Mary O’Brien

The Mesothelioma and Radical surgery randomized controlled trial: the Mars feasibility study.

Hypothesis: The effectiveness of extrapleural pneumonectomy (EPP) to extend quality-adjusted survival in malignant pleural mesothelioma within multimodality treatment should be proven in a randomized controlled trial if this radical surgery is to be regarded as the standard of care. The question was whether randomization to surgery versus no surgery would be possible. Methods: The Mesothelioma and Radical Surgery trial was planned to randomize 50 patients to test feasibility. There was a two-stage consent process. At first consent, the patients who were possible candidates for radical surgery were registered into the trial for completion of assessment and staging. All received platinum-based chemotherapy. If still eligible, they completed a second consent to be randomized to have either EPP followed by radical hemithorax radiotherapy or to have continued best care. Results: Patients were recruited through 11 collaborating centers in the United Kingdom. One hundred twelve potentially eligible patients gave informed consent to enter the registration phase and undergo chemotherapy. One died, 27 progressed, five were inoperable, four were treated off trial, and 18 withdrew either during or after chemotherapy but before final review. Additionally six were deemed inoperable at review after completing chemotherapy and one more patient withdrew. The remaining 50 were randomized; 24 to EPP and 26 to continued best care. Conclusions: In this study, 50/112 (45%) of patients entering the evaluation and induction phase of the trial went on to be randomized. We have shown that this randomization between surgery and no surgery is feasible. This was the primary aim of the Mesothelioma and Radical Surgery trial.

Systemic therapy of advanced non-small cell lung cancer: Major-developments of the last 5-years

The standard palliative treatment for advanced stage NSCLC remains a platinum doublet but by tailoring chemotherapy according to tumour histology the results can be improved through using pemetrexed-containing schemas in non-squamous-cell disease. In addition, maintenance chemotherapy appears to be effective in patients achieving clinical benefit by induction therapy. Targeted therapy based on the presence of activating epidermal growth factor receptor (EGFR) activating mutations or EML4-ALK gene rearrangement is becoming standard practice with high median survival rates, up to 30 months. There are still numerous other molecular targeted drugs in development. This review presents the most recent relevant progress in systemic anti-cancer therapy of advanced NSCLC in the past 5 years and delineates todays new treatment options.

The pathway study: results of a pilot feasibility study in patients suspected of having lung carcinoma investigated in a conventional chest clinic setting compared to a centralised two-stop pathway

UNLABELLED The best chance of cure in non-small cell lung cancer (NSCLC) is surgical resection, but UK rates of 8% compare poorly to 25% in the USA and Europe. Delays in diagnosis in the current UK system may be one reason for such discrepancy. To address this problem we set up a rapid diagnostic system and compared it to the conventional method of investigations in a pilot randomised trial. METHODS Eighty-eight patients were prospectively enrolled from three District General Hospitals and randomised to either investigation locally or to the rapid system at The Royal Marsden Hospital. The pilot end-points were feasibility and audit of radical treatment rates to enable estimates for patient numbers for the full study. RESULTS Forty-five and 43 patients were in the central and conventional arms, respectively (65% male, median age 69 years). There was a 4-week improvement in time to first treatment in those in the central arm (P=0.0025) with 13/30 (43%) and 9/27 (33%) patients having radical treatment in the central and conventional arms, respectively. Patients in the conventional arm felt the diagnostic process was too slow (P=0.02) while those in the central arm seemed to have a better care experience (P=0.01). There were significantly less visits to the general practitioner (GP) in the central arm (P=0.02). CONCLUSIONS This pilot study demonstrates that the full study is feasible but would require the commitment and involvement of a large number of patients and physicians. The results show several advantages to investigations and diagnosis in the central arm, particularly in time to treatment initiation, patient satisfaction and rate of radical treatments. The improved rate of radical treatment could lead to an improved survival rate.

Radical treatment of non-small cell lung cancer during the last 5 years

The management of non-small cell lung cancer (NSCLC) has continued to improve over the last 5 years due to advances in surgery, radiological staging, combined modality therapies and advances in radiation technology. We have an updated staging classification (7th Edition American Joint Committee on Cancer staging) and now in 2011, a new histology classification introducing the concepts of adenocarcinoma in situ and minimally invasive adenocarcinoma. This classification has profound surgical implications as the role of limited resection is reconsidered for early stage lesions. Surgery is curative in early stage disease. The role of surgery in locally advanced NSCLC remains controversial. The principal aim is a complete resection as this will determine long-term prognosis. Intraoperative staging of lung cancer is extremely important to determine the extent of resection according to the tumour and nodal status. Systematic nodal dissection is generally advocated to obtain accurate intraoperative staging and to help decide on adjuvant therapy. Radiotherapy currently plays a major role in the management of lung cancer as most patients are not surgical candidates due to disease stage, fitness and co-morbidities. In the last 5 years we have seen continuing optimisation of chemo-radiotherapy combinations and technological advances including the development of image guided radiotherapy (IGRT), stereotactic ablative body radiotherapy (SABR) and intensity modulated radiotherapy (IMRT). Quality of life evaluation is becoming increasingly important and should be considered when deciding on a specific treatment, especially in a multimodality setting.

Establishing an EGFR mutation screening service for non-small cell lung cancer – Sample quality criteria and candidate histological predictors

INTRODUCTION EGFR screening requires good quality tissue, sensitivity and turn-around time (TAT). We report our experience of routine screening, describing sample type, TAT, specimen quality (cellularity and DNA yield), histopathological description, mutation result and clinical outcome. METHODS Non-small cell lung cancer (NSCLC) sections were screened for EGFR mutations (M+) in exons 18-21. Clinical, pathological and screening outcome data were collected for year 1 of testing. Screening outcome alone was collected for year 2. RESULTS In year 1, 152 samples were tested, most (72%) were diagnostic. TAT was 4.9 days (95%confidence interval (CI)=4.5-5.5). EGFR-M+ prevalence was 11% and higher (20%) among never-smoking women with adenocarcinomas (ADCs), but 30% of mutations occurred in current/ex-smoking men. EGFR-M+ tumours were non-mucinous ADCs and 100% thyroid transcription factor (TTF1+). No mutations were detected in poorly differentiated NSCLC-not otherwise specified (NOS). There was a trend for improved overall survival (OS) among EGFR-M+ versus EGFR-M- patients (median OS=78 versus 17 months). In year 1, test failure rate was 19%, and associated with scant cellularity and low DNA concentrations. However 75% of samples with poor cellularity but representative of tumour were informative and mutation prevalence was 9%. In year 2, 755 samples were tested; mutation prevalence was 13% and test failure only 5.4%. Although samples with low DNA concentration (<2 ng/μL) had more test failures (30% versus 3.9% for [DNA]>2.2 ng/μL), the mutation rate was 9.2%. CONCLUSION Routine epidermal growth factor receptor (EGFR) screening using diagnostic samples is fast and feasible even on samples with poor cellularity and DNA content. Mutations tend to occur in better-differentiated non-mucinous TTF1+ ADCs. Whether these histological criteria may be useful to select patients for EGFR testing merits further investigation.

Oral vinorelbine in the treatment of non-small cell lung cancer: rationale and implications for patient management.

Vinorelbine is an established treatment for advanced non-small cell lung cancer (NSCLC), both as a single agent and in combination chemotherapy. Recently, an oral form of this agent has been developed. Before accepting an established agent in a different administration form, rigorous testing is required to answer such questions as reliable bioavailability, continued safety and preservation of efficacy. In addition, an oral agent must provide patient convenience and acceptance, while being an economically sound approach.Oral vinorelbine was found to have acceptable and reliable pharmacokinetic profiles at clinically relevant dosage levels. Oral vinorelbine was found to have approximately 40% bioavailability; thus, a dose of 80 mg/m2 orally is the equivalent of 30 mg/m2 intravenously, and 60 mg/m2 orally is the equivalent of 25 mg/m2 intravenously. Studies also concluded a lack of food effect on the administration of oral vinorelbine. In addition, no drug-drug interactions were found with a variety of commonly used antineoplastic agents.Vinorelbine, either orally or intravenously, has been investigated in randomised phase II trials as a single agent and in combination with cisplatin or carboplatin in patients with NSCLC. In general, response and survival results with oral vinorelbine appeared similar to the intravenous agent. Adverse-effect profiles were also similar for the two formulations. Clearly, the issue of venous irritation does not exist with oral vinorelbine; however, nausea and vomiting were more frequent when vinorelbine was administered orally compared with intravenously when no planned antiemetic therapy is given.

A Comparison of Immunohistochemical Assays and FISH in Detecting the ALK Translocation in Diagnostic Histological and Cytological Lung Tumor Material

Introduction: Detection of the ALK rearrangement in a solid tumor gives these patients the option of crizotinib as an oral form of anticancer treatment. The current test of choice is fluorescence in situ hybridization (FISH), but various cheaper and more convenient immunohistochemical (IHC) assays have been proposed as alternatives. Methods: Fifteen FISH-positive cases from patients, seven with data on crizotinib therapy and clinical response, were evaluated for the presence of ALK protein using three different commercially available antibodies: D5F3, using the proprietary automated system (Ventana), ALK1 (Dako), and 5A4 (Abcam). A further 14 FISH-negative and three uncertain (<15% rearrangement detected) cases were also retrieved. Of the total 32 specimens, 17 were excisions and 15 were computed tomography-guided biopsies or cytological specimens. All three antibodies were applied to all cases. Antibodies were semiquantitatively scored on intensity, and the proportion of malignant cells stained was documented. Cutoffs were set by receiver operating curve analysis for positivity to optimize correct classification. Results: All three IHC assays were 100% specific but sensitivity did vary: D5F3 86%, ALK 79%, 5A4 71%. Intensity was the most discriminating measure overall, with a combination of proportion and intensity not improving the test. No FISH-negative IHC-positive cases were seen. Two FISH-positive cases were negative with all three IHC assays. One of these had been treated with crizotinib and had failed to show clinical response. The other harbored a second driving mutation in the EGFR gene. Conclusions: IHC with all three antibodies is especially highly specific (100%) although variably sensitive (71%-86%), specifically in cases with scanty material. D5F3 assay was most sensitive in these latter cases. Occasional cases are IHC-positive but FISH-negative, suggesting either inaccuracy of one assay or occasional tumors with ALK rearrangement that do not express high levels of ALK protein.

EGFR and KRAS mutations, and ALK fusions: current developments and personalized therapies for patients with advanced non-small-cell lung cancer

Personalized therapy has significantly developed in lung cancer treatment over recent years. VEGF and EGF play a major role in non-small-cell lung cancer (NSCLC) tumor angiogenesis and aggressiveness. EGFR mutation as well as KRAS and ALK rearrangements are important biomarkers in the field owing to potential targeted therapies involved in clinical practice: erlotinib, geftinib, cetuximab and crizotinib. More recently, regulation of tumor immunity through CTLA4 and PD1/L1 has emerged as a promising field in NSCLC management. This review will focus on the current and future biomarkers in the advanced NSCLC field and also address potential related targeted therapies for these patients.

Low-Dose Oral Fluorouracil With Eniluracil as First-Line Chemotherapy Against Advanced Breast Cancer: A Phase II Study

PURPOSE Eniluracil (776C85) is an effective inactivator of dihydropyrimidine dehydrogenase that allows continuous low-dose oral fluorouracil (5-FU) to be given with predicable oral bioavailability. We have assessed this as first-line oral chemotherapy for patients with advanced/metastatic breast cancer. PATIENTS AND METHODS Patients with histologically proven, locally advanced or metastatic breast cancer without previous chemotherapy for advanced disease were entered onto this open-label phase II study. Patients received oral 5-FU 1.0 mg/m(2) with eniluracil 10 mg/m(2), both given twice daily for the first 28 days of each 35-day cycle, continuing until disease progression or unmanageable toxicity. RESULTS Thirty-three patients were entered, with a median age of 53 years. Sixteen partial responses were seen in twenty-nine assessable patients (55%; 95% confidence interval, 37% to 73%), including responses in four (40%) out of 10 patients who had received prior adjuvant 5-FU. Seven patients had stable disease for at least 3 months with symptom improvement. Median response duration was 14 months (range, 10 to 18+ months). Toxicity was low. There were only two episodes of drug-related grade 3 nonhematologic toxicity (diarrhea and infection), and only 6%, 3%, and 3% of patients developed granulocytopenia, thrombocytopenia, and neutropenic sepsis, respectively. Mild (grade 1/2) diarrhea occurred in 39% of patients, hand-foot syndrome in 15%, nausea in 27%, and mucositis in 18%. Toxicity-associated delay and dose reduction occurred in only 2% and 5% of courses, respectively. CONCLUSION First-line treatment with the combination of oral 5-FU and eniluracil has high activity in patients with advanced breast cancer comparable with the most active conventional cytotoxic agents but with strikingly less toxicity.

A phase II study of 18F-fluorodeoxyglucose PET–CT in non-small cell lung cancer patients receiving erlotinib (Tarceva®); objective and symptomatic responses at 6 and 12 weeks

BACKGROUND The aim of this study was to assess if (18)F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)-CT scanning could minimise the time non-responding patients were exposed to erlotinib (Tarceva). METHODS Patients were selected for clinical factors that would predict response to erlotinib. A FDG PET-CT and diagnostic contrast-enhanced (traditional) CT scan were carried out at baseline, and then a FDG PET-CT at 6 weeks and a traditional CT at 12 weeks were repeated. The primary end-point was rate of early progression in patients after 6 weeks, of which a minimum 12 out of 35 were required to make the study worthwhile. The responses at 6 (PET-CT) and 12 weeks (traditional CT) were compared and correlated with symptomatic response at both these time points. RESULTS Forty seven patients were recruited with 38 and 33 patients assessable by FDG PET-CT at 6 weeks and traditional CT at 12weeks, respectively. There was good correlation between Partial response (PR) at both time points and all 10 patients who had a PR at 12 weeks had a PR at 6 weeks. Of the 13 patients with progressive disease (PD) at 12 weeks, seven had PD at 6 weeks and could have had their treatment stopped early. No evaluable patient with stable disease (SD) (8/38) or PD (9/38) on FDG PET-CT at 6 weeks went on to have a later response. Symptomatic response at 6 or 12 weeks did not correlate well with objective response on scanning at either time point. CONCLUSIONS The primary end-point of this study was met as >12 (15/38) patients could have stopped treatment early on the basis of the FDG PET-CT scan result. A FDG PET-CT evaluable response of SD or PD at 6 weeks does predict future lack of response. No correlation was found between response and symptomatic response at either 6 or 12 weeks.