Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: A phase 3 comparison of dose intensification with 14-day versus 21-day cycles
Cunningham D.,Royal Marsden NHS Foundation Trust |
Hawkes E.A.,Royal Marsden NHS Foundation Trust |
Jack A.,St James Institute of Oncology |
Qian W.,Cambridge Cancer Trials Center |
And 13 more authors.
The Lancet | Year: 2013
Background Dose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups. Methods Patients (aged ≥18 years) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were randomly assigned centrally in a one-to-one ratio, using minimisation, to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab (R-CHOP-14) or eight cycles of R-CHOP every 21 days (R-CHOP-21). R-CHOP-21 was intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m 2, vincristine 1·4 mg/m2 (maximum dose 2 mg), and rituximab 375 mg/m2 on day 1, and oral prednisolone 40 mg/m 2 on days 1-5, administered every 21 days for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mg, rituximab 375 mg/m 2 on day 1, and oral prednisolone 100 mg on days 1-5, administered every 14 days for six cycles, followed by two further infusions of rituximab 375 mg/m2 on day 1 every 14 days. The trial was not masked. The primary outcome was overall survival (OS). This study is registered, number ISCRTN 16017947. Findings 1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of 46 months (IQR 35-57), 2-year OS was 82·7% (79·5-85·9) in the R-CHOP-14 group and 80·8% (77·5-84·2) in the R-CHOP-21 (standard) group (hazard ratio 0·90, 95% CI 0·70-1·15; p=0·3763). No significant improvement was noted in 2-year progression-free survival (R-CHOP-14 75·4%, 71·8-79·1, and R-CHOP-21 74·8%, 71·0-78·4; 0·94, 0·76-1·17; p=0·5907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not predictive for benefit from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of 534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor mandated in this group, whereas grade 3 or 4 thrombo cytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups. Interpretation R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma; therefore, R-CHOP-21 remains the standard first-line treatment in patients with this haematological malignancy. No molecular or clinical subgroup benefited from dose intensification in this study. Funding Chugai Pharmaceutical, Cancer Research UK, National Institute for Health Research Biomedical Research Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust, and Institute of Cancer Research.
Furtado M.,Derriford Hospital |
Johnson R.,St James Institute Of Oncology |
Kruger A.,Royal Cornwall Hospital |
Turner D.,Torbay Hospital |
Rule S.,Derriford Hospital
British Journal of Haematology | Year: 2015
The proteasome inhibitor, bortezomib, potentially increases cell sensitivity to chemotherapy. This study was performed to determine the overall response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicity of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) compared to CHOP + bortezomib chemotherapy in mantle cell lymphoma (MCL) patients at first relapse. Forty-six patients were randomly assigned to standard dose CHOP ± bortezomib 1·6 mg/m2 given on a 21-d cycle for up to eight cycles of treatment. Median age was 71 years (CHOP arm) and 69 years (CHOP-bortezomib arm). Median Eastern Cooperative Oncology Group performance status was 1 (CHOP) and 0 (CHOP-bortezomib) with 65% and 52%, respectively, having a disease stage of IV. ORR was 47·8% (CHOP) and 82·6% (CHOP-bortezomib). Complete response rate was 21·7% (CHOP) vs. 34·8% (CHOP-bortezomib); partial response rate was 26·1% (CHOP) vs. 47·8% (CHOP-bortezomib). Median OS was 11·8 months (CHOP) and 35·6 months (CHOP-bortezomib) (P = 0·01, Hazard ratio [HR] 0·37 [95% confidence interval (CI) 0·16-0·83)] and there was a non-significant improvement in PFS: 8·1 months (CHOP) and 16·5 months (CHOP-bortezomib) [P = 0·12, HR 0·60 (95% CI 0·31-1·15)]. Severe (≥grade 3) sensory neuropathy was similar in both arms (4·3% CHOP vs. 6·5% CHOP-bortezomib). We conclude that the addition of bortezomib to CHOP chemotherapy for relapsed MCL significantly improves outcome with a manageable increase in toxicity. © 2014 John Wiley & Sons Ltd.
Salembier C.,Europe Hospitals Brussels |
Rijnders A.,Europe Hospitals Brussels |
Henry A.,St James Institute Of Oncology |
Niehoff P.,Witten/Herdecke University |
And 2 more authors.
Journal of Contemporary Brachytherapy | Year: 2013
Purpose: To evaluate in a multicenter setting the ability of centers to perform pre-implant permanent prostate brachythe - rapy planning, fulfilling dosimetric goals and constraints based on the Groupe de Curiethérapie- European Society for Radiotherapy and Oncology guidelines in the setting of implantation after prior prostate transurethral resection (TURP). Material and methods: A reference transrectal ultrasound image set of the prostate gland from a patient who had undergone TURP was used. Contouring of the prostate, clinical target volume and organs at risk was performed by the coordinating center. Goals and constraints regarding the dosimetry were defined. Results: Seventeen of twenty-five centers invited to participate were able to import the Digital Imaging and Communications in Medicine-images into their planning computer and plan the implant using the defined guidelines. All centers were able to plan treatment, and achieve the recommended objectives and constraints. However, sector analysis has shown a risk of under-dosage in the anterior part of the prostate. Conclusions: Correct pre-implantation planning with adherence to protocol guidelines and in compliance with defined dosimetric constraints seems feasible in a post-TURP setting, at least on a theoretical basis. A prospective study evaluating the outcome of prostate brachytherapy performed after TURP can therefore be undertaken with an expectation of a correct dosimetry in the multicenter setting.
Swerdlow A.J.,Institute of Cancer Research |
Cooke R.,Institute of Cancer Research |
Bates A.,Southampton General Hospital |
Cunningham D.,Royal Marsden Hospital |
And 13 more authors.
Journal of the National Cancer Institute | Year: 2014
Background: Modern treatment of Hodgkin's lymphoma (HL) has transformed its prognosis but causes late effects, including premature menopause. Cohort studies of premature menopause risks after treatment have been relatively small, and knowledge about these risks is limited.Methods: Nonsurgical menopause risk was analyzed in 2127 women treated for HL in England and Wales at ages younger than 36 years from 1960 through 2004 and followed to 2003 through 2012. Risks were estimated using Cox regression, modified Poisson regression, and competing risks. All statistical tests were two-sided.Results: During follow-up, 605 patients underwent nonsurgical menopause before age 40 years. Risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea [BCNU], etoposide, cytarabine, melphalan) chemotherapy for stem cell transplantation, but was not statistically significantly raised after adriamycin, bleomycin, vinblastine, dacarbazine (ABVD). Menopause generally occurred sooner after ovarian radiotherapy (62.5% within five years of =5 Gy treatment) and BEAM (50.9% within five years) than after alkylating chemotherapy (24.2% within five years of =6 cycles), and after treatment at older than at younger ages. Cumulative risk of menopause by age 40 years was 81.3% after greater than or equal to 5Gy ovarian radiotherapy, 75.3% after BEAM, 49.1% after greater than or equal to 6 cycles alkylating chemotherapy, 1.4% after ABVD, and 3.0% after solely supradiaphragmatic radiotherapy. Tables of individualized risk information for patients by future period, treatment type, dose and age are provided.Conclusions: Patients treated with HL need to plan intended pregnancies using personalized information on their risk of menopause by different future time points. © The Author 2014. Published by Oxford University Press. All rights reserved.
SABRE 1 (Surgery Against Brachytherapy - A Randomised Evaluation): Feasibility randomised controlled trial (RCT) of brachytherapy vs radical prostatectomy in low-intermediate risk clinically localised prostate cancer
Eccles B.K.,University of Southampton |
Cross W.,St James's Hospital |
Rosario D.J.,University of Sheffield |
Doble A.,Addenbrookes Hospital |
And 5 more authors.
BJU International | Year: 2013
Objective To determine the feasibility of a phase III randomised controlled trial of brachytherapy vs radical prostatectomy (RP) in men with low-intermediate risk localised prostate cancer. Patients and Methods This parallel, two-group, multicentre, randomised controlled feasibility trial enrolled men with histologically confirmed localised, low-risk prostate cancer and good performance status from five UK hospitals. Participants were randomly allocated (1:1) by remote computer allocation to receive a decision aid (DA) DVD or standard information (control group), followed by a second randomisation (1:1) to brachytherapy or RP. There was no 'blinding' of staff or patients. Primary outcome was feasibility: a recruitment rate of six patients per centre over the last 6 months of recruitment would deem a phase III trial feasible. Results Between May 2009 and May 2011, 30 patients were randomised (15 in the DA group and 15 in the control group), and four continued to the second treatment randomisation (one from the DA group and three from the control group). One patient was allocated and received brachytherapy and three RP. SABRE 1 closed early due to poor recruitment. All patients were analysed. Screening logbook analysis showed that the main reasons for declining trial entry were a wish to choose treatment or opting for active monitoring. Results from the DA questionnaire (completed by 10 men) showed that four of the men 'felt surgery and radiotherapy had been proven in a high quality trial' and seven felt 'they should make their treatment decision while knowing their doctors opinion'. Conclusion Recruitment to a RP vs brachytherapy trial in localised prostate cancer was not feasible by the use of this two-step randomisation using a DA and previous trials in early prostate cancer have had similar difficulties in recruitment, with only a few achieving their accrual target. The best treatment method for treating low-risk prostate cancer is still unproven in a head-to-head trial and the increasing number of options will make choices correspondingly more difficulty without good quality comparative research. More sophisticated techniques for recruitment may be more successful in future trials in this patient population. © 2013 BJU International.
Lowry L.,University College London |
Smith P.,University College London |
Qian W.,MRC Clinical Trials Unit |
Falk S.,Bristol Oncology and Haematology Center |
And 7 more authors.
Radiotherapy and Oncology | Year: 2011
Purpose: This multicentre, prospective, randomised-controlled trial compared efficacy and toxicity of differing radiotherapy doses in non-Hodgkin lymphoma (NHL). Patients and methods: Patients with any histological subtype of NHL, requiring radiotherapy for local disease control, whether radical, consolidative or palliative, were included. Three hundred and sixty one sites of indolent NHL (predominantly follicular NHL and marginal zone lymphoma) were randomised to receive 40-45 Gy in 20-23 fractions or 24 Gy in 12 fractions. Six hundred and forty sites of aggressive NHL (predominantly diffuse large B cell lymphoma as part of combined-modality therapy) were randomised to receive 40-45 Gy in 20-23 fractions or 30 Gy in 15 fractions. Patients with all stages of disease, having first-line and subsequent therapies were included; first presentations of early-stage disease predominated. Results: There was no difference in overall response rate (ORR) between standard and lower-dose arms. In the indolent group, ORR was 93% and 92%, respectively, (p = 0.72); in the aggressive group, ORR was 91% in both arms (p = 0.87). With a median follow-up of 5.6 years, there was no significant difference detected in the rate of within-radiation field progression (HR = 1.09, 95%CI = 0.76-1.56, p = 0.64 in the indolent group; HR = 0.98, 95%CI = 0.68-1.4, p = 0.89 in the aggressive group). There was also no significant difference detected in the progression free or overall survival. There was a trend for reduced toxicities in the low-dose arms; only the reduction in reported erythema reached significance. Conclusion: In a large, randomised trial, there was no loss of efficacy associated with radiotherapy doses of 24 Gy in indolent NHL and 30 Gy in aggressive NHL, compared with previous standard doses of 40-45 Gy. © 2011 Elsevier Ltd. All rights reserved.
Arden-Close E.,University of Sheffield |
Absolom K.,St James Institute of Oncology |
Greenfield D.M.,Sheffield Teaching Hospitals NHS Trust |
Hancock B.W.,University of Sheffield |
And 2 more authors.
Psycho-Oncology | Year: 2011
Objectives: Gender differences in perceived vulnerability to late effects and views about follow-up among cancer survivors have received little attention. As lymphoma affects both genders similarly, we compared the consequences of cancer (late effects, perceived vulnerability and quality of life (health-related quality of life (HRQoL)), and satisfaction with clinic visits between genders. Methods: A cohort of 115 younger adults (18-45 years, >5 years disease-free survival), who had been treated for lymphoma participated. Questionnaires (n = 91) were completed before and after (n = 62) routine consultant-led appointments. Survivors (n = 24) without appointments were recruited by post. Questionnaires included HRQoL, late effects, perceived vulnerability, issues survivors wanted to discuss and reported discussing in clinic, time waiting in clinic and consultation satisfaction. Results: There were no gender differences in number of self-reported late effects or perceived vulnerability. Men with more late effects reported worse psychological HRQoL (r = 0.50, p<0.001). While men wanted to discuss more topics than they did, women were able to discuss the topics they wanted (ANOVA, p = 0.01). Multiple regression analyses showed a shorter wait in clinic (r = -0.46, p = 0.009) and discussing more topics (r = 0.34, p = 0.06) explained 30.6% of the variance in consultation satisfaction for men. Conclusions: Issues surrounding follow-up provision are increasingly important given the length of survival in young adults following treatment for lymphoma. Men may experience poor psychological well-being due to distress about unanswered concerns. Consideration of their concerns should be prioritised, given that satisfaction and ultimately continued attendance at clinic and HRQoL may be dependent on the extent to which follow-up meets survivors' expectations. © 2010 John Wiley & Sons, Ltd.
Clifford R.,University of Oxford |
Louis T.,French National Center for Scientific Research |
Robbe P.,University of Oxford |
Ackroyd S.,Bradford Teaching Hospitals |
And 24 more authors.
Blood | Year: 2014
SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase and a nuclease that restricts HIV-1 in noncycling cells. Germ-line mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal whole genome sequencing study of chronic lymphocytic leukemia (CLL), we revealed a SAMHD1 mutation as a potential founding event. Here, we describe an AGS patient carrying a pathogenic germ-line SAMHD1 mutation who developed CLL at 24 years of age. Using clinical trial samples, we show that acquired SAMHD1 mutations are associated with high variant allele frequency and reduced SAMHD1 expression and occur in 11% of relapsed/refractory CLL patients. We provide evidence that SAMHD1 regulates cell proliferation and survival and engages in specific protein interactions in response to DNA damage. We propose that SAMHD1 may have a function in DNA repair and that the presence of SAMHD1 mutations in CLL promotes leukemia development. © 2014 by The American Society of Hematology.
Loch T.,University of Kiel |
Carey B.,St James Institute Of Oncology |
Walz J.,Institute Paoli Calmettes Cancer Center |
Fulgham P.F.,Texas Health Presbyterian Hospital Dallas
European Urology | Year: 2015
Background The terminology and abbreviations used in urologic imaging have generally been adopted on an ad hoc basis by different speciality groups; however, there is a need for shared nomenclature to facilitate clinical communication and collaborative research. Objective This work reviews the current nomenclature for urologic imaging used in clinical practice and proposes a taxonomy and terminology for urologic imaging studies. Design, setting, and participants A list of terms used in urologic imaging were compiled from guidelines published by the European Association of Urology and the American Urological Association and from the American College of Radiology Appropriateness Criteria. Outcome measurements and statistical analysis Terms searched were grouped into broad categories based on technology, and imaging terms were further stratified based on the anatomic extent, contrast or phases, technique or modifiers, and combinations or fusions. Terms that had a high degree of utilisation were classified as accepted. Results and limitations We propose a new taxonomy to define a more useful and acceptable nomenclature model acceptable to all health professionals involved in urology. The major advantage of a taxonomic approach to the classification of urologic imaging studies is that it provides a flexible framework for classifying the modifications of current imaging modalities and allows the incorporation of new imaging modalities. The adoption of this hierarchical classification model ranging from the most general to the most detailed descriptions should facilitate hierarchical searches of the medical literature using both general and specific terms. This work is limited in its scope, as it is not currently all-inclusive. This will hopefully be addressed by future modification as others embrace the concept and work towards uniformity in nomenclature. Conclusions This paper provides a noncomprehensive list of the most widely used terms across different specialties. This list can be used as the basis for further discussion, development, and enhancement. Patient summary In this paper we describe a classification system for urologic imaging terms with the aim of aiding health professionals and ensuring that the terms used are more consistent. © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Snee M.,St James Institute of Oncology
Clinical Oncology | Year: 2014
The place of bevacizumab in the management of advanced non-small cell lung cancer (NSCLC) was reviewed. Particular reference has been made to the recent research on the systemic treatment of NSCLC indicating that treatment tailored to specifically identified morphology or genetic profile has recently changed practice. The result of this recent research means that bevacizumab has little, if any, place in the treatment of NSCLC. © 2014 The Royal College of Radiologists.