Daria Handkiewicz-Junak

Total Thyroidectomy and Adjuvant Radioiodine Treatment Independently Decrease Locoregional Recurrence Risk in Childhood and Adolescent Differentiated Thyroid Cancer

We sought to assess whether extensive surgical treatment, postsurgical radioiodine therapy, or both decrease the risk of locoregional recurrence (LR) after curative primary treatment in children and adolescents diagnosed with differentiated thyroid cancer (DTC) at age ≤18 y. Methods: To determine the incidence of and identify predictive factors for thyroid bed recurrence (TBR) or lymph node recurrence (NR), we performed a chart review and retrospective multivariate Cox regression analysis on 235 patients with DTC diagnosed at age ≤18 y and managed with curative intent at our tertiary referral center from 1973 to 2002; 40 of these patients had distant metastases at diagnosis. We also determined overall and recurrence-free survival and generated curves for these variables using Kaplan–Meier and Cox univariate analysis. Results: During a median follow-up of 82 mo (range, 5–402 mo), no DTC-related deaths occurred, 203 (86%) children remained recurrence-free, and 32 (14%) children had LR, including TBR in 9 (28% of LR), NR in 20 (63% of LR), and both in 3 (9% of LR). Among patients treated with radical intent and showing no distant metastases, the most recent thyroglobulin level was <1 ng/mL in all but 4% of cases. The median time from the first surgery to LR was 37 mo (range, 9–280 mo). In multivariate analysis, significant risk factors for TBR were less than total thyroidectomy and lack of postsurgical radioiodine treatment (respective risk increases of 9.5 [P = 0.04] and 11 times [P = 0.03]). For NR, classic papillary histology, incomplete primary lymph node management (i.e., lack of modified lymphadenectomy of affected lymph nodes or lack of confirmation of disease-free nodes by intraoperative staging), and absence of adjuvant radioiodine therapy were independent significant predictive factors that increased the recurrence risk by 1.9 (P = 0.02), 3.3 (P = 0.02), and 3.2 (P = 0.02) times, respectively. Age or sex did not correlate with LR risk. Conclusion: In DTC patients ≤18 y of age, extensive initial therapy—consisting of total thyroidectomy combined with modified lymphadenectomy performed in case of lymph node metastases and followed by radioiodine therapy—is associated with a substantial decrease of DTC LR risk.

Molecular prognostic markers in papillary and follicular thyroid cancer: Current status and future directions.

Gene expression profiling shows that, by gene signature, the difference between BRAF-positive and BRAF-negative PTC is so distinct that BRAF-positive cancer may be regarded as a molecular subtype of papillary thyroid cancer (PTC). Since much enthusiasm surrounds the BRAF-oncogene as a molecular prognostic factor, a central focus of our consideration is to weigh the current arguments for and against applying BRAF mutation status of the tumor in clinical practice. The frequency of BRAF mutation in PTC is high-45% on average, with values over 70-80% in some populations. This will mean that implementing BRAF mutation as a factor of poor prognosis will shift many PTC patients, considered up to now as low risk ones, to the more extensive treatment. We estimate that 31% of all PTC patients and 39% of those diagnosed with stage I-II disease will face the risk of overtreatment if the decision will be based on the BRAF-positivity of their tumors. Also, the risk of undertreatment in the young patients with BRAF-negative tumors is evaluated with 26%. We think that, as of now, the evidence-based support for such consequences is still weak. Thus, there is urgent need to look for genes or gene signatures which will be helpful in the stratification of BRAF-positive tumors to specify these with poor prognosis with higher accuracy, needed for clinical decisions. Considering this, in the review we summarize the present status of knowledge on other prognosis-related gene expression changes in papillary and follicular cancer and relate them to he tumors biology.

Receptor radionuclide therapy with 90Y-DOTATOC in patients with medullary thyroid carcinomas.

UNLABELLED Metastatic medullary thyroid cancer (MTC) shows a progressive course. Surgery is the only curative treatment. In advanced disease, chemo- and radiotherapy show poor results. Newly developed somatostatin analogue [DOTA0,Tyr3]octreotide (DOTATOC) labeled to 90Y is administered in patients with endocrine tumors expressing somatostatin receptors, like MTC. Preliminary studies demonstrated that 90Y-DOTATOC could be safely administered, resulting in objective responses in 27% of patients. AIMS To evaluate the efficacy of 90Y-DOTATOC therapy in metastatic MTC patients with positive OctreoScan, progressing after conventional treatments. Twenty-one patients were retrospectively evaluated after therapy, receiving 7.5-19.2 GBq in 2-8 cycles. RESULTS Two patients (10%) obtained a complete response (CR), as evaluated by CT, MRI and/or ultrasound, while a stabilization of disease (SD) was observed in 12 patients (57%); seven patients (33%) did not respond to therapy. The duration of the response ranged between 3-40 months. Using biochemical parameters (calcitonin and CEA), a complete response was observed in one patient (5%), while partial response in five patients (24%) and stabilization in three patients (14%). Twelve patients had progression (57%). Complete responses were observed in patients with lower tumor burden and calcitonin values at the time of the enrollment. CONCLUSIONS This retrospective analysis is consistent with the literature, regarding a low response rate in medullary thyroid cancers treated with 90Y-DOTATOC. Patients with smaller tumors and higher uptake of the radiopeptide tended to respond better. Studies with 90Y-DOTATOC administered in earlier phases of the disease will help to evaluate the ability of this treatment to enhance survival. New more specific peptides and new isotopes will also represent the key of a better treatment of MTC.

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.

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 MethodsIn 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).Results13-CRA induced radioiodine uptake in 9 (17%) of patients. In the univariate analysis neither the patients 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.ConclusionOur 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.

Sorafenib for the treatment of thyroid cancer: an updated review.

Introduction: Sorafenib (Nexavar) is an oral multi-kinase inhibitor targeting B-type Raf kinase (BRAF) (both wild type and BRAFV600E), VEGFR1, VEGFR2, VEGFR3, PDGFRβ and RET (also RET/PTC) influencing both differentiated thyroid cancer (DTC) cell proliferation and angiogenesis. Areas covered: Encouraging results achieved in numerous Phase II trials were confirmed in a Phase III study conducted in radioiodine-refractory DTC. Sorafenib compared to placebo significantly prolongs progression-free survival, 10.8 versus 5.8 months, respectively. However, its administration resulted mainly in disease stabilization. No complete remission was obtained in any study. Beneficial effects were also demonstrated for medullary and anaplastic thyroid cancer; however further studies fulfilling evidence based medicine criteria are necessary. Its toxicity profile is convergent with other VEGFR inhibitors. The most common treatment-related side-effects involve skin toxicity (predominantly hand-foot skin reaction, different rashes and alopecia), gastrointestinal disturbances (diarrhea, abdominal pain), constitutional adverse reactions (anorexia, weight loss, fatigue) and hypertension. Although most adverse reactions are manageable, > 50% of patients required dose reduction. Expert opinion: Sorafenib constitutes the first line treatment option in advanced, radioiodine-refractory DTC. However, there are still no data on its efficacy in patients progressed after another tyrosine kinase inhibitor. Other applications of the drug, such as use as adjuvant therapy to 131-I treatment, requires further studies.

The Risk of Relapse in Papillary Thyroid Cancer (PTC) in the Context of BRAFV600E Mutation Status and Other Prognostic Factors.

Introduction The risk of over-treatment in low-advanced PTC stages has prompted clinicians to search for new reliable prognostic factors. The presence of BRAF mutation, the most frequent molecular event in PTC, seems to be a good candidate. However, there is still lack of randomised trials and its significance has been proved by retrospective analyses, involving a large group of patients. The question arises whether this factor is useful in smaller populations, characterised for specialised centres. Thus, the aim of the study was to evaluate the use of BRAF mutation as a potential predictive marker in PTC patients. Material 233 PTC subjects treated between 2004-2006, were retrospectively analysed. Stage pT1 was diagnosed in 64.8% patients and lymph node metastases in 30.9%. Median follow-up was 7.5 years. BRAFV600E mutation was assessed postoperatively in all cases. Results BRAF V600E mutation was found in 54.5%. It was more frequent in patients > 45 years (p=0.0001), and associated with larger tumour size (p=0.004). Patients with tumours <= 10 mm were over-represented among BRAF negative population (p=0.03). No association between BRAF mutation and other clinicopathological factors was observed. BRAF status was associated neither with relapse nor with disease-free survival (DFS) (p=0.76). Nodal status, extrathyroidal invasion and tumour size significantly influenced DFS. Conclusion The risk of PTC recurrence is mainly related to the presence of lymph node metastases and extrathyroidal invasion, whereas no impact of BRAF V600E mutation has been demonstrated.

EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer

Radium Ra-223 dichloride (radium-223, Xofigo®) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is the first targeted alpha therapy in this indication providing a new treatment option, with evidence of a significant survival benefit, both in overall survival and in the time to the first symptomatic skeletal-related event. The skeleton is the most common metastatic site in patients with advanced prostate cancer. Bone metastases are a clinically significant cause of morbidity and mortality, often resulting in bone pain, pathologic fracture, or spinal cord compression necessitating treatment. Radium-223 is selectively accumulated in the bone, specifically in areas of high bone turnover, by forming complexes with the mineral hydroxyapatite (the inorganic matrix of the bone). The alpha radiation generated during the radioactive decay of radium-223 produces a palliative anti-tumour effect on the bone metastases. The purpose of this guideline is to assist nuclear medicine specialists in evaluating patients who might be candidates for treatment using radium-223, planning and performing this treatment, understanding and evaluating its consequences, and improving patient management during therapy and follow-up.

Diagnostics and treatment of differentiated thyroid carcinoma in children - Guidelines of Polish National Societies.

1Department of Paediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Poland 2Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice Branch, Gliwice, Poland. 3Department of Paediatrics and Paediatric Endocrinology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland 4Department of Oncological and Reconstructive Surgery, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice Branch, Gliwice, Poland 5Department of Oncological Endocrinology and Nuclear Medicine, Centre of Oncology – Maria Sklodowska-Curie Memorial Institute, Warsaw, Poland 6Department of Tumour Pathology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice Branch, Gliwice, Poland 7Department of Paediatrics and Endocrinology, Medical University, Warsaw, Poland 8Department of General and Oncological Surgery, Medical University of Lodz, Lodz, Poland 9Private practice, Katowice, Poland 10Department of Paediatric Surgery and Urology, Wroclaw Medical University, Wroclaw, Poland 11Department of Morphometry of Endocrine Glands, Chair of Endocrinology, Medical University of Lodz, Lodz, Poland 12Department of Dental Pathology, Medical University of Lodz, Lodz, Poland 13Department of Tumour Pathology, Poznan University of Medical Sciences, Poznan, Poland 14Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland 15Department of Endocrinology and Metabolic Diseases, Polish Mother’s Memorial Hospital-Research Institute, Medical University of Lodz, Lodz, Poland

Recombinant human thyrotropin preparation for adjuvant radioiodine treatment in children and adolescents with differentiated thyroid cancer.

AIM Although recombinant human thyrotropin (rhTSH) is widely used in treating differentiated thyroid cancer (DTC), almost all clinical investigation has been in adults. The aim of our retrospective study was to evaluate outcomes of adjuvant, rhTSH-aided radioiodine treatment in children/adolescents with DTC and to compare them to (131)I therapy during l-thyroxin withdrawal (THW). METHODS Patients with the diagnosis of DTC who were ≤18 years of age and had no signs of persistent disease at the time of (131)I treatment were included; 48 patients were treated after rhTSH (rhTSH group) and 82 after THW group. The median time of follow-up after therapy was 67 months and was longer in the THW group (99 vs 43 months, P<0.05). RESULTS On the day of (131)I administration, all but one patient had TSH levels above 25 μIU/ml. Peak TSH concentration was significantly higher in the rhTSH group (152 μIU/ml vs 91 μIU/ml). Similarly, the thyroglobulin concentration was higher in the rhTSH group (9.7 ng/ml vs 1.8 ng/ml). No side effects requiring medical intervention were recorded after rhTSH administration. The evaluation of disease outcomes during TSH stimulation (6-18 months after (131)I treatment) revealed equal rates of thyroid ablation (71%) in both groups. During subsequent follow-up, five patients showed recurrence (P>0.05). CONCLUSIONS In children/adolescents, rhTSH-aided adjuvant radioiodine treatment is associated with rates of remnant ablation and short-term recurrence similar to THW. As this preparation has several advantages over THW, rhTSH may become the preferred method of TSH stimulation once studies of long-term outcomes show non-inferiority to THW in this age group.

EANM guidelines for radionuclide therapy of bone metastases with beta-emitting radionuclides

The skeleton is the most common metastatic site in patients with advanced cancer. Pain is a major healthcare problem in patients with bone metastases. Bone-seeking radionuclides that selectively accumulate in the bone are used to treat cancer-induced bone pain and to prolong survival in selected groups of cancer patients. The goals of these guidelines are to assist nuclear medicine practitioners in: (a) evaluating patients who might be candidates for radionuclide treatment of bone metastases using beta-emitting radionuclides such as strontium-89 (89Sr), samarium-153 (153Sm) lexidronam (153Sm-EDTMP), and phosphorus-32 (32P) sodium phosphate; (b) performing the treatments; and ©) understanding and evaluating the treatment outcome and side effects.