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We would like to thank Drs Cardillo and Treasure [1Cardillo G. Treasure T. Recurrent lung metastases: evidence of benefit from surgery requires a randomized trial.Ann Thorac Surg. 2017; 104 (letter): 1435Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar] for their interest in our article [2Hishida T. Tsuboi M. Okumura T. et al.Does repeated lung resection provide long-term survival for recurrent pulmonary metastases of colorectal cancer? Results of a retrospective Japanese multicenter study.Ann Thorac Surg. 2017; 103: 399-405Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar] and for their kind invitation to join the ongoing Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) randomized trial, which prospectively compares resection versus active monitoring (no resection) for pulmonary metastases (PM) of colorectal cancer (CRC) [3Treasure T. Fallowfield L. Lees B. Farewell V. Pulmonary metastasectomy in colorectal cancer: the PulMiCC trial.Thorax. 2012; 67: 185-187Crossref PubMed Scopus (92) Google Scholar]. Pulmonary metastasectomy for PM-CRC has been broadly reported in many retrospective series [4Salah S. Watanabe K. Welter S. et al.Colorectal cancer pulmonary oligometastases: pooled analysis and construction of a clinical lung metastasectomy prognostic model.Ann Oncol. 2012; 23: 2649-2655Crossref PubMed Scopus (88) Google Scholar, 5Gonzalez M. Poncet A. Combescure C. Robert J. Ris H.B. Gervaz P. Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis.Ann Surg Oncol. 2013; 20: 572-579Crossref PubMed Scopus (291) Google Scholar, 6Iida T. Nomori H. Shiba M. et al.Prognostic factors after pulmonary metastasectomy for colorectal cancer and rationale for determining surgical indications: a retrospective analysis.Ann Surg. 2013; 257: 1059-1064Crossref PubMed Scopus (120) Google Scholar]. However, there has been no definite proof that metastasectomy confers a survival benefit because of the lack of a randomized controlled trial. In our study, the survival rate after repeated lung resection (RLR) was favorable and equivalent to that after an initial metastasectomy (5-year overall survival 75.3% after RLR vs 65.7% after initial metastasectomy). Similar results were reported previously [7Pastorino U. Buyse M. Friedel G. et al.Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases.J Thorac Cardiovasc Surg. 1997; 113: 37-49Abstract Full Text Full Text PDF PubMed Scopus (1307) Google Scholar], and it is considered that optimal patient selection contributes to favorable survival after RLR, which would have been amplified by repeated selection [8Treasure T. Mineo T. Ambrogi V. Fiorentino F. Survival is higher after repeat lung metastasectomy than after a first metastasectomy: too good to be true?.J Thorac Cardiovasc Surg. 2015; 149: 1249-1252Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar]. The patients who underwent RLR might have had indolent tumors, which would be associated with favorable survivability without an immediate metastasectomy. The PulMiCC trial is the first randomized trial that has a potential to answer the long-standing clinical question whether pulmonary metastasectomy can provide a survival benefit for PM-CRC. This trial considers patients with “uncertain” PM-CRC for whom even discussion by a multidisciplinary cancer team would result in indecision. The patients are informed that there is some uncertainty, and they consent to be randomly allocated to either pulmonary metastasectomy or active monitoring [3Treasure T. Fallowfield L. Lees B. Farewell V. Pulmonary metastasectomy in colorectal cancer: the PulMiCC trial.Thorax. 2012; 67: 185-187Crossref PubMed Scopus (92) Google Scholar]. We are honored to have received the kind invitation from Drs Cardillo and Treasure to join the PulMiCC trial; however, there are several concerns for our Japanese investigators. PM-CRC can be roughly classified into three categories: (1) resectable with favorable features, eg, a solitary or a few lesions; (2) potentially or uncertainly resectable; and (3) definitely unresectable group, eg, multiple bilateral lesions scattered throughout several lobes. Previous retrospective series considered mainly group 1 and partially group 2 for an analysis of pulmonary metastasectomy. By contrast, the PulMiCC trial targets group 2. Our first concern is that the definition of group 2 is ambiguous and the borders between groups are unclear. In Japanese clinical practice, we try to strictly distinguish between group 1 (resectable cases) and group 3 (unresectable cases). In the current setting, eligible candidates (group 2) seem to account for only a minor population. A more clear-cut definition of enrolled candidates might be helpful for us. Second, if metastasectomy is not performed in our clinical practice, systemic chemotherapy is indicated in addition to active monitoring. When a patient is allocated to the active monitoring (no resection) group, he or she may hope to receive immediate systemic chemotherapy. For some of them, conversion surgical procedures would also be indicated if a remarkable effect of chemotherapy is obtained. It is helpful for us if the study protocol can describe more information about acceptable treatment in the active monitoring (no resection) group. Again, we are pleased to have received the kind invitation to join the PulMiCC trial. Several concerns need to be addressed before our group would be able to make a meaningful contribution, but we may be willing to call for discussion among Japanese investigators. Recurrent Lung Metastases: Evidence of Benefit From Surgery Requires a Randomized TrialThe Annals of Thoracic SurgeryVol. 104Issue 4PreviewIncreasing numbers of people are living longer with metastatic cancer. This provides the opportunity for more metastasectomy operations [1], but how much of that added survival is due to lung metastasectomy? Exceptionally long survival may be due to individuals’ mix of cancer biology and response to systemic treatments, and the resulting distribution of survival times is heavily skewed. The patients selected for metastasectomy are from the longer-lived tail of this skewed distribution. The plateaus at the beginning of all six of Hishida’s survival curves illustrates immortal time bias [2]. Full-Text PDF