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Background: Combining bevacizumab with first-line chemotherapy significantly improves progression-free survival (PFS) in HER2-negative metastatic breast cancer (mBC). However, identification of patients benefitting most from bevacizumab remains elusive. The AVADO trial included an extensive optional exploratory biomarker programme. Methods: Patients with HER2-negative mBC were randomised to receive docetaxel with placebo or bevacizumab. The primary end point was PFS. Plasma samples were analysed using a multiplex ELISA. Blood mRNA expression was assessed using quantitative PCR. Tumour tissue samples were analysed by immunohistochemistry. Single-nucleotide polymorphisms (SNPs) involved in the VEGF pathway were analysed in germline DNA. Results: Samples for biomarker analysis were available from 24–54% of the 736 treated patients (depending on specimen type). The most consistent potential predictive effect was observed with plasma VEGF-A and VEGFR-2; high baseline concentrations were associated with greater treatment effect. Blood mRNA analyses suggested a greater bevacizumab effect in patients with high VEGF 121 . No consistent predictive effect was seen for tumour neuropilin or other candidate tumour markers by immunohistochemistry, or for any of the SNPs investigated. Conclusion: Plasma VEGF-A and VEGFR-2 are potential predictive markers for bevacizumab efficacy, supporting findings in gastric and pancreatic cancers. Plasma VEGF-A is being evaluated prospectively in mBC in the MERiDiAN trial.

Background Infusion of high-dose intravenous methotrexate (MTX) has been demonstrating to penetrate the blood-brain barrier. The aim of this present study was to assess the efficacy and safety of high dose MTX in patients with central nervous system (CNS) metastases of breast cancer. Methods Twenty-two patients with CNS metastases treated by MTX (3 g/m2) between April 2004 and October 2009 were enrolled. Clinical response rate, time to progression (TTP), overall survival (OS), and safety were assessed. Results In terms of brain metastases, 2 patients (9%) achieved a partial response, 10 patients (45%) had disease stabilization, and 10 patients (45%) had disease progression. In others metastatic sites, 7 patients (39%) achieved a disease stabilization, and 11 patients (61%) had disease progression. TTP and OS were 2.1 (95%CI 1.4–2.9) and 6.3 (95%CI 1.8–10) months, respectively. Conclusion High-dose MTX demonstrated a moderate activity at 3 g/m 2 . Nonetheless, the favorable toxicity profile should suggest the possibility to increase the dosage and further study are planned.

PurposeA 4-weekly schedule of pegylated liposomal doxorubicin (PLD) has been approved for the treatment of metastatic breast cancer (MBC). Phase II trials have suggested interest in a 2-weekly regimen. This study aimed to compare the efficacy and safety of these two schedules.MethodsData from MBC patients treated with PLD between 2011 and 2021 were retrospectively collected. The objective was to demonstrate the noninferiority of the 2-weekly versus the 4-weekly schedule in terms of 6-month progression-free survival (PFS). The prespecified noninferiority margin was calculated as 1.20. A propensity score to receive either schedule was estimated using a gradient boosting algorithm. Survival analyses using Cox regression models weighted by the propensity score were performed to compare the schedules.ResultsAmong the 192 patients included, 96 (50%) underwent each schedule. The median number of previous systemic therapies was 4 (IQR, 3 to 6). Anthracyclines were previously given in early breast cancer in 63.9% of patients. The median follow-up was 10.0 months (IQR, 5.0 to 20.1). A comparable distribution of adverse events was observed. The median PFS was 3.2 months (95% CI, 2.9 to 3.9), and the median overall survival was 12.1 months (95% CI, 10.8 to 14.9). The weighted hazard ratio for PFS was 1.12 (90% CI, 0.82 to 1.54), including the noninferiority boundaries.ConclusionPLD appeared to be a well-tolerated drug in this heavily pretreated MBC population. The efficacy and safety of the 2-weekly schedule did not provide any advantage, suggesting no interest in changing the registered regimen.

Purpose Everolimus has demonstrated its efficacy in metastatic renal cell carcinoma (mRCC). Preliminary studies have shown high variability of everolimus blood concentrations (EBC). In other settings, its activity was correlated with EBC. We therefore decided to monitor EBC in patients treated with mRCC to assess its influence on oncologic outcomes. Patients and methods Our study analyzed first 3 months’ trough EBC levels in 42 patients treated in 4 French oncologic centers between March 2010 and August 2013. Patients presented a histologically confirmed diagnosis of mRCC and have failed prior anti-angiogenic (AA) therapies. Results Median follow-up was 25.9 months. A total of 113 EBC were analyzed. The median trough concentration was 14.1 μg/L (range 2.6–91.5). Fourteen patients (67 %) versus 8 (38 %) patients with median EBC above or below 14.1 μg/L were free from progression at 6 months ( p  = 0.06). Median progression-free survival was 13.3 versus 3.9 months (HR 0.66 95 % CI 0.33–1.31; p  = 0.23), and the median overall survival was 26.2 versus 9.9 months (HR 0.62 95 % CI 0.28–1.37; p  = 0.24), for patients above or below the median value of trough concentrations, respectively. Conclusion Impact of drug exposure for AA tyrosine kinase inhibitors activity has been demonstrated in mRCC setting. Interpatients EBC variability was confirmed in the present study, and the results suggest a relationship between initial EBC within the first 3 months and the drug activity. It underlines the need to prospectively include EBC monitoring in future clinical trials to determine the need of its implementation in routine use.

Purpose: Our previously published data showed rapidly increasing rates of prostate cancer screening in men aged 50–74, which rose from 36 % in 2005 to 48 % in 2008. Based on men's reported intentions at that time, this was expected to rise to 70 % in 2011. Here we report the actual rate of prostate cancer screening. Method: Three nationwide observational telephone surveys (EDIFICE opinion polls) were conducted in 2005, 2008, and 2011. The overall target was a representative sample of >1,500 individuals living in France and aged 40–75 years, including 481 men aged 50–74 years. Results: Within this male population, the rate of screening reported remained stable between 2008 and 2011 (48 and 49 %, respectively). However, comparison of privileged versus disadvantaged populations showed significant differences, with a relative decrease in screening among those of higher socioprofessional status (p = 0.03) and from higher-income groups (p = 0.02). For households with a monthly income above 2,500€, the screening rate decreased from 61 % in 2008 to 51 % in 2011 (p = 0.05), while for those with an income below 2,500€, it increased from 36 % in 2008 to 44 % in 2011 (p = 0.18). Conclusion: A plateau or even a reduction in prostate cancer screening is currently being observed; this is possibly due to progressive recognition among the population at large of the controversy surrounding prostate cancer screening, whereas this speculation was formerly limited to health-care professionals. After previously being more likely to undergo prostate cancer screening, it is the younger, wealthier populations that are currently showing the most noteworthy step backwards.

An earlier report documented significant improvement in progression-free survival among patients with metastatic breast cancer treated with fulvestrant and a cyclin-dependent kinase inhibitor, ribociclib. With longer follow-up, it is clear that fulvestrant and ribociclib also prolong overall survival.

Background Treatment with third generation aromatase inhibitors (AI) is associated with occurrence of arthralgia, with an incidence ranging from 25 to 45 %. In these patients, arthralgia may also be related to other conditions such as osteoarthritis, common tendinitis or auto immune diseases. Objectives The aim of this study was to study patients treated with AI and reporting arthralgia, and comparing patients with new onset to patients with pre existing arthralgia and exacerbation under AI, to look for associated etiologic factors. Methods Patients followed in a tertiary oncology center for breast cancer treated with AI and reporting arthralgia were prospectively screened for rheumatologic clinical evaluation, as well as biologic (ESR, CRP, RF, ANA, ACPA) or imaging (X-Rays of symptomatic regions) investigation. Type of cancer, duration, treatment, type of AI, duration of AI treatment. Patients were divided in two groups : patients with new onset of arthralgia under AI, and patients with pre existing and exacerbation of arthralgia under AI. The two groups are compared using t test for quantitative variables (significance : p less than 0.05). Results Seventy five women were included, mean age (SD): 64.8 (9.2) years, time from cancer diagnosis : 34 (25) months. Adjuvant chemotherapy and/or radiotherapy were noted in respectively 52 and 64 cases. AI was Anastrozole (n = 6), Letrozole (55), Exemestane (14). Mean duration AI treatment since onset or exacerbation of arthralgia : 179 (224) days. Mean number of painful joints : 7.6 (9.7); locations (number of patients) :shoulder 36, elbow 22, wrist 25, MCP 27, PIP 26, knee 26, MTP28. Mean ESR : 29 (25)mm/h; CRP : 3 (7.6) mg/l). New onset arthralgia : n = 38; pre existing and exacerbation of arthralgia : n = 37. No statistical differences were found between these two groups for type of cancer, presence of chemotherapy or radiotherapy, presence of metastases, duration and type of AI treatment, VAS pain, number and distribution of tender joints, ESR, CRP, ANA, RF, ACPA positivity, and radiographic findings. Positive lymph nodes and radiographic signs of rotator cuff dysfunction were statistically more frequent in the pre existing and exacerbation group. Some specific diagnoses were done after evaluation : 2 CREST syndrome (one in each group), 1 RA and 1 Sjögren syndrome in the new onset symptom group. Conclusions Arthralgia under AI treatment is frequent. Our study argues for an absence of specificity of these arthralgia, without particular difference between new onset or exacerbation of pre existing arthralgia, auto immune disease seem more frequent in the new onset symptom group, and thus possibly related to anti aromatase therapy. Disclosure of Interest None Declared

Background: HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model. Method: Data were derived from a phase I study of 26 patients receiving HuHMFG1 at doses ranging from 1 to 16 mg kg −1 . Data were analysed using NONMEM software and covariates were included. A limited sampling strategy (LSS) was developed using training and a validation data set. Results: A linear two-compartment model was shown to be adequate to describe data. Covariate analysis indicated that weight was not related to clearance. An LSS was successfully developed on the basis of the model, in which one sample is collected immediately before the start of an infusion and the second is taken at the end of infusion. Conclusion: A two-compartment population PK model successfully describes HuHMFG1 behaviour. The model suggests using a fixed dose of HuHMFG1, which would simplify dosing. The model could be used to optimise dose level and dosing schedule if more data on the correlation between exposure and efficacy become available from future studies. The derived LSS could optimise further PK assessment of this antibody.

Background: Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis. Methods: Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with ( n =26) or without ( n =29) epinephrine were analysed using NONMEM. Results: Epinephrine halves clearance between peritoneum and serum (IPCL) and increases the Pt central volume of distribution, IP exposure and penetration in tissue. IPCL has a better predictive value than any other parameter with respect to renal toxicity. Conclusion: This confirms that IPCL could be useful in assessing renal toxicity. As IPCL is also linked to tissue penetration and IP exposure, it may be proposed as biomarker. In addition to a Bayesian estimation, we propose a single-sample calculation-way to assess it. Prospective studies are needed to validate IPCL as a biomarker in this context.

The effect of additional treatments after surgery in patients with primary cardiac sarcoma (PCS) remains unknown. The present study aims to evaluate the benefit of chemotherapy in patients with non-metastatic cardiac sarcomas after optimal resection. Between October 1979 and December 1995, 15 patients with a median age of 45 (range 16-66) and a resected primary cardiac sarcoma [angiosarcoma (six), malignant fibrous histiocytoma (three), leiomyosarcoma (two), rhabdomyosarcoma (two), liposarcoma (one) and synoviosarcoma (one)] received a doxorubicin-containing regimen within 6 weeks of surgery. Adjuvant chemotherapy combinations included cyclophosphamide, vincristine and dacarbazine in four patients; ifosfamide in nine; methotrexate and vincristine in one; and doxorubicin alone in one patient. At present, 13 patients have relapsed (five during therapy), with a median time to progression of 10 months. Twelve patients developed local relapse, in four cases without metastatic disease. Two patients remain in complete remission 27 and 25 months after surgery. The median time to progression was shorter in patients presenting a cardiac angiosarcoma than other histological types (3 vs 14 months, P < 0.01). Twelve patients have died, with a median overall survival of 12 months. The 2-year survival rate is 26%. Survival was significantly longer for patients with completely resected tumours (22 vs 7 months; P = 0.02) and those who did not have angiosarcoma (18 vs 7 months; P = 0.04). In conclusion, post-operative conventional doxorubicin-based chemotherapy failed to modify the natural history of patients with resected cardiac sarcomas. Locoregional failure remains the main problem even after histologically complete resection. New approaches must be tested in patients with primary cardiac sarcoma.