Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Phosphatidylinositol 3-kinase (PI3K) pathway activation in squamous cell carcinoma of the head and neck contributes to treatment resistance and disease progression. Buparlisib, a pan-PI3K inhibitor, has shown preclinical antitumour activity and objective responses in patients with epithelial malignancies. We assessed whether the addition of buparlisib to paclitaxel improves clinical outcomes compared with paclitaxel and placebo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS: In this multicentre, randomised, double-blind, placebo-controlled phase 2 study (BERIL-1), we recruited patients aged 18 years and older with histologically or cytologically confirmed recurrent and metastatic squamous cell carcinoma of the head and neck after disease progression on or after one previous platinum-based chemotherapy regimen in the metastatic setting. Eligible patients were enrolled from 58 centres across 18 countries and randomly assigned (1:1) to receive second-line oral buparlisib (100 mg once daily) or placebo, plus intravenous paclitaxel (80 mg/m2 on days 1, 8, 15, and 22) in 28 day treatment cycles. Randomisation was done via a central patient screening and randomisation system with an interactive (voice and web) response system and stratification by number of previous lines of therapy in the recurrent and metastatic setting and study site. Patients and investigators (including local radiologists) were masked to treatment assignment from randomisation until the final overall survival analysis. The primary endpoint was progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in all randomly assigned patients. Efficacy analyses were done on the intention-to-treat population, whereas safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01852292, and is ongoing but no longer enrolling patients. FINDINGS: Between Nov 5, 2013, and May 5, 2015, 158 patients were enrolled and randomly assigned to receive either buparlisib plus paclitaxel (n=79) or placebo plus paclitaxel (n=79). Median progression-free survival was 4·6 months (95% CI 3·5-5·3) in the buparlisib group and 3·5 months (2·2-3·7) in the placebo group (hazard ratio 0·65 [95% CI 0·45-0·95], nominal one-sided p=0·011). Grade 3-4 adverse events were reported in 62 (82%) of 76 patients in the buparlisib group and 56 (72%) of 78 patients in the placebo group. The most common grade 3-4 adverse events (occurring in ≥10% of patients in the buparlisib group vs the placebo group) were hyperglycaemia (17 [22%] of 76 vs two [3%] of 78), anaemia (14 [18%] vs nine [12%]), neutropenia (13 [17%] vs four [5%]), and fatigue (six [8%] vs eight [10%]). Serious adverse events (regardless of relation to study treatment) were reported for 43 (57%) of 76 patients in the buparlisib group and 37 (47%) of 78 in the placebo group. On-treatment deaths occurred in 15 (20%) of 76 patients in the buparlisib group and 17 (22%) of 78 patients in the placebo group; most were caused by disease progression and none were judged to be related to study treatment. INTERPRETATION: On the basis of the improved clinical efficacy with a manageable safety profile, the results of this randomised phase 2 study suggest that buparlisib in combination with paclitaxel could be an effective second-line treatment for patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck. Further phase 3 studies are warranted to confirm this phase 2 finding. FUNDING: Novartis Pharmaceuticals Corporation.

Hazai tapasztalatok metasztatikus kolorektális karcinóma bevacizumabbal kiegészített indukciós kemoterápiás kezelésével (AVACONT vizsgálat).

The primary aim of AVACONT was to collect data in the course of routine oncological care from patients with metastatic colorectal cancer (mCRC) treated with bevacizumab supplemented fluoropyrimidine-based chemotherapy doublet in an open, multicentre, observational study in Hungary. Primary endpoint of the study was to determine progression-free survival (PFS). The Full Analysis Set (FAS) comprised 280 patients. Median PFS calculated from enrolment was 270 days in the FAS population. The metastatic involvement of the liver or more than one organ significantly decreased (250 and 245 days), while a clinical response achieved significantly increased (partial response: 404, complete response: 623 days) the mPFS calculated from enrolment. PFS calculated from the start of the first-line treatment was significantly decreased by the presence of mutant RAS gene (481 vs. 395 days). The results confirm the efficacy, known prognostic factors and safety profile of bevacizumab in combination with chemotherapy dosed during standard oncology care in Hungarian centres.

Platinum-based chemotherapy plus cetuximab in head and neck cancer.

BACKGROUND: Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck. We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. METHODS: We randomly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin (at a dose of 100 mg per square meter of body-surface area on day 1) or carboplatin (at an area under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion on day 1) plus fluorouracil (at a dose of 1000 mg per square meter per day for 4 days) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour intravenous infusion, then 250 mg per square meter, as a 1-hour intravenous infusion per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first. RESULTS: Adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum-fluorouracil) significantly prolonged the median overall survival from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab (hazard ratio for death, 0.80; 95% confidence interval, 0.64 to 0.99; P=0.04). The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months (hazard ratio for progression, 0.54; P<0.001) and increased the response rate from 20% to 36% (P<0.001). The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia (19% and 13%, respectively), neutropenia (23% and 22%), and thrombocytopenia (11% in both groups). Sepsis occurred in 9 patients in the cetuximab group and in 1 patient in the chemotherapy-alone group (P=0.02). Of 219 patients receiving cetuximab, 9% had grade 3 skin reactions and 3% had grade 3 or 4 infusion-related reactions. There were no cetuximab-related deaths. CONCLUSIONS: As compared with platinum-based chemotherapy plus fluorouracil alone, cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. (ClinicalTrials.gov number, NCT00122460.)

Capecitabine in Combination with Docetaxel in First Line in HER2-Negative Metastatic Breast Cancer: an Observational Study.

Due to the limited experience with capecitabine plus docetaxel (XT) combination in the first-line treatment of metastatic breast cancer in Hungary, the main objective of the study was to analyze the effectiveness and tolerability of XT therapy. A prospective, open-label, non-randomized, single-arm, multicenter, observational study was designed. All female patients were eligible whose metastatic breast cancer could be treated with the XT protocol according to the summary of product characteristics of the drugs. The median progression free survival was 9.9 ± 3.0 months. Time to treatment failure was 4.6 ± 5.1 months on average. The overall response rate was 28.9 %, the clinical benefit rate was 73.3 %. The treatment was discontinued in 35.6 % of patients due to disease progression and in 20.0 % due to adverse events (AE). 33 patients with a total of 73 AEs have been reported, and 13 of them had serious adverse events (SAE). The efficacy and the safety profile of XT chemotherapy proven in the study are consistent with the results demonstrated in randomized trials. First-line XT chemotherapy effectively improves the PFS in metastatic breast cancer.

[The results of ovarian cancer therapy in the Hungarian Centers in 2002-2003]. / Petefészekrákos betegek kezelési eredményei a hazai centrumokban 2002-2003-ban.

UNLABELLED: Authors presented data of treatment results and course of disease in 487 ovarian cancer patients treated by primary surgery and paclitaxel-carboplatin combination chemotherapy between July 1, 2002 and December 31, 2003. PATIENTS: Most of our patients (87.8%) belonged to the age-group between 40-70 years. Distribution of their histological diagnosis was as 69.6% serous, 10.7% mucinous, 5.1% endometrial and 4.7% undifferentiated carcinoma. The grade distribution was found as 8.4% grade 1, 40.9% grade 2 and 35.9% grade 3. RESULTS: The primary surgery was evaluated as optimal in 41.7%, suboptimal in 37.3% and exploration was performed in 21.1%. Most patients started chemotherapy 20 days after surgery and 74.2% of them got six courses. During the evaluation period 61 intervallum laparotomies were performed, and resulted on 55.7% optimal debulking. Complete remission was found in 58.9%, and partial remission in 14.7% of patients. This treatment resulted on a complete remission in 40.9% at the follow-up of 12 months.

Familial clustering of nasopharyngeal carcinoma in a non-endemic geographical region. Report of two Hungarian cases and a review of the literature.

The aim of this study was to investigate the familial clustering of nasopharyngeal carcinoma (NPC) in a non-endemic geographical region on the basis of two case reports and a review of the literature. Following an upper respiratory infection, NPC (WHO type III) was detected in a 57-year-old female (Case 1) who presented with nasal symptoms and a year later in her 36-year-old son (Case 2) who presented with enlarged lymph nodes. After a full diagnostic work-up, cT2a cN0 cM0 (stage IIA; Case 1) and cT2a cN2 cM0 (stage III; Case 2) disease were identified, and telecobalt irradiation was administered to both patients. The mother achieved complete remission and has been disease-free during a 14-year follow-up period. After initial complete remission, the son experienced regional (cervical) and base of the skull relapses within 2 years, which were treated unsuccessfully by means of radical neck dissection, a second course of radiotherapy and chemotherapy. Epstein-Barr virus (EBV) was detected in pathology sections from both patients. The authors review 20 additional well-documented cases of familial clustering of NPC in non-endemic geographical regions from the English language literature. This clinical entity typically has WHO type III histology; it may occur following an upper respiratory tract infection, and EBV-related serological titers were elevated in all 20 investigated cases. No consequent promoting factors were identified. The present two cases and the review of the literature strongly suggest that familial clustering of NPC in non-endemic geographical areas may be related to EBV infections. The difference in outcome of our two cases may be explained by the fact that the disease in Case 2 was diagnosed 1 year later than that in Case 1 and hence at a more advanced stage.

[PET scan in patients with epipharyngeal tumors]. / Epipharynx-daganatok PET-vizsgálata.

Whole-body FDG PET examinations in 10 cases of epipharyngeal tumour (8 males, 2 females, mean age: 48 years) have been performed since January 1999. The PET examinations were aimed at the accurate staging, follow-up of the patients after the treatment, identification of recurrencies and localization of the unknown primary tumor. Functional imaging resulted in "upstaging" in 3 patients as compared to staging by the conventional diagnostic tools. Four additional patients with hyperplastic epipharyngeal tissue were investigated for occult primary cancer after negative results of multiple excisions, resulting in one case of primary epipharyngeal cancer. Correct staging, early detection of recurrencies, localization of occult primary tumor and the better post-therapeutic assessment of epipharyngeal masses all facilitate a more reasonable therapeutic approach, which may improve survival results.

[Status report on the chemotherapy of ovarian cancer at special cancer centers in Hungary (2002-2003)]. / A petefészekrák gyógykezelésének helyzete a különkeretes Centrumokban 2002-2003-ban Magyarországon.

Data on the first-line treatment of ovarian cancer in special centers of Hungary 2002 and 2003 are presented, involving 283 and 416 patients, respectively. Patients' age, clinical stage and histological type of the tumor were highly similar to literature data, while grades were different. Surgical effectiveness in case of IIIc staged tumors with >1 cm residual mass was 37%. The ratio of interval laparotomy was about 15%. Overall response rates of the first-line treatment of ovarian cancer was 82%, while the rate of complete remissions was 60%. The authors provide detailed analysis of factors that can improve the chemotherapy of ovarian cancer in Hungary.

First-line bevacizumab-paclitaxel in 220 patients with metastatic breast cancer: results from the AVAREG study.

BACKGROUND: First-line bevacizumab-paclitaxel therapy demonstrated a median progression-free survival (PFS) of 11 months in three randomized phase III trials on metastatic breast cancer (mBC) (E2100, TURANDOT and CALGB 40502). We assessed the efficacy and safety of bevacizumab-paclitaxel in a routine oncology practice study. PATIENTS AND METHODS: Patients with previously untreated mBC received bevacizumab-paclitaxel according to the approved indication in Hungary. The primary end-point was PFS. Secondary end-points included time-to-treatment discontinuation, 1-year survival rate, PFS in patients with triple-negative breast cancer (TNBC) and safety. RESULTS: Median PFS in the 220 treated patients was 9.3 (95%CI 7.8-10.8) months. The 1-year survival rate was 68%. In patients with TNBC (N=106), median PFS was 8.3 months (95%CI 7.8-8.8). Adverse events were consistent with the established safety profile of bevacizumab-paclitaxel. CONCLUSION: Bevacizumab-paclitaxel is an active and well-tolerated first-line treatment for mBC, with notable activity in TNBC.

Quimioterapia basada en platino más cetuximab en el cáncer de cabeza y cuello / Platinum plus cetubimab based quimiotherapy in head and neck cancer

Antecedentes: Cetuximab resulta efectivo en el carcinoma metastático o recurrente de células escamosas de cabeza y cuello, resistente al platino. Se investigó la eficacia de cetuximab más quimioterapia basada en platino como tratamiento de primera línea en pacientes con carcinoma metastático o recurrente de células escamosas de cabeza y cuello. Métodos: Se asignaron al azar 220 pacientes de 442 pacientes elegibles con carcinoma metastático o recurrente de células escamosas de cabeza y cuello sin tratamiento, para recibir cisplatino (a una dosis de 100mg por metro cuadrado de área de superficie corporal el día 1) o carboplatino (en un área por debajo de la curva de 5mg por mililitro por minuto, como infusión intravenosa de 1 hora el día 1) más fluorouracilo (a una dosis de 1000mg por metro cuadrado por día, durante 4 días) cada 3 semanas, por un máximo de 6 ciclos, y 222 pacientes para recibir la misma quimioterapia más cetuximab (a una dosis de 400mg por metro cuadrado en forma inicial, como infusión intravenosa de 2 horas, luego 250mg por metro cuadrado, como infusión intravenosa de 1 hora por semana) durante un máximo de 6 ciclos. Los pacientes con enfermedad estable que recibieron quimioterapia más cetuximab continuaron recibiendo cetuximab hasta la progresión de la enfermedad o hasta la aparición de efectos tóxicos inaceptables, lo que ocurriera primero. Resultados: El agregado de cetuximab a la quimioterapia basada en platino con fluorouracilo (platino-fluorouracilo) prolongó de manera significativa la mediana de la supervivencia global, de 7.4 meses en el grupo de quimioterapia sola a 10.1 meses en el grupo que recibía quimioterapia más cetuximab (índice de riesgo para muerte = 0.80; intervalo de confianza 95%: 0.64-0.99; p = 0.04). El agregado de cetuximab prolongó la mediana del tiempo de supervivencia libre de progresión de 3.3 meses a 5.6 meses (índice de riesgo para la progresión = 0.54; p < 0.001) y aumentó la tasa de respuesta de 20% a 36% (p < 0.001).