A study of non small cell lung cancer (NSCLC) patients with brain metastasis: A single centre experience.

BACKGROUND: Lung cancer is the leading cause of cancer death with the majority of cases being non-small cell lung cancer (NSCLC) [1]. A common complication of NSCLC is brain metastasis (BM) [2, 3], where the prognosis remains poor despite new treatments. Real world data complements data gained from clinical trials, providing information on patients excluded from prospective research [4]. However, information from patient notes may prove incomplete and difficult to extract. We developed an algorithm to identify patients in our clinical database with brain metastasis from the electronic health record (EHR). METHODS: We retrospectively extracted data from the EHR of patients managed at a large teaching hospital between 2007 and 2018. Using the ICD-10 code C34, for lung cancer, our algorithm used phrases associated with BMs to search the unstructured text of radiology reports. Summary statistics and univariant analysis was performed for overall survival. RESULTS: 818 patients were identified as potentially having BM and 453 patients were confirmed on clinical review of their records. The median age of patients was 69 years, 50% were female and 66% had a performance status of >2. 12.2% had an identifiable mutation and 11.5% were identified as PD-L1 positive. In the first line setting, 65% of patients received symptomatic treatment, 23% received systemic anticancer therapy (SACT), 6.1% surgery and 10% radiotherapy, of which 6.5% had external beam and 3.5% stereotactic radiosurgery. Regarding those treated with SACT, 35% had an intracranial response to treatment (3% had complete response, 32% had a partial response). Median survival was 2 months (1.9 - 2.4 months 95% CI). CONCLUSION: The real-world prognosis for NSCLC patients with BMs is poor. By using an algorithm, we have reported outcomes on a comprehensive cohort of patients which helps identify those for whom an active treatment approach is appropriate.

[Prophylactic cranial irradiation in patients with extensive disease caused by small-cell lung cancer responsive to chemotherapy: fewer symptomatic brain metastases and improved survival]. / Profylactische schedelbestraling bij patiënten met uitgebreid kleincellig longcarcinoom dat reageert op chemotherapie: minder symptomatische hersenmetastasen en betere overleving.

OBJECTIVE: To determine the effect of prophylactic cranial irradiation (PCI) in patients with extensive-disease small-cell lung cancer (ED-SCLC) who responded to chemotherapy. DESIGN: Randomised, controlled clinical trial; phase III study (EORTC nr 08993-22993; www.clinicaltrials.gov, nr NCT00016211). METHOD: Patients aged 18-75 years with a functional status according to WHO < or = 2, and with ED-SCLC and any response to chemotherapy, were randomized to observation (standard care) or PCI. The primary endpoint was time to symptomatic brain metastases. If any pre-defined, key symptom suggesting brain metastases presented, a CT or MRI scan of the brain was performed. The size of the study (143 patients per arm) was determined to detect a hazard ratio (HR) of 0.44 at 80% power with 2-sided alpha = 0.05. RESULTS: The study accrued 286 patients. PCI decreased the risk of developing symptomatic brain metastases (HR = 0.27 (95% CI: 0.16-0.44; p < 0.001)). The cumulative incidence of developing brain metastases within 1 year was 40% in the control group (95% CI: 32-49) and 15% in the PCI group (95% CI: 8-21). PCI prolonged disease-free (HR = 0.76; 95% CI: 0.59-0.96, p = 0.02) and overall survival (HR = 0.68; 95% CI; 0.52-0.88, p = 0.003). The 1-year survival rate was 27% (95% CI: 19-36) for the PCI group versus 13% (95% CI: 8-20) for controls. Acute and late treatment toxicity was acceptable. These side effects did not significantly impact on quality of life. CONCLUSIONS: PCI significantly reduced the incidence of symptomatic brain metastases and prolonged both disease-free and overall survival and should be part of standard care in SCLC patients who respond to chemotherapy.

Low-dose prophylactic cranial irradiation in patients with poor prognosis small-cell lung cancer.

AIMS: In small-cell lung cancer (SCLC), prophylactic cranial irradiation (PCI) provides a survival advantage in good performance status patients with limited disease. Its role in those with poor performance status limited disease or extensive disease is unclear. A low-dose PCI schedule has been used in these groups, and outcomes have been analysed. MATERIALS AND METHODS: Retrospective analyses of brain metastasis-free survival and overall survival of patients receiving low-dose PCI over a 2-year period. RESULTS: Fifty-six patients were treated, with 55 evaluable due to missing notes for one. No major treatment-related toxicity was observed. Median brain metastasis-free survival and overall survival for the group were 44 and 46 weeks, respectively. The median brain metastasis-free survival were 32 and 50 weeks, and median overall survival were 39 and 57 weeks, in those with extensive and limited disease, respectively. A total of 10 patients developed clinical or radiological evidence of brain metastases, four (16%) with limited disease and six (21%) with extensive disease. Thirteen (52%) with limited disease and 10 (36%) with extensive disease survived 1 year. CONCLUSIONS: Symptomatic brain metastases occurred less frequently than would be expected, with most patients developing widespread metastatic disease. Low-dose PCI may benefit these groups, and the results of an ongoing EORTC randomised-controlled trial in extensive disease should provide more information.

Stereotactic Ablative Radiotherapy (SABR) in Patients with Medically Inoperable Peripheral Early Stage Lung Cancer: Outcomes for the First UK SABR Cohort.

AIMS: To report outcomes for the first UK cohort treated for early stage peripheral lung cancer using stereotactic ablative radiotherapy (SABR). MATERIALS AND METHODS: Patients were included who received SABR between May 2009 and May 2012. Electronic medical records were reviewed for baseline characteristics, treatment details and outcomes. Patients were treated according to the UK SABR Consortium Guidelines. Univariate and multivariate Cox regression was used to determine factors that influenced overall survival and local control. RESULTS: In total, 273 patients received SABR for 288 lesions in the time period examined. The median follow-up was 19.7 months. The median overall survival for all patients was 27.3 months, with 1, 2 and 3 year overall survival of 78.0, 54.9 and 38.6%, respectively. The 1, 2 and 3 year rates of local control were 98.2, 95.7 and 95.7%, respectively. All patients completed the planned course of treatment and rates of Common Toxicity Criteria grade 3+ toxicity were low. On multivariate analysis, patients with Medical Research Council (MRC) breathlessness scores of 3-5 had worse overall survival compared with patients with scores of 1-2 (hazard ratio: 2.10; 95% confidence interval: 1.25-3.59) and the presence of histological diagnosis conferred improved overall survival (hazard ratio: 0.54; 95% confidence interval: 0.31-0.93), probably reflecting that patients who are considered well enough to undergo biopsy are generally fitter overall. No factors were identified that significantly influenced local control. CONCLUSIONS: SABR is an effective and well-tolerated treatment option for patients with early stage peripheral lung cancer who are not suitable for surgery. No patient cohort was identified in whom SABR was considered inappropriate. This series adds to the existing positive data that support SABR for this patient group.

The SABRTooth feasibility trial protocol: a study to determine the feasibility and acceptability of conducting a phase III randomised controlled trial comparing stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I non-small cell lung cancer (NSCLC) considered to be at higher risk of complications from surgical resection.

BACKGROUND: Stage I non-small cell lung cancer (NSCLC) is potentially curable, and surgery is considered to be the standard of care for patients with good performance status and minimal co-morbidity. However, a significant proportion of patients with stage I NSCLC have a poorer performance status and significant medical co-morbidity that make them at higher risk of morbidity and mortality from surgery. Stereotactic ablative radiotherapy (SABR), which uses modern radiotherapeutic techniques to deliver large doses of radiation, has shown superiority over conventional radiotherapy in terms of local control and toxicity and is a standard of care for patients with stage I NSCLC who are at too high risk for surgery. However, it is not known whether surgery or SABR is the most effective in patients with stage I NSCLC who are suitable for surgery but are less fit and at higher risk surgical complications. Previous randomised studies have failed to recruit in this setting, and therefore, a feasibility study is required to see whether a full randomised control trial would be possible. METHODS/DESIGN: SABRTooth is a UK-based, multi-centre, open-label, two-group individually (1:1) randomised controlled feasibility study in patients with peripheral stage I NSCLC considered to be at higher risk from surgical resection. The study will assess the feasibility of conducting a definitive large-scale phase III trial. The primary objective is to assess recruitment rates to provide evidence that, when scaled up, recruitment to a large phase III trial would be possible; the target recruitment being 54 patients in total, over a 21-month period. There are multiple secondary and exploratory objectives designed to explore the optimum recruitment and data collection strategies to help optimise the design of a future phase III trial. DISCUSSION: To know whether SABR is a better, equivalent or inferior alternative to surgery for higher risk patients is a key question in lung cancer. Other studies comparing SABR to surgery have closed early due to poor recruitment, and therefore, the SABRTooth feasibility study has been designed around the UK National Health Service (NHS) cancer pathway incorporating many design features in order to maximise recruitment for a future definitive phase III trial. TRIAL REGISTRATION: controlled-trials.com ISRCTN13029788.

Erratum to: The SABRTooth feasibility trial protocol: a study to determine the feasibility and acceptability of conducting a phase III randomised controlled trial comparing stereotactic ablative radiotherapy (SABR) with surgery in patients with peripheral stage I non-small cell lung cancer (NSCLC) considered to be at higher risk of complications from surgical resection.

[This corrects the article DOI: 10.1186/s40814-016-0046-2.].

Protocol for PIT: a phase III trial of prophylactic irradiation of tracts in patients with malignant pleural mesothelioma following invasive chest wall intervention.

INTRODUCTION: Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT-guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention site and patients can develop tumour nodules within the chest wall. In an effort to prevent nodules developing, it has been widespread practice across Europe to irradiate intervention sites postprocedure--a practice known as prophylactic irradiation of tracts (PIT). To date there has not been a suitably powered randomised trial to determine whether PIT is effective at reducing the risk of chest wall nodule development. METHODS AND ANALYSIS: In this multicentre phase III randomised controlled superiority trial, 374 patients who can receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will be 21 Gy in three fractions. Subsequent chemotherapy is given at the clinicians' discretion. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6 months after randomisation would be clinically significant. All patients will be followed up for up to 2 years with monthly telephone contact and at least four outpatient visits in the first year. ETHICS AND DISSEMINATION: PIT was approved by NRES Committee North West-Greater Manchester West (REC reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to be randomised by the end of 2015. The analysis of the primary end point, incidence of chest wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer reviewed journal and results will also be presented at scientific meetings and summary results published online. A follow-up analysis is expected to be published in 2018. TRIAL REGISTRATION NUMBER: ISRCTN04240319; NCT01604005; Pre-results.

Stereotactic ablative body radiotherapy for lung cancer.

Lung stereotactic ablative radiotherapy (SABR) is a method of delivering high 'ablative' doses of radiotherapy to tumours in the lung. It was developed at the Karolinska Institute in the early 1990s using the methods established in cranial radiosurgery with multiple beams prescribed to an isodose and using a custom designed stereotactic body frame for immobilisation. Since then, aligned with the advances in radiotherapy technology and techniques (e.g. four-dimensional computed tomography simulation and image-guided radiotherapy), there has been a rapid increase in the use of lung SABR for both early stage lung cancer and lung metastases. For peripheral primary lung cancers less than 5 cm in diameter, high rates of local control and low levels of acute and late toxicity are consistently reported in the published literature. Compared with historical control rates of stage I lung cancers treated with conventionally fractionated radiotherapy, SABR seems to offer higher rates of local control, lower levels of acute toxicity and a better quality of life after treatment. However, the full results of randomised controlled trials of SABR versus conventionally fractionated are awaited and will provide higher-level evidence. For central lung tumours, very high SABR doses can be associated with significant toxicity. Dose-adapted fractionation schedules seem to have much lower rates of toxicity and prospective trials, including the completed RTOG 0813 study and the on-going EORTC LUNGTEC study, should provide further evidence of safety and establish organ at risk tolerances. SABR can also be used for tumours metastatic to the lung with high rates of local control and is a reasonable alternative to surgery in selected patients. Going forward, prospective trials are underway to establish the safety and efficacy of SABR in oligometastatic disease. Population-based outcomes will be crucial in supporting/establishing SABR as the treatment of choice in medically inoperable patients with peripheral stage I lung cancers. Randomised phase III trials will hopefully extend the evidence base and show the safety and the utility of SABR in early central tumours and oligometastatic disease.

Metastatic carcinoma from unknown primary site: the experience of a large oncology centre.

The case records of patients presenting with metastases from an unknown primary cancer (MUP) have been reviewed. Important prognostic variables were performance status and the presence of disease in more than one system. Patients of poor performance status and disease in multiple organs had a median survival of one month and 87% were dead within three months. Those patients of good performance status and disease apparent in only one organ had a median survival of seven months. Patients with carcinoma confined to lymph nodes in the high cervical region who received treatment with radiotherapy had 3- and 5-year survival rates of 26% and 17% respectively.

Routine follow-up of breast cancer patients.

The outcome of routine follow-up of women treated for breast cancer by mastectomy has been analysed. Over 157 woman-years of follow-up, 315 routine visits were made by 33 women who had been subjected to mastectomy. At these routine clinics two asymptomatic recurrences were diagnosed. Both of these patients died within 2 years of relapse. At 26 routine clinic visits, a diagnosis other than recurrence of breast cancer was made. Routine follow-up of women treated for breast cancer by mastectomy has limited value.

A patient with spontaneous regression of urothelial malignancy.

A 65-year-old male presented with prostatic transitional cell carcinoma, metastatic to lungs and lymph nodes. He was treated with palliative radiotherapy to the primary site. No other anticancer treatment was given. Almost 2 years later he is well with no signs or symptoms of progressive disease and the lung metastases seen on his chest radiograph have completely disappeared.

Single-agent mitomycin for advanced non-small cell lung cancer.

In the treatment of patients with advanced non-small cell lung cancer with chemotherapy, there is no consensus concerning the optimum regimen. Survival is poor and the activity of drugs has to be balanced against toxicity. There is therefore continued interest in the use of single-agent chemotherapy for this condition. I report the treatment of non-small cell lung cancer with mitomycin. In 20 patients, four responses were observed, giving a response rate of 20% (95% confidence interval (CI) 3-37); median survival was 26 weeks (95% CI 13-30). One patient who presented with bone and liver metastases survived for 27 months after treatment.

Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria.

OBJECTIVE: To examine whether the observed excess of childhood leukaemia and lymphoma near the Sellafield nuclear plant is associated with established risk factors or with factors related to the plant. DESIGN: A case-control study. SETTING: West Cumbria health district. SUBJECTS: 52 Cases of leukaemia, 22 of non-Hodgkin's lymphoma, and 23 of Hodgkin's disease occurring in people born in the area and diagnosed there in 1950-85 under the age of 25 and 1001 controls matched for sex and date of birth taken from the same birth registers as the cases. MAIN OUTCOME MEASURES: Antenatal abdominal x ray examinations, viral infections, habit factors, proximity to and employment characteristics of parents at Sellafield. RESULTS: Expected associations with prenatal exposure to x rays were found, but little information was available on viral illnesses. Relative risks for leukaemia and non-Hodgkin's lymphoma were higher in children born near Sellafield and in children of fathers employed at the plant, particularly those with high radiation dose recordings before their child's conception. For example, the relative risks compared with area controls were 0.17 (95% confidence interval 0.05 to 0.53) for being born further than 5 km from Sellafield 2.44 (1.04 to 5.71) for children of fathers employed at Sellafield at their conception, and 6.42 (1.57 to 26.3) for children of fathers receiving a total preconceptual ionising radiation dose of 100 mSv or more. Other factors, including exposure to x rays, maternal age, employment elsewhere, eating seafood, and playing on the beach did not explain these relationships. Focusing on Seascale, where the excess incidence has predominantly been reported, showed for the four out of five cases of leukaemia and one case of non-Hodgkin's lymphoma whose fathers were employed at Sellafield and for whom dose information was obtained that the fathers of each case had higher radiation doses before their child's conception than all their matched control fathers; the father of the other Seascale case (non-Hodgkin's lymphoma) was not employed at the plant. These results seem to explain statistically the geographical association. For Hodgkin's disease neither geographical nor employment associations with Sellafield were found. CONCLUSIONS: The raised incidence of leukaemia, particularly, and non-Hodgkin's lymphoma among children near Sellafield was associated with paternal employment and recorded external dose of whole body penetrating radiation during work at the plant before conception. The association can explain statistically the observed geographical excess. This result suggests an effect of ionising radiation on fathers that may be leukaemogenic in their offspring, though other, less likely, explanations are possible. There are important potential implications for radiobiology and for protection of radiation workers and their children.

Methods and basic data of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria.

OBJECTIVE: To examine whether the observed excess of childhood leukaemia and lymphoma near the Sellafield nuclear plant is associated with established risk factors or with factors related to the plant. DESIGN: A case-control study. SETTING: West Cumbria health district. SUBJECTS: 52 Cases of leukaemia, 22 of non-Hodgkin's lymphoma, and 23 of Hodgkin's disease occurring in people born in the area and diagnosed there in 1950-85 under the age of 25 and 1001 controls matched for sex and date of birth taken from the same birth registers as the cases. MAIN OUTCOME MEASURES: Antenatal abdominal x ray examinations, viral infections, habit factors, proximity to and employment characteristics of parents at Sellafield. RESULTS: Ascertainment of cases through multiple sources was as complete as possible, and the diagnosis was established for nearly all cases from hospital records and by independent pathological review when suitable material (60% (58) of cases) was available. Identification and tracing of the parents of cases and controls enabled questionnaires to be forwarded to 730 (66%), and 467 (64%) of the questionnaires were returned completed. Obstetric records were located for 481 (44%) of the relevant births, more frequently in recent years. Linkage of study subjects to the Sellafield workforce file enabled dates of employment and records on external doses of whole body ionising radiation to be obtained. Concordance of information from duplicate sources (when available) was reasonably high with no indications of bias. CONCLUSION: Overall the collected data were sufficiently reliable for detailed analysis and careful interpretation.

Bevacizumab in non-small cell lung cancer: an overview of practice in the era of molecular testing.

The place of bevacizumab in the management of advanced non-small cell lung cancer (NSCLC) was reviewed. Particular reference has been made to the recent research on the systemic treatment of NSCLC indicating that treatment tailored to specifically identified morphology or genetic profile has recently changed practice. The result of this recent research means that bevacizumab has little, if any, place in the treatment of NSCLC.

SOCCAR: A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer and good performance status.

BACKGROUND: Cure of lung cancer is impossible without local tumour control. This can be compromised by accelerated repopulation of tumour cells during radiotherapy and chemotherapy. A strategy to minimise accelerated repopulation might improve local control. We investigated whether concurrent chemo-radiotherapy could be given safely over four weeks. METHODS: We conducted a randomised phase II trial in which patients with inoperable Stage III Non-Small Cell Lung Cancer (NSCLC) received a radical radiation dose over four weeks rather than conventional fractionation. Treatment was given either sequentially or concurrently with three to four cycles of cisplatinum and vinorelbine. 130 patients with inoperable stage III NSCLC and PS 0-1 were randomised to receive cisplatinum and vinorelbine with either sequential or concurrent chemo-radiation using 55Gy in 20 fractions over four weeks. The primary end-point was treatment related mortality. Secondary end-points were toxicity and survival. FINDINGS: Treatment related mortality was: 2.9% (exact 95% confidence interval [CI] 0.36-10.2%) and 1.7% (exact 95% CI 0.043-9.1%) for the Concurrent and Sequential group respectively; relative risk (RR) 1.25; (95% CI 0.55, 2.84). Toxicity was similar between arms; grade 3 or worse oesophagitis was 8.8% versus 8.5%; RR 1.02 (95% CI 0.58, 1.79). OS HR was 0.92; 95% CI (0.60-1.39; p=0.682). The 2 year overall survival rates were: 50% versus 46%; RR 1.06 (95% CI 0.77, 1.46) for Concurrent versus Sequential. INTERPRETATION: A strategy to minimise the effects of accelerated repopulation using accelerated hypofractionated radiotherapy with chemotherapy is feasible, and reasonably safe for patients with stage III NSCLC. The reported two year survival is promising and suggests that a four week regime of radiotherapy should be compared with conventionally fractionated radiotherapy in an adequately powered randomised controlled phase III trial.