Thyroid cancer: emerging role for targeted therapies

The histology and clinical behavior of thyroid cancer are highly diverse. Although most are indolent tumors with a very favorable outcome with the current standard of care therapy, a small subset of tumors may be among the most lethal malignancies known to man. While surgery and radioactive iodine are the standard of care for differentiated thyroid cancers (DTC) and are effective in curing a majority of such patients, those with iodine-resistant cancers pose a great challenge for clinicians, as these patients have limited treatment options and poor prognoses. Medullary thyroid carcinoma (MTC) has no effective systemic therapy despite the genetic and signaling defects that have been well characterized for the last two decades. Anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors that remains fatal despite conventional multimodality therapy. Increased understanding of the pathogenesis of papillary thyroid carcinoma, the most common type of DTC, as well as ATC, has led to the development of targeted therapies aimed at signaling pathways and angiogenesis that are critical to the development and/or progression of such tumors. Development of tyrosine kinase inhibitors targeting known pathogenetic defects in MTC has led to testing of such agents in the clinic. Numerous clinical trials have been conducted over the last 5 years to examine the effects of these targeted molecular therapies on the outcomes of patients with iodine-refractory DTC, MTC and ATC. Conduction of such trials in the last few years represents a major breakthrough in the field of thyroid cancer. Several trials testing targeted therapies offer promise for setting new standards for the future of patients with progressive thyroid cancer. The purpose of this paper is to outline the recent advances in understanding of the pathogenesis of thyroid cancer and to summarize the results of the clinical trials with these targeted therapies.     

Lenvatinib: Role in thyroid cancer and other solid tumors

Despite recent breakthroughs in treatment of advanced thyroid cancers, prognoses remain poor. Treatment of advanced, progressive disease remains challenging, with limited treatment options. Small-molecule tyrosine kinase inhibitors, including vandetanib, cabozantinib, sorafenib, and lenvatinib, which are now FDA-approved for thyroid cancer, have shown clinical benefit in advanced thyroid cancer. Lenvatinib is approved for treatment of locally recurrent or metastatic, progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). It has been studied in phase II and III trials for treatment of advanced RAI-refractory DTC, and in a phase II trial for medullary thyroid cancer (MTC). Lenvatinib targets vascular endothelial growth factor receptors 1–3 (VEGFR1–3), fibroblast growth factor receptors 1–4 (FGFR-1–4), RET, c-kit, and platelet-derived growth factor receptor α (PDGFRα). Its antitumor activity may be due to antiangiogenic properties and direct antitumor effects. Lenvatinib has demonstrated antitumor activity in a variety of solid tumors, including MTC, in phase I and II clinical trials. In a phase II study in advanced RAI-refractory DTC, lenvatinib-treated patients achieved a 50% response rate (RR), with median progression-free survival (PFS) of 12.6 months. In a phase III trial in RAI-refractory DTC, median PFS in lenvatinib-treated patients was 18.3 months, with a 65% overall RR, versus 3.6 months in placebo-treated patients, with a 2% RR. Adverse events occurring in >50% of patients included hypertension, diarrhea, fatigue/asthenia, and decreased appetite. Lenvatinib is a promising new agent for treatment of patients with advanced thyroid cancer.     

The importance of measuring quality of life in phase I/II trials of cancer therapy – the effects of antibody targeted therapy: part I

Phase I/II trials of new cancer therapies are designed to determine safety, efficacy and the optimal regimen for treatment. In order to uphold the principle that ‘the interests of the subject must prevail over the interests of science and society’ as laid down in the Declaration of Helsinki the effects of these trials on quality of life must be determined. Antibody-targeted therapies are a new form of cancer therapy designed to selectively deliver cytotoxic agents to cancer cells. Twenty-four patients with advanced colorectal cancer were enrolled into trials of three different treatment modalities based on this theme. Quality of life was measured using the Hospital Anxiety and Depression Scale and the Rotterdam Symptom Checklist prior to and 4 weeks after treatment. The Common Toxicity Criteria of the NCI were used to assess treatment related toxicity. There was no significant difference between pre- and post-treatment scores for all three treatment modalities. There was also no significant correlations between toxicity and physical or psychological morbidity. We suggest that the quality of life of patients undergoing phase I/II clinical trials with antibody targeted therapies for metastatic colorectal carcinoma was not adversly affected. We feel that in part this can be attributed to the high level and the intensity of support provided for the patients undergoing these treatments.     

Novel therapeutic agents in ovarian cancer.

AimsEpithelial ovarian cancer is responsible for 4% of all cancer deaths in women, and the five-year overall survival of patients with advanced disease is 30–40%. Treatment currently comprises a combination of surgery and chemotherapy with carboplatin and paclitaxel. The main reason for treatment failure is that the majority of patients present with advanced disease, and current drugs are unable to effect a cure even in chemosensitive patients. This article systematically reviews novel therapeutic strategies that have been evaluated in patients with ovarian cancer in the last 5 years.MethodsPubmed (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=pubmed) and American Society of Clinical Oncology Annual conference abstracts were searched using the terms “(phase I OR phase II OR phase III OR phase 1 OR phase 2 OR phase 3) AND (ovary OR ovarian) AND (cancer OR carcinoma)” from January 2000 to May 2005 to identify studies for potential inclusion in this review. Reviews of novel therapies in ovarian cancer were also used to identify additional clinical trials.FindingsA wide range of therapeutic strategies are currently being evaluated in ovarian cancer. These include novel cytotoxics, small molecule inhibitors, monoclonal antibodies, gene therapy and immuno-therapy strategies. The rationale for the development of these agents includes enhancement of efficacy by targeting novel biological pathways, re-sensitisation to existing drugs, simplification of drug administration and/or reduction of drug-toxicity.ConclusionsCurrent developments have the potential to result in substantial improvements in the outlook for women with ovarian cancer.     

Sorafenib: key lessons from over 10 years of experience

Introduction: In 2005, sorafenib was the first targeted therapy approved for advanced renal cell carcinoma (RCC), transforming treatment. In hepatocellular carcinoma (HCC), for more than a decade, sorafenib remained the only approved systemic therapy to have demonstrated a survival benefit in first-line unresectable HCC. In 2013, sorafenib was the first targeted agent approved for patients with differentiated thyroid cancer (DTC) refractory to radioactive iodine treatment.

Areas covered: This review discusses the development, advances, and challenges associated with sorafenib use in RCC, HCC, and DTC over the past decade. A search was performed on PubMed and key congresses as required, with no time limits.

Expert commentary: Sorafenib has had a lasting impact on the therapeutic landscape of RCC, HCC, and DTC, and remains an important treatment option despite a rapidly evolving treatment landscape. Extensive clinical and real-world experience has been invaluable in improving patient management and maximizing benefit from treatment. Ongoing clinical trials continue to evaluate sorafenib in different settings, and in combination with other therapies in HCC and DTC. We have no doubt that sorafenib will continue to be an important treatment option in the coming years.     

Early evolutionary divergence between papillary and anaplastic thyroid cancers

BackgroundPapillary thyroid cancer (PTC) is the most common thyroid carcinoma and exhibits an almost uniformly good prognosis, while anaplastic thyroid cancer (ATC) is less frequent and is one of the most aggressive cancers usually resistant to conventional treatment. Current hypothesis posits that ATC derives from PTC through the progressive acquisition of a discrete number of genomic alterations and implies that the mutational landscape of ATC resembles that of PTC. However, the clinical behaviour of ATC and PTC is radically different. We decided to address the disconnection between the clinical behaviour of ATC and PTC and the proposed model of the progressive development of ATC from PTC.Patients and methodsWe carried out exome sequencing of DNA from 14 ATC specimens including three cases of concomitant ATC and PTC as well as their corresponding normal DNA from 14 patients. The sequencing results were validated using droplet digital PCR. We carried out immunohistochemistry and immunofluorescence studies of the concomitant ATC and PTC cases. In addition, we integrated our sequencing results with the existing TCGA data.ResultsMost of the somatic mutations identified in the ATC component differed from the ones in PTC in the cases of concomitant ATC and PTC. The trunks of the phylogenetic trees representing the somatic mutations were short with long branches. In one case of concomitant PTC and ATC specimens, we observed an infiltration of PTC cells within the ATC component. Moreover, we integrated our results with data obtained from TCGA and observed that the most frequent mutations found in ATC presented high cancer cell fraction values and were significantly different from the PTC ones.ConclusionATC diverge from PTC early in tumour development and both tumour types evolve independently. Our work allows the understanding of the relationship between ATC and PTC facilitating the clinical management of these malignancies.     

Dabrafenib and Trametinib Therapy for Advanced Anaplastic Thyroid Cancer – Real-World Outcomes From UK Centres

AimsAnaplastic thyroid cancer (ATC) is a rare but aggressive form of thyroid cancer with a median survival of 4 months. Recent advances in molecular profiling have shown that up to half of ATCs harbour the BRAF-V600E mutation. The aim of this study was to provide real-world data and experience on the use of combination therapy dabrafenib and trametinib in patients with BRAF-V600E-mutated advanced ATC.Materials and methodsWe retrospectively evaluated patients with confirmed BRAF-V600E-mutated ATC, defined as patients with locally advanced or metastatic ATC with no locoregional, radical treatment options. Outcomes measured were overall survival, progression-free survival, response rate, discontinuation rate, dose reduction rate and toxicity data.ResultsSeventeen patients were evaluated and the mean age was 68 years. Ten patients died by the time of censoring. The median duration of follow-up was 12 months (3–43 months). The estimated median overall survival was 6.9 months (95% confidence interval 2.46 months – upper confidence interval not reached) and the median progression-free survival was 4.7 months (95% confidence interval 1.4–7.8 months). Dose interruptions and/or reductions were common, but none of the patients had to permanently discontinue treatment because of toxicities. Severe toxicities (grades 3 and 4) were uncommon.ConclusionsThis study supports the indication of dabrafenib and trametinib in BRAF-V600E-mutated ATC as an effective and well-tolerated treatment in an historically difficult to treat cancer.     

Comparative genomic hybridization defines frequent loss on 16p in human anaplastic thyroid carcinoma.

Anaplastic thyroid cancer (ATC) is one of the malignant tumors with the poor prognosis that is thought to arise from well-differentiated thyroid cancer (DTC). To investigate the molecular mechanism of ATC, we studied genomic alterations of eight ATC cell lines and three DTC cell lines by means of the comparative genomic hybridization (CGH) method. Loss of 16p was observed in five of eight ATC cell lines (62. 5%), but none of the three DTC cell lines showed loss of this chromosome arm. It is notable that loss of 18q [7/8 of ATC (87.5%), 2/3 of DTC (67%)] and gain of 20q [5/8 of ATC (62.5%), 3/3 of DTC (100%)] were frequently seen in both histologic types. Our results suggest that there is a gene in 16p that is closely associated with transformation from well-differentiated thyroid cancer to anaplastic cancer.     

ONYX-411, a conditionally replicative oncolytic adenovirus, induces cell death in anaplastic thyroid carcinoma cell lines and suppresses the growth of xenograft tumors in nude mice

Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid cancer variant, accounting for 1-2% of all cases, but 33% of deaths, and exhibiting an average life expectancy of 5 months. ATC is largely unresponsive to radioactive iodine, chemotherapy, external beam radiation or surgery, underscoring the need for new and effective therapies. We evaluated the therapeutic potential of an oncolytic adenovirus, ONYX-411, that replicates selectively in and kills cells with dysfunction of the retinoblastoma (RB) pathway. In the present study, we report that ONYX-411 is able to induce cell death in eight human anaplastic carcinoma cell lines in vitro. The cytopathic effect of the virus is specific to cells with RB dysfunction, which appears to be frequent in ATC. We confirmed the expression of the coxsackie adenovirus receptor, CAR, in all ATC cell lines, demonstrating the potentially universal application of this oncolytic viral therapy to ATC. In addition, the growth of xenograft tumors induced in athymic mice with the ARO and DRO cell lines was significantly reduced by ONYX-411 treatment. These results indicate that ONYX-411 can be a potential therapeutic agent for the treatment of ATC, rendering this class of conditionally replicating adenoviruses an attractive candidate for clinical trials.     

Update on Gynecologic Oncology Group (GOG) trials in ovarian cancer

The Gynecologic Oncology Group (GOG) has conducted a series of randomized trials in advanced ovarian cancer patients, both with early-stage disease (FIGO stages I and II) and advanced-stage disease (FIGO stages III and IV). In patients with early-stage disease, the current standard of therapy is three cycles of paclitaxel and carboplatin-based combination chemotherapy. In patients with advanced-stage ovarian cancer, the GOG standard is six cycles of the same regimen. The GOG has also performed prospective randomized trials of consolidation and maintenance therapy with intraperitoneal (IP) radioisotomes and additional cycles of paclitaxel, respectively. Neither of these modalities has shown improvement in survival. In addition, the GOG has performed randomized trials of IP chemotherapy, and while it has been demonstrated that the regimens that included IP cisplatin led to improved outcomes, the toxicity of this approach has precluded widespread acceptance of this modality. Currently, the GOG is performing additional pilot studies to evaluate less toxic IP regimens. The GOG has also been at the forefront of developing new combination chemotherapy regimens based on the activity of second-line agents, such as topotecan, gemcitabine, and encapsulated doxorubicin. The GOG is also exploring molecular-targeted therapies in phase II trials with the goal of ultimately incorporating biological therapies in newly diagnosed patients with advanced disease.     

Clinical evidence for the first-line treatment of advanced urothelial carcinoma: Current paradigms and emerging treatment options

BackgroundPatients with advanced urothelial carcinoma (UC) have poor outcomes, with 5-year survival rates of <5% for those with metastatic, stage IV disease. We have reviewed current treatment paradigms and emerging treatment options for these patients.MethodsThe websites of seven national or international organizations were searched for metastatic UC treatment guidelines. Systematic literature reviews were conducted to identify evidence from randomized controlled trials (RCTs) of chemotherapy for patients with previously untreated, unresectable, stage IV UC. Searches included congress databases and articles published between 1990 and 2018. In order to align with the latest treatment paradigms in first-line advanced UC, a focused literature search was conducted to identify evidence supporting immuno-oncology (IO) agents.ResultsFor advanced UC, guidelines universally recommend cisplatin-based chemotherapy as first-line treatment for eligible patients and carboplatin-based regimens for those unfit to receive cisplatin. Despite the evaluation of a number of different cytotoxic regimens over the years, including triplet combinations, survival outcomes have not improved markedly with chemotherapy. Median overall survival with standard of care chemotherapy is ~13 months. Based on the results of single-arm, phase II studies, recent treatment guidelines have included atezolizumab (anti-PD-L1) and pembrolizumab (anti-PD-1) as first-line options for cisplatin-ineligible patients whose tumors express high levels of PD-L1. However, emerging evidence from RCTs of IO agents, including both cisplatin-eligible and cisplatin-ineligible patients, suggest that survival times exceeding 20 months are possible.ConclusionsAfter having reached a plateau with chemotherapy, the treatment landscape for advanced UC is evolving. Survival outcomes for patients with advanced UC are improving with treatment modalities involving IO agents.     

Differentiated thyroid cancers: a comprehensive review of novel targeted therapies

Differentiated thyroid carcinoma (DTC) accounts for more than 90% of new thyroid cancer diagnoses, and includes papillary, follicular and Hürthle cell carcinoma. The prognosis for the vast majority of individuals diagnosed with DTC is excellent, with current treatment that includes surgery, radioactive iodine ablation and postoperative thyroid-stimulating hormone suppression. Unfortunately, the small proportion of individuals who develop radioactive iodine-resistant recurrent disease have few treatment options, and the vast majority will eventually die from their disease. Recently, several novel targets for anticancer agents have been identified and offer new hope for thyroid cancer patients diagnosed with progressive disease. In addition to targeting genes commonly altered in thyroid cancer, which include mutations in BRAF, RAS and RET, proangiogenic growth factor receptors and the sodium-iodide symporter have also been targeted. Several clinical trials evaluating tyrosine kinase and angiogenesis inhibitors for treatment of individuals diagnosed with metastatic or treatment-refractory DTC are currently underway. The objective of this review is to evaluate recent clinical trials that have studied novel targeted drugs for treatment of DTC.     

Anaplastic thyroid carcinoma: A comprehensive review of current and future therapeutic options

Anaplastic thyroid carcinoma (ATC) is the rarest, but deadliest histologic type among thyroid malignancies, with a dismal median survival of 3-9 mo. Even though ATC accounts for less than 2% of all thyroid tumors, it is responsible for 14%-39% of thyroid carcinoma-related deaths. ATC clinically presents as a rapidly growing mass in the neck, associated with dyspnoea, dysphagia and vocal cord paralysis. It is usually locally advanced and often metastatic at initial presentation. For operable diseases, the combination of radical surgery with adjuvant radiotherapy or chemotherapy, using agents such as doxorubicin and cisplatin, is the best treatment strategy. Cytotoxic drugs for advanced/metastatic ATC are poorly effective. On the other hand, targeted agents might represent a viable therapeutic option. Axitinib, combretastatin A4, sorafenib and imatinib have been tested in small clinical trials of ATC, with a promising disease control rate ranging from 33% to 75%. Other clinical trials of targeted therapy for thyroid carcinoma are currently ongoing. Biological agents that are under investigation include pazopanib, gefitinib and everolimus. With the very limited therapeutic armamentarium available at the present time, targeted therapy constitutes an exciting new horizon for ATC. In future, biological agents will probably represent the standard of care for this aggressive malignancy, in the same fashion as it has recently occurred for other chemo-refractory tumors, such as kidney and hepatic cancer.     

Management of Differentiated Thyroid Cancer with Rising Thyroglobulin and Negative Diagnostic Radioiodine Whole Body Scan

BackgroundDifferentiated thyroid carcinoma (DTC) with rising thyroglobulin (Tg) level and negative radioiodine whole body scan results has been observed in follow-up studies. The management of this condition remains controversial. Most studies support blind ¹³¹I treatment while others oppose this approach.AimsTo assess the effects of ¹³¹I therapy for DTC with rising Tg and negative scan results.Selection criteriaRandomised controlled clinical trials, prospective controlled clinical trials and any trials using ¹³¹I treatment or no treatment for Tg-positive and radioiodine-negative disease were included in this review.ResultsDue to the lack of any suitable randomised or prospective controlled trials in this area, it was not possible to undertake a meta-analysis. Eighteen trials were retrieved for further overall assessment. Of 438 patients from 16 studies who were treated empirically with ¹³¹I for Tg-positive and radioiodine-negative disease, 267 (62%) displayed pathological uptake in the thyroid bed, lungs, bone, mediastinum and lymph nodes. In studies in which data were available for serum Tg levels during thyroid-stimulating hormone (TSH) suppression therapy or TSH withdrawal, 188 of 337 patients (56%) showed a decrease in serum Tg. Of 242 patients from five studies who received no specific treatment for Tg-positive and radioiodine-negative disease, 106 (44%) showed spontaneous normalisation and a significant decrease in serum Tg.ConclusionsThe currently available evidence is insufficient for reliable assessment of the potential of ¹³¹I treatment for DTC with elevated Tg and negative scan results. A decrease in serum Tg in 62% of patients with DTC with elevated Tg and negative scan results suggests that ¹³¹I therapy has a therapeutic effect for more than one-half of patients when the Tg level is considered an index of tumour burden. However, considering that 44% of patients with DTC with elevated Tg and negative scan results showed spontaneous normalisation and a significant reduction in serum Tg without any specific treatment, ¹³¹I therapy should be individualised according to clinical characteristics. Other diagnostic techniques are strongly recommended for patients with Tg-positive and radioiodine-negative disease. If these diagnostic results are positive, treatment options such as surgery, external radiotherapy and tumour embolisation should be considered. If diagnostic results are negative, one course of ¹³¹I treatment may be considered in high-risk patients with serum Tg >10 ng/mL after TSH withdrawal or >5 ng/mL under recombinant human TSH stimulation. No further ¹³¹I therapy is indicated for patients with a negative post-therapy radioiodine scan.     

Outcomes in 144 Patients With Colorectal Cancer Treated in a Phase I Clinic: The MD Anderson Cancer Center Experience

BackgroundPatients with advanced colorectal cancer have a poor prognosis once standard therapies fail. This retrospective study presents the characteristics and outcomes in 144 patients treated in phase I clinical trials.MethodsWe retrospectively reviewed the clinical outcomes in 144 consecutive patients with colorectal cancer referred to the phase I clinic at MD Anderson.ResultsMedian age was 60 years (range, 35-86 years). The median number of previous systemic therapies was 4 (range, 1-7). The median PFS with the last line of conventional systemic treatment was 12.3 weeks (95% confidence interval [CI], 11.0-14.4); the median PFS of the best phase I treatment was shorter at 8.1 weeks (95% CI, 7.9-8.7 weeks; log-rank test, P < .0001). In the multivariate analysis that included the RMH score, sex (male vs. female, P = .02; hazard ratio [HR], 1.57), hemoglobin (< 10.5 vs. ≥ 10.5 g/dL; P = .03; HR 1.79), and the RMH score (2-3 vs. 0-1; P < .003; HR, 1.85) were significant predictors of poor survival. Conclusion: The PFS of patients with colorectal cancer in phase I treatment was shorter than it was on their last line of conventional systemic treatment. Multivariate analysis confirmed the value of the RMH score for predicting overall survival in patients with colorectal cancer enrolled in phase I studies.     

In Reply

Sarcopenia caused by hyperthyroidism from thyroid-stimulating hormone-suppressive therapy is one possible explanation for sorafenib dose-limiting toxicity in patients with differentiated thyroid cancer (DTC). Another possible explanation is that DTC patients in the considered trial were treated approximately twice as long as the renal-cell and hepatocellular carcinoma patients.We appreciate the interest of Huillard et al. in our study [1] and acknowledge that safety results are extremely important. It is certainly an interesting observation that toxicities in patients with differentiated thyroid cancer (DTC) treated with sorafenib differ significantly from other cancer populations. Indeed, sarcopenia has been associated with dose-limiting toxicities in renal-cell carcinoma (RCC) and hepatocellular carcinoma (HCC) patients treated with sorafenib, but this has not been reported in DTC. We agree that sarcopenia caused by hyperthyroidism from thyroid-stimulating hormone-suppressive therapy may be one possible explanation. It would be of great interest to analyze the body composition and PK data from the phase III DECISION trial [2] that was recently published. Another possible explanation for why DTC patients have greater toxicity to sorafenib is that they were treated approximately twice as long as the phase III RCC or HCC clinical trial patients. Median duration on therapy was 10.6 months in the sorafenib-treated patients on the phase III DTC trial compared with 5.7 and 5.3 months in sorafenib-treated patients on the RCC [3] and HCC [4] phase III trials, respectively.     

Anti-PD-1/PD-L1 therapy augments lenvatinib's efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer

Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite multimodal therapy with surgery and chemoradiation. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, as well as checkpoint inhibitors targeting the programmed cell death pathway, have proven effective in some patients with advanced thyroid cancer. Combination of these therapies is a potential means to boost effectiveness and minimize treatment resistance in ATC. We utilized our novel immunocompetent murine model of orthotopic ATC to demonstrate that lenvatinib led to significant tumor shrinkage and increased survival, while combination therapy led to dramatic improvements in both. Lenvatinib monotherapy increased tumor-infiltrating macrophages, CD8⁺ T-cells, regulatory T-cells, and most notably, polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs). While both combination therapies led to further increases in CD8⁺ T-cells, only the lenvatinib and anti-PD-1 combination decreased PMN-MDSCs. PMN-MDSC expansion was also seen in the blood of mice and one patient receiving lenvatinib therapy for ATC. RNA-Seq of the ATC cell line used in our mouse model demonstrated that lenvatinib has multifaceted effects on angiogenesis, response to hypoxia, the epithelial-to-mesenchymal transition, and on multiple pathways implicated in inflammation and host immunity. Combination of lenvatinib with anti-Gr-1 antibody ameliorated lenvatinib's expansion of MDSCs and significantly improved lenvatinib's anti-tumor effect. These data suggest that MDSCs play a negative role in ATC's response to lenvatinib and support future study of their role as a potential biomarker and treatment target.     

分化型甲状腺癌碘拮抗相关基因研究进展

甲状腺癌是最常见的内分泌系统恶性肿瘤,其中分化型甲状腺癌占多数,后者的主要治疗手段有手术治疗、术后碘放射性同位素(131I)治疗和促甲状腺激素抑制治疗等.131I在分化型甲状腺癌的诊断与治疗中有较为广泛的应用,然而,一部分分化型甲状腺癌患者因钠-碘转运体基因、BRAF基因、双链复合蛋白8、微小RNA、细胞角蛋白19等基因的改变而降低或丧失对131I的摄取能力.这些基因在分化型甲状腺癌的治疗中尤为重要,可作为肿瘤治疗疗效评估的重要指标.     

Spanish consensus for the management of patients with anaplastic cell thyroid carcinoma

Anaplastic thyroid cancer (ATC) is the most aggressive solid tumor and almost uniformly lethal in humans. The Boards of the Thyroid Cancer Group of the Spanish Society of Endocrinology and Nutrition and the Grupo Español de Enfermedades Huérfanas e Infrecuentes of the Spanish Society of Oncology requested that an independent task force draft a more comprehensive consensus statement regarding ATC. All relevant literature was reviewed, including serial PubMed searches together with additional articles. This is the first, comprehensive Spanish consensus statement for ATC and includes the characteristics, diagnosis, initial evaluation, treatment goals, recommendations and modalities for locoregional and advanced disease, palliative care options, surveillance, and long-term monitoring. Newer systemic therapies are being investigated, but more effective combinations are needed to improve patient outcomes. Though more aggressive radiotherapy has reduced locoregional recurrences, median overall survival has not improved in more than 50 years.     

Research trends in the treatment of neoplasms of the exocrine pancreas

To-date, the therapeutic standards, defined by randomized studies for carcinoma of the exocrine pancreas are disappointing. Obviously, there is much interest in the improvement of these results based on the evidence of additional clinical trials. To identify some trends in the clinical research in this field, some characteristics of 31 ongoing trials, described in the web site of the National Cancer Institute were examined. 28/31 trials are coordinated by Centers of the U.S.A. and 3/31 trials specifically concern symptom palliation. Excluding the latter, 4 trials enroll patients with operable neoplasms, 8 with inoperable tumors, 4 with metastatic neoplasm and 12 involve both latter categories. Four of the 5 phase I or I-II studies concern concomitant radiochemotherapy of inoperable neoplasms; the 16 phase II studies and the 7 phase III studies involve the use of different combined modality therapies in all patient categories. Overall, 18 trials test innovative treatment modalities (new drugs, immunotherapy, monoclonal antibodies). Eight trials include the evaluation of the quality of life between endpoints. Based on this assessment of some of the ongoing clinical trials, hopefully, there will be: 1. a greater interest in the prospective therapies for this neoplasm, especially at the European level, considering the high incidence of this disease; 2. more careful attention to the possibility of downstaging of locally advanced neoplasms considering the present, proven possibility to achieve better clinical responses in pancreatic carcinoma; 3. a more widespread interest in the establishment of parameters for the quality of life, considering the frequently "palliative" intent of available therapies.