Advanced Anaplastic Thyroid Cancer Research Articles

Interaction between tumor stage and age on survival outcomes of patients with anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is an aggressive, rare malignancy associated with rapid growth and metastasis, and a very poor prognosis. We investigated the clinical characteristics, survival outcomes and independent prognostic factors associated with anaplastic thyroid cancer. To assess to what extent the interaction between age and tumor stage affects mortality. A total of 622 patients diagnosed with anaplastic thyroid cancer, between 2010 and 2017 were enrolled in our study by retrieving data from the Surveillance, Epidemiology and End Results (SEER) database. We analyzed demographics, clinical characteristics, overall mortality (OM) and cancer specific mortality (CSM) of ATC. Variables with a P value < 0.1 were incorporated into the multivariate cox model to determine the independent prognostic factors. Furthermore, we analyzed the interaction between age and tumor stage on mortality. In the multivariate analyses, the divorced/separated population had a lower OM [hazard ratio (HR) = 0.63, 95%CI: 0.42-0.94, P < 0.05] and CSM (HR = 0.61, 95%CI: 0.40-0.92, P < 0.05). OM was higher in tumors with direct extension only (HR = 6.26, 95%CI: 1.29-30.42, P < 0.05) and tumors with distant spread (HR = 5.73, 95%CI: 1.34-24.51, P < 0.05). CSM was also higher in tumors with direct extension (HR = 5.05, 95%CI: 1.05-24.19, P < 0.05) and tumors with distant spread (HR = 4.57, 95%CI: 1.08-19.29, P < 0.05). Mortality was not adversely affected by lymph node involvement. OM was lower in patients who received radiation (HR = 0.66, 95%CI: 0.53-0.83, P < 0.01), chemotherapy (HR = 0.63, 95%CI: 0.50-0.79, P < 0.01) or surgery (HR = 0.53, 95%CI: 0.43-0.66, P < 0.01). CSM was also lower in patient who received radiation (HR = 0.64, 95%CI: 0.51-0.81, P < 0.01), chemotherapy (HR = 0.62, 95%CI: 0.50-0.78, P < 0.01) or surgery (HR = 0.51, 95%CI: 0.41-0.63, P < 0.01). There was no significant interaction between age and tumor stage that affected mortality. In this large US SEER database retrospective study, we found the mortality to be higher in advanced stage tumors with direct extension and distant metastasis. However, patients who received aggressive therapy showed a better overall survival. The aim of our study is to emphasize the importance of detecting ATC at an early stage and provide aggressive therapy to these patients. Since advanced stage ATC is associated with a dismal prognosis, we emphasize the need for randomized control trials and development of novel therapies that will be used to treat ATC.

The efficacy and safety of antiangiogenesis tyrosine kinase inhibitors in patients with advanced anaplastic thyroid cancer: A meta-analysis of prospective studies.

The poor prognosis of anaplastic thyroid cancer (ATC) patients is associated with limited effective therapeutic strategies. Multiple antiangiogenesis tyrosine kinase inhibitors (TKIs) have been applied in later-line treatment of ATC; however, the results reported in clinical trials were controversial. In this study, we reconstructed the patient-level data to pooled-analyze the survival data, responses, and adverse events. Online databases (PubMed, Web of Science, Embase, and Cochrane CENTRAL) were searched on September 03, 2023. R software combined with the "metaSurvival" and "meta" packages were used to reconstruct the survival curves and summarize the response rates. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were survival rate, objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events. Six prospective clinical trials involving 140 ATC patients were enrolled. Four types of TKIs (imatinib, pazopanib, sorafenib, and lenvatinib) were included. When advanced ATC patients were treated with the TKIs, the median OS was 4.8 months and the median PFS was 2.6 months. The pooled ORR and DCR were 9% and 53%. Hypertension, decreased appetite, rash, and lymphopenia were the most common grade ≥ 3 treatment-related adverse events. Mono-anitangiogenesis TKI therapy showed limited improvements in treating advanced ATC patients. Combining antiangiogenesis TKI therapy with chemotherapy, radiotherapy, or immunotherapy could be the direction of future studies.

Tyrosine kinase inhibitors in patients with advanced anaplastic thyroid cancer: an effective analysis based on real-world retrospective studies.

Tyrosine kinase inhibitors (TKIs) contribute to the treatment of patients with anaplastic thyroid cancer (ATC). Although prospective clinical studies of TKIs exhibit limited efficacy, whether ATC patients benefit from TKI treatment in real-world clinical practice may enlighten future explorations. Therefore, we conducted this effective analysis based on real-world retrospective studies to illustrate the efficacy of TKI treatment in ATC patients. We systematically searched the online databases on September 03, 2023. Survival curves were collected and reconstructed to summarize the pooled curves. Responses were analyzed by using the "meta" package. The primary endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). 12 studies involving 227 patients were enrolled in the study. Therapeutic strategies included: anlotinib, lenvatinib, dabrafenib plus trametinib, vemurafenib, pembrolizumab plus dabrafenib and trametinib, pembrolizumab plus lenvatinib, pembrolizumab plus trametinib, and sorafenib. The pooled median OS and PFS were 6.37 months (95% CI 4.19-10.33) and 5.50 months (95% CI 2.17-12.03). The integrated ORR and DCR were 32% (95% CI 23%-41%) and 40% (95% CI 12%-74%). In real-world clinical practice, ATC patients could benefit from TKI therapy. In future studies, more basic experiments and clinical explorations are needed to enhance the effects of TKIs in the treatment of patients with ATC.

First effectiveness data of lenvatinib and pembrolizumab as first-line therapy in advanced anaplastic thyroid cancer: a retrospective cohort study

BackgroundAnaplastic thyroid cancer (ATC) is a rare and aggressive neoplasm. We still lack effective treatment options, so survival rates remain very low. Here, we aimed to evaluate the activity of the combination of lenvatinib and pembrolizumab as systemic first-line therapy in ATC.MethodsIn a retrospective analysis, we investigated the activity and tolerability of combined lenvatinib (starting dose 14 to 24 mg daily) and pembrolizumab (200 mg every three weeks) as first-line therapy in an institutional cohort of ATC patients.ResultsFive patients with metastatic ATC received lenvatinib and pembrolizumab as systemic first-line therapy. The median progression-free survival was 4.7 (range 0.8–5.9) months, and the median overall survival was 6.3 (range 0.8-not reached) months. At the first follow-up, one patient had partial response, three patients had stable disease, and one patient was formally not evaluable due to interference of assessment by concomitant acute infectious thyroiditis. This patient was then stable for more than one year and was still on therapy at the data cutoff without disease progression. Further analyses revealed deficient DNA mismatch repair, high CD8+ lymphocyte infiltration, and low macrophage infiltration in this patient. Of the other patients, two had progressive disease after adverse drug reactions and therapy de-escalation, and two died after the first staging. For all patients, the PD-L1 combined positive score ranged from 12 to 100%.ConclusionsThe combination of lenvatinib and pembrolizumab was effective and moderately tolerated in treatment-naïve ATC patients with occasional long-lasting response. However, we could not confirm the exceptional responses for this combination therapy reported before in pretreated patients.

Clinical case of successful treatment of a patient with anaplastic thyroid cancer in combination with ischemic heart disease and critical multivessel coronary artery disease

The article presents a clinical case of a patient with locally advanced anaplastic thyroid cancer and concomitant cardiovascular pathology. Anaplastic thyroid cancer is a very rare and highly aggressive disease requiring long-term multistage treatment, often using cardiotoxic drugs. Combination of this pathology with ischemic heart disease affecting coronary arteries is a complex clinical problem requiring timely evaluation of cardiac risk at every stage. Treatment of this patient cohort is possible only by a multidisciplinary team of specialists.

METTL3 inhibition induced by M2 macrophage-derived extracellular vesicles drives anti-PD-1 therapy resistance via M6A-CD70-mediated immune suppression in thyroid cancer.

The treatment options for advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) refractory to standard therapies are limited. Although anti-PD-1 therapy has a manageable safety profile and has been effective in a small percentage of patients with advanced PTC and refractory ATC, the majority of the patients either do not respond or develop resistance to anti-PD-1 therapy. N6-methyladenosine (m6A) modification is a critical determinant of the complexity of the tumor microenvironment (TME). However, it is unclear whether and how m6A modification in tumor cells shapes the immune landscape of PTC and ATC. In this study, we performed bulk and single cell RNA sequencing analysis of PTC and ATC tissues, and found that low METTL3 expression not only correlated to poor response to immune checkpoint blockade (ICB) but was also associated with increased TNF family-related ligand-receptor interactions in the immunosuppressive Tregs and exhausted T cells. Furthermore, overexpression of METTL3 in PTC and ATC cells enhanced the efficacy of anti-PD-1 therapy in a peripheral blood mononuclear cell humanized NCG (huPBMC-NCG) mouse model. Mechanistically, M2 macrophage-derived extracellular vesicles (M2 EVs) inhibited METTL3 expression in PTC and ATC cells via miR-21-5p. Downregulation of METTL3 promoted demethylation of CD70 mRNA, which prevented YTHDF2-mediated degradation of the transcripts. The stabilization of CD70 mRNA, and the subsequent upregulation in CD70 protein levels increased the abundance of the immunosuppressive Tregs and terminally exhausted T cells, thereby inducing resistance to anti-PD-1 therapy. Furthermore, blocking CD70 using cusatuzumab, a high-affinity monoclonal antibody, reversed the anti-PD-1 therapy resistance induced by M2 EVs in vivo. Finally, we demonstrated that METTL3 expression negatively correlated with CD70 expression and M2 macrophages and Tregs infiltration in PTC and ATC tissues. Our findings provide new insights into developing novel therapies for advanced PTC and ATC.

ICAM1 antibody drug conjugates exert potent antitumor activity in papillary and anaplastic thyroid carcinoma

Treatment options for anaplastic thyroid cancer (ATC) and refractory papillary thyroid carcinoma (PTC) are limited and outcomes remain poor. In this study, we determined via bioinformatic expression analyses and immunohistochemistry staining that intercellular adhesion molecule-1(ICAM1) is an attractive target for ATC and PTC. We designed and engineered two ICAM1-directed antibody-drug conjugate (I1-MMAE and I1-DXd), both of which potently and selectively ablate multiple human ATC and PTC cell lines without affecting non-plastic cells invitro. Furthermore, I1-MMAE and I1-DXd mediated a potent tumor regression in ATC and PTC xenograft models. To develop a precision medicine, we also explored magnetic resonance imaging (MRI) as a non-invasive biomarker detection method to quantitatively map ICAM1 antigen expression in heterogeneous thyroid tumors. Taken together, this study provides a strong rationale for the further development of I1-MMAE and I1-DXd as promising therapeutic candidates to treat advanced PTC and ATC.

Emergency Tracheostomy in Locally Advanced Anaplastic Thyroid Cancer.

Over 30% of cases may present with acute airway obstruction due to anaplastic thyroid cancer (ATC). In such situations, performing an emergency tracheostomy may be mandatory to save the life. A retrospective, single-centre study at our centre was conducted between 1 January 2021 to 31 December 2022. We had included 17 patients with asphyxia due to ATC and subsequently underwent tracheostomy for stridor. The overall survival (OS) ranged from 2days to 16months (median = 11months). The 30-day mortality was 17.6%. One-year overall survival was 36%. A statistically significant difference in the OS among patients with distant metastasis and Shin grade IV tracheal infiltration (p < 0.001, Log Rank (Mantel-Cox), CI:95%). The degree of tracheal deviation correlated with the patent age group (Pearson chi-square (pc), p = 0.031), type of anaesthesia used local versus general (pc, p < 0.001) and site of tracheostoma (pc, p = 0.028). The degree of tracheal infiltration correlated with the presence of distant metastasis (pc, p = 0.01) and OS (pc, p = 0.013). Tracheostomy in patients with ATC is performed in extreme circumstances to support an airway. Patients often require isthmectomy to obtain adequate access for a tracheostomy, highlighting the importance of having a highly experienced surgeon involved. An attempt to perform the tracheostomy in the ward or the emergency room under local anaesthesia should be avoided. Patients and relatives should be educated to communicate evolving issues and tracheostomy care in the patient's best interests, given the unusual context of ATC. Level of evidence, IV.

Targeted therapy of anaplastic thyroid cancer

Introduction. Anaplastic thyroid cancer (ATC) is a very rare malignant tumor of the thyroid comprising 1–2 % of all thyroid cancers. In this pathology, response rate for standard systemic therapy is less than 15 %, and long-term results remain unsatisfactory. Additionally, there are no data conclusively showing that cytotoxic chemotherapy improves survival or quality of life in patients with ATC.Aim. To improve the results of treatment of patients with ATC through evaluation of the effectiveness of targeted therapy in cases of BRAFV600E mutation.Materials and methods. The multicenter prospective study included 29 patients with ATC IVB–C, T4a–bN1a–bM0–1. The patients were divided into 2 groups. The Group 1 (control) included 15 patients with resectable / nonresectable, metastatic / nonmetastatic ATC (without BRAFV600E mutation), stages IVB–C who received standard types of treatment (surgical intervention, radiation, and chemotherapy). The Group 2 consisted of 14 patients with nonresectable or metastatic ATC, stages IVB–C, who received combination therapy (surgical intervention, radiation, and chemotherapy) with inclusion of inhibitors of BRAF dabrafenib and trametinib in neoadjuvant and adjuvant regimens.Results. The study showed the effectiveness of targeted therapy with inhibitors of BRAF mutations in treatment of locally advanced non-operable metastatic ATC with BRAFV600E mutation. Overall response (complete response + partial response) in the Group 1 was 0 %, in the Group 2 it was 64 %. Therefore, treatment scheme dabrafenib + trametinib is a prmising approach to combination targeted therapy in patients with ATC and BRAFV600E mutation. Conclusion. Dabrafenib + trametinib is a promising combination targeted therapy option for patients with ATC with a BRAFV600 mutation demonstrates a high overall response rate, a prolonged duration of response, and an increase in survival rates with controlled toxicity.

The internal mammary artery perforator flap for neck reconstruction after palliative resection of advanced anaplastic thyroid cancer: a case report

IntroductionDefects of the neck after palliative resection of exulcerated tumors could be reconstructed with different skin flaps.Case presentationThe present report describes the case of a 40-year-old Caucasian female patient with advanced anaplastic thyroid cancer. The exophytically growing, bad-smelling massive exulcerated tumor caused an esthetic defect, neck mobility restrictions, and mental state deterioration.Primary diagnosis, interventions, and outcomesPalliative debulking of the tumor was performed. The 10 × 5 cm skin defect of the neck was successfully reconstructed with an internal mammary artery perforator island flap. The donor site was closed primarily. The patient had an uneventful clinical course; the cosmetic results and mental state were very pleasing.ConclusionsThe present case illustrates that palliative resection of the tumor and plastic reconstruction of the neck defect promoted other treatments such as radiation or chemotherapy due to the improved local situation.

Phase I study of AIC100 in relapsed and/or refractory advanced thyroid cancer and anaplastic thyroid cancer.

6093 Background: ICAM-1 is a cell surface glycoprotein that is typically expressed on endothelial cells and immune cells and a ligand for LFA-1 integrin. It is also overexpressed in several malignancies, in particular anaplastic and advanced thyroid cancer. We designed an affinity tuned ICAM-1-directed CAR T cell (micromolar affinity) that preferentially binds overexpressed ICAM-1 on tumor cells and spares normal cells. The CAR T cells also express somatostatin receptor 2 (SSTR2), which allows tracking of CAR T cells in vivo via DOTATATE PET/CT scan. Murine studies showed excellent responses in ICAM-1 expressing thyroid cancer without significant toxicities. We are conducting a first-in-human phase 1 clinical trial to evaluate the feasibility, safety and preliminary efficacy of ICAM-1 in patients with relapsed/refractory thyroid cancer or anaplastic thyroid cancer who are BRAF wild-type, or BRAF mutated after failure of BRAF specific therapy (NCT04420754). Methods: This is a dose-escalation study with modified toxicity probability interval design and cohorts of 3 Patients. Patients receive a single dose of 1x 107 (Cohort 1), 1 x 108 (Cohort 2) or 5 x 108 (Cohort 3) ICAM-1 CAR T cells after FLU/CY lymphodepleting (LD) chemotherapy. Additional CAR T infusion is allowed if patients achieve partial response or stable disease. Whole-body Fluorodeoxyglucose (FDG) and DOTATATE PET/CT is used to stage tumor and track CAR T cells in vivo, respectively. Results: All ICAM-1 CAR T infusion products met target transduction efficiency. Two patients with progressive anaplastic thyroid cancer received ICAM-1 CAR T therapy at dose-level I. Evaluation of CAR T cellular kinetics demonstrated transient peripheral blood CAR T cell expansion. One patient developed grade 1 cytokine release syndrome (CRS) with fever. Several tumor lesions from this patient showed DOTATATE avidity, indicating CAR T homing to the tumor, concomitant with decrease in FDG avidity, suggesting biological activity at ̃2 weeks post CAR T infusion. DOTATATE avidity at 2 weeks post CAR T infusion also appeared to match that of CAR T abundance in the blood. Updated results on additional patients and cohorts will be presented. Conclusions: Adoptive cellular therapy with ICAM-1 directed CAR T is safe and feasible at dose level 1 in patients with anaplastic thyroid cancer. DOTATATE PET allows visualization of expansion and homing of SSTR2 expressing CAR T cells, while concomitant FDG PET permits correlation with biological activity. Clinical trial information: NCT04420754.

Abemaciclib in metastatic or locally advanced anaplastic thyroid cancer.

TPS6112 Background: Anaplastic thyroid cancer (ATC) is a rare and lethal tumor of thyroid epithelium, with disease-specific mortality approaching 100%. ATC accounts for &gt; 50% of the 1200 annual deaths attributable to thyroid cancer. In the pre-molecular era, treatment options were largely ineffective, reflected in a median overall survival of 3-4 months following diagnosis. Outcomes have improved in BRAF V600E-mutated ATC with the FDA approval of dabrafenib and trametinib (Subbiah et al. JCO, 2018). However, a significant need exists for patients with BRAF wild-type tumors and patients with BRAF-mutated tumors who progress following treatment with BRAF-directed therapies. Abemaciclib is a CDK4/6 inhibitor currently FDA-approved in combination with endocrine therapy for hormone-positive breast cancer. Genomic analyses of ATC have indicated the presence of an intact Rb (Retinoblastoma) expression as well as the existence of CDKN2A (the gene encoding human p16) mutations in up to 32% of patients with ATC (Khan et al., Head Neck, 2019). Moreover, Lee et al. in 2008 reported undetectable p16 levels in 24 out of 27 (89%) patients with ATC. Low p16 levels would be expected to result in accelerated S phase entry, leading to uncontrolled ATC growth. Finally, studies in mouse xenograft models have demonstrated that ribociclib (a CDK4/6 inhibitor) slows proliferation and induces apoptosis of ATC cells (Lee et al., Cancer Letters, 2018). These molecular alterations and pre-clinical data provide a mechanistic rationale by which to evaluate CDK4/6 inhibitors in ATC and, to date, no CDK4/6 inhibitors have been evaluated in thyroid cancer. Methods: This multicenter, single-arm Phase 2 study will evaluate the safety and efficacy of treatment with abemaciclib in patients with histologically confirmed unresectable or metastatic ATC, using an optimal Simon two-stage design. Patients with BRAF V600E+ ATC must have progressed on or have an intolerance to dabrafenib and trametinib. The study intervention is abemaciclib 200 mg orally twice daily. The primary endpoint is overall response rate at eight weeks from the start of treatment. Secondary endpoints include progression-free survival and overall survival. Currently, 6 patients have been enrolled. Planned genomic analysis will be conducted to identify potential predictive biomarkers. Clinical trial information: NCT04552769.

Survival Benefit of Intervention Treatment in Advanced Anaplastic Thyroid Cancer.

Background The management of anaplastic thyroid cancer (ATC) is controversial; thus, proper treatment and prognostic factors should be investigated. Objectives To compare the survival outcomes of the intervention and palliative treatment in ATC patients. Methods A hospital-based retrospective study was conducted at a single tertiary university hospital. The medical record charts were retrieved from November 20, 1987, to December 31, 2016. The final follow-up ended by December 31, 2017. The patients' demographic data, laboratory data, clinical presentation, and treatment modality results were analyzed. Results One hundred twenty-one records were analyzed with a one-year overall survival rate of 3.5% (median survival time: 77 days); however, 16 cases had insufficient data to classify staging and treatment modalities. Therefore, 105 ATC patients (37 with stage IVa, 39 with stage IVb, and 29 with stage IVc disease) were included with a one-year overall survival rate of 4.0% (median survival time of 82 days). Intervention treatment allowed longer median survival times (p < 0.05) and a better survival rate (p < 0.05). Among the interventional treatment groups, postoperative chemoradiation yielded the longest median survival time (187 days) and the highest survival rate (20%) (p < 0.05). The intervention modality allowed a better median survival time at all stages, particularly in stage IVa (p < 0.05). Unfavorable prognostic factors were adjusted for in a multiple Cox regression model showing that significant factors included age ≥65 years (hazard ratio HR: 2.57), palliative treatment (HR: 1.85), and leukocytosis ≥10,000 cells/mm3 (HR: 2.76). Conclusions Intervention treatment provided a better survival outcome in all stages, particularly in stage IVa, with a significantly better median survival time. Among interventional treatments, postoperative chemoradiation led to the longest survival rate, suggesting that this treatment should be considered in ATC patients with resectable tumors and no poor prognostic factors, such as older age and leukocytosis.

Augmentation of lenvatinib efficacy by topical treatment of miR-634 ointment in anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is one of the most lethal types of human tumors. Lenvatinib can improve the disease control and prognosis in patients with ATC. However, there is an unmet need to develop a therapeutically safer and non-invasive strategy that improves the efficacy of lenvatinib for advanced ATC tumors, which grow larger close to the skin. We previously demonstrated that the topical application of an ointment incorporating tumor suppressive microRNA (TS-miR), miR-634, is a useful strategy as a TS-miR therapeutics. Here, we found that the overexpression of miR-634 synergistically increased lenvatinib-induced cytotoxicity by concurrently downregulating multiple genes related to cytoprotective processes, including ASCT2, a glutamine transporter, in ATC cell lines. Furthermore, the topical application of a miR-634 ointment on subcutaneous tumors effectively augmented the anti-tumor effects of lenvatinib in an ATC xenograft mouse model. Thus, we propose topical treatment of a miR-634 ointment as a rational strategy for improving lenvatinib-based therapy for ATC.

Limited efficacy of lenvatinib in heavily pretreated anaplastic thyroid cancer: a French overview.

Anaplastic thyroid cancer (ATC) is a rare lethal disease. Lenvatinib is an off-label therapeutic option for ATC in most countries, except in Japan. The aim of this multicenter retrospective survey was to analyze the efficacy and the toxicity profile of off-label lenvatinib treatment in all adults advanced ATC patients, in France. Of the 23 patients analysed (14 males; mean age 64 years), 15 were pure ATC and 8 were mixed tumors (i.e. with a differentiated or poorly differentiated component). Prior treatments included neck external beam irradiation in 74%, at least one line of chemotherapy in 22 cases, two lines of chemotherapy in 11 patients, other TKI in 4 cases. A central RECIST assessment was performed. Since lenvatinib initiation, median PFS was 2.7 months (95% CI; 1.9-3.5) and median OS was 3.1 months (95% CI; 0.6-5.5). OS was significantly longer in case of mixed tumors compared with pure ATC (6.3 vs 2.7 months, P = 0.026). Best tumor response was partial response in two cases and stable disease in seven. Clinical improvement was achieved in seven patients. Lethal adverse events occurred in three patients, consisting in haemoptysis in two cases and pneumothorax in one case. Among long-surviving ATC patients (>6 months), four underwent biopsy of distant metastasis, revealing poorly differentiated histology; three of them had initial mixed ATC histology. Efficacy of lenvatinib appears limited, although pure vs mixed ATC disclose differences in disease aggressiveness and treatment response. Long-surviving ATC patients might benefit from biopsy of persistent disease, searching for histological transition or molecular target.

Nasogastric administration of lenvatinib solution in a mechanically ventilated patient with rapidly growing anaplastic thyroid cancer.

SummaryA 54-year-old woman was referred to our hospital with a cervical tumor. CT revealed a cervical tumor extending to the upper mediastinum, tracheal deviation and tumor infiltration in the cervical vessels. She was followed-up because no diagnosis of malignancy was made by cytology. However, 2 months later, a CT scan showed enlargement of the tumor and tracheal stenosis, and a surgical biopsy was performed and she was diagnosed with anaplastic thyroid cancer (ATC). The tracheal tube with tracheal stenosis could not be removed due to the rapid growth of the tumor, necessitating management by mechanical ventilation. Due to the difficulty of surgical resection, she was treated with lenvatinib. A lenvatinib solution was made and administered via a nasogastric tube. After lenvatinib treatment, the tumor volume decreased and the tracheal stenosis improved. The tracheal tube was removed and oral intake became possible. She was discharged and received ambulatory lenvatinib therapy. The tumor was significantly reduced in size, but gradually grew and was exposed through the cervical wound 6 months later. Esophageal perforation occurred 10 months after the start of treatment. Lenvatinib was re-administered via a nasogastric tube. Eleven months later, the patient died of massive bleeding from the exposed cervical tumor. Patients with advanced ATC may require management with mechanical ventilation for airway stenosis or with a nasogastric tube for esophageal stenosis and perforation. We experienced a case in which lenvatinib was safely administered via a nasogastric tube while performing mechanical ventilation.Learning points:An anaplastic thyroid cancer patient under mechanical ventilator management was treated with lenvatinib via a nasogastric tube.The lenvatinib solution can easily be prepared and administered via a nasogastric tube.The lenvatinib solution was effective for a patient with difficulty in oral intake.Lenvatinib could also improve the prognosis of an anaplastic thyroid cancer patient with severe airway and esophageal trouble.

Real-world experience of lenvatinib in patients with advanced anaplastic thyroid cancer.

We aimed to evaluate the clinical efficacy and safety of lenvatinib in patients with advanced anaplastic thyroid cancer (ATC) in real-world practice. This multicenter, retrospective cohort study included 14 patients with advanced ATC who received lenvatinib. We evaluated the response rate according to RECIST. Ten patients had de novo ATC, and lenvatinib was used as a neoadjuvant treatment in eight patients. During a median follow-up of 6.7 months, patients received lenvatinib at a median dose of 13 mg daily. Overall, four patients (29%) showed partial response, nine (64%) had stable disease, and one (7%) had progressive disease. Tumor burden was reduced in 13 patients (93%), and the median best percent change from the baseline was -15.8%. The median progression-free survival and overall survival were 5.7 months (95% confidence interval [CI], 2.2-8.3) and 6.7 months (95% CI, 3.0-8.4), respectively. All patients experienced adverse events (AEs). Most AEs were manageable but two AEs-tracheal perforation, and pneumothorax and pneumomediastinum-were life-threatening. One patient underwent flap surgery for reconstruction of their tracheal perforation, and another died of pneumothorax and pneumomediastinum, which seemed to be related to lenvatinib. In this multicenter real-world study, lenvatinib demonstrated limited clinical activity in advanced ATC. It effectively reduced the tumor burden but showed doubtful survival benefit. Although most AEs were manageable, one fatal AE was related to rapid tumor shrinkage. Further studies are needed to clarify the efficacy and optimal dose of lenvatinib in patients with advanced ATC.

Novel treatments for anaplastic thyroid carcinoma.

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and it is less than 2% of thyroid carcinomas (TCs). The standard treatment of ATC includes surgical debulking, accelerated hyperfractionated external beam radiation therapy (EBRT), and chemotherapy, in particular with cisplatin or doxorubicin, achieving about 10 months of median survival. Since ATC is a rare and aggressive tumor, it is still challenging to predict the patient clinical therapy responsiveness. Several genetic mutations have been described in ATC, involved in different molecular pathways linked to tumor progression, and novel therapies acting on these molecular pathways have been investigated, to improve the quality of life in these patients. Here we review the new targeted therapy of ATC. We report interesting results obtained with molecules targeting different pathways: angiogenesis (vandetanib, combretastatin, sorafenib, lenvatinib, sunitinib, CLM94, CLM3, etc.); EGFR (gefitinib, docetaxel); BRAF (dabrafenib/trametinib, vemurafenib); PPARγ agonists (rosiglitazone, pioglitazone, efatutazone); PD-1 and PD-L1 (pembrolizumab); TERT. To escape resistance to monotherapies, the evaluation of combination strategies with radiotherapy, chemotherapy, or targeted drugs is ongoing. The results of clinical trials with dabrafenib and trametinib led to the approval from FDA of this combination for patients with BRAF V600E mutated ATC with locally advanced, unresectable, or metastatic ATC. The anti-PD-L1 antibody immunotherapy, alone or combined with a BRAF inhibitor, has been shown also promising in the treatment of ATC. Furthermore, to increase the therapeutic success and not to use ineffective or even harmful treatments, a real tailored therapy should be pursued, and this can be achieved thanks to the new available genomic analysis methods and to the possibility to test in vitro novel treatments directly in primary cells from each ATC patient. Exploring new treatment strategies is mandatory to improve the survival of these patients, guaranteeing a good quality of life.

Outcomes of multimodal therapy in a large series of patients with anaplastic thyroid cancer.

The role of radiotherapy (RT) in the treatment of patients with anaplastic thyroid cancer (ATC) for local tumor control is critical because mortality often is secondary to complications of tumor volume rather than metastatic disease. Herein, the authors report the long-term outcomes of RT for patients with ATC. A total of 104 patients with histologically confirmed ATC were identified who presented to the study institution between 1984 and 2017 and who received curative-intent or postoperative RT. Locoregional progression-free survival (LPFS), overall survival (OS), and distant metastasis-free survival were assessed. The median age of the patients was 63.5years. The median follow-up was 5.9months (interquartile range, 2.7-17.0months) for the entire cohort and 10.6months (interquartile range, 5.3-40.0months) for surviving patients. Thirty-one patients (29.8%) had metastatic disease prior to the initiation of RT. Concurrent chemoradiation was administered in 99 patients (95.2%) and 53 patients (51.0%) received trimodal therapy. Systemic therapy included doxorubicin (73.7%), paclitaxel with or without pazopanib (24.3%), and other systemic agents (2.0%). The 1-year OS and LPFS rates were 34.4% and 74.4%, respectively. On multivariate analysis, RT ≥60 Gy was associated with improved LPFS (hazard ratio [HR], 0.135; P=.001) and improved OS (HR, 0.487; P=.004), and trimodal therapy was associated with improved LPFS (HR, 0.060; P=.017). The most commonly observed acute grade 3 adverse events included dermatitis (20%) and mucositis (13%), with no grade 4 subacute or late adverse events noted (adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). RT appears to demonstrate a dose-dependent, persistent LPFS and OS benefit in patients with locally advanced ATC with an acceptable toxicity profile. Aggressive RT should be strongly considered for the treatment of patients with ATC as part of a trimodal treatment approach.

Anaplastic thyroid cancer: A report of six consecutive cases treated successfully with nab-paclitaxel.

e17586 Background: Advanced anaplastic thyroid cancer is a disease with very few treatment options. Poor response rates have been reported with cisplatin / doxorubicin and modest response noted in a single phase 2 trial with 24 hour paclitaxel infusion. The 50% response rate has not been reproduced by other investigators but raises questions about the possible utility of taxanes. Although paclitaxel is not approved for this indication in Australia, nab-Paclitaxel is available on a compassionate access scheme. We report 6 consecutive cases treated with nab-paclitaxel (as an alternative to paclitaxel infusion) who all exhibited a response to treatment. Methods: 6 consecutive patients with histologically proven advanced anaplastic thyroid cancer were assessed and imaged to document extent of disease. They were all treated with nab-paclitaxel 100mg/M2 given weekly either continuously or for 3 weeks out of every 4. Clinical and radiological response to treatment was documented. Results: The number of cycles given ranged from 3 to 8. Two patients required dose reductions due to neuropathy. Of the 6 patients; 5 had measurable metastatic disease and 5 had measurable local disease. Four patients showed clinical response to treatment with shrinkage of measurable local disease. One patient showed response to treatment with shrinkage of the primary tumour. Three patients with stridor developed considerable relief from this distressing symptom. Three patients with inoperable disease subsequently became operable and were resected to obtain local disease control. One patient with no evaluable disease after resection (Stage 4B) who received adjuvant nab-paclitaxel remains free of recurrence at 4 years. Conclusions: Anaplastic thyroid cancer is generally regarded as malignancy untreatable by chemotherapy. Our pilot series suggests nab-Paclitaxel warrants further evaluation and should be considered as a chemotherapy backline for combination with targeted agents.