Michael Snee

Guidelines on the radical management of patients with lung cancer.

A joint initiative by the British Thoracic Society and the Society for Cardiothoracic Surgery in Great Britain and Ireland was undertaken to update the 2001 guidelines for the selection and assessment of patients with lung cancer who can potentially be managed by radical treatment.

Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial

Summary Background Malignant pleural mesothelioma is almost always fatal, and few treatment options are available. Although active symptom control (ASC) has been recommended for the management of this disease, no consensus exists for the role of chemotherapy. We investigated whether the addition of chemotherapy to ASC improved survival and quality of life. Methods 409 patients with malignant pleural mesothelioma, from 76 centres in the UK and two in Australia, were randomly assigned to ASC alone (treatment could include steroids, analgesic drugs, bronchodilators, palliative radiotherapy [n=136]); to ASC plus MVP (four cycles of mitomycin 6 mg/m2, vinblastine 6 mg/m2, and cisplatin 50 mg/m2 every 3 weeks [n=137]); or to ASC plus vinorelbine (one injection of vinorelbine 30 mg/m2 every week for 12 weeks [n=136]). Randomisation was done by minimisation, with stratification for WHO performance status, histology, and centre. Follow-up was every 3 weeks to 21 weeks after randomisation, and every 8 weeks thereafter. Because of slow accrual, the two chemotherapy groups were combined and compared with ASC alone for the primary outcome of overall survival. Analysis was by intention to treat. This study is registered, number ISRCTN54469112. Findings At the time of analysis, 393 (96%) patients had died (ASC 132 [97%], ASC plus MVP 132 [96%], ASC plus vinorelbine 129 [95%]). Compared with ASC alone, we noted a small, non-significant survival benefit for ASC plus chemotherapy (hazard ratio [HR] 0·89 [95% CI 0·72–1·10]; p=0·29). Median survival was 7·6 months in the ASC alone group and 8·5 months in the ASC plus chemotherapy group. Exploratory analyses suggested a survival advantage for ASC plus vinorelbine compared with ASC alone (HR 0·80 [0·63–1·02]; p=0·08), with a median survival of 9·5 months. There was no evidence of a survival benefit with ASC plus MVP (HR 0·99 [0·78–1·27]; p=0·95). We observed no between-group differences in four predefined quality-of-life subscales (physical functioning, pain, dyspnoea, and global health status) at any of the assessments in the first 6 months. Interpretation The addition of chemotherapy to ASC offers no significant benefits in terms of overall survival or quality of life. However, exploratory analyses suggested that vinorelbine merits further investigation. Funding Cancer Research UK and the Medical Research Council (UK).

Prophylactic Cranial Irradiation in Extensive Disease Small-Cell Lung Cancer: Short-Term Health-Related Quality of Life and Patient Reported Symptoms—Results of an International Phase III Randomized Controlled Trial by the EORTC Radiation Oncology and Lung Cancer Groups

PURPOSE Prophylactic cranial irradiation (PCI) in patients with extensive-disease small-cell lung cancer (ED-SCLC) leads to significantly fewer symptomatic brain metastases and improved survival. Detailed effects of PCI on health-related quality of life (HRQOL) are reported here. PATIENTS AND METHODS Patients (age, 18 to 75 years; WHO < or = 2) with ED-SCLC, and any response to chemotherapy, were randomly assigned to either observation or PCI. Health-related quality of life (HRQOL) and patient-reported symptoms were secondary end points. The European Organisation for the Research and Treatment of Cancer core HRQOL tool (Quality of Life Questionnaire C30) and brain module (Quality of Life Questionnaire Brain Cancer Module) were used to collect self-reported patient data. Six HRQOL scales were selected as primary HRQOL end points: global health status; hair loss; fatigue; and role, cognitive and emotional functioning. Assessments were performed at random assignment, 6 weeks, 3 months, and then 3-monthly up to 1 year and 6-monthly thereafter. RESULTS Compliance with the HRQOL assessment was 93.7% at baseline and dropped to 60% at 6 weeks. Short-term results up to 3 months showed that there was a negative impact of PCI on selected HRQOL scales. The largest mean difference between the two arms was observed for fatigue and hair loss. The impact of PCI on global health status as well as on functioning scores was more limited. For global health status, the observed mean difference was eight points on a scale 0 to 100 at 6 weeks (P = .018) and 3 months (P = .055). CONCLUSION PCI should be offered to all responding ED SCLC patients. Patients should be informed of the potential adverse effects from PCI. Clinicians should be alert to these; monitor their patients; and offer appropriate support, clinical, and psychosocial care.

Early Compared With Late Radiotherapy in Combined Modality Treatment for Limited Disease Small-Cell Lung Cancer: A London Lung Cancer Group Multicenter Randomized Clinical Trial and Meta-Analysis

PURPOSE To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC). PATIENTS AND METHODS Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks. RESULTS TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17). CONCLUSION This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT.

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.

Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): An open-label, phase 3, randomised, superiority trial

Summary Background Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer. Methods The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0–2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin–etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up. Findings Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35–58), median overall survival was 30 months (95% CI 24–34) in the twice-daily group versus 25 months (21–31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95–1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50–62) in the twice-daily group and 51% (45–57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI −3·2% to 13·7%]). The most common grade 3–4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3–4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3–4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group). Interpretation Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting. Funding Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups).

Protocol for the CONVERT trial—Concurrent ONce-daily VErsus twice-daily RadioTherapy: an international 2-arm randomised controlled trial of concurrent chemoradiotherapy comparing twice-daily and once-daily radiotherapy schedules in patients with limited stage small cell lung cancer (LS-SCLC) and good performance status

Introduction Concurrent ONce-daily VErsus twice-daily RadioTherapy (CONVERT) is the only multicentre, international, randomised, phase III trial open in Europe and Canada looking at optimisation of chemoradiotherapy (RT) in limited stage small cell lung cancer (LS-SCLC). Following on from the Turrisi trial of once-daily versus twice-daily (BD) concurrent chemoradiotherapy, there is a real need for a new phase III trial using modern conformal RT techniques and investigating higher once-daily radiation dose. This trial has the potential to define a new standard chemo-RT regimen for patients with LS-SCLC and good performance status. Methods and analysis 447 patients with histologically or cytologically proven diagnosis of SCLC were recruited from 74 centres in eight countries between 2008 and 2013. Patients were randomised to receive either concurrent twice-daily RT(45 Gy in 30 twice-daily fractions over 3 weeks) or concurrent once-daily RT(66 Gy in 33 once-daily fractions over 6.5 weeks) both starting on day 22 of cycle 1. Patients are followed up until death. The primary end point of the study is overall survival and secondary end points include local progression-free survival, metastasis-free survival, acute and late toxicity based on the Common Terminology Criteria for Adverse Events V.3.0, chemotherapy and RTdose intensity. Ethics and dissemination The trial received ethical approval from NRES Committee North West—Greater Manchester Central (07/H1008/229). There is a trial steering committee, including independent members and an independent data monitoring committee. Results will be published in a peer-reviewed journal and presented at international conferences. Trial registration number ISRCTN91927162; Pre-results.

Improving Survival with Thoracic Radiotherapy in Patients with Small Cell Lung Cancer. The CONVERT and the REST Trials

Clinical trials testing systemic therapies in small cell lung cancer (SCLC) have been associated with disappointing results in the last two decades, and so the standard chemotherapy treatment remains platinum and etoposide chemotherapy [1]. On a more optimistic note, major advances have beenmade since the 1980swith radiotherapy in this disease. These advances include improvements in radiotherapy techniques, the use of prophylactic cranial irradiation (PCI) for all stages of SCLC [2,3] and improved understanding in the combination of chemotherapy and radiotherapy [4]. The standard of care in good performance status limited-stage SCLC is early concurrent chemoradiotherapy, with the best survival results being achieved with twice daily radiation [4,5]. As a result of the implementation of the best standard of care, the 5 year survival of limited-stage SCLC patients has increased from less than 10% with chemotherapy alone to 25% with early concurrent chemoradiotherapy [4,6]. In extensive-stage disease, chemotherapy is the standard of care. Thoracic radiotherapy is generally given to alleviate symptoms, whereas PCI in extensive-stage SCLC patients who respond to chemotherapy was recently proven to double survival at 1 year [3]. As most patients will succumb to their disease it is crucial that patients with SCLC are given the opportunity to participate in clinical research in order to try to improve their outcome. Ongoing clinical trials addressing radiotherapy-related questions include the CONVERT (Concurrent ONce daily VErsus twice daily RadioTherapy) study, the US Intergroup study (CALGB 30610/RTOG 0538) and the

Radical radiotherapy with or without gemcitabine in patients with early stage medically inoperable non-small cell lung cancer

BACKGROUND Preclinical and phase I data suggest gemcitabine to be a potent radiosensitiser. This multicentre study addressed whether the addition of low dose gemcitabine to radical radiotherapy improved 2 year event-free survival in patients with medically inoperable stages I-II non-small cell lung cancer. AIM To determine whether low dose gemcitabine increased event-free survival in patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery. METHODS Patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery were randomised to 3D conformal radiotherapy delivering 55 Gy in 20 fractions over 4 weeks to known sites of cancer with (Arm B) or without (Arm A) 100mg/m(2) weekly gemcitabine. RESULTS Study entry was terminated early because of slow accrual. 111 patients were randomised between March 2003 and December 2005, of whom 4 withdrew consent and 2 were lost to follow-up. Median age was 75 (range 49-88)years and 67 (63%) were male. 86 (81%) were PS 0-1 and 31 (30%) Charlson index 2 or greater. Event-free survival in arm A and B, respectively, was 42% and 46% at 2 years and 20% and 31% at 5 years (p=0.72), while overall survival was 56% and 52% at 2 years and 20% and 33% at 5 years (p=0.87). Two deaths from accelerated interstitial lung disease were seen in arm B, but toxicity was otherwise mild. CONCLUSION No evidence of an improvement in event-free survival was seen with the addition of weekly gemcitabine at this dose for patients with early stage NSCLC unfit for surgery, although the power of the study was low.