Olaparib maintenance versus placebo in platinum-sensitive non-small cell lung cancer: the Phase 2 randomized PIPSeN trial.

BACKGROUND: Platinum-sensitivity is a phenotypic biomarker of Poly (ADP-ribose) polymerase inhibitors (PARPi) sensitivity in histotypes where PARPi are approved. Approximately one-third of non-small cell lung cancers (NSCLC) are platinum-sensitive. The double-blind, randomized phase II PIPSeN (NCT02679963) study evaluated olaparib, a PARPi, as maintenance therapy for patients with platinum-sensitive advanced NSCLC. METHODS: Chemonaïve patients with ECOG performance status of 0-1, platinum-sensitive, EGFR- and ALK-wild-type, stage IIIB-IV NSCLC were randomized (R) to receive either olaparib (O) maintenance or a placebo (P). The primary objective was progression-free survival (PFS) from R. Secondary objectives included overall survival (OS) and safety. With an anticipated hazard ratio of 0.65, 144 patients were required to be randomized, and approximately 500 patients enrolled. RESULTS: The trial was prematurely terminated because anti-PD(L)1 therapy was approved during the trial recruitment. A total of 182 patients were enrolled, with 60 patients randomized: 33 and 27 in the O and P arms, respectively. Patient and tumor characteristics were well-balanced between arms, except for alcohol intake (33% vs 11% in the O and P arms, respectively, p = 0.043). The median PFS was 2.9 and 2.0 months in the O and P arms, respectively (logrank p = 0.99). The median OS was 9.4 and 9.5 months in the O and P arms, respectively (p = 0.28). Grade ≥3 toxicities occurred in 15 and 8 patients in O and P arms, with no new safety concerns. CONCLUSION: PIPSeN was terminated early after enrollment of only 50% of the pre-planned population, thus being statistically underpowered. Olaparib maintenance did neither improve median PFS nor OS in this patient population.

Clinical activity of a htert (vx-001) cancer vaccine as post-chemotherapy maintenance immunotherapy in patients with stage IV non-small cell lung cancer: final results of a randomised phase 2 clinical trial.

BACKGROUND: The cancer vaccine Vx-001, which targets the universal tumour antigen TElomerase Reverse Transcriptase (TERT), can mount specific Vx-001/TERT572 CD8 + cytotoxic T cells; this immune response is associated with improved overall survival (OS) in patients with advanced/metastatic non-small cell lung cancer (NSCLC). METHODS: A randomised, double blind, phase 2b trial, in HLA-A*201-positive patients with metastatic, TERT-expressing NSCLC, who did not progress after first-line platinum-based chemotherapy were randomised to receive either Vx-001 or placebo. The primary endpoint of the trial was OS. RESULTS: Two hundred and twenty-one patients were randomised and 190 (101 and 89 patients in the placebo and the Vx-001 arm, respectively) were analysed for efficacy. There was not treatment-related toxicity >grade 2. The study did not meet its primary endpoint (median OS 11.3 and 14.3 months for the placebo and the Vx-001, respectively; p = 0.86) whereas the median Time to Treatment Failure (TTF) was 3.5 and 3.6 months, respectively. Disease control for >6months was observed in 30 (33.7%) and 26 (25.7%) patients treated with Vx-001 and placebo, respectively. There was no documented objective CR or PR. Long lasting TERT-specific immune response was observed in 29.2% of vaccinated patients who experienced a significantly longer OS compared to non-responders (21.3 and 13.4 months, respectively; p = 0.004). CONCLUSION: Vx-001 could induce specific CD8+ immune response but failed to meet its primary endpoint. Subsequent studies have to be focused on the identification and treatment of subgroups of patients able to mount an effective immunological response to Vx-001. CLINICAL TRIAL REGISTRATION: NCT01935154.

Phase II trial of ifosfamide in combination with the VEGFR inhibitor sorafenib in advanced soft tissue sarcoma: a Spanish group for research on sarcomas (GEIS) study.

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.

Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial.

We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m(2), days 1-21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.

SIADH-related hyponatremia in hospital day care units: clinical experience and management with tolvaptan.

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.

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.

Long-term survival of glioblastoma: A systematic analysis of literature about a case.

INTRODUCTION: In spite of the changes for the treatment of glioblastoma since 2005, we have not seen differences between long-survival patients of more than 10 years showing a value minor than 1%. MATERIAL AND METHOD: We realize a systematic analysis and identify important factors for long survivor patients. We also show an own case with more of 20 years of survival. We make a new pathological study of the old paraffin block of this patient. RESULTS: The most important variable associated with long-survival between all multivariant studies is the age. When we try to find genetic and molecular alterations in glioblastoma associated with prolongated survival, the MGMT promoter methylation play the most important role. We find a correct diagnosis in the current analysis of our patient's sample with very long survival. CONCLUSIONS: Multiple variables are found that affect long survival of glioblastoma series but analyzed studies are very heterogeneous and it is very difficult comparation between them. Most articles we review are obtained from databases of different countries with hundreds of patients. It would be very interesting to promote the use of a single database in Spain that allows us to study these long-term glioblastoma survivors.

SEOM clinical guideline emesis (2021).

Among the side effects of anticancer treatment, chemotherapy-induced nausea and vomiting (CINV) is one of the most feared given its high prevalence, affecting up to 40% of patients. It can impair patient's quality of life and provoke low adherence to cancer treatment or chemotherapy dose reductions that can comprise treatment efficacy. Suffering CINV depends on factors related to the intrinsic emetogenicity of antineoplastic drugs and on patient characteristics. CINV can appear at different times regarding the administration of antitumor treatment and the variability of risk according to the different antitumor regimens has, as a consequence, the need for a different and adapted antiemetic treatment prophylaxis to achieve the desired objective of complete protection of the patient in the acute phase, in the late phase and in the global phase of emesis. As a basis for the recommendations, the level of emetogenicity of anticancer treatment is considered and they are classified as high, moderate, low and minimal emetogenicity and these recommendations are based on the use of antiemetic drugs with a high therapeutic index: anti 5-HT, anti-NK and steroids. Despite having highly effective treatments, clinical reality shows that they are not applied enough, so evidence-based recommendations are needed to show the best options and help in decision-making. To cover all the antiemetic prophylaxis options, we have also included recommendations for oral treatments, multiday regimens and radiation-induced emesis prevention.

Clinical and pathological features of Merkel cell carcinoma: A 4-year follow-up observational retrospective study in Spain.

BACKGROUND: Merkel cell carcinoma (MCC) is a malignant skin cancer with a 5-year survival rate of approximately 50%. Knowledge of MCC has increased in recent years mostly due to improved diagnosis techniques. In Spain there is lack of information regarding the incidence and tumour characteristics, and the treatment approaches are not standardised. The objective of this study was to provide information of the clinical and epidemiological characteristics of MCC patients in Spain. METHODS: Retrospective, observational study involving 192 patients from 25 Spanish hospitals. Evaluated variables included overall survival and incidence rate of Merkel cell polyomavirus, in patients diagnosed from 2012 to 2016. RESULTS: The Spanish incidence rate was estimated 0.32/100,000 inhabitants/year, with variations according to geographical regions, being slightly higher in areas with greater sunlight exposure. In total, 61.5% of tumours showed expansive growth (progressive growth of the tumour), 78.6% showed localisation in UV-exposed skin. 97.4% of patients were diagnosed by excisional biopsy. Surgery was the first line treatment in 96.6% of patients, radiotherapy in 24.6%, and chemotherapy in 6.3%. These treatments were not mutually exclusive. Median overall survival was 38.3 months (78.4% at 12 months and 60% at 24 months). MCPyV was present in 33.8% of patients. CONCLUSION: The incidence of MCC in Spain is one of the highest in Europe, with a slight predominance in men. The sample has shown that a biopsy is available for diagnosis in most cases. Moreover, the treatment is surgical when the tumour is localized and is associated with lymphadenectomy, and/or it is radiotherapy if widespread.

Adherence to the Sociedad Española de Oncología Médica (SEOM) Algorithm for the Treatment of Hyponatremia in Oncology Patients in Spain: The ALGA Study.

INTRODUCTION: The ALGA study explored adherence of Spanish treatment centers to the Sociedad Española de Oncología Médica (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. METHODS: 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. RESULTS: 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. CONCLUSION: 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 Española de Oncología Médica 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.

Prospective Exploratory Analysis of Angiogenic Biomarkers in Peripheral Blood in Advanced NSCLC Patients Treated With Bevacizumab Plus Chemotherapy: The ANGIOMET Study.

Finding angiogenic prognostic markers in advanced non-small-cell lung cancer is still an unmet medical need. We explored a set of genetic variants in the VEGF-pathway as potential biomarkers to predict clinical outcomes of patients with non-small-cell lung cancer treated with chemotherapy plus bevacizumab. We prospectively analyzed the relationship between VEGF-pathway components with both pathological and prognostic variables in response to chemotherapy plus bevacizumab in 168 patients with non-squamous non-small-cell lung cancer. Circulating levels of VEGF and VEGFR2 and expression of specific endothelial surface markers and single-nucleotide polymorphisms in VEGF-pathway genes were analyzed. The primary clinical endpoint was progression-free survival. Secondary endpoints included overall survival and objective tumor response. VEGFR-1 rs9582036 variants AA/AC were associated with increased progression-free survival (p = 0.012 and p = 0.035, respectively), and with improved overall survival (p = 0.019) with respect to CC allele. Patients with VEGF-A rs3025039 harboring allele TT had also reduced mortality risk (p = 0.049) compared with the CC allele. The VEGF-A rs833061 variant was found to be related with response to treatment, with 61.1% of patients harboring the CC allele achieving partial treatment response. High pre-treatment circulating levels of VEGF-A were associated with shorter progression-free survival (p = 0.036). In conclusion, in this prospective study, genetic variants in VEGFR-1 and VEGF-A and plasma levels of VEGF-A were associated with clinical benefit, progression-free survival, or overall survival in a cohort of advanced non-squamous non-small-cell lung cancer patients receiving chemotherapy plus antiangiogenic therapy.

Phase II clinical trial with metronomic oral vinorelbine and tri-weekly cisplatin as induction therapy, subsequently concomitant with radiotherapy (RT) in patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC). Analysis of survival and value of ctDNA for patient selection.

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-naïve stage III NSCLC deemed surgically unresectable by a multidisciplinary team were treated with 2 cycles of induction cisplatin at 80 mg/m2 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.

ASTRIS, a large real-world study to evaluate the efficacy of osimertinib in epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer patients: Clinical characteristics and genotyping methods in a Spanish cohort.

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.

Phase II Trial of Palbociclib in Recurrent Retinoblastoma-Positive Anaplastic Oligodendroglioma: A Study from the Spanish Group for Research in Neuro-Oncology (GEINO).

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. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, identifier NCT0253032 (retrospectively registered on 21 August 2015).

A phase II randomized, multicenter, open-label trial of continuing adjuvant temozolomide beyond 6 cycles in patients with glioblastoma (GEINO 14-01).

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 < 0.001), thrombocytopenia (P < 0.001), and nausea and vomiting (P = 0.001). 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.

Pyrosequencing versus methylation-specific PCR for assessment of MGMT methylation in tumor and blood samples of glioblastoma patients.

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.

Oral vinorelbine versus etoposide with cisplatin and chemo-radiation as treatment in patients with stage III non-small cell lung cancer: A randomized phase II (RENO study).

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 randomized1:1 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.

Translational research in glioblastoma multiforme: molecular criteria for patient selection.

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.

14-3-3sigma methylation in pretreatment serum circulating DNA of cisplatin-plus-gemcitabine-treated advanced non-small-cell lung cancer patients predicts survival: The Spanish Lung Cancer Group.

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 14-3-3sigma, 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 14-3-3sigma methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine-treated advanced NSCLC patients. RESULTS: 14-3-3sigma 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 14-3-3sigma 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 14-3-3sigma 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.