200 results on '"Parmar, Mahesh K. B."'
Search Results
2. Multi-arm multi-stage (MAMS) randomised selection designs: impact of treatment selection rules on the operating characteristics
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Choodari-Oskooei, Babak, Blenkinsop, Alexandra, Handley, Kelly, Pinkney, Thomas, and Parmar, Mahesh K. B.
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- 2024
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3. The effectiveness of interventions to disseminate the results of non-commercial randomised clinical trials to healthcare professionals: a systematic review
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South, Annabelle, Bailey, Julia V., Parmar, Mahesh K. B., and Vale, Claire L.
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- 2024
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4. Statistical analysis plan for the motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART)
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Parker, Richard A., Weir, Christopher J., Pham, Tra My, White, Ian R., Stallard, Nigel, Parmar, Mahesh K. B., Swingler, Robert J., Dakin, Rachel S., Pal, Suvankar, and Chandran, Siddharthan
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- 2023
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5. The role of placebo control in clinical trials for neurodegenerative diseases
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Mehta, Arpan R., Carpenter, James R., Nicholas, Jennifer M., Chataway, Jeremy, Virgo, Bruce, Parmar, Mahesh K. B., Chandran, Siddharthan, and Pal, Suvankar
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- 2023
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6. The DURATIONS randomised trial design: estimation targets, analysis methods and operating characteristics
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Quartagno, Matteo, Carpenter, James R., Walker, A. Sarah, Clements, Michelle, and Parmar, Mahesh K. B.
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Statistics - Methodology - Abstract
Background. Designing trials to reduce treatment duration is important in several therapeutic areas, including TB and antibiotics. We recently proposed a new randomised trial design to overcome some of the limitations of standard two-arm non-inferiority trials. This DURATIONS design involves randomising patients to a number of duration arms, and modelling the so-called duration-response curve. This article investigates the operating characteristics (type-1 and type-2 errors) of different statistical methods of drawing inference from the estimated curve. Methods. Our first estimation target is the shortest duration non-inferior to the control (maximum) duration within a specific risk difference margin. We compare different methods of estimating this quantity, including using model confidence bands, the delta method and bootstrap. We then explore the generalisability of results to estimation targets which focus on absolute event rates, risk ratio and gradient of the curve. Results. We show through simulations that, in most scenarios and for most of the estimation targets, using the bootstrap to estimate variability around the target duration leads to good results for DURATIONS design-appropriate quantities analogous to power and type-1 error. Using model confidence bands is not recommended, while the delta method leads to inflated type-1 error in some scenarios, particularly when the optimal duration is very close to one of the randomised durations. Conclusions. Using the bootstrap to estimate the optimal duration in a DURATIONS design has good operating characteristics in a wide range of scenarios, and can be used with confidence by researchers wishing to design a DURATIONS trial to reduce treatment duration. Uncertainty around several different targets can be estimated with this bootstrap approach., Comment: 4 figures, 1 table + additional material
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- 2020
7. Handling an uncertain control group event risk in non-inferiority trials: non-inferiority frontiers and the power-stabilising transformation
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Quartagno, Matteo, Walker, A. Sarah, Babiker, Abdel G., Turner, Rebecca M., Parmar, Mahesh K. B., Copas, Andrew, and White, Ian R.
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Statistics - Methodology - Abstract
Background. Non-inferiority (NI) trials are increasingly used to evaluate new treatments expected to have secondary advantages over standard of care, but similar efficacy on the primary outcome. When designing a NI trial with a binary primary outcome, the choice of effect measure for the NI margin has an important effect on sample size calculations; furthermore, if the control event risk observed is markedly different from that assumed, the trial can quickly lose power or the results become difficult to interpret. Methods. We propose a new way of designing NI trials to overcome the issues raised by unexpected control event risks by specifying a NI frontier, i.e. a curve defining the most appropriate non-inferiority margin for each possible value of control event risk. We propose a fixed arcsine difference frontier, the power-stabilising transformation for binary outcomes. We propose and compare three ways of designing a trial using this frontier. Results. Testing and reporting on the arcsine scale leads to results which are challenging to interpret clinically. Working on the arcsine scale generally requires a larger sample size compared to the risk difference scale. Therefore, working on the risk difference scale, modifying the margin after observing the control event risk, might be preferable, as it requires a smaller sample size. However, this approach tends to slightly inflate type I error rate; a solution is to use a lower significance level for testing. When working on the risk ratio scale, the same approach leads to power levels above the nominal one, maintaining type I error under control. Conclusions. Our proposed methods of designing NI trials using power-stabilising frontiers make trial design more resilient to unexpected values of the control event risk, at the only cost of requiring larger sample sizes when the goal is to report results on the risk difference scale., Comment: ~4000 words + 5 figures + 1 table + additional material (2 appendices, 1 table, 4 figures)
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- 2019
8. Re-thinking non-inferiority: a practical trial design for optimising treatment duration
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Quartagno, Matteo, Walker, A. Sarah, Carpenter, James R., Phillips, Patrick P. J., and Parmar, Mahesh K. B.
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Statistics - Methodology - Abstract
Background: trials to identify the minimal effective treatment duration are needed in different therapeutic areas, including bacterial infections, TB and Hepatitis--C. However, standard non-inferiority designs have several limitations, including arbitrariness of non-inferiority margins, choice of research arms and very large sample sizes. Methods: we recast the problem of finding an appropriate non-inferior treatment duration in terms of modelling the entire duration-response curve within a pre-specified range. We propose a multi-arm randomised trial design, allocating patients to different treatment durations. We use fractional polynomials and spline-based methods to flexibly model the duration-response curve. We compare different methods in terms of a scaled version of the area between true and estimated prediction curves. We evaluate sensitivity to key design parameters, including sample size, number and position of arms. Results: a total sample size of $\sim 500$ patients divided into a moderate number of equidistant arms (5-7) is sufficient to estimate the duration-response curve within a $5\%$ error margin in $95\%$ of the simulations. Fractional polynomials provide similar or better results than spline-based methods in most scenarios. Conclusions: our proposed practical randomised trial design is an alternative to standard non-inferiority designs, avoiding many of their limitations, and yet being fairly robust to different possible duration-response curves. The trial outcome is the whole duration-response curve, which could be used by clinicians and policy makers to make informed decisions, facilitating a move away from a forced binary hypothesis testing paradigm.
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- 2018
9. Practical guidance for running late-phase platform protocols for clinical trials: lessons from experienced UK clinical trials units
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Love, Sharon B., Cafferty, Fay, Snowdon, Claire, Carty, Karen, Savage, Joshua, Pallmann, Philip, McParland, Lucy, Brown, Louise, Masters, Lindsey, Schiavone, Francesca, Hague, Dominic, Townsend, Stephen, Amos, Claire, South, Annabelle, Sturgeon, Kate, Langley, Ruth, Maughan, Timothy, James, Nicholas, Hall, Emma, Kernaghan, Sarah, Bliss, Judith, Turner, Nick, Tutt, Andrew, Yap, Christina, Firth, Charlotte, Kong, Anthony, Mehanna, Hisham, Watts, Colin, Hills, Robert, Thomas, Ian, Copland, Mhairi, Bell, Sue, Sebag-Montefiore, David, Jones, Robert, Parmar, Mahesh K. B., and Sydes, Matthew R.
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- 2022
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10. Accumulation of copy number alterations and clinical progression across advanced prostate cancer
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Grist, Emily, Friedrich, Stefanie, Brawley, Christopher, Mendes, Larissa, Parry, Marina, Ali, Adnan, Haran, Aine, Hoyle, Alex, Gilson, Claire, Lall, Sharanpreet, Zakka, Leila, Bautista, Carla, Landless, Alex, Nowakowska, Karolina, Wingate, Anna, Wetterskog, Daniel, Hasan, A. M. Mahedi, Akato, Nafisah B., Richmond, Malissa, Ishaq, Sofeya, Matthews, Nik, Hamid, Anis A., Sweeney, Christopher J., Sydes, Matthew R., Berney, Daniel M., Lise, Stefano, Parmar, Mahesh K. B., Clarke, Noel W., James, Nicholas D., Cremaschi, Paolo, Brown, Louise C., and Attard, Gerhardt
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- 2022
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11. Accessing routinely collected health data to improve clinical trials: recent experience of access
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Macnair, Archie, Love, Sharon B., Murray, Macey L., Gilbert, Duncan C., Parmar, Mahesh K. B., Denwood, Tom, Carpenter, James, Sydes, Matthew R., Langley, Ruth E., and Cafferty, Fay H.
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- 2021
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12. Handling an uncertain control group event risk in non-inferiority trials: non-inferiority frontiers and the power-stabilising transformation
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Quartagno, Matteo, Walker, A. Sarah, Babiker, Abdel G., Turner, Rebecca M., Parmar, Mahesh K. B., Copas, Andrew, and White, Ian R.
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- 2020
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13. A framework for prospective, adaptive meta-analysis (FAME) of aggregate data from randomised trials
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Tierney, Jayne F., Fisher, David J., Vale, Claire L., Burdett, Sarah, Rydzewska, Larysa H., Rogozinska, Ewelina, Godolphin, Peter J., White, Ian R., and Parmar, Mahesh K. B.
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Oncology, Experimental -- Methods ,Meta-analysis -- Methods ,Secondary data analysis -- Methods ,Clinical trials -- Methods ,Cancer -- Research ,Biological sciences - Abstract
Background The vast majority of systematic reviews are planned retrospectively, once most eligible trials have completed and reported, and are based on aggregate data that can be extracted from publications. Prior knowledge of trial results can introduce bias into both review and meta-analysis methods, and the omission of unpublished data can lead to reporting biases. We present a collaborative framework for prospective, adaptive meta-analysis (FAME) of aggregate data to provide results that are less prone to bias. Also, with FAME, we monitor how evidence from trials is accumulating, to anticipate the earliest opportunity for a potentially definitive meta-analysis. Methodology We developed and piloted FAME alongside 4 systematic reviews in prostate cancer, which allowed us to refine the key principles. These are to: (1) start the systematic review process early, while trials are ongoing or yet to report; (2) liaise with trial investigators to develop a detailed picture of all eligible trials; (3) prospectively assess the earliest possible timing for reliable meta-analysis based on the accumulating aggregate data; (4) develop and register (or publish) the systematic review protocol before trials produce results and seek appropriate aggregate data; (5) interpret meta-analysis results taking account of both available and unavailable data; and (6) assess the value of updating the systematic review and meta-analysis. These principles are illustrated via a hypothetical review and their application to 3 published systematic reviews. Conclusions FAME can reduce the potential for bias, and produce more timely, thorough and reliable systematic reviews of aggregate data., Author(s): Jayne F. Tierney *, David J. Fisher, Claire L. Vale, Sarah Burdett, Larysa H. Rydzewska, Ewelina Rogozinska, Peter J. Godolphin, Ian R. White, Mahesh K. B. Parmar Background The [...]
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- 2021
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14. Effectiveness and acceptability of methods of communicating the results of clinical research to lay and professional audiences: protocol for a systematic review
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South, Annabelle, Bailey, Julia, Parmar, Mahesh K. B., and Vale, Claire L.
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- 2019
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15. Mind the gap? The platform trial as a working environment
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Morrell, Liz, Hordern, Joshua, Brown, Louise, Sydes, Matthew R., Amos, Claire L., Kaplan, Richard S., Parmar, Mahesh K. B., and Maughan, Timothy S.
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- 2019
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16. Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons
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Hague, Dominic, Townsend, Stephen, Masters, Lindsey, Rauchenberger, Mary, Van Looy, Nadine, Diaz-Montana, Carlos, Gannon, Melissa, James, Nicholas, Maughan, Tim, Parmar, Mahesh K. B., Brown, Louise, Sydes, Matthew R., and for the STAMPEDE and FOCUS4 investigators
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- 2019
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17. Combined test versus logrank/Cox test in 50 randomised trials
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Royston, Patrick, Choodari-Oskooei, Babak, Parmar, Mahesh K. B., and Rogers, Jennifer K.
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- 2019
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18. Data provenance and integrity of health-care systems data for clinical trials
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Murray, Macey L, primary, Love, Sharon B, additional, Carpenter, James R, additional, Hartley, Suzanne, additional, Landray, Martin J, additional, Mafham, Marion, additional, Parmar, Mahesh K B, additional, Pinches, Heather, additional, and Sydes, Matthew R, additional
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- 2022
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19. Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial
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Parker, Chris C., James, Nicholas D., Brawley, Christopher D., Clarke, Noel W., Ali, Adnan, Amos, Claire L., Attard, Gerhardt, Chowdhury, Simon, Cook, Adrian, Cross, William, Dearnaley, David P., Douis, Hassan, Gilbert, Duncan C., Gilson, Clare, Gillessen, Silke, Hoyle, Alex, Jones, Rob J., Langley, Ruth E., Malik, Zafar I., Mason, Malcolm D., Matheson, David, Millman, Robin, Rauchenberger, Mary, Rush, Hannah, Russell, J. Martin, Sweeney, Hannah, Bahl, Amit, Birtle, Alison, Capaldi, Lisa, Din, Omar, Ford, Daniel, Gale, Joanna, Henry, Ann, Hoskin, Peter, Kagzi, Mohammed, Lydon, Anna, O’Sullivan, Joe M., Paisey, Sangeeta A., Parikh, Omi, Pudney, Delia, Ramani, Vijay, Robson, Peter, Srihari, Narayanan Nair, Tanguay, Jacob, Parmar, Mahesh K. B., Sydes, Matthew R., for the STAMPEDE Trial Collaborative Group, and Brenton, James Derek
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Switzerland - epidemiology ,Male ,Docetaxel - therapeutic use ,SDG 3 - Good Health and Well-being ,Prostate - pathology ,Quality of Life ,Humans ,Prostatic Neoplasms - pathology ,General Medicine - Abstract
BackgroundSTAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL).Methods and findingsPatients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire.Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively.ConclusionsProstate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC.
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- 2022
20. Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in the STAMPEDE Randomized Controlled Trial
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James, Nicholas D, primary, Ingleby, Fiona C, additional, Clarke, Noel W, additional, Amos, Claire L, additional, Attard, Gerhardt, additional, Brawley, Christopher D, additional, Chowdhury, Simon, additional, Cross, William, additional, Dearnaley, David P, additional, Gilbert, Duncan C, additional, Gillessen, Silke, additional, Jones, Robert J, additional, Langley, Ruth E, additional, Macnair, Archie, additional, Malik, Zafar I, additional, Mason, Malcolm D, additional, Matheson, David J, additional, Millman, Robin, additional, Parker, Chris C, additional, Rush, Hannah L, additional, Russell, J Martin, additional, Au, Carly, additional, Ritchie, Alastair W S, additional, Mestre, Ricardo Pereira, additional, Ahmed, Imtiaz, additional, Birtle, Alison J, additional, Brock, Susannah J, additional, Das, Prantik, additional, Ford, Victoria A, additional, Gray, Emma K, additional, Hughes, Robert J, additional, Manetta, Caroline B, additional, McLaren, Duncan B, additional, Nikapota, Ashok D, additional, O’Sullivan, Joe M, additional, Perna, Carla, additional, Peedell, Clive, additional, Protheroe, Andrew S, additional, Sundar, Santhanam, additional, Tanguay, Jacob S, additional, Tolan, Shaun P, additional, Wagstaff, John, additional, Wallace, Jan B, additional, Wylie, James P, additional, Zarkar, Anjali, additional, Parmar, Mahesh K B, additional, and Sydes, Matthew R, additional
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- 2022
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21. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease
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Wong, Charis, primary, Dakin, Rachel S, additional, Williamson, Jill, additional, Newton, Judith, additional, Steven, Michelle, additional, Colville, Shuna, additional, Stavrou, Maria, additional, Gregory, Jenna M, additional, Elliott, Elizabeth, additional, Mehta, Arpan R, additional, Chataway, Jeremy, additional, Swingler, Robert J, additional, Parker, Richard Anthony, additional, Weir, Christopher J, additional, Stallard, Nigel, additional, Parmar, Mahesh K B, additional, Macleod, Malcolm R, additional, Pal, Suvankar, additional, and Chandran, Siddharthan, additional
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- 2022
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22. Cost-utility analysis of adding abiraterone acetate plus prednisone/prednisolone to long-term hormone therapy in newly diagnosed advanced prostate cancer in England: Lifetime decision model based on STAMPEDE trial data
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Clarke, Caroline S., primary, Hunter, Rachael M., additional, Gabrio, Andrea, additional, Brawley, Christopher D., additional, Ingleby, Fiona C., additional, Dearnaley, David P., additional, Matheson, David, additional, Attard, Gerhardt, additional, Rush, Hannah L., additional, Jones, Rob J., additional, Cross, William, additional, Parker, Chris, additional, Russell, J. Martin, additional, Millman, Robin, additional, Gillessen, Silke, additional, Malik, Zafar, additional, Lester, Jason F., additional, Wylie, James, additional, Clarke, Noel W., additional, Parmar, Mahesh K. B., additional, Sydes, Matthew R., additional, and James, Nicholas D., additional
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- 2022
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23. Smarter adaptive platform clinical trials in neurology: a showcase for UK innovation
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Mehta, Arpan R, primary, Pal, Suvankar, additional, Chataway, Jeremy, additional, Carpenter, James R, additional, Parmar, Mahesh K B, additional, and Chandran, Siddharthan, additional
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- 2022
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24. Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5‐year follow‐up results from the STAMPEDE randomised trial (NCT00268476)
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James, Nicholas D., Clarke, Noel W., Cook, Adrian, Ali, Adnan, Hoyle, Alex P., Attard, Gerhardt, Brawley, Christopher D., Chowdhury, Simon, Cross, William R., Dearnaley, David P., de Bono, Johann S., Diaz‐Montana, Carlos, Gilbert, Duncan, Gillessen, Silke, Gilson, Clare, Jones, Rob J., Langley, Ruth E., Malik, Zafar I., Matheson, David J., Millman, Robin, Parker, Chris C., Pugh, Cheryl, Rush, Hannah, Russell, J. Martin, Berthold, Dominik R., Buckner, Michelle L., Mason, Malcolm D., Ritchie, Alastair W. S., Birtle, Alison J., Brock, Susannah J., Das, Prantik, Ford, Dan, Gale, Joanna, Grant, Warren, Gray, Emma K., Hoskin, Peter, Khan, Mohammad M., Manetta, Caroline, McPhail, Neil J., O'Sullivan, Joe M., Parikh, Omi, Perna, Carla, Pezaro, Carmel J., Protheroe, Andrew S., Robinson, Angus J., Rudman, Sarah M., Sheehan, Denise J., Srihari, Narayanan N., Syndikus, Isabel, Tanguay, Jacob S., Thomas, Carys W., Vengalil, Salil, Wagstaff, John, Wylie, James P., Parmar, Mahesh K. B., Sydes, Matthew R., James, Nicholas D., Clarke, Noel W., Cook, Adrian, Ali, Adnan, Hoyle, Alex P., Attard, Gerhardt, Brawley, Christopher D., Chowdhury, Simon, Cross, William R., Dearnaley, David P., de Bono, Johann S., Diaz‐Montana, Carlos, Gilbert, Duncan, Gillessen, Silke, Gilson, Clare, Jones, Rob J., Langley, Ruth E., Malik, Zafar I., Matheson, David J., Millman, Robin, Parker, Chris C., Pugh, Cheryl, Rush, Hannah, Russell, J. Martin, Berthold, Dominik R., Buckner, Michelle L., Mason, Malcolm D., Ritchie, Alastair W. S., Birtle, Alison J., Brock, Susannah J., Das, Prantik, Ford, Dan, Gale, Joanna, Grant, Warren, Gray, Emma K., Hoskin, Peter, Khan, Mohammad M., Manetta, Caroline, McPhail, Neil J., O'Sullivan, Joe M., Parikh, Omi, Perna, Carla, Pezaro, Carmel J., Protheroe, Andrew S., Robinson, Angus J., Rudman, Sarah M., Sheehan, Denise J., Srihari, Narayanan N., Syndikus, Isabel, Tanguay, Jacob S., Thomas, Carys W., Vengalil, Salil, Wagstaff, John, Wylie, James P., Parmar, Mahesh K. B., and Sydes, Matthew R.
- Abstract
Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10−9) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group.
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- 2022
25. Uptake of the multi-arm multi-stage (MAMS) adaptive platform approach: a trial-registry review of late-phase randomised clinical trials
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Noor, Nurulamin M, primary, Love, Sharon B, additional, Isaacs, Talia, additional, Kaplan, Richard, additional, Parmar, Mahesh K B, additional, and Sydes, Matthew R, additional
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- 2022
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26. Additional file 3 of Accumulation of copy number alterations and clinical progression across advanced prostate cancer
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Grist, Emily, Friedrich, Stefanie, Brawley, Christopher, Mendes, Larissa, Parry, Marina, Ali, Adnan, Haran, Aine, Hoyle, Alex, Gilson, Claire, Lall, Sharanpreet, Zakka, Leila, Bautista, Carla, Landless, Alex, Nowakowska, Karolina, Wingate, Anna, Wetterskog, Daniel, Hasan, A. M. Mahedi, Akato, Nafisah B., Richmond, Malissa, Ishaq, Sofeya, Matthews, Nik, Hamid, Anis A., Sweeney, Christopher J., Sydes, Matthew R., Berney, Daniel M., Lise, Stefano, Parmar, Mahesh K. B., Clarke, Noel W., James, Nicholas D., Cremaschi, Paolo, Brown, Louise C., and Attard, Gerhardt
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Additional file 3. Contains supplemental methods-full list of STAMPEDE trial eligibility criteria and criteria for inclusion in the CN-300 cohort.
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- 2022
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27. Additional file 5 of Accumulation of copy number alterations and clinical progression across advanced prostate cancer
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Grist, Emily, Friedrich, Stefanie, Brawley, Christopher, Mendes, Larissa, Parry, Marina, Ali, Adnan, Haran, Aine, Hoyle, Alex, Gilson, Claire, Lall, Sharanpreet, Zakka, Leila, Bautista, Carla, Landless, Alex, Nowakowska, Karolina, Wingate, Anna, Wetterskog, Daniel, Hasan, A. M. Mahedi, Akato, Nafisah B., Richmond, Malissa, Ishaq, Sofeya, Matthews, Nik, Hamid, Anis A., Sweeney, Christopher J., Sydes, Matthew R., Berney, Daniel M., Lise, Stefano, Parmar, Mahesh K. B., Clarke, Noel W., James, Nicholas D., Cremaschi, Paolo, Brown, Louise C., and Attard, Gerhardt
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Additional file 5. List of STAMPEDE investigators.
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- 2022
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28. Additional file 1 of Accumulation of copy number alterations and clinical progression across advanced prostate cancer
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Grist, Emily, Friedrich, Stefanie, Brawley, Christopher, Mendes, Larissa, Parry, Marina, Ali, Adnan, Haran, Aine, Hoyle, Alex, Gilson, Claire, Lall, Sharanpreet, Zakka, Leila, Bautista, Carla, Landless, Alex, Nowakowska, Karolina, Wingate, Anna, Wetterskog, Daniel, Hasan, A. M. Mahedi, Akato, Nafisah B., Richmond, Malissa, Ishaq, Sofeya, Matthews, Nik, Hamid, Anis A., Sweeney, Christopher J., Sydes, Matthew R., Berney, Daniel M., Lise, Stefano, Parmar, Mahesh K. B., Clarke, Noel W., James, Nicholas D., Cremaschi, Paolo, Brown, Louise C., and Attard, Gerhardt
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Additional file 1. Contains supplemental figures 1-12.
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- 2022
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29. Additional file 2 of Accumulation of copy number alterations and clinical progression across advanced prostate cancer
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Grist, Emily, Friedrich, Stefanie, Brawley, Christopher, Mendes, Larissa, Parry, Marina, Ali, Adnan, Haran, Aine, Hoyle, Alex, Gilson, Claire, Lall, Sharanpreet, Zakka, Leila, Bautista, Carla, Landless, Alex, Nowakowska, Karolina, Wingate, Anna, Wetterskog, Daniel, Hasan, A. M. Mahedi, Akato, Nafisah B., Richmond, Malissa, Ishaq, Sofeya, Matthews, Nik, Hamid, Anis A., Sweeney, Christopher J., Sydes, Matthew R., Berney, Daniel M., Lise, Stefano, Parmar, Mahesh K. B., Clarke, Noel W., James, Nicholas D., Cremaschi, Paolo, Brown, Louise C., and Attard, Gerhardt
- Abstract
Additional file 2: Table S1. STAMPEDE trial sites contributing patients to the CN-300 cohort. Table S2. Cohort characteristics of the CN-300 biomarker cohort compared to the full trial comparison group. Table S3. Survival at 4 years follow-up for different metastatic states (Kaplan-Meier estimates). Table S4. Number of events within the CN-300 cohort within trial endpoints. Table S5. Summary of estimated association between copy number burden and hazard of outcome from univariable and multivariable survival modelling. Table S6. Summary of estimated association between copy number burden and hazard of outcome from multivariable survival models, including interaction with metastatic status.
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- 2022
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30. Additional file 1 of Practical guidance for running late-phase platform protocols for clinical trials: lessons from experienced UK clinical trials units
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Love, Sharon B., Cafferty, Fay, Snowdon, Claire, Carty, Karen, Savage, Joshua, Pallmann, Philip, McParland, Lucy, Brown, Louise, Masters, Lindsey, Schiavone, Francesca, Hague, Dominic, Townsend, Stephen, Amos, Claire, South, Annabelle, Sturgeon, Kate, Langley, Ruth, Maughan, Timothy, James, Nicholas, Hall, Emma, Kernaghan, Sarah, Bliss, Judith, Turner, Nick, Tutt, Andrew, Yap, Christina, Firth, Charlotte, Kong, Anthony, Mehanna, Hisham, Watts, Colin, Hills, Robert, Thomas, Ian, Copland, Mhairi, Bell, Sue, Sebag-Montefiore, David, Jones, Robert, Parmar, Mahesh K. B., and Sydes, Matthew R.
- Abstract
Additional file 1. Trials whose staff experiences added to this paper.
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- 2022
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31. Clinical trials in amyotrophic lateral sclerosis: a systematic review and perspective
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Wong, Charis, primary, Stavrou, Maria, additional, Elliott, Elizabeth, additional, Gregory, Jenna M, additional, Leigh, Nigel, additional, Pinto, Ashwin A, additional, Williams, Timothy L, additional, Chataway, Jeremy, additional, Swingler, Robert, additional, Parmar, Mahesh K B, additional, Stallard, Nigel, additional, Weir, Christopher J, additional, Parker, Richard A, additional, Chaouch, Amina, additional, Hamdalla, Hisham, additional, Ealing, John, additional, Gorrie, George, additional, Morrison, Ian, additional, Duncan, Callum, additional, Connelly, Peter, additional, Carod-Artal, Francisco Javier, additional, Davenport, Richard, additional, Reitboeck, Pablo Garcia, additional, Radunovic, Aleksandar, additional, Srinivasan, Venkataramanan, additional, Preston, Jenny, additional, Mehta, Arpan R, additional, Leighton, Danielle, additional, Glasmacher, Stella, additional, Beswick, Emily, additional, Williamson, Jill, additional, Stenson, Amy, additional, Weaver, Christine, additional, Newton, Judith, additional, Lyle, Dawn, additional, Dakin, Rachel, additional, Macleod, Malcolm, additional, Pal, Suvankar, additional, and Chandran, Siddharthan, additional
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- 2021
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32. Bayesian Analysis [with Reply]
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Grossman, Jason, Parmar, Mahesh K. B., Burton, Paul, Gurrin, Lyle, and Campbell, Michael
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- 1999
33. Association of bone metastatic burden with survival benefit from prostate radiotherapy in patients with newly diagnosed metastatic prostate cancer
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Ali, Adnan, Hoyle, Alex, Haran, Áine M., Brawley, Christopher D., Cook, Adrian, Amos, Claire, Calvert, Joanna, Douis, Hassan, Mason, Malcolm D., Dearnaley, David, Attard, Gerhardt, Gillessen, Silke, Parmar, Mahesh K. B., Parker, Christopher C., Sydes, Matthew R., James, Nicholas D., and Clarke, Noel W.
- Abstract
Importance Prostate radiotherapy (RT) improves survival in men with low-burden metastatic prostate cancer. However, owing to the dichotomized nature of metastatic burden criteria, it is not clear how this benefit varies with bone metastasis counts and metastatic site.\ud\udObjective To evaluate the association of bone metastasis count and location with survival benefit from prostate RT.\ud\udDesign, Setting, and Participants This exploratory analysis of treatment outcomes based on metastatic site and extent as determined by conventional imaging (computed tomography/magnetic resonance imaging and bone scan) evaluated patients with newly diagnosed metastatic prostate cancer randomized within the STAMPEDE trial’s metastasis M1 RT comparison. The association of baseline bone metastasis counts with overall survival (OS) and failure-free survival (FFS) was assessed using a multivariable fractional polynomial interaction procedure. Further analysis was conducted in subgroups.\ud\udInterventions Patients were randomized to receive either standard of care (androgen deprivation therapy with or without docetaxel) or standard of care and prostate RT.\ud\udMain Outcomes and Measures The primary outcomes were OS and FFS.\ud\udResults A total of 1939 of 2061 men were included (median [interquartile range] age, 68 [63-73] years); 1732 (89%) had bone metastases. Bone metastasis counts were associated with OS and FFS benefit from prostate RT. Survival benefit decreased continuously as the number of bone metastases increased, with benefit most pronounced up to 3 bone metastases. A plot of estimated treatment effect indicated that the upper 95% CI crossed the line of equivalence (hazard ratio [HR], 1) above 3 bone metastases without a detectable change point. Further analysis based on subgroups showed that the magnitude of benefit from the addition of prostate RT was greater in patients with low metastatic burden with only nonregional lymph nodes (M1a) or 3 or fewer bone metastases without visceral metastasis (HR for OS, 0.62; 95% CI, 0.46-0.83; HR for FFS, 0.57; 95% CI, 0.47-0.70) than among patients with 4 or more bone metastases or any visceral/other metastasis (HR for OS, 1.08; 95% CI, 0.91-1.28; interaction P = .003; HR for FFS, 0.87; 95% CI, 0.76-0.99; interaction P = .002).\ud\udConclusions and Relevance In this exploratory analysis of a randomized clinical trial, bone metastasis count and metastasis location based on conventional imaging were associated with OS and FFS benefit from prostate RT in M1 disease.
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- 2021
34. Take-Home Emergency Naloxone to Prevent Heroin Overdose Deaths after Prison Release: Rationale and Practicalities for the N-ALIVE Randomized Trial
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Strang, John, Bird, Sheila M., and Parmar, Mahesh K. B.
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- 2013
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35. Chemotherapy and radiotherapy in locally advanced head and neck cancer : an individual patient data network meta-analysis
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Petit, Claire, Lacas, Benjamin, Pignon, Jean-Pierre, Le, Quynh Thu, Grégoire, Vincent, Grau, Cai, Hackshaw, Allan, Zackrisson, Björn, Parmar, Mahesh K. B., Lee, Ju-Whei, Ghi, Maria Grazia, Sanguineti, Giuseppe, Temam, Stéphane, Cheugoua-Zanetsie, Maurice, O'Sullivan, Brian, Posner, Marshall R., Vokes, Everett E., Cruz Hernandez, Juan J., Szutkowski, Zbigniew, Lartigau, Eric, Budach, Volker, Suwiński, Rafal, Poulsen, Michael, Kumar, Shaleen, Ghosh Laskar, Sarbani, Mazeron, Jean-Jacques, Jeremic, Branislav, Simes, John, Zhong, Lai-Ping, Overgaard, Jens, Fortpied, Catherine, Torres-Saavedra, Pedro, Bourhis, Jean, Aupérin, Anne, Blanchard, Pierre, Petit, Claire, Lacas, Benjamin, Pignon, Jean-Pierre, Le, Quynh Thu, Grégoire, Vincent, Grau, Cai, Hackshaw, Allan, Zackrisson, Björn, Parmar, Mahesh K. B., Lee, Ju-Whei, Ghi, Maria Grazia, Sanguineti, Giuseppe, Temam, Stéphane, Cheugoua-Zanetsie, Maurice, O'Sullivan, Brian, Posner, Marshall R., Vokes, Everett E., Cruz Hernandez, Juan J., Szutkowski, Zbigniew, Lartigau, Eric, Budach, Volker, Suwiński, Rafal, Poulsen, Michael, Kumar, Shaleen, Ghosh Laskar, Sarbani, Mazeron, Jean-Jacques, Jeremic, Branislav, Simes, John, Zhong, Lai-Ping, Overgaard, Jens, Fortpied, Catherine, Torres-Saavedra, Pedro, Bourhis, Jean, Aupérin, Anne, and Blanchard, Pierre
- Abstract
BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensi
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- 2021
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36. Predictive classifier for intensive treatment of head and neck cancer
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Zakeri, Kaveh, Rotolo, Federico, Lacas, Benjamin, Vitzthum, Lucas K., Le, Quynh-Thu, Gregoire, Vincent, Overgaard, Jens, Hackshaw, Allan, Zackrisson, Björn, Parmar, Mahesh K. B., Burtness, Barbara A., Ghi, Maria Grazia, Sanguineti, Giuseppe, O'Sullivan, Brian, Fortpied, Catherine, Bourhis, Jean, Shen, Hanjie, Harris, Jonathan, Michiels, Stefan, Pignon, Jean-Pierre, Mell, Loren K., Zakeri, Kaveh, Rotolo, Federico, Lacas, Benjamin, Vitzthum, Lucas K., Le, Quynh-Thu, Gregoire, Vincent, Overgaard, Jens, Hackshaw, Allan, Zackrisson, Björn, Parmar, Mahesh K. B., Burtness, Barbara A., Ghi, Maria Grazia, Sanguineti, Giuseppe, O'Sullivan, Brian, Fortpied, Catherine, Bourhis, Jean, Shen, Hanjie, Harris, Jonathan, Michiels, Stefan, Pignon, Jean-Pierre, and Mell, Loren K.
- Abstract
Background This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer. Methods This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta-Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the omega score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH-NC data set. The study tested for interactions between the omega score and treatment effects on overall survival (OS). Results Factors associated with a higher omega score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16-negative/unknown status. The effect of AFX on OS was greater in patients with high omega scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85-0.99) and medium omega scores (HR, 0.91; 95% CI, 0.84-0.98) versus low omega scores (HR, 0.97; 95% CI, 0.90-1.05;Pfor interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high omega scores (HR, 0.81; 95% CI, 0.75-0.88) and medium omega scores (HR, 0.86; 95% CI, 0.78-0.93) versus low omega scores (HR, 0.96; 95% CI, 0.86-1.08;Pfor interaction = .011). Conclusions LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher omega score, selectively benefit from more intensive treatment.
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- 2020
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37. Comparison of aggregate and individual participant data approaches to meta-analysis of randomised trials: An observational study
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Tierney, Jayne F., primary, Fisher, David J., additional, Burdett, Sarah, additional, Stewart, Lesley A., additional, and Parmar, Mahesh K. B., additional
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- 2020
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38. Speeding up the Evaluation of New Agents in Cancer
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Parmar, Mahesh K. B., Barthel, Friederike M.-S., Sydes, Matthew, Langley, Ruth, Kaplan, Rick, Eisenhauer, Elizabeth, Brady, Mark, James, Nicholas, Bookman, Michael A., Swart, Ann-Marie, Qian, Wendi, and Royston, Patrick
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- 2008
39. Re: Visualizing Length of Survival in Time-to-Event Studies: A Complement to Kaplan–Meier Plots
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Royston, Patrick, Parmar, Mahesh K. B., and Altman, Douglas G.
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- 2008
40. Visualizing Length of Survival in Time-to-Event Studies: A Complement to Kaplan–Meier Plots
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Royston, Patrick, Parmar, Mahesh K. B., and Altman, Douglas G.
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- 2008
41. The accuracy of clinical staging of stage I-IIIa non-small cell lung cancer : an analysis based on individual participant data
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Navani, Neal, Fisher, David J., Tierney, Jayne F., Stephens, Richard J., Burdett, Sarah, Rydzewska, Larysa H. M., Auperin, Anne, Le Chevalier, Thierry, Le Pechoux, Cécile, Pignon, Jean-Pierre, Arriagada, Rodrigo, Johnson, David H., van Meerbeeck, Jan, Parmar, Mahesh K. B., Stewart, Lesley A., Bunn, Paul A., Dautzenberg, Bertrand, Gilligan, David, Groen, Harry, Knuuttila, Aija, Vallieres, Eric, Rosell, Rafael, Roth, Jack, Scagliotti, Giorgio, Tsuboi, Masahiro, Waller, David, Westeel, Virginie, Yi-Long, Wu, Yang, Xue-Ning, and NSCLC Meta Anal Collaborative Grp
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meta-analysis ,Pulmonary and Respiratory Medicine ,staging ,Human medicine ,Critical Care and Intensive Care Medicine ,Cardiology and Cardiovascular Medicine ,non-small cell lung cancer - Abstract
BACKGROUND: Clinical staging of non-small cell lung cancer (NSCLC) helps determine the prognosis and treatment of patients; few data exist on the accuracy of clinical staging and the impact on treatment and survival of patients. We assessed whether participant or trial characteristics were associated with clinical staging accuracy as well as impact on survival. METHODS: We used individual participant data from randomized controlled trials (RCTs), supplied for a meta-analysis of preoperative chemotherapy (+/- radiotherapy) vs surgery alone (+/- radiotherapy) in NSCLC. We assessed agreement between clinical TNM (cTNM) stage at randomization and pathologic TNM (pTNM) stage, for participants in the control group. RESULT: Results are based on 698 patients who received surgery alone (+/- radiotherapy) with data for cTNM and pTNM stage. Forty-six percent of cases were cTNM stage I, 23% were cTNM stage II, and 31% were cTNM stage IIIa. cTNM stage disagreed with pTNM stage in 48% of cases, with 34% clinically understaged and 14% clinically overstaged. Agreement was not associated with age (P = .12), sex (P = .62), histology (P = .82), staging method (P = .32), or year of randomization (P = .98). Poorer survival in understaged patients was explained by the underlying pTNM stage. Clinical staging failed to detect T4 disease in 10% of cases and misclassified nodal disease in 38%. CONCLUSION: This study demonstrates suboptimal agreement between clinical and pathologic staging. Discrepancies between clinical and pathologic T and N staging could have led to different treatment decisions in 10% and 38% of cases, respectively. There is therefore a need for further research into improving staging accuracy for patients with stage I-IIIa NSCLC.
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- 2019
42. 850PD - Benefit of prostate radiotherapy for patients with lymph node only or < 4 bone metastasis and no visceral metastases: Exploratory analyses of metastatic site and number in the STAMPEDE 'M1|RT comparison'
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Ali, Adnan, Hoyle, Alex, James, Nicholas D, Parker, Christopher C, Brawley, Christopher D, Attard, Gerhardt, Douis, Hassan, Mason, Malcolm D, Parmar, Mahesh K B, Sydes, Matthew R., and Clarke, Noel
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Manchester Cancer Research Centre ,ResearchInstitutes_Networks_Beacons/mcrc - Abstract
Background Prostate radiotherapy (PRT) with androgen deprivation therapy (ADT) is now recommended as a first line option for de-novo low burden metastatic prostate cancer. In the STAMPEDE “M1|RT comparison” metastatic burden was a determinant of benefit, based on pre-specified prognostic criteria. We have now performed exploratory analyses of metastases as defined by site and number to improve prediction of treatment benefit from PRT. Methods Patients (pts) randomized to the ADT (± docetaxel) vs PRT + ADT (± docetaxel) were studied. Metastatic site, distribution and number were evaluated based on conventional imaging and used to explore treatment effects to refine the metastatic burden definition. Results focused on the trial’s key outcome measures: overall (OS) & failure-free survival (FFS), analysed using standard survival analysis methods. HR < 1 indicates benefit associated with PRT + ADT (±docetaxel) over ADT (±docetaxel). Results Following exclusions (imaging unavailable for central review, n = 122), 1939 pts randomized in “M1|RT comparison” were included. Of these, 181 pts had only lymph node (LN) mets, 1587 had bone (±LN) mets and 171 had other visceral mets (±bone/LN). Baseline characteristics such as age (median 68 years), PSA (median 98 ng/ml) were balanced between the arms. In LN only pts, PRT improved OS (HR = 0.62, 95%CI 0.35-1.09) & FFS (HR = 0.64, 95%CI 0.43-0.96). In bone (±LN) pts with 0.1) for baseline factors such as age, N stage, Gleason score, RT schedule or docetaxel use. Conclusions Prostate RT + ADT (± docetaxel) improved OS & FFS in pts with only LN or < 4 bone mets (±LN) regardless of location. Clinical trial identification NCT00268476.
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- 2019
43. Oral Sodium Clodronate for Nonmetastatic Prostate Cancer—Results of a Randomized Double-Blind Placebo-Controlled Trial: Medical Research Council PR04 (ISRCTN61384873)
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Mason, Malcolm D., Sydes, Matthew R., Glaholm, John, Langley, Ruth E., Huddart, Robert A., Sokal, Michael, Stott, Mark, Robinson, Anne C., James, Nicholas D., Parmar, Mahesh K. B., and Dearnaley, David P.
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- 2007
44. A Double-Blind, Placebo-Controlled, Randomized Trial of Oral Sodium Clodronate for Metastatic Prostate Cancer (MRC PR05 Trial)
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Dearnaley, David P., Sydes, Matthew R., Mason, Malcolm D., Stott, Mark, Powell, Christopher S., Robinson, Anne C. R., Thompson, Peter M., Moffat, Leslie E., Naylor, Sharon L., and Parmar, Mahesh K. B.
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- 2003
45. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial
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Cook, Audrey, Beesley, Sharon, O'Sullivan, Joe M, Birtle, Alison J, Thalmann, George, Graham, John D, Spears, Melissa R, Brock, Susannah, Srinivasan, Rajaguru, Protheroe, Andrew, Sydes, Matthew R, Laing, Robert, Cross, William, Matheson, David, Tsang, David, Parmar, Mahesh K B, Sundar, Santhanam, McKinna, Fiona, Parikh, Omi, Chowdhury, Simon, Robinson, Angus J, De Bono, Johann, Elliott, Tony, Mason, Malcolm D, Parker, Christopher C, Alzouebi, Mymoona, Gibbs, Stephanie, Dearnaley, David P, Millman, Robin, Russell, J Martin, Tolan, Shaun, Chakraborti, Prabir, Cathomas, Richard, Srihari, Narayanan, Clarke, Noel W, Peedell, Clive, James, Nicholas D, Staffurth, John, Gale, Joanna, Hetherington, John, Amos, Claire, Attard, Gerhardt, Hughes, Robert, Jones, Rob J, Ritchie, Alastair W S, McLaren, Duncan B, Wagstaff, John, STAMPEDE investigators, Adab, F., Adeyoju, A., Ahmed, I., Alcock, C., Al-hasso, A., Alonzi, R., Alzouebi, M., Andrade, G., Andrews, S., Ansari, J., Anyamene, N., Azzabi, A., Bahl, A., Ballesteros-Quintail, D., Banerjee, G., Barber, J., Baria, K., Beaney, R., Beesley, S., Beresford, M., Bertelli, G., Bhalla, N., Bhana, R., Birtle, A., Bloomfield, D., Bowen, J., Brady, J., Brierly, R., Brock, S., Brown Richard, B., Brown, S., Button, M., Camilleri, P., Capaldi, L., Castell, F., Chadwick, E., Chakraborti, P., Chan, A., Chan, O., Charnley, N., Chetiyawardana, S., Choudhurey, A., Choudhury, A., Chowdhury, S., Churn, M., Clarke, A., Clarke, N., David, J.C., Cook, A., Cowan, R., Crabb, S., Crawford, M., Crellin, P., Cross, W., Das, T., Davies, J., Dearnaley, D., Dickson, J., Durrani, S., Edwards, A., Eichholz, A., Elliott, T., Eswar, C., Falconer, A., Ferguson, C., Ford, D., Ford, V., Frew, J., Frim, O., Gale, J., Gibbs, S., Glen, H., Graham, J.D., Grant, W., Gray, E., Guerrero-Urbano, T., Gupta, N., Hamid, A., Hamilton, J., Hardman, J., Harland, S., Harper, P., Heath, C., Henry, A., Herbert, C., Hetherington, J., Hill, E., Hilman, S., Hingorani, M., Hofmann, U., Hoskin, P., Huddart, R., Hughes, R., Hughes, S., Ibrahim, A., Jain, S., James, N., Jenkins, P., Jones, R., Kagzi, M., Karp, S., Kehagioglou, P., Kelly, K., Koh, P.K., Keni, M., Khaksar, S., Khan, O., Khoo, V., Kirkbride, P., Kumar, A., Kumar, M., Kumar, S., Laing, R., Lamb, C., Lau, M., Lees, K., Leone, P., Lester, J., Littler, J., Livsey, J., Logue, J., Loughrey, C., Lydon, A., Macgregor, C., Maddineni, S., Mahmood, R., Malik, Z., Mangar, S., Mason, M., Mazhar, D., McGovern, U., McKinna, F., McLaren, D., McMenemin, R., McPhail, N., Melcher, L., Mills, J., Mitchell, D., Mithal, N., Money-Kyrle, J., Montazeri, A., Morris, S., Mort, D., Mukhopadhyay, T., Muthukumar, D., Neave, F., Newby, J., Newman, H., Nicoll, J., Nikapota, A., O'Donnell, H., Ostler, P., O'Sullivan, J., Palaniappan, N., Panades, M., Pantelides, M., Panwar, U., Parikh, O., Parker, C.C., Pattu, P., Paul, A., Payne, H., Pedley, I., Peedell, C., Mau, D.P., Pickering, L., Pigott, K., Plataniotis, G., Popert, R., Porfiri, E., Prashant, R., Prescott, S., Protheroe, A., Pudney, D., Pwint, T., Ramachandra, P., Raman, R., Rimmer, Y., Robinson, A.J., Robson, P., Rogers, P., Russell, M., Sabharwal, A., Sadozye, A., Sangar, V., Sarwar, N., Saunders, D., Sayers, I., Scrase, C., Sentamans, C., Shaffer, R., Shakespeare, D., Sheehan, D., Poh, L.S., Sidek, N., Simms, M., Sivapalasuntharam, A., Sizer, B., Smith-Howell, M., Sparrow, G., Sreenivasan, T., Srihari, N., Srinivasan, R., Staffurth, J., Stewart, D., Stewart, S., Stockdale, A., Subramaniam, R., Sundar, S., Syndikus, I., Tanguay, J., Taylor, H., Thomas, C., Thompson, A., Tipples, K., Tolan, S., Tran, A., Tsang, D., Van der Voet, H., Varela Maria, V., Varughese, M., Venkitaraman, R., Venugopal, B., Wagstaff, J., Walker, G., Wallace, J., Wells, P., Westbury, C., Wheater, M., Whelan, P., Wilkins, M., Wilson, P., Wise, M., Wood, K., Woodward, C., Worlding, J., Wylie, J., Zarkar, A., Berthold, D., Cathomas, R., Durr, D., Engeler, D., Herrera, F., Jichlinski, P., Popescu, R., Prensser, S., Rentsch, C., Roth, B., Seifest, B., Siciliano, D., Strebel, R., and Thalmann, G.
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RC0254 ,Medicine(all) ,SDG 3 - Good Health and Well-being ,610 Medicine & health ,Adult ,Aged ,Aged, 80 and over ,Androgen Antagonists/administration & dosage ,Androgen Antagonists/adverse effects ,Antineoplastic Agents, Hormonal/administration & dosage ,Antineoplastic Agents, Hormonal/adverse effects ,Antineoplastic Combined Chemotherapy Protocols/adverse effects ,Antineoplastic Combined Chemotherapy Protocols/therapeutic use ,Diphosphonates/administration & dosage ,Diphosphonates/adverse effects ,Disease Progression ,Docetaxel ,Drug Administration Schedule ,Humans ,Imidazoles/administration & dosage ,Imidazoles/adverse effects ,Kaplan-Meier Estimate ,Male ,Middle Aged ,Neoplasm Metastasis ,Prostatic Neoplasms/drug therapy ,Taxoids/administration & dosage ,Taxoids/adverse effects ,Treatment Outcome ,Zoledronic Acid - Abstract
BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.
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- 2016
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46. Re: New Guidelines to Evaluate the Response to Treatment in Solid Tumors [Ovarian Cancer]
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Vergote, Ignace, Rustin, Gordon J. S., Eisenhauer, Elisabeth A., Kristensen, Gunnar B., Pujade-Lauraine, Eric, Parmar, Mahesh K. B., Friedlander, Michael, Jakobsen, Anders, and Vermorken, Jan B.
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- 2000
47. Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials
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Vergote, I., Coens, C., Nankivell, Matthew, Kristensen, G.B., Parmar, Mahesh K. B., Ehlen, T., Ottevanger, P.B., Reed, N.S., Kehoe, Sean, Vergote, I., Coens, C., Nankivell, Matthew, Kristensen, G.B., Parmar, Mahesh K. B., Ehlen, T., Ottevanger, P.B., Reed, N.S., and Kehoe, Sean
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- 2018
48. Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial
- Author
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Dearnaley, David P, Jovic, Gordana, Syndikus, Isabel, Khoo, Vincent, Cowan, Richard A, Graham, John D, Aird, Edwin G, Bottomley, David, Huddart, Robert A, Jose, Chakiath C, Matthews, John H L, Millar, Jeremy L, Murphy, Claire, Russell, J Martin, Scrase, Christopher D, Parmar, Mahesh K B, and Sydes, Matthew R
- Subjects
Oncology - Abstract
SummaryBackgroundThe aim of this trial was to compare dose-escalated conformal radiotherapy with control-dose conformal radiotherapy in patients with localised prostate cancer. Preliminary findings reported after 5 years of follow-up showed that escalated-dose conformal radiotherapy improved biochemical progression-free survival. Based on the sample size calculation, we planned to analyse overall survival when 190 deaths occurred; this target has now been reached, after a median 10 years of follow-up.MethodsRT01 was a phase 3, open-label, international, randomised controlled trial enrolling men with histologically confirmed T1b–T3a, N0, M0 prostate cancer with prostate specific antigen of less than 50 ng/mL. Patients were randomly assigned centrally in a 1:1 ratio, using a computer-based minimisation algorithm stratifying by risk of seminal vesicle invasion and centre to either the control group (64 Gy in 32 fractions, the standard dose at the time the trial was designed) or the escalated-dose group (74 Gy in 37 fractions). Neither patients nor investigators were masked to assignment. All patients received neoadjuvant androgen deprivation therapy for 3–6 months before the start of conformal radiotherapy, which continued until the end of conformal radiotherapy. The coprimary outcome measures were biochemical progression-free survival and overall survival. All analyses were done on an intention-to-treat basis. Treatment-related side-effects have been reported previously. This trial is registered, number ISRCTN47772397.FindingsBetween Jan 7, 1998, and Dec 20, 2001, 862 men were registered and 843 subsequently randomly assigned: 422 to the escalated-dose group and 421 to the control group. As of Aug 2, 2011, 236 deaths had occurred: 118 in each group. Median follow-up was 10·0 years (IQR 9·1–10·8). Overall survival at 10 years was 71% (95% CI 66–75) in each group (hazard ratio [HR] 0·99, 95% CI 0·77–1·28; p=0·96). Biochemical progression or progressive disease occurred in 391 patients (221 [57%] in the control group and 170 [43%] in the escalated-dose group). At 10 years, biochemical progression-free survival was 43% (95% CI 38–48) in the control group and 55% (50–61) in the escalated-dose group (HR 0·69, 95% CI 0·56–0·84; p=0·0003).InterpretationAt a median follow-up of 10 years, escalated-dose conformal radiotherapy with neoadjuvant androgen deprivation therapy showed an advantage in biochemical progression-free survival, but this advantage did not translate into an improvement in overall survival. These efficacy data for escalated-dose treatment must be weighed against the increase in acute and late toxicities associated with the escalated dose and emphasise the importance of use of appropriate modern radiotherapy methods to reduce side-effects.FundingUK Medical Research Council.
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- 2014
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49. Role of radiotherapy fractionation in head and neck cancers (MARCH) : an updated meta-analysis
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Lacas, Benjamin, Bourhis, Jean, Overgaard, Jens, Zhang, Qiang, Gregoire, Vincent, Nankivell, Matthew, Zackrisson, Björn, Szutkowski, Zbigniew, Suwinski, Rafal, Poulsen, Michael, O'Sullivan, Brian, Corvo, Renzo, Laskar, Sarbani Ghosh, Fallai, Carlo, Yamazaki, Hideya, Dobrowsky, Werner, Cho, Kwan Ho, Garden, Adam S., Langendijk, Johannes A., Viegas, Celia Maria Pais, Hay, John, Lotayef, Mohamed, Parmar, Mahesh K. B., Auperin, Anne, van Herpen, Carla, Maingon, Philippe, Trotti, Andy M., Grau, Cai, Pignon, Jean-Pierre, Blanchard, Pierre, Lacas, Benjamin, Bourhis, Jean, Overgaard, Jens, Zhang, Qiang, Gregoire, Vincent, Nankivell, Matthew, Zackrisson, Björn, Szutkowski, Zbigniew, Suwinski, Rafal, Poulsen, Michael, O'Sullivan, Brian, Corvo, Renzo, Laskar, Sarbani Ghosh, Fallai, Carlo, Yamazaki, Hideya, Dobrowsky, Werner, Cho, Kwan Ho, Garden, Adam S., Langendijk, Johannes A., Viegas, Celia Maria Pais, Hay, John, Lotayef, Mohamed, Parmar, Mahesh K. B., Auperin, Anne, van Herpen, Carla, Maingon, Philippe, Trotti, Andy M., Grau, Cai, Pignon, Jean-Pierre, and Blanchard, Pierre
- Abstract
Background: The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck(MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials. Methods: For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival. Findings: Comparison 1 (conventional fractionation radiotherapy vs altered fractionation r
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- 2017
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50. Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis.
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UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Service de radiothérapie oncologique, Lacas, Benjamin, Bourhis, Jean, Overgaard, Jens, Zhang, Qiang, Grégoire, Vincent, Nankivell, Matthew, Zackrisson, Björn, Szutkowski, Zbigniew, Suwiński, Rafał, Poulsen, Michael, O'Sullivan, Brian, Corvò, Renzo, Laskar, Sarbani Ghosh, Fallai, Carlo, Yamazaki, Hideya, Dobrowsky, Werner, Cho, Kwan Ho, Beadle, Beth, Langendijk, Johannes A, Viegas, Celia Maria Pais, Hay, John, Lotayef, Mohamed, Parmar, Mahesh K B, Aupérin, Anne, van Herpen, Carla, Maingon, Philippe, Trotti, Andy M, Grau, Cai, Pignon, Jean-Pierre, Blanchard, Pierre, MARCH Collaborative Group, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Service de radiothérapie oncologique, Lacas, Benjamin, Bourhis, Jean, Overgaard, Jens, Zhang, Qiang, Grégoire, Vincent, Nankivell, Matthew, Zackrisson, Björn, Szutkowski, Zbigniew, Suwiński, Rafał, Poulsen, Michael, O'Sullivan, Brian, Corvò, Renzo, Laskar, Sarbani Ghosh, Fallai, Carlo, Yamazaki, Hideya, Dobrowsky, Werner, Cho, Kwan Ho, Beadle, Beth, Langendijk, Johannes A, Viegas, Celia Maria Pais, Hay, John, Lotayef, Mohamed, Parmar, Mahesh K B, Aupérin, Anne, van Herpen, Carla, Maingon, Philippe, Trotti, Andy M, Grau, Cai, Pignon, Jean-Pierre, Blanchard, Pierre, and MARCH Collaborative Group
- Abstract
BACKGROUND: The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials. METHODS: For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival. FINDINGS: Comparison 1 (conventional fractionation radiotherapy vs altered fractionation
- Published
- 2017
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