Expert Consensus on the Management of Adverse Events from EGFR Tyrosine Kinase Inhibitors in the UK.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib are standard-of-care for first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC). These drugs have a proven benefit in terms of higher response rate, delaying progression and improvement of quality of life over palliative platinum-based chemotherapy. The most common adverse events (AEs) are gastrointestinal (GI) (diarrhoea and stomatitis/mucositis) and cutaneous (rash, dry skin and paronychia). These are usually mild, but if they become moderate or severe, they can have a negative impact on the patient's quality of life (QOL) and lead to dose modifications or drug discontinuation. Appropriate management of AEs, including prophylactic measures, supportive medications, treatment delays and dose reductions, is essential. A consensus meeting of a UK-based multidisciplinary panel composed of medical and clinical oncologists with a special interest in lung cancer, dermatologists, gastroenterologists, lung cancer nurse specialists and oncology pharmacists was held to develop guidelines on prevention and management of cutaneous (rash, dry skin and paronychia) and GI (diarrhoea, stomatitis and mucositis) AEs associated with the administration of EGFR-TKIs. These guidelines detail supportive measures, treatment delays and dose reductions for EGFR-TKIs. Although the focus of the guidelines is to support healthcare professionals in UK clinical practice, it is anticipated that the management strategies proposed will also be applicable in non-UK settings.

Feasibility of home delivery of pemetrexed in patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVES: To evaluate the feasibility and adherence to home delivery (HD) of pemetrexed maintenance treatment in patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC). MATERIALS AND METHODS: Exploratory, prospective, single-arm, Phase II study in advanced nsqNSCLC patients, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1 that did not progress after 4 first-line induction cycles of a platinum doublet. The first cycle of pemetrexed (500mg/m(2)) was hospital administered, further cycles were HD until progressive disease or discontinuation. Feasibility was assessed by the adherence rate to HD (probability of reversion to hospital administration or treatment discontinuation due to HD) as primary endpoint, and by health-related quality-of-life (HRQoL: EQ-5D, lung cancer symptom scale [LCSS]), satisfaction with HD, overall survival (OS), and safety. RESULTS: 52 patients (UK & Sweden) received a median of 4 (range 1-19) pemetrexed maintenance cycles. Adherence rate up to Cycle 6 was 98.0% (95% confidence interval [CI]: 86.4%, 99.7%). All but 2 patients remained on HD. 1 patient discontinued after Cycle 1 (patient decision), and 1 after Cycle 6 (non-compliance with oral dexamethasone). 87% (33/38) of the patients preferred home to hospital treatment and in 90% (28/31) of cases, physicians were satisfied with distant management of patients. During HD Cycles 2-4 mean change from baseline ranged from 3.0 to 7.7 for EQ-5D visual analog scale. The 6-month OS rate was 73% (95% CI: 58%, 83%). 1 patient had an HD-related adverse event (device-related infection, Grade 2) and 1 patient died after Cycle 1, before HD, due to a possibly drug-related atypical pneumonia. CONCLUSION: HD of pemetrexed maintenance treatment in patients with advanced nsqNSCLC was feasible, safe, and preferred by patients, while maintaining HRQoL. Physicians were satisfied with distant patient management.

Afatinib use in non-small cell lung cancer previously sensitive to epidermal growth factor receptor inhibitors: the United Kingdom Named Patient Programme.

INTRODUCTION: Afatinib prolongs progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) who were previously sensitive to erlotinib or gefitinib. This study investigated experience of afatinib under a Named Patient Use (NPU) programme. PATIENTS AND METHODS: Retrospective data for 63 patients were collected, including demographics, dose, toxicity and clinical efficacy. RESULTS: Response rate and median PFS were 14.3% and 2.6months, respectively. Diarrhoea and rash were the most common toxicities; 46% of patients required a dose reduction and 41% had a dose delay. CONCLUSIONS: Efficacy and safety in the NPU programme are consistent with the LUX-Lung 1 trial.

2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on first line/second and further lines of treatment in advanced disease.

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study.

BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

Using bevacizumab to treat metastatic cancer: UK consensus guidelines.

Concise guidance is lacking for the use of bevacizumab by practicing oncologists. Eight oncologists with experience of bevacizumab were joined by a cardiologist interested in treating hypertension to develop practical guidelines for managing patients receiving bevacizumab, using available clinical data.

Patient satisfaction with GP-led melanoma follow-up: a randomised controlled trial.

BACKGROUND: There are no universally accepted guidelines for the follow-up of individuals with cutaneous melanoma. Furthermore, to date, there have been no randomised controlled trials of different models of melanoma follow-up care. This randomised controlled trial was conducted to evaluate the effects of GP-led melanoma follow-up on patient satisfaction, follow-up guideline compliance, anxiety and depression, as well as health status. METHODS: A randomised controlled trial of GP-led follow-up of cutaneous melanoma was conducted over a period of 1 year with assessment by self-completed questionnaires and review of general practice-held medical records at baseline and 12 months later. It took place in 35 general practices in North-east Scotland. Subjects were 142 individuals (51.4% women 48.6% men; mean (s.d.) age 59.2 (15.2) years previously treated for cutaneous melanoma and free of recurrent disease. The intervention consisted of protocol-driven melanoma reviews in primary care, conducted by trained GPs and supported by centralised recall, rapid access pathway to secondary care and a patient information booklet. The main outcome measure was patient satisfaction measured by questionnaire. Secondary outcomes were adherence to guidelines, health status measured by Short Form-36 and the Hospital Anxiety and Depression Scale. RESULTS: There were significant improvements in 5 out of 15 aspects of patient satisfaction during the study year in those receiving GP-led melanoma follow-up (all P

James Willocks and the innovation of fetal cephalometry.

James Willocks (1928-2004), a Glasgow obstetrician, was an important pioneer of obstetric ultrasound and the originator of the first clinically useful technique of fetal cephalometry. He collaborated with Tom Duggan, an engineer, who designed and built an electronic cephalometer to be used in conjunction with a Kelvin Hughes industrial flaw detector. Working in the Royal Maternity Hospital, Willocks was able to measure the biparietal diameter to an accuracy of better than 2mm. This major innovation enabled fetal growth in the third trimester to be accurately charted and thus greatly improved the detection of placental insufficiency, as well as the management of antepartum haemorrhage, hypertension and other complications of late pregnancy.

Scientific knowledge and clinical authority in dentistry: James Sim Wallace and dental caries.

Once the germ theory had become generally accepted within medicine, the importance of experimental science to the improvement of medical practice could no longer be reasonably doubted. However, clinicians still sought to retain control of how knowledge that had originated in the laboratory was interpreted and applied within practical diagnostics and therapeutics. Thus how practitioners incorporated new scientific knowledge into their medical discourse and practice is a matter for careful empirical inquiry. James Sim Wallace, born in Renfrewshire in 1869 and a graduate in medicine from the University of Glasgow, was a leading figure in British dentistry throughout the first half of the twentieth century. Through an examination of his voluminous writings, we explore how the new 'chemico-parasitical' theory of dental caries was accommodated within dentists' understanding of oral hygiene. The paper also looks at the controversies that surrounded the application of the vitamin theory to the problems of rickets and dental caries, focusing on the contentious interaction between Sim Wallace and his colleagues, on the one hand, and the eminent physiologists May and Edward Mellanby, on the other.

The impact of primary tumour origins in patients with advanced oesophageal, oesophago-gastric junction and gastric adenocarcinoma--individual patient data from 1775 patients in four randomised controlled trials.

BACKGROUND: It is unclear if differential chemotherapy effects exist on overall survival (OS), response rate (RR) and toxicity depending on primary tumour origin [oesophageal versus oesophago-gastric junction (OGJ) versus gastric adenocarcinoma]. PATIENTS AND METHODS: A total of 2110 patients were enrolled in four randomised controlled trials (RCTs) assessing fluoropyrimidine +/- platinum-based chemotherapy. This analysis used individual patient data and restricted to patients with adenocarcinoma who received one or more dose of chemotherapy. Gastric origin was the control in comparisons of tumour origin. RESULTS: Of the 2110 patients randomised, 1775 (84%) patients had adenocarcinoma with oesophageal (n = 485), OGJ (n = 457) and gastric (n = 833) origins. The median OS was 9.5 months in oesophageal, 9.3 months in OGJ and 8.7 months in gastric cancer (P = 0.68). RR was 44.1% in oesophageal, 41.1% in OGJ and 35.6% in gastric cancers (P = 0.11 and 0.27, respectively, compared with gastric cancer on multivariate analysis). Toxicity composite end point occurred in 46%, 47% and 45% in oesophageal, OGJ and gastric cancers, respectively (P = 0.85 and 0.62 compared with gastric). CONCLUSIONS: In our large multicentre RCT dataset, no significant differences were demonstrated on multivariate analyses in OS, RR and toxic effects among patients with advanced oesophageal, OGJ and gastric adenocarcinoma. Future RCTs should not exclude oesophageal adenocarcinoma.

Factors contributing to the time taken to consult with symptoms of lung cancer: a cross-sectional study.

OBJECTIVES: To determine what factors are associated with the time people take to consult with symptoms of lung cancer, with a focus on those from rural and socially deprived areas. METHODS: A cross-sectional quantitative interview survey was performed of 360 patients with newly diagnosed primary lung cancer in three Scottish hospitals (two in Glasgow, one in NE Scotland). Supplementary data were obtained from medical case notes. The main outcome measures were the number of days from (1) the date participant defined first symptom until date of presentation to a medical practitioner; and (2) the date of earliest symptom from a symptom checklist (derived from clinical guidelines) until date of presentation to a medical practitioner. RESULTS: 179 participants (50%) had symptoms for more than 14 weeks before presenting to a medical practitioner (median 99 days; interquartile range 31-381). 270 participants (75%) had unrecognised symptoms of lung cancer. There were no significant differences in time taken to consult with symptoms of lung cancer between rural and/or deprived participants compared with urban and/or affluent participants. Factors independently associated with increased time before consulting about symptoms were living alone, a history of chronic obstructive pulmonary disease (COPD) and longer pack years of smoking. Haemoptysis, new onset of shortness of breath, cough and loss of appetite were significantly associated with earlier consulting, as were a history of chest infection and renal failure. CONCLUSION: For many people with lung cancer, regardless of location and socioeconomic status, the time between symptom onset and consultation was long enough to plausibly affect prognosis. Long-term smokers, those with COPD and/or those living alone are at particular risk of taking longer to consult with symptoms of lung cancer and practitioners should be alert to this.

Melanoma incidence and mortality in Scotland 1979-2003.

We studied 12,450 cases of invasive melanoma diagnosed in Scotland in 1979-2003, by thickness, pathological type, and body site at ages under 40, 40-59, and 60 years and over. Melanoma incidence trebled in males from 3.57 to 10.93/10(5) per year, and increased 2.3-fold in females from 5.60 to 12.96/10(5) per year. The rate of increase fell in each successive 5-year period. The greatest increase was in males aged 60 years and over at diagnosis. Significant incidence increases were seen in melanomas < 1 mm in all three age groups, but those > 4 mm only increased significantly at ages 60 years and over. All histological types increased significantly at ages 60 years and over, and in this age group the greatest increase was seen on the head and neck. Five-year disease-free survival improved steadily. Survival figures for 1994-1998 ranged from 93.6% for males and 95.8% for females with tumours < 1 mm, to 52.4 and 48.3%, respectively, for those with tumours > 4 mm. Over the 25 years, melanoma mortality doubled in males from 1.1 to 2.4/10(5) per year, but was unchanged in females at 1.5/10(5) per year. Public education on melanoma is required both for primary prevention and earlier diagnosis, particularly for older males.

A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer: a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1).

BACKGROUND: Phase III studies suggest that non-small-cell lung cancer (NSCLC) patients treated with cisplatin-docetaxel may have higher response rates and better survival compared with other platinum-based regimens. We report the final results of a randomised phase III study of docetaxel and carboplatin versus MIC or MVP in patients with advanced NSCLC. PATIENTS AND METHODS: Patients with biopsy proven stage III-IV NSCLC not suitable for curative surgery or radiotherapy were randomised to receive four cycles of either DCb (docetaxel 75 mg/m(2), carboplatin AUC 6), or MIC/MVP (mitomycin 6 mg/m(2), ifosfamide 3 g/m(2) and cisplatin 50 mg/m(2) or mitomycin 6 mg/m(2), vinblastine 6 mg/m(2) and cisplatin 50 mg/m(2), respectively), 3 weekly. The primary end point was survival, secondary end points included response rates, toxicity and quality of life. RESULTS: The median follow-up was 17.4 months. Overall response rate was 32% for both arms (partial response = 31%, complete response = 1%); 32% of MIC/MVP and 26% of DCb patients had stable disease. One-year survival was 39% and 35% for DCb and MIC/MVP, respectively. Two-year survival was 13% with both arms. Grade 3/4 neutropenia (74% versus 43%, P < 0.005), infection (18% versus 9%, P = 0.01) and mucositis (5% versus 1%, P = 0.02) were more common with DCb than MIC/MVP. The MIC/MVP arm had significant worsening in overall EORTC score and global health status whereas the DCb arm showed no significant change. CONCLUSIONS: The combination of DCb had similar efficacy to MIC/MVP but quality of life was better maintained.

Efficacy and tolerability of chemotherapy in elderly patients with advanced oesophago-gastric cancer: A pooled analysis of three clinical trials.

The aim of this study was to determine the benefits of chemotherapy for oesophago-gastric cancer (OGC) in patients 70 years and above (> or =70) in comparison to younger patients. 1080 patients were enrolled into three randomised controlled trials assessing fluorouracil-based combination chemotherapy. Patients received either a platinum-containing regimen (ECF, MCF), PVI 5-FU (protracted venous infusion of 5-fluorouracil)+/-mitomycin C (MMC), or FAMTX. Of the 1080 patients randomised, 257 (23.8%) were aged > or =70 years. There were no significant differences in the incidence of grades 3/4 toxicity between the two cohorts. Objective and symptomatic response rates, failure-free and overall survival were not significantly different. In a multivariate analysis, independent prognostic factors for survival were performance status and locally advanced disease, not age. Patients > or =70 years with OGC obtained similar benefits from palliative chemotherapy with respect to symptomatic response, tumour regression and survival, without increased toxicities.

Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF.

The purpose of the study was to establish the optimal dose of capecitabine (X) to be used within a multicentre, randomised study evaluating the potential roles of oxaliplatin (O) and X in chemonaive patients (pts) with advanced oesophagogastric cancer. Two by two design was used, and pts were randomised to one of four regimens and stratified for extent of disease, performance status (PS) and centre. The treatment regimens are epirubicin, cisplatin, 5-fluorouracil (ECF), EOF, ECX or EOX. Doses: E 50 mg m(-2), C 60 mg m(-2) and O 130 mg m(-2) i.v. 3 weekly; F 200 mg m(-2) day(-1) i.v. and X 500 mg m(-2) b.i.d.(-1) (escalated to 625 mg m(-2) b.i.d.(-1) after results of first interim analysis) p.o., continuously. First interim analysis was performed when 80 pts had been randomised. Dose-limiting fluoropyrimidine toxicities were stomatitis, palmar plantar erythema (PPE) and diarrhoea; 5.1% of X-treated pts experienced grade 3/4 toxicity. Protocol planned dose escalation of X to 625 mg m(-2) b.i.d.(-1) was instituted and a second interim analysis has been performed; results are presented in this paper. A total of 204 pts were randomised at the time of the protocol planned 2nd interim analysis. Grade 3/4 fluoropyrimidine-related toxicity was seen in 13.7% pts receiving F, 8.4% pts receiving X 500 mg m(-2) b.i.d.(-1) and 14.7% pts receiving X 625 mg m(-2) b.i.d.(-1). Combined complete and partial response rates were ECF 31% (95% CI 18.7-46.3), EOF 39% (95% CI 25.9-53.1), ECX 35% (95% CI 21.4-50.3), EOX 48% (95% CI 33.3-62.8). Grade 3/4 fluoropyrimidine toxicity affected 14.7% of pts treated with X 625 mg m(-2) b.i.d.(-1), which is similar to that observed with F, confirming this to be the optimal dose. The replacement of C by O and F by X does not appear to impair efficacy. The trial continues to total accrual of 1000 pts.

Hyaline membrane and neonatal radiology--Ian Donald's first venture into imaging research.

While he was working at the Royal Postgraduate Medical School, Ian Donald (later Regius Professor of Midwifery, University of Glasgow and a pioneer of diagnostic ultrasound) collaborated with Albert Claireaux and Robert Steiner on histological and radiological studies of hyaline membrane disease. In 1953, Donald and Steiner published thefirst radiological study of a series of cases. The success of this research stimulated Donald's interest in imaging technologies.

Patient motivations surrounding participation in phase I and phase II clinical trials of cancer chemotherapy.

Successful advances in the treatment of advanced malignant diseases rely on recruitment of patients into clinical trials of novel agents. However, there is a genuine concern for the welfare of individual patients. The aim of this study was to examine motives of patients entering early clinical trials of novel cancer therapies. Questionnaire survey with both open- and close-ended questions. The patients were surveyed after they had given informed consent and before or during the first cycle of treatment. In all, 38 phase I/II trial patients participated and completed the survey. Obtaining possible health benefit was listed by 89% as being a 'very important' factor in their decision to participate, with only 17% giving reasons of helping future cancer patients and treatment. Other items cited as a 'very important' motivating factor were 'trust in the doctor' (66%), 'being treated by the latest treatment available' (66%), 'better standard of care and closer follow-up' (61%), and 'closer monitoring of patients in trials' (58%). Only 47% patients indicated that someone had explained to them about any 'reasonable' alternatives to the trial. In total, 71% strongly agreed that 'surviving for as long time as possible was the most important thing (for them)'. Nearly all (97%) indicated that they knew the purpose of the trial and had enough time to consider participation in the trial (100%). In this survey, most patients entering phase I and II clinical trials felt they understood the purpose of the research and had given truly informed consent. Despite this, most patients participated in the hope of therapeutic benefit, although this is known to be a rare outcome in this patient subset. Trialists should be aware, and take account of the expectations that participants place in trial drugs.

Mucosal malignant melanoma of the head and neck: the Marsden experience over half a century.

We reviewed patients treated at The Royal Marsden Hospital for mucosal malignant melanoma of the head and neck between 1945 and 1996. The analysis included 89 patients, and this study is the largest so far reported from a single institution in the literature. The overall 5-year survival rate for the patient population was 23% (95% confidence interval: 14-33) and the 10-year survival rate was 12%, (6-21%). The only significant predictor of survival was the tumour stage at presentation. Radical local excision was the only treatment that provided a chance of cure. Adding radiotherapy to surgery in tumours that could be radically excised did not confer any statistically significant advantage in reducing local recurrence or improving survival.