Treatment of Recurrent and Metastatic Disease

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Recurrence in the thyroid bed or cervical lymph nodes develops in 5-20% of patients with DTC. Surgery is the dominant treatment for loco-regional recurrence and complete resection should be attempted. Selective dissection is preferable to single lymph node excision. Even if tumor cannot be completely removed, surgical debulking is beneficial and facilitates subsequent use of therapeutic radioiodine [5]. External beam radiotherapy (EBRT) can control local disease but the full potential of iodine treatment should first be exploited. Repeat doses of radioiodine may be required with each administered activity ranging from 3.7 to 10.1 GBq (100 to 270 mCi) at 3-12-month intervals. There is no maximum limit to the cumulative 131I dose that can be given to patients with persistent disease if benefit can be documented, providing that individual doses do not exceed 2Gy total body exposure and there is at least a 6-month interval between doses. A normal blood count must be confirmed prior to each administration and impairment of renal function would demand a lower dose.

The British Thyroid Association recommends withdrawal of thyroxine (T4) 4 weeks before radioiodine, or triiodothyronine (T3) 2 weeks before so that endogenous TSH levels rise to above 30mU/L, thereby optimizing iodine uptake [50]. This will induce symptomatic hypothyroidism, which may result in lethargy, cognitive impairment, or depression. Quality of life may be significantly impaired and many patients are unable to drive or work. This symptomatic period may be shortened by substitution of T3 for T4 4 weeks with discontinuation of

T3 14 days prior to admission. If patients are unable to tolerate hypothyroidism, 131I may be given following rhTSH stimulation, with continuation of thyroid hormone replacement, although it remains unlicensed for this purpose. Retention of radioiodine is reduced due to rapid clearance in the euthyroid state, whereas renal excretion is reduced when thyroid hormone withdrawal is performed [51]. This may result in higher activities of radioiodine being necessary for therapy with rhTSH[34].

A retrospective audit of Royal Marsden Hospital practice of thyroid hormone withdrawal prior to 131I administration has recently been performed as we normally discontinue T4 for only 21 days and T3 for only 10 days. Of 95 patients who stopped thyroid hormone as we advised, 80/95 (84%) had TSH levels above 30mU/L and uptake appeared to be adequate in the remainder. Based on these results our current practice remains unchanged, although a prospective study to assess the optimal period of withdrawal is required.

A whole-body scan 2-6 days after iodine administration provides scintigraphic assessment of disease and response to treatment. Diagnostic scans using a tracer dose of 131I are not required prior to therapy and may have an adverse effect by causing tumor stunning and reducing the uptake of therapeutic 131I [52]. Furthermore, in a significant proportion of patients with residual tumor as evidenced by an elevated Tg level, uptake has been documented in the posttherapy scan despite a prior negative diagnostic scan. The use of 123I as a scanning agent has been suggested to prevent stunning because of its short half-life [53]. However, it remains expensive and not widely available.

The real benefit of iodine ablation is well documented. Mazzaferri and Kloos demonstrated the beneficial effects of ablation in 1510 patients without distant metastases [11]. Radioiodine was an independent variable that favored lower local recurrence (P < 0.0005), distant recurrence (P < 0.0001) and death (P < 0.0001) in patients over 40 with tumors greater than 1.5 cm in diameter. In 1998, a Canadian study of 382 patients with DTC demonstrated total thy-roidectomy and ablation to be associated with a significantly lower rate of local relapse independent of tumor stage [12].

The benefit from 131I therapy is more difficult to quantify. Younger patients who have limited volume metastases mainly in the lungs, and who achieve a complete response to 131I, have been shown consistently to have the best prognosis, with a 15-year survival of 89% [54]. In contrast, older patients and those with large metastases or bone involvement are less likely to respond [55]. Although distant metastases may remain stable for years, there is evidence that early treatment benefits outcome. Microscopic foci are more radioresponsive; complete response was reported in 82% of patients with uptake in lung metastases not seen on chest radiography but in only 15% of those with visible micro- or macronodules [21]. The radioresistance of large deposits may be due to poor vascularity, resulting in limited and inhomogeneous iodine distribution, or to the appearance of radioresistance clones. Bone lesions are associated with a low response rate; surgical excision when possible, or external beam radiotherapy should be added [56,57]. We recommend surgical resection with curative intent for patients with a solitary deposit that does not concentrate iodine adequately [58].

Therapeutic efficacy of 131I therapy is related to the ability of tumor to concentrate and retain iodine [59]. The sodium iodide symporter (NIS) is a plasma glycoprotein that actively transports iodide into thyroid follicular cells as the first step in thyroid hormone biosynthesis. Cloning of the gene and the development of specific NIS antibodies have allowed the characterization of the pathogenic role of NIS in thyroid cancer [60]. In tumors that no longer have the capacity to concentrate iodine, reduced NIS expression has been demonstrated. Up to 80% of differentiated thyroid cancers have the ability to concentrate iodine but when tumors are non-iodine avid, despite meticulous patient preparation, further 131I should be avoided [61]. This is more commonly seen in older male patients with poorly differentiated tumors, Hurthle cell variant, and tall cell or insular subtypes [62] (Figure 15.3). Reduced ability to concentrate iodine is often associated with more aggressive growth and metastatic spread (Figure 15.4).

Retinoic acid, a derivative of vitamin A, can enhance NIS expression in vitro [63]. In cell cultures, redifferentiation of thyroid follicular cancer results in increased iodine uptake. Grunwald et al. [64] treated 12 patients with non-iodine avid tumors with retinoic acid for 2 months prior to radioiodine therapy. In two patients a significant increase in radioiodine uptake was seen, with a further three patients demonstrating faint uptake; seven patients did not benefit. Response was associated with a significant rise in Tg levels, suggesting restoration of Tg synthesis. A more recent study of 25 patients [65] administered retinoic acid (1mg/ kg) for 3 months prior to 131I therapy. Only five patients demonstrated slight increase in 131I uptake but Tg failed to correlate with either success or failure of treatment. Side effects occurred in two thirds of patients comprising sunburn, cheilitis, mucositis, conjunctivitis, and raised transaminases, although all were reversible. The Royal Marsden Hospital prospective trial results were equally disappointing. The initial promise of redifferentiation therapy has therefore not been fulfilled and is no longer recommended.

Figure 15.3 Diagnostic indium octreotide scan (posterior view): patient with non-iodine avid Hurthle cell carcinoma previously treated with total thyroidectomy. Octreotide uptake is seen in the neck, right chest, right of midline at L5 level and left pelvis. Pelvic radiotherapy was followed by 4 treatments with yttrium-90 octreotide labeled DOTATOC with good response.

Figure 15.3 Diagnostic indium octreotide scan (posterior view): patient with non-iodine avid Hurthle cell carcinoma previously treated with total thyroidectomy. Octreotide uptake is seen in the neck, right chest, right of midline at L5 level and left pelvis. Pelvic radiotherapy was followed by 4 treatments with yttrium-90 octreotide labeled DOTATOC with good response.

Figure 15.4 Stimulated 18FDG-PET scan: patient with differentiated thyroid cancer and elevated serum thyroglobulin but no demonstrable disease despite 131I whole-body scan, 111In-octreotide scan, and CT neck and chest. A stimulated 18FDG-PET following recombinant TSH demonstrated subcarinal and right hilar uptake.

Figure 15.4 Stimulated 18FDG-PET scan: patient with differentiated thyroid cancer and elevated serum thyroglobulin but no demonstrable disease despite 131I whole-body scan, 111In-octreotide scan, and CT neck and chest. A stimulated 18FDG-PET following recombinant TSH demonstrated subcarinal and right hilar uptake.

True Hurthle cell carcinoma (consisting of at least 75% Hurthle cells) is usually differentiated and expresses Tg. In our retrospective series of 50 patients, none of the 20 with recurrent or metastatic disease showed uptake at sites of known disease; alternative treatment comprising further surgery or EBRT was therefore necessary. However, because of its worse prognosis, follow-up of Hurthle carcinoma needs to be diligent and initial 131I ablation is beneficial in rendering Tg monitoring more accurate. In the more recently published series of 89 patients with Hurthle cell carcinoma from the M.D. Anderson Cancer Center [66] those who received 131I ablation had better outcomes. Of the 37 patients with known metastases, 38% showed radioiodine uptake in lymph nodes, bone, or lung.

The effectiveness of 131I therapy could theoretically be improved by increasing radioiodine uptake by tumor or altering tumor metabolism so that iodine retention is prolonged. Administration of a higher activity is the simplest approach but repeated activities greater than the empirical standard of 5.5GBq are associated with an increased risk of bone marrow suppression, leukemia, lung fibrosis (for patients with miliary metastases), and salivary gland damage; benefit remains unproven. A retrospective study of 38 patients with advanced DTC treated with 9GBq (243mCi) 131I, who had previously failed to respond to standard activities of 5.5GBq (150mCi) [67], was not advantageous. Complete response was observed in 18% (7/38), stable disease in 11% (4/38), and progressive disease in 71% (27/38). Grade 3 (9.7%) and grade 4 (3.2%) hematological toxicity was limited based on WHO criteria but significant salivary gland morbidity was identified. A persistent dry mouth was present in 30% of individuals with a further 27% complaining of salivary gland swelling and discomfort.

Metastatic tumor may persist despite administration and uptake of repeated doses of 131I. This may be the consequence of rapid turnover of radioiodine (short effective half-life) with discharge before adequate energy has been deposited. The effective half-life in metastases responding to therapy has been shown to be longer than in those not responding: 5.5 days compared with 3.2 days [68].

Lithium carbonate reduces the release rate of radioiodine from normal thyroid as well as from thyroid tumors. Its administration in doses that produce blood levels of 0.8-1.2 mmol/L prolonged the biological half-life in 10 of 12 thyroid tumors, without increasing the radiation dose received by the whole body [69]. However, lithium blood levels need to be monitored closely to avoid toxicity and psychiatric expertise is valuable such that its routine use is often impracticable in many hospitals, although a number of centers in the USA use this tactic, without psychiatric consultation, to increase tumor retention of 131I.

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