EPOCK study protocol: a mixed-methods research program evaluating cancer care coordination nursing occupations in France as a complex intervention.

BACKGROUND: Facing the increasing cancer incidence and cancer survivorship, many national strategic cancer plans have identified cancer care coordination as a priority for health service improvement. However, the high variability of practices, the diversity of definitions and underlying concepts increases the existing difficulty to standardise, replicate, transpose and assess care coordination within the French health system context. The EPOCK national study aims at evaluating practices and the working context of hospital-based cancer care coordination nurses, based on a previously designed reference framework for care coordination within the French health system context. METHODS: EPOCK is based on a comprehensive evaluation of nursing professions in cancer care coordination, considered as a complex intervention. Phase 1 (theoretical phase) will define and design a theoretical reference framework for care coordination in France through an international literature review, aiming to identify relevant models and all components of the expected framework and a structured consensus method, the Nominal group technique, aiming to select and prioritise the most relevant components already found in the literature review with regard to the French healthcare system; phase 2 (Operational phase) will consist in an in-depth analysis of practices, contexts, perceptions and attitudes related to care coordination occupations by nurses in oncology and all stakeholders (related professionals, patients and their caregivers) through a multicentric cross-sectional mixed-method evaluative study. The observed practices and contexts will be finally compared with the theoretical reference framework using both inductive and deductive approaches. DISCUSSION: This study will result in an evaluation framework identifying key models and key elements relative to cancer care coordination interventions that can be used to guide management of cancer care coordination nursing occupations within the French healthcare system. EPOCK would also assist in public decision-making to identify optimal targets, skills profiles and scope of actions for cancer coordination professions. Finally, EPOCK will describe typology of nurse practices in cancer care coordination and thus obtain precise preliminary information essential for drafting a medico-economic evaluation study of these new nursing professions' impact. TRIAL REGISTRATION: Clinicaltrial.gov registration: NCT03350776 , 11/22/2017.

Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial.

Background: Adjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59-0.98; two-sided P = 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial. Patients and methods: Patients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Results: Patients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases. Conclusions: In S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects. Clinical trial registration: ClinicalTrials.gov, NCT00375674.

How to report toxicity associated with targeted therapies?

BACKGROUND: In the era of personalized medicine, molecularly targeted therapies (MTT) have modified the outcome of some cancer types. The price of tumor control needs to be balanced with toxicity since these new therapies are administered continuously for several months or sometimes for several years. For cytotoxic drugs, the incidence of adverse event (AE) was traditionally reported as frequency and intensity. This simple measure is not sufficient to capture the recurrent nature and duration of AE. This paper presents two methods to better describe the toxicity burden across the time: prevalence and Q-TWiST. PATIENTS AND METHODS: Limitation of worst-grade method and advantages of prevalence and Q-TWiST in the analysis of toxicity were illustrated using data from a phase II trial and a hypothetically simulated clinical trial. RESULTS: Prevalence integrates the recurrent nature of AE. Using prevalence, it is possible to obtain a time profile of AE. Q-TWiST method evaluates the weighted time spent in each health state and also considers the recurrent nature of side-effects in order to assess the 'risk-benefit' ratio of a treatment. When interpreting Q-TWiST results, it is necessary to take into account overall survival and progression-free survival and to define a clinically relevant difference according to the setting. CONCLUSION: The two methods presented here capture different effects. They are helpful for physicians in their treatment choice (balance benefit risk), to counsel patients and to optimize supportive care. In order to ensure consistency and provide critical information required for medical decision-making, it is important to encourage the use of alternative statistical methods in the analysis of toxicities associated with MTT. CLINICAL TRIAL: NCT00541008.

Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy.

BACKGROUND: Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta-analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety. PATIENTS AND METHODS: Data were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately. RESULTS: The rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62-1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66-1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)]. CONCLUSIONS: Stomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines.

Outcomes from second-line therapy in long-term responders to first-line tyrosine kinase inhibitor in clear-cell metastatic renal cell carcinoma.

BACKGROUND: Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1). PATIENTS AND METHODS: Retrospective multicenter study (2004-2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). END POINTS: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM). RESULTS: Sequence effect in the overall cohort was in favor of the TKI-TKI sequence over the TKI-mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI-TKI superiority was attributed in large part to the 11-22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9-12.2) versus 3.9 (3.0-5.5), P = 0.003; TTF(months): 8.0 (5.5-11.0) versus 3.6 (3.0-4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI. CONCLUSIONS: m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.

First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group (GETUG)†.

BACKGROUND: Papillary renal cell carcinoma (PRCC), type 1 and type 2, represents 10%-15% of renal cell carcinomas (RCC). There is no standard first-line treatment of metastatic PRCC (mPRCC). Anti-angiogenics have shown activity in retrospective studies but no prospective studies in pure papillary histology have been reported, but one with foretinib. PATIENTS AND METHODS: A prospective phase II study evaluated sunitinib in first-line treatment of mPRCC. The primary end point was overall response rate (ORR). Secondary end points were progression-free survival (PFS) and overall survival (OS). RESULTS: Fifteen and 46 patients, respectively, with type 1 and type 2 mPRCC were enrolled. Using the MSKCC scoring system: 12 (20%), 33 (55%) and 9 (15%) patients were, respectively, in the favourable, intermediate or poor risk group and 7 undetermined. Median follow-up is 51.4 months. In type 1, 2 patients 13% [95% confidence interval (CI) 0.1-30.5] had a partial response (PR), 10 had stable disease (SD) with 5 (33%) ≥12 weeks. In type 2, 5 patients 11% (95% CI 1.9-20.3) had a PR, 25 had SD with 10(22%) ≥12 weeks. Median PFS was 6.6 months (95% CI 2.8-14.8) in type 1 and 5.5 months (95% CI 3.8-7.1) in type 2. Median OS was 17.8 (95% CI 5.7-26.1) and 12.4 (95% CI 8.2-14.3) months, respectively, in type 1 and 2. Safety was as expected with sunitinib for metastatic RCC. CONCLUSION: Sunitinib showed activity in treatment of type 1 and 2 mPRCC but lower than in clear-cell mRCC. Both PFS and OS are longer in type I PRCC. Sunitinib represents an acceptable option in first-line treatment of mPRCC.

RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon α-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma.

BACKGROUND: The open-label, phase II RECORD-2 trial compared efficacy and safety of first-line everolimus plus bevacizumab (EVE/BEV) with interferon plus bevacizumab (IFN/BEV) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Previously untreated patients were randomized 1:1 to bevacizumab 10 mg/kg every 2 weeks with either everolimus 10 mg/day (EVE/BEV) or interferon (9 MIU 3 times/week, if tolerated) (IFN/BEV). Tumor assessments occurred every 12 weeks. The primary objective was the assessment of treatment effect on progression-free survival (PFS), based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). RESULTS: Baseline characteristics were balanced between the EVE/BEV (n = 182) and IFN/BEV (n = 183) arms. The median PFS was 9.3 and 10.0 months in the EVE/BEV and IFN/BEV arms, respectively (P = 0.485). The predicted probability of phase III success was 5.05% (hazard ratio = 0.91; 95% confidence interval 0.69-1.19). The median duration of exposure was 8.5 and 8.3 months for EVE/BEV and IFN/BEV, respectively. The percentage of patients discontinuing because of adverse events (AEs) was 23.4% for EVE/BEV and 26.9% for IFN/BEV. Common grade 3/4 AEs included proteinuria (24.4%), stomatitis (10.6%), and anemia (10.6%) for EVE/BEV and fatigue (17.1%), asthenia (14.4%), and proteinuria (10.5%) for IFN/BEV. The median overall survival was 27.1 months in both arms. CONCLUSIONS: The efficacy of EVE/BEV and IFN/BEV appears similar. No new or unexpected safety findings were identified and, with the exception of proteinuria in about one-fourth of the population, EVE/BEV was generally well tolerated. CLINICAL TRIAL REGISTRY AND TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00719264.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

Multiparametric magnetic resonance imaging for the differentiation of low and high grade clear cell renal carcinoma.

PURPOSE: To retrospectively evaluate the ability of magnetic resonance (MR) imaging to differentiate low from high Fuhrman grade renal cell carcinoma (RCC). MATERIALS AND METHODS: MR images from 80 consecutive pathologically proven RCC (57 clear cell, 16 papillary and 7 chromophobe) were evaluated. Double-echo chemical shift, dynamic contrast-enhanced T1- and T2-weighted images and apparent diffusion coefficient (ADC) maps were reviewed independently. Signal intensity index (SII), tumour-to-spleen SI ratio (TSR), ADC ratio, wash-in (WiI) and wash-out indices (WoI) between different phases were calculated and compared to pathological grade and size. The Fuhrman scoring system was used. Low grade (score ≤ 2) and high grade (score ≥ 3) tumours were compared using univariate and multivariate analyses. RESULTS: No associations between grade and imaging factors were found for papillary and chromophobe RCCs. For clear cell RCCs, there was a significant association between the grade and parenchymal WiI (WiI2) (P = 0.02) or ADCr (P = 0.03). A significant association between tumour grade and size (P = 0.01), WiI2 (P = 0.02) and ADCr (P = 0.05) remained in multivariate analysis. CONCLUSIONS: Multiparametric MRI can be used to accurately differentiate low Fuhrman grade clear cell RCC from high grade. High Fuhrman grade (≥ 3) RCCs were larger, had lower parenchymal wash-in indices and lower ADC ratios than low grade. KEY POINTS: • Fuhrman grade of clear cell RCC can be differentiated with multiparametric MR imaging. • Fuhrman grade significantly differed for size, parenchymal wash-in index and ADC ratio. • No significant associations were found for papillary and chromophobe renal cell carcinoma.

Adverse event management in patients with advanced cancer receiving oral everolimus: focus on breast cancer.

BACKGROUND: Everolimus, an orally administered rapamycin analogue, inhibits the mammalian target of rapamycin (mTOR), a highly conserved intracellular serine-threonine kinase that is a central node in a network of signaling pathways controlling cellular metabolism, growth, survival, proliferation, angiogenesis, and immune function. Everolimus has demonstrated substantial clinical benefit in randomized, controlled, phase III studies leading to approval for the treatment of advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, renal angiomyolipoma and subependymal giant-cell astrocytoma associated with tuberous sclerosis complex, as well as advanced hormone-receptor-positive (HR(+)) and human epidermal growth factor receptor-2-negative advanced breast cancer. MATERIALS AND METHODS: We discuss clinically relevant everolimus-related adverse events from the phase III studies, including stomatitis, noninfectious pneumonitis, rash, selected metabolic abnormalities, and infections, with focus on appropriate clinical management of these events and specific considerations in patients with breast cancer. RESULTS: The majority of adverse events experienced during everolimus therapy are of mild to moderate severity. The safety profile and protocols for toxicity management are well established. The class-effect adverse event profile observed with everolimus plus endocrine therapy in breast cancer is (as expected) distinct from that of endocrine therapy alone, but is similar to that observed with everolimus in other solid tumors. Information gained from the experience in other carcinomas on prompt diagnosis and treatments to optimize drug exposure, treatment outcomes, and patients' quality of life also applies to the patient population with advanced breast cancer. CONCLUSIONS: As with all orally administered agents, education of both physicians and patients in the management of adverse events for patients receiving everolimus is critical to achieving optimal exposure and clinical benefit. Active monitoring for early identification of everolimus-related adverse events combined with aggressive and appropriate intervention should lead to a reduction in the severity and duration of the event.

Routinely performed multiparametric magnetic resonance imaging helps to differentiate common subtypes of renal tumours.

OBJECTIVES: To retrospectively evaluate the ability of multiparametric magnetic resonance (MR) imaging to differentiate renal tumours. METHODS: MR images from 100 consecutive pathologically proven solid renal tumours without macroscopic fat [57 clear cell, 16 papillary and 7 chromophobe renal cell carcinomas (RCCs), 16 oncocytomas and 4 minimal fat angiomyolipomas (AMLs)] between 2009 and 2012 were evaluated. Two radiologists blinded to pathology results independently reviewed double-echo chemical shift, dynamic contrast-enhanced T1- and T2-weighted images and apparent diffusion coefficient (ADC) maps. Signal intensity index (SII), tumour-to-spleen SI ratio (TSR), ADC ratio, wash-in (WiI) and wash-out indices (WoI) between different phases were calculated. RESULTS: There were significant differences between papillary RCCs and other renal tumours for arterial WiI (P < 0.001), initial WoI (P = 0.006) and ADC ratio (P < 0.001); between chromophobe RCCs and oncocytomas for TSR (P = 0.02), parenchymal WiI (P = 0.03), late WiI (P = 0.02), initial WoI (P = 0.03) and late WoI (P = 0.04); and between clear cell RCCs and oncocytomas for SII (P = 0.01) and parenchymal WiI (P = 0.01). Papillary RCCs were distinguished from other tumours (sensitivity 37.5 %, specificity 100 %) and oncocytomas from chromophobe RCCs (sensitivity 25 %, specificity 100 %) and clear cell RCCs (sensitivity 100 %, specificity 94.2 %). CONCLUSION: MR imaging provides criteria able to accurately distinguish papillary RCCs from other tumours and oncocytomas from chromophobe and clear cell RCCs. KEY POINTS: • Multiparametric MR parameters accurately distinguish papillary RCCs with high specificity (100 %). • Oncocytomas can be distinguished from chromophobe RCCs with high specificity (100 %). • Oncocytomas can be distinguished from clear cell RCCs with high specificity (94.2 %). • In oncocytomatosis, imaging follow-up with such parameters analysis could be promoted.

[Quantitative imaging in uro-oncology]. / L'imagerie d'évaluation thérapeutique en pratique clinique d'oncologie urologique.

INTRODUCTION: Imaging currently performed in uro-oncology could provide useful information. The use of all this information could help to better understand tumor growth and response to treatment. Therefore, it seems interesting to review the knowledge, to describe the main techniques currently available in many centers or in process and to clarify their results. MATERIALS AND METHODS: A systematic literature review was conducted in the PubMed database to identify all imaging techniques performed for therapeutic evaluation in uro-oncology. The keywords used were: cancer, kidney, bladder, prostate, urology biomarkers, imaging, ultrasound, CT-scan, MRI, PET-CT, RECIST, BOLD, ASL, gold DWI Diffusion, contrast, F-miso. The first publications identified were analyzed to search unidentified studies by the selected keywords. RESULTS: From simple to more complex morphology data from functional imaging (PET, MRI), data obtained from imaging helps to better understand tumor growth and response to treatment. Although optimizations are coming, all the techniques reported are available in many centers or going to be. CONCLUSION: The imaging evaluation in onco-urology can bring a large amount of information. Integrating to research protocols is now essential to sustain this activity.

Clinical biomarkers of response in advanced renal cell carcinoma.

There are now a range of effective targeted agents available for the first- and second-line treatment of advanced renal cell carcinoma (RCC). However, patients with advanced RCC have varied responses to therapy; some experience long-term responses while others may not respond, or even progress rapidly. Characteristics or markers that could be used to determine which patients will benefit most from which agent may enable us to select the optimal treatment of each individual patient, thereby improving efficacy and avoiding unnecessary toxic effects. These characteristics may be at the cellular or genetic level. Alternatively, the occurrence of adverse events may act as surrogate markers of a drug's on treatment activity, enabling prediction of outcomes during treatment. Recently, it has been suggested that during some targeted therapy for advanced RCC, the occurrence of specific adverse events, such as hypertension, hypothyroidism, hand-foot syndrome or fatigue/asthenia, may be associated with improved efficacy. This article reviews the evidence supporting clinical biomarkers in patients with advanced RCC receiving targeted agents. We also consider how these clinical biomarkers may affect the future management of patients with advanced RCC.

Phase I and pharmacokinetic study of IV vinflunine in cancer patients with liver dysfunction.

Vinflunine is a novel tubulin-targeted agent that is currently indicated as a monotherapy in bladder cancer patients. The recommended dose of 320 mg/m(2) is given as an intravenous infusion once every 3 weeks. Vinflunine is metabolized through CYP3A4 and mainly eliminated via the feces. A phase I trial was designed to explore the tolerability and pharmacokinetics of vinflunine in cancer patients with ranging degrees of liver dysfunction (LD). A sequential design was used for patient accrual, with the objective of determining the maximum tolerated dose (MTD) and the recommended dose (RD) of vinflunine in 3 groups of increasing LD levels. Vinflunine and its only active metabolite 4-O-deacetylvinflunine were quantified in serial whole blood samples. PK parameters were derived and compared between LD groups and with a reference PK database. Vinflunine and 4-O-deacetylvinflunine PK parameters were not affected in any of the explored LD levels. Geometric mean values for vinflunine total clearance were 47.8, 37.5 and 45.4 L/h in the 3 groups of increasing degrees of LD, as compared to 42.5 L/h in reference patients with no LD. No relationship was found between vinflunine clearance and the presence or absence of cirrhosis, nor was it found with the presence or absence of liver metastasis or with liver-related biochemical parameters. Based on the observed tolerability profile, the recommended doses of i.v. vinflunine are 320 mg/m(2), 250 mg/m(2) or 200 mg/m(2) for patients with increasing degrees of liver dysfunction.

Ten-year experience of percutaneous image-guided radiofrequency ablation of malignant renal tumours in high-risk patients.

OBJECTIVES: To evaluate survival and outcomes after percutaneous radiofrequency ablation (RFA) of malignant renal tumours in high-risk patients with long-term follow-up. METHODS: Between 2002 and 2009, 62 patients (71 tumours), with a median age of 73.5 years (20-87), consecutively treated with RFA under ultrasound or computed tomography guidance for malignant renal tumours were retrospectively selected and prospectively followed until 2012, including 25 patients (40.3 %) with solitary kidney and 7 cystic cancers. Maximal tumour diameters were between 8 and 46 mm (median: 23 mm). RESULTS: Radiofrequency ablation was technically possible for all patients. Mean follow-up was 38.8 months (range: 18-78 months). Primary and secondary technique effectiveness was 95.2 % and 98.4 % per patient respectively. The rates of local tumour progression and metastatic evolution were 3.2 % and 9.7 % per patient and were associated with tumour size >4 cm (P = 0.005). The disease-free survival rates were 88.3 % and 61.9 % at 3 and 5 years. No significant difference in glomerular filtration rates before and after the procedure was observed (P = 0.107). The major complications rate was 5.9 % per session with an increased risk in the case of central locations (P = 0.006). CONCLUSIONS: Percutaneous renal RFA appears to be safe and effective with useful nephron-sparing results. KEY POINTS: • Radiofrequency ablation (RFA) is a well-tolerated technique according to mid-term results. • RFA for malignant renal tumours preserved renal function in high-risk patients. • Mid-term efficacy of RFA was close to that of formal conservative surgery. • Tumour size and central location limit the efficacy and safety of RFA.

Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis.

BACKGROUND: A relevant percentage of patients with metastatic renal cell carcinoma develop intolerance to vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) and require careful selection of subsequent treatment. This retrospective analysis evaluated the safety and efficacy of everolimus in patients enrolled in the phase-III RECORD-1 trial who discontinued previous VEGFr-TKI therapy because of toxicity. METHODS: Patients with an adverse event (AE) as their primary reason for discontinuation of previous VEGFr-TKI therapy were included. Median progression-free survival (PFS) for VEGFr-TKI-intolerant patients in each arm was estimated using the Kaplan-Meier method, and effect on PFS (hazard ratio (HR)) was calculated using the Cox proportional hazard model. RESULTS: In VEGFr-TKI-intolerant patients (n=58, 14%), median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR: 0.32; P=0.004). In sunitinib-intolerant patients (n=26), median PFS was 5.1 months with everolimus and 2.8 months with placebo (HR: 0.28; P=0.033). Grade 3/4 AEs reported with everolimus in VEGFr-TKI-intolerant patients included infections (16%), fatigue (7%) and stomatitis (4%). The toxicity profile of everolimus was similar in the VEGFr-TKI-intolerant and overall study populations. CONCLUSION: Everolimus is well tolerated and efficacious with no increased toxicity in patients intolerant to VEGFr-TKI therapy.

Incidence and management of mTOR inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma.

The administration of mammalian target of rapamycin (mTOR) inhibitors can give rise to a potentially life-threatening adverse event, often referred to as 'non-infectious pneumonitis' (NIP), which is characterized by non-infectious, non-malignant, and non-specific inflammatory infiltrates. Patients usually present with cough and/or dyspnoea. We provide a brief description of the mechanism of action of mTOR inhibitors and their overall safety in patients with metastatic renal cell carcinoma (mRCC) and review the literature on mTOR inhibitor-associated NIP in patients with solid tumours. The review was used to derive questions on the diagnosis, management, and monitoring of mRCC patients with NIP, and to develop a decision tree for use in routine clinical practise. A key recommendation was the subdivision of grade 2 NIP into grades 2a and 2b, where grade 2a is closer to grade 1 and grade 2b to grade 3. This subdivision is important because it takes into account the nature and severity of clinical symptoms potentially related to NIP, either the onset of new symptoms or the worsening of existing symptoms, and thus determines the type and frequency of follow-up. It also helps to identify a subgroup of patients in whom treatment, if effective, may be continued without dose adjustment.