Management of resectable metastatic colorectal cancer (MNG14)
Systemic recurrence may occur in up to 40% of patients after curative treatment of their primary colorectal cancer. Although less common, some patients may also present with stage IV disease at the time of initial presentation.
Liver and lungs are the most common sites of metastases. Liver and lung metastases may be amendable to curative resection, thereby improving survival. With improved imaging, surgical technique, understanding of what drives long-term survival, as well as improved chemotherapy options, clinicians are now increasingly aggressive with the oncological management of these metastases.
Bony metastases, brain metastases, other soft tissue metastases and metastases to distant, non-draining nodal basins such as the para-aortic nodes, are less common. Although palliative interventions may be required to prevent complications, metastases at these sites are generally not amendable to curative surgical interventions.
While liver resection has been accepted as the standard of care for patients with resectable liver metastases, the role of curative resection at other sites remains unclear.
The purpose of this review was to determine the role of curative surgery in patients with synchronous or metachronous metastatic disease in patients with colorectal cancer.
Systematic review evidence[edit source]
In patients with resectable synchronous or metachronous metastatic colorectal cancer, what are the outcomes of surgical resection, with or without chemotherapy, when compared with non-surgical /palliative interventions (overall survival, disease-free survival, progression-free survival, quality of life and complications)? (MNG14)
A systematic review was performed to compare outcomes of surgical resection (with or without chemotherapy) with non-surgical or palliative interventions in the management of metastatic colorectal cancer. The outcomes of interest included survival, disease free survival, quality of life, and complications.
Five cohort studies were identified, all of which involved patients with liver metastases:
- An European Organization for Research Treatment of Cancer (EORTC) multicentre cohort study  reported outcomes in 356 patients, of whom 263 underwent hepatectomy and 93 received palliative treatments. The most commonly performed liver resections were segmentectomies (46%) and hemihepatectomies (34.6%), followed by wedge resections of the liver (8.7%). Palliative treatment included chemotherapy (91%) and radiofrequency ablation (6%). Patients in the palliative group were twice as likely to have symptomatic hepatic disease (19% versus 8.4%) and were less likely to have disease detected as part of surveillance (31% versus 58.6%), compared with the hepatectomy group, which suggests that these patients had more extensive disease at diagnosis. The primary objective of this study was to test the validity and reliability of the EORTC Cancer Quality of Life questionnaire liver module (QLQ-LMC21), an EORTC quality-of-life instrument for patients with liver metastases. Follow-up was limited to 3 months only, as the QLQ-LMC21 was re-administered after treatment.
- A Japanese single-centre cohort study  reported outcomes in 41 patients with synchronous liver metastatic disease (defined as liver metastases that occurred within 12 months of resection of the primary colorectal cancer), of whom 15 (37%) underwent liver resection and 26 (63%) received palliative treatment. The main aim of the study was to evaluate the benefit of alternating hepatic artery infusion and systemic chemotherapy in patients who did and did not undergo hepatectomy. Of the hepatectomy group, seven patients underwent synchronous resection of the metastatic disease and the primary colorectal cancer. Although the authors did not define what constituted disease that was amendable to simultaneous liver and colorectal resection, they referred to Japanese guidelines for managing colorectal cancer. Duration of follow-up was 3 years.
- An Australian study  using data from the South Australian Metastatic Colorectal Cancer Database reported outcomes for 455 patients with liver-only metastases who underwent either the combination of chemotherapy and surgery with curative intent (121), surgery alone with curative intent (87), or chemotherapy alone (247). The cohort included 317 patients (69.7%) with synchronous liver metastases and 139 (30.5%) with metachronous liver metastases. The large proportion of patients with synchronous liver metastases in this study suggests that it is much more likely for patients with metachronous liver metastases to receive no intervention or to have metastatic disease not confined to the liver alone. Clear resection margins at hepatectomy were achieved in 86.2% of patients who underwent surgery alone and 95.9% of those who received combinational therapy (p = 0.038). In patients treated with chemotherapy and surgery, chemotherapy regimens varied considerably and were most commonly oxaliplatin-based. Timing of chemotherapy was preoperative (33.9%), perioperative (26.4%), or postoperative (37.2%). Median follow-up was 16.7 months.
- A US single-centre cohort study based on Memorial Sloan-Kettering Cancer Center’s prospectively maintained surgical and interventional radiology databases  reported outcomes in 52 patients with solid liver metastases of colorectal cancer, of whom 30 underwent non-anatomic wedge resection of the liver, with or without adjuvant systemic chemotherapy, and 22 underwent radiofrequency ablation, which routinely included tract ablation. The main aim of the study was to compare outcomes between non-anatomic wedge resections of the liver with radiofrequency ablation of solitary liver metastases. The surgical database identified 1144 patients with liver metastatic disease from colorectal cancer, of whom 580 patients had solitary liver metastases and only 30 (2.6%) underwent a non-anatomic wedge resection of the liver. Patients undergoing radiofrequency ablation were much more likely to have previously undergone liver resection(s) than those undergoing non-anatomic wedge resection (55% versus 23%; p < 0.01). Follow-up was carried out at 3- to 6-monthly intervals, with routine imaging for 2–3 years after treatment.
- A Polish single-centre cohort study study  reported outcomes for 130 patients with synchronous (50; 38%) or metachronous (80; 62%) liver metastases who underwent either liver resection with or without adjuvant systemic chemotherapy (96 patients), or palliative radiofrequency ablation with or without palliative liver resection (34 patients). Of the resection group, 48 underwent hemihepatectomies, 28 underwent segmentectomies and 20 underwent metastasectomies. R0 resection (defined R0 as a microscopically clear resection margin including cases where the margins were clear by < 1 mm) was achieved in 78 (81%) of patients and 18 (19%) of patients had a R1 resection margin. Postoperatively, 25 (26%) patients in the resection group received adjuvant chemotherapy. Overall, the mean follow-up period was 39.3 months (range 2–156 months). Group-specific follow-up, however, was considerably longer for patients in the liver resection group (mean 44 months, range 6–156 months) than for the thermoablation group (mean 26 months, range 2–67 months).
The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.
Survival outcomes[edit source]
Survival outcomes for curative surgical resection versus chemotherapy were reported by four studies: the Japanese cohort study, the South Australian Metastatic Colorectal Cancer Database study, the Memorial Sloan-Kettering Cancer Center database study, and the Polish cohort study. Overall, survival outcomes favoured the curative treatment group.
Overall survival[edit source]
All four studies reported overall survival. All studies reported improved overall survival in the curative group relative to the non-curative group:
- In the Japanese cohort study, overall survival rates were higher in the hepatectomy group than the palliative group at 1 year (90% versus 63%), 2 years (72% versus 55%) and 3 years (52% versus 0%), but statistical analysis was not reported.
- In the South Australian Metastatic Colorectal Cancer Database study, 1-year overall survival rates were 95.1% in the surgery alone group, 98.3% in the surgery plus adjuvant chemotherapy group, and 63.8% in the palliative group.13 At 3 years, overall survival was 73.8% in the surgery alone group, 73.7% in the surgery plus adjuvant chemotherapy group, and 19.5% in the palliative group. Statistical analysis was not reported.
- In the Memorial Sloan-Kettering Cancer Center database study, overall survival at 1 year was 100% in both groups, but this rapidly declined in the non-curative group to 69% at 2 and 27% at 3 years, compared with 88% and 82% in the curative group at 2 and 3 years, respectively. Statistical analysis was not reported.
- The Polish cohort study reported significantly higher overall survival rates in the liver resection group than the palliative radiofrequency ablation group at 3 years (64.5% versus 33%) and at 5 years (46.6% versus 9.5%) (p = 0.002 for both comparisons).
Disease-free survival[edit source]
Disease-free survival was reported by the Polish cohort study only for the curative group: 32% at 3 years and 30.5% at 5 years.
Progression-free survival[edit source]
Progression-free survival was reported only by the Memorial Sloan-Kettering Cancer Center database study. At 1-year follow-up, progression free survival rates were 88% in the curative group and 29% in the non-curative group. At 2-year follow-up progression-free survival rates were 55% in the curative group and 18% in the non-curative group. Statistical analyses were not reported.
Mean survival[edit source]
Mean survival was reported only by the Japanese cohort study, which reported a significantly longer survival in the curative group compared with the non-curative group (1441 days versus 748 days; p = 0.038).
Perioperative mortality, morbidity and adverse events[edit source]
In both studies, complication rates were significantly higher in the curative group, compared with the non-curative group.
The Memorial Sloan-Kettering Cancer Center database study reported a significantly higher rate of major complications of in the curative group than the non-curative group (14% versus 4%; (p < 0.01).
The Polish cohort study reported a post-operative complication rate of 24.9% in the curative group, compared with a post-operative complication rate of 8.7% in the non-curative group.15 Rates for all complications were higher in the curative group. The most common were sepsis pneumonia, wound infection and urinary tract infection (13.5%), followed by intestinal complications and prolonged biliary drainage (5.2% each) and postoperative bleeding (1%). No statistical comparisons between groups were made.
Quality-of-life outcomes[edit source]
Only the EORTC study reported quality-of-life outcomes, measured using the EORTC QLQ-C30 questionnaire, for which reduction in functional or global health status score equates to worse function or quality of life while greater symptom status scores equates to higher level of symptomatology.
For patients in the hepatectomy group, there was a reduction in the global quality of life score as well as a reduction in scores in three of five domains (physical function, role function and social function, but not emotional function). These decreases in scores were all statistically significant for this group (p values ranged from < 0.001 to 0.033). This contrasts with patients in the palliative treatment group, where the only domain which was affected was the physical function domain which declined (p < 0.001).
At baseline, patients in the palliative group had worse symptoms (pain, fatigue, and nausea and vomiting) measured using symptom scores, compared with patients in the hepatectomy group. Although symptoms worsened for all patients at 3 months compared with pre-treatment levels, patients in the hepatectomy group had a greater increase in symptom severity compared with patients in the palliative group. This difference was statistically significant for all three symptoms in the hepatectomy group only (p-values ranging from < 0.001-0.002).
Quality of life and symptoms were also measured using the EORTC QLQ-LMC21 questionnaire. At baseline, patients in the palliative group also generally had worse symptoms in most aspects (nutritional problems, fatigue, pain, emotional problems, weight loss, taste problems, dry mouth, jaundice, social problems and sexual problems) compared with patients in the hepatectomy group, consistent with more advanced disease at baseline. At 3 months, patients in both groups had worsening of symptoms, except for emotional problems in the palliative group and talking problems in both treatment groups, where there was either no change or slight improvement.
The deterioration in symptoms were slightly greater in the hepatectomy group compared to the palliative group (p-value range from <0.001 to 0.459), with the exception of taste problems, dry mouth, sore mouth, peripheral neuropathy, talking problems and sexual problems, where the deterioration was greater for the palliative group (p-value range from <0.001 to 0.658).
It is however also noteworthy that this study was designed to validate the EORTC QLQ-LMC21. The follow up time period of only 3 months was probably insufficient to allow full recovery of quality of life after surgery in the liver resection group which in turn accounts for the worse quality of life in the short term. The short follow up period in this study is a limitation of the study. Furthermore, despite the statistical differences between groups, the minimal important difference was not clear. Therefore, whether or not the differences were also clinically significant is somewhat unclear.
Evidence summary and recommendations[edit source]
|In observational studies of patients with hepatic metastases, liver resection with or without adjuvant therapy improved survival, compared with non-curative treatment options.||III-2||, , , |
|In an observational study with a limited follow up of 3 months of patients with hepatic metastases, liver resection, with or without adjuvant therapy, was associated with a faster decline in quality of life compared with palliative treatment. However whether or not these changes were also clinically relevant is unclear.||III-2|||
|In observational studies of patients with hepatic metastases, liver resection was associated with higher rates of complications compared with non-curative treatment options.||III-2||, |
|In patients with resectable liver metastases, liver resection should be offered, as this improves overall and progression free survival.||D|
|Patients referred for liver resection should be counselled about the potential complications associated with liver resection in comparison with non-curative treatments.||D|
Patients at higher risk of recurrence should receive adjuvant therapy following liver resection, so as to reduce the likelihood of further local or systemic recurrences.
In patients with pulmonary metastases, pulmonary resection improves locoregional control and may improve survival.
Systemic adjuvant chemotherapy following complete resection of pulmonary metastases may reduce the likelihood of further systemic or local recurrences.
In patients with other isolated metastases, metasectomy may be appropriate in a well-informed patient after appropriate investigations and discussion in a multi-disciplinary team meeting.
Patients with liver metastases should be referred to a centre with expertise in the management of these malignancies, for consideration of liver resection, if appropriate.
Following curative treatment of liver metastases, patients need ongoing regular follow-up so as to permit early detection of further recurrences that may be amendable to further therapy.
Considerations in making these recommendations[edit source]
In patients with liver metastases, a clear resection margin is the most important factor that predicts for survival benefit and reduces the likelihood of further local recurrences within the liver.
Although the systematic review did not identify any suitable studies that compared curative surgery (with or without chemoradiation) for pulmonary metastases, the same principles that applies to patients with liver metastases are likely to be applicable to patients with pulmonary metastases. At present, patients should be considered for pulmonary resection provided the pulmonary metastases can be resected with clear margins.
An important consideration when offering liver or lung resection is ensuring that the remnant liver or lung retains adequate functional capacity while ensuring adequate resection with a clear resection margin. Multiple techniques (e.g. portal vein embolization or ligation) have been described to encourage hemi hypertrophy of the liver so as to increase remnant liver size and functional capacity. Some of these techniques remain experimental and more studies are needed to evaluate the safety of these techniques.
Patients with liver metastases should be discussed in an experienced multidisciplinary team because of the ongoing progress and evolution in the surgical options available to these patients. Broadly speaking, patients with liver metastases may be sub-classified into one of three categories based on the extent of their disease: those with definitely resectable disease, those with borderline resectable disease and those with nonresectable disease. The current systematic review supports liver resection in patients who belong to the definitely resectable category. However, the definition of what constitutes resectable disease may vary between centres, depending on the experience and expertise of the multidisciplinary team.
Decision making in the case of an individual patient is often complex and requires thorough consideration of performance status and accurate staging, as well as patient preferences and circumstances. For patients in the borderline resectable category, neoadjuvant chemotherapy should be considered, as the disease may become resectable following chemotherapy.
The experience of the multidisciplinary team is crucial to ensure optimal outcomes are achieved and it is now accepted as standard practice for patients with metastatic disease. The composition of the multidisciplinary team in patients with liver metastases should also include an experienced liver surgeon. In a recent review of the multidisciplinary team in an English centre without liver expertise, 60% of patients with liver metastases were denied potentially curative resection as compared to when the patients’ imaging were reviewed by experienced liver surgeons.
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Health system implications[edit source]
Clinical practice[edit source]
The management of patients with metastatic disease requires a multidisciplinary approach. The expertise needed is not restricted to surgeons alone and includes experienced radiologists, medical and radiation oncologists. The input from each member will allow clinicians to arrive at the appropriate recommendation which should be individually tailored to the patient’s disease. These guidelines and recommendations may result in more referrals to tertiary referral centres and may therefore increase the workload of these centres.
The peri-operative management of these patients can be complex and typically requires the input of intensive care physicians, rehabilitation physicians, pain physicians as well as senior nursing and allied health members. With increased awareness and demand, there may be the need for more experienced centres to be established.
Barriers to implementation[edit source]
No barriers to the implementation of these recommendations are envisaged.
Unresolved issues[edit source]
Liver metastases[edit source]
In patients with multiple liver metastases, the extent of liver resection needs to be balanced against the functioning capacity of the liver remnant so as to avoid liver failure. Techniques such as portal vein embolisation or ligation to trigger hemi-hypertrophy of the non-ligated half of the liver from the ischaemic insult have been increasingly utilised (see Management of non-resectable locally recurrent disease and metastatic disease). Although feasibility and safety of such techniques have been demonstrated, these techniques have not been fully evaluated in comparative studies.
The same principles of treatment may be applied to patients who present with stage IV disease at the time of presentation where there is isolated liver metastases alone. However, unlike primary non-metastatic colorectal cancer, the appropriate sequence of interventions remain unclear. These patients often require chemotherapy, resection of their colorectal primary and liver resection at some stage. Whether a liver first approach is superior or whether a more conventional surgical approach is more appropriate is unclear. Currently, clinicians usually tailor treatment sequence to the individual patient’s disease, but the evidence behind this approach is also somewhat limited.
The role of adjuvant therapy in reducing further systemic or local recurrences needs to be defined and warrants further evaluation in prospective randomised trials.
Other sites of metastasis[edit source]
There is inadequate evidence at present to inform recommendations about the role of lung resection in patients with resectable pulmonary colorectal metastases. A large multicentre randomised trial evaluating the role of pneumonectomy for colorectal metastases has recently been completed and the results of this are awaited.
Similarly contentious are resection of other colorectal metastases such as para-aortic node resection, and bony resection for seemingly isolated metastases. As isolated metastases involving these sites are rare, multicentre collaborations are likely necessary to gain insight into the role of these resections.
Studies currently underway[edit source]
A large multicentre randomised trial evaluating the role of pneumonectomy in patients with resectable pulmonary metastases have recently been completed. Outcomes are awaited and will be highly informative about the role of pneumonectomy in these patients.
Future research priorities[edit source]
Metasectomy of metastases involving sites other than liver needs to be evaluated to determine the utility of surgical resection at these sites.
In patients with stage IV disease with liver metastases at presentation, the optimal treatment sequence needs further evaluation. Techniques such as portal vein ligation, embolisation or other techniques to stimulate liver hypertrophy, so as to boost potential functional capacity of the liver, warrant further evaluation.
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