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Two large randomised trials of patients with well-differentiated thyroid cancer reported in 2012 (HiLo and ESTIMABL1) found similar post-ablation success rates at 6-9 months between a low administered radioactive iodine (HiLo was a non-inferiority, parallel, open-label, randomised controlled factorial trial done at 29 centres in the UK. Eligible patients were aged 16-80 years with histological confirmation of differentiated thyroid cancer requiring radioactive iodine ablation (performance status 0-2, tumour stage T1-T3 with the possibility of lymph-node involvement but no distant metastasis and no microscopic residual disease, and one-stage or two-stage total thyroidectomy). Patients were randomly assigned (1:1:1:1) to 1·1 GBq or 3·7 GBq ablation, each prepared with either recombinant human thyroid-stimulating hormone (rhTSH) or thyroid hormone withdrawal. Patients were followed up at annual clinic visits. Recurrences were diagnosed at each hospital with a combination of established methods according to national standards. We used Kaplan-Meier curves and hazard ratios (HRs) for time to first recurrence, which was a pre-planned secondary outcome. This trial is registered with ClinicalTrials.gov, number NCT00415233.Between Jan 16, 2007, and July 1, 2010, 438 patients were randomly assigned. At the end of the follow-up period in Dec 31, 2017, median follow-up was 6·5 years (IQR 4·5-7·6) in 434 patients (217 in the low-dose group and 217 in the high-dose group). Confirmed recurrences were seen in 21 patients: 11 who had 1·1 GBq ablation and ten who had 3·7 GBq ablation. Four of these (two in each group) were considered to be persistent disease. Cumulative recurrence rates were similar between low-dose and high-dose radioactive iodine groups (3 years, 1·5% vs 2·1%; 5 years, 2·1% vs 2·7%; and 7 years, 5·9% vs 7·3%; HR 1·10 [95% CI 0·47-2·59]; p=0·83). No material difference in risk was seen for T3 or N1 disease. Recurrence rates were also similar among patients who were prepared for ablation with rhTSH and those prepared with thyroid hormone withdrawal (3 years, 1·5% vs 2·1%; 5 years, 2·1% vs 2·7%; and 7 years, 8·3% vs 5·0%; HR 1·62 [95% CI 0·67-3·91]; p=0·28). Data on adverse events were not collected during follow-up.The recurrence rate among patients who had 1·1 GBq radioactive iodine ablation was not higher than that for 3·7 GBq, consistent with data from large, recent observational studies. These findings provide further evidence in favour of using low-dose radioactive iodine for treatment of patients with low-risk differentiated thyroid cancer. Our data also indicate that recurrence risk was not affected by use of rhTSH.Cancer Research UK.

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Randomized trials show that low-dose (1.1 GBq [30 mCi]) radioiodide (RAI) has efficacy equivalent to high-dose RAI (3.7 GBq [100 mCi]) in thyroid remnant ablation (TRA) for differentiated thyroid cancer. Long-term follow-up is required to ensure detection of late recurrences and to confirm equivalence in terms of survival end points. However, median follow-up duration within randomized trials is currently limited.We studied 53 patients undergoing TRA for differentiated thyroid cancer with long-term follow-up in the Thyroid Unit of The Royal Marsden Hospital (Sutton, United Kingdom).Patients were treated with TRA using low-dose (1.1 GBq) RAI.Disease-free survival, overall survival, and the incidence of second malignancies were measured. Multivariable analysis was used to determine clinical risk factors for failure to achieve TRA after low-dose RAI.Median follow-up was 24 (range, 4-34) years. Low-dose RAI TRA was successful in 26 (49%) patients (successful ablation [SA] group), whereas 27 (51%) patients required further treatment (unsuccessful ablation [UA] group). Thirty-year disease-free survival was 92% in the SA group vs 87% in the UA group (P = .601). Thirty-year overall survival was 81% in the SA group vs 62% in the UA group (P = .154). Nine (17%) patients developed second malignancies (4 in the SA group and 5 in the UA group). Predictors of failure to achieve TRA with low-dose RAI were male sex and stage pT4 disease.There is no evidence from long-term follow-up of our cohort that treatment outcomes are compromised for patients that fail TRA with low-dose RAI and subsequently receive high-dose RAI.

Background It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. Methods At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. Results A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radi...

Objective To review the early and late toxicity associated with radioiodine (131I) therapy, highlighting the need for early detection and, where possible, preventive measures. Methods We performed a literature search on MEDLINE using the terms radioiodine, 131I toxicity, complications, Graves disease, and thyroid cancer and chose the most relevant studies for this review. Where appropriate, we refer to our own published series of patients as well. Results Uptake of 131I into the salivary glands, lacrimal glands, fetal thyroid, and adult thyroid accounts for the early toxic effects of radioiodine therapy. Delayed radiation effects to the gonads, bone marrow, and cell nuclei give rise to late complications. Toxicity may also arise from uptake into metastatic tumors located at vulnerable sites, including the spinal cord, brain, and lungs. Conclusion Although radioiodine therapy for benign and malignant thyroid disorders is usually well tolerated, clinicians involved in the management of thyroid disorders need to be aware of the potential toxicity of radioiodine and take all measures to reduce these effects to a minimum. (Endocr Pract. 2010;16:1064-1070)

The aim of this study was to determine the range of absorbed doses delivered to thyroid remnants, blood, and red marrow from fixed administrations of radioiodine and to ascertain whether the success of ablation is more dependent on these absorbed doses than on the administered activity. Twenty-three patients received 3,000 MBq radioiodine following near-total thyroidectomy. The maximum absorbed dose to remnants was calculated from subsequent single photon emission tomography scans. Absorbed doses delivered to blood and red marrow were calculated from blood samples and from whole-body retention measurements. The protein bound iodine (PBI) was also calculated. Maximum absorbed doses to thyroid remnants ranged from 7 to 570 Gy. Eighteen of the 23 patients had a successful ablation. A significant difference was seen between the absorbed doses delivered to thyroid remnants, blood, and red marrow for those patients that had a successful ablation compared to those with a failed ablation (p = 0.030, p = 0.043 and p = 0.048, respectively). The difference between the PBI values acquired at day 1 and day 6 were also indicative of response (p = 0.074). A successful ablation is strongly dependent on the absorbed dose to the thyroid remnant. Dosimetry-based personalized treatment can prevent both sub-optimal administrations, which entails further radioiodine therapy, and excessive administration of radioactivity, which increases the potential for radiation toxicity.

Purpose Anaplastic thyroid carcinoma (ATC) is one of the most aggressive cancers, and the current protocol of hyperfractionated accelerated radiotherapy was initiated to improve survival while limiting toxicities. Methods and Materials All patients with ATC from 1991 to 2002 were accrued and received megavoltage radiotherapy from the mastoid processes to the carina up to 60 Gy in twice-daily fractions of 1.8 and 2 Gy, 6 hours apart. Results Thirty-one patients were accrued with a median age of 69 years, and 55% were women. Debulking was performed in 26%, and total thyroidectomy, in 6%, whereas 68% received radical radiotherapy alone. Local control data were available for 27 patients: 22% had a complete response, 26% had a partial response, 15% showed progressive disease, and 37% showed static disease. Median overall survival for all 31 patients was 70 days (95% confidence interval, 40–99). There was no significant difference in median survival between patients younger (70 days) and older than 70 years (42 days), between men (70 days) and women (49days), and between patients receiving postoperative radiotherapy (77 days) and radical radiotherapy alone (35 days). Grade III or higher skin erythema was seen in 56% patients; desquamation in 21%; dysphagia in 74%; and esophagitis in 79%. Conclusion The current protocol failed to offer a significant survival benefit, was associated with severe toxicities, and thus was discontinued. There is a suggestion that younger patients with operable disease have longer survival, but this would require a larger study to confirm it.

Background and purpose This phase 1 study was designed to determine the toxicity of accelerated fractionation IMRT in locally advanced thyroid cancer. Methods Patients with high risk locally advanced thyroid cancer who required post-operative EBRT were recruited. A single-phase inverse-planned-simultaneous-boost was delivered by IMRT: 58.8Gy/28F (daily) to the primary tumour and involved nodes and 50Gy/28F to the elective nodes. Acute (NCICTCv.2.0) and late toxicity (RTOG and modified LENTSOM) was collected. Results Thirteen patients were treated (7 medullary thyroid, 2 Hurthle cell and 4 well differentiated thyroid cancer). G3 and G2 radiation dermatitis rates were 38.5% and 31%; G3 and G2 mucositis rates 8% and 53% and G3 and G2 pain 23% and 54%. Thirty-one percentage required enteral feeding. G3 and G2 xerostomia rates were 0% and 31%. Recovery was seen, with 62% patients having dysphagia G ⩽1 2 months after IMRT. Thirty percent of patients developed L'Hermitte's syndrome. No grade 4 toxicity was observed. No dose limiting toxicity was found. Conclusions Accelerated fractionation IMRT in this group of patients is feasible and safe. The acute toxicity appeared acceptable and early indicators of late toxicity moderate and similar to what would be expected with conventional RT. Longer follow up is required to quantify late side effects.

Radioiodine ablation of the thyroid remnant after thyroidectomy is commonly performed in the management of patients with differentiated thyroid cancer. Although many centers administer an activity of 100 mCi, there is uncertainty over using a lower activity.A systematic review of the published literature was used to compare the success rates of remnant ablation using approximately 30 mCi with approximately 100 mCi (1.1 vs. 3.7 GBq).Data were obtained from MEDLINE and EMBASE for the years 1966 to March 2006.All studies that reported rates of successful ablation associated with approximately 30 or approximately 100 mCi of radioiodine were reviewed.Studies were based on reviews of patient case notes (n = 41), prospective cohorts (n = 12), and randomized trials (n = 6). We obtained the success of thyroid remnant ablation according to different administered activities of radioiodine. Where a study reported on two or more activities, the risk ratio of having a successful ablation (approximately 30 vs. approximately 100 mCi) was calculated and combined in a meta-analysis.Observational studies confirmed the high ablation success rate ( approximately 80%) using approximately 100 mCi, although 22% of studies reported a rate of 90% or greater. The pooled ablation success rate in these studies was 10% lower using 30 mCi compared with 100 mCi (95% confidence interval, 3-17%; P = 0.01). The meta-analysis of the randomized trials produced equivocal results. For example, the rate of successful ablation in patients given 30 mCi was 8% lower compared with 100 mCi (95% confidence interval, 29% lower or up to 20% greater, P = 0.58), consistent with there being no difference or that 30 mCi is much less effective.From the published data, it is not possible to reliably determine whether ablation success rates using 30 mCi are similar to using 100 mCi. Large randomized trials are needed to resolve the issue and guide clinical practice.

Objective: To determine, based on published literature and expert clinical experience, current indications for the post-surgical administration of a large radioiodine activity in patients with differentiated thyroid cancer. Design and methods: A literature review was performed and was then analyzed and discussed by a panel of experts from 13 European countries. Results: There is general agreement that patients with unifocal microcarcinomas = 1 cm in diameter and no node or distant metastases have a Conclusion: This survey confirms that post-surgical radioiodine should be used selectively. The modality is definitely indicated in patients with distant metastases, incomplete tumor resection, or complete tumor resection but high risk of recurrence and mortality. Probable indications include patients with tumors >1 cm and with suboptimal surgery (less than total thyroidectomy or no lymph node dissection), with age

Objective To assess clinical features and long-term results of treatment of familial medullary thyroid carcinoma (FMTC). Design Retrospective analysis of all patients with familial forms of MTC diagnosed between 1949–2000 and treated in our unit. Results Fifty five patients (25 males, 30 females) were identified with at least two first-degree relatives affected by medullary thyroid cancer; 26 were classified as MEN 2A, 1 as MEN 2B and 28 as FMTC. Median age at diagnosis was 35 years (MEN 2A), 25 (MEN 2B) and 47.5 (FMTC). Median follow-up was 9 years (range: 4–24). Total or near-total thyroidectomy was performed in all patients and 11 received adjuvant external beam radiotherapy. Cause specific survival was 89% at 10 years and 77% at 20 years for MEN patients, 51% and 32% for those with sporadic MTC, and 46% and 26% for those with FMTC. In multivariate analysis, factors predicting survival were presence of metastases, nodal status and age at diagnosis. Conclusions Improved survival rates associated with familial types of MTC can be accounted for by the earlier stage at which disease is detected and the younger age at presentation. These observations emphasize the need for early detection in those at risk.

Benign thyroid disorders are strong risk factors for nonmedullary thyroid cancer (NMTC). Germline variation in Tg (thyroglobulin) and TSHR (thyroid stimulating hormone receptor) confers an increased risk of benign thyroid disorders. To explore the hypothesis that polymorphic variation in these genes affects the risk of NMTC we compared the frequency of TgQ2511R, TSHR-P52T and TSHRD727E genotypes in two series of NMTC cases and controls (group 1, Canadian 102 cases and 102 controls; group 2, British 202 cases and 298 controls). No significant association was seen with TSHR-P52T and TSHR-D727E genotypes and risk of NMTC. However, the frequency of the R-allele of TgQ2511R was over represented in NMTC cases in both study populations. The odds ratios associated with hetero- and homozygosity for the R-allele were 1.6 (95% confidence interval, 1.1-- 2.5) and 2.0 (95% confidence interval, 1.2-- 3.3), respectively. Although the risk of NMTC associated with the TgQ2511R R-allele is modest, its high prevalence in the general population suggests it may make a significant contribution to the incidence of NMTC.

Purpose: A correlation of treatment for uterine sarcoma with outcome, prognostic importance of pathology, and clinical parameters. Patients and Methods: One hundred forty-one patients (median age: 56 years, range: 19 - 85 years) with a histologically verified uterine sarcoma were identified from a database compiled at the Royal Marsden Hospital and the University of Florence between 1974 and 2001. Seventy-two patients had leiomyosarcoma, 42 had mixed mullerian tumors, 22 had endometrial stromal sarcoma, 1 hemangiopericytoma, 1 rhabdomyosarcoma, and 3 patients had unspecified sarcoma. According to FIGO classification, Stage I, II, III, and IV tumors were identified in 71, 13, 31, and 26 patients, respectively. Results: At the time of analysis, 73.7% of patients were dead, and 26.3% were alive with a median survival of 2 years from initial diagnosis. Univariate analysis for cause-specific survival demonstrated statistical significance for histology (p 0.02), grade (p 0.003), stage (p 0.007), and age (p 0.02). Multivariate analysis demonstrated significant prognostic values for stage ( p 0.02) and histology (p 0.05) only. Postoperative radiotherapy with a total dose higher than 50 Gy seems to be significant ( p 0.001) in reducing local recurrence. Conclusions: Our data favor treatment for Stages I, II, and III of uterine sarcoma with radical surgery plus radical dose irradiation comprising both external beam radiotherapy and brachytherapy. © 2003 Elsevier Inc. Brachytherapy, Radiotherapy, Uterine sarcoma.

Treatment of differentiated thyroid cancer is a success of modern medicine with the use of radioiodine ((131)I). However, a significant proportion of thyroid cancers may be non-iodine avid. Thyroid tumours are known to express somatostatin receptors. Octreotide, an analogue of somatostatin, can be combined with a radioactive isotope, such as (111)In-DTPA(0) to visualise tumours with high concentrations of somatostatin receptors. We assessed 18 patients with histologically proven metastatic or locally recurrent non-iodine avid thyroid carcinoma to determine the usefulness of (111)In-DTPA(0) octreotide scintigraphy compared to conventional radiology in diagnosing sites of metastasis. The diagnosis of metastatic disease was made using conventional radiology and all had prospective scintigraphy using (111)In-DTPA(0)octreotide. Of the 18 patients, 14 had octreotide-positive scans. In eight, the octreotide scans identified the same sites of metastases as conventional radiology, that is, were concordant. In nine patients, conventional radiology showed more extensive disease than revealed on the octreotide scans. In one patient with widespread bone metastases, octreotide gave a more detailed assessment of metastatic disease than conventional radiology. These data indicate that (111)In-DTPA(0)octreotide imaging for patients with non-iodine avid carcinoma of the thyroid may be a useful diagnostic and staging tool. One patient with Hurthle cell carcinoma metastatic to bone and a positive octreotide scan has been treated with (90)yttrium-labelled octreotide.

Background The authors assessed the biologic behavior of differentiated thyroid carcinoma in patients age 70 years or older and evaluated factors that influenced long-term survival. Methods Among 1448 patients with differentiated thyroid carcinoma who were treated at the authors' institution over the past 60 years, 111 patients were identified who were age 70 years or older at the time of their initial diagnosis (range, 70-93 years). The authors conducted a retrospective analysis of the outcome of these 111 patients, who had a median follow-up of 9 years (range, 2-9 years). Results There were 83 female patients and 28 male patients (female to male ratio, 3:1). Fifty-eight tumors were papillary, 46 tumors were follicular, and 7 tumors were Hurthle cell carcinoma. Eighty percent of patients presented with a thyroid mass, and 70% of tumors were pathologic stage T3 (pT3) or pT4. Lymph node disease was evident at presentation in 44% of patients, and distant metastases were documented at diagnosis in 23% of patients. Forty-six patients underwent total thyroidectomy, and the remaining patients underwent subtotal thyroidectomy or biopsy only. Radioiodine was administered to 80 patients, and external beam radiotherapy was administered to 19 patients. The cause specific survival rates were 75%, 50%, and 50% at 5 years, 10 years, and 15 years, respectively. Multivariate analysis showed that the presence of metastases was the most important independent prognostic factor for survival. External beam radiotherapy was associated with a poorer prognosis, in that it was reserved for patients with either inoperable disease or residual disease after surgery and patients with no uptake of radioiodine. Conclusions A large proportion of thyroid tumors showed extrathyroid spread and distant metastases, which frequently were not iodine-avid. The prevalent histologic type was papillary, often with features of poor differentiation. Thyroid carcinoma in the elderly appears to behave more aggressively, and they have a less favorable prognosis compared with younger adults.

Testicular dose and fertility in men following I-131 therapy for thyroid cancer. OBJECTIVE Young adults with differentiated thyroid cancer are treated with high doses of radioiodine and have an excellent long-term prognosis. However, there is limited information on the effects of this treatment on the gonads and fertility in male patients. We have reviewed the outcome of treatment in our centre with respect to male fertility. We have also assessed directly the radiation dose received by the testes. DESIGN Retrospective analysis of males attending the thyroid clinic at the Royal Marsden Hospital for treatment of differentiated thyroid cancer. A prospective study was also performed to assess radiation dose to testes in 14 consecutive patients attending for thyroid cancer treatment. PATIENTS Males under the age of 40 years at the time of treatment with a minimum of 3 years follow-up. MEASUREMENTS Number of children fathered by patients and number of congenital malformations. For the prospective study: gonadal function assessed by serum FSH, LH and testosterone measurements; radiation dose to the testes (Gy) measured by thermoluminescent dosimetry. RESULTS Fertility was assessed in 122 men with a median follow-up of 21 years (range 3-39) of whom 93 were under active follow-up. One hundred and six children were fathered by 59 patients; the remainder had no wish to have children. No major malformations were reported. Of these 59 patients, 12 had received a single 3GBq ablation dose, 19 had been treated with up to 14 GBq radioiodine and 28 had received up to 44 GBq. In 14 patients followed prospectively, the median estimated radiation dose to each testis was 6.4 cGy following 3 GBq, 14.1 cGy following 5.5 GBq and 21.2 cGy following 9.2 GBq. There was a transient elevation in serum FSH after radioiodine which normalized within 9 months from the last administration. CONCLUSIONS Radioiodine treatment for thyroid cancer may result in transient impairment of gonadal function. The radiation dose absorbed by the testis after a single ablative dose of radioiodine is well below that associated with permanent damage to germinal epithelium and the risk of infertility in these patients is minimal. Patients requiring multiple administrations for persistent or metastatic thyroid cancer may be at greater risk of gonadal damage although even in this group, we found no evidence of infertility.

Well differentiated thyroid cancer is a rare disease in the UK. It is the only cancer which, having metastasized, remains curable by radioisotope therapy with 131I. The main indication for administering repeat doses of 131I is the appearance of abnormal uptake in a whole body scan following diagnostic or therapeutic 131I administration. False positive scans, showing the presence of 131I uptake in the absence of residual thyroid tissue or metastases can occur, although they are uncommon. Unless recognized as a false positive, 131I uptake may result in diagnostic error and lead to administration of an unnecessary therapy dose. We describe a series of nine patients in whom the scans showed false positive uptake of 131I, including cases where the cause of the uptake is still uncertain. We demonstrate the common sites of false positive uptake, discuss the underlying mechanisms and suggest a systematic approach to the interpretation of whole body scans in order to prevent unnecessary treatment with 131I.

The rarity of endometrial stromal sarcoma (ESS) and its poor response to treatment provides fertile ground for investigational therapies. An accelerated regimen of carboplatin and paclitaxel is investigated. A patient with a recent history of treated tuberculosis of the lung represented with infertility and acute abdominal pain from suspected fibroids, and underwent a laparotomy with a diagnosis of a high-grade ESS. A novel therapeutic approach using a regimen of carboplatin and paclitaxel with the reinfusion of filgrastim-mobilized peripheral blood progenitor cells is described. A partial response was observed following six cycles of chemotherapy. Grade IV thrombocytopenia occurred after the last cycle, with recovery prior to pelvic radiotherapy. The patient remained well 1 year post-diagnosis. High-grade ESS is responsive to combination chemotherapy with paclitaxel and carboplatin, and requires further evaluation. The use of an accelerated regimen may also have contributed to the response and this question awaits randomized trials.

The first child with well-differentiated thyroid cancer treated at the Royal Marsden Hospital presented in 1917. Since that time 30 children under the age of 16 years have been treated over a period during which many new treatments have been introduced. We have reviewed their management and outcome. The median follow-up is 22.5 years (range: 1-66). The median time to recurrence was 7 years (range: 2-44). There were events up to 44 years after presentation. The risk of recurrence was higher in children aged 10 years or younger [HR 3.45, 95% CI (1.04-11.11) P = 0.03]. Thyroid stimulating hormone (TSH) suppression was the only intervention to be shown to reduce the recurrence rate [HR 11, 95% CI (2.27-50) P = 0.0003]. The median overall survival is 53 years. The only presenting feature predictive of poorer survival was the presence of metastases (HR 28.96, 95% CI 2.51-334, P < 0.001). Patients who developed recurrence had a higher risk of death (HR 9.90, 95% CI 0.98-100, P = 0.02) and a shorter median survival of 30 years. No therapeutic intervention could be shown statistically to impact on survival. Our recommendation for treatment is total or near-total thyroidectomy for all patients and radioiodine ablation for all except those with early T stage node-negative disease aged over 10 years. Modified neck dissection is recommended for children with clinically positive neck nodes and TSH suppression for all. Follow-up with serial thyroglobulin measurement should be lifelong.

Background and purpose : Anaplastic thyroid cancer responds poorly to conventional radiotherapy and prognosis in the absence of effective chemotherapy is dismal. The median survival following diagnosis is only 4 months and the majority of patients die with uncontrolled local disease. This study describes the use of accelerated radiotherapy aiming to improve local response in patients with anaplastic thyroid carcinoma. Toxicity was assessed prospectively. Patients and methods : Seventeen patients with anaplastic thyroid carcinoma were treated and assessed for both outcome and treatment toxicity. Eight further patients with primary carcinomas arising in the neck were also treated with this protocol but were assessed for treatment toxicity only. Patients were treated twice daily, 5 days a week, to a total dose of 60.8 Gy in 32 fractions over 20–24 days in two or three phases. Results : Three patients with anaplastic carcinoma demonstrated a complete clinical response and seven patients achieved a partial response. Five patients had stable disease and two patients died before radiotherapy was completed. Toxicity from oesophagitis and dysphagia was high with 10 patients requiring intravenous fluids or nasogastric tube feeding. Conclusion : This approach improved the response rate to radiotherapy but toxicity was unacceptable. A modified accelerated radiotherapy protocol is being explored.

The importance of thyroid cancers far exceeds their frequency, since they are uncommon tumours accounting for only 1% of all malignancies and for even smaller proportion of cancer deaths (0.2%). A variety of distinct tumour types arise in the thyroid gland, with variable natural histories resulting from different rates of growth and biological aggressiveness. The long natural history of the majority of thyroid neoplasms imposes a commitment for long-term follow-up and stresses the importance of planning treatment so as to avoid delayed complications that impair the quality of life of patients. The management of thyroid cancer is multidisciplinary, requiring consultation and active intervention by surgeons, endocrinologists and radiotherapists. Surgery is of paramount importance in the successful eradication of the tumours while radioiodine offers a unique therapeutic approach. Treatment must be strongly influenced by consideration of prognostic variables.

One hundred and ninety-seven patients with early stage breast cancer, who were treated initially with conservative surgery, were evaluated prospectively for acute toxicity after completing post-operative irradiation. Eighty-seven of these patients had synchronous chemotherapy with the 3M regimen (mitoxantrone, methotrexate and Mitomycin-C) during radiotherapy. The results indicate that patients receiving chemotherapy and radiotherapy (CRT) showed no significant difference in acute skin toxicity (AST) when compared with those treated with radiotherapy alone (RTO), with an odds ratio (OR = 0.6) and 95% confidence intervals (0.3-1.1) of developing either a moderate or severe, compared with a mild, skin reaction. Even after controlling for other confounding factors, such as treatment technique and beam energy, patients treated with the supine technique using 6-10 MV photons still displayed no significant difference in AST, with 12/74 (16%) patients in the CRT group and 14/66 (21%) in the RTO group developing a moderate or severe skin reaction (OR = 0.7 (95% CI 0.3-1.7)). Four of the 87 patients treated with CRT developed symptomatic acute radiation pneumonitis, three of whom were found to have > 3 cm of lung length on their simulator or check films. The volume of lung included within the treatment field was found to be statistically significant (P = 0.005) in predicting the onset of radiation pneumonitis in the CRT group. None of these patients has suffered any symptomatic late lung toxicity. We conclude that synchronous chemotherapy and radiotherapy, when using the 3M regimen, is feasible for patients having adjuvant treatment for early stage breast carcinoma and there is no significant increase in AST. However, it is associated with an increase in acute radiation pneumonitis when a significant volume of lung is included within the radiation treatment field.

The results are presented of a prospective study of acute skin toxicity in 197 patients with early stage breast cancer, who were treated by conservative surgery and postoperative radiotherapy. We have examined the factors determining the severity of the acute skin reaction with particular reference to the degree of dry or moist desquamation at the completion of treatment. One hundred and ten patients had treatment with radiotherapy alone. The remaining 87 received synchronous chemotherapy with breast irradiation, using either the 3M or the 2M regimen, consisting of mitoxantrone and methotrexate, with (3M) or without Mitomycin-C (2M). Patients were analysed according to both the severity and the site of the skin reaction, age, dose, dose variation across the central outline, treatment technique, beam energy, field separation and breast size. A univariate analysis of these results, which has been presented as an odds ratio of the likelihood of developing a moderate or severe reaction in comparison with those scored as mild, has shown that several factors are associated with an increase in the acute skin reaction. These include the use of the semi-supine technique (odds ratio (OR) = 7.3 (95% CI 3.7-14.6)), beam energy (60Co: 6-10 MV photons OR = 5.9 (95% CI 2.6-13.4)), field separation (or = 20 cm:20 cm OR = 4.1 (95% CI 2.2-7.8)), dose variation across the central outline (or = 10%:10% OR = 9.7 (95% CI 2.6-36.4)), inclusion of the axilla (OR = 4.6 (95% CI 2.4-8.9)), and bust size (bra cup size C and D: A and B OR = 4.6 (95% CI 2.7-11.9)). Using multivariate logistic regression, the technique of radiation delivery and bust size were shown to be independently significant variables affecting acute skin reaction. In view of the high correlation between variables (e.g. radiotherapy technique and beam energy) it is still not possible to specify with definite certainty which is the primary variable causing the skin reaction. However 20/57 (35%) of patients treated by the semisupine technique sustained a severe skin reaction, with10% dry or moist desquamation in the treatment field. This compares with only 6/140 (4%) patients treated by the supine method. A possible mechanism by which treatment using the semisupine technique may enhance acute toxicity is discussed. We conclude that there are both treatment and patient related factors that will increase the acute skin reaction after breast irradiation.

We present a retrospective review of six patients who developed brain metastases in our series of 649 with differentiated thyroid carcinoma seen at the Royal Marsden Hospital between 1936 and 1991. Prognosis was poor, with survival 1-19 months from the diagnosis of brain metastases in five patients. One patient remains alive at 18 months. A dosimetric approach may help to individualize and optimize treatment.

Background . Relatively little evidence exists to guide the decision pathway regarding thoracic metastasectomy for thyroid malignancy. Methods . Single-institution 10-year review. Results . Sixteen patients had surgical treatment for intrathoracic metastatic thyroid malignancy: 12 men and 4 women, mean age 43.7 years (range 19 to 77). Histopathologic type was papillary in 6 cases, follicular in 4, Hurthle cell in 3, and medullary in 3. Indication was either "bulky" disease (8 patients) or poor response to radiotherapy (8 patients). We performed 11 sternotomies and five thoracotomies. Operative mortality was 6.25%. Operative morbidity was 6.25%. Mean survival was 39.5 months (0 to 144). Nine patients died during follow-up (mean survival of 41.2 months). Six patients survived, 4 free of disease (mean survival 70 months) and 2 with further relapse (mean survival 17 months). Five-year survival was 32.5%. Conclusions . The cohort studied is one of the largest in the literature on the topic. Surgical treatment achieved a reasonable survival in a small subgroup of patients where radiotherapy had failed or was deemed inappropriate because of the size or location of the tumor. Further follow-up and more observations will be required for evaluating these preliminary findings.

In order to assess the value of computed tomographic scanning of the axilla and brachial plexus in the management of patients with arm symptoms following treatment for breast cancer, the case notes and diagnostic films of 102 such patients who underwent scanning between 1985 and 1990 at this institution were analysed retrospectively. The clinical indications for requesting computed tomography (CT) of the brachial plexus and axilla included arm oedema (52 patients, 51%), brachial plexus neuropathy (73 patients, 72%), and/or the presence of a palpable axillary mass (18 patients, 18%). Of 102 CT scans, 80 showed either no abnormality (31 patients, 30%), or axillary fibrosis (49 patients, 48%), and 22 (21%) showed radiological evidence of recurrent tumour. Only 4 of 84 patients with no palpable mass had computed tomographic evidence of occult recurrent tumour; all of these had concurrent evidence of distant metastatic disease (lung, liver, bone). Patients have been followed up for from between 1 and 15 years from diagnosis (median 5.5 years). The extremely low yield of tumour recurrence on computed tomographic scanning in the absence of a palpable axillary mass (4/84 patients, 5%; 95% CI 1–12), cannot justify CT as a method of screening for clinically occult axillary relapse in patients with arm symptoms following axillary surgery and radiotherapy for breast cancer. Computed tomographic scanning in these patients should only be employed to confirm the clinical suspicion of tumour as a baseline prior to further treatment.

Eighty-four patients with chemodectoma of the head and neck presented to the Royal Marsden Hospital between 1949 and 1985. For tumors arising at the skull base (glomus jugulare and glomus tympanicum) 46 were treated with radiotherapy alone resulting in an actuarial local control rate of 73% at 25 years; 13 were treated with surgery plus radiotherapy with no recurrences during a median follow-up of 9 years; 4 had surgery alone but all recurred by 7 years. For tumors of the soft tissues of the neck (carotid body and glomus vagale) 13 were treated with surgery alone with an actuarial control rate of 54% at 15 years; 4 were treated with radiotherapy which resulted in local control at 1, 2, 8 and 11 years; and one patient who received both surgery and radiotherapy remained controlled at 1 year. Although comparison between radiotherapy and surgery in terms of tumor control is not simple, the case is argued for more frequent use of radiotherapy at all sites. This case is strengthened by minimal morbidity from radiotherapy in doses which appear effective: in the range of 45–50 Gy in 25 daily fractions over 5 weeks.

We describe three patients with well-differentiated thyroid carcinoma in whom no rise in serum thyroid-stimulating hormone (TSH) was observed after the discontinuation of thyroid hormone. In one patient, TSH deficiency was due to panhypopituitarism secondary to the empty sella syndrome. This patient initially failed to respond to (131)I but was subsequently given purified porcine TSH prior to further (131)I therapy. This resulted in a significant fall in the thyroglobulin level. In two further patients, TSH levels were suppressed by functioning follicular thyroid cancer. There was an unexpectedly good (131)I uptake by metastases and they responded clinically. The failure of TSH levels to rise after thyroid hormone withdrawal should prompt investigation of the pituitary-thyroid axis. In patients with hypopituitarism, exogenous TSH is recommended, to increase the (131)I uptake. In contrast, when TSH is suppressed by functioning tumour, radio-iodine treatment may still be effective.

OBJECTIVE: To assess the outcome of thyroid cancer diagnosed during pregnancy. DESIGN: Retrospective analysis of patients diagnosed between 1949 and 1997 with thyroid cancer presenting during pregnancy. RESULTS: Nine women with a median age of 28 years were identified. A thyroid nodule was discovered by the clinician during routine antenatal examination in four cases, the remainder had noted a lump in the neck. In all patients, the nodule was reported to almost double in size during the pregnancy. One patient underwent subtotal thyroidectomy during the second trimester; eight were operated on within 3 to 10 months from delivery. Total thyroidectomy was performed in five and subtotal thyroidectomy in four. All tumours were well differentiated and ranged in size from 1 to 6 cm. OUTCOME: The median follow-up was 14 years (5-31 years). One patient relapsed locally requiring further surgery. One patient developed bone metastases dying 7 years after presentation; her planned treatment had been delayed because of an intervening pregnancy. Eight of the original cohort of patients are currently disease free. CONCLUSIONS: Differentiated thyroid cancer presenting in pregnancy generally has an excellent prognosis. When the disease is discovered early in pregnancy, surgery should be considered in the second trimester but radioiodine scans and treatment can be safely delayed until after delivery. In all cases, treatment should not be delayed for more than a year.

Introduction: Previous studies have included Hurthle cell carcinoma (HCC) as a variant of follicular thyroid carcinoma in analysis of clinical outcome and others have failed to adequately distinguish between benign and malignant Hurthle cell neoplasms. The aim of this study was to report our experience of histologically confirmed malignant HCC, identifying patient, tumour and treatment factors that predict outcome. Methods: A retrospective review was undertaken of all patients treated with HCC between 1946 and 2003. Study end-points were disease free survival (DFS) and cause-specific survival (CSS). Demographic, pathological and treatment-related factors were all correlated with the study end-points. Results: Sixty-two patients were followed up for a median (range) of 58 months (2-629). On multivariate analysis, only extent of surgery (p < 0.001) was an independent factor affecting CSS. Lymph node status (p = 0.008), presence of metastases at diagnosis (p = 0.005) and turnout, stage (p = 0.009) were independent predictors of DFS. Conclusions: HCC appears to be a separate entity from follicillar thyroid carcinoma (IFTC), with a more aggressive disease profile. Lymph node status, tumour stage, and the presence of metastases are independent predictors of DFS. Radical surgery may improve outcome in HCC. (C) 2008 Elsevier Ltd. All riahts reserved.

Background and aims To report our experience and review the literature of thyroid cancer obstructing the great veins in the neck, highlighting clinical aspects and response to treatment. Methods Clinical data were collected from the thyroid cancer register and from follow-up clinic visits of patients referred to the Thyroid Unit at the Royal Marsden Hospital. A Medline literature search was conducted between 1980 and 2007. Results Of 1448 patients with thyroid cancer on our cancer register and treated in our unit over the last 60 years, we identified five patients, four women and one man, aged 43 – 81 years with a median follow up of 28 (24–78) months in whom tumour had occluded the great veins in the neck. All patients underwent total thyroidectomy and all subsequently received ablative 131I with the exception of patient 3 whose post-operative isotope scan shown no significant 131I uptake. External beam radiotherapy to the neck and upper mediastinum was used for residual disease control in the 5 patients. The median survival was 28 months and the disease-free survival was 24 months. One patient remains asymptomatic but with disease 53 months after initial presentation. Survival in this small series is significantly better than that previously reported for this condition. Conclusion A multimodality therapeutic approach comprising surgery, radioiodine and external beam radiotherapy may give the best results for patients in whom thyroid cancer is occluding the great veins.

Struma ovarii are rare tumours and just over 400 cases are reported in the world literature (Gould et al, 1983). The incidence of malignancy is reported as 5–10% of all cases of struma ovarii (Marcus & Marcus, 1961) but has been reported as less (Gould et al, 1983). The metastasis rate is estimated to be 5–6% (Emge, 1940) and only 21 cases with metastases have so far been reported (Dalley, 1970; Pardo-Mindan & Vazquez, 1983; Willemse et al, 1987; Rosenblum et al, 1989). Owing to their rarity, there is no universal agreement as to management. Surgical excision continues to remain the initial definitive primary treatment. However, metastatic and recurrent malignant struma ovarii have been treated with radioactive 131I (Woodruff et al, 1966; Kempers et al, 1970; Willemse et al, 1987). Intra-peritoneal radiocolloids (Woodruff et al, 1966; Rosenblum et al, 1989) and external beam radiotherapy (Gonzalez-Angulo et al, 1963; Woodruff et al, 1966; Pardo-Mindan & Vazquez, 1983) have also found a useful role in pall...

Thyrotoxicosis due to functioning metastases in differentiated thyroid cancer (DTC) is exceedingly rare. We report a case of follicular carcinoma in a 54-year- old manager, who presented with thyrotoxicosis, shortness of breath and lung metastases. Transbronchial biopsy of a pulmonary nodule demonstrated normal thyroid. This was interpreted as representing very well-differentiated thyroid cancer. CT, 131 I whole-body imaging and dosimetry is described following total thyroidectomy and repeated radioiodine administration (cumulative activity 34.6 GBq). The patient became asymptomatic with almost complete eradication of the pulmonary metastases. Potential complications of thyroid storm, bone marrow failure and pulmonary fibrosis following radioiodine are discussed, together with methods to minimise these risks.

Aims Salivary gland toxicity is a common, but not widely appreciated, adverse effect of high-dose radioiodine ( 131 I). This study was carried out to determine the incidence of symptoms of salivary gland damage after 131 I treatment for differentiated thyroid cancer. Materials and methods This was a prospective study of 76 consecutive patients attending thyroid cancer treatment. Symptoms of salivary gland damage (dry mouth, pain and swelling) were assessed during hospital admission and at follow-up visits. Additionally, a retrospective analysis was carried out of patients recorded in our database as having chronic salivary gland swelling after 131 I ablation. Results Twenty patients (26%) developed salivary gland toxicity, 11 (15%) had symptoms within the first 48h, continuing for 12 months in seven of these patients. The onset of toxicity in a further nine (12%) patients with persistent symptoms did not occur until 3 months after therapy. In total, 16 (21%) patients had evidence of chronic toxicity, typically xerostomia, at 12 months. Toxicity was more common after repeated 131 I administration. After searching our thyroid cancer database, we identified an additional five patients to have chronic salivary gland swelling (chronic sialadenitis or pleomorphic adenoma) 20 months to 23 years after 131 I. Conclusions Pain, swelling and dry mouth occurred frequently after 131 I, with some developing symptoms months or years after administration. Early recognition of salivary gland complications may help to reduce morbidity in these patients.

cancer in general is due to the preponderance of well-differentiated carcinoma, a subset of rare thyroid tumors exist that exhibit aggressive behavior and poor prognosis. These require careful consideration and different treatment paradigms to optimize clinical outcome. Extremely rare types of thyroid cancer include thymus-like tumors, mucoepidermoid carcinoma, spindle cell tumor, mixed medullary follicular cancers, and teratoma. In view of the limited literature on their management these extremely rare types are not covered in this chapter.

Metastatic thyroid carcinoma causing superior vena caval obstruction diagnosed on I-131 scan An 80-year-old woman was referred for a painless mass arising in right side of her neck of 4 months' duration. Ultrasound revealed a multinodular goiter, but cytology confirmed a follicular carcinoma. Thyroid function was normal. Total thyroidectomy was performed with evidence of tumor infiltration into the strap muscles extending up to the right submandibular gland and right internal jugular vein, which was completely occluded. Radioiodine was considered as the treatment of choice postoperatively. This is an unusual case of SVC obstruction caused by tumor embolus diagnosed on I-131 scan.

Summary Background Differentiated thyroid cancer (DTC) presenting with distant metastases is uncommon. Prognostic factors that affect survival remain unclear. Aim To evaluate factors influencing the survival of patients with DTC presenting with distant metastases. Method A retrospective study of 111 patients (62 F, 49 M) with DTC who presented with distant metastases (M1) treated at the Royal Marsden Hospital from 1940 to 2002. Results The median follow-up of living patients was 3·9 years (0·3–48) with a 10-year cause-specific survival rate of 31%. Histology identified 46 papillary, 60 follicular and five Hurthle cell cancers. Sites of metastases comprised 54 lung (49%), 27 bone (24%), 21 multiple sites (19%) and nine with other single sites affected (8%). Near-total, total or completion thyroidectomy was performed in 56% of patients, radioiodine ablation in 76% and radioiodine therapy in 67%. External beam radiotherapy was given to 12 patients and the same number received chemotherapy. Univariate analysis was performed with cause-specific survival as the main outcome measure. Age over 70, poorly differentiated tumours and Hurthle cell cancers were associated with worse outcomes (P

A retrospective review was conducted of patients treated for thyroid non-Hodgkin's lymphoma (TNHL) at the Royal Marsden Hospital between 1936 and 1996 to determine the effect of radiotherapy (RT) on outcome. 91 patients were identified from the Thyroid Unit Database. There were 77 females and 14 males with a median age of 65 years (range 22-87 years). RT was delivered according to two separate policies: (1) involved field radiotherapy (IFRT) to the thyroid bed and cervical lymph nodes; (2) extended field radiotherapy (EFRT) covering the thyroid bed, cervical and mediastinal lymph nodes. 89 patients received RT as part of definitive treatment following surgery, to a dose of approximately 40 Gy. 25 patients received IFRT and 64 patients EFRT. 27 patients received cytotoxic chemotherapy. 18 patients (72%) treated with IFRT died of TNHL with a median relapse free survival (RFS) of 10 months and a median overall survival (OS) of 21 months. In contrast, only 29 patients (46%) treated with EFRT died of TNHL with a median RFS of 76 months (p = 0.01 for RFS with respect to IFRT and p = 0.04 for OS). Significantly more patients treated with IFRT relapsed locally (52% vs 27%). There was no difference in the rates of systemic relapse (20% vs 22%). EFRT alone for Stage I, but not for Stage II disease, yielded acceptable rates of local control and disease free survival with doses of at least 40 Gy. These historical data strongly support the addition of combination chemotherapy to the treatment regimen in all patients with Stage II disease. Indeed, in recent years this has become the standard of care for all cases of thyroid lymphoma unless the histology is of marginal zone type (mucosa associated lymphoma tissue (MALT) lymphoma).

Aims Radio-iodine is effective in treating metastatic differentiated thyroid cancers. In 20% of cases, however, these tumours fail to take up radio-iodine, and treatment options are then limited. Failure of iodine uptake might be reversible using redifferentiating agents. Retinoids redifferentiate a variety of cell types and increase iodine uptake in thyroid tumour cells in vitro . The aim of this study was to assess whether oral isotretinoin could increase radio-iodine uptake in patients with iodine-uptake-negative metastatic thyroid cancer. Methods Patients who had iodine-uptake-negative metastatic papillary or follicular thyroid cancers were selected from the thyroid database at The Royal Marsden Hospital and enrolled to an open-label, non-randomised phase II trial. Sites of metastatic disease were assessed using computed tomography or magnetic resonance imaging, and absence of iodine uptake was confirmed using a diagnostic radio-iodine scan before study entry. In eligible patients, isotretinoin was prescribed at 1.5mg/kg/day orally for 8 weeks. Response was assessed within 2 weeks of completing treatment with repeat radio-iodine scan. All patients were reviewed every 2 weeks during treatment for assessment of toxicity. Results Sixteen patients were treated with isotretinoin between January 2001 and July 2002: nine with metastatic papillary thyroid cancer, five with metastatic follicular cancer and two with Hurthle cell carcinoma. Median age was 57 years. All patients tolerated 8 weeks of oral isotretinoin. Mucocutaneous side-effects and minor changes in biochemical or lipid profiles were documented in most patients. In one patient, radio-iodine uptake increased after retinoid administration; however, this was not large enough to permit a significant dose of iodine to be given to sites of metastatic disease. In the other 15 patients, no radio-iodine uptake was documented. Conclusion Treatment with isotretinoin does not reliably increase radio-iodine uptake in patients with metastatic thyroid cancer. This treatment alone does not enable radio-iodine to be used for further treatment.

Four patients are presented, who were initially diagnosed and treated for differentiated thyroid carcinoma, but subsequently discovered to have medullary carcinoma. We suggest that tumour histopathology needs to be carefully reviewed in all cases of thyroid cancer, especially those having atypical clinical or pathological features. This should be completed prior to further therapeutic intervention, such as the administration of ablative radioactive iodine.