A prospective clinical trial to assess the efficacy of radioiodine ablation as an alternative to completion thyroidectomy in patients with differentiated thyroid cancer undergoing sub-total thyroidectomy

Abstract

We conducted a prospective clinical trial to evaluate whether radioiodine ablation can be an effective alternative to completion thyroidectomy in patients undergoing sub-total thyroidectomy and if yes, the optimum activity of ¹³¹I and frequency of ablation. A total of 85 patients (F–63; M–22) with mean age of 37.9±12.3 years were recruited in this study. The pre-ablation mean 24 hour radioiodine neck uptake, effective half-life, residual thyroid tissue weight and TSH values were 13.9±8.5%, 4.5±0.9 days, 9.6±3.6 g and 11.7±6.4 µIU/ml, respectively. Thyroid tissue was completely ablated in 50 patients (58.8%, 95% CI:50–68%) after mean 1^st administered activity of 32.3±10.7 mCi of ¹³¹I and the cumulative ablation rate was 91.8% after two doses of ¹³¹I. During mean follow-up duration of 49 months no local/distant recurrence has been observed so far in this cohort. It appears that radioiodine ablation may be an attractive alternative to completion thyroidectomy and an activity as low as 35 mCi may achieve reasonable ablation.

Thyroidectomy remains the main stay of therapy for differentiated thyroid cancer. However, there is substantial controversy about the extent of thyroidectomy as there has never been a prospective randomized controlled trial comparing various operative procedures in these patients. There is general agreement however, regarding the choice of surgery in high-risk patients; it is either total or near-total thyroidectomy [1–3]. The problem arises in cases of inconclusive pre-surgical fine needle aspiration cytology (FNAC) or misinterpretation as benign lesions in the frozen section, with final histopathology turning out to be differentiated thyroid cancer. Therefore, a significant number of patients undergo sub-total thyroidectomy (STT) because of one or other reasons. Such patients may be left as such with thyroid suppression therapy, may be subjected to completion thyroidectomy or may undergo radioiodine ablation of the remaining thyroid tissue as a further management strategy [4]. Thyroid hormone suppression alone is considered a relatively weak form of adjuvant therapy [5]. The completion thyroidectomy following STT is not free from risks if operated by general surgeons not particularly trained for endocrine surgery, as both lobes of the thyroid have already been exposed and interfered with, and therefore, is associated with higher incidence of complications [6–8]. The frequently cited causes in surgical literature are the loss of anatomic planes due to florid fibrosis in post-operative period and obliteration of the land marks making identification of parathyroid glands and recurrent laryngeal nerve difficult.

There is no large study in the literature demonstrating the effectiveness of radioiodine ablation exclusively following STT. There is no guideline to recommend what should be the administered activity of ¹³¹I for this purpose and what is the frequency of ablation. We tried to examine the feasibility of ¹³¹I ablation of the large remnant thyroid tissue after STT in low risk patients of differentiated thyroid cancer (DTC) in order to offer an alternative to completion thyroidectomy, even though the ‘standard of treatment’ remains completion thyroidectomy in intermediate- and high-risk patients. Secondly, we have attempted to determine the optimum activity of ¹³¹I to be administered and frequency of ablation in this subset of patients.

Materials and methods

All India Institute of Medical Sciences, New Delhi, is a tertiary care referral teaching hospital catering services to half-a-billion people in northern and eastern India. We treat currently about 250–275 new thyroid cancer patients in a calendar year. A large number of thyroid cancer patients undergoing STT are referred to us for further management. The reasons offered for conservative surgical treatment include occult thyroid cancer, inconclusive pre-surgical FNAC, misinterpretation as benign lesions in the frozen section, some complication at the first surgery and/or patients’ refusal to undergo re-surgery. We conducted this prospective clinical trial from January 1997 to December 2002 to explore an alternative strategy in the form of radioiodine ablation of remaining thyroid tissue in such patients with approval of the Institute's ethics committee.

In all patients, the disease was confirmed to be limited to the thyroid by clinical, ultrasonological and per operative examination. As a policy at our institute, we do not start levothyroxine supplementation/suppression immediately after surgery before definitive decision is taken regarding further management. The serum samples were collected for determination of TSH level before uptake dose administration. All patients were given 5–10 µCi of ¹³¹I orally and 24 hour radioiodine neck uptake (RAIU) was calculated using a standard thyroid probe and neck phantom. Conventional post-surgical ¹³¹I whole body scans (WBS) were not done. Although, no low-iodine specific diet was recommended, patients were advised to avoid iodine rich food and drugs. In view of large amount of thyroid tissue to be ablated that may produce radiation induced thyroiditis, low activities of ¹³¹I (15–50 mCi) were administered empirically to the patients.

The calculation of the absorbed radiation dose to the thyroid gland was made using the formula described by Thomas et al. [9]: , where à (µCi-hr) is the cumulative activity; m (g) is the mass of the lesion, C₀ (µCi/g) is the fractional radionuclide concentration in the lesion, T_½eff (hr) is the effective half-time in the lesion, Δ_i (g − rad/µCi.hr) is the equilibrium dose constant, and Φ_i is the absorbed fraction. Remnant thyroid volume in each lobe was measured by high-resolution ultrasound. The length (a), breadth (b) and depth (c) were measured in centimeters. Then the volume (V) in each lobe was calculated according to the following spherical ellipsoid formula () and summed up to obtain total thyroid volume [10]. From this value, residual thyroid mass was calculated by assuming tissue density to be one. We determined the effective half-life by taking two readings after administration of uptake dose of ¹³¹I: one at 24 hours and other at 96 hours. In those whom we could not measure due to logistic reasons, we made the assumption of effective t_½ of five days as described by Snyder et al. [11].

Whole body post-therapy scans (PTS) were performed before patients were discharged from the hospital or after 48–72 hours, if patients were not admitted in the hospital, to look for any occult metastasis. The patients were then advised to take thyroid suppression therapy consisting of levothyroxine (2 µg/kg body weight) daily on an empty stomach. This was continued until 4–6 weeks prior to the diagnostic studies 6 months later. The repeat diagnostic studies consisted of 2–3 mCi ¹³¹I whole body scan, 48 hour neck uptake, TSH, thyroglobulin (Tg) and anti-Tg antibody assay. The criteria for ablation were as follows: major criterion- negative ¹³¹I whole body scan and any one of the minor criteria- 48 hour RAIU ≤ 0.2% and thyroglobulin ≤ 10 ng/ml [12]. If, after first post-therapeutic evaluation, patients did not meet the criteria for thyroid ablation, further ¹³¹I therapy was given. Repeat therapeutic ¹³¹I doses were administered until thyroid ablation was achieved, after which annual check-ups were planned. Informed consents were obtained from all adult patients or from legal guardians of minor patients, before administration of ¹³¹I.

Statistical analysis

The values were expressed as mean±standard deviation. Under univariate analysis, unpaired‘t’ test and χ² test was used to compare quantitative and qualitative parameters, respectively with the first ¹³¹I administered activity outcome (ablation/no-ablation). However, for skewed data like duration of illness, interval between surgery and therapy, non-parametric tests i.e., Mann Whitney ‘U’ statistic was applied. Paired ‘t’ test was applied in order to assess whether there is any significance difference between RAIU values obtained before and after giving ¹³¹I therapy. In addition to that χ² test for trend was applied in order to examine the existence of linear trend among ablation rates at various dosages of ¹³¹I.

Results

Ninety-five consecutive patients with sub-total thyroidectomy were referred to us during this period for possible ¹³¹I ablation of remaining thyroid tissue and further management. Four patients were lost to follow-up (they didn't come for any further evaluation after administration of the first dose of ¹³¹I) and in six patients pulmonary or skeletal metastases were revealed in post-therapy scan, thus upstaged and managed differently. These patients were excluded from the final analysis.

Demographic and radioiodine treatment profile of the remaining 85 patients is given in Table I and Table II, respectively. There were 63 females and 22 males. The mean serum TSH value at the time of pre-ablation evaluation was 11.7±6.4 µIU/ml (range 0.91–24.8). The average 24 hour RAIU at first visit was 13.9±8.5% (4.2–36%). The mean thyroid remnant mass by ultrasonography was 9.6±3.6 g (3.2–14.0). The mean effective half-life was 4.5±0.9 days ranging from 1.9 to 6.1 days. An average activity of 32.3±10.7 mCi of ¹³¹I was given to the patients as first dose. The average radiation absorbed dose to the thyroid tissue from the first dose was 220±78 Gy. Around 50% of patients, in whom remnant thyroid tissue was ablated with single dose of radioiodine, received ≤200 Gy. Thirteen patients (15.3%) complained of throat discomfort and neck pain. All of them were managed with mild analgesic and no such problem was noticed during subsequent ¹³¹I therapies.

Table I.  Demographic profile of patients.

Characteristics	Values
Total no.	85
F:M	2.9
Mean Age (years)*	37.9±12.3
range	8–65
Histopathology
PTC	65
FTC	20

*value is expressed as mean±S.D.

Table II.  Radioiodine treatment profile of all patients.

Characteristics	Values
Pre-ablation 24-h RAIU	13.9±8.5 (4.2–36)%
Residual Thyroid Mass (gram)	9.6±3.6 (3.2–14.0)
Pre-ablation serum TSH (µIU/ml)	11.7±6.4 (0.91–24.8)
Effective half-life (days)	4.5±0.9 (1.9–6.1)
1^st administered activity of ^131I (range)	32.3±10.7 (15–50) mCi
RAD after 1^st dose	220±78 (190–473) Gy
48-h RAIU at 1^st Follow-up in non-ablated patients	4.8±2.1 (0.5–9.1)%
2^nd administered activity of ^131I	43.2±19.3 mCi
	1.6±0.7 GBq
3^rd administered activity of ^131I	65.7±33.2 mCi
	2.4±1.2 GBq
Cumulative administered activity of ^131I	53.3±35.9 (15–190) mCi
	1.9±1.3 (0.56–7.0) GBq

RAIU: Radioactive iodine neck uptake; RAD: Radiation absorbed dose.

All values are expressed as mean±S.D.

In 50/85 (58.8%) patients, the thyroid tissue was ablated with the first dose of ¹³¹I. In the rest of the patients, the average 48 hour RAIU was reduced to 4.8±2.1% as compared to preablation uptake of 13.9±8.5% and it was statistically significant (p = 0.001). Out of 35 patients, whom a second dose of 43.2±19.3 mCi of ¹³¹I was administered, ablation was achieved in 28/35 (80%) patients. In rest of the patients thyroid tissue was ablated after the third dose. The cumulative activity of ¹³¹I administered to the patients was 52.3±35.7 mCi (15–190). The over all cumulative success rates after first, second and third doses of ¹³¹I were 58.8%, 91.8% and 100%, respectively (¹³¹I treatment outcome is given in Table III).

Table III.  ¹³¹I treatment outcome.

	Single dose outcome	Cumulative outcome
Success after first administered activity of ^131I	50/85 (58.8%)	50/85 (58.8%)
After second administered activity of ^131I	28/35 (80.0%)	78/85 (91.8%)
After third administered activity of ^131I	7/7 (100%)	85/85 (100%)

Interestingly, out of all independent co-variants like age, sex, histopathology, duration of illness, pre-ablation neck uptake, residual thyroid mass, serum TSH value, effective half-life, first administered activity of ¹³¹I and absorbed dose etc., univariate analysis found only ¹³¹I administered activity (p = 0.02) to be significantly associated with the 1^st dose outcome (see Table IV). However, χ² test for trend analysis of first dose outcome did not reveal any significant linear trend between ablation rate and various administered activities (χ²=2.889, p = 0.089).

Table IV.  Association of independent categorical and quantitative variables with first dose outcome (ablation/no ablation).

Variables	Ablated	Non-ablated	p-value
Sex
Male	12	10	0.636
Female	38	25
Histopathology
Papillary	38	27
Follicular	12	8	0.903
Age (years)	36.30±11.02	40.25±13.74	0.16
Duration of illness (mo)	51.92±54.78	48.16±47.40	0.78
Tumor size (cm)	5.97±3.15	5.25±2.18	0.49
Interval between surgery & ^131I treatment (mo)	5.15±8.02	8.91±15.24	0.22
Post-surgical RAIU (%)	12.89±7.82	15.42±9.17	0.19
Residual thyroid mass (gram)	8.9±2.3	10.5±3.1	0.31
Serum TSH (µIU/ml)	9.6±4.1	12.4±5.2	0.76
Effective half-life (days)	4.6±1.5	4.3±1.8	0.93
First administered activity of ^131I	35.74±14.25	30.00±10.64	0.02
RAD (Gy)	218±75	221±81	0.92

RAIU: Radioactive iodine neck uptake; RAD: Radiation absorbed dose.

All values are expressed as mean±S.D.

Further, looking at the first dose ablation rates per se at different administered activity level, it appeared that beyond 35 mCi the ablation rate became more or less stabilized. To verify this observation, we grouped all patients into two categories considering 35 mCi of ¹³¹I as cut-off level (≤35 mCi; n = 59 & > 35 mCi; n = 26), and then applied χ² test against the outcome variable namely ablation/no ablation. The mean first administered activity of ¹³¹I in first group was 26.6±6.9 mCi and in second group 48.7±10.7 mCi. We found that there was significant association between ¹³¹I activity and outcome (51% vs 77%; p = 0.03). Therefore, it seems at least 35 mCi should be administered to achieve significant ablation rate in STT patients.

Discussion

The presence of large amount of remnant thyroid tissue, which is the case after subtotal thyroidectomy, makes detection and treatment of nodal or distant metastases difficult [13], [14]. High TSH levels necessary to enhance tumor ¹³¹I uptake cannot be ordinarily achieved with a large thyroid remnant [15] and serum Thyroglobulin (Tg) measurement made under TSH stimulation, which is the most sensitive test for the detection of recurrence, is not reliable in the presence of large thyroid remnant. Thus, absence of remnant thyroid tissue facilitates subsequent follow up [16]. Some authors also argue that removal of remnant thyroid tissue may probably exclude the probability of any residual follicular cells becoming malignant over time [17] and will remove any occult multifocal cancer which may recur years later [2], [3], [8], [18–21], thereby reducing tumor recurrence and probably, mortality rate [21–25]. It is, therefore, imperative to remove the large amount of remnant thyroid tissue either by completion thyroidectomy (surgical ablation as standard of treatment) or by ¹³¹I (radioiodine ablation as an adjuvant treatment) in cases where patients had undergone subtotal thyroidectomy because of one or other reason and histopathology turned out to be differentiated thyroid cancer. As surgery was ruled out in our patients, we attempted to ablate the remaining thyroid tissue with ¹³¹I so as to a) prevent recurrence or spread (local or distant) of occult tumor (if any), b) to reveal and treat any occult metastasis, and c) last but not the least to make the follow-up more meaningful and effective.

The large amount of thyroid tissue might suppress high TSH levels necessary for tumor ¹³¹I uptake [18] and is said to be difficult to be ablated completely [26], [27]. True, in our study, we found pre-ablation serum TSH level was 11.7±6.4 µIU/ml (range 0.91–24.8) indicating a large amount of remnant thyroid tissue. However, one should not forget that the tissue we are talking about is mostly normal thyroid, not the residual tumor tissue. The iodine uptake of normal thyroid tissue in the presence of normal serum TSH is 10–250 times higher than the tumor tissue. Thus, unlike residual or metastatic tumor, it is possible to achieve ablation of normal thyroid tissue in the presence of low serum TSH. Further, it is believed that a large amount of ¹³¹I would be required to ablate this large amount of thyroid tissue. Contrary to these believes, in our study, following the mean first administered activity of only 32.3±10.7 mCi of ¹³¹I, the ablation rate was 58.8% and there was significant reduction in the RAIU in remaining patients i.e. achieving significant partial ablation. Second dose success rate was 80.0%, similar to radioiodine remnant ablation rate after near-total thyroidectomy in any series [28]; no one needed more than three doses of ¹³¹I. The mean cumulative activity administered to the patients in this study group was also low (53.3±35.9 mCi). Similarly in a small number of patients, Lin et al. [29] from Taiwan found that repeated 30 mCi ¹³¹I treatments were adequate for most thyroid remnant ablations after subtotal thyroidectomy in DTC patients, unless distant metastases were present at the time of operation. Similar to our results, they had also achieved 56% and 72% ablation rates after one and two doses of ¹³¹I, respectively, when low dose of ¹³¹I was used.

Although, it is feared that attempt to ablate large amount of thyroid tissue with ¹³¹I may produce radiation thyroiditis with serious pain and swelling, sialadenitis, odynophagia, facial and cervical edema and sometimes features of thyrotoxicosis [26], [30], [31], no such serious complication was noted in our cohort as we used lower activities of ¹³¹I. Further, use of low activity of ¹³¹I meant that most of these patients could be treated on ambulatory basis, as their total body burden was low enough to send them home with specific instructions. Few cases that required hospitalization, the period of hospital stay was only for one or two days. Maxon et al. [27] had advocated that one should aim to deliver 300 Gy to achieve remnant thyroid ablation. However, in our group, ablation was achieved in a patient receiving only 190 Gy of radiation absorbed dose, while a radiation absorbed dose of 473 Gy, couldn't achieve ablation in another patient. Around 50% of patients, in whom remnant thyroid tissue was ablated with the first dose of ¹³¹I, received ≤ 200 Gy. Radiosensitivity of thyroid tissue remains an essential factor that affects radioiodine ablation. This can be considered as the main cause of unpredictable outcome of radioablation in individual patients.

We would also like to emphasize that, in six patients pulmonary or skeletal metastases were revealed in post-therapy scans (as pulmonary metastases were x-ray negative and since patients with skeletal metastases were asymptomatic, no skeletal survey was done). Probably they had these occult/asymptomatic metastases from the time of initial presentation, even if they were otherwise considered as low risk patients. Had nothing been done to ablate their remaining thyroid tissue after the initial surgery, these metastases would have remained undetected until a later stage, when they would have manifested themselves clinically or radiologically; probably increasing overall morbidity and mortality. Also, no local or distant recurrence has been observed so far in this cohort during mean follow-up duration of 49 months (minimum 18 and maximum 90 months).

In summary, we can conclude that although completion thyroidectomy remains the standard of treatment after sub-total thyroidectomy in patients with differentiated thyroid cancer, radioiodine ablation may be simple, cheap and non-invasive alternative to surgery for those who refuse to undergo completion thyroidectomy or had complication during initial surgery and an activity as low as 35 mCi may achieve reasonable ablation.