Tumor size does not predict risk of metastatic disease or prognosis of small renal cell carcinomas.

PURPOSE: We characterized the clinicopathological features and the prognosis of small solid renal tumors defined as tumors 4 cm or smaller. MATERIALS AND METHODS: We identified 1,208 patients who were treated with nephrectomy at 5 international academic centers for small solid renal tumors. Clinicopathological parameters and outcome data were collected for each patient and analyzed. RESULTS: Of the tumors 88% were renal cell carcinoma and 12% were benign. Of those with renal cell carcinoma 995 (93%) were localized (N0M0) and 72 (7%) presented with metastatic disease. Tumor size did not predict synchronous metastatic disease. The incidence of metastatic disease in the tumor size ranges 0.1 to 1.0, 1.1 to 2.0, 2.1 to 3.0 and 3.1 to 4.0 cm was 7%, 6%, 5% and 8%, respectively (p = 0.322). Survival rates were excellent. The majority of patients who died of renal cell carcinoma (54%) presented with synchronous metastatic disease, but 3% of patients with localized disease also died of renal cell carcinoma. In patients with localized disease there was a 7% chance of recurrence post nephrectomy at 5 years. Progression-free survival (28 months) was better than for patients with metastatic disease having a primary tumor greater than 4 cm (8 months). Tumor size was not retained as an independent prognostic factor of survival in multivariate analyses. The University of California Integrated Staging System and the Karakiewicz nomogram were the best predictors of cancer specific survival for all renal cell carcinoma stages (c-index 0.87). CONCLUSIONS: More than 85% of small solid renal tumors are renal cell carcinoma. The majority of localized small renal tumors can be cured with existing surgical approaches. However, there is a small but not insignificant risk of synchronous and metachronous metastatic disease and cancer associated death. Patients considering experimental therapies such as ablation and surveillance should be aware of this. Tumor size alone is not sufficient to distinguish renal cell carcinoma with benign behavior from aggressive small renal cell carcinoma. Survival of patients with small metastatic renal cell carcinoma is better then expected. The biology of these unique tumors should be further studied.

Pathobiology and prognosis of chromophobe renal cell carcinoma.

OBJECTIVES: To analyze pathobiology and prognosis of chromophobe renal cell carcinoma (CRCC). PATIENTS AND METHODS: We studied 124 patients with CRCC who underwent nephrectomy from 1989 to 2006 at two institutions. Clinicopathological characteristics and survival were compared with 1,693 consecutive patients with clear-cell RCC. RESULTS: Compared with clear cell RCC, patients with CRCC presented with less advanced tumors, but had a higher prevalence of concomitant sarcomatoid features (15% vs. 6%, P < 0.001). Metastatic CRCC showed a high incidence of sarcomatoid features (50%) and a predilection for liver metastases. The 5-year DSS rate for all patients with CRCC was 78% compared with 60% for patients with clear-cell RCC (P = 0.008). When adjusted for metastatic status, this survival difference disappeared. Nonmetastatic RCCs had similar prognosis (P = 0.157), whereas survival of metastatic CRCC was inferior to that of patients with metastatic clear-cell tumors (median: 6 vs. 19 months, P = 0.0095). In multivariate analysis, ECOG PS, symptomatic presentation, T stage, N stage, M stage, nuclear grade, and presence of sarcomatoid features, but not histological sub-type, were independent prognostic factors of DSS. Ten patients received immunotherapy, none of whom were responders. CONCLUSIONS: Compared with clear-cell RCC, patients with CRCC present with less advanced tumors, which lead to better survival rates on the whole. However, adjustment for metastatic status negates this difference. Patients with metastatic CRCC show a high prevalence of sarcomatoid features, predilection for liver metastases, no response to immunotherapy, and exhibit poor prognosis.

Pretreatment with interferon-alpha2a modulates perioperative immunodysfunction in patients with renal cell carcinoma.

INTRODUCTION: Complex perioperative immunodysfunction occurs in patients with renal cell carcinoma undergoing surgery. Here, we report on the effect of preoperative treatment with interferon-alpha2a (IFN-alpha2a). MATERIALS AND METHODS: 30 patients with a renal tumour received preoperative IFN-alpha2a for 6 days beginning 1 week before nephrectomy, 30 did not. Parameters of cellular and humoral immunity were measured in venous blood at various intervals using flow cytometry and ELISA. Endpoints included effects on immune parameters, toxicity, and survival. RESULTS: Toxicity was grade 1 in 52%, 2 in 30%, and 3 in 4%. During IFN-alpha2a administration, leukocytes, monocytes, granulocytes, B-cell marker CD19, activation markers, CD4+CD25+ regulatory T-cells, and vascular endothelial growth factor (VEGF) dropped significantly, but no difference was observed in T-cell and natural killer (NK)-cell markers, and IL-10. Postoperatively, T-cell and activation markers decreased in both groups, but CD4, CD28, IL-6, IL-10, and HLA-DR alterations were significantly less accentuated in patients who had been treated with IFN-alpha2a. After a median follow-up of 23 months, survival did not differ between the groups (p = 0.54). CONCLUSIONS: Perioperative immunodysfunction can be modulated by preoperative administration of IFN- alpha2a. IFN-alpha2a decreased the level of VEGF and CD4+CD25+ regulatory T-cells implicating a potential combination with tyrosine kinase inhibitors and vaccines.

Evaluation of peri-operative peripheral and renal venous levels of pro- and anti-angiogenic factors and their relevance in patients with renal cell carcinoma.

OBJECTIVE: To evaluate peri-operative peripheral and renal venous plasma levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor type BB (PDGF-BB), transforming growth factor (TGF)-beta1, endostatin, and thrombospondin-1 (TSP-1) in relation to pathological variables and prognosis, as pro- and anti-angiogenic factors are important for tumour growth and treatment of patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: The study included 74 consecutive patients with sporadic RCC who had tumour nephrectomy. Peripheral venous blood was drawn 1 day before, immediately and 1, 3 and 5 days after surgery. Renal venous blood was collected in a subgroup of 33 patients during surgery. The variables were analysed using quantitative enzyme-linked immunoassay kits, and associated with pathological variables and disease-specific survival. RESULTS: Soon after surgery, peripheral venous VEGF, PDGF-BB and TGF-beta1 levels were decreased, whereas endostatin levels were significantly increased. Renal venous VEGF, PDGF-BB and TGF-beta1 levels were higher than in the general venous blood pool. Renal venous VEGF levels were correlated with tumour diameter and associated with grade and vascular invasion. After a mean follow-up of 30 months, higher peripheral preoperative, early peripheral postoperative and renal venous VEGF levels were associated with a poorer prognosis. However, in a multivariate analysis only Tumour-Node-Metastasis stage and Eastern Cooperative Oncology Group performance status were independent prognosticators of disease-specific survival. CONCLUSIONS: Circulating pro- and anti-angiogenic factors change early after nephrectomy. VEGF, PDGF-BB and TGF-beta1 are higher in the renal vein than in the general venous blood pool. Higher renal venous and peripheral levels of VEGF might be associated with a poorer prognosis.

Prognostic impact of tumor size on pT2 renal cell carcinoma: an international multicenter experience.

PURPOSE: The current tumor classification for renal cell carcinoma classifies pT2 tumors as larger than 7 cm in greatest dimension and limited to the kidney. We examined the current pT2 tumor classification of renal cell carcinoma and determined whether a tumor size cutoff exists that would improve prognostic accuracy. MATERIALS AND METHODS: We studied 706 patients with pT2 renal cell carcinoma treated with surgical extirpation at 9 international academic centers. Data collected from each patient included age at diagnosis, gender, 2002 TNM (tumor, node, metastasis) stage, tumor size, nuclear grade, performance status, histological subtype and disease specific survival. Disease specific survival was evaluated with univariate and multivariate analysis. RESULTS: Median followup was 52 months. Univariate Cox regression analysis showed a significant association of tumor size with disease specific survival (HR 1.11, p<0.001). An ideal tumor size cutoff of 11 cm was identified, which led to the stratification of 2 groups with respect to disease specific survival (p<0.0001) with 5 and 10-year survival rates of 73% and 65% for pT2 11 cm or less, and 57% and 49% for pT2 larger than 11 cm, respectively. The incidence of metastases was significantly greater in the larger than 11 cm group, while Eastern Cooperative Oncology Group performance status, Fuhrman grade and histological subtype were similar. Multivariate Cox regression analysis retained tumor size as an independent prognostic factor and as the strongest prognostic factor for patients with pT2N0M0 disease. CONCLUSIONS: Our data suggest that the current pT2 classification can be improved by subclassification into pT2a and pT2b based on a tumor size cutoff of 11 cm. Patients in the proposed pT2bN0M0 group are at higher risk for death from renal cell carcinoma and should be considered for adjuvant therapies. External validation is warranted before suggesting change to the TNM classification.

Characterization of prognostic factors and efficacy in a phase-II study with docetaxel and estramustine for advanced hormone refractory prostate cancer.

BACKGROUND: Docetaxel based chemotherapy not only reduces pain and improves quality of life in advanced hormone refractory prostate cancer (HRPC), but it also improves survival. We investigated the combination of docetaxel and estramustine in patients with HRPC regarding efficacy and prognostic parameters. PATIENTS AND METHODS: We conducted a phase-II trial, administering docetaxel (70 mg/m(2) i.v., day 2, every 3 weeks) and estramustine (280 mg 3 times daily p.o., 1 day prior to docetaxel, on 5 consecutive days) to patients with HRPC. Patients were monitored for PSA (prostate-specific antigen) response and toxicity. RESULTS: 62 patients were treated. The median age was 67.5 years, the median PSA was 177.9 ng/ml. The median number of cycles was 6. The median time to progression (TTP) and median survival time were 14 (+/-2) and 24 (+/-5) months, respectively. A = 50% decrease in PSA levels from baseline occurred in 38 (61.3%) patients of whom 25 (40.3%) had a = 75% PSA decrease. The main grade 3-4 hematologic toxicities were neutropenia 34% and anemia 18%. CONCLUSIONS: The combination of docetaxel and estramustine exerts substantial activity in HRPC suggesting an overall survival benefit with manageable toxicity. This trial also demonstrated a survival advantage for patients with early chemotherapeutic intervention. We identified PSA relapse, baseline PSA and hemoglobin as valuable prognostic factors in this setting.

Analysis of the inflammatory network in benign prostate hyperplasia and prostate cancer.

INTRODUCTION: The complexity of acute and chronic inflammatory processes may either lead to benign prostate hyperplasia (BPH) and/or prostate cancer. Obviously, various tissue cells are activated by chemokines via different chemotaxin receptors which then trigger subsequent processes in angiogenesis, cellular growth, and extravasation as well as neoplasia. METHODS: Using the surgically obtained tissue of patients (n = 36) with BPH or prostate carcinoma (PCA), we studied among others the expression of chemokines (Rantes, IL-8), chemotaxin receptors (CXCR-3 and -4, CCR-3, CCR-5), of matrixmetalloproteinases (MMP-2 and 9), of Toll-like (TL) receptors 1, 2, 3, 4, 5, 7, and 9 and of the inducible cyclooxygenase-2 (cox-2) by RT-PCR. Further support for the different properties of tissue from PCA was obtained using two different PCA cell lines (PC3 = androgen resistant cell) or LNCAP cells (androgen sensitive) with emphasis on IL-8, Il-6, and PGE(2) release. Cell lines were stimulated with either the tumor necrosis factor-alpha (TNF-alpha) and lipopolysacharide (LPS) over time. In addition to cytokine release, the quantification of mRNA by lightcycler for cox-2, IL-6, and IL-8 was performed on these cell lines. RESULTS: Remarkable differences in expression were obtained by RT-PCR when BPH tissue versus PCA was analyzed. Expression of CXCR-1 after incubation with LPS and TNF-alpha showed time-dependent differences for androgen-sensitive LNCAP as compared to androgen-resistant PC-3 cells. TNF-alpha incubation leads to a time-dependent induction of cox-2 expression unlike to activation with LPS. Differences with regard to cox-2, IL-6, and IL-8 expression were seen by quantitative lightcycler analysis. Significant differences were also observed when TL receptors 4, 5, 7, and 9 were analyzed which were significantly expressed in BPH- as compared to PCA-tissue. CONCLUSIONS: Our data clearly demonstrate that various inflammatory and cell biological cascades are involved which either lead to BPH or can be linked to the development of PCA. The exact cell biological mechanisms may provide novel therapeutic options in the treatment of both diseases.

Loss of heterozygosity on chromosome 5p13-12 predicts adverse prognosis in advanced bladder cancer independent of tumor stage and grade.

PURPOSE: The individual prognosis in patients with bladder cancer is only partially predicted by tumor stage and grade. Various molecular markers have been shown to correlate with disease progression and prognosis but few add some predictive capacity beyond that offered by standard clinical and pathological parameters. MATERIALS AND METHODS: A total of 191 urothelial carcinomas from 157 patients were analyzed. Paired normal and tumor cells were microdissected by manual and microbeam-microdissection of membrane mounted native tissue, and analyzed for loss of heterozygosity (LOH) at a critical region of LOH on chromosome 5p13-12 that is involved in bladder cancer progression. LOH data were correlated with progression-free and tumor specific survival by multivariate analysis. RESULTS: Informativity of the assay was 60.7%. Log rank analysis of 100 evaluable patients showed a progression-free survival benefit without LOH at 5p13-12 of more than 3 years (p <0.01). Mean followup was 36 months. Multivariate analysis revealed that this benefit was not predicted by tumor stage and grade alone in advanced disease (stages T3/4 and/or N+/M+, stages III/IV). CONCLUSIONS: LOH at the critical region on chromosome 5p13-12 is a molecular marker of adverse prognosis in advanced bladder carcinoma independent of tumor stage and grade.