Sunitinib and bevacizumab for first-line treatment of metastatic renal cell carcinoma: a systematic review and indirect comparison of clinical effectiveness

Background:

Two new agents have recently been licensed for use in the treatment of metastatic renal cell carcinoma (RCC) in Europe. This paper aims to systematically review the evidence from all available randomised clinical trials of sunitinib and bevacizumab (in combination with interferon-α (IFN-α)) in the treatment of advanced metastatic RCC.

Methods:

Systematic literature searches were performed in six electronic databases. Bibliographies of included studies were searched for further relevant studies. Individual conference proceedings were searched using their online interfaces. Studies were selected according to the predefined criteria. All randomised clinical trials of sunitinib or bevacizumab in combination with IFN for treating advanced metastatic RCC in accordance with the European licensed indication were included. Study selection, data extraction, validation and quality assessment were performed by two reviewers with disagreements being settled by discussion. The effects of sunitinib and bevacizumab (in combination with IFN-α) on progression-free survival were compared indirectly using Bayesian Markov Chain Monte-Carlo (MCMC) sampling in Win BUGS, with IFN as a common comparator.

Results:

Three studies were included. Median progression-free survival was significantly prolonged with both interventions (from approximately 5 months to between 8 and 11 months) compared with IFN. Overall survival was also prolonged, compared with IFN, although the published data are not fully mature. Indirect comparison suggests that sunitinib is superior to bevacizumab plus IFN in terms of progression-free survival (hazard ratios 0.796; 95% CI 0.63–1.0; P=0.0272).

Conclusion:

There is evidence to suggest that treatment with sunitinib and treatment with bevacizumab plus IFN has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC.     

Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer

Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1–3, fibroblast growth factor receptors 1–4, RET, KIT, and platelet-derived growth factor receptor-α. Lenvatinib is approved as a monotherapy for the treatment of radioiodine-refractory differentiated thyroid cancer and in combination with everolimus for the second-line treatment of advanced renal cell carcinoma. Lenvatinib is also under investigation for the treatment of several malignancies including unresectable hepatocellular carcinoma. Although lenvatinib is associated with favorable efficacy, it is associated with adverse events (AEs) that the clinician will have to closely monitor for and proactively manage. Most of these AEs are known class effects of VEGF-targeted therapies, including hypertension, diarrhea, fatigue or asthenia, decreased appetite, and weight loss. This review summarizes the safety profile of lenvatinib and offers guidance for the management of both frequent and rare AEs. We discuss the potential mechanisms underlying these AEs and present practical recommendations for managing toxicities. The development of treatment plans that include prophylactic and therapeutic strategies for the management of lenvatinib-associated AEs has the potential to improve patient quality of life, optimize adherence, minimize the need for dose reductions, treatment interruptions, or discontinuations, and maximize patient outcomes.     

手术治疗分化型甲状腺癌76例临床分析

目的:分析分化型甲状腺癌的临床特点,探讨其手术治疗方式。方法:回顾性分析2012年1月至2014年6月期间我院普外二科收治的76例分化型甲状腺癌患者的临床资料。结果:所有患者均行手术治疗并行术中快速冰冻切片及术后石蜡病理检查。双侧甲状腺全切除术8例、患侧腺叶+峡部全切+对侧腺叶次全切除54例、患侧腺叶加峡部切除10例、患侧腺叶切除4例。20例行颈部中央区淋巴结清扫,8例行功能性颈部淋巴结清扫。围手术期无死亡病例。结论:外科手术是治疗分化型甲状腺癌的首选方法。手术方式应根据肿瘤临床分期进行个体化选择。     

Recurrence-associated mortality in patients with differentiated thyroid carcinoma

Differentiated thyroid carcinoma (DTC) is associated with prolonged natural history, and even recurrent tumor is not necessarily followed by increased mortality. Prognostic factors and different treatment strategies, therefore, are difficult to assess. One hundred and fifty-seven patients were followed in our clinic. In an attempt to predict mortality from this tumor, we evaluated the risk factors in 36 patients who presented with recurrent disease. Ten of these patients died. Age above 40 years at initial diagnosis was the predominant risk factor associated with 44% mortality after recurrence. Male sex, lack of radioiodine treatment, and distant site of initial recurrence were all associated with a trend towards increased mortality. Tumor histology and local invasion or extent of initial surgical treatment failed to affect mortality. In conclusion, this approach may be used to identify those patients who will die from their disease, despite currently available treatment. It remains to be seen, however, if new treatment protocols can be developed to improve the prognosis of these patients. © 1993 Wiley-Liss, Inc.     

New approaches for patients with advanced radioiodine-refractory thyroid cancer

The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma (DTC) has exponentially increased. Approximately 10% of patients with DTC exhibit recurrent or metastatic disease, and about two-thirds of the latter will be defined as refractory to radioactive iodine (RAIR) treatment. Since this condition implies 10-year survival rates less than 10% after detection, using available treatments, such as systemic and targeted therapies, have become increasingly relevant. The initiation of these treatments aims to reach stabilization, tumor volume reduction, and/or symptom improvement and it should be decided by highly specialized endocrinologists/ oncologists on the basis of patient’s features. Considering that despite enlarged progression-free survival was proven, multikinase inhibitors remain non-curative, their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction. In this context, molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy, progression free survival, overall survival and adverse events profile. This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC, including approved target therapies as well as those for off-label use, RAI resensitization agents, and immunotherapy.     

分化型甲状腺癌再次手术临床分析

目的：探讨分化型甲状腺癌再次手术的原因、时机及对策。方法：对5年来收治的甲状腺手术后病理证实为分化型甲状腺癌,需要再次手术治疗的30例临床病理资料进行回顾性分析。结果：24例再次手术的原因为将分化型甲状腺癌误诊为甲状腺良性病变,手术切除范围不够,4例原因为分化型甲状腺癌术后复发,2例原因为131I治疗前的甲状腺清除。结论：分化型甲状腺癌的误诊是造成甲状腺癌再次手术的主要原因,应强调术中快速冰冻病理检查在甲状腺手术中的常规应用。     

分化型甲状腺癌再次手术临床分析

目的:探讨分化型甲状腺癌再次手术的原因、时机及对策。方法:对5年来收治的甲状腺手术后病理证实为分化型甲状腺癌,需要再次手术治疗的30例临床病理资料进行回顾性分析。结果:24例再次手术的原因为将分化型甲状腺癌误诊为甲状腺良性病变,手术切除范围不够,4例原因为分化型甲状腺癌术后复发,2例原因为131I治疗前的甲状腺清除。结论:分化型甲状腺癌的误诊是造成甲状腺癌再次手术的主要原因,应强调术中快速冰冻病理检查在甲状腺手术中的常规应用。     

The concepts in poorly differentiated carcinoma of the thyroid: a review article

Poorly differentiated carcinomas of the thyroid have evolved over the past half century into a specific entity in the classification of thyroid carcinomas. The need for a consensus diagnostic criteria has been stressed in view of the wide discrepancies and confusion among pathologists and clinicians. This review attempts to understand the concept, the evolution, clarity and validity of the concepts in poorly differentiated carcinomas of the thyroid.     

分化型甲状腺癌患者体质量指数与瘦素表达的相关性

目的：探讨体质量指数与甲状腺癌组织瘦素（Leptin）表达水平的相关性,为临床诊断及治疗分化型甲状腺癌提供依据。方法：选择分化型甲状腺癌患者167例,根据体质量指数分为体重正常组（n ＝64）、超重组（n ＝47）和肥胖组（n ＝56）,观察各组的甲状腺组织 Leptin 及其受体（OB －R）表达水平。结果：正常组的肿瘤大小以＜1cm 为主,而肥胖组则以≥1cm 居多（P ＜0．05）;正常组肿瘤分期 I、Ⅱ期比例居多,肥胖组以Ⅲ、Ⅳ期为主（P ＜0．05）;三组患者的 Leptin、OB －R 表达水平随着患者体质量指数的增加而逐渐升高（P ＜0．05）;甲状腺癌患者体质量指数与 Leptin 表达水平呈正相关。结论：Leptin 与甲状腺癌的发生、进展密切相关,同时 Leptin 与患者体质量指数密切相关。     

分化型甲状腺癌的微创手术治疗

目的:探讨将腔镜技术应用于分化型甲状腺癌的手术治疗的近期疗效及适应证.方法:回顾性分析56例分化型甲状腺癌在腔镜辅助下手术(研究组)和传统手术(对照组)治疗,在疗效、美容效果、合并症、手术时间、出血量等方面的差异.两组均行甲状腺癌联合根治手术—甲状腺切除术加同侧颈淋巴结清扫术.结果:两组患者经5-36个月的随访均无复发和转移;在手术切除范围相同的情况下,手术时间上研究组较对照组手术时间延长,存在明显差异(P≤0.05);术中出血量研究组较对照组增加(P≤0.05);术后引流量研究组与对照组未见明显差异(P≥0.5);美观度研究组明显优于对照组(P≤0.01).结论:腔镜辅助下甲状腺癌联合根治手术是安全可行的,美容效果明显,但在手术时间、术中出血量方面劣于传统手术,需要严格掌握适应证.     

Family history of cancer and risk of sporadic differentiated thyroid carcinoma

BACKGROUND:

Thyroid cancer incidence in the United States, particularly in women, has increased dramatically since the 1980s. Although the causes of thyroid cancer in most patients remain largely unknown, evidence suggests the existence of an inherited predisposition to development of differentiated thyroid carcinoma (DTC). Therefore, the authors explored the association between sporadic DTC and family history of cancer.

METHODS:

In a retrospective hospital‐based case‐control study of prospectively recruited subjects who completed the study questionnaire upon enrollment, unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as estimates of the DTC risk associated with first‐degree family history of cancer.

RESULTS:

The study included 288 patients with sporadic DTC and 591 cancer‐free controls. Family history of thyroid cancer in first‐degree relatives was associated with increased DTC risk (adjusted OR, 4.1; 95% CI, 1.7‐9.9). All DTC cases in patients with a first‐degree family history of thyroid cancer were cases of papillary thyroid carcinoma (PTC) (adjusted OR, 4.6; 95% CI, 1.9‐11.1). Notably, the risk of PTC was highest in subjects with a family history of thyroid cancer in siblings (OR, 7.4; 95% CI, 1.8‐30.4). In addition, multifocal primary tumor was more common among PTC patients with first‐degree family history of thyroid cancer than among PTC patients with no first‐degree family history of thyroid cancer (68.8% vs 35.5%, P = .01).

CONCLUSIONS:

The study suggests that family history of thyroid cancer in first‐degree relatives, particularly in siblings, is associated with an increased risk of sporadic PTC. Cancer 2012;. © 2011 American Cancer Society.     

Well‐differentiated thyroid carcinoma: The role of post‐operative radioactive iodine administration

Post‐operative management of differentiated thyroid cancer (DTC) often involves administration of radioactive iodine (RAI) for remnant ablation or adjuvant therapy. However, given the favorable prognosis associated with DTC, the risk versus benefit ratio of RAI remains unclear. RAI is associated with substantial, albeit rare side effects, including a possible increased risk of secondary malignancy and altered fertility, which must be balanced against the magnitude of benefit for decreasing recurrence and improving survival. J. Surg. Oncol. 2013;107:665–672. © 2012 Wiley Periodicals, Inc.     

分化型甲状腺癌患者的临床特点及预后分析

目的 分析分化型甲状腺癌患者的临床特点及预后影响因素.方法 收集147例分化型甲状腺癌患者的临床资料,包括一般资料、手术方法、术后基本情况及临床特征,采用Logistic回归模型分析分化型甲状腺癌患者预后的影响因素.结果 147例分化型甲状腺癌患者中,单侧发病95例,双侧发病52例;单发59例,多发88例;91.16％...     

超声对低分化和未分化甲状腺癌的诊断价值

目的 探讨超声对低分化甲状腺癌(PDTC)和未分化(间变性)甲状腺癌(UTC)的诊断价值.方法 应用彩色多普勒超声对22例PDTC和UTC的甲状腺形态、大小、回声、边界、内部砂粒、血流分布等声像图表现及其内部血流状况进行观察,并与手术、活组织病理检查病理结果对照;扫查颈部及气管食管沟区淋巴结.根据甲状腺双叶或单叶弥漫性病变及局部淋巴结的超声表现,结合临床表现,判断甲状腺病变的性质.结果 术前或活组织病理检查前超声检出甲状腺单叶肿物16例,左甲9例,右甲7例.双叶肿物6例.超声提示UTC 2例,甲状旁腺癌1例,慢性淋巴细胞性甲状腺炎1例,其余提示甲状腺恶性肿瘤.结论 超声检查可提高PDTC和UTC的检出率和诊断率.     

Circulating endogenous sex steroids and risk of differentiated thyroid carcinoma in men and women

Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow-up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri-menopausal women, 111 in post-menopausal women, and 70 in men) and 706 cancer-free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre-menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96–2.92, p_trend = .06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96–3.30, p_trend = .06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28–1.05, p_trend = .07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post-menopausal women and men but may suggest an involvement of altered sex steroid production in pre-menopausal women.     

Contemporary considerations in adjuvant radioiodine treatment of adults with differentiated thyroid cancer

Differentiated thyroid cancer (DTC) is the most common endocrine malignancy with a growing incidence worldwide. The initial conventional management is surgery, followed by consideration of ¹³¹I treatment that includes three options. These are termed remnant ablation (targeting benign thyroid remnant), adjuvant (targeting presumed microscopic DTC) and known disease (targeting macroscopic DTC) treatments. Some experts mostly rely on clinicopathologic assessment for recurrence risk to select patients for the ¹³¹I treatment. Others, in addition, apply radioiodine imaging to guide their treatment planning, termed theranostics (aka theragnostics or radiotheragnostics). In patients with low-risk DTC, remnant ablation rather than adjuvant treatment is generally recommended and, in this setting, the ATA recommends a low ¹³¹I activity. ¹³¹I adjuvant treatment is universally recommended in patients with high-risk DTC (a primary tumor of any size with gross extrathyroidal extension) and is generally recommended in intermediate-risk DTC (primary tumor >4 cm in diameter, locoregional metastases, microscopic extrathyroidal extension, aggressive histology or vascular invasion). The optimal amount of ¹³¹I activity for adjuvant treatment is controversial, but experts reached a consensus that the ¹³¹I activity should be greater than that for remnant ablation. The main obstacles to establishing timely evidence through randomized clinical trials for ¹³¹I therapy include years-to-decades delay in recurrence and low disease-specific mortality. This mini-review is intended to update oncologists on the most recent clinical, pathologic, laboratory and imaging variables, as well as on the current ¹³¹I therapy-related definitions and management paradigms, which should optimally equip them for individualized patient guidance and treatment.     

82例分化型甲状腺癌再手术临床分析

目的：探讨分化型甲状腺癌术前诊断,首次手术方式的选择及补充性二次手术的必要性。方法：分析近10年来收治的82例分化型甲状腺癌再手术的临床资料。再手术中采用快速病理检查,根据肿瘤浸润的范围及淋巴结转移情况行甲状腺残叶、峡部、对侧大部分切除,甲状腺全切及同侧淋巴结功能性清扫术。结果：58例行患侧残留腺体峡部及对侧腺体大部分切除,17例行甲状腺全切术。7例因肿瘤侵及范围较广泛仅行姑息性切除。35例因肿瘤侵及甲状腺包膜或术中发现淋巴结肿大,而行同侧功能性淋巴清扫术。术后病理：淋巴结转移22例（62.9%）,癌残留52例（63.4%）。再手术造成喉返神经损伤4例,其中3例半年后恢复,1例未见明显改善。甲状旁腺损伤3例,经近期处理后恢复。食管损伤1例。结论：分化型甲状腺癌术前定性诊断较困难,局部切除癌残留率较高,应及时做补充性二次手术。小于一叶切除的手术方式应废止。     

Ps-Tg水平在分化型甲状腺癌诊疗中的应用

血清甲状腺球蛋白（thyroglobulin,Tg）是分化型甲状腺癌（differentiated thyroid carcinoma,DTC）术后随访最常用的血清标志物,用于监测DTC复发及转移。然而血清Tg的检测受到多种因素的干扰,如术后残余甲状腺组织、促甲状腺激素（thyroid stimulating hormone,TSH）、甲状腺球蛋白抗体(thyroglobulin antibody,TgAb)、甲状腺过氧化物酶抗体(thyroid peroxidase antibody,TPOAb)等。因此已往认为术后131I治疗前检测激性 Tg（preablative stimulated thyroglobulin,ps-Tg）（TSH>30 μIU/ml刺激状态下的 Tg 水平）水平意义不大。2009年美国ATA指南指出,DTC 患者ps-Tg水平在疾病状态的预测中有一定作用。近年来也有越来越多的研究表明,术前血清 Tg 水平的监测具有重要的临床价值。本文旨在对Tg在甲状腺癌患者疾病监测中的所受到的干扰因素及DTC 术后诊疗过程中的意义进行综述。     

Parenteral oestrogen in the treatment of prostate cancer: a systematic review

The objectives of this study were to assess the effectiveness and safety of parenteral oestrogen in the treatment of prostate cancer, and to examine any dose relationship. A systematic review was undertaken. Electronic databases, published paper and internet resources were searched to locate published and unpublished studies with no restriction by language or publication date. Studies included were randomised controlled trials of parenteral oestrogen in patients with prostate cancer; other study designs were also included to examine dose-response. Study selection, appraisal, data extraction and quality assessment were performed by one reviewer and independently checked by another. Twenty trials were included in the review. The trials differed with regard to the included patients, formulation and dose of parenteral oestrogen, comparator used, outcome measures reported and the duration of follow-up. The results provide no evidence to suggest that parenteral oestrogen, in doses sufficient to produce castrate levels of testosterone, is less effective than luteinising hormone-releasing hormone (LHRH) or orchidectomy in controlling prostate cancer, or that it is consistently associated with an increase in cardiovascular mortality. Further well-conducted trials of parenteral oestrogen are required. A pilot randomised controlled trial comparing transdermal oestrogen to LHRH analogues in men with locally advanced or metastatic prostate cancer is underway in the United Kingdom.