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Sophie Papa,
Sanjay Popat,
Riyaz Shah,
A Toby Prevost,
Rohit Lal,
Blair McLennan,
Paul Cane,
Loic Lang-Lazdunski,
Zaid Viney,
Joel T Dunn,
Sally Barrington,
David Landau, James Spicer
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ABSTRACT: 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.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2013; · 4.55 Impact Factor
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ABSTRACT: Background:Despite the high prevalence and impact of episodic breathlessness, information about characteristics and patterns is scarce.Aim:To explore the experience of patients with advanced disease suffering from episodic breathlessness, in order to describe types and patterns.Design and participants:Qualitative design using in-depth interviews with patients suffering from advanced stages of chronic heart failure, chronic obstructive pulmonary disease, lung cancer or motor neurone disease. As part of the interviews, patients were asked to draw a graph to illustrate typical patterns of breathlessness episodes. Interviews were tape-recorded, transcribed verbatim and analysed using Framework Analysis. The graphs were grouped according to their patterns.Results:Fifty-one participants (15 chronic heart failure, 14 chronic obstructive pulmonary disease, 13 lung cancer and 9 motor neurone disease) were included (mean age 68.2 years, 30 of 51 men, mean Karnofsky 63.1, mean breathlessness intensity 3.2 of 10). Five different types of episodic breathlessness were described: triggered with normal level of breathlessness, triggered with predictable response (always related to trigger level, e.g. slight exertion causes severe breathlessness), triggered with unpredictable response (not related to trigger level), non-triggered attack-like (quick onset, often severe) and wave-like (triggered or non-triggered, gradual onset). Four patterns of episodic breathlessness could be identified based on the graphs with differences regarding onset and recovery of episodes. These did not correspond with the types of breathlessness described before.Conclusion:Patients with advanced disease experience clearly distinguishable types and patterns of episodic breathlessness. The understanding of these will help clinicians to tailor specific management strategies for patients who suffer from episodes of breathlessness.
Palliative Medicine 03/2013; · 2.38 Impact Factor
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ABSTRACT: CONTEXT: Unlike pain, where the concept of breakthrough and background pain has been widely characterized and defined, breathlessness as a symptom has not yet been fully explored and has been rarely categorized. OBJECTIVES: To explore patients' experiences and descriptions of breathlessness to categorize breathlessness. METHODS: Qualitative study using in-depth interviews with patients suffering from four life-limiting and advanced diseases (chronic heart failure, chronic obstructive pulmonary disease, lung cancer, and motor neuron disease). Interviews were tape-recorded, transcribed verbatim, and analyzed using Framework analysis method. RESULTS: A total of 51 participants were interviewed (mean ± SD age 68.2 ± 11.6 years; 30 of 51 male; median Karnofsky 60%; mean ± SD breathlessness intensity 3.2 ± 1.7 of 10). Episodic breathlessness and continuous breathlessness were the main categories, with subcategories of triggered and non-triggered episodic breathlessness and continuous breathlessness for short and long periods. Episodic breathlessness triggered by exertion, non-triggered episodic breathlessness, and continuous breathlessness for a long period ("constant variable") were the most frequent and important categories with a high impact on daily living. Exertional breathlessness occurred in nearly all participants. Participants could differentiate episodic breathlessness (seconds, minutes, or hours) and continuous breathlessness (days, weeks, or months) by time. Episodic breathlessness occurred in isolation or in conjunction with continuous breathlessness. CONCLUSION: Participants categorize their breathlessness by time and triggers. The categorization needs further verification, similar to that already established in pain, and can be used as a new evidence-based categorization to advance our understanding of this under-researched, yet high impact, symptom to optimize management.
Journal of pain and symptom management 09/2012; · 2.42 Impact Factor
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ABSTRACT: The treatment of malignant pleural mesothelioma (MPM) remains controversial. We present a prospective study of patients treated at our institution with neoadjuvant chemotherapy, extrapleural pneumonectomy (EPP), and radical radiotherapy.
Patients with MPM who were eligible for EPP and multimodality therapy were included in this study. Staging was through computed tomography and positron emission tomography and computed tomography (PET/CT) scanning, video-assisted thoracoscopic surgery (VATS), and mediastinoscopy. Our protocol involved three cycles of cisplatin-based neoadjuvant chemotherapy followed by extrapleural pneumonectomy and adjuvant radiotherapy (54 Gy). All patients were followed up every 3-6 months until death.
From March 2004 through October 2008, 25 patients were referred for EPP following neoadjuvant chemotherapy. EPP was performed in all but three patients, who were found to have T4 disease at surgery. Surgical complications included arrhythmias (28%), bronchopleural fistulas (12 %), reoperations for bleeding (8%), acute respiratory distress syndrome (4%), pneumonia (4%), septicemia (4%), vocal cord palsy (4%), and Horner's syndrome (4%). The 30-day mortality was 4%. Adjuvant radiotherapy was administered to 81% of patients after EPP. Radiotherapy toxicities included thrombocytopenia, radiation pneumonitis, pulmonary embolus, radiation hepatitis, herpes zoster, transverse myelitis, and late constrictive pericarditis. Median survival from diagnosis was 12.8 months (95% confidence interval 7.8-17.7 months). One-year survival was 54.5%; 2-year survival was 18.2%. Disease progression occurred in 77.3% of patients. Nodal status (N0 disease versus N1-N2) or histology (epithelioid versus biphasic) had no significant impact on survival.
Despite recent advances in chemotherapy, surgery, and radiotherapy, survival rates remain low for patients with MPM completing multimodality therapy including EPP.
General Thoracic and Cardiovascular Surgery 05/2012; 60(5):289-96.
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ABSTRACT: 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.
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.
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.
In our experience, P/D, hyperthermic pleural lavage with povidone-iodine, and adjuvant chemotherapy were superior to neoadjuvant chemotherapy, EPP, and adjuvant radiotherapy.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2012; 7(4):737-43. · 4.55 Impact Factor
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Judith M Bliss,
Gill Coombes,
Liz Darlison,
John Edwards,
James Entwisle,
Lucy S Kilburn,
David Landau,
Loic Lang-Lazdunski,
Mary O'Brien,
Ken O'Byrne,
Julian Peto,
Suresh Senan,
Michael Snee, James Spicer,
Carol Tan,
Gill Thomas,
Tom Treasure,
David Waller
The lancet oncology 11/2011; 12(12):1094-5. · 14.47 Impact Factor
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ABSTRACT: The incidence of small cell lung cancer (SCLC) is often quoted as 'around 20%' of all lung cancers but is reportedly decreasing over time. We analysed the trends in incidence of SCLC and compared these with the trends in lung cancer overall among males and females in South East England.
We identified 237,792 patients diagnosed with lung cancer (ICD-10 C33-C34) between 1970 and 2007. We used a Poisson regression age-cohort model to estimate the age-specific rates in the 1890-1960 birth cohorts. We computed age-standardised incidence rates using the European standard population. In addition, we analysed the trends of lung cancer subtypes according to morphology.
In the most recent time period, SCLC accounted for 10% and 11% of cases of all lung cancer among males and females, respectively. Among the morphologically specified lung cancers, SCLC accounted for 15% and 17% among males and females, respectively. There was a decrease of SCLC incidence over time and by birth cohort in both sexes. The decrease in SCLC was more marked than that in all lung cancers.
The decrease in SCLC incidence rates may reflect decreases in the prevalence of cigarette smoking, and changes in the type of cigarettes smoked.
Lung cancer (Amsterdam, Netherlands) 09/2011; 75(3):280-4. · 3.14 Impact Factor
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ABSTRACT: 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.
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.
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).
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.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2011; 6(10):1746-52. · 4.55 Impact Factor
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Tom Treasure,
Loic Lang-Lazdunski,
David Waller,
Judith M Bliss,
Carol Tan,
James Entwisle,
Michael Snee,
Mary O'Brien,
Gill Thomas,
Suresh Senan,
Ken O'Byrne,
Lucy S Kilburn, James Spicer,
David Landau,
John Edwards,
Gill Coombes,
Liz Darlison,
Julian Peto
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ABSTRACT: The effects of extra-pleural pneumonectomy (EPP) on survival and quality of life in patients with malignant pleural mesothelioma have, to our knowledge, not been assessed in a randomised trial. We aimed to assess the clinical outcomes of patients who were randomly assigned to EPP or no EPP in the context of trimodal therapy in the Mesothelioma and Radical Surgery (MARS) feasibility study.
MARS was a multicentre randomised controlled trial in 12 UK hospitals. Patients aged 18 years or older who had pathologically confirmed mesothelioma and were deemed fit enough to undergo trimodal therapy were included. In a prerandomisation registration phase, all patients underwent induction platinum-based chemotherapy followed by clinical review. After further consent, patients were randomly assigned (1:1) to EPP followed by postoperative hemithorax irradiation or to no EPP. Randomisation was done centrally with computer-generated permuted blocks stratified by surgical centre. The main endpoints were feasibility of randomly assigning 50 patients in 1 year (results detailed in another report), proportion randomised who received treatment, proportion eligible (registered) who proceeded to randomisation, perioperative mortality, and quality of life. Patients and investigators were not masked to treatment allocation. This is the principal report of the MARS study; all patients have been recruited. Analyses were by intention to treat. This trial is registered, number ISRCTN95583524.
Between Oct 1, 2005, and Nov 3, 2008, 112 patients were registered and 50 were subsequently randomly assigned: 24 to EPP and 26 to no EPP. The main reasons for not proceeding to randomisation were disease progression (33 patients), inoperability (five patients), and patient choice (19 patients). EPP was completed satisfactorily in 16 of 24 patients assigned to EPP; in five patients EPP was not started and in three patients it was abandoned. Two patients in the EPP group died within 30 days and a further patient died without leaving hospital. One patient in the no EPP group died perioperatively after receiving EPP off trial in a non-MARS centre. The hazard ratio [HR] for overall survival between the EPP and no EPP groups was 1·90 (95% CI 0·92-3·93; exact p=0·082), and after adjustment for sex, histological subtype, stage, and age at randomisation the HR was 2·75 (1·21-6·26; p=0·016). Median survival was 14·4 months (5·3-18·7) for the EPP group and 19·5 months (13·4 to time not yet reached) for the no EPP group. Of the 49 randomly assigned patients who consented to quality of life assessment (EPP n=23; no EPP n=26), 12 patients in the EPP group and 19 in the no EPP group completed the quality of life questionnaires. Although median quality of life scores were lower in the EPP group than the no EPP group, no significant differences between groups were reported in the quality of life analyses. There were ten serious adverse events reported in the EPP group and two in the no EPP group.
In view of the high morbidity associated with EPP in this trial and in other non-randomised studies a larger study is not feasible. These data, although limited, suggest that radical surgery in the form of EPP within trimodal therapy offers no benefit and possibly harms patients.
Cancer Research UK (CRUK/04/003), the June Hancock Mesothelioma Research Fund, and Guy's and St Thomas' NHS Foundation Trust.
The lancet oncology 06/2011; 12(8):763-72. · 14.47 Impact Factor
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Amy E Gilbert,
Panagiotis Karagiannis,
Tihomir Dodev,
Alexander Koers,
Katie Lacy,
Debra H Josephs,
Pooja Takhar,
Jenny L C Geh,
Ciaran Healy,
Mark Harries,
Katharine M Acland,
Sarah M Rudman,
Rebecca L Beavil,
Philip J Blower,
Andrew J Beavil,
Hannah J Gould, James Spicer,
Frank O Nestle,
Sophia N Karagiannis
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ABSTRACT: Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.
PLoS ONE 01/2011; 6(4):e19330. · 4.09 Impact Factor
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ABSTRACT: 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.
PLoS ONE 01/2011; 6(9):e25191. · 4.09 Impact Factor
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ABSTRACT: The optimal treatment for Masaoka stage IVA thymoma remains controversial. Whilst extrapleural pneumonectomy (EPP) has been proposed, we sought to examine the results of our institutional preference for induction chemotherapy, cytoreductive surgery and intraoperative hyperthermic pleural irrigation. We undertook a retrospective study of patients undergoing surgery for Masaoka stage IVA thymoma following induction chemotherapy over a three-year period at our institution. Between February 2007 and February 2010, 42 patients underwent surgery for thymoma. Six patients underwent surgery with intent to perform cytoreductive surgery and intraoperative hyperthermic pleural irrigation. Complete cytoreductive surgery was not feasible in one patient and thymectomy only was performed. One patient had re-operation for recurrent disease 24 months after the first operation and there were therefore seven procedures undertaken in six patients during the study period. There were no in-hospital deaths. Median follow-up was 18.8 months (range 1.5-31.9 months). One patient died 14 months postoperatively from an acute cardiovascular event. The four remaining patients are alive and well with no evidence of disease recurrence. Multimodality therapy consisting of induction chemotherapy and cytoreductive surgery is a safe, feasible treatment for stage IVA thymoma. Our experience suggest that full pleurectomy is an alternative to EPP.
Interactive cardiovascular and thoracic surgery 12/2010; 12(5):744-7.
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Charles Comins, James Spicer,
Andrew Protheroe,
Victoria Roulstone,
Katie Twigger,
Christine M White,
Richard Vile,
Alan Melcher,
Matt C Coffey,
Karl L Mettinger,
Gerard Nuovo,
David E Cohn,
Mitch Phelps,
Kevin J Harrington,
Hardev S Pandha
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ABSTRACT: REOLYSIN (Oncolytics Biotech) consists of a wild-type oncolytic reovirus, which has selective cytotoxicity for tumor cells while sparing normal cells. In a phase I study as a single agent, repeated infusions of reovirus were safe with evidence of antitumor activity. Preclinical studies indicate potential for synergy between reovirus and chemotherapeutic agents. A multicenter, phase I dose escalation study was designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer.
Patients received 75 mg/m(2) docetaxel (day 1) and escalating doses of reovirus up to 3 × 10(10) TCID(50) (days 1-5) every 3 weeks.
Twenty-five patients were enrolled, and 24 patients were exposed to treatment, with 23 completing at least one cycle and 16 suitable for response assessment. Dose-limiting toxicity of grade 4 neutropenia was seen in one patient, but the maximum tolerated dose was not reached. Antitumor activity was seen with one complete response and three partial responses. A disease control rate (combined complete response, partial response, and stable disease) of 88% was observed. Immunohistochemical analysis of reovirus protein expression was observed in posttreatment tumor biopsies from three patients.
The combination of reovirus and docetaxel is safe, with evidence of objective disease response, and warrants further evaluation in a phase II study at a recommended schedule of docetaxel (75 mg/m(2), three times weekly) and reovirus (3 × 10(10) TCID(50), days 1-5, every 3 weeks).
Clinical Cancer Research 10/2010; 16(22):5564-72. · 7.74 Impact Factor
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Timothy A Yap,
Laura Vidal,
Jan Adam,
Peter Stephens, James Spicer,
Heather Shaw,
Jooern Ang,
Graham Temple,
Susan Bell,
Mehdi Shahidi,
Martina Uttenreuther-Fischer,
Peter Stopfer,
Andrew Futreal,
Hilary Calvert,
Johann S de Bono,
Ruth Plummer
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ABSTRACT: Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy.
Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state.
Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non-small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting > or = 6 months.
Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.
Journal of Clinical Oncology 09/2010; 28(25):3965-72. · 18.37 Impact Factor
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Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2010; 5(6):921-3. · 4.55 Impact Factor
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Lars Holmberg,
Fredrik Sandin,
Freddie Bray,
Mike Richards, James Spicer,
Mats Lambe,
Asa Klint,
Mick Peake,
Trond-Eirik Strand,
Karen Linklater,
David Robinson,
Henrik Møller
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ABSTRACT: BACKGROUND Countries with a similar expenditure on healthcare within Europe exhibit differences in lung cancer survival. Survival in lung cancer was studied in 2001-2004 in England, Norway and Sweden. METHODS Nationwide cancer registries in England, Norway and Sweden were used to identify 250 828 patients with lung cancer from England, 18 386 from Norway and 24 886 from Sweden diagnosed between 1996 and 2004, after exclusion of patients registered through death certificate only or with missing, zero or negative survival times. 5-Year relative survival was calculated by application of the period approach. The excess mortality between the countries was compared using a Poisson regression model. RESULTS In all subcategories of age, sex and follow-up period, the 5-year survival was lower in England than in Norway and Sweden. The age-standardised survival estimates were 6.5%, 9.3% and 11.3% for men and 8.4%, 13.5% and 15.9% for women in the respective countries in 2001-2004. The difference in excess risk of dying between the countries was predominantly confined to the first year of follow-up. The relative excess risk ratio during the first 3 months of follow-up comparing England with Norway 2001-2004 varied between 1.23 and 1.46, depending on sex and age, and between 1.56 and 1.91 comparing England with Sweden. CONCLUSION Access to healthcare and population awareness are likely to be major reasons for the differences, but it cannot be excluded that diagnostic and therapeutic activity play a role. Future improvements in lung cancer management may be seen early in follow-up.
Thorax 05/2010; 65(5):436-41. · 6.84 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2010; 5(3):385-8. · 4.55 Impact Factor
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Tom Treasure,
David Waller,
Carol Tan,
James Entwisle,
Mary O'Brien,
Ken O'Byrne,
Gill Thomas,
Michael Snee, James Spicer,
David Landau,
Loïc Lang-Lazdunski,
Judith Bliss,
Clare Peckitt,
Shaun Rogers,
Erica Marriage Née Denholm,
Gillian Coombes,
Mark Webster-Smith,
Julian Peto
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ABSTRACT: 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.
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.
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.
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.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2009; 4(10):1254-8. · 4.55 Impact Factor
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Alison H M Reid,
Andrew Protheroe,
Gerhardt Attard,
Nikki Hayward,
Laura Vidal, James Spicer,
Heather M Shaw,
Elizabeth A Bone,
Joanne Carter,
Leon Hooftman,
Adrian Harris,
Johann S De Bono
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ABSTRACT: To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary therapeutic activity profile of CHR-2797 (tosedostat), a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases with antiproliferative and antiangiogenic activity in vitro.
A phase I study of accelerated titration design that escalated through nine doses (10-320 mg) in patients (Eastern Cooperative Oncology Group performance status, < or =2) with advanced solid tumors. CHR-2797 was administered once daily.
Forty patients (median age, 60 years; range, 24-80 years; male, 27; female, 13) were treated in 12 cohorts with once daily doses (10-320 mg). Dose-limiting toxicities were thrombocytopenia, dizziness, and visual abnormalities in one patient, and anemia, blurred vision, and vomiting in a second patient at 320 mg, resulting in an inability to complete 28 days of study drug. The most commonly observed toxicities were fatigue, diarrhea, peripheral edema, nausea, dizziness, and constipation. One patient had a partial response (renal cell carcinoma) and four patients had stable disease for >6 months. CHR-2797 and its active metabolite, CHR-79888, show dose-proportional increases in plasma AUC and C(max). The terminal half-life for CHR-2797 is approximately 1 to 3.5 hours and between 6 and 11 hours for CHR-79888. Intracellular (packed blood cells) exposure to CHR-79888 is consistent with intracellular levels that proved to be efficacious in xenograft models.
CHR-2797 is well tolerated and can be safely administered at doses that result in intracellular levels of CHR-79888 that are associated with activity in preclinical models. The recommended dose for single agent therapy in solid tumors is 240 mg/d.
Clinical Cancer Research 08/2009; 15(15):4978-85. · 7.74 Impact Factor
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ABSTRACT: Inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) has an established role in the treatment of advanced non-small cell lung cancer. The first-generation EGFR inhibitors erlotinib and gefitinib have been approved for treatment in the second- and third-line setting. Second-generation EGFR tyrosine kinase inhibitors are now in development aiming to improve efficacy and overcome primary and secondary resistance to the first-generation drugs. The two most common strategies being used to achieve these aims are irreversible binding of drug to target and kinase multi-targeting. This is an overview of the early clinical development of selected second-generation tyrosine kinase inhibitors focusing on the treatment of non-small cell lung cancer.
Expert Opinion on Investigational Drugs 04/2009; 18(3):293-301. · 5.27 Impact Factor
