWHM and matrix size of the Gaussian function) to check the accuracy of the algorithm. Simulated data were also used to test the algorithm with tumors having heterogeneous activity distribution. RESULTS: The results show that changing the size and shape of the ROI during initiation of the algorithm had no significant impact on the FV. An average FV overestimation of 30% and an average AC underestimation of 35% were observed for the smallest tumor (0.5 ml) over the entire range of noise and SBR level. The difference in average FV and AC estimations from the actual volumes were less than 5% as the tumor size increased to 16 ml. For tumors with heterogeneous activity profile, the overall volume error was less than 10%. The average overestimation of FV was less than 10% and classification error was around 11%. CONCLUSIONS: The algorithm developed herein was extensively tested and is not dependent on accurately quantifying the camera's PSF. This feature demonstrates the robustness of the algorithm and enables it to be applied on a wide range of noise and SBR within an image. The ultimate goal of the algorithm is to be able to be operated independent of the camera type used and the reconstruction algorithm deployed.

Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial.

BACKGROUND: It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 ((90) Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS: Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m(2) weekly for 4 weeks with (90) Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2-4). In the first part of the study, 19 patients received escalating weekly (90) Y doses of 6.5 mCi/m(2) , 9.0 mCi/m(2) , 12.0 mCi/m(2) , and 15.0 mCi/m(2) . In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m(2) or 12.0 mCi/m(2) . RESULTS: Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute's Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of (90) Y-hPAM4 was 12.0 mCi/m(2) weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m(2) weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses. CONCLUSIONS: Fractionated radioimmunotherapy with (90) Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma.

The prognostic value of functional tumor volume and total lesion glycolysis in patients with colorectal cancer liver metastases undergoing 90Y selective internal radiation therapy plus chemotherapy.

PURPOSE: Functional tumor volume (FTV) and total lesion glycolysis (TLG) are measures of metabolic activity of tumors determined by fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT images. These parameters could potentially have clinical value in response to treatment evaluation and disease prognostication. The objectives of this study were to investigate the relationship between functional tumor parameters (FTV and TLG) and clinical outcomes in patients with colorectal cancer liver metastases (CRCLM) undergoing (90)Y-resin microsphere selective internal radiation therapy (SIRT) (SIR-Spheres®, Sirtex Medical Limited, Lane Cove, NSW, Australia). METHODS: FDG PET/CT studies of 20 patients with unresectable CRCLM who underwent (90)Y SIRT under a phase II clinical trial were analyzed. FTV and TLG were calculated using PET VCAR (GE Healthcare, Milwaukee, WI, USA) on pretreatment and 4-week posttreatment scans. The effects of pretreatment and posttreatment functional tumor activity on patient survival were evaluated using Kaplan-Meier survival curves. RESULTS: The median survival in the study group was 14.8 months (range 2.0-27.7 months). The median survival for patients with pretreatment FTV values of above and below 200 cc were 11.2 and 26.9 months, respectively (p < 0.05). The median survival for patients with 4-week posttreatment FTV values of above and below 30 cc were 10.9 and 26.9 months, respectively (p < 0.05). The median survival for patients with pretreatment TLG values of above and below 600 g were 11.2 and 26.9 months, respectively (p < 0.05). The median survival for patients with 4-week posttreatment TLG values of above and below 100 g were 10.9 and 26.9 months, respectively (p < 0.05). CONCLUSION: Pretreatment and posttreatment FTV and TLG showed very strong association with survival. These values can be useful quantitative criteria for patient selection and disease prognostication when (90)Y SIRT is contemplated in patients with CRCLM.

Treatment of advanced pancreatic carcinoma with 90Y-Clivatuzumab Tetraxetan: a phase I single-dose escalation trial.

PURPOSE: Humanized antibody hPAM4 specifically binds a mucin glycoprotein expressed in pancreatic adenocarcinomas. This phase I study evaluated a single dose of (90)Y-clivatuzumab tetraxetan ((90)Y-labeled hPAM4) in patients with advanced pancreatic cancer. EXPERIMENTAL DESIGN: Twenty-one patients (4 stage III; 17 stage IV) received (111)In-hPAM4 for imaging and serum sampling before (90)Y-hPAM4. Study procedures evaluated adverse events, safety laboratories, computed tomography (CT) scans, biomarkers, pharmacokinetics, radiation dosimetry, and immunogenicity (HAHA). RESULTS: (111)In-hPAM4 showed normal biodistribution with radiation dose estimates to red marrow and solid organs acceptable for radioimmunotherapy and with tumor targeting in 12 patients. One patient withdrew before (90)Y-hPAM4; otherwise, 20 patients received (90)Y doses of 15 (n = 7), 20 (n = 9), and 25 mCi/m(2) (n = 4). Treatment was well tolerated; the only significant drug-related toxicities were (NCI CTC v.3) grade 3 to 4 neutropenia and thrombocytopenia increasing with (90)Y dose. There were no bleeding events or serious infections, and most cytopenias recovered to grade 1 within 12 weeks. Three patients at 25 mCi/m(2) encountered dose-limiting toxicity with grade 4 cytopenias more than 7 days, establishing 20 mCi/m(2) as the maximal tolerated (90)Y dose. Two patients developed HAHA of uncertain clinical significance. Most patients progressed rapidly and with CA19-9 levels increasing within 1 month of therapy, but 7 remained progression-free by CT for 1.5 to 5.6 months, including 3 achieving transient partial responses (32%-52% tumor diameter shrinkage). CONCLUSION: (90)Y-Clivatuzumab tetraxetan was well tolerated with manageable hematologic toxicity at the maximal tolerated (90)Y dose, and is a potential new therapeutic for advanced pancreatic cancer.

Hepatic structural dosimetry in (90)Y microsphere treatment: a Monte Carlo modeling approach based on lobular microanatomy.

UNLABELLED: Selective internal radiation treatment (SIRT) via intrahepatic arterial administration of (90)Y microspheres is an effective therapeutic modality. The conventional and generally applied MIRD schema is based on the premise that the distribution of microspheres in the liver parenchyma is uniform. In reality, however, the distribution of the microspheres follows a distinct pattern, requiring that a model be developed to more appropriately estimate radiation absorbed doses to the different structural/functional elements of the hepatic microanatomy. METHODS: A systematic investigation was performed encompassing a conventional average absorbed dose assessment, a compartmental macrodosimetric approach that accounts for the anticipated higher tumor-to-normal liver activity concentration ratio, dose point-kernel convolution-derived estimates, and Monte Carlo dose estimates employing a spherical and 3-dimensional hexagonal liver model, including various subunits of the hepatic anatomy, down to the micrometer level. RESULTS: Detailed specifics of the radiation dose deposition of (90)Y microspheres demonstrated a rapid decrease in absorbed dose in and around the portal tracts where the microspheres are deposited. The model also demonstrated that the hepatocellular parenchymal and central vein doses could be at significant levels because of a cross-fire effect. CONCLUSION: The reported microstructural dosimetry models can help in the detailed assessment of the dose distributions in the hepatic functional subunits and in relating these doses to their effects. These models have also revealed that the there is a consistent relationship between the average liver dose as calculated by MIRD macrodosimetry and the structural dosimetry estimates in support of the clinical utility of the MIRD methodology. This relationship could be used to more realistically assess patterns of hepatic toxicity associated with the (90)Y SIRT treatment.