Abstract
Introduction:
Up to 25% of colorectal cancer patients present with synchronous liver metastases which can be treated with two operations or a single, “simultaneous” operation. Morbidity and mortality appear similar between approaches, however, changes in health-related quality-of-life (QoL) following simultaneous resection are not well reported.
Methods:
A prospective, feasibility trial for simultaneous resection of synchronous colorectal liver metastases was conducted. Patients completed European Organization for Research and Treatment of Cancer QLQ-C30 and LMC21 at baseline (preoperatively), four, and twelve weeks postoperatively. Week 4 and 12 scores were compared to baseline using t-tests. Minimal important clinical differences (MICD) were considered as a 10-point difference from baseline.
Results:
C30 and QLQ-LMC21 were completed at baseline, 4 weeks, and 12 weeks by 39 (95%), 35 (85%) and 34 (83%) and 39 (95%), 33 (80%) and 33 (80%) respectively. 79% and 75% had at least one MICD according to QLQ-C30 at 4 and 12 weeks. At 4 weeks, physical functioning (mean difference (MD) −11.9%, p=0.002), role functioning (MD −23.6, p=0.007) and pain (MD +19.7, p=0.017) had significant worsening from baseline. At 12 weeks post-operatively, role functioning (MD −19.7, p=0.011) and fatigue (MD +14.3, p=0.03) were the only domains that remained significantly worse. By 12 weeks, pain and physical functioning had returned to baseline. There were no major demographic differences among those with and without an MICD at 12 weeks.
Conclusions:
Simultaneous resection of colorectal liver metastases led to clinically significant worsening fatigue and role functioning that persisted at 12 weeks post-surgery.
Introduction
Colorectal cancer is the third most common cancer worldwide and up to 25% of patients present with synchronous metastatic disease to the liver1,2. In select patients with stage IV disease, surgery and chemotherapy can still be curative with five-year overall survival greater than 50%3,4. Surgical resection of colon cancer and liver metastases can be performed either in a staged approach, in two separate operations, or with simultaneous resection in a single operation5–7.
Advocates of the traditional staged approach suggest that separating the operations leads to improved rates of chemotherapy and prevention of futile second operations in patients with aggressive biology7,8. Simultaneous resection is considered safe and effective but is more commonly used for more straightforward liver and right sided colon resections5,9,10. The simultaneous approach has gained popularity due to comparable overall complication rates and decreased cumulative hospital stay5,9,11. However, compared to the individual colon and liver resections in isolation, simultaneous resection is associated with a higher rate of complications in a single operation and therefore there is concern that this will adversely affect health-related quality of life (QoL).
Increasingly, surgical practice is being guided not only by standard outcomes of morbidity and mortality, but also by health-related QoL12. QoL is multifaceted, encompassing physical, functional, social and emotional wellbeing and scoring systems may be general or disease specific13. Historical data from colon and liver resections for colorectal cancer demonstrate that QoL is adversely affected in the domains of fatigue, pain, social and physical functioning in the early post-operative period, with return to baseline by 3 months14–16. As morbidity and mortality continue to improve after liver resection, QoL has become a leading issue from a patient’s point of view17.
In this study, we describe the QoL changes using EORTC QLQ-30 and QLQ-LMC21 collected during a multicentre single-arm feasibility trial of simultaneous resection for patients with synchronous colorectal liver metastases. Using data from our single arm study, we hope to provide clinicians with meaningful information on post-operative recovery in consent discussions with their patients.
Methods
This is the QoL analysis of data collected from a single arm feasibility trial at three hepatobiliary centres in Ontario, Canada18. Hepatobiliary surgery is condensed to specialized hospitals in Ontario, Canada’s most populous province, and more than half of provincial hepatobiliary surgery is performed at these three sites. Institutional ethics approval was obtained at all participating sites and this feasibility trial was registered with clinicaltrials.gov (NCT02954913).
Potentially eligible participants consecutively presented with synchronous and resectable colorectal and liver metastases and were deemed candidates for simultaneous resection19. Exclusion criteria included primary tumors resected by transanal approaches or primaries invading adjacent organs, extrahepatic disease, liver disease requiring two stage liver resections, prior liver resection and pregnancy. Participants who were candidates for neoadjuvant therapy were assessed following completion of this.
Participants were planned to undergo resection of the primary and liver disease in a single anesthetic by one or more surgeons. Surgeons decided the appropriate operation, with major liver resection being defined as three or more liver segments20. The primary outcome of that study was the enrollment rate of eligible patients, and secondary outcomes included complications and QoL data. Complications were classified according to Clavien-Dindo21.
Health Related Quality of Life
Following enrolment, QoL was assessed using two QoL questionnaires: EORTC QLQ-C30 and QLQ-LMC2122,23. This was considered the baseline assessment. Patients were then reassessed at 4 weeks (+/− 1 week) and 12 weeks (+/− 2 weeks) post-operatively. The C30 contains 28 questions on a 4-point Likert scale, and two questions on a 7-point Likert scale regarding the preceding week of symptoms22. C30 contains was scored according to EORTC guidelines to yield six functioning scores and nine symptom scores. LMC21 was designed specifically for patients with colorectal liver metastases and contains 21 questions on a 4-point Likert scale, 20 of which regard the preceding week while one pertains to the preceding 4 weeks23. LMC21 was scored to yield eleven symptomatic domains. Higher scores are better for functional scales and worse for symptom scales.
Statistics
QoL scores were summarized using mean and standard deviation. Differences between baseline and post-operative scores were compared using paired t-tests. Minimal important clinical difference (MICD) was defined for each domain as a score worsening by more than 10% points from their baseline score and presented as proportions24. All statistical analysis was performed using Rstudio25.
Results
Survey Completion
41 patients were enrolled in this trial and their demographics are presented elsewhere (Table 1)18. Both questionnaires were completed at all time points by 33 patients (80%). QLQ-C30 was completed at baseline, 4 weeks, and 12 weeks by 39 (95%), 35 (85%) and 34 (83%) respectively. QLQ-LMC21 was completed at baseline, 4 weeks, and 12 weeks by 39 (95%), 33 (80%) and 33 (80%) respectively. When questionnaires were completed, all questions were answered and no items were left empty.
Table 1:
Demographics
| Overall (N=41) | |
|---|---|
| Age (y) | |
| Median [IQR] | 57.0 [50, 67] |
| Sex | |
| Female | 13 (32%) |
| Charlson Comorbidity Score | |
| 0 or 1 | 10 (24.4%) |
| 2 or higher | 31 (75.6%) |
| ECOG Performance Status | |
| 0 | 19 (46.3%) |
| 1 | 13 (31.7%) |
| ASA Class | |
| 3 | 15 (36.6%) |
| 4 | 25 (61.0%) |
| Primary | |
| Rectum | 18 (43.9%) |
| Left Colon | 11 (26.8%) |
| Right Colon | 12 (29.3%) |
| Operative Approach | |
| Colon or Liver Only | 3 (7.3%) |
| No Resection | 3 (7.3%) |
| Simultaneous | 32 (78.0%) |
| Staged | 3 (7.3%) |
| Type of Liver Resection | |
| Major Anatomic Resection | 12 (29.3%) |
| Minor Anatomic Resection | 13 (31.7%) |
| Minor Non-Anatomic | 11 (26.8%) |
| No Liver Resection | 5 (12.2%) |
| Type of Colon Resection | |
| Right Hemicolectomy | 12 (29.3%) |
| Left Hemicolectomy | 1 (2.4%) |
| Low Anterior Resection | 16 (39.0%) |
| Abdominoperineal Resection | 6 (14.6%) |
| Subtotal Colectomy | 2 (4.9%) |
| No Colon Resection | 4 (9.8%) |
| Neoadjuvant | |
| Chemotherapy | 27 (65.9%) |
| Radiation | 16 (39.0%) |
C30 Quality of Life Domains
Following enrollment for simultaneous resection of colorectal liver metastases there was an overall trend towards reduced quality of life (Figure 1). At week 4, 27 of 34 (79%) participants had an MICD in at least one domain. Physical functioning and role functioning were the two domains with the highest proportion of MICD, at 65% and 59% respectively (Table 2). Physical functioning, role functioning, and social functioning all had a mean MICD worsening (−11.9, −23.6, −10.9 respectively). Only physical functioning and role functioning had a statistically significant worsening at four weeks post operatively (p=0.002, p=0.007).
Figure 1:
EORTC QLQ-C30 Domain Scores.
Table 2: EORTC QLQ-C30 Domain Scores.
P values are calculated using t-test. “MICD” – Minimal Important Clinical Difference, conveys the proportion of patients who had a clinically significant worsening of their score, i.e., > 10% worse than baseline.
| Baseline | Week 4 | Week 12 | |||||
|---|---|---|---|---|---|---|---|
| Mean (SD) | Mean | p | MICD | Mean | p | MICD | |
| Global Quality of Life | 67.5 (25) | 61.5 | 0.291 | 45% | 64.1 | 0.520 | 39% |
| Physical Functioning | 86.3 (17) | 72.4 | 0.007 | 65% | 83.1 | 0.455 | 38% |
| Role Functioning | 75.6 (30) | 52.0 | 0.002 | 59% | 56.3 | 0.011 | 53% |
| Emotional Functioning | 80.0 (20) | 82.6 | 0.609 | 33% | 79.4 | 0.889 | 39% |
| Cognitive Functioning | 81.6 (24) | 89.2 | 0.144 | 12% | 88.0 | 0.178 | 13% |
| Social Functioning | 77.6 (23) | 66.7 | 0.088 | 33% | 66.7 | 0.080 | 42% |
At week 12, 24 of 32 (75%) subjects had an MICD in at least one domain. Only role functioning had a statistically significant worsening compared to baseline (mean difference −19.7, p=0.011). Compared to week 4 data, there were no MICD worsening; however, physical functioning improved by mean score 10.7.
LMC21 Symptom Scores
At four weeks following enrollment, symptom scores worsened slightly in all domains except anxiety (Figure 2). At week 4, 26 of 33 (79%) subjects had an MICD in at least one symptom domain according to LMC21. Pain and fatigue had a mean worsening by the MICD (12.5, p=0.017; 12.2, p=0.060). Anxiety improved slightly, from a score of 38% to 34%, though this was not statistically significant and 30% of patients had a MICD worsening.
Figure 2:
EORTC QLQ - LMC21 Domain Scores.
At twelve weeks, 24 of 32 (75%) participants had an MICD in at least one symptom domain according to LMC21. Compared to baseline, only fatigue had a statistically significant worsening at week 12 compared to baseline (mean difference 14.3, p=0.03). Pain returned to near baseline level at week 12, with a mean score of 16 compared to 13 at baseline and 26 at week 4.
Patient Demographics
Demographics of patients who underwent surgery with persistent worsening in at least one QoL domain as per EORTC QLQ-C30 at week 12 are presented in Table 4. Preoperative characteristics appeared similar between those who did and did not have an MICD in at least one domain, including age, gender, Charlson score and primary location. There did appear to be a trend towards improved QoL domains at 12 weeks with open surgery (6/8 (75%) vs 10/24 (42%)) and for those without an ostomy (2/8 (25%) without vs 13/24 (54%) with). Major complications and rates of post-operative chemotherapy appeared similar.
Table 4: Demographics by MICD worsening in EORTC QLQ-C30 domains for those who underwent simultaneous resection.
Patients are stratified by the presence of an MICD in at least one domain at 12 weeks. Those who did not complete QoL questionnaires at all time points are included in the column, “Incomplete”. Patients who did not receive simultaneous resection were excluded.
| QLQ-C30 at 12wks | ||||
|---|---|---|---|---|
| Total (N=32) |
No MCID (N=8) |
≥1 MCID (N=20) |
Incomplete (N=4) |
|
| Sex | ||||
| Female | 11 (34 %) | 4 (50 %) | 7 (35 %) | 0 (0 %) |
| Age (years) | ||||
| Mean (SD) | 57 (± 16) | 58 (± 9.4) | 54 (± 17) | 69 (± 14) |
| Charlson Comorbidity Score | ||||
| 1 | 7 (22 %) | 2 (25 %) | 4 (20 %) | 1 (25 %) |
| 2 or higher | 23 (72 %) | 6 (75 %) | 14 (70 %) | 3 (75 %) |
| Primary | ||||
| Rectum | 14 (44 %) | 4 (50 %) | 9 (45 %) | 1 (25 %) |
| Left Colon | 8 (25 %) | 2 (25 %) | 6 (30 %) | 0 (0 %) |
| Right Colon | 10 (31 %) | 2 (25 %) | 5 (25 %) | 3 (75 %) |
| Neoadjuvant Treatment | ||||
| Chemotherapy | 22 (69 %) | 5 (62 %) | 14 (70 %) | 3 (75 %) |
| Radiation | 12 (38 %) | 1 (12 %) | 10 (50 %) | 1 (25 %) |
| Laparoscopy | ||||
| Open | 18 (56 %) | 6 (75 %) | 10 (50 %) | 2 (50 %) |
| Laparoscopic | 13 (41 %) | 2 (25 %) | 9 (45 %) | 2 (50 %) |
| Lap converted to open | 1 (3 %) | 0 (0 %) | 1 (5 %) | 0 (0 %) |
| Colon Margins | ||||
| Negative | 30 (94 %) | 8 (100 %) | 19 (95 %) | 3 (75 %) |
| R1 | 2 (6 %) | 0 (0 %) | 1 (5 %) | 1 (25 %) |
| Liver Margins | ||||
| Negative | 24 (75 %) | 7 (88 %) | 15 (75 %) | 2 (50 %) |
| R1 | 7 (22 %) | 1 (12 %) | 4 (20 %) | 2 (50 %) |
| Any Major Complication | 13 (41 %) | 3 (38 %) | 7 (35 %) | 3 (75 %) |
| ER Visit | 7 (22 %) | 1 (12 %) | 5 (25 %) | 1 (25 %) |
| Ostomy | 15 (47 %) | 2 (25 %) | 12 (60 %) | 1 (25 %) |
| Adjuvant Chemotherapy | 20 (62 %) | 5 (62 %) | 13 (65 %) | 2 (50 %) |
Discussion
There are limited data on the effects of simultaneous resection for synchronous colorectal cancer liver metastases on QoL. This QoL analysis of prospectively collected data demonstrates that these major operations are associated with decreases in QoL in keeping with historical controls. While short term worsening in physical functioning and pain existed, clinically significant worsening of role functioning and fatigue persisted beyond 12 weeks.
Our data demonstrate similar domains for which patients have worsened QoL compared to data on colon resection in the literature14,26,27. In three studies examining QoL following colon resection, role functioning, physical functioning, and social functioning had consistent changes, as did fatigue and pain14,26,27. Similar trends were observed for liver resection alone15,17. In a study comparing laparoscopic versus open colon resection, role and physical functioning had returned to baseline by the twelve week mark, whereas pain and fatigue had actually improved at week 12 compared to baseline27. In two studies on enhanced recovery after colon resection and QoL after liver resection, fatigue remained worse with clinical and statistical significance compared to baseline at week 1215,26. Overall, the changes in QoL following simultaneous resection do not appear substantially different from that of patients undergoing colon or liver resection in isolation based on the literature reviewed.
Our data demonstrated persistent fatigue and role functioning at week 12, which could represent the effects of a bigger operation than these comparison studies, or the effects of stage IV disease and the prospect of adjuvant therapy. Relevant literature suggests that QoL returns to baseline in most domains by three months following surgery, but resumption of chemotherapy is also targeted within this time frame17,26–29. The effects of cancer recurrence and metastatic disease on long term QoL is not well understood, likely due to loss to follow up in QoL studies14,29. However, patients undergoing chemotherapy for colorectal cancer have been found to have decreased social and physical functioning30. While there was not an obvious difference in chemotherapy rates between those who did and did not have a clinically significant worsening in QoL, high rates of chemotherapy could contribute to the persistent fatigue at three months.
QoL data are an important part of clinical decision making, particularly in the setting of clinical equipoise. For synchronous colorectal cancer liver metastases, the ideal treatment regimen remains unknown and randomized data is difficult to come by due to recruitment issues11,18. With a current understanding that complication and survival rates between simultaneous and staged resections are similar, patients’ understanding that their quality of life will not be greatly altered by randomization to one or the other may aid in recruitment in future trials.
To our knowledge, this secondary analysis of a prospective trial is the first to examine QoL in the setting of simultaneous resection of synchronous colorectal cancer liver metastases. While there is a good response rate and inclusion of two appropriate questionnaires, the study is limited by its sample size, lack of control group and relatively short follow up. While we are able to detect that trends in QoL are similar to existing literature, our study was underpowered to determine predictors of worsening QoL as well as unable to compare directly to patients undergoing staged resections. Follow up to three months is the typical time point of resolution of QoL differences in the literature but potentially confounded by our lack of information on post-operative adjuvant chemotherapy. This is particularly relevant given that another large operation, hyperthermic intraperitoneal chemotherapy, is associated with a prolonged return to baseline at six months31. Furthermore, while our QoL tools are validated and the standard in this setting, semi-structured patient interviews may have revealed more information regarding the roots of decreased QoL32.
In conclusion, this analysis of QoL following simultaneous resection of colorectal liver metastases reveals that changes in QoL are similar to existing evidence around each operation in isolation. Sustained worsening in fatigue and role functioning suggest appropriate targets for intervention; however, the overall stability around QoL should lend researchers support in enrolling patients in clinical trials examining simultaneous resection in this clinical setting.
Table 3: EORTC QLQ – LMC21 Domain Scores.
P values are calculated using t-test. “MICD” – Minimal Important Clinical Difference, conveys the proportion of patients who had a clinically significant worsening of their score, ie. > 10% worse than baseline.
| Baseline | Week 4 | Week 12 | |||||
|---|---|---|---|---|---|---|---|
| Mean (SD) | Mean | p | MICD | Mean | p | MICD | |
| Nutritional Problems | 9.4 (18) | 12.1 | 0.533 | 27% | 13.5 | 0.291 | 34% |
| Pain | 13.4 (18) | 25.9 | 0.017 | 42% | 16.3 | 0.521 | 25% |
| Fatigue | 33.3 (26) | 45.5 | 0.060 | 58% | 47.6 | 0.031 | 59% |
| Social Problems | 20.5 (18) | 24.2 | 0.443 | 42% | 24.3 | 0.399 | 34% |
| Anxiety | 38.0 (27) | 33.8 | 0.522 | 30% | 40.4 | 0.704 | 31% |
Synopsis:
Simultaneous resection of synchronous colorectal cancer with liver metastases led to persistent fatigue and worsening role functioning three months after surgery.
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