Addition of nintedanib or placebo to neoadjuvant gemcitabine and cisplatin in locally advanced muscle-invasive bladder cancer (NEOBLADE): a double-blind, randomised, phase 2 trial.

BACKGROUND: Recurrence is common after neoadjuvant chemotherapy and radical treatment for muscle-invasive bladder cancer. We investigated the effect of adding nintedanib to neoadjuvant chemotherapy on response and survival in muscle-invasive bladder cancer. METHODS: NEOBLADE was a parallel-arm, double-blind, randomised, placebo-controlled, phase 2 trial of neoadjuvant gemcitabine and cisplatin chemotherapy with nintedanib or placebo in locally advanced muscle-invasive bladder cancer. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 15 hospitals in the UK. Patients were randomly assigned (1:1) to nintedanib or placebo using permuted blocks with random block sizes of two or four, stratified by centre and glomerular filtration rate. Treatments were allocated using an interactive web-based system, and patients and investigators were masked to treatment allocation throughout the study. Patients received oral nintedanib (150 mg or 200 mg twice daily for 12 weeks) or placebo, in addition to usual neoadjuvant chemotherapy with intravenous gemcitabine 1000 mg/m2 on days 1 and 8 and intravenous cisplatin 70 mg/m2 on day 1 of a 3-weekly cycle. The primary endpoint was pathological complete response rate, assessed at cystectomy or at day 8 of cyclde 3 (plus or minus 7 days) if cystectomy did not occur. Primary analyses were done in the intention-to-treat population. The trial is registered with EudraCT, 2012-004895-01, and ISRCTN, 56349930, and has completed planned recruitment. FINDINGS: Between Dec 4, 2014, and Sept 3, 2018, 120 patients were recruited and were randomly allocated to receive nintedanib (n=57) or placebo (n=63). The median follow-up for the study was 33·5 months (IQR 14·0-44·0). Pathological complete response in the intention-to-treat population was reached in 21 (37%) of 57 patients in the nintedanib group and 20 (32%) of 63 in the placebo group (odds ratio [OR] 1·25, 70% CI 0·84-1·87; p=0·28). Grade 3 or worse toxicities were observed in 53 (93%) of 57 participants who received nintedanib and 50 (79%) of 63 patients in the placebo group (OR 1·65, 95% CI 0·74-3·65; p=0·24). The most common grade 3 or worse adverse events were thromboembolic events (17 [30%] of 57 patients in the nintedanib group vs 13 [21%] of 63 patients in the placebo group [OR 1·63, 95% CI 0·71-3·76; p=0·29]) and decreased neutrophil count (22 [39%] in the nintedanib group vs seven [11%] in the placebo group [5·03, 1·95-13·00; p=0·0006]). 45 treatment-related serious adverse events occurred in the nintedanib group and 43 occurred in the placebo group. One treatment-related death occurred in the placebo group, which was due to myocardial infarction. INTERPRETATION: The addition of nintedanib to chemotherapy was safe but did not improve the rate of pathological complete response in muscle-invasive bladder cancer. FUNDING: Boehringer Ingelheim.

Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial.

BACKGROUND: No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients. METHODS: This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum-based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with Clinicaltrials.gov, NCT03063450. FINDINGS: Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11·6 months (IQR 7·2-16·8). Median progression-free survival was 3·0 months (95% CI 2·8-4·1) in the nivolumab group versus 1·8 months (1·4-2·6) in the placebo group (adjusted hazard ratio [HR] 0·67 [95% CI 0·53-0·85; p=0·0012). Median overall survival was 10·2 months (95% CI 8·5-12·1) in the nivolumab group versus 6·9 months (5·0-8·0) in the placebo group (adjusted HR 0·69 [95% CI 0·52-0·91]; p=0·0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment-related deaths in either group. INTERPRETATION: Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy. FUNDING: Stand up to Cancer-Cancer Research UK and Bristol Myers Squibb.

Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.

BACKGROUND: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. METHODS: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). INTERPRETATION: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. FUNDING: Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.

Retrospective analysis of real-world treatment patterns and clinical outcomes in patients with advanced non-small cell lung cancer starting first-line systemic therapy in the United Kingdom.

BACKGROUND: The treatment landscape for advanced non-small cell lung cancer (aNSCLC) has evolved rapidly since immuno-oncology (IO) therapies were introduced. This study used recent data to assess real-world treatment patterns and clinical outcomes in aNSCLC in the United Kingdom. METHODS: Electronic prescribing records of treatment-naive patients starting first-line (1 L) treatment for aNSCLC between June 2016 and March 2018 (follow-up until December 2018) in the United Kingdom were assessed retrospectively. Patient characteristics and treatment patterns were analyzed descriptively. Outcomes assessed included overall survival (OS), time to treatment discontinuation, time to next treatment, and real-world tumor response. RESULTS: In all, 1003 patients were evaluated (median age, 68 years [range, 28-93 years]; 53.9% male). Use of 1 L IO monotherapy (0-25.9%) and targeted therapy (11.8-15.9%) increased during the study period, but chemotherapy remained the most common 1 L treatment at all time points (88.2-58.2%). Median OS was 9.5 months (95% CI, 8.8-10.7 months) for all patients, 8.1 months (95% CI, 7.4-8.9 months) with chemotherapy, 14.0 months (95% CI, 10.7-20.6 months) with IO monotherapy, and 20.2 months (95% CI, 16.0-30.5 months) with targeted therapy. In the 28.6% of patients who received second-line treatment, IO monotherapy was the most common drug class (used in 51.6%). CONCLUSIONS: Although use of 1 L IO monotherapy for aNSCLC increased in the United Kingdom during the study period, most patients received 1 L chemotherapy. An OS benefit for first-line IO monotherapy vs chemotherapy was observed but was numerically smaller than that reported in clinical trials. Targeted therapy was associated with the longest OS, highlighting the need for improved treatment options for tumors lacking targetable mutations.

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).

A randomised Phase II trial of carboplatin and gemcitabine ± vandetanib in first-line treatment of patients with advanced urothelial cell cancer not suitable to receive cisplatin.

OBJECTIVES: To assess the efficacy and tolerability of the dual epidermal growth factor receptor/vascular endothelial growth factor receptor inhibitor, vandetanib, in combination with carboplatin and gemcitabine in the first-line treatment of patients with advanced transitional cell carcinoma urothelial cancer (UC) who were unsuitable for cisplatin. PATIENTS AND METHODS: From 2011 to 2014, 82 patients were randomised from 16 hospitals across the UK into the TOUCAN double-blind, placebo-controlled randomised Phase II trial, receiving six 21-day cycles of intravenous carboplatin (target area under the concentration versus time curve 4.5, day 1) and gemcitabine (1000 mg/m2 days 1 and 8) combined with either oral vandetanib 100 mg or placebo (once daily). Progression-free survival (PFS; primary endpoint), adverse events, tolerability and feasibility of use, objective response rate and overall survival (OS) were evaluated. Intention-to-treat and per-protocol analyses were used to analyse the primary endpoint. RESULTS: The 82 patients were randomised 1:1 to vandetanib (n = 40) or placebo (n = 42), and 25 patients (30%) completed six cycles of all allocated treatment. Toxicity Grade ≥3 was experienced in 80% (n = 32) and 76% (n = 32) of patients in the vandetanib and placebo arms, respectively. The median PFS was 6.8 and 8.8 months for the vandetanib and placebo arms, respectively (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.65-1.76; P = 0.71); the median OS was 10.8 vs 13.8 months (HR 1.41, 95% CI 0.79-2.52; P = 0.88); and radiological response rates were 50% and 55%. CONCLUSION: There is no evidence that vandetanib improves clinical outcome in this setting. Our present data do not support its adoption as the regimen of choice for first-line treatment in patients with UC who were unfit for cisplatin.

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.

BACKGROUND: Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy. METHODS: We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476. FINDINGS: Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63-73) and median amount of prostate-specific antigen of 97 ng/mL (33-315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68-0·84; p<0·0001) but not overall survival (0·92, 0·80-1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3-4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy). INTERPRETATION: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.

Performance status agreement assessed by the patient and clinician in a rapid access lung cancer service: Can either predict completion of treatment?

INTRODUCTION: Clinician-rated performance status (C-PS) is used routinely to predict whether patients are fit enough to undergo treatment for lung cancer. However, a good proportion of those with seemingly good C-PS do not go on to receive, let alone complete treatment. The value of C-PS in accurately predicting this is unclear, as is the merit of evaluating patient-rated PS (P-PS). OBJECTIVES: Our aim was to prospectively assess Eastern Cooperative Oncology Group (ECOG) and Karnofsky C-PS and P-PS in patients attending a rapid access lung cancer service (RALCS), the agreement between these scores, and whether any score could predict receipt and completion of multidisciplinary team (MDT)-planned treatment. RESULTS: ECOG and Karnofsky scores were highly correlated (Spearman's rho -0.79 for C-PS and -0.828 for P-PS, both p < 0.001). There was poor agreement between C-PS and P-PS scores (kappa statistics 0.275 for ECOG and 0.172 for Karnofsky); however, clinicians did not tend to consistently under- or overestimate patients' scores. ECOG P-PS showed an association with completion of MDT-planned treatment (p = 0.007), but C-PS did not. CONCLUSION: Clinician-rated PS was not associated with completion of MDT-planned treatment, but there may be a role for patient-rated PS. C-PS and P-PS were poorly correlated in a RALCS.

Effect of Single-Fraction vs Multifraction Radiotherapy on Ambulatory Status Among Patients With Spinal Canal Compression From Metastatic Cancer: The SCORAD Randomized Clinical Trial.

Importance: Malignant spinal canal compression, a major complication of metastatic cancer, is managed with radiotherapy to maintain mobility and relieve pain, although there is no standard radiotherapy regimen. Objective: To evaluate whether single-fraction radiotherapy is noninferior to 5 fractions of radiotherapy. Design, Setting, and Participants: Multicenter noninferiority randomized clinical trial conducted in 42 UK and 5 Australian radiotherapy centers. Eligible patients (n = 686) had metastatic cancer with spinal cord or cauda equina compression, life expectancy greater than 8 weeks, and no previous radiotherapy to the same area. Patients were recruited between February 2008 and April 2016, with final follow-up in September 2017. Interventions: Patients were randomized to receive external beam single-fraction 8-Gy radiotherapy (n = 345) or 20 Gy of radiotherapy in 5 fractions over 5 consecutive days (n = 341). Main Outcomes and Measures: The primary end point was ambulatory status at week 8, based on a 4-point scale and classified as grade 1 (ambulatory without the use of aids and grade 5 of 5 muscle power) or grade 2 (ambulatory using aids or grade 4 of 5 muscle power). The noninferiority margin for the difference in ambulatory status was -11%. Secondary end points included ambulatory status at weeks 1, 4, and 12 and overall survival. Results: Among 686 randomized patients (median [interquartile range] age, 70 [64-77] years; 503 (73%) men; 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer), 342 (49.8%) were analyzed for the primary end point (255 patients died before the 8-week assessment). Ambulatory status grade 1 or 2 at week 8 was achieved by 115 of 166 (69.3%) patients in the single-fraction group vs 128 of 176 (72.7%) in the multifraction group (difference, -3.5% [1-sided 95% CI, -11.5% to ∞]; P value for noninferiority = .06). The difference in ambulatory status grade 1 or 2 in the single-fraction vs multifraction group was -0.4% (63.9% vs 64.3%; [1-sided 95% CI, -6.9 to ∞]; P value for noninferiority = .004) at week 1, -0.7% (66.8% vs 67.6%; [1-sided 95% CI, -8.1 to ∞]; P value for noninferiority = .01) at week 4, and 4.1% (71.8% vs 67.7%; [1-sided 95% CI, -4.6 to ∞]; P value for noninferiority = .002) at week 12. Overall survival rates at 12 weeks were 50% in the single-fraction group vs 55% in the multifraction group (stratified hazard ratio, 1.02 [95% CI, 0.74-1.41]). Of the 11 other secondary end points that were analyzed, the between-group differences were not statistically significant or did not meet noninferiority criterion. Conclusions and Relevance: Among patients with malignant metastatic solid tumors and spinal canal compression, a single radiotherapy dose, compared with a multifraction dose delivered over 5 days, did not meet the criterion for noninferiority for the primary outcome (ambulatory at 8 weeks). However, the extent to which the lower bound of the CI overlapped with the noninferiority margin should be considered when interpreting the clinical importance of this finding. Trial Registration: ISRCTN Identifiers: ISRCTN97555949 and ISRCTN97108008.

The value of physical performance measurements alongside assessment of sarcopenia in predicting receipt and completion of planned treatment in non-small cell lung cancer: an observational exploratory study.

INTRODUCTION: The presence of muscle mass depletion is associated with poor outcomes and survival in cancer. Alongside muscle mass, assessment of muscle strength or physical performance is essential for the diagnosis of sarcopenia. Non-small cell lung cancer (NSCLC) is a prevalent form of cancer with high mortality, and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is commonly used to assess patients' suitability for treatment. However, a significant proportion of patients with good PS are unable to complete multidisciplinary team (MDT)-planned treatment. Little is known about the ability of objective measurements of physical performance in predicting patients' ability to complete MDT-planned treatment and outcomes in NSCLC. OBJECTIVES: We sought to establish whether physical performance, utilising the short physical performance battery (SPPB), alongside muscle mass measurements, was able to predict receipt and completion of MDT-planned treatment, with a focus on chemotherapy in NSCLC. MATERIALS AND METHODS: Participants with NSCLC treated through a single lung cancer MDT and ECOG PS 0-2 were recruited and the following assessed: body composition [bioelectrical impedance (BIA) and whole body dual-energy X-ray absorptiometry (DXA) in a subset], physical performance (SPPB), PS and nutritional status. We recorded receipt and completion of chemotherapy, as well as any adverse effects, hospitalisations, and treatment delays. RESULTS: We included a total of 62 participants with NSCLC, and in 26 of these, the MDT-planned treatment was chemotherapy. Participants with earlier stage disease and weight loss of <10% were more likely to complete MDT-planned treatment (p < 0.001 and p < 0.05). Patients with a higher total SPPB score were more likely to complete more cycles of chemotherapy as well as the full course. Quicker gait speeds and sit-to-stand times were associated with completion of three or more cycles of chemotherapy (all p < 0.05). For every unit increase in SPPB score, there was a 28.2% decrease in adverse events, hospitalisations and delays of chemotherapy (incidence rate ratio 0.718, p = 0.001), whilst ECOG PS showed no correlation with these outcomes. CONCLUSION: Assessing physical performance by SPPB is quick and simple to do in clinical settings and may give better indication of likely chemotherapy treatment course completion than muscle mass alone and ECOG PS. In turn, this may identify specific targets for early functional intervention and impact on MDT decision-making and prudent use of resources.

Tracking genomic cancer evolution for precision medicine: the lung TRACERx study.

The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types.

Association of sarcopenia and observed physical performance with attainment of multidisciplinary team planned treatment in non-small cell lung cancer: an observational study protocol.

BACKGROUND: Non-small cell lung cancer (NSCLC) frequently presents in advanced stages. A significant proportion of those with reportedly good ECOG performance status (PS) fail to receive planned multidisciplinary team (MDT) treatment, often for functional reasons, but an objective decline in physical performance is not well described. Sarcopenia, or loss of muscle mass, is an integral part of cancer cachexia. However, changes in both muscle mass and physical performance may predate clinically overt cachexia, and may be present even with normal body mass index. Physical fitness for treatment is currently subjectively assessed by means of the PS score, which may be inadequate in predicting tolerance to treatment. This study aims to evaluate whether measuring physical performance and muscle mass at baseline in NSCLC patients, in addition to PS score, is able to predict commencement and successful completion of MDT-planned treatment. METHODS/DESIGN: This is a prospective, single-centre exploratory study of NSCLC patients attending a Rapid Access Lung Cancer clinic. Baseline data collected are (methods in brackets): physical performance (Short Physical Performance Battery), muscle mass (bioelectrical impedance ± dual energy x-ray absorptiometry), patient and physician-assessed PS (ECOG and Karnofsky), nutritional status and presence of cachexia. Longitudinal data consists of receipt and completion of MDT treatment plan. The primary outcome measure is commencement of MDT-planned treatment, and important secondary outcomes include successful completion of treatment, length of stay in surgical patients, and risk of chemotherapy- and radiotherapy-related side effects. DISCUSSION: A more comprehensive assessment of phenotype, particularly with regards to physical performance and muscle mass, will provide additional discriminatory information of patients' fitness for treatment. If positive, this study has the potential to identify targets for early intervention in those who are at risk of deterioration. This will subsequently enable optimisation of performance of patients with NSCLC, in anticipation of systemic treatment.

Palliative radiotherapy regimens for patients with thoracic symptoms from non-small cell lung cancer.

BACKGROUND: Palliative radiotherapy to the chest is often used in patients with lung cancer, but radiotherapy regimens are more often based on tradition than research results. This is an update of a Cochrane review first published in 2001 and previously updated in 2006. OBJECTIVES: The two objectives of this review were:1. To assess the effects of different palliative radiotherapy regimens on improving thoracic symptoms in patients with locally advanced or metastatic non-small cell lung cancer who are not suitable for radical RT given with curative intent.2. To assess the effects of radiotherapy dose on overall survival in patients with locally advanced or metastatic non-small cell lung cancer who are not suitable for radical RT given with curative intent. SEARCH METHODS: The electronic databases MEDLINE (1966 - Jan 2014), EMBASE and the Cochrane Central Register of Controlled Trials, reference lists, handsearching of journals and conference proceedings, and discussion with experts were used to identify potentially eligible trials, published and unpublished.Two authors (FM and RS) independently identified all studies that may be suitable for inclusion in the review.We updated the search up to January 2014. SELECTION CRITERIA: Randomised controlled clinical trials comparing different regimens of palliative thoracic radiotherapy in patients with non-small cell lung cancer. DATA COLLECTION AND ANALYSIS: The reviewers assessed search results independently and possible studies were highlighted and the full text obtained. Data were extracted and attempts were made to contact the original authors for missing information.The primary outcome measure was improvement in major thoracic symptoms (degree and duration). Secondary outcome measures were short and long term toxicities, effect on quality of life and overall survival.Patient reported outcomes were reported descriptively. Quantitative data such as survival and toxicity were analysed as dichotomous variables and reported using relative risks (RR).For this update of the review a meta-analysis of the survival data was carried out. MAIN RESULTS: Fourteen randomised controlled trials (3576 patients) were included, with no new studies added in this update.There were important differences in the doses of radiotherapy investigated, the patient characteristics including disease stage and performance status and the outcome measures.The doses of RT investigated ranged from 10 Gy in 1 fraction (10Gy/1F) to 60 Gy/30F over six weeks, with a total of 19 different dose/ fractionation regimens.Potential biases were identified in some studies. Methods of randomisation, assessment of symptoms and statistical methods used were unclear in some papers. Withdrawal and drop-outs were accounted for in all but one study.All 13 studies that investigated symptoms reported that major thoracic symptoms improved following RT.There is no strong evidence that any regimen gives greater palliation. Higher dose regimens may give more acute toxicity and some regimens are associated with an increased risk of radiation myelitis. Variation in reporting of toxicities, in particular the absence of clear grading, means results of the meta-analysis should be treated with caution.Meta-analysis of overall survival broken down by performance status, a key variable, is included in this update. Further information was sought from all the original authors if stratified data was not included in the original publication. Three published studies contained sufficient data and seven authors were able to provide further information which represented 1992 patients (56% of all patients). The absence of data for nearly half of the patients has affected the quality of evidence.The meta-analysis showed no significant difference in 1-year overall survival between regimens with fewer radiotherapy fractions compared with regimens with more when patients were stratified by performance status. The results of the meta-analysis of 1-year overall survival for patients with good performance status (WHO performance status 0-1) showed moderately high heterogeneity and a summary result was not thought meaningful. The results of 1-year overall survival for patients with poor performance status was RR 0.96 (95% CI 0.91 to 1.02; moderate quality of evidence). AUTHORS' CONCLUSIONS: Radiotherapy for patients with incurable non-small cell lung cancer can improve thoracic symptoms. Care should be taken with the dose to the spinal cord to reduce the risk of radiation myelopathy. The higher dose, more fractionated palliative radiotherapy regimens do not provide better or more durable palliation and their use to prolong survival is not supported by strong evidence. More research is needed into reducing the acute toxicity of large fraction regimens and into the role of radical compared to high dose palliative radiotherapy. In the future, large trials comparing different RT regimens may be difficult to set up because of the increasing use of systemic chemotherapy. Trials looking at how best to integrate these two modalities, particularly in good PS patients, need to be carried out.

Olaparib maintenance versus placebo monotherapy in patients with advanced non-small cell lung cancer (PIN): A multicentre, randomised, controlled, phase 2 trial.

Background: Impaired double strand DNA repair by homologous repair deficiency (HRD) leads to sensitivity to poly ADP ribose polymerase (PARP) inhibition. Poly-ADP ribose polymerase (PARP) inhibitors target HRD to induce synthetic lethality and are used routinely in the treatment of BRCA1 mutated ovarian cancer in the platinum-sensitive maintenance setting. A subset of non-small cell lung cancers (NSCLCs) harbour impaired DNA double strand break repair. We therefore hypothesised that patients with metastatic non-small cell lung cancer exhibiting partial responses to platinum doublet-based chemotherapy, might enrich for impaired HRD, rendering these tumours more sensitive to inhibition of PARP inhibition by olaparib. Methods: The Olaparib Maintenance versus Placebo Monotherapy in Patients with Advanced Non-Small Cell Lung Cancer trial (PIN) was a multicentre double-blind placebo controlled randomised phase II screening trial. This study was conducted at 23 investigative hospital sites in the UK. Patients had advanced (stage IIIB/IV) squamous (Sq) or non-squamous (NSq) NSCLC, and had to be chemo-naive, European Cooperative Oncology Group (ECOG) performance status 0-1. Prior immunotherapy with a PD1 or PDL1 inhibitor was allowed. Patients could be registered for PIN prior to (stage 1), or after (stage 2) initiation of induction chemotherapy. If any tumour shrinkage was observed (any shrinkage of RECIST target lesions), following a minimum of 3 cycles of platinum doublet chemotherapy, patients were randomised 1:1 using a centralised online system, to either olaparib (300 mg twice daily by mouth in 21-day cycles) or placebo, which was continued until disease progression, or unacceptable toxicity. Intention to treat (ITT) analyses of the primary endpoint included all randomised participants. Per protocol (PP) safety analysis included all participants who received at least one dose of study drug. Primary endpoint was progression-free survival (PFS), with a one-sided p-value of 0.2 to demonstrate statistical significance. Hazard ratios (HR) for PFS were both unadjusted and adjusted for the randomisation balancing factors (smoking status and histology). The trial was registered with ClinicalTrials.gov (NCT01788332) and EudraCT (2012-003383-51). Findings: A total of 940 patients were assessed for stage 1 eligibility of whom 263 were registered between Feb 24, 2014 and Nov 7, 2017. 194 patients were excluded prior to stage 2 (no tumour shrinkage or unevaluable) and 70 were randomised; 32 (46%) to Olaparib and 38 (54%) to placebo. 4% (3/70) of patients randomised had a CR and 96% (67/70) had a PR (or other evidence of tumour response/mixed stable) during induction therapy. A total of 36 patients were registered in stage 2 only, i.e., post induction therapy. Intention to treat (ITT) unadjusted analysis showed a PFS hazard ratio (HR) of 0.83 (one-sided 80% CI upper limit 1.03, one-sided unadjusted log rank test p-value=0.23). ITT Cox-adjusted model showed a HR 0.73 (one-sided 80% CI upper limit 0.91, one sided p-value 0.11). Adverse events were reported in 31/32 subjects (97%) in the olaparib arm and 38/38 (100%) in the placebo group. The most commonly reported adverse events in the olaparib group were fatigue (20/31; 65%), nausea (17/31; 55%), anaemia (15/31; 48%) and dyspnea (13/31; 42%). In the placebo group the most common adverse events were fatigue (25/38; 66%), coughing (22/38; 58%), dyspnea (15/38; 39%) and nausea (11/38; 29%). There were no treatment-related deaths. Interpretation: PFS was longer in the olaparib arm, but this did not reach statistical significance. When the PFS HR was adjusted for smoking status and histology, a significant difference at the one-sided 0.2 level was observed, suggesting that tumour control may be achieved for chemosensitive NSCLC treated with PARP monotherapy. We speculate that this signal may be driven by a molecular subgroup harbouring HRD. Funding: This study was funded between AstraZeneca CRUK, National Cancer Research Institute, and Cancer Research UK Feasibility Study Committee.

Prognostic factors for survival and ambulatory status at 8 weeks with metastatic spinal cord compression in the SCORAD randomised trial.

BACKGROUND: Metastatic spinal cord compression (MSCC) carries a poor prognosis and management is based on the likelihood of maintaining mobility and predicted survival. PATIENTS AND METHOD: SCORAD is a randomised trial of 686 patients comparing a single dose of 8 Gy radiotherapy with 20 Gy in 5 fractions. Data was split into a training set (412, 60%) and a validation set (274, 40%). A multivariable Cox regression for overall survival (OS) and a logistic regression for ambulatory status at 8 weeks were performed in the training set using baseline factors and a backward selection regression to identify a parsimonious model with p ≤ 0.10. Receiver Operating Characteristic (ROC) analysis evaluated model prognostic performance in the validation set. Validation of the final survival model was performed in a separate registry dataset (n = 348). RESULTS: The survival Cox model identified male gender, lung, gastrointestinal, and other types of cancer, compression at C1-T12, presence of non-skeletal metastases and poor ambulatory status all significantly associated with worse OS (all p < 0.05). The ROC AUC for the selected model was 75% (95%CI: 69-81) in the SCORAD validation set and 68% (95%CI: 62-74) in the external validation registry data. The logistic model for ambulatory outcome identified primary tumour breast or prostate, ambulatory status grade 1 or 2, bladder function normal and prior chemotherapy all significantly associated with increased odds of ambulation at 8 weeks (all p < 0.05). The ROC AUC for the selected model was 72.3% (95% CI 62.6-82.0) in the validation set. CONCLUSIONS: Primary breast or prostate cancer, and good ambulatory status at presentation, are favourable prognostic factors for both survival and ambulation after treatment.

Active symptom control with or without oral vinorelbine in patients with relapsed malignant pleural mesothelioma (VIM): A randomised, phase 2 trial.

Background: Currently, there is no US Food and Drug Administration approved therapy for patients with pleural mesothelioma who have relapsed following platinum-doublet based chemotherapy. Vinorelbine has demonstrated useful clinical activity in mesothelioma, however its efficacy has not been formally evaluated in a randomised setting. BRCA1 expression is required for vinorelbine induced apoptosis in preclinical models. Loss of expression may therefore correlate with vinorelbine resistance. Methods: In this randomised, phase 2 trial, patients were eligible if they met the following criteria: age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, histologically confirmed pleural mesothelioma, post platinum-based chemotherapy, and radiological evidence of disease progression. Consented patients were randomised 2:1 to either active symptom control with oral vinorelbine versus active symptom control (ASC) every 3 weeks until disease progression, unacceptable toxicity or withdrawal at an initial dose of 60 mg/m2 increasing to 80 mg/m2 post-cycle 1. Randomisation was stratified by histological subtype, white cell count, gender, ECOG performance status and best response during first-line therapy. The study was open label. The primary endpoint was progression-free survival (PFS), measured from randomisation to time of event (or censoring). Analyses were carried out according to intention-to-treat (ITT) principles. Recruitment and trial follow-up are complete. This trial is registered with ClinicalTrials.gov, number NCT02139904. Findings: Between June 1, 2016 and Oct 31, 2018, we performed a randomised phase 2 trial in 14 hospitals in the United Kingdom. 225 patients were screened for eligibility, of whom 154 were randomly assigned to receive either ASC + vinorelbine (n = 98) or ASC (n = 56). PFS was significantly longer for ASC+vinorelbine compared with ASC alone; 4.2 months (interquartile range (IQR) 2.2-8.0) versus 2.8 months (IQR 1.4-4.1) for ASC, giving an unadjusted hazard ratio (HR) of 0·60 (80% CI upper limit 0.7, one-sided unadjusted log rank test p = 0.002); adjusted HR 0.6 (80% CI upper limit 0.7, one-sided adjusted log rank test p < 0.001). BRCA1 did not predict resistance to ASC+vinorelbine. Neutropenia was the most common grades 3, 4 adverse events in the ASC +vinorelbine arm. Interpretation: Vinorelbine plus ASC confers clinical benefit to patients with relapsed pleural mesothelioma who have progressed following platinum-based doublet chemotherapy. Funding: This study was funded by Cancer Research UK (grant CRUK A15569).

Cost-utility analysis of adding abiraterone acetate plus prednisone/prednisolone to long-term hormone therapy in newly diagnosed advanced prostate cancer in England: Lifetime decision model based on STAMPEDE trial data.

Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011-2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE's £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP's indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup.

Tyrosine Kinase Inhibitors for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer: A Clash of the Generations.

The availability of 3 generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with different pharmacologic characteristics and clinical profiles has provided oncologists with a potentially confusing choice for the treatment of EGFR mutation-positive non-small-cell lung cancer. Although recent head-to-head clinical trials have demonstrated improved efficacy with second-generation (ie, afatinib, dacomitinib) and third-generation (ie, osimertinib) TKIs compared with the first-generation TKIs (eg, erlotinib, gefitinib), acquired resistance has been inevitable, regardless of which agent has been chosen as first-line therapy. Thus, the potential availability of subsequent treatment options is an important consideration. Recent data have demonstrated that osimertinib confers an overall survival benefit compared with first-generation EGFR TKIs, and dacomitinib has shown an overall survival benefit compared with gefitinib in an exploratory analysis. However, the relative benefits of different sequential EGFR-TKI regimens, especially those involving second- and third-generation agents, have remained uncertain and require prospective evaluation. Few such data currently exist to inform treatment choices. In the present review, we examined the pharmacologic characteristics and current clinical data for EGFR TKIs, including emerging information on the molecular mechanisms of resistance across the different generations of TKIs. Given the uncertainties regarding the optimal treatment choice, we have focused on the factors that might help determine the treatment decisions, such as efficacy and safety in patient subgroups. We also discussed the emerging real-world data, which have provided some insights into the benefits of sequential regimens in everyday clinical practice.

Chemotherapy decision-making in advanced lung cancer: a prospective qualitative study.

OBJECTIVE: To study how treatment decisions are made alongside the lung cancer clinical pathway. METHODS: A prospective, multicentre, multimethods, five-stage, qualitative study. Mediated discourse, thematic, framework and narrative analysis were used to analyse the transcripts. RESULTS: 51 health professionals, 15 patients with advanced lung cancer, 15 family members and 18 expert stakeholders were recruited from three UK NHS trusts. Multidisciplinary team (MDT) members constructed treatment recommendations around patient performance status, pathology, clinical information and imaging. Information around patients' social context, needs and preferences were limited. The provisional nature of MDTs treatment recommendations was not always linked to future discussions with the patient along the pathway, that is, patients' interpretation of their prognosis, treatment discussions occurring prior to seeing the oncologist. This together with the rapid disease trajectory placed additional stress on the oncologist, who had to introduce a different treatment option from that recommended by the MDT or patient's expectations. Palliative treatment was not referred to explicitly as such, due to its potential for confusion. Patients were unaware of the purpose of each consultation and did not fully understand the non-curative intent of treatment pathways. Patients' priorities were framed around social and family needs, such as being able to attend a family event. CONCLUSION: Missed opportunities for information giving, affect both clinicians and patients; the pathway for patients with non-small cell lung cancer focuses on clinical management at the expense of patient-centred care. Treatment decisions are a complex process and patients draw conclusions from healthcare interactions prior to the oncology clinic, which prioritises aggressive treatment and influences decisions.

Assessment of contour variability in target volumes and organs at risk in lung cancer radiotherapy.

AIMS: This study aimed to examine whether any significant differences existed in trial protocol compliance in target volumes (TV) and organs at risk (OARs) contouring amongst clinical oncologists specialised in lung cancer radiotherapy. MATERIALS/METHODS: Two lung radiotherapy trials that require all prospective investigators to submit pre-trial outlining quality assurance (QA) benchmark cases were selected. The contours from the benchmark cases were compared against a set of reference contours which were defined by the trial management group (TMG). In order to quantify the degree of variation in TV and OARs contouring, the matching index (MI), Dice coefficient (DICE), Jaccard index (JI), Van't Riet Index and geographical miss index (GMI) were calculated. RESULTS: A total of 198 structures contoured by 21 clinicians were collected from the outlining benchmark cases. There were 40 clinical target volumes (CTV), 32 spinal cord, 36 oesophagus, 36 heart and 54 lungs volumes included in the study. Analysis of the pre-trial benchmark cases revealed statistically significant differences (p ≤ 0.05) in trial protocol compliances between clinical oncologists' target volume and organs at risk contours. Our results demonstrated that the lung contours had the highest level of conformity, followed by heart, CTV, spinal cord and oesophagus respectively. CONCLUSIONS: This study showed that there was a statistically significant difference in trial protocol compliance for lung clinical oncologists' TV and OARs contouring within the pre-trial QA benchmark cases. Trial protocol compliances of TV and OARs delineation can be identified through assessing outlining QA benchmark cases.