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125I seed implantation for hepatocellular carcinoma with portal vein tumor thrombus: A systematic review and meta-analysis.
Yuan, D, Gao, Z, Zhao, J, Zhang, H, Wang, J
Brachytherapy. 2019;(4):521-529
Abstract
PURPOSE Advanced hepatocellular carcinoma often combined with portal vein tumor thrombus (PVTT), transcatheter arterial chemoembolization (TACE) is recommended as an effective treatment. Recent studies showed that TACE plus iodine-125 (125I) seed for hepatocellular carcinoma with PVTT can improve the remission rate. This study aimed to systematically evaluate the efficacy and safety of 125I seed implantation in patients with PVTT. METHODS AND MATERIALS The Embase, Medline/PubMed, Cochrane Library, and OVID databases were systematically searched from the earliest to October 2018. The references included in the literature were searched. The primary endpoints were remission rate and overall survival, and the secondary endpoints were portal venous pressure and adverse event. The odds ratio (OR) and hazard ratio (HR) were combined using either fixed or random effects model. Meta-analysis was performed using Stata 12.0 software. RESULTS Eight studies were included with 1098 patients, 591 patients received 125I seed implantation, and 507 in the control group. Meta-analysis showed that 125I seed implantation improved the remission rate in patients with PVTT (OR = 2.24, 95% confidence interval (CI) = 1.68-2.99, p = 0.000) and survival rate (HR = 0.27, 95% CI = 0.14-0.40, p = 0.000); it also reduced patient's mortality risk (HR = 0.46, 95% CI = 0.37-0.54, p = 0.000). Subgroup analysis suggested that the death risk of patients who responded to 125I seed implantation declined 55% (HR = 0.45, 95% CI = 0.34-0.55, p = 0.000). 125I seed implantation is more effective against PVTT delivered at a dose higher than 110 Gy. There was no difference in the occurrence adverse event between the two groups (OR = 1.07, 95% CI = 0.92-1.25, p = 0.262). CONCLUSION TACE plus 125I seed implantation is more effective in treating PVTT. The use of 125I seeds dose >110 Gy will show better results.
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2.
Lenvatinib complementary with radioiodine therapy for patients with advanced differentiated thyroid carcinoma: case reports and literature review.
Sheu, NW, Jiang, HJ, Wu, CW, Chiang, FY, Chiou, HC, Hsiao, PJ
World journal of surgical oncology. 2019;(1):84
Abstract
BACKGROUND The prognosis for patients with advanced differentiated thyroid carcinoma (ADTC) with disseminated distant metastases is very poor. Tyrosine kinase inhibitors targeting tumor angiogenesis have been shown to improve progression-free survival in patients with advanced thyroid carcinoma and progressive radioiodine-refractory thyroid carcinoma. Tyrosine kinase inhibitor has been reported as a successful neoadjuvant for total thyroidectomy to reduce tumor burden. However, the special indications for prompt treatment with lenvatinib as a rescue therapy to reduce tumor burden and prolong a durable response to radioiodine therapy have not been explored. CASE PRESENTATION Here, we present two ADTC cases with distant metastases who were effectively treated by total thyroidectomy combined with lenvatinib to prolong a durable response to radioiodine therapy. Case 1 was a 66-year-old male diagnosed with ADTC and disseminated brain, lung, and bone metastases. Lenvatinib was initiated via compassionate access because of rapidly progressive tumor growth even after second doses of radioiodine therapy and external beam radiation therapy for his brain metastases. The result was a durable response to lenvatinib, slowing progressive tumor growth for 3 years and allowing a third course of radioiodine therapy to treat the bone metastases. Case 2 was a 45-year-old male diagnosed with ADTC and diffuse disseminated lung metastases. Respiratory failure ensued after total thyroidectomy, requiring mandatory support by respirator. Lenvatinib was started as a rescue therapy to reduce tumor burden rapidly. The patient was successfully weaned off the respirator only 1 week after using lenvatinib. The patient was then maintained on a low dose of lenvatinib, allowing three subsequent courses of radioiodine therapy. Currently, his lung metastasis remains well controlled with decreased lung infiltrating nodules and the patient can tolerate exercise well. CONCLUSION Our case experience indicated that lenvatinib has significant value as salvage therapy, reducing tumor burden, producing a durable response and maintaining quality of life. For ADTC patients with progressive life-threatening metastases, our experience suggests that lenvatinib treatment can be used as an urgent rescue therapy as well as a complement to radioiodine therapy to improve tumor eradication.
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3.
Radioactive Iodine-Refractory Differentiated Thyroid Cancer and Redifferentiation Therapy.
Liu, J, Liu, Y, Lin, Y, Liang, J
Endocrinology and metabolism (Seoul, Korea). 2019;(3):215-225
Abstract
The retained functionality of the sodium iodide symporter (NIS) expressed in differentiated thyroid cancer (DTC) cells allows the further utilization of post-surgical radioactive iodine (RAI) therapy, which is an effective treatment for reducing the risk of recurrence, and even the mortality, of DTC. Whereas, the dedifferentiation of DTC could influence the expression of functional NIS, thereby reducing the efficacy of RAI therapy in advanced DTC. Genetic alternations (such as BRAF and the rearranged during transfection [RET]/papillary thyroid cancer [PTC] rearrangement) have been widely reported to be prominently responsible for the onset, progression, and dedifferentiation of PTC, mainly through activating the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling cascades. These genetic alternations have been suggested to associate with the reduced expression of iodide-handling genes in thyroid cancer, especially the NIS gene, disabling iodine uptake and causing resistance to RAI therapy. Recently, novel and promising approaches aiming at various targets have been attempted to restore the expression of these iodine-metabolizing genes and enhance iodine uptake through in vitro studies and studies of RAI-refractory (RAIR)-DTC patients. In this review, we discuss the regulation of NIS, known mechanisms of dedifferentiation including the MAPK and PI3K pathways, and the current status of redifferentiation therapy for RAIR-DTC patients.
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4.
Expert consensus on computed tomography-assisted three-dimensional-printed coplanar template guidance for interstitial permanent radioactive 125I seed implantation therapy.
Wang, J, Chai, S, Wang, R, Zheng, G, Zhang, K, Huo, B, Huo, X, Jiang, Y, Ji, Z, Jiang, P, et al
Journal of cancer research and therapeutics. 2019;(7):1430-1434
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Abstract
Interstitial permanent radioactive seed implantation delivers a high local dose to tumors and sharply drops off at surrounding normal tissues. Radioactive seeds implanted via ultrasound or computed tomography (CT) guidance are minimally invasive and facilitate quick recovery. Transrectal ultrasound-guided 125I seed implantation assisted by a transperineal plane template is standard for early-stage prostate carcinoma, with a highly consistent target volume dose distribution. The postplan dose evaluation is consistent with the preplan evaluation. Until now, there was no workflow for seed implantation elsewhere in the body, and it was difficult to effectively preplan for seed implantation because of patients' position changes, organ movement, and bone structure interference. Along with three-dimensional (3D) printing techniques and seed implantation planning systems for brachytherapy, coplanar and X Y axis coordinate templates were created, referred to as 3D-printed coplanar templates (3D-PCT). 125I seed implantation under CT guidance with 3D-PCT assistance has been very successful in some carcinomas. Preplanning was very consistent with postplanning of the gross tumor volume. All needles are kept parallel for 3D-PCT, with no coplanar needle rearrangement. No standard workflow for 3D-PCT-assisted seed implantation exists at present. The consensus topics for CT-assisted guidance compared to 3D-PCT-assisted guidance for seed implantation are as follows: Indications for seed implantation, preplanning, definition of radiation doses and dosimetry evaluation, 3D-PCT workflow, radiation protection, and quality of staff. Despite current data supporting 125I seed implantation for some solid carcinomas, there is a need for prospectively-randomized multicenter clinical trials to gather strong evidence for using 125I seed implantation in other solid carcinomas.
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Transcutaneous electrical nerve stimulation attenuates cardiac sympathetic drive in heart failure: a 123MIBG myocardial scintigraphy randomized controlled trial.
Campos, MO, Nóbrega, ACL, Miranda, SM, Ribeiro, ML, Guerra, TRB, Braghirolli, AMS, Mesquita, CT, Fernandes, IA
American journal of physiology. Heart and circulatory physiology. 2019;(2):H226-H233
Abstract
Cardiac sympathetic overdrive provides inotropic support to the failing heart. However, as myocardial insult evolves, this compensatory response impairs contractile function and constitutes an independent mortality predictor and a primary target in the treatment of heart failure (HF). In this prospective, randomized, double-blind, controlled crossover trial, we proposed cervicothoracic transcutaneous electrical nerve stimulation (CTENS) as a nonpharmacological therapy on cardiac sympathetic activity in patients with HF. Seventeen patients with HF were randomly assigned to an in-home CTENS (30 min twice daily, 80-Hz frequency, and 150-μs pulse duration) or a control intervention (Sham) for 14 consecutive days. Following a 60-day washout phase, patients were crossed over to the opposite intervention. The heart-to-mediastinum ratio (HMR) and washout rate (WR) (indexes of sympathetic innervation density and activity from planar 123iodo-metaiodobenzylguanidine myocardial scintigraphy images, respectively), as well as blood pressure (BP) and heart rate (HR), were quantified before and after each intervention. HMR, BP, and HR did not change throughout the study. Nonetheless, CTENS reduced WR (CTENS -4 ± 10 vs. Sham +5 ± 15%, P = 0.03) when compared with Sham. When allocated in two independent groups, preserved (PCSI, HMR > 1.6, n = 10) and impaired cardiac sympathetic innervation (ICSI, HRM ≤1.6, n = 7), PCSI patients showed an important attenuation of WR (-11 ± 9 vs. Sham +8 ± 19%, P = 0.007) after CTENS. Nonetheless, neither Sham nor CTENS evoked changes in WR of the ICSI patients (P > 0.05). These findings indicate that CTENS attenuates the cardiac sympathetic overdrive in patients with HF and a preserved innervation constitutes an essential factor for this beneficial neuromodulatory impact. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Identifier: NCT03354689. NEW & NOTEWORTHY We found that short-term cervicothoracic transcutaneous electrical nerve stimulation (CTENS) attenuates cardiac sympathetic overdrive in patients with heart failure and a preserved autonomic innervation may constitute an essential factor to maximize this beneficial neuromodulatory effect. CTENS then emerges as an alternative noninvasive and nonpharmacological strategy to attenuate exaggerated cardiac sympathetic drive in patients with heart failure.
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The effect of radioiodine treatment on the diseased thyroid gland.
Riley, AS, McKenzie, GAG, Green, V, Schettino, G, England, RJA, Greenman, J
International journal of radiation biology. 2019;(12):1718-1727
Abstract
Purpose: Radioiodine (I131) therapy is the treatment mainstay for several benign and malignant thyroid disorders, however I131 is known to cause DNA damage and liberation of thyroidal self-antigens inducing secondary immunoreactivity. The exact mechanisms underpinning cellular death and subsequent induction of autoimmune thyroid disease following I131 treatment have not yet been fully elucidated. This manuscript aims to review the literature concerning the effects of I131 on the thyroid gland.Conclusion: The effects of I131 on malignant thyroid cells appears to depend on absorbed dose with the literature demonstrating a clear initial delay in the triggering of apoptosis in response to I131-mediated cellular damage. Some studies also observed necrotic cellular death following high-dose I131 treatment. Liberation of thyroidal self-antigen following I131 treatment helps to explain phenomena such as the subsequent induction of autoimmune thyroid disease. The clinical utility of cytokines and autoantibodies for prognostication of hypothyroidism and treatment failure following I131 remains uncertain and further appropriately-powered studies are required to clarify their role. The potential role of other cell death mechanisms activated after treatment with I131 should also be explored in order to fully delineate the thyroidal response.
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A systematic review of lenvatinib and sorafenib for treating progressive, locally advanced or metastatic, differentiated thyroid cancer after treatment with radioactive iodine.
Fleeman, N, Houten, R, Chaplin, M, Beale, S, Boland, A, Dundar, Y, Greenhalgh, J, Duarte, R, Shenoy, A
BMC cancer. 2019;(1):1209
Abstract
BACKGROUND Treatment with radioactive iodine is effective for many patients with progressive, locally advanced or metastatic, differentiated thyroid cancer. However, some patients become refractory to treatment. These types of patients are considered to have radioactive iodine refractory differentiated thyroid cancer (RR-DTC). METHODS We searched Embase, MEDLINE, PubMed and the Cochrane Library from January 1999 through January 2017. Reference lists of included studies and ongoing trial registries were also searched. Reports of randomized controlled trials (RCTs), prospective observational studies, and systematic reviews/indirect comparisons were eligible for inclusion. In the absence of direct clinical trial evidence comparing lenvatinib versus sorafenib, we assessed the feasibility of conducting an indirect comparison to obtain estimates of the relative efficacy and safety of these two treatments. RESULTS Of 2364 citations, in total, 93 papers reporting on 2 RCTs (primary evidence), 9 observational studies and 13 evidence reviews (supporting evidence) were identified. Compared to placebo, RCT evidence demonstrated improvements with lenvatinib or sorafenib in median progression-free survival (PFS) and objective tumour response rate (ORR). Overall survival (OS) was confounded by high treatment crossover (≥75%) in both trials. Adverse events (AEs) were more common with lenvatinib or sorafenib than with placebo but the most common AEs associated with each drug differed. Primarily due to differences in the survival risk profiles of patients in the placebo arms of the RCTs, we considered it inappropriate to indirectly compare the effectiveness of lenvatinib versus sorafenib. ORR and AE findings for lenvatinib and sorafenib from the supporting evidence were broadly in line with RCT evidence. Health-related quality of life (HRQoL) data were limited. CONCLUSIONS Lenvatinib and sorafenib are more efficacious than placebo (a proxy for best supportive care) for treating RR-DTC. Uncertainty surrounds the extent of the impact on OS and HRQoL. Lenvatinib could not reliably be compared with sorafenib. Choice of treatment is therefore likely to depend on an individual patient's circumstances.
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Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer.
Cabanillas, ME, Takahashi, S
Seminars in oncology. 2019;(1):57-64
Abstract
Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, RET, KIT, and platelet-derived growth factor receptor-α. Lenvatinib is approved as a monotherapy for the treatment of radioiodine-refractory differentiated thyroid cancer and in combination with everolimus for the second-line treatment of advanced renal cell carcinoma. Lenvatinib is also under investigation for the treatment of several malignancies including unresectable hepatocellular carcinoma. Although lenvatinib is associated with favorable efficacy, it is associated with adverse events (AEs) that the clinician will have to closely monitor for and proactively manage. Most of these AEs are known class effects of VEGF-targeted therapies, including hypertension, diarrhea, fatigue or asthenia, decreased appetite, and weight loss. This review summarizes the safety profile of lenvatinib and offers guidance for the management of both frequent and rare AEs. We discuss the potential mechanisms underlying these AEs and present practical recommendations for managing toxicities. The development of treatment plans that include prophylactic and therapeutic strategies for the management of lenvatinib-associated AEs has the potential to improve patient quality of life, optimize adherence, minimize the need for dose reductions, treatment interruptions, or discontinuations, and maximize patient outcomes.
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Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial.
Dehbi, HM, Mallick, U, Wadsley, J, Newbold, K, Harmer, C, Hackshaw, A
The lancet. Diabetes & endocrinology. 2019;(1):44-51
Abstract
BACKGROUND 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 (131I) dose (1·1 GBq) and the standard high dose (3·7 GBq). However, recurrence rates following radioactive iodine ablation have previously only been reported in observational studies, and recently in ESTIMABL1. We aimed to compare recurrence rates between radioactive iodine doses in HiLo. METHODS 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. RESULTS 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. INTERPRETATION 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. FUNDING Cancer Research UK.
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Age, thyroglobulin levels and ATA risk stratification predict 10-year survival rate of differentiated thyroid cancer patients.
Kelly, A, Barres, B, Kwiatkowski, F, Batisse-Lignier, M, Aubert, B, Valla, C, Somda, F, Cachin, F, Tauveron, I, Maqdasy, S
PloS one. 2019;(8):e0221298
Abstract
INTRODUCTION Differentiated thyroid cancer (DTC) is the most common of endocrine cancers. Many studies have focused on recurrence-free survival of DTC patients, however, few studies have addressed overall survival rates. Given its very good prognosis, estimating overall or long-term survival in patients with DTC seems rational. So far, neither the impact of pre- and post-ablation thyroglobulin, nor that of initial American Thyroid Association (ATA) risk stratification on long-term disease-specific survival, have been sufficiently studied. OBJECTIVE The aim of this study was to determine the factors that influence long-term disease-specific survival and thyroglobulin levels in patients with DTC who have been previously treated with thyroidectomy and radioactive iodine (RAI) remnant ablation. PATIENTS AND METHODS This observational retrospective study included 1093 patients who were treated for DTC between 1995 and 2010 and are still monitored in our tertiary center. Only patients who needed RAI ablation after thyroidectomy were included in this study. Patients who were treated with RAI following rhTSH stimulation, patients who presented positive anti-thyroglobulin antibodies, and patients who had micro-cancers were excluded. Pre-ablation stimulated thyroglobulin (Pre-ablation sTg) was measured after thyroid hormone withdrawal (THW), just before RAI. RESULTS According to ATA standards, 29 patients (2.7%) were classified as high-risk patients. Initial ATA high-recurrence risk rating (HR 21.9; 95% CI: 8.5-56.3), age>55 years (HR 23.8; 95%-CI: 7.5-75.3) and pre-ablation sTg≥30 μg/l (HR 8.4; 95% CI: 4.6-15.3) significantly impacted ten-year survival. Moreover, age over 45 years, ATA moderate-risk and follicular DTC were also significant. Ten-year survival was lower in ATA high-risk patients (51% vs 95% and 93% for the low and intermediate risk; p<10-7), patients older than 55 years (82% vs 98%; p<10-7), and in patients with pre-ablation sTg≥30 (78% vs 95%; p<10-7). Three rates of long-term survival were distinguished: excellent (survival rate of 99% in patients<55 years with pre-ablation sTg <30μg/l) representing 59% of the cohort, moderate (survival rate of 94.5% in patients <55 years with pre-ablation sTg ≥30μg/l or ≥55 years with pre-ablation sTg <30 μg/l) representing 38% of the cohort, and low (survival rate of 49% in patients ≥55 years with pre-ablation sTg ≥30μg/l) representing 3% of the cohort. CONCLUSION Initial ATA high-risk classification, age over 55 years old and pre-ablation sTg ≥30 μg/l are the main negative factors that influence the ten-year survival in DTC. We suggest three categories of overall survival rates. Patients older than 55 years with pre-ablation sTg ≥30 μg/l have the worst survival rate.