DTC Patients Research Articles

Prevalence and Risk Factors of Developing Fistula or Organ Perforation in Patients Treated with Lenvatinib for Radioiodine-Refractory Thyroid Cancer

Introduction: Tyrosine kinase inhibitors represent a better treatment in patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Lenvatinib is usually well-tolerated, but sometimes, it is associated with serious and even life-threatening side effects. The aim of this study was to evaluate the prevalence of and the potential risk factors for fistula and/or organ perforation in RAI-R DTC patients treated with lenvatinib. Methods: This study included data from advanced and progressive RAI-R DTC patients treated with lenvatinib from February 2011 to February 2020 who were followed up at a single center. The clinical-pathological features and the biochemical and morphological results of the patients were collected at the time of starting lenvatinib and during the follow-up. Results: Fourteen of 95 (14.7%) locally advanced or metastatic RAI-R DTC patients treated with lenvatinib developed a fistula or organ perforation. Nine of 14 (64.3%) patients had tumor infiltration of the trachea, bronchus, esophagus, pleura, or bladder. Five of 14 (35.7%) had a bowel perforation, but only 2 had preexisting diverticulosis. Evaluation of the risk factors for developing a fistula or organ perforation showed that the presence of tumor infiltration and the tumor histology (papillary and poorly differentiated vs. follicular and Hurthle thyroid cancer) were significantly correlated with the development of a fistula or organ perforation (p = 0.003 and p = 0.02, respectively). In the subgroup of patients with tumor infiltration, we found that the papillary thyroid cancer histotype was the only potential predictor of fistula development. External beam radiation therapy (EBRT), the starting dose of lenvatinib, and the duration of treatment were not relevant for the development of fistula. Conclusions: In metastatic thyroid cancer patients treated with lenvatinib, the presence of tumor infiltration and histological type should be considered as potential risk factors for the development of fistula or organ perforation, although they do not represent an absolute contraindication. Although EBRT and the presence of diverticulosis were not significantly associated with the development of fistula and organ perforation, they should be regarded as potential additional reasons for the development of these complications. According to our findings, there is no reason to start lenvatinib at a lower daily dose when tumor infiltration is present.

Long-Term Outcomes and Prognoses of Elderly Patients (≥65-Years-Old) With Distant Metastases From Well-Differentiated Thyroid Cancer During Radioiodine Therapy and Follow-Up

ObjectiveThe objective of this study was to investigate the clinicopathological characteristics, long-term outcomes, and prognostic factors of elderly patients with distant metastases at initial diagnosis from well-differentiated thyroid cancer (WDTC) during radioactive iodine (131I) treatment and follow-up.MethodsA retrospective review of medical records identified 183 elderly patients with DTC who underwent 131I treatment at our institution between 2006 and 2019.ResultsIn total, 57 elderly WDTC patients with distant metastases were enrolled in this study. After 131I treatment, 32 (56.14%) patients had 131I avidity and 25 (43.86%) had non-131I avidity; 35 (61.40%) cases were classified as radioiodine refractory (RR)-WDTC and 22 (38.60%) as non-RR-WDTC. At the end of follow-up, 25 (43.86%) patients had died and 32 (56.14%) were alive. The 5- and 10-year overall survival (OS) rates were 71.50% and 30.49%, respectively, while the 5- and 10-year disease-specific survival (DSS) rates were 76.89% and 48.71%, respectively. Multivariate analyses showed that gross extrathyroidal extension and RR-DTC were independent prognostic factors for poor OS (P=0.04 and P=0.03, respectively), while gross extrathyroidal extension, extrapulmonary distant metastases, and RR-WDTC were independent prognostic factors for poor DSS at the end of follow-up (P=0.02, P=0.03, and P=0.02, respectively).ConclusionsWDTC with distant metastases at initial diagnosis accounted for 31.15% of all elderly patients with DTC. Gross extrathyroidal extension and RR-DTC were the major factors associated with poor OS; gross extrathyroidal extension, extrapulmonary distant metastases, and RR-DTC were independent prognostic factors for poor DSS in elderly DTC patients with distant metastases.

Diagnostic Value of Exosomal miR-148a-3p in the Serum of Patients with Differentiated Thyroid Cancer.

The current study aims to evaluate the expression and diagnostic value of exosomal miR-148a-3p in the serum of DTC patients. Exosomes were isolated from the serum of DTC patients and were identified using a transmission electron microscope. RT-PCR was performed to determine the level of exosomal miR-148a-3p in DTC patients. The possible target gene of miR-148a-3p was determined using dual luciferase reporter assay. ROC analysis was performed to determine the diagnostic value of exosomal miR-148a-3p in DTC patients. We identified a novel exosomal miRNA, exosomal miR-148a-3p, that was significantly decreased in the serum of DTC patients compared with that of benign thyroid tumor patients and healthy controls. Further study showed that exosomal miR-148a-3p was correlated with the malignant characteristics of DTC, including tumor diameter, lymph node metastasis (LNM), and higher TNM staging. Dual luciferase reporter assay indicated that IGF-1 was a target gene of miR-148a-3p. ROC analysis demonstrated that the AUC of exosomal miR-148a-3p was better than TgAb and Tg in DTC patients. More importantly, combined use of exosomal miR-148a-3p, TgAb, and Tg significantly enhanced the sensitivity and specificity, indicating exosomal miR-148a-3p is a sensitive biomarker in DTC patients. Altogether, reduced exosomal miR-148a-3p was associated with the risk of DTC and may be used as a biomarker for the diagnosis of DTC.

Значимость персональных клинико-диагностических показателей при оценке побочного радиационного воздействия для больных раком щитовидной железы, получающих радиойодтерапию

The radioiodine therapy is the most well-known branch of radionuclide therapy. The therapy composed of thyroidectomy and iodine-131 radiopharmaceutical is the “gold standard” for treat-ment of differentiated thyroid cancer patients (DTC). Given metastases in lymph nodes such therapy is absolutely exclusive treatment mode. At the same time, despite the targeted effect of radioiodine on pathological foci a side internal exposure of healthy organs and tissues is noted in the course of radioiodine therapy. Therefore, a reliable assessment of the side exposure is nec-essary taking into account the individual characteristics of patients considering that the side dose varies significantly from patient to patient. For this reason, the identification of significance of personal clinic-diagnostic factors determined the side whole body exposure is the vital and im-portant task. In this aspect, the cytogenetic examination of DTC patients by means of the analysis of chromosomal aberrations in peripheral blood lymphocytes is the goal of essential importance. The certain types of chromosomal aberrations are specific radiation markers that unequivocally indicate radiation exposure. Using the frequency of radiation markers the side absorbed dose can be reliably estimated. In the present work, the statistical analysis of the significance of vari-ous clinic-diagnostic factors in relation to the induction of radiation markers in the blood lympho-cytes was performed. For that end the results of the cytogenetic examination of the group com-prised of 38 DTC patients have been used. The examined patients underwent a course of radio-iodine therapy in the department of radionuclide therapy of the A.F. Tsyb MRRC, Obninsk. The slide preparation and cytogenetic analysis were carried out in the laboratory of radiation cytoge-netic of the same Center. The performed analysis of the correlation matrix with respect to the dependence of the increased frequency of stable and unstable markers resulted from a one-time course of radioiodine therapy showed no meaningfulness at the level R>0.3 for all the studied factors. For the absolute value of the frequency of radiation markers, both before and after radioiodine therapy, the meaningful relationship was found at the level R>0.7 for unsta-ble and at the level R>0.8 for stable markers with a total administered activity of radioiodine dur-ing all the previous courses of radioiodine therapy.

The Value of Stimulated Thyroglobulin Before the First Radioactive Iodine Treatment in Metastasis for Differentiated Thyroid Carcinoma.

To evaluate the value of preablative stimulated thyroglobulin (ps-Tg) before the first radioactive ablation iodine (RAI) treatment to predict the postoperative metastasis of DTC. A total of 235 DTC patients, who underwent total thyroidectomy and neck lymph node dissection, were enrolled. On the basis of the presence or absence of metastasis, all patients were divided into metastasis (M1) and non-metastasis (M0) groups. Besides, the patients in the M1 group were further divided into two subgroups according to sites of metastasis. These groups included cervical lymph node metastasis and distant metastasis groups. Subsequently, the level of serum ps-Tg was measured 3 - 4 days before the first RAI ablation treatment, whereas 131I whole-body imaging and SPECT/CT tomography were performed 5 - 7 days after radio ablation. Subsequently, the Mann Whitney U test was used to compare the different levels of ps-Tg between the two groups. Additionally, the relationship between ps-Tg and the metastasis of DTC was analyzed through correlation analysis, regression analysis, and the ROC curve. The ps-Tg level in the M1 group was higher than that in the M0 group. Further analysis discovered that the ps-Tg in the distant metastasis group was higher than that in the cervical lymph node metastasis and non-metastasis groups. Also, the ps-Tg level was positively correlated with distant metastasis (r = 0.599, p = 0.000). Besides, the results of multivariate logistic regression analysis outlined that the level of ps-Tg was an independent risk factor for the development of distant metastasis (OR = 1.008, p = 0.018). Subsequently, the results from the ROC analysis also showed a good diagnostic performance for ps-Tg in treating distant metastasis (AUC = 0.964, p = 0.000), and the optimal cutoff value was 61.87 ng/mL. The ps-Tg in patients with DTC before the first RAI ablation treatment is an independent risk factor and a meaningful indicator in predicting postoperative distant metastasis.

The spectrum of 124I uptake in the lacrimal gland and nasolacrimal sac/duct on PET/CT imaging.

124I PET/CT in 31 DTC patients was performed at 2, 24, 48, 72, and 96 h after oral administration of 31.5 or 62.9 MBq (0.85 or 1.7 mCi) of 124I after either recombinant human thyroid-stimulating hormone injections or thyroid hormone withdrawal. All but two patients had a history of prior 131I therapy. Patterns of 124I uptake in the lacrimal glands and nasolacrimal sac/ducts (NLD) were assessed. A total of 173 individual 124I PET/CT scans (forming 35 sets of scans) were reviewed for 31 patients. Lacrimal glands were visualized bilaterally in only 4 patients. The focal mild uptake (grade 2), best seen on the 2-h images, was crescent-shaped and located in the lateral upper quadrant of the orbit. In contrast, the NLDs were identified in all patients (bilateral in 29 of 31 patients) with high focal uptake (grade 4) peaking on the 2- and 24-h timepoints; however, the overall pattern of uptake was variable. Of the 29 patients with prior 131I therapy, three patients had a relatively fixed and unchanging pattern of uptake on at least one side of the NLDs. In patients with DTC, 124I activity in the NLDs is more frequently visualized, more intense, more prolonged, and more variable than in the lacrimal glands. The lack of clearance may suggest possible obstruction or stasis of an NLD.

Rethinking the 8th AJCC System: Is It Suitable for Patients Aged

PurposeThe newest (8th) edition of the TNM staging system published in 2017. In this edition, some significant changes happened from the previous edition. As a result, down-staging appeared in nearly one third of DTC patients. However, we don’t know whether the new system predicts the survival of FVPTC patients accurately. Therefore, it is necessary to thoroughly evaluate the correlation between the new system and survival prediction in terms of FVPTC.MethodsWe enrolled 17,662 FVPTC patients from the Surveillance, Epidemiology, and End Results database. Factors associated with survival were identified by Cox regression analyses. The mortality rates per 1,000 person-years were calculated and compared. Cox proportional hazards regression quantified the risk of survival, and survival curves were produced by Kaplan-Meier analyses using log-rank tests.ResultsAge at diagnosis, race, T-stage at diagnosis, distant metastasis, radiation therapy, and surgery were independent factors associated with cancer-specific survival. Patients aged <55 years with stage T4N1M0 FVPTC had higher mortality rates per 1,000 person-years than patients in the same stage according to the 8th AJCC System. Cox proportional hazards regression reflected that patients aged <55 years with stage T1-3, any N, M0 or T4N0M0 disease (p=0.001) and patients aged ≥55 years with T1-2N0M0 disease (p=0.004) had significantly lower risks of cancer-specific survival (CSS) than those aged <55 years with stage T4N1M0 disease. The CSS curve of patients aged <55 years with stage T4N1M0 disease showed a decline on comparison with others belonging to stage I (p<0.001); and the curve was even not different from patients in stage II and stage III (p>0.05).ConclusionPatients aged <55 years with stage T4N1M0 FVPTC had worse survival than patients in stage I; no difference was seen on comparison with stage II patients. We recommend this group of patients be upstaged in the 8th AJCC system.

Micronuclei Formation upon Radioiodine Therapy for Well-Differentiated Thyroid Cancer: The Influence of DNA Repair Genes Variants.

Radioiodine therapy with 131I remains the mainstay of standard treatment for well-differentiated thyroid cancer (DTC). Prognosis is good but concern exists that 131I-emitted ionizing radiation may induce double-strand breaks in extra-thyroidal tissues, increasing the risk of secondary malignancies. We, therefore, sought to evaluate the induction and 2-year persistence of micronuclei (MN) in lymphocytes from 26 131I-treated DTC patients and the potential impact of nine homologous recombination (HR), non-homologous end-joining (NHEJ), and mismatch repair (MMR) polymorphisms on MN levels. MN frequency was determined by the cytokinesis-blocked micronucleus assay while genotyping was performed through pre-designed TaqMan® Assays or conventional PCR-restriction fragment length polymorphism (RFLP). MN levels increased significantly one month after therapy and remained persistently higher than baseline for 2 years. A marked reduction in lymphocyte proliferation capacity was also apparent 2 years after therapy. MLH1 rs1799977 was associated with MN frequency (absolute or net variation) one month after therapy, in two independent groups. Significant associations were also observed for MSH3 rs26279, MSH4 rs5745325, NBN rs1805794, and tumor histotype. Overall, our results suggest that 131I therapy may pose a long-term challenge to cells other than thyrocytes and that the individual genetic profile may influence 131I sensitivity, hence its risk-benefit ratio. Further studies are warranted to confirm the potential utility of these single nucleotide polymorphisms (SNPs) as radiogenomic biomarkers in the personalization of radioiodine therapy.

Lenvatinib as first-line treatment for advanced thyroid cancer: long progression-free survival.

Lenvatinib (LEN) has been approved for the treatment of patients with progressive radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Real-life studies reported a lower progression-free survival (PFS) than the registration study, likely due to the more advanced stage of tumors, the more frequent pretreatment with other TKIs, the limited follow-up, and the worse clinical condition of the patients included. We evaluated the clinical data of our cohort of 13 consecutive patients, all receiving LEN as a first-line TKI treatment, and followed-up in a single tertiary Center. All patients had an ECOG of 0-1 and regional or distant metastases were documented in 61.5% and 77% of patients, respectively. Median PFS was 22 months (95% CI 14-35) with partial response in 69% and stable disease in 31% of patients. All patients experienced at least one adverse event (AE), the most frequent being fatigue, anorexia, diarrhea, and hypertension. The daily dose was reduced in 70% of patients and only one patient (7.7%) discontinued the drug for AEs. In this series of RAI-R DTC patients, with the unique features to have an ECOG 0 or 1 and to be naive for TKI treatments, PFS was the longest among all real-life published so far, with the highest rate of patients with partial response and one of the lowest drug discontinuation rate for AEs. The correct timing of treatment start, the tailoring of the dose, and a proper management of the AEs may have a significant impact on the treatment response to LEN.

Determination of thyroglobulin levels by radioimmunoassay method in anti thyroglobulin positive differentiated thyroid patients: One center clinical experience

It is very crucial to determine Tg accurately and precisely in thyroid cancer cases. Although there are many studies on the detection of Tg in thyroid cases in the literature, there are no sufficient clinical studies examining many cases with different features by using RIA methodology. Here, a radiometric and chromatographic method has been studied for the first time to eliminate the interference from anti-Tg positive patients. In this paper, radioimmunoassay (RIA) and immunoradiometric (IRMA) techniques were used for the analysis of 302 sera collected from patients for Tg and TgAb quantification. By the RIA technique, a reliable result was obtained by calculating the real Tg value quantitatively in 41 patients showing TgAb positivity out of 208 patients. Our findings show that the RIA assay is the most suitable approach for detection of changeable (low or undetectable) Tg value and metastases detected by post-therapeutic imaging in early-stage DTC cases showing preoperative and postoperative TgAb positivity. The new immunoradiometric method allows the real (%) Tg value to be reached in a part of TgAb-positive DTC. Even if TgAb positive in the metastatic and nonmetastatic DTC patient group. This allows the accurate clinical follow-up of patients.

Diagnostic and prognostic value of preoperative systemic inflammatory markers in anaplastic thyroid cancer.

Easily accessible, generalized, and inexpensive methods are expected to differentiate anaplastic thyroid carcinoma (ATC) from advanced differentiated thyroid cancer (aDTC). We aimed to explore potential diagnostic and prognostic value of systematic inflammatory markers (SIMs) in ATC and aDTC. About 22 ATC, 101 aDTC, and 100 matched early DTC patients were analyzed retrospectively. SIMs included the comprehensive index, neutrophil-monocyte-platelet-to-lymphocyte ratio (NMPLR) and the previously reported ones. Receiver operating characteristic, Kaplan-Meier, and COX regression analyses were mainly conducted. NMPLR exhibited the highest area under the curve value 0.806 (P < .0001) to diagnose ATC from aDTC. NMPLR was identified as an independent risk factor for overall survival (OS) (hazard ratio [HR]: 47.821, 95% confidence interval [CI], 2.863-798.765, P = .007) in ATC, as well as for OS (HR: 7.360, 95% CI, 1.620-33.430, P = .010) and recurrence-free survival (HR: 4.172, 95% CI, 1.139-15.286, P = .031) in aDTC. Taken both refractory types (ATC and aDTC) together, NMPLR could independently predict OS (HR: 6.470; 95% CI, 2.134-19.616; P = .001). NMPLR is a generalized index. It showed excellent potential in differential diagnosis and survival prediction in refractory thyroid cancer. However, it needs to be validated in larger cohort and clinical practice.

Effectiveness and toxicity of lenvatinib in refractory thyroid cancer: Dutch real-life data.

The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodine-refractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial. From three Dutch centres Electronic Health Records (EHRs) of patients treated in the lenvatinib compassionate use program or as standard of care were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in other studies. A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade ≥3 toxicities were hypertension (n = 11, 28%), diarrhoea (n = 7, 18%), vomiting (n = 4, 10%), and gallbladder disease (n = 3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI): 4.0-15.5) and 18.3 (95% CI: 4.9-31.7) months, respectively, response rate was 38% (95% CI: 23-54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (P = 0.04). PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real-life population and the SELECT study population regarding patient characteristics should be taken into account.

Pediatric Differentiated Thyroid Carcinoma: Outcome in Response to Initial Treatment

Introduction: Though the differentiated thyroid carcinoma in children is a common pediatric endocrine malignancy, its prognosis is excellent with a proper initial treatment. Objectives: This is to evaluate the initial treatment patern for a good prognosis with longterm outcome in pediatric DTC patients. Methods: This study is a prospective one done in BSMMU during a period of 10 years in 52 post-operative pediatric DTC patients after excluding the follow-up missing patients. These patients are yet in a regular follow-up were outcome evaluated with clinical, pathological &amp; imaging studies. Results: All the patients got initial treatment of total thyroidectomy. About half of the group had undergone neck dissection along with total thyroidectomy. Forty six patients had taken 131-I therapy. The survival is 100%. Conclusion: The life expectancy for children with DTC is excellent. However, many patients experience adverse effects from thyroid surgery, resulting in life long complications. Bangladesh J of Otorhinolaryngology; October 2018; 24(2): 143-148

Drip and ship for mechanical thrombectomy within the Neurovascular Network of Southwest Bavaria

To determine feasibility and safety of stroke care organization within our Neurovascular Network of Southwest Bavaria (NEVAS) in a rural area with distances of up to 100 kilometers, we compared patients who underwent mechanical thrombectomy (MT) in large vessel occlusion admitted directly to our center (direct to center [DTC]) to patients who were transferred for MT via NEVAS (drip and ship [DS]). This is a retrospective analysis of prospectively collected data of all MT patients between January 2015 and May 2018. Successful recanalization was defined as a thrombolysis in cerebral infarction score of 2b-3. Symptomatic intracerebral hemorrhage (sICH) was defined according to European Cooperative Acute Stroke Study 3. Modified Rankin Scale (mRS) score of 0-2 at 3 months indicated good outcome. MT was performed in 410 patients: 221 DTC and 189 DS. Median NIH Stroke Scale (NIHSS) score was 16 and premorbid mRS score was 0. Thrombolysis was applied in 62.2% with the same time from symptom onset in both groups (94.5 vs 95 minutes). Successful recanalization (79.3% vs 77.8%) and NIHSS score reduction from admission to discharge (16-7 vs 17-6) were comparable. Time delay from onset to revascularization was 96 minutes in DS (212 vs 308 minutes, p = 0.001). At follow-up, DTC patients had a trend to better outcome (33.5% vs 24.3%, p = 0.056). Neither sICH (6.3% vs 5.9%, p = 0.840) nor mortality (31.2% vs 34.4%, p = 0.387) differed between the groups. DS patients benefit from MT without relevant safety concerns, but with a trend to unfavorable outcome compared to DTC patients. These results suggest that DS is suitable to provide MT in rural areas where DTC is not possible.

Assessment of the impact of 2015 American Thyroid Association guidelines in management of differentiated thyroid cancer patients.

A total of 138 DTC patients were stratified according to ATA 2009 and 2015 guidelines into low (LR), intermediate (IR) and high (HR) risk groups. Change in RS and in intention of RAI use was calculated. Deviation in administered RAI dosage from the guidelines was assessed. 1-year follow-up data was audited to assess how the DRS modified the initial risk estimate. A total of 11.6% of patients changed their RS categories in 2015 guidelines. A total of 10.1% got upstaged to HR, and 1.4% got downstaged to LR. In 2.17% of patients' intention of RAI use changed to remnant ablation from adjuvant therapy and 65% of the LR patients won't require any RAI therapy. A total of 26.7% of patients had received significantly more RAI dosage according to ATA 2015. At 1-year follow-up according to DRS 84% of LR, 75% of IR and 44% of HR patients showed excellent response (ER). More patients changed RS to HR than to LR. Intention of RAI use changed in only a small number of patients. Significantly higher dosage of RAI is being administered to patients in current practice. The effect of DRS in modifying the initial RS was most prominent in IR, with most showing ER to initial therapy.

Variations in radioiodine ablation: decision-making after total thyroidectomy.

The role of radioiodine treatment following total thyroidectomy for differentiated thyroid cancer is changing. The last major revision of the American Thyroid Association (ATA) Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer in 2015 changed treatment recommendations dramatically in comparison with the European Association of Nuclear Medicine (EANM) 2008 guidelines. We hypothesised that there is marked variability between the different treatment regimens used today. We analysed decision-making in all Swiss hospitals offering radioiodine treatment to map current practice within the community and identify consensus and discrepancies. RESULTSAND CONCLUSION: We demonstrated that for low-risk DTC patients after thyroidectomy, some institutions offered only follow-up, while RIT with significant activities is recommended in others. For intermediate- and high-risk patients, radioiodine treatment is generally recommended. Dosing and treatment preparation (recombinant human thyroid stimulation hormone (rhTSH) vs. thyroid hormone withdrawal (THW)) vary significantly among centres.

Scheduled cessation in treatment using lenvatinib for differentiated thyroid carcinoma

Abstract Backgrounds Recently, multi-targeted tyrosine kinase inhibitors(m-TKIs) have become a treatment strategy for radioactive iodine-refractory differentiated thyroid carcinoma (RR-DTC).m-TKIs often require dose reduction or cessation due to various adverse events (AEs). Moreover, these AEs often lose the motivation of patients for the continuation of treatment. We therefore tried scheduled cessation of lenvatinib (LEN) to avoid or reduce AEs during the course of long-term administration. Methods We tried scheduled cessation for five of 20 DTC patients who started LEN administration between Jul. 2015 and Oct. 2017. These five patients experienced intolerable toxicities resulting in frequent interruptions and dose reductions of LEN before introduction of scheduled cessation. Results All were females and aged 66-83 years. Two patients underwent LEN administration of 8 mg/day for two weeks and cessation for one week. Others underwent LEN administration of 10 mg/day for three weeks and cessation for one week, of 10-14 mg/day for two weeks and cessation for one week, and of 10 mg/day for two weeks and cessation for one week. Direct reasons for introduction of scheduled cessation were fatigue and anorexia for three patients, hand-foot-syndrome for one patient, and proteinuria for one patient, respectively. With a median follow-up period of 26.7 months, no patients showed further deterioration of AEs, enabling all patients to continue LEN in these schedules. One patient showed progression of metastatic lesions, but the remaining four patients achieved stable disease during these periods. Conclusions Scheduled cessation can relieve AEs of patients, and may be considered as an effective strategy to continue treatment of LEN with maintaining the motivation of patients.

Unstimulated high-sensitive thyroglobulin is a powerful prognostic predictor in patients with thyroid cancer.

Background Differentiated thyroid carcinoma (DTC) has an excellent prognosis and the role of high-sensitive thyroglobulin measured during levothyroxine (ON-T4 hs-Tg) testing to discriminate patients with structural from not-evidence of disease (SED and NED, respectively) has been investigated. We conducted a systematic review and meta-analysis evaluating the performance of ON-T4 hs-Tg in two clinical scenarios considering its negative predictive value (NPV) as primary outcome: (1) diagnostic performance of Tg when undetectable value and NED status are simultaneously demonstrated; (2) prognostic performance of undetectable Tg in predicting NED in the subsequent follow-up. Methods This systematic review and meta-analysis were registered on PROSPERO (CRD42019125092). PubMed, Scopus, CENTRAL and Web of Science were searched until February 12, 2019. Original articles reporting data on SED/NED in patients with detectable/undetectable ON-T4 hs-Tg were selected. Summary operating points were estimated using a random-effects model. Results Out of 1413 retrieved papers, 10 studies evaluating 1796 patients were included. Participants were outpatients diagnosed with DTC, treated with near-total (NTx) or total thyroidectomy (TTx) with or without radioactive iodine (RAI). The NPV of ON-T4 hs-Tg for diagnostic and prognostic performance was 99.4% (95% CI 98.9-99.9; I2 = 13%) and 99.4% (95% CI 98.8-100; I2 = 0%), respectively. Conclusions Our findings show that ON-T4 hs-Tg is an excellent diagnostic tool and prognostic factor to rule-out SED. A high level of evidence is provided to decrease the intensity and frequency of follow-up in those DTC patients having undetectable high-sensitive Tg.

Age, thyroglobulin levels and ATA risk stratification predict 10-year survival rate of differentiated thyroid cancer patients.

IntroductionDifferentiated 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.ObjectiveThe 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 methodsThis 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.ResultsAccording 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.ConclusionInitial 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.

Lenvatinib in differentiated thyroid carcinoma: the Italian experience.

Future OncologyVol. 15, No. 24s SupplementFree AccessLenvatinib in differentiated thyroid carcinoma: the Italian experienceAlessandro PiovesanAlessandro Piovesan*Author for correspondence: E-mail Address: apiovesan@cittadellasalute.to.itOncological Endocrinology Unit, Città della Salute e della Scienza Hospital, Turin, ItalySearch for more papers by this authorPublished Online:6 Aug 2019https://doi.org/10.2217/fon-2019-0179AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: case reportdifferentiated thyroid cancerlenvatinibtreatmentDifferentiated thyroid carcinoma (DTC) shows an increasing incidence worldwide [1–3]. The standard treatment for this condition is represented by surgery, followed by radioactive iodine (RAI) administration if necessary and levothyroxine therapy [4,5]. RAI can further be administered to treat persistent disease, local recurrences and distant metastases. However, a significant proportion of DTC patients ultimately becomes refractory to RAI [4,5] or a too high cumulative dose of I131 is reached. Until a few years ago, treatment options in this population were limited by poor efficacy and tolerability.Several molecular pathways are involved in the development of DTC, including rearrangements of RET/PTC oncogenes, alterations of the BRAF, NRAS and HRAS pathways and altered interplay of EGF/VEGF receptor and EGF/EGF receptors. All these pathways play a key role in tumor progression and invasiveness [6], and can be targeted by specific therapeutic agents. On these bases, multitargeted tyrosine kinase inhibitors, including sorafenib and lenvatinib, have been largely investigated for the treatment of DTC [5].In particular, lenvatinib is an oral inhibitor of VEGFR1–3, FGFR1–4, PDGFRα, RET and KIT, which showed activity in several types of cancer [5,7]. In the pivotal Phase III SELECT trial, lenvatinib significantly prolonged progression-free survival (18.3 vs 3.6 months; p < 0.001) and increased overall response rate (64.8 vs 1.5%) compared with placebo in 392 patients with advanced RAI-resistant DTC [8]. A difference in overall survival was not reported in this trial; however, this was likely due to permitting crossover to lenvatinib after progression in the placebo group [5,8] Moreover, in a subsequent subanalysis of the SELECT data, a prolonged survival was evident in older patients treated with lenvatinib [9]. Based on the favorable results of the SELECT trial, lenvatinib has been approved for the treatment of locally recurrent or metastatic, progressive, RAI-refractory DTC.‘Field practice’ experience on lenvatinib is still scant [10], and reporting interesting experiences on the use of this molecule in daily practice and in peculiar clinical cases can be of the highest interest, in order to investigate issues not usually addressed in pivotal trials and to gain knowledge on the potential toxicities of this molecule [5,11,12].Therefore, we have decided to develop this Supplement, which reports relevant clinical cases from Italian experts in the use of lenvatinib. Moreover, Gay et al. documented the use of lenvatinib in neoadjuvant setting in a patient affected by invasive poorly DTC; La Torre et al. reported on the use of lenvatinib in a patient with cardiological comorbidities – a relevant issue, since hypertension was frequently reported in the SELECT trial [8]. On a similar note, Marina et al. investigated QT-corrected prolongation in a lenvatinib recipient. In their paper, Porcelli et al. describe the management of a patient who developed oligoprogression during treatment with lenvatinib. Sperone et al. present a case of long-term disease control and high clinical benefit in a patient with advanced DTC. Last, Simontacchi et al. describe the excellent clinical and radiological response to lenvatinib and ablative stereotactic radiotherapy.We do hope that these experiences can represent the first step toward a more generalized collection of case reports and observational ‘field-practice’ analyses on the use of lenvatinib in DTC, in order to further clarify and expand on the use of this molecule.DisclaimerThe supporting company was not offered the opportunity to revise the manuscript and had no role in the decision to submit.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Medical writing support was provided by L Giacomelli and A Shah of Polistudium (Milan, Italy), on behalf of Content Ed Net and were funded for their assistance by Eisai.