J. Roigas

Phase II Study of Sunitinib Administered in a Continuous Once-Daily Dosing Regimen in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma

PURPOSEnSunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen.nnnPATIENTS AND METHODSnEligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures.nnnRESULTSnOne hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM.nnnCONCLUSIONnSunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.

In search of suitable reference genes for gene expression studies of human renal cell carcinoma by real-time PCR

BackgroundHousekeeping genes are commonly used as endogenous reference genes for the relative quantification of target genes in gene expression studies. No conclusive systematic study comparing the suitability of different candidate reference genes in clear cell renal cell carcinoma has been published to date. To remedy this situation, 10 housekeeping genes for normalizing purposes of RT-PCR measurements already recommended in various studies were examined with regard to their usefulness as reference genes.ResultsThe expression of the potential reference genes was examined in matched malignant and non-malignant tissue specimens from 25 patients with clear cell renal cell carcinoma. Quality assessment of isolated RNA performed with a 2100 Agilent Bioanalyzer showed a mean RNA integrity number of 8.7 for all samples. The between-run variations related to the crossing points of PCR reactions of a control material ranged from 0.17% to 0.38%. The expression of all genes did not depend on age, sex, and tumour stage. Except the genes TATA box binding protein (TBP) and peptidylprolyl isomerase A (PPIA), all genes showed significant differences in expression between malignant and non-malignant pairs. The expression stability of the candidate reference genes was additionally controlled using the software programs geNorm and NormFinder. TBP and PPIA were validated as suitable reference genes by normalizing the target gene ADAM9 using these two most stably expressed genes in comparison with up- and down-regulated housekeeping genes of the panel.ConclusionOur study demonstrated the suitability of the two housekeeping genes PPIA and TBP as endogenous reference genes when comparing malignant tissue samples with adjacent normal tissue samples from clear cell renal cell carcinoma. Both genes are recommended as reference genes for relative gene quantification in gene profiling studies either as single gene or preferably in combination.

The tumour-targeting human L19-IL2 immunocytokine: Preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma

BACKGROUNDnL19-IL2, a tumour-targeting immunocytokine composed of the recombinant human antibody fragment L19 (specific to the alternatively-spliced EDB domain of fibronectin, a well characterised marker of tumour neo-vasculature) and of human IL2, has demonstrated strong therapeutic activity in animal cancer models. This phase I/II trial was performed to evaluate safety, tolerability, recommended phase II dose (RD) and early signs of activity of L19-IL2.nnnPATIENTS AND METHODSnFive cohorts of patients with progressive solid tumours (n=21) received an intravenous infusion of L19-IL2 (from 5 to 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 3 weeks. This treatment cycle was repeated up to six times. In the following expansion phase, patients with metastatic renal cell carcinoma (RCC) (n=12) were treated at the RD of L19-IL2. Clinical data and laboratory findings were analysed for safety, tolerability and activity.nnnRESULTSnPreclinical studies in rats and monkeys did not raise any safety concerns. The RD was defined to be 22.5 Mio IU IL2 equivalent. Pharmacokinetics of L19-IL2 was dose proportional over the tested range, with a terminal half-life of 2-3h. Toxicities were manageable and reversible with no treatment-related deaths. We observed stable disease in 17/33 patients (51%) and 15/18 with mRCC (83%) after two cycles. Median progression-free survival of RCC patients in the expansion phase of the study was 8 months (1.5-30.5).nnnCONCLUSIONSnL19-IL2 can be safely and repeatedly administered at the RD of 22.5 Mio IU IL2 equivalent in advanced solid tumours. Preliminary evaluation suggests clinical activity of L19-IL2 in patients with mRCC.

ICUD-EAU International Consultation on Kidney Cancer 2010: Treatment of Metastatic Disease

CONTEXTnUntil the development of novel targeted agents directed against angiogenesis and tumour growth, few treatment options have been available for the treatment of metastatic renal-cell carcinoma (mRCC).nnnOBJECTIVEnThis review discusses current targeted therapies for mRCC and provides consensus statements regarding treatment algorithms.nnnEVIDENCE ACQUISITIONnMedical literature was retrieved from PubMed up to April 2011. Additional relevant articles and abstract reviews were included from the bibliographies of the retrieved literature.nnnEVIDENCE SYNTHESISnTargeted treatment for mRCC can be categorized for the following patient groups: previously untreated patients, those refractory to immunotherapy, and those refractory to vascular endothelial growth factor (VEGF)-targeted therapy. Sunitinib and bevacizumab combined with interferon alpha are generally considered first-line treatment options in patients with favourable or intermediate prognoses. Temsirolimus is considered a first-line treatment option for poor-risk patients. Either sorafenib or sunitinib may be valid second-line treatments for patients who have failed prior cytokine-based therapies. For patients refractory to treatment with VEGF-targeted therapy, everolimus is now recommended. Pazopanib is a new treatment option in the first- and second-line setting (after cytokine failure). Sequential and combination approaches, and the roles of nephrectomy and tumour metastasectomy will also be discussed.nnnCONCLUSIONSnIncreasing clinical evidence is clarifying appropriate first- and second-line treatments with targeted agents for patients with mRCC. Based on phase 2 and 3 trials, a sequential approach is most promising, while combination therapy is still investigational. The role of nephrectomy in mRCC is being evaluated in ongoing phase 3 clinical trials.

Laparoscopic radical prostatectomy—an analysis of factors affecting operating time

OBJECTIVESnAlthough laparoscopic radical prostatectomy (LRP) is accomplished within 2 to 3 hours by experienced surgeons, less is known about the operating times (OTs) for recently trained surgeons or the influence of additional factors. As of November 2001 at our institution, two senior surgeons had each performed more than 100 cases of LRP and two junior surgeons had each performed fewer than 30. We prospectively studied the next 100 consecutive LRPs to assess the factors influencing the OT.nnnMETHODSnTransperitoneal LRPs were performed by two senior (n = 62) and two junior surgeons (n = 38) with random case assignment. We assessed body mass index, prostate size, prior abdominal surgery, androgen deprivation, surgeon experience, procedures in addition to LRP, lymph node dissection, nerve sparing, and sural nerve grafting as potential predictors of the OT.nnnRESULTSnProstate weight, androgen deprivation, and prior abdominal surgery did not significantly affect the OT, but grade 1 obesity increased the OT by an average of 38 minutes. The mean OT by surgeon experience was 214 minutes for seniors and 347 minutes for juniors (P <0.001). By procedure type, the OT ranged from 180 minutes for LRP only by seniors to 459 minutes for LRP plus lymph node dissection plus sural nerve grafting by juniors. Lymph node dissection and sural nerve grafting significantly increased the OT by 46 and 101 minutes, respectively, and nerve sparing did not. For each combination of procedures, seniors averaged significantly shorter times than did juniors. A multiple regression model with stepwise selection showed that prostate weight, sural nerve grafting, pelvic lymph node dissection, use of a surgical robot, and surgeon experience significantly affected the OT.nnnCONCLUSIONSnThe results of this prospective study of 100 cases of LRP showed that the OT for senior surgeons averaged 2 to 3 hours, but less experienced surgeons, and additional procedures, add significantly to the OT.

Fast-track surgery in laparoscopic radical prostatectomy: basic principles

Fast-track surgery describes innovative treatment concepts ensuring a faster convalescence phase. The aim of this study was to allow hospital discharge 3xa0days after surgery without additional complications in patients receiving LRPE for localized prostate cancer. Twenty-five patients each were randomized in the study groups to verify if a fast-track regimen could be transferred into clinical routine. The perioperative data, early complications, hospital stay as well as readmission rate were analyzed. The mean postoperative stay was 3.6xa0days in the fast-track group versus 6.7xa0days in the conventional group. The overall complications were significantly less in the fast-track procedure. The readmission rate was low and not significant. Patients receiving an LRPE benefit from a suitable fast-track concept. The postoperative hospital stay could be shortened nearly by half with a significantly decreased overall complication rate. Thus, fast-track concepts might contribute to saving resources in the long term. However, more evidence based on larger prospective trials is needed to achieve optimal quality of life for patients perioperatively.

Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).

To evaluate the efficacy and safety of gemcitabine and cisplatin in combination with sorafenib, a tyrosine‐kinase inhibitor, compared with chemotherapy alone as first‐line treatment in advanced urothelial cancer.

Positive margins after laparoscopic radical prostatectomy: A prospective study of 100 cases performed by 4 different surgeons

OBJECTIVEnLaparoscopic radical prostatectomy (LRP) has been refined by experienced surgeons into a competitive treatment alternative for localized prostate cancer. Less is known, however, about the outcomes of learning curve cases from newly trained surgeons. We prospectively studied 100 cases of LRP performed by 2 senior and 2 junior surgeons and addressed the rates of positive margins-an important early endpoint of oncologic efficacy.nnnMETHODSn100 consecutive cases of LRP were performed by two senior (n=62) and two junior surgeons (n=38) by a 5-port transperitoneal route. Whole-mount step-section prostate specimens were examined by Stanford protocol.nnnRESULTSnPositive margins occured in 25% of cases: 18% for pT2a (2/11), 18% for pT2b (11/61), 45% for pT3a (10/22), and 50% for pT3b (2/4) (p=0.002 pT2 vs. pT3). By surgeon experience, the rates were 19% (12/62) for senior and 34% (13/38) for junior (p=0.04). However, in a multiple logistic regression analysis, only pathologic stage (p=0.083) and Gleason sum (p=0.0133) reached statistical significance, while surgeon experience did not (p=0.0992).nnnCONCLUSIONnPositive margin rates after laparoscopic radical prostatectomy are significantly influenced by pathologic stage and Gleason score, and are within the range reported from open series. The higher positive margin rate from junior surgeons, although not statistically significant, suggests the need for further study and continued mentoring during surgery and/or video review of cases to improve oncologic results.

Body size and weight as predisposing factors in varicocele.

Objective. The literature regarding the constitutional type of children and adolescents with varicocele is inconsistent. The aim of this investigation was to examine a possible influence of weight, height and body mass index (BMI) on the formation of varicoceles during childhood and adolescence. Material and methods. In a retrospective data analysis, 193 Caucasian children and adolescents aged 9–19 years (mean age 14.7 years) with left-sided varicocele grade 2–3 were studied. The weight, height and BMI of the subjects were compared with the age-correlated normal values currently accepted in Germany. Additionally, the familial disposition for varicocele and the occurrence of relevant concurrent diseases were considered. Results. In the group of patients examined, the mean percentiles of weight (57th) and height (58th) were significantly above and the mean BMI percentile (42th) was significantly below the age-correlated 50th percentile for the normal population (p=0.019, 0.005 and 0.002). In our case material, 12.2% of all brothers of the patients had varicoceles. Conclusions. The results of this investigation suggest a correlation between physical appearance and the formation of a varicocele during childhood or adolescence. We were able to demonstrate that patients with varicocele were heavier and taller than an age-correlated normal population, but had a distinctly lower BMI. Further studies are needed to verify whether this rather athletic habitus, together with the postulated difference in muscle:fat ratio, represents an important etiologic factor for varicocele formation.

Dyadic planning of health-behavior change after prostatectomy : a randomized-controlled planning intervention

In this study, we investigated the role of dyadic planning for health-behavior change. Dyadic planning refers to planning health-behavior change together with a partner. We assumed that dyadic planning would affect the implementation of regular pelvic-floor exercise (PFE), with other indicators of social exchange and self-regulation strategies serving as mediators. In a randomized-controlled trial at a German University Medical Center, 112 prostatectomy-patients with partners were randomly assigned to a dyadic PFE-planning condition or one of three active control conditions. Questionnaire data were assessed at multiple time points within six months post-surgery, measuring self-reported dyadic PFE-planning and pelvic-floor exercise as primary outcomes and social exchange (support, control) and a self-regulation strategy (action control) as mediating mechanisms. There were no specific intervention effects with regard to dyadic PFE-planning or pelvic-floor exercise, as two active control groups also showed increases in either of these variables. However, results suggested that patients instructed to plan dyadically still benefited from self-reported dyadic PFE-planning regarding pelvic-floor exercise. Cross-sectionally, received negative control from partners was negatively related with PFE only in control groups and individual action control mediated between self-reported dyadic PFE-planning and PFE for participants instructed to plan PFE dyadically. Longitudinally, action control mediated between self-reported dyadic PFE-planning and pelvic-floor exercise for all groups. Findings provide support for further investigation of dyadic planning in health-behavior change with short-term mediating effects of behavior-specific social exchange and long-term mediating effects of better self-regulation.