European Journal of Cancer

A phase I and pharmacokinetic study of plitidepsin in children with advanced solid tumours: An Innovative Therapies for Children with Cancer (ITCC) study

2011-11-28

Abstract: Aims: To determine the maximum tolerated dose, the recommended dose (RD) for phase II studies, dose-limiting toxicities and pharmacokinetics (PK) for plitidepsin administered as a 3-h intravenous infusion every 2weeks (one cycle) to children with refractory or relapsed solid tumours.Methods: Consecutive cohorts of patients were treated according to a standard ‘3+3’ design with escalating doses of plitidepsin at 4, 5 and 6mg/m2. Additional 15 patients were recruited at the RD to further evaluate safety and pharmacokinetic associations with respect to age, dose level and toxicity.Results: Thirty-eight of 41 patients registered received plitidepsin. Dose-limiting toxicities during the first three treatment cycles related to myalgia, elevated creatine phosphokinase, transaminase increase and nausea/vomiting. The RD for plitidepsin is 5mg/m2. PK analyses revealed high inter-patient variability in plasma, but a similar clearance of plitidepsin in children and adolescents. One partial response confirmed at 4weeks in a patient with neuroblastoma and one unconfirmed partial response in a pancreatoblastoma were observed; four other patients with neuroblastoma, medulloblastoma, glioblastoma and rhabdoid tumour had disease stabilisations lasting ⩾3months.Conclusion: Plitidepsin administered to children as a 3-h infusion every 2weeks is received with manageable toxicity for children with cancer, and the RD is 5mg/m2. Pharmacokinetic parameters in children and adolescents are comparable to adults. Future phase II studies of plitidepsin are warranted, and our results suggest that plitidepsin could be appropriately developed in combination with other antitumour where myelosuppression is dose-limiting.

Physical activity in a German breast cancer patient cohort: One-year trends and characteristics associated with change in activity level

2011-09-19

Abstract: Background: Physical activity (PA) is increasingly discussed as concomitant therapy after breast cancer diagnosis and can add to the alleviation of therapy- and disease-related symptoms. The objectives of this study were to describe PA behaviour in the course of breast cancer and to identify factors associated with change in PA.Methods: 1,067 German postmenopausal breast cancer patients were asked about their PA behaviour before breast cancer diagnosis, during therapy and 1year after surgery. MET-hours per week (MET=metabolic equivalent) were calculated based on quantitative information about walking, bicycling for transportation purposes and sports by multiplying the average hours per week spent at each activity with an individual intensity score. Factors associated with change in MET·h/week in the course of breast cancer were identified using multiple linear regression.Results: Median PA decreased significantly during therapy from 36 to 14MET·h/week (p<.001). Patients treated with chemo- and/or radiotherapy had a stronger decline in PA compared to patients without adjuvant therapy or those treated only with hormones (adjusted β=−9.73 to −13.54). The presence of medical risk factors (β=−5.56) was also associated with a decrease of PA during therapy. In contrast, participation in rehabilitation (β=7.62) was associated with an increase of PA after therapy.Conclusion: In the light of the drastic decline in PA during therapy, programs promoting PA seem obligatory for all breast cancer patients. Patients treated with chemo- and/or radiotherapy and those with medical risk factors should particularly be assisted in reaching recommended activity levels by targeted interventions during and after therapy.

Tetraploidy in BRCA2 breast tumours

2011-12-02

Abstract: Tetraploidy and aneuploidy can be caused by cell division errors and are frequently observed in many human carcinomas. We have recently reported delayed cytokinesis in primary human fibroblasts from BRCA2 mutation carriers, implying a function for the BRCA2 tumour suppressor in completion of cell division. Here, we address ploidy aberrations in breast tumours derived from BRCA2 germline mutation carriers. Ploidy aberrations were evaluated from flow cytometry histograms on selected breast tumour samples (n=236), previously screened for local BRCA mutations. The ploidy between BRCA2-mutated (n=71) and matched sporadic (n=165) cancers was compared. Differences in ploidy distribution were examined with respect to molecular tumour subtypes, previously defined by immunohistochemistry on tissue microarray sections. Tetraploidy was significantly 3 times more common in BRCA2 breast cancers than sporadic. However, no differences were found in the overall ploidy distribution between BRCA2-mutation carriers and non-carriers. In BRCA2 cancers, tetraploidy was associated with luminal characteristics. The increased frequency of tetraploidy in BRCA2 associated cancers may be linked to cell division errors, particularly cytokinesis. Additionally, tetraploidy emerges predominantly in BRCA2 breast cancers displaying luminal rather than triple-negative phenotypes.

Health-related quality of life in patients with advanced renal cell carcinoma receiving pazopanib or placebo in a randomised phase III trial

2011-06-20

Abstract: Background: In a double-blind, randomised phase III trial of advanced renal cell carcinoma patients, pazopanib 800mg QD (n=290) versus placebo (n=145) significantly prolonged progression-free survival (hazard ratio (HR)=0.46, 95% confidence interval [CI] 0.34–0.62, p-value<0.0001), without important differences in health-related quality of life (HRQoL). This post-hoc analysis evaluated time to HRQoL deterioration and whether tumour response/stabilisation was associated with HRQoL improvement.Methods: HRQoL was assessed using EORTC QLQ-C30 and EQ-5D. Effect of pazopanib on time to ⩾20% decline from baseline in summary scores was estimated for all patients and by prior treatment. Analyses were conducted for different HRQoL deterioration thresholds. HRQoL changes were stratified by benefit and compared: complete response (CR) or partial response (PR) versus progressive disease (PD); CR/PR versus stable disease (SD), and SD versus PD.Results: There was a trend for pazopanib patients to be less likely than placebo patients to experience ⩾20% HRQoL deterioration in EORTC-QLQ-C-30 global health status/QOL scale (HR=0.77; 95% CI 0.57–1.03, not significant). Results by prior treatment and different HRQoL deterioration thresholds were similar. Patients with CR/PR and SD experienced significantly less HRQoL deterioration than those with PD (p<0.001, p=0.0024, respectively); mean differences between patients with CR/PR and PD exceeded the pre-determined minimally important difference (MID). Differences between patients with SD and PD did not exceed pre-determined MID. Results were generally consistent across treatment and EQ-5D summary scores.Conclusion: Results support the favourable benefit-risk profile of pazopanib and suggest patients experiencing tumour response/stabilisation also may have better HRQoL compared to those without this response.

An international expanded-access programme of everolimus: Addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy

2011-08-01

Abstract: Background and objectives: The RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC.Patients and methods: REACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3months for the first year and every 6months thereafter.Results: A total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14weeks.Conclusion: Everolimus is well tolerated in patients with mRCC and demonstrates a favourable risk–benefit ratio.

Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study

2012-01-03

Abstract: Introduction: In the phase III RECORD-1 trial (ClinicalTrials.gov: NCT00410124), patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy were randomised 2:1 to everolimus 10mg once daily (n=277) or placebo (n=139). Median progression-free survival (PFS) was 4.9months with everolimus and 1.9months with placebo (hazard ratio [HR], 0.33; P<.001). This preplanned, prospective sub-analysis evaluated PFS benefit of everolimus versus placebo in patients who had previously received 1 or 2 VEGFr-TKIs.Patients and methods: Median PFS was estimated using the Kaplan–Meier method, and Cox proportional hazards model was used to analyse differences in PFS.Results: All patients (100%) received ⩾1 previous VEGFr-TKI; 26% of patients received 2 previous VEGFr-TKIs. Among patients who received 1 previous VEGFr-TKI, median PFS was 5.4months with everolimus and 1.9months with placebo (HR, 0.32; 95%confidence interval [CI], 0.24–0.43; P<.001). Among patients who received 2 previous VEGFr-TKIs, median PFS was 4.0months with everolimus and 1.8months with placebo (HR, 0.32; 95%CI, 0.19–0.54; P<.001). The everolimus safety profile was similar for both groups.Conclusions: Everolimus was associated with prolonged PFS relative to placebo in patients who received 1 or 2 previous VEGFr-TKIs. Patients who received only 1 previous VEGFr-TKI had apparently longer PFS with everolimus in reference to those who received 2 previous VEGFr-TKIs. These results support the use of everolimus as the standard of care in patients who fail initial VEGFr-TKI therapy.

The risk of skin rash and stomatitis with the mammalian target of rapamycin inhibitor temsirolimus: A systematic review of the literature and meta-analysis

2011-12-29

Abstract: Objective: We conducted a systematic review of the literature and performed a meta-analysis to determine the risk of developing skin rash and stomatitis among patients receiving temsirolimus.Methods: Databases from PubMed and Web of Science from January, 1998 until June, 2011 and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through 2011 were searched to identify relevant studies. The incidence and relative risk (RR) of skin rash and stomatitis were calculated using random-effects or fixed-effects model depending on the heterogeneity of included studies.Results: A total of 779 patients from 10 clinical trials were included in this analysis. The overall incidence of all-grade rash was 45.8% (95% confidence interval (CI): 35.6–56.3%), with a RR of 7.6 (95%CI: 4.4–13.3; p<0.001). The overall incidence of high-grade rash was 3.3% (95%CI: 1.9–5.6%), with a RR of 13.70 (95%CI: 0.82–227.50, p=0.07). The overall incidence of all-grade stomatitis was 44.3% (CI: 32.1–57.1%), with a RR of 11.10, 95%CI: 5.60–22.00; p<0.001). The overall incidence of high-grade stomatitis was 3.2% (95%CI: 1.9–5.4%), with a RR of 13.2 (95%CI: 0.80–218.50, p=0.07).Conclusion: There is a significant risk of developing skin rash and stomatitis in cancer patients receiving temsirolimus. The risk is independent of underlying tumour. Adequate monitoring and early intervention are recommended to prevent debilitating toxicity and suboptimal dosing.

Treatment influencing down-staging in EORTC Melanoma Group sentinel node histological protocol compared with complete step-sectioning: A national multicentre study

2011-10-24

Abstract: Aim: Metastasis size in melanoma sentinel lymph nodes (SLNs) is an emerging prognostic factor. Two European melanoma treatment trials include SLN metastasis diameters as inclusion criteria. Whilst diameter estimates are sensitive to the number of sections examined, the level of this bias is largely unknown. We performed a prospective multicentre study to compare the European Organisation for Research and Treatment of Cancer (EORTC) recommended protocol with a protocol of complete step-sectioning.Methods: One hundred and thirty-three consecutive SLNs from seven SLN centres were analysed by five central sections 50μm apart (EORTC Protocol) followed by complete 250μm step-sectioning.Results: Overall, 29 patients (21.8%) were SLN-positive. The EORTC Protocol missed eight of these metastases (28%), one metastasis measuring less than 0.1mm in diameter, seven measuring between 0.1 and 1mm. Complete step-sectioning at 250μm intervals (Extensive Protocol) missed one metastasis (3%) that measured less than 0.1mm. Thirteen treatment courses (34%) performed if inclusion was based on the Combined Protocol would not be performed if assessed by the EORTC Protocol. Thus, 10 patients would be without completion lymph node dissection (EORTC MINITUB study), whilst three patients would not be eligible for anti-CTLA4 trial (EORTC protocol 18071). The corresponding number with the Extensive Protocol would be three; one patient for the MINITUB registration study and two patients for the anti-CTLA4 study.Conclusions: Examining SLNs by close central sectioning alone (EORTC Protocol) misses a substantial number of metastases and underestimates the maximum metastasis diameter, leading to important changes in patient eligibility for various treatment protocols.

Central nervous system atypical teratoid rhabdoid tumours: The Canadian Paediatric Brain Tumour Consortium experience

2011-10-24

Abstract: Background: Atypical teratoid rhabdoid tumours (ATRT) are aggressive brain tumours mostly occurring in early childhood. Largest published series arise from registries and institutional experiences (1–4). The aim of this report is to provide population-based data to further characterise this rare entity and to delineate prognostic factors.Patients and methods: A national retrospective study of children ⩽18years diagnosed with a central nervous system (CNS) ATRT between 1995 and 2007 was undertaken. All cases underwent central pathology review.Results: There were 50 patients (31 males; median age at diagnosis of 16.7months). Twelve patients were >36months. Infratentorial location accounted for 52% of all cases. Nineteen patients (38%) had metastatic disease. Fifteen (30%) underwent gross total resection (GTR). Ten patients (20%) underwent palliation. Among the 40 remaining patients, 22 received conventional chemotherapy and 18 received high dose chemotherapy regimens (HDC); nine received intrathecal chemotherapy and 15 received adjuvant radiation.Thirty of the 40 treated patients relapsed/progressed at a median time of 5.5months (0–32). The median survival time of the entire cohort was 13.5months (1–117.5months).Age, tumour location and metastatic status were not prognostic. Patients with GTR had a better survival (2years overall survival (OS): 60%±12.6 versus 21.7%±8.5, p=0.03). HDC conferred better outcome (2years OS 47.9%±12.1 versus 27.3%±9.5, p=0.036). Upfront radiation did not provide survival benefit. Six of the 12 survivors (50%) did not receive radiation.Conclusion: The outcome of CNS ATRT remains poor. However, the use of HDC provides encouraging results. GTR is a significant prognostic factor. The role of adjuvant radiation remains unclear.

The prophylactic use of granulocyte-colony stimulating factor during remission induction is associated with increased leukaemia-free survival of adults with acute lymphoblastic leukaemia: A joint analysis of five randomised trials on behalf of the EWALL

2011-12-26

Abstract: Background: Granulocyte-colony stimulating factor (G-CSF) is used to prevent febrile neutropenia and support intense chemotherapy. However, its impact on long-term outcome in oncological patients including adults with acute lymphoblastic leukaemia (ALL) has not been determined so far.Methods: In the current study follow-up data from individual patients recruited in five multicentre, prospective, randomised trials were pooled to perform a joint analysis. Among 347 adults and adolescents with ALL, 185 were assigned to receive prophylactically G-CSF along with induction chemotherapy while 162 patients were treated without G-CSF support.Results: With the median follow-up of 5.3years, there was a tendency towards increased 5year probability of the overall survival for the G-CSF arm compared to the controls (32%±4% versus 23%±4%, p=.07), which reached statistical significance in a subgroup of T-ALL (51%±8% versus 29%±9%, p=.01) and among patients aged 21–40years (44%±6% versus 27%±6%, p=.03). The probability of leukaemia-free survival was 38%±4% and 24%±4% (p=.01) while the median remission duration equalled 33 and 17months (p=.007), respectively. In a multivariate analysis the prophylactic use of G-CSF was independently associated with reduced risk of relapse (hazard ratio (HR)=.64, p=.007) and treatment failure (HR=.67, p=.02).Conclusions: The prophylactic use of G-CSF during induction of ALL is associated with improved long-term outcome and should be recommended especially in a setting of T-ALL and in ‘young adults’. Our analysis provides the first direct evidence coming from prospective trials for the impact of primary G-CSF prophylaxis on disease-free survival of oncological patients.

Evolution of requests to hasten death among patients managed by palliative care teams in France: A multicentre cross-sectional survey (DemandE)

2011-10-31

Abstract: Background: Strongly marked ideological positions on the impact of palliative care and limited hard data plague the debate on physician-assisted death.Methods: A national cross-sectional study on the requests to hasten death (RHD) was conducted among 789 French palliative care organisations. Data were collected for all patients with RHD encountered during year 2010. Data on patients’ characteristics, medical, psychological and social context, symptoms, nature of palliative management, patient’s evolution and palliative care team’s interpretation of the request were obtained.Findings: A majority of centres responded and 342 teams provided descriptions of 783 RHD, 476 by a patient, 258 by relatives or close friends and 49 by the nursing staff. Cancer was the most frequent pathology (72%) and 68% of the patients had entered terminal stage. Patients rarely appeared with uncontrolled pain (3.7%), but had difficulties with feeding (65%), moving (54%), excretion (49%), or were cachectic (39%); 31% were considered to be anxio-depressive; 79% did not give physical reasons for their request; 37% of RHD were maintained and 24% fluctuated despite provision of regular follow-up by a palliative care team to 83% of all cases; 68% of patients died within a month; the interpretation of RHD by the staff was a wish for relief (69%), patient’s inextricable situation (44%), actual desire not to continue living (36%) or to be helped to die (30%).Interpretation: The large number of described cases provides, for the first time, comprehensive hard data on the evolution of RHDs in a country that has not legalised euthanasia. Whatever the way RHD are expressed, they are frequently maintained despite adequate palliative care with suitable control of pain and psychological support by specialists.

Outcome, quality of life and cognitive function of patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03)

2011-11-17

Abstract: Purpose: Patients with brain metastases (BM) rarely survive longer than 6months and are commonly excluded from clinical trials. We explored two combined modality regimens with novel agents with single agent activity and radiosensitizing properties.Patients and methods: In this randomised phase II trial patients with BM from NSCLC were randomly assigned to 30Gy WBRT with either concomitant gefitinib (GFT) 250mg/day continuously or temozolomide (TMZ) 75mg/m2 for 21/28days. The primary end-point was overall survival, with quality of life and cognitive function as secondary end-points.Results: We enrolled 59 patients (GFT 16, TMZ 43), and 56 patients have died, mainly (80%) from disease progression. Four patients succumbed complications of the disease or corticosteroids (intestinal perforation (2), CNS haemorrhage and pulmonary emboli). Median overall survival in the gefitinib arm was 6.3months (95% CI 2.1–14.6), and 4.9months (95% CI 2.3–5.6) in TMZ treated patients. Fatigue was the main complaint.Conclusions: No relevant toxicity with those therapeutic regimens was observed. Fatal outcome in three patients may have been related to corticosteroids. Cognitive function improved during treatment. However, median overall survival for all patients was only 4.9months (95% CI 2.3–5.7) and 1-year survival 25.4% (95% CI 15.4–37.0%).

Poor correlation between progression-free and overall survival in modern clinical trials: Are composite endpoints the answer?

Eitan Amir, Bostjan Seruga, Ryan Kwong, Ian F. Tannock, Alberto Ocaña — 2011-11-24

Abstract: It can be difficult to identify endpoints that accurately reflect patient benefit in metastatic solid tumors. Overall survival (OS) is the gold standard although progression-free survival (PFS) is sometimes used as a surrogate for OS. Statistical modelling has suggested that the association between OS and PFS becomes weaker in diseases with longer survival post-progression (SPP). To evaluate these statistical hypotheses we determined the relationship between PFS and OS in control and experimental arms of randomised trials conducted in the last 10years, which have led to drug approval. Our data confirm that PFS is a poor surrogate for OS when SPP is long, but it is a better surrogate where SPP is short. In cancers with short SPP designing trials to show OS benefit is feasible and, therefore, remains the preferred approach. In tumours with long SPP, PFS is not clinically meaningful unless it is also associated with improvement in patient reported outcomes such as quality of life. The oncology community should consider the further development and validation of composite endpoints including patient reported outcomes and PFS across different disease sites. Such endpoints have been successfully used in cancer trials in the past. With improvements in therapy and prolonged survival of patients with many cancers, and with increasing pressure from healthcare payers to prove that treatment leads to patient benefit, the choice of optimal endpoints for clinical trials is increasingly important. Composite measures comprising patient reported outcomes and intermediate endpoints such as PFS may be the solution and should be investigated further.

Targeting Raf/MEK/ERK pathway in pituitary adenomas

Zhang Suojun, Wan Feng, Guo Dongsheng, Lei Ting — 2011-11-28

Abstract: Pituitary adenomas are the common neoplasms that cause mass effect and/or endocrine dysfunction. Studies in the pathogenesis and functional regulation of pituitary adenomas are mainly focused on the following two topics: (a) the origin of pituitary adenomas and abnormal physical adjustment due to the activation of oncogenes and loss of function for tumour-suppressor genes; and (b) the mechanistic anomalies of the intracellular signal transduction. Among which, the Raf/MEK/ERK signalling has been considered to be one of the major and central pathways in disease aetiology. Raf/MEK/ERK signalling is evolutionarily conserved that controls cellular growth, differentiation and survival. Altered functionality of this signalling pathway has been found to be involved in the development of several types of cancers in humans including pituitary adenomas. This review summarises the roles of Raf/MEK/ERK signalling pathway in pituitary tumourigenesis and highlights the clinical potential of this signalling pathways to be a therapeutic target for intervention and treatment of pituitary adenomas.

The phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 is effective in inhibiting regrowth of tumour cells after cytotoxic therapy

2011-12-09

Abstract: Purpose: Regrowth of tumour cells between cycles of chemotherapy is a significant clinical problem. Treatment strategies where antiproliferative agents are used to inhibit tumour regrowth between chemotherapy cycles are attractive, but such strategies are difficult to test using conventional monolayer culture systems.Methods: We used the in vitro tumour spheroid model to study regrowth of 3-D colon carcinoma tissue after cytotoxic therapy. Colon carcinoma cells with wild-type or mutant phosphatidyl inositol 3-kinase catalytic subunit (PI3KCA) or KRAS alleles were allowed to form multicellular spheroids and the effects of different pharmacological compounds were studied after sectioning and staining for relevant markers of cell proliferation and apoptosis.Results: Studies using colon cancer cells with gene disruptions suggested that the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway was essential for proliferation in 3-D culture. The dual PI3K-mTOR inhibitor NVP-BEZ235, currently in clinical trials, was found to inhibit phosphorylation of the mTOR target 4EBP1 in 3-D cultured cells. The ability of NVP-BEZ235 to inhibit tumour cell proliferation and to induce apoptosis was markedly more pronounced in 3-D cultures compared to monolayer cultures. It was subsequently found that NVP-BEZ235 was effective in inhibiting regrowth of 3-D cultured cells after treatment with two cytotoxic inhibitors of the ubiquitin–proteasome system (UPS), methyl-13-hydroxy-15-oxokaurenoate (MHOK) and bortezomib (Velcade®).Conclusions: The dual PI3K-mTOR inhibitor NVP-BEZ235 was found to reduce cell proliferation and to induce apoptosis in 3-D cultured colon carcinoma cells, NVP-BEZ235 is a promising candidate for use in sequential treatment modalities together with cytotoxic drugs to reduce the cell mass of solid tumours.

Corrigendum to “Single-agent irinotecan or 5-fluorouracil and leucovorin (FOLFIRI) as second-line chemotherapy for advanced colorectal cancer; results of a randomised phase II study (DaVINCI) and meta-analysis” [Eur J Cancer 47 (12) (2011) 1826–1836]

2011-12-29

Please note that the title of this article was expanded incorrectly during editing but unfortunately this error was not picked up during proof correction. The correct title is as follows: