Guidelines on bladder cancer

OBJECTIVES: On behalf of the European Association of Urology (EAU) guidelines for diagnosis, therapy and follow-up of bladder cancer patients were established. Criteria for recommendations were evidence based, and included aspects of cost-effectiveness and clinical feasibility. METHOD: A systematic literature research using Medline Services was conducted. References were weighted by a panel of experts. RESULTS: TNM 1997 classification and WHO grading 1998 are recommended. Recommendations are developed for diagnosis for bladder cancer in general, treatment of superficial and infiltrative bladder cancer, and follow-up after different types of treatment modalities, such as intravesical instillations, radical cystectomy, urinary diversions, radiotherapy and chemotherapy.     

Guidelines on testicular cancer

OBJECTIVE: To up-date the 2001 version of the EAU testicular cancer guidelines. METHODS: A non-structured literature review until January 2005 using the MEDLINE database has been performed. Literature has been classified according to evidence-based medicine levels. RESULTS: Testicular cancer is a highly curable disease. Excellent cure rates have been achieved by standardization of treatment, interdisciplinary management, and tremendous success in performing clinical trials. Currently, the aims of testicular cancer treatment are as follows: for patients with low-stage disease, a reduction in treatment is proposed to improve long-term toxicity in these patients with unaltered life expectancy; for about 10% of patients with advanced disease and poor prognosis, intensification of treatment (including high-dose chemotherapy and new drugs as well as aggressive surgical approaches) is being investigated to improve long-term cure rates. CONCLUSION: Guidelines will improve clinical practice only if they are regularly updated. This update presents the state-of-the-art management of testicular cancer patients in 2005.     

Chemotherapy in metastatic renal cell cancer

Currently, there is no standard treatment for patients with advanced renal cell carcinoma (RCC) who do not respond to or progress after transient remission to first-line immunotherapy. At the end of the 1990s, no single chemotherapeutic drug, alone or in combination with interleukin-2 (IL-2) or interferon-alfa (IFN), had shown activity beyond the one expected by immunotherapy alone. New drugs on the market such as the pyrimidine analog gemcitabine or taxane-based chemotherapeutics may show promising tumor activity in combination with targeted therapy, but this has to be substantiated in upcoming trials. There is a great need to develop effective systemic therapy for advanced MRCC and to evaluate the efficacy of new drugs in clinical trials.     

Preoperative imaging in renal cell cancer

Renal cell cancer (RCC) represents the fifth most common cancer in men, with a rising incidence. Radical cancer surgery remains the only curative treatment in localized and advanced RCC. Therefore, preoperative imaging is most important for the planning of the surgical approach and strategy. The aim of any preoperative imaging in RCC is to differentiate benign from malignant lesions, to adequately assess tumor size, localization and organ confinement, to identify lymph node and/or visceral metastases, and to reliably predict the presence and extent of any thrombus of the vena cava. It is our aim to review the current status of preoperative imaging modalities in RCC. Computed tomography (CT) remains the most appropriate imaging modality to differentiate benign from malignant lesions. Although RCC can appear as iso-, hyper- or hypodense lesions on native CT scans, it usually demonstrates a significant contrast enhancement of about 115 HU and intratumoral areas of necrosis following the intravenous application of contrast medium. Benign masses such as renal oncocytoma are most often homogenous lesions exhibiting hypodensity compared to the normal renal parenchyma following the i.v. application of contrast dye. CT accurately predicts the tumor size with only a 0.5 cm difference as compared to the pathological size of the lesion. The identification of lymph node metastases still remains a problem since the limiting size is 4 mm and CT will result in a false negative rate of about 10%, especially in the presence of micrometastases; the false positive rate of 3–43% is mainly due to reactive hyperplasia. New technologies, such as the multidetector CT with thin collimation and multiplanar reformatting, might result in a diagnostic improvement. The involvement of the adrenal gland can be accurately predicted by CT scans or MRI, allowing an adrenal sparing approach in the case of unsuspicious findings. The detection of visceral metastases appears to be crucial since it has been shown that even patients with metastatic disease might benefit from radical nephrectomy followed by systemic immunotherapy in the case of a good performance status, and the presence of lymph node and pulmonary metastases only. Involvement of the renal vein and the vena cava with tumor thrombus formation will change the surgical strategy. Preoperatively, the presence and the cranial extent of the thrombus need to be known in order to plan the surgical approach. With regard to the extent of renal vein thrombi, a three phase helical CT scan is most appropriate; for vena caval thrombi only a MRI examination is able to accurately identify any infra- or suprahepatic as well as intracardial extension of the thrombus. The identification of multifocal lesions remains another unsolved problem in preoperative imaging techniques for RCC. Compared to the pathohistological analysis of nephrectomy specimens, neither ultrasonography, color duplex sonography nor regular CT scans are able to identify multifocal lesions with acceptable sensitivity and specificity. The evaluation of unenhanced CT scans together with the enhanced corticomedullary and the nephrogenic phase result in a 100% sensitivity and might represent a valuable option. Angiography has basically been abandoned from the armory of routine imaging techniques. It has, however, a current role in terms of the embolization of large tumors to reduce intraoperative blood loss, and in the palliative management of pain and bleeding due to RCC not amenable to surgery. Finally, we present a diagnostic algorithm for the most informative imaging techniques in the evaluation of RCC.Written on behalf of the European Society of Oncological Urology     

Surgery for metastatic renal cell cancer

Renal cell carcinoma (RCC) often presents in its metastatic form, or progresses after curative treatment. While the management of metastatic RCC has historically been mainly surgical, contemporary approaches often incorporate systemic immunotherapy. This review examines the current indications and scope of surgical treatment of patients with metastatic RCC. Surgery is sometimes indicated for symptom palliation at either the primary or secondary sites. However, other less invasive therapies may be equally effective, and should be considered carefully. Cytoreductive surgery prior to immunotherapy appears to confer a survival advantage, but only selected patients are suitable for this treatment regimen. Primary immunotherapy followed by surgical removal of the tumour in partial responders is an alternative treatment strategy, which has not yet been evaluated as in randomized trials. As immunotherapy develops further, the precise timing and role of surgery in multimodality treatment will need to be carefully evaluated. Occasionally, the complete surgical excision of metastases, and the primary tumour, if present, is feasible and this may prolong survival. Empirically, it would seem that such patients should also be treated with adjuvant immunotherapy, as eventual relapse is frequent. Surgery with the aim of inducing spontaneous tumour regression is not justifiable, given the rarity of this phenomenon.     

Cytokine therapy in renal cell cancer

Despite extensive investigations with many different treatment modalities, metastatic renal cell carcinoma (RCC) remains a disease highly resistant to systemic therapy. The outlook for patients with metastatic RCC is poor, with a 5-year survival rate of less than 10%. Late relapses after nephrectomy, prolonged stable disease in the absence of systemic therapy, and rare spontaneous regression are clinical observations that suggest host immune mechanisms could be important in regulating tumor growth. Interleukin-2 (IL-2) and interferon- (IFN-) have been extensively studied in advanced RCC with responses in the 10 to 20% range. Two randomized trials suggest that treatment with IFN- compared with vinblastine or medroxyprogesterone results in a small improvement in survival. Prolonged responses with high-dose IL-2 is significant but is accompanied by formidable toxicity. Although the combination of IFN- and IL-2 compared with monotherapy with IFN- or IL-2 increases the response proportion, no improvement in survival could be demonstrated in a recent randomized trial. In addition, three randomized trials showed no survival benefit associated with IFN- therapy given as adjuvant therapy following complete resection of locally advanced RCC. Small numbers of patients exhibit complete or partial responses to IFN- and/or IL-2, but most patients do not respond and there are few long-term survivors. Clinical investigation of new agents and treatment programs to identify improved antitumor activity against metastases remain the highest priorities in this refractory disease.     

Heteromorphic grade of renal cell cancer

The present study demonstrates by means of histopathologic analysis that most of the renal adenocarcinomas are microscopically heterogeneous--named by authors as heteromorphic. This heteromorphism means the mixture of different cell types, histological patterns and fields of tumor with different nuclear atypia. 300 surgical specimens of renal cell cancer (RCC) were reclassified retrospectively. The histologic classification was as follows: 1. Nuclear atypia (nuclear grading according to Skinner); 2. Histological structure (compact, tubular, papillary, cystic); 3. Tumor cell types (clear, chromophobe, chromophilic basophilic, chromophilic eosinophilic). Homogeneous tumors consist of the three categories of this basic classifications. Heteromorphic tumors have combinations the three categories: different cell types (clear and granular) and/or histological elements (tubulo-papillary) and/or nuclear structure. Heteromorphism of RCC can be graded as: G-I: homogeneous structure (three patterns, one-one pattern of the three categories; G-II: 3 + 1 patterns.... G-III: 3 + 2 patterns.... G-IV: 3 + 3 or more patterns of the classification given above. This grading system is recommended for the heteromorphism of renal adenocarcinomas.     

In vitro cytotoxicity studies in bladder and renal cell cancer.

Attempts to obtain cell lines from bladder and renal cancer patients were done in 42 patients, with success to obtain primary cultures in 25 and long-term cultures in 7. Cell-mediated and humoral immunity was demonstrated in both tumors by microcytotoxicity in vitro. No cytotoxicity could be deomonstrated against target cells obtained from metastatic cancer tissue. Abrogation of cell-mediated immunity by serum factors was demonstrated. No recurrence was obtained in the group of patients showing positive lymphocytotoxicity during follow-up.     

Division of the left renal vein. Guidelines and consequences.

Ligation and division of the left renal vein is a reasonable safe procedure in selected patients when exposure of the perirenal aorta is crucial. This manipulation is possible because of extensive venous collateralization from the left kidney in man. Measurement of the venous stump pressure before ligation is recommended to assess the degree of collateralization, and the upper limit within which the vein may be divided safely is probably in the neighborhood of 60 cm of water. Reanastomosis of the vein is not necessary for preservation of renal function, although transient left renal dysfunction may occur. Examination of the urine and careful monitoring of renal function should be routine in the postoperative period. Intravenous urography and left spermatic venography later in the postoperative course can indicate the ultimate degree of function of the left kidney and the pathways of venous collateralization. Preservation of normal function and venous architecture at the renal hilum should be the rule.     

Incisional hernia following hand-assisted laparoscopic surgery for renal cell cancer.

OBJECTIVES: For renal cell cancer, the hand-assisted laparoscopic approach provides several advantages while maintaining equal advantages with regards to patient recovery. We offer our experience with laparoscopic hand-assisted radical nephrectomy and the incidence of ventral wall hernia. METHODS: Between February 1999 and July 2002, we performed 50 laparoscopic hand-assisted radical nephrectomies. A midline or a muscle splitting right lower quadrant incision was used depending on the side of the tumor. Hand-port incisions were all between 7 cm and 8 cm and closed with #1 polydioxanone sulfate suture in a running fashion. Three (6%) patients developed hand-port incisional hernias. All hernias occurred in midline hand-port sites. The average body weight of those who developed an incisional hernia was 137 kg. Although the cause of incisional hernia is multifactorial, we believe that obesity plays a significant role. The technical limitations involved in closing a short, deep ventral incision combined with the earlier return to activity of laparoscopy patients put this patient population at significant risk. CONCLUSION: We now perform an interrupted closure with nonabsorbable suture for the hand-assist incision and limited activity for 4 weeks to 6 weeks post procedure in high-risk patients. We have had no further wound hernias since adopting these changes.     

Treatment of metastatic renal cell carcinoma and renal pelvic cancer

A better understanding of the molecular biology of renal cell carcinoma (RCC) and the emergence of molecular targeted drugs have revolutionized the treatment for patients with metastatic RCC (mRCC). Multi-targeted tyrosine kinase inhibitors (sorafenib and sunitinib) and mammalian target of rapamycin inhibitors (temsirolimus and everolimus) have recently shown superiority over interferon-α or placebo. However, while the molecular targeted drugs have demonstrated encouraging results, these drugs have also sometimes induced unexpected adverse events. Control of adverse events is important to obtain the maximum effectiveness and sustain quality of life for patients. Because renal pelvic cancer has many similarities in pathogenesis with urinary bladder cancer, the same chemotherapeutic regimen is often proposed for patients with metastatic renal pelvic cancer. Combined chemotherapy with gemcitabine and cisplatin is now widely considered to be first-line chemotherapy against these metastatic diseases; however, there are still unresolved problems with this treatment, including the limited survival benefit. To select new therapeutic modalities, a more profound understanding of the molecular biology of renal pelvic cancer is crucial. The purpose of this review is to summarize the current evidence supporting the role and activities of new chemotherapeutic agents and to reveal potential future directions in the management of mRCC and renal pelvic cancer.     

Current insights in renal cell cancer pathology

In recent years molecular biologists and pathologists have described new entities of renal cell cancer (RCC) with a totally different morphology and biology among the histotypes of renal carcinoma, but always referring to the same renal cancer disease. The evidence of a distinct biological behavior and long-term prognosis among these makes the correct pathological diagnosis of renal cancer critically important for the clinician. Advances in understanding of the pathogenesis, behavior, and importance of prognostic factors for RCC have paved the way for a revision of its classification and staging. We reviewed the role of histological classification, microscopic tumor necrosis, microscopic venous invasion, lymph node involvement and, particularly, pathological stage. In our series of patients who underwent renal surgery for neoplasm, a retrospective study established the predictive role of tumor size on recurrence rate, compared with other known prognostic factors, and we conclude that histological grade, pathological stage and tumor size remain relevant prognosticators in early stage RCC patients. In order to optimize the management of patients with RCC it is necessary to develop an interdisciplinary approach (surgeon, radiologist, pathologist, oncologist) and find new prognostic parameters at molecular and cellular levels. Many efforts are ongoing to integrate molecular data (from tissue microarrays) and clinical data (traditional prognosticators) into a molecular integrated staging system. In the postgenomic era, new tumor-associated antigens and molecules can be identified at the protein level using proteomics, providing a major opportunity for screening and finding novel targets that are the basis of new emerging therapies for RCC.     

Incidental detection of renal cell cancer]

In the present study, a comparative analysis of clinical-prognostic factors in symptomatic and incidentally found renal cell carcinomas is evaluated. A total of 141 patients with renal cell carcinoma were analyzed according to the TNMG system and involvement of the adrenals. More than 50% of surgically treated renal cell carcinomas are found incidentally. Prognostically, this group has advantageous factors.     

Treating renal cell cancer in the elderly

OBJECTIVE: To determine whether age and comorbidity are predictors of peri-operative complications and/or mortality in surgery for renal cell cancer in a retrospective study of patients aged >75 years. PATIENTS AND METHODS: Between 1993 and 2003, 1023 radical nephrectomies or nephron-sparing surgery for renal cell cancer were performed in 115 consecutive patients aged > or = 75 years and in 908 consecutive patients aged <75 years. The preoperative American Society of Anesthesiologists (ASA) score was used for risk stratification. Operative mortality and early complications (within 30 days of surgery) were reviewed. RESULTS: The younger patients had significantly lower ASA scores than the older patients. There were early complications in 31 of the 908 younger patients (3.4%) and in two of the 115 older patients (1.7%). Peri-operative mortality was higher in the older than in the younger patients (1.7% vs 0.3%; P = 0.29). Overall morbidity and mortality correlated with increasing ASA score but not with age (P < 0.05). CONCLUSIONS: Despite greater comorbidity in older patients, their morbidity and mortality did not differ significantly from that of younger patients. Advanced age alone should thus not be used as a criterion to deny surgery for renal cell carcinoma. However, older patients should be counselled regarding a tendency for increased comorbidity-related peri-operative mortality.     

Cytokine-based therapy for metastatic renal cell cancer

The use of recombinant gene technology to produce commercially available amounts of cytokines heralded an era of clinical applications of immunotherapy. Although the response rates to cytokine therapies are modest and sometimes occur at the expense of great cost and toxicity, they are proof of the principal that even large tumor burdens can be overcome by purely immune modulation. The interleukins and the interferons have been used in various phases of clinical trials in RCC. The maturation and final results of phase III trials are needed to guide clinical practice. In the meantime, the knowledge gained clinically and in the laboratory should lead to continued improvements and outcomes in immunotherapy for RCC.     

Expression of major histocompatibility complex antigens and intercellular adhesion molecule-1 (ICAM-1) on renal cell cancer. De novo expression and modulation by cytokines on renal cell cancer cell lines]

Major histocompatibility complex (MHC) antigens and intercellular adhesion molecule-1 (ICAM-1) play important roles in immune response. In order to investigate the association between renal cell cancer (RCC) and host's immune system, expression of MHC antigens and ICAM-1 was examined on RCC. Immunohistochemical analysis revealed a positive correlation between the expression of MHC antigens and ICAM-1. In general, tumor with higher degree of mononuclear cell infiltration expressed MHC antigens and ICAM-1 more frequently and intensely. Among cytokines which were reported to be potent inducers of ICAM-1 on malignant melanoma cell lines, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha augmented the expression of ICAM-1 on ACHN cells whereas ICAM-1 and class I antigens on KRC/Y cells. IFN-alpha enhanced MHC class I antigens but not ICAM-1. Class II antigen expression of both cell lines was augmented by only IFN-gamma. These results suggest that cytokines which could be produced by tumor-infiltrating mononuclear cells, especially IFN-gamma and TNF-alpha, might modulate expression of MHC antigens and ICAM-1, and influence host immune response against RCC.