An approach to randomization into surgical clinical trials

Treasure, Tom; Baum, Michael

doi:10.1002/bjs.10420

Cited by 13 publications

(10 citation statements)

References 5 publications

(5 reference statements)

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“…The overriding limitation of this study is its small size with only 65 participants. This was, in large, part due to the difficulty clinicians had in presenting uncertainty to patients who were referred to them in the hope of cure [25]. It was also clear that the default of MDTs was to offer intervention rather than randomisation with a chance of assignment to a Non-metastasectomy arm.…”

Section: Discussionmentioning

confidence: 99%

“…Any future trial would have a power calculation informed by PulMiCC data but the implementation of the protocol would need to overcome the bias clearly exercised resulting failure to randomise such a high proportion of participants. Better training by methods such as QuinteT should be employed but it would also be important for clinicians with a vested interest in delivering particular treatments, including surgery, radiotherapy and other ablative techniques, to not be able to subvert the process of unbiased assignment, for reasons set out above [25]. In the light of the PulMiCC findings it seems improbable that the effect of excision or ablation of lung metastases can be as great as is believed at present.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial

Treasure

Farewell

Macbeth

et al. 2019

Trials

174

144

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BackgroundLung metastasectomy in the treatment of advanced colorectal cancer has been widely adopted without good evidence of survival or palliative benefit. We aimed to test its effectiveness in a randomised controlled trial (RCT).MethodsMultidisciplinary teams in 13 hospitals recruited participants with potentially resectable lung metastases to a multicentre, two-arm RCT comparing active monitoring with or without metastasectomy. Other local or systemic treatments were decided by the local team. Randomisation was remote and stratified by site with minimisation for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, the number of metastases, and carcinoembryonic antigen level. The central Trial Management Group were blind to patient allocation until completion of the analysis. Analysis was on intention to treat with a margin for non-inferiority of 10%.ResultsBetween December 2010 and December 2016, 65 participants were randomised. Characteristics were well-matched in the two arms and similar to those in reported studies: age 35 to 86 years (interquartile range (IQR) 60 to 74); primary resection IQR 16 to 35 months previously; stage at resection T1, 2 or 3 in 3, 8 and 46; N1 or N2 in 31 and 26; unknown in 8. Lung metastases 1 to 5 (median 2); 16/65 had previous liver metastases; carcinoembryonic antigen normal in 55/65. There were no other interventions in the first 6 months, no crossovers from control to treatment, and no treatment-related deaths or major adverse events. The Hazard ratio for death within 5 years, comparing metastasectomy with control, was 0.82 (95%CI 0.43, 1.56).ConclusionsBecause of poor and worsening recruitment, the study was stopped. The small number of participants in the trial (N = 65) precludes a conclusive answer to the research question given the large overlap in the confidence intervals in the proportions still alive at all time points. A widely held belief is that the 5-year absolute survival benefit with metastasectomy is about 35%: 40% after metastasectomy compared to < 5% in controls. The estimated survival in this study was 38% (23–62%) for metastasectomy patients and 29% (16–52%) in the well-matched controls. That is the new and important finding of this RCT.Trial registrationClinicalTrials.gov, ID: NCT01106261. Registered on 19 April 2010

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial

Treasure

Farewell

Macbeth

et al. 2019

Trials

174

144

View full text Add to dashboard Cite

show abstract

“…The surgeon then is in a more natural position of explaining the operation rather than trying to point out its deficiencies. The surgeon has to avoid giving advice which may induce bias and therefore the surgical consultation and the randomization meeting should be separated (9). We have adopted a more straightforward selection criterion to offer a more pragmatic all inclusive trial but the concern remains that the trial may not be sufficiently powered to allow for sub group analysis.…”

Section: Mistakesmentioning

confidence: 99%

Randomized controlled trials in malignant pleural mesothelioma surgery—mistakes made and lessons learned

Waller

Dawson

2017

Ann. Transl. Med.

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Randomized surgical trials are of the most difficult to design and recruit, however, they are the only robust method available to establish a new surgical procedure. Mesothelioma is a disease with a perceived poor prognosis for which surgical intervention has relatively high complications and not insignificant mortality. This review will consider the mesothelioma and radical surgery (MARS) 1 and 2 trials, SAKK 17/04 trial and the EORTC 1205 trial all aimed at assessing the potential benefit of radical surgery for malignant pleural mesothelioma. In addition, MesoVATS and MesoTRAP will be explored assessing the value of debulking surgery for malignant pleural mesothelioma. We also endeavour to identify the mistakes made and the lessons learned which will inform future randomized controlled clinical trials in the field of malignant pleural mesothelioma. Despite the insurmountable problems with randomized controlled clinical trials, we show that they are possible and continuing with uncontrolled experiments will perpetuate unproven and potentially harmful operations.

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“…Better training by methods such as QuinteT should be employed but it would also be important for clinicians with a vested interest in delivering particular treatments, including surgery, radiotherapy and other ablative techniques, to not be able to subvert the process of unbiased assignment, for reasons set out above. (25) In the light of PulMiCC findings it seems improbable that the effect of excision or ablation of lung metastases can be as great as is at present believed. There was a two stage consent process for all the randomised patients who are the subject of this trial publication.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multi-centre randomized clinical trial

Treasure

Farewell

Macbeth

et al. 2019

Preprint

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(348/of 350 allowed) Background: Lung metastasectomy in the treatment of advanced colorectal cancer has been widely adopted without good evidence of survival or palliative benefit. We aimed to test its effectiveness in a randomised trial (RCT). Methods: Multidisciplinary teams in 13 hospitals recruited participants with potentially resectable lung metastases to a multicentre 2-arm RCT comparing active monitoring with or without metastasectomy. Other local or systemic treatments were decided by the local team. Randomisation was remote and stratified by site with minimisation for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, the number of metastases, and carcinoembryonic antigen. The central trial management group were blind to patient allocation until completion of the analysis. Analysis was on intention to treat with a margin for non-inferiority of 10%. Results: Between December 2010 and December 2016, 65 participants were randomised. Characteristics were well-matched in the two arms and similar to those in reported studies: age 35 to 86 (Inter Quartile Range (IQR) 60 to 74); primary resection IQR 16 to 35 months previously; stage at resection T1, 2 or 3 in 3, 8 and 46; N1 or N2 in 31 and 26; unknown in 8. Lung metastases 1 to 5 (median 2); 16/65 had previous liver metastases; carcinoembryonic antigen normal in 55/65. There were no other interventions in the first 6 months, no cross overs from control to treatment, and no treatment-related deaths or major adverse events. Hazard ratio for death within 5 years, comparing metastasectomy with control, was 0.82 (95%CI 0.43, 1.56). Conclusions: Because of poor and worsening recruitment, the study was stopped. The small number of participants in the trial (N=65) precludes a conclusive answer to the research question given the large overlap in the confidence intervals in the proportions still alive at all time points. A widely held belief is that the five-year absolute survival benefit with metastasectomy is about 35%: 40% after metastasectomy compared to <5% in controls. The estimated survival in this study was 38% (23-62%) for metastasectomy patients and 29% (16-52%) in the well-matched controls. That is the new and important finding of this RCT. Funding: Cancer Research UK funding Grant No. C7678/A11393 Trial registration: Clintrial.gov Registration number: NCT01106261 Date 19 th April 2010

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An approach to randomization into surgical clinical trials

Abstract: Making randomization easier

Cited by 13 publications

References 5 publications

Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial

Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multicentre randomised clinical trial

Randomized controlled trials in malignant pleural mesothelioma surgery—mistakes made and lessons learned

Pulmonary Metastasectomy versus Continued Active Monitoring in Colorectal Cancer (PulMiCC): a multi-centre randomized clinical trial

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