Zbynek Bortlicek

Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study

BACKGROUND A retrospective, registry-based analysis to assess the outcomes of metastatic renal cell cancer (mRCC) patients treated with sunitinib and sorafenib who developed dermatologic adverse events was performed. PATIENTS AND METHODS Data on mRCC patients treated with sunitinib or sorafenib were obtained from the Czech Clinical Registry of Renal Cell Cancer Patients. Outcomes of patients who developed hand-foot syndrome (HFS) of any grade and/or grade 3/4 rash during the treatment were compared with patients without HFS and no, mild, or moderate rash. RESULTS The cohort included 705 patients treated with sunitinib and 365 patients treated with sorafenib. For sunitinib, the median overall survival (OS) was 43.0 months versus 31.0 months (P = 0.027) and median progression-free survival (PFS) 20.8 months versus 11.1 months (P = 0.007) for patients with versus without dermatologic toxicity, respectively. For sorafenib, the median OS and PFS were 27.9 and 24.6 months (P = 0.244), and 12.2 and 8.8 months (P = 0.050), respectively. In multivariable Cox regression, the skin toxicity was significantly associated with longer OS in the sunitinib cohort. CONCLUSION The presence of skin toxicity is associated with improved OS and PFS in patients with mRCC treated with sunitinib.

Outcomes for Patients with Metastatic Renal Cell Carcinoma Achieving a Complete Response on Targeted Therapy: A Registry-based Analysis

BACKGROUND It is currently not known whether treatment with anti-vascular endothelial growth factor agents for metastatic renal cell carcinoma (mRCC) can be safely discontinued in patients achieving a complete response (CR). OBJECTIVE To assess outcomes for patients with mRCC achieving CR on targeted therapy (TT) and the survival of patients discontinuing TT after CR. DESIGN, SETTING, AND PARTICIPANTS A national registry was used to identify patients achieving CR during first-line TT using bevacizumab, sunitinib, sorafenib, or pazopanib. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Relationships with outcomes were analysed using a log-rank test. RESULTS AND LIMITATIONS A total of 100 patients achieving CR were identified out of 2803 patients. The median time to CR was 10.1 mo. Median progression-free survival (PFS) from TT initiation was 3.8 yr (95% confidence interval [CI] 2.9-4.6 yr) and the 5-yr overall survival (OS) was 80% (95% CI 70-91%). Patients discontinuing TT within 1 mo after achieving CR and those continuing TT beyond CR had similar OS (CI for difference in 2-yr post-CR OS -13% to 19%; p=0.3) and PFS (CI for difference in 2-yr post-CR PFS -29% to 17%; p=0.7). The limitations include the retrospective, registry-based data analysis. CONCLUSIONS Achievement of CR on TT for mRCC was associated with excellent long-term prognosis. No significant differences in post-CR survival were observed between patients discontinuing TT after the date of CR and those who continued on TT, although the wide CIs cannot exclude important differences between the groups. PATIENT SUMMARY According to this registry-based analysis, patients with metastatic renal cancer with no signs of disease (complete response) after treatment with targeted agents experience excellent long-term survival even if the treatment does not continue beyond the date of complete response.

Radiotherapy with rituximab may be better than radiotherapy alone in first-line treatment of early-stage follicular lymphoma: is it time to change the standard strategy?

Early-stage follicular lymphoma (FL) has traditionally been treated with involved-field radiotherapy (RT). Rituximab (R) is a low-toxic, efficient systemic therapy for FL, but there are no data about its clinical impact in early FL. We retrospectively analyzed 93 patients with stage I–II indolent FL treated with RT (n = 65) or RT + R (n = 14) or R alone (n = 14). Median follow-up was 5.0 years for patients with RT, 2.8 years for the RT + R subgroup and 2.5 years for patients treated with R. The complete response rate was 92%, 100% and 86% (not significant) and the median PFS was 3.3 years, not reached and 4.9 years (p = 0.035) for the RT, RT + R and R arms, with no impact on overall survival. R combined with RT seems to give better results in terms of global FL control, but longer follow-up and prospective comparison are needed to verify these results.

Factors associated with weight changes in successful quitters participating in a smoking cessation program.

OBJECTIVE To identify possible predictors of post-cessation weight gain in smoking abstainers. PATIENTS AND METHODS A sample of 607 successful abstainers seen at the Centre for Tobacco-Dependent in Prague, Czech Republic, between 2005 and 2010, was included in this analysis. This sample was followed up for 1year and included 47.9% women (N=291) with the mean age of 48years (18-85). FINDINGS Post-cessation weight gain occurred in 88.6% of the 607 abstainers. The mean weight gain after one year post-quit was 5.1kg (95% confidence interval 4.7-5.5kg). Baseline characteristics associated with increased weight gain included a higher baseline smoking rate (p<0.001), more severe cigarette dependence (p=0.003), less physical activity (p=0.008), and a report of increased appetite on the baseline assessment of withdrawal symptoms (p<0.001). CONCLUSIONS Smokers who are more dependent and have minimal physical activity are at increased risk for post-cessation weight gain. For these smokers, incorporating interventions targeting the weight issue into tobacco dependence treatment is recommended. Further research should be done to identify reasons for this important quitting complication.

Skin rash as useful marker of erlotinib efficacy in NSCLC and its impact on clinical practice.

Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor used in treatment of advanced NSCLC. Patients harboring EGFR or KRAS mutations represent minority of all patients in caucasian population and there is no available predictor for a predominant group of patients harboring the wild-type EGFR and wild-type KRAS genes. Skin rash is the most frequent manifestation of cutaneous toxicity of erlotinib. Rash is associated with a good therapeutic response. We aimed at the evaluation of rash as a predictor of therapeutic effect of erlotinib in patients harboring the wild-type EGFR and KRAS wild-type genes and to assess its possible usage in a clinical practice.Totally 184 patients with advanced stage NSCLC (IIIB, IV) harboring the wild-type EGFR and wild-type KRAS genes were analysed. Comparison of ORR, PFS and OS according to the occurrence of rash was performed. In order to assess the impact of rash in clinical practice it was conducted landmark analysis of the group of patients whose rash was observed during first month of treatment (n=124). Patients in whom progression was observed during the first month of treatment were excluded from the landmark analysis. The comparison of ORR was performed using Fishers exact test, visualization of survival was performed using Kaplan-Meier survival curves and the differences in survival were tested using the log-rank test. Median PFS in patients who were observed with rash during the treatment was 3.0 vs. 1.2 months in patients with no rash (p<0.001), median of OS in patients who were observed with rash during the treatment was 13.9 vs. 5.8 months in patients with no rash (p<0.001). ORR in patients who were observed with rash during the treatment was 17.4% vs. 3.3% in patients with no rash (p=0.001). Median of PFS after 1 month of treatment in patients who were observed with rash during the first month was 2.9 vs. 1.1 months in patients with no rash (p=0.027). Median of OS after 1 month of treatment in patients who were observed with rash during the first month was 13.8 vs. 9.9 months in patients with no rash (p=0.082). Rash is strongly associated with better survival and ORR in patients harboring wild-type EGFR and wild-type KRAS genes. Occurrence of rash during the first month of treatment is a useful predictor of better effect of erlotinib after one month of treatment. Patients who were not observed with rash during the first month of treatment are in high risk of progression. Optimization of the treatment of these patients can contribute restaging after two months of treatment, assessment of plasma levels of erlotinib and eventually attempt to dose escalation.

Surface-enhanced laser desorption ionization/time-of-flight (SELDI-TOF) mass spectrometry (MS) as a phenotypic method for rapid identification of antibiotic resistance.

Based on experiments with 10 defined strains of Escherichia coli, we present a new method for bacterial phenotyping using SELDI-TOF mass spectrometry. Changes in bacterial protein profiles in the context of the time of cultivation and the antibiotic environment were minimal. Proteom subprofiling may further distinguish between strains with specific susceptibility to antimicrobials. Mass spec-based methods may become common in the future of bacterial pathogen identification in clinical microbiology diagnostics.

Various forms of (18)F-FDG PET and PET/CT findings in patients with polymyalgia rheumatica.

AIM Polymyalgia rheumatica (PMR) is a disease presenting with pain and stiffness, mainly in shoulders, hip joints and neck. Laboratory markers of inflammation may bolster diagnosis. PMR afflicts patients over 50 years old, predominantly women, and may also accompany giant cell arteritis. PATIENTS AND METHODS 67 patients, who fullfiled Healey´s criteria for PMR in the period between 2004 and 2013 and had positive FDG PET (PET/CT) findings were retrospectively evaluated. FDG uptake was assessed in large arteries, proximal joints (shoulders, hips and sternoclavicular joints), in extraarticular synovial structures (interspinous, ischiogluteal and praepubic bursae). RESULTS Articular/periarticular involvement (A) was detected in 59/67 (88.1%) patients and extrarticular synovial involvement (E) in 51/67 (76.1%) patients either individually or in combinations. Vascular involvement (V) was detected in 27/67 (40.3%) patients only in combination with articular (A) and/or extraarticular synovial (E) involvement. These combinations were: A+E involvement in 30/67 (44.8%) patients, A+V involvement in 8/67 (11.9%) patients, E+V involvement in 6/67 (9%) patients and A+E+V in 13/67 (19.4%) patients. CONCLUSIONS PMR presents by articular/periarticular synovitis, extraarticular synovitis and can be accompanied by giant cell arteritis. All types of involvement have their distinct FDG PET (PET/CT) finding, which can be seen either individually or in any of their 4 combinations. FDG PET (PET/CT) examination seems to be an advantageous one-step examination for detecting different variants of PMR, for assessing extent and severity and also for excluding occult malignancy.

Clinical and laboratory prognostic factors in patients with metastatic renal cell carcinoma treated with sunitinib and sorafenib after progression on cytokines

OBJECTIVES The aim of this retrospective study was to analyze prognostic factors in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors (TKIs) sunitinib or sorafenib after progression on cytokine therapy. MATERIALS AND METHODS A national database of patients treated with targeted agents was used as the data source. A total of 319 patients treated with sunitinib (n = 181) or sorafenib (n = 138) after progression on cytokine therapy were analyzed. RESULTS Prognostic factors significantly associated with poor overall survival in a multivariable Cox model included the time from diagnosis to the start of treatment with TKIs<1 year, increased neutrophil counts, increased lactate dehydrogenase, and Eastern Oncology Cooperative Group performance status 2 or higher. The parameters showing statistically significant association with progression-free survival included time from diagnosis to the beginning of treatment with TKI<1 year, increased lactate dehydrogenase, and Eastern Oncology Cooperative Group performance status 2 or higher. We have also validated the International Metastatic Renal Cell Carcinoma Database Consortium prognostic model in our cohort of patients. CONCLUSION We demonstrate that the International Database Consortium prognostic model performs well for European patients treated with TKIs, including sunitinib or sorafenib, after progression on cytokines and suggest that a reduction from original 6 down to 4 parameters is possible.

Tobacco Treatment Outcomes in Patients With and Without a History of Depression, Czech Republic, 2005-2010

Introduction Higher prevalence of smoking among depressed patients, as well as the risk of depression in smokers, is well documented. The proportion of patients with a history of depression among those seeking intensive treatment of tobacco dependence is also high. In contrast, evidence of treatment success in this subgroup of patients is controversial. The aim of this study was to compare smoking abstinence rates after tobacco treatment in smokers with and without a history of depression. Methods We reviewed retrospective data from 1,730 smokers seeking treatment in Prague, Czech Republic. History of depression was defined as past diagnosis of depression or current treatment of depression. After a 1-year, self-reported smoking status was validated by expired-air carbon monoxide. We used logistic regression to analyze associations between abstinence rates, history of depression, and other factors (eg, age, sex, tobacco dependence). Results Of 1,730 smokers treated, 289 (16.7%) had a history of depression. The smoking abstinence rate at 1 year was 32.5% for smokers with a history of depression and 38.7% for those with no history (P = .048). Among women, abstinence did not differ between groups (35.0% vs 35.7%; P = .86). However, among men, those with a history of depression had lower rates of abstinence (27.4% vs 41.3%; P = .009). After adjustment for baseline covariates, history of depression was not significantly associated with smoking abstinence in men or women. Conclusion Intensive outpatient tobacco treatment programs can achieve abstinence rates among smokers with a history of depression similar to rates among the general population.

Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: a registry-based analysis.

OBJECTIVES The aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS A national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs. RESULTS Median progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013. CONCLUSION PFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy.