Harry R. Maxon

Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma.

BACKGROUND To detect recurrent disease in patients who have had differentiated thyroid cancer, periodic withdrawal of thyroid hormone therapy may be required to raise serum thyrotropin concentrations to stimulate thyroid tissue so that radioiodine (iodine-131) scanning can be performed. However, withdrawal of thyroid hormone therapy causes hypothyroidism. Administration of recombinant human thyrotropin stimulates thyroid tissue without requiring the discontinuation of thyroid hormone therapy. METHODS One hundred twenty-seven patients with thyroid cancer underwent whole-body radioiodine scanning by two techniques: first after receiving two doses of thyrotropin while thyroid hormone therapy was continued, and second after the withdrawal of thyroid hormone therapy. The scans were evaluated by reviewers unaware of the conditions of scanning. The serum thyroglobulin concentrations and the prevalence of symptoms of hypothyroidism and mood disorders were also determined. RESULTS Sixty-two of the 127 patients had positive whole-body radioiodine scans by one or both techniques. The scans obtained after stimulation with thyrotropin were equivalent to the scans obtained after withdrawal of thyroid hormone in 41 of these patients (66 percent), superior in 3 (5 percent), and inferior in 18 (29 percent). When the 65 patients with concordant negative scans were included, the two scans were equivalent in 106 patients (83 percent). Eight patients (13 percent of those with at least one positive scan) were treated with radioiodine on the basis of superior scans done after withdrawal of thyroid hormone. Serum thyroglobulin concentrations increased in 15 of 35 tested patients: 14 after withdrawal of thyroid hormone and 13 after administration of thyrotropin. Patients had more symptoms of hypothyroidism (P<0.001) and dysphoric mood states (P<0.001) after withdrawal of thyroid hormone than after administration of thyrotropin. CONCLUSIONS Thyrotropin stimulates radioiodine uptake for scanning in patients with thyroid cancer, but the sensitivity of scanning after the administration of thyrotropin is less than that after the withdrawal of thyroid hormone. Thyrotropin scanning is associated with fewer symptoms and dysphoric mood states.

Relation between Effective Radiation Dose and Outcome of Radioiodine Therapy for Thyroid Cancer

We used a combination of radioiodine scanning and quantitative radiation dosimetry to evaluate responses to therapeutic irradiation with 131I in 76 patients with thyroid adenocarcinoma. Fifty patients received 131I treatment for ablation of residual thyroid tissue after surgical thyroidectomy, and 26 had 131I treatment for metastatic thyroid cancer. Successful ablation was observed in patients receiving higher radiation doses to the thyroid--about 4.4 times those in patients whose lesions were not ablated--largely because of a longer effective half-life of 131I in residual thyroid tissue in the patients with ablated lesions. Patients with metastases that persisted after 131I therapy tended to have more advanced disease and received significantly lower radiation doses per millicurie of administered 131I than did persons whose lesions responded to treatment. Initial 131I treatment resulting in radiation doses of at least 30,000 rad to thyroid remnants and 8000 rad to metastases was associated with a significant increase in the rate of response to therapy.

Ionizing irradiation and the induction of clinically significant disease in the human thyroid gland

Because of increasing concern over continuing medical and potential nonmedical exposure of the thyroid to radiation, risk estimates have been developed for acute thyroiditis, hypothyroidism, and both benign and malignant thyroid nodules following exposure of the human thyroid to external and internal sources of ionizing radiation. These estimates are unique in that they are based entirely on data in human subjects are included corrections for the spontaneous occurrence of thyroid disease in human populations not subjected to radiation whenever possible.

Outcome after Treatment of High-Risk Papillary and Non-Hurthle-Cell Follicular Thyroid Carcinoma

The treatment of thyroid cancer has been investigated extensively, but disagreement remains about the degree of aggressiveness needed in its management. Despite the general perception that the prognosis is excellent, 9% of patients with thyroid cancer die of the disease [1]. Patients with the less differentiated types of thyroid cancer or those presenting at a more advanced stage face higher mortality rates [2, 3]. In addition, the recurrence rate after surgery is more than 20% in persons with differentiated thyroid cancer [2]. Therefore, the ability to define the most effective therapeutic interventions on the basis of patient stratification by histologic type and stage of cancer at initial presentation should improve survival and decrease recurrence rates. The initial treatment for thyroid cancer is surgery, but the extent of surgery needed to improve outcome remains controversial [4-6]. Some studies have shown that more extensive thyroid resection reduces the recurrence rate but has a less definite effect on survival [2, 7]. More extensive surgery may be associated with a higher prevalence of complications, usually hypoparathyroidism or recurrent laryngeal nerve damage (or both), in 3% to 15% of patients [8-10]. The indications for postoperative ablative radioiodine therapy and the required administered activity are also under debate. Multifocality and lymph node involvement at presentation in 46% of persons with papillary thyroid cancer (of whom 25% face persistent or recurrent disease) argue in favor of this therapy [2, 11, 12], despite the risk for sialoadenitis, gastrointestinal symptoms, occasional bone marrow suppression, and possible second cancers [13]. The role of external radiation in the treatment of differentiated thyroid cancer is also highly controversial. Increased recurrence [14], no therapeutic benefit [15-17], and improved local control [18, 19] have all been reported. The National Thyroid Cancer Treatment Cooperative Study Registry was established in 1986 to define clinical practice and to address the effectiveness of therapies on morbidity and mortality by prospectively enrolling a large population of patients from multiple institutions. Patients have been stratified by uniform criteria and followed prospectively from the time of initial diagnosis and treatment. This 9-year report from the registry describes outcomes in patients with high-risk, differentiated thyroid cancer, a group of patients expected to have substantial morbidity and mortality in this time period. Methods A total of 1607 patients in whom thyroid cancer was diagnosed on or after 1 January 1987 were prospectively enrolled in the registry by the 14 participating institutions. No more than 20% of cases came from any single institution or city. Data forwarded to the registry were coded, and individual identifiers, such as name and Social Security number, were kept confidentially by the principal investigator at each institution. Because the patients therapy was not altered by participation in the registry, requirements for informed consent were determined by the institutional review boards at each participating institution, and their mandates were followed. Age, sex, ethnic background, histologic diagnosis, size of primary tumor, multifocality, local invasiveness, and regional or distant metastases were documented. The histologic diagnosis was established at each institution. All variants of papillary cancer, including so-called mixed papillary and follicular carcinomas, were included in the papillary group. Analyses for papillary carcinomas that included and excluded the more aggressive tall-cell variant were performed. The Hurthle cell (oxyphilic) variant of follicular carcinoma was excluded from the follicular group. Patients were stratified on the basis of pathologic diagnosis, age, tumor size, local invasiveness, and extent of metastases at the time of first surgical intervention as determined by gross and histologic findings at surgery, whole-body radioiodine scans, chest radiographs, and other radiologic studies. This stratification system was established empirically before initiation of the registry by a group of experienced clinicians on the basis of information available in 1985. The criteria for categorization as high risk are noted in Table 1. Patients with preoperative vocal cord paresis or with postoperative hypocalcemia or vocal cord paresis that persisted 2 months or less were not designated as having these complications of surgery. The extent of initial surgery, use of postoperative radioiodine therapy, and application of external radiation therapy were analyzed for impact on outcome. With rare exceptions, all patients received thyroxine therapy. Table 1. Criteria for Stratification to High-Risk Groups Outcomes were death due to thyroid cancer or to complications of its treatment, progression (defined as a patient alive with progressive thyroid cancer or dead because of thyroid cancer or complications of its treatment at last follow-up), and disease-free survival (defined as a patient alive with no known residual thyroid cancer or free of thyroid cancer at the time of death from other causes). Statistical Analysis All data were extracted by using a computer-based integrated data management package (Med-log, Information Analysis Corporation, Incline Village, Nevada). Cox proportional-hazards models were performed to determine whether each predictor variable was associated on univariate analysis (Table 2) with survival, progression, and disease-free survival (SAS Institute, Cary, North Carolina). The hazard model was also used to identify the set of predictor variables that best explained the probabilities of overall survival, cancer-specific mortality, progression of disease, or disease-free survival (Table 3). A P value of 0.05 or less was considered statistically significant. Risk ratios obtained from the Cox proportional-hazards analyses are given with 95% CIs. Risk ratios less than 1 indicate improved outcome, and those greater than 1 indicate a worsened outcome. Table 2. Variables Associated with Mortality, Progression, and Disease-Free Survival (by Univariate Analysis) Table 3. Variables That Best Predict Overall Mortality, Cancer-Specific Mortality, Progression of Disease, or Disease-Free Survival (by Multivariate Analysis) Results Follow-up Three hundred three patients with papillary carcinoma and 82 patients with follicular carcinoma were considered to have high-risk thyroid cancer. Twenty patients (5.2%) were lost to follow-up. An additional 64 patients were not included in the survival analyses because no information on patient status was available (n = 60), no cause of death was recorded (n = 2), or patients were alive with no cancer status reported (n = 2). Demographic characteristics of the two groups were similar regardless of whether these cases were included. Patients were followed for a mean of 3.1 years after the date of surgery; 35% were men. The mean (SD) age at entry was 57 15 years. Sex and Age Compared with men, women with papillary cancer had a lower risk for overall mortality (risk ratio [RR], 0.03 [95% CI, 0.23 to 0.92]) but not cancer-specific mortality. Older age did not affect outcome in patients with papillary carcinoma or those with follicular carcinoma, but an age effect might be masked by the fact that age was a factor in defining these high-risk patients. Histologic Type Only 18 patients with papillary cancer had the tall-cell variant (P not significant by multivariate analysis). By univariate analysis, radioiodine therapy was associated with reduced disease progression (risk ratio, 0.10 [CI, 0.01 to 0.72]; P = 0.02). Thyroid Surgery The first surgical procedure on the thyroid and any surgical therapy of the thyroid that occurred within the next 4 months were classified as initial thyroid surgery. Data were not sufficient to allow analysis of the effect of modified neck dissections on complication rates. Of 300 patients with papillary cancer, 256 (85.3%) had a total or near-total thyroidectomy as initial thyroid surgery, 10 (3.3%) had bilateral subtotal thyroidectomy, 26 (8.7%) had lobectomy, 1 (0.3%) had lumpectomy, 4 (1.3%) had biopsy only, and 3 (1.0%) had nonspecified surgery. Of 80 patients with follicular cancer, 57 (71.3%) had total or near-total thyroidectomy as initial thyroid surgery, 2 (2.5%) had bilateral subtotal thyroidectomy, 13 (16.3%) had lobectomy, 4 (5.0%) had lumpectomy, and 4 (5.0%) had biopsy only. The charts of all patients with reported surgical complications were reviewed. The complication rate of initial surgery varied among centers. The overall rate of some type of complication was 14.4% (52 of 360 patients). Specific data on complications were available for 286 of 303 patients with papillary cancer and 74 of 82 patients with follicular thyroid cancer. Hypoparathyroidism alone occurred in 19 of 286 (6.6%) patients with papillary cancer and 3 of 74 (4.0%) patients with follicular cancer. Vocal cord palsy alone was noted in 17 of 286 (5.9%) patients with papillary cancer and 6 of 74 (8.0%) patients with follicular cancer. Combined hypoparathyroidism and vocal cord palsy occurred in 4 of 286 (1.4%) patients with papillary cancer and no patients with follicular cancer. Data were not sufficient to allow analysis of any effect of modified neck dissections on complication rates. Overall mortality from papillary cancer improved with total or near-total thyroidectomy compared with other surgical procedures (RR, 0.41 [CI, 0.20 to 0.85]) (Table 2). Progression of disease and disease-free survival were not improved by more extensive surgery, and surgery did not affect mortality, progression, or disease-free survival in patients with follicular cancer by univariate (Table 2) or multivariate (Table 3) analyses. Radioiodine Therapy Postoperative radioiodine therapy with iodine-131 was administered to 258 of 302 (85.4%) patients with papillary cancer; the init

Recurrence after treatment of micropapillary thyroid cancer.

BACKGROUND Despite very low mortality associated with micropapillary thyroid cancer, locoregional recurrence is common and controversy exists regarding optimal surgical treatment and the role of adjunctive radioiodine. METHODS The National Thyroid Cancer Treatment Cooperative Study Group Registry was analyzed for recurrences in patients with unifocal versus multifocal micropapillary cancer, with or without nodal disease, depending upon the extent of surgery and the use of adjunctive radioiodine. Six hundred eleven patients considered disease-free after initial therapy were followed for 2572 person-years. RESULTS Thirty patients (6.2%) had recurrences detected at a mean 2.8 years after primary treatment. Recurrences did not differ between patients with unifocal and multifocal disease overall; however, among patients who received less than a near-total thyroidectomy (NTT), those with multifocal disease had more recurrences than those with unifocal disease (18% vs. 4%, p = 0.01). Patients with multifocal disease who had a total (T) or NTT trended toward fewer recurrences than those undergoing less than an NTT (6% vs. 18%, p = 0.058). In patients who did not receive radioiodine therapy, recurrence was more common in patients with multifocal disease versus unifocal disease (7% vs. 2%, p = 0.02). However, radioiodine did not reduce recurrences in patients with multifocal disease or patients with positive nodes. Patients with positive nodes had more recurrences than node-negative patients regardless of surgical extent or use of radioiodine. CONCLUSIONS Patients with micropapillary multifocal disease have a reduced risk of recurrence after a T/NTT compared with less surgery. A randomized, controlled trial is necessary and feasible to determine if radioiodine ablation of thyroid remnants is advantageous in patients with intrathyroidal micropapillary cancer.

The chemistry of rhenium and technetium as related to the use of isotopes of these elements in therapeutic and diagnostic nuclear medicine.

The beta emitting isotopes 186Re and 188Re are logical choices on which to base therapeutic radiopharmaceuticals that might be expected to be analogous to diagnostic radiopharmaceuticals based on 99mTc. However, the chemistry of rhenium is sufficiently different from that of technetium so that the development of Re radiopharmaceuticals often cannot be predicated on the known chemistry and biological behavior of 99mTc radiopharmaceuticals. The relevant chemical differences involve the greater stability of the higher oxidation states of Re (and thus the greater tendency of reduced Re radiopharmaceuticals to undergo re-oxidation to perrhenate), and the greater substitution inertness of reduced Re complexes. These differences are illustrated in the preparation and use of 186Re (Sn)-HEDP and 99mTc(Sn)-HEDP diphosphonate radiopharmaceuticals designed, respectively, for palliative therapy and diagnosis of metastatic cancer to bone, and in the preparation and biodistribution of tr[186Re(DMPE)2Cl2]+ and [186Re(DMPE)3]+, analogs to the potential myocardial perfusion imaging agents tr-[99mTc(DMPE)2Cl2]+ and [99mTc(DMPE)3]+. [HEDP = (1-hydroxyethylidene)diphosphonate; DMPE = 1,2-bis(dimethylphosphino)ethane].

Low iodine diet in I-131 ablation of thyroid remnants.

A low-iodine diet was developed for used in decreasing iodine intake and excretion in patients undergoing evaluation with radioactive I-131 for ablation of thyroid remnants as treatment for thyroid cancer. It has been demonstrated to effectively lower iodine excretion to less than 25% of basal values. Preliminary calculations suggest that such iodine depletion may be potentially useful in increasing the radiation dose per mCi of administered activity in I-131 ablative therapy.

The Impact of Age and Gender on Papillary Thyroid Cancer Survival

CONTEXT Thyroid cancer predominately affects women, carries a worse prognosis in older age, and may have higher mortality in men. Superimposed on these observations is the fact that most women have attained menopause by age 55 yr. OBJECTIVE The objective of the study was to determine whether men contribute disproportionately to papillary thyroid cancer (PTC) mortality or whether menopause affects PTC prognosis. DESIGN Gender-specific mortality was normalized using age-matched subjects from the U.S. population. Multivariate Cox proportional hazard regression models incorporating gender, age, and National Thyroid Cancer Treatment Cooperative Study Group stage were used to model disease-specific survival (DSS). PARTICIPANTS AND SETTING Patients were followed in a prospective registry. MAIN OUTCOME MEASURE The relationships between gender, age, and PTC outcomes were analyzed. RESULTS The unadjusted hazard ratio (HR) for DSS for women was 0.40 [confidence interval (CI) 0.24-0.65]. This female advantage diminished when DSS was adjusted for age at diagnosis and stage with a HR encompassing unity (HR 0.72, CI 0.44-1.19). Additional multivariate models of DSS considering gender, disease stage, and various age groupings showed that the DSS for women diagnosed at under 55 yr was improved over men (HR 0.33, CI 0.13-0.81). However, the HR for DSS increased to become similar to men for women diagnosed at 55-69 yr (HR 1.01, CI 0.42-2.37) and at 70 yr or greater (HR 1.17, CI 0.48-2.85). CONCLUSIONS Although the overall outcome of women with PTC is similar to men, subgroup analysis showed that this composite outcome is composed of two periods with different outcomes. The first period is a period with better outcomes for women than men when the diagnosis occurs at younger than 55 yr; the second is a period with similar outcomes for both women and men diagnosed at ages greater than 55 yr. These data raise the question of whether an older age cutoff would improve current staging systems. We hypothesize that older age modifies the effect of gender on outcomes due to menopause-associated hormonal alterations.

Rhenium-186 hydroxyethylidene diphosphonate for the treatment of painful osseous metastases

Rhenium-186 (tin)hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that localizes in skeletal metastases in patients with advanced cancer. A single intravenous administration of approximately 34 mCi (1,258 MBq) resulted in significant improvement in pain in 33 of 43 evaluable patients (77%) following the initial injection, and in 7 of 14 evaluable patients (50%) following a second treatment. Patients responding to treatment experienced an average decrease in pain of about 60%, with one in five treatments resulting in a complete resolution of pain. The only adverse clinical reaction was the occurrence after about 10% of the administered doses of a mild, transient increase in pain within a few days following injection. Statistically significant but clinically unimportant decreases in total white blood cell counts and total platelet counts were observed within the first 8 weeks following the injection; no other toxicity was apparent. Rhenium-186(Sn)HEDP is a useful new compound for the palliation of painful skeletal metastases.

Quantitative External Counting Techniques Enabling Improved Diagnostic and Therapeutic Decisions in Patients with Well-Differentiated Thyroid Cancer

A quantitative technique is described which allows the physician to predict more accurately whether a recurrent or metastatic well-differentiated thyroid carcinoma is amenable to radioiodine-131 therapy or is better treated by other means. A calibrated uptake probe and scaler system is used to obtain conjugate view (i.e., diametrically opposed) counting rates for both the whole body and for any areas of abnormal uptake (lesion) at 24,48 annd 72 hours following the administration of 2 mCi 131l. Quantitative calculations accounting for patient attenuation, lesion size and geometrical factors then provide a determination of the lesion uptake as well as the effective half-life of 131l in the lesion. The radiation dose which would be delivered to the lesion by a given therapeutic amount of 131l may then be calculated to help determine the desirability of 131l treatment. The results of patient studies indicate the potential benefit of such quantitative evaluation.