Bertrand Billemont

Transcription Factor E3 and Transcription Factor EB Renal Cell Carcinomas: Clinical Features, Biological Behavior and Prognostic Factors

PURPOSE Translocation renal cell carcinomas represent a distinct clinicopathological entity. Studying the natural history, biological behavior and potential prognostic factors are crucially warranted. MATERIALS AND METHODS We selected 54 patients with renal cell carcinoma with positive nuclear transcription factor E3 and transcription factor EB expression from the Juvenile RCC Network. Recurrence-free survival and overall survival were assessed. RESULTS Median patient age was 24 years (range 1 to 64) and the male-to-female ratio was 1:1.4. At diagnosis 35 patients (65%) had local disease while 19 (35%) presented with distant metastases. The latter patients were older (median age 36 years) and predominantly male (male-to-female ratio 2) whereas the former group had a median age of 16 years and a male-to-female ratio of 1:2.5. Overall 36 patients underwent complete tumor resection and of these 8 had recurring cancer. On univariate analysis only lymph node involvement and American Joint Committee on Cancer stage were associated with poor recurrence-free survival. When stratified according to lymph node status age 25 years or older was found to predict relapse (p = 0.03). With a median followup of 19.2 months (range 1 to 58) 3-year overall survival was 14.3% in patients with distant metastasis and 70.6% in those without distant metastasis. Distant metastasis developed in the 2 patients with ASPSCR1-TFE3 fusion vs 1 of 11 with other fusion genes. CONCLUSIONS Transcription factor E3 and transcription factor EB renal cell carcinoma display different clinical behavior according to gender and age. Lymph node involvement represents the only factor that predicts recurrence. ASPSCR1-TFE3 might be the most aggressive among the transcription factor E3 fusion genes.

Renal toxicity of targeted therapies.

The use of molecular targeted therapies for the treatment of cancer has increased over the last decade. The benefits of these compounds in terms of efficacy are often relatively modest and counter balanced by the occurrence of significant toxicities. Many of these newer agents used in clinical practice lack specificity and selectivity and have a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined and numerous class-specific toxicities have been described. The kidney is an organ where most of these targeted pathways are expressed. Preclinical data and human renal biopsies have generated an understanding of the mechanisms involved in how targeted agents can cause renal toxicity. This review article discusses the observed nephrotoxicity with this burgeoning class of therapeutics and reviews both the biological reasons for its occurrence and possible ways to prevent significant renal damage.

Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours

BACKGROUND To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). PATIENTS AND METHODS In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks. RESULTS Two grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg. CONCLUSION Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks.

Regression of brain metastases of renal cell carcinoma with antiangiogenic therapy

We report the occurrence of a major volume reduction of cerebelar metastasis after 6 weeks of treatment with the antiangiogenic compound sunitinib [1], an oral inhibitor of several tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR). A 60-year-old female presented in June 2003 with a tumor developed in the left kidney. There were no distant metastases on total body CT-scan. A radical nephrectomy was performed. The pathological exam found a 9 cm clearcell carcinoma (Furhman grade 4). In May 2005, the patient presented difficulties walking. Brain MRI was performed and two focal lesions were found: the right cerebelar lesion was removed and the right frontal lesion was treated by stereotaxic radiation therapy. Bone metastases (right femoral head) were treated by IV bisphosphonates. In October 2006, 40 months later after the initial diagnosis, two new cerebellar lesions were found on a brain MRI. The right frontal lesion had remained stable (Fig. 1a) .We began a treatment with SUNITINIB 50 mg a day given orally over a period of four weeks. MRI evaluation at week 6 showed a significant regression of the two cerebelar lesions associated with necrosis (Fig. 1b). The frontal lesion remained stable. The treatment with SUNITINIB was then continued alternating with 2-weeks rest periods. Sunitib has demonstrated a significant advantage over interferon-a for the treatment of metastatic RCC in a large phase 3 study [2]. There is a lack of information about sunitinib efficacy on brain metastases because patients with brain metastases were systematically excluded from previous studies. Brain metastases are refractory to most conventional chemotherapy regimens given for the treatment of solid tumors [3]. Putative activity of anti-angiogenic therapy on brain metastases is controversial. VEGF and all the mechanisms pulling (entailing) a dysregulation of the local angiogenesis participate in a global increase of the permeability of the BBB [4]. This increase of BBB permeability allows pericytes from peripheral blood to participate in the forming of neo-vessels intended for the tumor irrigation. VEGF also plays a major role in the brain revascularisation after an ischemic accident by increasing the permeability of the BBB, through NO synthetase [5]. Our observations suggest that sunitinib has significant benefit for the treatment of brain metastases. The safety and the efficacy of this strategy should be addressed in a future prospective trial. We thank the Fondation Martine Midy for support of this study.

Axitinib induces paradoxical erythropoietin synthesis in metastatic renal cell carcinoma.

TO THE EDITOR: In a recent letter, Alexandrescu et al reported thoughtful data to address the occurrence of erythrocytosis after treatment with tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib for metastatic cancers. In addition, it has been previously reported that patients with von Hippel-Lindau (VHL) disease treated with semaxanib, a TKI targeting vascular endothelial growth factor receptor 2 (VEGFR-2) and cKit, may experience a supra-additive increase in hematocrit level. Experimental studies showing hepatic erythropoietin (EPO) synthesis related to VEGF blockage could explain this iatrogenic polycythemia. We report a case of polycythemia in a patient treated for metastatic renal cell carcinoma with axitinib, another TKI targeting VEGFR-2. Our findings were the opposite of those in the report by Alexandrescu et al. A 52-year-old man, with no significant past medical history, underwent a right radical nephrectomy for clear renal cell carcinoma. In October 2002, a partial response was achieved with interferon-alfa treatment for lung metastases. In March 2004, the lung metastases progressed in number and size, and the patient subsequently was enrolled onto an axitinib phase II trial. Oral axitinib was administered continuously at the fixed dose of 5 mg twice daily. Minor adverse effects were reported, including diarrhea and asthenia. During the initiation of the second cycle (week 5), we observed an increase in hematocrit, which was confirmed during the subsequent cycles. An isotopic measurement of RBCs confirmed the diagnosis of polycythemia. Treatment was continued for 36 months, with a documented complete response by the third cycle. However, repeated therapeutic phlebotomies for polycythemia remained necessary. There was no alternative cause of polycythemia, including the absence of clinical evidence of VHL disease. In addition, no somatic VHL mutation in the tumor sample was found in polymerase chain reaction analysis. Endogenous EPO blood levels and VEGF-A levels were monitored, and results are listed in Table 1. Tam et al demonstrated that erythropoiesis is regulated by endogenous VEGF. In Tam’s preclinical study, high-grade VEGF blockage induced the repression of adult hepatic EPO production. The absence of VEGFR-2 expression on hepatocytes suggests the participation of liver sinusoidal endothelial cells with homeostatic VEGFR-2– dependant paracrine signaling. In our observation, axitinib treatment was associated with a paradoxical VEGF increase, as reported both in vivo and in a cohort of patients with metastatic gastrointestinal stromal tumors treated with sunitinib, another TKI with VEGFR-2 inhibition. However, we speculate that axitinib mimics VEGF starvation in organs (such as the liver) through VEGFR-2 blockade, and leads to hepatic EPO production. Finally, we cannot exclude an axitinib interaction with the hypoxiainducible factor pathway, which induces nitric oxide release, cutaneous vascular flow modification, and increased systemic EPO expression. Further investigation in clinical trials is warranted to determine the utility of EPO blood level as a marker of VEGF/ VEGFR modulator activity.