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Background: The management of Breakthrough cancer Pain (BTcP) remains unsatisfactory. Although many barriers to BTcP management have been identified, oncologists have not been able to overcome them. The aim of this study is to identify the barriers preventing proper BTcP management that Spanish medical oncologists have found, and to reach a consensus in order to draft the appropriate recommendations to overcome them. Methods: This study is based on two surveys conducted by oncologists. The first survey was designed to reach a consensus on the main barriers (related to patients, physicians and healthcare organizations) that stand in the way of BTcP control. The second survey (a Delphi questionnaire) was based on the barriers evaluated in the first survey, including recommendations assessed using the two-round Delphi methodology.

Purpose Osimertinib has proven efficacy in EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) patients; however, its benefits have not been evaluated in a real-world setting. Methods ASTRIS is a single-arm, open-label, multinational study to evaluate the efficacy and safety of osimertinib for the treatment of EGFR T790M mutation-positive NSCLC. We present the study design and preliminary cut-off analysis results (as of October 2017) describing the baseline characteristics and methodology for T790M mutation detection in the Spanish cohort. Results The Spanish cohort included 131 patients from a total 3014 patients. Forty patients (28.1%) were still undergoing therapy at the time of cut-off; 68.7% were women and 97.7% were Caucasian, with a mean age of 64.8 (SD 11.7) years. The most common type of sample for evaluating T790M mutations was tissue (55.0%), and samples were obtained from the primary tumor in 61.1% of cases. Mutation analysis was performed by the local laboratory in 60.3% of cases and using the Roche Cobas® EGFR assay in 43.5% of cases. Conclusions ASTRIS is expected to confirm the benefits of osimertinib in a real-world setting. Data on real-world practices for the detection of the EGFR T790M mutation may provide additional information for the designing of guidelines for best practices.

Circulating biomarkers in blood may provide an interesting alternative to risky tissue biopsies in the diagnosis and follow-up of glioblastoma patients. We have assessed MGMT methylation status in blood and tissue samples from unresected glioblastoma patients who had been included in the randomized GENOM-009 trial. Paired blood and tissue samples were assessed by methylation-specific PCR (MSP) and pyrosequencing (PYR). After establishing the minimum PYR cut-off that could yield a significant difference in overall survival, we assessed the sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the analyses. Methylation could be detected in cfDNA by both MSP and PYR but with low concordance with results in tissue. Sensitivity was low for both methods (31% and 38%, respectively), while specificity was higher for MSP in blood than for PYR in plasma (96% vs 76%) and NPV was similar (56 vs 57%). Concordance of results in tissue by MSP and PYR was 84.3% (P < 0.001) and correlated with outcome. We conclude that detection of cfDNA in the blood of glioblastoma patients can be an alternative when tumor tissue is not available but methods for the detection of cfDNA in blood must improve before it can replace analysis in tumor tissue.

Background: Little progress has been achieved in non-small cell lung cancer (NSCLC) patients with unresectable stage III disease and new drug schemes are warranted. Material and methods: In this open-label, single-arm, phase II trial 65 treatment-naive stage III NSCLC deemed surgically unresectable by a multidisciplinary team were treated with 2 cycles of induction cisplatin at 80 mg/m(2) every 21 days plus metronomic oral vinorelbine at 50 mg/day every Monday, Wednesday and Friday. During the concomitant treatment with thoracic radiotherapy cisplatin was administered in the same manner but oral vinorelbine was reduced to 30 mg/day. The objective was to administer a total radiotherapy dose of 66 Gy in 33 daily fractions of 2 Gy. The primary endpoint was progression-free survival (PFS). Correlation between circulating tumor DNA (ctDNA) levels and survival was also evaluated. Results: Fifty-five (78.5 %) patients completed treatment. Overall response rate, by RECIST criteria, was 66.2 %. Four (6.2 %) patients had complete response, 39 (60.0 %) partial response and 12 (18.5 %) stable disease. Seven patients (10.8 %) had progressive disease during the induction period. Median follow-up was 29.1 months (m), median PFS was 11.5 m (95 %CI: 9.6-15.4). PFS at 12 m in the intention-to-treat (ITT) population was 47.8 % (95 %CI: 35.1-59.4 %) and median OS was 35.6 m (95 %CI: 24.4-46.8). Grade >= 3 treatment-related adverse events occurred in 14 (21.5 %) patients during induction and in 13 (24.5 %) patients during concomitant treatment with esophagitis occurring in 3% and pneumonitis in 1.5 % of the patients. Patients with undetectable ctDNA after 3 m follow-up had median PFS and OS of 18.1 m (95 %CI: 8.8-NR) and not reached (NR) (95 %CI: 11.3-NR), respectively, compared with 8.0 m (95 %CI: 2.7-NR) and 24.7 m (95 %CI: 5.7-NR) for patients who remained ctDNA positive at that time point. Conclusions: Metronomic oral vinorelbine and cisplatin obtains similar efficacy results with significantly lower toxicity than the same chemotherapy at standard doses. ctDNA can identify populations with particularly good prognosis.

The ALGA study explored adherence of Spanish treatment centers to the Sociedad Espanola de Oncologia Medica (SEOM) treatment algorithm for oncology patients with hyponatremia that requires treatment as the main cause of hospitalization, and evaluated the impact of adherence to this algorithm on patient outcomes. This retrospective study recruited patients aged at least 18 years with cancer, treated for at least one episode of hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The primary outcome was the proportion of patients whose treatment adhered to the SEOM algorithm, evaluated using a pre-defined decision tree. Secondary outcomes included length of hospitalization, and time to serum sodium level improvement. Perceived center adherence to the SEOM algorithm was also assessed. Seventy patients from four treatment centers were included. Twenty (28.6%; 95% confidence interval [CI] 18.0, 39.2) patients on hyponatremia treatment adhered to the SEOM algorithm, with a perceived adherence of 51.0–75.0%. Algorithm adherence in candidates for chemotherapy was 36.4% (n = 8) versus 25.0% (n = 12) for non-candidates for chemotherapy. Median time to serum sodium level improvement in patients managed adherently was 80.5 h (95% CI 38.3, 331.4) versus 134.6 h (33.2, 444.9) in patients managed non-adherently. Median time to hospital discharge was 16.5 days (95% CI 8.0, 27.0) in patients managed adherently versus 9.5 days (7.0, 22.0) in patients managed non-adherently. In Spanish centers, the SEOM algorithm was adhered to in less than one-third of patients, in contrast to higher levels of perceived adherence. This requires further investigation; however, algorithm use could require further clarification, especially in non-candidates for chemotherapy. Low levels of sodium in the blood occur in almost half of patients with cancer who are hospitalized. In some patients, this may be fatal. A care pathway was developed by the Sociedad Espanola de Oncologia Medica in 2014 to support doctors in providing the best care for these patients. Clinical records for 70 patients with cancer at four Spanish hospitals were reviewed to determine whether treatment was given according to the care pathway. Less than one-third of patients were found to have been treated according to the pathway. Patients receiving chemotherapy were more likely to have been treated according to the pathway; however, doctors believed that more patients were treated in line with the pathway. In general, health outcomes were similar for those patients treated according to and not treated according to the pathway. The difference between doctors’ belief that the pathway was followed when it might not have been needs to be examined further, say the authors. They suggest several reasons for the difference. The doctor providing feedback on whether the patient was treated according to the pathway may not have been the only doctor involved in a patient’s care and may not have been aware of all the treatment choices made. Lack of clarity within the pathway may have led doctors to believe that it was being followed more often than it was. Importantly, a doctor’s judgment may need to override pre-defined pathways in some situations to achieve the best outcome for the patient.

Background Standard treatment for glioblastoma is radiation with concomitant and adjuvant temozolomide for 6 cycles, although the optimal number of cycles of adjuvant temozolomide has long been a subject of debate. We performed a phase II randomized trial investigating whether extending adjuvant temozolomide for more than 6 cycles improved outcome. Methods Glioblastoma patients treated at 20 Spanish hospitals who had not progressed after 6 cycles of adjuvant temozolomide were centrally randomized to stop (control arm) or continue (experimental arm) temozolomide up to a total of 12 cycles at the same doses they were receiving in cycle 6. Patients were stratified by MGMT methylation and measurable disease. The primary endpoint was differences in 6-month progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and safety (Clinicaltrials.gov NCT02209948). Results From August 2014 to November 2018, 166 patients were screened, 7 of whom were ineligible. Seventy-nine patients were included in the stop arm and 80 in the experimental arm. All patients were included in the analyses of outcomes and of safety. There were no differences in 6-month PFS (control 55.7%; experimental 61.3%), PFS, or OS between arms. MGMT methylation and absence of measurable disease were independent factors of better outcome. Patients in the experimental arm had more lymphopenia (P Conclusions Continuing temozolomide after 6 adjuvant cycles is associated with greater toxicity but confers no additional benefit in 6-month PFS. Key Points 1. Extending adjuvant temozolomide to 12 cycles did not improve 6-month PFS. 2. Extending adjuvant temozolomide did not improve PFS or OS in any patient subset. 3. Extending adjuvant temozolomide was linked to increased toxicities.

[Background]: The cell cycle checkpoint G1/S, dependent on cyclin-dependent kinase (CDK) 4 amplification/overexpression and retinoblastoma phosphorylation, is altered in most anaplastic oligodendrogliomas (AOs). [Objective]: We aimed to evaluate the efficacy of palbociclib, an oral inhibitor of CDK4/6 with proven efficacy in breast cancer, in patients with AO. The primary endpoint was progression-free survival at 6 months. [Patients and Methods]: We conducted a multicenter, open-label, phase II trial evaluating the efficacy and safety of palbociclib in patients with AO who progressed on radiotherapy and chemotherapy with histologically and molecularly confirmed grade 3 oligodendroglioma and conserved retinoblastoma protein (pRb) expression by immunohistochemistry. Patients were treated with palbociclib (125 mg/day) for 3/1 weeks on/off. [Results]: Overall, 34 patients were enrolled across 10 hospitals in the Spanish Group of Neuro-Oncology (GEINO) study. The study was stopped early owing to the lack of efficacy, with 74% of evaluable patients progressing within 6 months, which was insufficient to consider palbociclib as an active drug in this population. Within the median follow-up of 12 months, the median progression-free survival was 2.8 months [95% confidence interval (CI) 2.6–3.1] and the median overall survival was 32.1 months (95% CI 5.1–59.2). There were no partial or complete responses; only 13 patients (38%) achieved stable disease as the best response. Palbociclib was well tolerated, with neutropenia (grade 3 or higher: 58.8%) and thrombocytopenia (grade 3 or higher: 14.7%) as the most common adverse events (AEs). Both AEs had no significant impact. [Conclusion]: Despite the good tolerance, palbociclib monotherapy did not show favorable efficacy against recurrent AO., Palbociclib was provided by Pfizer under a cooperative research agreement with the Spanish Group for Research in NeuroOncology (GEINO). Funding research was supported by Pfzer under the Investigator-Initiated Research Award, number WI174842.

Background Sorafenib is a potent targeted-therapy that blockades angiogenesis and has demonstrated activity against some sarcoma subtypes. Preclinical studies suggested that treatment with sorafenib plus cytotoxic agents could result in additive efficacy. Methods Patients with advanced soft tissue sarcoma, with or without anthracycline pretreatment were included. Patients received oral sorafenib 400 mg twice daily starting on Day +2, ifosfamide 2.0 g/m2 iv infusion lasting 4 h on days 1, 2 and 3 with concurrent mesna 400 mg/m2 every three weeks until disease progression or unacceptable toxicity or up to a maximum of 6 cycles of ifosfamide (sorafenib could be continued until progressive disease or unacceptable toxicity). Primary objective was progression-free rate (PFR) at 3 and 6 months; secondary objectives were overall response rate (ORR), Progression-free survival (PFS), Overall survival (OS) and safety. This article reports the phase II part of a phase I/II clinical trial. Results Thirty-five patients were enrolled. PFR at 3 and 6 months was 66% (95% CI 48–81) and 37% (95% CI 22–55). Six patients (17%) achieved partial response and 17 (49%) stable disease. Median PFS was 4.8 months (CI 95% 1.94–6.36) and overall survival 16.2 months (95% CI 8.75-NA). Conclusion Treatment with sorafenib plus ifosfamide achieved a significant clinical benefit with an acceptable safety profile in patients with advanced soft tissue sarcoma resistant to anthracyclines, which warrants a more detailed study in randomized clinical trials.

Objectives: Concomitant chemo-radiation is the standard treatment for unresectable stage III non-small cell lung cancer (LA-NSCLC), The aim of this study was to assess the safety and efficacy of oral vinorelbine and cisplatin (OVP) compared with etoposide and cisplatin (EP), both in combination with radiotherapy, in this setting. Material and methods: An open-label, randomized phase II trial was undertaken including 23 hospitals in Spain. Adults with untreated unresectable stage III NSCLC were randomizedl:1 to receive: oral vinorelbine (days 1 and 8 with cisplatin on day 1 in 3-week cycles; 2 cycles of induction, 2 cycles in concomitance) or etoposide (days 1-5 and 29-32 with cisplatin on days 1 and 8 in 4-week cycles; 2 cycles in concomitance). Both groups received concomitant radiotherapy 2 Gy/day (66 Gy). The primary endpoint was progression free survival (PFS). Results: One hundred and forty patients were enrolled. Sixty-nine patients received OVP and 71 received EP. Globally adverse events grade 3/4 per cycle were fewer in the vinorelbine arm (19.4%) than in the etoposide arm (62.6%) (p < 0.001). One patient (1.5%) in the OVP arm and 12 pts (17.6%) in the EP arm presented esophagitis grade 3/4 (p = 0.002). Median PFS was similar in both groups (10.8 [95% CI 7.7-13.8] and 9.6 months [95% CI 4.4-14.8]; p = 0.457, respectively). Preliminary median overall survival was 30 months in the OVP arm and 31.9 months in the EP arm (p = 0.688). Conclusions: Our findings show that OVP could be considered a standard combination with similar efficacy and better safety profile for the treatment of LA-NSCLC patients.

Molecular profiling and functional assessment of signalling pathways of advanced solid tumours are becoming increasingly available. However, their clinical utility in guiding patients' treatment remains unknown. Here, we assessed whether molecular profiling helps physicians in therapeutic decision making by analysing the molecular profiles of 1057 advanced cancer patient samples after failing at least one standard of care treatment using a combination of next-generation sequencing (NGS), immunohistochemistry (IHC) and other specific tests. The resulting information was interpreted and personalized treatments for each patient were suggested. Our data showed that NGS alone provided the oncologist with useful information in 10-50% of cases (depending on cancer type), whereas the addition of IHC/other tests increased extensively the usefulness of the information provided. Using internet surveys, we investigated how therapy recommendations influenced treatment choice of the oncologist. For patients who were still alive after the provision of the molecular information (76.8%), 60.4% of their oncologists followed report recommendations. Most treatment decisions (93.4%) were made based on the combination of NGS and IHC/other tests, and an approved drug- rather than clinical trial enrolment- was the main treatment choice. Most common reasons given by physicians to explain the non-adherence to recommendations were drug availability and cost, which remain barriers to personalised precision medicine. Finally, we observed that 27% of patients treated with the suggested therapies had an overall survival > 12 months. Our study demonstrates that the combination of NGS and IHC/other tests provides the most useful information in aiding treatment decisions by oncologists in routine clinical practice., SCOPUS: ar.j, info:eu-repo/semantics/published

Hyponatremia (Na ˂ 135 mmol/l) is the most frequent electrolyte disorder in clinical practice, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the commonest cause of hyponatremia in cancer patients. Correcting hyponatremia in these patients can reduce morbidity and mortality, increase the response to anti-cancer agents, and help reduce hospital length of stay and costs. Tolvaptan is an oral medication used to treat SIADH-related hyponatremia patients that needs to be initiated at hospital so patients can have their serum sodium monitored. If tolvaptan could be initiated in hospital day care units (DCUs), performing the same tests, hospitalization could be avoided, quality of life improved, and costs reduced. This is the first publication where a panel of oncologists are sharing their experience and making some recommendations with the use of tolvaptan to treat SIADH-related hyponatremia in DCU after collecting and examining 35 clinical cases with these type of patients. The conclusion from this retrospective observational analysis is that the use of tolvaptan in DCU is safe and effective in the therapeutic management of SIADH-related hyponatremia.

2038 Background: The pRB-dependent cell cycle checkpoint is altered in the vast majority of anaplastic oligodendrogliomas (AO), either by homozygous deletion or by hypermethylation of CDKN2A and/or CDKN2B, or by amplification and/or overexpression of CDK4. Palbociclib is an oral inhibitor of CDK4 and 6 that has already been shown to be highly active in breast cancer. Methods: We conducted a multicenter, open-label, phase II trial evaluating efficacy and safety of Palbociclib in patients with AO that progressed to radiotherapy and more than one chemotherapy regimen containing Temozolomide and/or Lomustine. Inclusion criteria included: histologically and molecularly confirmed grade III oligodendroglioma (WHO 2016 classification, IDH1/2 mutation and 1p/19 codeletion were mandatory), recurrence after radiotherapy and 1 or 2 chemotherapy regimens and conserved RB protein expression by immunohistochemistry (IHC). Patients were treated with Palbociclib 125 mg/daily 3 weeks on/1off. The primary objective of the study was progression-free survival at 6 months (6M-PFS). Results: Between October 2015 and September 2018, 34 patients were enrolled across ten hospitals. The study was stopped early secondary to lack of efficacy, with 74% of evaluable patients progressing within 6 months. Number of patients alive and free from progression at 6 months after the enrollment was 9 (26%) out of the first 34 patients, below the minimum number required (18 out of 40) to consider Palbociclib as an active drug in this population. With a median follow-up of 11.2 months, the median PFS was 3 months (95% CI: 2.5-3.5 months). Median overall survival (OS) was 23.1 months (95% CI: 17.2-25 months). There were no partial or complete responses and only 11 patients (32%) achieved stable disease as best response. Palbociclib was well tolerated with neutropenia (Grade 3 or 4: 40%) and thrombocytopenia (Grade 3 or 4: 15%) as the most common adverse effects (AEs). Both AEs had no significant impact since there were no episodes of febrile neutropenia or bleeding. Conclusions: Despite the good tolerance and drug exposure, Palbociclib monotherapy did not show favorable activity in recurrent AO. Clinical trial information: NCT02530320.

2001 Background: The GEINO-14-01 trial (NCT02209948) investigated the role of extending temozolomide (TMZ) for 6 cycles after the standard 6 cycles to improve 6m-PFS, SLP and OS in newly diagnosed glioblastoma (GBM) patients (p). Methods: Between 08/2014 and 11/2018, 166 p were screened and 159 randomized to extend (80p) or not (79p) TMZ treatment for 6 cycles after proving stable disease in the MRI performed before inclusion. Centralized review of histology and determination of MGMT status, if not previously available, were performed before randomizing patients. Two criteria of stratification were used: MGMT status and presence/absence of residual disease on the basal MRI (defined as a residual enhancement larger than 1cm in one). The primary endpoint was differences in 6mPFS, secondary endpoints were differences in PFS, OS, toxicity, between arms and per stratification factors. Results: Median age was 60.3 (range 29-83), 97p (61%) were methylated, basal MRI showed residual disease in 57p (35.8%). After a median follow up of 14.0 months, with 121 p(76.1%) already progressed and 81p (50.9%) already dead, median PFS is presented. Median (m) PFS is 8.0 months (95%CI: 5.7-10.2). There is no difference in mPFS between arms (adjusted HR = 0.98, 95% CI: 0.82-1.18, P = 0.907). Methylated tumors had longer mPFS (HR=0.57, 95% CI: 0.39-0.83, P=0.004) irrespectively to the study treatment. Conclusions: There is not apparent benefit of continuing TMZ treatment for more than 6 cycles. Data will be actualized for the congress.Supported by a Grant of the ISCIII: PI13/01751. Clinical trial information: NCT02209948.

2613 Background: Solid pediatric tumors that appear in adulthood are a heterogeneous group characterized by a low incidence, lack of standard therapeutic options and reduced survival. We have designed the first phase II clinical trial of nivolumab and ipilimumab in this setting, Here, we present the results of the first cohort with 30 evaluable patients. Methods: This is a multicenter, open-label, single arm Phase II study conducted in 15 centers of the Spanish Group for Rare Cancer (GETHI). We aimed to evaluate efficacy and safety of the combination of nivolumab and ipilimumab in adult patients ( 18 years) with locally advanced or metastatic childhood malignancies that have progressed or are not candidates to standard therapy. Treatment consisted on nivolumab 3 mg/kg IV q2w + ipilimumab 1 mg/kg IV q6w for 6 months or until progression/unacceptable toxicity, for a maximum of 24 months. Primary endpoint was overall response rate (ORR) according to RECIST v1.1 criteria. We used a Simon optimal two-stage design, with a first stage including first 30 evaluable patients. Results: 20 patients were male and median age was 43 (range 20-75). Most frequent histologies were medulloblastoma (4) neuroblastoma (4) and Ewing family tumors (3). 90% had received prior systemic therapy with 37% presenting progressive disease as best response. Median previous treatment lines were 3 (range 1-9). 27 patients were PS0-1, and 3 PS2. 6 patients have been treated for ≥6 months . Only one discontinued for adverse events. With a median follow up of 4,3 months (range 0,4-11,3), 1 patient has achieved a deep partial response (PR) (3,6%), 10 stable disease (SD) (35,7%) and 17 progressive disease (PD) (60,7%). 2 patients died before radiologic evaluation. Clinical benefit rate (CR+PR+SD) was 39,3%. Median progression free survival (PFS) was 1,8 months (95% CI 1,3-2,3), with a 3-months-PFS of 32,7% and 6-months-PFS of 20%. Median overall survival (OS) was 6,8 months (95% CI 3,3-10,2). 12 (40%) patients presented adverse events (AE) of any grade and 6 (20%) experienced a grade AE deemed as possibly related to treatment. Conclusions: The combination of nivolumab and ipilimumab showed significant clinical benefit in this population with little therapeutic options. One case of metastatic esthesioneuroblastoma, achieved a dramatic tumor response and represents the first patient with this extremely rare histology treated with immunotherapy. Clinical trial information: EudraCT 2016-003946-99.

Purpose Doxorubicin and trabectedin are considered active drugs in soft tissue sarcoma (STS). The combination of both drugs was hypothesized to be advantageous and safe on the basis of preclinical evidence and a previous phase I trial, respectively. The aim of this study was to compare the clinical outcome of trabectedin plus doxorubicin with doxorubicin as first-line treatment of advanced STS patients. Patients and Methods In this open-label randomized phase II trial, the main end point was progression-free survival (PFS). Trabectedin 1.1 mg/m2 in a 3-hour infusion plus doxorubicin 60 mg/m2 as the experimental arm and doxorubicin 75 mg/m2 as the control arm were administered for up to six cycles. Translational research was planned to correlate the expression of apoptotic and DNA repair genes with clinical outcome. Results In 115 randomly assigned patients, the median PFS was 5.5 months in the control arm and 5.7 months in the experimental arm (hazard ratio, 1.16; 95% CI, 0.79 to 1.71; P = .45) in the intent-to-treat analysis. The trial was stopped for futility after the interim analysis, because the results in the experimental arm showed the risk reduction for the main end point to be < 9.64%. The proportion of patients with grade 3 or 4 thrombocytopenia, asthenia, and liver toxicity was significantly higher in the experimental arm. FAS and p53 were shown to be prognostic factors for PFS (7.0 months if FAS+ and p53−; 3.4 months if FAS+/p53+ or FAS−/p53−; and 0.7 months if FAS− and p53+; P < .001) and for overall survival. Conclusion Trabectedin plus doxorubicin did not show superiority over doxorubicin alone as first-line treatment of advanced STS. The prognostic role of apoptotic key genes, FAS and p53, was shown to be robust enough to continue this research line.

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. This work has been supported by Ministerio de Economía y Competitividad/FEDER, Spain [grant number MTM2015-71200-R], Consejería de Educación Cultura y Deporte from Junta de Comunidades de Castilla-La Mancha, Spain [grant number PEII-2014-031-P] and James S. Mc. Donnell Foundation 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer [Special Initiative Collaborative – Planning Grant 220020420 and Collaborative award 220020450]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

8537Background: CT-RT is the standard treatment for unresectable LA-NSCLC. P plus vinorelbine is widely used. Metronomic CT is a frequent administration of low doses of CT. mOV has shown good effic...

TPS3123Background: Solid pediatric tumors that appear in adulthood are a heterogeneous group that share some characteristics such as low incidence, lack of standard therapeutic options and reduced ...

e13608Background: The Spanish Lung Cancer Group (GECP) initiated a Tumor Thoracic Register (RTT) in September 2016 with the aim of evaluating accurate, basic data concerning this oncological pathol...

e20521Background: This study aims to compare efficacy and safety of two widely used combinations of cisplatin (P) in this setting: as etoposide (E) and vinorelbine. This last, in its oral formulati...

Purpose To assess the progression-free survival (PFS) and antitumor response to standard-dose doxorubicin compared with sequential dose-dense doxorubicin and ifosfamide in first-line treatment of advanced soft tissue sarcoma. Patients and Methods Patients with measurable advanced soft tissue sarcoma, Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2, between the ages 18 and 65 years, and with adequate bone marrow, liver, and renal function were entered in the study. The stratifications were: ECOG PS (0 v 1), location of metastases, and potentially resectable disease. Patients were randomly assigned to either doxorubicin 75 mg/m2 given as a bolus injection every 3 weeks for 6 cycles (arm A) or doxorubicin at 30 mg/m2 per day for 3 consecutive days once every 2 weeks for 3 cycles followed by ifosfamide at 12.5 g/m2 delivered by continuous infusion over 5 days once every 3 weeks for 3 cycles with filgastrim or pegfilgastrim support (arm B). Results Between December 2003 and September 2007, 132 patients were entered onto the study. Febrile neutropenia, asthenia, and mucositis were more frequent in the arm B. The interim preplanned analysis for futility allowed the premature closure. Objective responses were observed in 23.4% of assessable patients in arm A and 24.1% in arm B. PFS was 26 weeks in the arm A and 24 weeks in arm B (P = .88). Overall survival did not differ between the two therapeutic arms (P = .14). Conclusion Single-agent doxorubicin remains the standard treatment in fit patients with advanced soft tissue sarcoma.

Purpose To assess the impact of different factors on response rate (RR), time to tumor progression (TTP), and overall survival time (OS) in patients with locally advanced or metastatic soft tissue sarcoma (ASTS), included in three protocols with high-dose ifosfamide (HDIF). Patients and Methods One hundred fifty six ASTS patients included in three consecutive phase II trials with HDIF (>10 g/m2), alone or in combination with doxorubicin (DX), were analyzed. Cofactors were institution, trial, gender, age, performance status, histologic type, grade of malignancy, prior radiotherapy, presence of locoregional disease, metastatic site, salvage surgery, number of organs involved, and disease-free interval. Results By multivariate analysis performance status >0 and lack of salvage surgery correlated with a poorer survival. A good-risk and a poor-risk group were identified, with median survival time (OS) of 29, 5, and 10 months, respectively (P = 0.00001). The 1-, 2-, and 3-year OS for 83 good-risk patients (either with PS = 0 or receiving salvage surgery) was 83, 44, and 29%, respectively, those figures being 37, 7, and 3% for 73 poor-risk patients. Conclusion The design of randomized trials in ASTS including HDIF should consider those prognostic factors as stratification variables. J. Surg. Oncol. 2004;88:44–49. © 2004 Wiley-Liss, Inc.

Irinotecan and raltitrexed are active against advanced colorectal cancer, act through different mechanisms, and have non-overlapping toxicity profiles. In vitro studies have shown a schedule-dependent synergism between both drugs. The aim of this multicenter study was to determine the maximum tolerated dose (MTD) of this combination. Patients with 5-fluorouracil-refractory, advanced colorectal cancer were eligible. Dose escalation consisted of irinotecan (250–350 mg/m2 as a 60-min infusion) in combination with a fixed dose of raltitrexed (3 mg/m2 as a 15-min infusion, 1 h after irinotecan). Courses were repeated every 21 days. Three to 6 patients were to be included at each dose level. Dose limiting (NCI-CTC grade 3–4) toxicities (DLT) were assessed during the first 2 cycles. Thirteen patients were recruited (4, 3 and 6 in levels I, II and III, respectively). Main toxicity was diarrhea and asthenia, whereas myelotoxicity was mild. At level III, 2/6 patients experienced DLT (grade 4 diarrhea and neutropenia). The MTD was not reached, but further dose escalation was not attempted. Among 12 patients with measurable disease, 2 partial responses were observed for an overall response rate of 17%. The combination of single-agent full doses of irinotecan (350 mg/m2) and raltitrexed (3 mg/m2) in a 3-weekly schedule is feasible, with mild toxicity and a promising clinical activity. Diarrhea is the DLT, but it is not more common or severe than that described with irinotecan alone.

8538Background: This study aims to compare efficacy and safety of two widely used combinations of cisplatin (P) in this setting: as etoposide (E) and vinorelbine. This last, in its oral formulation...

e15141Background: Clinical trials have studied the efficacy and safety of neoadjuvant chemotherapy (CT) and CRT in PRRC. Chau published his data on PRRC studied with MRI: tumors within 1 mm of meso...

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 125mg/m(2) (or 340mg/m(2) 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. Anti-Cancer Drugs 23: 659-665 (C) 2012 Wolters Kluwer Health broken vertical bar Lippincott Williams & Wilkins.

BACKGROUND: Neoadjuvant therapy (NA: treatment administered before radiation) is barely accepted in clinical trial methodology. Nevertheless, it could be an effective way to test de activity of new agents. In this study we analyzed the impact of objective response to NA therapy on the final outcome of patients included in three neoadjuvant trials carried on by GEINO: GENOM 99 (39p: Phase II cisplatin and temozolomide), GENOM 008 (12p: Phase II sunitinib) an GENOM 09 (93p: randomized phase II temozolomide versus temozolomide and bevacizumab). METHODS: We merged data bases of the 3 studies (SPSS program), and studied their characteristics, treatment response and prognostic factors related to OS. RESULTS: One hundred and forty-four patients were included: male/female: 45.1%/79%; PS: 0,1,2: 20.8%, 47.2%, 31.9%; MMS

One of the standard treatments for metastatic non-small-cell lung cancer patients is the combination of cisplatin plus vinorelbine. This regimen is associated with a high rate of severe neutropenia, and a hemogram is therefore routinely performed on day 8 before the administration of vinorelbine. However, no study has ever examined the rate of neutropenia detected in this hemogram or the rate of discontinuation of chemotherapy as a result. Since one of the objectives in the treatment of advanced lung cancer is to maintain quality of life, we have retrospectively analyzed a Spanish Lung Cancer Group study of cisplatin plus vinorelbine to address the question of whether this hemogram on day 8 could be avoided, thus eliminating unnecessary venipunctures without endangering patient safety. Between April 2004 and January 2006, 180 chemotherapy-naïve, advanced NSCLC patients were included from 35 centers. They received intravenous doses of cisplatin 75mg/m(2) on day 1 plus vinorelbine 25mg/m(2) on days 1 and 8, every 3 weeks, for a maximum of six cycles. Median age was 62.5 years; 87.2% were males; 80.6% were smokers; 48.2% were adenocarcinomas and 36% were squamous cell carcinomas; 17.2% were stage IIIB and 82.8% stage IV. Of 750 cycles analyzed, vinorelbine was administered on day 8 in 661 (88.1%), and the dose was reduced or canceled in 15 (2%) due to hematological toxicity. Among patients aged70 with no dose modification in previous cycles, the likelihood of observing hematological toxicity at day 8 was only 0.8% (95% CI, 0.1-3%). We speculate that the hemogram on day 8 could potentially be avoided in this subgroup of patients while still maintaining an acceptable safety margin. Prospective clinical studies to further examine this hypothesis are warranted.

In spite of the dismal outcome of glioblastoma multiforme (GBM), we are in a position to provide a ray of hope to patients and families. Methylation of MGMT in tumor occurs in approximately a third of patients and predicts meaningful response and survival to adjuvant radiotherapy plus temozolomide. Limited access to tumor tissue in some patients could be circumvented by examining MGMT methylation in circulating serum DNA, although this approach needs to be validated. Molecular signatures are also promising prognostic and predictive markers, and clinical trials should be carried out to validate their use in the selection of patients for specific targeted therapies. Gene expression by quantitative PCR of key components of these molecular signatures could pave the way for easy identification of different subgroups of patients. Translational clinical trials are warranted in order to detect the subgroups of patients resistant to radiotherapy who may derive benefit from novel therapies, including antiangiogenic drugs.

Purpose Survival in patients with advanced non–small-cell lung cancer (NSCLC) who are treated with platinum-based chemotherapy is rather variable. Methylation-dependent transcriptional silencing of 14-3-3σ, a major G2-M checkpoint control gene, could be a predictor of longer survival. Patients and Methods A sensitive methylation-specific polymerase chain reaction assay was used to evaluate 14-3-3σ methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine–treated advanced NSCLC patients. Results 14-3-3σ methylation was observed in all histologic types of 39 patients (34%). After a median follow-up of 9.8 months, median survival was significantly longer in the methylation-positive group (15.1 v 9.8 months; P = .004). Median time to progression was 8 months in the methylation-positive group and 6.3 months in the methylation-negative group (log-rank test, P = .027). A multivariate Cox regression model identified only 14-3-3σ methylation status and Eastern Cooperative Oncology Group performance status as independent prognostic factors for survival. In an exploratory analysis, median survival for 22 methylation-positive responders has not been reached, whereas survival was 11.3 months for 29 methylation-negative responders (P = .001). Conclusion Methylation of 14-3-3σ is a new independent prognostic factor for survival in NSCLC patients receiving platinum-based chemotherapy. It can be reliably and conveniently detected in the serum, thus obviating the need for tumor tissue analysis.

e19014 Background: In NS-NSCLC CPB achieved median OS > 1 y and supported use of B. A broad range of predictive/prognostic markers explored for B use. In VEGF pathway ligands and receptors play an ...

10500 Background: Nucleotide excision and homologous recombination DNA repair pathways are the most recognized antitumor mechanism of action of trabectedin in STS. Additionally, our group has shown...

e20686 Background: To evaluate whether echocardiographic parameters and serum biomarkers may predict early cardiac dysfunction in patients treated with taxanes, anthracyclines with / without trastu...

2028 Background: We compared the efficacy and safety of treatment with TMZ or TMZ+BEVprior to and concomitant with radiotherapy in unresectable(GBM) patients. Methods: Between December 2009 and Apr...

10523 Background: Recent studies suggest that VEGFR inhibition could play a role in the treatment of soft tissue sarcoma (STS). Prior studies by our group showed that the combination of ifosfamide with sorafenib resulted in preclinical additive activity and that was feasible and safe in the phase I trial. Methods: Patients (pts) with advanced STS, previously treated with doxorubicin, no prior ifosfamide, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were enrolled in this multicenter phase II study, receiving sorafenib 400 mg bid po continuously and ifosfamide 2 g/m2 iv for 3 days together with mesna 400 mg/m2 every 3 weeks. The primary endpoint was progression-free rate (PFR) at 3 months. A one-sample binomial design was used (PFR P0=40%, P1=60%, α=0.10, β=0.20), requiring at least 19 of 35 pts free of progression at 3 months to be considered positive. Results: From September 09 to March 12, 35 pts were enrolled at 11 centers. Median age was 55 (18-73). PS: 0-13, 1-18; 2-4 pts. Histologic types were: LMS 12, Lipo 6, SS 5, MPNST 2, other 10 pts. . The median number of cycles administered per patient was 4. PFR at 3 months was 67%, with 23 pts being free of progression at 3 months. Median progression-free survival was 4.8 months (95% CI, 1.9-6.3) and median overall survival was 16.2 months. PR was achieved in 17% pts. Most common grade 3-4 toxicities were asthenia (25%), hand-foot syndrome (11%) and neutropenia (20%) resulting in 3 episodes of neutropenic fever. Other common toxicities (G1-4) included emesis (34%), rash (22%), diarrhea (34%), hypertension (11%) and mucositis (9%). Conclusions: The combination of ifosfamide and sorafenib is active and has acceptable toxicity in pts with doxorubicin pretreated STS. The PFR at 3 months might exceed the expected with ifosfamide alone warranting further investigation. Clinical trial information: EudraCT: 2007-002176-34.

LBA8002 Background: Findings from the SLCG phase II customized chemotherapy trial (NCT00883480) showed that RAP80, a component of the BRCA1 complex, influenced outcome both in p with low BRCA1 expression treated with cisplatin (cis)/gemcitabine (gem) and in p with intermediate/high BRCA1 levels treated with cis/docetaxel (doc) or with doc alone. Together with the French Lung Cancer Group, the SLCG has performed a prospective, randomized phase III trial comparing noncustomized cis/doc with customized therapy in metastatic NSCLC p. A parallel phase II study (ChiCTR-TRC-12001860) is being carried out in China under the auspices of the SLCG. Methods: Since 6 March 2008, 391 p with wild-type EGFR have been randomized 1:1 to the control or experimental arm. p in the control arm receive cis/doc; p in the experimental arm receive treatment according to their BRCA1 and RAP80 levels: p with low RAP80, regardless of BRCA1 levels, cis/gem; p with intermediate/high RAP80 and low/intermediate BRCA1, cis/doc; p with int...

1531 Background: Gender differences in lung cancer (LC) have been reported, but with many unresolved issues yet. Tobacco causes the majority of women lung cancer (WLC), although the rate of never-smoking WLC is higher than in men. Several factors may play etiologic roles, and an in-depth understanding is needed. Methods: WORLD07 is a Spanish prospective, multicenter, epidemiologic female-specific LC database sponsored by ICAPEM, a professional association committed with WLC research. In order to improve the knowledge on never-smoking WLC, information has been extracted from WORLD07 database. Results: From October/2007 to October/2011, 1371 newly diagnosed WLC were included in an e-database from 32 centers, 539 (39.3%) never-smoking. Patient (p) characteristics: median age 71.1 years(y); median age of menarche 13y.; motherhood 91.2% (median 2.3 children, median age at first child 26.4y); oral contraceptive use 11.9%; postmenopausal 88.9% (median age of menopause 49y); HRT 5.2%; second-hand smokers 40% (work-exposure 17.1%, home-exposure 88.8%); obesity 16.3%; familiar history of cancer 39.9% (LC 29.8%); previous history of cancer 13% (breast/lung/cervix: 41.4/5.7/2.9%); current LC histology(%): adenocarcinoma/SqCC/LCC/SCLC: 83.4/6.2/5.5/3.9; EGFR mut+ (268 p analyzed): 55.5% (exon 19/20/21(%): 61.1/7.4/36.9); TNM NSCLC I/II/III/IV(%): 14/3.3/19.8/60.3. Treatment: EGFR-TKI in p EGFR mut+, stage IV(1st-/2nd-line)(%): 51.7/15.4; stage IV NSCLC (1st-line/2nd-line): platinum-based CT 42.5%, EGFR-TKI 33.5%, combinations with bevacizumab 2.9% / EGFR-TKI 15.8%. Overall survival: median 27 months(m), 1/2-y(%) 74.8/55.2; stage IV NSCLC: median 20.5m, 1/2-y(%) 67/46; EGFR-mut+ p: median 27.3m, 1/2-y(%) 75/54.3. Conclusions: According to our e-database, WLC showed high rates of never-smokers (39.3%), and of relatives diagnosed with malignant tumours (39.9%, ≅1/3 LC). Adenocarcinoma was the most frequent histology (76.1%), and more than half of the cases analyzed harboured EGFR mutations. Although 40% were second-hand smokers, further investigations are warranted. Survival outcomes remain satisfactory, as expected from this selected subgroup of p. Additional epidemiologic and treatment data will be presented.

Background: The WORLD07 project is a female specific database to prospectively analyze the characteristics of Spanish women with lung cancer. Patients and Methods: We analyzed and compared lung cancer features in women with and without a family history of cancer/lung cancer. Results: Two thousand and sixty women were included: 876 had a family history of cancer (lung cancer, 34%) and 886 did not, with no significant differences between groups, except for smoking status (p=0.036). We found statistically significant correlations between epidermal growth factor receptor (EGFR) mutation and smoking status in patients with a family history of cancer (r=-0.211; p

Single nucleotide polymorphisms (SNPs) in the metabolic pathways of S-adenosylmethionine have been related to global hypomethylation and a lower number of hypermethylated CpG islands of tumor suppressor genes. Hypermethylation of checkpoint and DNA repair genes has been shown to be indicative of chemosensitivity. In the present study, we have examined the SNP of methylenetetrahydrofolate reductase (MTHFR) C677T, which affects DNA methylation patterns and is linked to elevated plasma homocysteine levels in 208 patients with gemcitabine/cisplatin-treated stage IV non–small-cell lung cancer (NSCLC). No differences in response rate were observed according to the MTHFR genotype. However, time to progression was 7.4 months for 68 patients with CC genotype, 5.5 months for 108 patients with heterozygous CT genotype, and 5.2 months for 28 patients with TT genotype. These findings can lead us to distinguish different outcome patterns among patients with stage IV NSCLC whose similar clinical prognostic factors would otherwise indicate similar outcomes. Carriers of the MTHFR 677T allele could benefit from supplementation with folic acid and vitamin B12. The Spanish Lung Cancer Group has undertaken a phase III randomized trial to elucidate this concept.

Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and cisplatin are commonly used in the treatment of many solid tumors, although the impact of chemotherapy is limited in metastatic non-small cell lung cancer. However, in clinical practice, there is a minority of patients who can attain long-term survival. Upregulation of mRNA transcripts has been linked to chemoresistance, and in some instances, mRNA expression has been correlated with polymorphisms. Cisplatin resistance is directly linked to the nucleotide excision repair system, specifically to the transcription-coupled nucleotide excision repair pathway that involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. Overexpression of ERCC1 correlates with poor survival in gemcitabine/cisplatin-treated non-small cell lung cancer patients. At the preclinical level, ERCC1 and XPD mRNA expression correlate with each other, and overexpression of XPD causes selective cisplatin resistance in human tumor cell lines. XPD polymorphisms have been associated with lower DNA repair capacity. In our experience, time to progression is significantly higher in gemcitabine/cisplatin-treated patients with the Lys751Gln genotype (9.6 months) than in those with the Lys751Lys genotype (4.2 months; P = .03). Other polymorphisms involved in parallel DNA repair systems may well provide the same information, indicating a high degree of biologic redundancy. The overexpression of the subunit M1 of ribonucleotide reductase (RRM1) has been linked to gemcitabine resistance in our retrospective assessment. Preliminary findings that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and RRM1 mRNA levels show a significantly longer survival and highlight the possibilities of individually tailored chemotherapy.