Duration of response to first androgen deprivation therapy, time to castration resistance prostate cancer, and outcome of metastatic castration resistance prostate cancer patients treated with abiraterone acetate.

Abiraterone acetate (AA) demonstrated its efficacy in the treatment of patients with metastatic castration resistance prostate cancer (mCRPC) in predocetaxel and postdocetaxel setting. However, we learn from pivotal studies that forms of primary and acquired resistance to this drug exist. Patient selection becomes so crucial to optimize treatment results. Potential predictive biomarkers have been identified but are not yet validated. In this scenario, clinical features and disease characteristics may still be of value in selecting patients for different treatments. The objective of this retrospective study was to assess whether or not a correlation between duration of response to first androgen deprivation therapy (ADT), time to castration-resistant prostate cancer (TTCRPC), and outcome of AA therapy exists. A retrospective analysis of clinical data of mCRPC patients treated with AA at two Italian cancer centers was carried out. The Kaplan-Meier method and Cox proportional hazard model were used to analyze survival data. Correlation between median duration of response to first ADT or median TTCRPC and the outcome of patients treated with AA was analyzed. From January 2015 to November 2015, data of 59 patients with mCRPC were collected. We observed no differences in patient's median progression-free survival (PFS) and biochemical progression-free survival (bPFS), according to both median duration of response to first-line ADT (duration of first ADT<13 months: median PFS and bPFS were 11 and 5 months, respectively; duration of ADT≥13 months: median PFS and bPFS were 9 and 6 months, respectively) and median TTCRPC (TTCRPC<28 months: median PFS and bPFS were 8 and 5 months, respectively; TTCRPC≥28 months: median PFS and bPFS were 10 and 9 months, respectively). Overall survival, in the same group, did not differ between patients with a duration of response to first ADT over or under 13 months (P=0.90) but in patients with a TTCRPC of 28 months or more, there was a trend toward longer survival than patients with TTCRPC less than 28 months (5-year overall survival was 74 vs. 50%; P=0.14). The duration of response to first-line ADT and the TTCRPC showed no significant association with outcome of AA therapy in patients with mCRPC. However, large prospective trials are desirable to confirm these data.

Docetaxel rechallenge in metastatic castration-resistant prostate cancer: any place in the modern treatment scenario? An intention to treat evaluation.

BACKGROUND: We evaluated the possible advantages of a docetaxel (DCT) rechallenge strategy in metastatic castration-resistant prostate cancer (mCRPC) patients, also given the possible earlier positioning of this treatment option in the modern scenario. PATIENTS & METHODS: All mCRPC patients planned for DCT chemotherapy rechallenge in our institutions were evaluated. RESULTS: Of 128 patients, 98 achieved disease control on the initial DCT round. After a treatment holiday of 8.3 months, the 98 responsive patients underwent a second DCT round, with 56 cases achieving again disease control. After a 5.7-month off-treatment period, 32 of these cases underwent a third DCT round, and 16 responded. Lastly, after a further 4.2-month treatment holiday, eight patients underwent a fourth DCT round and two responded. Median time to definitive disease progression for the whole population was 16.4 months. CONCLUSIONS: Rechallenge with DCT may be considered a suitable treatment option for mCRPC patients recurring after a successful DCT chemotherapy. The interest in this strategy may be increased because of the showed efficacy of early DCT chemotherapy in patients with bulky disease (CHAARTED study) and the potential lower efficacy of the new hormonal agents abiraterone acetate and enzalutamide when used in a immediate sequencing.

Sorafenib as first- or second-line therapy in patients with metastatic renal cell carcinoma in a community setting.

AIM: The Italian Retrospective Analysis of Sorafenib as First or Second Target Therapy study assessed the efficacy and safety of sorafenib in metastatic renal cell carcinoma patients treated in the community. PATIENTS & METHODS: Patients receiving first- or second-line single-agent sorafenib between January 2008 and December 2010 were eligible. Retrospective data collection started in 2012 and covers at least 1-year follow-up. The primary end point was overall survival (OS). RESULTS: Median OS was 17.2 months (95% CI: 15.5-19.6): 19.9 months (95% CI: 15.9-25.3) in patients treated with first-line sorafenib and 16.3 months (95% CI: 13.1-18.2) with second-line sorafenib. Overall median (95% CI) progression-free survival was 5.9 months (95% CI: 4.9-6.7): 6.6 (95% CI: 4.9-9.3) and 5.3 months (95% CI: 4.3-6.0) in first- and second-line patients, respectively. CONCLUSION: The efficacy and safety of sorafenib in routine community practice was generally good, especially in relation to OS in patients treated in the second line, where results were similar to those seen in recent prospective clinical trials.

Functional and pharmacodynamic evaluation of metronomic cyclophosphamide and docetaxel regimen in castration-resistant prostate cancer.

AIM: The aim of our study was to investigate the association of docetaxel and metronomic cyclophosphamide (CYC) in castration-resistant prostate cancer (CRPC). MATERIALS & METHODS: CRPC xenografts were established with PC3 cells. Mice were treated with a combination of CYC (50 mg/kg/day) and docetaxel (10-30 mg/kg/week) or with docetaxel alone. Docetaxel plasma levels were analyzed in patients receiving the drug alone or combined with CYC. RESULTS: Metronomic CYC is an effective adjuvant in blocking tumor growth in vivo, with comparable efficacy and less toxic effects compared with docetaxel treatment. CYC acts by downregulating cell proliferation and inducing apoptosis thorough upregulation of p21 and inhibition of angiogenesis. Finally, CYC increases docetaxel plasma levels in patients. CONCLUSION: Metronomic CYC exerts anti-tumoral effects in an in vivo model of prostate cancer and in patients with CRPC, and also increases the bioavailability of docetaxel. These results explain the favorable toxicity and activity profiles observed in patients treated with this regimen.

Pharmacokinetics of gemcitabine at fixed-dose rate infusion in patients with normal and impaired hepatic function.

BACKGROUND AND OBJECTIVES: Gemcitabine (2,2-difluorodeoxycytidine [dFdC]) can be administered in a standard 30-minute infusion or in a fixed-dose-rate (FDR) infusion to maximize the rate of accumulation of triphosphate, its major intracellular metabolite. The standard 30-minute infusion requires dose adjustment in patients with organ dysfunction, especially in patients with elevated baseline serum bilirubin levels. On the other hand, the FDR infusion is burdened by increased haematological toxicity. The primary aim of this study was to evaluate the pharmacokinetics of dFdC and its metabolite difluorodeoxyuridine (dFdU) in patients with normal and impaired hepatic function. PATIENTS AND METHODS: In this prospective study, patients with pancreatic or biliary tract carcinoma and normal or impaired hepatic function tests were considered eligible for recruitment. Patients were recruited according to the following criteria: (i) serum bilirubin <1.6 mg/dL and AST and ALT <2 times the upper the limit of normal (ULN) [cohort I]; and (ii) serum bilirubin >1.6 mg/dL and/or AST/ALT >2 times the ULN (cohort II). An FDR infusion of gemcitabine 1000 mg/m2 was administered on days 1, 8 and 15 every 4 weeks. The pharmacokinetic analysis of gemcitabine and dFdU was performed with high-performance liquid chromatography-tandem mass spectrometry assay in cycles 1 and 2. RESULTS: Thirteen patients were enrolled, four in cohort I and nine in cohort II. All patients were assessable for toxicity and pharmacokinetic analysis. The grade and rate of toxicities were similar in both groups, and patients with elevation of bilirubin and/or transaminases did not require dose reduction of gemcitabine. Pharmacokinetic analysis revealed a reduction of the experimental area under the plasma concentration-time curve for gemcitabine and dFdU in patients with hepatic dysfunction when compared with patients with normal hepatic function. All other pharmacokinetic parameters were similar in the two cohorts. No statistical difference was demonstrated for all parameters evaluated between cycle 1 and cycle 2 in the two groups. CONCLUSION: Gemcitabine 1000 mg/m2 can be administered as an FDR infusion in patients with altered hepatic function without causing additional toxicity compared with patients with normal hepatic function.

Is Axitinib Still a Valid Option for mRCC in the Second-Line Setting? Prognostic Factor Analyses From the AXIS Trial.

BACKGROUND: Axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting. PATIENTS AND METHODS: AXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors. RESULTS: Of 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments. CONCLUSION: In patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.

Taxanes and gemcitabine doublets in the management of HER-2 negative metastatic breast cancer: towards optimization of association and schedule.

The management of human epidermal receptor-2 (HER-2) negative metastatic breast cancer (MBC) is usually problematic, since no standard therapy exists in this setting. For some patients, combination chemotherapy represents a valuable approach, although its use is often limited by the risks of increased toxicity as well as impairments in quality of life (QoL) that often outweigh the marginal efficacy benefit. Against this background, the use of taxanes, either paclitaxel or docetaxel, in combination with gemcitabine as first-line treatment of HER-2 negative MBC is supported by the evidence of the single-agent activity of these drugs, beneficial pharmacological interactions, different mechanisms of action and largely non superimposable toxicity profiles. A number of phase II studies have explored the activity of a taxane plus gemcitabine in both chemonaïve and pretreated MBC patients, all showing remarkably high response rates and exceptional tolerability. In randomized phase III trials, the paclitaxel and gemcitabine combination showed significant improvements in objective responses, time to progression and overall survival, as compared to paclitaxel monotherapy, whereas the docetaxel and gemcitabine doublet demonstrated equal efficacy and better tolerability, as compared to docetaxel plus capecitabine. In addition to standard threeweekly dosing regimens, alternative schedules of administration of taxanes and gemcitabine doublets (weekly, twoweekly) might deserve further investigation due to their potential usefulness in reducing pharmacological toxicity while maintaining or increasing dose-intensity and clinical efficacy. Furthermore, uncertainty exists on which taxane should be preferred in combination with gemcitabine, since no head-to-head comparison between paclitaxel-gemcitabine and docetaxel-gemcitabine has been performed so far. Ongoing trials will address these issues and future investigations will also include the evaluation of bevacizumab, the monoclonal antibody targeted against vascular endothelial growth factor (VEGF), in combination with taxanes and gemcitabine doublets.

Major bleedings in the comparisons between low-molecular weight heparin versus oral anticoagulant therapy for venous thromboembolism.

To evaluate the safety (major bleedings) of long-term treatment of symptomatic venous thromboembolism (VTE) using low molecular weight heparin (LMWH) compared with oral anticoagulant therapy (OAT) given for at least 3 months, we analyzed 10 randomized clinical trials enrolling a total of 2817 patients with objectively diagnosed symptomatic deep vein thrombosis, pulmonary embolism or both. The relative risk (RR, incidence of recurrent symptomatic VTE) was combined across the studies, using the inverse variance and the Mantel-Haenszel method. During treatment, major bleeding complications occurred in 2.8% of the patients in the LMWH arm versus 4% in the OAT arm: no statistically significant difference was observed (p=0.31). No differences in major bleeding were registered in the additional 3-9 months of follow-up (p=0.98). Long-term treatment with LMWH does not seem to be significantly safer than OAT. However, no conclusive interpretation from different studies with different designs is possible.

Is recurrent venous thromboembolism after therapy reduced by low-molecular-weight heparin compared with oral anticoagulants?

PURPOSES: To evaluate whether the incidence of recurrent venous thromboembolism (VTE) events after therapy differs for patients treated with long-term low-molecular-weight heparin (LMWH) or oral anticoagulant therapy (OAT). METHODS: All randomized studies were searched through computerized queries of MEDLINE, the Cochrane Controlled Trials Register, the American Society of Hematology abstract database, and the American Society of Clinical Oncology abstract database. RESULTS: Eleven studies including 2,907 patients were identified. Seven studies evaluated a period of 3 to 9 months after cessation of the allocated treatment: 5.4% of patients in the LMWH group vs 4% in the arm allocated to OAT had an episode of recurrent symptomatic VTE. Combined analysis showed a nonsignificant trend in lowering recurrent symptomatic VTE in favor of OAT (relative risk [RR], 1.29; 95% confidence interval [CI], 0.82 to 2.02; p = 0.27). By contrast, during active treatment, a statistically significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH over OAT was registered (RR, 0.63; 95% CI, 0.47 to 0.83; p = 0.001). Regarding cancer patients only, 37 of 569 patients (6.5%) in the LMWH group had recurrent symptomatic VTE vs 69 of 546 patients (12.6%) in the OAT group, with a statistically significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH (RR, 0.52; 95% CI, 0.35 to 0.76; p = 0.001). CONCLUSIONS: Despite the significant reduction of the risk of recurrent symptomatic VTE in favor of LMWH over OAT during treatment, patients treated with long-term LMWH do not seem to have more frequently recurrent VTE events compared with OAT after cessation of therapy. The significant difference favoring LMWH over OAT among all patients receiving treatment comes mostly from studies enrolling cancer patients.

Bi-weekly chemotherapy with cisplatin, epirubicin, folinic acid and 5-fluororacil continuous infusion plus g-csf in advanced gastric cancer: a multicentric phase II study.

BACKGROUND: It has been demonstrated that the 3-weekly PELF regimen is superior to FAM and FAMTX in advanced gastric cancer. The aim of this multicentric phase II study was to evaluate the efficacy and tolerability of a PELF regimen, given every 2 weeks as a first-line therapy in patients with unresectable or metastatic gastric carcinoma. METHODS: Fifty-nine patients were treated with the following schedule: cisplatin (40 mg/m2, day 1), epirubicin (30 mg/m2, day 1), 5-fluorouracil (400 mg/m2 bolus, followed by 600 mg/m2, 22 h continuous infusion, day 1 and 2) and folinic acid (100 mg/m2, 2-h infusion, day 1 and 2). G-CSF (5 microg/kg) was administered on day 6, 8, 10, and 12. Cycles were repeated every 2 weeks for a maximum of twelve courses. RESULTS: Of the 52 evaluable patients, three (5.8%) complete responses, and 15 (28.8%) partial responses were observed, for an overall response rate of 34.6%. The median duration of response was 8 months. Nineteen patients had stable disease and 15 progressed on therapy. At a median follow-up of 12 months, the median time to progression was 8 months and the median survival duration was 13 months, with a 1-year survival rate of 53.5%. Grade 3 or 4 observed toxicities were: neutropenia in 26 patients (44%), thrombocytopenia in four patients (6.7%), and mucositis in seven patients (11.9%). CONCLUSIONS: The bi-weekly PELF regimen seems to be feasible with an acceptable toxicity profile and an activity comparable to the 3-weekly schedule.

Pegylated liposomal doxorubicin in combination with gemcitabine: a phase II study in anthracycline-naïve and anthracycline pretreated metastatic breast cancer patients.

BACKGROUND: The aim of the study was to assess the toxicity profile, activity in terms of response rate, time to progression, overall survival, and quality of life of pegylated liposomal doxorubicin (PLD) and gemcitabine combination in chemo-naïve and pretreated metastatic breast cancer (MBC) women. METHODS: Patients were eligible if they had disease progression to prior chemotherapy (anthracycline-including or not) for early breast cancer or MBC. Patients received PLD 25 mg/m(2) intravenously on day 1 plus gemcitabine 800 mg/m(2) intravenously on days 1 and 8 of each 21-day cycle. RESULTS: Of 50 patients enrolled, 37 had received prior adjuvant chemotherapy (24 with an anthracycline) and 23 prior chemotherapy for metastatic disease (6 with an anthracycline). Two complete responses and 20 partial responses were achieved in 46 assessable patients (overall response rate: 47.8%). Responses were observed in 14 (46.6%) of 30 patients with previous anthracycline exposure. Median response duration was 7 months, median duration of clinical benefit 8 months, time to progression 7 months. At a median follow-up of 10 months, 79.4% patients were alive at 1 year. No neutropenic complication was observed. Non-hematological toxicities were mild. One patient previously treated with an anthracycline developed a transient decrease (26%) in the left ventricular ejection fraction, with cardiac function recovering within 6 months. CONCLUSION: Because of the non-overlapping toxicity profiles of both PLD and gemcitabine, this combination can be regarded as a reliable therapeutic option for patients who have failed previous treatments, including anthracycline, for MBC.

Bone and lung metastases from intracranial meningioma.

Fifteen percent of intracranial tumors are represented by meningiomas. Meningioma is usually a benign neoplasm; malignant histology is rare and represents about 2-10% with a 43% incidence of metastasis. The most frequent site of metastasis is the lung and rare are other sites. There are no definitive criteria to predict the recurrence or metastases of meningioma and histological grading, according to WHO criteria, is the most important predictor of malignancy. A rare case of a woman with a relapse of intracranial meningioma in the right frontal lobe who subsequently developed simultaneous bone and intrapulmonary metastases is reported. According to these sites of metastases, it is suggested that in patients with a history of relapsed meningioma, a total body CT scan should be performed in order to investigate other possible sites of disease.

Bone metastases affect prognosis but not effectiveness of third-line targeted therapies in patients with metastatic renal cell carcinoma.

INTRODUCTION: Treatment of metastatic renal cell carcinoma (mRCC) has improved with the use of targeted therapies, but bone metastases continue to be negative prognostic factor. METHODS: Patients with mRCC treated with everolimus (EV) or sorafenib (SO) after two previous lines of targeted therapies were included in the analysis. Overall survival (OS) and progression-free survival (PFS) were assessed based on the presence of bone metastases and type of therapy; they were also adjusted based on prognostic criteria. RESULTS: Of the 233 patients with mRCC, 76 had bone metastases. Of the 233 patients, EV and SO were administered in 143 and 90 patients, respectively. Median OS was 10.4 months in patients with BMs and 17.4 months in patients without bone metastases (p = 0.002). EV decreased the risk of death by 18% compared to SO (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.74-0.91; p < 0.001), with comparable effects in patients with or without bone metastases. In the same manner, EV decreased the risk of progression by 12% compared to SO (adjusted HR 0.88, 95% CI 0.82-0.96; p = 0.002), but this difference was not significant in patients without bone metastases. The major limitations of the study are its retrospective nature, the heterogeneity of the methods to detect bone metastases, and the lack of data about patients treated with bisphosphonates. CONCLUSIONS: The relative benefit of targeted therapies in mRCC is not affected by the presence of bone metastases, but patients without bone metastases have longer response to therapy and overall survival.

The changes of lipid metabolism in advanced renal cell carcinoma patients treated with everolimus: a new pharmacodynamic marker?

BACKGROUND: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between the baseline values and treatmentrelated modifications of total serum cholesterol (C), triglycerides (T), body mass index (BMI), fasting blood glucose level (FBG) and blood pressure (BP) levels and the outcome of patients treated with everolimus for mRCC. METHODS: 177 patients were included in this retrospective analysis. Time to progression (TTP), clinical benefit (CB) and overall survival (OS) were evaluated. RESULTS: Basal BMI was significantly higher in patients who experienced a CB (p=0,0145). C,T and C+T raises were significantly associated with baseline BMI (p=0.0412, 0.0283 and 0.0001). Median TTP was significantly longer in patients with T raise compared to patients without T (10 vs 6, p=0.030), C (8 vs 5, p=0.042) and C+T raise (10.9 vs 5.0, p=0.003). At the multivariate analysis, only C+T increase was associated with improved TTP (p=0.005). T raise (21.0 vs 14.0, p=0.002) and C+T increase (21.0 vs 14.0, p=0.006) were correlated with improved OS but were not significant at multivariate analysis. CONCLUSION: C+T raise is an early predictor for everolimus efficacy for patients with mRCC.

Bone metastases in patients with metastatic renal cell carcinoma: are they always associated with poor prognosis?

PURPOSE: Aim of this study was to investigate for the presence of existing prognostic factors in patients with bone metastases (BMs) from RCC since bone represents an unfavorable site of metastasis for renal cell carcinoma (mRCC). MATERIALS AND METHODS: Data of patients with BMs from RCC were retrospectively collected. Age, sex, ECOG-Performance Status (PS), MSKCC group, tumor histology, presence of concomitant metastases to other sites, time from nephrectomy to bone metastases (TTBM, classified into three groups: <1 year, between 1 and 5 years and >5 years) and time from BMs to skeletal-related event (SRE) were included in the Cox analysis to investigate their prognostic relevance. RESULTS: 470 patients were enrolled in this analysis. In 19 patients (4%),bone was the only metastatic site; 277 patients had concomitant metastases in other sites. Median time to BMs was 16 months (range 0 - 44y) with Median OS of 17 months. Number of metastatic sites (including bone, p = 0.01), concomitant metastases, high Fuhrman grade (p < 0.001) and non-clear cell histology (p = 0.013) were significantly associated with poor prognosis. Patients with TTBM >5 years had longer OS (22 months) compared to patients with TTBM <1 year (13 months) or between 1 and 5 years (19 months) from nephrectomy (p < 0.001), no difference was found between these two last groups (p = 0.18). At multivariate analysis, ECOG-PS, MSKCC group and concomitant lung or lymph node metastases were independent predictors of OS in patients with BMs. CONCLUSIONS: Our study suggest that age, ECOG-PS, histology, MSKCC score, TTBM and the presence of concomitant metastases should be considered in order to optimize the management of RCC patients with BMs.

Management of metastatic renal cell carcinoma patients with poor-risk features: current status and future perspectives.

With seven agents approved for renal cell carcinoma within the past few years, there has undoubtedly been progress in treating this disease. However, patients with poor-risk features remain a challenging and difficult-to-treat population, with the mTOR inhibitor, temsirolimus, the only agent approved in the first-line setting. Phase III trial data are still lacking VEGF-pathway inhibitors in patients with poor prognostic features. Poor-risk patients need to be considered as a heterogeneous population. Further understanding of biomarkers can lead to a better selection of patients who may benefit the most from treatment and improvements in prognosis. The presence of poor Karnofsky scores and liver or CNS disease may affect the outcome of these patients much more than other identified factors. This consideration may provide the rationale to further stratify poor-risk patients further subgroups destined to receive either cure or palliation.

Natural history of malignant bone disease in renal cancer: final results of an Italian bone metastasis survey.

BACKGROUND: Bone metastasis represents an increasing clinical problem in advanced renal cell carcinoma (RCC) as disease-related survival improves. There are few data on the natural history of bone disease in RCC. PATIENTS AND METHODS: Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 398 deceased RCC patients (286 male, 112 female) with evidence of bone metastasis were statistically analyzed. RESULTS: Median time to bone metastasis was 25 months for patients without bone metastasis at diagnosis. Median time to diagnosis of bone metastasis by MSKCC risk was 24 months for good, 5 months for intermediate, and 0 months for poor risk. Median number of SREs/patient was one, and 71% of patients experienced at least one SRE. Median times to first, second, and third SRE were 2, 5, and 12 months, respectively. Median survival was 12 months after bone metastasis diagnosis and 10 months after first SRE. Among 181 patients who received zoledronic acid (ZOL), median time to first SRE was significantly prolonged versus control (n = 186) (3 months vs 1 month for control; P<0.05). CONCLUSIONS: RCC patients with bone metastasis are at continuous risk of SREs, and in this survey ZOL effectively reduced this risk.