Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy.

AIM: The goal of this study was to estimate the cumulative activity of (131)I to be administered to patients with distant metastases from thyroid carcinoma. METHODS: A total of 444 patients were treated from 1953-1994 for distant metastases from papillary and follicular thyroid carcinoma: 223 had lung metastases only, 115 had bone metastases only, 82 had both lung and bone metastases, and 24 had metastases at other sites. Treatment consisted of the administration of 3.7 GBq (100 mCi) (131)I after withdrawal of thyroid hormone treatment, every 3-9 months during the first 2 yr and then once a year until the disappearance of any metastatic uptake. Thyroxine treatment was given at suppressive doses between (131)I treatment courses. RESULTS: Negative imaging studies (negative total body (131)I scans and conventional radiographs) were attained in 43% of the 295 patients with (131)I uptake; more frequently in those who were younger, had well-differentiated tumors, and had a limited extent of disease. Most negative studies (96%) were obtained after the administration of 3.7-22 GBq (100-600 mCi). Almost half of negative studies were obtained more than 5 yr after the initiation of the treatment of metastases. Among patients who achieved a negative study, only 7% experienced a subsequent tumor recurrence. Overall survival at 10 yr after initiation of (131)I treatment was 92% in patients who achieved a negative study and 19% in those who did not. CONCLUSION: (131)I treatment is highly effective in younger patients with (131)I uptake and with small metastases. They should be treated until the disappearance of any uptake or until a cumulative activity of 22 GBq has been administered. In the other patients, other treatment modalities should be used when tumor progression has been documented.

Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience.

BACKGROUND: Patients with thyroid microcarcinoma (TMC) have favorable long term prognoses. However, recurrences in the neck and distant metastases have been reported. The authors investigated independent factors associated with recurrence in an effort to define therapeutic guidelines. METHODS: Two hundred eighty-one patients (207 females, 74 males; mean age, 41.9 years) with a differentiated thyroid carcinoma < or = 1 cm in greatest dimension (mean size +/- standard deviation, 5.9+/-3.3 mm) were analyzed. The median follow-up time was 7.3 years. RESULTS: TMC diagnosis was incidental in 189 patients, and metastases were the first manifestation of the disease in the other 92 patients. Therapy included near-total thyroidectomy for 195 patients, lymph node dissection for 195, and therapeutic administration of radioiodine for 124. Eleven recurrences (3.9%) were observed 4.3+/-2.7 years (mean +/- standard deviation) after initial treatment: all had locoregional recurrence (4 in the thyroid bed and 7 in the lymph nodes), and in one of these the local recurrence was associated with lung metastases. Multivariate analysis showed that two parameters significantly influenced TMC recurrence, namely, the number of histologic foci (P < 0.002) and the extent of initial thyroid surgery (P < 0.01). Only 3.3% of patients with unifocal TMC treated with loboisthmusectomy had tumor recurrence. CONCLUSIONS: The recurrence rate for TMC appears to be low (3.9%). In the authors' view, loboisthmusectomy is the treatment of choice for patients with TMC when only one focus of cancer is found histologically, and total thyroidectomy is the optimal treatment for patients with multiple foci.

Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma.

UNLABELLED: We assessed the therapeutic benefits of 131I treatment in patients with distant metastases of differentiated thyroid carcinoma. METHODS: Of 2200 patients treated for differentiated thyroid carcinoma at our institution, 394 had lung and/or bone metastases. RESULTS: Two-thirds of the patients had 131I uptake in their metastases, but only 46% achieved a complete response. Prognostic factors for complete response were: younger age, presence of 131I uptake in the metastases and small extent of disease. The survival rate was 33% at 15 yr. As shown by multivariate analysis, favorable prognostic factors for survival were: younger age and time of metastases detection, well-differentiated histologic type of the thyroid tumor, presence of 131I type uptake in the metastases, small extent of the disease and year of discovery of metastases. CONCLUSION: In terms of survival, the benefits of 131I therapy cannot be demonstrated by prospective controlled studies. The present study clearly demonstrates, however, that treatment with 131I is one of the factors which accounts for survival; patients whose metastases concentrated 131I and who could be treated with radioiodine had higher survival rates. Patients who achieved complete response following treatment of distant metastases had a 15-yr survival rate of 89%, while those who did not achieve complete response had a survival rate of only 8%. The survival rate improved with the year of discovery of distant metastases, after 131I total-body imaging and serum thyroglobulin measurements were routinely used.

Immunoscintigraphy in Hodgkin's disease and anaplastic large cell lymphomas: results in 18 patients using the iodine radiolabeled monoclonal antibody HRS-3.

Immunoscintigraphy (IS) using the HRS-3 Hodgkin associated monoclonal antibody (MoAb) was performed in 18 patients with Hodgkin's Disease (HD) at staging or restaging. Either F(ab')2 fragments (14 patients) or whole HRS-3 (4 patients) labeled with 77-260 Mbq 131-I were used. Whole body images, including anterior and posterior views, were taken from a digital gamma camera, within 4 to 8 hours after injection and then daily for 5 days. In one patient IS was discontinued due to iodine intolerance. Seventeen patients were evaluable: 14 showed a true positive result including 2 cases which were reviewed as anaplastic large cell lymphoma (ALCL). Nodal, splenic, bone marrow and muscle involvements were imaged, many of these sites were previously unsuspected. In 7 patients with true positive findings the Pressman Specificity Index, as measured from biopsied material, ranged from 1.5-3 in 4 patients and from 5 to greater than 100 in 3 patients. Imaging was equivocal or failed in 1 patient (lymph nodes). In 2 patients, IS imaging was truly negative due to the absence of active HD, and a false negative result occurred once (inguinal node). In none of the patients a false positive image was observed. In order to rule out non-specific iodine uptake a control, anti-ACE MoAb, labeled with 125-Iodine was injected simultaneously in 10 patients. The evaluation of the study gave a sensitivity of 87% and a good specificity. IS using radioiodine labeled MoAbs is feasible and represents a reliable non-invasive diagnostic method for the staging and follow-up of HD and ALCL.

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.

Positive anticalcitonin immunoscintigraphy in patients with medullary thyroid carcinoma.

A cocktail of three monoclonal F(ab')2 fragments against three distinct epitopes of calcitonin or PDN 21 was labelled with either 111In or 131I. These F(ab')2 fragments, a control 125I-F(ab')2 fragment and 99mTc-pertechnetate were injected into four patients suffering from medullary thyroid carcinoma. Scintigraphy data were processed by energy factor analysis for an optimal separation of images corresponding to each isotope. The best tumor detection was obtained 1-3 days after injection of the 111In-F(ab')2 cocktail which clearly labeled the thyroid tumors in the four patients (smallest tumor detected, 0.6 cm) as well as lymph node and bone metastases. In the liver, positive detection was only successful with the 131I-labeled cocktail. These results were confirmed by counting rates of resected specimens which provided average specificity indices ranging from 3.3 to 13.1. Anticalcitonin antibodies could be particularly useful for immunoscintigraphy detection of residual or recurrent medullary thyroid carcinoma in patients with elevated calcitonin serum level.

[In vivo imaging of Hodgkin's lymphomas using monoclonal antibodies]. / In-vivo-Imaging von Hodgkin-Lymphomen mit monoklonalen Antikörpern.

The Hodgkin- and Reed-Sternberg cell associated monoclonal antibody HRS-1 was labeled with radioactive iodine and injected into 6 patients with Hodgkin's lymphoma for immunoscintigraphic imaging. Four of five patients who received 131I-labeled HRS-1 had a positive immunoscintigram. In the sixth patient, the HRS-1 Mab was labeled with 123I in order to utilize tomoscintigraphy instead of linear scintigraphy. Bony disease was demonstrated by immunoscintigraphy in this patient. These preliminary results demonstrate that immunoscintigraphy with iodine-labeled HRS-1 Mab is feasible and informative in Hodgkin's lymphoma. The real clinical value of immunoscintigraphy in Hodgkin's lymphoma must be determined in a larger series of patients. Several modifications of the technique such as the use of Fab or F(ab')2 fragments should further improve the results.

Radiolabeled monoclonal antibodies against Reed-Sternberg cells for in vivo imaging of Hodgkin's disease by immunoscintigraphy.

The Hodgkin Reed-Sternberg (HRS-1) monoclonal antibody (Mab) was raised against the L 428 Hodgkin's disease (HD) cell line. The HRS-1 Mab was labeled with radioactive iodine and injected into six patients with Hodgkin's disease of varied histological subtypes for immunoscintigraphic imaging. In five patients, the HRS-1 Mab was labeled with 131I; a control anti-alpha-fetoprotein (AFP) Mab was injected simultaneously in two of these five cases. Four of five patients had a positive scan (nodal, splenic and hepatic involvements), the results in the fifth patient being equivocal. In the sixth patient, the HRS-1 Mab was labeled with 123I in order to utilize tomoscintigraphy instead of linear scintigraphy. Although the immunoscintigraphy (IS) was performed secondary to effective chemotherapy, images of bony disease were demonstrated. These preliminary results demonstrate that IS with iodine-labeled HRS-1 Mab is feasible and informative in Hodgkin's lymphoma. The real clinical value and the specificity of IS deserves confirmation in a larger series of patients. Several techniques such as the use of Fab or F(ab')2 fragments should further improve the results.

Bone marrow metastases in children's neuroblastoma studied by magnetic resonance imaging.

Forty-one patients (pts) presenting with a neuroblastoma underwent 52 MRI to detect bone marrow metastases. Mean age was 4 years. Acquisitions were done with a 1.5 tesla unit. T1 and T2 weighted images were obtained in coronal (legs and pelvis) and sagittal (dorso-lumbar spine) sections. In 13 cases MRI was performed for initial staging, in 30 during the follow-up. 43/52 examinations were evaluable. Out of 24 anatomically proven medullary involvement (19 pts), MRI showed focal abnormal signals in 23 (18 pts): foci hypersignal in T2 weighted images and hyposignal in T1 weighted images compared to the normal bone marrow (BM) and fat tissue. The lesions were more often detected in lower limbs than dorso-lumbar vertebral body or iliac bone. Nineteen examinations were performed in 15 pts with cytologically and histologically normal BM. MRI raised suspicion of BM metastases in 5 pts (7 MRI). Out of those 5 pts, 1 (2 MRI) had BM relapse 9 months later; 1 (2 MRI) had intra cranial relapse 6 months later; 1 (1 MRI) is disease free 1 1/2 year later; the follow-up is too short for 2 remaining pts (2 MRI). MRI's specificity was 88.9% and sensitivity 84.4%.

Radiolabelled monoclonal antibodies against alpha-fetoprotein for in vivo localization of human hepatocellular carcinoma by immunotomoscintigraphy.

Two high affinity monoclonal antibodies, designated AF01 and AF04, directed against distinct epitopes of human alpha-fetoprotein (AFP) and the Fab fragments of one of them, were labelled with 131I and injected into 18 patients with AFP producing hepatocellular carcinoma (HCC) in order to carry out imaging studies by tomoscintigraphy. Twelve patients were injected with whole antibody, only three of seven patients injected with AF01 and two of five patients injected with AF04 had a positive scan. In contrast, five out of six patients injected with labelled Fab fragments of AF04 had positive imaging. These results confirm that tumour imaging of HCC using 131I labelled monoclonal antibody against AFP is feasible. Moreover, utilization of tomoscintigraphy in place of linear scintigraphy and Fab fragments instead of whole immunoglobulin may improve the sensitivity of radioimmunolocalization. This technique provides useful information on the in vivo distribution of monoclonal antibodies directed against AFP and on the practicability of the eventual therapeutic use of anti-AFP antibodies in HCC.

Tumor localization in patients by radiolabeled monoclonal antibodies against colon carcinoma.

A radiolabeled monoclonal antibody (MAb) that has been shown to react specifically in vitro and ex vivo to human colorectal carcinoma and to inhibit growth of human carcinomas grafted in nude mice was administered to 52 colorectal carcinoma patients and 15 patients with other types of cancer. Of 63 colorectal carcinoma tumor sites studied, 34 showed significant accumulation of antibody by external photoscanning and tomoscintigraphy, whereas none of the 20 sites of other cancer types gave positive results. One-third of the patients received F(ab')2 fragments of the MAb, which gave a slightly higher percentage (61%) of positive results than did intact MAbs (51%). A few patients scheduled for tumor resection were given injections simultaneously of 131I-labeled MAb and 125I-labeled normal immunoglobulin G. Antibody concentration in resected tumors was 3.6 to 6.3 times higher than the average antibody concentration in adjacent normal tissues (1.5, 3.4, and 9.4 as compared with normal mucosa, serosa, and fat, respectively), and the specificity indices, calculated by differential radioactivity analysis, ranged from 2.1 to 5.1. The results show the potential value and limitations of this particular MAb for tumor detection by immunoscintigraphy.

Tomoscintigraphy for detecting gastrointestinal and medullary thyroid cancers: first clinical results using radiolabelled monoclonal antibodies against carcinoembryonic antigen.

Transaxial tomoscintigraphy (or single-photon emission computerised tomography) was used to detect secondary deposits of carcinoma in 17 patients who had been injected with iodine-131-labelled monoclonal antibodies against carcinoembryonic antigen. Of 17 tumor sites studied by tomoscintigraphy 16 were detected (sensitivity 94%); five sites had a volume smaller than 10 cm3. Tomoscintigraphy also detected three unknown tumour deposits later confirmed by surgery or radiology. In contrast, when 21 tumour sites in the same patients were studied by rectilinear scintigraphy, only nine tumour sites were detected (sensitivity 43%), of which eight had a volume larger than 50 cm3.

Use of radiolabelled monoclonal anti-CEA antibodies for the detection of human carcinomas by external photoscanning and tomoscintigraphy.

Paul Ehrlich's inspired concept of 'magic bullets' for the cure of diseases has been revitalized by recent advances in immunology(1). In particular, the development of cell fusion technology allowing the production of monoclonal antibodies (Mabs) with exquisite specificities(2) triggered new hopes that we may now have the perfect carrier molecules with which to deliver cytotoxic drugs(3) or toxins(4) to the hidden cancer cells. This article reviews data on one aspect of the magic bullet concept, the use of radiolabelled antibodies as tracers for tumour localization. It will also discuss the very recent clinical use of (131)I-labelled Mabs against carcinoembryonic antigen (CEA)(5) to detect carcinoma either by conventional external photoscanning or by single photon emission computerized tomography (SPELT). This alliance of the most modern tools from immunology (Mabs) and nuclear medicine (SPELT) appears promising as a way to improve the sensitivity of 'immunoscintigraphy'. However, this approach is not yet ready, for widespread clinical use.