Abstract Background Primary malignant brain tumours are rare but represent a serious health burden due to their poor survival. This manuscript describes the survival of malignant brain tumours in adults diagnosed 2000–2007 in Europe. Methods For this study we analysed patients archived in 86 European population-based cancer registries, followed up to 31st December 2008. Only primary malignant neuroepithelial brain tumours (with pathological confirmation) and primary malignant unspecified brain tumours without pathological confirmation were included. We estimated 1-year and 5-year relative survival (RS) weighted by age group and country. We also estimated country-specific and age-specific survival, together with survival differences between time periods (for 1999–2001, 2002–2004 and 2005–2007). Results Glioblastoma represents 49% of all brain tumours, followed by other/unspecified astrocytoma (18%), oligodendroglioma/oligoastrocytoma (9%), ependymoma (1.5%) and embryonal tumours (1%). Five-year RS was 20% for all tumours combined, but ranged from 58% for ependymoma to only 6% for glioblastoma and sharply decreased with increasing age. Differences between countries were relatively small, but generally RS in Ireland/United Kingdom (UK) and Eastern Europe was below the average. An increase in 1-year RS (up to 10–12%) was noted over time, being largest in Central and Northern Europe in patients between 45 and 74 years of age. Conclusions Despite an increase in 1-year RS in most European regions, the survival of primary malignant brain tumours is still poor. Disparities between countries were evident, being even larger at the end of the study period than at the beginning, suggesting differences in availability of the latest treatment modalities.

Background The stem of Marsdenia tenacissima (Roxb.) Wight et Arn. has long been used as a medicine to treat cancer in China. Our previous results showed that M tenacissima extract (MTE) overcomes gefitinib resistance in NSCLC cells. Methods The present study investigated in vivo anti-tumour activity of MTE combined with gefitinib. H460 (K-RAS mutation) or H1975 cells (T790M mutation) were subcutaneously inoculated into nude mice. Tumour volume and body weight were measured during the experiment. The resected tumours were weighed after animals were sacrificed. Cellular proliferation and apoptosis in xenografts tumour tissue were assessed. EGFR downstream pathways and c-Met expression was evaluated by western blotting. In accordance with the previous in vitro study, MTE at low dose (5 g/kg) was chosen to assess whether it can restore gefitinib sensitivity in vivo. Findings MTE enhanced gefitinib efficacy in resistant H460 and H1975 xenografts. The combination significantly inhibited tumour proliferation and induced cell apoptosis in both resistant NSCLC xenografts. Constitutive activation of PI3K/Akt and MEK/ERK pathway is related to EGFR-TKI resistance. Accordingly, phosphorylation of PI3K/Akt/mTOR and ERK1/2 was suppressed after the combined treatment. Simultaneously, the cross-talk between c-Met and EGFR was also lowered in the presence of MTE combined with gefitinib. Interpretation This study provides in vivo evidence of MTE enhancing gefitinib efficacy in resistant NSCLC xenografts, and suggests that the combination of MTE and gefitinib could be a promising approach against NSCLC.

Abstract Background Cabozantinib (XL184), an orally bioavailable inhibitor of vascular endothelial growth factor receptor 2 and MET, was assessed in a cohort of ovarian carcinoma patients as part of a phase 2 randomised discontinuation trial (RDT) with cohorts from nine different tumour types. Patients and methods Patients received 100-mg cabozantinib daily. Those with stable disease (SD) per Response Evaluation Criteria in Solid Tumors at week 12 were randomised to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) after random assignment. Results Seventy patients with ovarian carcinoma, 50% of whom were platinum refractory/resistant, were enrolled in this RDT. Median PFS from day 1 was 5.5 months for all patients. The ORR at week 12 was 21%; one patient achieved a complete response (CR), and 14 patients (20%) achieved a confirmed partial response (PR). The overall disease control rate (CR + PR + SD) at week 12 was 50%. Throughout the study, 70% of the patients with ≥1 postbaseline scan had tumour regression, and randomisation was discontinued early. For patients with SD randomised to cabozantinib, PFS was 5.9 months after randomisation. The most common grade 3/4 adverse events were diarrhoea (14%), palmar-plantar erythrodysesthesia syndrome (6%), asthenia (6%), hypertension (6%) and neutropenia (6%). Dose reductions were required in 37% of the patients during the first 12 weeks. Conclusion Cabozantinib demonstrates clinical activity, with acceptable toxicities, in patients with ovarian carcinoma based on ORR and regression of tumour target lesions. Registration This trial is registered at ClinicalTrial.gov (NCT00940225).

Background This study aimed to evaluate the dosimetric effect of anatomical and volumetric changes in tumour size on target volumes (TVs) and organ at risks (OARs) during intensity-modulated radiotherapy (IMRT), and to compare the dose distribution with or without replanning in locally advanced head and neck cancer (LAHNC). Methods 20 patients with LAHNC treated by IMRT were enrolled in a prospective study. Planning computed tomography (CT) scans were acquired both pre-treatment and after 20 fractions (midcourse) of radiotherapy. An original treatment plan based on initial planning CT scan was generated and implemented. A hybrid plan was generated for each patient by applying beam configuration of the original plan to the anatomy of the midcourse CT scan. The dose-volume histograms of the original plan and hybrid plan were compared for second phase of treatment. A midcourse adaptive replan based on the interim CT scan was done, and dose distribution for TVs and OARs was compared with or without replanning. Findings Planned doses (D98%, D95%, and D2%) to TVs for second phase of radiotherapy (hybrid plan) were not significantly different from the actually delivered doses. However, an increase in volume by 110% was observed in the HPLAN in comparison with the original plan. With replanning, dose distribution to TV was made more homogenous as compared with the hybrid plan (p = 0.00). Re-planning significantly reduced V > 110% and V < 93% as compared with the hybrid plan (p < 0.05). There was a significant increase in delivered doses (Dmax and D2%) to spinal cord as compared with the planned dose (p < 0.05). Adaptive replanning resulted in decrease in Dmax and D2% of spinal cord (p < 0.05). The mean dose to ipsilateral parotid was significantly higher in the hybrid plan in comparison with the original plan (p < 0.05). On comparing the hybrid plan and adaptive replan, dose to ipsilateral parotid was significantly reduced with replanning. Interpretation Replanning with midcourse CT simulation significantly improves the TV coverage and reduces the dose to OARs.

Abstract Cell-free DNA for perinatal screening is a growing industry. Non-invasive prenatal testing (NIPT) is based on the premise that foetal DNA is able to cross the placental barrier and enter the mother’s circulation, where it can be examined for chromosomal abnormalities, such as trisomy 13, 18 or 21. Such tests are expected to be widely used by pregnant women, with the annual market expected to surpass $1 billion. Recently, a number of case reports have emerged in the haematology-oncology literature. The routine use of NIPT has led to the discovery of maternal neoplasms. Most writers have concluded that this is yet another benefit of the test; however, a closer examination of the cases reveals that this incidental detection may not improve patient outcomes. In some cases, early detection provides lead time bias, but does not change the ultimate clinical outcome, and in other cases, detection constitutes earlier knowledge of a cancer whose natural history cannot be altered. Here, we explore in detail cases where cancer was incidentally discovered among women undergoing routine non-invasive pregnancy testing, and investigate whether or not these women were benefitted by the discovery.

Abstract Background Wild type RAS (RAS-wt) status is predictive of the activities of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab (C) and panitumumab (P). We examined the impact of C and P on progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) in advanced colorectal cancer (CRC) patients who have RAS-wt/BRAF-mutant (BRAF-mut) status. Methods Randomised trials that compared C or P plus chemotherapy (or C or P monotherapy) with standard therapy or best supportive care (BSC) were included. We used published hazard ratios (HRs) if they were available, or we derived treatment estimates from other survival data. Pooled estimates of the treatment efficacy of anti-EGFR-based therapy with C or P for the RAS-wt/BRAF-mut subgroup were calculated with the random-effect inverse variance weighted method. All statistical tests were two-sided. Results Nine phase III trials and one phase II trial (six first-line and two second-line trials, plus two trials involving chemorefractory patients), that included 463 RAS-wt/BRAF-mut CRC patients, were analysed. Overall, the addition of C or P treatment in the BRAF-mut subgroup did not significantly improve PFS (HR, 0.88; 95% confidence interval (CI), 0.67–1.14; p = 0.33), OS (HR, 0.91; 95% CI, 0.62–1.34; p = 0.63) and ORR (relative risk, 1.31; 95% CI 0.83–2.08, p = 0.25) compared with control regimens. Conclusions C- or P-based therapy did not increase the benefit of standard therapy or the BSC in RAS-wt/BRAF-mut CRC patients. These findings support BRAF mutation assessment before initiation of treatment with anti-EGFR monoclonal antibodies.

Background Long term survival after curative resection for locally advanced gastric cancer is still low; 5-year survival after diagnosis is 10–21%. Neoadjuvant chemotherapy allows higher curative (R0) resection rates to be achieved and treats micrometastases early. The present study was undertaken to evaluate the feasibility and efficacy of NACT in gastric cancer. Methods Fifty patients were enrolled and randomised into two groups. Group A received epirubicin, cisplatin, and fluorouracil (ECF regimen) and group B received cisplatin, calcium leucovorin, and fluorouracil (CCF regimen). The aim of this study was compare the efficacy of the two neoadjuvant regimens in terms of curative resection rate. Findings Twenty four of 25 patients in group A and 22 of 25 patients in group B received three to four cycles of chemotherapy. No deaths were reported in either group. Haematological adverse effects were seen more in group A whereas non-hematological effects were seen more in group B, with the exception of nausea and alopecia, which were more common in group A. Complete responses were seen in two patients in group A. Partial responses were seen in 17 (68%) patients in group A and 14 (56%) in group B. Two (8%) patients in group A and four (16%) patients in group B progressed to metastatic disease. Curative resection was achieved in 18 (72%) patients in group A and 16 (64%) in group B. Partial pathological responses were seen more with ECF than with CCF (38.9% versus 25%). Median progression-free survival was 14.8 months in group A and 13.4 months in group B. Overall survival at 24 months median follow-up was 52% in group A and 44% in group B. Interpretation Neoadjuvant chemotherapy in locally advanced gastric cancer is safe and improves the curative resection rate, decreases recurrence, and improves survival.

Abstract Background The national confidential enquiry into patient outcomes and death (NCEPOD) set important benchmarks in assessing the quality of care received by patients dying within 30 days of systemic anticancer therapy (SACT). Monthly morbidity and mortality audits conducted to recommendations in the NCEPOD were commenced at the Christie NHS Foundation Trust in 2009, specifically to assess and improve patient outcomes. Methods We evaluated the outcomes of patients who died within 30 days of SACT over a 4 year period 2009–2013. We collated audit findings to determine the number of treatment related deaths, clinical characteristics of patients, causes of death and quality of care received. We examined the benefit of the audit in decreasing 30 day mortality during the 4 years and considered factors that may be associated with an increased risk of SACT related death. Results A total of 31,183 patients were treated at the Christie from 2009 to 2013. Of these 4% died within 30 days of SACT. Death was treatment related in 11%. The decision to treat with SACT was appropriate in 87% of but there was room for improvement in care in 24%. Mortality decreased over the 4 years. Possible factors associated with 30 day mortality post SACT included performance status ⩾2, presence of comorbidities, treatment type and treatment setting. Conclusions We demonstrated that our audit process is feasible and robust. Further areas of research to determine predictive scores for patient treatment selection and improve outcomes were highlighted and are ongoing.

Abstract Background Circulating tumour cell (CTC) counting could be a new biomarker for better evaluation of tumour response to molecules tested in phase I trials. Patients and methods Consenting patients with advanced metastatic cancer referred to various phase I units were enrolled prospectively in this study. CTCs from 7.5 ml of whole blood drawn at baseline and after starting experimental therapy were counted using the CellSearch system, and tumour response was assessed using RECIST 1.1 criteria at baseline and 2 months after treatment initiation. Results Between March 2010 and May 2013, a total of 326 patients were enrolled, among whom 214 were evaluable (49% male, median age = 56; main cancer types: lung [28], colon [53], ovarian [18], breast [28]). At baseline, we detected ≥1 CTC/7.5 ml in 113/214 patients (53%), and at day 30, we observed ≥1 CTC/7.5 ml in 103/214 patients (48%). Two months after treatment initiation, 11 (5%) of the 214 patients were classified as having a partial response, with no CTCs in 9 of them or a decrease in the CTC count after therapy. In contrast, among the 104 patients (49%) classified as having progressive disease, 38 patients had a higher CTC count. The remaining 99 patients (49%), 33 of whom (33%) had a lower CTC count, were classified as having stable disease. The sensitivity and specificity of CTC variation for predicting progressive disease were 41% (32–51%) and 80% (73–88%) respectively. Conclusion An early CTC change following therapy does not correlate with RECIST response in patients with advanced cancer enrolled in phase I trials.

Abstract At present, there is no standardised approach for the radiological evaluation of soft tissue sarcomas following radiotherapy (RT). This manuscript, produced by a European Organisation for Research and Treatment of Cancer – Soft Tissue and Bone Sarcoma Group (EORTC – STBSG) and Imaging Group endorsed task force, aims to propose standardisation of magnetic resonance imaging techniques and interpretation after neoadjuvant RT for routine use and within clinical trials.