Tomasz Demkow

Sorafenib for Treatment of Renal Cell Carcinoma: Final Efficacy and Safety Results of the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial

PURPOSE Mature survival data and evaluation of vascular endothelial growth factor (VEGF) as a prognostic biomarker from the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) study in patients with renal cell carcinoma (RCC) are reported. PATIENTS AND METHODS Nine hundred three previously treated patients were randomly assigned to receive sorafenib versus placebo. On demonstration of progression-free survival (PFS) benefit with sorafenib, patients assigned to placebo were offered sorafenib. Overall survival (OS) was determined at two planned interim analyses and one final analysis, with a secondary OS analysis conducted by censoring placebo patients who crossed over to sorafenib. The relationships between baseline VEGF level and prognosis and efficacy were evaluated. RESULTS The final OS of patients receiving sorafenib was comparable with that of patients receiving placebo (17.8 v 15.2 months, respectively; hazard ratio [HR] = 0.88; P = .146); however, when post-cross-over placebo survival data were censored, the difference became significant (17.8 v 14.3 months, respectively; HR = 0.78; P = .029). Adverse events at 16 months after cross over were similar to those previously reported. Baseline VEGF levels correlated with Eastern Cooperative Oncology Group performance status (P < .0001), Memorial Sloan-Kettering Cancer Center score (P < .0001), and PFS and OS in univariate (PFS, P = .0013; OS, P = .0009) and multivariate (PFS, P = .0231; OS, P = .0416) analyses of placebo patients and with short OS by multivariate analysis of patients receiving sorafenib (P = .0145). Both high-VEGF (P < .01) and low-VEGF (P < .01) groups benefited from sorafenib. CONCLUSION Although an OS benefit was not seen on a primary intent-to-treat analysis, results of a secondary OS analysis censoring placebo patients demonstrated a survival advantage for those receiving sorafenib, suggesting an important cross-over effect. VEGF levels are prognostic for PFS and OS in RCC. The results of TARGET establish the efficacy and safety of sorafenib in advanced RCC.

Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma.

PURPOSE An open-label, phase II study to evaluate progression-free survival (PFS), overall best response, adverse events (AEs), and patient-reported outcomes with sorafenib versus interferon alfa-2a (IFN-alpha-2a) in patients with untreated, advanced renal cancer. PATIENTS AND METHODS A total of 189 patients were randomly assigned to oral sorafenib 400 mg twice daily or to subcutaneous IFN-alpha-2a 9 million U three times weekly (period 1). Sorafenib patients who progressed were dose-escalated to 600 mg twice daily; IFN-alpha-2a patients who progressed were switched to sorafenib 400 mg twice daily (period 2). RESULTS In period 1 PFS was similar for sorafenib-treated (n = 97; 5.7 months) and IFN-alpha-2a-treated patients (n = 92; 5.6 months); more sorafenib-treated patients had tumor shrinkage (68.2% v 39.0%). Common drug-related AEs (Grades > or = 3) for sorafenib were hand-foot skin reaction (11.3%), diarrhea (6.2%), and rash/desquamation (6.2%); for IFN-alpha-2a, these were fatigue (10.0%), nausea (3.3%), flu-like syndrome (2.2%), and anorexia (2.2%). Sorafenib-treated patients reported fewer symptoms, better quality of life (QOL), and greater treatment satisfaction. In period 2, 41.9% of patients who received sorafenib 600 mg twice daily (n = 43) experienced tumor reduction (median PFS, 3.6 months). After the switch to sorafenib 400 mg twice daily, tumors were reduced in 76.2% of 50 patients (median PFS, 5.3 months). AEs were mostly grade 1 to 2; no increase in AEs of grades > or = 3 occurred after sorafenib dose escalation. CONCLUSION In this study, sorafenib resulted in similar PFS as IFN-alpha-2a in patients with untreated RCC. However, sorafenib-treated patients experienced greater rates of tumor size reduction, better QOL, and improved tolerability. Both dose escalation of sorafenib after progression and a switch to sorafenib after progression on IFN-alpha-2a resulted in clinical benefit.

Multinational, Double-Blind, Phase III Study of Prednisone and Either Satraplatin or Placebo in Patients With Castrate-Refractory Prostate Cancer Progressing After Prior Chemotherapy: The SPARC Trial

PURPOSE This multinational, double-blind, randomized, placebo-controlled, phase III trial assessed the efficacy and tolerability of the oral platinum analog satraplatin in patients with metastatic castrate-refractory prostate cancer (CRPC) experiencing progression after one prior chemotherapy regimen. PATIENTS AND METHODS Nine hundred fifty patients were randomly assigned (2:1) to receive oral satraplatin (n = 635) 80 mg/m(2) on days 1 to 5 of a 35-day cycle and prednisone 5 mg twice daily or placebo (n = 315) and prednisone 5 mg twice daily. Primary end points were progression-free survival and overall survival (OS). The secondary end point was time to pain progression (TPP). RESULTS A 33% reduction (hazard ratio [HR] = 0.67; 95% CI, 0.57 to 0.77; P < .001) was observed in the risk of progression or death with satraplatin versus placebo. This effect was maintained irrespective of prior docetaxel treatment. No difference in OS was seen between the satraplatin and placebo arms (HR = 0.98; 95% CI, 0.84 to 1.15; P = .80). Compared with placebo, satraplatin significantly reduced TPP (HR = 0.64; 95% CI, 0.51 to 0.79; P < .001). Satraplatin was generally well tolerated, although myelosuppression and GI disorders occurred more frequently with satraplatin. CONCLUSION Oral satraplatin delayed progression of disease and pain in patients with metastatic CRPC experiencing progression after initial chemotherapy but did not provide a significant OS benefit. Satraplatin was generally well tolerated. These results suggest activity for satraplatin in patients with CRPC who experience progression after initial chemotherapy.

Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases.

8 Background: Radium-223 chloride (Ra-223) is a first-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy alpha-particles of extremely short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared efficacy, in terms of overall survival (OS), and safety of Ra-223 plus best standard of care (BSC) vs placebo plus BSC in patients (pts) with bone mets in CRPC. METHODS Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4 wks or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. A planned interim analysis (IA) was conducted to assess the effect of Ra-223 on the primary endpoint (OS) using a predefined threshold. Survival data were compared using a stratified log-rank test. RESULTS 922 pts (Ra-223, n = 615; placebo, n = 307) were randomized from 6/2008-2/2011. 445 (58%) of 809 pts in the IA data set received prior treatment with docetaxel. Ra-223 significantly improved OS in pts with CRPC with bone mets vs placebo (two-sided P = 0.00185; HR = 0.695; 95% CI, 0.552-0.875; median OS 14.0 mo vs 11.2 mo, respectively). Safety and tolerability of Ra-223 were highly favorable and showed low incidence of myelosuppression (eg, grades 3/4 neutropenia in 1.8% and 0.8% and thrombocytopenia in 4% and 2% of the Ra-223 and placebo groups, respectively). CONCLUSIONS Ra-223 is an effective therapy that improved OS with a highly favorable safety profile, and may provide a new standard of care for the treatment of CRPC pts with bone mets. [Table: see text].

Trebananib (AMG 386) in Combination With Sunitinib in Patients With Metastatic Renal Cell Cancer: An Open-Label, Multicenter, Phase II Study

PURPOSE Trebananib, an investigational recombinant peptide-Fc fusion protein, neutralizes the receptor-ligand interaction between Tie2 and angiopoietin-1/2. This phase II study was conducted to evaluate trebananib plus sunitinib, a vascular endothelial growth factor receptor inhibitor, in patients with metastatic clear cell renal cell carcinoma. PATIENTS AND METHODS Adults with metastatic renal cell carcinoma were enrolled sequentially onto two cohorts that received sunitinib 50 mg once per day for 4 weeks on and 2 weeks off and intravenous trebananib once per week at a dose of 10 mg/kg in cohort A or 15 mg/kg in cohort B. The primary end points were incidences of adverse events (AEs) and dose interruptions of sunitinib during the first 12 weeks of treatment. Secondary end points included objective response rate and progression-free survival. RESULTS Eighty-five patients were enrolled: 43 in cohort A, and 42 in cohort B. During the first 12 weeks of treatment, 58% and 57% of patients in cohorts A and B, respectively, had sunitinib dose interruptions (dose decrease, withholding, or withdrawal). The most frequent AEs were diarrhea (cohort A, 74%; cohort B, 67%), mucosal inflammation (cohort A, 49%; cohort B, 60%), and hypertension (cohort A, 52%; cohort B, 45%). AEs of grade 3 or greater occurred in 58% of patients in cohort A and in 69% of patients in cohort B. The objective response rate was 58% and 63% in cohorts A and B, respectively. The median progression-free survival time was 13.9 months (95% CI, 10.4 to 19.2) and 16.3 months (95% CI, 13.1 to 21.4) in cohorts A and B, respectively. The median overall survival time was 36 months (95% CI, 25.2 to not estimable) in cohort A and was not estimable (median follow-up, 25 months) in cohort B. CONCLUSION Trebananib plus sunitinib seemed to increase toxicity at the tested doses. Efficacy results suggest a potential benefit for the addition of trebananib to sunitinib.

Radium-223 chloride impact on skeletal-related events in patients with castration-resistant prostate cancer (CRPC) with bone metastases: A phase III randomized trial (ALSYMPCA).

9 Background: Radium-223 chloride (Ra-223) is a 1st-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy alpha-particles of short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) vs placebo (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included skeletal-related events (SREs). METHODS Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4 wks or matching pbo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. RESULTS 922 pts (Ra-223, n = 615; pbo, n = 307) were randomized from 6/2008-2/2011. Based on data from a planned interim analysis (n = 809), unblinded June 2011, Ra-223 significantly improved OS in pts with CRPC with bone mets vs pbo (median OS 14.0 vs 11.2 mo, respectively; two-sided P = 0.00185; HR = 0.695; 95% CI, 0.552-0.875). SREs were lower in the Ra-223 vs pbo group, and time to 1st SRE was significantly delayed (median time to SRE 13.6 mo vs 8.4 mo, respectively; P = .00046; HR = .610; 95% CI, .461-.807). CONCLUSIONS Ra-223 significantly delayed time to 1st SRE and SRE components, except surgical intervention. These reductions in SREs, particularly SCC, are noteworthy. Ra-223 is an effective therapy with a highly favorable safety profile and may provide a new standard of care for treatment of CRPC pts with bone mets. [Table: see text].

Sorafenib dose escalation in treatment-naïve patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study.

To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma (mRCC).

Chemotherapy-Induced Takotsubo Syndrome

Cardiovascular complications are a significant problem in systemically treated cancer patients. One such complication is Takotsubo cardiomyopathy, also known as Takotsubo syndrome. It is most frequently defined as a sudden and transient left or right ventricular systolic dysfunction; mimicking acute coronary syndrome, but without the associated changes in coronary arteries. Takotsubo syndrome is a relatively little known complication that appears in the course of oncological treatment, and its incidence has not yet been established. In this study, we reviewed Medline database according to case reports concerning takotsubo syndrome appearing after systemic treatment in oncological patients. We took into consideration all types of anticancer drugs. We reviewed the changes reported in the electrocardiography, echocardiography, and coronary angiography, and also the level of troponin, a marker of acute coronary syndrome elevation. In view of the increasing frequency of cardiac complications reported in patients receiving systemic oncological treatment, Takotsubo syndrome appears to be underdiagnosed. However, the syndrome may be linked to potentially fatal complications such as cardiogenic shock or cardiac arrest. Therefore, it seems essential to carry out appropriate diagnostic procedures for every patient experiencing clinical side effects of onco-pharmacotherapy. In patients with chest pain and dyspnea during or after treatment, Takotsubo syndrome should be considered, particularly that the syndrome requires a different therapy approach than that used in a coronary syndrome. Diagnostic procedures should include echocardiogram and the assessment of myocardial necrosis markers and natriuretic peptides.

Testicular teratomas: a growing problem?

Testicular teratomas represent a specific entity within the group of germ-cell tumours. They may comprise elements of all three germ layers. In contrast to prepubertal benign teratomas observed in infants and adolescents, postpubertal teratomas originate from the malignant germ-cell precursor. Given the good prognosis and curability of most patients with germ-cell tumour, medical oncologists and urological surgeons must be well acquainted with the principles of teratomas management. Surgery plays the decisive part in teratomas treatment, as these tumours are resistant to radio- and, to some extent, chemotherapy. In this article we concentrate on the management of post-chemotherapy resection of teratomatous masses, with special attention to the phenomenon of ‘growing teratoma syndrome’ and somatic-type transformation of teratomas. To understand the nature of teratomas better, we begin with a glimpse of their biological, molecular and immunohistochemical features. Managing germ-cell tumours, teratomas in particular, in high-volume reference centres is of utmost importance to maintain and increase the survivorship rate in these patients.

The prospective assessment of the prostatic cancer mortality with PSA progression in the groups treated or not treated by salvage local brachytherapy.

85Background: The effectiveness of diagnostics of local recurrence of prostatic adenocarcinoma after radical radiotherapy and local retreatment high definition brachytherapy and its influence on the prostatic cancer survival. Methods: 55 patients with locally advanced prostatic adenocarcinoma with rising PSA level after radical radiotherapy and exclusion of distant metastases underwent prostatic biopsy. ECOG performance status 0-1 were eligible. The histopathological confirmation was obtained in 22 cases, and 33 patients had negative biopsy. In the case of positive biopsy radical salvage brachytherapy was performed in all patients. In the case of negative biopsy definitive anti-androgen therapy was administered in patients with PSA progression. Anti – androgen therapy was performed as adjuvant and neoadjuvant treatment after brachytherapy. In the course of the long (median 108months) observation we assessed prostatic specific mortality in both groups. In addition we assessed time to PSA progression during...