Penella J Woll

The University of Sheffield, Sheffield, England, United Kingdom

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Publications (75)392.38 Total impact

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    ABSTRACT: Purpose: Smoking is a major cause of lung cancer, and continued smoking may compromise treatment efficacy and quality of life (health-related quality of life (HRQoL)) in patients with advanced lung cancer. Our aims were to determine (i) preference for treatments which promote quality over length of life depending on smoking status, (ii) the relationship between HRQoL and smoking status at diagnosis (T1), after controlling for demographic and clinical variables, and (iii) changes in HRQoL 6 months after diagnosis (T2) depending on smoking status. Methods: Two hundred ninety-six patients with advanced lung cancer were given questionnaires to assess HRQoL (EORTC QLQ-C30), time-trade-off for life quality versus quantity (QQQ) and smoking history (current, former or never smoker) at diagnosis (T1) and 6 months later (T2). Medical data were extracted from case records. Results: Questionnaires were returned by 202 (68.2 %) patients at T1 and 114 (53.3 %) at T2. Patients favoured treatments that would enhance quality of life over increased longevity. Those who continued smoking after diagnosis reported worse HRQoL than former smokers or those who never smoked. Smoking status was a significant independent predictor of coughing in T1 (worse in smokers) and cognitive functioning in T2 (better in never smokers). Conclusions: Smoking by patients with advanced lung cancer is associated with worse symptoms on diagnosis and poorer HRQoL for those who continue smoking. The results have implications to help staff explain the consequences of smoking to patients.
    No preview · Article · Sep 2015 · Supportive Care in Cancer
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    ABSTRACT: A strong association between smoking and SCLC is noted whereas the dose–response relationships are less clear. We demonstrate that cumulative smoking of the first 50 pack-years is associated with a sharper increase in SCLC risk. Moreover, although the relationship between smoking and COPD or COPD and SCLC is well-established, no study has investigated the causal pathway among smoking, COPD, and SCLC. Here we reveal the risks of smoking behaviors on SCLC which are partially mediated (up to 7.6%) through COPD. The findings warrant further experimental study to elucidate the mechanisms in this causal pathway.
    Full-text · Article · Sep 2015 · EBioMedicine
  • Shobha C Silva · Caroline Wilson · Penella J Woll
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    ABSTRACT: Over a third of patients with lung cancer will develop bone metastases during the course of their disease, resulting in symptoms of pain and immobility, and skeletal-related events (SREs) such as fracture, hypercalcaemia, surgery or radiotherapy to bones, and malignant spinal cord compression. These reduce quality of life and increase mortality. Preclinical research has identified the interactions between tumour cells and bone that are key to tumour cell survival and associated osteolysis. These data have led to the development of drugs to prevent osteoclast-mediated bone breakdown, such as zoledronic acid and denosumab, which are now licensed for use in patients with bone metastases from solid tumours. Both zoledronic acid and denosumab reduce the risk of SREs and increase time to first SRE, with minimal side effects. In addition, denosumab improved survival in patients with lung cancer compared with zoledronic acid. Ongoing trials are testing whether these drugs can prevent the development of bone metastases from lung cancer. New bone-targeted agents showing promise in breast and prostate cancer include radium-223, cabozantinib and Src inhibitors. These agents require further evaluation in patients with lung cancer.
    No preview · Article · Jul 2015
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    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.
    Full-text · Article · Jun 2015 · European journal of cancer (Oxford, England: 1990)
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    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.
    Full-text · Article · May 2015 · Journal of the National Cancer Institute

  • No preview · Article · Jan 2015 · Lung Cancer
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    Full-text · Article · Jan 2015 · Lung Cancer
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    ABSTRACT: Background: Angiosarcoma is a rare subtype of soft tissue sarcoma (STS). Doxorubicinis 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. Methods: Pooled data were analysed from 11 prospective randomised and non-randomized European Organisation for Research and Treatment of Cancer (EORTC) clinical trials of first-line anthracycline-based chemotherapy for advanced STS. Baseline patient characteristics, chemotherapy response, progression free survival (PFS) and overall survival (OS) of angiosarcoma patients were compared with other STS patients. Analysis was performed to identify factors prognostic for angiosarcoma response to chemotherapy, PFS and OS. Results: With a median follow-up of 4.2 years, data from 108 locally advanced and metastatic angiosarcoma patients and 2557 patients with other STS histologies were analysed. 25% of angiosarcoma patients had a complete or partial response to chemotherapy compared to 21% for other STS histotypes. The median PFS was 4.9 months and OS 9.9 months, which were not significantly different from other STS histotypes. In univariate analysis, bone metastases were an adverse prognostic factor for OS (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.03–2.67; p = 0.036). Tumour grade was as an adverse prognostic factor for PFS (HR 1.72, 95% CI 1.01–2.92; p = 0.044) and OS (HR 2.03; 95% CI 1.16–3.56; p = 0.011). Compared to single agent anthracyclines, doxorubicin + ifosfamide was associated with improved PFS (HR 0.53, 95% CI 0.33–0.86; p = 0.010) and OS (HR 0.53, 95% CI 0.32–0.90; p = 0.018). Conclusions: Angiosarcoma response and survival following first-line anthracycline-based chemotherapy was similar to other STS histotypes. Our analysis provides a useful measure of angiosarcoma response to chemotherapy for comparison with future clinical trials.
    No preview · Article · Dec 2014 · European Journal of Cancer
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    ABSTRACT: Aim Switch maintenance is an effective strategy in advanced NSCLC treatment. Pz is an orally active, multi-targeted tyrosine kinase inhibitor (TKI), potentially effective in lung cancer. EORTC 08092 evaluated Pz given as maintenance following standard first line platinum-based chemotherapy (CT) in pts with advanced NSCLC. Methods Pts with non-progressive disease after 4-6 cycles of CT were randomized to receive either Pz 800 mg/day or matched placebo until progression or unacceptable toxicity. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and safety. Assuming 80% power and 5% 2-side type I error and taking into account an Interim Analysis (IA) for futility based on PFS, 587 pts had to be randomized in order to improve median overall survival (OS) from 9.7 to 12.7 months. Results After 102 pts were randomized to Pz (n = 50) or P (n = 52), the trial was prematurely stopped due to an early IA. Median age was 64 years in both arms. Baseline characteristics for Pz and P arms (%): male/female: 57/43 and 55/45; squamous/non-squamous-cell: 78/22 and 82/18; ECOG PS 0/1/2: 21/75/4 and 36/64/0; Prior Chemotherapy Response CR-PR/SD: 27/73 and 32/68; current/former/never smoker/NA: 8/67/19/6 and 22/52/22/4. OS was not significantly different, median 17.4 months(m) for Pz vs. 12.3 m for P (adjusted HR was 0.72 [95% CI 0.40-1.28]; p = 0.257). Median PFS was 4.3 m vs. 3.2 m (HR 0.67, [95% CI 0.43,1.03]), p = 0.068. PFS rates at 4 months were 56% and 45% respectively. Pz was well tolerated: the majority of treatment-related adverse events (AEs) were grade 1/2. Reported grade 3/4 AEs (% Pz vs. P) were neutropenia (8% vs. 0%), hypertension (38% vs. 8%) and elevated SGPT (6% vs. 0%). Only 22% of pts receiving Pz withdrew due to a treatment-related AE. Conclusions Switch maintenance with Pazopanib following platinum-based chemotherapy in pts with advanced NSCLC was well tolerated. This study was stopped for futility following an IA due to lack of efficacy judging by a stringent criteria for PFS.
    No preview · Conference Paper · Sep 2014
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    ABSTRACT: Background: The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point 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 End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). Methods: We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. Results: Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. Conclusion: Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.
    Full-text · Article · Jul 2014 · Annals of Oncology
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    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.
    No preview · Article · Jun 2014 · Experimental and Molecular Pathology
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    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.
    Full-text · Article · Apr 2014 · Supportive and Palliative Care
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    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.
    No preview · Article · Jan 2014 · Experimental and Molecular Pathology
  • R J Young · P J Woll · C A Staton · M W R Reed · N J Brown
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    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.
    No preview · Article · Nov 2013 · Cancer Chemotherapy and Pharmacology
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    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.
    No preview · Article · Oct 2013 · Supportive Care in Cancer
  • Fiona Taylor · M Dawn Teare · Angela Cox · Penella J Woll

    No preview · Article · Oct 2013
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    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.
    Full-text · Article · Aug 2013 · International Journal of Cancer
  • J. Chiramel · M. Alzoubi · P.M. Fisher · P.J. Woll

    No preview · Article · Jan 2013 · Lung Cancer

  • No preview · Article · Jan 2013 · Lung Cancer

  • No preview · Article · Jan 2013 · Lung Cancer

Publication Stats

2k Citations
392.38 Total Impact Points

Institutions

  • 2004-2015
    • The University of Sheffield
      • • Academic Unit of Clinical Oncology
      • • Department of Oncology
      • • Department of Biomedical Science
      • • Institute for Cancer Studies
      Sheffield, England, United Kingdom
  • 2010-2013
    • Sheffield Teaching Hospitals NHS Foundation Trust
      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
  • 2000-2005
    • 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