Prostate-specific antigen flare induced by 223RaCl2 in patients with metastatic castration-resistant prostate cancer.

PURPOSE: Prostate-specific antigen (PSA) flare is a well-known phenomenon in patients with prostate cancer, but its impact during radium-223 dichloride (223RaCl2) therapy is still unclear. This radioisotope has shown to improve overall survival in metastatic castration-resistant prostate cancer (mCRPC). We sought to evaluate the impact of PSA flare on survival and its relation with metabolic parameters on 18F-labeled sodium fluoride PET/CT. METHODS: We conducted a retrospective study of 168 patients with mCRPC (median age 69; median PSA 29.7) receiving 223RaCl2. Overall survival (OS) and progression-free survival (PFS), estimated by the Kaplan-Meier method and compared using a log-rank test, were evaluated for patient groups corresponding to different definitions of PSA flare. Metabolic 18F-fluoride PET/CT data were analyzed as well. RESULTS: Immediate PSA decline was observed in 49 patients (29.2%), whereas no PSA response was observed in 59 patients (35.1%). PSA flare (defined as rise after the first cycle followed by decrease below the baseline) was observed in 20 patients (11.9%) and PSA flare followed by a decrease from peak but not below baseline was observed in 40 (23.8%). The first flare subgroup had a median PFS and OS of 20.8 and 23.9 months, respectively. These outcomes were not significantly different from patients with immediate PSA decrease, but were significantly better than in patients with persistent PSA elevation (3.1 months for PFS and 11.5 months for OS, p < 0.001). Moreover, the PSA flare group showed an alkaline phosphatase (ALP) decrease significantly greater than non-responders (p = 0.003). Metabolic 18F-fluoride PET/CT data were available in 35 patients at baseline and during 233RaCl2 therapy. The tumor burden reduction, expressed by ΔTLF10 and ΔFTV10, was more evident within PSA flare group below baseline than non-responders (p = 0.005 and 0.001, respectively). CONCLUSIONS: This report suggests that a flare does not necessarily indicate lack of response to 223RaCl2 therapy.

Sodium fluoride (Na18F) PET Response Criteria in Solid Tumors (NAFCIST): a framework for response assessment in bone tumors.

The current Response Evaluation Criteria in Solid Tumors for measuring tumor response in osteosarcoma may be sub-optimal, as even responsive bone tumors may show limited change in tumor diameters. This limits the use of traditional imaging assessment tools. Therefore, discerning osteosarcoma response to therapy on magnetic resonance imaging before surgery is often difficult, and it is typically evaluated after surgery by assessing the amount of necrosis in resected surgical specimens. To address these challenges, sodium fluoride (Na18F) positron emission tomography/computed tomography (PET/CT) scans can be utilized to better image bone response to therapy, as, fluoride is avidly taken up by bone. Na18F Response Criteria in Solid Tumors (NAFCIST) has been developed as a novel method to evaluate treatment response using Na18F PET/CT. Current evidence supporting NAFCIST comes from a pilot study that evaluated alpha particle radium-223 in patients with osteosarcoma. In this review, practical guidance for utilizing NAFCIST in the context of bone tumors is illustrated to aid future studies.

Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: Approximately 25% of patients with esophageal cancer (EC) who undergo preoperative chemoradiation, achieve a pathologic complete response (pathCR). We hypothesized that a model based on clinical parameters could predict pathCR with a high (≥60%) probability. PATIENTS AND METHODS: We analyzed 322 patients with EC who underwent preoperative chemoradiation. All the patients had baseline and postchemoradiation positron emission tomography (PET) and pre- and postchemoradiation endoscopic biopsy. Logistic regression models were used for analysis, and cross-validation via the bootstrap method was carried out to test the model. RESULTS: The 70 (21.7%) patients who achieved a pathCR lived longer (median overall survival [OS], 79.76 months) than the 252 patients who did not achieve a pathCR (median OS, 39.73 months; OS, P = 0.004; disease-free survival, P = 0.003). In a logistic regression analysis, the following parameters contributed to the prediction model: postchemoradiation PET, postchemoradiation biopsy, sex, histologic tumor grade, and baseline (EUS)T stage. The area under the receiver-operating characteristic curve was 0.72 (95% confidence interval [CI] 0.662-0.787); after the bootstrap validation with 200 repetitions, the bias-corrected AU-ROC was 0.70 (95% CI 0.643-0.728). CONCLUSION: Our data suggest that the logistic regression model can predict pathCR with a high probability. This clinical model could complement others (biomarkers) to predict pathCR.

Circulating tumor cells and bone metastases as detected by FDG-PET/CT in patients with metastatic breast cancer.

BACKGROUND: We evaluated the relationship between the detection and prognostic significance of circulating tumor cells (CTCs) and sites of metastases detected by 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: From May 2004 to January 2008, 195 patients with relapsed/progressive MBC underwent whole-body FDG-PET/CT and provided blood samples for assessment of CTC count. RESULTS: Higher CTC numbers were detected in patients with bone metastases relative to those with no bone lesions (mean 65.7 versus 3.3, P = 0.0122) and in patients with multiple bone metastases relative to those with one or two bone lesions (mean 77.7 versus 2.6, P < 0.001). CTCs predicted overall survival (OS) in 108 patients with multiple sites of metastases including bone (P = 0.0008) but not in 58 without bone metastases (P = 0.4111) and in 29 with bone involvement only (P = 0.3552). All 15 patients but one with human epidermal growth factor receptor 2 (HER-2) positive tumors who were treated with trastuzumab-based regimens had <5 CTCs at progression. In multivariate analysis, CTCs, but not bone metastases, remained a significant predictor of OS. CONCLUSION: Presence of extensive bone metastases as detected by FDG-PET/CT is associated with increased CTC numbers in MBC.

ROC study and SUV threshold using quantitative multi-modal SPECT for bone imaging.

BACKGROUND: We investigated the clinical performance of a quantitative multi-modal SPECT/CT reconstruction platform for yielding radioactivity concentrations of bone imaging with 99mTc-methylene diphosphonate (MDP) or 99mTc-dicarboxypropane diphosphonate (DPD). The novel reconstruction incorporates CT-derived tissue information while preserving the delineation of tissue boundaries. We assessed image-based reader concordance and confidence, and determined lesion classification and SUV thresholds from ROC analysis. METHODS: Seventy-two cancer patients were scanned at three US and two German clinical sites, each contributing two experienced board-certified nuclear medicine physicians as readers. We compared four variants of the reconstructed data resulting from the Flash3D (F3D) and the xSPECT Bone™ (xB) iterative reconstruction methods and presented images to the readers with and without a fused CT, resulting in four combinations. We used an all-or-none approach for inclusion, compiling results only when a reader completed all reads in a subset. After the final read, we conducted a "surrogate truth" reading, presenting all data to each reader. For any remaining discordant lesions, we conducted a consensus read. We next undertook ROC analysis to determine SUV thresholds for differentiating benign and lesional uptake. RESULTS: On a five-point rating scale of image quality, xB was deemed better by almost two points in resolution and one point better in overall acceptance compared to F3D. The absolute agreement of the rendered decision between the nine readers was significantly higher with CT information either inside the reconstruction (xB, xBCT) or simply through image fusion (F3DCT): 0.70 (xBCT), 0.67 (F3DCT), 0.64 (xB), and 0.46 (F3D). The confidence level to characterize the lesion was significantly higher (3.03x w/o CT, 1.32x w/CT) for xB than for F3D. There was high correlation between xB and F3D scores for lesion detection and classification, but lesion detection confidence was 41% higher w/o CT, and 21% higher w/CT for xB compared to F3D. Without CT, xB had 6.6% higher sensitivity, 7.1% higher specificity, and 6.9% greater AUC compared to F3D, and similarly with CT-fusion. The overall SUV-criterion (SUVc) of xB (12) exceeded that for xSPECT Quant™ (xQ; 9), an approach not using the tissue delineation of xB. SUV critical numbers depended on lesion volume and location. For non-joint lesions > 6 ml, the AUC for xQ and xB was 94%, with SUVc > 9.28 (xQ) or > 9.68 (xB); for non-joint lesions ≤ 6 ml, AUCs were 81% (xQ) and 88% (xB), and SUVc > 8.2 (xQ) or > 9.1 (xB). For joint lesions, the AUC was 80% (xQ) and 83% (xB), with SUVc > 8.61 (xQ) or > 13.4 (xB). CONCLUSION: The incorporation of high-resolution CT-based tissue delineation in SPECT reconstruction (xSPECT Bone) provides better resolution and detects smaller lesions (6 ml), and the CT component facilitates lesion characterization. Our approach increases confidence, concordance, and accuracy for readers with a wide range of experience. The xB method retained high reading accuracy, despite the unfamiliar image presentation, having greatest impact for smaller lesions, and better localization of foci relative to bone anatomy. The quantitative assessment yielded an SUV-threshold for sensitively distinguishing benign and malignant lesions. Ongoing efforts shall establish clinically usable protocols and SUV thresholds for decision-making based on quantitative SPECT.

Unusual adrenal metastasis and abdominal carcinomatosis secondary to Hurthle cell carcinoma of the thyroid.

Hurthle cell carcinoma (HCC) of the thyroid is an uncommon and relatively rare differentiated thyroid neoplasm. To our knowledge, no reported case of adrenal metastases with abdominal carcinomatosis secondary to HCC of the thyroid has been demonstrated by F-18 FDG PET/CT imaging. One report of adrenal uptake on I-131 whole-body scan with HCC exists. In this case report, we describe a patient with HCC who had a left adrenal metastasis with abdominal carcinomatosis that was discovered using F-18 FDG PET/CT imaging.

Attenuation correction of PET cardiac data with low-dose average CT in PET/CT.

We proposed a low-dose average computer tomography (ACT) for attenuation correction (AC) of the PET cardiac data in PET/CT. The ACT was obtained from a cine CT scan of over one breath cycle per couch position while the patient was free breathing. We applied this technique on four patients who underwent tumor imaging with 18F-FDG in PET/CT, whose PET data showed high uptake of 18F-FDG in the heart and whose CT and PET data had misregistration. All four patients did not have known myocardiac infarction or ischemia. The patients were injected with 555-740 MBq of 18F-FDG and scanned 1 h after injection. The helical CT (HCT) data were acquired in 16 s for the coverage of 100 cm. The PET acquisition was 3 min per bed of 15 cm. The duration of cine CT acquisition per 2 cm was 5.9 s. We used a fast gantry rotation cycle time of 0.5 s to minimize motion induced reconstruction artifacts in the cine CT images, which were averaged to become the ACT images for AC of the PET data. The radiation dose was about 5 mGy for 5.9 s cine duration. The selection of 5.9 s was based on our analysis of the respiratory signals of 600 patients; 87% of the patients had average breath cycles of less than 6 s and 90% had standard deviations of less than 1 s in the period of breath cycle. In all four patient studies, registrations between the CT and the PET data were improved. An increase of average uptake in the anterior and the lateral walls up to 48% and a decrease of average uptake in the septal and the inferior walls up to 16% with ACT were observed. We also compared ACT and conventional slow scan CT (SSCT) of 4 s duration in one patient study and found ACT was better than SSCT in depicting average respiratory motion and the SSCT images showed motion-induced reconstruction artifacts. In conclusion, low-dose ACT improved registration of the CT and the PET data in the heart region in our study of four patients. ACT was superior than SSCT for depicting average respiration motion in a patient study.

Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients.

PURPOSE: To evaluate the efficacy and toxicity of sequential, dose-intensified chemotherapy with paclitaxel/ifosfamide and carboplatin/etoposide administered plus peripheral blood-derived stem-cell (PBSC) support for patients with germ cell tumors (GCT) who have unfavorable prognostic features in response to conventional-dose salvage programs. Carboplatin was dose escalated by target area under the curve (AUC; in [milligrams per milliliter] x minutes) among patient cohorts, and pharmacokinetic studies were performed for comparison. PATIENTS AND METHODS: Thirty-seven previously treated patients who had cisplatin-resistant GCT and unfavorable prognostic features for response to conventional-dose salvage therapy were treated. Two cycles of paclitaxel 200 mg/m(2) plus ifosfamide 6 g/m(2) were given 2 weeks apart with leukapheresis, followed by three cycles of carboplatin plus etoposide given 14 to 21 days apart with reinfusion of PBSCs. The dose of etoposide was 1, 200 mg/m(2), and the carboplatin target AUC ranged among cohorts from 12 to 32 (mg/mL) x min. Pharmacokinetic studies of carboplatin were performed for comparison of target to measured AUC. RESULTS: Twenty-one patients (57%) achieved a complete response and an additional two patients (5%) achieved a partial response with normal tumor markers; therefore, 23 (62%) achieved a favorable response. Eight patients relapsed, and 15 (41%) of the favorable responses remained durable at a median follow-up of 30 months. Myelosuppression was the major toxicity; 58% of carboplatin/etoposide cycles were associated with hospitalization for nadir fever. The AUC of carboplatin measured in serum was lower than the target AUC; this may be related to underestimation of the glomerular filtration rate used in the dosing formula. CONCLUSION: Dose-intense therapy with sequential, accelerated chemotherapy of paclitaxel/ifosfamide and carboplatin/etoposide administered with PBSC support was relatively well tolerated. The durable complete response proportion was substantial in patients with unfavorable prognostic features for achieving durable complete response to conventional-dose salvage programs. Optimal dosing of carboplatin in the high-dose setting warrants further investigation.

Attenuation correction of PET images with respiration-averaged CT images in PET/CT.

UNLABELLED: Attenuation correction (AC) of PET images with helical CT (HCT) in PET/CT matches only the spatial resolution of CT and PET, not the temporal resolution. We therefore proposed the use of respiration-averaged CT (ACT) to match the temporal resolution of CT and PET and evaluated the improvement of tumor quantification in PET images of the thorax with ACT. METHODS: First, we examined 100 consecutive clinical PET/CT studies for the frequency and magnitude of misalignment at the diaphragm position between the HCT and the PET data. Patients were injected with 555-740 MBq of (18)F-FDG and scanned 1 h after injection. The HCT data were acquired at the following settings: 120 kV, 300 mA, pitch of 1.35:1, collimation of 8 x 1.25 mm, and rotation cycle of 0.5 s. Patients were instructed to hold their breath at midexpiration during HCT of the thorax. The PET acquisition was 3 min per bed. Second, we retrospectively analyzed studies of 8 patients (1 with esophageal cancer and 7 with lung cancer). Each study included regular PET/CT followed by 4-dimensional (4D) CT for radiation treatment planning. We compared the results of AC of the PET data with HCT and ACT. There were 13 tumors in these 8 patients. The 4D CT data were acquired at the following settings: 120 kV, 50-150 mA, cine duration of 1 breathing cycle plus 1 s, collimation of 8 x 1.25 mm, and rotation cycle of 0.5 s. The acquisition was taken when the patient was in the free-breathing state. We averaged the 10 phases of the 4D CT data to obtain ACT for AC of the PET data. Both the ACT and the HCT data were used for AC of the same PET data. RESULTS: There was a misalignment between the HCT and the PET data in 50 of 100 patient studies. In 34 studies, the misalignment was greater than 2 cm. In a comparison of HCT and ACT, 5 tumors had differences in standardized uptake values (SUV) between HCT-and ACT-attenuation-corrected PET of less than 20%, and 4 tumors had differences in SUV of more than 50%. The latter 4 tumors were found in the patient with esophageal cancer and in 2 of the patients with lung cancer. The PET data from these 3 patients had a misalignment of 2-4.5 cm relative to the HCT data. Breathing artifacts were significantly reduced by ACT. Seven of the 8 patients had a lower diaphragm position on HCT than on ACT, suggesting that the patients tended to hold a deeper breath during HCT than during ACT. CONCLUSION: The high rate of misalignment suggested a potential mismatch between the HCT and the PET data with the limited-breath-hold CT protocol. In the comparison of HCT and ACT, significant differences (>50%) in SUV were attributable to different breathing states between HCT and PET. The PET data corrected by ACT did not show breathing artifacts, suggesting that ACT may be more accurate than HCT for AC of the PET data.

Fludeoxyglucose positron emission tomography in the diagnosis of giant cell arteritis.

We describe a case in which fludeoxyglucose F 18 positron emission tomography (PET) led directly to the diagnosis of giant cell arteritis in an elderly woman with a fever of unknown origin. The patient presented with a 3-month history of fatigue, fever, headache, visual disturbance, jaw claudication, and anemia. A computed tomographic scan showed an anterior mediastinal mass that was suspected of being malignant. A fludeoxyglucose F 18 PET scan performed for preoperative evaluation identified striking uptake of fludeoxyglucose F 18 in the walls of the entire aorta, left main coronary artery, and subclavian, carotid, and common iliac arteries bilaterally, suggestive of an arteritis, a diagnosis subsequently confirmed by the findings of an arterial biopsy. Her erythrocyte sedimentation rate was 129 mm/h. There was normalizaton of the PET scan 2 weeks following treatment with prednisolone. This case suggests that fludeoxyglucose F 18 PET contributes to the noninvasive diagnosis of giant cell arteritis, as well as to the evaluation of the extent of disease, response to therapy, and disease recurrence.

Prognostic value of [18F]fluorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer.

Poorly differentiated thyroid cancer lesions often lose the ability to concentrate radioactive [131I]iodine (RAI) and exhibit increased metabolic activity, as evidenced by enhanced glucose uptake. We incorporated [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning into the routine follow-up of a cohort of thyroid cancer patients undergoing annual evaluations. One hundred and twenty-five patients who had previous thyroidectomies were included. They had diagnostic RAI whole body scans, serum thyroglobulin measurements, and additional imaging studies as clinically indicated. During 41 months of follow-up, 14 patients died. Univariate analysis demonstrated that survival was reduced in those with age over 45 yr, distant metastases, PET positivity, high rates of FDG uptake, and high volume of the FDG-avid disease (>125 mL). Survival did not correlate with gender, RAI uptake, initial histology, or grade. Multivariate analysis demonstrated that the single strongest predictor of survival was the volume of FDG-avid disease. The 3-yr survival probability of patients with FDG volumes of 125 mL or less was 0.96 (95% confidence interval, 0.91, 1.0) compared with 0.18 (95% confidence interval, 0.04, 0.85) in patients with FDG volume greater than 125 mL. Only 1 death (of leukemia) occurred in the PET-negative group (n = 66). Of the 10 patients with distant metastases and negative PET scans, all were alive and well. Patients over 45 yr with distant metastases that concentrate FDG are at the highest risk. Once distant metastases are discovered in patients with differentiated thyroid carcinoma, FDG-PET can identify high and low risk subsets. Subjects with a FDG volume greater than 125 mL have significantly reduced short term survival.

[18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography localizes residual thyroid cancer in patients with negative diagnostic (131)I whole body scans and elevated serum thyroglobulin levels.

Progressive dedifferentiation of thyroid cancer cells leads to a loss of iodine-concentrating ability, with resultant false negative, whole body radioactive iodine scans in approximately 20% of all differentiated metastatic thyroid cancer lesions. We tested the hypothesis that all metastatic thyroid cancer lesions that did not concentrate iodine, but did produce thyroglobulin (Tg), could be localized by [18F]2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET). We performed FDG-PET on 37 patients with differentiated thyroid cancer after surgery and radioiodine ablation who had negative diagnostic 131I whole body scans during routine follow-up. Serum Tg, Tg autoantibodies, neck ultrasounds, and other clinically indicated imaging procedures were performed to detect residual disease. In those with elevated Tg levels, FDG-PET localized occult disease in 71%, was false positive in one, and was false negative in five patients. The majority of false negative FDG-PET occurred in patients with minimal cervical adenopathy. Surgical resections, biopsies, 131 therapy, and differentiation therapy were performed based on the PET results. The FDG-PET result changed the clinical management in 19 of the 37 patients. In patients with elevated Tg levels, FDG-PET had a positive predictive value of 92%. In patients with low Tg levels, FDG-PET had a negative predictive value of 93%. No FDG-PET scans were positive in stage I patients; however, they were always positive in stage IV patients with elevated Tg levels. An elevated TSH level (i.e. hypothyroidism) did not increase the ability to detect lesions. FDG-PET is able to localize residual thyroid cancer lesions in patients who have negative diagnostic 131I whole body scans and elevated Tg levels, although it was not sensitive enough to detect minimal residual disease in cervical nodes.

Mathematical model of 5-[125I]iodo-2'-deoxyuridine treatment: continuous infusion regimens for hepatic metastases.

PURPOSE: Due to the cytotoxicity of DNA-bound iodine-125, 5-[125I]Iodo-2'-deoxyuridine ([125I]IUdR), an analog of thymidine, has long been recognized as possessing therapeutic potential. In this work, the feasibility and potential effectiveness of hepatic artery infusion of [125I]IUdR is examined. METHODS: A mathematical model has been developed that simulates tumor growth and response to [125I]IUdR treatment. The model is used to examine the efficacy and potential toxicity of prolonged infusion therapy. Treatment of kinetically homogeneous tumors with potential doubling times of either 4, 5, or 6 days is simulated. Assuming uniformly distributed activity, absorbed dose estimates to the red marrow, liver and whole-body are calculated to assess the potential toxicity of treatment. RESULTS: Nine to 10 logs of tumor-cell kill over a 7- to 20-day period are predicted by the various simulations examined. The most slowly proliferating tumor was also the most difficult to eradicate. During the infusion time, tumor-cell loss consisted of two components: A plateau phase, beginning at the start of infusion and ending once the infusion time exceeded the potential doubling time of the tumor; and a rapid cell-reduction phase that was close to log-linear. Beyond the plateau phase, treatment efficacy was highly sensitive to tumor activity concentration. CONCLUSIONS: Model predictions suggest that [125I]IUdR will be highly dependent upon the potential doubling time of the tumor. Significant tumor cell kill will require infusion durations that exceed the longest potential doubling time in the tumor-cell population.

Technetium-99m-MIBI versus fluorine-18-FDG in diffuse multiple myeloma.

Experience of scintigraphic detection of bone lesion and active bone marrow involvement of multiple myeloma, especially with sestamibi and FDG-PET scans is in evolution. We report a case of intense sestamibi uptake in bone marrow correlating with the extent of the disease, while FDG-PET scans showed activity only in areas of active disease progression associated with pain. Technetium-99m-sestamibi appears to indicate the extent of the disease, while [18F]FDG-PET scans show sites of active tumor proliferation and may be useful in directing local therapy such as radiation.

Visualization of myocardial metastasis of carcinoid tumor by indium-111-pentetreotide.

We present a case of metastatic carcinoid tumor metastatic to the heart, presenting as ventricular arrhythmia and diagnosed by 111Inpentetreotide scintiscan despite negative endocardial biopsy. The incidence and diagnosis of carcinoid heart disease is discussed, as well as the complementary role of high-resolution anatomical images (CT, MRI) with functional images (SPECT, PET) to determine the correct diagnosis of this rare condition.

Image registration of SPECT and CT images using an external fiduciary band and three-dimensional surface fitting in metastatic thyroid cancer.

Image registration of 131I SPECT with CT scans was performed in a patient with metastatic thyroid carcinoma using an external fiduciary band and a three-dimensional surface-fitting algorithim. Areas of metastatic disease taking up 131I were accurately localized to the liver, lungs and vertebral bodies; providing information that could not be obtained by planar or SPECT images alone. Based on these findings, further invasive diagnostic procedures were not performed, therefore considerably altering management in this patient. This approach to image registration has immediate clinical utility in the registration and interpretation of SPECT studies with corresponding CT or MRI scans.

Pharmacokinetics and dosimetry of iodine-125-IUdR in the treatment of colorectal cancer metastatic to liver.

UNLABELLED: The radiotoxicity of 125I is highly sensitive to the site of decay relative to nuclear DNA. This paper describes a new approach, based upon pharmacokinetic clearance of radioactivity from the tumor, with which to quantify the fraction of [125I]IUdR incorporated within the DNA of tumor cells. METHODS: Patients were injected with [125I]IUdR through the hepatic artery. Iodine-131-IUdR was used as a tracer for imaging and quantitation. Both conventional and DNA-level dosimetry were performed. RESULTS: We calculated that if 15% of the tumor cells were in S phase at the time of injection, there would be 250 decays of 125I in the DNA per tumor cell after an infusion of 5 mCi [125I]IUdR. According to in vitro data based on 5 x 10(8) cells per g tumor, 99% of these cells in S phase would be killed. CONCLUSION: The estimate of cell inactivation is strongly dependent on the number of cells per gram and the fraction of cells in S phase at the time of injection, which indicates that repeat injections would be necessary to achieve a therapeutic effect.

Pilot clinical trial of 5-[125I]iodo-2'-deoxyuridine in the treatment of colorectal cancer metastatic to the liver.

UNLABELLED: The thymidine analog, 5-iodo-2'-deoxyuridine (IUdR), is incorporated in the DNA of cells in the S phase. When incorporated into DNA, short-range Auger electrons emitted by 125I-labeled IUdR can cause double-strand breaks, delivering a lethal radiation dose to the cell. We conducted therapeutic trial to evaluate[125I/131I]IUdR pharmacokinetics in liver metastases from colorectal cancer. Dosimetry, safety, and therapeutic potential were assessed. METHODS: Four patients were each infused with 5 mCi [125I]IUdR and 10 mCi [131I]IUdR through the sideport of a hepatic artery pump. Iodine-131 images were quantitated and used for pharmacokinetic studies. The radioactivity in the DNA of biopsy samples of tumor, normal liver and bone marrow, obtained 24 or 48 hr after injection, was counted. RESULTS: All patients had [125I]IUdR and [131I]IUdR uptake in tumor, with a biexponential clearance. Repeat injections in individual patients showed little variation in tumor uptake, especially in the slow clearance component. On planar images, no long-term retention was seen in bone marrow or other actively dividing normal tissues. Radioactivity in all tumor DNA samples was greater than background, while that in normal liver cell DNA was at background levels. Radioactivity in the DNA of one marrow sample taken at 24 hr was above background, but in another taken at 48 hr it was equal to background levels. No side effects were noted, no hematologic toxicity was observed in any patients and no tumor responses were seen. CONCLUSION: There is persistent uptake of [125I]IUdR in hepatic tumors, thereby making hepatic artery infusion a suitable mode of delivery for therapy. Repeat injections will be needed because only 15%-50% of tumor cells are in the S phase. Based on results from this pilot study, a therapeutic regimen is being planned.

Imaging of brain tumor proliferative activity with iodine-131-iododeoxyuridine.

METHODS: Iodine-131-iododeoxyuridine (IUdR) uptake and retention was imaged with SPECT at 2 and 24 hr after administering a 10-mCi dose to six patients with primary brain tumors. The SPECT images were directly compared to gadolinium contrast-enhanced MR images as well as to [18F]fluorodeoxyglucose (FDG) PET scans and 201Tl SPECT scans. RESULTS: Localized uptake and retention of IUdR-derived radioactivity was observed in five of six patients. The plasma half-life of [131I]IUdR was short (1.6 min) in comparison to the half-life of total plasma radioactivity (6.4 hr). The pattern of [131I]IUdR-derived radioactivity was markedly different in the 2-hr compared to 24-hr images. Radioactivity was localized along the periphery of the tumor and extended beyond the margin of tumor identified by contrast enhancement on MRI. The estimated levels of tumor radioactivity at 24 hr, based on semiquantitative phantom studies, ranged between < 0.1 and 0.2 microCi/cc (< 0.001% and 0.002% dose/cc); brain levels were not measurable. CONCLUSIONS: Iodine-131-IUdR SPECT imaging of brain tumor proliferation has low (marginal) sensitivity due to low count rates and can detect only the most active regions of tumor growth. Imaging at 24 hr represents a washout strategy to reduce 131I-labeled metabolites contributing to background activity in the tumors, and is more likely to show the pattern of [131I]IUdR-DNA incorporation and thereby increase image specificity. Iodine-123-IUdR SPECT imaging at 12 hr and the use of [124I]IUdR and PET will improve count acquisition and image quality.

Clinical validation of SPECT and CT/MRI image registration in radiolabeled monoclonal antibody studies of colorectal carcinoma.

UNLABELLED: Registration methods combine the anatomic localizing ability of CT or MRI with SPECT images of radiolabeled monoclonal antibodies (Mabs), allowing the accurate staging of patients prior to surgery or following treatment. METHODS: Twenty-four patients (15 males and 9 females, mean age 55 yr, range 29-70 yr) were studied with this technique. Ten patients had suspected colorectal cancer recurrence and were infused with 10 mCi of 131I-CC49 prior to staging laparotomy. Fourteen patients treated in a Phase I radioimmunotherapy study with 131I-CC49 were also studied. All patients underwent SPECT imaging of the abdomen and pelvis 5-7 days following infusion of Mab. RESULTS: Phantom studies demonstrated a 3.6-mm surface fitting mean accuracy of datasets for the liver and 1.8 mm for an intrahepatic tumor. In the presurgical group, SPECT and CT/MRI registration allowed more accurate identification of uptake abnormal sites. Areas of metastatic disease > 1 cm confirmed at surgery were found in six of nine patients with liver lesions and in two patients with extrahepatic (including one patient with pelvic) disease. In patients imaged following radioimmunotherapy, all lesions > 1.5 cm seen on CT/MRI were identified, and activity distribution in tumor and normal tissue could be more accurately assessed. CONCLUSIONS: Routine registration of SPECT and CT/MRI images is feasible and allows more accurate anatomic assessment of sites of abnormal uptake in radiolabeled Mab studies.