The FACS trial has its merits…. However, the study findings and the investigators’ conclusions failed to impact my current approach to surveillance of my patients with locally advanced disease.
—Cathy Eng, MD, FACP
Colorectal cancer is a common malignancy that will impact 1.4 million individuals globally each year.1 Approximately 70% to 75% of patients will present with locally advanced disease. For patients with stage III colon cancer, adjuvant chemotherapy is commonly offered, whereas chemotherapy for those with stage II disease is of questionable benefit. In any case, following surgical resection, patients are commonly followed on surveillance for up to 5 years before being deemed disease-free.
Common surveillance recommendations for stage II/III patients (eg, ASCO and National Comprehensive Cancer Network guidelines) include quarterly physical exam for years 1 to 3, then biannual exam in years 4 and 5, with a computed tomography (CT) scan of the chest, abdomen, and pelvis annually. A colonoscopy is typically completed 1 year from the original surgical date and then every 3 years thereafter. It has been reported that 72% to 80% of all recurrences occur within the first 3 years.2
FACS Trial Design
As recently reported in JAMA and reviewed in this issue of The ASCO Post, Primrose et al have completed the FACS (Follow-up After Colorectal Surgery) trial.3 Between January 2003 and August 2009, 1,202 patients from 39 UK hospitals were randomly assigned to one of four arms: intensive monitoring with carcinoembryonic antigen (CEA) only, CT only, CEA plus CT, or minimum follow-up. CEA was measured every 3 months for 2 years and then every 6 months for 3 years, and CT scans of the chest, abdomen, and pelvis were performed every 6 months for 2 years and then annually for 3 years; the minimum follow-up group received follow-up if symptoms occurred.
The original primary endpoint was overall survival, but due to slow accrual, the trial was amended. The revised primary endpoint was surgical treatment of recurrence with curative intent after a minimum follow-up of 3 years.
It was determined that a sample size of 590 patients was needed per factorial group (CEA vs no CEA, CT vs no CT) for 80% power to detect a minimum 3% absolute effect of intensive monitoring. Statistical modeling indicated that a 3% difference in treatment with curative intent translated into overall survival would be the smallest difference indicating cost-effectiveness. For comparison of the minimal intervention group with the CEA, CT, and CEA-plus-CT groups, a sample size of 1,180 would provide 51%, 70%, and 84% power to detect differences of 3%, 4%, and 5%, respectively.
Treatment of Recurrence
After a median follow-up of 4.4 years, cancer recurrence was detected in 16.6% of patients, with no statistical difference noted between the investigational arms (P = .08). Overall, 65.3% of all recurrences were detected on scheduled follow-up, with clinical symptoms or incidental findings accounting for detection of recurrence in the remaining patients.
In brief, 5.9% of patients underwent surgical treatment with curative intent for disease recurrence. The absolute difference between surgical intervention and minimal follow-up in each arm ranged from 4.3% to 5.7%. The authors noted there was no significant difference in all four arms for overall mortality (P = .45) or colorectal cancer–specific mortality (P = .85). They concluded that intensive surveillance improved the likelihood of surgical intervention for curative intent, but the combined approach of CEA plus CT is unlikely to demonstrate improved benefit in overall survival.
Given concerns about the rising cost of health care, the FACS trial has its merits. The investigators attempted to determine if one method of surveillance was of greater benefit for detection of cancer recurrence using one of two very accessible modalities—CEA level or CT scan of the chest, abdomen, and pelvis—or the two modalities in combination. However, the study findings and the investigators’ conclusions failed to impact my current approach to surveillance of my patients with locally advanced disease.
For patients with surgically resected locally advanced disease, a control arm of minimal follow-up without any scheduled follow-up (excluding a single CT scan of the chest, abdomen, and pelvis at 12–18 months) would be considered ethically, medically, and legally inappropriate. Furthermore, it would be difficult to believe that with a mean participant age of 69 years, these patients who are largely residing in an urban environment were not still under the supervision of at least a primary care physician, given their previous diagnosis of cancer.
None of the arms takes into account the actual physical examination of the patient. As medical students, we were instilled with the knowledge that the majority of your diagnosis is in fact determined by a thorough history and physical. The case report forms provided documented data on treatment recurrence and intent. No mention of the actual examination or the extent of examination was made.
The authors also failed to acknowledge that the baseline CEA level is not elevated in approximately 15% to 30% of colorectal cancer patients. In these instances, a CT scan may be our only option for detection of cancer recurrence. However, these patients were randomized independently, regardless of detection or no detection of an elevated baseline CEA.
Oddly enough, the investigational arm of CT follow-up included performance of a CT scan biannually for the first 2 years. Why the investigators chose such a close interval of CT monitoring is unclear; this is unlikely to be cost-effective. Current guidelines recommend only an annual CT scan.
It is presumed that central diagnostic imaging review was also not completed, given that there is no mention of that process in the published report. However, if the endpoint is surgical intervention, diagnostic imaging quality and capabilities would be of critical importance. It is also appears that the pathology specimens were also not centrally reviewed for surgical margins, optimal number of lymph nodes dissected, or circumferential radial margin in the rectal carcinoma specimens. Moreover, there was no mention of deferral of adjuvant chemotherapy, type of chemotherapy provided in stage III colon cancers, or role of neoadjuvant chemoradiation therapy in the rectal cancer patients.
The primary endpoint of surgical intervention for recurrence is also not a standard endpoint, but was adopted in acknowledgment of the lack of feasibility in completing the trial. If we are to really make an impact on use of surveillance as a tool in colorectal cancer, colorectal cancer–specific survival would be a more appropriate primary endpoint. Thereby, early detection could not only document the impact of surgical intervention with curative intent but would also address the importance of initiating systemic chemotherapy in patients with recurrent disease that is not deemed to be surgically resectable. ■
Disclosure: Dr. Eng reported no potential conflicts of interest.
1. American Cancer Society: Global Cancer Facts & Figures, 2nd ed. Atlanta, American Cancer Society, 2011.
2. Sargent DJ, Patiyil S, Yothers G, et al: End points for colon cancer adjuvant trials: Observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 25:4569-4574, 2007.
3. Primrose JN, Perera R, Gray A, et al: Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: The FACS randomized clinical trial. JAMA 311:263-270, 2014.
Dr. Eng is Associate Professor, GI Medical Oncology Department, Associate Medical Director, Colorectal Center, The University of Texas MD Anderson Cancer Center, and Co-Chair, SWOG Rectal Subcommittee.
In the FACS trial, reported in JAMA, John N. Primrose, MD, FRCS, of University of Southampton, England, and colleagues compared outcomes with intensive follow-up with carcinoembryonic antigen (CEA) measurement, computed tomography (CT), both, or minimum follow-up after curative surgery for primary...