Pulmonary metastasectomy in colorectal cancer: health utility scores by EQ-5D-3L in a randomized controlled trial show no benefit from lung metastasectomy

Aim The aim was to assess the health utility of lung metastasectomy in the treatment of patients with colorectal cancer (CRC) using the EQ-5D-3L questionnaire. Methods Multidisciplinary CRC teams at 14 sites recruited patients to a two-arm randomized controlled trial—Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC). Remote randomization was used, stratified by site and with minimization for seven known confounders. Participants completed the EQ-5D-3L questionnaire together with other patient reported outcome measures at randomization and then again at 3, 6, 12 and 24 months. These were returned by post to the coordinating centre. Results Between December 2010 and December 2016, 93 participants were randomized, 91 of whom returned questionnaires. Survival and patient reported quality of life have been published previously, revealing no significant differences between the trial arms. Described here are patient reported data from the five dimensions of the EQ-5D-3L and the visual analogue scale (VAS) health state. No significant difference was seen at any time point. The estimated difference between control and metastasectomy patients was −0.23 (95% CI –0.113, 0.066) for the composite 0 to 1 index scale based on the descriptive system and 0.123 (95% CI –7.24, 7.49) for the 0 to 100 VAS scale. Conclusions Following lung metastasectomy for CRC, no benefit was demonstrated for health utility, which alongside a lack of a survival or quality of life benefit calls into question the widespread use of the procedure.


| INTRODUC TI ON
The results of the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) randomized controlled trial (RCT) showed no survival benefit from lung metastasectomy for colorectal cancer (CRC). Hence any survival benefit that might be revealed by a much larger trial is likely to be far smaller than has generally been supposed [1]. Quality of life (QoL) in PulMiCC included four patient reported outcome measures: the general and anaemia scale of the Functional Assessment of Cancer Therapy (FACT-G-An) [2], selected items from the lung cancer brief symptom index [3] and the short form of the Spielberger State/Trait Anxiety Inventory (STAI) [4]. These were chosen as the most relevant assessments for a thoracic oncological surgical intervention. No significant differences were found between the control and metastasectomy arms of the trial for any QoL outcomes and minimally important differences in these measures were largely ruled out [5].
In the absence of a demonstrable benefit in either survival or QoL in PulMiCC, we examined the health utility of surgical removal of CRC lung metastases. Here we report analysis of the data from the EQ-5D-3L questionnaire. This is a standardized health utility questionnaire, developed by the EuroQol Group that provides a simple, generic measure of health for clinical and economic appraisal [6].
It is most often used in health economics studies to generate quality adjusted life years. The PulMiCC EQ-5D-3L results reported here complement the trial survival data [1] (Figure 1) and will contribute to a future health economics evaluation. As full details of the RCT have been previously reported [1,5] the trial design is provided only briefly. PulMiCC had two stages of consent.

What does this paper add to the literature?
First, following written informed consent, patients with lung metastases were registered for assessment. Those subsequently found to be eligible for metastasectomy, according to current practice, were invited to consent to randomization, which was either to continued standard care (control) or metastasectomy. Sussex Health Outcomes Research and Education in Cancer (SHORE-C), University of Sussex, administered and coordinated all patient reported outcome measures.
The full trial protocol can be accessed online: https://www.ucl.

| Participants
Patients were eligible for inclusion if they had undergone resection of primary CRC with a prospect of cure and had pulmonary metastasis confirmed at a multidisciplinary team meeting. The discovery of the metastases could be synchronous or metachronous. In line with usual practice, there had to be no clinical indications of active CRC other than the known lung metastases. Prior liver resection for metastases did not preclude entry to the trial.
Following consent to randomization, patients were given the EQ-  on a scale of 0 (worst) to 1 (best), based on the five well-being scores were developed. No index was found for Serbia so the UK index was calculated for all patients where the majority of trial centres were based. Of the randomized patients, 70% were in the UK, and Serbian patients were similarly represented in both arms by stratification.

| Statistical methods
To analyse the longitudinal EQ-5D-3L health state and index data, with adjustment for within-patient correlation, we used linear regression models with estimation using generalized estimating equations, using an independence working covariance assumption. The primary analysis estimated a common effect of metastasectomy over the follow-up times of 3, 6, 12 and 24 months, with adjustment for follow-up time, but variation of the treatment effect over time was examined. The potential impact of losses to follow-up was examined through fitting singular linear increment models [8].

| RE SULTS
Fourteen sites randomized 93 patients (Table 1)   Reported minimally important differences for this measure in a UK population range from 0.10 to 0.12, suggesting that there is no evidence of any important difference in the index values between the randomized groups [9].  finding of no survival or QoL benefit in the PulMiCC RCT [1,5].
Lung metastasectomy is sometimes considered for psychological benefit but, as previously shown when using a comprehensive assessment of anxiety (STAI), no difference was evident in the anxiety and depression dimension of the EQ-5D-3L. The number of patients reporting 'no problems' in all the five dimensions of wellbeing diminished at a similar rate in controls (left) ( Figure 2) and metastasectomy patients.
Evaluation of treatment of metastatic disease is a research priority for the Association of Coloproctology of Great Britain and Ireland (ACPGBI) [10] and is one of the targets in management of patients with CRC. It is a treatment considered in the Improving Management of Patients with Advanced Colorectal Tumours, the IMPACT initiative of the ACPGBI [11]. Small effects cannot be ruled out by the findings of PulMiCC but they do not show a survival or QoL benefit from metastasectomy [5]. The additional study results reported here make it unlikely that there is a significant gain of health utility if patients are subjected to pulmonary metastasectomy. PulMiCC trial results may help to guide further research in this important area.

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 content of this submission.

E TH I C A L A PPROVA L
The National Research Ethics Service (NRES) granted ethical approval (no.10/H0720/5) on 26th January 2010.

DATA AVA I L A B I L I T Y S TAT E M E N T
All data are available by an approach to the Chief Investigator and the Trial Centre (SITU, UCL).