The Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) burden of care study: Analysis of local treatments for lung metastases and systemic chemotherapy in 220 patients in the PulMiCC cohort

The aim of this work was to examine the burden of further treatments in patients with colorectal cancer following a decision about lung metastasectomy.


INTRODUC TI ON
A 5-year survival rate of 40% following lung metastasectomy was reported in a meta-analysis of 2925 colorectal cancer (CRC) patients in 25 studies [1]. An editorial in the European Journal of Cardio-thoracic Surgery put this at 60% based on selected reports [2]. A consensus statement from the US Society of Thoracic Surgeons stated that without metastasectomy 'survival is assumed to be zero' [3]. The increased survival attributable to metastasectomy was thus widely believed to be up to 60%.

The Pulmonary Metastasectomy in Colorectal Cancer
(PulMiCC) study has reported an analysis of the full cohort of 512 patients. Of these, 263 nonrandomized patients had metastasectomy and 128 did not. Most if not all of the difference in the 5-year survival rates of 47% and 22%, respectively, appeared to be largely related to selection, with differences in the number of metastases, carcinoembryonic antigen (CEA), liver disease, age, lung function and performance status [4]. In the randomized controlled trial (RCT) nested within it, comparative survival, quality of life and health utility were also reported [5][6][7]. The RCT showed no difference in survival at any time point, but with 93 patients could not exclude the possibility of a small long-term survival benefit [5].
Taken together the PulMiCC RCT and the cohort preclude the assumption of zero survival [3] and show that any survival benefit from metastasectomy is much smaller than has been claimed. The recently published analysis of Surveillance, Epidemiology and End Results database also found no difference in survival associated with lung metastasectomy [8].
Since the publication of PulMiCC, commentators have shifted their emphasis towards local control of metastatic disease, including other ablative treatments, repeated interventions and chemotherapy [9,10]. This includes the concept that lung metastasectomy spares patients the side effects of systemic treatments by providing a chemotherapy 'holiday' [11].
In this paper we report on second and subsequent local interventions for lung metastases and the use of systemic chemotherapy in subsets of patients treated at five of the PulMiCC study sites from which data were available for these treatments. This analysis suggests how the impression of benefit has arisen in uncontrolled analyses of survival. These data may make a useful contribution to the research initiative of the Association of Coloproctology of Great Britain and Ireland (ACPGBI) [12] and the IMPACT initiative (Improving Management of Patients with Advanced Colorectal Cancer) of the ACPGBI [13].

ME THOD
Details of the methods of the PulMiCC study have been published [5,6]. The UK National Research Ethics Service (NRES) granted ethical approval (10/H0720/5) and recruitment began at each site after approval from the local ethics committees. One-year follow-up, adverse events and the date and cause of death were collected on case report forms covered by Stage 1 enrolment written informed Oncology Group scores and lung function at baseline. Four sites provided information on chemotherapy in 139 patients: 79 (57%) had one to five courses of chemotherapy, to a total of 179 courses. The patterns of survival after one or multiple metastasectomy interventions showed evidence of guarantee-time bias contributing to an impression of benefit over no metastasectomy. After repeated metastasectomy, a significantly higher risk of death was observed, with no apparent reduction in chemotherapy usage.
Conclusion: Repeated metastasectomy is associated with a higher risk of death without reducing the use of chemotherapy. Continued monitoring without surgery might reassure patients with indolent disease or allow response assessment during systemic treatment.
Overall, the carefully collected information from the PulMICC study provides no indication of an important survival benefit from metastasectomy.

K E Y W O R D S
burden of care, chemotherapy, colorectal cancer, pulmonary metastasectomy

What does this paper add to the literature?
Lung metastasectomy has generally been reported in isolation with survival explicitly attributed to surgery and without reference to other treatments. Further metastasectomies and ablations are frequent, and chemotherapy is very often given with and without metastasectomy. This study adds an overview of the total management in a prospective cohort study. consent. In February 2019 the NRES gave ethical approval for an audit of clinical care.
Five trial sites, including the four largest recruiting centres, provided records of additional treatments. The selection of these sites and the collection of their data were carried out without prior knowledge of the treatments or outcomes, but solely on the availability of data (Table 1).
For comparative analyses the patients were divided into three groups: (1) no lung metastasectomy; (2) one lung metastasectomy; (3) second and subsequent lung metastasectomy and other local interventions.
The PulMiCC protocol allowed for other local interventions, including radiotherapy, stereotactic radiotherapy and image-guided thermal ablation.

Selection analyses
To examine the factors used in selection, this analysis excluded ran- Separate (transition) rates, using a time scale in years, were estimated for moving through the first four states and for death rates from these states. For all rates a Markov assumption was made of constant rates over the follow-up period, except for the transition to the metastasectomy state that was allowed to change after 1 year (estimated to be a lower rate). The model was used to estimate the probability of being in each state at various follow-up times, both from the entry state and from the metastasectomy state. Maximum likelihood estimation of the model was implemented using the R package 'msm' [14,15]

Survival analysis
For illustrative and descriptive purposes, Kaplan-Meier estimates of survival were prepared for the three groups. For a more detailed inspection of patients having just one metastasectomy operation and for those who had a second metastasectomy or other local treatments with various times of origin, a Cox relative regression model [16] was also fitted to compare the rate of death for patients with one metastasectomy with that of patients having had a second.

Exploration of guarantee-time bias
When classifying patient groups by events which occur some time after enrolment to the study-such as having one metastasectomy or having two or more interventions for metastases-the problem of guarantee-time bias (GTB) arises [17]. In comparing patients who had no metastasectomy with those who had one or more operations, the classifying events occur at various times after enrolment.
In order to study the effect graphically, the life line displays as suggested by Maringe and colleagues have been adopted and adapted [18]. The three groups defined above were used to classify patients.

Baseline data
The data collected during the PulMiCC trial for the five trial sites were used for this analysis of further treatments from 220 patients (see Table S1 in the Supporting Information). There was a high level of completion of baseline data with 1249/1329 (95%) present for the six items potentially available for each of 220 patients. Demographics, patient performance data and oncological characteristics are presented in Table 1 in the three specified groups. Numbers of alternative local interventions used to treat lung metastases are set out in Table 2.

Selection analyses
The distributions and frequency of patient performance and oncological factors are in Table S2 and these baseline data were used in selection analyses. These results are provided in Tables S3 and S4.
Oncological factors that made metastasectomy significantly less likely were history of a prior liver resection, elevated CEA and more than two lung metastases. Patient factors making metastasectomy significantly less likely were impaired Eastern Cooperative Oncology Group (ECOG) performance status (PS) and poorer lung function. In multivariate analyses, if ECOG PS is not included then log(CEA), the number of metastases and a history of liver metastases remain influential but numbers for the analyses are reduced. If ECOG PS is included, the same variables remain significant but only the highest category for the number of metastases is significant.
There was a smaller influence of baseline factors on selection for a second metastasectomy for those patients who had an initial TA B L E 1 Baseline characteristics in the three groups of 51, 114 and 55 patients who had no metastasectomy, one metastasectomy or multiple local interventions and distributions of characteristic in quartiles Abbreviations: RFA, radio frequency ablation; SABR, stereotactic radiotherapy.

TA B L E 2
Alternatives to surgical lung metastasectomy used in the 220-patient subset first metastasectomy, perhaps because it is quite a different process that is being examined.

Multistate model
The observed data on state changes for the 220 patients which were used to fit the multistate model are in Table S5. The multistate model was used to provide the estimates of being in the various model states, including death, 1 to 10 years after cohort entry (Table   S6, Figure 2). Similar estimates are provided in Table 3

Kaplan-Meier analyses
Estimated survival curves for the three groups, presented in Figure 3, show the similarity in the pattern of survival of patients in the two groups who had metastasectomy and the difference from those who did not. These curves serve to illustrate the data but they cannot be formally compared because the definition of the groups is based on events after the time of origin, which introduces GTB.
Estimated survival for patients who had just one metastasectomy and those who had two and more interventions are again depicted in Figure 4(A) and (B). The first is a comparison of patients who had one and those who had two or more metastasectomies,   Table 1.

Chemotherapy usage
Of the further subset of 139 patients at four sites for whom data were available, 79 (57%) had chemotherapy, with a total of 179 courses ( Table 4)  There are patients who had one or two metastasectomies who did not have chemotherapy and had relatively long survival. We cannot attribute any causal relationships but it does indicate that these patients were intensively treated with chemotherapy.

DISCUSS ION
The fundamental limitation of this report is that no causal relation-  and/or use of chemotherapy is evidence of progressive disease.
Among the 220 patients in this analysis 33.3% had a further metastasectomy. In our analysis, a Cox model demonstrated that a significantly greater likelihood of death remained after a second intervention.
The PulMICC data provide an explanation for an impression of benefit. GTB is an umbrella term for forms of bias which include immortal-time bias [17]. The effect was seen in the early days of heart transplantation when the worst affected patients died waiting for an available heart, thus inflating the apparent benefit [19]. This was illustrated in an analysis of liver resection data in the English National Health Service. The shape of the survival curve was in marked contrast to the cancer survival curves in the same publication [20]. The effect can be seen in Figure 3 and is explained in the stacked life lines (SLL) diagram in Figure 5. The top group containing patients who were selected to not have metastasectomy, and whose survival is measured from study entry, shows an initial steeper fall which then flattens. This is familiar in cancer registry data. The other curves show the effect of GTB because the interventions by which patients were classified into the two groups occurred some time after the date of registration from which their survival is measured [18]. This may result from the 'test of time' which is either explicitly or inherently part of the process of selecting patients for metastasectomy or ablation [21]. The SLL diagrams and the Kaplan-Meier survival plots ( Figure 3) clearly illustrate GTB, a common source of bias in observational studies of lung metastasectomy.

F I G U R E 5
Stacked life line depiction of 220 patients separated into those who had no metastasectomy (n = 51, top), those who had only one local intervention (n = 114, middle) and those who had multiple interventions (n = 55, bottom Abbreviations: CPP, courses per patient; TCC, total chemotherapy courses. Note: These are the data behind the Sankey flow chart ( Figure 6). This does not include adjuvant therapy at the time of primary resection. These are treatments within the PulMiCC study so represent treatments for advanced colorectal cancer.  [24]. An outstanding example of an integrated system of assessing these patients has recently been reported from Finland [25]. However, without large and collaborative controlled trials we will not produce conclusive answers and we will fail to ensure that our patients have proven treatments and are spared the harm of treatments that are not beneficial. The IMPACT F I G U R E 7 Stacked life line depiction of the 139 patients in the Sankey diagram in Figure 6. The groups are classified as in Figure 5. The numbers in the groups are 28, 74 and 37, respectively. The colours change with successive courses of chemotherapy from one to five. Taken together, all the evidence from the PulMiCC cohort study [4] and the nested RCT [5][6][7] undermines the belief that pulmonary metastasectomy significantly improves survival or symptoms. This study does not support the suggestion that, in practice, repeated metastasectomy spares patients systemic chemotherapy (Table 4). It would instead be entirely appropriate to use lung metastases, as the most readily imaged site of disseminated CRC, to monitor disease progress. Reassurance for patients with slow-growing disease might spare them chemotherapy at that stage and the response to treatment when needed could be more easily monitored. Victoria Lake. Many research staff and clinicians helped by returning data and responding to queries during the ten years of the study and its analysis. With apologies to those not mentioned we are grateful to those listed here.

CO N FLI C T O F I NTE R E S T
None of the authors has a conflict of interest with respect to any of the contents of this submission.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data are available on application to the corresponding author.