Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer.

BACKGROUND: Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known. METHODS: We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib. RESULTS: Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia. CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).

Complete blood counts are frequently abnormal 1 year after dosimetry-guided radioactive iodine therapy for metastatic thyroid cancer.

OBJECTIVE: Radioactive iodine (RAI) has been associated with hematologic abnormalities. Previous research has shown that even a single dose of RAI can cause changes in the peripheral complete blood count (CBC). It is unclear if the use of dosimetry guidance would prevent the effects of high doses of RAI on bone marrow suppression. METHODS: CBC at baseline was compared to a CBC obtained 1 year after the last RAI treatment in 50 thyroid cancer patients that received ≥250 mCi RAI during the course of their disease. Cumulative dose, number of treatments, patients' age, and the use of external beam radiation therapy (EBRT) were considered in the analysis. RESULTS: We observed a small but statistically significant decrease in hemoglobin (Hb), hematocrit (Hct), and platelet (Plt) counts at 1 year in 50 patients who had received ≥250 mCi RAI. We did not find a significant change in white blood cell count (WBC). Approximately 60% of patients who developed anemia had concomitant WBC and Plt abnormalities. RAI dose, number of treatments, and age at diagnosis did not confer a higher risk of bone marrow suppression. CONCLUSION: High cumulative activities of RAI administered under dosimetric guidance are associated with a small but statistically significant decreases in Hb, Hct, and Plt counts. The clinical implications of these changes, if any, are unclear. The benefits obtained with high doses of RAI, when indicated, are likely to outweigh the minimal hematologic risks observed in the present study.

Imaging surrogates of tumor response to therapy: anatomic and functional biomarkers.

This article addresses the current status of quantitative imaging as a surrogate biomarker for the assessment of tumor response to therapy with non-small cell lung cancer as an example. In addition, the article discusses the limitations of conventional response criteria in the new era of molecular-targeted agents for cancer treatment; the increasing need for more accurate and early response-assessment methods, particularly for volumetric CT; new tumor-specific radiotracers and molecular imaging technologies; and the future applications of molecular imaging with PET for studying various features of cancer metabolism, endocrine status, hypoxia, and oncofetal and differentiation antigens.

Reproducibility of intratumor distribution of (18)F-fluoromisonidazole in head and neck cancer.

PURPOSE: Hypoxia is one of the main causes of the failure to achieve local control using radiotherapy. This is due to the increased radioresistance of hypoxic cells. (18)F-fluoromisonidazole ((18)F-FMISO) positron emission tomography (PET) is a noninvasive imaging technique that can assist in the identification of intratumor regions of hypoxia. The aim of this study was to evaluate the reproducibility of (18)F-FMISO intratumor distribution using two pretreatment PET scans. METHODS AND MATERIALS: We enrolled 20 head and neck cancer patients in this study. Of these, 6 were excluded from the analysis for technical reasons. All patients underwent an (18)F-fluorodeoxyglucose study, followed by two (18)F-FMISO studies 3 days apart. The hypoxic volumes were delineated according to a tumor/blood ratio >or=1.2. The (18)F-FMISO tracer distributions from the two (18)F-FMISO studies were co-registered on a voxel-by-voxel basis using the computed tomography images from the PET/computed tomography examinations. A correlation between the (18)F-FMISO intensities of the corresponding spatial voxels was derived. RESULTS: A voxel-by-voxel analysis of the (18)F-FMISO distributions in the entire tumor volume showed a strong correlation in 71% of the patients. Restraining the correlation to putatively hypoxic zones reduced the number of patients exhibiting a strong correlation to 46%. CONCLUSION: Variability in spatial uptake can occur between repeat (18)F-FMISO PET scans in patients with head and neck cancer. Blood data for one patient was not available. Of 13 patients, 6 had well-correlated intratumor distributions of (18)F-FMISO-suggestive of chronic hypoxia. More work is required to identify the underlying causes of changes in intratumor distribution before single-time-point (18)F-FMISO PET images can be used as the basis of hypoxia-targeting intensity-modulated radiotherapy.

Radioactive iodine therapy in poorly differentiated thyroid cancer.

BACKGROUND: A 55-year-old male was diagnosed with poorly differentiated thyroid cancer after total thyroidectomy, which was performed because of progressive enlargement of a dominant thyroid nodule. He developed an early cervical recurrence that was treated with modified neck dissection. He subsequently developed biopsy-proven progressive pulmonary metastases. INVESTIGATIONS: Neck and chest CT scans, laboratory tests, CT-guided fine-needle aspiration biopsy, [18F]-2-fluoro-2-deoxy-D-glucose-PET scan, lesional dosimetry using 124I PET scan, diagnostic radioactive iodine (RAI) scanning, whole-body and blood RAI dosimetry, and single-photon-emission CT. DIAGNOSIS: Stage IV poorly differentiated thyroid cancer. MANAGEMENT: Surgical resection of cervical recurrence, RAI therapy.

Is the serum thyroglobulin response to recombinant human thyrotropin sufficient, by itself, to monitor for residual thyroid carcinoma?

The serum thyroglobulin (Tg) response to elevated TSH is one of the most sensitive indexes of residual thyroid carcinoma. We have explored the possibility that this test alone would be sufficient to detect residual thyroid carcinoma in thyroid cancer patients after total thyroidectomy and radioiodine remnant ablation. We used recombinant human TSH (rhTSH) to elevate serum TSH, rather than withdraw the patients from thyroid hormone. Routine evaluations, including diagnostic radioiodine whole body scans (DxWBS) and serum Tg, were performed on 366 patients after preparation by rhTSH, over a 2-yr interval. A retrospective analysis of the data from these patients revealed that 76% of those whose stimulated Tg rose to more than 2 microg/liter had evidence for residual thyroid carcinoma, whereas the same was true for only 13% of those whose stimulated Tg was 2 microg/liter or less. Using risk group stratification, we analyzed outcomes in a low risk subset (which excluded patients with elevated Tg levels on suppression, known metastatic disease, and clinical or histological evidence of aggressive disease). In this low risk group, we found that a stimulated Tg of 2 microg/liter or less had a 91.7% negative predictive value. No low risk patient who had had a prior negative DxWBS and a stimulated Tg of 2 microg/liter or less had any evidence of residual thyroid carcinoma. We conclude that the stimulated Tg alone is not sufficient by itself to screen unselected patients, but that it may be sufficient in low risk patients, especially those who have had a prior negative DxWBS.

Reduction of respiratory motion artifacts in PET imaging of lung cancer by respiratory correlated dynamic PET: methodology and comparison with respiratory gated PET.

UNLABELLED: This study proposes a new method to reduce respiratory motion artifacts in PET images of lung cancer. The method is referred to as respiratory-correlated dynamic PET (RCDPET). RCDPET enables the acquisition of 4-dimensional PET data without the need for a respiratory tracking device. In this article, we compare this method with respiratory-gated PET (RGPET). Both methods provide the ability to correct for motion artifacts and more accurately quantitate radiotracer uptake within lung lesions. Both methods were evaluated in phantom studies and 1 patient. METHODS: With RCDPET, data are acquired in consecutive 1-s time frames. A point source attached to a rigid foam block is set on the patient's abdomen and is extended into the camera field of view at the level of the lesion by means of a low-density rod. The position of this source is used to track respiratory motion through the consecutive dynamic frames. Image frames corresponding to a user-selected lesion position within the breathing cycle, in correlation with the point source position, are then identified after scanning. The sinograms of the selected image frames are summed and then reconstructed using iterative reconstruction with segmented attenuation correction. RESULTS: The results from phantom studies with both RGPET and RCDPET were within 10% agreement, for both activity quantitation and image noise levels. In a clinical application, the quantitation of the SUV(max) and the lesion's size showed a 6% and 2% difference, respectively, between RCDPET and RGPET measurements. CONCLUSION: RCDPET can be considered as a comparable, or alternative, method to RGPET in reducing the smearing effects due to respiration and improving quantitation of PET in the thorax. One advantage of RCDPET over RGPET is the ability to retrospectively reconstruct the PET data at any phase or amplitude in the breathing cycle.

Correction for oral contrast artifacts in CT attenuation-corrected PET images obtained by combined PET/CT.

UNLABELLED: Recent studies have shown increased artifacts in CT attenuation-corrected (CTAC) PET images acquired with oral contrast agents because of misclassification of contrast as bone. We have developed an algorithm, segmented contrast correction (SCC), to properly transform CT numbers in the contrast regions from CT energies (40-140 keV) to PET energy at 511 keV. METHODS: A bilinear transformation, equivalent to that supplied by the PET/CT scanner manufacturer, for the conversion of linear attenuation coefficients of normal tissues from CT to PET energies was optimized for BaSO(4) contrast agent. This transformation was validated by comparison with the linear attenuation coefficients measured for BaSO(4) at concentrations ranging from 0% to 80% at 511 keV for PET transmission images acquired with (68)Ge rod sources. In the CT images, the contrast regions were contoured to exclude bony structures and then segmented on the basis of a minimum threshold CT number (300 Hounsfield units). The CT number in each pixel identified with contrast was transformed into the corresponding effective bone CT number to produce the correct attenuation coefficient when the data were translated by the manufacturer software into PET energy during the process of CT attenuation correction. CT images were then used for attenuation correction of PET emission data. The algorithm was validated with a phantom in which a lesion was simulated within a volume of BaSO(4) contrast and in the presence of a human vertebral bony structure. Regions of interest in the lesion, bone, and contrast on emission PET images reconstructed with and without the SCC algorithm were analyzed. The results were compared with those for images obtained with (68)Ge-based transmission attenuation-corrected PET. RESULTS: The SCC algorithm was able to correct for contrast artifacts in CTAC PET images. In the phantom studies, the use of SCC resulted in an approximate 32% reduction in the apparent activity concentration in the lesion compared with data obtained from PET images without SCC and a <7.6% reduction compared with data obtained from (68)Ge-based attenuation-corrected PET images. In one clinical study, maximum standardized uptake value (SUV(max)) measurements for the lesion, bladder, and bowel were, respectively, 14.52, 13.63, and 13.34 g/mL in CTAC PET images, 59.45, 26.71, and 37.22 g/mL in (68)Ge-based attenuation-corrected PET images, and 11.05, 6.66, and 6.33 g/mL in CTAC PET images with SCC. CONCLUSION: Correction of oral contrast artifacts in PET images obtained by combined PET/CT yielded more accurate quantitation of the lesion and other, normal structures. The algorithm was tested in a clinical case, in which SUV(max) measurements showed discrepancies of 2%, 1.3%, and 5% between (68)Ge-based attenuation-corrected PET images and CTAC PET images with SCC for the lesion, bladder, and bowel, respectively. These values correspond to 6.5%, 62%, and 66% differences between CTAC-based measurements and (68)Ge-based ones.

Phase I clinical trial with fractionated radioimmunotherapy using 131I-labeled chimeric G250 in metastatic renal cancer.

UNLABELLED: This trial was performed to determine the maximum tolerated whole-body radiation-absorbed dose of fractionated (131)I-cG250. METHODS: This was a phase 1 dose escalation trial. Dose escalation refers here to the escalation of average whole-body absorbed dose. Fifteen patients with measurable metastatic renal cancer were studied. For each treatment cycle, patients initially received a "scout" administration consisting of 5 mg of cG250 antibody labeled with 185 MBq (5 mCi) of (131)I. Whole-body and serum activity was measured for 1 wk, and a simple pharmacokinetic model was fitted to the measured data. The pharmacokinetic model was used to calculate the required activities, administered in a fractionated pattern with 2-3 d between fractions, projected to deliver the prescribed whole-body absorbed dose. The initial cohort of 3 patients was prescribed an average whole-body absorbed dose of 0.50 Gy. In subsequent cohorts this was increased in 0.25-Gy increments. The first fraction in each cycle was 1,110 MBq (30 mCi) of (131)I conjugated to 5 mg of antibody. Subsequent fractions consisted of variable activities depending on the patient-specific whole-body clearance rates and the times between fractions. Patients without evidence of disease progression were retreated after recovery from toxicity if there was no evidence of altered pharmacokinetics or serum human antichimeric antibody titers, for a total of no more than 3 treatments. RESULTS: For the initial treatment course, the pharmacokinetics of the scout dose accurately predicted the pharmacokinetics of fractionated (131)I-cG250 therapy. In 2 patients, altered clearance accurately predicted development of human antichimeric antibody. Targeting to known disease >or= 2 cm in diameter was noted in all patients. Dose-limiting toxicity was hematopoietic, and the maximum tolerated dose per cycle was 0.75 Gy. CONCLUSION: Measurements of whole-body and serum clearance of cG250 antibody can be used to accurately predict the clearance of subsequent administrations, thus enabling rational treatment planning. An additional practical benefit of real-time pharmacokinetic monitoring is that therapy can be altered dynamically to reduce toxic side effects. However, there was no evidence for fractionation-induced sparing of the hematopoietic system in this study.

Effect of respiratory gating on quantifying PET images of lung cancer.

UNLABELLED: We have developed a new technique to gate lung 18F-FDG PET images in synchronization with the respiratory motion to reduce smearing due to breathing and improve quantitation of 18F-FDG uptake in lung lesions. METHODS: A camera-based respiratory gating system, the real-time position management (RPM), is used to monitor the respiratory cycle. The RPM provides a trigger to the PET scanner to initiate the gating cycle. Each respiratory cycle is divided into discrete bins triggered at a defined amplitude or phase within the patient's breathing motion, into which PET data are acquired. The acquired data within the time bins correspond to different lesion positions within the breathing cycle. The study includes 5 patients with lung cancer. RESULTS: Measurements of the lesions' volumes in the gated mode showed a reduction of up to 34% compared with that of the nongated measurement. This reduction in the lesion volume has been accompanied by an increase in the intensity in the 18F-FDG signal per voxel. This finding has resulted in an improvement in measurement of the maximum standardized uptake value (SUV(max)), which increased in 1 patient by as much as 159%. The total lesion glycolysis, defined as the product of the SUV(max) and the lesion volume, was also measured in gated and nongated modes and showed a consistency between the 2 measurements. CONCLUSION: We have shown that image smearing can be reduced by gating 18F-FDG PET images in synchronization with the respiratory motion. This technique allows a more accurate definition of the lesion volume and improves the quantitation specific activity of the tracer (in this case, 18F-FDG), which are distorted because of the breathing motion.

Clinical outcomes following empiric radioiodine therapy in patients with structurally identifiable metastatic follicular cell-derived thyroid carcinoma with negative diagnostic but positive post-therapy 131I whole-body scans.

BACKGROUND: While radioiodine (RAI) therapy remains the most effective treatment modality for RAI-avid distant metastatic follicular cell-derived thyroid cancer, the therapeutic utility of empiric RAI therapy in patients with structurally identifiable distant metastases that demonstrate RAI avidity only on the post-therapy scan (negative diagnostic whole-body scan [DxWBS]) remains uncertain. METHODS: We report a retrospective assessment of the structural response to RAI therapy in 27 patients (median age 54 years, 59% male) with metastatic thyroid cancer (45% classical papillary thyroid cancer, 21% poorly differentiated, 15% tall-cell variant, 15% follicular variant, and 4% Hurthle cell carcinoma) with structurally identifiable distant metastases (86% pulmonary metastases) in whom a properly conducted DxWBS was negative, and the post-therapy scan showed RAI-avid metastatic lesions at the time of RAI remnant ablation. RESULTS: In response to the initial RAI ablation, none of the selected patients demonstrated structural disease regression, and no patient was rendered free of disease. However, 12 patients (44%) demonstrated stable lesions on serial structural imaging after an RAI ablation. Structural disease progression was seen in the remaining 56% (15/27), a median of 6 months after ablation. Unfortunately, additional RAI therapies given to 12/15 patients with progressive disease and 5/12 patients with stable lesions failed to cause structural disease regression, cure, or conversion from progressive to stable disease in any patient. All of the disease-specific deaths (7/27) were in patients who had structural disease progression (n=15) in response to RAI ablation. None of the patients with persistent but stable lesions on structural imaging (n=12) have died of thyroid cancer over a median follow-up period of 3.7 years. CONCLUSIONS: While 44% of patients with the DxWBS-negative/post-therapy scan-positive macroscopic distant metastasis will have stable cross-sectional imaging after RAI remnant ablation, the other 56% will demonstrate structural disease progression that cannot be effectively treated with repeated empiric RAI activities. Furthermore, the high disease-specific mortality rate seen within the first few years of remnant ablation in this small subset of patients with persistent progressive disease despite a positive post-therapy RAI scan argues that treatments other than repeated empiric RAI dosing be strongly considered.

Molecular targeting of carbonic anhydrase IX in mice with hypoxic HT29 colorectal tumor xenografts.

BACKGROUND: Carbonic anhydrase IX (CAIX) is a membrane spanning protein involved in the enzymatic regulation of tumor acid-base balance. CAIX has been shown to be elevated in a number of hypoxic tumor types. The purpose of this study was to determine the efficiency of intact and IgG fragments of cG250 to target CAIX in vivo in a hypoxic tumor model. METHODOLOGY/PRINCIPAL FINDINGS: Conventional biodistribution studies were performed with (111)In-DO3A-cG250, (111)In-DO3A-F(ab')(2)-cG250 and (111)In-DO3A-Fab-cG250. Additional ex vivo analysis of the tumor was performed with markers for tumor hypoxia, blood perfusion and endogenous CAIX expression. All four data sets were digitally correlated to determine the optimal agent for determining hypoxia in a HT29 colon cancer xenograft. The HT29 human colorectal tumor xenografts show strong CAIX expression in hypoxic areas of poor blood perfusion. The intact IgG had an initial high focal uptake at the periphery of these hypoxic regions and penetration into the areas of highest CAIX expression over the 7-day study period. The lower molecular weight antibody fragments had a faster uptake into areas of high CAIX expression, but had a much lower absolute uptake at the optimal imaging times. CONCLUSIONS/SIGNIFICANCE: For the clinical detection of hypoxia induced CAIX using cG250 antibody based agents, imaging with the intact IgG at 7 days post injection would allow for the most sensitive and accurate detection of CAIX.

Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer.

PURPOSE: Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy. PATIENTS AND METHODS: Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was > or = 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated. RESULTS: A > or = 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naïve and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from > or = 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen. CONCLUSION: AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations.

FDG-PET detected thyroid incidentalomas: need for further investigation?

BACKGROUND: Incidental thyroid abnormalities are increasingly detected in patients undergoing PET scans. The aim of this study was to review our experience with the management of PET detected thyroid incidentalomas in a large single institution series. METHODS: All PET scans performed from May 2003 to July 2005 were reviewed and patients with incidental thyroid abnormalities were identified. From this group, patients that underwent further investigation were analyzed. Data relating to PET scan findings, FNA diagnoses, operative details, and histopathology was reviewed. RESULTS: In 8,800 patients, 16,300 PET scans were performed of whom 263 patients (2.9% of patients and 1.6% of PET scans) had findings positive for thyroid abnormality. Thyroid malignancy was noted in 42% (24 patients) of the 57 patients that underwent FNA. In the group of 27 patients that were subjected to operative intervention, 74% (20 patients) were noted to have a malignant diagnosis. The final histopathology revealed primary thyroid carcinoma in all these 20 patients (19 patients with papillary carcinoma and one patient with primary thyroid lymphoma). The factors that correlated with an increased risk of malignancy were the presence of physical finding (p = 0.01) and focal (p < 0.01) or unilateral uptake (p < 0.01) on PET scan. The average SUV was not useful in differentiating benign (9.2) from malignant lesions (8.2, p = 0.7). CONCLUSIONS: PET detected incidental thyroid abnormalities are rare. In patients with positive PET scan findings and suspicious features, the incidence of primary thyroid malignancy is very high. These patients warrant further investigation followed by possible operative intervention.