Follow-up diagnostic whole body scans after ablation of remnant

All the earlier mentioned parameters are taken into consideration. The dose of ¹³¹I used is 3-5 mCi. (111-185 MBq). This amount of activity is administered in order to have detectable counts in the smaller foci of metastases.

Radioiodine therapy following surgery of primary thyroid cancer

Radioiodine therapy of well-differentiated thyroid cancer involves the administration of large quantities of the radionuclide needed to destroy the cancer. As a result, radiation induced sequelae may manifest and hence, radioiodine therapy should be given after careful consideration and when there is a reasonable hope that it will benefit the patient. ¹³¹I therapy for thyroid cancer has frequently been divided into radioiodine ‘ablation’ and radioiodine

‘treatment’ [11.27]. The term ‘ablation’ indicates administration of radioiodine to destroy the normal remnant thyroid tissue which is left behind either inadvertently or deliberately by the surgeon in an attempt to prevent any damage to the parathyroid glands, recurrent laryngeal nerves and other structures in the neck during the surgery [11.28].

The term radioiodine ‘treatment’ is often used to indicate treatment given to residual thyroid cancer in the thyroid bed as well as the treatment of recurrent disease in the thyroid bed and functioning metastases.

While there is no controversy regarding the treatment of metastatic disease or recurrent thyroid cancer in the thyroid bed with radioiodine, the problem arises in the treatment of the residual thyroid tissue remaining in the thyroid bed post-surgery [11.29-11.30]. The difficult question is to identify the presence of microscopic cancer cells which may be present among the normal thyroid cells. Herein lies the constant debate which has not yet been resolved.

Advocates for radioiodine treatment consider the following conditions:

• Residual thyroid cancer is present or likely to be present in the remnant thyroid tissue after surgery. This is based on the incidence of multicentricity or multifocality of thyroid cancers which is generally quite high and there is always a possibility of a focus

of cancer being present in the remnant thyroid after surgery. If there is pathological evidence of extra-thyroidal extension or capsular penetration of primary cancer then it would be prudent to consider the remnant to have residual thyroid cancer.

• Inadequate surgery has been performed, and the surgeon informs that thyroid tissue has been deliberately left behind.

• The residual thyroid cancer or normal tissue concentrates radioiodine

• The treatment with radioiodine will deliver an effective radiation dose to the cancer or thyroid tissue without risk of major complications.

• In the presence of normal residual thyroid tissue, the detection of distant metastases is difficult and often missed. This is because the radioiodine uptake function of normal tissue is greater than the metastatic tissue and diagnostic radioiodine doses are mopped up by the normally functioning residual tissues.

Uncertainty often arises in the interpretation of post-operative thyroid scans done with diagnostic doses of ¹³¹I, 4-6 weeks after thyroid surgery, especially when the uptake is in or near the thyroid bed. After total thyroidectomy it is presumed that the uptake visualised in the thyroid bed is due to residual thyroid tissue. In the midline, the uptake is due to residual pyramidal lobe and/or thyroid cells in the distal thyroglossal duct and that immediately above the upper poles is due to residual tissue of the extension of the upper pole. As long as there is no pathological evidence of extracapsular or extra-thyroidal extension of the thyroid cancer seen on histology, these areas of radioiodine uptake can be presumed to be normal tissue.

However, if there is evidence of extracapsular or extra-thyroidal extension and there is uptake in that portion of the thyroid bed, then it can be presumed that this could have residual thyroid cancer and should be treated for the same. The presence of residual thyroid cancer is more obvious when there is an incomplete surgery for removal of the primary cancer in biopsy proven inoperable cancers and in recurrent invasive cancer in thyroid bed.

Ablation of residual normal thyroid

The ablation of residual normal thyroid tissue although a widely practiced procedure remains controversial [11.31, 11.32]. It is because no randomized control trial is yet published in this field and there are many difficulties to realize this goal also in near future [11.33]. The proponents for the use of ¹³¹I have shown evidence to suggest that ¹³¹I destroys residual tissue and microscopic thyroid cancer which is difficult to detect clinically. Secondly, its use greatly simplifies the follow-up evaluation for secondaries especially using serum thyroglobulin as a tumour marker. In the presence of large remnant thyroid tissue, secondaries may remain undetected for long periods of time.

Papillary carcinoma of the thyroid tends to be bilateral, microscopically multicentric, metastasises to regional lymph nodes and has a higher incidence of persistent or recurrent disease. Both papillary and follicular cancers have a tendency to be invasive and locally infiltrate and this leads to a high probability for recurrence. This feature of invasiveness is often missed on histology if not looked for carefully. All these features argue for ablation of residual thyroid tissue. In a retrospective analysis of 1599 patients with differentiated thyroid cancer, it was observed that ¹³¹I therapy was the single most important prognostic indicator by Cox proportional hazards regression model for prolonging “disease free survival” [11.6]. ¹³¹I improved the outcome of high risk and low risk patients in this study. The incidence of recurrence was reduced by 50% in the low risk given ¹³¹I for ablation of residual tissue. Even the incidence of pulmonary metastases was reduced by more than 50% when subtotal thyroidectomy was supplemented by ¹³¹I treatment. Another large study of 1578 patients

reported from 13 Canadian hospitals where ¹³¹I or external irradiation was employed for ablation of residual thyroid tissue, local disease in those with residual microscopic papillary cancer was controlled in 82-90% of patients as compared to 26% of those on T4 suppression alone [11.24]. Similarly survival at 20 years was 90% in patients treated with ¹³¹I or external irradiation while it was 40% when only surgery was performed. Strong support for use of extensive initial surgery and post-operative ¹³¹I in papillary carcinoma with a tumour size more than 1 cm, showed a decreased risk of recurrence and death.

Another supportive study showed that, patients given ¹³¹I to ablate normal residual thyroid tissue in low, intermediate and high risk groups, the incidence of recurrences was lesser in treated group as compared to those with only post-operative thyroid hormone therapy [11.5]

especially when the tumour size was more than 1.5 cm. Radioiodine ablation prolongs life expectancy of patients who were apparently disease free after surgical treatment for thyroid cancer [11.32]. It was estimated that even the modest increase in the life expectancy shown was comparable to the absolute gain obtained by accepted medical interventions like screening mammography and lowering cholesterol levels in the blood.

In a 25 year prospective study, no patient died of cancer when complete ¹³¹I tumour ablation was achieved, whereas 70% died with incomplete ablation. Nevertheless, there are reservations expressed by some physicians who have shown no benefit arising from treatment with ¹³¹I of low risk group patients [11.35, 11.36]. Tumour recurrence, especially papillary cancer recurrence in regional lymph nodes is not associated with a fatal outcome. However, one should take local recurrence as a warning for adverse outcome which may precede or accompany distant metastases. A report in an International symposium in which 160 surgeons, endocrinologists, pathologists and nuclear medicine physicians participated, suggested a total thyroidectomy with post-operative thyroid remnant ablation, for most differentiated thyroid cancer regardless of patients age. Hemithyroidectomy was recommended for papillary cancer confined to one lobe or with ipsilateral nodes and follicular cancer confined to one lobe with minimal tumour capsular invasion. In another study of internationally recognized experts, total thyroidectomy was advised by 60% for papillary and 74% for follicular. Radioiodine for thyroid remnant ablation was recommended by 81% of respondents for papillary carcinoma and by 97% for follicular cancer [11.30]. In a recent meta-analysis of published literature on remnant ablation, Sawka, et al. [11.37] concluded that those who underwent remnant ablation, the evidence did support the reduction of relative risk of local and distant metastases.

Methods of ablation of residual/remnant thyroid tissue

The ablation of residual thyroid tissue can be achieved in three ways viz. with Low dose of

131I, High dose of ¹³¹I and calculated dose of ¹³¹I.

High dose ablation

The first approach is the administration of high radioiodine doses varying from 2980-5550 MBq (80-150 mCi) ¹³¹I as an inpatient therapy. The proponents of high dose ablation suggest that higher doses may actually be considered as a ¹³¹I adjuvant radiotherapy for occult metastases not detected on diagnostic ¹³¹I imaging studies [11.38-11.40]. The studies show that, 87% of patients with residual thyroid bed tissue can achieve total ablation with 3700-7400 MBq (100-200 mCi) and no significant increase was observed by giving higher doses. It was also suggested that, with low dose therapy where ablation rate is not as high, multiple small doses require multiple periods of hypothyroidism which is an inefficient, costly

approach that requires significant time investment on the patients’ part. In fact, evidence suggests that sublethal radiation doses to the thyroid cells may decrease the biological half-life of subsequent radioiodine doses, thereby decreasing the effectiveness of therapy. The doses of radioiodine needed for ablation of normal thyroid tissue with high radioiodine uptakes are generally higher and these are more difficult to ablate.

The usual practice in treating thyroid cancer is to give a standard amount of ¹³¹I to all patients.

Most centres give between 100-200 mCi (3.7-7.4 GBq) and the doses of up to 7.4 GBq (200 mCi) are generally without serious complications [11.41]. A common variation is to adjust the amount of radioiodine based on the location of the cancer; 3.7 GBq (100 mCi) is given for presumed residual tissue in the thyroid bed, 5550-6475 MBq (150-175 mCi) give for lymph node metastases, 6475-7400 MBq (175-200 mCi) for lung metastases and 7.4 GBq (200 mCi) for bone metastases.

Low dose ablation therapy

McCowan, et al. [11.42] in 1976, reported that doses of 2960-3700 MBq (80-100 mCi) were not more effective than 1100 MBq (30 mCi). Subsequently, other retrospective studies, confirmed similar finding [11.42]. In addition, prospective studies reported by Creutzig [11.44], Johansen, et al. [11.45], Leung, et al. [11.46] and Bal, et al. [11.47] have also shown that ablation with low dose ¹³¹I is as effective as high dose in achieving successful ablation with a single dose. An overall analysis of Radiation Medicine Centre experience in treating 579 residual thyroid tissue (Table 11.1) with radioiodine therapy 95.5% (553/579) of patient’s residual thyroid can be easily ablated within two therapy sessions and only rarely does one come across patients who show radioresistance and require several dose schedules.

TABLE 11.1. RESPONSE OF RESIDUAL THYROID TISSUE TO ¹³¹I THERAPY No. of therapies

Ablation

1 2 3 4 5 Complete (n= 564) 499 (88.5%) 54 ( 9.6%) 5 ( 0.9%) 4 ( 0.7%) 2 (0.3%)

Partial (n= 6) --- 5 (83.3%) --- 1 (16.7%) ---

None (n= 9) 5 (55.6%) 1 (11.1%) 1 (11.1%) 2 (22.2%) --- The philosophy of large dose ¹³¹I ablation for remnant thyroid tissue is based on a contentious issue of “large dose not only ablates remnant thyroid but also ablates possible micrometastatic deposits”. The proponents of initial high dose ¹³¹I ablation argue that low doses are less effective for ablation of the micrometastases that are not visualized in post-therapy whole body scan, which at later date may result in higher local as well as distal recurrence rate. In a recent study, Mazzaferri and Jhiang [11.5] have reported no difference in long term tumour recurrence rate (7% versus 9%) between low dose 1073-1850 MBq (29-50 mCi) and high dose 1887-7400 MBq (51-200 mCi) ¹³¹I remnant ablation groups.

Calculated dose ablation

The third approach is that of ablation based on radiation dose delivered rather than empirical administration of a fixed amount or varying amounts of radioiodine. This approach advocates individualized treatment so that each patient receives a maximum ‘safe’ dose of less than

200 rads to the blood and 4440 MBq (120 mCi) of ¹³¹I retained at 48 hours after treatment.

Average doses of 11433 MBq (309 mCi) 2775-24383 MBq (75-659 mCi) have been administered without permanent bone marrow suppression, leukaemia or pulmonary fibrosis [11.48]. The dosimetric calculations require determination of whole blood radioiodine concentration and whole body retention for 4 days after administration of tracer doses. Whole body retention may be calculated from urinary excretion or by counting the patient at a suitable distance from an uncollimated scintillation crystal. The results indicate that 3700-7400 MBq (100-200 mCi) usually eradicates uptake in iodine concentrating tissue in the thyroid bed or cervical lymph nodes. On the basis of radiation dosimetry it was estimated that a minimal dose required to ablate a normal thyroid gland is between 30-40 000 cGy and may be as high as 50 000 cGy and requires about 37 MBq (1 mCi) of ¹³¹I per estimated gram of thyroid tissue [11.49]. In this study a detailed analysis was done on the use of low dose, high dose radioiodine and the radiation dose delivered to the residual thyroid tissue in the thyroid bed [11.50].

11.3. Optimisation of radiation dose and dose rate for ablation of remnant thyroid tissue