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Recurrent and Metastatic Colorectal Cancer
There are approximately 40,000 new diagnoses of rectal cancer in the United States each year. Developments such as total mesorectal excision (TME) and neoadjuvant chemoradiotherapy (NACXRT) as well as international guidelines have improved the prognosis of primary rectal cancer. But despite these advances, local recurrence after surgery remains a significant issue. Historically, local recurrence and metastatic disease signified an incurable condition, but there has increasingly been a shift from a palliative approach to a multimodal treatment approach with curative intent. Good outcomes from salvage surgery within a multidisciplinary approach have been demonstrated.
Tumor Relapse
Incidence of Recurrent Disease
In the modern series, the incidence of local recurrence after rectal cancer surgery ranges from 5% to 15%, and this number appears to be decreasing. Approximately half of patients who present with locally recurrent rectal cancer (LRRC) will be considered candidates for curative resection. The likelihood of relapse was historically believed to be highest within the first 2 years after primary resection, but recent reports suggest that the median time to recurrence is increasing, especially for rectal cancers, and surveillance beyond 5 years may be necessary.
Prior to the widespread adoption of TME technique, most recurrences were extraluminal in the lymph node bearing tissue. Now that TME is the standard of care, there is a higher percentage of intraluminal recurrences, up to 30% to 50% of recurrences in several published series, as well as extraluminal recurrences, even in patients who were lymph node negative at the original operation.
Factors That Influence Recurrence
A large number of risk factors have been associated with relapses of colorectal cancer ( Table 171.1 ).
TABLE 171.1
Factors Associated With a High Risk of Relapse for Colorectal Cancer
| TUMOR FACTORS |
|
| TECHNICAL FACTORS |
|
Tumor Stage
The extent of disease, or tumor stage, is to date the single most important predictor of relapse and survival. The American Joint Committee on Cancer (AJCC) Colorectal Cancer Staging system is shown in Table 171.2 . The risk of local recurrence is increased when the tumor has invaded beyond the confines of the bowel wall (T3 to T4) or involves nodes (N+) and is highest in patients with both.
TABLE 171.2
American Joint Committee on Cancer TNM Cancer Staging for Colorectal Cancer, Seventh Edition
| PRIMARY TUMOR (T) |
|
| REGIONAL LYMPH NODES (N) |
|
| DISTANT METASTASIS (M) |
|
TNM, Tumor-node-metastasis.
Other Tumor Factors
Certain histologic features have been correlated with aggressive behavior, including poor tumor differentiation, high tumor grade, mucin production, and venous, lymphatic, and perineural invasion. Involvement of the circumferential radial margin (CRM) is also prognostic for both colon and rectal carcinoma. Other high-risk features include bowel obstruction, perforation, and tumor adherence to local organs. A long disease-free interval between primary tumor resection and LRRC may also indicate more favorable tumor biology.
Molecular Features
High microsatellite instability phenotype, which is present in approximately 20% of colorectal cancers, has been associated with an improved prognosis. Conversely, the presence of low microsatellite instability has been associated with a worse prognosis.
Technical Factors
Technical factors also influence rates of local recurrence and overall survival. Local recurrence rates range from 4% to 40%, which is at least partially dependent on the individual operating surgeon. Some authors have shown increased local recurrence rates when tumors are in the distal rectum, possibly related to increased technical difficulty. At a minimum, it is vital that wide anatomic resection of the tumor in all dimensions (mesorectal, distal, circumferential, and en bloc resection of adherent organs) is achieved.
In 2000, a consensus panel was convened to discuss surgical guidelines for colon and rectal cancer to combine the best evidence to balance oncologic results with functional outcomes. In summary, all margins should be negative. For rectal cancers, a minimum distal margin of 2 cm is ideal and a margin of more than 1 mm is acceptable where the tumor is not locally advanced, after neoadjuvant therapy and abdominoperineal resection (APR) is the only alternative. Circumferential margins should be as wide as possible, ideally greater than 2 mm.
Total mesorectal clearance should be routine. Sharp dissection should be performed in the areolar tissue behind the mesentery, just in front of the sacrum and particularly at the level of Waldeyer fascia. The fascia propria should be removed intact with proper rectal dissection. Therefore a TME is advised for all cancers of the distal rectum for which APR or low anterior resection and coloanal anastomosis are planned. In the management of more proximal rectal cancers, it seems reasonable to use a margin of approximately 5 cm of distal mesorectum as a benchmark, because tumor deposits in the mesorectum are rarely reported 4 cm beyond the tumor. Despite optimization of surgical techniques, adjuvant radiation treatment remains an independent factor for reducing the incidence of local relapse.
Other Factors
Failure to administer neoadjuvant chemoradiation therapy (NACXRT) or postoperative adjuvant therapy, when it is indicated, is a risk factor for recurrence.
Routine clearance of the lateral pelvic sidewall lymph nodes during primary rectal cancer surgery is not standard in the United States due to the difficulty of the procedure and the associated sexual and urinary morbidity. When lateral lymph nodes are presumed positive before neoadjuvant therapy and then not removed, the risk of lateral compartment recurrence is increased. The Japanese JCOG0212 trial randomized patients to TME with routine lateral compartment lymph node dissection versus TME alone for primary stage II–III rectal cancer, but survival results have not yet been reported.
Anastomotic leak following primary surgery has been shown in some studies to be associated with LRRC but not distant recurrence. Inadequate lymph node harvest may also be a risk factor, but this remains controversial as lymph node (LN) counts are often low following neoadjuvant therapy.
Detection of Relapse
Key to the detection of relapse is the implementation of surveillance guidelines. Detection of the recurrence is the first step and then confirmatory tests are used to delineate the extent of disease and the suitability for resection and adjuvant therapies. Historically, 90% of recurrences occur within the first 5 years, but Coco et al. found that when primary rectal cancer was treated with NACXRT, 30% of the LRRCs were found greater than 5 years later (while 90% of the distant metastases presented within 5 years). Similar results have been reported by others.
Surveillance Guidelines
A 2007 Cochrane review of eight randomized trials that investigated the impact of intensive surveillance strategies confirmed a significant survival advantage at 5 years in patients participating in more intensive surveillance after curative resection of colorectal cancer. Moreover, the group with more intensive follow-up had more frequent operations with curative intent as well. Additional meta-analyses of these trials have confirmed reduction in death rates and cost-effectiveness of intensive surveillance strategies in some cases. Unfortunately, each of the surveillance strategies within the eight trials was unique, and it is not clear which specific component(s) of the proposed surveillance programs is most responsible for improving survival. Several cancer and specialty societies, including the American Society of Colon and Rectal Surgeons (ASCRS), the American Society of Clinical Oncology (ASCO), and the National Cancer Comprehensive Network (NCCN) have published guidelines for surveillance strategies. Each strategy is unique, but there are several generalities, including frequent physical examinations with serum carcinoembryonic antigen (CEA) measurement, at least annual chest and abdominal imaging for 3 to 5 years, and colonoscopy. Current ASCRS guidelines for surveillance after rectal cancer surgery include an office visit and CEA every 3 to 6 months for 2 years and then every 6 months until 5 years; computed tomography (CT) of the chest, abdomen, and pelvis annually for 5 years; colonoscopy 1 year after surgery and every 3 to 5 years thereafter; and proctoscopy every 6 to 12 months for patients with a rectal anastomosis.
History and Physical Examination
Patients should be asked about pain (abdominal, pelvic, perineal), change in bowel habits, symptoms of obstruction, anorexia or weight loss, malaise, and bleeding or discharge. Physical examination should include abdomen, rectal and vaginal/perineal, and lymph node basins. The history and physical exam also provides valuable information on the general health status of the patient, which is vital in determining suitability for aggressive resection.
Laboratory and Imaging Studies
CEA is the only known tumor marker for colorectal cancer, and it is simple to obtain. It has been shown to be effective in detecting the presence of local and liver recurrences before the disease is clinically apparent. In a meta-analysis of 20 studies, the overall sensitivity and specificity of CEA for detecting colorectal cancer recurrence was 64% and 90%, respectively.
The Cochrane review suggested a survival benefit in patients who underwent liver imaging with those who did not, so routine CT scans of the abdomen and pelvis have been adopted by all societies.
Endoscopy
The aim of endoscopy is the detection of anastomotic recurrences and metachronous lesions, the latter being more common. Full colonoscopy is required to detect metachronous lesions, but the frequency of surveillance colonoscopies remains the subject of debate. For average-risk patients, a colonoscopy at 1 and 5 years seems the most common practice. ASCRS guidelines suggest colonoscopy at 3- to 5-year intervals. For patients with genetic susceptibilities, the interval should be 1 to 2 years depending on the certainty and magnitude of the risk. Also, patients who did not receive a preoperative colonoscopy (because of emergency presentation and obstruction) should undergo colonoscopy as early as 3 to 6 months after resection.
For patients with rectal anastomoses, it is reasonable to perform more frequent examinations of the anastomosis using flexible sigmoidoscopy.
Positron Emission Tomography
Positron emission tomography (PET), an imaging modality based on the detection of 2-( 18 F)-fluoro-2-deoxyglucose, is not recommended for routine use in colorectal cancer surveillance. PET may play a greater role as a confirmatory study in verifying the presence of a recurrence in the setting of a rising CEA or equivocal imaging studies. However, as discussed later, a positive finding on PET scan is not equivalent to histology and is not sufficient evidence to proceed to surgical exploration. PET may also be used to confirm that metastases are limited to a single site prior to operative therapy, for example, prior to major liver resection.
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