Everolimus for renal cell carcinoma: predictive factors for response and future directions

Mammalian target of rapamycin (mTOR) inhibitors have emerged as a major addition to the therapeutic armamentarium for renal cell carcinoma. Temsirolimus extended survival when employed as frontline therapy for poor-risk advanced renal cell carcinoma. Everolimus has demonstrated improved progression-free survival for all risk groups of RCC in the salvage setting following other anti-angiogenic agents. Preliminary data indicates that baseline activation of the mTOR signaling pathway and increased FDG-PET uptake as well as early pharmacodynamic modulations of the mTOR pathway and down-modulation of FDG-PET uptake may predict for the activity of mTOR inhibitors. Ongoing trials are attempting to validate these data with everolimus therapy for metastatic RCC and may enable the goal of personalized therapy.     

Everolimus for renal cell carcinoma: predictive factors for response and future directions

Mammalian target of rapamycin (mTOR) inhibitors have emerged as a major addition to the therapeutic armamentarium for renal cell carcinoma. Temsirolimus extended survival when employed as frontline therapy for poor-risk advanced renal cell carcinoma. Everolimus has demonstrated improved progression-free survival for all risk groups of RCC in the salvage setting following other anti-angiogenic agents. Preliminary data indicates that baseline activation of the mTOR signaling pathway and increased FDG-PET uptake as well as early pharmacodynamic modulations of the mTOR pathway and down-modulation of FDG-PET uptake may predict for the activity of mTOR inhibitors. Ongoing trials are attempting to validate these data with everolimus therapy for metastatic RCC and may enable the goal of personalized therapy.     

Targeted therapy for metastatic renal cell carcinoma: a home run or a work in progress?

Recent advances in the understanding of the biology of renal cell carcinoma (RCC) have been translated into clinical treatment options in metastatic disease. The introduction of targeted therapy against the vascular endothelial growth factor (VEGF) pathway and related elements has produced robust clinical effects, exceeding those of historical treatment options. Sunitinib (Sutent) and bevacizumab (Avastin) plus interferon have established roles in the initial treatment of metastatic RCC. Sorafenib (Nexavar) is established for cytokine-refractory RCC and is being explored in other settings. Temsirolimus (Torisel) is the only agent to extend overall survival to date, although this finding has been restricted to a poor-risk population. Several clinical questions have thus emerged in regard to the optimal timing, type, and sequence of targeted therapy in metastatic RCC. Novel agents targeting the VEGF or alternative pathways have also emerged and are beginning to undergo clinical testing.     

Current Data with Mammalian Target of Rapamycin Inhibitors in Advanced Renal Cell Carcinoma

Mammalian target of rapamycin (mTOR) is the key regulator of cell growth and proliferation. Alterations in the mTOR signaling pathway can lead to neoplastic transformation and progression. The inhibition of mTOR blocks the progression of the cell cycle from G1 to S phase, leading to cell growth arrest and apoptosis. Thus, mTOR is a promising target for the treatment of human malignancies. Rapamycin and its analogues, including temsirolimus, everolimus, and AP23573, block the mTOR signaling pathway and induce a cellular state akin to starvation, with significant antitumor activity in a variety of malignancies, including renal cell carcinoma (RCC). Current data from ongoing clinical trials suggest that mTOR-targeted therapy with rapamycin derivatives is well tolerated with significant clinical activity in patients with advanced-stage RCC. Specifically, temsirolimus as monotherapy has demdemonstrated improved progression-free and overall survival in patients with poor-risk advanced-stage RCC. Everolimus has also demonstrated promising antitumor activity in patients with metastatic RCC. However, optimal dose, treatment schedule, selection of patients, and appropriate combination strategies with other novel agents need to be defined for mTORtargeted therapies in the treatment of advanced-stage RCC.     

Current data with mammalian target of rapamycin inhibitors in advanced-stage renal cell carcinoma

Mammalian target of rapamycin (mTOR) is the key regulator of cell growth and proliferation. Alterations in the mTOR signaling pathway can lead to neoplastic transformation and progression. The inhibition of mTOR blocks the progression of the cell cycle from G1 to S phase, leading to cell growth arrest and apoptosis. Thus, mTOR is a promising target for the treatment of human malignancies. Rapamycin and its analogues, including temsirolimus, everolimus, and AP23573, block the mTOR signaling pathway and induce a cellular state akin to starvation, with significant antitumor activity in a variety of malignancies, including renal cell carcinoma (RCC). Current data from ongoing clinical trials suggest that mTOR-targeted therapy with rapamycin derivatives is well tolerated with significant clinical activity in patients with advanced-stage RCC. Specifically, temsirolimus as monotherapy has demdemonstrated improved progression-free and overall survival in patients with poor-risk advanced-stage RCC. Everolimus has also demonstrated promising antitumor activity in patients with metastatic RCC. However, optimal dose, treatment schedule, selection of patients, and appropriate combination strategies with other novel agents need to be defined for mTORtargeted therapies in the treatment of advanced-stage RCC.     

Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology.

PURPOSE: To define outcome data for patients with metastatic renal cell carcinoma (RCC) with histology other than clear-cell type, including collecting duct (or medullary carcinoma), papillary, chromophobe, and unclassified histologies. PATIENTS AND METHODS: Sixty-four patients with metastatic non-clear-cell RCC histology were the subjects of this retrospective review. Included in the analysis were 22 (8%) of 286 patients from a clinical trials database, 19 of 1,166 patients from a surgery database, and 23 of 357 patients from a pathology database. RESULTS: The prevalent histology was collecting duct, present in 26 (41%) patients. The number of patients with chromophobe and papillary histologies was 12 (19%) and 18 (28%), respectively. Eight (12%) of the patients had tumors that could not be classified for specific tumor histology. Among the 43 patients treated with 86 systemic therapies, including 37 cytokine therapies, two patients (5%) were observed to have a partial response. The median overall survival time was 9.4 months (95% confidence interval, 8 to 14 months). The survival was longer for patients with chromophobe tumors compared with collecting duct or papillary histology, and this group included four patients with survival of greater than 3 years. CONCLUSION: RCC consists of a heterogeneous group of tumors including clear-cell, papillary, chromophobe, collecting duct, and unclassified cell types. Non-clear-cell histologies constitute less than 10% of patients in general populations of patients with advanced RCC treated on clinical trials. Metastatic non-clear-cell RCC is characterized by a resistance to systemic therapy and poor survival, with the survival for patients with chromophobe tumors longer than that for patients with metastatic collecting duct or papillary RCC. Treatment with novel agents on clinical trials is warranted.     

The clinical potential of temsirolimus in second or later lines of treatment for metastatic renal cell carcinoma

An impressive variety of targeted therapies has been approved for the treatment of metastatic renal cell carcinoma (mRCC). Despite promising progress, there are still unmet clinical needs. The optimal sequence of these agents in the therapeutic setting has not yet been determined. Most available data address first- and second-line therapy of clear cell RCC. The mTOR inhibitor temsirolimus has been approved for first-line treatment of mRCC, and there are new data addressing the use of temsirolimus in later therapeutic lines. Temsirolimus has discerning features compared with other currently registered drugs, such as its intravenous administration route–providing predictable bioavailability and adherence to treatment–and potential benefit in nonclear cell histologies. Here, we review the available literature on temsirolimus, with reference to data also available for everolimus, to determine its clinical potential in mRCC.     

Renal cell carcinoma: evolving approaches to advanced non-clear cell carcinoma

The treatment of metastatic renal cell carcinoma (RCC) has changed dramatically with the introduction of targeted therapies including sunitinib, sorafenib, and temsirolimus. Because patients with conventional clear cell histology account for 75–80% of all patients with RCC, there has been little accumulated evidence on the treatment of patients with non-clear cell histologies. Most clinical trials have excluded them from enrolment, except for randomized studies investigating temsirolimus. Many retrospective studies on the use of all three of these targeted therapies in patients with non-clear cell histology have demonstrated response rates ranging from 3.7%–16%. Although response rates may not be as high compared to patients with clear cell histologies, targeted therapy does provide a clinically meaningful response.     

The High-Dose Aldesleukin (IL-2) “Select” Trial: A Trial Designed to Prospectively Validate Predictive Models of Response to High-Dose IL-2 Treatment in Patients With Metastatic Renal Cell Carcinoma

For patients with metastatic renal cell carcinoma (RCC), the prognosis is poor. Despite the recent approval of drugs such as sorafenib, sunitinib, and temsirolimus, durable remissions of metastatic disease are rare. This is largely due to the fact that these drugs, while effective, do not result in the eradication of disease. In 1992, the FDA approved the use of high-dose interleukin-2 (IL-2) for the treatment of patients with metastatic RCC because of a small number of patients that achieved durable responses. However, IL-2 has not become a mainstay of treatment because of the expense and toxicity associated with this therapy. This review article discusses a phase II trial that investigates predictive biomarkers that might help clinicians identify the patient population with metastatic RCC that would benefit from IL-2 therapy and therefore limit patients who receive this toxic therapy to those most likely to benefit.     

Optimizing treatment for metastatic renal cell carcinoma

With the advent of targeted antiangiogenic therapies for renal cell carcinoma (RCC), the prognosis for patients with locally advanced or metastatic disease has significantly improved. Indeed, the results of several randomized clinical trials have demonstrated that targeted therapies, such as tyrosine kinase inhibitors (TKIs), provide superior efficacy and tolerability compared with traditional cytokine-based treatments. However, TKI therapy is still associated with significant toxicities related to off-target inhibition that are detrimental to patient quality of life. The results of ongoing head-to-head trials will determine how these agents compare with each other in terms of efficacy, and whether TKIs that interact with fewer off-target kinases have improved tolerability profiles. Furthermore, examining how these agents could be integrated with surgery to provide a multimodal approach to the treatment of metastatic RCC could further improve the outlook for RCC patients.     

Optimizing treatment for metastatic renal cell carcinoma

With the advent of targeted antiangiogenic therapies for renal cell carcinoma (RCC), the prognosis for patients with locally advanced or metastatic disease has significantly improved. Indeed, the results of several randomized clinical trials have demonstrated that targeted therapies, such as tyrosine kinase inhibitors (TKIs), provide superior efficacy and tolerability compared with traditional cytokine-based treatments. However, TKI therapy is still associated with significant toxicities related to off-target inhibition that are detrimental to patient quality of life. The results of ongoing head-to-head trials will determine how these agents compare with each other in terms of efficacy, and whether TKIs that interact with fewer off-target kinases have improved tolerability profiles. Furthermore, examining how these agents could be integrated with surgery to provide a multimodal approach to the treatment of metastatic RCC could further improve the outlook for RCC patients.     

Temsirolimus in metastatic chromophobe renal cell carcinoma after interferon and sorafenib therapy

Chromophobe renal cell carcinoma (chRCC) is a common subtype of renal cell carcinoma (RCC), occurring in 6-11% of renal carcinoma patients. Limited clinical trial data have shown minimal activity with cytokines and chemotherapy, although small-molecule inhibitors of the vascular endothelial growth factor and platelet-derived growth factor pathways such as sunitinib and sorafenib, which are associated with significant clinical activity in clear-cell RCC (ccRCC), have been associated with a 25% response rate in chRCC. The mammalian target of rapamycin kinase inhibitor temsirolimus demonstrates good clinical activity in ccRCC patients with poor prognosis, with further data suggesting it is an effective treatment for all RCC tumour histologies. This report describes the case of a patient with chRCC who experienced rapid improvement in his general condition and stable disease on treatment with temsirolimus, following disease progression on interferon alfa and sorafenib treatment. This case report suggests that temsirolimus is an effective and appropriate treatment for this RCC tumour subtype.     

转移性肾癌的靶向治疗

转移性肾癌是一种对于传统化、放疗较不敏感的不可治愈性疾病。虽然免疫治疗对部分患者具一定疗效，但疗效通常并不持久，且治疗可能导致严重的毒副作用。随着近年来对肾癌生物学及分子发病机制的加深理解，针对使用多种靶向治疗药物治疗肾癌的研究取得了可喜的成果。无论针对初治或以往治疗失败的患者，靶向治疗均显示出高于传统治疗的优越性。此外，治疗的耐受性非常良好，并不影响患者的生存质量。本综述将依据最新的临床证据，着重围绕目前主要的治疗进展加以分别阐述，同时简单概括相关的治疗靶点信息，力求使读者在基础和临床两方面对转移性肾癌的靶向治疗获得较为深刻的认识。     

Second-line systemic therapy for the treatment of metastatic renal cell cancer

The discovery of molecular mechanisms driving the progression of renal cell carcinoma (RCC) has led to the development of drugs that target RCC at the molecular level. Inhibition of VEGF-targeting pathways is successful as a front-line treatment in patients with metastatic RCC. In addition, bevacizumab/IFN-α, sunitinib and pazopanib are recommended for first-line use in good- or intermediate-risk patients, whereas temsirolimus is approved for poor-risk patients. Second-line options are valuable as these patients eventually progress. The present review addresses which drug is best in this second-line setting. Options for sequential therapy include tyrosine kinase inhibitor (TKI)-mTOR inhibitor or TKI-TKI sequences. We also address the question of whether sequential therapy with TKIs or the combination of VEGF followed by mTOR inhibition is the best choice for specific patients, and which sequence of TKIs is most beneficial.     

Second-line systemic therapy for the treatment of metastatic renal cell cancer

The discovery of molecular mechanisms driving the progression of renal cell carcinoma (RCC) has led to the development of drugs that target RCC at the molecular level. Inhibition of VEGF-targeting pathways is successful as a front-line treatment in patients with metastatic RCC. In addition, bevacizumab/IFN-α, sunitinib and pazopanib are recommended for first-line use in good- or intermediate-risk patients, whereas temsirolimus is approved for poor-risk patients. Second-line options are valuable as these patients eventually progress. The present review addresses which drug is best in this second-line setting. Options for sequential therapy include tyrosine kinase inhibitor (TKI)–mTOR inhibitor or TKI–TKI sequences. We also address the question of whether sequential therapy with TKIs or the combination of VEGF followed by mTOR inhibition is the best choice for specific patients, and which sequence of TKIs is most beneficial.     

Immunological Heterogeneity of the RCC Microenvironment: Do Targeted Therapies Influence Immune Response?

The introduction of targeted agents has substantially improved treatment of metastatic clear-cell renal cell carcinoma (RCC). However, complete responses are rare and therapy is not curative. Moreover, information on the latest generation of potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) suggests that a plateau has been reached in terms of efficacy. Recent data reveal that targeted agents are involved in modulating immune responses in RCC. In addition, current research adds to our understanding of how RCC escapes an effective anti-tumor response with the potential to modulate these processes by drug development. This review provides specific insight into targeted therapy induced changes in the immunological microenvironment of RCC, summarizes the available evidence, and discusses potential therapeutic implications.     

Current Algorithms and Prognostic Factors in the Treatment of Metastatic Renal Cell Carcinoma

Metastatic renal cell carcinoma (RCC) is highly resistant to chemotherapy but responds modestly to cytokine therapy. The prognosis for longterm survival is poor. Approximately 10% of patients who present with metastatic disease or relapse after nephrectomy are alive at 5 years. Identification of prognostic or predictive factors for individual patient outcomes is necessary in order to develop tailored treatments that reduce the risk of relapse and enhance the chance of successful management. The relationship between pretreatment clinical features and survival has been evaluated in studies leading to the creation of a Memorial Sloan- Kettering Cancer Center (MSKCC) risk model. Additionally, the cloning of the von Hippel—Lindau tumor suppressor gene, and the elucidation of its role in upregulating growth factors associated with angiogenesis, has provided insight into RCC biology and defined a series of targets for novel therapeutic agents. These targeted agents, including sunitinib, sorafenib, temsirolimus, everolimus, and bevacizumab plus interferon-α, have shown benefit in phase III trials in first- and second-line therapy. Analysis of the data from these trials and use of prognostic models have resulted in a new paradigm for the treatment of metastatic RCC. Herein, we review these targeted agents, the MSKCC risk model, and the new paradigm for treatment of metastatic RCC.     

胆囊罕见恶性透明细胞肿瘤的临床病理观察

目的:探讨胆囊罕见恶性透明细胞肿瘤的临床病理特征、免疫表型、诊断和鉴别诊断、治疗以及预后特点，以提高病理医生对其临床及病理改变的认识。方法:对收治于我院的胆囊透明细胞腺癌和胆囊转移性肾细胞癌的临床资料及病理学特征进行回顾性分析，对石蜡包埋组织切片进行HE染色和免疫组化染色，并复习相关文献进行讨论。结果:本文于国内首次报道了1例转移至双侧附件的胆囊原发性透明细胞腺癌和5例罕见胆囊转移性肾细胞癌。镜下两者形态非常相似，大部分肿瘤细胞核圆居中、深染，胞浆透亮，细胞界限清楚，形成实性巢状或腺泡状结构；但胆囊透明细胞腺癌伴有高级别上皮内瘤变和普通型腺癌的成分，而胆囊转移性肾细胞癌中不伴随其他肿瘤性成分，并且大部分胆囊转移性肾细胞癌的病例中肿瘤细胞可见嗜酸性小核仁，而胆囊透明细胞腺癌中则未见核仁。免疫组化方面，胆囊透明细胞腺癌表达CA19-9、CEA、Keratin和p53，而胆囊转移性肾细胞癌表达EMA、CD10、Keratin、RCC、Pax-2、Pax-8和Vimentin。结论:胆囊具有“透明细胞形态特征”的良恶性病变种类颇多，形态学上有所重叠，仔细观察这些透明细胞的镜下特点、排列方式、分布特点以及有无伴随其他肿瘤性成分等情况并结合免疫组化特点和特殊染色结果有助于病理医师做出正确的诊断。     

Key considerations in patient selection for the use of targeted therapy in metastatic renal cell carcinoma

The number of treatment options for patients with renal cell carcinoma (RCC) and the extent of clinical evidence available to support treatment decisions are increasing. Targeted agents such as the tyrosine kinase inhibitors sunitinib and sorafenib have set new standards in this challenging condition and several are now approved for use in patients with metastatic RCC. Accurate prediction of prognosis in metastatic RCC is essential for counselling and understanding the potential implications of prognostic factors on treatment outcome can help guide therapeutic interventions. In metastatic RCC, key prognostic factors include performance status, histological subtype, and number and location of metastases. Data on the implications of these prognostic factors alone or as part of validated risk models will be presented and recommendations for treatment of key patient groups provided.     

Nephrectomy for metastatic renal cell carcinoma: A component of systemic treatment regimens

New immunotherapeutic and chemotherapeutic regimens have altered the medical approach to metastatic renal cell carcinoma (RCC). Surgery for metastatic RCC needs to be reappraised in the context of these developments. We retrospectively examined the course of 25 patients with metastatic RCC who underwent nephrectomy or resection of renal fossa recurrences as an adjunct to intended systemic therapy. Four patients (16%) had complications and there was no perioperative mortality. Of 23 patients who had surgery first, 17 received subsequent systemic therapy and 2 experienced a response. Two patients underwent nephrectomy after achieving a partial response with systemic therapy. Overall, 3 patients (12%) are alive without detectable disease, 8 (32%) are alive with disease, and 14 (56%) are dead of disease, with a median survival of 23.5 months. Nephrectomy for metastatic renal cell carcinoma may be associated with less morbidity and mortality than previously reported. When initial nephrectomy is performed, most patients go on to receive systemic therapy. Within the context of a systemic treatment regimen, nephrectomy continues to play a role in the management of selected patients with metastatic RCC. © Wiley-Liss, Inc.