Criteria for Selection of Cases

Medical records of dogs referred to Veterinary Oncology Specialties between October 1990 and September 2003 for ¹³¹I therapy because of suspected or confirmed thyroid carcinoma were reviewed. Dogs were included in the study if a definitive diagnosis had been made on the basis of results of histologic or cytologic examination or, if a definitive diagnosis had not been made (eg, dogs with a solitary cranial mediastinal mass) but a presumptive diagnosis had been made on the basis of high serum T₄ concentration in conjunction with abnormal accumulation of sodium pertechnetate Tc 99m during scintigraphy. Dogs in which the tumor had regrown following previous surgery were considered for inclusion in the study. However, dogs were included only if the thyroid tumor was determined to be nonresectable. Dogs were excluded if any other medical (eg, chemotherapy) or radiation treatments were administered in conjunction with ¹³¹I therapy for primary treatment of the tumor. However, dogs in which tumor volume was sufficiently reduced following ¹³¹I therapy to allow subsequent surgical removal with curative intent were included in the study.

Procedures

Information abstracted from each record included signalment; clinical signs; previous surgery; physical examination findings; results of clinicopathologic testing, including CBCs, serum biochemical profiles, urinalyses, and measurements of serum T₄ concentration; and results of histologic and cytologic analyses, thoracic radiography, and scintigraphy. For staging purposes, tumor volume was estimated from physical measurements of the tumor or from estimates of tumor diameter obtained from scintigraphic images. Dogs were retrospectively staged according to World Health Organization criteria.¹⁹

Thyroid scintigraphy was performed in all dogs prior to administration of ¹³¹I therapy. Sodium pertechnetate Tc 99m (0.19 to 0.74 GBq [5 to 20 mCi]) was administered IV, and static images of the cervical area and thorax were acquired with a low-field-of-view gamma camera^a within 60 minutes. Ventrodorsal and left and right lateral views of the cervical area and left and right lateral views of the thorax were obtained with a low-energy, all-purpose collimator and 256 X 256 X 16 matrix, for a total of 500,000 to 1,000,000 counts. Images were stored on a dedicated nuclear medicine computer workstation^b for later review.

In dogs with high serum T₄ concentrations (ie, > 4.0 μg/dL), ¹³¹I therapy was administered shortly after thyroid scintigraphy. In contrast, in dogs with low (ie, < 0.8 μg/dL) or normal (ie, 0.8 to 4.0 μg/dL) serum T₄ concentrations, thyroid scintigraphy was performed, and dogs were then discharged with instructions that they be fed a diet low in iodine for 3 weeks. Following this, thyroid scintigraphy was repeated and ¹³¹I therapy was administered.

On scintigraphic images, radionuclide uptake of the thyroid tumor was subjectively assessed relative to uptake of the parotid salivary glands and contralateral thyroid lobe. Images were also evaluated for size and uniformity of the affected lobe, heterogeneity of uptake in the affected lobe, and evidence of tumor extension into extracapsular structures. Results of thyroid scintigraphy were considered abnormal, and the dog was considered a candidate for ¹³¹I therapy, if radionuclide uptake of the affected thyroid lobe was greater than uptake in the parotid salivary glands or contralateral thyroid lobe and the affected thyroid lobe was enlarged.

The dose of sodium iodide I 131 used for ¹³¹I therapy was empirically determined on the basis of tumor size, results of thyroid scintigraphy, and serum T₄ concentration at the time of initial examination. Sodium iodide was diluted in sterile water and administered IV or SC. Following ¹³¹I administration, body weight and appetite were monitored daily. Dogs were discharged from the hospital when exposure rate measured with a survey meter 6 inches from the region of the thyroid tumor was < 2 mR/h. Serum T₄ concentration was measured at the time of discharge from the hospital.

A recheck physical examination and assessment of the thyroid tumor were conducted within 1 month after ¹³¹I therapy at Veterinary Oncology Specialties or by the referring veterinarian. Hypothyroid dogs were treated with levothyroxine sodium^c (0.022 mg/kg [0.01 mg/lb], PO, q 12 h for 1 to 2 months, then q 24 h). Serum T₄ concentration was monitored by the referring veterinarian, and the levothyroxine dosage was adjusted as necessary. Follow-up scintigraphy was performed as needed.

During recheck examinations, a complete response was defined as disappearance of all nodules, serum T₄ concentration < 4.0 μg/dL, resolution of clinical signs, and no evidence of radionuclide uptake in the area of the tumor on follow-up scintigraphy. A partial response was defined as > 50% reduction in the size of the mass, a reduction in radionuclide uptake on follow-up scintigraphic images, compared with pretreatment images, or both. Stable disease was defined as < 50% reduction or no change in the size of the mass or no change in radionuclide uptake on follow-up scintigraphic images. Progressive disease was defined as enlargement of the original tumor by > 25% or identification of additional neoplastic nodules during physical examination and follow-up scintigraphy.

Dogs with cervical thyroid tumors were evaluated 3 to 6 weeks after ¹³¹I therapy to determine whether resection was feasible because of a reduction in tumor size or consolidation of the tumor (ie, increased tumor mobility during physical examination and decreased tumor size with reduced or absent radionuclide uptake during follow-up scintigraphy). Surgery was not considered for dogs with tumors located in the base of the tongue or mediastinum. Surgery was performed between 6 and 12 weeks after initial ¹³¹I therapy, and resected tissue was submitted for histologic examination to determine the completeness of resection. In dogs that were not candidates for resection of the tumor, additional ¹³¹I therapy was considered if there was evidence of progressive disease or tumor metastasis or if serum T₄ concentration increased.

Data analysis—Survival time was defined as the time from initial ¹³¹I therapy until euthanasia or death. Because of the retrospective nature of the study, time to progression of disease in dogs that initially responded could not be accurately determined in a sufficient number of dogs to allow for statistical analysis. The Kaplan-Meier method was used to determine whether various factors were associated with survival time. Factors that were examined included clinical stage (stage II or III vs stage IV), site (cervical vs any other site), dose of sodium iodide I 131 (< vs ≥ median dose), age (< vs ≥ median age), body weight (< vs ≥ median weight), treatment (¹³¹I therapy alone vs ¹³¹I therapy followed by surgery), and serum T₄ concentration prior to ¹³¹I therapy (≤ 4.0 μg/dL vs > 4.0 μg/dL). Dogs lost to follow-up and dogs that were still alive at the time of the study were censored in survival analyses, but dogs that died of causes unrelated to the thyroid tumor were not. Multivariate analysis with the Cox proportional hazards model was planned for all factors found to be significant in univariate analyses.

All analyses were performed with standard software.^d Values of P < 0.05 were considered significant.

Results

A total of 111 dogs suspected or confirmed to have thyroid carcinoma were referred to Veterinary Oncology Specialties during the study period. Of these, 58 received ¹³¹I therapy; however, 19 of the 58 were excluded because of insufficient follow-up or because they also received chemotherapy or external beam radiation therapy. The remaining 39 dogs were included in the study.

Mean ± SD age at the time of initial examination for dogs included in the study was 10.5 ± 2.8 years (median, 10.7 years; range, 4.5 to 14.8 years). Mean body weight was 27.4 ± 10.8 kg (60.3 ± 23.8 lb; median, 27.5 kg [60.5 lb]; range, 2.2 to 46.6 kg [4.8 to 102.5 lb]). There were 17 neutered females, 16 neutered males, and 6 sexually intact males. Ten of the 39 dogs were Golden Retrievers.

Clinical signs reported at the time of initial examination included a palpable cervical mass (n = 21), signs of hyperthyroidism (ie, weight loss, polyuria, polydipsia, and hyperactivity; 4), respiratory tract disease (3), weakness (1), or a combination of these signs (10). Duration of clinical signs prior to examination ranged from 3 days to 23 months (mean ± SD, 3.6 ± 5.5 months; median, 1.5 months). Thirty-two of the 39 dogs had a solitary mass located in the ventral cervical region (n = 25), base of the tongue (5), or cranial portion of the mediastinum (2). The remaining 7 dogs had metastatic masses in conjunction with a cervical mass (n = 4) or signs of respiratory tract disease (ie, dyspnea, panting, or cough; 3). The 32 dogs with a solitary mass were classified as having stage II (n = 16) or III (16) disease; the remaining 7 dogs were classified as having stage IV disease. Twentyone of the 39 (54%) dogs had high serum T₄ concentrations at the time of initial examination; in these dogs, serum T₄ concentration ranged from 4.1 to 11.0 μg/dL. Two dogs were hypothyroid at the time of initial examination, and the remaining 16 dogs had serum T₄ concentrations within reference limits.

In 23 dogs, the diagnosis was confirmed on the basis of results of histologic examination of tumor tissue. Eleven of the 23 had follicular carcinoma, and 12 had other carcinomas (ie, thyroid adenocarcinoma, thyroid carcinoma, or other carcinoma). In 8 dogs, the diagnosis was confirmed on the basis of results of cytologic examination of aspirate samples. In the remaining 8 dogs, results of cytologic examination of aspirate samples were inconclusive. For 7 of these 8 dogs, a presumptive diagnosis was made on the basis of high serum T₄ concentration and positive results of thyroid scintigraphy. The remaining dog was euthyroid, but a presumptive diagnosis of thyroid carcinoma was made on the basis of a palpable cervical mass, regional lymph node enlargement, and diffuse pulmonary metastases in conjunction with positive results of thyroid scintigraphy.

The first 3 dogs that were treated were intentionally given low doses of sodium iodide I 131 (0.41, 2.10, and 1.70 GBq [11, 56, and 45 mCi]) so that the time dogs would have to be confined after treatment could be determined. In the remaining dogs, the dose of sodium iodide I 131 was determined on the basis of serum T₄ concentration, estimated tumor volume, uptake of sodium pertechnetate on thyroid scintigrams, and body weight. For all dogs, mean ± SD dose of sodium iodide I 131 was 3.60 ± 1.40 GBq (97 ± 37 mCi; median, 3.70 GBq [100 mCi]; range, 0.41 to 7.10 GBq [11 to 191 mCi]). On a body weight basis, mean dose of sodium iodide I 131 was 0.15 ± 0.07 GBq/kg (4.1 ± 1.8 mCi/kg; median, 0.16 GBq/kg [4.2 mCi/kg]; range, 0.02 to 0.36 GBq/kg [0.5 to 9.8 mCi/kg]). Five dogs, including 2 dogs with metastasis, received > 1 treatment with ¹³¹I (4 dogs were treated twice, and 1 dog was treated 3 times).

Serum T₄ concentration was measured just prior to discharge (ie, 7 to 14 days after ¹³¹I therapy) in 30 of the 39 dogs. Twenty-nine of the 30 dogs were hypothyroid, and levothyroxine was prescribed. In the remaining dog, serum T₄ concentration at the time of discharge was > 4.0 μg/dL; this dog had pulmonary metastatic disease. Mean ± SD serum T₄ concentration at the time of discharge was 0.86 ± 1.3 μg/dL (median, 0.5 μg/dL; range, 0.4 to 7.7 μg/dL).

Follow-up thyroid scintigraphy was performed in 19 of the 39 dogs; time from initial ¹³¹I therapy to follow-up scintigraphy ranged from 30 to 150 days. Six dogs had no uptake after treatment; 9 dogs had reduced uptake, compared with uptake prior to treatment (Figure 1); and 3 dogs had no change in uptake (ie, stable disease). Results of follow-up thyroid scintigraphy were unavailable for the remaining dog.

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Ventrodorsal (A) and right lateral (B and C) scintigraphic images of a dog with a thyroid carcinoma in the cranial portion of the mediastinum. Images were obtained before (A and B) and 4 months after (C) treatment with sodium iodide I 131. Arrows indicate abnormal radionuclide uptake prior to ¹³¹I therapy; notice that there is a lack of normal radionuclide accumulation in the area of the thyroid glands as a result of thyroid gland suppression by the functional thyroid carcinoma. On the image obtained after ¹³¹I therapy (C), there is no longer any evidence of abnormal radionuclide accumulation in the mediastinum.

Citation: Journal of the American Veterinary Medical Association 229, 4; 10.2460/javma.229.4.542

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In 12 dogs, the tumor was resected 3 to 6 weeks after ¹³¹I therapy. Histologic examination of resected tumor tissue revealed variable amounts of tumor necrosis and hemorrhage. Excision was considered complete in 8 dogs and incomplete in 4. Additional treatment was not given to the 4 dogs with incomplete excision.

Median survival time for dogs with local or regional tumors (ie, stage II or III) was significantly (P = 0.016) longer (839 days) than median survival time for dogs with metastasis (366 days; Figure 2). Site (cervical vs ectopic; P = 0.95), dose of sodium iodide I 131 (< vs ≥ 3.7 GBq [median dose]; P = 0.98), age (< vs ≥ 10.7 years [median age]; P = 0.98), body weight (< vs ≥ 27.5 kg [median weight]; P = 0.56), treatment (¹³¹I therapy alone vs ¹³¹I therapy followed by surgery; P = 0.28), and serum T₄ concentration prior to ¹³¹I therapy (≤ vs > 4.0 μg/dL; P = 0.26) were not significantly associated with survival time. Multivariate analysis was not performed because only a single factor (clinical stage) was significantly associated with survival time.

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Kaplan-Meier survival curves for dogs with thyroid carcinoma treated with sodium iodide I 131. The dashed line represents dogs with stage IV tumors. The solid line represents dogs with stage II or III tumors. Tick marks represent dogs that were censored.

Citation: Journal of the American Veterinary Medical Association 229, 4; 10.2460/javma.229.4.542

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Twelve dogs died of progressive thyroid carcinoma (n = 9) or treatment-related myelosuppression (3). Eighteen dogs died of nonthyroid causes, 6 dogs were lost to follow-up between 294 and 1,016 days after ¹³¹I therapy, and 3 dogs were still alive at the time of the study between 197 and 1,108 days after ¹³¹I therapy.

Toxicoses related to ¹³¹I administration occurred in 3 dogs. All 3 dogs developed bone marrow suppression secondary to ¹³¹I administration and died of anemia, neutropenia-induced sepsis, or thrombocytopenia-associated hemorrhage. Survival times were 26, 37, and 124 days after ¹³¹I therapy. Two of those 3 dogs had low serum T₄ concentrations before ¹³¹I therapy, and 1 was euthyroid before ¹³¹I therapy. No specific factor associated with development of toxicosis was identified, although in all 3, the dose of sodium iodide I 131 was higher than the median dose on a body weight basis (0.22, 0.20, and 0.21 GBq/kg [5.9, 5.5, and 5.8 mCi/kg]).

Two dogs developed neurologic complications secondary to surgical removal of the thyroid tumor; 1 dog developed laryngeal paralysis and the other developed megaesophagus and dysphagia.

Discussion

Results of the present study suggested that ¹³¹I therapy may result in prolonged survival times in dogs with nonresectable thyroid tumors. Previous reports^7–11of ¹³¹I therapy in dogs with thyroid carcinoma were limited to 8 dogs. However, responses of dogs in these previous reports were consistent with results of the present study. In a recent study¹² of 43 dogs with thyroid carcinoma treated with ¹³¹I therapy alone or in combination with surgery, median survival times were 30 and 34 months, respectively. These values are similar to the median survival time for dogs in the present study with stage II or III thyroid tumors (839 days [27.6 months]) and are similar to survival times reported for dogs with invasive cervical thyroid tumors treated with external beam radiation therapy.^4–6,20

Our data indicated that prolonged survival times may be achieved with ¹³¹I therapy regardless of ultimate tumor regression because survival times for dogs in which residual tumor was surgically removed following ¹³¹I therapy were not significantly different from survival times for dogs that underwent ¹³¹I therapy alone. In dogs with thyroid tumors that undergo external beam radiation therapy, regression of the tumor may be prolonged, with maximum tumor regression occurring in some dogs > 1 year after radiation therapy.⁶ The reason for this delayed response following radiation therapy is not known, but histologic examination of tumors resected from dogs in the present study following ¹³¹I therapy revealed evidence of radiation-induced hemorrhage and necrosis. Collectively, these data support the suggestion that radiation therapy, regardless of the technique, results in prolonged control of thyroid neoplasia in dogs.

Traditionally, dogs with a possible thyroid mass have undergone surgical resection before thyroid gland imaging was performed and prior to administration of other treatments.^1,2 However, there are many risks associated with surgical excision of thyroid tumors, including the potential for tumor dissemination; damage to the innervation of the esophagus, larynx, and pharynx; and severe hemorrhage.

In humans, resection is typically the first treatment for thyroid masses, but thyroid tumors in humans are often smaller and less invasive than thyroid tumors in dogs, and surgery often results in complete tumor excision with few complications.^21,22 In contrast, thyroid tumors in dogs are often not identified until they are large enough to be palpated or cause clinical signs. Routine, thorough palpation of the cervical region in dogs could facilitate earlier detection of thyroid tumors.

Complete diagnostic testing is important for selection of an appropriate treatment regimen for dogs with thyroid carcinomas. In general, dogs with palpable masses in the ventral cervical region should undergo nuclear imaging to assist in diagnosis of thyroid neoplasia and selection of an appropriate therapeutic regimen. The only exception would be dogs with small, movable thyroid masses. Unfortunately, thyroid scintigraphy may not always be available or feasible because of cost.

Measurement of serum T₄ concentration should also be a routine part of the diagnostic testing for dogs suspected to have a thyroid tumor. Conventional opinion has been that ¹³¹I therapy is indicated only for dogs with high T₄ concentrations.^7,12,23 However, in the present study, ¹³¹I therapy was effective in euthyroid and hypothyroid dogs and we did not detect a significant association between survival time and pretreatment serum T₄ concentration. Thyroid scintigraphy in euthyroid and hypothyroid dogs was repeated after 3 weeks on a diet low in iodine to improve the uptake of sodium pertechnetate and is an additional consideration in the evaluation of dogs with possible thyroid tumors. High serum T₄ concentrations have been reported to occur in approximately 10% to 25% of dogs with thyroid carcinomas,^2,24–26 although 21 of the 39 (54%) dogs in the present study had high serum T₄ concentrations at the time of initial examination. The high proportion of dogs in the present study with high serum T₄ concentrations likely reflected the fact that dogs with high concentrations were more likely to be referred for ¹³¹I therapy because of a belief that such therapy is more likely to be successful in dogs with thyrotoxicosis. Our findings, however, indicate that ¹³¹I therapy should not be limited to dogs with high serum T₄ concentrations.

In humans with thyroid carcinoma, serum T₄ concentrations are used to determine the dose of sodium iodide I 131 to be administered.²⁷ In particular, the dose of sodium iodide may be reduced by 20% to 60% in patients with high serum T₄ concentrations because of the increased risk of toxicosis associated with circulating ¹³¹I-labeled thyroid hormone, which may persist for 2 to 5 days after sodium iodide administration.²⁷ Patients with low serum T₄ concentrations eliminate ¹³¹I more rapidly and, thus, may tolerate a higher dose.²⁷

Radioiodine targets thyroid tumor tissue as well as normal thyroid tissue. Generally, it is associated with minimal adverse effects. However, 3 of the 39 (8%) dogs in the present study died of radioiodine-associated myelosuppression. All 3 of these dogs developed myelosuppression within the first 3 months after sodium iodide treatment. Therefore, monitoring is recommended at least during this period. Transient bone marrow suppression secondary to sodium iodide treatment has been reported previously in a dog⁷ and is a well-known potential adverse effect of high-dose systemic radioiodine administration (> 0.67 GBq/kg [18 mCi/kg]) in humans.^15,28 The dose of sodium iodide I 131 in the present study was broad, and all 3 dogs that developed myelosuppression received doses higher than the median dose. Other dogs, however, that received similar or higher doses did not develop severe myelosuppression.

None of the 3 dogs in the present study that developed myelosuppression had high serum T₄ concentrations prior to undergoing ¹³¹I therapy. In humans, it has been observed that high thyroid hormone concentrations have been associated with a higher risk of toxicosis.²⁷ We were not able to identify any specific reason for the severe myelosuppression in the 3 dogs described in the present report and believe that this adverse effect relates to the complexity of sodium iodide dosimetry and individual susceptibility to bone marrow toxicosis. In comparison, cats with thyroid carcinoma are treated with doses of sodium iodide I 131 ranging from 1.1 to 1.5 GBq (30 to 40 mCi), which represents a dose range of approximately 0.19 to 0.37 GBq/kg (5 to 10 mCi/kg) on a body weight basis, without any reported bone marrow toxicosis.^17,29 Radiation sensitivity of the bone marrow in dogs is apparently closer to that of humans than cats or rodents.³⁰ Thus, we recommend that the maximum dose of sodium iodide I 131 used in dogs should be 0.19 GBq/kg (5.0 mCi/kg). Additional doses of sodium iodide may be administered if necessary, although more study is required to determine appropriate fractionation of ¹³¹I therapy.

Iodine 131 therapy is useful for any thyroid tumor tissue that can accumulate organic iodine. Thus, it is appropriate not only for management of ventral cervical masses, but also for treatment of ectopic thyroid tumors and metastatic lesions.^7,8,14,15,31 In the present study, we did not find any significant difference in survival time between dogs with solitary cervical masses and dogs with solitary sublingual and cranial mediastinal masses. In addition, several dogs with disseminated tumors had prolonged survival times (range, 120 to 432 days), suggesting that metastatic masses responded to ¹³¹I therapy.

The sodium iodide I 131 dosing strategy that provides the best chance for disease control in dogs with thyroid tumors has yet to be determined. A previous report⁹ described a mathematical model for calculation of sodium iodide dose, but this model requires administration of a tracer dose of ¹³¹I and calculation of the biological and effective half-life of ¹³¹I in individual dogs. Sodium pertechnetate is typically used for thyroid scintigraphy because it is inexpensive, safe, and convenient to use and because it can accurately reveal thyroid gland anatomy and degree of invasiveness of thyroid tumors.^7,26,32–36 Unlike ¹³¹I, however, sodium pertechnetate is not organified by thyroid tissue, and the kinetics of sodium pertechnetate uptake in the thyroid gland and the biological and physical halflives of sodium pertechnetate differ substantially from values for ¹³¹I.^34,37,38 Therefore, uptake of sodium pertechnetate may not accurately reflect uptake or organification of ¹³¹I.^{8,26,32,34,37,38} Additionally, pretreatment imaging with ¹³¹I may reveal metastatic lesions not identified with sodium pertechnetate imaging. Nevertheless, sodium pertechnetate imaging is still considered valuable as a diagnostic test for thyroid tumors.^39,40

Dogs with thyroid tumors that do not accumulate sodium pertechnetate are not considered eligible for ¹³¹I therapy,³⁰ but the extent to which sodium pertechnetate accumulation predicts the ability of a tumor to accumulate and trap a therapeutic dose of ¹³¹I is not currently^{8,9,26,34,38,41} In a previous study,⁶ 3 of 25 dogs with thyroid tumors that had abnormal sodium pertechnetate uptake did not accumulate tracer ¹³¹I. Nevertheless, until more information is available, we believe that ¹³¹I therapy may be considered for most dogs that accumulate sodium pertechnetate in an abnormal pattern.

In summary, results of the present study suggest that ¹³¹I therapy may be beneficial in dogs with thyroid tumors, even if they do not have high serum T₄ concentrations, and the prolonged survival times we observed provide justification for further refinement of this therapeutic option. Important issues that must be resolved include the best method for selecting patients likely to benefit from ¹³¹I therapy, optimal dosimetry, and appropriate follow-up protocols. The advantages of ¹³¹I therapy in dogs with inoperable or metastatic thyroid tumors and the ability to administer multiple doses of radioiodine in dogs with only a partial response make this treatment modality particularly attractive. Obvious limitations of ¹³¹I therapy include the potential for systemic toxicosis, the requirement that dogs be hospitalized after treatment until exposure rates are sufficiently low, the limited availability of facilities capable of handling ¹³¹I-contaminated waste products from treated dogs, and the public health considerations of radiation exposure of personnel.