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Thomas B.M.,Velindre Cancer Center | Smith C.,Velindre NHS Trust | Evans J.,Wales Cancer Trials Unit | Button M.R.,Velindre NHS Trust | And 5 more authors.
Medical Oncology | Year: 2013

Docetaxel has been shown to improve survival in patients with metastatic castrate-resistant prostate cancer (mCRPC). There is no clear consensus regarding the optimum duration of chemotherapy. If patients at greater risk of rapid disease relapse could be identified when on chemotherapy, appropriate follow-up strategies could be put into place. The aim of our study was to find prostate specific antigen (PSA) characteristics that predict a shorter disease response to docetaxel chemotherapy. Data from 41 consecutive mCRPC patients treated with three-weekly docetaxel chemotherapy at a single centre between February 2010 and February 2012 were retrospectively analysed. All patients had ≥50 % reduction in their PSA with chemotherapy. The relationship between time to PSA nadir (TTN) and PSA halving time with time to PSA progression and overall chemotherapy response duration was analysed. TTN was a strong predictor of the duration of chemotherapy response and time to PSA progression. When TTN was ≥16 weeks, the mean duration of response to chemotherapy was 37.5 weeks compared to 19.9 weeks when TTN <16 weeks (95 % CI, 12.66-22.60; p = 1.239 × 10-8). The mean time to PSA progression was 12.8 weeks if TTN was ≥16 weeks and 8.2 weeks TTN was <16 weeks (95 % CI 0.63-8.60; p = 0.024). We observed that a TTN from the initiation of chemotherapy of <16 weeks for patients with mCRPC is an independent predictor of shorter duration of response and shorter progression-free survival. © 2013 Springer Science+Business Media New York.


Borley A.,Velindre Cancer Center | Mercer T.,University of Cardiff | Morgan M.,University of Wales | Dutton P.,Wales Cancer Trials Unit | And 3 more authors.
British journal of cancer | Year: 2014

Adjuvant trastuzumab with chemotherapy is standard treatment for HER2-positive breast cancer, defined as either HER2 IHC3+ or IHC2+ and FISH amplified. The aim of this study was to investigate the degree to which HER2 amplification in terms of HER2 gene copy numbers in HER2+IHC2+ cancers affected the outcome in a community setting. Case records of 311 consecutive patients with early breast cancer presenting between 1st January 2005 and 31st December 2008 were reviewed. Progression-free survival and overall survival were calculated with the Kaplan-Meier method using STATA 13. Among 3+ cases (n=230) 163 received T vs 67 no-T. Among 2+ cases (n=81) 59 received T vs 22 no-T. Among 59 IHC2+-treated cases n=28 had an average of >12, n=13 had >6 to <12, and n=18 had >2 to <6 HER2 gene copies, respectively. The time of progression and overall survival of high and low copy number patients was similar and better than the intermediate copy number and the untreated cohorts. High HER2 copy number (>12) appears to be associated with consistently better response compared with patients with intermediate HER2 copy numbers (6-12). In light of emerging data of patients showing insensivity to trastuzumab therapy, we propose that the HER2 gene copy number value should be included as an additional indicator for stratifying both the management and the follow-up of breast cancer patients.


Mitchell H.,Betsi Cadwaladr University Health Board | Noble S.,University of Cardiff | Finlay I.,Velindre Hospital | Nelson A.,Wales Cancer Trials Unit
BMJ Supportive and Palliative Care | Year: 2015

Background Within the UK, general practitioners (GPs) are required to maintain a register of palliative patients under their care. The term 'palliative' when applied to patients encompasses a highly heterogeneous population with varying meanings amongst health professionals. We explored GPs views of what defines a palliative care patient in the context of identifying clinical service needs. Methods Audiotaped semi-structured interviews were conducted with GPs to explore how they identify patients requiring inclusion on a palliative care register. Thematic analysis was undertaken and emerging themes identified. Results Major themes suggested GPs found it difficult to define the palliative care patient. The decision to include a patient on the palliative care register was made as a multidisciplinary team. Patients not identified as 'palliative' were often discussed unofficially if care requirements were significant or prognosis uncertain. The needs of patients with non-malignant disease were considered equal to those with cancer but the challenges of identifying such patients greater. More emphasis was placed on intensity of care required than prognosis. Inclusion on a register triggered greater professional input and was considered beneficial to patient care. Conclusions No definition of the palliative care patient exists in working practice and without one there is a risk that some patients with palliative needs will not receive the necessary support, while others may access valuable resources before time. Achieving health policy targets which require identification of palliative patients will continue to be a challenge until a workable and reliable definition of the term 'palliative' is agreed upon.


PubMed | Wales Cancer Trials Unit, Betsi Cadwaladr University Health Board, University of Cardiff and Velindre Hospital
Type: Journal Article | Journal: BMJ supportive & palliative care | Year: 2015

Within the UK, general practitioners (GPs) are required to maintain a register of palliative patients under their care. The term palliative when applied to patients encompasses a highly heterogeneous population with varying meanings amongst health professionals. We explored GPs views of what defines a palliative care patient in the context of identifying clinical service needs.Audiotaped semi-structured interviews were conducted with GPs to explore how they identify patients requiring inclusion on a palliative care register. Thematic analysis was undertaken and emerging themes identified.Major themes suggested GPs found it difficult to define the palliative care patient. The decision to include a patient on the palliative care register was made as a multidisciplinary team. Patients not identified as palliative were often discussed unofficially if care requirements were significant or prognosis uncertain. The needs of patients with non-malignant disease were considered equal to those with cancer but the challenges of identifying such patients greater. More emphasis was placed on intensity of care required than prognosis. Inclusion on a register triggered greater professional input and was considered beneficial to patient care.No definition of the palliative care patient exists in working practice and without one there is a risk that some patients with palliative needs will not receive the necessary support, while others may access valuable resources before time. Achieving health policy targets which require identification of palliative patients will continue to be a challenge until a workable and reliable definition of the term palliative is agreed upon.


Gwynne S.,Velindre Cancer Center | Hurt C.,Wales Cancer Trials Unit | Evans M.,Velindre Cancer Center | Holden C.,University of Cardiff | And 2 more authors.
Clinical Oncology | Year: 2011

Aims: A retrospective analysis was carried out of 291 cases of oesophageal cancer treated with definitive chemoradiotherapy (dCRT) at a single UK cancer centre between 1995 and 2009. Our protocol consisted of two cycles of neoadjuvant platinum-based chemotherapy followed by two further cycles given concurrently with 50. Gy of external beam radiotherapy delivered in 25 fractions over 5 weeks. Materials and methods: Demographic, patient and outcome data were recorded prospectively through an electronic health record and retrospectively analysed, using appropriate statistical tools. Results: Data on 266 patients were available for analysis. The median age was 66.6 years, 53% were adenocarcinomas. dCRT was used instead of surgery because of age/co-morbidity in 44% and disease extent in 39%. Ninety-three per cent of patients completed treatment according to protocol. Grade 3 and 4 toxicities were seen in 42 and 7%, respectively. Median survival was 20.6 months; 2, 3 and 5 year survival rates were 43.6, 32.9 and 19.5%, respectively. Advanced disease was associated with a worse outcome. Shorter disease length was associated with a better median survival, but some patients with disease >10. cm had long-term disease control. The effect of other patient- and disease-related factors was also analysed. Conclusion: We present data showing that dCRT is well tolerated and should be considered as an alternative to surgery for all patients with locally advanced oesophageal cancer, not only those with co-morbidity. Furthermore, the benefits of dCRT are not confined to carcinomas with squamous histology. © 2010 The Royal College of Radiologists.


Huggett M.T.,University College London | Passant H.,Velindre Cancer Center | Hurt C.,Wales Cancer Trials Unit | Pereira S.P.,University College London | And 2 more authors.
Tumori | Year: 2014

Aims and background. The ABC-02 trial has defined the standard therapy for patients with advanced biliary tract cancer (ABC); however, outcome in an unselected patient population in the UK has not been described. We aimed to investigate the outcome of a series of patients with ABC from two large UK cancer networks. Methods and study design. We retrospectively reviewed all cases of ABC presenting to two UK cancer networks over a nine-year period. Overall survival (OS) and factors influencing OS were assessed. Results. Four hundred and two patients were available for analysis. The median OS was 6.2 months. On univariate analysis, age e70 years (P = 0.047), advanced disease stage (P <0.001), gall bladder primary (P = 0.033), poor performance status (P <0.001) and lack of chemotherapy (P <0.001) were associated with worse outcome. Survival was superior in the 36.4% of patients who received palliative chemotherapy (12.5 vs 4.3 months; P <0.001). On multivariate analysis of patients who had chemotherapy, those who did not receive fluoropyrimidine-based regimens (HR = 5.12; P = 0.022) or gemcitabine-based regimens (HR = 5.01; P = 0.021) had a higher mortality, whereas the effect of platinum-containing regimens was of borderline significance (HR = 2.23; P = 0.086). Sites, age, and multi-agent regimens were not significant. Conclusions. This is one of the largest retrospective studies reporting outcome of palliative chemotherapy for ABC. It confirms the benefit of palliative chemotherapy in an unselected group of patients. Fluoropyrimidine-based regimens appear to be as effective as gemcitabine-based treatments. Copyright - Il Pensiero Scientifico Editore.


Warren S.,University of Oxford | Partridge M.,University of Oxford | Carrington R.,Velindre Hospital | Hurt C.,Wales Cancer Trials Unit | And 2 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2014

Methods and Materials: Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm3. A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA62.5) was compared to a standard dose plan of 50 Gy/25 fractions (RA50). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared.Results: Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA50) to 56.3% (RA62.5), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA50) versus 5.6% (RA62.5) P<.001 and median lung NTCP 6.5% (RA50) versus 7.5% (RA62.5) P<.001.Conclusions: Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials.Purpose: This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity. © 2014 The Authors. Published by Elsevier Inc. All rights reserved.


Warren S.,University of Oxford | Partridge M.,University of Oxford | Bolsi A.,Paul Scherrer Institute | Lomax A.J.,Paul Scherrer Institute | And 3 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2016

Purpose Planning studies to compare x-ray and proton techniques and to select the most suitable technique for each patient have been hampered by the nonequivalence of several aspects of treatment planning and delivery. A fair comparison should compare similarly advanced delivery techniques from current clinical practice and also assess the robustness of each technique. The present study therefore compared volumetric modulated arc therapy (VMAT) and single-field optimization (SFO) spot scanning proton therapy plans created using a simultaneous integrated boost (SIB) for dose escalation in midesophageal cancer and analyzed the effect of setup and range uncertainties on these plans. Methods and Materials For 21 patients, SIB plans with a physical dose prescription of 2 Gy or 2.5 Gy/fraction in 25 fractions to planning target volume (PTV)50Gy or PTV62.5Gy (primary tumor with 0.5 cm margins) were created and evaluated for robustness to random setup errors and proton range errors. Dose-volume metrics were compared for the optimal and uncertainty plans, with P<.05 (Wilcoxon) considered significant. Results SFO reduced the mean lung dose by 51.4% (range 35.1%-76.1%) and the mean heart dose by 40.9% (range 15.0%-57.4%) compared with VMAT. Proton plan robustness to a 3.5% range error was acceptable. For all patients, the clinical target volume D98 was 95.0% to 100.4% of the prescribed dose and gross tumor volume (GTV) D98 was 98.8% to 101%. Setup error robustness was patient anatomy dependent, and the potential minimum dose per fraction was always lower with SFO than with VMAT. The clinical target volume D98 was lower by 0.6% to 7.8% of the prescribed dose, and the GTV D98 was lower by 0.3% to 2.2% of the prescribed GTV dose. Conclusions The SFO plans achieved significant sparing of normal tissue compared with the VMAT plans for midesophageal cancer. The target dose coverage in the SIB proton plans was less robust to random setup errors and might be unacceptable for certain patients. Robust optimization to ensure adequate target coverage of SIB proton plans might be beneficial. © 2016 The Authors.


PubMed | Wales Cancer Trials Unit, University of Oxford, Velindre Hospital and Paul Scherrer Institute
Type: Comparative Study | Journal: International journal of radiation oncology, biology, physics | Year: 2016

Planning studies to compare x-ray and proton techniques and to select the most suitable technique for each patient have been hampered by the nonequivalence of several aspects of treatment planning and delivery. A fair comparison should compare similarly advanced delivery techniques from current clinical practice and also assess the robustness of each technique. The present study therefore compared volumetric modulated arc therapy (VMAT) and single-field optimization (SFO) spot scanning proton therapy plans created using a simultaneous integrated boost (SIB) for dose escalation in midesophageal cancer and analyzed the effect of setup and range uncertainties on these plans.For 21 patients, SIB plans with a physical dose prescription of 2 Gy or 2.5 Gy/fraction in 25 fractions to planning target volume (PTV)50Gy or PTV62.5Gy (primary tumor with 0.5 cm margins) were created and evaluated for robustness to random setup errors and proton range errors. Dose-volume metrics were compared for the optimal and uncertainty plans, with P<.05 (Wilcoxon) considered significant.SFO reduced the mean lung dose by 51.4% (range 35.1%-76.1%) and the mean heart dose by 40.9% (range 15.0%-57.4%) compared with VMAT. Proton plan robustness to a 3.5% range error was acceptable. For all patients, the clinical target volume D98 was 95.0% to 100.4% of the prescribed dose and gross tumor volume (GTV) D98 was 98.8% to 101%. Setup error robustness was patient anatomy dependent, and the potential minimum dose per fraction was always lower with SFO than with VMAT. The clinical target volume D98 was lower by 0.6% to 7.8% of the prescribed dose, and the GTV D98 was lower by 0.3% to 2.2% of the prescribed GTV dose.The SFO plans achieved significant sparing of normal tissue compared with the VMAT plans for midesophageal cancer. The target dose coverage in the SIB proton plans was less robust to random setup errors and might be unacceptable for certain patients. Robust optimization to ensure adequate target coverage of SIB proton plans might be beneficial.


PubMed | Wales Cancer Trials Unit, University of Oxford and Velindre Hospital
Type: Comparative Study | Journal: International journal of radiation oncology, biology, physics | Year: 2014

This study investigated the trade-off in tumor coverage and organ-at-risk sparing when applying dose escalation for concurrent chemoradiation therapy (CRT) of mid-esophageal cancer, using radiobiological modeling to estimate local control and normal tissue toxicity.Twenty-one patients with mid-esophageal cancer were selected from the SCOPE1 database (International Standard Randomised Controlled Trials number 47718479), with a mean planning target volume (PTV) of 327 cm(3). A boost volume, PTV2 (GTV + 0.5 cm margin), was created. Radiobiological modeling of tumor control probability (TCP) estimated the dose required for a clinically significant (+20%) increase in local control as 62.5 Gy/25 fractions. A RapidArc (RA) plan with a simultaneously integrated boost (SIB) to PTV2 (RA62.5) was compared to a standard dose plan of 50 Gy/25 fractions (RA50). Dose-volume metrics and estimates of normal tissue complication probability (NTCP) for heart and lungs were compared.Clinically acceptable dose escalation was feasible for 16 of 21 patients, with significant gains (>18%) in tumor control from 38.2% (RA50) to 56.3% (RA62.5), and only a small increase in predicted toxicity: median heart NTCP 4.4% (RA50) versus 5.6% (RA62.5) P<.001 and median lung NTCP 6.5% (RA50) versus 7.5% (RA62.5) P<.001.Dose escalation to the GTV to improve local control is possible when overlap between PTV and organ-at-risk (<8% heart volume and <2.5% lung volume overlap for this study) generates only negligible increase in lung or heart toxicity. These predictions from radiobiological modeling should be tested in future clinical trials.

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