Management of synchronous primary colorectal cancer with unresectable metastatic disease
At the time of diagnosis, up to 25% of patients with colorectal cancer present with synchronous metastases.2 Most patients (70%–90%) with metastatic disease are unsuitable for curative surgical treatment, and early chemotherapy in association with targeted therapies has been demonstrated to provide optimal palliation in terms of survival and quality of life or tumour down-staging.
Initial management of the primary site in patients who present with metastatic disease is controversial and there does not appear to be a consensus amongst international guidelines. The choice and sequence of treatment is guided by the presence and absence of symptoms from the primary tumour, whether or not the metastases are potentially resectable, patient co-morbidity, performance status and life expectancy.
With the exception of obstructing perforated or bleeding primary tumours, where surgical intervention is often indicated, it is still controversial whether either primary tumour resection followed by chemotherapy or immediate chemotherapy without primary tumour resection is the best therapeutic option.
Overview of evidence (non-systematic literature review)[edit source]
No systematic reviews were undertaken for this topic. Practice points were based on selected published literature. Please see Guidelines Development for more information.
Impact of palliative resection of primary on survival in patients with non-resectable metastatic colorectal cancer[edit source]
Several studies have assessed the impact of primary tumour resection for colorectal cancer with non-resectable metastases. Published studies were predominantly non-randomised, mostly retrospective and reported by single institutions. The major draw backs in these studies were that surgery was offered to the patients with the best performance status and the preferred treatment for the other patients was systemic therapy alone. In addition, those patients with a heavy burden of metastatic disease were more likely to be offered systemic therapy rather than surgery. Another limitation is that the majority of published studies have included colon and rectal cancers together; the issues can be very different for these two localisations. Surgery is often more complex for rectal cancer patients and symptoms relating to local progression of rectal tumours can be associated with significant morbidity (e.g. rectal pain) which can be difficult to manage.
A meta-analysis of 21 studies (including 44,226 patients) evaluating the effect of primary tumour resection in patients with non-resectable metastatic colorectal cancer concluded that there was a significantly lower mortality risk compared with no resection: odds ratio (OR) 0.28; 95% confidence interval (CI) 0.165 to 0.474. This translated into a difference in mean survival of approximately 6.4 months in favour of resection. The authors acknowledged significant cross-study heterogeneity and selection biases in the majority of studies, with healthier patients and those felt to have better prognosis more likely to undergo resection.
Importantly, none of the above series reporting a survival benefit for resection of the primary site has assessed the contribution of systemic chemotherapy to outcomes, or controlled for all possible variables that could have favourably affected outcomes in the resected patients.
Results of meta-analyses that have taken the effect of chemotherapy into account have been conflicting. A meta-analysis of data from randomised controlled trials (RCTs) of first-line chemotherapy for metastatic colorectal cancer (which included patients with non-resectable disease) found that primary tumour resection was independently associated with better overall survival in multivariate analysis: hazard ratio (HR) for death 0.63 (95% CI 0.53 to 0.75).
To the contrary, a Cochrane review of seven non-randomised studies, totalling 1086 patients, concluded that resection of the primary cancer in asymptomatic patients with non-resectable metastatic colorectal cancer managed with chemo/radiotherapy was not associated with consistent improvement in overall survival and did not significantly reduce the risk of primary site complications (i.e. bleeding, perforation, obstruction). Despite conflicting evidence, retrospective data show that approximately 50% of all patients with mCRC undergo resection of the primary tumour. This is in keeping with Australian data indicating that the majority of palliative metastatic colorectal cancer patients in clinical practice have their colorectal primary tumours resected. A retrospective analysis of the prospective Treatment of Recurrent and Advanced Colorectal Cancer registry reported on just over 1000 synchronous metastatic colorectal cancer patients between July 2009 and November 2015. Of those patients, 70% were considered palliative at multidisciplinary team meeting. And of those 45% had their colorectal primary tumours resected. Reasons for primary resection in the palliative group were surgeon decision (45%) and obstruction (33%) but 4% achieved curative resection of metastases. In this study, performance status, metastasis resection (R0 versus R1 versus R2 versus no resection), resection of the colorectal primary and treatment intent determined at multidisciplinary team meeting were the most significant factors for progression-free and overall survival. These data, in the setting of modern chemotherapy management, add to the literature supporting routine colorectal primary resection even when the metastases are not resectable.
Two RCTs of primary site resection in patients who present with non-resectable metastatic disease are yet to be reported and may influence recommendations for this group of patients:
- the Dutch Colorectal Cancer Group’s CAIRO4 study comparing systemic therapy (fluoropyrimidine-based chemotherapy in combination with bevacizumab) only, with resection of the primary tumour followed by systemic therapy, in patients with synchronous unresectable metastases of colorectal cancer and few or no symptoms of the primary tumour
- the German SYNCHRONOUS study comparing resection of the primary tumour before systemic chemotherapy, with no resection, in patients with synchronous unresectable metastases and no symptoms of the primary tumour.
Morbidity of primary tumour resection in the setting of non-resectable mCRC[edit source]
For patients operated for their primary tumour as part of their initial management, the question of the potential extra-risk of postoperative morbidity associated with the resection of the tumor in metastatic setting should be considered. Several studies have suggested that resection of the primary tumor in the presence of metastatic disease is associated with high postoperative morbidity and mortality rates. One study by Stelzner et al. reported that 15 out of 128 patients (11.7%) patients died within 30 days of surgery. The results however, are likely biased as many of these patients were symptomatic and underwent emergency surgery. The same series found a 27.8% mortality rate in patients who underwent emergency surgery compared to a 7.3% mortality rate for elective procedures (p = 0.002). These mortality rates were higher than those found in a recently-published meta-analysis in which collectively, perioperative mortality was 1.7% (95% CI 0.7%-3.9%). Most patients within this meta-analysis were asymptomatic and were managed electively likely explaining the lower reported mortality. In this meta-analysis, postoperative morbidity occurred in 68 of 299 patients for a pool proportion of 23% (95% CI 18.5-21.8). The most frequent complication was wound infection which could be managed conservatively; however, in some instances, a major complication arose requiring additional surgery. Anastomotic leakage, occurring in 1.7% of patients (5/299 patients) can lead to sepsis, significantly prolongs hospital stays and delays or even precludes the administration of chemotherapy.
The type of surgery performed may be important as suggested by another systematic review and meta-analysis that identified five studies comparing open palliative colectomies with laparoscopic palliative colectomies in this setting and found laparoscopic procedures were associated with reduced post-operative complications, blood loss and length of hospital stays.
Asymptomatic primary tumour[edit source]
The decision to surgically resect the primary in asymptomatic patients with non-resectable metastatic colorectal cancer is complex and requires careful consideration of the risk to benefit ratio for the patient. The impact of prophylactic surgery in this setting is uncertain.
Leaving the primary tumour intact may not lead to unacceptable local complications (or significantly compromise survival). There is a relatively low risk of bleeding (3%) or obstruction/perforation (7–14%) in patients who present with metastatic colorectal cancer and an intact asymptomatic primary managed at least initially without resection.
Moreover, this group of patients appear to have higher rates of postoperative morbidity (20–30%) and perioperative mortality (1–6% percent) which may lead to delays in the initiation of systemic therapy and detrimental effects on survival.
The prospective multicentre phase II NSABP C-10 trial showed that patients with an asymptomatic primary colon tumour and non-resectable metastatic disease who received modFOLFOX with bevacizumab experienced an acceptable level of morbidity without upfront resection of the primary tumour. In this study, survival did not appear to be compromised by leaving the primary tumour intact and improvement in the primary site can be seen within the first two weeks of systemic therapy.
Systemic chemotherapy is generally the favoured treatment for patients presenting with synchronous metastatic colorectal cancer with asymptomatic primary. Although with modern chemotherapy regimens there may be a response within the primary tumour, this response may not be as robust as seen in the metastatic disease sites. Thus, for patients with an intact primary site it is imperative to evaluate the primary site periodically. There are no guidelines for identifying non-resectable metastatic colorectal cancer patients with intact primaries who are more likely to suffer complications and require surgery during systemic therapy. Some have shown that even patients who appear to be at a high risk for subsequent complications based on tumour site or colonoscopy findings (i.e. nearly obstructing lesion or inability to advance the scope beyond the tumour) can avoid palliative surgery and obtain good control with systemic therapy. The current National Comprehensive Cancer Network Guidelines recommend leaving the primary tumour intact and starting systemic therapy first in patients with non-resectable metastatic colorectal cancer and asymptomatic intact primaries.
Symptomatic primary tumour[edit source]
A small number of patients (approximately 6%) with mCRC present with acute complications related to their primary tumours such as obstruction, significant haemorrhage, and perforation, where an urgent intervention is usually indicated prior to starting systemic therapy.
For bowel perforation, surgery should be considered to either remove the tumour when it is easily resectable (such as a right hemicolectomy for right-side colon lesions or sigmoid colectomy for sigmoid lesions), or to create a stoma (left colon) in cases requiring more technical surgery, such as low rectal resections.
Nonsurgical methods of palliation can be considered for patients not suitable for surgical procedures. Successful local palliation of an obstructing or nearly obstructing tumour may be achieved through endoscopic or radiographic placement of self-expanding metal stent (SEMS). Among the advantages of SEMS over palliative surgery are a faster recovery time (permitting earlier administration of chemotherapy) and a shorter hospital stay If the tumour is not completely obstructing, electrofulguration or laser ablation (using an Nd:YAG or argon ion [argon plasma coagulation or APC] laser) can be attempted to maintain the patency of the lumen. Radiation therapy directed at the primary tumour is another alternative to control bleeding.
Practice points[edit source]
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