Pulmonary Metastasectomy: Association Is Not Causation

Reply by the Authors of the Original Article

The recent paper by Dudek et al[1] reports a retrospective institutional case series of patients who had undergone pulmonary metastasectomy (PM) for a wide variety of tumors. It is a comparatively large series, providing a wealth of detail, and the overall survival results (47.1% at 5 years) are claimed to be due to the surgical intervention. They state: “The use of PM as a part of multimodal treatment is in [a] selected population justified.” This conclusion is misleading because without a comparable unoperated control group the apparently favorable outcome could be largely or entirely the result of the selection process alone. Without good evidence of benefit, the risks of surgery, however low, may not be justified.

They cite our report of PulMiCC (Pulmonary Metastasectomy in Colorectal Cancer), the only randomized controlled trial (RCT), that has addressed this question. As they say, it closed early with 93 patients randomized.[2] But it was nested within a cohort of 512 patients[3] and to fully understand the results, both should be considered. In the cohort, 263 patients with lung metastases from colorectal cancer had PM. Five-year survival was 47% (the same as Dudek's) in compared with 22% among 128 patients who did not have PM. Patients selected for metastasectomy had better Eastern Cooperative Oncology Group scores and % predicted forced expiratory volume in 1 second, while fewer had elevated carcinoembryonic antigen or a history of liver metastasectomy. Notably 65% patients had a solitary metastasis in compared to 31% patients selected to not have PM. The differences in prognostic factors could easily explain the survival difference. In contrast, the two arms of the RCT were very well balanced for all prognostic factors. There was no difference in survival at any time point ([Fig. 1]) We cannot exclude an eventual small benefit, but the widely believed survival difference of 40 to 50% is precluded by the survival rates of non-PM patients in both the large cohort study and the RCT.

Fig. 1 Kaplan–Meier analysis of Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC). There are few deaths in either group in the first 1 to 2 years. This is typical of randomized controlled trial results due to guarantee time bias inherent in prospective studies. Thereafter, the curves weave in and out of each other. There is no significant difference at any time. Median survival was longer in the controls at 3.8 years compared with 3.5 in the pulmonary metastasectomy arm.

Dudek et al imply that because PulMiCC failed to recruit fully, further RCTs are unlikely to succeed. Unfortunately, that may well be correct unless clinicians allow themselves the possibility of doubt, but they are wrong to say that a “well-designed large multicenter cohort study including a control group… could also efficiently (assess) the value of the PM for particular types of metastatic cancer.” Even if it were possible to find such a control group balanced for known prognostic factors, unrecorded confounding factors would always make such a study misleading.

Their final conclusion is: “Our 10-year single-center experience demonstrates that PM is associated with long-term survival benefits.” An association has indeed been shown. But association is not an evidence of causation and this study provides no new evidence to support the very widespread but as yet unproven belief that PM has a major effect on the survival of the patients to whom it is recommended.

Publication History

Received: 03 June 2021

Accepted: 29 June 2021

Article published online:
08 February 2022

• References

• 1 Dudek W, Schreiner W, Haj Khalaf M, Sirbu H. Surgery for pulmonary metastases: long-term survival in 281 patients. Thorac Cardiovasc Surg 2021
• 2 Milosevic M, Edwards J, Tsang D. et al. Pulmonary metastasectomy in colorectal cancer: updated analysis of 93 randomized patients - control survival is much better than previously assumed. Colorectal Dis 2020; 22 (10) 1314-1324
• 3 Treasure T, Farewell V, Macbeth F. et al. Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) Cohort Study: analysis of case selection, risk factors and survival in a prospective observational study of 512 patients. Colorectal Dis 2021