In patients with well-differentiated neuroendocrine tumours, there is no apparent benefit of somatostatin analogues after disease control by peptide receptor radionuclide therapy.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) and somatostatin analogues (SSAs) are commonly combined as primary treatment for neuroendocrine neoplasms (NEN), and SSAs given as maintenance. We sought to evaluate whether sequential therapy with PRRT followed by SSAs has progression or survival benefits in patients with NEN after disease control by PRRT. METHODS: This prospective, randomised, single-centre study had as principal eligibility criteria: unresectable, locally advanced, or metastatic, histologically confirmed well-differentiated NEN; no symptoms/biochemical diagnosis of carcinoid syndrome; no SSAs or ≤ 3 months of SSAs before PRRT; and stable disease or partial or complete response after PRRT. Altogether, 115 patients were randomised 2:1 to an SSA group (n = 74) given octreotide acetate LAR every 4 weeks, or a control group (n = 41) receiving only best supportive care. Octreotide treatment was to stop upon intolerable toxicity or patient refusal, or, at physician/patient discretion, upon NEN progression. The primary endpoint was progression-free survival (PFS), the secondary endpoint, and overall survival (OS). RESULTS: Median (25th-75th percentile) follow-up from the first PRRT activity to death or latest observation was 6.6 (3.18-10.22) years. During that time, 71/115 patients (62%) progressed, 52/74 (70%) in the SSA group, and 19/41 (46%) in the control group (p = 0.01). Eighty-eight/115 patients (76%) died, 58/74 (78%) in the SSA group, and 30/41 (73%) in the control group (p = 0.52). Median (95% CI) PFS was 4.7 (2.8-7.7) years in the SSA group, and 6.4 (4.1-not reached) years in controls. Overall, median OS was 6.6 years. Neither PFS nor OS differed between groups (p = 0.129, p = 0.985, respectively). CONCLUSIONS: In patients with disease control after PRRT, subsequent SSA treatment appeared not to be associated with better PFS or OS. Whether to continue SSA administration upon progression after PRRT requires evaluation in a prospective, randomised, controlled multicentre study with a relatively homogeneous sample.

Stereotactic radiotherapy is a useful treatment option for patients with medullary thyroid cancer.

The role of radiotherapy in advanced medullary thyroid carcinoma (MTC) is confined to patients in whom surgical treatment or the administration of tyrosine kinase inhibitors are not possible or contraindicated. High fractionated radiation doses during radiosurgery or fractionated stereotactic radiotherapy are applied to reduce cancer-related symptoms and stabilize irradiated lesions. This study aimed to retrospectively evaluate the therapeutic effect of stereotactic radiotherapy in MTC patients. MATERIAL AND METHODS: The study group involved 11 MTC patients, treated due to 16 cancer lesions, mainly bone metastases (10 lesions), lymph node (2 lesions) metastases, or liver metastases (2 lesions), one primary thyroid tumor, and one MTC recurrence in the thyroid bed. The fractionated and total radiation doses ranged between 5 and 12 Gy and 8-44 Gy, respectively. Six lesions were treated with a single radiation fraction, three lesions with 2 fractions, another 6 lesions with 3 fractions, whereas the remaining one metastatic lesion with 9 fractions of stereotactic radiosurgery. RESULTS: The beneficial effect of stereotactic radiosurgery was obtained in all treated lesions. None of treated lesions progressed in the further disease course. Fourteen lesions were stable (87.5 %), including eight lesions showing progression before radiosurgery (good response). Disease control was obtained in all soft-tissue metastases. Regarding bone metastases, partial regression was achieved in 20 % lesions, whereas in 30 % lesions progressive before radiotherapy, the treatment led to disease stabilization. CONCLUSIONS: Our data pointed to the effectiveness of high-dose fractionated radiotherapy in MTC. However, an observation of a larger group of patients is required to confirm it.

Thyroid remnant ablation with radioiodine activity of 30, 60, and 100 mCi in patients with differentiated thyroid cancer - a prospective comparison of long-term outcomes.

Introduction: The aim of this prospective study was to evaluate long-term outcomes in differentiated thyroid cancer (DTC) patients postoperatively treated with distinct RAI activities of 30 mCi, 60 mCi, and 100 mCi. Material and methods: The analysis involved 277 low-risk and 46 intermediate-risk patients, who underwent radioiodine (RAI) ablation with 30 mCi, 60 mCi or 100 mCi under prospective, randomized clinical trials. Seventy-eight patients from the low-risk group received 30 mCi, whereas 125 and 74 patients received 60 mCi and 100 mCi, respectively. Regarding the intermediate-risk group, 20 patients were given 60 mCi, and 26 subjects were given 100 mCi. The mean time of follow-up was 11 years. Results: An excellent treatment response was obtained in 88%, 89% and 90% of low-risk patients treated with 30 mCi, 60 mCi, and 100 mCi, respectively, and in 85% of intermediate-risk patients, who were administered 60 or 100 mCi. An indeterminate response was achieved in 9.4% and 6.5%, whereas an incomplete structural response was obtained in 1.4% and 6.5% of low-risk and intermediate-risk patients, respectively. An incomplete biochemical response was observed only in 2.2% of intermediate-risk patients. The differences in treatment response regarding RAI activity were not significant. Conclusions: RAI activity of 30 mCi demonstrates a comparable efficacy as 60 mCi and 100 mCi in low-risk DTC. RAI activity of 60 mCi seems to be effective in intermediate-risk DTC.

Only peak thyroglobulin concentration on day 1 and 3 of rhTSH-aided RAI adjuvant treatment has prognostic implications in differentiated thyroid cancer.

OBJECTIVE: In patients with differentiated thyroid carcinoma (DTC), serum thyroglobulin levels measured at the time of remnant ablation after thyroid hormone withdrawal were shown to have prognostic value for disease-free status. We sought to evaluate serial thyroglobulin measurements at the time of recombinant human thyroid-stimulating hormone (rhTSH)-aided iodine 131 (131I) adjuvant treatment as prognostic markers of DTC. METHODS: Six hundred-fifty patients with DTC given total/near-total thyroidectomy and adjuvant radioiodine post-rhTSH stimulation were evaluated. Thyroglobulin was measured on day 1 (Tg1; at the time of the first rhTSH injection), day 3 (Tg3; 1 day after the second, final rhTSH injection), and day 6 (Tg6; 3 days post-radioiodine administration). Treatment failure was defined as histopathologically confirmed locoregional recurrence, or radiologically-evident distant metastases (signs of disease on computer tomography (CT) or magnetic resonance imaging (MRI), or abnormal foci of radioiodine or [18F] fluorodeoxyglucose ([18F]FDG) uptake. RESULTS: In univariate analysis, Tg1 (p < 0.001) and Tg3 (p < 0.001), but not Tg6, were significantly associated with structural recurrence. In multivariate analysis of the overall cohort, only Tg3 was independently associated with structural recurrence. In multivariate analysis of the subgroup (n = 561) with anti-Tg antibodies titers below the institutional cut-off, 115 IU/mL, Tg1 was an independent prognostic marker. Tg1 and Tg3 cutoffs to best predict structural recurrence were established at 0.7 ng/mL and 1.4 ng/mL, respectively. CONCLUSIONS: Tg1 and Tg3, measurements made after rhTSH stimulation but before radioiodine treatment, independently predict a low risk of treatment failure in patients with DTC. Levels measured post-radioiodine application (e.g., Tg6) are highly variable, lack prognostic value, and hence can be omitted.

TERT Promoter Mutations and Their Impact on Gene Expression Profile in Papillary Thyroid Carcinoma.

BACKGROUND: Telomerase reverse transcriptase promoter (TERTp) mutations are related to a worse prognosis in various malignancies, including papillary thyroid carcinoma (PTC). Since mechanisms responsible for the poorer outcome of TERTp(+) patients are still unknown, searching for molecular consequences of TERTp mutations in PTC was the aim of our study. METHODS: The studied cohort consisted of 54 PTCs, among them 24 cases with distant metastases. BRAF V600E, RAS, and TERTp mutational status was evaluated in all cases. Differences in gene expression profile between TERTp(+) and TERTp(-) PTCs were examined using microarrays. The evaluation of signaling pathways and gene ontology was based on the Gene Set Enrichment Analysis. RESULTS: Fifty-nine percent (32/54) of analyzed PTCs were positive for at least one mutation: 27 were BRAF(+), among them eight were TERTp(+), and 1 NRAS(+), whereas five other samples harbored RAS mutations. Expression of four genes significantly differed in BRAF(+)TERTp(+) and BRAF(+)TERTp(-) PTCs. Deregulation of pathways involved in key cell processes was observed. CONCLUSIONS: TERTp mutations are related to higher PTC aggressiveness. CRABP2 gene was validated as associated with TERTp mutations. However, its potential use in diagnostics or risk stratification in PTC patients needs further studies.

Postoperative Radioiodine Treatment within 9 Months from Diagnosis Significantly Reduces the Risk of Relapse in Low-Risk Differentiated Thyroid Carcinoma.

PURPOSE: Although postoperative radioiodine (RAI) therapy has been used in patients with differentiated thyroid carcinoma (DTC) for many years, there is still lack of data defining the timing of RAI administration. A retrospective analysis was carried out to answer the question whether the time of postoperative RAI treatment demonstrated any impact on long-term outcomes, particularly in low-risk DTC. MATERIAL: The analyzed group involved 701 DTC patients staged pT1b-T4N0-N1M0, who underwent total thyroidectomy and postoperative RAI therapy. According to the time interval between DTC diagnosis and RAI administration, patients were allocated to one of three groups: up to 9 months (N = 150), between 9 and 24 months (N = 323), and > 24 months (N = 228). Median follow-up was 12.1 years (1.5-15.2). RESULTS: Based on an initial DTC advancement and postoperative stimulated thyroglobulin concentration patients were stratified as a low-, intermediate-, and high-risk group. Low-risk patients, who received RAI therapy up to 9 months, demonstrated significantly lower risk of relapse comparing to those, in whom RAI was administered between 9 and 24 months and after 24 months since DTC diagnosis: 0%, 5.5%, and 7.1%, respectively. Regarding intermediate- and high-risk groups, the differences in the timing of postoperative RAI treatment were not significant. CONCLUSION: If postoperative RAI treatment is considered in low-risk DTC, any delay in RAI administration above 9 months since diagnosis may be related to poorer long-term outcomes.

The role of postoperative adjuvant radiotherapy in the local control in medullary thyroid carcinoma.

BACKGROUND: The value of postoperative radiotherapy in the treatment of medullary thyroid carcinoma (MTC) has not been unequivocally demonstrated. Therefore our study aimed to answer the question of whether adjuvant radiotherapy showed any impact on the risk of local recurrence and whether there were any differences in response to radiotherapy between hereditary and sporadic MTC. METHODS: A retrospective analysis involved 254 MTC patients, among them 73 patients with a hereditary disease. Two hundred and twenty-four patients, including 43 persons at high risk of local relapse, underwent only initial surgery, 18 other patients were operated due to MTC recurrences, whereas the remaining 12 patients had cytoreductive procedure or were not amenable for surgery. Radiotherapy was carried out in 132 patients. One hundred and twenty patients underwent adjuvant radiotherapy, among them 102 patients after initial surgery. The median follow up was 10 years (range 0.5-29 years). RESULTS: Local recurrence occurred in 107/254 patients, among them in 63 subjects after prior radiotherapy. The frequency of relapse showed significant, increasing trend toward higher MTC stages (p<0.001). More relapses were noticed in patients with lymph node metastases at diagnosis. Adjuvant radiotherapy was associated with a lower risk of nodal recurrence only in high-risk patients, particularly if lymph node metastases were present at MTC diagnosis. The differences between hereditary and sporadic subgroups were not significant. CONCLUSIONS: Adjuvant radiotherapy has a limited importance in MTC treatment. It should be considered in high-risk MTC patients. The presence of RET mutation does not influence the response to radiation.

[131I-MIBG therapy in the treatment of pheochromocytoma in children--own experiences]. / Terapia 131I-MIBG w leczeniu guzów chromochlonnych u dzieci--doswiadczenia wlasne.

Three cases of pheochromocytoma in children/adolescents or young adults treated by 131I-MIBG are presented in this study. In one patient 131I-MIBG was administrated after ineffective surgical treatment and chemotherapy of a benign retroperitoneal tumor, whereas in two other patients 131I-MIBG therapy was carried out because of malignant pheochromocytoma dissemination. In a child with retroperitoneal paraganglioma decrease of tumor size and its fibrosis after 131I-MIBG therapy allowed radical surgery and complete recovery. In two other cases partial remission was achieved. All patients showed a good subjective response with improvement of the general condition and better blood pressure control. In two children adverse reactions such as leucopenia, hypothyroidism or hypogonadism were observed. The presented data confirm effectiveness and acceptable tolerance of 131I-MIBG treatment in pheochromocytoma, what is very important in pediatric patients.

Guidelines of Polish National Societies Diagnostics and Treatment of Thyroid Carcinoma. 2018 Update.

Significant advances have been made in thyroid can-cer research in recent years, therefore relevant clinical guidelines need to be updated. The current Polish guidelines "Diagnostics and Treatment of Thyroid Carcinoma" have been formulated at the "Thyroid Cancer and Other Malignancies of Endocrine Glands" conference held in Wisla in November 2015 [1].

Managing tyrosine kinase inhibitors side effects in thyroid cancer.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are a new group of drugs that show the activity against receptors of different growth factors leading to the inhibition of tumor cells growth and proliferation. To date, four different TKIs have been approved for RAI-refractory DTC or MTC: sorafenib, lenvatinib, vandetanib and cabozantinib. METHODS: This review focuses on treatment toxicity related to above-mentioned TKIs administration in thyroid carcinoma. RESULTS: TKIs cause a variety of side effects in nearly all treated patients, among them: hypertension, gastrointestinal disturbances (diarrhea, abdominal pain, nausea, vomiting), skin reactions (rashes, acne, hand-foot syndrome), fatigue and weight loss. Most of side effects are mild and moderate and manageable by dose adjustment (dose interruptions and dose reductions) and concomitant therapy. However, some complications although rare may be life-threatening or even fatal. Conclusion​: TKIs shows an acceptable toxicity profile in patients with advanced and progressive RAI refractory DTC and MTC but only in experienced hands familiar with TKIs, particularly with diagnostics and management of treatment-related complications and also with thyroid carcinoma, what is essential to safely care for the patients and keep them on kinase inhibitor therapy as long as the treatment is beneficial without an unfavorable impact on their quality of life.

Ongoing risk stratification for differentiated thyroid cancer (DTC) - stimulated serum thyroglobulin (Tg) before radioiodine (RAI) ablation, the most potent risk factor of cancer recurrence in M0 patients.

INTRODUCTION: Adequate postoperative risk assessment currently constitutes the principle of DTC treatment and further management. The aim of the study - a retrospective assessment of risk factors influencing DTC relapse. MATERIAL AND METHODS: The study group consisted of 510 DTC staged pT1b-T4N0-N1M0, in whom total thyroidectomy and complementary radioiodine (RAI) treatment were carried out. In 71% papillary thyroid cancer was diagnosed, whereas in the remaining 29% - follicular thyroid carcinoma. Based on TNM classification from 1997, T1 feature was diagnosed in 11.6%, T2 in 35.1%, T3 in 8.4%, T4 in 9,4%, while in 35.5% - Tx. Lymph node metastases were present in 24.7% of cases. Median follow-up was 12.1 years (1.5-15.2). RESULTS: Age at DTC diagnosis, tumour diameter (T), lymph node metastases (N1), stimulated thyroglobulin, and RAI uptake in thyroid bed at qualification for RAI ablation significantly influenced freedom from progression time (FFP) in a multivariate analysis. When postoperative stimulated Tg was > 30 ng/mL the risk of relapse increased nearly six-fold, whereas the presence of N1 feature - four-fold. The total risk of relapse in the whole group was 12.55% while median FFP was 154.8 months. Five-year and 10-year FFP was 90.1% and 87.5%, respectively. CONCLUSIONS: Postoperative stimulated thyroglobulin level was the most potent, independent risk factor influencing FFP in DTC patients. Age above 60 years, an initial DTC stage (T and N features), and low RAI uptake in thyroid bed ( < 1%) were related to a higher risk of DTC relapse, whereas the investigated histopathological features were insignificant.

Radioactive iodine (RAI) treatment of hyperthyroidism is safe in patients with Graves' orbitopathy--a prospective study.

INTRODUCTION: Radioactive iodine (RAI) therapy may induce or worsen orbitopathy (GO) in Graves' disease (GD). The aim of this study was a prospective assessment of the risk of GO exacerbation in a GD patients cohort submitted to RAI therapy for hyperthyroidism. MATERIAL AND METHODS: 208 consecutive GD patients treated with 131I in 2007 were enrolled. The analysis was performed on 156 patients strictly monitored for one year. Glucocorticosteroid (GCS) prophylaxis was administered if GO symptoms or GO history were present, and in cases of tobacco smokers even without GO symptoms. Clinical and biochemical evaluation at one, three, six, and 12 months after therapy was performed in the whole group, then at 24 months in 138 patients. RESULTS: There was no severe GO progression in patients without GO symptoms at the time of RAI treatment. The risk of severe GO worsening for preexisting GO patients (demanding systemic GCS administration) during the 12-month follow-up after RAI therapy was 10%. 12 and 24 months after 131I administration, stable improvement compared to the initial GO status had been achieved in most (98-96%) patients. CONCLUSIONS: 1. In patients with mild GO, the risk of severe GO worsening after RAI therapy is acceptable, as long as RAI therapy is applied with GCS cover. 2. In patients without GO symptoms at the time of RAI therapy but with a history of GO and with subclinical GO diagnosed by MRI only, the risk of severe progression is minimal. 3. Distant outcomes of RAI treatment confirmed its safety in GO patients.

Radioiodine thyroid remnant ablation in patients with differentiated thyroid carcinoma (DTC): prospective comparison of long-term outcomes of treatment with 30, 60 and 100 mCi.

BACKGROUND: The aim of this study is to compare the effectiveness of 131I therapy between three groups of DTC patients who received 30, 60 or 100 mCi for thyroid remnant ablation after total thyroidectomy and were postoperatively judged with low risk of cancer recurrence. METHODS: The project was designed as a two-stage, prospective randomized clinical trial. In 1998-2001 in a randomized prospective study the early comparison of treatment with 30 mCi vs 60 mCi suggested the lower 131I activity to be less effective, whereas in 2003-2005 the comparison between 60 vs 100 mCi showed no significant differences. The present study comprises the long-term assessment of the disease course in 3 study groups. RESULTS: A group of 309 DTC patients (285 women and 24 men) with no clinical, histopathological, sonographical or biochemical signs of persistent disease were included after total thyroidectomy and appropriate extent of neck lymph node dissection (265 with papillary and 44 with follicular thyroid cancer). For radioiodine thyroid remnant ablation, 30 mCi of 131I was applied in 86 patients, whereas 60 mCi in 128 and 100 mCi in 95 patients. The median follow-up was 10 years (2-12) for subjects treated with 30 mCi and 60 mCi and 6 years (2-6) for patients treated with 100 mCi of 131I. In the first evaluation, published previously, we observed that because of incomplete thyroid remnant ablation, the second 131I treatment was necessary in 10% patients, without difference between groups treated with 60 and 100 mCi and in 22% patients treated with 30 mCi. All patients entered full remission. To evaluate the long-term outcome of the adjuvant 131I treatment, the course of the follow-up and the most recent disease status were assessed by sonography, radiological examinations and serum Tg estimation (on LT4-suppressive treatment). Within the whole observation period local relapse was stated in 2 (2.4%), 4 (3%) and 3 (3%) patients treated with 131I activities of 30 mCi, 60 mCi and 100 mCi respectively and serum Tg concentration on LT4-suppressive treatment was low, without differences between groups. CONCLUSIONS: No significant differences in the 5 years efficacy of thyroid remnant radioiodine ablation using 30, 60 and 100 mCi were observed in low-risk DTC patients operated by total thyroidectomy and neck lymph node dissection. However, patients treated initially with 30 mCi, required second course of radioiodine in 22%, while this was necessary only in 13,3% and 11,2% of patients treated with 60 mCi and 100 mCi respectively.

13-cis-retinoic acid re-differentiation therapy and recombinant human thyrotropin-aided radioiodine treatment of non-Functional metastatic thyroid cancer: a single-center, 53-patient phase 2 study.

UNLABELLED: In 30-50% of patients with metastatic non-medullary thyroid cancer the metastases are not radioiodine-avid and so there is no effective treatment. Retinoids have demonstrated inhibition of thyroid tumor growth and induction of radioiodine uptake. The aim of our study was to assess benefits of the retinoic acid (RA) treatment to re-differentiate non-functional NMTC metastases. PATIENTS AND METHODS: In this prospective study, 53 patients with radioiodine non avid metastatic disease (45) or hyperthyroglobulinemia (8) were treated with 13-cis-retinoic acid (13-CRA) [1.0 mg/kg/day over 1st week and then 1.5 mg/kg] for six weeks prior to I-131 treatment performed under rhTSH stimulation. The re-differentiating effect of RA was evaluated by serum thyroglobulin (Tg) monitoring before and after cessation of RA treatment and by qualitative analysis of iodine uptake on the post-therapeutic whole body scan (rxWBS). RESULTS: 13-CRA induced radioiodine uptake in 9 (17%) of patients. In the univariate analysis neither the patient's gender, age, tumor histopathology, uptake in thyroid bed nor time since thyroid cancer diagnosis was associated with results of rxWBS.41 (77%) patients were evaluable for Tg response before and after to 13-CRA treatment. There was a statistically significant increase in median Tg level (60 v. 90 ng/ml, p < 0.05). There was no difference in Tg increase between scintigraphic responders and non-responders.13-CRA and RIT was repeated at least once in 8 of 9 scintigraphic responders. None of them showed tumor regression by radiological imaging within 12 months after the first treatment, 4/9 (44%) of them had disease progression.13-CRA treatment was well-tolerated. All but one patient complained of at least one side effect the most prevalent being lip dryness (98%). All side effects were transient and resolved within 2 weeks after 13-CRA cessation. CONCLUSION: Our results show that in patients with non-functional metastases from NMTC, 13-CRA is able to exert some re-differentiation effect by induction of radioiodine uptake in <20% of patients and increase of Tg serum level in about 30% of them. Nevertheless, this does not transfer into clinical benefit as it neither induces measurable tumor response nor prevents disease progression.