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Use of Radioactive Iodine in Patients with Papillary and Follicular Thyroid Cancer: Towards A Selective Approach

Institut Gustave-Roussy 94805 Villejuif Cedex, France Ian D. Hay Mayo Clinic Rochester, Minnesota 55905

	Introduction

Top Introduction Radioactive iodine ablation Does RAI ablation decrease... Is Tg measurement and... Is post-ablation 131I-TBS... Conclusion Is follow-up diagnostic... Is 131I therapy for... References

 
Radioactive iodine (RAI) plays a major diagnostic and therapeutic role in the management of patients with follicular cell-derived thyroid cancer. It is used post-operatively to ablate normal thyroid remnants, during follow-up for whole body scanning and in patients with recurrent disease for treatment. RAI should, however, be used selectively in these three situations.

	Radioactive iodine ablation

Top Introduction Radioactive iodine ablation Does RAI ablation decrease... Is Tg measurement and... Is post-ablation 131I-TBS... Conclusion Is follow-up diagnostic... Is 131I therapy for... References

 
RAI ablation of thyroid remnants has been defined as "the destruction of residual macroscopically normal thyroid tissue following surgical thyroidectomy" (1). In theory, it is beneficial in three contexts:

1. By eradicating microscopic residual postoperative tumor foci, RAI may decrease the recurrence and mortality rates.
   
2. By ablating residual macroscopically normal thyroid tissue, RAI facilitates the early detection of recurrences by serum thyroglobulin (Tg) measurement and ¹³¹I total body scan (¹³¹I-TBS).
   
3. By administering a high dose of ¹³¹I, it permits a highly sensitive TBS to be performed 4–7 days after the dose, which may uncover previously undetected foci of uptake outside the thyroid bed.
   

Each of these theoretical benefits should be carefully examined.

	Does RAI ablation decrease the recurrence and death rates?

Top Introduction Radioactive iodine ablation Does RAI ablation decrease... Is Tg measurement and... Is post-ablation 131I-TBS... Conclusion Is follow-up diagnostic... Is 131I therapy for... References

 
The available data demonstrating apparently beneficial effects of RAI ablation in terms of recurrence and mortality rates are not particularly convincing (2).

RAI ablation is clearly not beneficial to patients with small intrathyroid tumors (<1–1.5 cm) (3, 4) and does not influence recurrence rates in patients with node-positive papillary thyroid microcarcinoma (5).

In patients with larger tumors (1.5 cm) and multifocality, tumor extension beyond the thyroid capsule or lymph node metastases, the beneficial effects of RAI continue to be debated (2, 3, 4, 5, 6, 7, 8, 9, 10). Mazzaferri’s studies showed in patients with a primary tumor at least 1.5 cm in diameter that the recurrence rate at 30 yr was 16% in his 138 RAI-treated patients, significantly less than the 38% rate observed in the 802 patients treated with T₄ alone. Even more remarkable were the reported mortality rates: no cancer-related death was observed in RAI-treated patients, significantly less than the 8% rate seen after 30 yr in the patients who did not receive such treatment (4). However, these favorable results were not confirmed in an analysis performed in an identical fashion on a series of 1542 patients with similar disease stages treated at the Mayo Clinic (2). At 30 yr, recurrence rates were comparable in the RAI group (16.6%) and in the no-RAI group (19.1%) (P = 0.89); the death rates, which were respectively 5.9% and 7.8%, were also similar (P = 0.43). Differences between these series may be related to the extent and completeness of surgical excision. This is suggested by the considerably lower 30-yr recurrence rate in the no-RAI group at the Mayo Clinic than those reported by other institutions. Other data support this conclusion. In patients with microscopic residual papillary or follicular carcinoma treated in 13 Canadian hospitals, local disease was controlled significantly more often, and survival at 20 years was better in patients treated postoperatively with either RAI ablation or external radiotherapy or both together than those treated with thyroid hormone alone (P < 0.001). In contrast, RAI ablation in patients without obvious residual disease did not significantly increase survival (9). Earlier studies at the Institut Gustave-Roussy (Villejuif, France) had led to the same conclusion (10).

	Is Tg measurement and 131I-TBS improved after RAI ablation?

Top Introduction Radioactive iodine ablation Does RAI ablation decrease... Is Tg measurement and... Is post-ablation 131I-TBS... Conclusion Is follow-up diagnostic... Is 131I therapy for... References

 
In patients with nonablated normal thyroid remnants, either normal or neoplastic thyroid tissue may be responsible for Tg production. After total thyroid ablation by surgery and RAI, however, any detectable Tg level should signify the presence of neoplastic disease. Therefore, a potential advantage of RAI ablation is that Tg measurement may be rendered more specific for the detection of persistent or recurrent disease. However, experience has shown that, during the long-term follow-up in patients after total thyroidectomy, in whom thyroid uptake is low (<2%), the Tg level is undetectable in 93% during LT₄ treatment and in 80% after withdrawal of thyroid hormone therapy (11). Tg measurement can thus be used accurately to follow DTC patients treated by (near) total thyroidectomy, even if not RAI ablated. This also means in low-risk patients, that RAI ablation may simply be indicated in those with a detectable Tg level on T₄ treatment, some months after surgery. Of note, the Tg level remains detectable for some weeks after surgery in some patients, and then becomes undetectable.

On the other hand, ¹³¹I-TBS is more sensitive after RAI ablation of normal thyroid remnants, because thyroid remnants with a high uptake may preclude the visualization of neoplastic foci in which the uptake is lower.

	Is post-ablation 131I-TBS worthwhile?

Top Introduction Radioactive iodine ablation Does RAI ablation decrease... Is Tg measurement and... Is post-ablation 131I-TBS... Conclusion Is follow-up diagnostic... Is 131I therapy for... References

 
A number of studies have shown that the sensitivity of ¹³¹I-TBS for detecting thyroid cancer is improved when the amount of radioactivity is increased.

As compared to diagnostic ¹³¹I-TBS, post-therapy ¹³¹I scans may detect new lesions in up to 50% of patients, with a significant proportion of the newly found lesions being distant metastases (12). During follow-up, in 80% of DTC patients with a detectable Tg level but no other evidence of disease, including a negative ¹³¹I-TBS with a 2–5 mCi dose, a TBS performed with 100 mCi revealed neoplastic uptake in the neck or at distant sites (13, 14, 15).

These data clearly show that a TBS should be performed whenever a large amount of ¹³¹I is administered. Post-ablation ¹³¹I-TBS may reveal useful information, provided an adequate apparatus is used: it can demonstrate the completeness of surgical excision and may show foci of uptake outside the thyroid bed, in lymph node areas, or at distant sites. These findings may prompt further treatment and could have an impact on the ultimate outcome. Of interest, in high risk-patients after (near) total thyroidectomy, post-ablation ¹³¹I-TBS results were closely related to Tg levels on the day of ¹³¹I administration (16).

	Conclusion

Top Introduction Radioactive iodine ablation Does RAI ablation decrease... Is Tg measurement and... Is post-ablation 131I-TBS... Conclusion Is follow-up diagnostic... Is 131I therapy for... References

 
Despite reassuring data on long-term side effects, the persistent uncertainties regarding its effectiveness should dictate a selective use of adjuvant RAI. In fact, the cost and the inconvenience to the patient may be significant enough to outweigh its potential benefits (17, 18, 19, 20, 21, 22, 23).

In patients with a thyroid carcinoma of less than 1.0 to 1.5 cm in diameter, who represent one fifth to one third of all thyroid cancer patients, the prognosis is so favorable after surgery alone that other therapeutic procedures appear superfluous. Routine RAI ablation is clearly not indicated.

In patients with primary tumors exceeding 1.0–1.5 cm in diameter, the benefits of RAI ablation in terms of recurrence and survival rates are still controversial after what appears to be complete surgical excision. In low risk patients, the prognosis is so favorable after surgery alone that ¹³¹I is not indicated. RAI ablation should be restricted to patients with poor prognostic indicators for relapse or death who represent only a small minority of DTC patients. Remnant ablation permits a highly sensitive ¹³¹I-TBS to be performed, and relapses are readily detected at an earlier stage during follow-up.

At present, the benefits of RAI ablation in terms of recurrence and survival can only be demonstrated in patients with known or suspected residual neoplastic disease. These patients are selected for RAI ablation on the basis of well-established prognostic indicators that take into account both the initial extent of the disease and the surgeon’s and pathologist’s reports. With time, the number of these patients will decrease, as lesions are diagnosed earlier and as surgeons become more experienced with this type of procedure. If not given post-operatively, ¹³¹I ablation therapy may be given some months later, in those with persistent elevated Tg levels.

	Is follow-up diagnostic radioiodine scanning worthwhile?

Top Introduction Radioactive iodine ablation Does RAI ablation decrease... Is Tg measurement and... Is post-ablation 131I-TBS... Conclusion Is follow-up diagnostic... Is 131I therapy for... References

 
Diagnostic radioiodine scans are the most commonly used imaging procedures during the follow-up of DTC patients, but the data yielded in unselected patients is low. Furthermore, patients may complain about the frequent withdrawal of thyroxine provoking morbid hypothyroidism, and the cumulative dose of radiation over many years can be significant. Recent trials have demonstrated that recombinant human TSH can stimulate uptake and Tg production similar to that obtained after withdrawal of thyroxine treatment and will probably be used routinely in the near future (24).

In many patients with papillary of follicular cancer a ¹³¹I total body scan (TBS) with 2–5 mCi is performed within a year of initial treatment, either to check the completeness of RAI ablation or to visualize the thyroid remnants in patients who have not undergone RAI ablation. Furthermore, with the withdrawal of thyroxine, serum thyroglobulin (Tg) can be measured under the most sensitive conditions. However, the necessity for ¹³¹I-TBS in such circumstances is not established for at least two reasons: first, almost all patients who have undergone (near) total thyroidectomy are totally ablated; second, a ¹³¹I-TBS performed with 2–5 mCi has a much lower sensitivity for the detection of disease than that performed after ablation, with a much larger dose. In fact, in 200 patients followed at Institut Gustave-Roussy, from 1994 to 1996, such a TBS did not detect any unknown disease.

Subsequent follow-up should be based on patient and tumor-related risk factors, the clinical examination, ultrasonography of the neck, and the serum Tg level measured both while on T₄ treatment and after its withdrawal. There is an excellent correlation between the serum Tg level and the clinical status of patients without interfering auto-antibodies. However, it should be recognized that serum Tg is undetectable during T₄ treatment in about 20% of patients with isolated lymph node metastases in the neck, in about 5% of patients with lung metastases not visible on standard chest X-rays, and in less than 1% of patients with large distant metastases. Tg will increase to a high level in the majority of these patients, following T₄ withdrawal (11, 25). This has prompted several authors to advocate periodic T₄ withdrawal with Tg measurement and eventually a diagnostic ¹³¹I-TBS. In reality, these patient categories are not frequently encountered: recurrent lymph node metastases occur in 10–15% of patients with papillary thyroid carcinoma and are frequently detected by clinical or ultrasonographic examination of the neck, while distant metastases occur during follow-up in less than 5–10% of patients. Most patients at risk of developing a relapse can be identified at the time of initial treatment simply by using prognostic factors and scoring systems (2, 25). Finally, most patients likely to relapse already have a detectable Tg level off T₄ treatment at the time of the first diagnostic ¹³¹I-TBS.

Consequently, low-risk patients with no evidence of recurrence, and with an undetectable serum Tg level off T₄ treatment at the time of initial diagnostic ¹³¹I-TBS, do not require any imaging procedure during subsequent follow-up. At Institut Gustave-Roussy, none of these patients developed a clinical recurrence with a follow-up of 20 years.

By contrast, high-risk patients with clinical or biochemical parameters suggestive of recurrence may require multiple imaging procedures, starting with a ¹³¹I-TBS. As the sensitivity of ¹³¹I-TBS is higher with a high amount of ¹³¹I, consideration should be given to administration of a high dose of ¹³¹I (100 mCi) in those patients with a Tg level either detectable during T₄ treatment or above 10 ng/mL following T₄ withdrawal. In these patients in whom the likelihood of recurrent disease is high, diagnostic ¹³¹I-TBS should be discouraged as it will not preclude the subsequent administration of a high dose of ¹³¹I and may stun the ¹³¹I uptake by any thyroid tissue (26). If the high dose TBS is negative, it should not be repeated within a short interval of time.

In the near future, the availability of recombinant human TSH will allow the omission of T₄ withdrawal during follow-up, while permitting the measurement of serum Tg in sensitive conditions (24). Also, this will allow selection of those patients with a detectable Tg level, who may benefit from ¹³¹I-TBS.

	Is 131I therapy for recurrent disease worthwhile?

Top Introduction Radioactive iodine ablation Does RAI ablation decrease... Is Tg measurement and... Is post-ablation 131I-TBS... Conclusion Is follow-up diagnostic... Is 131I therapy for... References

 
In these patients, high doses of ¹³¹I are used both for the work-up (¹³¹I-TBS) and for treatment. The efficacy of ¹³¹I treatment depends upon the radiation dose delivered to the neoplastic foci, which is related to the ratio between ¹³¹I uptake and the mass of the neoplastic foci (1). Experience has shown that small neoplastic foci respond better to ¹³¹I than larger ones (27).

In most patients with small, nonpalpable neck recurrences, repeated ¹³¹I treatments have led to complete remission, and only 16% of those patients underwent surgery for persistent uptake (28). However, recurrences that are either easily palpable or seen at ultrasonography, are best treated by a combination of ¹³¹I and surgery. The following protocol is applied at the Institut Gustave-Roussy: 4–7 days after a large dose of ¹³¹I (100 mCi), a highly sensitive TBS is performed; then surgery is undertaken. Its extent is guided by the TBS and with the help of an intraoperative probe; a post-surgical TBS, performed using residual ¹³¹I activity, will then control for the completeness of surgical excision. This has led to cure in 92% of these patients (29).

¹³¹I therapy can achieve a complete remission in a third of patients with distant metastases. ¹³¹I therapy is given after T₄ withdrawal every 3–6 months until the complete disappearance of ¹³¹I uptake on post-therapy ¹³¹I-TBS. Diagnostic ¹³¹I scanning is of limited utility before planned therapy and, moreover, may stun the ¹³¹I uptake by the neoplastic foci. Standard treatment doses range between 100 and 200 mCi. Significant prognostic indicators for complete remission include a young patient age, positive ¹³¹I uptake, and small metastases. In patients with lung metastases, a complete remission was observed in 83% of lesions that were not visible on chest X-rays, in 53% of micronodular (<1 cm) and in only 14% of macronodular (>1 cm) metastases (27). Bone metastases are usually large when discovered, and only a few responses have been obtained after ¹³¹I treatment.

In patients without ¹³¹I uptake on the first high-dose ¹³¹I-TBS, further ¹³¹I treatments are pointless.

In conclusion, ¹³¹I therapy is mostly effective in patients with small foci of recurrent disease. This underlines the prognostic significance of early detection, which is facilitated by an appropriate initial treatment and follow-up strategy, mainly based on knowledge of initial prognostic factors and periodic serum Tg measurement.

	Footnotes

 
Address all correspondence regarding these controversies and requests for reprints to: Dr. Leonard Wartofsky, M.D., Chairman, Department of Medicine, Washington Hospital Center, 110 Irving Street, N.W., Washington, DC 20010-2975.

Accepted June 8, 1998.

	References

Top Introduction Radioactive iodine ablation Does RAI ablation decrease... Is Tg measurement and... Is post-ablation 131I-TBS... Conclusion Is follow-up diagnostic... Is 131I therapy for... References

 

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