Publisher Correction: The National Lung Matrix Trial of personalized therapy in lung cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The National Lung Matrix Trial of personalized therapy in lung cancer.

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.

The clinical role of VeriStrat testing in patients with advanced non-small cell lung cancer considered unfit for first-line platinum-based chemotherapy.

PURPOSE: We previously demonstrated that the median survival of patients with poor prognosis non-small cell lung cancer (NSCLC) considered unfit for first-line platinum chemotherapy was <4 months. We evaluated whether VeriStrat could be used as a prognostic or predictive biomarker in this population. EXPERIMENTAL DESIGN: We conducted a randomised double-blind trial among patients with untreated advanced NSCLC considered unfit for platinum chemotherapy because of poor performance status (PS) or multiple comorbidities. All patients received active supportive care (ASC) and were treated with either oral erlotinib or placebo daily. Five hundred twenty-seven patients had plasma samples for VeriStrat classification: good (VeriStrat Good [VSG]) or poor (VeriStrat Poor [VSP]). Main end-point was overall survival. RESULTS: Fifty-five percent patients had VSG, and 83% had Eastern Cooperative Oncology Group (ECOG) 2-3 at baseline. VeriStrat was strongly associated with survival. Among patients managed with ASC only, the adjusted hazard ratio (HR) was 0.54 (p < 0.001) for VSG versus VSP. The association was consistent across patient factors: HR = 0.25 (p = 0.004) and HR = 0.56 (p < 0.001) for ECOG 0-1 and 2-3, respectively, HR = 0.49 (0070 < 0.001) for age≥75 years and HR = 0.59 (p = 0.007) for stage IV. Several ECOG 2-3 patients had long survival: 2-year survival was 8% for VSG patients who had ASC, compared with 0% for VSP. VeriStrat status did not predict benefit from erlotinib treatment because the HRs for erlotinib versus placebo were similar between VSG and VSP patients. CONCLUSIONS: VeriStrat was not a predictive marker for survival when considering first-line erlotinib for patients with NSCLC who had poor PS and were not recommended for platinum doublet therapies. However, VeriStrat was an independent prognostic marker of survival. It represents an objective measurement that could be considered alongside other patient factors to provide a more refined assessment of prognosis for this particular patient group. VSG patients could be selected for treatment trials because of better survival, while VSP patients can continue to be treated conservatively or offered trials of less toxic agents. TRIAL REGISTRATION ISRCTN NUMBER: ISRCTN02370070.

Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial.

BACKGROUND: The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. METHODS: We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. FINDINGS: Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19-1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. INTERPRETATION: Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. FUNDING: Research for Patient Benefit Programme from the UK National Institute for Health Research.

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.

First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Many patients with advanced non-small-cell lung cancer (NSCLC) receive only active supportive care because of poor performance status or presence of several comorbidities. We investigated whether erlotinib improves clinical outcome in these patients. METHODS: TOPICAL was a double-blind, randomised, placebo-controlled, phase 3 trial, done at 78 centres in the UK. Eligibility criteria were newly diagnosed, pathologically confirmed NSCLC; stage IIIb or IV; chemotherapy naive; no symptomatic brain metastases; deemed unsuitable for chemotherapy because of poor (≥2) Eastern Cooperative Oncology Group performance status or presence of several comorbidities, or both; and estimated life expectancy of at least 8 weeks. Patients were randomly assigned (by phone call, in a 1:1 ratio, stratified by disease stage, performance status, smoking history, and centre, block size 10) to receive oral placebo or erlotinib (150 mg per day) until disease progression or unacceptable toxicity. Investigators, clinicians, and patients were masked to assignment. The primary endpoint was overall survival. Analyses were by intention to treat, and prespecified subgroup analyses included development of a rash due to erlotinib within 28 days of starting treatment. This study is registered, number ISRCTN 77383050. FINDINGS: Between April 14, 2005, and April 1, 2009, we randomly assigned 350 patients to receive erlotinib and 320 to receive placebo. We followed up patients until March 31, 2011. 657 patients died; median overall survival did not differ between groups (erlotinib, 3·7 months, 95% CI 3·2-4·2, vs placebo, 3·6 months, 3·2-3·9; unadjusted hazard ratio [HR] 0·94, 95% CI 0·81-1·10, p=0·46). 59% (178 of 302) of patients assigned erlotinib and who were assessable at 1 month developed first-cycle rash, which was the only independent factor associated with overall survival. Patients with first-cycle rash had better overall survival (HR 0·76, 95% CI 0·63-0·92, p=0·0058), compared with placebo. Compared with placebo, overall survival seemed to be worse in the group that did not develop first-cycle rash (1·30, 1·05-1·61, p=0·017). Grade 3 or 4 diarrhoea was more common with erlotinib than placebo (8% [28 of 334] vs 1% [four of 313], p=0·0001), as was high-grade rash (23% [79 of 334] vs 2% [five of 313], p<0·0001); other adverse events were much the same between groups. INTERPRETATION: Patients with NSCLC who are deemed unsuitable for chemotherapy could be given erlotinib. Patients who develop a first-cycle rash should continue to receive erlotinib, whereas those who do not have a rash after 28 days should discontinue erlotinib, because of the possibility of decreased survival. FUNDING: Cancer Research UK, Roche.

The decision to operate: role of integrated computed tomography positron emission tomography in staging oesophageal and oesophagogastric junction cancer by the multidisciplinary team.

OBJECTIVE: Our objective was to assess the role of fusion positron emission tomography-computed tomography (PET-CT) in staging patients for minimally invasive oesophagectomy (MIO) with potentially resectable disease from the perspective of a multidisciplinary team (MDT) deciding on operability with conventional staging investigations. METHODS: Fifty consecutive patients presenting with potentially operable oesophageal or oesophagogastric junctional tumours were staged with computed tomography (CT) and endoluminal ultrasound (EUS). The MDT categorised patients as group A (n=33; CT N0M0) or group B (n=17; CT N1/possible M1). All patients underwent FDG PET-CT. Patients with localised disease (at T3), including single level N1 disease on PET-CT, were deemed suitable for induction chemotherapy followed by surgery. RESULTS: PET-CT re-categorised 12% of patients as inoperable on grounds of distant metastases (four in group A, two in group B). Five patients did not proceed to resection for other reasons. Two had metastatic disease at thoracoscopy. Resection specimens (n=37) contained 24 nodes (median). Compared with pN status, positive predictive value of PET-CT was 40% and negative predictive value was 43%. The expected PET-CT N1 group had the highest mean number of involved nodes. Median survival for all patients (n=50) was 31.9 months for group A compared with 17.3 months for group B (not statistically significant). There was no significant difference between patients who were PET-CT N0 or N1 in survival or disease-free survival in patients undergoing surgery (n=37). CONCLUSIONS: PET-CT informs the MDT decision to operate in avoiding futile surgery in stage IV disease or widespread nodal disease. In this study, overall PET-CT N1 status has low positive and negative predictive value for overall pN status.

The clinical impact of expert pathological review on lymphoma management: a regional experience.

The All Wales Lymphoma Panel (AWLP) was established in January 1998 to provide a central expert pathological review service for district general hospital pathologists. A discordance rate of 20% between the submitted and reviewed diagnosis has previously been identified. It has not been known whether this change in diagnosis affects clinical management. Ninety-nine patients whose diagnosis was changed as a result of central pathological review are presented. Between January 1998 and August 2000, 125 of 745 (17%) specimens submitted for AWLP review had a consequent change in pathological diagnosis. Of these 125 specimens, 99 (79%) complete case notes were recovered. In all 99 cases, a hypothetical management plan was generated using collected data, clinical protocols and the submitted pathological diagnosis. These plans were compared with the actual management patients received based on the reviewed diagnosis proffered by the AWLP. Forty-six of 99 (46%) cases had a change in management as a result of central pathological review. Overall, management was changed in 8% of cases referred for central pathological review. In conclusion, expert central pathological review has a direct effect on patient management.

Palliative thoracic radiotherapy for non-small-cell lung cancer: a systematic review.

Non-small-cell lung cancer is one of the most common malignant tumors worldwide. The majority of patients are not treatable with curative intent because of the extent of disease or patient comorbidity. Radiotherapy to the primary intrathoracic tumor is used with the aim of palliating troublesome local symptoms in approximately 25% of patients. The dose/fractionation regimens used evolved empirically, and surveys have shown widespread variation. It has not yet been clearly established which regimens give the most benefit and least toxicity. This systematic review identified 12 randomized controlled trials comparing palliative external beam radiotherapy regimens. Narrative synthesis has been performed. Palliative radiotherapy is effective in controlling symptoms. There is no strong evidence that better palliation is obtained with higher radiation doses but good evidence that toxicity is greater. There is evidence of a modest survival benefit with higher dose schedules in patients with good performance status. The majority of patients should receive short courses (one or two fractions) of hypofractionated radiotherapy, Selected patients with good performance status should be considered for higher dose regimens if the chance of modest improvement in survival and palliation is considered worth the additional inconvenience and toxicity.

Short-course preoperative radiation therapy for operable rectal cancer.

BACKGROUND: Short course neoadjuvant radiation has been shown to provide improved local control of rectal cancer in a clinical trial population even in the presence of standardized surgical techniques. However, this use of hypofractionated radiotherapy has been limited in North America owing to concerns over toxicity. METHODS: Patients considered to have locally advanced rectal carcinoma received a radiation dose of 25 Gy given in five fractions to the posterior pelvis. Definitive surgery was then performed within 2 weeks. Retrospective analysis was performed. RESULTS: Sixty-three patients, of whom 60 were assessable, were treated with preoperative short course radiotherapy at the British Columbia Cancer Agency between 1991 and 1998, and 97% proceeded to R0 resection. Local recurrence developed in 3 patients (5%). Five-year actuarial overall and relapse-free survival rates for the group were 71% and 69%, respectively. The actuarial rates of relapse-free survival by stage at 5 years were stage 1 83%, stage II 75%, stage III 62%, and stage 4 0%. Eleven patients (18%) experienced a postoperative complication. CONCLUSION: Short course preoperative radiotherapy for operable rectal cancer can be delivered to a general population and produce high pelvic control rates with acceptable toxicity.