Posterior Reversible Encephalopathy Syndrome Associated with Sorafenib and Successful Retreatment.

Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological syndrome characterized by acute hypertension, headache, decreased level of consciousness, visual disturbances and seizures associated with characteristic neuroimaging changes indicative of vasogenic edema of the posterior cerebral white matter. Several medical conditions have been associated with PRES including hypertensive encephalopathy and eclampsia. The use of cytotoxic and immunosuppressant drugs, such as those which target vascular endothelial growth factor (VEGF), have also been implicated. We report here the case of a 71-year-old woman with metastatic clear cell renal carcinoma who developed PRES 3 months after commencing sorafenib. Elevated blood pressure (BP) was recorded, and MRI of the brain) of the brain showed asymmetric areas of increased signal intensity within the supratentorial white matter suggestive of PRES. Clinical and radiological features rapidly improved with BP control and discontinuation of sorafenib. Sorafenib was resumed with no sign of PRES recurrence. The present case report supports the hypothesis that, in selected patients, the re-introduction of anti-VEGF therapies after PRES is feasible.

Randomized Phase II Study of Cabazitaxel Versus Methotrexate in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With Platinum-Based Therapy.

LESSONS LEARNED: Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. For the first time, cabazitaxel was investigated in incurable patients with recurrent SCCHN. Patients were randomly assigned to cabazitaxel every 3 weeks or weekly methotrexate.This phase II study did not meet its primary endpoint.Cabazitaxel has low activity in SCCHN.The toxicity profile in this population also was not favorable owing to the high rate of febrile neutropenia observed (17%). BACKGROUND: Cabazitaxel is a second-generation taxane that improves the survival of patients with metastatic castrate-resistant prostate cancer following docetaxel therapy. Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. In this randomized phase II trial, we investigated cabazitaxel in patients with recurrent SCCHN. METHODS: Patients with incurable SCCHN with progression after platinum-based therapy were randomly assigned to cabazitaxel every 3 weeks (cycle 1, 20 mg/m2, increased to 25 mg/m2 for subsequent cycles in the absence of nonhematological adverse events [AEs] greater than grade 2 and hematological AEs greater than grade 3) or methotrexate (40 mg/m2/week). The patients were stratified according to their performance status and previous platinum-based chemotherapy for palliation versus curative intent. The primary endpoint was the progression-free survival rate (PFSR) at 18 weeks. RESULTS: Of the 101 patients, 53 and 48, with a median age of 58.0 years (range, 41-80), were randomly assigned to cabazitaxel or methotrexate, respectively. The PFSR at 18 weeks was 13.2% (95% confidence interval [CI], 5%-25%) for cabazitaxel and 8.3% (95% CI, 2%-20%) for methotrexate. The median progression-free survival was 1.9 months in both arms. The median overall survival was 5.0 and 3.6 months for cabazitaxel and methotrexate, respectively. More patients experienced serious adverse events with cabazitaxel than with methotrexate (54% vs. 36%). The most common drug-related grade 3-4 AE in the cabazitaxel arm was febrile neutropenia (17.3%). CONCLUSION: This study did not meet its primary endpoint. Cabazitaxel has low activity in recurrent SCCHN.

Phase II study of dual phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma.

OBJECTIVE: To assess, in a multicentre phase II trial, the safety and efficacy of BEZ235, an oral pan-class I phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) complex1/2 inhibitor, in locally advanced or metastatic transitional cell carcinoma (TCC) after failure of platinum-based therapy. PATIENTS AND METHODS: Patients with locally advanced or metastatic TCC progressing after platinum therapy were prospectively stratified by PI3K/Akt/mTOR pathway alterations, defined as PTEN loss and PIK3CA mutation. All patients received BEZ235 until progressive disease or unacceptable toxicity. The primary endpoint was the progression-free survival (PFS) rate at 16 weeks. This study was, however, closed prematurely because BEZ235 was withdrawn from further development. RESULTS: A total of 20 patients (18 without and two with PI3K/Akt/mTOR alterations) were enrolled and received BEZ235. One partial response (5%) and two cases of stable disease (10%) were observed, all in patients without PI3K/mTOR pathway alterations. The PFS rate at 8 and 16 weeks was 15 and 10%, respectively; the median (range) PFS was 62 (38-588) days (95% confidence interval [CI] 53-110); and the median (range) overall survival was 127 (41-734) days (95% CI 58-309). Among the 90% of patients who experienced drug-related adverse events of any grade, 50% experienced grade 3-4 adverse events, including stomatitis (15%), fatigue (5%), nausea (5%), diarrhoea (5%), renal failure (5%), cutaneous rash (5%), hepatotoxicity (5%) and hypertension (5%). CONCLUSION: BEZ235 showed modest clinical activity and an unfavourable toxicity profile in patients with advanced and pretreated TCC; however, a minority of patients experienced a clinical benefit, suggesting that a complete blockade of the PI3K/mTOR axis could improve outcome in some specific patients. Furthermore, this study showed that molecular stratification of patients for personalized medicine before treatment is feasible.

Which Factors Predict Overall Survival in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With Abiraterone Acetate Post-Docetaxel?

BACKGROUND: Abiraterone acetate (AA) increases overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel. However, survival time varies substantially between individuals. Our goal was to identify prognostic factors that better estimate OS. MATERIALS AND METHODS: This is a retrospective multicentric analysis of 368 patients with mCRPC starting AA with prednisone after docetaxel. Cox proportional hazards statistics were applied. A multivariate model was constructed based on significant univariate predictors by using a manual stepwise forward and backward selection strategy. Model performance was determined by using receiver operating characteristic (ROC) curves. RESULTS: Univariate analysis identified 20 significant OS predictors. A multivariate model was constructed, based on 220 patients, incorporating 5 independent risk factors for decreased OS at the time of AA initiation: hemoglobin < 12 g/dL (hazard ratio [HR] 2.02), > 10 metastases (HR 1.80), ECOG performance status ≥ 2 (HR 1.88), radiographic progression (HR 1.50), and time since diagnosis < 90 months (HR 1.66, all P < .05). Patients were stratified into 3 groups: good (0-2 risk factors, median OS 22.6 months), intermediate (3 risk factors, median OS 13.9 months), and poor prognosis (4-5 risk factors, median OS 6.2 months). The area under the ROC curve based on the event "death by the time of median OS (13.3 months)" was 0.736 (95% confidence interval 0.670-0.803). CONCLUSION: We identified 5 readily available risk factors independently associated with decreased OS. The resulting model may be used for patient counseling in daily clinical practice, as well as patient stratification in clinical trials.

Abiraterone acetate post-docetaxel for metastatic castration-resistant prostate cancer in the Belgian compassionate use program.

BACKGROUND: Abiraterone acetate (AA) is licensed for treating metastatic castration-resistant prostate cancer (mCRPC). Real-world data on oncological outcome after AA are scarce. The current study assesses efficacy and safety of AA in mCRPC patients previously treated with docetaxel who started treatment during the Belgian compassionate use program (January 2011-July 2012). PATIENTS AND METHODS: Records from 368 patients with mCRPC from 23 different Belgian hospitals who started AA 1000mg per day with 10mg prednisone or equivalent were retrospectively reviewed (September 2013-December 2014). Prostate-specific antigen (PSA) response (decrease≥50%), time to PSA progression (increase>50% over PSA nadir in case of PSA response/>25% in absence of PSA response), time to radiographic progression (on bone scans or for soft tissue lesions using Response Evaluation Criteria In Solid Tumors 1.1), overall survival and adverse event rate (Common Terminology Criteria for Adverse Events v4.03) were analyzed. Kaplan-Meier statistics were applied. RESULTS: Overall, 92 patients (25%) had an Eastern Cooperative Oncology Group performance status≥2. Median age was 73 years, median PSA was 103ng/dl. PSA response was observed in 131 patients (37.4%). Median time to PSA and radiographic progression was 4.1 months (95% CI: 3.6-4.6) and 5.8 months (5.3-6.4), respectively. Median overall survival was 15.1 months (13.6-16.6). Most common grade 3 to 4 adverse events were anemia (13.9%), hypokalemia (7.3%), fatigue (6.8%), and pain (6.3%). Median duration of AA treatment was 5.3 months (interquartile range: 2.8-10.3). The main study limitation is its retrospective design. CONCLUSIONS: These real-world data on post-docetaxel AA efficacy are in line with the COU-AA-301 trial. Importantly, incidence of severe anemia and hypokalemia is up to 50% higher than reported in previous studies.

Patient outcome in the Belgian medical need program on bevacizumab for recurrent glioblastoma.

Bevacizumab (BEV) has demonstrated anti-tumor activity in patients with recurrent glioblastoma (rGB). Given the unmet need for active therapeutic options in rGB patients, a medical need program was initiated by the Belgian competent authorities. Between November 2010 and February 2013, a total of 313 patients with rGB initiated treatment with BEV administered at a dose of 10 mg/kg every 2 weeks. All patients had failed prior treatment with at least radiation therapy and temozolomide and the majority of patients (70 %) were treated with corticosteroids at baseline. Patients received a median of 6 BEV administrations (range 1-53). Overall, BEV was well tolerated. During BEV treatment the WHO-Performance Score (WHO-PS) improved in 59 patients (19 %) and stabilized for at least 6 weeks in an additional 139 (44 %) patients. Corticosteroid treatment could be stopped in 16 % or reduced in dose in 32 % of patients. The best objective tumor response rate using RANO criteria (investigator's assessment) was 3.5 % CR, 22 % PR, 38 % SD and 37 % PD. The median and 6-month PFS were 13 weeks (95 % CI 12.7-14) and 27.3 % (95 % CI 22.3-32.5), median and 6-month OS rates were 26 weeks (23-29) and 52 % (46.4-58.6), respectively. WHO-PS (0-1 vs. 2-3) and baseline steroid use were significantly correlated with PFS and OS. Our observations support the use of BEV as a monotherapy for patients with rGB who have no alternative treatment options. Optimal benefit from BEV treatment is likely to be obtained when treatment is initiated before the performance status deteriorates to two or less.

The Prognostic Significance of Metabolic Response Heterogeneity in Metastatic Colorectal Cancer.

BACKGROUND: Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC). METHODS: Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions. RESULTS: Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8-10.5) and 4.2 months (95% CI: 3.4-4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21-0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36-0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS. CONCLUSION: The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01290926.

Prospective randomized study comparing docetaxel, estramustine, and prednisone with docetaxel and prednisone in metastatic hormone-refractory prostate cancer.

PURPOSE: To assess the efficacy and toxicity of the addition of estramustine to docetaxel (D) for the treatment of metastatic hormone-refractory prostate cancer. PATIENTS AND METHODS: One hundred fifty patients were randomly assigned to D alone (35 mg/m(2) on days 2 and 9, every 3 weeks) or D in combination with estramustine (D/E; 280 mg orally three times a day on days 1 to 5 and 8 to 12, every 3 weeks). All patients received prednisone (10 mg/d). The primary end point was prostate-specific antigen (PSA) response rate, which was defined as a decrease in PSA > or = 50% from baseline. The study was powered to test the hypothesis that D/E would improve the PSA response rate by 25%. RESULTS: The PSA response rate was not statistically different between the two groups. PSA of less than 4 ng/mL occurred in 29 (41%) of 71 patients receiving D/E and in 17 (25%) of 69 patients receiving D (P = .05). No significant differences were found for median time to PSA progression (D/E, 6.9 months; D, 7.3 months) or median overall survival time (D/E, 19.3 months; D, 21 months). More patients had at least one grade 3 or 4 toxicity with D/E (45%) compared with D (21%; P = .005), mainly as a result of grade 3 or 4 GI toxicity (P = .05). Serious adverse events were more frequent with D/E (n = 20) than with D (n = 9; P = .04). CONCLUSION: The addition of estramustine to weekly D does not provide any clinically relevant advantage. Both regimens are well tolerated, although the toxicity profile favors D without estramustine.