Paul Cane

British Thoracic Society guidelines for the investigation and management of pulmonary nodules: accredited by NICE

This guideline is based on a comprehensive review of the literature on pulmonary nodules and expert opinion. Although the management pathway for the majority of nodules detected is straightforward it is sometimes more complex and this is helped by the inclusion of detailed and specific recommendations and the 4 management algorithms below. The Guideline Development Group (GDG) wanted to highlight the new research evidence which has led to significant changes in management recommendations from previously published guidelines. These include the use of two malignancy prediction calculators (section ‘Initial assessment of the probability of malignancy in pulmonary nodules’, algorithm 1) to better characterise risk of malignancy. There are recommendations for a higher nodule size threshold for follow-up (≥5 mm or ≥80 mm3) and a reduction of the follow-up period to 1 year for solid pulmonary nodules; both of these will reduce the number of follow-up CT scans (sections ‘Initial assessment of the probability of malignancy in pulmonary nodules’ and ‘Imaging follow-up’, algorithms 1 and 2). Volumetry is recommended as the preferred measurement method and there are recommendations for the management of nodules with extended volume doubling times (section ‘Imaging follow-up’, algorithm 2). Acknowledging the good prognosis of sub-solid nodules (SSNs), there are recommendations for less aggressive options for their management (section ‘Management of SSNs’, algorithm 3). The guidelines provide more clarity in the use of further imaging, with ordinal scale reporting for PET-CT recommended to facilitate incorporation into risk models (section ‘Further imaging in management of pulmonary nodules’) and more clarity about the place of biopsy (section ‘Non-imaging tests and non-surgical biopsy’, algorithm 4). There are recommendations for the threshold for treatment without histological confirmation (sections ‘Surgical excision biopsy’ and ‘Non-surgical treatment without pathological confirmation of malignancy’, algorithm 4). Finally, and possibly most importantly, there are evidence-based recommendations about the information that people …

Pleurectomy/Decortication is Superior to Extrapleural Pneumonectomy in the Multimodality Management of Patients with Malignant Pleural Mesothelioma

Introduction: To compare the outcomes of two different multimodality regimens involving neoadjuvant chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant radiotherapy versus pleurectomy/decortication (P/D), hyperthermic pleural lavage with povidone-iodine, and adjuvant chemotherapy in patients with malignant pleural mesothelioma. Methods: Nonrandomized prospective study of patients treated by multimodality therapy and operated on between January 2004 and June 2011. Second-line treatments were administered when appropriate. Survival and prognostic factors were analyzed by the Kaplan Meier method, log rank test, and Cox regression analysis. Results: Twenty-five consecutive patients received neoadjuvant chemotherapy, 22 underwent EPP, and 17 received adjuvant radiotherapy. Over the same period, 54 consecutive patients underwent P/D and hyperthermic pleural lavage and received prophylactic radiotherapy and adjuvant chemotherapy. The 30-day mortality rate was 4.5%in the EPP group and nil in the P/D group. Fifteen patients (68%) in the EPP group and 15 (27.7%) in the P/D group experienced complications. There were no differences between the EPP and P/D groups for age, sex, histology, pathologic stage, and nodal status. Trimodality therapy was completed by 68%of the patients in the EPP group and 100%in the P/D group. Survival was significantly better in the P/D group: median survival was 23 months versus 12.8 months, 2-year survival was 49%versus 18.2 %, and 5-year survival was 30.1%versus 9%, respectively (p = 0.004). At multivariate analysis, epithelioid histology, P/D, and completeness of resection were independent prognostic factors. Conclusions: In our experience, P/D, hyperthermic pleural lavage with povidone-iodine, and adjuvant chemotherapy were superior to neoadjuvant chemotherapy, EPP, and adjuvant radiotherapy.

Screening for EGFR and KRAS mutations in endobronchial ultrasound derived transbronchial needle aspirates in non-small cell lung cancer using COLD-PCR.

EGFR mutations correlate with improved clinical outcome whereas KRAS mutations are associated with lack of response to tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Endobronchial ultrasound (EBUS)-transbronchial needle aspiration (TBNA) is being increasingly used in the management of NSCLC. Co-amplification at lower denaturation temperature (COLD)–polymerase chain reaction (PCR) (COLD-PCR) is a sensitive assay for the detection of genetic mutations in solid tumours. This study assessed the feasibility of using COLD-PCR to screen for EGFR and KRAS mutations in cytology samples obtained by EBUS-TBNA in routine clinical practice. Samples obtained from NSCLC patients undergoing EBUS-TBNA were evaluated according to our standard clinical protocols. DNA extracted from these samples was subjected to COLD-PCR to amplify exons 18–21 of EGFR and exons two and three of KRAS followed by direct sequencing. Mutation analysis was performed in 131 of 132 (99.3%) NSCLC patients (70F/62M) with confirmed lymph node metastases (94/132 (71.2%) adenocarcinoma; 17/132 (12.8%) squamous cell; 2/132 (0.15%) large cell neuroendocrine; 1/132 (0.07%) large cell carcinoma; 18/132 (13.6%) NSCL-not otherwise specified (NOS)). Molecular analysis of all EGFR and KRAS target sequences was achieved in 126 of 132 (95.5%) and 130 of 132 (98.4%) of cases respectively. EGFR mutations were identified in 13 (10.5%) of fully evaluated cases (11 in adenocarcinoma and two in NSCLC-NOS) including two novel mutations. KRAS mutations were identified in 23 (17.5%) of fully analysed patient samples (18 adenocarcinoma and five NSCLC-NOS). We conclude that EBUS-TBNA of lymph nodes infiltrated by NSCLC can provide sufficient tumour material for EGFR and KRAS mutation analysis in most patients, and that COLD-PCR and sequencing is a robust screening assay for EGFR and KRAS mutation analysis in this clinical context.

Phase 2 Study of Sorafenib in Malignant Mesothelioma Previously Treated with Platinum-Containing Chemotherapy

Introduction: The incidence of mesothelioma is rising. First-line cisplatin and pemetrexed confers a survival benefit, with a median progression-free survival (PFS) of 5.7 months. Sorafenib inhibits tyrosine kinases, including receptors for vascular endothelial growth factor, which are implicated in mesothelioma pathogenesis by preclinical and clinical data. Methods: Sorafenib, at 400 mg twice daily, was assessed in a single-arm multicenter phase 2 study, using Simon’s two-stage design. Eligible patients had received platinum combination chemotherapy earlier. The primary endpoint was PFS at 6 months, with secondary endpoints, including response rate and metabolic response, assessed using fluorodeoxyglucose positron emission tomography. Published reference values for PFS in mesothelioma provide a benchmark for the null hypothesis of 28% progression-free at 6 months, and for moderate or significant clinical activity of 35% or 43% progression-free at 6 months, respectively. Results: Fifty-three patients (72%) were treated. Most had epithelioid histology. Ninety-three percent of patients had a performance status 0 or 1. Treatment was well tolerated with few grade 3 or 4 toxicities. Median PFS was 5.1 months, with 36% of patients being progression-free at 6 months. Nine percent of patients remained on study beyond 1 year. Changes in fluorodeoxyglucose positron emission tomography parameters did not predict clinical outcome. Conclusions: Sorafenib is well tolerated in patients with mesothelioma after completion of platinum-containing chemotherapy. PFS of sorafenib compares favorably with that reported for other targeted agents, and suggests moderate activity in this disease.

PD‐L1 testing for lung cancer in the UK: recognizing the challenges for implementation

A new approach to the management of non‐small‐cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD‐1) and its ligand programmed death ligand 1 (PD‐L1). Several drugs targeting PD‐1 (pembrolizumab and nivolumab) or PD‐L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD‐1 inhibitors may be predicted by expression of PD‐L1 on neoplastic cells. Hence, there is considerable interest in using PD‐L1 immunohistochemical staining to guide the use of PD‐1‐targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD‐L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre‐analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory‐devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD‐L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available.

Pleurectomy/Decortication, Hyperthermic Pleural Lavage with Povidone-Iodine Followed by Adjuvant Chemotherapy in Patients with Malignant Pleural Mesothelioma

Introduction: Malignant pleural mesothelioma is a fatal neoplasm related to asbestos exposure. We investigated the effects of pleurectomy/decortication (P/D), hyperthermic pleural lavage with povidone-iodine and adjuvant chemotherapy in patients with malignant pleural mesothelioma. Patients and Methods: Observational prospective study of patients referred for multimodality therapy and operated on at our institution between October 2004 and May 2010. Thirty-six selected patients underwent P/D and hyperthermic pleural lavage, prophylactic radiotherapy, and adjuvant chemotherapy. All patients were reviewed at 4 weeks and then 6 monthly in the outpatient clinic, with positron-emission tomography-computed tomography. Second-line treatments were administered when appropriate. Results: Thirty-day mortality was nil. Nine patients experienced postoperative complications: persistent air leak (n = 5, 13.9%), chylothorax requiring surgical intervention (n = 4, 11%), and adult respiratory distress syndrome (n = 1, 3.9%). Fourteen of 36 patients were alive at last follow-up (median follow-up: 33 months, range: 12–63 months). Ten patients were alive with no evidence of disease recurrence, four patients were alive with disease recurrence, and 22 patients had died of disease progression. Overall median survival (Kaplan-Meier) was 24 months (95% confidence interval: 18.5–29.4 months). One-year survival was 91.7%, and 2-year survival was 61%. Patients undergoing complete macroscopical resection (R0–R1) had a significantly better survival than those undergoing an incomplete macroscopical resection (R2) (median overall survival: 32 months versus 18.9 months, p = 0.012). Conclusion: In our experience, P/D combined with hyperthermic pleural lavage with povidone-iodine and adjuvant chemotherapy is a well-tolerated multimodality treatment associated with low morbidity and mortality. This multimodality treatment compares favorably with classical trimodality regimens involving chemotherapy, extrapleural pneumonectomy, and adjuvant radiotherapy, in our experience. Study limitations include small sample size, nonrandomization, and patient selection bias.

Risk Factors for Regional Nodal Relapse in Breast Cancer Patients With One to Three Positive Axillary Nodes

PURPOSE In many centers, supraclavicular fossa radiotherapy (SCF RT) is not routinely offered to breast cancer patients with one to three positive lymph nodes. We aimed to identify a subgroup of these patients who are at high risk of supra or infraclavicular fossa relapse (SCFR) such that they can be offered SCFRT at the time of diagnosis to improve long term locoregional control. METHODS AND MATERIALS We performed a retrospective analysis of the pathological features of 1,065 cases of invasive breast cancer with one to three positive axillary lymph nodes. Patients underwent radical breast conserving surgery or mastectomy. A total of 45% of patients received adjuvant chest wall/breast RT. No patients received adjuvant SCFRT. The primary outcome was SCFR. Secondary outcomes were chest wall/breast recurrence, distant metastasis, all death, and breast-cancer specific death. Kaplan-Meier estimates were used to calculate actuarial event rates and survival functions compared using log-rank tests. Multivariate analyses (MVA) of factors associated with outcome were conducted using Cox proportional hazards models. RESULTS Median follow-up was 9.7 years. SCFR rate was 9.2%. Median time from primary diagnosis to SCFR was 3.4 years (range, 0.7-14.4 years). SCFR was associated with significantly lower 10-year survival (18% vs. 65%; p < 0.001). Higher grade and number of positive lymph nodes were the most significant predictors of SCFR on MVA (p < 0.001). 10 year SCFR rates were less than 1% in all patients with Grade 1 cancers compared with 30% in those having Grade 3 cancers with three positive lymph nodes. Additional factors associated with SCFR on univariate analysis but not on MVA included larger nodal deposits (p = 0.002) and proportion of positive nodes (p = 0.003). CONCLUSIONS Breast cancer patients with one to three positive lymph nodes have a heterogenous risk of SCFR. Patients with two to three positive axillary nodes and/or high-grade disease may warrant consideration of SCFRT.

Role of Integrated 18-Fluorodeoxyglucose Position Emission Tomography-Computed Tomography in Patients Surveillance after Multimodality Therapy of Malignant Pleural Mesothelioma

Introduction: To investigate the role of 18-fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG-PET-CT) in the surveillance of patients after multimodality treatment of malignant pleural mesothelioma. Methods: Retrospective study of patients who had chemotherapy, radical surgery, extrapleural pneumonectomy or pleurectomy/decortication, and radiotherapy for mesothelioma in our unit. PET-CT was performed after multimodality therapy to evaluate response to treatment or when disease recurrence was suspected. 18-FDG-PET scans were acquired from skull base to upper thigh with low-dose CT scans for attenuation correction and image fusion. Results: Forty-four patients had extrapleural pneumonectomy (21) or pleurectomy/decortication (23) between January 2004 and July 2008. Twenty-five patients had PET-CT performed after multimodality therapy. This was performed in 11 patients in whom disease recurrence was suspected at a median of 9 (range, 6–16) months after treatment. PET-CT correctly diagnosed recurrent disease in eight patients and missed microscopic recurrence in one. Surveillance PET-CT was performed in 14 asymptomatic patients at a median of 11 (range, 7–13) months after treatment. It showed unsuspected recurrences in four patients. The standard uptake value max of recurrent mesothelioma was 8.9 ± 4.0 (4–18.4). PET-CT had a sensitivity of 94%, a specificity of 100%, and the positive and negative predictive values of 100 and 88%, respectively. Conclusions: 18-FDG-PET-CT is useful in diagnosing disease recurrence after multimodality therapy for malignant pleural mesothelioma. We propose a prospective study to fully assess its value in this group of patients.

Routine EGFR and KRAS Mutation analysis using COLD-PCR in non-small cell lung cancer

Aims:  Epidermal growth factor receptor (EGFR) antagonists are particularly active in non‐small cell lung cancer (NSCLC) patients with tumours bearing mutations in the EFGR gene. EGFR mutation prevalence is very low in squamous histology. Response rates using these drugs in patients with KRAS mutations are low, so available KRAS mutation information may aid treatment selection in the second‐line setting. Since 2009, patients presenting to this hospital with non‐squamous histology have been routinely screened for mutations in both the EGFR and KRAS genes, with results used to inform treatment. We present an analysis of 215 consecutive patients for whom EGFR mutation analysis was informative.

Respiratory papillomatosis of lung and F-18 FDG PET-CT

Abstract: Recurrent respiratory papillomatosis (RRP) is the most common benign tumor of the larynx in children. Papillomas in RRP are usually benign and are localized to the larynx. Lung involvement is rare. The papillomas in the laryngotracheal and bronchioloalveolar region may undergo malignant degeneration to squamous cell carcinoma and are reported to have a poor prognosis. A 28-year-old woman presented with hemoptysis. She had known RRP in the trachea but no previous lung involvement. A chest radiograph and CT scan revealed multiple nodules, some of which were cavitating and some were with a predominantly cystic appearance. PET/CT showed increased F-18 FDG uptake in these nodules and guided biopsy.