Avivit Peer

Pretreatment Neutrophil-to-Lymphocyte Ratio in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Ketoconazole: Association with Outcome and Predictive Nomogram

BACKGROUND The neutrophil-to-lymphocyte ratio (NLR), an inflammation marker, is prognostic in several cancers. We assessed the association between the pretreatment NLR and outcome of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the CYP17 inhibitor ketoconazole. METHODS This was an international, retrospective study of 156 mCRPC patients treated with ketoconazole. The independent effect of the pretreatment NLR and factors associated with treatment outcome were determined by multivariate analysis. RESULTS Seventy-eight patients (50%) had a ≥50% decline in prostate-specific antigen (PSA). The median progression-free survival (PFS) time was 8 months. Excluded from the analysis were 23 patients without available data on their NLR and those with a recent health event or treatment associated with a blood count change. Sixty-two patients (47%) had a pretreatment NLR >3. Risk factors associated with the PFS outcome were a pretreatment NLR >3 and PSA doubling time (PSADT) <3 months and a prior response to a gonadotropin-releasing hormone agonist of <24 months or to an antiandrogen of <6 months. The number of risk factors was used to form a predictive nomogram by patient categorization into favorable (zero or one factor), intermediate (two factors), and poor (three or four factors) risk groups. CONCLUSIONS In mCRPC patients treated with ketoconazole, the pretreatment NLR and PSADT, and prior response to androgen-deprivation therapy, may be associated with the PFS time and used to form a risk stratification predictive nomogram.

Bisphosphonates combined with sunitinib may improve the response rate, progression free survival and overall survival of patients with bone metastases from renal cell carcinoma

BACKGROUND Bisphosphonates are used to prevent skeletal events of bone metastases, and may exhibit antitumour effects. We aimed to evaluate whether bisphosphonates can bring a response rate (RR), progression free survival (PFS) and overall survival (OS) benefit to patients with bone metastasis from renal cell carcinoma (RCC) that is treated with sunitinib. METHODS We performed a multicentre retrospective study of patients with bone metastases from RCC that was treated with sunitinib. The effect of bisphosphonates on RR, PFS and OS was tested with adjustment for known prognostic factors using a chi-square test from contingency table and partial likelihood test from Cox regression model. RESULTS Between 2004 and 2011, 209 patients with metastatic RCC were treated with sunitinib, 76 had bone metastases, 35 bisphosphonates users and 41 non-users. The groups of bisphosphonates users and non-users were balanced regarding known prognostic factors. Objective response was partial response/stable disease 86% (n = 30) versus 71% (n = 29), and progressive disease 14% (n = 5) versus 29% (n = 12) (p = 0.125, OR 2.48) in users versus non-users, respectively. Median PFS was 15 versus 5 months (HR = 0.55, p<0.0001), and median OS was not reached (with a median follow-up time of 45 months) versus 14 months (HR = 0.4, p = 0.029), in favour of users. In multivariate analysis of the entire patient cohort (n = 76), factors associated with PFS were bisphosphonates use (HR = 0.58, p = 0.035), and pre-treatment neutrophil to lymphocyte ratio >3 (HR = 3.5, p = 0.009). Factors associated with OS were bisphosphonates use (HR = 0.5, p = 0.008), elevated pre-treatment alkaline phosphatase (HR = 2.9, p = 0.003) and sunitinib induced HTN (HR = 0.63, p<0.0001). CONCLUSIONS Bisphosphonates may improve the RR, PFS and OS of sunitinib treatment in RCC with bone metastases.

Active Smoking May Negatively Affect Response Rate, Progression-Free Survival, and Overall Survival of Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib

BACKGROUND Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). METHODS An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. RESULTS Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002). CONCLUSION Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.

Activity of Cabazitaxel After Docetaxel and Abiraterone Acetate Therapy in Patients With Castration-Resistant Prostate Cancer

BACKGROUND Cabazitaxel and AA have been approved by the US Food and Drug Administration for use after docetaxel in mCRPC. Recently, CAB appeared to be active when given after AA. AA is capable of inducing AR splice variants that confer ligand-independent AR transactivation. Because microtubule-targeting agents impair AR nuclear transport and activity, we raised concerns about CAB efficacy after AA failure in mCRPC. PATIENTS AND METHODS One hundred thirty mCRPC patients received AA after docetaxel treatment in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data using conventional methods. RESULTS Twenty-four patients received a median of 4 (range, 1-13) CAB cycles. Nineteen (79.1%) of them received primary prophylaxis with growth factors. Median patient characteristics were: age 65 (range, 57-85) years; Gleason score: 8 (range, 6-10); and PSA: 128.1 (range, 0.01-1700) ng/mL. A PSA response (≥ 50% decrease from baseline) occurred in 6 (31.5%) of 19 evaluable patients (95% confidence interval [CI], 11.8-54.2%). CAB therapy obtained a partial response in 2 of the 13 (15.3%) evaluable patients (95% CI, 2.9-45.4%). Median survival from initiation of CAB was 8.2 (95% CI, 3.34-13.05) months, from AA 16.1 (95% CI, 11.56-20.64) and from docetaxel 32.0 (95% CI, 11.56-39.69). CONCLUSION A limited number of patients with mCRPC received CAB after docetaxel and AA treatment. In this selected population, CAB was active.

Comparison of abiraterone acetate versus ketoconazole in patients with metastatic castration resistant prostate cancer refractory to docetaxel

Abiraterone, a potent CYP 17 inhibitor, is standard treatment in docetaxel refractory, metastatic castrate resistant prostate cancer (mCRPC). However, in countries where abiraterone has not been approved yet, or for patients who cannot afford it, ketoconazole is used as an alternative CYP 17 inhibitor. Although preclinical data suggests that ketoconazole is a less potent inhibitor of CYP 17, there are limited clinical data comparing both agents. We aimed to compare the clinical effectiveness of abiraterone versus ketoconazole in docetaxel refractory mCRPC.

Activity of cabazitaxel following docetaxel and abiraterone acetate in patients with castration-resistant prostate cancer.

186 Background: Cabazitaxel (CAB) and abiraterone-acetate (AA) have been approved after docetaxel in castration resistant prostate cancer (CRPC). Both exhibit hormonal effects. AA depletes androgen in microenvironment; taxanes affect the microtubule-dependent trafficking of the androgen receptor. Recently, clinical cross-resistance has been suggested between AA and taxanes. This prompted evaluation of CAB following docetaxel and AA in CRPC. METHODS Over 13 months until December 2011, 130 CRPC patients received AA after docetaxel in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data (PCWG2/RECIST and NCI toxicity criteria). RESULTS Fourteen (58.3%) received CAB/prednisone at 20 mg/m2 and 10 patients 25 mg/m2, overall a median of 4 (1-13) cycles. Nineteen (79.1%) received primary G-CSF support. Patient characteristics (median, range in parenthesis): Age 65 (57-85) years, Gleason- 8 (6-10), K.S- 80 (50-90) %. Metastatic sites: liver- 5 (20.8%), visceral- 8 (33.3%), osseous- 22 (91.6%), No. sites involved- 2 (1-4). Lab-work: PSA- 128.1 (0.01-1700) ng/ml, PSA Doubling time- 2.16 (0.64-7.41) months, alkaline phosphatase 129 (35-1200) u/L. Castration sensitive period - 16.2 (2.0-92.1) months. Using Cox univariate analysis, only K.S was near-significant for prediction of survival after initiating CAB, p=0.075, OR=0.315, 95% C.I (0.88-1.125). A PSA response of 30%, 95% C.I (11,8-54,2)% was observed after CAB with non progression occurring in 6 (26%) out of 23 evaluable patients, 95% CI (10.2-48.4)%. At analysis 11 patients are alive. Median survival from initiation of CAB was 8.2 (95% C.I 3.34-13.05) months, from AA 16.1 (95 C.I 11.56-20.64) and from docetaxel 32.0 (95% C.I 11.56-39.69). Non-progression with docetaxel (but not AA) was associated with longer survival with CAB, p=0.049, 43.1 v.s 17.4 months. Four (16.6%) patients developed infectious complications, including one death due to septic shock. CONCLUSIONS Limited number of patients with CRPC received CAB following docetaxel and AA. In this selected population CAB was active. Response to prior docetaxel was associated with prolonged survival to CAB therapy.

Re-treatment with radium-223 : first experience from an international, open-label, phase I/II study in patients with castration-resistant prostate cancer and bone metastases

Abstract Background Six radium-223 injections at 4-week intervals is indicated for patients with castration-resistant prostate cancer and symptomatic bone metastases. However, patients usually develop disease progression after initial treatment. This prospective phase I/II study assessed re-treatment safety and efficacy of up to six additional radium-223 injections. Patients and methods Patients had castration-resistant prostate cancer and bone metastases and six initial radium-223 injections with no on-treatment bone progression; all had subsequent radiologic or clinical progression. Concomitant agents were allowed at investigator discretion, excluding chemotherapy and initiation of new abiraterone or enzalutamide. The primary endpoint was safety; additional exploratory endpoints included time to radiographic bone progression, time to total alkaline phosphatase and prostate-specific antigen progression, radiographic progression-free survival, overall survival, time to first symptomatic skeletal event (SSE), SSE-free survival, and time to pain progression. Results Among 44 patients, 29 (66%) received all six re-treatment injections. Median time from end of initial radium-223 treatment was 6 months. Forty-one (93%) reported ≥1 treatment-emergent adverse event. No grade 4–5 hematologic treatment-emergent adverse events occurred. Only one (2%) patient had radiographic bone progression; eight (18%) had radiographic soft tissue tumor progression (three lymph node and five visceral metastases). Median times to total alkaline phosphatase and prostate-specific antigen progression were not reached and 2.2 months, respectively. Median radiographic progression-free survival was 9.9 months (12.8-month maximum follow-up). Five (11%) patients died and eight (18%) experienced first SSEs. Median overall survival, time to first SSE, and SSE-free survival were not reached. Five (14%) of 36 evaluable patients (baseline worst pain score ≤7) had pain progression. After 2 years of follow-up, 28 (64%) patients died, and the median overall survival was 24.4 months. Conclusions Re-treatment with a second course of six radium-223 injections after disease progression is well tolerated, with minimal hematologic toxicity and low radiographic bone progression rates in this small study with limited follow-up. Favorable safety and early effects on disease progression indicate that radium-223 re-treatment is feasible and warrants further evaluation in larger prospective trials.

Influence of risk factors for renal cell carcinoma (RCC) on outcome of patients (pts) with metastatic disease treated with sunitinib.

437 Background: Obesity, smoking, hypertension (HTN) and diabetes (DM) are risk factors for RCC development. Their presence has been associated with a worse outcome of therapy (tx) in various metastatic cancers. We sought to determine their influence on the progression free survival (PFS) and overall survival (OS) of Su tx in mRCC. METHODS We performed a multicentre retrospective study of pts with mRCC, who were treated with Su. We analyzed the pre-tx status of smoking (active vs past vs never), BMI (obese=BMI≥30 vs overweight=BMI 25-29.9 vs normal weight=BMI <25), HTN, DM, and known prognostic factors including past nephrectomy, clear cell/non clear cell histology, time from initial diagnosis to Su tx, > 2 metastasis (mets) sites, lung/liver/bone mets, ECOG performance status, anemia, calcium level > 10 mg/dL, elevated alkaline phosphatase (AP), platelets count, pre-tx neutrophil to lymphocyte ratio (NLR) >3, Su induced HTN, use of angiotensin system inhibitors (ASIs), past cytokines/targeted tx, and mean Su dose/cycle. PFS and OS were determined by the Kaplan-Meier method. Multivariate analyses using Cox Regression model were performed to determine their independent effect. RESULTS Between 2004-2011, 209 pts with mRCC were treated with Su. 40 pts were active smoker, 51 obese, 55 diabetic, and 122 had pre-tx HTN. In the entire pt cohort, median PFS was 8 months (mos) and OS 15 mos. Factors associated with PFS were active smoking (HR 2.5, p= 0.005, median PFS 4 vs 10 mos in past smokers vs 10 mos in never smokers), non clear cell histology (HR 1.8, p=0.023), pre-tx NLR >3 (HR 0.2, p<0.0001) and the use of ASIs (HR 1.66, p=0.028). Factors associated with OS were were active smoking (HR 2.1, p= 0.03, median OS 8.5 vs 18 mos in past smokers vs 18 mos in never smokers), AP (HR 1.76, p=0.049), pre-tx NLR >3 (HR 0.294, p<0.0001), and liver mets (HR 0.553, p=0.04). BMI, DM, and pre-tx HTN were not associated with PFS or OS. CONCLUSIONS Active smoking may decrease the PFS and OS of pts with mRCC that are treated with Su. BMI, DM, and pre-tx HTN were not found to be associated with outcome. These results should be investigated prospectively, and if validated applied in clinical practice and clinical trials.

Effect of bisphosphonates (Bis) combined with sunitinib (Su) on the response rate (RR), progression-free survival (PFS), and overall survival (OS) of patients (pts) with bone metastases (mets) from renal cell carcinoma (RCC).

379 Background: Bis are used to prevent skeletal events of bone mets, and may exhibit anti tumor effects. We aimed to evaluate whether Bis can bring a RR, PFS, and OS benefit to pts with bone mets from RCC that are treated with Su. METHODS We performed a multicentre retrospective study of pts with bone mets from RCC who were treated with Su. Pts were divided into Bis users (group 1) and nonusers (group 2). The effect of Bis on RR, PFS and OS, was tested with adjustment for known prognostic factors using a chisquare test from contingency table and partial likelihood test from Cox regression model. RESULTS Between 2004-2011, 209 pts with metastatic RCC were treated with Su. 76 pts had bone mets, 35 group 1 and 41 group 2. The groups were balanced regarding the following known prognostic factors: past nephrectomy, clear cell/non clear cell histology, time from initial diagnosis to sunitinib treatment (tx), the presence of > 2 mets sites, the presence of lung/liver mets, ECOG performance status, anemia, calcium level >10 mg/dL, elevated alkaline phosphatase, platelets count, pre-tx neutrophil to lymphocyte ratio (NLR) >3, sunitinib induced HTN, and the use of angiotensin system inhibitors. They were also balanced with regard to past cytokines/targeted tx, and mean sunitinib dose/cycle. Objective response was partial response/stable disease 86% (n=30) vs 71% (n=29), and progressive disease 14% (n=5) vs 29% (n=12) (p=0.125, OR 2.48) in group 1 vs 2 respectively. Median PFS was 15 vs 5 months (HR 2.6, p < 0.0001), and median OS 21 vs 13 months (HR 2.1, p=0.029), in favor of group 1. In multivariate analysis of the entire pt cohort (n=76), factors associated with PFS were Bis use (HR 2.2, p=0.035) and pre-tx NLR >3 (HR 0.38, p=0.009). Factors associated with OS were Bis use (HR 2.8, p=0.008), elevated alkaline phosphatase level (HR 0.287, p=0.0003), and Su induced HTN (HR 5.57, p < 0.0001). CONCLUSIONS Bis may improve the outcome of Su tx in RCC with bone mets. Whether this is generalizable to other TKIs is not known. This should be investigated prospectively, and if validated applied in clinical practice and clinical trials.

FDG PET/CT differentiating two malignant tumors in the same patient

remain [5]. In patients with an intact GTV a “suitable margin” is given by the radiation oncologist to account for microscopic spread of disease (or the CTV). Literature for the extent of this margin (derived from pathological series, imaging data, wisdom earned from pattern of recurrences) is limited for most sites [6]. In brief, the gun of radiation delivery is reasonably precise, but the issue of target definition remains ever controversial. To conclude, the biology, behaviour and even the correct radiology interpretation of cancer is far from understood. Defining targets and treating them, both in the context of medical as well as radiation oncology is challenging. The oncology community has made some preliminary progress towards the goal of real targeted therapy. But as readily evident, it is not the time to celebrate but to introspect. If needed, we should redefine our priorities and concepts, even if it means beginning afresh in some areas. We are yet so far from understanding cancer and its mystic ways. And real targeted therapy is not even on the anvil yet. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.