Radium-223 for patients with metastatic castration-resistant prostate cancer with asymptomatic bone metastases progressing on first-line abiraterone acetate or enzalutamide: A single-arm phase II trial.

PURPOSE: The paper aims to evaluate the efficacy and safety of 223Ra in patients who progressed after first-line androgen deprivation therapy. PATIENTS AND METHODS: EXCAAPE (NCT03002220) was a multicentre, single-arm, open-label, non-controlled phase IIa trial in 52 patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases who have progressed on abiraterone acetate or enzalutamide, up to six doses of 223Ra (55 kBq/kg of body weight per month). The primary end-point was radiographic progression-free survival (rPFS). Secondary end-points included rPFS based on androgen receptor splice variant 7 (AR-V7) expression in circulating tumour cells (CTCs), overall survival, and safety. RESULTS: Median rPFS was 5.5 months (95% CI 5.3-5.5). Median rPFS of patients with AR-V7(-) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2-not reached) and was significantly greater for AR-V7(-) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01). 223Ra was well tolerated; anaemia and thrombocytopenia were the most common grade 3/4 adverse events (5.8% and 11.5%, respectively). CONCLUSIONS: 223Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile.

First-line osimertinib in patients with epidermal growth factor receptor-mutant non-small-cell lung cancer and with a coexisting low allelic fraction of Thr790Met.

AIM OF THE STUDY: The AZENT (NCT02841579) study aimed to assess the efficacy and safety of first-line osimertinib in patients with epidermal growth factor receptor(EGFR)mutation-positive advanced non-small-cell lung cancer (NSCLC) and with a coexisting low allelic fraction of Thr790Met. METHODS: In this multicentre, single-arm, open-label, phase IIa study, patients with locally advanced or metastatic NSCLC harbouring centrally confirmedEGFR Thr790Met mutation received 80 mg osimertinib daily. The primary end-point was objective response rate (ORR). The secondary end-points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Efficacy was assessed as per Response Evaluation Criteria in Solid Tumours, version 1.1. Blood samples collected at baseline, end of week 2 and disease progression were analysed using next-generation sequencing. As osimertinib was approved as a first-line therapy during the trial, this led to early termination of phase II; thus, analysis is considered exploratory. RESULTS: Twenty-two patients were enrolled and received osimertinib. All 22 patients were included in the efficacy and safety analysis. At the data cutoff, 10 (50%) patients remained on treatment. The median duration of follow-up was 24.4 months (interquartile range 12.9 to 26.0). The ORR was 77.3% (17/22 [95% confidence interval {CI} 54.6 to 89.3]). The DCR was 86.4% (19/22, [95% CI 65.1 to 97.1]). The median PFS was 23.1 months (95% CI 14.1 to NE). The median OS was 28·4 months (95% CI 25.6 to NE). CONCLUSION: Despite early study termination, osimertinib first-line therapy yields an overall PFS of 23.1 months in EGFR-mutant patients harbouring a coexisting low allelic fraction of EGFR Thr790Met mutation.

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.

Intercalated Dosing Schedule of Erlotinib and Docetaxel as a Therapeutic Strategy to Avoid Antagonism and Optimize Its Benefits in Advanced Non-Small-Cell Lung Cancer. A Randomized Phase II Clinical Trial.

INTRODUCTION: The purpose of this study was to assess whether an intercalated dosing schedule of erlotinib and docetaxel could avoid possible negative interactions and optimize the benefit obtained as second-line therapy in non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: A phase II randomized clinical trial was designed for advanced NSCLC patients in whom previous chemotherapy treatment had failed. The experimental arm with 33 patients consisted of erlotinib 150 mg/d orally, intermittent administration on days 2 to 16 every 21 days, combined with docetaxel 75 mg/m(2) every 21 days; the control arm with 35 patients consisted of erlotinib 150 mg/d orally, administered continuously. The study's primary end point was the proportion of patients who remained progression-free at 6 months in the 2 arms. RESULTS: The proportion of patients who remained progression-free at 6 months was of 5 patients (15%) in the intercalated arm and 3 patients (9%) in the erlotinib monotherapy arm respectively. Median progression-free survival (PFS) was 3.0 versus 2.1 months (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.39-1.06; P = .086). Median overall survival (OS) was 7.5 and 5.2 months (HR, 0.70; 95% CI, 0.41-1.19; P = .19). Disease control rates were 51.7% and 36.4%, respectively. No new safety signals were observed. CONCLUSION: Erlotinib and docetaxel with intermittent administration of erlotinib improved PFS, OS, and disease control rates compared with erlotinib alone. All of our results indicated that an intercalated dosing schedule of erlotinib and docetaxel could be more efficient than erlotinib treatment alone. Therefore, further studies should be developed in a larger number of patients. This study has shown the absence of antagonism between docetaxel and erlotinib when given in an intercalated fashion.

Primary squamous cell carcinoma of the ovary associated with endometriosis.

OBJECTIVE: To analyze the clinical, therapeutic, and pathologic features of published cases presenting primary squamous cell carcinoma (SCC) of the ovary associated with endometriosis. METHODS: A case report, 15 cases of infiltrating SCC of the ovary associated with or arising from endometriosis, and 1 case of synchronous carcinoma in situ in the cervix and ovary from a review of the literature were studied. RESULTS: Young age, advanced stage of the disease, and hypogastric pain were frequent at the time of diagnosis. There was no ascites, but infiltration of neighboring organs was common. The tumor was associated with 80% patient mortality in the first few months. Adjuvant chemotherapy with paclitaxel and carboplatin or cisplatin appeared to improve the results. CONCLUSION: Primary SCC of the ovary associated with endometriosis is extremely rare and has a poor prognosis. The best therapeutic results are obtained with paclitaxel and carboplatin or cisplatin after radical surgery.

Analysis of c-kit expression in small cell lung cancer: prevalence and prognostic implications.

c-kit, a growth factor receptor with tyrosine kinase activity, plays an important role in the biology of cancer. Its expression has been documented in several malignancies. We performed a retrospective study in 85 patients diagnosed with small cell lung cancer (SCLC) to determine the prevalence and role of c-kit as a possible prognostic marker in this lung cancer malignancy. Demographic and clinical data were obtained from patient charts. c-kit, analyzed as immunohistochemical expression in paraffin-embedded tumour tissues, was observed in 60% of patients. All patients were former or present smokers. At diagnosis, 46% of the patients had limited disease (LD) and 54% extended disease (ED). c-kit expression was observed in 59% of LD and 61% of ED patients (p=0.4). Patients received a median of 4 cycles first-line combination chemotherapy (platinum and etoposide). In LD patients, time to progression (TTP) was 11.5 months in c-kit (+) versus 5.9 in c-kit (-) patients (p=0.14), and median survival 15.4 and 12.8 months, respectively (p=0.33). In the ED group, TTP was 5.5 months in c-kit (+) versus 3.8 in c-kit (-) patients (p=0.34), whereas median survival was 6.3 and 7.9 months, respectively (p=0.45). With the limited number of patients in mind, our findings tended towards an association between c-kit expression and survival in the LD group.

Quantification in the serum of the catalytic fraction of reverse telomerase: a useful prognostic factor in advanced non-small cell lung cancer.

The purpose of this analysis was to study the association between the quantity of free circulating DNA and clinical variables in 99 advanced non-small cell lung cancer patients (NSCLC). The quantification in the serum of the gene of the catalytic fraction of telomerase (hTERT) by RT-PCR was used as a reference of the total amount of free DNA in blood. Patients were treated with cisplatin and docetaxel. The median hTERT level for patients in stage IIIB was 70.7 ng/ml vs. 53.1 ng/ml in patients in stage IV (p= 0.35). There was no association between hTERT values and therapy response, 53.9 ng/ml in the complete response (CR) + partial response (PR) group vs. 54.1 ng/ml in the stable disease (SD) + progressive disease (PD) group (p=0.23). In the multivariate analysis, hTERT was an independent predictive variable for time to progression (TTP) Hazard ratio (HR) 2.0, CI 95% 1.2-3.4, p=0.009) and overall survival (OS) (HR 2.4 CI 95% 1.3-4.3, p=0.004). The analysis of TTP and OS with a cut-off of hTERT at 40 ng/ml revealed that patients about this level had statistically poorer TTP (4 vs. 7 months, p= 0.009) and OS (5 vs. 15 months, p<0.0001). In conclusion, in advanced NSCLC, high serum hTERT levels may be a poor prognostic indicator for TTP and OS.

Weekly paclitaxel as second/third-line treatment in advanced non-small cell lung cancer patients: efficacy and tolerability.

BACKGROUND: The aim of the present study was to evaluate the efficacy and toxicity of weekly paclitaxel as second- or third-line treatment in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: The outcome measured in 37 patients were: response rates, symptom relief (dyspnoea, asthenia and pain), toxicity, overall survival (OS) and time to progression (TTP). RESULTS: Objective response was seen in 8%, stable disease in 27% and disease progression in 62%. Three paclitaxel courses reduced the frequency of WHO grade 2-3 dyspnoea and asthenia from 38% and 43% to 13.5% and &1%, respectively. Moderate to severe pain (VAS score 3-8) was reduced from 35.1% to 24.3%. Median OS was 38 weeks and TTP 12 weeks. Haematological toxicity included anaemia (30% grade 2-3) and neutropenia (8% grade 3). Nonhaematological toxicity included peripheral neuropathy (41% grade 1-2). CONCLUSION: In the routine outpatient setting, weekly paclitaxel is feasible, active and well-tolerated as second/third-line chemotherapy in patients with advanced NSCLC.

[Qualitative analysis of the perception of people who participate in a clinical trial, Navarra]. / Análisis cualitativo de la percepción que tienen las personas que participan en un ensayo clínico, Navarra.

BACKGROUND: The objective of this study is to explore the perception that participants in a clinical trial have about the information disclosured by the physician, during patient recruitment and along the study as a preliminary stage for drafting a questionnaire. METHODS: Qualitative study by means of quasi-structure interviews to subjects of different features taken from a patients list obtained by randomized selection of participants in clinical trials approved within the 1998-1999 period. For conducting the interviews, a guide was prepared based on the recommendations of the Helsinki Declaration. RESULTS: Six (6) interviews were held with 7 individuals, as one married couple was interviewed. Most of the categories encountered belonged to the Helsinki Declaration. In addition, others being related to the fulfillment of expectations and to the balance of the risks/benefits done by the individuals for deciding to take part in the study. CONCLUSIONS: The patients were acceptably informed of the most points dealt with under the Helsinki Declaration. The existence of lacking areas having a major impact on the fulfillment of their expectations however having been revealed.

Análisis cualitativo de la percepción que tienen las personas que participan en un ensayo clínico, Navarra / A qualitative analysis of patient's perceptions on the participation in clinical trials, Navarra, Spain

Fundamento: El objetivo del estudio es explorar la percepción que tienen los participantes en un ensayo clínico de la información facilitada por el médico, en el proceso de captación y durante la realización del mismo, como fase previa a la realización de un cuestionario. Métodos: Estudio cualitativo mediante entrevistas semiestructuradas a sujetos de distintas características, extraídos de un listado de pacientes mediante selección aleatoria de participantes en ensayos clínicos aprobados entre los años 1998-99. Para la realización de las entrevistas se elaboró un guión que recogía las recomendaciones de la Declaración de Helsinki. De la transcripción de las entrevistas se realizó el análisis de contenido. Resultados: Se realizaron 6 entrevistas a 7 personas, pues se entrevistó conjuntamente a un matrimonio. La mayor parte de las categorías encontradas pertenecían a la Declaración de Helsinki. Además, aparecieron otras relacionadas con la satisfacción de expectativas y con el balance riesgo/beneficio que los individuos realizan para tomar la decisión de participar en un ensayo. Conclusiones: Los pacientes fueron aceptablemente informados de muchos de los puntos que considera la Declaración de Helsinki, pero se puso de manifiesto la existencia de áreas más deficitarias con importante repercusión en el cumplimiento de sus expectativas (AU)

Background: The objective of this study is to explore the perception that participants in a clinical trial have about the information disclosured by the physician, during patient recruitment and along the study as a preliminary stage for drafting a questionnaire. Methods: Qualitative study by means of quasi-structure interviews to subjects of different features taken from a patients list obtained by randomized selection of participants in clinical trials approved within the 1998-1999 period. For conducting the interviews, a guide was prepared based on the recommendations of the Helsinki Declaration. Results: Six (6) interviews were held with 7 individuals, as one married couple was interviewed. Most of the categories encountered belonged to the Helsinki Declaration. In addition, others being related to the fulfillment of expectations and to the balance of the risks/benefits done by the individuals for deciding to take part in the study. Conclusions: The patients were acceptably informed of the most points dealt with under the Helsinki Declaration. The existence of lacking areas having a major impact on the fulfillment of their expectations however having been revealed (AU)