Hoskin P.J.,Mount Vernon Cancer Center |
Kirkwood A.A.,University College London |
Popova B.,University College London |
Smith P.,University College London |
And 9 more authors.
The Lancet Oncology | Year: 2014
Background: Follicular lymphoma has been shown to be highly radiosensitive with responses to doses as low as 4 Gy in two fractions. This trial was designed to explore the dose response for follicular lymphoma comparing 4 Gy in two fractions with 24 Gy in 12 fractions. Methods: FORT is a prospective randomised, unblinded, phase 3 non-inferiority study comparing radiotherapy given as 4 Gy in two fractions with a standard dose of 24 Gy in 12 fractions. Entry criteria included all patients aged over 18 years, having local radiotherapy for radical or palliative local control, with follicular lymphoma or marginal zone lymphoma, who had received no previous treatment for at least 1 month before. The primary outcome was time to local progression analysed on an intention-to-treat basis. Randomisation was centralised through the Cancer Research UK and University College London Cancer Trials Centre. Radiotherapy target sites were randomised (1:1) with minimisation stratified by histology (follicular lymphoma vs marginal zone lymphoma), treatment intent (palliative or curative) and centre. This trial is registered with ClinicalTrials.gov number, NCT00310167. Findings: 299 sites were randomly assigned to 24 Gy and 315 sites to 4 Gy between April 7, 2006, and June 8, 2011, at 43 centres in the UK. After a median follow-up of 26 months (range 0·39-75·4), 91 local progressions had been recorded (21 in the 24 Gy group and 70 in the 4 Gy group). Time to local progression with 4 Gy was not non-inferior to 24 Gy (hazard ratio 3·42, 95% CI 2·09-5·55, p<0·0001). Eight (3%) of 282 patients in the 24 Gy group and four (1%) of 300 in the 4 Gy group had acute grade 3-4 toxic effects. Four (1%) patients in the 24 Gy group and four (1%) patients in the 4 Gy group had late toxic effects. Mucositis was the most common event in the 24 Gy group (two patients with acute mucositis and two with late mucositis; all grade 3) and was not reported in the 4 Gy group. The most common acute effect was pain at the site of irradiation (two patients in the 4 Gy group, one patient in the 24 Gy group; all grade 3), and the most common late effect was fatigue (two patients in the 4 Gy group, one patient in the 24 Gy group; all grade 3). Interpretation: 24 Gy in 12 fractions is the more effective radiation schedule for indolent lymphoma and should be regarded as the standard of care. However, 4 Gy remains a useful alternative for palliative treatment. Funding: Cancer Research UK. © 2014 Elsevier Ltd.
Theis V.S.,University of Liverpool |
Sripadam R.,Clatterbridge Center for Oncology |
Ramani V.,Clatterbridge Center for Oncology |
Lal S.,Intestinal Failure Unit
Clinical Oncology | Year: 2010
Chronic radiation enteritis is an increasing problem, as more patients receive radiotherapy as part of their cancer therapy and as the long-term survival of these patients improves. This review addresses the causes, investigation, treatment and prevention of this disease. A review of published studies was carried out using a variety of search terms, including radiation enteritis, investigation, treatment and prevention. Chronic radiation enteritis has been reported in up to 20% of patients receiving pelvic radiotherapy, although this may underestimate its true prevalence, as not all patients with gastrointestinal symptoms after radiotherapy will seek medical attention. Predisposing factors to chronic radiation enteritis include a low body mass index, previous abdominal surgery and the presence of co-morbid conditions; the radiation dose, fractionation and technique, as well as the concomitant use of chemotherapy, may also play a role. Clinical features of chronic radiation enteritis are multiple as the disease can affect any part of the gastrointestinal tract. Moreover, symptom aetiology within any one patient may be multifactorial and therefore it is important to adopt a structured approach when planning investigations. The evidence base for current therapies is limited, but nutrition, anti-diarrhoeals, anti-inflammatories, antibiotics, probiotics, pentoxifylline, tocopherol, cholestyramine, hyperbaric oxygen, endoscopic and surgical therapies have all received attention. Given the significant morbidity and mortality associated with chronic radiation enteritis, current available preventative strategies are reviewed, including tissue-sparing radiotherapy techniques. In conclusion, the evidence base for therapeutic and preventative strategies in treating chronic radiation enteritis is limited, but adopting a structured approach to investigating gastrointestinal symptoms after radiotherapy should allow better targeting of current therapies. Closer collaboration between oncologists and gastroenterologists will facilitate a more structured approach, not only in managing individual patients, but also in establishing clinical and research networks for this expanding disease, in order to improve the evidence base for its management. © 2009 The Royal College of Radiologists.
Mayles W.P.M.,Clatterbridge Center for Oncology
Clinical Oncology | Year: 2010
Aims: To determine the availability of intensity-modulated radiotherapy (IMRT) treatment in the UK and to assess the magnitude of the shortfall in terms of patient treatments. In addition, the availability of image-guided radiotherapy (IGRT) was also reviewed. Materials and methods: A survey was carried out between July and September 2008 of the use of advanced technology in radiotherapy. Results: In total, 50 centres responded out of the 58 National Health Service centres canvassed, representing about 89% of patients treated in the UK. Forty-six centres had at least two machines capable of IMRT and 26 centres had at least one machine capable of IGRT. Thirty-two centres were carrying out forward-planned IMRT and 18 centres were carrying out the more complex inverse-planned IMRT. In all, 38 centres (76% of respondents) were offering either forward- or inverse-planned IMRT to some of their patients. All the centres with IGRT capability were using IGRT for at least some of their patients. Respondents were asked to list the total number of radical and palliative patients being treated according to the treatment site. Forty-two per cent of respondents took the option to list the total number of radical and palliative patients only. Based on these data, 10.7% of radical patients are currently being given forward-planned IMRT, mainly for breast cancer (18.6% of such patients) and 2.2% of radical patients are being given inverse-planned IMRT, mainly for prostate (7.5% of such patients) and head and neck cancer (6.7% of such patients). Whereas at present only 18 centres are able to treat with inverse-planned IMRT, 45 centres expected to be able to do so by 2010. Respondents were asked to estimate the percentage of patients who should be given IMRT for each site and this was used to estimate the shortfall in IMRT provision. Conclusions: Based on the consensus of opinion, 32% of radically treated patients should receive inverse-planned IMRT and 22% forward-planned IMRT, making a total of 55%. In fact, 2% receive inverse-planned IMRT and 11% the less complex forward-planned IMRT. Thus, with an estimated 75 948 radical treatments being carried out with megavoltage radiotherapy, the professional opinion is that 41 421 of patients would benefit from treatment with IMRT. In fact, only 9775 were so treated in 2008; a shortfall of 32 497 patients treated instead with conventional radiotherapy. © 2010 The Royal College of Radiologists.
Shakeshaft J.,Clatterbridge Center for Oncology
Clinical Oncology | Year: 2010
In recent years, the use of the Picture Archiving and Communications System (PACS) has become widespread in the area of diagnostic radiology for archival, review and reporting of patient data. However, the adoption of PACS within the field of radiotherapy is still very limited, despite the fact that most radiotherapy systems now use Digital Imaging and Communications in Medicine (DICOM) for both storage and communication. This paper discusses the challenges of integrating PACS into a radiotherapy department as a long-term archive of patient treatments. A possible solution based on a large English department is used as an example. © 2010 The Royal College of Radiologists.
Ruggieri R.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst |
Naccarato S.,Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst |
Nahum A.E.,Clatterbridge Center for Oncology
Acta Oncologica | Year: 2010
Background. The current rationale for severely hypofractionated schedules (35 fractions) used in stereotactic-body-radiotherapy (SBRT) of non-small-cell lung cancer (NSCLC) is the small size of the irradiated volumes. Being the dose prescribed to the 6080% isodose line enclosing the PTV, a non-homogeneous tumour-dose-delivery results which might impact on tumour hypoxia. A comparison between homogeneous and SBRT-like non-homogeneous tumour-dose-delivery is then proposed here, using severe hypofractionation on large tumour volumes where both dose prescription strategies are applicable. Materials and methods. For iso-NTCP hypofractionated schedules (1f/d*5d/w) with respect to standard fractionation (d=2Gy), computed from the individual DVHs for lungs, oesophagus, heart and spinal cord (Lyman-Kutcher-Burman NTCP-model), TCP values were calculated (α-averaged Poissonian-LQ model) for homogeneous and SBRT-like non-homogeneous plans both with and without tumour hypoxia. Two different estimates of the oxygen-enhancement-ratio (OER) in combination with two distinct assumptions on the kinetics of reoxygenation were considered. Homogeneous and SBRT-like non-homogeneous plans were finally compared in terms of therapeutic ratio (TR), as the product of TCP and the four (1-NTCPi) values. Results. For severe hypofractionation (35 fractions) and for any of the hypotheses on the kinetics of reoxygenation and the OER, there was a significant difference between the computed TRs with or without inclusion of tumour hypoxia (anova, p=0.01) for homogeneous tumour-dose-delivery, but no significant difference for the SBRT-like non-homogeneous one. Further, a significantly increased mean TR for the group of SBRT-like non-homogeneous plans resulted (t-test, p=0.05) with respect to the group with homogeneous target-dose-coverage. Conclusions. SBRT-like dose-boosting seems to counterbalance the loss of reoxygenation within a few fractions. For SBRT it then seems that, in addition to the high level of dose-sparing to the adjacent normal tissues, when severe hypofractionation is adopted it is probably the intrinsic ability of stereotactic techniques to perform intra-tumour simultaneous dose-boosting which yields the reported high clinical efficacy. © 2010 Informa Healthcare.
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.
Syndikus I.,Clatterbridge Center for Oncology |
Morgan R.C.,Cancer Group |
Sydes M.R.,Cancer Group |
Graham J.D.,Musgrove Park Hospital |
Dearnaley D.P.,Royal Marsden Hospital
International Journal of Radiation Oncology Biology Physics | Year: 2010
Purpose: In men with localized prostate cancer, dose-escalated conformal radiotherapy (CFRT) improves efficacy outcomes at the cost of increased toxicity. We present a detailed analysis to provide further information about the incidence and prevalence of late gastrointestinal side effects. Methods and Materials: The UK Medical Research Council RT01 trial included 843 men with localized prostate cancer, who were treated for 6 months with neoadjuvant radiotherapy and were randomly assigned to either 64-Gy or 74-Gy CFRT. Toxicity was evaluated before CFRT and during long-term follow-up using Radiation Therapy Oncology Group (RTOG) grading, the Late Effects on Normal Tissue: Subjective, Objective, Management (LENT/SOM) scale, and Royal Marsden Hospital assessment scores. Patients regularly completed Functional Assessment of Cancer Therapy--Prostate (FACT-P) and University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) questionnaires. Results: In the dose-escalated group, the hazard ratio (HR) for rectal bleeding (LENT/SOM grade ≥2) was 1.55 (95% CI, 1.17-2.04); for diarrhea (LENT/SOM grade ≥2), the HR was 1.79 (95% CI, 1.10-2.94); and for proctitis (RTOG grade ≥2), the HR was 1.64 (95% CI, 1.20-2.25). Compared to baseline scores, the prevalence of moderate and severe toxicities generally increased up to 3 years and than lessened. At 5 years, the cumulative incidence of patient-reported severe bowel problems was 6% vs. 8% (standard vs. escalated, respectively) and severe distress was 4% vs. 5%, respectively. Conclusions: There is a statistically significant increased risk of various adverse gastrointestinal events with dose-escalated CFRT. This remains at clinically acceptable levels, and overall prevalence ultimately decreases with duration of follow-up. Crown Copyright © 2010.
Sacco J.J.,Clatterbridge Center for Oncology |
Botten J.,Velindre Cancer Center |
Macbeth F.,Velindre Cancer Center |
Bagust A.,University of Liverpool |
Clark P.,Clatterbridge Center for Oncology
PLoS ONE | Year: 2010
The majority of chemotherapy drugs are dosed based on body surface area (BSA). No standard BSA values for patients being treated in the United Kingdom are available on which to base dose and cost calculations. We therefore retrospectively assessed the BSA of patients receiving chemotherapy treatment at three oncology centres in the UK between 1st January 2005 and 31st December 2005. A total of 3613 patients receiving chemotherapy for head and neck, ovarian, lung, upper GI/ pancreas, breast or colorectal cancers were included. The overall mean BSA was 1.79 m2 (95% CI 1.78-1.80) with a mean BSA for men of 1.91 m2 (1.90-1.92) and 1.71 m2 (1.70-1.72) for women. Results were consistent across the three centres. No significant differences were noted between treatment in the adjuvant or palliative setting in patients with breast or colorectal cancer. However, statistically significant, albeit small, differences were detected between some tumour groups. In view of the consistency of results between three geographically distinct UK cancer centres, we believe the results of this study may be generalised and used in future costings and budgeting for new chemotherapy agents in the UK. © 2010 Sacco et al.
Rutkowska E.,University of Liverpool |
Baker C.,University of Liverpool |
Nahum A.,Clatterbridge Center for Oncology
Physics in Medicine and Biology | Year: 2010
A radiobiologically based 3D model of normal tissue has been developed in which complications are generated when 'irradiated'. The aim is to provide insight into the connection between dose-distribution characteristics, different organ architectures and complication rates beyond that obtainable with simple DVH-based analytical NTCP models. In this model the organ consists of a large number of functional subunits (FSUs), populated by stem cells which are killed according to the LQ model. A complication is triggered if the density of FSUs in any 'critical functioning volume' (CFV) falls below some threshold. The (fractional) CFV determines the organ architecture and can be varied continuously from small (series-like behaviour) to large (parallel-like). A key feature of the model is its ability to account for the spatial dependence of dose distributions. Simulations were carried out to investigate correlations between dose-volume parameters and the incidence of 'complications' using different pseudo-clinical dose distributions. Correlations between dose-volume parameters and outcome depended on characteristics of the dose distributions and on organ architecture. As anticipated, the mean dose and V20 correlated most strongly with outcome for a parallel organ, and the maximum dose for a serial organ. Interestingly better correlation was obtained between the 3D computer model and the LKB model with dose distributions typical for serial organs than with those typical for parallel organs. This work links the results of dose-volume analyses to dataset characteristics typical for serial and parallel organs and it may help investigators interpret the results from clinical studies. © 2010 Institute of Physics and Engineering in Medicine.
Waddell T.,Royal Marsden NHS Foundation Trust |
Chau I.,Royal Marsden NHS Foundation Trust |
Cunningham D.,Royal Marsden NHS Foundation Trust |
Gonzalez D.,Royal Marsden NHS Foundation Trust |
And 17 more authors.
The Lancet Oncology | Year: 2013
Background: EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. Methods: In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. Findings: Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6-13·0) compared with 8·8 months (7·7-9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07-1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 [13%] vs 74 [28%]). Interpretation: Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. Funding: Amgen, UK National Institute for Health Research Biomedical Research Centre. © 2013 Elsevier Ltd.