Gaspar Reynés

Circulating Endothelial Cells and Microparticles as Prognostic Markers in Advanced Non-Small Cell Lung Cancer

Background Circulating endothelial cells and microparticles have prognostic value in cancer, and might be predictors of response to chemotherapy and antiangiogenic treatments. We have investigated the prognostic value of circulating endothelial cells and microparticles in patients treated for advanced non-small cell lung cancer. Methodology/Principal Findings Peripheral blood samples were obtained from 60 patients before first line, platinum-based chemotherapy +/− bevacizumab, and after the third cycle of treatment. Blood samples from 60 healthy volunteers were also obtained as controls. Circulating endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Phosphatidylserine-positive microparticles were evaluated by flow cytometry. Microparticle-mediated procoagulant activity was measured by the endogen thrombin generation assay. Results: pre- and posttreatment levels of markers were higher in patients than in controls (p<0.0001). Elevated levels of microparticles were associated with longer survival. Elevated pretreatment levels of circulating endothelial cells were associated with shorter survival. Conclusions/Significance Circulating levels of microparticles and circulating endothelial cells correlate with prognosis, and could be useful as prognostic markers in patients with advanced non-small cell lung cancer.

Bevacizumab plus irinotecan in recurrent malignant glioma shows high overall survival in a multicenter retrospective pooled series of the Spanish Neuro-Oncology Research Group (GEINO).

There is no ‘standard of care’ for recurrent malignant glioma (MG). Our aim is to confirm the efficacy and safety of bevacizumab 10 mg/kg plus irinotecan 125 mg/m2 (or 340 mg/m2 if enzyme-inducing antiepileptic drugs) every 2 weeks for a maximum of 1 year in a retrospective pooled series of patients with recurrent MG. The inclusion criteria were as follows: age 18 years and above, histology of MG, progression after radiation and temozolomide, Karnofsky performance status (KPS) of at least 60, and signed informed consent for bevacizumab compassionate use. Response was assessed by MRI using the Macdonald criteria and evaluation of the FLAIR sequence every 8 weeks. A total of 130 patients were enrolled; 72% had glioblastoma (GBM). The median age of the patients was 53 years (20–78); the median KPS was 80%; the median number of prior chemotherapy lines was 2 (1–5); the median interval between the diagnosis of MG and inclusion was 14.6 months (2–166); and the median number of bevacizumab infusions was 8 (1–39). The median follow-up duration was 7.2 months (1–47). The median overall survival (OS) was 8.8 months for GBM and 11.2 months for anaplastic glioma (AG). The median progression-free survival was 5.1 months for GBM and 4.6 months for AG. The response rate was 56% for GBM and 68% for AG. Neurological and KPS improvements were observed in 49 and 45% of patients. Only KPS less than 80% was associated with a worse significant response rate (odds ratio, 0.57; 95% confidence interval, 0.22–0.96). The most frequent grades 3–4 toxicities were asthenia (7%), diarrhea (6%), and thromboembolic events (5%). There were five toxic deaths (4%). Bevacizumab plus irinotecan in recurrent MG improves responses, progression-free survival, and OS compared with historical data. KPS of at least 80% was a predictive factor for response and OS.

Usefulness of bone turnover markers as predictors of mortality risk, disease progression and skeletal-related events appearance in patients with prostate cancer with bone metastases following treatment with zoledronic acid: TUGAMO study

Background:Owing to the limited validity of clinical data on the treatment of prostate cancer (PCa) and bone metastases, biochemical markers are a promising tool for predicting survival, disease progression and skeletal-related events (SREs) in these patients. The aim of this study was to evaluate the predictive capacity of biochemical markers of bone turnover for mortality risk, disease progression and SREs in patients with PCa and bone metastases undergoing treatment with zoledronic acid (ZA).Methods:This was an observational, prospective and multicenter study in which ninety-eight patients were included. Patients were treated with ZA (4 mg every 4 weeks for 18 months). Data were collected at baseline and 3, 6, 9, 12, 15 and 18 months after the beginning of treatment. Serum levels of bone alkaline phosphtase (BALP), aminoterminal propeptide of procollagen type I (P1NP) and beta-isomer of carboxiterminal telopeptide of collagen I (β-CTX) were analysed at all points in the study. Data on disease progression, SREs development and survival were recorded.Results:Cox regression models with clinical data and bone markers showed that the levels of the three markers studied were predictive of survival time, with β-CTX being especially powerful, in which a lack of normalisation in visit 1 (3 months after the beginning of treatment) showed a 6.3-times more risk for death than in normalised patients. Levels of these markers were also predictive for SREs, although in this case BALP and P1NP proved to be better predictors. We did not find any relationship between bone markers and disease progression.Conclusion:In patients with PCa and bone metastases treated with ZA, β-CTX and P1NP can be considered suitable predictors for mortality risk, while BALP and P1NP are appropriate for SREs. The levels of these biomarkers 3 months after the beginning of treatment are especially important.

Circulating Endothelial Cells and Procoagulant Microparticles in Patients with Glioblastoma: Prognostic Value

Aim Circulating endothelial cells and microparticles are prognostic factors in cancer. However, their prognostic and predictive value in patients with glioblastoma is unclear. The objective of this study was to investigate the potential prognostic value of circulating endothelial cells and microparticles in patients with newly diagnosed glioblastoma treated with standard radiotherapy and concomitant temozolomide. In addition, we have analyzed the methylation status of the MGMT promoter. Methods Peripheral blood samples were obtained before and at the end of the concomitant treatment. Blood samples from healthy volunteers were also obtained as controls. Endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Microparticles were quantified by flow cytometry. Microparticle-mediated procoagulant activity was measured by endogen thrombin generation and by phospholipid-dependent clotting time. Methylation status of MGMT promoter was determined by multiplex ligation-dependent probe amplification. Results Pretreatment levels of circulating endothelial cells and microparticles were higher in patients than in controls (p<0.001). After treatment, levels of microparticles and thrombin generation decreased, and phospholipid-dependent clotting time increased significantly. A high pretreatment endothelial cell count, corresponding to the 99th percentile in controls, was associated with poor overall survival. MGMT promoter methylation was present in 27% of tumor samples and was associated to a higher overall survival (66 weeks vs 30 weeks, p<0.004). Conclusion Levels of circulating endothelial cells may have prognostic value in patients with glioblastoma.

Neoadjuvant cisplatin and etoposide, with or without tamoxifen, prior to radiotherapy in high-grade gliomas: a single-center experience.

Neoadjuvant chemotherapy (CT), prior to radical radiotherapy (RT), in the treatment of high-grade gliomas may offer several advantages over standard adjuvant CT. The addition of tamoxifen, which can circumvent P-glycoprotein (P-gp)-mediated chemo-resistance, also merits attention. We have evaluated the neoadjuvant regimen of cisplatin and etoposide after surgery of grade III–IV gliomas and prior to radical RT, with regard to response rates (RRs), overall survival (OS) and time to progression (TTP). The synergistic activity between etoposide and tamoxifen was also studied. Forty-four patients were included. CT regime: cisplatin 100 mg/m2 on day +1 and etoposide 100 mg/m2 on days +1 to +3 every 3 weeks for 3 cycles. The initial 24 were also treated with high-dose tamoxifen, 275 mg/m2 on days –3 to +3. An immunohistochemical analysis of P-gp, p53, vascular endothelial growth factor, Ki67 and bcl-2 was also performed. Median follow-up was 11.57 months. In the 16 patients with measurable disease after surgery, a RR of 12.5% was seen, with 37.5% of disease stabilizations and 31.25% of progressions. The median OS and TTP were 11.3 and 5.7 months. Excluding the three deaths possibly related to tamoxifen, grade 3–4 was low, mainly emesis. Favorable prognostic factors were age less than 60 years, extent of surgery, absence of measurable disease, and the absence of radiological necrosis and ring enhancement. Only high p53 expression was associated with better OS. We conclude that neoadjuvant cisplatin and etoposide is a feasible regime, although any real advantage over standard adjuvant CT is dubious. Short-course high-dose tamoxifen should not be used alongside primary CT.

Circulating endothelial and endothelial progenitor cells in non-small-cell lung cancer

New treatments have recently been introduced for treating non-small-cell lung cancer. Chemotherapeutic agents, such as pemetrexed, and targeted therapies, such as bevacizumab, erlotinib or gefitinib, have extended treatment options for selected histological subgroups. Antiangiogenic treatments, either associated with conventional chemotherapeutic drugs or given alone as maintenance therapy, constitute an active clinical research field. However, not all lung cancer patients benefit from antiangiogenic compounds. Moreover, tumour response assessment is often difficult when using these drugs, since targeted therapies generally do not cause rapid and measurable tumour shrinkage but, rather, long stabilisations and slight density changes on imaging tests. The finding of clinical or biological factors that might identify patients who will better benefit from these treatments, as well as identifying surrogate markers of tumour response and prognosis, is an issue of great interest. In that sense, different research lines have investigated the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) pathways. Circulating endothelial (CECs) and endothelial progenitor cells (CEPCs) are of prognostic value in different types of cancers, and relevant data are published about their potential usefulness as predictors of response to chemotherapy and antiangiogenic treatments. In this review, we discuss the data available on the role of CECs and CEPCs as prognostic factors and as surrogate markers of treatment response in non-small-cell lung cancer.

A phase I study of irinotecan in combination with metronomic temozolomide in patients with recurrent glioblastoma.

To determine the maximum tolerated dose of irinotecan administered every 2 weeks, in combination with a fixed and continuous administration of temozolomide, in patients with glioblastoma at first relapse. Patients received oral temozolomide at a fixed and continuous dose of 50 mg/m2 divided into three daily doses, except for a single 100 mg/m2 dose, administered before every irinotecan infusion. Irinotecan was given intravenously on days 8 and 22 of 28-day cycles. The starting dose of irinotecan was 100 mg/m2, and this was escalated by increments of 15 mg/m2 in cohorts of 3–6 evaluable patients. Determination of the dose-limiting toxicity was based on toxicities recorded from day 1 of the first cycleto day 8 of the third cycle. Enzyme-inducing antiepileptic drugs were not allowed. Tumor response was assessed by MRI every 8 weeks. Twelve patients were enrolled in this phase I study. The three patients enrolled at dose level 1 and six of nine patients enrolled at dose level 2 were evaluable for toxicity. The maximum tolerated dose of irinotecan was 100 mg/m2. The dose-limiting toxicities were hematologic and gastrointestinal. Nine patients were evaluable for response: one patient achieved a partial response, four patients remained stable, and four patients had disease progression. The combination of metronomic temozolomide and irinotecan every 2 weeks can be safely administered at the recommended doses; a phase II study with this combination was started and has completed accrual.

Phase II trial of dacomitinib, a pan–human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification

Background We conducted a multicenter, 2-stage, open-label, phase II trial to assess the efficacy and safety of dacomitinib in adult patients with recurrent glioblastoma (GB) and epidermal growth factor receptor gene (EGFR) amplification with or without variant III (EGFRvIII) deletion. Methods Patients with first recurrence were enrolled in 2 cohorts. Cohort A included patients with EGFR gene amplification without EGFRvIII mutation. Cohort B included patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs). Primary endpoint was progression-free survival (PFS; RANO criteria) at 6 months (PFS6). Results Thirty patients in Cohort A and 19 in Cohort B were enrolled. Median age was 59 years (range 39-81), 65.3% were male, and Eastern Cooperative Oncology Group Performance Status 0/1/2 were 10.2%/65.3%/24.5%, respectively. PFS6 was 10.6% (Cohort A: 13.3%; Cohort B: 5.9%) with a median PFS of 2.7 months (Cohort A: 2.7 mo; Cohort B: 2.6 mo). Four patients were progression free at 6 months and 3 patients were so at 12 months. Median overall survival was 7.4 months (Cohort A: 7.8 mo; Cohort B: 6.7 mo). The best overall response included 1 complete response and 2 partial responses (4.1%). Stable disease was observed in 12 patients (24.5%: eight in Cohort A and four in Cohort B). Diarrhea and rash were the most common AEs; 20 (40.8%) patients experienced grade 3-4 drug-related AEs. Conclusions Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients who could benefit from dacomitinib.

Geometrical Measures Obtained from Pretreatment Postcontrast T1 Weighted MRIs Predict Survival Benefits from Bevacizumab in Glioblastoma Patients

Background Antiangiogenic therapies for glioblastoma (GBM) such as bevacizumab (BVZ), have been unable to extend survival in large patient cohorts. However, a subset of patients having angiogenesis-dependent tumors might benefit from these therapies. Currently, there are no biomarkers allowing to discriminate responders from non-responders before the start of the therapy. Methods 40 patients from the randomized GENOM009 study complied the inclusion criteria (quality of images, clinical data available). Of those, 23 patients received first line temozolomide (TMZ) for eight weeks and then concomitant radiotherapy and TMZ. 17 patients received BVZ+TMZ for seven weeks and then added radiotherapy to the treatment. Clinical variables were collected, tumors segmented and several geometrical measures computed including: Contrast enhancing (CE), necrotic, and total volumes; equivalent spherical CE width; several geometric measures of the CE ‘rim’ geometry and a set of image texture measures. The significance of the results was studied using Kaplan-Meier and Cox proportional hazards analysis. Correlations were assessed using Spearman correlation coefficients. Results Kaplan-Meier and Cox proportional hazards analysis showed that total, CE and inner volume (p = 0.019, HR = 4.258) and geometric heterogeneity of the CE areas (p = 0.011, HR = 3.931) were significant parameters identifying response to BVZ. The group of patients with either regular CE areas (small geometric heterogeneity, median difference survival 15.88 months, p = 0.011) or those with small necrotic volume (median survival difference 14.50 months, p = 0.047) benefited substantially from BVZ. Conclusion Imaging biomarkers related to the irregularity of contrast enhancing areas and the necrotic volume were able to discriminate GBM patients with a substantial survival benefit from BVZ. A prospective study is needed to validate our results.

SEOM guideline for the treatment of malignant glioma

High-grade gliomas are an infrequent disease diagnosed usually in the fifth or sixth decade. Careful histopathological diagnosis is essential because tumour grade and type condition the treatment. Magnetic resonance with gadolinium is considered the standard radiologic exploration and should be followed by tissue sampling. Treatment of these patients should be decided in a multidisciplinary committee. Surgery, radiotherapy and chemotherapy are the basis of patients’ treatment, with the best results obtained when the three of them can be used.