Marcel Ricard

Strategies of Radioiodine Ablation in Patients with Low-Risk Thyroid Cancer

BACKGROUND It is not clear whether the administration of radioiodine provides any benefit to patients with low-risk thyroid cancer after a complete surgical resection. The administration of the smallest possible amount of radioiodine would improve care. METHODS In our randomized, phase 3 trial, we compared two thyrotropin-stimulation methods (thyroid hormone withdrawal and use of recombinant human thyrotropin) and two radioiodine ((131)I) doses (i.e., administered activities) (1.1 GBq and 3.7 GBq) in a 2-by-2 design. Inclusion criteria were an age of 18 years or older; total thyroidectomy for differentiated thyroid carcinoma; tumor-node-metastasis (TNM) stage, ascertained on pathological examination (p) of a surgical specimen, of pT1 (with tumor diameter ≤1 cm) and N1 or Nx, pT1 (with tumor diameter >1 to 2 cm) and any N stage, or pT2N0; absence of distant metastasis; and no iodine contamination. Thyroid ablation was assessed 8 months after radioiodine administration by neck ultrasonography and measurement of recombinant human thyrotropin-stimulated thyroglobulin. Comparisons were based on an equivalence framework. RESULTS There were 752 patients enrolled between 2007 and 2010; 92% had papillary cancer. There were no unexpected serious adverse events. In the 684 patients with data that could be evaluated, ultrasonography of the neck was normal in 652 (95%), and the stimulated thyroglobulin level was 1.0 ng per milliliter or less in 621 of the 652 patients (95%) without detectable thyroglobulin antibodies. Thyroid ablation was complete in 631 of the 684 patients (92%). The ablation rate was equivalent between the (131)I doses and between the thyrotropin-stimulation methods. CONCLUSIONS The use of recombinant human thyrotropin and low-dose (1.1 GBq) postoperative radioiodine ablation may be sufficient for the management of low-risk thyroid cancer. (Funded by the French National Cancer Institute [INCa] and the French Ministry of Health; ClinicalTrials.gov number, NCT00435851; INCa number, RECF0447.).

Relationship Between Tumor Burden and Serum Thyroglobulin Level in Patients with Papillary and Follicular Thyroid Carcinoma

Serum thyroglobulin (Tg) is a reliable marker for detecting recurrent and persistent disease during the follow-up of patients with papillary and follicular thyroid carcinoma. The goal of this study was to assess the relationship between the serum Tg level measured after thyroid hormone withdrawal and the tumor mass in thyroid cancer patients who underwent surgery with the use of an intraoperative probe for lymph node metastases with (131)I uptake. Patients were classified into one of three groups according to the Tg level: undetectable (n = 18); 1-10 ng/mL (n = 21); and greater than 10 ng/mL (n = 33). The main clinical characteristics and the extent of the disease at the time of initial treatment were similar in these three groups. Lymph node metastases were found in 13 of the 18 patients with undetectable Tg level. Eight patients had persistent foci of uptake after surgery that were located behind the sterno-clavicular joint in six patients. The number of metastatic lymph nodes and their total surface (in mm(2)) or their total volume (in mm(3)) were significantly linked with serum Tg/thyrotropin [TSH] level (p = 0.002 and p < 0.0001, respectively). For a given metastatic surface or volume, the serum Tg/TSH value was no longer linked with the number of metastatic lymph nodes (p = 0.32), suggesting that the total surface or total volume is the characteristic that best summarizes the influence of the disease on the serum Tg/TSH level. In conclusion, patients with higher serum Tg levels tend to have more extensive disease and should undergo more aggressive treatment modalities. Nevertheless, undetectable serum Tg should not be considered as a reliable criteria to exclude a minimal tumor burden in patients who have already been treated with (131)I.

131I Effective Half-Life and Dosimetry in Thyroid Cancer Patients

131I treatment in thyroid cancer patients may induce side effects, including extrathyroidal cancer and leukemia. There are still some uncertainties concerning parameters that may influence the effective half-life of 131I and the absorbed doses by extrathyroidal organs. Methods: Whole-body retention of radioiodine was measured in 254 patients, and repeated quantitative whole-body scans and measurements of the urinary excretion of 131I were performed on 30 of these patients. Results: The mean effective half-life (10.5 h) was shorter by 31%, with little difference between patients, in the 36 patients who received recombinant human thyroid-stimulating hormone than in the 218 patients who underwent thyroid hormone withdrawal (15.7 h). The residence times in the stomach and in the rest of the body were significantly shorter in patients who received recombinant human thyroid-stimulating hormone than in patients who underwent withdrawal, but the residence times were similar in the colon and bladder. Conclusion: In patients who undergo thyroid hormone withdrawal, the longer mean effective half-life is mainly due to delayed renal excretion of 131I and results in dose estimates higher than the data in report 53 of the International Commission on Radiological Protection, which were obtained from healthy, euthyroid subjects.

Therapeutic Administration of 131I for Differentiated Thyroid Cancer: Radiation Dose to Ovaries and Outcome of Pregnancies

Radiation is known to be mutagenic. The present study updates a 10-y-old study regarding pregnancy outcome and the health of offspring of women previously exposed to radioiodine (131I) during thyroid carcinoma treatment, by doubling the number of pregnancies that occurred after exposure. Methods: Data on 2,673 pregnancies were obtained by interviewing female patients who were treated for thyroid carcinoma but had not received significant external radiation to the ovaries. Results: The incidence of miscarriages was 10% before any treatment for thyroid cancer; this percentage increased after surgery for thyroid cancer, both before (20%) and after (19%) 131I treatment, with no variation according to the cumulative dose. In contrast to previously reported data, miscarriages were not significantly more frequent in women treated with radioiodine during the year before conception, not even in women who had received more than 370 MBq during that year. The incidences of stillbirths, preterm births, low birth weight, congenital malformations, and death during the first year of life were not significantly different before and after 131I therapy. The incidences of thyroid and nonthyroid cancers were similar in children born either before or after the mothers exposure to radioiodine. Conclusion: There is no evidence that exposure to radioiodine affects the outcomes of subsequent pregnancies and offspring. The question as to whether the incidences of malformations and thyroid and nonthyroid cancers are related to gonadal irradiation remains to be established. The doubling dose is still being heatedly debated, and the value of 1 Gy as the doubling dose in humans should be reevaluated.

Radiation and inhibition of angiogenesis by canstatin synergize to induce HIF-1α–mediated tumor apoptotic switch

Tumor radioresponsiveness depends on endothelial cell death, which leads in turn to tumor hypoxia. Radiation-induced hypoxia was recently shown to trigger tumor radioresistance by activating angiogenesis through hypoxia-inducible factor 1-regulated (HIF-1-regulated) cytokines. We show here that combining targeted radioiodide therapy with angiogenic inhibitors, such as canstatin, enhances direct tumor cell apoptosis, thereby overcoming radio-induced HIF-1-dependent tumor survival pathways in vitro and in vivo. We found that following dual therapy, HIF-1alpha increases the activity of the canstatin-induced alpha(v)beta(5) signaling tumor apoptotic pathway and concomitantly abrogates mitotic checkpoint and tetraploidy triggered by radiation. Apoptosis in conjunction with mitotic catastrophe leads to lethal tumor damage. We discovered that HIF-1 displays a radiosensitizing activity that is highly dependent on treatment modalities by regulating key apoptotic molecular pathways. Our findings therefore support a crucial role for angiogenesis inhibitors in shifting the fate of radiation-induced HIF-1alpha activity from hypoxia-induced tumor radioresistance to hypoxia-induced tumor apoptosis. This study provides a basis for developing new biology-based clinically relevant strategies to improve the efficacy of radiation oncology, using HIF-1 as an ally for cancer therapy.

Improvement of internal dose calculations using mathematical models of different adult heights.

In internal dosimetry for both nuclear medicine and radiation protection, the adult morphology is represented by a limited number of anthropomorphic models that may not be suitable for all patients. To develop more patient-specific dosimetry, we derived six mathematical models for adults of different height. Three male models (160 cm, 170 cm and 180 cm) and three female models (150 cm, 160 cm and 170 cm), based on the MIRD model design, were developed from the statistical analysis of anthropometric data gathered from autopsies. Monte Carlo calculations were used to provide an example of estimations of S value for these new models for iodine 131 uniformly distributed successively in the stomach or in the urinary bladder. On average, for both male and female models, an increase in the model height of 10 cm leads to a mean reduction in the S value for iodine-131 by 20% and 29% when the stomach and the urinary bladder respectively are selected as source regions. Similarly, when the model height increases by 20 cm, the S values decrease on average by 35% and 48%. This study presents the use of anthropometric data to develop new mathematical models for adults of different height, and shows the significant influence of the morphology on dosimetric parameters.

/sup 18/F-FDG PET images segmentation using morphological watershed: a phantom study

Segmentation of 18F-FDG PET images could be helpful for delineation of tumor volume in radiotherapy and patient follow-up. The most commonly implemented method on clinical workstations is maximum intensity thresholding, which is inappropriate for heterogeneous uptakes. Our aim was to develop and evaluate a more sophisticated segmentation method, based on the morphological watershed. We developed a segmentation method taking into account PET images characteristics. We evaluated it first on phantom images, using an integrated PET/CT unit and taking CT images as reference images. To simulate tumors in a background activity, we used 6 homogeneous spheres of various volumes in a cylindrical phantom and 3 heterogeneous cylinders in an anthropomorphic phantom. The quality of segmentation was evaluated in terms of volume, shape and position. We compared the results with a maximum intensity threshold segmentation method fitting the volume, taken as reference segmentation. A quantitation analysis completed the phantom study. For both phantom acquisitions, the segmentation obtained with the watershed based algorithm gave satisfying results with the index integrating volume, shape and position. Results considering this index were not significantly different from the reference segmentation (p > 0.5). Errors of volume recovery reached 18% for watershed segmentation. The quantitation analysis on phantoms highlighted partial volume effect, with an error of activity concentration measurement on segmented images ranging between 42% and 51%. Performances of the watershed method evaluated in this study were comparable with an optimized segmentation on phantom images. The quantitation recovery of PET regions with this method was similar with to other segmentation methods.

Intraoperative detection of pheochromocytoma with iodine-125 labelled meta-iodobenzylguanidine : a feasibility study

We evaluated the feasibility of intraoperative detection of pheochromocytoma sites after injection of meta-iodobenzylguanidine labelled with iodine-125. Six patients with multiple or recurrent pheochromocytoma were injected for intraoperative detection. During surgery, all count rates were recorded using a CdTe detector diode. Tumour foci were found in all cases. Tumour count rates ranged from 50 to 1000 counts per second (mean ≈400). Blood activity, used as a reference level, ranged from 10 to 50 counts per second (mean ≈35). In all patients, the intraoperative probe was helpful to the surgeon and facilitated the discovery of the pathological foci even when they were small (<1 cm). Complete resection under probe control was correlated with postoperative normalization of urinary normetanephrine excretion. The use of a probe designed to detect low-energy gamma-ray radionuclides bound to a highly specific molecule provides an accurate detection tool which is well adapted for ectopic localizations and for small foci.

How the availability of recombinant human TSH has changed the management of patients who have thyroid cancer

Recombinant human TSH (rhTSH) is used in patients who have had surgery for thyroid cancer but are at low risk of recurrence. The rhTSH is used for the preparation of postoperative administration of 3.7 GBq (100 mCi) of radioiodine for thyroid-remnant ablation and for the determination of serum thyroglobulin levels during follow-up. In these two conditions, the efficiencies of levothyroxine withdrawal and rhTSH administration are similar; however, rhTSH can be administered during levothyroxine treatment, and its use avoids the hypothyroid period induced by levothyroxine withdrawal, reduces whole body exposure after radioiodine administration, avoids potential morbidity and maintains a better quality of life compared with hormone withdrawal.

Immunoscintigraphy of Hodgkin's disease: In vivo use of radiolabelled monoclonal antibodies derived from Hodgkin cell lines

The Hodgkin associated monoclonal antibody (Mab) HRS-1 reacts with Hodgkin and Reed-Sternberg cells (HR-S) in all HD subtypes. HRS-1 Mab was labelled with radioiodine and injected into 10 patients for immunoscintigraphy (IS). Seven patients were injected with HRS-1 Mab radiolabelled with 131I and three patients were injected with HRS-1 Mab labelled with 123I. A control anti-alpha-fetoprotein (anti-AFP) Mab was radiolabelled with another iodine isotope and was injected simultaneously in five cases. Six out of eight patients with proven HD had a true positive scan (nodal, splenic and bony involvement). Imaging was equivocal or failed in the two other patients. In the last two patients IS imaging was truly negative due to the absence of residual HD in one patient and to an erroneous histological diagnosis of HD in another patient. These results, although preliminary, demonstrate that IS with radioiodine-labelled HRS-1 Mab is feasible and may prove to be informative in the staging of HD.