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Effectiveness of Individual Tests
History & Physical Examination
There is no proven benefit for history and physical examination performed during surveillance. The Cochrane meta-analysis found no survival benefit to clinic visits versus no clinic visits, or more versus fewer clinic visits in resected colorectal cancers. Among patients in the Phase III randomized Int-0089 trial of adjuvant chemoradiation in rectal cancer, routine physician examination failed to identify a single resectable recurrence and was therefore the least cost-effective surveillance modality employed.
Despite the lack of evidence, most recommendations still include physician visits to coordinate surveillance tests and discuss the results.. These visits are thus advocated for additional holistic benefits, for example, to build physician–patient rapport and permit physicians to reinforce healthy lifestyle behaviors. In a pilot study by Stiggelbout et al., quality of life appears to be improved in patients participating in follow-up programs. Regular contact with a physician can reassure patients while causing only slight anticipatory anxiety.
CEA
CEA is a serum oncofetal protein that is elevated in a number of cancers, including colorectal cancer. CEA is elevated in 60-70% of colorectal cancer recurrances.. Its sensitivity ranges from 58 to 89% and specificity ranges from 75 to 98%. As with all tests where the readout comprises a continuous variable, the sensitivity and specificity of CEA for detecting a postoperative recurrence depends on the threshold level above which results are considered abnormal. Using a CEA cutoff of 10 IU/l, the sensitivity and specificity for detecting any recurrence were 44 and 90%, respectively, as compared with 80 and 42%, respectively, when a cutoff of 6 IU/l was used. Even with a low cutoff, 20% of the patients are CEA negative and will not be detected by CEA surveillance.
CEA is most sensitive for hepatic and retroperitoneal metastases but less sensitive for local recurrences, pulmonary or peritoneal metastases. Serum CEA levels may rise with a median lead-time of between 5 and 8 months prior to the development of cancer-related symptoms. This combined with its sensitivity for hepatic metastases, which is the site of relapse most amenable to curative therapy, offers the main justification for following patients with serial CEA monitoring.
CEA is most frequently the first test that detects recurrence (38–66% of the cases), especially when relapses involve the liver (~80% in the liver vs 40% in other sites). Although, this may be due to the fact that as a blood test, CEA can be assayed much more frequently than imaging modalities or endoscopy. Being a simple blood test, CEA is also found to be the most cost-effective approach in detecting potentially resectable metastases. Most importantly, in meta-analyses, CEA was identified to contribute to a reduction in all-cause mortality and improvement in survival in patients on follow-up.
However, CEA testing has limitations. CEA tests are associated with substantial false positives (~10%) and false negatives (~30%). In addition, by the time CEA is elevated, tumors may already be quite large. In the randomized Phase III Int-0035 trial of adjuvant chemotherapy, 50% of the patients with hepatic resection after CEA level elevation had large lesions (range: 4–10 cm in diameter). Hence, while CEA may detect hepatic metastasis in individual patients, there is concern that detection may not occur sufficiently early to consistently translate into a survival benefit. Several blood based markers, discussed later, are being developed with increased sensitivity and specificity for cancer recurrences while still maintaining the inherent advantages of noninvasive serial testing that blood-based assays provide.
Liver Imaging (CT & Ultrasound Abdomen)
The liver is the most common site of metastasis. Thus, the role of liver imaging in surveillance of colorectal carcinoma has been extensively studied. While individual small studies such as those by Sugarbaker et al. and Schoemaker et al. report that radiographic evaluation of the liver, performed annually, did not increase the number of curative hepatectomies, pooled meta-analysis provided more encouraging results. Renehan's meta-analysis found that performing regular CT scans was associated with survival benefit. Two other meta-analyses also reported a survival benefit (25% lower mortality) specifically with liver imaging. This benefit may be derived from the resection of limited hepatic only metastases.
The optimal imaging modality for liver metastases is debatable. A meta-analysis by Kinkel et al. showed no differences in diagnostic accuracy between ultrasonography (US) and CT in detecting liver recurrence. However, most guidelines currently recommend routine CT, in particular helical CT, which has good sensitivity and specificity, and detects a high percentage of liver recurrence (between 70 and 90%). Some studies have shown increased overall survival if helical CT is carried out at 6-month interval. On the contrary, advocates of ultrasound contend that it is a noninvasive, low-cost procedure with better compliance. They point to similar false- versus true-positive ratios with ultrasound as with CT imaging. In community practice, ultrasound remains a frequently employed surveillance modality.
Chest Radiography & CT Scans
Between 5 and 20% of patients develop pulmonary metastases and between 2 and 12% of patients develop resectable pulmonary metastases. Asymptomatic patients with pulmonary recurrences often do not have elevated CEA tests and hence may not otherwise be detected.
Chest radiography may identify resectable pulmonary metastases during follow ups. It is a low-cost convenient investigation with uncommon false positives. However, it is insensitive and there is a paucity of data regarding its efficacy in colorectal cancer surveillance. In Schoemaker et al.'s trial, among patients randomized to intensive surveillance which involved annual chest radiography, only one instance of curative resection and long-term survival was attributed to asymptomatic chest radiography-detected lung metastasis.
Indirect evidence supports incorporating chest CT scans in surveillance programs. In the Intergroup 0114 trial, lung recurrences were as common as liver relapses in rectal cancer patients and represented the largest proportion of resected metastases. In a retrospective UK series of 540 stage 2/3 colorectal cancer patients of which 154 relapses occurred, the largest proportion of resectable recurrences were also discovered with thoracic CT scans.
Colonoscopy
Compared with the general population, patients with a prior sporadic colorectal cancer have a 1.5- to threefold risk of a second primary colorectal tumor. Synchronous colon cancers occur in 2–5% of colorectal cancer patients. Metachronous lesions develop in 1.5–3% of the patients in the first 5 years postoperatively. More than half of these may represent synchronous cancers which were initially missed. Anastomotic recurrences occur in 5–10% of the patients. At least 80% of these are detected within 2.5 years of the primary resection, with the majority being recurrent rectal cancers.
In light of the above, pre- or peri-operative colonoscopy is important to document an otherwise cancer- and polyp-free colon. Follow-up serial colonoscopy is also the most widely accepted surveillance modality for evaluating anastomotic recurrence and metachronous colorectal cancers and is included in most published colorectal cancer guidelines.
However, two randomized trials failed to show improved survival or increased resectability of recurrent cancer in patients who undergo regular colonoscopy. The major theoretical benefit of endoscopy is thus detection of polyps and preinvasive disease, removal of which reduces risk of subsequent colorectal cancer. The Polyp Surveillance Study in the USA showed that there was a 75–90% reduction in colorectal cancer incidence when surveillance colonoscopy was used in the setting of polyps.
MRI of the Pelvis
A recent study found no difference between MRI and conventional follow-up tests in their ability to detect cases suitable for surgery. Thus, pelvic surveillance by MRI is currently not recommended as part of the routine follow-up. Its role is to selectively image patients with clinical, colonoscopic and/or biochemical suspicion of recurrent disease.
Proctosigmoidoscopy
Since anastomotic recurrence is more likely to occur in patients with rectal cancer compared with colon cancer, proctosigmoidoscopy may be useful in rectal cancer patients. However, the effectiveness of proctosigmoidoscopy for detection of curable anastomotic recurrence is not established.
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