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Should We Routinely Offer a Second Admission for Radioiodine to Patients with High-risk Differentiated Thyroid Cancer?
Clinical Oncology 22 (2010) 136–139 Contents lists available at ScienceDirect
Clinical Oncology journal homepage: www.elsevier.com/locate/clon
Original Article
Should We Routinely Offer a Second Admission for Radioiodine to Patients with High-risk Differentiated Thyroid Cancer? G.E. Gerrard, L. O’Toole, F. Roberts St James Institute of Oncology, St James’s Hospital, Becket Street, Leeds LS9 7TF, UK Received 1 October 2009; received in revised form 14 December 2009; accepted 21 December 2009
Abstract Aims: To assess whether an elective second admission for radioiodine is useful for patients with high-risk differentiated thyroid cancer (DTC). Materials and methods: A retrospective analysis was carried out on 47 high-risk DTC patients treated with a second admission for radioiodine at our centre during the 2007–2008 period. Results: In 21 patients (45%), the surgeon described an incomplete resection. Twenty-six (55%) had surgical macroscopic complete resection, but cancer cells at the margin of excision histologically. Overall, at the second admission for radioiodine, 27 patients (57%) had a normal post-treatment scan and undetectable thyroid-stimulating hormone (TSH) stimulated thyroglobulin. Twenty patients (43%) had raised stimulated thyroglobulin at second admission for radioiodine, of whom only six (13%) had abnormal uptake (>0.1%) on the post-treatment scan. Conclusions: A second admission for radioiodine could have been avoided in most patients. Instead, information from stimulated thyroglobulin and a diagnostic radioiodine scan would have been sufficient to guide further management. This study also provides interesting outcome data on incompletely resected DTC. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: High-risk DTC; postoperative residual cancer; radioiodine; radiotherapy; raised thyroglobulin; thyroid cancer
Introduction It is widely believed that the first ‘ablation dose’ of radioiodine is preferentially taken up by normal thyroid cells rather than thyroid cancer cells [1]. After the normal thyroid has been ablated, then, in theory, any residual thyroid cancer cells would be destroyed by the second therapeutic radioiodine dose. A prospective audit was designed to test this assumption and to determine if highrisk differentiated thyroid cancer (DTC) patients were being over-treated with a second therapeutic radioiodine dose. Also, some high-risk patients may benefit from adjuvant postoperative external beam radiotherapy. The British Thyroid Association guidelines [2] state that radiotherapy should be considered if there is ‘gross evidence of local tumour invasion at surgery, presumed to have significant macro- or microscopic residual disease, particularly if the
Author for correspondence: G.E. Gerrard, St James Institute of Oncology, St James’s Hospital, Becket Street, Leeds LS9 7TF, UK. Tel: þ44-113-2068336; Fax: þ44-113-2067534. E-mail address: [email protected] (G.E. Gerrard).
residual tumour fails to concentrate sufficient amounts of radioiodine’. This study questions the definition of ‘failure to concentrate radioiodine’, which could mean no abnormal uptake on a post-therapy radioiodine scan (PTS). Alternatively, it could mean no abnormal uptake on a diagnostic radioiodine scan. Before this study, our patients with highrisk disease received two admissions for radioiodine followed by neck radiotherapy if there was insignificant uptake on the PTS and the TSH stimulated thyroglobulin was raised. This practice changed when the results of this study became available.
Materials and Methods Early in 2007, a protocol was written for high-risk DTC patients receiving radioiodine at the Leeds Oncology Centre. All such patients who were referred to our centre in 2007 and 2008 and treated by this protocol were audited. The protocol stated that any patient with postoperative residual cancer should be admitted for a second therapeutic radioiodine dose. Postoperative cancer was determined by discussion with the surgeon at the multidisciplinary team
0936-6555/$36.00 Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2010.01.002
G.E. Gerrard et al. / Clinical Oncology 22 (2010) 136–139
meeting, from the operation notes or histologically when the pathologist reported tumour at the excision margin. All thyroid cancer cases from the region have their pathology reviewed at the Cancer Centre in Leeds. All patients in the study had either an initial thyroidectomy or a two-stage thyroidectomy. The ablation activity was 3.7 GBq of radioiodine and the second therapeutic radioiodine dose activity was 5 GBq. Patients with known distant metastases were excluded from this study. Patients were also excluded if their post-ablation scan was normal and their stimulated thyroglobulin was undetectable at the time of ablation. There was a 6–8 month interval between the first admission for ablation and the second therapeutic radioiodine dose. Outcome measures included the amount of radioiodine uptake on post-ablation and PTS. The other outcome measure, stimulated thyroglobulin, was measured at each admission. All patients had thyroid hormone withdrawal before radioiodine to stimulate TSH, except for one patient who was aged 91 years and was prepared with recombinant TSH injections. Patients were asked to follow a low iodine diet for 2 weeks before their admission for radioiodine and for 5 weeks thereafter. The DPC Immulite assay was used to measure thyroglobulin; we expect a thyroglobulin level <1 for patients who have had a thyroidectomy and radioiodine ablation. Thyroglobulin antibodies were measured in all cases. The PTS was considered to be normal if there was <0.1% uptake present.
Results Forty-seven patients were treated according to the above protocol in 2007 and 2008. Data were collected prospectively. Thirty-one (66%) were women and 16 (34%) were men. The median age was 51 years (range 19–91). Forty-two (89%) had papillary thyroid cancer, four (9%) had Hurthle cell carcinoma and one (2%) had follicular thyroid cancer. All patients had tumours that had penetrated the thyroid capsule with cancer cells present at the margin of excision. In 21 (45%) cases, the surgeon reported that it was extremely likely that there were residual cancer cells present postoperatively either because tumour had been shaved off a structure such as the larynx or in one case the patient had refused to have a selective neck dissection and only agreed to excision of a lymph node that was extensively replaced by papillary thyroid cancer. This group will subsequently be referred to as the ‘incomplete resection’ subgroup. In 26 (55%) cases, their surgeon said that a macroscopic complete resection had been achieved, but the pathologist found cancer cells at the margin of excision. This group will
137
subsequently be referred to as ‘positive margin alone’ patients. Twenty-seven (57%) patients had a level VI neck dissection and 18 (38%) patients had either a unilateral or a bilateral selective neck dissection. There were no missing data on the desired outcome measures. No patient had more than 0.1% abnormal uptake on PTS with undetectable stimulated thyroglobulin on the day of admission for the second therapeutic radioiodine dose. All patients had a TSH > 28 mlU/l on the day of admission for radioiodine. The following subgroups are of interest (Table 1). Abnormal PTS and raised stimulated thyroglobulin: six (13%) patients had abnormal uptake (greater than 0.1% uptake) on the PTS and raised stimulated thyroglobulin at the time of the second therapeutic radioiodine dose. Interestingly, all of these patients had undergone an incomplete resection. The neck was the only site of abnormal uptake. No distant metastases were seen on any PTS. Normal PTS and raised stimulated thyroglobulin: 14 patients (30%) had a normal PTS but stimulated thyroglobulin >1 (at the time of the second therapeutic radioiodine dose). We would expect a thyroglobulin level <1 for patients who have had a thyroidectomy and radioiodine ablation. Ten of these 14 patients had an incomplete resection and four had positive margins alone. Persistent cancer was found in nine of these 14 patients to date. All nine patients had incomplete resection. Normal PTS and undetectable thyroglobulin: 27 (57%) had a normal PTS and undetectable stimulated thyroglobulin. Six patients in this group (22%) had incomplete resection and 21 (78%) had positive margins alone. Thyroglobulin antibodies: five of the 47 patients (11%) had thyroglobulin antibodies that could have invalidated the thyroglobulin levels, although there was no clinical evidence for this. Interestingly, two of the five patients with thyroglobulin antibodies had abnormal uptake on the PTS. These two patients had a raised thyroglobulin level as well as detectable thyroglobulin antibodies. The other three patients with thyroglobulin antibodies had an undetectable thyroglobulin level, a normal PTS and were in the ‘positive margin alone’ group. After several months of follow-up their thyroglobulin antibodies disappeared and their thyroglobulin level is persistently undetectable. Therefore, the DPC Immulite thyroglobulin assay may still be clinically useful even in the presence of thyroglobulin antibodies. In the incomplete resection vs the positive margin subgroups: 21 patients had an incomplete resection. Five of these (24%) had normal PTS and undetectable stimulated thyroglobulin. Six (29%) had substantial neck uptake and raised stimulated thyroglobulin. Ten (47%) had a normal PTS, but raised stimulated thyroglobulin. Radioiodine-resistant
Table 1 Findings at second radioiodine dose
Incomplete resection Positive margin alone Overall
PTS normal sTg <1
PTS normal sTg >1
PTS abnormal sTg <1
PTS abnormal sTg >1
Total
5 22 27
10 4 14
0 0 0
6 0 6
21 26 47
PTS, post-therapy scan; sTg, stimulated thyroglobulin.
138
G.E. Gerrard et al. / Clinical Oncology 22 (2010) 136–139
thyroid cancer was found in neck nodes in seven of these 10 patients and lung metastases (discovered on computed tomography) in two patients. Therefore, 16 (76%) had raised stimulated thyroglobulin (6 months after ablation) and residual cancer has been found in all except one of these patients. Incomplete resection is a good predictor of who will probably have a raised thyroglobulin level 6 months after ablation (76%) and who will probably have residual disease (15/21patients, 71%) discovered after a short follow-up period. In contrast, only four of the 26 patients (24%) in the ‘positive margin only’ subgroup had raised stimulated thyroglobulin and no site for the elevated stimulated thyroglobulin has been found on subsequent imaging. Considering Hurthle cell thyroid cancer cases: four patients had Hurthle cell cancer and one of these had abnormal uptake on PTS. This patient had further admissions for radioiodine in 2009. One of the four patients had an incomplete resection, a normal PTS, but raised stimulated thyroglobulin. A neck node was discovered on a neck ultrasound scan and resected with a fall in thyroglobulin level. The two remaining patients with Hurthle cell cancer had a positive margin only, a normal PTS and undetectable stimulated thyroglobulin. Regarding patients with cancer that had been shaved off a neck structure: in some centres, postoperative neck external beam radiotherapy is offered to patients whose cancer has been shaved off a structure such as the trachea. This is recommended by the European Association of Nuclear Medicine guidelines [3]. It is difficult for the surgeon to say if s/he is shaving through cancer or fibrosis. Eleven of the 21 patients in the incomplete resection subgroup had operation notes that documented shaving off the cancer from a neck structure. Three of these 11 patients had a normal PTS and undetectable stimulated thyroglobulin. Two of the 11 were found to have lung metastases and one patient had retropharyngeal and mediastinal nodes that took up large amounts of radioiodine. Therefore, radiotherapy to the neck seemed to be contraindicated in five of these 11 patients. However, a longer follow-up is required. Five other patients had further admissions for radioiodine because there was a significant amount of uptake in the neck. One of the 11 patients had a normal PTS but raised stimulated thyroglobulin and a site for the elevated thyroglobulin has not yet been discovered. Considering the incidence of dry mouth: The minimum follow-up time from the date of admission for ablation was 9 months. A study is now underway to investigate the incidence of dry mouth and sialadenitis 6 weeks after each admission and 1 and 2 years thereafter. Preliminary results suggest that considerably more patients have a dry mouth after a second therapeutic radioiodine dose than after the first admission for ablation.
Discussion There are no publications to help answer the question of whether a second admission for radioiodine is useful in patients with DTC that is incompletely excised. It is not
discussed in the most recent guideline/consensus documents [2–5]. The British Thyroid Association guidelines recommend a diagnostic follow-up radioiodine scan and stimulated thyroglobulin to be carried out about 6 months after the ablation dose of radioiodine. If our study group had been managed in this way, most of the patients would have avoided a second admission and the increased risk of a dry mouth. The other side-effects of radioiodine, such as sialadenitis and second malignancies, have not yet been assessed in this study, with its short follow-up, but have been described in other published studies. The 57% of patients who had undetectable 6 month stimulated thyroglobulin could subsequently have been followed up with a suppressed thyroglobulin level alone and are unlikely to need further treatment. Our experience is that patients can occasionally develop recurrence years after having undetectable stimulated thyroglobulin (heralded by a rising suppressed thyroglobulin level). It is impossible to say if micrometastases may have taken up radioiodine. If so, they were not detectable by our current biochemical or radiological tests. The 43% of patients who had raised 6 month stimulated thyroglobulin would obviously have been discovered without the need for a second therapeutic radioiodine dose, as thyroglobulin would have been measured at the same time as the follow-up diagnostic scan. It is controversial how to manage patients with raised stimulated thyroglobulin together with an abnormal follow-up diagnostic radioiodine scan (as would have been the case in six of our patients). Some oncologists would routinely admit these patients for a second therapeutic radioiodine dose. Alternatively, anatomical scans, e.g. computed tomography of the chest and ultrasound/magnetic resonance imaging of the neck, or functional scans, e.g. positron emission tomography–computed tomography, could be carried out with the aim of discovering operable disease. If neck nodes alone were discovered then excision could be attempted and if the postoperative thyroglobulin level was undetectable then a second therapeutic radioiodine dose could be withheld. However, some of our patients with neck uptake had inoperable residuum, e.g. cancer stuck to the carotid artery, and would probably have required a second therapeutic radioiodine dose after the follow-up scan showed radioiodine-avid disease in the neck. Seven of our patients with incomplete resection, a raised stimulated thyroglobulin level and a normal PTS, had neck nodes detected on ultrasound or magnetic resonance imaging neck scans. Neck dissections were carried out and all seven patients had a postoperative thyroglobulin level < one. The tumour cells in the neck failed to take up radioiodine. A second therapeutic radioiodine dose was useful to determine radioiodine resistance, but otherwise did not help in the management of these patients over and above the information that would have been obtained with a diagnostic follow-up radioiodine scan with stimulated thyroglobulin. The two patients with lung metastases would have been given an empirical dose of radioiodine if they had been discovered before the second therapeutic radioiodine dose.
G.E. Gerrard et al. / Clinical Oncology 22 (2010) 136–139
In this study, these two patients had radioiodine-resistant lung metastases on the PTS. If they had been managed according to the British Thyroid Association 2007 guidelines, they would have had a follow-up radioiodine scan and stimulated thyroglobulin. The raised thyroglobulin would have prompted us to request a computed tomography of the chest (along with other scans), which would have shown the lung metastases. The patients would then have been admitted for a second therapeutic radioiodine dose. Our study protocol would have spared them an extra episode of TSH stimulation. However, the other 45 patients in our study underwent a second therapeutic radioiodine dose when they could have had a follow-up scan and stimulated thyroglobulin alone. Sixteen patients had raised stimulated thyroglobulin and incomplete resection. Ten (62%) were found to have radioiodine-resistant cancer. Four of these patients were under 45 years of age. There is no equivalent study group in the literature. Some guidelines debate whether a follow-up radioiodine scan is of use in addition to the stimulated thyroglobulin. The British, European and American Thyroid Association guidelines do not recommend it for low-risk patients (with an undetectable thyroglobulin level) and advise it for highrisk patients. This study shows that it can give some useful information. None of the guidelines discuss what to do if the stimulated thyroglobulin is elevated and the radioiodine scan is normal. This study suggests that computed tomography of the chest (without contrast) and ultrasound or magnetic resonance imaging of the neck would be fruitful, especially in patients with incomplete excision. If these scans fail to show disease, then rTSH-stimulated positron emission tomography–computed tomography is useful and, if normal, repeat stimulated thyroglobulin about 1 year later is recommended, with repeat scans if the thyroglobulin level is rising. Four of 26 (15%) patients with positive margins alone had a normal PTS, but raised stimulated thyroglobulin at the time of the second therapeutic radioiodine dose. They could have either residual dying normal thyroid gland, which is not taking up enough radioiodine to be seen on the scan or residual thyroid cancer that is either radioiodine resistant or not large enough or iodine avid enough to be seen on the scan. Our experience is that some patients with a large amount of uptake on the postablation scan and raised stimulated thyroglobulin 6 months later have a subsequent fall in stimulated thyroglobulin over the next year or two, which probably reflects slowly dying thyroid tissue. So far none of these patients has been found to have residual disease on scanning and further follow-up is required. This is the first study to describe the outcome of a cohort of patients with incompletely resected locally advanced DTC
139
who have not as yet been given external beam radiotherapy to the neck. To date, 13/21 (62%) have been found to have persistent cancer in the neck, which has been treated with a therapeutic dose of radioiodine alone (six patients) and further surgery (seven patients) with a fall in thyroglobulin. Twenty-four per cent (5/21) had a normal PTS and undetectable stimulated thyroglobulin. The British and European Thyroid Association guidelines [2,4] recommend external beam radiotherapy for patients with gross evidence of local tumour invasion at surgery, presumed to have significant macro- or microscopic residual disease, particularly if the residual tumour fails to concentrate sufficient amounts of radioiodine. All 47 patients in this study had presumed microscopic residuum and have so far avoided external beam radiotherapy to the neck. Our aim is to withhold radiotherapy from these patients unless they develop inoperable locally recurrent disease that is radioiodine resistant. This is debateable, but reasonable, if there is no evidence of disease after radioiodine ablation.
Conclusions The practice of routinely giving a therapeutic dose of radioiodine is to be discontinued in Leeds. Instead, our patients will be assessed at 6–9 months with a diagnostic radioiodine scan and stimulated thyroglobulin.
Acknowledgement The authors thank Wendy James for typing this manuscript.
References [1] Spitzweg C, Harrington KJ, Pinke LA, Vile RG, Morris JC. Clinical review 132: the sodium iodide symporter and its potential role in cancer therapy. J Clin Endocrinol Metab 2001;86(7):3327–3335. [2] British Thyroid Association. Guidelines for the management of thyroid cancer. British Thyroid Association, Royal College of Physicians. Report of the Thyroid Cancer Guidelines Update Group, 2nd edn. London: Royal College of Physicians; 2007. [3] Luster M, Clarke SE, Dietlein M, et al. Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging 2008;35:1941–1945. [4] Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JWA, Wiersinga W. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 2006;154:787–803. [5] Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19(11):1167–1214.
Clinical Oncology journal homepage: www.elsevier.com/locate/clon
Original Article
Should We Routinely Offer a Second Admission for Radioiodine to Patients with High-risk Differentiated Thyroid Cancer? G.E. Gerrard, L. O’Toole, F. Roberts St James Institute of Oncology, St James’s Hospital, Becket Street, Leeds LS9 7TF, UK Received 1 October 2009; received in revised form 14 December 2009; accepted 21 December 2009
Abstract Aims: To assess whether an elective second admission for radioiodine is useful for patients with high-risk differentiated thyroid cancer (DTC). Materials and methods: A retrospective analysis was carried out on 47 high-risk DTC patients treated with a second admission for radioiodine at our centre during the 2007–2008 period. Results: In 21 patients (45%), the surgeon described an incomplete resection. Twenty-six (55%) had surgical macroscopic complete resection, but cancer cells at the margin of excision histologically. Overall, at the second admission for radioiodine, 27 patients (57%) had a normal post-treatment scan and undetectable thyroid-stimulating hormone (TSH) stimulated thyroglobulin. Twenty patients (43%) had raised stimulated thyroglobulin at second admission for radioiodine, of whom only six (13%) had abnormal uptake (>0.1%) on the post-treatment scan. Conclusions: A second admission for radioiodine could have been avoided in most patients. Instead, information from stimulated thyroglobulin and a diagnostic radioiodine scan would have been sufficient to guide further management. This study also provides interesting outcome data on incompletely resected DTC. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: High-risk DTC; postoperative residual cancer; radioiodine; radiotherapy; raised thyroglobulin; thyroid cancer
Introduction It is widely believed that the first ‘ablation dose’ of radioiodine is preferentially taken up by normal thyroid cells rather than thyroid cancer cells [1]. After the normal thyroid has been ablated, then, in theory, any residual thyroid cancer cells would be destroyed by the second therapeutic radioiodine dose. A prospective audit was designed to test this assumption and to determine if highrisk differentiated thyroid cancer (DTC) patients were being over-treated with a second therapeutic radioiodine dose. Also, some high-risk patients may benefit from adjuvant postoperative external beam radiotherapy. The British Thyroid Association guidelines [2] state that radiotherapy should be considered if there is ‘gross evidence of local tumour invasion at surgery, presumed to have significant macro- or microscopic residual disease, particularly if the
Author for correspondence: G.E. Gerrard, St James Institute of Oncology, St James’s Hospital, Becket Street, Leeds LS9 7TF, UK. Tel: þ44-113-2068336; Fax: þ44-113-2067534. E-mail address: [email protected] (G.E. Gerrard).
residual tumour fails to concentrate sufficient amounts of radioiodine’. This study questions the definition of ‘failure to concentrate radioiodine’, which could mean no abnormal uptake on a post-therapy radioiodine scan (PTS). Alternatively, it could mean no abnormal uptake on a diagnostic radioiodine scan. Before this study, our patients with highrisk disease received two admissions for radioiodine followed by neck radiotherapy if there was insignificant uptake on the PTS and the TSH stimulated thyroglobulin was raised. This practice changed when the results of this study became available.
Materials and Methods Early in 2007, a protocol was written for high-risk DTC patients receiving radioiodine at the Leeds Oncology Centre. All such patients who were referred to our centre in 2007 and 2008 and treated by this protocol were audited. The protocol stated that any patient with postoperative residual cancer should be admitted for a second therapeutic radioiodine dose. Postoperative cancer was determined by discussion with the surgeon at the multidisciplinary team
0936-6555/$36.00 Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2010.01.002
G.E. Gerrard et al. / Clinical Oncology 22 (2010) 136–139
meeting, from the operation notes or histologically when the pathologist reported tumour at the excision margin. All thyroid cancer cases from the region have their pathology reviewed at the Cancer Centre in Leeds. All patients in the study had either an initial thyroidectomy or a two-stage thyroidectomy. The ablation activity was 3.7 GBq of radioiodine and the second therapeutic radioiodine dose activity was 5 GBq. Patients with known distant metastases were excluded from this study. Patients were also excluded if their post-ablation scan was normal and their stimulated thyroglobulin was undetectable at the time of ablation. There was a 6–8 month interval between the first admission for ablation and the second therapeutic radioiodine dose. Outcome measures included the amount of radioiodine uptake on post-ablation and PTS. The other outcome measure, stimulated thyroglobulin, was measured at each admission. All patients had thyroid hormone withdrawal before radioiodine to stimulate TSH, except for one patient who was aged 91 years and was prepared with recombinant TSH injections. Patients were asked to follow a low iodine diet for 2 weeks before their admission for radioiodine and for 5 weeks thereafter. The DPC Immulite assay was used to measure thyroglobulin; we expect a thyroglobulin level <1 for patients who have had a thyroidectomy and radioiodine ablation. Thyroglobulin antibodies were measured in all cases. The PTS was considered to be normal if there was <0.1% uptake present.
Results Forty-seven patients were treated according to the above protocol in 2007 and 2008. Data were collected prospectively. Thirty-one (66%) were women and 16 (34%) were men. The median age was 51 years (range 19–91). Forty-two (89%) had papillary thyroid cancer, four (9%) had Hurthle cell carcinoma and one (2%) had follicular thyroid cancer. All patients had tumours that had penetrated the thyroid capsule with cancer cells present at the margin of excision. In 21 (45%) cases, the surgeon reported that it was extremely likely that there were residual cancer cells present postoperatively either because tumour had been shaved off a structure such as the larynx or in one case the patient had refused to have a selective neck dissection and only agreed to excision of a lymph node that was extensively replaced by papillary thyroid cancer. This group will subsequently be referred to as the ‘incomplete resection’ subgroup. In 26 (55%) cases, their surgeon said that a macroscopic complete resection had been achieved, but the pathologist found cancer cells at the margin of excision. This group will
137
subsequently be referred to as ‘positive margin alone’ patients. Twenty-seven (57%) patients had a level VI neck dissection and 18 (38%) patients had either a unilateral or a bilateral selective neck dissection. There were no missing data on the desired outcome measures. No patient had more than 0.1% abnormal uptake on PTS with undetectable stimulated thyroglobulin on the day of admission for the second therapeutic radioiodine dose. All patients had a TSH > 28 mlU/l on the day of admission for radioiodine. The following subgroups are of interest (Table 1). Abnormal PTS and raised stimulated thyroglobulin: six (13%) patients had abnormal uptake (greater than 0.1% uptake) on the PTS and raised stimulated thyroglobulin at the time of the second therapeutic radioiodine dose. Interestingly, all of these patients had undergone an incomplete resection. The neck was the only site of abnormal uptake. No distant metastases were seen on any PTS. Normal PTS and raised stimulated thyroglobulin: 14 patients (30%) had a normal PTS but stimulated thyroglobulin >1 (at the time of the second therapeutic radioiodine dose). We would expect a thyroglobulin level <1 for patients who have had a thyroidectomy and radioiodine ablation. Ten of these 14 patients had an incomplete resection and four had positive margins alone. Persistent cancer was found in nine of these 14 patients to date. All nine patients had incomplete resection. Normal PTS and undetectable thyroglobulin: 27 (57%) had a normal PTS and undetectable stimulated thyroglobulin. Six patients in this group (22%) had incomplete resection and 21 (78%) had positive margins alone. Thyroglobulin antibodies: five of the 47 patients (11%) had thyroglobulin antibodies that could have invalidated the thyroglobulin levels, although there was no clinical evidence for this. Interestingly, two of the five patients with thyroglobulin antibodies had abnormal uptake on the PTS. These two patients had a raised thyroglobulin level as well as detectable thyroglobulin antibodies. The other three patients with thyroglobulin antibodies had an undetectable thyroglobulin level, a normal PTS and were in the ‘positive margin alone’ group. After several months of follow-up their thyroglobulin antibodies disappeared and their thyroglobulin level is persistently undetectable. Therefore, the DPC Immulite thyroglobulin assay may still be clinically useful even in the presence of thyroglobulin antibodies. In the incomplete resection vs the positive margin subgroups: 21 patients had an incomplete resection. Five of these (24%) had normal PTS and undetectable stimulated thyroglobulin. Six (29%) had substantial neck uptake and raised stimulated thyroglobulin. Ten (47%) had a normal PTS, but raised stimulated thyroglobulin. Radioiodine-resistant
Table 1 Findings at second radioiodine dose
Incomplete resection Positive margin alone Overall
PTS normal sTg <1
PTS normal sTg >1
PTS abnormal sTg <1
PTS abnormal sTg >1
Total
5 22 27
10 4 14
0 0 0
6 0 6
21 26 47
PTS, post-therapy scan; sTg, stimulated thyroglobulin.
138
G.E. Gerrard et al. / Clinical Oncology 22 (2010) 136–139
thyroid cancer was found in neck nodes in seven of these 10 patients and lung metastases (discovered on computed tomography) in two patients. Therefore, 16 (76%) had raised stimulated thyroglobulin (6 months after ablation) and residual cancer has been found in all except one of these patients. Incomplete resection is a good predictor of who will probably have a raised thyroglobulin level 6 months after ablation (76%) and who will probably have residual disease (15/21patients, 71%) discovered after a short follow-up period. In contrast, only four of the 26 patients (24%) in the ‘positive margin only’ subgroup had raised stimulated thyroglobulin and no site for the elevated stimulated thyroglobulin has been found on subsequent imaging. Considering Hurthle cell thyroid cancer cases: four patients had Hurthle cell cancer and one of these had abnormal uptake on PTS. This patient had further admissions for radioiodine in 2009. One of the four patients had an incomplete resection, a normal PTS, but raised stimulated thyroglobulin. A neck node was discovered on a neck ultrasound scan and resected with a fall in thyroglobulin level. The two remaining patients with Hurthle cell cancer had a positive margin only, a normal PTS and undetectable stimulated thyroglobulin. Regarding patients with cancer that had been shaved off a neck structure: in some centres, postoperative neck external beam radiotherapy is offered to patients whose cancer has been shaved off a structure such as the trachea. This is recommended by the European Association of Nuclear Medicine guidelines [3]. It is difficult for the surgeon to say if s/he is shaving through cancer or fibrosis. Eleven of the 21 patients in the incomplete resection subgroup had operation notes that documented shaving off the cancer from a neck structure. Three of these 11 patients had a normal PTS and undetectable stimulated thyroglobulin. Two of the 11 were found to have lung metastases and one patient had retropharyngeal and mediastinal nodes that took up large amounts of radioiodine. Therefore, radiotherapy to the neck seemed to be contraindicated in five of these 11 patients. However, a longer follow-up is required. Five other patients had further admissions for radioiodine because there was a significant amount of uptake in the neck. One of the 11 patients had a normal PTS but raised stimulated thyroglobulin and a site for the elevated thyroglobulin has not yet been discovered. Considering the incidence of dry mouth: The minimum follow-up time from the date of admission for ablation was 9 months. A study is now underway to investigate the incidence of dry mouth and sialadenitis 6 weeks after each admission and 1 and 2 years thereafter. Preliminary results suggest that considerably more patients have a dry mouth after a second therapeutic radioiodine dose than after the first admission for ablation.
Discussion There are no publications to help answer the question of whether a second admission for radioiodine is useful in patients with DTC that is incompletely excised. It is not
discussed in the most recent guideline/consensus documents [2–5]. The British Thyroid Association guidelines recommend a diagnostic follow-up radioiodine scan and stimulated thyroglobulin to be carried out about 6 months after the ablation dose of radioiodine. If our study group had been managed in this way, most of the patients would have avoided a second admission and the increased risk of a dry mouth. The other side-effects of radioiodine, such as sialadenitis and second malignancies, have not yet been assessed in this study, with its short follow-up, but have been described in other published studies. The 57% of patients who had undetectable 6 month stimulated thyroglobulin could subsequently have been followed up with a suppressed thyroglobulin level alone and are unlikely to need further treatment. Our experience is that patients can occasionally develop recurrence years after having undetectable stimulated thyroglobulin (heralded by a rising suppressed thyroglobulin level). It is impossible to say if micrometastases may have taken up radioiodine. If so, they were not detectable by our current biochemical or radiological tests. The 43% of patients who had raised 6 month stimulated thyroglobulin would obviously have been discovered without the need for a second therapeutic radioiodine dose, as thyroglobulin would have been measured at the same time as the follow-up diagnostic scan. It is controversial how to manage patients with raised stimulated thyroglobulin together with an abnormal follow-up diagnostic radioiodine scan (as would have been the case in six of our patients). Some oncologists would routinely admit these patients for a second therapeutic radioiodine dose. Alternatively, anatomical scans, e.g. computed tomography of the chest and ultrasound/magnetic resonance imaging of the neck, or functional scans, e.g. positron emission tomography–computed tomography, could be carried out with the aim of discovering operable disease. If neck nodes alone were discovered then excision could be attempted and if the postoperative thyroglobulin level was undetectable then a second therapeutic radioiodine dose could be withheld. However, some of our patients with neck uptake had inoperable residuum, e.g. cancer stuck to the carotid artery, and would probably have required a second therapeutic radioiodine dose after the follow-up scan showed radioiodine-avid disease in the neck. Seven of our patients with incomplete resection, a raised stimulated thyroglobulin level and a normal PTS, had neck nodes detected on ultrasound or magnetic resonance imaging neck scans. Neck dissections were carried out and all seven patients had a postoperative thyroglobulin level < one. The tumour cells in the neck failed to take up radioiodine. A second therapeutic radioiodine dose was useful to determine radioiodine resistance, but otherwise did not help in the management of these patients over and above the information that would have been obtained with a diagnostic follow-up radioiodine scan with stimulated thyroglobulin. The two patients with lung metastases would have been given an empirical dose of radioiodine if they had been discovered before the second therapeutic radioiodine dose.
G.E. Gerrard et al. / Clinical Oncology 22 (2010) 136–139
In this study, these two patients had radioiodine-resistant lung metastases on the PTS. If they had been managed according to the British Thyroid Association 2007 guidelines, they would have had a follow-up radioiodine scan and stimulated thyroglobulin. The raised thyroglobulin would have prompted us to request a computed tomography of the chest (along with other scans), which would have shown the lung metastases. The patients would then have been admitted for a second therapeutic radioiodine dose. Our study protocol would have spared them an extra episode of TSH stimulation. However, the other 45 patients in our study underwent a second therapeutic radioiodine dose when they could have had a follow-up scan and stimulated thyroglobulin alone. Sixteen patients had raised stimulated thyroglobulin and incomplete resection. Ten (62%) were found to have radioiodine-resistant cancer. Four of these patients were under 45 years of age. There is no equivalent study group in the literature. Some guidelines debate whether a follow-up radioiodine scan is of use in addition to the stimulated thyroglobulin. The British, European and American Thyroid Association guidelines do not recommend it for low-risk patients (with an undetectable thyroglobulin level) and advise it for highrisk patients. This study shows that it can give some useful information. None of the guidelines discuss what to do if the stimulated thyroglobulin is elevated and the radioiodine scan is normal. This study suggests that computed tomography of the chest (without contrast) and ultrasound or magnetic resonance imaging of the neck would be fruitful, especially in patients with incomplete excision. If these scans fail to show disease, then rTSH-stimulated positron emission tomography–computed tomography is useful and, if normal, repeat stimulated thyroglobulin about 1 year later is recommended, with repeat scans if the thyroglobulin level is rising. Four of 26 (15%) patients with positive margins alone had a normal PTS, but raised stimulated thyroglobulin at the time of the second therapeutic radioiodine dose. They could have either residual dying normal thyroid gland, which is not taking up enough radioiodine to be seen on the scan or residual thyroid cancer that is either radioiodine resistant or not large enough or iodine avid enough to be seen on the scan. Our experience is that some patients with a large amount of uptake on the postablation scan and raised stimulated thyroglobulin 6 months later have a subsequent fall in stimulated thyroglobulin over the next year or two, which probably reflects slowly dying thyroid tissue. So far none of these patients has been found to have residual disease on scanning and further follow-up is required. This is the first study to describe the outcome of a cohort of patients with incompletely resected locally advanced DTC
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who have not as yet been given external beam radiotherapy to the neck. To date, 13/21 (62%) have been found to have persistent cancer in the neck, which has been treated with a therapeutic dose of radioiodine alone (six patients) and further surgery (seven patients) with a fall in thyroglobulin. Twenty-four per cent (5/21) had a normal PTS and undetectable stimulated thyroglobulin. The British and European Thyroid Association guidelines [2,4] recommend external beam radiotherapy for patients with gross evidence of local tumour invasion at surgery, presumed to have significant macro- or microscopic residual disease, particularly if the residual tumour fails to concentrate sufficient amounts of radioiodine. All 47 patients in this study had presumed microscopic residuum and have so far avoided external beam radiotherapy to the neck. Our aim is to withhold radiotherapy from these patients unless they develop inoperable locally recurrent disease that is radioiodine resistant. This is debateable, but reasonable, if there is no evidence of disease after radioiodine ablation.
Conclusions The practice of routinely giving a therapeutic dose of radioiodine is to be discontinued in Leeds. Instead, our patients will be assessed at 6–9 months with a diagnostic radioiodine scan and stimulated thyroglobulin.
Acknowledgement The authors thank Wendy James for typing this manuscript.
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