North Wales Cancer Treatment Center

Rhyl, United Kingdom

North Wales Cancer Treatment Center

Rhyl, United Kingdom
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Fuller C.,Ysbyty Gwynedd | Bale C.,Ysbyty Gwynedd | Bishop J.,North Wales Cancer Treatment Center | Cool P.,The Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust
Clinical medicine (London, England) | Year: 2016

Breast cancer diagnosed during pregnancy is a relatively uncommon event. This challenging situation presents clinicians with difficult decisions, often requiring a multidisciplinary approach at a time of heightened anxiety for the patient and their family. This paper describes the case of a young woman with metastatic breast cancer diagnosed in early pregnancy, and outlines how this complex clinical situation was managed. © Royal College of Physicians 2016. All rights reserved.


Hurt C.N.,University of Cardiff | Nixon L.S.,University of Cardiff | Nixon L.S.,Cardiff NCRI RTTQA group | Griffiths G.O.,University of Cardiff | And 7 more authors.
BMC Cancer | Year: 2011

Background: Chemoradiotherapy is the standard of care for patients with oesophageal cancer unsuitable for surgery due to the presence of co-morbidity or extent of disease, and is a standard treatment option for patients with squamous cell carcinoma of the oesophagus. Modern regimens of chemoradiotherapy can lead to significant long-term survival. However the majority of patients will die of their disease, most commonly with local progression/recurrence of their tumours. Cetuximab may overcome one of the principal mechanisms of tumour radio-resistance, namely tumour repopulation, in patients treated with chemoradiotherapy.The purpose of this research is first to determine whether the addition of cetuximab to definitive chemoradiotherapy for treatment of patients with non-metastatic carcinoma of the oesophagus is active (in terms of failure-free rate), safe, and feasible within the context of a multi-centre randomised controlled trial in the UK. If the first stage is successful then the trial will continue to accrue sufficient patients to establish whether the addition of cetuximab to the standard treatment improves overall survival.Methods/Design: SCOPE1 is a two arm, open, randomised multicentre Phase II/III trial. Eligible patients will have histologically confirmed carcinoma of the oesophagus and have been chosen to receive definitive chemoradiotherapy by an accredited multidisciplinary team including a specialist Upper GI surgeon. 420 patients will be randomised to receive definitive chemoradiotherapy with or without cetuximab using a 1:1 allocation ratio.During Phase II of the study, the trial will assess safety (toxicity), activity (failure-free rate) and feasibility (recruitment rate and protocol dose modifications/delays) in 90 patients in the experimental arm. If the experimental arm is found to be active, safe, and feasible by the Independent Data Monitoring Committee then recruitment will continue into Phase III. This second stage will recruit a further 120 patients into each arm and compare the overall survival of both groups.All patients randomised into Phase II will contribute to the Phase III comparison of overall survival. In addition to overall survival, Phase III of the study will also assess toxicity, health related quality of life and cost effectiveness. A detailed radiotherapy protocol and quality assurance procedure has been incorporated into this trial.Trial registration: ISRCTN: ISRCTN47718479. © 2011 Hurt et al; licensee BioMed Central Ltd.


Crosby T.,Velindre Hospital | Hurt C.N.,University of Cardiff | Falk S.,Bristol Haematology and Oncology Center | Gollins S.,North Wales Cancer Treatment Center | And 11 more authors.
The Lancet Oncology | Year: 2013

Background: Definitive chemoradiotherapy (CRT) is an alternative to surgery for the curative treatment of oesophageal carcinoma. The SCOPE1 trial aimed to investigate the addition of cetuximab to cisplatin and fluoropyrimidine-based definitive CRT in patients with localised oesophageal squamous-cell cancer and adenocarcinomas to assess activity, safety, and feasibility of use. Methods: In this multicentre, randomised, open-label, phase 2/3 trial, we recruited patients aged 18 years and older from UK radiotherapy centres who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous-cell, or undifferentiated; WHO status 0-1; stage I-III disease) and been selected to receive definitive CRT. Patients were randomly assigned (1:1) via a central computerised system using stratified minimisation (with an 80:20 random element) to receive CRT alone or CRT with cetuximab (400 mg/m2 on day 1 followed by 250 mg/m2 weekly), stratified by recruiting hospital, primary reason for not having surgery, tumour histology, and tumour stage. CRT consisted of cisplatin 60 mg/m2 (day 1) and capecitabine 625 mg/m2 twice daily (days 1-21) for four cycles; cycles three and four were given concurrently with 50 Gy in 25 fractions of radiotherapy. The primary endpoint was the proportion of patients who were treatment failure free at week 24 for the phase 2 trial and overall survival for the phase 3 trial, both measured from randomisation. We analysed data by intention to treat. This trial is an International Standard Randomised Controlled Trial, number 47718479. Findings: 258 patients (129 assigned to each treatment group) from 36 UK centres were recruited between Feb 7, 2008, and Feb 22, 2012. Recruitment was stopped without continuation to phase 3 because the trial met criteria for futility, but we continued to follow-up recruited patients until all had reached at least 24-week follow-up (median follow-up of patients who survived was 16·8 months [IQR 11·2-24·5]). Fewer patients were treatment failure free at 24 weeks in the CRT plus cetuximab group (79 of 119 patients [66·4%, 90% CI 58·6-73·6]) than in the CRT only group (93 of 121 patients [76·9%, 69·7-83·0]). The CRT plus cetuximab group also had shorter median overall survival (22·1 months [95% CI 15·1-24·5] vs 25·4 months [20·5-37·9]; adjusted HR 1·53 [95% CI 1·03-2·27]; p=0·035). Patients who received CRT plus cetuximab had more non-haematological grade 3 or 4 toxicities (102 [79%] of 129 patients vs 81 [63%] of 129 patients; p=0·004). The most common grade 3 or 4 toxicities were low white blood cell count (14 [11%] in the CRT plus cetuximab group vs 21 [16%] in the CRT only group), low absolute neutrophil count (15 [12%] vs 24 [19%]), fatigue (26 [20%] vs 25 [19%]), and dysphagia (35 [27%] vs 37 [29%]). Interpretation: The addition of cetuximab to standard chemotherapy and radiotherapy cannot be recommended for patients with oesophageal cancer suitable for definitive CRT. Funding: Cancer Research UK. © 2013 Elsevier Ltd.


James R.D.,Kent Cancer Center | Glynne-Jones R.,Mount Vernon Hospital | Meadows H.M.,University College London | Cunningham D.,Royal Marsden Hospital | And 13 more authors.
The Lancet Oncology | Year: 2013

Background: Chemoradiation became the standard of care for anal cancer after the ACT I trial. However, only two-thirds of patients achieved local control, with 5-year survival of 50%; therefore, better treatments are needed. We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response, and whether maintenance chemotherapy after chemoradiation improves survival. Methods: In this 2×2 factorial trial, we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK. Patients were randomly assigned to one of four groups, to receive either mitomycin (12 mg/m2 on day 1) or cisplatin (60 mg/m2 on days 1 and 29), with fluorouracil (1000 mg/m2 per day on days 1-4 and 29-32) and radiotherapy (50·4 Gy in 28 daily fractions); with or without two courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14). The random allocation was generated by computer and patients assigned by telephone. Randomisation was done by minimisation and stratified by tumour site, T and N stage, sex, age, and renal function. Neither patients nor investigators were masked to assignment. Primary endpoints were complete response at 26 weeks and acute toxic effects (for chemoradiation), and progression-free survival (for maintenance). The primary analyses were done by intention to treat. This study is registered at controlled-trials.com, number 26715889. Findings: We enrolled 940 patients: 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5·1 years (IQR 3·9-6·9). 391 of 432 (90·5%) patients in the mitomycin group versus 386 of 431 (89·6%) in the cisplatin group had a complete response at 26 weeks (difference -0·9%, 95% CI -4·9 to 3·1; p=0·64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3-4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69-77; maintenance) versus 73% (95% CI 68-77; no maintenance; hazard ratio 0·95, 95% CI 0·75-1·21; p=0·70). Interpretation: The results of our trial-the largest in anal cancer to date-show that fluorouracil and mitomycin with 50·4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK. Funding: Cancer Research UK. © 2013 Elsevier Ltd.


Glynne-Jones R.,Mount Vernon Center for Cancer Treatment | Sebag-Montefiore D.,University of Leeds | Adams R.,University of Cardiff | Gollins S.,North Wales Cancer Treatment Center | And 3 more authors.
Cancer | Year: 2013

Background: Only 2 prospective studies have previously reported prognostic factors for anal cancer, European Organization for Research and Treatment of Cancer trial 22861 (EORTC 22861) and Radiation Therapy Oncology Group trial 98-11 (RTOG 98-11). Both of those trials reported that clinically positive lymph nodes and male sex predicted poorer overall survival (OS). The EORTC 22861 trial indicated that the same factors were prognostic for locoregional control. In the current report, the authors investigated potential prognostic factors from the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I), in which patients were randomized to receive either radiotherapy alone or chemoradiation (CRT) with concurrent 5-fluorouracil/ mitomycin C. METHODS: In the ACT I trial, associations between several baseline characteristics and 3 endpoints were investigated: locoregional failure (LRF), anal cancer death (ACD), and OS. The analyses were restricted to 292 patients who received CRT, which subsequently became standard treatment. A score was derived using multivariable Cox regression to identify the set of factors that, together, had the best prognostic performance. This score was then validated with a large, independent prospective trial (the ACT II trial). RESULTS: Palpable, clinically positive lymph nodes were associated with LRF (P =.012), a greater risk of ACD (P =.031), and decreased OS (P =.006) in multivariable analyses. Men had worse outcomes than women for LRF (P =.036), ACD (P =.039), and OS (P =.008). On average, a lower hemoglobin level had an adverse effect on ACD (P =.008), and a higher white blood cell count had an adverse effect on OS (P =.001). However, external validation of the score was poor for LRF (area under the curve [AUC] = 54%) but was better for ACD (AUC = 67%) and OS (AUC = 63%). CONCLUSIONS: The results from this analysis of the ACT I trial supported evidence for palpable lymph nodes and male sex as prognostic factors for LRF and OS, and lower hemoglobin levels and a higher white blood cell count were identified as prognostic factors for ACD and OS, respectively. Cancer 2013. © 2012 American Cancer Society. This analysis of the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I) complements 2 other studies, adding further evidence that palpable inguinal lymph node status and sex are independently prognostic of overall survival, locoregional failure, and anal cancer death. In addition, after adjusting for sex and lymph node status, presenting hemoglobin level is identified as another prognostic factor for anal cancer death. Copyright © 2012 American Cancer Society.


Glynne-Jones R.,Mount Vernon Cancer Center | Sebag-Montefiore D.,St James's Hospital | Adams R.,University of Cardiff | McDonald A.,Beatson West of Scotland Cancer Center | And 5 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011

Purpose: The United Kingdom Coordinating Committee on Cancer Research anal cancer trial demonstrated the benefit of combined modality treatment (CMT) using radiotherapy (RT), infusional 5-fluorouracil, and mitomycin C over RT alone. The present study retrospectively examines the impact of the recommended 6-week treatment gap and local RT boost on long-term outcome. Methods and Materials: A total of 577 patients were randomly assigned RT alone or CMT. After a 6-week gap responders received a boost using either additional external beam radiotherapy (EBRT) (15 Gy) or iridium-192 implant (25 Gy). The effect of boost, the gap between initial treatment (RT alone or CMT) and boost (Tgap), and overall treatment time (OTT) were examined for their impact on outcome. Results: Among the 490 good responders, 436 (89%) patients received a boost after initial treatment. For boosted patients, the risk of anal cancer death decreased by 38% (hazard ratio [HR]: 0.62, 99% CI 0.35-1.12; p = 0.04), but there was no evidence this was mediated via a reduction in locoregional failure (LRF) (HR: 0.90, 99% CI 0.48-1.68; p = 0.66). The difference in Tgap was only 1.4 days longer for EBRT boost, compared with implant (p = 0.51). OTT was longer by 6.1 days for EBRT (p = 0.006). Tgap and OTT were not associated with LRF. Radionecrosis was reported in 8% of boosted, compared with 0% in unboosted patients (p = 0.03). Conclusions: These results question the benefit of a radiotherapy boost after a 6-week gap. The higher doses of a boost may contribute more to an increased risk of late morbidity, rather than local control. © 2011 Elsevier Inc.


Renehan A.G.,University of Manchester | Renehan A.G.,The Christie NHS Foundation Trust | Malcomson L.,University of Manchester | Emsley R.,University of Manchester | And 10 more authors.
The Lancet Oncology | Year: 2016

Background: Induction of a clinical complete response with chemoradiotherapy, followed by observation via a watch-and-wait approach, has emerged as a management option for patients with rectal cancer. We aimed to address the shortage of evidence regarding the safety of the watch-and-wait approach by comparing oncological outcomes between patients managed by watch and wait who achieved a clinical complete response and those who had surgical resection (standard care). Methods: Oncological Outcomes after Clinical Complete Response in Patients with Rectal Cancer (OnCoRe) was a propensity-score matched cohort analysis study, that included patients of all ages diagnosed with rectal adenocarcinoma without distant metastases who had received preoperative chemoradiotherapy (45 Gy in 25 daily fractions with concurrent fluoropyrimidine-based chemotherapy) at a tertiary cancer centre in Manchester, UK, between Jan 14, 2011, and April 15, 2013. Patients who had a clinical complete response were offered management with the watch-and-wait approach, and patients who did not have a complete clinical response were offered surgical resection if eligible. We also included patients with a clinical complete response managed by watch and wait between March 10, 2005, and Jan 21, 2015, across three neighbouring UK regional cancer centres, whose details were obtained through a registry. For comparative analyses, we derived one-to-one paired cohorts of watch and wait versus surgical resection using propensity-score matching (including T stage, age, and performance status). The primary endpoint was non-regrowth disease-free survival from the date that chemoradiotherapy was started, and secondary endpoints were overall survival, and colostomy-free survival. We used a conservative p value of less than 0·01 to indicate statistical significance in the comparative analyses. Findings: 259 patients were included in our Manchester tertiary cancer centre cohort, 228 of whom underwent surgical resection at referring hospitals and 31 of whom had a clinical complete response, managed by watch and wait. A further 98 patients were added to the watch-and-wait group via the registry. Of the 129 patients managed by watch and wait (median follow-up 33 months [IQR 19-43]), 44 (34%) had local regrowths (3-year actuarial rate 38% [95% CI 30-48]); 36 (88%) of 41 patients with non-metastatic local regrowths were salvaged. In the matched analyses (109 patients in each treatment group), no differences in 3-year non-regrowth disease-free survival were noted between watch and wait and surgical resection (88% [95% CI 75-94] with watch and wait vs 78% [63-87] with surgical resection; time-varying p=0·043). Similarly, no difference in 3-year overall survival was noted (96% [88-98] vs 87% [77-93]; time-varying p=0·024). By contrast, patients managed by watch and wait had significantly better 3-year colostomy-free survival than did those who had surgical resection (74% [95% CI 64-82] vs 47% [37-57]; hazard ratio 0·445 [95% CI 0·31-0·63; p<0·0001), with a 26% (95% CI 13-39) absolute difference in patients who avoided permanent colostomy at 3 years between treatment groups. Interpretation: A substantial proportion of patients with rectal cancer managed by watch and wait avoided major surgery and averted permanent colostomy without loss of oncological safety at 3 years. These findings should inform decision making at the outset of chemoradiotherapy. Funding: Bowel Disease Research Foundation. © 2016 Elsevier Ltd.


PubMed | Clatterbridge Cancer Center, University Institute of Health Sciences, University of Manchester, The Christie NHS Foundation Trust and 3 more.
Type: Comparative Study | Journal: The Lancet. Oncology | Year: 2016

Induction of a clinical complete response with chemoradiotherapy, followed by observation via a watch-and-wait approach, has emerged as a management option for patients with rectal cancer. We aimed to address the shortage of evidence regarding the safety of the watch-and-wait approach by comparing oncological outcomes between patients managed by watch and wait who achieved a clinical complete response and those who had surgical resection (standard care).Oncological Outcomes after Clinical Complete Response in Patients with Rectal Cancer (OnCoRe) was a propensity-score matched cohort analysis study, that included patients of all ages diagnosed with rectal adenocarcinoma without distant metastases who had received preoperative chemoradiotherapy (45 Gy in 25 daily fractions with concurrent fluoropyrimidine-based chemotherapy) at a tertiary cancer centre in Manchester, UK, between Jan 14, 2011, and April 15, 2013. Patients who had a clinical complete response were offered management with the watch-and-wait approach, and patients who did not have a complete clinical response were offered surgical resection if eligible. We also included patients with a clinical complete response managed by watch and wait between March 10, 2005, and Jan 21, 2015, across three neighbouring UK regional cancer centres, whose details were obtained through a registry. For comparative analyses, we derived one-to-one paired cohorts of watch and wait versus surgical resection using propensity-score matching (including T stage, age, and performance status). The primary endpoint was non-regrowth disease-free survival from the date that chemoradiotherapy was started, and secondary endpoints were overall survival, and colostomy-free survival. We used a conservative p value of less than 001 to indicate statistical significance in the comparative analyses.259 patients were included in our Manchester tertiary cancer centre cohort, 228 of whom underwent surgical resection at referring hospitals and 31 of whom had a clinical complete response, managed by watch and wait. A further 98 patients were added to the watch-and-wait group via the registry. Of the 129 patients managed by watch and wait (median follow-up 33 months [IQR 19-43]), 44 (34%) had local regrowths (3-year actuarial rate 38% [95% CI 30-48]); 36 (88%) of 41 patients with non-metastatic local regrowths were salvaged. In the matched analyses (109 patients in each treatment group), no differences in 3-year non-regrowth disease-free survival were noted between watch and wait and surgical resection (88% [95% CI 75-94] with watch and wait vs 78% [63-87] with surgical resection; time-varying p=0043). Similarly, no difference in 3-year overall survival was noted (96% [88-98] vs 87% [77-93]; time-varying p=0024). By contrast, patients managed by watch and wait had significantly better 3-year colostomy-free survival than did those who had surgical resection (74% [95% CI 64-82] vs 47% [37-57]; hazard ratio 0445 [95% CI 031-063; p<00001), with a 26% (95% CI 13-39) absolute difference in patients who avoided permanent colostomy at 3 years between treatment groups.A substantial proportion of patients with rectal cancer managed by watch and wait avoided major surgery and averted permanent colostomy without loss of oncological safety at 3 years. These findings should inform decision making at the outset of chemoradiotherapy.Bowel Disease Research Foundation.


Gollins S.,North Wales Cancer Treatment Center | Sebag-Montefiore D.,University of Leeds
Clinical Oncology | Year: 2016

Improved surgical technique plus selective preoperative radiotherapy have decreased rectal cancer pelvic local recurrence from, historically, 25% down to about 5-10%. However, this improvement has not reduced distant metastatic relapse, which is the main cause of death and a key issue in rectal cancer management.The current standard is local pelvic treatment (surgery ± preoperative radiotherapy) followed by adjuvant chemotherapy, depending on resection histology. For circumferential resection margin (CRM)-threatened cancer on baseline magnetic resonance imaging, downstaging long-course preoperative chemoradiation (LCPCRT) is generally used. However, for non-CRM-threatened disease, varying approaches are currently adopted in the UK, including straight to surgery, short-course preoperative radiotherapy and LCPCRT. Clinical trials are investigating intensification of concurrent chemoradiation. There is also increasing interest in investigating preoperative neoadjuvant chemotherapy (NAC) as a way of exposing micro-metastatic disease to full-dose systemic chemotherapy as early as possible and potentially reducing metastatic relapse. Phase II trials suggest that this strategy is feasible, with promising histological response and low rates of tumour progression during NAC. Phase III trials are needed to determine the benefit of NAC when added to standard therapy and also to determine if it can be used instead of neoadjuvant radiotherapy-based schedules. Although several measures of neoadjuvant treatment response assessment based on imaging or pathology are promising predictive biomarkers for long-term survival, none has been validated in prospective phase III studies. The phase III setting will enable this, also providing translational opportunities to examine molecular predictors of response and survival. © 2015 The Royal College of Radiologists.


PubMed | North Wales Cancer Treatment Center and University of Leeds
Type: Journal Article | Journal: Clinical oncology (Royal College of Radiologists (Great Britain)) | Year: 2016

Improved surgical technique plus selective preoperative radiotherapy have decreased rectal cancer pelvic local recurrence from, historically, 25% down to about 5-10%. However, this improvement has not reduced distant metastatic relapse, which is the main cause of death and a key issue in rectal cancer management. The current standard is local pelvic treatment (surgery preoperative radiotherapy) followed by adjuvant chemotherapy, depending on resection histology. For circumferential resection margin (CRM)-threatened cancer on baseline magnetic resonance imaging, downstaging long-course preoperative chemoradiation (LCPCRT) is generally used. However, for non-CRM-threatened disease, varying approaches are currently adopted in the UK, including straight to surgery, short-course preoperative radiotherapy and LCPCRT. Clinical trials are investigating intensification of concurrent chemoradiation. There is also increasing interest in investigating preoperative neoadjuvant chemotherapy (NAC) as a way of exposing micro-metastatic disease to full-dose systemic chemotherapy as early as possible and potentially reducing metastatic relapse. Phase II trials suggest that this strategy is feasible, with promising histological response and low rates of tumour progression during NAC. Phase III trials are needed to determine the benefit of NAC when added to standard therapy and also to determine if it can be used instead of neoadjuvant radiotherapy-based schedules. Although several measures of neoadjuvant treatment response assessment based on imaging or pathology are promising predictive biomarkers for long-term survival, none has been validated in prospective phase III studies. The phase III setting will enable this, also providing translational opportunities to examine molecular predictors of response and survival.

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