Evaluation of axitinib to downstage cT2a renal tumours and allow partial nephrectomy: a phase II study.

OBJECTIVE: To evaluate the ability of neoadjuvant axitinib to reduce the size of T2 renal cell carcinoma (RCC) for shifting from a radical nephrectomy (RN) to a partial nephrectomy (PN) indication, offering preservation of renal function. PATIENTS AND METHODS: Patients with cT2aN0NxM0 clear-cell RCC, considered not suitable for PN, were enrolled in a prospective, multicentre, phase II trial (AXIPAN). Axitinib 5 mg, and up to 7-10 mg, was administered twice daily, for 2-6 months before surgery, depending on the radiological response. The primary outcome was the number of patients receiving PN for a tumour <7 cm in size after neoadjuvant axitinib. RESULTS: Eighteen patients were enrolled. The median (range) tumour size and RENAL nephrometry score were 76.5  (70-98) mm and 11 (7-11), respectively. After axitinib neoadjuvant treatment, 16 tumours decreased in diameter, with a median size reduction of 17% (64.0 vs 76.5 mm; P < 0.001). The primary outcome was considered achieved in 12 patients who underwent PN for tumours <7 cm. Sixteen patients underwent PN. Axitinib was tolerated in the present study, as has been previously shown in the metastatic setting. Five patients had grade 3 adverse events. Five patients experienced Clavien III-V post-surgery complications. At 2-year follow-up, six patients had metastatic progression, and two had a recurrence. CONCLUSION: Neoadjuvant axitinib in cT2 ccRCC is feasible and, even with a modest decrease in size, allowed a tumour shrinkage <7 cm in 12 cases; however, PN procedures remained complex, requiring surgical expertise with possible morbidity.

Adherence and patients' attitudes to oral anticancer drugs: a prospective series of 201 patients focusing on targeted therapies.

OBJECTIVES: Patient adherence is a challenge in oncology and hematology practice. Hormone therapy data in breast cancer suggest insufficient adherence and poor persistence. Limited data are available for targeted therapies (TT) including tyrosine kinase and mammalian target of rapamycin inhibitors. METHODS: We performed a prospective survey using a 15-item questionnaire in patients with solid tumors and hematologic malignancies receiving oral anticancer therapy. Treatment duration, setting (adjuvant vs. metastatic), cancer type, age, and comedication were recorded. RESULTS: 201 patients (median age 65.5 years) participated, 102 with TT and 99 with hormone therapy or chemotherapy (HC). The median time of drug intake was 11.0 months. Written information was more frequently given to TT patients (68.6 vs. 23.2%, p < 0.0001). TT and HC patients showed equal adherence to therapy (72.5 vs. 69.6%, p = n.s.) despite TT patients experiencing more side effects (p < 0.0001) and taking more concomitant oral medication (p = 0.0042). Forgotten doses were the leading cause of nonadherence in HC patients (83%, as compared to 54% in the TT group), whereas dose reduction by the patient was higher in the TT group (32 vs. 17%). CONCLUSIONS: Despite advances in providing information to patients leading to better adherence among TT patients, efforts towards better patient education are warranted including dedicated staff for monitoring outpatient anticancer oral therapy.

New strategies for medical management of castration-resistant prostate cancer.

Although advanced prostate cancer patients respond very well to front-line androgen deprivation, failure to hormonal therapy most often occurs after a median time of 18-24 months. The care of castration-resistant prostate cancer (CRPC) has significantly evolved over the past decade, with the onset of first-line therapy with docetaxel. Although numerous therapy schedules have been investigated alongside docetaxel, in either first-line or salvage therapy, results were dismal. However, CRPC chemotherapy is currently evolving, with, on the one hand, new agents targeting androgen metabolism and, on the other hand, significant progress in chemotherapy drugs, particularly for second-line therapy. The aim of the present review is to describe the current treatments for CRPC chemotherapy alongside their challengers that might shortly become new standards. In this article, we discuss the most recent data from clinical trials to provide the reader with a comprehensive, state-of-the-art overview of CRPC chemotherapy and hormonal therapy.

[Management of side-effects of targeted therapies in renal cancer: cardiovascular side-effects]. / Gestion des effets secondaires des thérapies ciblées dans le cancer du rein : effets secondaires cardiovasculaires.

Several types of cardiovascular complications can occur during treatment with targeted therapies: heart failure, QTc lengthening, arterial and venous thrombosis. A clinical examination, ECG and cardiac ultrasound are essential before starting treatment with targeted therapy. Patients with no medical history, who are asymptomatic with a normal ECG and a left ventricular ejection fraction (LVEF) greater than 50% can begin molecular targeted therapy (MTT). Patients must be assessed by a cardiologist before the introduction of MTT if they have a history of ischemic or valvular heart disease, heart failure, atrial fibrillation, stroke, transient ischemic attack, or ECG anomalies (Q wave, supraventricular arrhythmia, QT greater than 500ms), or LVEF less than 50%. In patients who are symptomatic (dyspnoea, angina, syncope, embolism etc.) and/or present with a modification to the ECG or alteration to the LVEF, MTT must be stopped and reassessment by a cardiologist is indicated. The restarting of MTT following a cardiovascular complication must be subject to a multidisciplinary discussion taking into account the severity of the cardiac event, its reversibility with cardiac treatment, life expectancy of the patient as well as the expected efficacy of the drug.

Identification of novel truncated androgen receptor (AR) mutants including unreported pre-mRNA splicing variants in the 22Rv1 hormone-refractory prostate cancer (PCa) cell line.

Advanced prostate cancer (PCa) has emerged as a public health concern due to population aging. Although androgen deprivation has proven efficacy in this condition, most advanced PCa patients will have to face failure of androgen deprivation as a treatment. Mutations in the androgen receptor (AR) from tumor cells have been shown to induce androgen independency both in PCa cell lines and in the clinic. We have investigated the molecular events leading to androgen independency in the 22Rv1 cell line, a commonly used preclinical model of PCa. Besides AR mutants that have been described so far, including nonsense mutations, recent data have focused on AR pre-mRNA aberrant splicing as a new mechanism leading to constitutively active truncated AR variants. In this article, we describe two novel variants arising from aberrant splicing of AR pre-mRNA, characterized by long mRNA transcripts that encode truncated, constitutively active proteins. We also describe several new nonsense mutants that share ligand independency and transcriptional activity. Finally, we show that alongside these mutants, 22Rv1 cells also express a mutant AR lacking exon 3 tandem duplication, a major feature of this cell line. By describing unreported AR mutants in the 22Rv1 cell line, our data emphasize the complexity and heterogeneity of molecular events that occur in preclinical models, and supposedly in the clinic. Future work on the 22Rv1 cell line should take into account the concomitant expression of various AR mutants.

Adriamycin, cisplatin, ifosfamide and paclitaxel combination as front-line chemotherapy for locally advanced and metastatic angiosarcoma. Analysis of three case reports and review of the literature.

Angiosarcoma represents 1 to 2% of soft tissue tumors. It originates from endothelial cells of small blood vessels and may affect a variety of organs, including the retroperitoneum, skeletal muscle, subcutis, liver, heart and breast. The outcome of angiosarcoma is poor for those patients in whom aggressive surgery cannot be considered. Chemotherapy, generally consisting of the combination of anthracyclines and ifosfamide, has little, but consistent effect. We report three cases of angiosarcoma in which first-line chemotherapy with adriamycin 40 mg/m2 day 1, ifosfamide 3 g/m2 day 1-2, cisplatin 35 mg/m2 day 1-2 and paclitaxel 175 mg/m2 day 3 led to clinically meaningful responses. The clinical relevance of incorporating paclitaxel in conventional soft tissue chemotherapy schedules in the light of both literature data and our experience is discussed. We emphasize the need for designing trials specifically dedicated to angiosarcomas, as this rare and severe condition may be a target for new antiangiogenic drugs.

Prospective Evaluation of the Impact of Antiangiogenic Treatment on Cognitive Functions in Metastatic Renal Cancer.

BACKGROUND: Little is known about the cognitive effects of antiangiogenic therapies (AATs) in metastatic renal cell carcinoma (mRCC) and their relation with fatigue. OBJECTIVE: To evaluate the impact of AATs on cognition and its connection with fatigue and quality of life (QoL) in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS: This prospective study enrolled 75 patients starting AAT as first or second line for mRCC and assessed them at 3 mo (n=58) and 6 mo (n=50). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed objective cognitive decline with a neuropsychological battery of tests and cognitive complaint, fatigue, and QoL with validated self-reported questionnaires using the Fisher exact test, Wilcoxon test, and Spearman correlation coefficient. RESULTS AND LIMITATIONS: A decline of cognitive functions was observed in 18 patients (31%) including 13 without cognitive impairment at baseline. The score of fatigue was increased in all patients except one. A relationship between cognitive complaints and fatigue was observed (p<0.05) but not with objective cognitive decline. Cognitive complaints and fatigue had a significant impact on most of the domains of QoL (p<0.01). A positive correlation was found between fatigue and inflammatory markers but not with cognition. The main limitation of this study is the absence of a control group. CONCLUSIONS: AAT induced cognitive decline in patients with mRCC independently of fatigue. These side effects affecting QoL should be better assessed in clinical trials and taken into account in routine practice. PATIENT SUMMARY: Fatigue is a well-known effect of antiangiogenic therapies (AATs) of cancer. The study performed in patients with treated metastatic renal cancer shows a decline of cognitive functions induced by AATs, such as information-processing speed or working memory, in a third of patients, independently of fatigue. Patients on AATs should be informed of these possible adverse effects.

A yeast-based functional assay for the detection of the mutant androgen receptor in prostate cancer.

OBJECTIVE: Mutations in the ligand-binding domain of the human androgen receptor (AR) figure among the ways used by prostate adenocarcinoma (PCa) cells to escape androgen dependence. These mutations may broaden the specificity and/or affinity of the AR to other hormones, resulting in inappropriate receptor activation and thus affecting the PCa response to physiological stimuli and hormonal therapies. DESIGN: In order to clarify the impact of these mutations on disease progression and treatment, we have developed a yeast-based functional assay that allows the detection of mutant ARs and the analysis of their transactivation capacities in response to different ligands. METHODS: AR cDNA was directly cloned into an expression vector in a yeast strain that carries a reporter gene (ADE2) linked to an androgen-dependent promoter. The expression of the ADE2 gene and consequently the yeast cell growth in a selective medium depleted in adenine depends on the specificity of the AR for the ligand added to the medium. RESULTS: By analysing the transactivation capacities of different AR molecules in response to a broad range of steroid and non-steroid ligands, we have demonstrated that this assay can discriminate among wild-type AR, T877A, C685Y and L701H mutant ARs and that at least 1% of mutant ARs could be detected when mutant and wild-type ARs were mixed at the cDNA level. CONCLUSIONS: The data presented here show that this simple AR assay is convenient for the routine detection of mutant ARs in PCa and is also suitable to evaluate the antagonist activities of anti-androgen molecules.

[Saccharomyces cerevisiae: an efficient tool and model system for anticancer research]. / La levure Saccharomyces cerevisiae: un modèle et un outil performant pour la recherche en oncologie.

The major mechanisms of cell function, such as metabolic pathways, DNA repair and cell cycle control have been conserved throughout DNA evolution from yeast to human, despite the former lacks cancer-related features. The S. cerevisiae genome has been entirely sequenced and not only reveals sequence similarity to the human, but a number of proteins also have a conserved function. Owing to its genetic features, yeast has been used as a remarkable model and tool to study important enzymes that are also targets for anticancer drugs, particularly in the field of the pyrimidine salvage pathway. In this review, we describe the recent developments in using yeast for anticancer research, focusing on metabolic pathway analysis, systematic drugs screening with yeast mutants or prospects in gene therapy with yeast enzymes.

mTOR inhibitors in advanced renal cell carcinomas: from biology to clinical practice.

To date, oral everolimus is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with vascular endothelial growth factor-targeted therapy, and intravenous temsirolimus for the first-line treatment of patients with poor prognosis metastatic renal cell carcinoma. However, some factors could guide the treatment choice aiming to individualize a treatment plan. Besides the crucial issue of treatment efficacy, other factors are to be considered such as disease status, histological subtype, extent of the disease, patient-specific factors, and agent-specific factors. All of these considerations have to stay in the frame of guideline recommendations which represent evidence-based medicine. The purpose of this article is to summarize the main pharmacological and pharmacokinetic characteristics of mTOR inhibitors, and to define targeted populations according to prognostic indexes.

Complete remission with tyrosine kinase inhibitors in renal cell carcinoma.

PURPOSE: Complete remission (CR) is uncommon during treatment for metastatic renal cell carcinoma (mRCC) with tyrosine kinase inhibitors (TKIs), but it may occur in some patients. It remains a matter of debate whether therapy should be continued after CR. METHODS: A multicenter, retrospective analysis of a series of patients with mRCC who obtained CR during treatment with TKIs (sunitinib or sorafenib), either alone or with local treatment (surgery, radiotherapy, or radiofrequency ablation), was performed. RESULTS: CR was identified in 64 patients; 36 patients had received TKI treatment alone and 28 had also received local treatment. Most patients had clear cell histology (60 of 64 patients), and all had undergone previous nephrectomy. The majority of patients were favorable or intermediate risk; however, three patients were poor risk. Most patients developed CR during sunitinib treatment (59 of 64 patients). Among the 36 patients who achieved CR with TKI alone, eight continued TKI treatment after CR, whereas 28 stopped treatment. Seventeen patients who stopped treatment (61%) are still in CR, with a median follow-up of 255 days. Among the 28 patients in CR after TKI plus local treatment, 25 patients stopped treatment, and 12 of these patients (48%) are still in CR, with a median follow-up of 322 days. CONCLUSION: CR can occur after TKI treatment alone or when combined with local treatment. CR was observed at every metastatic site and in every prognostic group.

Successful treatment of a granulocytic sarcoma of the uterine cervix in complete remission at six-year follow-up.

Background. Localized granulocytic sarcoma of the uterine cervix in the absence of acute myelogenous leukemia (AML) at presentation is very rare, its diagnosis is often delayed, and its prognosis almost always ominous evolving into refractory AML. Case. We present the case of a 30-year-old woman with vaginal bleeding and a large cervical mass. Further evaluation confirmed the presence of a granulocytic sarcoma but failed to reveal systemic involvement. Results. AML type chemotherapy followed by radiotherapy of the uterus led to a durable complete remission. She remains in complete remission six years after diagnosis. Conclusion. Granulocytic sarcoma of the cervix is a rare entity for which early intensive AML type therapy is effective.

Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d'Etudes des Tumeurs Uro-Génitales) study.

PURPOSE: Collecting duct carcinoma of the kidney is a rare and aggressive neoplasm of the distal collecting tubules for which there is no established treatment. Since the histology of collecting duct carcinoma is similar to that of urothelial carcinoma, the standard chemotherapy regimen defined by a gemcitabine and platinum salts combination was prospectively investigated in patients with metastatic collecting duct carcinoma. MATERIALS AND METHODS: A total of 23 patients with metastatic collecting duct carcinoma with no prior systemic chemotherapy were treated with 1,250 mg/m(2) gemcitabine on days 1 and 8 plus 70 mg/m(2) cisplatin or carboplatin (AUC 5) in patients with renal insufficiency on day 1. The drugs were repeated every 21 days for 6 cycles according to toxicity and efficacy. The objective response rate was the primary end point. RESULTS: There were 1 complete and 5 partial responses for an objective response rate of 26% (95% CI 8 to 44). Median progression-free and overall survival was 7.1 (95% CI 3 to 11.3) and 10.5 months (95% CI 3.8 to 17.1), respectively. Toxicity was mainly hematological with grade 3-4 neutropenia and thrombocytopenia in 52% and 43% of patients, respectively. The severity of granulocytopenia and the number of metastatic sites were associated with overall survival on univariate and multivariate analyses. CONCLUSIONS: To our knowledge this is the first prospective, multicenter, phase II study showing that the platinum salts combination is an active and safe regimen as first line treatment in patients with metastatic collecting duct carcinoma. This platinum based chemotherapy should be considered the standard regimen in these patients.

Phase I/II trial of temsirolimus combined with interferon alfa for advanced renal cell carcinoma.

PURPOSE: Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC. PATIENTS AND METHODS: Patients were enrolled onto a multicenter, ascending-dose study of temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information. RESULTS: Seventy-one patients were entered to receive one of six dose levels. The recommended dose was temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hypophosphatemia, asthenia, anemia, and hypertriglyceridemia for all patients and those who received the recommended dose. Among patients who received the recommended dose (n = 39), 8% achieved partial response and 36% had stable disease for at least 24 weeks. Median progression-free survival for all patients in the study was 9.1 months. CONCLUSION: The combination of temsirolimus and IFN has an acceptable safety profile and displays antitumor activity in patients with advanced RCC. Temsirolimus 15 mg plus IFN 6 MU is the recommended dose for evaluation in a randomized phase III study.

Diffuse primary angiosarcoma of the pleura: a case report and review of the literature.

Primary pleural angiosarcoma is an extremely rare tumor. We report the case of a patient who presented with recurrent massive bilateral hemothoraxes. Although thoracoscopy was performed, biopsy samples of the pleura were inconclusive. The delayed onset of skin metastases led to the diagnosis of angiosarcoma, however the patient died from pleuropulmonary progression before treatment could be started. We review the literature of primary pleuropulmonary angiosarcoma and discuss its treatment modalities.

Constitutive activation of the androgen receptor by a point mutation in the hinge region: a new mechanism for androgen-independent growth in prostate cancer.

Androgen receptor (AR) mutations that modify both the ligand binding and the transactivation capacities of the AR represent one of the mechanisms involved in the transition of prostate cancer (PCa) from androgen-dependent to androgen-independent growth. We use a yeast-based functional assay to detect and analyze mutant ARs in PCa. We report the detection of 2 different mutant ARs within the same metastatic tumour sample harvested in a patient with advanced PCa who had escaped androgen deprivation. Concomitantly to the widely described T877A mutant AR, we identified an additional double mutant AR harboring the nonsense mutation Q640Stop just downstream the DNA binding domain together with the T877A point mutation. This type of mutation, which leads to a c-terminal truncated AR, has not been described yet in PCa. Using luciferase reporter assays we demonstrated that this truncated AR exhibited constitutive transactivation properties. In conclusion, our data suggest that mutation-induced constitutive activation of the AR could be a mechanism used by PCa cells to escape androgen deprivation.