Pre-treatment global quality of health predicts progression free survival in metastatic kidney cancer patients treated with sorafenib or sunitinib.

PURPOSE: Our goal was to prospectively evaluate self-reported quality-of-life (QoL) during second-line therapy in 51 consecutive patients with cytokine-refractory kidney cancer treated with sorafenib or sunitinib. METHODS: QoL was assessed by the EORTC QoL questionnaire QLQ-C30 at baseline and at weeks 4, 6, 10, 12 and 16. RESULTS: Global QoL deteriorated significantly during the first 4 weeks of treatment (P < 0.0001). Patients experienced a reduction of their role, cognitive, and social function (all P < 0.0001). In addition, fatigue (P < 0.0001), nausea/vomiting (P = 0.003), and pain (P < 0.0001) as well as dyspnoea (P < 0.0001), insomnia (P = 0.026), appetite loss (P = 0.013), and diarrhoea (P < 0.0001) increased significantly. After 16 weeks, fatigue (P < 0.0001), pain (P = 0.015), appetite loss (P = 0.002) and diarrhoea (P = 0.038) were still influenced by the therapy, while all functional scales recovered. Global QoL at baseline was predictive of overall response (P = 0.006) and progression free survival (PFS) (P < 0.0001). A better physical function at baseline, a better ECOG performance status, and a low risk profile according to MSKCC risk groups correlated with a longer PFS (all P < 0.0001). No significant differences regarding QoL were found between sorafenib and sunitinib during the study period. CONCLUSIONS: Second-line therapy with sorafenib or sunitinib does not adversely affect patients global QoL after 16 weeks of treatment. Evaluation of baseline QoL can help to further stratify patients into risk groups predicting overall response and PFS.

Clinical staging error in prostate cancer: localization and relevance of undetected tumour areas.

OBJECTIVE: To describe the localization and to assess the clinical implications of areas of undetected prostate cancer in radical prostatectomy (RP) specimens, focusing on patients with unilaterally negative preoperative biopsy cores. PATIENTS AND METHODS: The study included 149 of 559 consecutive patients (26.7%) who had RP for prostate cancer. Unilateral prostate cancer was diagnosed from prostate biopsies, taken by several physicians, but > or = pT2c disease was present in the RP specimen. The prostate was dissected by standardized transversal cuts and tumour areas were mapped by one genitourinary pathologist. To estimate the tumour size and location, areas of prostate cancer were transferred to a digital grid database representing the prostate by 794 units. RESULTS: The most frequent location of undetected prostate cancer was in the dorsalateral region and in the apex of the prostate. The mean tumour volume of the false-negative lobe was significantly lower than contralaterally (18.9 vs 47.5 units, P < 0.001). In 36 of 149 patients (24.2%), the tumour volume on the negative biopsy side was equal or higher than on the positive biopsy side; in the final RP specimen, 60 patients (40.3%) had capsular involvement on the negative biopsy side. CONCLUSION: Significantly many patients with newly diagnosed prostate cancer remain clinically understaged. The apical and dorsolateral region of the prostate are not adequately represented in current biopsy strategies. Undetected tumour areas are often clinically significant by size and capsular involvement, indicating a direct clinical implication when planning nerve-sparing RP or focal therapy. Our results show a continuing need for optimized and standardized biopsy protocols.

Discordant total and free prostate-specific antigen (PSA) assays: does calibration with WHO reference materials diminish the problem?

Prostate-specific antigen (PSA) assay-dependent variations could result in misinterpretation of individual PSA values. Therefore, the situation for clinical interpretation of PSA or percent free PSA (%fPSA) results is complicated. This review summarizes the differences in various total PSA (tPSA) and free PSA (fPSA) assays, and results obtained using the new World Health Organization (WHO) calibrated Access assays from various studies. Method comparisons between the traditionally calibrated Hybritech PSA and fPSA assays and the new "standardized" WHO calibrated assays yield results that are approximately 25% lower for PSA and fPSA. A PSA cut-off of 3 or 3.1 microg/L should be considered for WHO calibrated assays in order to achieve the same sensitivity/specificity profile as with a cut-off of 4 microg/L in traditionally calibrated assays. The %fPSA cut-offs could be retained.

Prospective comparison of sorafenib and sunitinib for second-line treatment of cytokine-refractory kidney cancer patients.

OBJECTIVES: It was the aim of this study to investigate the clinical differences between the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib as second-line treatment for cytokine-refractory kidney cancer patients. METHODS: Twenty consecutive patients received continuous treatment of oral sorafenib at a dose of 400 mg twice daily in 6-week cycles. Sunitinib was administered to the remaining 20 patients at 50 mg once daily in repeated 6-week cycles consisting of daily therapy for 4 weeks, followed by a 2-week off-treatment period. We correlated best treatment responses and progression-free survival (PFS) with either TKI treatment. Adverse events were evaluated and differences were compared between both treatment groups. RESULTS: In the sorafenib group, 2 (10%) patients showed a partial response (PR) and 4 (20%) patients had progressive disease (PD) versus 6 (30%) PRs and 3 (15%) PDs in the sunitinib group, respectively (p = 0.195). The median PFS was 6.4 months for sorafenib and 7.4 months for sunitinib (p = 0.969). In contrast to gender, age and the number of prior cytokine therapy cycles, the Eastern Cooperative Oncology Group performance status (p = 0.024) and the Memorial Sloan-Kettering Cancer Center risk groups for second-line treatments (p = 0.015) were independent predictive parameters of PFS. Gastrointestinal symptoms were found to occur with greater frequency in the sunitinib group (p = 0.03). CONCLUSIONS: Both TKIs showed comparable clinical benefits. The Eastern Cooperative Oncology Group performance status and the Memorial Sloan-Kettering Cancer Center risk groups can help determine which patients might benefit from alternative drug treatments.

The role of the endothelin axis and microvessel density in bladder cancer - correlation with tumor angiogenesis and clinical prognosis.

Endothelin-1 (ET-1) and its receptors, entothelin-A (ETAR) and endothelin-B (ETBR), commonly referred to as the endothelin (ET)-axis, are involved in tumor biology and growth. We investigated the effects of the ET-axis on microvessel density (MVD) and the clinicopathological parameters of patients with invasive bladder cancer. Paraffin tumor sections of 120 patients who had undergone radical cystectomy were assessed immunohistochemically using mono- and polyclonal antibodies for ET-1, ETAR, ETBR and CD34 (MVD). Staining intensities were analyzed semiquantitatively and the MVD was calculated as vessels per field. The results were correlated with various pathological and clinical factors, as well as with disease-free and overall survival. Transitional cell carcinomas (MVD=23.7) were better vascularized than squamous cell carcinomas (MVD=17.8, p=0.04). Organ-confined tumors (MVD=32.2) were better vascularized than T3- and T4-tumors (MVD=21.2, p=0.02) and ET-1 was overexpressed in this subgroup (p=0.027). Patients with metastatic regional lymph nodes (MVD=20.9) tended to have less MVD than patients without regional lymph node metastases (MVD=24.1) (p=0.15). The account of MVD did not reveal any significant differences in disease-free or overall survival. Organ-confined tumors and ET-1 overexpression are associated with upregulated microvessel density. These results suggest that MVD and ET-1 could be considered good prognostic factors.

VEGF-C, VEGF-D and Flt-4 in transitional bladder cancer: relationships to clinicopathological parameters and long-term survival.

BACKGROUND: Our aim was to determine the role of the lymphangiogenic markers VEGF-C, VEGF-D and Flt-4 in transitional bladder cancer. MATERIALS AND METHODS: Archival cystectomy tumor blocks of 286 patients were selected for construction of a tissue microarray (TMA). Paraffin sections were assessed immunohistochemically using polyclonal antibodies against VEGF-C, VEGF-D and Flt-4. Staining results were evaluated semiquantitatively and analyzed for their association with various clinicopathological factors. RESULTS: There was no association of VEGF-C with histopathological parameters or clinical outcome. Patients with VEGF-D overexpression had higher pathological tumor stages (p =0.021) and regional lymph node metastasis (p=0.008). Furthermore, they had a significantly reduced disease-free survival (p=0.042). Overexpression of Flt-4 was particularly present in the subgroup of G3 and G4 tumors (p=0.001) and was associated with a shorter disease-free survival (p=0.041). In multivariate analysis, only tumor stage and lymph node metastasis were independent prognostic parameters. CONCLUSION: Targeting VEGF-D and Flt-4 could be a useful tool to predict and control progression of bladder cancer.

Negative predictive value of systematic ultrasound-guided prostate biopsy: which tumours do we miss?

BACKGROUND: The aim of the study was the determination of the negative predictive value of sextant core prostate biopsy. PATIENTS AND METHODS: Prostate cancer was diagnosed in 126 patients by systematic ultrasound-guided sextant biopsy and was subsequently treated with radical prostatectomy. The prostatectomy specimens were examined histopathologically using the whole-mount section technique. RESULTS: 81 patients were diagnosed with unilateral and 45 with bilateral prostate cancer after biopsy. In 15/81 patients, the diagnosis of unilateral disease was confirmed by the whole-mount sections; 66 patients turned out to have bilateral disease. In 14/66 cases, the missed tumour foci were diminutive. In the remaining 52 patients, an erroneous diagnosis of unilateral prostate cancer had been made after biopsy, although the missed tumour foci were not diminutive. The negative predictive value of sextant core biopsy with respect to unilateral disease was 36%. CONCLUSION: An unexpectedly high number of tumour foci are missed by systematic ultrasound-guided sextant prostate biopsy.

Pre-analytical in-vitro stability of [-2]proPSA in blood and serum.

OBJECTIVES: [-2]proPSA may discriminate prostate cancer from benign biopsy results. We characterized the pre-analytical stability of [-2]proPSA. DESIGN AND METHODS: 22 volunteers, total PSA of 4.5-19.3microg/L, had blood drawn simultaneously. Baseline measurements were performed and samples were stored under various conditions prior to measurements. Freeze-thaw cycles were performed. [-2]proPSA was measured with the p2PSA automated research use only immunoassay on the Access analyzer. RESULTS: Mean [-2]proPSA increases with clotting time, exceeding 10% change in recovery after 3h. In serum, [-2]proPSA values decline over time under investigated storage conditions. Serum samples kept frozen show less than 10% variation in recoveries over the course of 2 freeze-thaw cycles. CONCLUSIONS: For proper measurement of [-2]proPSA, blood samples should be centrifuged within 3h of blood draw. Serum may be stored at RT or refrigerated (+4 degrees C) for a maximum of 48h and should be frozen if stored for a longer period. Two freeze-thaw cycles have no effect on [-2]proPSA stability.

Multimodality treatment paradigms for renal cell carcinoma: surgery versus targeted agents.

For decades, advanced renal cancer was almost resistant to systemic therapy. Only a few patients with metastatic disease derived clinical benefit from immunotherapy after nephrectomy. Recent advances in understanding the molecular biology of advanced and metastatic renal cancer led to the development of several targeted agents that showed impressive anti-tumor efficacy and prolongation of progression-free survival. The integration of these drugs into clinical practice did not only revolutionize the management of renal cancer, but also created controversy about the necessity, patient selection for and timing of the extirpation of the primary tumor, as well as metastasectomy. Data from ongoing preclinical investigations, including basic science and translational research, are presented and carried forward into multimodal considerations to optimize clinical efficacy of concomitant surgical treatments in the era of targeted agents. In addition to these analyses, this article highlights available clinical data regarding the disputable importance of surgical treatment approaches and explores the need of multimodality treatment paradigms within interdisciplinary decision making.

Histologic subtype of metastatic renal cell carcinoma predicts response to combined immunochemotherapy with interleukin 2, interferon alpha and 5-fluorouracil.

OBJECTIVES: Combined immunochemotherapy with interleukin 2 (IL-2), interferon alpha (IFN-alpha), and 5-fluorouracil (5-FU) is an established first-line therapy for metastatic renal cell carcinoma (RCC). However, data on histologic parameters predictive of clinical benefit are rare. In this study, we evaluated the response to immunochemotherapy in the main histologic subtypes of renal cell carcinoma and performed a subgroup analysis of inoperable patients. METHODS: From 164 patients treated with one or two cycles of combined immunochemotherapy, radical nephrectomy had revealed 22 cases of papillary RCC (pRCC; 13.4%) and 131 cases of clear cell RCC (ccRCC; 79.9%). In the remaining 11 (6.7%) their disease was inoperable. The overall response rates were evaluated according to World Health Organization criteria. RESULTS: For ccRCC and inoperable disease, responses of 34.4% and 27.3% after one cycle and 28.8% and 16.7% after two cycles, respectively, were noted. In contrast, no patient with pRCC showed any response after two cycles of combined immunochemotherapy. CONCLUSIONS: No objective response was seen in patients with pRCC. Hence, the use of immunotherapeutic agents must be questioned in this histologic subtype.