Thyroid uptake and radiation dose after (131)I-lipiodol treatment: is thyroid blocking by potassium iodide necessary?

In radionuclide therapy with iodine-131 labelled pharmaceuticals, free (131)I may be released and trapped by the thyroid, causing an undesirable radiation burden. To prevent this, stable iodide such as potassium iodide (KI) can be given to saturate the thyroid before (131)I is administered. The guidelines of the European Association of Nuclear Medicine do not, however, recommend special precautions when administering (131)I-lipiodol therapy for hepatocellular carcinoma. Nevertheless, some authors have reported (131)I uptake in the thyroid as a consequence of such therapy. In this study, the influence of prophylactic KI on the thyroid uptake and dose (MIRD dosimetry) was prospectively investigated. (131)I-lipiodol was given as a slow bolus selectively in the proper hepatic artery or hyperselectively in the right and/or left hepatic artery. Patients were prospectively randomised into two groups. One group received KI in a dose of 100 mg per day starting 2 days before (131)I-lipiodol administration and continuing until 2 weeks after therapy (KI group; n=31), while the other group received no KI (non-KI group; n=37). Thyroid uptake was measured scintigraphically as a percentage of administered activity 7 days after (131)I-lipiodol ( n=68 treatments). The absorbed radiation dose to the thyroid was assessed by scintigraphy after 7 and 14 days using a mono-exponential fitting model and MIRD dosimetry ( n=40 treatments). The mean activity of (131)I-lipiodol administered was 1,835 MBq in a volume of 2 ( n=17) or 4 ( n=51) ml. Thyroid uptake was lower in the KI group, being 0.23%+/-0.06% of injected activity ( n=31) compared with 0.42%+/-0.20% in the non-KI group ( n=37); the mean thyroid dose was 5.5+/-1.6 Gy in the KI group ( n=19) versus 11.9+/-5.9 Gy in the non-KI group ( n=21). These differences were statistically significant ( P<0.001). No effect of the amount of added cold lipiodol (4 vs 2 ml total volume) or selectivity of (131)I-lipiodol administration was evident ( P>0.1). (131)I-lipiodol is associated with a generally low thyroid uptake and dose that may be significantly decreased by KI premedication. Given the low cost and the very good tolerance of the KI treatment, we believe the use of KI should be recommended in the majority of the patients.     

Patient dosimetry for 131I-lipiodol therapy

Patient dosimetry data for intra-arterial()iodine-131 lipiodol therapy for hepatocellular carcinoma (HCC) are scarce. The aim of this study was to determine the absorbed dose (D) to the tumour and healthy tissues, as well as the effective dose (E), by different methods for 17 therapies in 15 patients who received a mean activity of 1.9 GBq (SD 0.2) (131)I-lipiodol. Eight patients received thyroid blocking by potassium iodide (KI). Patient dosimetry was performed based on bi-planar total body scans using the Monte Carlo simulation program MCNP-4B and the MIRDOSE-3 standard software program. CT images of each patient were used to determine liver and tumour volume and position. The total body dose to the patient was also determined by biological dosimetry with the in vitro micronucleus (MN) assay. From the increase in micronucleus yield after therapy, the equivalent total body dose (ETBD) was calculated. Results for D and E were comparable between MCNP and MIRDOSE (liver: mean 7.8 Gy, SD 1.8, lungs: 6.8 Gy, SD 2.9, E: 2.01 Gy, SD 0.58). MIRDOSE gave a systematic overestimation for the tumour dose, especially for tumours <3 cm (15%). The MCNP method is more accurate since the dose contributions from tumour to organs and vice versa can be accounted for. The absorbed dose to the thyroid was significantly lower for patients who received KI (7.2 Gy, SD 2.2) than for the other patients (13.8 Gy, SD 5.0). MN yields could be obtained for only 12 of the 17 therapies due to hypersplenism. A mean ETBD of 1.66 Gy (SD 0.73) was obtained, but the MN results showed no correlation between the ETBD and the total body dose values of the physical dosimetry. Also, in all except one of the patients, no further reduction in the number of thrombocytes was observed after therapy, probably due to the existing hypersplenism. It is concluded that in view of the high E values, patient dosimetry is necessary for patients receiving (131)I-lipiodol therapy. Except in the case of the smaller tumours, comparable results were obtained with MCNP and MIRDOSE. Due to hypersplenism, biological dosimetry results based on the MN assay are not reliable.     

Safe radiation exposure of medical personnel by using simple methods of radioprotection while administering 131I-lipiodol therapy for hepatocellular carcinoma

The intra-arterial administration of 131I-lipiodol is a therapeutic approach increasingly used for the treatment of inoperable hepatocellular carcinomas. This technique has even become the reference treatment for hepatocellular carcinomas with portal thrombosis and is the only effective treatment to reduce the risk of recurrence among patients who could benefit from surgical operation. Currently, few data have been published concerning the levels of exposure for personnel carrying out this type of treatment. We undertook a dosimetric study targeted mainly on the exposure of the person performing the injection of 131I-lipiodol to show that this treatment can be carried out with an exposure at the extremities distinctly lower than the regulatory annual threshold by using simple means of radioprotection. The point of puncture was carried out at the level of left femoral artery, the preparation and injection of the therapeutic dose was carried out extemporaneously by the nuclear medicine specialist using a 10 ml syringe (for an injected volume of 4 ml) fitted with an adapted syringe protector. The injection was carried out as rapidly as possible under scopic control while avoiding reflux, with compression carried out by the radiologist. This study comprises 52 intra-arterial injections of 131I-lipiodol (2016+/-92 MBq). For the nuclear medicine specialists, 52 measurements were carried out at the level of the thorax and 41 on the fingers. For the radiologists, 22 measurements were carried out at the level of the thorax and six on their index fingers; nine measurements were carried out at the level of the thorax for the technologist and four at the level of the thorax for the stretcher bearer. For the nuclear medicine specialists, the average dose received at the level of the fingers varies between 140 and 443 microSv (according to the fingers) and the average dose at the thorax is 17 microSv. For the radiologists, the average dose received is 215 microSv at the level of the fingers and 15 microSv at the thorax. These results show that the administration of high therapeutic activities of 131I-lipiodol can be carried out for the exposed personnel with a dose at the level of the fingers much lower than the European regulatory limit of 500 mSv.     

Biologic dosimetry of 188Re-HDD/lipiodol versus 131I-lipiodol therapy in patients with hepatocellular carcinoma.

One approach to treatment of primary hepatocellular carcinoma (HCC) is intraarterial injection of (131)I-lipiodol. Although clinical results have been positive, the therapy can be improved by using (188)Re instead of (131)I as the radionuclide. (188)Re is a high-energy beta-emitter, has a shorter half-life than (131)I, and has only low-intensity gamma-rays in its decay. The present study compared the cytotoxic effect of the radionuclide therapy in HCC patients treated with (131)I-lipiodol and (188)Re-4-hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD)/lipiodol. To this end, dicentric chromosomes (DCs) were scored in metaphase spreads of peripheral blood cultures. The equivalent total-body dose was deduced from the DC yields using an in vitro dose-response curve. METHODS: Twenty (131)I-lipiodol treatments and 11 (188)Re-HDD/lipiodol treatments were performed on, respectively, 16 and 7 patients with inoperable HCC. Patients received a mean activity of 1.89 GBq of (131)I-lipiodol or 3.56 GBq of (188)Re-HDD/lipiodol into the liver artery by catheterization. For each patient, a blood sample was taken during the week before therapy. A blood sample was also taken 7 and 14 d after administration for the patients treated with (131)I-lipiodol and 1 or 2 d after administration for the patients treated with (188)Re-HDD/lipiodol. RESULTS: The mean DC yield of (188)Re-HDD/lipiodol therapy (0.087 DCs per cell) was significantly lower than that of (131)I-lipiodol therapy (0.144 DCs per cell) for the administered activities. Corresponding equivalent total-body doses were 1.04 Gy for (188)Re-HDD/lipiodol and 1.46 Gy for (131)I-lipiodol. Data analysis showed that, in comparison with (131)I-lipidol, (188)Re-HDD/lipiodol yielded a smaller cytotoxic effect and a lower radiation exposure for an expected higher tumor-killing effect. CONCLUSION: (188)Re is a valuable alternative for (131)I in the treatment of HCC with radiolabeled lipiodol, and a dose escalation study for (188)Re-HDD/lipiodol therapy is warranted.     

Dosimetry-guided radioactive iodine treatment in patients with metastatic differentiated thyroid cancer: largest safe dose using a risk-adapted approach.

This study is a retrospective analysis of 124 differentiated thyroid cancer patients who underwent dosimetric evaluation using MIRD methodology over a period of 15 y. The objectives of the study were to demonstrate the clinical use of dosimetry-guided radioactive iodine ([RAI] (131)I) treatment and the safe and effective application of a 3-Gy bone marrow (BM) dose in patients with differentiated thyroid cancer. METHODS: Tumor and BM dose estimates were obtained. The administered activity that would deliver a maximum safe dose to the organ at risk (red BM or lungs) was determined as well as the resulting doses to the metastases. The clinical benefit of an individual RAI treatment was predicted on the basis of the dose estimates and the expected therapeutic response. Each patient's response to treatment was assessed clinically and by monitoring the hematologic profile. RESULTS: One hundred twenty-four patients underwent 187 dosimetric evaluations. One hundred four RAI treatments were performed. A complete response at metastatic deposits was attained with absorbed doses of >100 Gy. No permanent BM suppression was observed in patients who received absorbed doses of <3 Gy to BM. The maximum administered dose was 38.5 GBq (1,040 mCi) with the BM dose limitation. CONCLUSION: Dosimetry-guided RAI treatment allows administration of the maximum possible RAI dose to achieve the maximum therapeutic benefit. Estimation of tumor dose rates helps to determine the curative versus the palliative intent of the therapy.     

Impact of 131I diagnostic activities on the biokinetics of thyroid remnants.

Recent publications described many discrepant findings about thyroid "stunning" after the administration of (131)I diagnostic activities to patients with differentiated thyroid carcinoma. Stunning may play a major role in reducing the therapeutic efficacy of high (131)I activities given for ablation therapy. METHODS: Participation in a multicenter study to investigate differences in iodine biokinetics in the hypothyroid state and after the application of recombinant human thyroid-stimulating hormone enabled us to study quantitative changes in thyroid iodine biokinetics after the administration of 74 MBq of (131)I twice within 6 wk and an ablation activity of 3-4 GBq 7-12 d after the second diagnostic administration of (131)I in 6 patients. RESULTS: The uptake and half-life of the first 74 MBq of (131)I were significantly reduced to a mean of 44% and a mean of 51%, respectively, after the second diagnostic administration and further reduced to a mean of 40% and a mean of 30%, respectively, during ablation therapy. The residence times were reduced to 25% in the second dosimetric assessment and to 10% during therapy compared with the value in the first assessment. For one patient, an estimated absorbed dose as high as 38 Gy was found in the first diagnostic study. The mean dose for all patients after the first assessment was 15 Gy; after each further assessment, the dose was reduced according to the decrease in residence time. CONCLUSION: This study shows a severe impact of 74 MBq of (131)I on the biokinetics of thyroid remnants during subsequent radioiodine therapy.     

Bone marrow dosimetry and safety of high 131I activities given after recombinant human thyroid-stimulating hormone to treat metastatic differentiated thyroid cancer.

Recombinant human thyroid-stimulating hormone (rhTSH) recently was introduced as a radioiodine administration adjunct that avoids levothyroxine (LT-4) withdrawal and resultant hypothyroidism. The pharmacokinetics of 131I after rhTSH administration are known to differ from those after LT-4 withdrawal but are largely nondelineated in the radioiodine therapy setting. We therefore sought to calculate the red marrow absorbed dose of high therapeutic activities of 131I given after rhTSH administration to patients with metastatic or inoperable locally recurrent differentiated thyroid cancer. We also sought to evaluate the clinical and laboratory effects of this therapy on the bone marrow. METHODS: Fourteen consecutive patients received in total 17 131I treatments (7.4 GBq). Blood and urine samples were obtained at fixed intervals, and their activities were measured in a well counter. Based on blood activity, renal clearance of the activity, and residence times in red marrow and the remainder of the body, the red marrow absorbed dose was calculated using the MIRD schema. Additionally, we monitored for potential hematologic toxicity and compared platelet counts before and 3 mo after treatment. RESULTS: The mean +/- SD absorbed dose per unit of administered (131)I in the red marrow was 0.16 +/- 0.07 mGy/MBq. The corresponding total red marrow absorbed dose was 1.15 +/- 0.52 Gy (range, 0.28-1.91 Gy). In none of the patients was hematologic toxicity observed. The mean +/- SD platelet count (n = 13 treatments) was 243 +/- 62 x 10(9)/L before treatment and 233 +/- 87 x 10(9)/L 3 mo later, a slight and statistically insignificant decrease. After rhTSH-aided administration of high activities of 131I, the bone marrow absorbed dose remained under 2 Gy, the level long considered the safety threshold for all radioiodine therapy. CONCLUSION: Our specific findings imply that when clinically warranted, rhTSH should allow an increase in the therapeutic radioiodine activity. Such an increase might improve efficacy while preserving safety and tolerability; this possibility should be assessed in further studies.     

Thyroid stunning in vivo and in vitro

AIM: To review published in-vivo and in-vitro quantitative dosimetric studies on thyroid stunning in order to derive novel data applicable in clinical practice. METHODS: A non-linear regression analysis was applied to describe the extent of thyroid stunning in thyroid remnants, as a function of the radiation absorbed dose of diagnostic radioiodine-131 (I), in thyroid cancer patients investigated in four in-vivo studies. The regression curves were fitted using individual patient absorbed doses or the mean absorbed doses for the groups of patients. Fitted curves were compared with two recent models, the first found in patients with benign thyroid disease and the second found in cultured thyroid cells after I irradiation. RESULTS: The extrapolated absorbed doses for the onset of thyroid stunning were 0 Gy delivered to thyroid cells in vitro, and < or =4 Gy and 34 Gy delivered to thyroid cells in vivo (malignant and benign conditions, respectively). Thyroid stunning amounted to roughly 50% in the case of 2 Gy delivered to thyroid cells in vitro, and in the case of < or =30 Gy and 472 Gy delivered to thyroid cells in vivo (malignant and benign conditions, respectively). CONCLUSIONS: There is no scintigraphically sufficient diagnostic amount of I that can be given prior to I therapy for thyroid cancer that does not cause thyroid stunning, i.e. it is not recommended to deliver pre-therapeutically more than a few gray (<5 Gy) into thyroid remnants. More investigations are required to confirm the proposed in-vitro and benign in-vivo models, but characteristic absorbed doses presented so far for in-vitro vs. in-vivo malignant vs. in-vivo benign thyroid environments differ roughly by an order of magnitude.     

Adjuvant intraarterial injection of 131I-labeled lipiodol after resection of hepatocellular carcinoma: progress report of a case-control study with a 5-year minimal follow-up.

Recurrences after resection of hepatocellular carcinoma are frequent. A single postoperative injection of (131)I-labeled lipiodol in the hepatic artery was shown in 1999 by Lau and colleagues to be an effective adjuvant treatment, and those results were strengthened by our experience with a case-control study, reported in 2003. The goal of this paper is to update the 2003 results for a minimal follow-up of 5 y. METHODS: Between January 1999 and September 2001, 38 patients were given an adjuvant postoperative intraarterial injection of (131)I-lipiodol and were matched (for Okuda group and tumor size) with 38 patients who had undergone resection between January 1997 and January 1999 without postoperative treatment. The 2 groups were similar. RESULTS: There were 28 recurrences in the control group and 22 in the (131)I-lipiodol group (not statistically significant), and the mean time of recurrence was 21 and 26.5 mo, respectively, after surgery (statistically significant). The number of recurrences was lower in the first 2 y in the (131)I-lipiodol group (statistically significant). Disease-free survival was better (P < 0.03) in the (131)I-lipiodol group than in the control group (2-, 3-, and 5-y rates [+/-95% confidence interval] of 77% +/- 7%, 63% +/- 8%, and 42% +/- 8.5%, respectively, for the (131)I-lipiodol group vs. 47% +/- 8%, 34% +/- 8%, and 27% +/- 8%, respectively, for the control group). Overall survival did not differ between the 2 groups (P = 0.09), even though there was a trend toward better survival in the (131)I-lipiodol group (2-, 3-, and 5-y rates of 76% +/- 7%, 68% +/- 7.5%, and 51% +/- 9%, respectively, vs. 68% +/- 7.5%, 53% +/- 8%, and 39% +/- 8%, respectively, in the control group). CONCLUSION: With a longer follow-up, the results of this retrospective case-control study still favor a single postoperative injection of (131)I-lipiodol. These retrospective findings point out the need for a large-scale, prospective, randomized study.     

Radioisotope therapy of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine--absorbed dose assessments using SPECT]

The correlation of absorbed doses D (rad) of tumors in 4 patients with malignant pheochromocytoma, who were treated by 131I-MIBG (3.7 GBq), with their clinical courses were analyzed and the clinical significance of determination of absorbed dose was discussed. Absorbed doses of 131I-MIBG in the tumors were measured by using SPECT at the time of therapy. Absorbed dose was calculated based on the MIRD (medical internal radiation dose committee) equation. Tumor volumes were ranged from 17 g-100 g (mean 40 g), effective half lives were ranged from 1.3 days-5.9 days (mean 3.6 days), and tumor absorbed doses were varied between 5.4 Gy-68 Gy (mean 40 Gy). When the absorbed doses of the tumor exceeded over 40 Gy, good clinical responses were obtained. The initial treatment seemed to be important for 131I-MIBG therapy, since the absorbed doses in the following therapy became reduced. These results indicate that the quantitative SPECT for radioisotope therapy is clinically valid and that the calculated absorbed doses correlate well with clinical responses.     

Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study.

The objective was to perform dosimetry and evaluate dose-response relationships in newly diagnosed patients with malignant brain tumors treated with direct injections of (131)I-labeled anti-tenascin murine 81C6 monoclonal antibody (mAb) into surgically created resection cavities (SCRCs) followed by conventional external-beam radiotherapy and chemotherapy. METHODS: Absorbed doses to the 2-cm-thick shell, measured from the margins of the resection cavity interface, were estimated for 33 patients with primary brain tumors. MRI/SPECT registrations were used to assess the distribution of the radiolabeled mAb in brain parenchyma. Results from biopsies obtained from 15 patients were classified as tumor, radionecrosis, or tumor and radionecrosis, and these were correlated with absorbed dose and dose rate. Also, MRI/PET registrations were used to assess radiographic progression among patients. RESULTS: This therapeutic strategy yielded a median survival of 86 and 79 wk for all patients and glioblastoma multiforme (GBM) patients, respectively. The average SCRC residence time of (131)I-mu81C6 mAb was 76 h (range, 34-169 h). The average absorbed dose to the 2-cm cavity margins was 48 Gy (range, 25-116 Gy) for all patients and 51 Gy (range, 27-116 Gy) for GBM patients. In MRI/SPECT registrations, we observed a preferential distribution of (131)I-mu81C6 mAb through regions of vasogenic edema. An analysis of the relationship between the absorbed dose and dose rate and the first biopsy results yielded a most favorable absorbed dose of 44 Gy. A correlation between decreased survival and irreversible neurotoxicity was noted. A comparative analysis, in terms of median survival, was performed with previous brachytherapy clinical studies, which showed a proportional relationship between the average boost absorbed dose and the median survival. CONCLUSION: This study shows that (131)I-mu81C6 mAb increases the median survival of GBM patients. An optimal absorbed dose of 44 Gy to the 2-cm cavity margins is suggested to reduce the incidence of neurologic toxicity. Further clinical studies are warranted to determine the effectiveness of (131)I-mu81C6 mAb based on a target dose of 44 Gy rather than a fixed administered activity.     

Lung toxicity in radioiodine therapy of thyroid carcinoma: development of a dose-rate method and dosimetric implications of the 80-mCi rule.

Based on an extensive dataset analyzed by Benua et al., a whole-body retention threshold of 2.96 GBq (80 mCi) at 48 h has been used to limit the radioactivity of (131)I administered to thyroid cancer patients with diffuse pulmonary metastases. In this work, the 80-mCi activity retention limit is used to derive lung-absorbed doses and dose rates. The resulting dose-rate-based limits make it possible to account for patient-specific differences in lung geometry. This is particularly important, for example, in pediatric patients exhibiting diffuse lung metastases. The approach also highlights the impact of altered radioiodine kinetics as seen with recombinant human thyroid-stimulating hormone. METHODS: The dose-rate constraint (DRC) was defined as the absorbed dose rate to the lungs of the adult female reference phantom when 80 mCi of (131)I are in the body and 90% of this is uniformly distributed in the lungs. With this definition, the 80-mCi rule was generalized by calculating the activity required to yield a dose rate equal to DRC using lung-to-lung S factor values corresponding to different reference phantoms. RESULTS: A DRC value of 43.6 cGy/h was obtained. Applying this DRC to the adult male phantom and to the phantom of a 15-y-old yields equivalent 48-h activity limits of 3.72 GBq (101 mCi) and 2.45 GBq (66.2 mCi), respectively. Depending on model parameters, the absorbed doses to lungs ranged from 57 to 112 Gy; the photon-only portion, which better reflects the dose to normal lung parenchyma, ranged from 4.9 to 55 Gy. CONCLUSION: A dose-rate-based version of the 80-mCi rule is derived and used to demonstrate application of this rule to pediatric patients and to adult male patients. The implications of the 80-mCi rule are also examined. The assumption of uniform energy deposition in the lungs leads to substantially overestimated absorbed doses. Severe radiation-induced lung toxicity, expected at normal lung absorbed doses of 25-27 Gy, is avoided, probably because most of the local electron dose is delivered to tumor tissue instead of to normal lung parenchyma. The possibility of using a DRC to adjust treatment for different clinical situations is illustrated. The analysis suggests that a dosimetry-based approach will be particularly important in the treatment of patients with lung metastases when a recombinant human thyroid-stimulating hormone protocol is used.     

Reduced iodide transport (stunning) and DNA synthesis in thyrocytes exposed to low absorbed doses from 131I in vitro.

Thyroid stunning refers to reduced uptake of (131)I in the thyroid tissue (or tumor) during radioiodine ((131)I) therapy compared with the uptake measured after the previous administration of (131)I for diagnostic purposes. The phenomenon is clinically important, as it can potentially lead to the undertreatment of thyroid cancer or to unnecessarily high absorbed doses in critical organs. Previous clinical and experimental studies indicated that thyroid stunning is absorbed dose dependent. The aim of this study was to investigate the effects of (131)I irradiation on (125)I(-) transport and cell proliferation at low absorbed doses in vitro. METHODS: Primary cultured porcine thyroid cells were grown to form a confluent monolayer of epithelial cells on a filter in a bicameral culture system. The cells were continuously irradiated with (131)I in the culture medium for 48 h to obtain 0.0015-1.5 Gy. At 3 d after irradiation was stopped, the transepithelial iodide transport capacity was evaluated by measuring (125)I(-) transport from the basal chamber compartment to the apical chamber compartment. The effect of (131)I irradiation on DNA synthesis was estimated by pulse labeling with (3)H-thymidine of both subconfluent and confluent cells irradiated with up to 9 Gy. Total DNA content was measured to quantify cell numbers. RESULTS: A statistically significant reduction in (125)I(-) transport was seen at absorbed doses of >or=0.15 Gy, with a 50% reduction at 1.5 Gy, compared with the results observed for nonirradiated control cells. (3)H-Thymidine incorporation was already statistically significantly reduced at absorbed doses of 0.01-0.1 Gy, but 0.15-0.3 Gy did not affect DNA synthesis. However, absorbed doses of >or=1 Gy again resulted in reduced DNA synthesis. A 50% reduction was obtained at 4 Gy. Total DNA measurements revealed a statistically significant reduction in cell numbers at 8 Gy. CONCLUSION: The lowest absorbed dose from (131)I that reduced iodide transport was 0.15 Gy. Because stunning was found at low absorbed doses, it might occur for (131)I treatment not only of thyroid cancer but also of thyrotoxicosis. On the basis of differences in dose responses, radiation-induced thyroid stunning and cell cycle arrest may be independent phenomena.     

A practical methodology for patient release after tositumomab and (131)I-tositumomab therapy.

A methodology was developed determining patient releasability after radioimmunotherapy with tositumomab and (131)I-tositumomab for the treatment of non-Hodgkin's lymphoma. METHODS: Dosimetry data were obtained and analyzed after 157 administrations of (131)I-tositumomab to 139 patients with relapsed or refractory non-Hodgkin's lymphoma. Tositumomab and (131)I-tositumomab therapy included dosimetric (low activity) and therapeutic (high activity) administrations. For each patient, the total-body residence time was calculated after the dosimetric administration from total-body counts obtained over 6 or 7 d and was then used to determine the appropriate therapeutic activity to deliver a specific total-body radiation dose. Patient dose rates at 1 m were measured immediately after the therapeutic infusion. Patient-specific calculations based on the measured total-body residence time and dose rate for (131)I-tositumomab were derived to determine the patient's maximum releasable dose rate at 1 m, estimated radiation dose to maximally exposed individuals, and the amount of time necessary to avoid close contact with others. RESULTS: The mean administered activity (+/-SD), determined by dosimetry studies for each patient before therapy, was 3,108 +/- 1,073 MBq (84 +/- 29 mCi) (range, 1,221 +/- 5,957 MBq [33--161 mCi]). Immediately after treatment, the mean measured dose rate (+/- SD) at 1 m was 0.109 +/- 0.032 mSv/h (10.9 +/- 3.2 mrem/h; range, 0.04--0.24 mSv/h [4--24 mrem/h]). The measured dose rates were 60% (range, 37%--90%; P < 0.0001) of the theoretic dose rates from a point source in air predicted using the dose equivalent rate per unit activity of (131)I (5.95 x 10(-5) mSv/MBq h [0.22 mrem/mCi h] at 1 m). The mean estimated radiation dose to the maximally exposed individual was 3.06 mSv (306 mrem) (range, 1.95--4.96 mSv [195--496 mrem]). On the basis of current regulatory patient-release criteria, all (131)I-tositumomab--treated patients were determined to be releasable by comparing the dose rate at 1 m with a predetermined maximum releasable dose rate. Detailed instructions were provided to limit family members' exposure. CONCLUSION: A methodology has been developed for the release of patients administered radioactive materials based on the new Nuclear Regulatory Commission regulations. This approach uses a patient-specific dose calculation based on the measured total-body residence time and dose rate. This analysis shows the feasibility of outpatient radioimmunotherapy with tositumomab and (131)I-tositumomab.     

The outcome of 131I treatment in Graves' patients pretreated or not with methimazole

Despite extensive use of iodine-131 ((131)I) treatment for Graves' hyperthyroidism, the optimal regimen of pretreatment with antithyroid drugs is still a matter of discussion. Our aim was to evaluate the success of (131)I treatment in patients with Graves' disease without and with pretreatment with methimazole (MMI). In a prospective randomized study 156 patients with Graves' disease were treated with fixed activity of 550 MBq (131)I. First group of 59 patients received only (131)I. The second group of 50 patients received MMI which was stopped seven days before (131)I. The third group of 47 patients received MMI until (131)I application. Patients were followed clinically and biochemically 1, 3, 6 and 12 months after (131)I treatment. Absorbed dose of (131)I and thyroid volume were measured in each patient. Our result showed that (131)I treatment success after twelve months was equally effective in the first and second group (96.6% and 96%, respectively), while in the third group, success was significantly lower (63.8%). Accordingly, the absorbed dose of (131)I was significantly higher in the first and in second group (144±104 Gy and 164±107 Gy, respectively), and lower in the third group (105±58 Gy). Thyroid volume gradually decreased without any significant difference between the three groups. In conclusion, our study provides evidence that application of (131)I is equally effective in the nonpretreated with MMI group and in the group discontinuing MMI one week before (131)I treatment, and it is more effective in these two groups as compared to the group in which pretreatment with MMI was administered till the day of (131)I application.     

Does thyroid stunning exist? A model with benign thyroid disease

With regard to the treatment of differentiated non-medullary thyroid carcinoma, there is controversy over whether radiation from a diagnostic radioiodine (131I) application really does have a suppressive effect on the uptake of subsequent therapeutic 131I (so-called thyroid stunning). However, inherent difficulties in exact remnant/metastatic tissue volumetry make it difficult to quantify how much diagnostic 131I is actually absorbed (absorbed energy dose) and hence to decide whether a threshold absorbed dose exists beyond which such stunning would occur. Since in benign thyroid disease the target volume can be readily quantified by ultrasonography, we sought to determine definitely whether stunning of thyroid cells occurs upon a second application of radioiodine 4 days following the first one. We therefore studied 171 consecutive patients with benign thyroid disease (diffuse goitre, Graves' disease, toxic nodular goitre) who received two-step 131I therapy during a single in-patient stay. For application of both calculated 131I activities we performed kinetic dosimetry of 131I uptake, effective half-life and absorbed dose. At the second application, patients showed significant stunning (a 31.7% decrease in 131I uptake, from 34.7% +/- 15.4% at first application to 23.7% +/- 12.3% at second application, P < 0.0005) without a significant difference in effective half-life (4.9 +/- 1.3 vs 5.0 +/- 1.7 days, P > 0.2). ANOVA showed that the extent of stunning was influenced significantly only by the absorbed energy dose at first application (F = 13.5, P < 0.0005), while first-application 131I activity, target volume, gender and thyroid function had no influence (all F < or = 0.71, all P > 0.4). There was no significant correlation between extent of thyroid stunning and first-application 131I activity ( r = 0.07, P > 0.3), whereas there was a highly significant correlation between thyroid stunning and first absorbed energy dose (r = 0.64, P < 0.00005), the latter correlation fitting a logarithmic model best. Multivariate factor analysis also revealed first absorbed energy dose to be the only decisive stunning factor. In conclusion, our study confirms that stunning exists in benign thyroid conditions and that it is a purely radiobiological inhibitory phenomenon related to absorbed dose.     

A study of the possibility of curing Graves' disease based on the desired reduction of thyroid mass (volume) as a consequence of 131I therapy: a speculative paper

PURPOSE: The possibility of predicting the final volume of Graves' disease thyroids submitted to 131I therapy could allow the physician to decide what activity to administer based on the desired volume reduction instead of on a fixed value of the thyroid radiation absorbed dose. In this paper the relationship between maximum uptake of 131I, fractional reduction of thyroid volume and outcome of Graves' disease is discussed. METHODS: The results are based on ultrasonography thyroid volume measurements before administration of therapy and at the moment of recovery from Graves' disease (thyroid stimulating hormone >0.3 microIU x ml(-1) in the absence of anti-thyroid drug therapy) and on measurements of 131I uptake in 40 patients. It is shown that the possibility of curing Graves' disease may be individually related to the final volume of the patient's thyroid. An equation is presented to calculate the 'optimal' final thyroid volume. RESULTS: A comparison between the traditional method, based on absorbed dose, and the final method, based on volume, has been carried out retrospectively. In the first case a median activity of 529 MBq has been administered; in the second, a median activity of 394 MBq (non-parametric Wilcoxon test, P<0.05) should be administered. The corresponding thyroid median absorbed doses are, respectively, 353 Gy and 320 Gy (non-parametric Wilcoxon test, P<0.02). CONCLUSION: A method to evaluate individually the 'optimal' final thyroid mass is presented and discussed. The method based on 'volume reduction' could probably reduce the activity and the thyroid absorbed dose compared to the method based on 'empirical' calculations, thus allowing the administration of 131I therapy to be optimized.     

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

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.     

Lung dosimetry for radioiodine treatment planning in the case of diffuse lung metastases.

The lungs are the most frequent sites of distant metastasis in differentiated thyroid carcinoma. Radioiodine treatment planning for these patients is usually performed following the Benua-Leeper method, which constrains the administered activity to 2.96 GBq (80 mCi) whole-body retention at 48 h after administration to prevent lung toxicity in the presence of iodine-avid lung metastases. This limit was derived from clinical experience, and a dosimetric analysis of lung and tumor absorbed dose would be useful to understand the implications of this limit on toxicity and tumor control. Because of highly nonuniform lung density and composition as well as the nonuniform activity distribution when the lungs contain tumor nodules, Monte Carlo dosimetry is required to estimate tumor and normal lung absorbed dose. Reassessment of this toxicity limit is also appropriate in light of the contemporary use of recombinant thyrotropin (thyroid-stimulating hormone) (rTSH) to prepare patients for radioiodine therapy. In this work we demonstrated the use of MCNP, a Monte Carlo electron and photon transport code, in a 3-dimensional (3D) imaging-based absorbed dose calculation for tumor and normal lungs. METHODS: A pediatric thyroid cancer patient with diffuse lung metastases was administered 37 MBq of (131)I after preparation with rTSH. SPECT/CT scans were performed over the chest at 27, 74, and 147 h after tracer administration. The time-activity curve for (131)I in the lungs was derived from the whole-body planar imaging and compared with that obtained from the quantitative SPECT methods. Reconstructed and coregistered SPECT/CT images were converted into 3D density and activity probability maps suitable for MCNP4b input. Absorbed dose maps were calculated using electron and photon transport in MCNP4b. Administered activity was estimated on the basis of the maximum tolerated dose (MTD) of 27.25 Gy to the normal lungs. Computational efficiency of the MCNP4b code was studied with a simple segmentation approach. In addition, the Benua-Leeper method was used to estimate the recommended administered activity. The standard dosing plan was modified to account for the weight of this pediatric patient, where the 2.96-GBq (80 mCi) whole-body retention was scaled to 2.44 GBq (66 mCi) to give the same dose rate of 43.6 rad/h in the lungs at 48 h. RESULTS: Using the MCNP4b code, both the spatial dose distribution and a dose-volume histogram were obtained for the lungs. An administered activity of 1.72 GBq (46.4 mCi) delivered the putative MTD of 27.25 Gy to the lungs with a tumor absorbed dose of 63.7 Gy. Directly applying the Benua-Leeper method, an administered activity of 3.89 GBq (105.0 mCi) was obtained, resulting in tumor and lung absorbed doses of 144.2 and 61.6 Gy, respectively, when the MCNP-based dosimetry was applied. The voxel-by-voxel calculation time of 4,642.3 h for photon transport was reduced to 16.8 h when the activity maps were segmented into 20 regions. CONCLUSION: MCNP4b-based, patient-specific 3D dosimetry is feasible and important in the dosimetry of thyroid cancer patients with avid lung metastases that exhibit prolonged retention in the lungs.     

131I radioimmunotherapy and fractionated external beam radiotherapy: comparative effectiveness in a human tumor xenograft.

This article compares the effectiveness of radiation delivered by a radiolabeled monoclonal antibody, 131I-labeled A33, that targets colorectal carcinoma, with that of 10 fractions of conventional 320 kVp x-rays. METHODS: Human colorectal cancer xenografts (SW1222) ranging between 0.14 and 0.84 g were grown in nude mice. These were treated either with escalating activities (3.7-18.5 MBq) of 131I-labeled A33 or 10 fractions of 320 kVp x-rays (fraction sizes from 1.5 to 5 Gy). Tumor dosimetry was determined from a similar group of tumor-bearing animals by serial kill, tumor resection and counting of radioactivity in a gamma counter. The relative effectiveness of the two radiation therapy treatment approaches was compared in terms of tumor regrowth delay and probability of tumor cure. RESULTS: The absorbed dose to tumor per MBq administered was estimated as 3.7 Gy (+/-1 Gy; 95% confidence interval). We observed a close to linear increase in tumor regrowth delay with escalating administered activity. Equitumor response of 1311 monoclonal antibody A33 was observed at average radiation doses to the tumor three times greater than when delivered by fractionated external beam radiotherapy. The relationship between the likelihood of tumor cure and administered activity was less predictable than that for regrowth delay. CONCLUSION: The relative effectiveness per unit dose of radiation therapy delivered by 131I-labeled A33 monoclonal antibodies was approximately one third of that produced by fractionated external beam radiotherapy, when measured by tumor regrowth delay.