A comparison of the relative merits of video-assisted pulmonary metastasectomy versus thoracotomy is predicated on the assumption that removal of asymptomatic lung metastases favourably influences survival and that it does so by a large degree. Recently published but long-awaited evidence from a prospective cohort study and a randomised trial of Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) challenges that assumption

Macbeth, Fergus

Treasure, Tom

Williams, Norman R.

PubMed

Treasure, T

Williams, NR

Macbeth, F

UCL Discovery

Treasure et al. Journal of Cardiothoracic Surgery            (2022) 17:9  https://doi.org/10.1186/s13019-022-01757-2LETTER TO THE EDITORThe full cohort of 512 patients and the nested controlled trial in 93 patients in the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) study raise doubts about the effective size at present claimedTom Treasure1* , Norman R. Williams2 and Fergus Macbeth3 Abstract A comparison of the relative merits of video-assisted pulmonary metastasectomy versus thoracotomy is predicated on the assumption that removal of asymptomatic lung metastases favourably influences survival and that it does so by a large degree. Recently published but long-awaited evidence from a prospective cohort study and a randomised trial of Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) challenges that assumption.Keywords: Lung metastases, Colorectal cancer, Randomised controlled trial, PulMiCC trial, Prospective cohort study© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.We read with interest the report of 483 patients with suspected lung metastases of whom 251 had metasta-sectomy [1]. We are grateful to Dr. Markowiak and col-leagues for making reference to our study: Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC). They referred to the initial publication in December 2019. This clearly documents that there was a prospective study in existence, contrary to their statement. Their summary of the circumstances needs correction. After discus-sion with the Independent Data Monitoring Committee, we had closed the trial in January 2017 for the explicit purpose of further follow-up and analysis of the ran-domised controlled trial (RCT) data and the prospective cohort study within which it was nested. We published the results in 93 randomised patients in early May 2020 [2]. While randomisation “faltered” the cohort study had recruited well to a total of 512 patients. It has also been published [3].The 25 multidisciplinary teams recruiting patients internationally selected 263 of the non-randomised patients for lung metastasectomy and 128 to not have that operation. It is no surprise that those selected for metastasectomy had better 5-year survival which was 47% compared with 22% for those turned down. There were differences in the oncological and performance characteristics between these two groups. All differences favoured the operated group. These had been appropri-ately used in selecting patients most likely to live longer after metastasectomy. The data are given in the table with the hazard ratios derived by the meta-analysis of Gonza-lez et al. [4] (Table 1).Open Access*Correspondence:  tom.treasure@gmail.com1 Clinical Operational Research Unit, University College London, London, UKFull list of author information is available at the end of the articlePage 2 of 3Treasure et al. Journal of Cardiothoracic Surgery            (2022) 17:9 In contrast, in the RCT these and others known con-founders were very well matched and there was no differ-ence in survival at any time point (Fig. 1) [2]. At 4 years, survival appears better in the control arm and at 5 years in the metastasectomy arm but the confidence intervals preclude claiming that either is a real difference. It is not possible to exclude a small difference in the long term. But two things are clear: the assumption of zero survival without metastasectomy [5] is contradicted, and any dif-ference is much less than is widely believed. Analysis of health utility showed no benefit from colorectal lung metastasectomy [6].The patients reported by Markowiak et al. were highly selected with high proportions of patients in both groups having a single metastasis and no extrapulmonary metas-tases. In the light of the PulMiCC findings it cannot be concluded that the apparently good survival in Markow-iak’s study can be attributed solely, or perhaps at all, to surgery whether open or by VATS.Fig. 1 The Kaplan Meier analysis of the PulMiCC randomised controlled trial. The unadjusted hazard ratio for death within 5 years was 0.93 (95% CI 0.56–1.56). There is no significant difference at any time point with the curves weaving in and out of each other, but the median survival was longer in the control group at 3.8 (95% CI 3.1–4.6) years compared with median survival after metastasectomy 3.5 (95% CI 3.1–6.6)Page 3 of 3Treasure et al. Journal of Cardiothoracic Surgery            (2022) 17:9  • fast, convenient online submission •  thorough peer review by experienced researchers in your field•  rapid publication on acceptance•  support for research data, including large and complex data types•  gold Open Access which fosters wider collaboration and increased citations  maximum visibility for your research: over 100M website views per year •  At BMC, research is always in progress.Learn more biomedcentral.com/submissionsReady to submit your research ?  Choose BMC and benefit from: AbbreviationsRCT : Randomised controlled trial; PulMiCC: Pulmonary Metastasectomy in Colorectal Cancer; VATS: Video assisted thoracic surgery.AcknowledgementsWe acknowledge the contributions of many participants to the PulMiCC stud-ies. They are all named in the cited publicationsAuthors’ contributionsThe authors contributed equally to the studies referred to and share author-ship of this letter. All authors read and approved the final manuscript.FundingThe trial referred to was funded until 2016 by a grant from Cancer Research UK No. C7678/A11393. There has been no funding for this work in the last 5 years.Availability of data and materialsThe original data are available upon appropriate and reasonable application to the corresponding author.DeclarationsEthics approval and consent to participateFor the PulMiCC cohort and the nested RCT was granted by the National Research Ethics Committee London—Hampstead 10/H0720/5. This required written informed consent which was obtained for every patient.Consent for publicationThe journal “Colorectal Disease” has given full permission to republish the figure which was originally published there. The authors of this letter all give their consent for publication.Competing interestsThe authors TT NRW and FM have no competing interests to declare.Author details1 Clinical Operational Research Unit, University College London, London, UK. 2 Surgical and Interventional Trials Unit, University College London, London, UK. 3 Centre for Trials Research, Cardiff University, Cardiff, UK. Received: 23 April 2021   Accepted: 8 January 2022References 1. Markowiak T, Dakkak B, Loch E, et al. Video-assisted pulmonary metas-tectomy is equivalent to thoracotomy regarding resection status and survival. J Cardiothorac Surg. 2021;16(1):84. https:// doi. org/ 10. 1186/ s13019- 021- 01460-8. 2. Milosevic M, Edwards J, Tsang D, Dunning J, Shackcloth M, Batchelor T, et al. Pulmonary metastasectomy in colorectal cancer: updated analysis of 93 randomized patients—control survival is much better than previ-ously assumed. Colorectal Dis. 2020;22(10):1314–24. 3. Treasure T, Farewell V, Macbeth F, Batchelor T, Milosevic M, King J, et al. Pulmonary metastasectomy in colorectal cancer (PulMiCC) cohort study: analysis of case selection, risk factors and survival in a prospective obser-vational study of 512 patients. Colorectal Dis. 2021;23:1793–803. 4. Gonzalez M, Poncet A, Combescure C, Robert J, Ris HB, Gervaz P. Risk fac-tors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis. Ann Surg Oncol. 2013;20(2):572–9. 5. Handy JR, Bremner RM, Crocenzi TS, Detterbeck FC, Fernando HC, Fidias PM, et al. Expert consensus document on pulmonary metastasectomy. Ann Thorac Surg. 2019;107(2):631–49. 6. Brew-Graves C, Farewell V, Monson K, Milosevic M, Williams NR, Morris E, et al. Pulmonary metastasectomy in colorectal cancer: health utility scores by EQ-5D-3L in a randomized controlled trial show no benefit from lung metastasectomy. Colorectal Dis. 2021;23(1):200–5.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in pub-lished maps and institutional affiliations.Table 1 Favourable factors for survival were better in the metastasectomy groupa Easter Cooperative Oncology Group 0–5 where zero is unimpairedb Forced Expiratory Volume in 1st second as a percentage of predicted values based on height and sexc The hazard ratio is for multiple versus solitary. Here are given the % of patients with a solitary metastasis in each groupd The tumour marker carcinoembryonic antigen. All hazard ratios are from the meta-analysis of Gonzalez et al. [4]Patient factors Metastasectomy No metastasectomy Hazard ratioN = 263 N = 128ECOG  zeroa 68% 36%Median %FEV1b 96% 87%Solitary  metastasisc65% 31% 2.04CEA < 5 ng/mld 31% 21% 1.91No liver metas-tases36% 28% 1.22Five-year survival 47% 22%

English

The full cohort of 512 patients and the nested controlled trial in 93 patients in the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) study raise doubts about the effective size at present claimed

Online Research @ Cardiff

https://orca.cardiff.ac.uk/id/eprint/147634/1/s13019-022-01757-2-1.pdf

The full cohort of 512 patients and the nested controlled trial in 93 patients in the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) study raise doubts about the effective size at present claimed

Abstract

Similar works

Full text

Available Versions

UCL Discovery

Online Research @ Cardiff