Temsirolimus in Daily Use: Results of a Prospective Multicentre Noninterventional Study of Patients with Metastatic Kidney Cancer

Background

Temsirolimus (TEMSR) was approved for treating advanced renal cell carcinoma (RCC) in 2007. Based on the data from a single phase 3 trial, it is recommended explicitly as first-line therapy for patients with a poor clinical prognosis.

Objective

The aim of this prospective multicentre trial (STARTOR) was to examine the effectiveness of TEMSR in daily clinical practice with a broader indication in the treatment of metastatic RCC.

Design, setting, and participants

Metastatic RCC patients treated with 25 mg of TEMSR weekly were submitted to a prospective systematic evaluation and follow-up in 87 German centres between January 2008 and October 2011 using standardised procedures.

Outcome measurements and statistical analysis

All data were centrally analysed by an independent clinical research organisation.

Results and limitations

This interim analysis of the STARTOR study included 386 patients. The observed toxicity was tolerable, the median dose intensity was 91% (interquartile range: 79–100%), and the median treatment duration was 20.1 wk (95% confidence interval [CI], 17.0–23.3 wk). Clinical benefit was seen in 157 patients (40.7%); the median progression-free and overall survival were 4.9 mo (95% CI, 4.2–5.6) and 11.6 mo (95% CI, 9.3–13.9), respectively. The effectiveness of TEMSR did not differ significantly in relation to the patient's age, histologic RCC subtype, or line of treatment. The major limitations were the noninterventional study design, limited information about Memorial Sloan-Kettering Cancer Center risk factors and detailed toxicity, and the lack of central radiologic review.

Conclusions

TEMSR is an effective and largely well-tolerated treatment alternative for metastatic RCC patients in daily clinical practice, irrespective of the patient's age, histologic RCC subtype, or line of treatment.     

Mayo Adhesive Probability Score: An Accurate Image-based Scoring System to Predict Adherent Perinephric Fat in Partial Nephrectomy

Background

Image-based renal morphometry scoring systems are used to predict the potential difficulty of partial nephrectomy (PN), but they are centered entirely on tumor-specific factors and neglect other patient-specific factors that may complicate the technical aspects of PN. Adherent perinephric fat (APF) is one such factor known to make PN difficult.

Objective

To develop an accurate image-based nephrometry scoring system to predict the presence of APF encountered during robot-assisted partial nephrectomy (RAPN).

Design, setting, and participants

We prospectively analyzed 100 consecutive RAPNs performed by one surgeon and defined APF as the need for subcapsular renal dissection to isolate the renal tumor for RAPN.

Outcome measurements and statistical analysis

The scoring algorithm to predict the presence of APF was developed with a multivariable logistic regression model using a forward selection approach with a focus on improvement in the area under the receiver operating characteristic curve.

Results and limitations

Thirty patients (30%; 95% confidence interval, 21–40) had APF. Single-variable analysis noted an increased likelihood of APF in male patients (p < 0.001), higher body mass index (p = 0.003), greater posterior perinephric fat thickness (p < 0.001), greater lateral perinephric fat thickness (p < 0.001), and those with perirenal fat stranding (p < 0.001). Two of these variables, posterior perinephric fat thickness and stranding, were most highly predictive of APF in multivariable analysis and were therefore used to create a risk score, termed Mayo Adhesive Probability (MAP) and ranging from 0 to 5, to predict the presence of APF. We observed APF in 6% of patients with a MAP score of 0, 16% with a score of 1, 31% with a score of 2, 73% with a score of 3–4, and 100% of patients with a score of 5.

Conclusions

MAP score accurately predicts the presence of APF in patients undergoing RAPN. Prospective validation of the MAP score is required.

Patient summary

The Mayo Adhesive Probability score that we we developed is an accurate system that predicts whether or not adherent perinephric, or “sticky,” fat is present around the kidney that would make partial nephrectomy difficult.     

ClearCode34: A Prognostic Risk Predictor for Localized Clear Cell Renal Cell Carcinoma

Background

Gene expression signatures have proven to be useful tools in many cancers to identify distinct subtypes of disease based on molecular features that drive pathogenesis, and to aid in predicting clinical outcomes. However, there are no current signatures for kidney cancer that are applicable in a clinical setting.

Objective

To generate a signature biomarker for the clear cell renal cell carcinoma (ccRCC) good risk (ccA) and poor risk (ccB) subtype classification that could be readily applied to clinical samples to develop an integrated model for biologically defined risk stratification.

Design, setting, and participants

A set of 72 ccRCC sample standards was used to develop a 34-gene classifier (ClearCode34) for assigning ccRCC tumors to subtypes. The classifier was applied to RNA-sequencing data from 380 nonmetastatic ccRCC samples from the Cancer Genome Atlas (TCGA), and to 157 formalin-fixed clinical samples collected at the University of North Carolina.

Outcome measurements and statistical analysis

Kaplan-Meier analyses were performed on the individual cohorts to calculate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Training and test sets were randomly selected from the combined cohorts to assemble a risk prediction model for disease recurrence.

Results and limitations

The subtypes were significantly associated with RFS (p < 0.01), CSS (p < 0.01), and OS (p < 0.01). Hazard ratios for subtype classification were similar to those of stage and grade in association with recurrence risk, and remained significant in multivariate analyses. An integrated molecular/clinical model for RFS to assign patients to risk groups was able to accurately predict CSS above established, clinical risk-prediction algorithms.

Conclusions

The ClearCode34-based model provides prognostic stratification that improves upon established algorithms to assess risk for recurrence and death for nonmetastatic ccRCC patients.

Patient summary

We developed a 34-gene subtype predictor to classify clear cell renal cell carcinoma tumors according to ccA or ccB subtypes and built a subtype-inclusive model to analyze patient survival outcomes.     

Vigilancia activa de masas renales pequeñas diagnosticadas en pacientes de edad avanzada o con comorbilidad: en busca de la mejor estrategia de tratamiento

IntroductionAim of this study is to provide our results after long-term active surveillance (AS) protocol for small renal masses (SRMs), and to report the outcomes of patients who remained in AS compared to those who underwent delayed surgical intervention.Patients and methodsWe retrospectively reviewed our database of 58 patients diagnosed with 60 contrast enhancing SRMs suspicious for renal cell carcinoma (RCC). All patients had clinical and radiological follow-up every 6 months. We evaluated the differences between patients who remained on AS and those who underwent surgical delayed intervention.ResultsThe mean age was 75 years, the mean follow-up was 88.5 months. The median initial tumor size at presentation was 2.6 cm, and the median estimated tumor volume was 8.7 cm³. The median linear growth rate of the cohort was 0.7 cm/year, and the median volumetric growth rate was 8.8 cm³/year. Death for metastatic disease occurred in 2 patients (3.4%). No correlation was found between initial tumor size and size growth rate. The mean linear and volumetric growth rates of the group of patients who underwent surgery was higher than in those who remained on surveillance (1.9 vs. 0.4 cm/year and 16.1 vs. 4.6 cm³/year, respectively; P < .001).ConclusionsMost of SRMs demonstrate to have an indolent course and low metastatic potential. Malignant disease could have faster linear and volumetric growth rates, thus suggesting the need for a delayed surgical intervention. In properly selected patients with low life-expectancy, AS could be a reasonable option in the management of SRMs.     

Implicación de las moléculas HLA de clase I en el escape inmunitario de tumores urológicos

Context and objectiveTo analyze the influence of different alterations in human leukocyte antigen class I molecules (HLA I) in renal cell carcinoma, as well as in bladder and prostate cancer. We also study the correlation between HLA I expression and the progression of the disease and the response after immunotherapy protocols.Evidences acquisitionIt has been shown, experimentally, that the immune system can recognize and kill neoplastic cells. By analyzing the expression of HLA I molecules on the surface of cancer cells, we were able to study the tumor escape mechanisms against the immune system.Evidences synthesisAlteration or irreversible damage in HLA I molecules is used by the neoplastic cells to escape the immune system. The function of these molecules is to recognize endogenous peptides and present them to T cells of the immune system. There is a clear relationship between HLA I reversible alterations and success of therapy. Irreversible lesions also imply a lack of response to treatment. The immune system activation can reverse HLA I molecules expression in tumors with reversible lesions, whereas tumors with irreversible ones do not respond to such activation. Determine the type of altered HLA I molecules in tumors is of paramount importance when choosing the type of treatment to keep looking for therapeutic success. Those tumors with reversible lesions can be treated with traditional immunotherapy; however, tumour with irreversible alterations should follow alternative protocols, such as the use of viral vectors carrying the HLA genes to achieve damaged re-expression of the protein.ConclusionFrom studies in urologic tumors, we can conclude that the HLA I molecules play a key role in these tumors escape to the immune system.     

The importance of intraoperative transoesophageal monitoring when operating on renal cancers that involve the right atrium

The surgical treatment of advanced renal cancers is challenging. Renal cell carcinoma is interesting in that it invades the vasculature and can extend up as far as the right atrium. Extension of tumour thrombus into the right atrium represents level IV disease, according to Robson staging. Transoesophageal echocardiography is useful for diagnostic purposes. It is also of great value for intraoperative cardiac monitoring and to confirm the extent of vascular involvement.     

In Vitro Comparison of Two Different Mechanical Circulatory Support Devices Installed in Series and in Parallel

This study investigates the novel approach of placing a ventricular assist pump in the descending aorta in series configuration with the heart and compares it with the two traditional approaches of left‐ventricle‐to‐ascending‐aorta (LV‐AA) and left‐ventricle‐to‐descending‐aorta (LV‐DA) placement in parallel with the heart. Experiments were conducted by using the in‐house simulator of the cardiovascular blood‐flow loop (SCVL). The results indicate that the use of the LV‐AA in‐parallel configuration leads to a significant improvement in the systemic and pulmonic flow as the level of continuous flow is increased; however, this approach is considered highly invasive. The use of the LV‐DA in‐parallel configuration leads to an improvement in the systemic and pulmonic flow at lower levels of continuous flow but at higher levels of pump support leads to retrograde flow. In both in‐parallel configurations, increasing the level of pump continuous flow leads to a decrease in pulsatility to a certain extent. The results of placing the pump in the descending aorta in series configuration show that the pressure drop upstream of the pump facilitates cardiac output as a result of afterload reduction. In addition, the pressure rise downstream of the pump may assist with renal perfusion. However, at the same time, the pressure drop generated at the proximal part of the descending aorta induces a slight drop in carotid perfusion, which would be autoregulated by the brain in a native cardiovascular system. The pulse wave analysis shows that placing the pump in the descending aorta leads to improved pulsatility in comparison with the traditional in‐parallel configurations.     

A Systematic Review and Meta-analysis of Adjuvant and Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma

Context

The role of adjuvant chemotherapy (AC) or neoadjuvant chemotherapy (NC) remains poorly defined for the management of upper tract urothelial carcinoma (UTUC), although some studies suggest a benefit.

Objective

To update the current evidence on the role of NC and AC for UTUC patients.

Evidence acquisition

We searched for all studies investigating NC or AC for UTUC in Medline, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from the American Society of Clinical Oncology meetings prior to February 2014. A systematic review and meta-analysis were performed.

Evidence synthesis

No randomized trials investigated the role of AC for UTUC. There was one prospective study (n = 36) investigating adjuvant carboplatin–paclitaxel and nine retrospective studies, with a total of 482 patients receiving cisplatin-based or non-cisplatin–based AC after nephroureterectomy (NU) and 1300 patients receiving NU alone. Across three cisplatin-based studies, the pooled hazard ratio (HR) for overall survival (OS) was 0.43 (95% confidence interval [CI], 0.21–0.89; p = 0.023) compared with those who received surgery alone. For disease-free survival (DFS), the pooled HR across two studies was 0.49 (95% CI, 0.24–0.99; p = 0.048). Benefit was not seen for non-cisplatin–based regimens. For NC, two phase 2 trials demonstrated favorable pathologic downstaging rates, with 3-yr OS and disease-specific survival (DSS) ≤93%. Across two retrospective studies investigating NC, there was a DSS benefit, with a pooled HR of 0.41 (95% CI, 0.22–0.76; p = 0.005).

Conclusions

There appears to be an OS and DFS benefit for cisplatin-based AC in UTUC. This evidence is limited by the retrospective nature of studies and their relatively small sample size. NC appears to be promising, but more trials are needed to confirm its utility.

Patient summary

After a comprehensive search of studies examining the role of chemotherapy for upper tract urothelial cancer, the pooled evidence shows that cisplatin-based adjuvant chemotherapy was beneficial for prolonging survival.