Combined, patient-level, analysis of two randomised trials evaluating the addition of denosumab to standard first-line chemotherapy in advanced NSCLC - The ETOP/EORTC SPLENDOUR and AMGEN-249 trials.

INTRODUCTION: The efficacy of adding denosumab to standard first-line chemotherapy for advanced NSCLC patients has been evaluated in two separate randomised trials (SPLENDOUR and AMGEN-249). In this pooled analysis, we will assess the combination-treatment effect in the largest available population, in order to conclude about the potential impact of denosumab in NSCLC. METHODS: Both trials included in this combined analysis, were randomised (SPLENDOUR 1:1, AMGEN-249 2:1) multi-centre trials stratified by histology, bone metastasis, geographical region and for SPLENDOUR only, ECOG PS. Cox proportional hazards models, were used to assess the treatment effect with respect to overall survival (OS; primary endpoint) and progression-free survival (PFS; secondary endpoint). Heterogeneity between trials was assessed, and subgroup analyses were performed. RESULTS: The pooled analysis was based on 740 randomised patients (SPLENDOUR:514; AMGEN-249:226), with 407 patients in the chemotherapy-denosumab arm and 333 in the chemotherapy-alone arm. In the chemotherapy-denosumab arm, at a median follow-up of 22.0 months, 277 (68.1%) deaths were reported with median OS 9.2 months (95%CI:[8.0-10.7]), while in the chemotherapy-alone arm, with similar median follow-up of 20.3 months, 230 (69.1%) deaths with median OS 9.9 months (95%CI:[8.2-11.2]). No significant denosumab effect was found (HR = 0.98; 95%CI:[0.82-1.18]; P = 0.85). Among subgroups, interaction was found between treatment and histology subtypes (P = 0.020), with a statistically significant benefit in the squamous group (HR = 0.70; 95%CI:[0.49-0.98]; P = 0.038), from 7.6 to 9.0 months median OS. With respect to PFS, 363 (89.2%) and 298 (89.5%) events were reported in the chemotherapy-denosumab and chemotherapy-alone arms, respectively, with corresponding medians 4.8 months (95%CI:[4.4-5.3]) and 4.9 months (95%CI:[4.3-5.4]). HR for PFS was 0.97(95%CI:[0.83-1.15]; P = 0.76), indicating that no significant denosumab benefit existed for PFS. CONCLUSION: In this pooled analysis, no statistically significant improvement was shown in PFS/OS with the combination of denosumab and chemotherapy for advanced NSCLC and no meaningful benefit in any of the subgroups.

A Randomized Open-Label Phase III Trial Evaluating the Addition of Denosumab to Standard First-Line Treatment in Advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial.

INTRODUCTION: Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC. METHODS: Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate. RESULTS: A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%. CONCLUSIONS: Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases.

Sample size computation in phase II designs combining the A'Hern design and the Sargent and Goldberg design.

This work focuses on the modification of two classical phase II trials designs, the A'Hern design, a single-arm single-stage design, and the Sargent and Goldberg design introduced in the context of flexible screening designs. In the first part of the paper, we have proposed a drift-adjusted A'Hern design, a hybrid design combining the A'Hern design and the Sargent and Goldberg design. Indeed, classical single-arm phase II designs such as the A'Hern design are still widely used in oncology. Conducting randomized comparative phase II trials may be challenging in many settings due to the increased sample size and this despite larger type 1 errors. Randomized non-comparative phase II designs first introduced by Herson and Carter include a simultaneous randomized standard-treatment reference arm to detect any drift in the reference arm assumption, but the trial is analyzed against historical controls as if it were a single-arm study. However, not incorporating at all an internal control arm in the trial design has been criticized in the literature. Our new design takes into account the observed response rate in a non-comparative reference arm to reduce the trial's risk of a false-positive conclusion. In the second part, we have proposed an alternative strategy to determining the sample size of the screened selection design. The latter, introduced in recent years by Yap et al. and Wu et al., extended the Sargent and Goldberg design to include a comparison to a historical control. However, their sample size computations may have potential weaknesses, which motivated us to revisit the existing approaches. A detailed simulation study has been carried out to evaluate the operating characteristics of the drift-adjusted A'Hern design and the different sample size strategies of the screened selection designs.

EORTC Lung Cancer Group survey on the definition of NSCLC synchronous oligometastatic disease.

BACKGROUND: Synchronous oligometastatic disease (sOM) has been described as a distinct disease entity; however, there is no consensus on OM definition (OM-d) in non-small-cell lung cancer (NSCLC). A consensus group was formed aiming to agree on a common OM-d that could be used in future clinical trials. A European survey was circulated to generate questions and input for the consensus group meeting. METHODS: A European Organisation for Research and Treatment of Cancer Lung Cancer Group (LCG)/sOM-d consensus group survey was distributed to LCG, sOM-d consensus group, and several European thoracic oncology societies' members. RESULTS: 444 responses were analysed (radiation oncologist: 55% [n = 242], pulmonologist: 15% [n = 66], medical oncologist: 14% [n = 64]). 361 physicians (81%) aimed to cure sOM NSCLC patients and 82% (n = 362) included the possibility of radical intent treatment in their sOM-d. The maximum number of metastases considered in sOM-d varied: 12% replied 1 metastasis, 42% ≤ 3, and 17% ≥ 5 metastases. 79% (n = 353) stated that number of organs involved was important for sOM-d, and most (80%, n = 355) considered that only ≤3 involved organs (excluding primary) should be included. 317 (72%) included mediastinal lymph node involvement in the sOM-d and 22% (n = 70/317) counted mediastinal lymph node as a metastatic site. Most physicians completed sOM staging with brain magnetic resonance imaging (91%, n = 403) and positron emission tomography/computed tomography (98%, n = 437). Pathology proof of metastatic disease was a requirement to define sOM for 315 (71%) physicians. The preferred primary outcome for sOM clinical trials was overall survival (73%, n = 325). CONCLUSION: Although consensual answers were obtained, several issues remain unresolved and will require further research to agree on a sOM-d.

Defining oligometastatic non-small cell lung cancer: A simulated multidisciplinary expert opinion.

INTRODUCTION: Synchronous oligometastatic non-small cell lung cancer (NSCLC) definition varies from 1 metastasis in 1 organ (tumour-node-metastasis 8 [TNM8]), 1-3 metastases (European Society for Medical Oncology [ESMO]), ≤3 metastases (including mediastinal nodes [MLN]) after systemic treatment to 3-5 metastases in ongoing trials. A single definition is however needed to design/compare trials. To assess oligometastatic NSCLC definitions used by clinical experts in daily practice and its evolution, we redistributed a 2012 case-based survey (Dooms, the World Congress of Lung Cancer 2013). METHODS: In December 2017, 10 real-life multidisciplinary team (MDT) discussed patients (good condition, no significant comorbidities, 18F-fluorodeoxyglucose positron emission tomography/brain magnetic resonance imaging staged, all < 5 metastases, 9/10 ≤ 3 metastases, oncogene-addicted or wild-type) were distributed to 33 international NSCLC experts involved in the European Organisation for Research and Treatment of Cancer oligometastatic NSCLC consensus group, questioning is this oligometastatic disease and if oligometastatic, which treatment proposal. The answers provided in 2017 were compared with the 2012 answers; real-life treatment and survival of the patients was added. RESULTS: Twenty-six of 33 experts (24 centres) replied: 8 medical oncologists, 7 pulmonologists, 7 radiation oncologists, 4 thoracic surgeons. Sixty-two percent of respondents discussed the cases with their MDT. One case had 100% oligometastatic consensus, and 3 cases had >90% consensus; the number of treatment proposals varied between 3 and 8. Radical treatment was more often offered in case of single metastasis or N0. Compared with 2012, there was a trend towards a more conservative oligometastatic definition and chemotherapy was more frequently included in the treatment proposal. CONCLUSIONS: Oligometastatic NSCLC definition was conservative. The number of organs, MLN status and radical treatment possibility seem to be components of daily practice oligometastatic definition.

Current management of limited-stage SCLC and CONVERT trial impact: Results of the EORTC Lung Cancer Group survey.

OBJECTIVES: The CONVERT trial showed that twice-daily (BD) concurrent chemoradiotherapy should continue to be considered the standard of care in localised LS-SCLC. A survey was conducted to assess the impact of the CONVERT trial in clinical practice and to identify any relevant research questions for future trials in this setting. METHODS AND MATERIALS: An EORTC Group online survey of LS-SCLC practice was distributed to the EORTC LCG and to members of several European thoracic oncology societies between April and December 2018. RESULTS: 198 responses were analysed. The majority of respondents (88%, n = 174) were aware of the CONVERT trial. Radiation oncologists comprised 56% of all respondents. Once-daily (OD) radiotherapy is still the most commonly used regimen, however the use of concurrent BD radiotherapy increased after the publication of CONVERT (n = 59/186, 32% prior to and n = 78/187, 42% after the publication, p = 0.053). The main reasons for not implementing BD after the CONVERT publication were logistical issues (n = 88, 44%), inconvenience for patients (n = 56, 28%), and the absence of a statistical survival difference between the two arms in CONVERT (n = 38, 19%). Brain MRI was used by 28% during staging but more than half (60%) of the respondents did not routinely image the brain during follow-up. The main research questions of interest in LS-SCLC were 1) integrating novel targeted therapies-immunotherapies (n = 160, 81%), 2) PCI (+/- hippocampal sparing) vs. MRI surveillance (n = 140, 71%) and, 3) biomarker driven trials (n = 92, 46%). CONCLUSION: Once daily radiotherapy (60-66 Gy in 30-33 fractions) remains the most prescribed radiotherapy fractionation, despite the findings suggested by the CONVERT trial.

Definition of Synchronous Oligometastatic Non-Small Cell Lung Cancer-A Consensus Report.

INTRODUCTION: Improved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process. METHODS: A pan-European multidisciplinary consensus group was established. Consensus questions were built on the basis of current controversies, and definitions were extracted from a survey, cases and a systematic review. This statement was formulated during a consensus meeting. RESULTS: It was determined that definition of sOM NSCLC is relevant when a radical treatment that may modify the disease course (leading to long-term disease control) is technically feasible for all tumor sites with acceptable toxicity. On the basis of the review, a maximum of five metastases and three organs was proposed. Mediastinal lymph node involvement was not counted as a metastatic site. Fludeoxyglucose F 18 positron emission tomography-computed tomography and brain imaging were considered mandatory. A dedicated liver magnetic resonance imaging scan was advised for a solitary liver metastasis, and thoracoscopy and biopsies of distant ipsilateral pleural sites were recommended for a solitary pleural metastasis. For mediastinal staging, fludeoxyglucose F 18 positron emission tomography-computed tomography was deemed the minimum requirement, with pathological confirmation recommended if this influences the treatment strategy. Biopsy of a solitary metastatic location was mandated unless the multidisciplinary team is of the opinion that the risks outweigh the benefits. CONCLUSION: A multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials.

Defining Synchronous Oligometastatic Non-Small Cell Lung Cancer: A Systematic Review.

INTRODUCTION: Synchronous oligometastatic (sOM) disease is an oncological concept characterized by a limited cancer burden. Patients with oligometastasis could potentially benefit from local radical treatments. Despite the fact that the sOM condition is well recognized, a universal definition, including a specific definition for NSCLC, is not yet available. The aim of this systematic review was to summarize the definitions of and staging requirements for use of the term synchronous oligometastatic in the context of NSCLC. METHODS: The key issue was formulated in one research question according to the population, intervention, comparator, and outcomes strategy. The question was introduced in MEDLINE (OvidSP). All articles dealing with sOM NSCLC and providing a definition of synchronous oligometastasis in NSCLC were selected and analyzed. RESULTS: A total of 21 eligible articles focusing on sOM NSCLC were retrieved and analyzed. In 17 studies (81%), patients had to be staged with magnetic resonance imaging or computed tomography of the brain, thoracic and abdominal computed tomography, and positron emission tomography. The total number of metastases allowed in the definitions ranged from one to eight, but in 38.1% of studies the maximum number was 5. Most of the publications did not define the number of involved organs or the maximum number of metastases per organ. For mediastinal lymph node involvement, only five articles (27.8%) counted this as a metastatic site. CONCLUSIONS: No uniform definition of sOM NSCLC could be retrieved by this systematic review. However, extended staging was mandated in most of the studies. An accepted oncological definition of synchronous oligometastasis is essential for patient selection to define prospective clinical trials.

Diversity of brain metastases screening and management in non-small cell lung cancer in Europe: Results of the European Organisation for Research and Treatment of Cancer Lung Cancer Group survey.

BACKGROUND: Brain metastases (BM) are frequent in non-small cell lung cancer (NSCLC) patients, but there is a lack of evidence-based management of this patient group. We aimed to capture a snapshot of routine BM management in Europe to identify relevant research questions for future clinical trials. METHODS: An EORTC Lung Cancer Group (LCG) online survey containing questions on NSCLC BM screening and treatment was distributed between 16/02/17 and 15/06/17 to worldwide EORTC LCG members, and through several European scientific societies in the thoracic oncology field. RESULTS: A total of 462 European physician responses (394 institutions) were analysed (radiation oncologist: 53% [n = 247], pulmonologist: 26% [n = 119], medical oncologist: 18% [n = 84]; 84% with >5 years' experience in NSCLC). Italy (18%, n = 85), Netherlands (15%, n = 68), UK (14%, n = 66), and France (12%, n = 55) contributed most. 393 physicians (85%) screened neurologically asymptomatic patients for BM at diagnosis (52% using magnetic resonance imaging). Most often screened patients were those with a driver mutation (MUT+; 51%, n = 234), stage III (63%, n = 289), and IV (43%, n = 199). 158 physicians (34%) used a prognostic classification to guide initial treatment decisions, and in 50%, lowest prognostic-score threshold to receive treatment differed between MUT+ and non-driver mutation (MUT-) patients. MUT+ patients with >4 BM were more likely to receive stereotactic radiosurgery (SRS) compared with MUT- (27% versus. 21%; p < 0.01). Most physicians (90%) had access to SRS. After single BM surgery, 50% systematically prescribed SRS or WBRT, and 45% only in case of incomplete resection. The preferred treatment in neurologically asymptomatic treatment-naive patients diagnosed with >5 BM was systemic treatment (79%). Of all, 45%/49% physicians stated that all tyrosine kinase inhibitors and immune checkpoint blockers were discontinued (timing varied) during SRS/WBRT, respectively. Drugs most often continued during SRS/WBRT were erlotinib (44%/40%), gefitinib (39%/34%), afatinib (29%/25%), crizotinib (33%/26%) and anti-PD-(L)-1 (28%/22%). CONCLUSION: BM management is highly variable in Europe: screening is not uniform, prognostic classifications are not often used and MUT+ NSCLC patients generally receive more intensive local treatment. Prospective assessment of BM management in MUT+ NSCLC patients is required.

A phase III study of lenalidomide maintenance after debulking therapy in patients with advanced cutaneous T-cell lymphoma - EORTC 21081 (NCT01098656): results and lessons learned for future trial designs.

EORTC 21081 was a randomized phase III study of observation alone versus lenalidomide maintenance (25 mg po for 21 days) after debulking therapy in patients with advanced-stage cutaneous T-cell lymphomas (CTCLs). The aim was to investigate whether maintenance treatment with lenalidomide prolonged response after debulking in patients who had not been previously treated with intravenous chemotherapy. A total of 26 centres from 10 different European countries registered 30 patients with advanced CTCL. Twenty-one patients were randomized (20% of the 105 patients initially deemed necessary for the study; the study was terminated early following withdrawal of funding support from Celgene). Of 30 registered patients, nine failed to be randomized, 12 were randomized to observation alone, and nine to lenalidomide maintenance. Median progression-free survival was 5.3 months (95% CI: 1.87-22.54) in the maintenance lenalidomide group and two months (95% CI: 0.92-7.82) in the observation alone group. Although statistical comparison in the study was severely underpowered and would not be meaningful, this study provides useful information, revealing rapid disease progression within four weeks in a third of patients, highlighting the need for maintenance therapy.

The APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients. EORTC 1613.

The AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients (APPLE) trial is a randomized, open-label, multicenter, 3-arm, phase II study in advanced, epidermal growth factor receptor (EGFR)-mutant and EGFR tyrosine kinase inhibitor (TKI)-naive non-small-cell lung cancer (NSCLC) patients, to evaluate the best strategy for sequencing gefitinib and osimertinib treatment. Advanced EGFR-mutant NSCLC patients, with World Health Organization performance status 0-2 who are EGFR TKI treatment-naive and eligible to receive first-line treatment with EGFR TKI will be randomized to: In all arms, a plasmatic ctDNA T790M test will be performed by a central laboratory at the Medical University of Gdansk (Poland) but will be applied as a predictive marker for making treatment decisions only in arm B. The primary objective is to evaluate the best strategy for sequencing of treatment with gefitinib and osimertinib in advanced NSCLC patients with common EGFR mutations, and to understand the value of liquid biopsy for the decision-making process. The progression-free survival rate at 18 months is the primary end point of the trial. The activity of osimertinib versus gefitinib to prevent brain metastases will be evaluated.

Sunitinib (SU11248) in patients with chemo naive extensive small cell lung cancer or who have a 'chemosensitive' relapse: A single-arm phase II study (EORTC-08061).

BACKGROUND: Targeted therapies have to date not been successful in the treatment of small cell lung cancer (SCLC). This study aimed to assess the therapeutic activity of sunitinib (an oral, multi-targeted tyrosine kinase inhibitor) using positron emission tomography (PET)-computed tomography (CT) imaging as an early indicator of response. METHODS: This was a single-arm phase II study of sunitinib in patients with SCLC who are either chemo naive (extensive disease) or have a 'sensitive' relapse. A loading dose of 150 mg sunitinib was given orally followed by 37.5 mg/d. The primary end-point was disease control rate (DCR) at 8 weeks after the start of treatment and secondary end-points included toxicity of treatment and overall response. PET-CT was carried out at 4 weeks into the treatment. The study was closed early because of low accrual with only 9 of required 48 patients (19%) accrued. RESULTS: Nine patients were registered, seven females and two males with a median age of 65 years and a median duration of sunitinib treatment of 7.4 weeks. DCR at 8 weeks was achieved in two patients, both of whom went on to long periods of disease control, one patient achieved a partial response which lasted 10 months and a second patient had stable disease (minor shrinkage) which lasted 20 months. One of these patients proved to have an atypical carcinoid tumour at rebiopsy after 10 months. DCR and PET-CT imaging both predicted these responses. Grade III-IV toxicities were encountered during treatment, most commonly neutropenia (n = 3), thrombocytopenia (n = 3) and hypermagnesaemia (n = 2). One toxic death occurred due to bronchial haemorrhage. CONCLUSION: This study emphasises the need for alternate study design and end-points for new drug assessment in SCLC. EudraCT number: 2006-002485-19.

Maintenance pazopanib versus placebo in Non-Small Cell Lung Cancer patients non-progressive after first line chemotherapy: A double blind randomised phase III study of the lung cancer group, EORTC 08092 (EudraCT: 2010-018566-23, NCT01208064).

BACKGROUND: Switch maintenance is an effective strategy in the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). Pazopanib is an oral, multi-targeted tyrosine kinase inhibitor (TKI). EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC. METHODS: Patients with non-progressive disease after 4-6 cycles of chemotherapy were randomised to receive either pazopanib 800mg/day or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival and secondary end-points were progression-free survival (PFS) and safety. RESULTS: A total of 600 patients were planned to be randomised. The trial was prematurely stopped following an early interim analysis, after 102 patients were randomised to pazopanib (n=50) or placebo (n=52). Median age was 64years in both arms. Median overall survival was 17.4 months for pazopanib and 12.3 months for placebo (adjusted hazard ratio (HR) 0.72 [95% confidence interval (CI) 0.40-1.28]; p=0.257). Median PFS was 4.3 months versus 3.2 months (HR 0.67, [95% CI 0.43-1.03], p=0.068). PFS rates at 4 months were 56% and 45% respectively. The majority of treatment-related adverse events (AEs) were grade 1-2. Grade 3-4 AEs (pazopanib versus placebo) were hypertension (38% versus 8%), neutropenia (8% versus 0%), and elevated SGPT (6% versus 0%). Of the patients randomised to pazopanib, 22% withdrew due to a treatment-related AE. CONCLUSIONS: Switch maintenance with pazopanib following platinum-based chemotherapy in advanced NSCLC patients had limited side-effects. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis.

New clinical research strategies in thoracic oncology: clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response.

In the genomics era, our main goal should be to identify large and meaningful differences in small, molecularly selected groups of patients. Classical phase I, II and III models for drug development require large resources, limiting the number of experimental agents that can be tested and making the evaluation of targeted agents inefficient. There is an urgent need to streamline the development of new compounds, with the aim of identifying "trials designed to learn", which could lead to subsequent "trials designed to conclude". Basket trials are often viewed as parallel phase II trials within the same entity, designed on the basis of a common denominator, which can be a molecular alteration(s). Most basket trials are histology-independent and aberration-specific clinical trials. Umbrella trials are built on a centrally performed molecular portrait and molecularly selected cohorts with matched drugs, and can include patients' randomisation and strategy validation. Beyond new designs, new end-points and new evaluation techniques are also warranted to finally achieve methodology and clinical improvements, in particular within immunotherapy trials.

Progression free survival rate at 9 and 18 weeks predict overall survival in patients with malignant pleural mesothelioma: an individual patient pooled analysis of 10 European Organisation for Research and Treatment of Cancer Lung Cancer Group studies and an independent study validation.

BACKGROUND: Response criteria have always been difficult to apply to malignant pleural mesothelioma (MPM), due to its unique pattern of growth. We developed some models to show that progression free survival rate (PFSR) could be a better predictor of overall survival (OS) than the response rate (RR) in MPM patients. The results were validated independently in the European Organisation for Research and Treatment of Cancer (EORTC) 08052, a phase II study in MPM. METHODS: Individual patient data from 10 EORTC-Lung Cancer Group (LCG) studies of first-line chemotherapy in MPM were pooled. Response to therapy was assessed according to World Health Organisation (WHO) criteria in all except the two most recent trials, which used Response Evaluation Criteria in Solid Tumours (RECIST). Landmark analyses (LA) at 9 weeks and 18 weeks after registration/randomisation were performed to assess the association between PFSR and OS. Independent validation of the results was conducted in EORTC 08052 study (82 patients) employing the same LA. RESULTS: All 10 studies (N=523 patients) were included in the LA of PFSR at 9 and 18 weeks (PFSR-9 and PFSR-18). PFSR-9 and PFSR-18 were confirmed as predictors of OS, with hazard ratio (HR) of 0.37 (95% confidence interval (CI), 0.30-0.47) and 0.50 (0.38-0.65) and C-index of 0.62 and 0.58, respectively. In the validation study, 28.4% achieved CR/PR and 77.8% had disease control (CR/PR/SD) as their best overall response. PFSR-9 and PFSR-18 weeks were both strongly correlated with OS (HR of 0.35 [80% CI, 0.25-0.49] and 0.46 (0.32-0.67) and C-index of 0.66 and 0.60, respectively). CONCLUSION: PFSR-18 was strongly correlated and discriminated patients with better OS from the poorer prognosis patients. An earlier end-point, PFSR-9 was also strongly correlated to OS with better discriminating capacity. The results were independently validated.

Attitudes and referral patterns of lung cancer specialists in Europe to Specialized Palliative Care (SPC) and the practice of Early Palliative Care (EPC).

PURPOSE: To examine availability of Palliative Care (PC) services and referral patterns of European Lung cancer specialists to PC. METHODS: All members of the EORTC Lung Cancer Group (LCG) were asked via email to participate in an on-line survey. RESULTS: 50 out of 170 (29.4%) replied: 24 medical oncologists, 14 radiation/clinical oncologists, 11 pulmonologists and 1 thoracic surgeon. All but two of respondents (96%) had access to at least one component of PC services. In terms of referral of patients to PC almost 75% of respondents would refer most of their patients when there were no treatment options or at the end of life, while only 22% would refer patients at earlier stages of disease. Barriers for referral to PC were negative attitudes of patients to PC (26%), lack of availability of PC services (20%), lack of expertise of PC physicians(18%), the belief that referral to PC signifies abandoning patients (8%), and that PC specialists discourage active oncological therapy (8%). Whilst most of the respondents expressed positive attitudes, 12-22% had overtly negative attitudes towards PC. Seventy-eight (78%) of respondents expressed an interest to participate in a trial of early PC (EPC). CONCLUSION: Despite good availability of SPC services at institutions of members of the EORTC LCG, and most respondents expressing positive attitudes towards PC, their practice involved referral of patients to PC late in the disease trajectory, hence Lung Cancer specialists in Europe have not adopted the practice of EPC concurrent with active oncological care.

Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052).

BACKGROUND: This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of malignant pleural mesothelioma (MPM) with validation of progression free survival rate at 18 weeks (PFSR-18)(1) as primary end-point. METHODS: Chemotherapy-naïve patients with histologically proven MPM and performance status (PS) 0/1, were treated with cisplatin 75 mg/m(2) on day 1 and bortezomib 1.3mg/m(2) on days 1, 4, 8, 11 every 3 weeks. The primary end-point validation utilised the landmark method. RESULTS: Between 2007 and 2010 82 patients were entered. PFSR-18 was 53% (80% confidence intervals, CIs, 42-64%). The overall survival (OS) was 13.5 months (95% CI 10.5-15) with 56% (95% CI 44-66%) alive at 1 year. The median PFS was 5.1months (95% CI 3.3-6.5) and the response rate was 28.4% (95% CI 18.9-39.5%). The most frequent grade 3-4 toxicities were hyponatremia (46%), hypokalaemia (17%), fatigue (12.2%), thrombocytopenia (11%), neutropenia (9.7%) and neurotoxicity (motor, sensory, other: 1.2%, 8.5%, 2.4%). There were two toxic deaths (32 and 74days) due to acute pneumonitis and cardiac arrest. End-point validation showed that patients with no progression/progression at 18 weeks had median OS of 16.9/11.9 months, respectively. Hazard ratio was 0.46 (CI 0.32-0.67), logrank test and C-index were 0.007 and 0.60. CONCLUSION: The 50% PFSR-18 for CB was contained within the 80% CI for (42-64%). Therefore the null hypothesis could not be rejected. Accordingly this combination does not warrant further investigation. PFSR-18 was confirmed as a strong predictor of survival.

Prospective international multicenter phase II trial of intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB advanced mycosis fungoides: final results from EORTC 21012.

PURPOSE: Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. There is a need for multicenter trials involving defined patient populations using rigorous assessment criteria. We have investigated pegylated liposomal doxorubicin (PLD) in a clearly defined patient population with advanced MF. PATIENTS AND METHODS: Eligible patients had stage IIB, IVA, or IVB MF, refractory or recurrent after at least two previous systemic therapies. Patients were registered to receive a maximum of six cycles of PLD 20 mg/m2 on days 1 and 15, every 28 days (one cycle). The primary end point was response rate (RR). RESULTS: Nine centers recruited 49 eligible patients. The median number of chemotherapy cycles received was five. There were no grade 3 to 4 hematologic toxicities. Grade 3 or 4 nonhematologic/nonbiochemical toxicities included cardiac symptom (2%), allergy/hypersensitivity (2%), constitutional symptom (4%), hand and foot reaction (2%), other dermatologic toxicity (6%), other GI toxicity (4%), infection (4%), pulmonary embolism (2%), and cardiac ischemia (2%). Of 49 patients, 20 (40.8%) were responders (complete clinical response [CCR] or partial response [PR] as overall response): three (6.1%) experienced CCRs, and 17 (34.7%) experienced PRs. A 50% or greater reduction of cutaneous manifestations was observed in 26 (60.5%) of 43 assessable patients. Two early deaths were reported, resulting from related cardiovascular toxicity and disease progression. The lower limit of the one-sided 90% CI for RR was 31.2%. Median time to progression and median duration of response were 7.4 and 6 months, respectively. CONCLUSION: PLD has an acceptable safety profile in patients with advanced MF. The efficacy of PLD seems promising.

High prevalence of osteoblastic bone reaction in computed tomography scans of an European Organisation for Research and Treatment of Cancer prospective randomised phase II trial in extensive stage small cell lung cancer.

BACKGROUND: Osteoblastic bone reaction is an important phenomenon defined by an increase in apparent bone density of previously known bone metastasis or development of new osteoblastic lesions in the presence of response in other tumour sites. Osteoblastic bone reaction in lung cancer has only been described in a few reports and mostly in patients with pre-existing bone metastasis. METHODS: In this report we present the data of an independent, blinded and preplanned radiological review of the occurrence of osteoblastic lesions in patients with extensive stage small cell lung cancer (SCLC). The computed tomography (CT) scans of the chest and upper abdomen of 71/88 patients who had an investigator reported complete response (CR), partial response (PR) or stable disease (SD) were retrospectively analysed for the development of osteoblastic lesions. Furthermore, baseline exams were reviewed for the presence and location of bone metastasis and local radiological reports were reviewed for any knowledge of bone metastasis. RESULTS: There were 14 patients with osteoblastic bone lesions in the reviewed follow-up CT scans. Three patients had known bone metastases at baseline, and 11 patients had no history or findings of bone metastases on the baseline scan. During the course of the disease, 13 out of 14 patients developed new osteoblastic lesions, while all responded in other sites. The prevalence of osteoblastic bone reaction in our study was 19.7%. CONCLUSION: In this study osteoblastic bone reaction was observed in a larger number of patients without previously documented bone metastases, indicating a high prevalence of occult bone metastases in SCLC. If bone metastases are not documented at diagnosis, then osteoblastic bone reaction may cause confusion in a responding patient.

Response to chemotherapy is predictive in relation to longer overall survival in an individual patient combined-analysis with pleural mesothelioma.

BACKGROUND: There is currently no early predictive marker of survival for patients receiving chemotherapy for malignant pleural mesothelioma (MPM). Tumour response may be predictive for overall survival (OS), though this has not been explored. We have thus undertaken a combined-analysis of OS, from a 42day landmark, of 526 patients receiving systemic therapy for MPM. We also validate published progression-free survival rates (PFSRs) and a progression-free survival (PFS) prognostic-index model. METHODS: Analyses included nine MPM clinical trials incorporating six European Organisation for Research and Treatment of Cancer (EORTC) studies. Analysis of OS from landmark (from day 42 post-treatment) was considered regarding tumour response. PFSR analysis data included six non-EORTC MPM clinical trials. Prognostic index validation was performed on one non-EORTC data-set, with available survival data. RESULTS: Median OS, from landmark, of patients with partial response (PR) was 12·8months, stable disease (SD), 9·4months and progressive disease (PD), 3·4months. Both PR and SD were associated with longer OS from landmark compared with disease progression (both p<0·0001). PFSRs for platinum-based combination therapies were consistent with published significant clinical activity ranges. Effective separation between PFS and OS curves provided a validation of the EORTC prognostic model, based on histology, stage and performance status. CONCLUSION: Response to chemotherapy is associated with significantly longer OS from landmark in patients with MPM.