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Original Studies |
Endocrinology and Nuclear Medicine Services, Departments of Medicine (R.J.R., R.M.T., R.N.S., H.K.R., W.D.D.), Pathology (R.A.G.), Radiology (S.M.L.), and Epidemiology and Biostatistics (A.S.), Memorial Hospital for Cancer and Allied Diseases, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
Address all correspondence and requests for reprints to: Richard J. Robbins, M.D., Endocrinology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021.
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Abstract |
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Introduction |
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Standard monitoring for residual thyroid cancer includes clinical examination, measurement of serum thyroglobulin (Tg) levels, and diagnostic whole-body radioactive iodine scanning (DxWBS) (2, 8, 9, 10). The serum Tg and the DxWBS are most sensitive at detecting residual disease when patients have elevated serum TSH levels after thyroid hormone withdrawal (THW) (11). The recent availability of recombinant human TSH (rhTSH) provides another means of elevating the TSH level without the need for hypothyroidism (12, 13). The first industry-sponsored prospective paired comparison of THW vs. rhTSH found that the THW preparation was statistically better when only the DxWBS was considered (14). A more recent report from the same group found no statistical difference between THW and rhTSH when they considered both the DxWBS and the stimulated Tg as primary end-points (15). One caveat regarding their conclusions was the fact that few patients with distant metastases were included in either study.
The decreased quality-of-life attendant with hypothyroidism, which often follows THW, can be a significant burden on many aspects of the patient’s life (16). It is not uncommon for patients to delay or refuse routine evaluations simply to avoid becoming hypothyroid. If the accuracy of testing done after rhTSH (on thyroxine) is the same or better than that after THW, it would be much more acceptable to most patients.
We hypothesized that the ability to detect residual thyroid carcinoma in patients who continued on thyroxine suppression and received rhTSH would not be significantly different from patients after THW. In a retrospective analysis, we compared the diagnostic accuracy of DxWBS and stimulated Tg, alone or in combination, in all thyroid cancer patients undergoing routine follow-up studies at one medical center over a 2-yr period.
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Materials and Methods |
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The patients in this retrospective study included all individuals who were referred to the Nuclear Medicine section of Memorial Hospital for Cancer and Allied Diseases between January 1, 1998 and December 31, 1999. Testing for residual thyroid carcinoma (DxWBS and Tg) was performed on 373 occasions in 289 different patients. During 1998, patients who could not produce sufficient endogenous TSH or those who could not tolerate hypothyroidism were studied with rhTSH under a compassionate need trial sponsored by the Genzyme Corp. (Cambridge, MA) and the United States Food and Drug Administration. During 1999, all patients had the choice of having the DxWBS performed after THW or with rhTSH while remaining on thyroxine. At the time of the choice, the published information on the accuracy of rhTSH-assisted diagnosis (14) had concluded that scans obtained after THW were more sensitive than those after rhTSH.
DxWBS
Formal dosimetric analysis was performed in each patient based on the blood and whole-body clearance of a tracer dose of 131I (17, 18). Mean scanning doses of 131I were 3.5 mCi (129.5 MBq) for the THW group and 4.2 mCi (155.4 MBq) for the rhTSH group (P = 0.28). THW patients were asked to stop their thyroid hormone, 4–6 weeks before the start of diagnostic studies. Some patients were also given triiodothyronine until 2 weeks before the start of testing. Patients in the rhTSH group remained on suppressive doses of thyroxine and received im injections of 0.9 mg rhTSH (Thyrogen, Genzyme Corp.), 24 and 48 h before the administration of 131I. All patients were provided with a low-iodine diet to follow for at least 1 week before dosimetry. For the DxWBS, a whole-body scan in the anterior and posterior projection was obtained using a dual-headed Genesys EPIC imaging system (ADAC Corporation, Malpitas, CA). Both anterior and posterior heads had high-energy general-purpose collimators, peak isotope energy of 364 kilo electron volts with a 20% energy window, a 256 x 256 x 16 matrix, and a scan speed of 8 cm/min. For all patients, a 10-min neck view was obtained at 24 and 72 h after the oral dose of 131I. The neck view was obtained with a 256 x 256 x 16 matrix, 38-cm CFOV with scatter window. Lateral neck views and other spot views were obtained, as required, at the discretion of the nuclear medicine physician.
Whole-body counts were obtained at 0, 2, 4, 24, 72, and 96 h after 131I administration for the THW patients and at 0, 2, 4, 24, 48, 72, and 120 h for the rhTSH patients. A standard fraction of the total dose administered (normally about 1%) is also counted just before patient counting. At each time interval, blood is drawn, and the fractional blood clearance is determined. Total body clearance curves are generated, and the mCi dose that will give a dose of 200 cGy to the blood is calculated using standard techniques (19). After treatment with radioactive 131I, a 1-week posttherapy whole-body scan is performed using identical collimators, with machine settings as described for the 72-h DxWBS, except that the scan speed is increased to 10–15 cm/min, depending on the therapeutic dose administered.
Tg
Serum Tg measurements were performed by the Optiquant IRMA (immunoradiometric assay; Kronus, Boise, ID). This assay has a sensitivity of 0.2 µg/L; however, all readings below 0.5 µg/L are reported to clinicians as: less than 0.5 µg/L. Patients in whom Tg autoantibodies were present were not assigned a specific value, because the reliability of the reading was not assured. For the purposes of statistical analysis, antibody-positive patients were eliminated from any analysis that considered serum Tg. Tg autoantibodies were present in 11 of the hypothyroid patients and in 8 of the rhTSH patients included in the analysis. For the rhTSH group, the baseline Tg was obtained before the first dose of rhTSH, and the stimulated Tg was obtained approximately 72 h after the second dose of rhTSH. In the THW group, the Tg was obtained 48 h before the DxWBS. This was the standard of care during the 2 yr covered by the study.
Other studies
When clinically indicated, the patients underwent standard radiography, computed tomography scans, and magnetic resonance imaging with or without contrast. All radioiodine scans were done no sooner than 6 months after scans with iodinated contrast. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning was performed when clinically indicated according to our prior report (20 , which showed that FDG could localize disease in patients with negative DxWBS and elevated serum Tg. Cervical ultrasonography performed, using a power Doppler instrument or plain films of any body region, were obtained when clinically indicated (21, 22).
Assignment of clinical status
The final clinical assignment was made by considering all of the clinical information. However, the results of the 1998–99 DxWBS and the stimulated Tg were not considered in assigning the final clinical status for accuracy testing. Eleven patients in whom a clinical status could not be assigned, because of a lack of complementary studies, were not considered in this analysis. Clinical status was judged as having metastatic disease based on the following criteria: 1) patients whose suppressed Tg was more than 2 µg/L, associated with an abnormal radiographic study (computed tomography, magnetic resonance imaging, posttherapy scan, PET, and/or ultrasonography) done within 6 months of the DxWBS, suggestive of a metastatic lesion (n = 108); 2) patients in whom the baseline suppressed Tg was greater than 10 µg/L and who had prior evidence of metastatic disease (n = 7); 3) patients with a low Tg and a positive posttherapy scan (n = 16); or 4) patients who had no other known malignancy and a positive FDG-PET scan (n = 8). Clinical status was judged as no evidence of disease (NED) in patients who had: baseline Tg levels less than or equal to 2 µg/L, NED on physical exam, no positive radiographic studies, and no distant metastases found on the last nuclear medicine evaluation. Finally, patients with no radiographic evidence of distant metastases, in whom the only radioiodine uptake on the most recent DxWBS was in the thyroid bed (TB), were assigned to the TB-only group. For the diagnostic accuracy testing, TB patients were not included in the statistical analyses.
Statistical analyses
The purpose of this study is to examine, retrospectively, whether 2 methods of preparation for diagnostic testing (rhTSH or THW) produce significantly different accuracy in 2 forms of testing (DxWBS and stimulated Tg), as well as in their combined diagnostic accuracy. Because patients in the study were examined annually, repeat visits were common within the 1998–99 period. Out of 373 observed visits, a total of 289 unique patients were analyzed. Because disease is considered to recur at random, patients with multiple visits had a single visit randomly selected to remain in the study. Visits not selected were excluded from analysis, to ensure independence of observations, both between and within samples.
The study compared two preparation methods based on measures of accuracy [sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)] of the various diagnostic tests in reference to a clinical determination. Because patients categorized as TB cannot be proven to either have or not have residual cancer, they were deleted from the statistical comparisons of accuracy. We considered adding the TB patients to the metastatic group or to the NED group for accuracy testing, but there were equally unacceptable biases inherent in those maneuvers (23, 24). For each diagnostic test, the four measures of accuracy are computed for each group, and P-values resulting from Fisher’s exact test (25) are presented for the difference between preparation methods in both PPV and NPV. In the case of the combined test analysis, the overall test was considered positive if either of the individual tests (DxWBS or stimulated Tg) were positive, and negative only when both tests were negative. S-PLUS for Windows (26) is used for all analyses.
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Results |
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The mean ages, gender, median stimulated Tg levels, and frequency
of total thyroidectomy were comparable between the 2 groups (Table 1
). Patients in the rhTSH group were
slightly older and less likely to be female, compared with the THW
group. The histological subtypes, the tumor (T) sizes, nodal (N)
status, presence of metastases (M), and American Joint Commission on
Cancer staging (27) at initial diagnosis were comparable
between groups. Patients were judged to be M1 if any distant
metastases were discovered by computed tomography, magnetic resonance
imaging, chest x-ray, or DxWBS within the first 3 months of the cancer
diagnosis. Based on all available clinical information, 66 (51%) of
the rhTSH and 73 (45%) of the THW patients had evidence of metastatic
thyroid carcinoma. Forty-seven patients (37%) in the rhTSH group and
28 patients (17%) in the THW group were NED. Sixty (37%) patients in
the THW group had TB uptake only, compared with 15 patients (12%) in
the rhTSH group. The range of TSH levels in the THW group were 2–234
µIU/L for TB patients, 30–576 µIU/L for those judged to be NED,
and 0.5–359 µIU/L for patients with metastatic disease. The mean TSH
in the THW group, at the time of the DxWBS, was 105.6 µIU/L. Only 5
(3%) of the 162 THW patients had TSH levels below 25 µIU/L. Peak TSH
levels were not measured in the rhTSH patients but are usually in the
130–150 µIU/L range, 24 h after the second dose of rhTSH
(14, 15, 28). There were only minor differences in tumor
characteristics between the groups (Table 1). The median stimulated Tg
levels for the rhTSH group were: 1 µg/L for NED, 7.7 µg/L for
metastatic disease, and 1 µg/L for TB. The median stimulated Tg
levels for the THW group were: 1 µg/L for NED, 38 µg/L for
metastatic disease, and 3.2 µg/L for TB. Of the patients judged to be
positive for metastatic disease, 59% of the rhTSH and 49% of the THW
patients had received 131I treatments before
enrollment in the study.
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)Forty-eight percent of the rhTSH group had focal 131I uptake on the DxWBS, compared with 75% of the THW group. The frequencies of bone, cervical, mediastinal, lung, and multicentric uptake were comparable between groups. Uptake in the TB only was present in 40% of the THW group, compared with 15% of the rhTSH group (P = 0.02).
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Sixty-six of the rhTSH patients and 40 of the THW patients had
negative DxWBS scans (Table 2
). Patient and tumor characteristics
between these groups were very similar (data not shown). There were 2
false-positive results in the THW group. One had uptake in an inflamed
gallbladder and the other had diffuse mediastinal uptake that was
judged to be thymus uptake. Eleven patients (4 in rhTSH and 7 in THW)
with evidence for metastatic disease had only TB uptake on the DxWBS
and were not included in the reduced tables because the result was
indeterminate (i.e. neither metastatic nor NED). However, 19
(29%) of the rhTSH group and 13 (33%) of the THW group had evidence
for metastatic disease. The stimulated Tg levels in these
false-negative DxWBS patients ranged from 1.0–5600 µg/L. Only 4
patients in this category had stimulated Tg levels less than 2 µg/L.
In the rhTSH patients who had metastatic disease and a negative DxWBS
(n = 19), 6 of 9 who were treated with high-dose
131I had uptake in metastatic sites, on
posttherapy scans. Ten of 13 patients who had FDG-PET scans
demonstrated positive metastatic uptake. Of the 19 patients, 9 had
disease in multiple sites, 8 had disease in cervical nodes, 8 had lung
uptake, and 3 had bone uptake. Of the THW patients who had negative
DxWBS and metastatic disease (n = 13), 5 of 6 who received
high-dose 131I had positive posttherapy scans and
5 of 7 who had FDG-PET scans had focal metastatic uptake. Overall, the
metastatic lesions were localized in 8 of the 8 THW patients who had
either a posttherapy scan or an FDG-PET scan.
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)Another indicator of residual thyroid tissue is a measurable serum Tg in the setting of an elevated TSH. Using a cutoff less than or equal to 2 µg/L as defining a negative stimulated Tg, 54 patients in the rhTSH and 61 patients in the THW group were negative. Of these, 9 in the rhTSH group and 22 in the THW group were TB. The clinical and tumor characteristics of the patients in these cohorts were comparable. Of the patients with low stimulated Tg, 9 (17%) in the rhTSH group and 15 (25%) in the THW group had evidence for metastases. Of the 9 rhTSH patients with low Tg levels and metastases, 8 had uptake in cervical nodes on either the DxWBS or the posttherapy scan. Of the 15 THW patients with low Tg and metastases, 10 had positive cervical nodes and 4 had lung uptake on either the DxWBS or the posttherapy scan. FDG-PET scans were performed in 9 of 15, and these scans localized disease in 5 cases. Disease was localized in all 15 by a combination of the posttherapy scan and the FDG-PET scans.
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)Thirty-seven patients in the rhTSH group and 25 patients in the THW group had double-negative test results. By definition, no TB patients can be in the double-negative groups. There were 8 false-positives in the rhTSH group and 5 in the THW group. Three patients in the THW group who had metastases (based on other testing) had TB uptake only on the DxWBS and were eliminated from the reduced tables as indeterminate outcomes. One patient (2.7%) in the rhTSH group and 3 patients (12%) in the THW group had metastatic disease. The disease in all 4 patients was localized by either the posttherapy scan or FDG-PET scanning. The 1 patient in the rhTSH group had diffuse lung nodules only seen on FDG-PET scanning, confirmed to be Hurthle cell carcinoma by biopsy. In the THW group, 2 patients had metastases in cervical nodes, localized by ultrasonography and seen on the posttherapy scans. One patient in the THW group had mediastinal and cervical uptake seen on FDG-PET scanning and on the posttherapy scan.
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Testing was done after eliminating the TB patients as an indeterminate test result. We could not unequivocally conclude that they did or did not have residual cancer. For analysis of the DxWBS testing, 19 of the 128 rhTSH, and 67 of the 161 THW patients were removed from the data, because they had TB status. For analysis of the stimulated Tg testing, we eliminated 13 of the 120 rhTSH patients and 52 of the 152 THW patients who had a TB status. For analysis of the combined test, we eliminated 13 of the 120 rhTSH patients and 55 of the 150 THW patients who had a TB status.
We performed statistical analyses on the predictive values, because
these have the most clinical applicability (24). The
sensitivity of the DxWBS was slightly better after THW, whereas the
specificity was slightly better with rhTSH. The PPV (P
= 0.50) and NPV (P = 0.66) of the DxWBS were comparable
between groups (Fig. 1). Using a stimulated Tg greater than 2 µg/L as
the definition of a positive Tg response, we found a higher sensitivity
in the rhTSH group, whereas the specificity was higher in the THW
group. The PPV (P = 0.21) and the NPV
(P = 0.09) of the stimulated Tg test were not
statistically different between groups, although there was a trend for
the NPV to be higher in the rhTSH group (Fig. 2).
When both the DxWBS and the stimulated Tg were considered together as a combined test, the sensitivity and specificity between groups was comparable. The PPV (P = 0.38) and the NPV (P = 0.14) of the combined test were not different between groups. However, when both the DxWBS and stimulated Tg were negative, only one patient in the rhTSH group had metastatic disease, producing a NPV of 97% (Fig. 3).
We also performed accuracy testing at 0.5 µg/L and at 5 µg/L. As expected, when stimulated Tg levels equal to or above 0.5 µg/L are used to define residual disease, the sensitivities increase (rhTSH = 0.98 and THW = 1.0) and the specificities drop (rhTSH = 0.18 and THW = 0.04). When a stimulated Tg level of 5 µg/L is used, the sensitivities drop (rhTSH = 0.70 and THW = 0.70) and the specificities rise (rhTSH = 0.98 and THW = 0.96). Of the three cutoff levels analyzed, the best balance of specificity and sensitivity (and PPV and NPV) is obtained with the 2-µg/L cutoff.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Unfortunately, patients in both phase III studies were generally low-risk, and only a small percentage had distant metastases, raising questions about applicability to high-risk patients. Nevertheless, based on the phase III data, we began to offer all patients the option of having formal dosimetric analysis in preparation for possible 131I therapy after either THW or with rhTSH, while remaining on suppressive doses of thyroxine. In this retrospective analysis, we found that the combination of the DxWBS and the stimulated Tg level had the same PPVs and NPVs whether the patients were prepared by THW or rhTSH. In fact, if both the DxWBS was negative and the stimulated Tg was equal to or less than 2 µg/L after rhTSH, there was only a 3% chance of having metastatic disease, compared with a 12% chance for the THW group. We conclude that the discomfort and reduced quality-of-life that often follows THW are no longer generally necessary, because rhTSH is an equally acceptable preparation.
A number of biases are likely present in our retrospective study. The patients who enrolled in 1998 were only offered the option of rhTSH if they qualified for a Food and Drug Administration-sponsored compassionate-need trial. When the1999 patients made their decision as to which preparation to choose, it was widely believed that the hypothyroid preparation, though more onerous, was more sensitive. It was also known that the cost of the only commercially available form of rhTSH (Thyrogen, Genzyme Corp.) might not be covered by some medical insurance payers. In addition, many patients were referred to us already withdrawn from thyroid hormone, and many of those patients chose to proceed with that route, because they were already partially prepared. Furthermore, individuals who had been through the hypothyroid phase of THW may have been more likely to choose the rhTSH option if their quality of life was poor when they were hypothyroid. Finally, in calculating the accuracy of the testing outcomes, some bias could occur by excluding the TB patients. However, we felt that forcing these patients either into a metastatic or an NED category would induce even greater bias, and we therefore eliminated them from the statistical comparisons.
With an awareness of these potential biases, we decided to
retrospectively analyze the ability to detect residual thyroid
carcinoma as a function of which type of preparation for the DxWBS was
used. Tables 1 and 2 demonstrate that the demographic and tumor
characteristics of the two groups were remarkably similar. The main
exception was that patients in the hypothyroid group who did not have
metastatic cancer were much more likely to have a TB remnant only, and
those in the rhTSH group were more likely to have no evidence of
residual disease. This again may have been a bias, because patients who
had been through hypothyroid testing in the past and knew that they had
a low likelihood of residual disease may have been less likely to
choose the reduced quality of life of hypothyroidism.
We found metastatic disease in patients who had negative DxWBS, patients with low stimulated Tg levels, and even in a small number of patients who had both negative DxWBS and low stimulated Tg. Although the percentage of such patients was always higher in the THW group than in the rhTSH group, no statistically significant differences were present. We are not aware of any previous publications that have addressed this issue, for comparison.
In our cohort, we found that the sensitivity of the DxWBS was 69% with rhTSH and 80% after THW. This compares to reported THW sensitivities of 48% (32), 50% (33), 55% (34), 57% (35), 71% (36), 78% (37), 80% (38), and 84% (39).
The sensitivity of stimulated Tg to detect residual thyroid carcinoma after thyroidectomy has been reported to be 83% (40), 85% (36), 86% (41), 95% (42, 43), and 97% (35). In our cohort, we found a sensitivity of 86% after rhTSH and 79% after THW. The slightly lower sensitivity in the THW group may be attributable to the spectrum of hypothyroidism that occurs after THW. The wide range of TSH values between 0.5 and 576 µIU/L may reflect the variable presence of remnant normal thyroid, the length of time off thyroxine, and the functional state of the malignant thyroid cells. On the other hand, there seems to be a relatively similar rise in TSH levels after two doses of rhTSH, with peak level in the 130 µIU/L range (14, 15).
We chose to statistically compare the predictive values of the various
tests because this seems to provide the clinician with information that
patients can use in decision making. No significant differences in the
predictive values of the tests were found between groups. When both a
negative DxWBS and a stimulated Tg 
2 µg/L were found, a
nonsignificant trend toward a higher NPV was present in the rhTSH
group. In that group, we found that 97% of our patients had no
evidence of distant metastases. The NPVs were comparable, between
groups, for the DxWBS alone and for the stimulated Tg alone.
In a recent publication, Cailleux et al. (44) recommended that, after a remnant ablation, it may be best to first test the Tg level after THW, before doing a DxWBS. For those with levels below 1 µg/L, they recommend no scanning, because significant disease is rare; whereas those with Tg levels above 10 µg/L should be scanned with 100 mCi (3.7 GBq), because the scans with 2–5 mCi (74–185 MBq) are too insensitive. This is an interesting proposal that will need independent confirmation.
Our results indicate that the accuracy of detecting significant residual or recurrent thyroid carcinoma is not significantly different whether the patient is prepared by THW or with rhTSH. From a strictly diagnostic perspective, there was no advantage, in our patients, of using the THW approach. The only patients for whom the THW approach seems reasonable, at present, are those for whom there is a high likelihood that a therapeutic dose of radioiodine would be given within a short time after the results of the DxWBS and the stimulated Tg. On the other hand, patients who have a low or unknown likelihood of needing a therapeutic dose of radioiodine could be offered the rhTSH approach. The cost of rhTSH is also a significant factor to be weighed by the patient and the attending physicians, with the cognizance that several weeks of hypothyroidism may result in a reduced quality of life, including possible lost time at work or at school. Based on our findings, the final choice between rhTSH and THW preparation will not need to consider the accuracy of diagnostic testing, which seems to be comparable.
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Acknowledgments |
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Received March 20, 2000.
Revised August 2, 2000.
Revised October 12, 2000.
Accepted October 19, 2000.
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References |
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L. Fugazzola, A. Mihalich, L. Persani, N. Cerutti, M. Reina, M. Bonomi, E. Ponti, D. Mannavola, E. Giammona, G. Vannucchi, et al. Highly Sensitive Serum Thyroglobulin and Circulating Thyroglobulin mRNA Evaluations in the Management of Patients with Differentiated Thyroid Cancer in Apparent Remission J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3201 - 3208. [Abstract] [Full Text] [PDF]
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R. J. Robbins, J. T. Chon, M. Fleisher, S. M. Larson, and R. M. Tuttle Is the Serum Thyroglobulin Response to Recombinant Human Thyrotropin Sufficient, by Itself, to Monitor for Residual Thyroid Carcinoma? J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3242 - 3247. [Abstract] [Full Text] [PDF]
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L. Wartofsky Using Baseline and Recombinant Human TSH-Stimulated Tg Measurements to Manage Thyroid Cancer without Diagnostic 131I Scanning J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1486 - 1489. [Full Text] [PDF]
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E. L. Mazzaferri and R. T. Kloos Is Diagnostic Iodine-131 Scanning with Recombinant Human TSH Useful in the Follow-Up of Differentiated Thyroid Cancer after Thyroid Ablation? J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1490 - 1498. [Abstract] [Full Text] [PDF]
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R. M. Tuttle, M. Fleisher, G. L. Francis, and R. J. Robbins Serum Vascular Endothelial Growth Factor Levels Are Elevated in Metastatic Differentiated Thyroid Cancer but Not Increased by Short-Term TSH Stimulation J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1737 - 1742. [Abstract] [Full Text] [PDF]
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