Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.

AIM: To investigate the efficacy and safety of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma overexpressing Her2. METHODS: The main eligibility criterion was Her2 overexpression on immunohistochemistry (IHC 2+ or 3+) of primary tumour tissue confirmed by fluorescence in situ hybridisation (FISH). Patients were randomised to Arm A: gemcitabine 1000mg/m(2) (days 1 and 8) plus either cisplatin (70mg/m(2)) or carboplatin (AUC=5) (day 1 every 3 weeks) or Arm B: added trastuzumab (8mg/kg loading dose, then 6 mg/kg every 21 days until progression). The primary end-point was progression-free survival (PFS). RESULTS: Among 563 screened patients, 75 (13.3%) were Her2 positive (IHC 2+/3+ and FISH+) and 61 met all eligibility criteria (median age, 64 years; 54/61 males; 50/61 baseline ECOG-PS 0-1; 11 locally advanced and 50 metastatic). There was no significant difference between Arms A and B in median PFS (10.2 versus 8.2 months, respectively, p=0.689), objective response rate (65.5% versus 53.2%, p=0.39), and median overall survival (15.7 versus 14.1 months, respectively, p=0.684). In an exploratory analysis, trastuzumab-treated patients receiving cisplatin rather than carboplatin-based chemotherapy fared better (PFS: 10.6 versus 8.0; OS: 33.1 versus 9.5 months). Myelosuppression was the main grade 3/4 toxicity. A case of grade 3 cardiotoxicity and one death from febrile neutropenia occurred in arm B. CONCLUSION: The unexpectedly low incidence of Her2 overexpression precluded the detection of a significant difference in efficacy on addition of trastuzumab to platinum-based chemotherapy with gemcitabine. However, the satisfactory tolerance of the combination warrants further studies, especially of the cisplatin-based combination, in well-defined patient subsets.

Prognostic impact of baseline serum C-reactive protein in patients with metastatic renal cell carcinoma (RCC) treated with sunitinib.

OBJECTIVE: To evaluate the impact of baseline serum C-reactive protein (CRP) level on outcome in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib. PATIENTS AND METHODS: We reviewed the charts of patients with mRCC who started sunitinib as a first targeted treatment between 2005 and 2012 in three hospitals in Belgium and France. Collected data included known prognostic factors for mRCC, anatomical location of metastatic sites, response rate (RR), progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 200 eligible patients were identified by retrospective chart review. The median PFS and OS were 12 and 20 months, respectively. We observed a clear impact of baseline CRP levels on outcome: the median PFS was 25 months in the group with baseline CRP ≤5 mg/L and 8 months in the group with baseline CRP >5 mg/L (hazard ratio [HR] 2.48, 95% CI 1.74-3.59). The median OS in each group was 50 vs 12 months, respectively (HR 3.17, 2.20-4.68). In the group with baseline CRP ≤5 mg/L, 61% of patients experienced a partial response compared with 32% of patients in the group with baseline CRP >5 mg/L (difference = 29%, 95% CI 15-42). When adding baseline CRP (with a log transformation) to the six variables of the International Metastatic RCC Database Consortium (IMDC) model in a multivariable Cox regression model, baseline CRP was independently associated with poor PFS (HR for each doubling in CRP level: 1.14, 95% CI 1.03-1.26; P = 0.01) and OS (HR: 1.29, 95% CI 1.16-1.43; P < 0.001). Adding baseline CRP to the model increased the c-statistic of PFS at 5 years from 0.63 (0.59-0.68) to 0.69 (0.65-0.73), and the c-statistic of OS at 5 years from 0.65 (0.60-0.69) to 0.70 (0.66-0.74). Patients with elevated baseline CRP levels had a poor prognosis independent of the IMDC risk group, whereas patients with a low baseline CRP in the IMDC favourable risk group had a very good outcome. CONCLUSION: Baseline serum CRP level is a strong independent variable linked with RR, PFS and OS in patients with mRCC treated with sunitinib.

VEGFR1 single nucleotide polymorphisms associated with outcome in patients with metastatic renal cell carcinoma treated with sunitinib - a multicentric retrospective analysis.

BACKGROUND: There are no validated markers that predict outcome in metastatic renal cell cancer (mRCC) patients treated with sunitinib. Recently, single nucleotide polymorphism (SNP) rs9582036 in VEGFR1 has been proposed as a predictor of progression-free survival (PFS) and overall survival (OS) to bevacizumab in patients with pancreatic cancer and rs7993418 in VEGFR1 as predictor for PFS in mRCC-patients treated with bevacizumab. Here, we aim to study the impact of these SNPs in mRCC patients treated with sunitinib. METHODS: We included patients with mRCC treated in 15 institutions in France and Belgium. Patients received sunitinib as first-line targeted therapy. We assessed response, time-to-tumor progression (TTP), OS, and clinical and biochemical parameters associated with outcome. We genotyped rs9582036 and rs7993418 as well as three other surrounding SNPs in VEGFR1: rs9554320, rs9554316 and rs9513070. Association between SNPs and treatment outcome were studied by univariate analysis and by multivariate Cox regression using relevant clinical factors associated with TTP and OS as covariates. FINDINGS: Ninety-one patients were included. We found that mRCC patients with the CC-variant in rs9582036 in VEGFR1 have a poorer response rate (RR) (0% vs. 46%, p = 0.028), a poorer PFS (10 vs. 18 months, p = 0.033 on univariate and 0.06 on multivariate analysis) and a poorer OS (14 vs. 31 months, p = 0.019 on univariate and 0.008 on multivariate analysis) compared to patients with the AC- and AA-genotypes. mRCC patients with the AA-variant in rs9554320 in VEGFR1 have a poorer PFS (12 vs. 21 months, p = 0.0066 on univariate and 0.005 on multivariate analysis) and a poorer OS (22 vs. 34 months, p = 0.019 on univariate and 0.067 on multivariate analysis) compared to patients with the AC- and CC-genotypes. Interpretation. mRCC patients with the CC-genotype in VEGFR1 SNP rs9582036 have a poorer response rate, PFS and OS when treated with sunitinib. These findings are in agreement with the association of rs9582036 and outcome observed in bevacizumab treated pancreatic cancer patients. Prospective validation of this SNP is warranted.

[Renal carcinoma: point on treatment of brain metastasis]. / Carcinome rénal : état des lieux de la prise en charge des métastases cérébrales.

Prognosis of patients with renal carcinoma has improved since the advent of targeted therapies. These last years, due to the improvement of patients overall survival, the incidence of brain metastasis among renal carcinoma patients has increased. This worsens the prognosis of patients. The present revue aims to do a point on treatment of brain metastasis from renal carcinoma. It will address both locoregional (surgery, radiotherapy and stereotactic radiosurgery) and systemic (targeted therapies) treatments.

Complete remission of pulmonary metastases of Bellini duct carcinoma with cisplatin, gemcitabine and bevacizumab.

BACKGROUND: Bellini carcinomas, rare tumors of kidney, are aggressive and have a poor prognosis. For these cancers, there is no standard treatment regimen and chemotherapy for urothelial cancer is usually used. CASE REPORT: In a 44-year-old man with hematuria, a tumor was diagnosed in the right kidney. After radical nephrectomy, pathologic analysis revealed Bellini carcinoma, staged pT3apN0, Fuhrman grade 3. Secondary pulmonary lesions occur one year later. Chemotherapy (gemcitabine, cisplatin and bevacizumab) was started and after 2 cycles of chemotherapy, Thoracic CT scans showed good response to treatment, with almost complete regression of the pulmonary lesions. After the third cycle of chemotherapy, maintenance treatment with bevacizumab continued. Fifteen months after diagnosing pulmonary metastases, hilar adenopathies progressed slightly and cisplatin-gemcitabine was started again leading to a partial response after five courses. Approximately 2 years after the diagnosis of lung metastases, the patient presented a second relapse, so carboplatin-gemcitabine was started, while bevacizumab was continued. 24 months after the diagnosis of lung metastases, the patient was still alive with controlled disease. CONCLUSIONS: In view of our findings, a prospective multicenter trial with cisplatin, gemcitabine and bevacizumab in patients with metastatic collecting duct carcinoma is planned.

Renal malacoplakia: Case report of a differential diagnosis for renal cell carcinoma.

BACKGROUND: Renal malacoplakia is a very rare chronic inflammatory disorder characterized by specific infiltration of tissue by inflammatory cells, and presents similar radiological characteristics to those of renal cell carcinoma. CASE REPORT: A 54-year old woman, with a 37-year history of smoking, weight loss, anorexia, asthenia, and night sweats, was included in an antiangiogenesis clinical trial. Clinical signs of inflammation were apparent in the right lumbar region without functional limitations. Previous imagery identified a mass infiltrating the lower pole of the right kidney, extending to the psoas, perinephretic region and ganglia. Biological testing revealed inflammation and a urinary tract infection, treated with ciprofloxacin. Based on histology of a renal puncture biopsy, clear cell carcinoma with oxyphilic cells was suspected but not confirmed by immunohistochemistry. Urine analysis was positive for Escherichia Coli. Computed tomodensitometry revealed three masses (right kidney, between right psoas and the inferior vena cava, and right psoas) and a second puncture biopsy confirmed malacoplakia. After successful antibiotherapy, a right-sided nephrectomy was performed. The patient now shows no evidence of disease. CONCLUSIONS: This case underscores the importance of excluding the differential diagnosis of renal malacoplakia before undertaking partial or total nephrectomy and/or initiating neoadjuvant treatment for renal cell carcinoma.

[Bellini tumours]. / La tumeur de Bellini.

In Europe, renal tumours are 7th in frequency of men cancers. They are rare tumours in 10 to 15% of cases. Collecting ducts carcinomas or Bellini tumours, described for the first time in 1949, are a distinct clinical and pathological entity. They represented 1% of epithelial cancers. Nephrectomy is the treatment of localised cancer. Because of lack of recommendations, usually in clinical practice, treatment is similar to urothelial carcinomas treatments (gemcitabine plus platinium). A 72% of response rate of urothelial carcinoma to association of bevacizumab with platinium and gemcitabine 1st line chemotherapy in metastatic setting was reported. More, cases of responses of metastatic Bellini cancers to antiangiogenic treatments associated to chemotherapy were reported these last years. Bellini cancers have a poor prognostic. Unless the fact that this cancer is aggressive, after nephrectomy, cancer specific survival seems not to be different to those of patients with clear cells renal carcinoma and could be related to latest stage of disease in patients. The evaluation of efficacy of association of bevacizumab to chemotherapy is still going on in this association.