PurposeCurrent systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).MethodsA panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.ResultsSunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.ConclusionsDespite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI–TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.
Docetaxel has shown promise for the treatment of hormone-refractory prostate cancer and has become the standard of care. The flare phenomenon is a known entity in androgen-deprivation therapy of advanced prostate cancer and it has also been described in palliative chemotherapy of hormone-refractory prostate cancer. The aim of this study was to evaluate the clinical impact of a prostate-specific antigen flare phenomenon in docetaxel-treated hormone-refractory prostate cancer patients. From December 2002 to August 2005, we treated 44 patients with hormone-refractory prostate cancer applying docetaxel-based regimens. Prostate-specific antigen levels were determined before therapy and weekly thereafter. Patients were divided into three groups: response (group 1), progression (group 2) and flare (group 3). Flare was defined as initially rising prostate-specific antigen under therapy, dropping thereafter to values below baseline. The groups were compared for overall survival by Kaplan-Meier analysis. We observed a prostate-specific antigen flare phenomenon in eight (18%) of 44 evaluable patients; 24 (54.5%) patients were primary responders and 12 (27.3%) experienced progressive disease. In group 3, prostate-specific antigen levels rose to 107-180% from baseline and then dropped to 21-68%. Kaplan-Meier analysis showed significantly better overall median survival for groups 1 (18 months, P=0.0005) and 3 (19 months, P=0.006) than for group 2 (7 months). Survival in groups 1 and 3 was comparable. Grade 3 and 4 toxicity was below 5% and equally distributed between the 3 groups. In our limited patient cohort, prostate-specific antigen flare phenomenon does not seem to be a clinically relevant issue in terms of overall survival. Thus, an initial rise of prostate-specific antigen under docetaxel therapy in hormone-refractory prostate cancer does not indicate therapeutic failure and should not lead to early withdrawal from therapy in the absence of clinical signs of progression.
Up to now, clinical tumor-markers for renal cell carcinoma (RCC) have been lacking. Increased plasma levels of transforming growth factor-beta1 (TGF-beta1) were described as a tumor-marker and prognostic factor in RCC. The aim of this study was to test the clinical suitability of plasma TGF-beta1 as a tumor-marker for RCC. The concentrations of active and latent TGF-beta1 were determined in plasma of patients with localized (n = 39) and metastasised (n = 17) RCC. A newly developed, highly sensitive ELISA, which is specific for the isoform beta1, was used. Active TGF was directly measured in the EDTA plasma. To determine the amount of latent TGF-beta1, which is bound predominantly at beta2-macroglobulin, an optimized activation procedure was applied. Patients with localized RCC showed median concentrations of 16,700 ng/l (6,200-54,800 ng/l) for latent TGF-beta1. A total of 94 patients with various nonmalignant urological diseases were recruited as a control group. In comparison, this group had median concentrations of 19,900 ng/l (2,640-52,300 ng/l) for latent TGF-beta1. There was no significant difference (nonparametric Kruskal-Wallis ANOVA) between these groups. Patients with metastatic RCC showed median concentrations of 34,500 ng/l (6,800-48,960 ng/l) for latent TGF-beta1. In comparison to the localized RCC group, a statistically significant difference was found. Plasma levels after operative therapy (days 1, 5 and 10) and during follow-up without evidence of disease (2-6 months) showed no significant differences. Contrary to other study groups, our results suggest that TGF-beta1 is not a suitable tumor-marker for the diagnosis of localized RCC. In the face of higher TGF-beta1 plasma levels in metastatic disease, TGF-beta1 may be useful in the early detection of RCC recurrence or to control the success of immunochemotherapy.
Studies in mice have identified the ob gene product, leptin, as a signaling factor regulating body weight homeostasis and energy balance. Defective production of the encoded protein may be one of the causes for the development of obesity. Using a high affinity antibody, that in immunohistochemical studies specifically stained human adipocytes, a radioimmunoassay was established and leptin immunoreactivity was quantified in plasma of lean and obese human subjects. Chromatographic analysis suggested that the immunoreactive material in plasma is identical to that found in extracts from human fat and represent a protein with a molecular size of approximately 16 kD. Fasting levels were measured in plasma of 75 lean and obese human subjects (body mass index (BMI) 17.7 - 87.3). The mean concentration of leptin in plasma of lean subjects (BMI < or = 28) was 69.3 +/- 36.9 fmol/ml plasma (mean +/- SD, n=27). The highest concentration measured in obese was 533.3 fmol/ml plasma. The levels showed a strong positive correlation with BMI (r=0.77, p<0.001). A subgroup of diabetic patients did not significantly differ in their leptin plasma levels from non-diabetic subjects with similar BMI.
There are no reliable serologic tumor markers for transitional cell carcinoma (TCC) of the urinary bladder and noninvasive urine investigations are inadequate. We used fluorescent microsatellite analysis (MSA) to detect serum DNA and urine-sediment DNA alterations in patients with bladder cancer and prospectively collected fresh tumor, peripheral blood, serum and spontaneous urine specimens from 39 consecutive patients treated for TCC of the bladder to obtain the corresponding DNA. Urinary bladder cancer accounts for approximately 3% of all newly diagnosed malignancies in Western countries. In contrast to most other tumors, bladder carcinoma offers the opportunity of noninvasive diagnosis via urinary cytology. Yet a reliable serologic tumor marker is not available. Follow-up for bladder carcinoma is demanding and time consuming, as most bladder cancers at diagnosis grow superficially and will recur in 70% of cases within 2 years of primary treatment. 1 The intensive follow-up for transitional cell carcinoma (TCC) of the bladder still relies on invasive diagnostic measures such as cystoscopy and bladder washings for urine cytology. Cytology has a low sensitivity in the diagnosis of well-differentiated papillary tumors. A reliable serologic marker and a highly sensitive urinary investigation could reduce the requirement and frequency of invasive procedures during follow-up.In recent studies molecular techniques have proved applicable for the detection of smallest amounts of free circulating tumor DNA in serum and plasma of cancer patients. 2,3 Using microsatellite analysis (MSA) Goessl et al. 3 identified plasma DNA alterations in 63% of patients with renal cell carcinoma. In recent studies MSA was also used to detect tumor-specific DNA alterations in urine sediment samples of patients with TCC of the urinary bladder. 4,5 In a pilot study Steiner et al. 4 achieved a sensitivity of 90% for the urinary cancer diagnosis with radiolabeled microsatellite markers. In contrast to cytology, this method is independent of tumor histomorphologic features, and thus offers high sensitivity in well-differentiated tumors. This molecular genetic assay, not previously looked at in TCC, could reliably identify tumor-specific alterations in the serum of patients and its use in follow-up after radical surgical therapy could lead to early tumor recurrence identification. In the case of superficial bladder cancers, MSA may be helpful in diagnosing local recurrence without the need for invasive measures dependent on morphologic tumor features. We therefore used MSA with 17 highly polymorphic fluorescently labeled microsatellite markers from the chromosomal regions 5q, 8p, 9p, 9q, 13q, 14q, 17p, 17q and 20q to detect serum DNA and sediment-DNA alterations from spontaneous urine samples of 39 consecutive patients treated for TCC of the urinary bladder, to evaluate the sensitivity of the method in the serologic and urinary diagnosis of bladder TCC. MATERIAL AND METHODS Tumor, blood and urine samplingIn 1999, we prospectively collected preo...
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