C. Parmentier

Long-term results and prognostic factors in patients with differentiated thyroid carcinoma

A multivariate analysis of the prognostic factors was carried out on a series of 546 differentiated thyroid cancers followed for 8 to 40 years. For survival, the highest risk factor was associated with age; tumors diagnosed in patients younger than 45 years had higher relapse‐free survival (RFS) and total survival (TS) rates and a slower growth rate. In children, although the RFS and TS at 15 years were high, they decreased later. The second independent prognostic factor was histology. There was no difference between papillary and follicular well‐differentiated (FWD) tumors, but follicular moderately differentiated (FMD) had lower TS and RFS. Among FMD cancers, relapses occurred earlier and the interval between relapse and death was shorter. The third factor was sex. Tumors tended to disseminate more in male than in female patients. The survival rate after relapse was the same, however, suggesting that the growth rates are not different. The presence of palpable lymph nodes also had a significant independent impact on both TS and RFS. Patients treated after 1960 have a better outcome than patients treated earlier, although they did not differ in age distribution, histologic characteristics, sex ratio, or incidence of palpable lymph nodes. The distribution of time intervals between treatment and relapse was not compatible with an exponential failure time model but fit with a log‐logistic model. Relapses can occur as late as 30 years or more after initial treatment. Elevated levels of circulating thyroglobulin have been observed in about 12% of the patients who had been in complete remission for longer than 20 years.

Microcarcinoma of the thyroid gland

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.

Malignant pheochromocytoma: Clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases

Twenty patients, 16 males and 4 females, aged 11–76 yr, were treated for a metastatic pheochromocytoma at our institution between 1985 and 1990. A neurofibromatosis was associated in 4. Thirteen patients had a unilateral adrenal tumor, 3 had an extraadrenal retroperitoneal tumor, 2 had a bilateral adrenal pheochromocytoma, one had a unilateral tumor with a contralateral medullary hyperplasia and one an adrenal and an extraadrenal pheochromocytoma. Metastases occurred in all patients, at presentation in 11,10 to 30 months later in 7, and 9 and 28 yr later, respectively in two. Histology did not afford conclusive evidence for malignancy. Catecholamine hyperproduction was present in all, predominantly affecting norepinephrine. Neuron Specific Enolase level was elevated in 11, Neuropeptide Y level in 9 and procalcitonin level in 11/18. High dopamine, methoxytyramine and homovanilic acid excretion levels seemed to correlate with large tumors or terminal stage. MIBG uptake was found in 16 after a diagnostic dose and in 1 only after a therapeutic dose. Surgery was performed on primary tumor in 18 and on distant métastase in 10. lodine-131 MIBG therapy was performed in 11, among whom 9 were évaluable. Cumulative activity ranged from 100 to 711 mCi, in 1 to 6 courses. Symptomatic improvement occurred in 5 patients, stabilization was observed in 3 and tumor partial response in two, which lasted for 28 and 9 months, respectively terminating in a rapidly progressing disease with bone marrow involvement. Moderate myelosuppression occurred in 4 patients. Chemotherapy gave no response in 7 evaluable patients. Fourteen patients died with a median survival of 16 months from diagnosis of metastases (range 3–60). Response to therapy was poor and warrants further cooperative trials.

Combination therapy for anaplastic giant cell thyroid carcinoma

Since 1981, 20 patients with anaplastic giant cell carcinoma of the thyroid have been prospectively treated according to a combination regimen of chemotherapy and external beam radiation therapy. Two types of chemotherapy were used every 4 weeks, depending on the patients age. For those younger than 65 years, a combination of doxorubicin (60 mg/m2) and cisplatin (90 mg/m2) was given, and for older patients mitoxantrone (14 mg/m2) was used. Radiotherapy was carried out between Day 10 and Day 20 of the first four cycles of chemotherapy. It delivered 17.5 Gy in 7 fractions to the neck and the superior mediastinum. Survival exceeding 20 months was observed in three patients. Complete neck tumor response was observed in five patients, among whom four had undergone previous operations. No response was seen in distant metastases, which were the cause of death in 14 patients. These treatment modalities are effective in some patients, both in terms of survival and of local control, avoiding death from local invasion. Gross tumor resection should be performed whenever possible but should not delay the commencement of this protocol. Toxicity was high and remains the main limiting factor.

Leukaemias and cancers following iodine-131 administration for thyroid cancer.

We studied 1771 patients treated for a thyroid cancer in two institutions. None of these patients had been treated with external radiotherapy and 1497 had received (131)I. The average (131)I cumulative activity administered was 7.2 GBq, and the estimated average dose was 0.34 Sv to the bone marrow and 0.80 Sv to the whole body. After a mean follow-up of 10 years, no case of leukaemia was observed, compared with 2.5 expected according to the coefficients derived from Japanese atomic bomb survivors (P = 0.1). A total of 80 patients developed a solid second malignant neoplasm (SMN), among whom 13 developed a colorectal cancer. The risk of colorectal cancer was found to be related to the total activity of (131)I administered 5 years or more before its diagnosis (excess relative risk = 0.5 per GBq, P = 0.02). These findings were probably caused by the accumulation of (131)I in the colon lumen. Hence, in the absence of laxative treatment, the dose to the colon as a result of (131)I administered for the treatment of thyroid cancer could be higher than expected from calculation of the International Commission on Radiological Protection (ICRP). When digestive tract cancers were excluded, the overall excess relative risk of second cancer per estimated effective sievert received to the whole body was -0.2 (P = 0.6).

Medullary thyroid carcinoma: Prognostic factors and treatment

Seventy-five patients with medullary thyroid carcinoma (MTC) have been treated at Institut Gustave-Roussy from 1932 to 1979. Of these, 13 patients had distant metastases and received palliative treatment, their median survival was 3 years. Sixty-two patients with MTC limited to the neck received curative treatment; 6 had exclusive external radiotherapy for inoperable disease and 56 were surgically treated: 23 by total thyroidectomy and 33 by partial thyroidectomy. After surgery 29 patients received external radiotherapy for cervical lymph node involvement (25/29) and/or incomplete surgical resection (12/27). The survival rate was 69% at 5 years and 48% at 10 years. It was lower in patients with distant metastases at presentation (p less than 10(-5)), with tumoral infiltration of the posterior tissue planes (p less than 0.025) and in patients in whom surgical excision had not been satisfactory (p less than 0.01). It was not correlated with cervical lymph node involvement probably because those patients with lymph node involvement had been irradiated. The 29 patients who received post-operative cervical radiotherapy had initially more extensive local disease (p less than 0.05) than the 27 patients treated by surgery alone, nevertheless their survival was slightly higher. No difference in survival rate was observed between patients treated by total thyroidectomy or partial thyroidectomy, among whom only 4 local recurrences occurred. Three of the 6 patients treated with external radiotherapy alone experienced long survival (4, 7 and 10 years) and a fourth is still in clinical remission 4 years after treatment. The effectiveness of chemotherapy in patients with metastases was poor, only one patient out of 6 had a partial remission following a treatment by adriamycin. In the familial form and multiple endocrine neoplasia type II, total thyroidectomy appears to be indicated. In the sporadic cases, partial thyroidectomy is usually sufficient. External radiotherapy is effective in MTC and seems to be able to eradicate small foci of residual tumor; it is indicated when surgical excision is impossible or incomplete.

Chemotherapy in metastatic nonanaplastic thyroid cancer: experience at the Institut Gustave-Roussy.

Forty-nine patients with metastatic nonanaplastic thyroid carcinoma were treated over a 10-year period. Five successive chemotherapeutic protocols were used: a combination of doxorubicin, etoposide, 5-fluorouracil and cyclophosphamide; elliptinium acetate; doxorubicin; cispiatin; and the combination of doxorubicin and cispiatin. Results obtained with the different protocols were very disappointing, with only two objective responses (3%). Phase II trials with new chemotherapeutic agents are warranted in selected cases of nonanaplastic metastatic thyroid carcinoma.

The values of calcitonin and carcinoembryonic antigen in the treatment and management of nonfamilial medullary thyroid carcinoma

Thirty‐one patients were studied to evaluate the prognostic value of both calcitonin (CT) and CEA levels determined after the initial treatment in medullary thyroid carcinoma (MTC). Twenty‐seven patients were evaluated three to nine months after initial treatment and four others afterwards. The CT and CEA levels were significantly higher and the survival rate lower in the eight patients with residual clinical disease as compared to the 19 patients in complete clinical remission. In patients in complete clinical remission, 11 had elevated CT level after treatment, and all had initial lymph node involvement. Five of these 11 relapsed and one died. None of the eight patients with normal CT levels after treatment relapsed. CEA levels were always abnormally high when patients relapsed. Fourteen patients in complete remission with high CT levels were followed for more than four years. Six had normal CEA levels and no relapse was observed. Eight of the 14 had pathological CEA levels and six of eight relapsed: five of these six patients presented CEA elevation from six to 36 months before the clinical relapse. In two of these six patients, a venous catheterization sampling method demonstrated infra clinical local recurrence. In two patients with liver metastases, the time course changes of CT and CEA levels were different and CEA appeared to be a more sensitive tumor marker than CT. These data are consistent with previous data concerning the values and limits of CT level for the management of MTC. Furthermore, this study demonstrates the prognostic significance of CEA determination in MTC. CEA appears to be a sensitive selective tumor marker capable of defining a high‐risk subgroup.

Construction and clinical validation of a sensitive and specific assay for serum mature calcitonin using monoclonal anti-peptide antibodies.

Using calcitonin (CT) as an hapten, we have generated a library of monoclonal antibodies. Six monoclonal antibodies were developed and analyzed with respect to affinity and specificity for epitopes on CT by enzyme linked immunosorbent assay and radioimmunoassay. These antibodies were used in the construction and the optimization of a two-site monoclonal immunoradiometric assay (m-IRMA) for CT. We used a combination of two monoclonal antibodies to develop an assay which is rapid (overnight incubation), sensitive (10 pg/ml) and strictly specific for the mature form of calcitonin, ie the 32 amino acid-long polypeptide bearing a prolineamide as the C-terminal residue. This assay was utilized to demonstrate that mature calcitonin circulates as heterogeneous molecular species resulting from polymerization of calcitonin by disulphide linkage and/or by aggregation on irrelevant proteins. The clinical relevance of this assay was studied on a series of patients with medullary carcinoma of the thyroid (MCT) and the characteristics of the assay was compared with those of a conventional polyclonal radioimmunoassay. The m-IRMA for CT proved to be useful for both the diagnosis and the follow-up of MCT.

Selective venous sampling catheterisation for localisation of persisting medullary thyroid carcinoma

Selective venous sampling catheterisation was performed in 19 patients with medullary thyroid carcinoma without known distant metastases for persistent hypercalcitoninaemia after surgery. Calcitonin (CT) gradients were found in the neck and/or the mediastinum in 18 patients and in five patients at distant sites also. After venous catheterisation, 13 patients were subjected to repeat surgery. Neck and/or mediastinal tumour foci were found in 12 patients at the sites of the CT gradients. Of these, nine patients had only cervicomediastinal CT gradients: after reoperation, the serum CT level normalised in one, significantly decreased in five, and did not change in three, and no neck relapse occurred after a mean follow-up of 5.3 years. Distant metastases emerged clinically in all five patients with distant gradients and in only one of the 14 patients with no distant gradient. In conclusion, selective venous catheterisation is the most sensitive tool for the localisation of residual disease and for the early detection of distant metastases. However, in patients with only local disease, biochemical cure is rarely obtained after reoperation.