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Original Article |
Departments of Endocrinology (F.S., V.B., R.E., L.M., A.P., F.P.), Radiology (S.M.), and Oncology (F.B.), University of Pisa, 56124 Pisa, Italy
Address all correspondence and requests for reprints to: Dr. Furio Pacini, Department of Endocrinology, University of Pisa, Via Paradisa 2, 56100 Pisa, Italy. E-mail: . fpacini{at}endoc.med.unipi.it
Abstract
Chemotherapy represents the only therapeutic option in most poorly differentiated thyroid carcinomas, although its effect is limited and short lasting. The aim of this study was to evaluate whether increasing the metabolic rate of thyroid cancer cells by TSH stimulation might result in higher response rate to chemotherapy. Fourteen patients with poorly differentiated thyroid carcinoma and nonfunctioning diffuse lung metastases detected at computed tomography scan, entered this study. A combination of carboplatinum and epirubicin was administered at 4- to 6-wk intervals for six courses. TSH stimulation was achieved by reduction of the daily dose of L-thyroxine resulting in mild hypothyroidism (eight patients) or by administration of recombinant human TSH (six patients). Two additional patients did not complete the therapeutic protocol due to severe hematological side effects. Results were evaluated by comparison of lung computed tomography scans before and after therapy. One patient had a complete remission. Five patients had partial remission, and seven patients had disease stabilization. One patient progressed to death. The overall rate of positive responses was 37% that rose to 81% when including patients with stable disease. Serum thyroglobulin after chemotherapy declined more than 50% in six patients, with respect to basal levels. Apparently, no difference in the response rate was observed between exogenous or endogenous TSH stimulation. At the time of this analysis, among the patients who completed the treatment courses, 9 of 14 patients (64.3%) are still alive (median survival from start of chemotherapy = 21 months, range: 15–34). Six of these patients did not show progression of lung disease, whereas regrowth of lung metastases was observed in three patients after 19, 20, and 21 months from chemotherapy, respectively. Five patients died of their disease, including the one who had progression of lung disease during chemotherapy, three who died for brain or bone metastases, and one who died for refractory local tumor invasion. No progression of lung metastases was observed until death in these four patients.
In conclusion, the response rate of poorly differentiated thyroid cancer to chemotherapy observed in this study was favorable and promising. TSH stimulation may have contributed to these results.
MOST DIFFERENTIATED THYROID carcinomas (papillary and follicular) can be successfully treated by the combination of surgery, radioiodine and L-thyroxine therapy (1). By this strategy, permanent remission is obtained in most patients with limited disease and in nearly 50% of those with distant metastases (2, 3, 4). The worst prognosis and outcome is carried by a minority of patients with poorly differentiated histotypes, in whom local or distant tumor that does not take up radioiodine is present at the time of diagnosis or develops during follow up (5). When these lesions are not surgically resectable, the remaining therapeutic options include chemotherapy, external radiotherapy, and arterial embolization.
Among various drugs, anthracyclines and platinum compounds appear the most effective agents in thyroid cancer, with an average 30% response rate in various series (6, 7, 8, 9, 10, 11). Unfortunately, responses are partial and short lasting. The cytotoxic activity of both drugs is maximal when tumor cells are proliferating (12). Patients with thyroid cancer are commonly treated with suppressive doses of L-thyroxine to block the TSH-stimulated thyroid cell proliferation and metabolic rate (13, 14). Conceivably, in this situation the cytotoxic effect of chemotherapy on neoplastic thyroid cells may be limited. The present study was undertaken to evaluate whether increasing the metabolic rate of thyroid cancer cells by TSH stimulation might results in a higher response rate to chemotherapy. To this purpose, we administered the chemotherapic regimen under TSH stimulation, achieved either by endogenous TSH through reduction of the daily dose of L-thyroxine or by administration of exogenous recombinant human TSH (rhTSH).
Patients and Methods
Patients
Between June 1997 and March 2000, 14 consecutive patients (7 males and 7 females, age range 39–64 yr) entered this study. Their clinical features are listed in Table 1
. Two additional patients entered the study and were considered in the overall efficacy analysis, although chemotherapy was discontinued after one and two courses, respectively, due to severe hematologic side effects. Inclusion criteria consisted of evidence of metastatic lung disease deprived of iodine uptake in a previous (within 24 months) posttherapy scan with 100 mCi 131-I, and evidence that the metastatic involvement was in progression. As in lungs, no uptake was visible in other metastatic foci outside the lungs. In two patients (nos. 5 and 9) with diffuse lung metastatic involvement, a few lesions were still up taking radioiodine, but this uptake was considered not significant for achieving a therapeutic effect. Contamination by stable iodine as a cause for negative whole body scan was ruled out by routine measurement of urinary iodine excretion before administering the therapeutic 131-I dose. In particular, four patients had an increase in the number of lung nodules in two consecutive computed tomography (CT) scans, and six had an increase in the volume of preexisting lung nodules and the appearance of new lesions. In four patients enrolled a few months after diagnosis, the CT scan showed diffuse macronodular lung involvement, which was not visible in a standard lung x-ray performed before surgery. Progression of the disease was observed in a range period of 2–6 months (the time elapsed between the imaging study at enrolment and the previous one). At start of chemotherapy, all patients had measurable pulmonary metastases. In all but three patients, residual local tumor and/or lymph node metastases were also present. Patients had received thyroid surgery, which in several cases was not radical due to local infiltration, and radioiodine therapy, if significant 131-I uptake was demonstrated. Afterwards, all patients had been treated with TSH-suppressive doses of L-thyroxine. With the exception of one patient with high titers of serum thyroglobulin-antibodies (Tg-Ab), all patients had detectable serum Tg concentrations. Informed consent was obtained by all patients. No eligible patient declined participation.
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Carboplatinum (300 mg/m2) in 500 ml of 5% dextrose was infused over 30 min. Four hours later, epirubicin (75 mg/m2) was given as a single bolus. The regimen was repeated at 4- to 6-wk intervals for a total of six courses, depending on hematological surveillance. Whenever hematological toxicity contraindicated additional therapy, we preferred to delay the subsequent course by 1 or 2 wk, rather than decreasing the dose of drugs. Anti-emetics were administered with the above regimen, consisting of 5 mg Tropisetron chloridrate and 40 mg methilprednisolon in 100 ml saline iv 15 min before the active drug. Tropisetron chloridrate was repeated 5 h after epirubicin administration.
To raise serum TSH, patients were alternately assigned to one of two groups by random. In group 1, endogenous TSH stimulation was obtained by reducing the daily dose of L-thyroxine therapy. In group 2, exogenous TSH stimulation was induced using a recently developed preparation of rhTSH (Thyrogen, Genzyme Corp., Cambridge, MA), whose biological activity in stimulating thyroid cancer cells has been fully demonstrated (15, 16). Any stimulated serum TSH level (above normal range) was considered sufficient to go on in the trial.
Serum Tg, free thyroid hormones (FT4 and FT3), TSH and antithyroid autoantibodies (Tg-Ab and thyroperoxidase antibodies) were measured at the time of enrolment, before each course of chemotherapy and after treatment, at the time of analyzing the responses. Serum Tg was measured using a commercial immunometric assay (Diagnostic Products, Los Angeles, CA) with a lower detection limit of 0.2 ng/ml and a functional sensitivity of 0.9 ng/ml. In our laboratory the intra- and interassay coefficient of variation of the method is 4.3% and 7.0%, respectively. Serum TSH was measured using an ultrasensitive commercial immunometric assay (Diagnostic Products). FT4 and FT3 were measured by commercial RIA kits (Ortho-Clinical Diagnostic, Amersham, UK).
Group 1 (8 patients).
Patients received chemotherapy while being mildly hypothyroid. To this purpose, the dose of L-thyroxine was lowered to 50 µg/d 45 d before treatment. L-triiodothyronine (10 µg 3 times a day) was added for 14 d during the intervals between treatment courses. Mean serum levels of TSH and FT4 on the day before starting each course of chemotherapy are shown in Fig. 1. Mean TSH ranged between 15 to 46 mU/liter in various courses, and mean FT4 ranged between 5.4 and 9 pg/ml. Suppressive doses of L-thyroxine were restarted at the end of the treatment.
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Assessment of the response rate
Therapeutic effects were assessed by comparing the chest CT scan performed before chemotherapy with that obtained 1–4 months after completion of treatment. Studies were performed using a Spiral CT (HiSpeed 3000; General Electric Medical System, Milwaukee, WI) before and after the administration of 110–130 ml of nonionic contrast medium (Visipaque, Nycomed Amersham plc, Princeton, NJ) at a low rate of 2 ml/sec, with a delay of 35 sec from the neck to the diaphragm during a single breath hold. Scanning parameters were: collimation of 5 mm, reconstruction index 5 mm, pitch between 1.6 and 1.8. Results were evaluated according to the following criteria:
Complete remission (CR) was defined as the complete disappearance of lung metastases at CT scan.
Partial remission (PR) was defined as a reduction in size greater than 50% in the sum of the products of the perpendicular diameters of all measurable lesions without the increase in size of any lesions nor the appearance of any new lesions.
Stable disease was assigned when the volume and/or the number of metastases were reduced less than 50% or were not modified.
Progressive disease occurred if metastases continued to increase in number and/or size.
The changes of serum Tg before chemotherapy and at the time of the second CT scan were also evaluated.
Results
Upon TSH stimulation, an increase of serum Tg levels ranging from 21–1300% (median = 184%) and from 15–920% (median = 170%) with respect to baseline values was observed in group 1 (endogenous stimulation) and group 2 (exogenous stimulation), respectively (Fig. 2). No significant difference in Tg increase was found between the two groups. In one patient, the results of serum Tg measurement were not informative for the presence of serum antithyroglobulin antibodies, which interfere in the Tg assay producing false negative results. The Tg responses to TSH stimulation can be considered as a strong evidence that a functional TSH receptor was present on the neoplastic cell surface.
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. One patient in Group 1 had a CR (6%). Five patients (31%) had PR (2 in Group 1 and 3 in Group 2). Stable disease was observed in 7 (44%) patients (4 in group 1 and 3 in group 2). One patient (6%), belonging to group 1, had progression of the disease. The overall rate of positive responses (CR + PR) was 37%. If stabilization of the disease is regarded among the positive responses, this rate would rise to 81%. No apparent correlation was found between degree of response and histological variant of the tumor. No difference was observed in the rate of responses in 6 patients treated soon after a therapeutic dose of 131-I (1–6 months) as compared with 8 patients treated more than 6 months after 131-I. Two representative CT scans of complete or partial remission of lung metastases are shown in Fig. 3.
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As shown in Fig. 2
, a decrease of serum Tg of more than 50% was observed at the time of the second CT scan, on TSH suppression, with respect to basal levels also on TSH suppression, in 3 patients of group 1 and in 3 patients of group 2. In 3 patients, serum Tg increased slightly, including 1 patient whose serum TSH was not suppressed at the time of the evaluation. Serum Tg remained unchanged in 4 patients and was not valuable in one patient because of anti-Tg auto antibodies. Altogether, these changes were not significant (P = 0.32 by paired Student’s t test). There was not significant correlation between the magnitude of TSH-induced Tg elevation and eventual Tg decline after chemotherapy. However, by examining the graphs in Fig. 2, it would in fact appear that the patients with the greatest reduction in serum Tg in group 2 were those whose Tg levels rose the greatest with TSH stimulation. In group 1, this relation is not obvious.
The two patients with a minor radioiodine uptake before chemotherapy received a further therapeutic dose of 131-I 1 yr after the previous one, but no restoration of radioiodine uptake was observed.
The drug regimen used in this study was well tolerated. Major toxicity requiring withdrawal from the study was experienced by two patients, both initially assigned to group 2, after one and two courses, respectively. These two patients could not complete the treatment courses due to life threatening anemia and leucopoenia. Less severe, transient, anemia and leucopoenia, requiring delay of the subsequent course of chemotherapy were observed in 6 patients. Other side effects included gastro-intestinal symptoms and urinary tract infections, responsive to common drugs. Alopecia was observed in all patients.
Discussion
In patients with thyroid carcinomas, chemotherapy is commonly employed only in case of progressive metastatic disease refractory to radioiodine treatment (1, 17) and not manageable by surgery. The response rate is low and the benefits are often too poor to advocate its extensive use, at least in the early phases of the disease.
A primary determinant of malignant phenotype in general oncology, including thyroid malignancies, is the uncontrolled growth rate compared with normal tissues. Most chemotherapeutic agents are cytotoxic mainly to actively cycling cells, and the different cytokinetic of normal and neoplastic cells allows chemotherapeutic agents to eradicate tumor cells without lethal host toxicity.
A milestone in the treatment of thyroid carcinoma is the use of TSH-suppressive therapy, based on the demonstration that the TSH receptor is conserved in most thyroid carcinomas (18) and, to some extent, controls the growth and activity (Tg secretion and 131-I uptake) of thyroid cancer cells (13, 19). Chemotherapy for thyroid carcinoma is commonly performed under TSH suppression, aimed to block proliferation of thyroid cells. This approach is in apparent contradiction with the postulate that cell-cycle-active antineoplastic drugs (as those used in our study) are most effective on tumors for which the growth fraction is maximal. In other words, it is conceivable that the cytostatic effect of L-thyroxine on follicular thyroid cells would counteract the efficacy of chemotherapeutic drugs and narrow their therapeutic index.
On this basis, we designed the present study to investigate whether the administration of chemotherapy under TSH stimulation of neoplastic thyroid cells would improve the efficacy of the treatment. Six out of 16 patients (37%) benefited from our treatment protocol, including one complete remission and 5 partial remissions. When the 7 patients with stabilization of the disease were considered as responders (as commonly done with aggressive nonthyroidal solid malignancies), the final successful rate was 81%. However, when dealing with thyroid cancer, one must be cautious in such an assumption, in view of the long lasting stable disease observed in some patients with metastatic differentiated thyroid cancer left untreated. In any case, the response rate observed in our study is probably the most favorable reported so far, and it appears most promising as compared with those reported in the literature for poorly differentiated thyroid cancer. Using adriamycin alone, without TSH stimulation, we have reported response rates not exceeding 30% in patients with similar histotypes (11). In our experience, even lower responses were obtained with the combination of adriamycin and bleomycin (10) in patients with undifferentiated or poorly differentiated thyroid carcinomas, the latter resembling the features of the patients in this study. In a survey published in 1987, positive responses were observed in one third of the cases, using adriamycin as a single drug (8). In another study, the addition of carboplatinum to adriamycin increased, but not significantly, the response rate (complete and partial responses) from 17–26%, and from 39–56% when including also stable disease (6). Disappointing results were found with carboplatinum compounds as single agents by Hoskin and Harmer (9).
Although we have no direct proof, we believe that the favorable results obtained in the present study are likely to be due to the addition of TSH stimulation during chemotherapy. TSH stimulation should increase the number of actively cycling cells, thus increasing the cytotoxic potential of the drugs. We have previously reported that in poorly differentiated thyroid carcinomas the rate of cell proliferation, as assessed by immunoistochemistry for proliferating-cell nuclear antigen, is rather low (nearly 20%), not different from well differentiated tumors and adenomas (20). This can explain the poor effect of traditional chemotherapic regimens, as opposed to the results of our study after TSH stimulation. An alternative explanation for our results may be a diminished clearance rate of the drug during hypothyroidism leading to a greater cumulative therapeutic effect. Some considerations seem to exclude such possibility. Our patients stimulated by endogenous TSH, were only mildly hypothyroid and some had only subclinical hypothyroidism, not sufficient to affect the clearance rate, as indicated by no change in serum creatinine and liver enzymes. Furthermore, if decreased clearance is important, we should observe a different response rate in patients stimulated by endogenous or exogenous TSH.
To advocate a role for TSH stimulation, a functional TSH receptor must be conserved by tumor cells. Indirect, but clear, evidence that this was the case in our patients is provided by the raise of serum thyroglobulin observed following TSH stimulation and by its reduction when L-thyroxine therapy at suppressive doses was resumed. It might be argued that the rise of serum Tg is not a consequence of TSH stimulation but rather of impaired Tg metabolism during hypothyroidism. This possibility is unlikely, because our patients were only mildly hypothyroid and sometimes even only subclinically hypothyroid. In these conditions the clearance rate of Tg is not significantly impaired. Furthermore, the rhTSH-stimulated patients were perfectly euthyroid, thus excluding any change of serum Tg clearance rate.
In patients enrolled soon after a therapeutic ablative dose of radioiodine, experiencing a positive response to chemotherapy, the question may rise of whether the favorable effect was due to the long-term effect of the previous radioiodine treatment (even if no radioiodine uptake was visible in the posttherapy scan) rather than to chemotherapy. Although empiric treatment with radioiodine in Tg positive/diagnostic 131-I negative whole body scan is advocated by several groups (21, 22), including us (23), we do not believe that this procedure has therapeutic effect when the posttherapy scan is negative and we do not recommend further radioiodine treatment in these patients (24). Restoration of radioiodine responsiveness after chemotherapy has been reported in one patient treated with doxorubicin (25). We are not able to confirm this finding because radioiodine therapy was repeated only in the two patients who showed a minor uptake before chemotherapy, and no restoration of 131-I uptake in metastatic nodules was observed.
No difference in the response rate was observed between exogenous or endogenous TSH stimulation. This finding rules out the possibility that the positive effect was due to hypothyroidism per se rather than to TSH stimulation. Stimulation by rhTSH would theoretically provide some advantages with respect to that obtained after induction of hypothyroidism: Following administration of rhTSH, a sharp peak of serum TSH occurs that simultaneously acts on thyroid cells; the stimulation by rhTSH is an acute one, limiting the period of cell stimulation to 5–6 d at each course, as opposed to the more prolonged period of stimulation occurring with hypothyroidism; finally, while treated with rhTSH patients do not suffer from hypothyroidism. At present, the small number of patients does not allow to validate by statistical analysis whether exogenous TSH stimulation has a therapeutic advantage over the endogenous.
In conclusion, our data suggest that adding TSH stimulation to a conventional regimen of chemotherapy increases its therapeutic effect in poorly differentiated thyroid cancer without additional morbidity for the patients. Further clinical trials on larger numbers of patients are required to confirm our findings. Molecular studies and serial PET imaging to determine the time course of cellular metabolic activity may be helpful to define the most appropriate protocol of TSH stimulation to be adopted.
Acknowledgments
Footnotes
This work was supported by grants from the Ministero dell’Università e della Ricerca Scientifica e Tecnologica (Rome, Italy): target proiect "Molecular differential diagnosis of thyroid nodules before surgery," Grant 2000—protocol MM06247581.001; Associazione Italiana per la Ricerca sul Cancro (Milano, Italy): target project "Studies on the human sodium-iodine symporter (NIS) gene expression in thyroid carcinomas lacking iodine uptake," 1998.
Abbreviations: Ab, Antibody; CR, complete remission; CT, computed tomography; FT3 and FT4, free thyroid hormones; PR, partial remission; rhTSH, recombinant human TSH; Tg, thyroglobulin.
Received July 16, 2001.
Accepted May 31, 2002.
References
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