Pulmonary Metastasectomy in Colorectal Cancer ( PulMiCC ) cohort study : analysis of case selection , risk factors and survival in a prospective observational study of 512 patients

46 249/250 words 47 Aim 48 We wanted to examine survival in patients with resected colorectal cancer (CRC) whose lung 49 metastases are and whose are not resected. 50 51 Methods 52 Teams participating in the study of Pulmonary Metastasectomy in Colorectal Cancer 53 (PulMiCC) identified potential candidates for lung metastasectomy and invited their consent 54 to join Stage 1. Baseline data related to CRC and fitness for surgery were collected. Eligible 55 patients were invited to consent for randomisation in the PulMiCC RCT(Stage 2). Sites were 56 provided with case report forms for non-randomised patients to record adverse events and 57 death at any time. They were all reviewed at one year. Baseline and survival data were 58 analysed for the full cohort. 59 60 Results 61 Twenty-five clinical sites recruited 512 patients from October 2010 to January 2017. Data 62 collection closed in October 2020. Before analysis 28 patients with non-CRC lung lesions 63 were excluded and 3 had withdrawn consent leaving 481. The date of death was known for 64 292 patients, 136 were alive in 2020, and 53 at earlier time points. Baseline factors and five65 year survival were analysed in three strata: 128 non-randomised patients did not have 66 metastasectomy; 263 had elective metastasectomy; 90 were from the randomised trial. The 67 proportions of solitary metastases for electively operated and non-operated patients were 69% 68 and 35%. Their respective five-year survivals were 47% and 22%. 69 70 Conclusion 71 Survival without metastasectomy was greater than widely presumed. Difference in survival 72 appeared to be largely related to selection. No inference can be drawn about the effect of 73 metastasectomy on survival in this observational study. 74 75 76 77 78 79 What this study adds to the literature 80 The assumed near zero survival without resection of patients with lung metastases from 81 colorectal cancer was not supported by this study. It seems likely that a much smaller part of 82 the 40% observed five-year survival can be attributed to lung metastasectomy than is widely 83 believed. 84


Aim
We wanted to examine survival in patients with resected colorectal cancer (CRC) whose lung 49 metastases are and whose are not resected.

52
Teams participating in the study of Pulmonary Metastasectomy in Colorectal Cancer 53 (PulMiCC) identified potential candidates for lung metastasectomy and invited their consent 54 to join Stage 1. Baseline data related to CRC and fitness for surgery were collected. Eligible 55 patients were invited to consent for randomisation in the PulMiCC RCT(Stage 2). Sites were 56 provided with case report forms for non-randomised patients to record adverse events and 57 death at any time. They were all reviewed at one year. Baseline and survival data were 58 analysed for the full cohort.  What this study adds to the literature 80 The assumed near zero survival without resection of patients with lung metastases from 81 colorectal cancer was not supported by this study. It seems likely that a much smaller part of 82 the 40% observed five-year survival can be attributed to lung metastasectomy than is widely The PulMiCC study was run in the context of a firm belief in the clinical effectiveness of 96 lung metastasectomy. In response to a paper arguing the case for a trial,(4) the European Neither statement was supported by control data. These publications in the leading thoracic 105 surgical journals invite the conclusion that lung metastasectomy provides 60% survival 106 benefit. This widely held belief and the climate of certainty resulted in multidisciplinary 107 teams (MDTs) having difficulty randomising patients into the PulMiCC trial. (Fig.1)

109
Although PulMiCC found no difference in survival, a small survival advantage due to 110 resection of lung metastases that prove to be the only site of residual CRC, cannot be 111 discounted. But the trial was large enough to refute the improbable 0% (8)  site's principal investigator (PI) who was either a thoracic surgeon or an oncologist. Patients 137 who were potential candidates for lung metastasectomy were given written information and 138 an explanatory DVD to take home. A healthcare professional training DVD was also 139 available for clinicians to aid their discussions with patients.

141
Interested patients were invited to sign Stage 1 to be assessed for lung metastasectomy within 142 PulMiCC and to be registered by the Trials Unit. They consented to collection of baseline 143 information: sex, age, height and weight to derive body mass index (BMI), the interval since 144 primary colorectal cancer (CRC) resection, whether they had prior liver metastasectomy, the 145 number of lung metastases, carcinoembryonic antigen assay (CEA) and tests of lung function.      3. Patients in the RCT formed the third stratum entering at the time of randomisation.

180
Results are summarised as hazard ratios (HRs) with confidence intervals (CIs). An HR 181 greater than 1 indicates that larger values of the risk factor are associated with poorer survival 182 and an HR less than one indicates that larger values are associated with improved survival.

183
For categorical risk factors, an HR >1 indicates poorer survival is associated with the 184 presence of the risk factor (e.g. for male sex) or with a risk factor category compared to the 185 reference category as for performance status using the Eastern Cooperative Oncology Group 186 (ECOG) scores.

188
For descriptive purposes, survival curves were also estimated based on the fixed grouping of 189 the patients into these three strata. The times of origin for these three curves are different and The baseline risk factors for the patients in the three strata are in Table 4. The proportions of 213 metastases in the three strata ( Fig.4) shows the predominance of solitary metastases (69%) in 214 the elective metastasectomy group. (Table 5).

216
Table 5a presents the results from single factor analyses of baseline factors derived from 217 stratified Cox regression models. The table includes the number of deaths examined in each 218 analysis as these vary depending on the number of patients for whom information is available on the various potential risk factors. The factors demonstrating evidence of a higher mortality 220 risk were higher values of log(CEA), a shorter interval from CRC to cohort entry, and higher 221 ECOG classes with a suggestive effect for male sex. Multiple lung metastases and prior liver 222 metastases also demonstrated limited potential for an increase in mortality so were also 223 considered for multi-factor analyses. There was some evidence that the effect for log ( metastasectomy and randomised groups respectively with no effect being demonstrable in the 227 elective metastasectomy group. Table 6b presents results from multi-factor stratified Cox regression models including criteria. This is also seen among patients in whom the decision is individualised. All patients 269 in the cohort were being considered for lung metastasectomy and therefore had favourable The relatively low hazard ratio of 1.19 for multiple versus single metastases in Table 6a is not 299 directly comparable with results derived only from metastasectomy patients. In the meta-300 analysis of 24 reports including 2589 patients already referred to, the hazard ratio for multiple  The analysis of the randomised stratum in PulMICC produced a hazard ratio of 2.15 which is 309 comparable with that in the meta-analysis of Gonzalez and colleagues.(9) A likely 310 explanation is that in more recent practice, aware of the hazard of multiple metastases, the 311 MDT will only recommend metastasectomy if the balance of other risk factors is favourable.

312
In randomised patients minimisation prevents trading off risk factors.

314
However, erosion of the effect of a risk factor as the practice becomes more selective has 315 been observed in the use of risk factors in case selection.(21) A simple analogy might help 316 explain. Looking at performance data of a large pool of high school basketball players an 317 analyst noted that youths ≥2 metres tall were higher scorers. They were preferentially picked 318 for the county team. When the analysis was run for elite teams, height was no longer such a 319 strong discriminator. They were nearly all very tall. Blackstone has called this effect "work 320 up bias". (22) The coach however continued to select for the squad one or two players ≤1.7 321 metres tall who could almost unerringly shoot and score from 15-20 metres away. As does 322 the coach, an MDT looks at all the factors. If a patient has 2-3 metastases that have remained 323 much the same over a year of observation, they know that patient is likely to have a longer 324 survival.

327
The major limitation of the PulMiCC Cohort Study is that it is not a randomised comparison 328 and cannot provide evidence about survival benefit attributable to metastasectomy. The best 329 currently available data is in the PulMiCC RCT report.(1)

331
We can confidently state that the five-year survival of people with lung metastases from 332 colorectal cancer is not zero. Among 481 patients in the cohort, 169 patients did not have a 333 metastasectomy and 37 of them were five-year survivors (22% 95%:CL 16%-29%). It is 334 possible but very unlikely that a few of these survivors did not in fact have malignant lung 335 lesions. We specifically sought information on long survivors, however treated, and the PIs 336 did not report any case in whom the diagnosis of CRC had been wrong.

338
In most cases after lung metastasectomy CRC recurs sooner or later but it is quite feasible 339 that in some cases the lung metastases are the only residual site of disease and 340 metastasectomy is curative. We hear anecdotal accounts(23) but documented proof of 341 disease-free survival at a long interval after lung metastasectomy are yet to be seen. Reported  The Big Data study in the English NHS already referred to showed that lung metastasectomy

352
This is a highly selective practice.

354
At this point discussants of observational studies tend to point to "the need for trials". In this 355 instance we refer to the PulMiCC RCT, a trial already done. It refutes the zero assumption 356 and substantially narrows the plausible effect size from the assumed 40% difference. Colorectal MDTs are in the best position to implement trials of treatments for advanced CRC.

389
Commenting on yet another round of the homoeopathy versus allopathy debate The Lancet 390 recognised that allopathy might have RCT evidence but homoeopathy has a following and           The numbers of lung metastases in the three strata based on available data as in Table 5.