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A Randomized Study of Lenvatinib 18 mg vs 24 mg in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer.
Brose, MS, Panaseykin, Y, Konda, B, de la Fouchardiere, C, Hughes, BGM, Gianoukakis, AG, Joo Park, Y, Romanov, I, Krzyzanowska, MK, Leboulleux, S, et al
The Journal of clinical endocrinology and metabolism. 2022;(3):776-787
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BACKGROUND Lenvatinib is a multikinase inhibitor approved to treat radioiodine-refractory differentiated thyroid cancer (RR-DTC) at a starting dose of 24 mg/day. This study explored, in a double-blinded fashion, whether a starting dose of 18 mg/day would provide comparable efficacy with reduced toxicity. METHODS Patients with RR-DTC were randomized to lenvatinib 24 mg/day or 18 mg/day. The primary efficacy endpoint was objective response rate as of week 24 (ORRwk24); the odds ratio noninferiority margin was 0.4. The primary safety endpoint was frequency of grade ≥3 treatment-emergent adverse events (TEAEs) as of week 24. Tumors were assessed using RECIST v1.1. TEAEs were monitored and recorded. RESULTS The ORRwk24 was 57.3% (95% CI 46.1, 68.5) in the lenvatinib 24-mg arm and 40.3% (95% CI 29.3, 51.2) in the lenvatinib 18-mg arm, with an odds ratio (18/24 mg) of 0.50 (95% CI 0.26, 0.96). As of week 24, the rates of TEAEs grade ≥3 were 61.3% in the lenvatinib 24-mg arm and 57.1% in the lenvatinib 18-mg arm, a difference of -4.2% (95% CI -19.8, 11.4). CONCLUSION A starting dose of lenvatinib 18 mg/day did not demonstrate noninferiority compared to a starting dose of 24 mg/day as assessed by ORRwk24 in patients with RR-DTC. The results represent a clinically meaningful difference in ORRwk24. The safety profile was comparable, with no clinically relevant difference between arms. These results support the continued use of the approved starting dose of lenvatinib 24 mg/day in patients with RR-DTC and adjusting the dose as necessary.
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A novel irradiation stent versus conventional irradiation stent for malignant dysphagia: A prospective randomized controlled trial.
Zhu, GY, Lu, J, Wang, C, Guo, JH
Journal of cancer research and therapeutics. 2021;(5):1261-1268
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AIM: To evaluate whether a novel irradiation stent (NIS) could decrease the rate of recurrent dysphagia, compared to the conventional irradiation stent (CIS) in patients with malignant dysphagia. MATERIALS AND METHODS We performed an open-label randomized controlled trial of participants with malignant dysphagia. A total of 94 participants were parallelly allocated into the NIS group or the NIS group between April 2019 and April 2020. The primary endpoint was the rate of recurrent dysphagia. The secondary endpoints included technical success, clinical success, overall survival, and adverse events. RESULTS The technical success rate and the clinical success rate was 100.0% (47/47) in both groups. The median follow-up period was 189 days (range 14-422 days). Recurrent dysphagia was observed in 12.8% (6/47) of patients in the NIS group and 31.9% (15/47) in the CIS group (P = 0.026). Tissue/tumor growth occurred in 4 patients (8.5%) after NIS placement and 12 (25.5%) after CIS placement (P = 0.028). Stent migration occurred in 2 patients (4.3%) after NIS placement and 3 (6.4%) after CIS placement (P = 0.646). No food obstruction was found in both groups. The median overall survival was 177 days (95% confidence interval [CI] 139-214) in the NIS group and 168 days (95% CI 153-183) in the CIS group (P = 0.932). The incidence of severe adverse events was comparable between the two groups (21.3% vs. 17.0%, P = 0.600). CONCLUSIONS In patients with malignant dysphagia, compared with CIS, NIS could decrease the rate of tissue/tumor growth without increase the rate of stent migration and therefore decrease the rate of recurrent dysphagia.
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Intermittent versus continuous administration of pazopanib in progressive radioiodine refractory thyroid carcinoma: Final results of the randomised, multicenter, open-label phase II trial PAZOTHYR.
de la Fouchardière, C, Godbert, Y, Dalban, C, Illouz, F, Wassermann, J, Do Cao, C, Bardet, S, Zerdoud, S, Chougnet, CN, Zalzali, M, et al
European journal of cancer (Oxford, England : 1990). 2021;:153-164
Abstract
INTRODUCTION Multikinase inhibitor (MKI) treatments have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC), but most patients experienced substantial adverse effects. This randomised multicentric study investigated intermittent versus continuous pazopanib administration. PATIENTS AND METHODS The PAZOTHYR study included RAIR-TC patients with progressive disease in the last 12 months, who may have received one prior MKI. RAIR-TC patients received pazopanib for 6 months, and patients with stable disease or tumour response were randomly assigned (1:1) to receive continuous (CP) or intermittent (IP) pazopanib until progression. The primary end-point was time to treatment failure (TTF) defined as the time from randomisation to permanent discontinuation of pazopanib, due to any cause. One hundred randomised patients were needed to demonstrate an increase from 50% (CP) to 70% (IP) (hazard ratio (HR) 0.515, 80% power) in the rate of patients still under treatment 6 months (6m-SuT) post-randomisation. Secondary end-points included the overall response rate (ORR), progression-free survival (PFS) under pazopanib and safety. RESULTS RAIR-TC patients (168) enrolled from June 18, 2013 to January 16, 2018, received 6-month pazopanib treatment and showed 35.6% (95% CI 28.2-43.6) best response rate and 89.4% (83.5-93.7) disease control rate. One hundred patients were randomised (IP:50; CP:50). With a median follow-up of 31.3 months, median TTF was not statistically different between arms (IP:14.7, 95% confidence interval (CI) 9.3-17.4; CP:11.9, 95% CI 7.5-15.6) months (HR 0.79, 0.49-1.27). 6m-SuT rates were similar (IP:80% 66.0-88.7%; CP:78% 63.8-87.2%). Median PFS under pazopanib were not statistically different (IP:5.7 4.8-7.8; CP: 9.2 7.3-11.1) months (HR 1.36, 0.88-2.12). Pazopanib-related adverse events grade 3-4 occurred in 36 (IP: 19, 38%; CP: 17, 34%) randomised patients. Seven pazopanib-related deaths occurred. CONCLUSIONS Intermittent administration of pazopanib did not demonstrate significant superiority in efficacy or tolerance compared with continuous treatment. An intermittent administration scheme cannot be recommended outside clinical trials. This study was registered with ClinicalTrial.gov, number NCT01813136.
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A phase I clinical trial for [131I]meta-iodobenzylguanidine therapy in patients with refractory pheochromocytoma and paraganglioma.
Wakabayashi, H, Inaki, A, Yoshimura, K, Murayama, T, Imai, Y, Higuchi, T, Jinguji, M, Shiga, T, Kinuya, S
Scientific reports. 2019;(1):7625
Abstract
Refractory pheochromocytoma and paraganglioma (PPGL) have a poor prognosis and the treatment strategy remains to be established. This multi-institutional phase I study was performed to determine the safety, dose-limiting toxicity (DLT), and efficacy of [131I]-meta-iodobenzylguanidine (131I-mIBG) therapy for refractory PPGLs. Twenty patients with refractory PPGL were enrolled in this study. We administered fixed doses of 131I-mIBG to all patients, delivering a second and third course of 131I-mIBG to eight and three patients, respectively. During the 20 weeks after 131I-mIBG injection, the authors surveyed the adverse events in accordance with the Common Terminology Criteria for Adverse Events. All patients experienced adverse events and adverse reactions, but none experienced a grade 4 adverse event. Twelve weeks after 131I-mIBG injection, examinations for the evaluation of therapeutic effects was performed in accordance with the Response Evaluation Criteria in Solid Tumours (RECIST). The best overall response rates (based on RECIST categories) were 10% (complete response), 65% (stable disease), 15% (progressive disease), and 10% (not all evaluated). The efficacy and safety of 131I-mIBG therapy was shown in patients with refractory PPGL, and DLT was observed in neither single nor repeated 131I-mIBG therapy, indicating a tolerability for 131I-mIBG therapy.
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Evaluating the effectiveness of computed tomography-guided 125I seed interstitial implantation in patients with secondary adrenal carcinoma.
Lin, ZY, Yang, JY, Chen, J, Chen, J
Journal of cancer research and therapeutics. 2019;(4):813-817
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AIM: This study aimed to evaluate the feasibility, safety, and clinical efficacy of computed tomography (CT)-guided 125 I seed interstitial implantation in patients with secondary adrenal carcinoma. MATERIALS AND METHODS Twenty patients with secondary adrenal carcinoma received CT-guided 125 I seed interstitial implantation. A three-dimensional treatment planning system was used to calculate the dose distribution before 125 I seed interstitial implantation. CT scans were performed every 2 months after the treatment to evaluate local therapeutic efficacy according to the Response Evaluation Criteria in Solid Tumors. RESULTS The mean follow-up time was 23.65 months (5-102 months). The mean maximum tumor diameter was 34.16 ± 18.94 mm at the beginning of follow-up and 14.42 ± 24.07 mm at the end of follow-up. Eleven patients had complete response (CR), seven had partial response (PR), one had stable disease, and one had progressive disease. Local control rate (CR + PR) was 90% (18/20). The median survival time was 19 months (5-71 months). The 1-, 2-, 3-, and 5-year overall survival rates were 83.70%, 46.8%, 20.80%, and 20.80%, respectively. CONCLUSION CT-guided 125 I radioactive seed interstitial implantation may be a feasible, safe, effective, and minimally invasive treatment for secondary adrenal carcinoma.
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A phase II study of radioimmunotherapy with intraventricular 131 I-3F8 for medulloblastoma.
Kramer, K, Pandit-Taskar, N, Humm, JL, Zanzonico, PB, Haque, S, Dunkel, IJ, Wolden, SL, Donzelli, M, Goldman, DA, Lewis, JS, et al
Pediatric blood & cancer. 2018;(1)
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BACKGROUND High-risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131 I-labeled 3F8 in patients with MB on a phase II clinical trial. METHODS Patients with histopathologically confirmed high-risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) 124 I-3F8 or 131 I-3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) 131 I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6-12 months thereafter. RESULTS Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0-2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3-55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18-0.88, P = 0.024). CONCLUSIONS cRIT with 131 I-3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent MB.
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A phase I study of pazopanib in combination with escalating doses of 131I in patients with well-differentiated thyroid carcinoma borderline refractory to radioiodine.
Chow, LQ, Santana-Davila, R, Pantel, A, Roth, M, Anderson, LN, Failor, A, Doot, R, Mankoff, D
PloS one. 2017;(6):e0178325
Abstract
OBJECTIVE This trial was conducted to evaluate the ability of pazopanib to overcome therapeutic 131I resistance. MATERIALS, METHODS AND PATIENTS This phase 1 trial assesses the combination of pazopanib and escalating doses of radioiodine (131I) in patients with recurrent or metastatic thyroid cancer that are borderline or relatively iodine refractory. Radioiodine uptake scans were assessed post therapy and compared to historical pre-treatment scans. Patients underwent FDG PET/CT before and after the initial pazopanib treatment to identify the impact of pazopanib on the cancer prior to 131I therapy. RESULTS A dose limiting toxicity (cardiac arrhythmia and grade 3 fatigue) in the first patient in the first cohort prompted expansion to a total of 6 patients. Additional grade 3-4 hematologic toxicity and low accrual in the expanded cohort led to the decision not to pursue further study of the regimen. In patients with measurable disease 4/5 (80%) achieved stable disease. Median progression free survival was 6.7 months. At 3 years of follow up, one patient died due to progressive disease, two are being treated with systemic therapy and 3 continue without requiring subsequent therapy at 15, 27 and 35 months from the last dose of pazopanib. There was no convincing impact of pazopanib on iodine uptake in scans performed pre- and post-therapy compared to scans from historical 131I treatments without pazopanib. CONCLUSION Despite a suggestion of therapeutic efficacy, combined pazopanib and 131I resulted in increased toxicity. There was no convincing evidence that the administration of pazopanib improved iodine uptake or retention. TRIAL REGISTRATION ClinicalTrials.gov NCT01413113.
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Brachytherapy with iodine 125 seeds for bone metastases.
Wang, W, Liu, Z, Zhu, J, Wu, C, Liu, M, Wang, Y, Wang, W, Liu, B, Li, Y
Journal of cancer research and therapeutics. 2017;(5):742-747
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OBJECTIVE To evaluate the treatment safety and efficacy of iodine 125 (I125) seeds implantation in patients with bone metastases and assess the availability of quality of life (QOL) as an index for efficacy evaluation. PATIENTS AND METHODS The study enrolled 98 patients with 133 bone metastases from July 2010 to January 2016, who had undergone computed tomography-guided brachytherapy with I125 seeds. Brief pain inventory was administered to assess the degree of pain at the preoperative (W0) and postoperative 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 24 weeks (W2, W4, W8, W12, and W24). Drug use, QOL score, and complications were also assessed. RESULTS Postoperative pain scores were significantly decreased and maintained for a long term. Numerical rating scale score at W0 was 7.3 ± 1.6, which was decreased to 4.5 ± 1.7 (P < 0.01), 3.7 ± 1.3 (P < 0.01), 2.5 ± 1.1 (P < 0.01), 1.9 ± 0.9 (P < 0.01), and 1.3 ± 0.5 (P < 0.01) at W2, W4, W8, W12, and W24, respectively. After standardized transformation, the dose of morphine for patients at W0 was 175.2 ± 24.5 mg, which was decreased to 91.2 ± 21.7 mg (P < 0.01), 89.4 ± 24.6 mg (P < 0.01), 89.4 ± 24.6 mg (P < 0.01), 72.8 ± 14.8 mg (P < 0.01), and 56.7 ± 11.3 mg (P < 0.01) at W2, W4, W8, W12, and W24, respectively. The efficiency reached 65.3%, 85.1%, 91.2%, 95.2%, and 92.7% at postoperative W2, W4, W8, W12, and W24, respectively. QOL score at W0 was 17.4 ± 3.3, which increased to 23.2 ± 4.5 (P < 0.01), 28.6 ± 7.6 (P < 0.01), 43.2 ± 9.1 (P < 0.01), 45.6 ± 10.3 (P < 0.01), and 47.6 ± 9.8 (P < 0.01) at W2, W4, W8, W12, and W24, respectively. CONCLUSION Brachytherapy with I125 seeds was safe and effective for treating bone metastases, offering a potential alternative to external-beam radiotherapy. QOL could be applied to evaluate the efficacy of I125 seeds implantation for treating bone metastases.
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SELIMETRY-a multicentre I-131 dosimetry trial: a clinical perspective.
Wadsley, J, Gregory, R, Flux, G, Newbold, K, Du, Y, Moss, L, Hall, A, Flanagan, L, Brown, SR
The British journal of radiology. 2017;(1073):20160637
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Treatment options for patients with thyroid cancer that is no longer sensitive to iodine therapy are limited. Those treatments which currently exist are associated with significant toxicity. The SELIMETRY trial (EudraCT No 2015-002269-47) aims to investigate the role of the MEK inhibitor Selumetinib in resensitizing advanced iodine refractory differentiated thyroid cancer to radioiodine therapy. Patients deemed to have sufficient iodine uptake in previously iodine refractory lesions after 4 weeks of Selumetinib therapy will be given an empirical activity of 5.5 GBq I-131, and response to therapy will be assessed. The trial presents an opportunity to investigate the dosimetric aspects of radioiodine therapy for advanced thyroid cancer. Patients will undergo serial I-123 single-photon emission CT (SPECT)/CT scans following Selumetinib therapy to determine whether there has been a change in the degree of iodine uptake to justify further I-131 therapy, and to allow dosimetric calculations to predict absorbed dose to target lesions following therapy. Patients receiving I-131 therapy will undergo a further series of post-therapy SPECT/CT scans to allow dosimetric calculations. We describe the challenges in setting up a multicentre trial in a relatively underinvestigated field, describing the work that has been carried out to calibrate and validate measurements to ensure that standardized image data are collected at each site. We hope that this trial will lead to individualization and optimization of therapy for patients with advanced thyroid cancer and that the ground work carried out in setting up a network of centres capable of standardized molecular radiotherapy dosimetry will lead to further clinical trials in this field.
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Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial.
Brose, MS, Cabanillas, ME, Cohen, EE, Wirth, LJ, Riehl, T, Yue, H, Sherman, SI, Sherman, EJ
The Lancet. Oncology. 2016;(9):1272-82
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BACKGROUND About half of patients with papillary thyroid cancer have tumours with activating BRAF(V600E) mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three patients with BRAF(V600E)-positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAF(V600E)-positive papillary thyroid cancer. METHODS We did an open-label, non-randomised, phase 2 trial at ten academic centres and hospitals worldwide in patients aged 18 years or older with histologically confirmed recurrent or metastatic papillary thyroid cancer refractory to radioactive iodine and positive for the BRAF(V600E) mutation. Participants either had never received a multikinase inhibitor targeting VEGFR (cohort 1) or had been treated previously with a VEGFR multikinase inhibitor (cohort 2). Patients received vemurafenib 960 mg orally twice daily. The primary endpoint was investigator-assessed best overall response in cohort 1 (confirmed on two assessments 4 weeks or longer apart). Analyses were planned to have a minimum median follow-up of 15 months (data cutoff April 18, 2014) and were done in safety, intention-to-treat, and per-protocol populations. This trial is closed and is registered at ClinicalTrials.gov, number NCT01286753. FINDINGS Between June 23, 2011, and Jan 15, 2013, 51 patients were enrolled to the study, 26 in cohort 1 and 25 in cohort 2. Median duration of follow-up was 18·8 months (IQR 14·2-26·0) in cohort 1 and 12·0 months (6·7-20·3) in cohort 2. Partial responses were recorded in ten of 26 patients in cohort 1 (best overall response 38·5%, 95% CI 20·2-59·4). Grade 3 or 4 adverse events were recorded in 17 (65%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2; the most common grade 3 and 4 adverse events were squamous cell carcinoma of the skin (seven [27%] in cohort 1, five [20%] in cohort 2), lymphopenia (two [8%] in each cohort), and increased γ-glutamyltransferase (one [4%] in cohort 1, three [12%] in cohort 2). Two individuals in cohort 2 died due to adverse events, one from dyspnoea and one from multiorgan failure, but neither was treatment related. Serious adverse events were reported for 16 (62%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2. INTERPRETATION Vemurafenib showed antitumour activity in patients with progressive, BRAF(V600E)-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients. FUNDING F Hoffmann-La Roche.