Radioiodine-refractory Differentiated Thyroid Cancer Patients Research Articles

Efficacy and safety of second-line treatment with surufatinib for anlotinib-resistant radioiodine-refractory differentiated thyroid cancer: An exploratory multicenter study.

e15127 Background: Radioiodine-refractory differentiated thyroid cancer (RR-DTC) resistant to first-line targeted therapy typically exhibits rapidly progressive nature, lacking standard treatment options. This study aimed to assess the efficacy and safety of surufatinib, targeting vascular endothelial growth factor receptor 1/2/3, fibroblast growth factor receptor 1, and colony-stimulating factor-1 receptor, in RR-DTC patients who had failed anlotinib treatment. Methods: This multicenter study enrolled patients aged ≥ 18 years with at least one measurable RR-DTC lesion (RECIST 1.1), who had previously received anlotinib treatment and experienced disease progression. Primary endpoint was progression-free survival (PFS); secondary endpoints were disease control rate and safety. Results: As of December 25, 2023, 9 patients were enrolled. Median age, 56 (range, 29-69) years; Male, 88.9%; ECOG PS 0, 88.9%; papillary carcinoma/follicular carcinoma, 77.8%/22.2%. Lung (77.8%) and bone (33.3%) were the most frequently involved organs. The duration of anlotinib treatment ≤ 12 months was found in 44.4% patients. All the 9 patients underwent at least one efficacy evaluation with a median PFS of 6.3 months and disease control rate of 88.9%. Subsequent analysis revealed that median PFS extended to 9.20 months in patients younger than 56 years, compared to 5.95 months in older individuals. Patients with over 12 months of prior anlotinib treatment exhibited mPFS of 9.20 months, versus 6.25 months in those with shorter prior treatment durations. Common treatment-emergent adverse events observed were hypertension (44.4%), proteinuria (22.2%), decreased platelets (22.2%), fatigue (11.1%), and hemoptysis (11.1%). Grade 3 adverse events included proteinuria (11.1%), fatigue (11.1%), and hemoptysis (11.1%). Conclusions: In patients with anlotinib-resistant RR-DTC, second-line surufatinib treatment yielded promising efficacy and tolerable toxicity, warranting randomized controlled studies on RR-DTC refractory to first-line targeted therapy. Clinical trial information: ChiCTR2100052020 .

Planned drug holidays during treatment with lenvatinib for radioiodine-refractory differentiated thyroid cancer: a retrospective study.

In the phase 3 SELECT study, lenvatinib significantly improved prognostic outcomes vs. placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, toxicity of lenvatinib is sometimes considerable and requires frequent dose interruptions and modifications. Recently, planned drug holidays have been proposed as a means of avoiding severe adverse events (AEs). We retrospectively reviewed medical records to compare the efficacy and safety of lenvatinib in RR-DTC patients who underwent planned drug holidays (planned holiday group) vs. those who received conventional daily oral administration (daily group). The subjects were 25 patients in the planned holiday group and 21 in the daily group. Median age was 73 years (range 43-84) and 62 years (range 42-75), and histologic subtype of papillary/follicular was 21/4 cases and 15/6 cases, respectively. Time to treatment failure (TTF) and overall survival (OS) were significantly longer in the planned holiday group than the daily group (not reached [NR] vs. 14.9 months, hazard ratio [HR] 0.25, 95% confidence interval [Cl] 0.11-0.58, p<0.001; NR vs. 26.6 months, HR 0.20, 95% CI 0.073-0.58, p=0.001, respectively). Median progression-free survival (PFS) was NR in the planned holiday group vs. 15.1 months in the daily group (HR 0.31, 95% CI 0.14-0.68, p=0.002). Duration of the period with lenvatinib dose ≥10 mg was significantly longer in the planned holiday group (NR vs. 6.5 months, HR 0.22, 95% CI 0.10-0.49, p<0.001), and the frequency of drug interruption due to intolerable AEs was lower (68.0% vs. 95.2%, p=0.027). Planned drug holidays for lenvatinib demonstrated significantly longer PFS, TTF, and OS than daily oral administration, and less intolerable toxicity leading to further unplanned treatment interruption. These benefits were apparently associated with a more extended period of lenvatinib administration at ≥10 mg. These findings might contribute to a favorable patient prognosis and safer toxicity profile.

Use of lenvatinib in the treatment of radioiodine-refractory differentiated thyroid cancer: a multidisciplinary perspective for daily practice.

Most thyroid cancers of follicular origin have a favorable outcome. Only a small percentage of patients will develop metastatic disease, some of which will become radioiodine refractory (RAI-R). Important challenges to ensure the best therapeutic outcomes include proper, timely, and appropriate diagnosis; decisions on local, systemic treatments; management of side effects of therapies; and a good relationship between the specialist, patients, and caregivers. With the aim of providing suggestions that can be useful in everyday practice, a multidisciplinary group of experts organized the following document, based on their shared clinical experience with patients with RAI-R differentiated thyroid cancer (DTC) undergoing treatment with lenvatinib. The main areas covered are patient selection, initiation of therapy, follow-up, and management of adverse events. It is essential to provide guidance for the management of RAI-R DTC patients with systemic therapies, and especially lenvatinib, since compliance and adherence to treatment are fundamental to achieve the best outcomes. While the therapeutic landscape in RAI-R DTC is evolving, with new targeted therapies, immunotherapy, etc., lenvatinib is expected to remain a first-line treatment and mainstay of therapy for several years in the vast majority of patients and settings. The guidance herein covers baseline work-up and initiation of systemic therapy, relevance of symptoms, multidisciplinary assessment, and patient education. Practical information based on expert experience is also given for the starting dose of lenvatinib, follow-up and monitoring, as well as the management of adverse events and discontinuation and reinitiating of therapy. The importance of patient engagement is also stressed.

Theranostic Options for Radioiodine-Refractory Differentiated Thyroid Carcinoma: Recent Advances, Challenges, and Road Ahead.

Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC), though uncommon, presents a considerable therapeutic challenge with poor long-term outcomes. Currently, tyrosine kinase inhibitors are the mainstay of treatment for advanced RAIR-DTC patients. However, these agents are associated with a multitude of adverse events with resultant deterioration in the quality-of-life of the patients. Targeted theranostic approaches with radiolabelled integrin binders and fibroblast activation protein- (FAP)-inhibitors seem to have a promising role in the management of such patients. This mini-review focuses on these novel theranostic strategies in RAIR-DTC, with emphasis on recent advances, existing challenges, and future directions.

68Ga-DOTA-FAPI-04 PET/CT imaging in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients.

This study aimed to assess the potential of 68Ga-DOTA-FAPI-04 PET/CT for the detection of the radioiodine-refractory differentiated thyroid cancer (RR-DTC) lesions. We analyzed the 68Ga-DOTA-FAPI-04 PET/CT imaging data of 24 RR-DTC patients (7 men and 17 women; 49.6 ± 10.5 year). Clinical data were collected including history, last post-therapeutic radioiodine whole body scan, contemporary CT, thyroglobulin, and antithyroglobulin. Target lesions were selected and measured by the RECIST 1.1. The mean growth rates of the target lesions in the past 6months were recorded. Tumor uptake of lesions were quantified by SUVmax and the tumor-to-background ratios. The correlation between SUVmax and target lesion growth rate and thyroglobulin was analyzed. On patient-based analysis, positive metastases were detected in 87.5% (21/24) patients. Except for the lymph node (LN) metastasis of 3 patients (patient 6, 12 and 17#) and the lung metastasis of another 3 patients (patient 9, 13 and 21#), most of the lesions were positive on 68Ga-DOTA-FAPI-04 PET/CT images, including LN metastasis and distant metastasis such as lung, bone and pleura. There were altogether 33 target lesions including 30 lung metastases and 3LN metastases with the mean SUVmax and the growth rate were 4.25 and 6.51%, respectively. SUVmax was statistically associated with the growth rates of the target lesions (p = 0.047). No statistically significant correlation was found between the SUVmax and the serum thyroglobulin levels (p = 0.139). 68Ga-DOTA-FAPI-04 PET/CT has a promising detection rate for RR-DTC metastasis. The FAPI uptake of the tumor may provide a potential therapeutic target for RR-DTC. NIH Clinical Trials.gov (NCT04499365).

A proposed clinical scoring system for initiation of lenvatinib treatment in radioiodine-refractory thyroid cancer patients.

The optimal timing for starting lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) has long been controversial because of the relatively slow-growing nature of differentiated thyroid cancer. The aim of this study was to establish a scoring system using known clinical factors to simplify decision-making in when to start lenvatinib in RR-DTC patients. We retrospectively analyzed RR-DTC patients treated with lenvatinib. We developed the clinical indication scoring algorithm on the basis of age, tumor-related symptoms, histology, metastatic sites, neutrophil-to-lymphocyte ratio, size of lung metastases, baseline sum of tumor diameters, and tumor-volume doubling time that was used to categorize patients into low-, intermediate-, and high-risk groups. A total of 59 patients were analyzed; 13 low-risk, 36 intermediate-risk, and 10 high-risk. The respective median progression-free survival from the initiation of lenvatinib was 93.7 months in the low-risk group, 20.3 months in the intermediate-risk group, and 6.2 months in the high-risk group (p < 0.02). Patients in the high-risk group had significantly worse overall survival compared with those in the low-risk (hazard ratio [HR] 6.59, 95% confidence interval [CI] 1.25-34.90, p < 0.03) or intermediate-risk (HR 2.99, 95% CI 1.03-8.63, p < 0.05) group. Using our proposed algorithm, patients in the intermediate-risk group showed treatment outcomes similar to that were observed in the pivotal trial of lenvatinib, and were the optimal patients to start lenvatinib. Our proposed scoring system can separate treatment outcomes and prognosis of RR-DTC patients treated with lenvatinib. This simple algorithm can be helpful for oncologists in deciding whether to start lenvatinib treatment in patients with RR-DTC.

Novel Fibroblast Activation Protein Inhibitor-Based Targeted Theranostics for Radioiodine-Refractory Differentiated Thyroid Cancer Patients: A Pilot Study.

Background: This exploratory study was meant to assess clinical and safety data with a novel fibroblast activation protein inhibitor-based targeted theranostics as a salvage treatment option in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients who had progressed on tyrosine kinase inhibitors. Methods: Patients with metastatic RR-DTC who progressed on sorafenib/lenvatinib were prospectively recruited. If [68Ga]Ga-DOTA.SA.FAPi positron emission tomography/computed tomography scan demonstrated moderate-to-excellent uptake in metastases, and patients had given informed consent, they received intravenous [177Lu]Lu-DOTAGA.(SA.FAPi)2 as therapy at eight-weekly intervals. The primary endpoints were thyroglobulin (Tg) response and functional imaging response. The secondary endpoints were visual analog score (VAS) and Eastern Cooperative Oncology Group (ECOG) performance status. The grading of toxicities was performed by using Common Terminology Criteria for Adverse Events (CTCAEV5.0). The sequential images were acquired by a dual-headed gamma camera, and dosimetric calculations were performed by using OLINDA/EXM V2.1. Results: Fifteen patients were recruited [age: 55 ± 9 years (range: 39-67)]. [177Lu]Lu-DOTAGA.(SA.FAPi)2 had median whole-body Teff of 88.06 hours (interquartile range [IQR]: 86.6-99). The colon was identified as a critical organ. The whole-body effective dose was 1.62E-01 ± 1.53E-02 mSv/MBq. A total of 45 cycles were administered, and the median cumulative administered activity was 8.2 ± 2.7 GBq (range 5.5-14 GBq). The median absorbed doses to the tumor lesions were 1.08E+01 (IQR: 4.16E+00 to 8.97E+01) mSv/MBq per cycle. The Serum Tg level significantly decreased after treatment [(median Tg: baseline-10,549 ng/mL (IQR: 3066.5-39,450) versus at the time of assessment: 5649 ng/mL (IQR: 939.5-17,099), p = 0.0005)]. Molecular response assessment revealed no complete response; however, partial response was documented in four, and stable disease in three patients. The VASmax scores [pre-therapy: 9 (IQR: 8-10) versus follow-up: 6 (3-6) (p-0.0001)], and ECOG [3, (IQR: 2-3 vs. 2, (IQR: 2-3) (p-0.0078)] performance scores significantly improved after treatment. None of the patients experienced grade III/IV hematological, renal, or hepatotoxicity. Conclusion: These preliminary data suggest that the novel molecule [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe, seems effective, and, most importantly, opens up a new avenue for the treatment of aggressive RR-DTC patients who have exhausted all standard line of treatments.

Radiomics-based prediction of response to multikinase inhibitors in radioiodine-refractory differentiated thyroid cancer patients.

6077 Background: Antiangiogenic tyrosine kinase inhibitors (TKIs) represent the first-line treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC). Currently, no predictive factors for the activity of these drugs are available. We investigated whether radiomics may have a predictive role in this setting. Methods: We retrospectively identified patients (pts) affected by metastatic RR-DTC, treated with TKIs between July 2008 and January 2020 at our Institution, with availability of computed tomography (CT) scans at baseline and after at least 2 courses of TKI. Response to TKIs was evaluated according to RECIST v1.1. Pts with complete or partial response at the first radiological evaluation were considered responders (R), pts with stable or progressive disease non-responders (NR). A dedicated radiologist segmented the target lesions as regions of interest (ROIs). Radiomic features related to multiple categories (shape and size, first order statistics, textural features) were extracted from each ROI and computed using the PyRadiomics library v. 3.0. A semi-supervised form of principal component analysis estimated principal components that were then used for response classification through a k nearest neighbors (kNN) classifier. The quality of the model was assessed through train-validation-test split (55% of the data used as training set, 25% as validation set, 20% as test set), repeated 100 times. Performance of the predictive models was quantified with the mean Area Under the ROC Curve (AUC) obtained in the test set. Results: A total of 51 pts with metastatic RR-DTC who had received lenvatinib (n=37), sorafenib (n=4), axitinib (n=3), or vandetanib (n=7) were analyzed. Median age was 64.6 years, with a male prevalence (72.5%). Metastatic sites were lung (84.3%), bone (35.3%), brain (9.9%). Median time from TKI treatment start to the first radiological evaluation was 2.77 months, 24 pts (47%) were R (all partial responses) and 27 (52.9%) NR. In the radiomic analysis, 851 features were computed and 4-19 principal components were selected. Models’ performance of prediction of early response to TKIs is presented in Table. For each value of AUC, the corresponding 95% confidence interval is reported in brackets. Conclusions: Radiomics predicted the response to TKIs of RR-DTC pts with an accuracy of 71%. Radiomics technique has the potential to enable clinicians to anticipate the probability of response to TKIs at baseline, directing toward the most suitable patient-tailored therapeutic path. Prospective studies may further validate these preliminary findings.[Table: see text]

Baseline Tumour Size as a Prognostic Factor for Radioiodine-refractory Differentiated Thyroid Cancer Treated With Lenvatinib.

Lenvatinib is standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC), although the optimal timing for starting treatment is still controversial. The aim of this study was to evaluate the prognostic impact of baseline tumour size (BTS) in patients with RR-DTC treated with lenvatinib. Fifty-one RR-DTC patients who had at least one measurable lesion and treated with lenvatinib were retrospectively analysed. BTS was defined as the sum of the longest dimensions of all measurable target lesions. Median progression-free survival (PFS) and overall survival (OS) in the larger BTS (≥42 mm) group were shorter than those in the smaller (<42 mm) group. This result was more significant in patients with fast-growing tumours. BTS was an independent prognostic factor for both PFS and OS. Starting lenvatinib at BTS <42 mm should be recommended to achieve good treatment outcomes in patients with RR-DTC.

Prognostic significance of 8 weeks’ relative dose intensity of lenvatinib in treatment of radioiodine-refractory differentiated thyroid cancer patients

Lenvatinib is a standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, because of the high incidence of adverse events resulting from this treatment, it is not easy to maintain the dose intensity of lenvatinib, especially in Japanese patients. Although the prognostic impact of lenvatinib dose interruption has been reported, the target dose intensity of lenvatinib to optimize survival benefits remains unknown. We therefore propose a target dose intensity of lenvatinib during the first 8 weeks of treatment. We retrospectively analyzed 42 RR-DTC patients who were treated with lenvatinib for more than 8 weeks. We performed receiver operating characteristic curve analysis to determine the cut-off value of 8 weeks' relative dose intensity (8w-RDI) to predict treatment response, and identified that the optimal cut-off value of 8w-RDI was 60% (sensitivity: 81.8%; specificity: 80.6%). Median progression-free survival (PFS) (not reached [NR] vs. 11.0 months; hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.11-0.72; p < 0.01) and overall survival (NR vs. 27.6 months; HR 0.44; 95% CI 0.11-0.91; p = 0.03) were longer in the higher 8w-RDI (≥60%) patients than in the lower 8w-RDI (<60%) patients. Multivariate analysis revealed that 8w-RDI at ≥60% was an independent prognostic factor for PFS (HR 0.29; 95% CI 0.09-0.96; p = 0.04). Targeting for ≥60% of the relative dose intensity during the first 8 weeks of lenvatinib treatment can be sufficient to achieve significant tumor shrinkage and prolong PFS in RR-DTC patients.

MON-LB76 Impact of Age on Survival and Prognostic Factors in Radioiodine Refractory Differentiated Thyroid Cancer Patients

BACKGROUNDAge has been identified as a major prognostic factor in differentiated thyroid cancer (DTC). Prognostic factors of radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) are poorly described. The objectives of our study were to analyze the influence of age on the survival of patients with RAIR-DTC and to determine their prognostic factors according to age.PATIENTS AND METHODThis single centre, retrospective study enrolled 155 patients diagnosed with a RAIR-DTC between 1991 and 2017. The primary end point was overall survival (OS). Secondary endpoints were progression free survival (PFS) and prognostic factors.RESULTSMedian OS was 8.2 years (95% IC: 5.3-9.6). There was no difference according to age (P = 0.47) with median OS at 8.3 years in patients < 65 (95% IC: 4.9-10), and 7.5 years in patients > 65 (IC: 4,9-11,3). PFS after RAIR-diagnosis was 2.1 years (95% IC: 0.8-3) in patients < 65, and 1 year in patients > 65 (95% IC: 0.34-0.68). In both groups, progressive disease despite 131I reduced OS, in comparison with other RAIR criteria. In patients < 65, an interval between the initial diagnosis of DTC and the diagnosis of RAIR metastatic disease more than 3 years was protective from poor OS (HR: 2.12; 95% CI: 1.05-4.27). In patients > 65, presence of a mediastinum metastasis at RAIR-diagnosis was a significant factor for decreased OS (HR: 0.22; 95% CI: 0.11-0.44).No difference was found between groups regarding therapeutic management. One third of patients received tyrosine kinase inhibitors in both groups (< 65 years: 20 patients (28%), ≥ 65 years: 28 (33%), P = 0.49). They were also similar regarding the number of lines received or the median duration of treatment (< 65 years: 19.5 months (2-59), ≥ 65 years: 19 months (1-64), p= 0.35). At least one line of TKI was transitorily or definitively withdrawn due to toxicity in 40% of patients (< 65 years: 8/20 patients (40%), ≥ 65 years: 13/28 (46%), p= 0,037).CONCLUSIONIn RAIR-DTC patients, age was not predictive of the outcome. In our study, older patients seem to have benefited from intensive therapeutic management. Continual progress made in the management of RAIR-DTC, especially with the implementation of systemic therapies should probably make reconsider the natural history and conventional prognostic factors of RAIR-DTC.

Sorafenib and radioiodine-refractory differentiated thyroid cancer (RR-DTC): a systematic review and meta-analysis.

Except conventional treatments, research on medical approach for radioiodine-refractory differentiated thyroid cancer (RR-DTC) was considered particularly challenging. Sorafenib, a novel biological agent, has been widely studied in the treatment of RR-DTC for years. We performed a systematic review and meta-analysis to explore the efficiency and safety of treating RR-DTC patients with sorafenib. An electronic search on PubMed/Medline and Embase was carried out to search associated articles. Fixed-effects or random-effects models were chose according to the heterogeneity. A total of 15 eligible studies (636 patients) were included. As shown by the only randomised clinical trial-DECISION, sorafenib significantly improved progression-free survival (PFS) compared with placebo in patients with progressive RR-DTC. The pooled analysis indicated that there were 26% patients (95% CI: 0.19-0.34) achieved partial response (PR), and 44% patients (98% CI: 0.39-0.48) achieved stable disease (SD). The most frequent adverse effects (AEs) observed included hand-foot syndrome (HFS), diarrhoea, fatigue, alopecia, weight loss (WS) and rash, the incidence of all grades AEs for which were 71%, 60%, 59%, 55%, 51% and 50%, respectively. There were 68% patients (252/368), who had a dose reduction because of the drug toxicities and AEs. Sorafenib could improve PFS in patients with progressive RR-DTC, comparing with placebo. Due to the resistance to conventional treatments, sorafenib is considered as a promising treatment for RR-DTC by most physicians specialised in this field. However, the use of sorafenib should be cautious due to a high incidence of AEs caused by the agent. More effective agents with less toxicities are warranted.

177Lu-DOTATATE Therapy in Radioiodine-refractory Differentiated Thyroid Cancer: A Single Center Experience.

Patients with radioiodine-refractory differentiated thyroid cancer (RrDTC) have a rather poor prognosis and are in need of novel treatments. As RrDTCs can in some cases express somatostatin receptors (SSRT), targeting of these receptors by Ga/Lu-DOTATATE could evolve as a novel theranostic option. Five RrDTC patients with limited further therapeutic options and documented expression of SSRT using Ga-DOTATATE-PET/CT received 2 to 4 cycles of PRRT with Lu-DOTATATE. Response to therapy was assessed by thyroglobulin (Tg) and morphological and metabolic criteria based on interim and follow-up Ga-DOTATATE-PET/CTs. Analysis was performed on a per-patient basis. In the post-therapy evaluation, only one out of five patients showed a partial response, whereas three patients had a progressive disease. One patient had discordant findings between stable imaging results albeit rising Tg levels. In this case study of five patients, Lu-DOTATATE therapy showed only heterogeneous response and efficacy in RrDTC patients despite good lesional uptake in pre-therapeutic PET.

PCN5 - TREATMENTS OF RADIOIODINE-REFRACTORY DIFFERENTIATED THYROID CANCER IN ROUTINE CLINICAL PRACTICE – A SYSTEMATIC REVIEW

To collate evidence from published studies evaluating the efficacy and safety of treatments for patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). A literature search was conducted in Embase®, Cochrane, MEDLINE® and MEDLINE In-Process to identify evidence published from inception until 2018. Grey literature including conference proceedings, heath technology assessments and trial registry websites were searched for relevant studies. The studies were assessed for eligibility against pre-defined inclusion criteria: English language, pharmacological intervention, non-randomised clinical and observational studies. Eighty-two unique studies (44 clinical; 38 observational) were included. Of these, 75 studies have non-comparative study design (43 clinical; 32 observational). The majority of clinical studies were Phase II trials (33), while two were Phase I trials; however, nine did not report the study phase. A majority of the studies (66) included tyrosine kinase inhibitors (TKIs) – sorafenib (19), lenvatinib (15), sunitinib (6), apatinib (4), selumetinib (2), and others/multiple TKIs (20). Among the majority (27) of the TKIs studies reporting objective response rates (ORR), response varied from 10.0% on axitinib to 69.0% on lenvatinib. One study reported no response among patients receiving bortezomib. The median overall survival (OS) varied from 12.7 months with sorafenib to 55.7 months with sunitinib. The ORR in the sorafenib and lenvatinib studies varied from 14.0%–62.5% and 50.0%–69.0%, respectively. The median OS varied from 12.7–36.6 months in sorafenib and 19.9–31.8 months across lenvatinib treated patients, respectively. The safety profile of TKIs indicates that >80.0% of patients had any grade adverse events (AEs), while 19.3%–35.0% had Grade ≥3 AEs. Major AEs across sorafenib recipients were hand–foot skin reactions and weight loss, whereas it was hypertension and appetite loss in lenvatinib treated patients. RR-DTC patients are frequently treated with TKIs in routine clinical practice. Lenvatinib has demonstrated promising results for the treatment of RR-DTC.

Number needed to treat in indirect treatment comparison.

For dichotomous outcomes, odds ratio (OR) is one of the usual summary measures of indirect treatment comparison. A corresponding number needed to treat (NNT) estimate may facilitate understanding of the treatment effect. We show how to estimate NNT based on OR results of a matching adjusted indirect comparison. We also have derived the explicit formula of its 95% CIs by applying the delta method, and as an alternative, a simulation-based method. The method was applied in a case study example in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients, comparing lenvatinib to sorafenib. For every two RR-DTC patients treated with lenvatinib instead of sorafenib, one fewer would have progressed and for every eight RR-DTC patients treated with lenvatinib instead of sorafenib, one fewer would have died. Using NNT to summarize the results of a matching adjusted indirect comparison can help the clinicians to better understand the results in addition to OR.

Clinical factors related to the efficacy of tyrosine kinase inhibitor therapy in radioactive iodine refractory recurrent differentiated thyroid cancer patients.

New insights in thyroid cancer biology propelled the development of targeted therapies as salvage treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC), and the tyrosine kinase inhibitor (TKI) lenvatinib has recently become available as a new line of therapy for RR-DTC. The aim of this study is to investigate clinical factors related to the efficacy of TKI therapy in recurrent RR-DTC patients and identify the optimal timing for the start of TKI therapy. The subjects consisted of 29 patients with progressive RR-DTC, 9 males and 20 females, median age 66 years. A univariate analysis was conducted in relation to progression free survival (PFS) and overall survival (OS) by the Kaplan-Meier method for the following variables: age, sex, histology of the primary tumor, thyroglobulin doubling time before the start of lenvatinib therapy, site of the target lesions, presence of a tumor-mediated symptom at the start of lenvatinib therapy, and baseline tumor size of the target lesions. Median duration of lenvatinib therapy was 14.7 months and median drug intensity was 9.5 mg. At the time of the data cut-off for the analysis, 9 patients (31.0%) have died of their disease (DOD), and a PR (partial response), SD (stable disease), and PD (progressive disease) were observed in 20 patients (69%), 6 patients (20.7%), 3 patients (10.3%), respectively. Univariate analyses showed that the presence of a symptom was the only factor significantly related to poorer PFS and OS. Clinical benefit of TKI therapy will be possibly limited when the therapy starts after tumor-mediated symptoms appear.

Risk factors for radioiodine-refractoriness and survival analysis of differentiated thyroid cancer with distant metastasis

Objective To analyze clinical risk factors for radioiodine(RAI)-refractoriness of DTC with distant metastasis and do survival analysis. Method The clinical data of 77 differentiated thyroid cancer(DTC) patients with distant metastasis admitted to the department of radionuclide therapeutics of Qilu Hospital from Jan 2002 to Sep 2015 were collected to make the retrospective analysis by dividing into radioiodine-refractory(RAI-R) group and radioiodine-efficient(RAI-E) group. Result (1)In DTC patients treated by 131I, there are 77(7.15%) patients with distant metastasis. Among DTC with distant metastasis, 25(32.47%) patients are identified as RAI-R DTC with average age of (56.2±16.0) years old, median age of 57 years old, and male-to female ratio of 1∶2.57. (2)Univariate analysis shows that age of distant metastasis older than 45 years and pathological type of follicular thyroid cancer(FTC) are two risk factors related to RAI-refractoriness. Logistic regression analysis indicates that age of distant metastasis older than 45 years and pathological type of FTC are the independent risk factors for RAI-refractoriness of DTC with distant metastasis. (3)3-year and 5-year survival rates of the 25 RAI-R DTC patients with distant metastasis are 75% and 62%, while RAI-E DTC patients were all alive. The survival of RAI-R DTC with distant metastasis is significantly worse than RAI-E DTC with distant metastasis. Conclusions (1)In the DTC with distant metastasis, the rate of RAI-R DTC is not low, and it is 32.47%. Females of RAI-R DTC are more than males. (2)Age of distant metastasis older than 45 years and pathological type of FTC are independent risk factors for RAI-refractoriness of DTC with distant metastasis. (3)The survival rate of RAI-R DTC with distant metastasis was significantly lower than that of RAI-E DTC with distant metastasis. (Chin J Endocrinol Metab, 2017, 33: 387-391) Key words: Radioiodine-refractory; Distant metastasis; Differentiated thyroid cancer

Overwhelming rapid metabolic and structural response to apatinib in radioiodine refractory differentiated thyroid cancer.

Currently, patients with radioiodine refractory differentiated thyroid cancer (RAIR-DTC) have limited treatment options. In this study, we aimed to assess the short-term efficacy and safety of apatinib in RAIR-DTC. Ten adult patients were prospectively enrolled to receive oral apatinib (750 mg q.d). The primary endpoints were change in serum thyroglobulin (Tg) concentration, disease control rate (DCR) and objective response rate (ORR) based on RECIST 1.1 criteria. The secondary endpoints included change in glucose metabolism, evaluated by maximum standard uptake value (SUVmax), and safety. As early as 2 weeks after apatinib treatment, the serum Tg concentration decreased by 21.0% in 8 patients available for detection without interference, and a further sharp decline by 81.4% compared with the baseline level occurred at 8 weeks post-treatment. The DCR and ORR were 100% (10/10) and 90% (9/10), respectively. The sum of tumor diameter shrank to 22.8±8.1 mm from 38.8±15.7 mm (P=0.001). Moreover, a significant decrease in SUVmax was observed from 6.53±5.14 to 2.56±1.67 and 2.45±1.48 at 4-week and 8-week time-points after treatment (P=0.032 and 0.020), respectively. The common grade 3 adverse events (AEs) included hand-foot-skin reaction (50%), hypertension (30%), and hypocalcemia (20%). No severe AE related to apatinib was observed during treatment. Hence, apatinib seems to be a promising therapeutic option for RAIR-DTC patients. Apart from RECIST 1.1 criteria, the biochemical marker (Tg) and glucose metabolism index (SUVmax) could be adopted in assessing the early response to TKI in RAIR-DTC.

Determination of the most appropriate method for extrapolating overall survival data from a placebo-controlled clinical trial of lenvatinib for progressive, radioiodine-refractory differentiated thyroid cancer.

BackgroundCost-effectiveness models for the treatment of long-term conditions often require information on survival beyond the period of available data.ObjectivesThis paper aims to identify a robust and reliable method for the extrapolation of overall survival (OS) in patients with radioiodine-refractory differentiated thyroid cancer receiving lenvatinib or placebo.MethodsData from 392 patients (lenvatinib: 261, placebo: 131) from the SELECT trial are used over a 34-month period of follow-up. A previously published criterion-based approach is employed to ascertain credible estimates of OS beyond the trial data. Parametric models with and without a treatment covariate and piecewise models are used to extrapolate OS, and a holistic approach, where a series of statistical and visual tests are considered collectively, is taken in determining the most appropriate extrapolation model.ResultsA piecewise model, in which the Kaplan–Meier survivor function is used over the trial period and an extrapolated tail is based on the Exponential distribution, is identified as the optimal model.ConclusionIn the absence of long-term survival estimates from clinical trials, survival estimates often need to be extrapolated from the available data. The use of a systematic method based on a priori determined selection criteria provides a transparent approach and reduces the risk of bias. The extrapolated OS estimates will be used to investigate the potential long-term benefits of lenvatinib in the treatment of radioiodine-refractory differentiated thyroid cancer patients and populate future cost-effectiveness analyses.

Sorafenib in the treatment of radioiodine-refractory differentiated thyroid cancer: a meta-analysis

The advent of biologically targeted agents and increased understanding of thyroid carcinogenesis have generated much interest in the development of biologically targeted therapeutic agents for thyroid cancer. Among them, sorafenib is the most commonly studied drug. The current meta-analysis was carried out to estimate the efficacy and safety of sorafenib administered in radioiodine-refractory differentiated thyroid cancer patients. An electronic search was conducted using PubMed/MEDLINE and EMBASE. Statistical analyses were carried out using either random-effects or fixed-effects models according to heterogeneity. All the statistical analyses were carried out using the Stata version 12.0 software. Seven eligible studies were identified. The final results indicated that 22% of the patients (95% CI: 15-28) achieved a partial response. Hand-foot syndrome, diarrhea, fatigue, rash, weight loss, and hypertension were the most frequently observed adverse effects (AEs) associated with sorafenib use and the incidence of these AEs (all grades) was 80% (95% CI: 68-91), 68% (95% CI: 59-77), 67% (95% CI: 57-78), 66% (95% CI: 50-82), 52%(95% CI: 33-72), and 31% (95% CI: 21-42) respectively. Sixty-two percent (95% CI: 36-89) patients required dose reductions due to toxicity of sorafenib. As far as PR and AEs are concerned, the results of this meta-analysis indicate that sorafenib has a modest effect in patients with radioiodine-refractory differentiated thyroid cancer and the high incidence of AEs associated with this agent may affect the quality of patients' lives. Though the use of sorafenib in the treatment of radioiodine-refractory differentiated thyroid cancer is considered promising by most physicians working in this field, more effective agents with less toxicity and cost are still needed.