Penella J Woll

The University of Sheffield, Sheffield, England, United Kingdom

Are you Penella J Woll?

Claim your profile

Publications (77)426.08 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Switch maintenance is an effective strategy in the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). Pazopanib is an oral, multi-targeted tyrosine kinase inhibitor (TKI). EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC. Patients with non-progressive disease after 4-6 cycles of chemotherapy were randomised to receive either pazopanib 800mg/day or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival and secondary end-points were progression-free survival (PFS) and safety. A total of 600 patients were planned to be randomised. The trial was prematurely stopped following an early interim analysis, after 102 patients were randomised to pazopanib (n=50) or placebo (n=52). Median age was 64years in both arms. Median overall survival was 17.4months for pazopanib and 12.3months for placebo (adjusted hazard ratio (HR) 0.72 [95% confidence interval (CI) 0.40-1.28]; p=0.257). Median PFS was 4.3months versus 3.2months (HR 0.67, [95% CI 0.43-1.03], p=0.068). PFS rates at 4months were 56% and 45% respectively. The majority of treatment-related adverse events (AEs) were grade 1-2. Grade 3-4 AEs (pazopanib versus placebo) were hypertension (38% versus 8%), neutropenia (8% versus 0%), and elevated SGPT (6% versus 0%). Of the patients randomised to pazopanib, 22% withdrew due to a treatment-related AE. Switch maintenance with pazopanib following platinum-based chemotherapy in advanced NSCLC patients had limited side-effects. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 06/2015; DOI:10.1016/j.ejca.2015.04.026 · 4.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided. The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)). These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    CancerSpectrum Knowledge Environment 05/2015; 107(5). DOI:10.1093/jnci/djv100 · 15.16 Impact Factor
  • Source
    Lung Cancer 01/2015; 87:S33. DOI:10.1016/S0169-5002(15)50084-6 · 3.74 Impact Factor
  • Lung Cancer 01/2015; 87:S20. DOI:10.1016/S0169-5002(15)50050-0 · 3.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiosarcoma is a rare subtype of soft tissue sarcoma (STS). Doxorubicin is the standard first-line chemotherapy for advanced STS. It is not known whether angiosarcoma response to anthracycline-based chemotherapy is different to other STS subtypes.
    European Journal of Cancer 12/2014; 50(18):3178-3186. DOI:10.1016/j.ejca.2014.10.004 · 4.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The use of potential surrogate endpoints for overall survival, such as disease-free-survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCT) in cancer. However, the definition of time-to-event (TTE) endpoints is rarely precise and lacks uniformity across trials. Endpoint definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE endpoints. We report guidelines for RCT in sarcomas and gastro-intestinal-stromal tumors (GIST).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiosarcomas are rare malignant vascular tumours. Angiosarcoma expression of vascular endothelial growth factor (VEGF) has previously been reported, but angiosarcoma expression of other angiogenic growth factors has not been systematically studied. Non-VEGF angiogenic growth factors are a potential mechanism of resistance to VEGF-targeted therapy, but they also represent potential therapeutic targets. Immunohistochemistry analysis evaluated the expression of 13 angiogenic growth factors and receptors in 27 separate benign and malignant archived human vascular tumour samples. The expression of 55 angiogenesis-related proteins was subsequently profiled in five fresh human angiosarcoma tumour samples using antibody arrays. Angiosarcomas expressed a variety of angiogenic growth factors. Significantly higher levels of Notch1 were detected compared with benign haemangiomas (p=0.033), but lower levels of basic fibroblast growth factor (bFGF) compared to benign haemangiomas (p=0.07) and inflammatory vascular lesions (p=0.009). Vascular tumour expression of FGF receptor (FGFR)-1 correlated with angiopoietin (Ang)-2, Tie2, hepatocyte growth factor (HGF) and Notch1 expression (p=0.001, p=0.001, p<0.001 and p<0.001 respectively). Notch1 also correlated with Tie2 expression (p=0.004). In conclusion, angiosarcomas express multiple angiogenic growth factors. Treatments could be targeted at individual angiogenic growth factors. However, our findings provide a rationale for combination therapy, or for treatments that target common downstream signalling intermediaries, such as Akt, mTOR or ERK.
    Experimental and Molecular Pathology 06/2014; 97(1). DOI:10.1016/j.yexmp.2014.06.010 · 2.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lung cancer is the most common cancer and smoking is the principal cause. Due to poor survival rates, symptom palliation and promotion of health-related quality of life (HRQoL) are primary outcomes for lung cancer patients. Given the established relationship between smoking and lung cancer, patients who have smoked may feel stigmatised or guilty after diagnosis, and more pessimistic about their illness and likely outcomes. This may have adverse implications for HRQoL. We explored HRQoL and support experiences among newly diagnosed patients with advanced lung cancer. Semistructured interviews were conducted with nine patients and analysed using interpretative phenomenological analysis. Patients described the physical, emotional and social impact of disease on HRQoL. Fear of compromising their immune system and adjusting to new relationship roles had a wide-ranging effect on patients' HRQoL. Patients acknowledged links between lung cancer and smoking but some continued to smoke. They were sensitive to the opinions of medical staff about smoking especially those who continued to smoke or recently quit. We conclude that staff should give clearer advice about the adverse implications of continued smoking. We discuss the potential value of diagnosis as a teachable moment for promoting smoking cessation among patients and family members.
    Supportive and Palliative Care 04/2014; DOI:10.1136/bmjspcare-2013-000589
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiosarcomas are rare malignant vascular tumours. Angiosarcoma expression of vascular endothelial growth factor (VEGF) has previously been reported, but angiosarcoma expression of other angiogenic growth factors has not been systematically studied. Non-VEGF angiogenic growth factors are a potential mechanism of resistance to VEGF-targeted therapy, but they also represent potential therapeutic targets. Immunohistochemistry analysis evaluated the expression of 13 angiogenic growth factors and receptors in 27 separate benign and malignant archived human vascular tumour samples. The expression of 55 angiogenesis-related proteins was subsequently profiled in five fresh human angiosarcoma tumour samples using antibody arrays. Angiosarcomas expressed a variety of angiogenic growth factors. Significantly higher levels of Notch1 were detected compared with benign haemangiomas (p = 0.033), but lower levels of basic fibroblast growth factor (bFGF) compared to benign haemangiomas (p = 0.07) and inflammatory vascular lesions (p = 0.009). Vascular tumour expression of FGF receptor (FGFR)-1 correlated with angiopoietin (Ang)-2, Tie2, hepatocyte growth factor (HGF) and Notch1 expression (p = 0.001, p = 0.001, p < 0.001 and p < 0.001 respectively). Notch1 also correlated with Tie2 expression (p = 0.004). In conclusion, angiosarcomas express multiple angiogenic growth factors. Treatments could be targeted at individual angiogenic growth factors. However, our findings provide a rationale for combination therapy, or for treatments that target common downstream signalling intermediaries, such as Akt, mTOR or ERK.
    Experimental and Molecular Pathology 01/2014; · 2.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiosarcomas are rare, aggressive vascular tumours known to express vascular endothelial growth factor (VEGF), a key pro-angiogenic growth factor. The aim of this study was to determine the potential effects of vascular-targeted agents for the treatment of angiosarcoma, using two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS), and human dermal microvascular endothelial cells (HuDMECs) for comparison. Protein arrays were used to assess the expression of angiogenesis-related proteins, and potential drug targets were assessed by ELISA and Western blotting. Response to vascular-targeted agents, including bevacizumab an anti-VEGF antibody, axitinib a VEGF-receptor tyrosine kinase inhibitor, everolimus an mTOR inhibitor, selumetinib a MEK inhibitor and vadimezan a vascular-disrupting agent were compared in functional in vitro cellular assays, including viability, differentiation and migration assays. ASM and ISO-HAS cells expressed a broad range of pro-angiogenic growth factors. ASM and ISO-HAS VEGF expression was significantly increased (p = 0.029) compared with HuDMECs. Striking responses were seen to vadimezan with an IC50 of 90 and 150 μg/ml for ASM and ISO-HAS cells, respectively. Selumetinib inhibited ASM with an IC50 of 1,750 ng/ml, but was not effective in ISO-HAS. Everolimus reduced both ASM and ISO-HAS viable cell counts by 20 % (p < 0.001). Minimal responses were observed to bevacizumab and axitinib in assays with ASM and ISO-HAS cells. Further studies are warranted to investigate mTOR inhibitors, MEK inhibitors and vascular-disrupting agents for the treatment of angiosarcoma.
    Cancer Chemotherapy and Pharmacology 11/2013; DOI:10.1007/s00280-013-2345-0 · 2.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma. Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening. Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71-0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %). Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.
    Supportive Care in Cancer 10/2013; 22(3). DOI:10.1007/s00520-013-2022-1 · 2.50 Impact Factor
  • 10/2013; 2(5):407-422. DOI:10.2217/lmt.13.47
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the association between cannabis smoking and lung cancer risk, data on 2159 lung cancer cases and 2985 controls were pooled from 6 case-control studies in the US, Canada, UK and New Zealand within the International Lung Cancer Consortium. Study-specific associations between cannabis smoking and lung cancer were estimated using unconditional logistic regression adjusting for sociodemographic factors, tobacco smoking status and pack-years; odds-ratio estimates were pooled using random effects models. Sub-group analyses were done for sex, histology, and tobacco smoking status. The shapes of dose-response associations were examined using restricted cubic spline regression. The overall pooled OR for habitual vs. non-habitual or never users was 0.96 (95% CI: 0.66-1.38). Compared to non-habitual or never users, the summary OR was 0.88 (95%CI: 0.63-1.24) for individuals who smoked 1 or more joint-equivalents of cannabis per day and 0.94 (95%CI: 0.67-1.32) for those consumed at least 10 joint-years. For adenocarcinoma cases the ORs were 1.73 (95%CI: 0.75-4.00) and 1.74 (95%CI: 0.85-3.55), respectively. However, no association was found for the squamous cell carcinoma based on small numbers. Weak associations between cannabis smoking and lung cancer were observed in never tobacco smokers. Spline modeling indicated a weak positive monotonic association between cumulative cannabis use and lung cancer, but precision was low at high exposure levels. Results from our pooled analyses provide little evidence for an increased risk of lung cancer among habitual or long-term cannabis smokers, although the possibility of potential adverse effect for heavy consumption cannot be excluded. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 08/2013; 136(4). DOI:10.1002/ijc.29036 · 5.01 Impact Factor
  • Lung Cancer 01/2013; 79:S9. DOI:10.1016/S0169-5002(13)70025-4 · 3.74 Impact Factor
  • Lung Cancer 01/2013; 79:S15–S16. DOI:10.1016/S0169-5002(13)70046-1 · 3.74 Impact Factor
  • Lung Cancer 01/2013; 79:S12. DOI:10.1016/S0169-5002(13)70035-7 · 3.74 Impact Factor
  • Lung Cancer 01/2013; 79:S15. DOI:10.1016/S0169-5002(13)70043-6 · 3.74 Impact Factor
  • Lung Cancer 01/2013; 79:S34. DOI:10.1016/S0169-5002(13)70098-9 · 3.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION:: Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma. METHODS:: Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan-Meier estimates and proportional hazards models, was performed for overall survival among patients with non-small-cell lung cancer (NSCLC) and SCLC. RESULTS:: Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA. CONCLUSION:: In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2012; 7(12):1823-1829. DOI:10.1097/JTO.0b013e31826aec2b · 5.80 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Many patients with advanced non-small-cell lung cancer (NSCLC) receive only active supportive care because of poor performance status or presence of several comorbidities. We investigated whether erlotinib improves clinical outcome in these patients. METHODS: TOPICAL was a double-blind, randomised, placebo-controlled, phase 3 trial, done at 78 centres in the UK. Eligibility criteria were newly diagnosed, pathologically confirmed NSCLC; stage IIIb or IV; chemotherapy naive; no symptomatic brain metastases; deemed unsuitable for chemotherapy because of poor (≥2) Eastern Cooperative Oncology Group performance status or presence of several comorbidities, or both; and estimated life expectancy of at least 8 weeks. Patients were randomly assigned (by phone call, in a 1:1 ratio, stratified by disease stage, performance status, smoking history, and centre, block size 10) to receive oral placebo or erlotinib (150 mg per day) until disease progression or unacceptable toxicity. Investigators, clinicians, and patients were masked to assignment. The primary endpoint was overall survival. Analyses were by intention to treat, and prespecified subgroup analyses included development of a rash due to erlotinib within 28 days of starting treatment. This study is registered, number ISRCTN 77383050. FINDINGS: Between April 14, 2005, and April 1, 2009, we randomly assigned 350 patients to receive erlotinib and 320 to receive placebo. We followed up patients until March 31, 2011. 657 patients died; median overall survival did not differ between groups (erlotinib, 3·7 months, 95% CI 3·2-4·2, vs placebo, 3·6 months, 3·2-3·9; unadjusted hazard ratio [HR] 0·94, 95% CI 0·81-1·10, p=0·46). 59% (178 of 302) of patients assigned erlotinib and who were assessable at 1 month developed first-cycle rash, which was the only independent factor associated with overall survival. Patients with first-cycle rash had better overall survival (HR 0·76, 95% CI 0·63-0·92, p=0·0058), compared with placebo. Compared with placebo, overall survival seemed to be worse in the group that did not develop first-cycle rash (1·30, 1·05-1·61, p=0·017). Grade 3 or 4 diarrhoea was more common with erlotinib than placebo (8% [28 of 334] vs 1% [four of 313], p=0·0001), as was high-grade rash (23% [79 of 334] vs 2% [five of 313], p<0·0001); other adverse events were much the same between groups. INTERPRETATION: Patients with NSCLC who are deemed unsuitable for chemotherapy could be given erlotinib. Patients who develop a first-cycle rash should continue to receive erlotinib, whereas those who do not have a rash after 28 days should discontinue erlotinib, because of the possibility of decreased survival. FUNDING: Cancer Research UK, Roche.
    The Lancet Oncology 10/2012; 13(11). DOI:10.1016/S1470-2045(12)70412-6 · 24.73 Impact Factor

Publication Stats

1k Citations
426.08 Total Impact Points

Institutions

  • 2004–2013
    • The University of Sheffield
      • • Department of Biomedical Science
      • • Department of Oncology
      • • Academic Unit of Clinical Oncology
      • • Medical School
      • • Institute for Cancer Studies
      Sheffield, England, United Kingdom
  • 2009
    • Papworth Hospital NHS Foundation Trust
      Papworth, England, United Kingdom
  • 2007
    • University of Southampton
      Southampton, England, United Kingdom
    • Ninewells Hospital
      Dundee, Scotland, United Kingdom
  • 2001–2005
    • University of Nottingham
      • Division of Pre-Clinical Oncology
      Nottigham, England, United Kingdom
  • 2003
    • University of Liverpool
      • Department of Human Anatomy & Cell Biology
      Liverpool, ENG, United Kingdom