Didier Jacqmin

The Epidemiology of Renal Cell Carcinoma

CONTEXT Kidney cancer is among the 10 most frequently occurring cancers in Western communities. Globally, about 270 000 cases of kidney cancer are diagnosed yearly and 116 000 people die from the disease. Approximately 90% of all kidney cancers are renal cell carcinomas (RCC). OBJECTIVE The causes of RCC are not completely known. We have reviewed known aetiologic factors. EVIDENCE ACQUISITION The data provided in the current review are based on a thorough review of available original and review articles on RCC epidemiology with a systemic literature search using Medline. EVIDENCE SYNTHESIS Smoking, overweight and obesity, and germline mutations in specific genes are established risk factors for RCC. Hypertension and advanced kidney disease, which makes dialysis necessary, also increase RCC risk. Specific dietary habits and occupational exposure to specific carcinogens are suspected risk factors, but results in the literature are inconclusive. Alcohol consumption seems to have a protective effect for reasons yet unknown. Hardly any information is available for some factors that may have a high a priori role in the causation of RCC, such as salt consumption. CONCLUSIONS Large collaborative studies with uniform data collection seem to be necessary to elucidate a complete list of established risk factors of RCC. This is necessary to make successful prevention possible for a disease that is diagnosed frequently in a stage where curative treatment is not possible anymore.

Radical nephrectomy with and without lymph-node dissection: final results of European Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881.

BACKGROUND Until now the therapeutic value of lymphadenectomy for renal-cell carcinoma has remained controversial. Several studies attempting to solve this controversy have been published, but none of them were set up as prospective randomized trials. OBJECTIVE To assess whether a complete lymph-node dissection in conjunction with a radical nephrectomy for renal-cell cancer is more effective than a radical nephrectomy alone. DESIGN, SETTING, AND PARTICIPANTS In 1988, the European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group started a randomized phase 3 trial comparing radical nephrectomy with a complete lymphadenectomy to radical nephrectomy alone. After the renal-cell carcinoma was judged to be N0M0 and resectable, patients were randomly selected prior to surgery to undergo either a radical nephrectomy with a complete lymph-node dissection or to undergo a radical nephrectomy alone. Postoperatively all patients were followed for progression of disease and mortality. INTERVENTION All patients underwent a radical nephrectomy with or without a complete lymph-node dissection. MEASUREMENTS All patients were postoperatively evaluated for time-to-progression, overall survival, and progression-free survival. Time-to-event curves were estimated based on the Kaplan-Meier method and compared using a two-sided log-rank test. RESULTS AND LIMITATIONS Of the 772 patients selected for randomization, 40 were not eligible for the study. 383 patients were randomly selected to receive a complete lymph-node dissection together with a radical nephrectomy, and 389 patients were randomly selected to undergo a radical nephrectomy alone. The complication rate did not differ significantly between the two groups. Complete lymph-node dissections in 346 patients revealed an absence of lymph-node metastases in 332 patients. The study revealed no significant differences in overall survival, time to progression of disease, or progression-free survival between the two study groups. CONCLUSIONS This study shows that, after proper preoperative staging, the incidence of unsuspected lymph-node metastases is low (4.0%) and that, notwithstanding a possible relationship to this low incidence rate, no survival advantage of a complete lymph-node dissection in conjunction with a radical nephrectomy could be demonstrated.

Photodynamic Diagnosis in Non–Muscle-Invasive Bladder Cancer: A Systematic Review and Cumulative Analysis of Prospective Studies

CONTEXT The clinical benefit of photodynamic diagnosis (PDD) with 5-aminolevulinic acid or hexaminolevulinate in addition to white-light cystoscopy (WLC) in bladder cancer has been discussed controversially. OBJECTIVE To assess in a systematic review the effect of PDD in addition to WLC on (1) the diagnosis and (2) the therapeutic outcome of primary or recurrent non-muscle-invasive bladder cancer investigated by cystoscopy or transurethral resection. EVIDENCE ACQUISITION An electronic database search of Medline, Embase, the Cochrane Library, and CancerLit was undertaken, plus hand searching of relevant congress abstracts and urologic journals. Trials were included if they prospectively compared WLC with PDD in bladder cancer. The review process followed the guidelines of the Cochrane Collaboration. Two reviewers evaluated independently both trial eligibility and methodological quality and data extraction. EVIDENCE SYNTHESIS The primary end point of diagnostic accuracy was additional detection rate. The primary end points of therapeutic outcome were residual tumour at second resection and recurrence-free survival (RFS). Seventeen trials were identified. Twelve diagnostic trials used WLC and PDD with the same patients. Seven reported results for the subgroup of patients with carcinoma in situ (CIS). Five randomised trials studied therapeutic outcome. The results were combined in random effects meta-analyses if end points, designs, and populations were comparable. Twenty percent (95% confidence interval [CI], 8-35) more tumour-positive patients were detected with PDD in all patients with non-muscle-invasive tumours and 39% (CI, 23-57) more when only CIS was analysed. Heterogeneity was present among diagnostic studies even when the subgroup of patients with CIS was investigated. Residual tumour was significantly less often found after PDD (odds ratio: 0.28; 95% CI, 0.15-0.52; p<0.0001). RFS was higher at 12 and 24 mo in the PDD groups than in the WLC-only groups. The combined p value of log-rank tests of RFS was statistically significant (0.00002). CONCLUSIONS PDD detects more bladder tumour-positive patients, especially more with CIS, than WLC. More patients have a complete resection and a longer RFS when diagnosed with PDD.

The Expanding Role of Partial Nephrectomy: A Critical Analysis of Indications, Results, and Complications

CONTEXT The gained expertise in the surgical technique of partial nephrectomy (PN) with excellent oncologic outcome and reduced morbidity has contributed to more frequent use of PN in many centres of reference, and the recent evidence favouring PN over radical nephrectomy (RN) in the prevention of chronic kidney disease and possibly linking it to a better overall survival (OS) will constitute a strong argument for wider use of PN. OBJECTIVE To objectively analyse the advantages of PN over RN and to evaluate the risk-benefit ratio of expanding the indications of PN T1b renal cortical tumours. EVIDENCE ACQUISITION Literature searches on English-language publications were performed using the National Library of Medicine database. The queries included the keywords partial nephrectomy and nephron sparing surgery. Eight hundred four references were scrutinised, and 175 publications were identified and reviewed. Sixty-nine articles were selected for this review. These references formed the basis for this analysis and were selected based on their relevance and the importance of their content. EVIDENCE SYNTHESIS The use of PN has been steadily increasing, particularly in tertiary care centres. This trend is now strengthened by evidence supporting the role of PN in reducing the risk of chronic kidney disease in patients with renal masses < or =4 cm. A wider use of PN for larger tumours, granted technical feasibility, is supported by the preliminary evidence, suggesting an OS advantage favouring PN over RN. However, the potential for selection bias and residual confounding factors may contribute to the observed difference. In the carefully selected patients with tumours >4 cm, PN obtained equivalent oncologic outcome to that achieved after RN. Although higher morbidity rates were seen after PN, the complication type and severity were not prohibitive. CONCLUSIONS The available evidence supports elective PN as the standard surgical treatment for renal cortical tumours < or =4 cm. For larger tumours, PN has demonstrated feasibility and oncologic safety in the carefully selected patient population studied.

Prognostic Value of Renal Vein and Inferior Vena Cava Involvement in Renal Cell Carcinoma

BACKGROUND The prognostic significance of venous tumor thrombus extension in patients with renal cell carcinoma (RCC) is a matter of many controversies in the current literature. OBJECTIVE To evaluate the prognostic role of inferior vena cava (IVC) involvement in a large series of pT3b and pT3c RCCs. DESIGN, SETTING, AND PARTICIPANTS A total of 1192 patients from 13 European institutions underwent a radical nephrectomy for pT3b and pT3c RCC between 1982 and 2003. The patients were evaluated in a retrospective manner. Age, gender, clinical symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, TNM stage, tumor size, adrenal invasion, perinephric fat invasion, histological type, and Fuhrman grade were reviewed. The log-rank and Cox uni- and multivariate regression analyses were used to evaluate prognostic factors for overall survival. MEASUREMENTS Overall survival and prognostic factors for overall survival in patients with RCC extending to the renal vein (RV) or to the IVC. RESULTS AND LIMITATIONS The median follow-up was 61.4 mo (56.3-66.5 mo). The mean age was 63.2 yr. The mean tumor size was 8.9 cm. Group 1 (Gr 1) included 933 patients with a renal vein tumor thrombus (78.3%), Group 2 (Gr 2) included 196 patients with a subdiaphragmatic IVC tumor thrombus (16.4%), and Group 3 (Gr 3) included 63 patients with a supradiaphragmatic IVC tumor thrombus (5.3%). Median survival was 52 mo for Gr 1, 25.8 mo for Gr 2, and 18 mo for Gr 3. In univariate analysis, Gr 1 had a significantly better overall survival than Gr 2 (p<0.001) and Gr 3 (p<or=0.001). No significant difference in survival was noted between Gr 2 and Gr 3 (p=0.613). Prognostic factors for overall survival in univariate analysis were clinical symptoms (p<0.001), tumor size (p<0.001), perinephric fat invasion (p<0.001), Fuhrman grade (p<0.001), histological type (p=0.021), lymph node invasion (p<0.001), and distant metastasis (p<0.001). Independent prognostic factors in multivariate analysis were tumor size (p=0.013), perinephric fat invasion (p=0.003), lymph node invasion (p<0.001), distant metastasis (p<0.001), and IVC invasion (p=0.008). CONCLUSIONS The level of tumor thrombus in the IVC does not significantly affect long-term overall survival in patients with renal cell carcinoma. The overall survival was statistically different for patients with a tumor thrombus in the RV compared to those with IVC involvement. This has to be considered for the next revision of the TNM system, and the pT3b and pT3c stages have to be redesigned.

Hexaminolevulinate-Guided Fluorescence Cystoscopy in the Diagnosis and Follow-Up of Patients with Non–Muscle-Invasive Bladder Cancer: Review of the Evidence and Recommendations

CONTEXT Compared with standard white-light cystoscopy, photodynamic diagnosis with blue light and the photosensitiser hexaminolevulinate has been shown to improve the visualisation of bladder tumours, reduce residual tumour rates by at least 20%, and improve recurrence-free survival. There is currently no overall European consensus outlining specifically where hexaminolevulinate is or is not indicated. OBJECTIVE Our aim was to define specific indications for hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and management of non-muscle-invasive bladder cancer (NMIBC). EVIDENCE ACQUISITION A European expert panel was convened to review the evidence for hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and management of NMIBC (identified through a PubMed MESH search) and available guidelines from across Europe. On the basis of this information and drawing on the extensive clinical experience of the panel, specific indications for the technique were then identified through discussion. EVIDENCE SYNTHESIS The panel recommends that hexaminolevulinate-guided fluorescence cystoscopy be used to aid diagnosis at initial transurethral resection following suspicion of bladder cancer and in patients with positive urine cytology but negative white-light cystoscopy for the assessment of tumour recurrences in patients not previously assessed with hexaminolevulinate, in the initial follow-up of patients with carcinoma in situ (CIS) or multifocal tumours, and as a teaching tool. The panel does not currently recommend the use of hexaminolevulinate-guided fluorescence cystoscopy in patients for whom cystectomy is indicated or for use in the outpatient setting with flexible cystoscopy. CONCLUSIONS Evidence is available to support the use of hexaminolevulinate-guided fluorescence cystoscopy in a range of indications, as endorsed by an expert panel.

The phosphoinositide 3-kinase/Akt pathway: a new target in human renal cell carcinoma therapy.

Metastatic renal cell carcinoma is resistant to current therapies. The phosphoinositide 3-kinase (PI3K)/Akt signaling cascade induces cell growth, cell transformation, and neovascularization. We evaluated whether targeting this pathway could be of therapeutic value against human renal cell carcinoma. The activation of the PI3K/Akt pathway and its role in renal cell carcinoma progression was evaluated in vitro in seven human cell lines by Western blot, cell counting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, terminal deoxyribonucleotide transferase-mediated nick-end labeling assays, and fluorescence-activated cell sorting analysis, using two PI3K inhibitors, LY294002 and wortmannin, as well as by transfection with various Akt constructs and through Akt knockdown by small interfering RNA (siRNA). In vivo nude mice bearing human renal cell carcinoma tumor xenografts were treated with LY294002 (75 mg/kg/wk, 4 weeks, i.p.). Tumor growth was measured and tumors were subjected to Western blot and immunohistochemical analysis. Akt was constitutively activated in all cell lines. Constitutive phosphorylation of glycogen synthase kinase-3 (GSK-3) was observed in all cell lines, whereas forkhead transcription factor and mammalian target of rapamycin, although expressed, were not constitutively phosphorylated. Exposure to LY294002 or wortmannin decreased Akt activation and GSK-3 phosphorylation and reduced cell growth by up to 70% through induction of cell apoptosis. These effects were confirmed by transfection experiments with Akt constructs or Akt siRNA. Importantly, LY294002 induced up to 50% tumor regression in mice through tumor cell apoptosis. Tumor neovascularization was significantly increased by LY294002 treatment. Blood chemistries showed no adverse effects of the treatment. Our results suggest an important role of PI3K/Akt inhibitors as a potentially useful treatment for patients with renal cell carcinoma.

Superselective Endo-Vascular Treatment of Renal Vascular Lesions

Embolization with platinum micro-coils delivered through the Tracker-18 micro-catheter was performed in 6 patients when peripheral selective catheterization with standard angiographic catheters was not possible. The patients had a total of 7 peripheral renal vascular lesions (3 arteriovenous fistulas, 2 false aneurysms, 1 direct vascular trauma and 1 arteriovenous malformation). In all patients we initially used platinum micro-coils as the embolic agent. Two patients required repeat embolization with glue. Endo-vascular treatment was technically successful in all cases and no complications were encountered. There was no renal parenchyma infarction in 3 patients and small peripheral infarctions (10 to 15% of the renal parenchyma) occurred in 3. Super selective endo-vascular treatment with a variable stiffness catheter is safe and useful technique when classical methods of embolization are not possible.

Assessment of painful ureterohydronephrosis during pregnancy by MR urography

The purpose of this study was to assess the value of the fast imaging sequence called RARE (rapid acquisition with relaxation enhancement) MR urography (or RMU) In pregnant women with painful ureterohydronephrosis. A total of 17 pregnant women with an acute flank pain were examined with RMU. Results were compared with those of US, X-rays and the evolution of symptoms. The gold standard techniques used to evaluate the results of MR urography were US when it showed the entire dilated urinary tract and the nature of the obstruction (9 cases), limited intravenous urography (IVU) when performed (3 cases) or endoscopic procedure (5 cases). The accuracy of RMU in the detection of urinary tract dilatation and the localization of the level of obstruction was excellent (sensitivity 100% in our series). The determination of the type of obstruction, intrinsic vs extrinsic, was always exact. The RMU technique alone could not specify the exact nature of the obstruction. The RMU technique is able to differentiate a physiological from a pathological ureterohydronephrosis during pregnancy. It could be considered as the procedure of choice when US failed to establish the differential diagnosis.

Natural History of Residual Renal Stone Fragments after ESWL

Objective: After extracorporeal shock wave lithotripsy (ESWL), residual fragments (RF) 4 mm or less are usually considered as clinically insignificant. We retrospectively reviewed the natural history and clinical significance of 97 noninfected and isolated RF (4 mm or less) observed 3 months after the last ESWL session on renal tomography.Patients and Methods: They represented 83 among 1,216 patients treated by ESWL over a 9–year period (1989–1997). These RF were mostly localized in the inferior calyx (62%). Median follow–up was 40.6 months (range: 7–96 months). Renal tomography was always performed at the end of follow–up.Results: Stone–free status, or a decreased, stable or increased amount of residual stone occurred in 27 (33%), 1 (1%), 24 (29%) and 31 (37%) of the 83 patients, respectively. During this study, 18 patients (22%) were proposed for a complementary treatment related to a size increase of the residual fragments (13 ESWL, 1 retrograde endoscopy, 3 percutaneous nephrolithotomy, and 1 polar inferior nephrectomy).Conclusion: The term clinically insignificant should not be employed to describe RF after ESWL. Efforts should be performed to obtain true stone–free status after ESWL.