Rajesh Shah

Tracking the Evolution of Non–Small-Cell Lung Cancer

BACKGROUND Among patients with non‐small‐cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early‐stage NSCLC. METHODS In this prospective cohort study, we performed multiregion whole‐exome sequencing on 100 early‐stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence‐free survival. RESULTS We observed widespread intratumor heterogeneity for both somatic copy‐number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy‐number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy‐number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10‐4), which remained significant in multivariate analysis. CONCLUSIONS Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601.)

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

TRACERx, a prospective study of patients with primary non-small cell lung cancer, aims to map the genomic landscape of lung cancer by tracking clonal heterogeneity and tumour evolution from diagnosis to relapse.

Are We Achieving the Current Waiting Time Targets in Lung Cancer Treatment? Result of a Prospective Study from a Large United Kingdom Teaching Hospital

Background: Recent United Kingdom National Cancer Plan guidelines have specified a number of waiting time targets to prevent delays in the treatment of lung cancer. This study was performed to compare our waiting times with national recommendations. Methods: All newly diagnosed cases of lung cancer presenting to our institution were entered into a prospective tracking study by a dedicated audit officer. From September 2003 to December 2005, a total of 342 patients were entered into the study. Of these, 193 (56%) were referred by general practitioners; the remaining 114 (46%) were internal referrals. The Cancer Plan waiting time targets are mainly applicable to general practitioners referrals, which formed the study group. Results: All the patients were seen in chest outpatient clinics within the recommended 2-week period. However, there was a delay in starting all forms of treatment. The median waiting time to any form of treatment was 60 days (recommendation, 62 days for all patients). From specialist referrals, the median waiting times for radiotherapy, surgery, and chemotherapy were 43, 25, and 16.5 days compared with recommended maximums of 28, 28, and 7 days, respectively. Conclusion: These data demonstrate that although patients receive outpatient consultation in the recommended time period, the National Cancer Plan treatment target of 62 days for patients referred by general practitioners is not being achieved. A concerted effort by all clinicians is required to meet the prescribed target times.

A phase II feasibility study of carboplatin followed by sequential weekly paclitaxel and gemcitabine as first-line treatment for ovarian cancer

A total of 53 women with chemotherapy-naïve stage Ic-IV ovarian cancer were treated with four cycles of carboplatin area under the curve 7 every 3 weeks, followed by four cycles of paclitaxel 70 mg m−2 (days 1, 8, and 15) and gemcitabine 1000 mg m−2 (days 1 and 8) every 3 weeks. In all, 37 (70%) had stage III/IV disease, with 22 (42%) having tumour >2 cm; 38 patients (72%) completed all planned treatment; 27 of the 32 (84%) patients with radiologically evaluable disease had partial or complete responses; and 30 of the 39 patients (77%) with elevated cancer antigen (CA) 125 had a greater than 75% fall in this value. At a median follow-up of 28 months, 31 patients had relapsed with a median progression-free survival of 19.5 months. In total, 79% of patients were alive at 2 years. Common Toxicity Criteria grade 3/4 haematological toxicity, predominantly neutropenia, was seen in 57% of the patients. A certain degree of pulmonary toxicity was observed; eight patients had symptomatic breathlessness, ± decreased diffusing capacity of the lung for carbon monoxide, and interstitial chest X-ray changes during the weekly phase. In all cases, this toxicity was reversible. No significant neurotoxicity was seen. This regimen is generally well tolerated with encouraging efficacy. However, the observation of pulmonary toxicity, potentially a feature of the weekly taxane–gemcitabine regimen, was of some concern. Alternative schedules, including 3-weekly taxanes, are currently being evaluated.

Prognostic and predictive biomarkers in early stage NSCLC: CTCs and serum/plasma markers

Resection of early stage non-small cell lung cancer (NSCLC) offers patients the best hope of cure, however recurrence rates post-resection remain high suggesting the presence of micro-metastatic disease at the time of surgery undetected by standard staging methods. A critical step in the metastatic cascade is the entry of tumor cells into the circulation enabling their distribution to and seeding of distant organs. This review explores the evidence for predictive and prognostic circulating biomarkers in the early stage NSCLC population. We summarize studies that have explored a variety of targets including circulating proteins, nucleic acids and more recently circulating tumor cells (CTCs) as potentially clinically relevant biomarkers in the early stage setting. Circulating biomarkers may add clinically relevant information about the biological behavior of tumors over and above that provided by pathological staging. Improvement in the stratification of patients according to the likelihood of metastatic relapse after radical treatments such as surgical resection could allow more effective targeting of systemic therapies such as adjuvant chemotherapy.

Is routine chest radiography indicated following chest drain removal after cardiothoracic surgery

A best evidence topic was written according to a structured protocol. The question addressed was whether routine chest radiography is indicated following chest drain removal in patients undergoing cardiothoracic surgery. A total of 356 papers were found using the reported searches; of which, 6 represented the best evidence to answer the clinical question. The authors, date, journal, study type, population, main outcome measures and results are tabulated. Reported measures were mean duration of drains left in situ, timing of drain removal, pathology detected on chest radiographs (CXRs), interventions following imaging and clinical assessment, complications in patients not undergoing routine CXRs and the cost saving of omitting routine CXRs. One large cohort study reported the detection of pathology in 79% of clinically indicated CXRs in comparison to 40% of routine CXRs (P = 0.005). Ninety-five per cent of the non-routine CXR cohort remained asymptomatic and required no intervention. One large observational study reported the detection of new pneumothoraces in 9.3% of patients, 70.3% of which were barely perceptible. Intervention following CXR was required in 0.25% and only one medium-sized pneumothorax would have been potentially missed without CXR. Another large observational study reported intervention following CXR in 1.9% and the presence of relevant clinical signs and symptoms to be a significant predictor of major intervention (P < 0.01). A smaller observational study reported no pathology detected or intervention following CXR in 98% and the cost saving of omitting a single CXR at £10 000 per annum. Another small observational study reported only 7% of CXRs to be clinically indicated with a false-positive rate of 100%, and a false-negative rate of 7% in CXRs not clinically indicated. The smallest study reported no complications in the non-CXR cohort and only one patient undergoing intervention in the routine CXR cohort. We conclude that there is evidence that routine post drain removal CXR provides no diagnostic or therapeutic advantage over clinically indicated CXR or simple clinical assessment. The best evidence studies reported the detection of pathology on routine CXR ranging from 2 to 40% compared with 79% in clinically indicated CXRs (P = 0.005). Whilst the rate of intervention following routine CXR was as high as 4% in the smallest study, clinical signs and symptoms suggestive of pathology were a significant predictor of major re-intervention (P < 0.01).

UK waiting time targets in lung cancer treatment: are they achievable? Results of a prospective tracking study

BackgroundRecent guidelines have specified a number of waiting time targets to prevent delay in the treatment of lung cancer. This study was carried out to assess the quality of lung cancer services and compare with national recommendations.MethodsAll newly diagnosed cases of lung cancer presenting to our institution via general practitioner referral were entered into a prospective tracking study by a dedicated audit officer. From September 2003 to March 2005 a total of 247 patients were entered into the study. Of these 133 (54%) were referred by general practitioners and the remainder 114 (46%) were internal referrals. The Cancer Plan waiting time targets are mainly applicable to GP referrals, which formed the study group.ResultsAll the patients were seen in chest out-patients clinic within the recommended two weeks period. However there was a delay in starting all forms of treatment. The median waiting time to any form of treatment was 60 days (recommendation 62 days for all patients).ConclusionThis data demonstrates that although patients receive out patient consultation in the recommended time period, the National Cancer Plan 62 days GP referral to treatment target is not being achieved. A concerted effort by all clinicians is required to meet the prescribed target times.

Circulating Tumor Cells Detected in the Tumor-Draining Pulmonary Vein Are Associated with Disease Recurrence after Surgical Resection of NSCLC

&NA; Tumor recurrence after surgical resection of NSCLC obstructs long‐term disease‐free survival in approximately 50% of cases. Our data suggest that combining circulating tumor cell enumeration (as single cells or clusters) in tumor‐draining pulmonary vein and peripheral blood (assessed by CellSearch) at the time of NSCLC surgery better identifies those patients at higher risk for lung cancer recurrence than does peripheral circulating tumor cell number alone.

Nodal staging in lung cancer: a risk stratification model for lymph nodes classified as negative by EBUS-TBNA.

Background: Over the last 10 years, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become established as the first-line nodal staging procedure of choice for lung cancer patients. However, the pathway for patients following a negative EBUS-TBNA has not been clearly defined. The primary aim of this study was to develop and validate a risk stratification model to categorize lymph nodes deemed negative by EBUS-TBNA into “low-risk” and “high-risk” groups, where “risk” refers to the risk of false negative sampling. Methods: A retrospective analysis of a prospectively maintained database at a UK tertiary EBUS-TBNA centre was performed. Only patients with primary lung cancer and only negative lymph nodes by EBUS-TBNA were included in the analysis. A risk stratification model was built from a derivation set using independent predictors of malignancy and the validation set used to evaluate the constructed model. The study period was from March 2010 to August 2013. Results: Three hundred twenty-nine lymph nodes were included in the analysis (derivation set n = 196, validation set n = 133). Lymph node standardized uptake value, the standardized uptake value ratio between the lymph node and primary tumor, and heterogeneous echogenicity during sonographic assessment were the only independent predictors of malignancy. Using a simplified scoring system based on the natural logs of the odds ratios from the multivariable analysis on the derivation sample, lymph nodes can be stratified into low risk (score ⩽1) and high risk (score ≥2). One hundred forty-one of 142 and 94 of 96 lymph nodes classified as low risk in the derivation and validation set, respectively, were ultimately proven to be benign and 35 of 54 and 24 of 37 lymph nodes classified as high risk were proven malignant. The negative predictive value of the risk stratification model for the derivation set and validation set was 99.3% (95% confidence interval 96.1%–99.6%) and 97.9% (95% confidence interval 92%–99.6%), respectively. Conclusion: This risk stratification model may assist lung cancer multidisciplinary teams in deciding which patients need further staging procedures and which may proceed directly to treatment after a negative EBUS.

Multiple synchronous primary tumours in a single lobe

We present the case of a 70-year-old man with three synchronous histologically different primary tumours in the same lobe. He initially presented with an intermittent productive cough, dyspnoea and non-specific abdominal pains. Radiological investigation revealed three areas of high-intensity fludeoxyglucose uptake of varying size within the right upper lobe. He underwent thoracoscopic right upper lobectomy. Histological analysis confirmed the three lesions to be undifferentiated squamous cell carcinoma, adenocarcinoma and atypical adenomatous hyperplasia. The reclassification of the T descriptors of the tumour-node-metastasis staging of a lung cancer has lead to the transition of classification of tumour nodules in the ipsilateral primary tumour lobe from T4 to T3. In the case of our patient, this has lead to the downstaging of the tumour allowing consideration for surgical management.