Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is no consensus on the detailed surveillance of renal cell cancer (RCC) patients after radical resection of the kidney. Where relapse is unlikely, one reasonable option would be to confine investigations to chest X-ray and abdominal ultrasound -- carried out at 3-month intervals during the first year, but less frequently thereafter. These investigations could be supplemented by annual computerised tomography (CT) of the chest and abdomen. Where risk is intermediate or high, more frequent CT should be undertaken, taking into account the risks of repeated radiation exposure. Since the emergence of new and more effective treatments for metastatic disease, follow-up has tended to become more challenging not only with respect to disease assessment but also for evaluation of toxicity [Level 5]. The diagnostic work-up in metastatic RCC should include a history, physical examination and comprehensive blood screen. In addition, patients to be treated with targeted agents should have a thyroid function test. In patients with a relevant clinical history or who are otherwise at risk, cardiac function should be assessed, and this is also advisable in asymptomatic patients [Level 2b]. Nephrectomy is an important component of the multimodality treatment of mRCC. This procedure induces spontaneous regression of metastases in a small number of patients [Level 4]. More generally, it improves the survival of patients who subsequently receive immunotherapy [Level 1]. However, it is not yet known whether this benefit is also seen in patients treated with targeted agents [Level 2b]. Certain patients with metastases (even at multiple sites) have lesions that are resectable. Surgery is potentially curative in these cases and can be undertaken prior to use of cytokines or targeted agents [Level 2b]. Vaccine-based therapies may have potential, particularly when disease burden is low [Level 4]. The outcome of ongoing trials is awaited. Metastatic RCC responds, albeit at a low rate, to cytokines. These agents may be helpful for a subgroup of patients. However, for the great majority, and certainly for those with intermediate- or poor-risk disease, cytokines confer no benefit [Level 1b]. Choice of initial medical management in patients with metastatic clear-cell RCC should be guided by the pivotal, randomised studies. On the evidence available, the first-line therapy in patients with good- or intermediate-risk mRCC should be either sunitinib [Level 1b] or bevacizumab plus interferon [Level 1a]. In patients ineligible for sunitinib or bevacizumab plus interferon, sorafenib is an option, as is high-dose interleukin 2 if performance status is sufficiently good [Level 2b]. In patients with poor prognosis (as defined in the pivotal trial), temsirolimus is recommended [Level 1b]. In this group, sunitinib could be an alternative [Level 2b]. The role of targeted agents in the treatment of patients with RCC of non-clear-cell histologies remains to be established. In cytokine refractory patients, sorafenib is recommended [Level 1b]. Everolimus is the agent of choice when patients have progressed on a tyrosine kinase inhibitor [Level 1b].
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PMID:EORTC-GU group expert opinion on metastatic renal cell cancer. 1915 61

Phaeochromocytoma and paraganglioma are rare neuroendocrine tumours (NETS). They may be benign or malignant but the pathological distinction is mainly made when metastases are present. Available treatments in the form of surgery, chemotherapy, and radionuclide therapy may improve symptoms and biochemical markers, but the results for the control of tumour bulk are less favourable. Furthermore, responses to treatment are frequently short-lived. This short review outlines the main molecular and histological features of malignant phaeochromocytoma and the difficulties in differentiating between benign and malignant disease. We list current therapies used for malignant pheochromocytoma; however, these generally achieve relatively low success rates. Hence, there is a need for new and more effective therapies. In vitro studies have implicated the PI3/Akt/mTOR pathway in the pathogenesis of malignant NETS, including phaeochromocytoma. Everolimus (RAD001, Novartis UK) is a compound that inhibits mTOR (mammalian Target Of Rapamycin) signalling. We have used RAD001 in four patients with progressive malignant paraganglioma/phaeochromocytoma in addition to other therapies (with institutional approval for compassionate use), and evaluated the effects of this treatment. We outline these four cases and review the theoretical background for this therapy, although the outcomes were relatively disappointing.
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PMID:Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001). 1942 40

Insulinomas are the most common, functioning, pancreatic neuroendocrine tumours. The great majority (>90%) of insulinomas are nonmetastatic at presentation and can be surgically cured. The <10% patients with distant (liver-bone) metastases have a median survival of < 2 years. Everolimus and sunitinib have been recently introduced as targeted therapies for metastatic pancreatic neuroendocrine tumours. An additional advantage of everolimus in the treatment of patients with metastatic insulinomas is its capability to increase blood glucose levels. Peptide receptor radiotherapy using radiolabelled somatostatin analogues has also been shown to be successful in controlling tumour growth of metastatic pancreatic neuroendocrine tumours. In patients with metastatic insulinomas, this therapeutic modality was also effective in controlling hypoglycaemia, even in the presence of tumour regrowth. With the introduction of these new therapeutic modalities, the therapeutic arsenal for the 'tailor-made' approach of patients with metastatic insulinomas is further expanded.
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PMID:New therapeutic options for metastatic malignant insulinomas. 2164 88

Although thymic epithelial tumors (TETs) are rare in the general population, they represent the most frequently diagnosed primary malignant tumor of the anterior mediastinum. Unlike localized disease, metastatic disease is invariably fatal. While several chemotherapy agents have proven to be effective in TETs, somatostatin analogs are the only targeted agents with an established role in this disease. Everolimus is an mTOR inhibitor with multiple application in oncology. In this report, we show for the first time that everolimus was effective in two heavily pretreated patients with advanced TETs, with a progression-free survival longer than 1 year and minimal toxicity.
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PMID:Everolimus plus long-acting somatostatin analogs in thymic epithelial malignancies. 2278 79

Treatment options for patients with high-grade pancreatic neuroendocrine tumors (pNET) are limited, especially for those with progressive disease and for those who experience treatment failure. Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has been approved for the treatment of patients with low- or intermediate-grade advanced pNET. In the randomized phase III RADIANT-3 study in patients with low- or intermediate-grade advanced pNET, everolimus significantly increased progression-free survival (PFS) and decreased the relative risk for disease progression by 65% over placebo. This case report describes a heavily pretreated patient with high-grade pNET and liver and peritoneal metastases who achieved prolonged PFS, clinically relevant partial radiologic tumor response, and resolution of constitutional symptoms with improvement in Karnofsky performance status while receiving a combination of everolimus and octreotide long-acting repeatable (LAR). Radiologic and clinical responses were maintained for 19 months, with minimal toxicity over the course of treatment. This case supports the findings that the combination of everolimus plus octreotide LAR may be considered for use in patients with high-grade pNET and progressive disease. Although behavior and aggressiveness are different between low- or intermediate-grade and high-grade pNET, some high-grade pNET may express mTOR; hence, everolimus should be considered in a clinical trial.
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PMID:Prolonged clinical benefit of everolimus therapy in the management of high-grade pancreatic neuroendocrine carcinoma. 2401 85

Antiresorptive agent-related osteonecrosis of the jaw results in appreciable morbidity in affected patients. Nowadays many physicians prescribe an antiangiogenic agent for the management of malignant metastases. Everolimus is a serine-threonine kinase that acts as an inhibitor of mammalian target of rapamycin, which results in reduced growth of cells, angiogenesis, and survival of cells. We report the first case to our knowledge of osteonecrosis of the jaw that seemed to result from the additive effect of everolimus.
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PMID:Osteonecrosis of the jaw related to everolimus: a case report. 2409 95

The systemic management of patients with pancreatic neuroendocrine tumors includes chemotherapy and targeted agents such as everolimus and sunitinib. Which treatment to favor in a particular patient is not known. The most commonly used chemotherapy agents are streptozocin and temozolamide, often prescribed in combination with fluoropyrimidines. A potential biomarker for selection of temozolomide-based chemotherapy is O-6-methylguanine-DNA-methyltrasferase expression. Chemotherapy yields higher response rates and may be preferable in patients with higher-grade tumors and those who are symptomatic. The mammalian target of rapamycin inhibitor everolimus has shown improvement in progression-free survival (PFS) in a robust, well-conducted phase III study. Everolimus, however, can induce limiting toxicities that may result in treatment discontinuation and does not improve survival. However, the objective response rate is very low. Sunitinib, likewise, increases PFS but the data comes from a smaller trial which was terminated early. Sunitinib displays a different toxicity profile and is associated with a trend towards improved overall survival. It is clear that biomarkers to properly select the most effective agents in an individual patient are needed.
Cancer Metastasis Rev 2014 Mar
PMID:Pancreatic NETs: where do we stand now? 2445 57

The inhibitors of mammalian target of rapamycin (mTOR) have documented antitumor activity via disruption of various signaling pathways leading to impaired cellular growth, proliferation, and survival. In preclinical studies, mTOR inhibitors use in combination with hormonal therapy has shown promising results in overcoming endocrine resistance in breast cancer cells. The role of everolimus in breast cancer was established in the Breast Cancer Trial of Oral Everolimus-2 (BOLERO-2) trial in combination with exemestane for patients with advanced metastatic hormone receptor-positive (HR+) breast cancer, who relapsed after initial hormonal manipulation. The study met its primary endpoint of significant improvement in progression free survival (PFS) with a median time to progression of 6.9 months in the combination group versus 2.8 months in exemestane group. Favorable improvements in PFS were reported across all patient subgroups regardless of age, Eastern Cooperative Oncology Group performance status, number of prior therapies, and presence of visceral metastases. Adverse events were mostly mild to moderate in severity and consistent with the known safety profile of everolimus. Major toxicities reported include stomatitis, non-infectious pneumonitis, and hyperglycemia. The purpose of this review is to discuss the role of everolimus as a valuable component in advanced metastatic breast cancer and delineate current strategies to prevent and manage the most common toxicities associated with this combination regimen.
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PMID:Targeting the mammalian target of rapamycin pathway with everolimus: implications for the management of metastatic breast cancer. 2496 67

Skeletal metastases are an incurable complication afflicting the majority of patients who die from advanced breast cancer. They are most often osteolytic, characterized by net bone destruction and suppressed new bone formation. Life expectancy from first diagnosis of breast cancer bone metastases is several years, during which time skeletal-related events - including pain, fracture, hypercalcemia, and spinal cord compression - significantly degrade quality of life. The bone marrow niche can also confer hormonal and chemo-resistance. Most treatments for skeletal metastases target bone-destroying osteoclasts and are palliative. Recent results from the Breast cancer trials of Oral Everolimus-2 trial suggest that agents such as the mammalian target of rapamycin inhibitor everolimus may have efficacy against breast cancer bone metastases in part via stimulating osteoblasts as well as by inhibiting tumor growth. Selective estrogen receptor modulators similarly inhibit growth of estrogen receptor-positive breast cancers while having positive effects on the skeleton. This review discusses the future role of bone-anabolic agents for the specific treatment of osteolytic breast cancer metastases. Agents with both anti-tumor and bone-anabolic actions have been tested in the setting of multiple myeloma, a hematological malignancy that causes severe osteolytic bone loss and suppression of osteoblastic new bone formation. Stimulation of osteoblast activity inhibits multiple myeloma growth - a strategy that might decrease breast cancer burden in osteolytic bone metastases. Proteasome inhibitors (bortezomib and carfilzomib) inhibit the growth of myeloma directly and are anabolic for bone. Drugs with limited anti-tumor activity but which are anabolic for bone include intermittent parathyroid hormone and antibodies that neutralize the WNT inhibitors DKK1 and sclerostin, as well as the activin A blocker sotatercept and the osteoporosis drug strontium ranelate. Transforming growth factor-beta inhibitors have little tumor antiproliferative activity but block breast cancer production of osteolytic factors and are also anabolic for bone. Some of these treatments are already in clinical trials. This review provides an overview of agents with bone-anabolic properties, which may have utility in the treatment of breast cancer metastatic to the skeleton.
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PMID:Role of bone-anabolic agents in the treatment of breast cancer bone metastases. 2575 19

Sequential endocrine treatments are recommended for estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER 2) negative metastatic breast cancers except in the case of symptomatic visceral disease. However, patients who suffer from disease progression while receiving a non-steroidal aromatase inhibitor (NSAI) have a very poor prognosis with standard endocrine therapy alone. Recently, based onthe results of the BOLERO 2 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus, combined with exemestane, a steroidal aromatase inhibitor, has been approved in Europe and the US for patients suffering from ER positive HER2 negative advanced breast cancer previously treated by a NSAI. The median progression-free survival (PFS) increased from 3.2 to 7.8 months in patients receiving everolimus and exemestane compared to placebo and exemestane. The magnitude of benefit was consistent in all pre-specified subgroups. Side effects were manageable and the quality of life was at least maintained. Everolimus has also beenrecently studied in HER2 positive locally advanced or metastatic disease in heavily pretreated patients (BOLERO 3 trial). This trial met its primary endpoint. The median PFS was increased in patients receiving trastuzumab, vinorelbine and everolimus compared to patients receiving trastuzumab, vinorelbine and placebo. We review pharmacological data and side effects of the drug. We also review the most important clinical trials leading to reimbursement of everolimus in metastatic breast cancer.
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PMID:[The drug of the month: everolimus (Afinitor) for the treatment of metastatic breast cancer]. 2579 60


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