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Originally published as JCO Early Release 10.1200/JCO.2005.03.8323 on December 19 2005 © 2006 American Society of Clinical Oncology.
Intensive Surveillance After Stage II or III Colorectal Cancer: Is It Worth It?Department of Medicine, Division of Hematology-Oncology, The University of North Carolina School of Medicine, Chapel Hill, NC After treatment for a newly diagnosed stage II or III colorectal cancer, the patient—hoping the worst is over—focuses on restored physical vigor and self confidence while resuming pre-illness roles. Meanwhile, practitioners focus on orchestrating patient follow-up, knowing that some 30% to 40% will recur or develop a second bowel cancer. Most residual disease will manifest itself as recurrence within 3 years, and almost all cases will be diagnosed within 5 years of initial diagnosis.1 How good is the evidence for choosing what follow-up examinations to order? For years, prevailing wisdom was that early recurrence detection, including for colorectal cancers, is seldom useful. In this scenario, intensive testing leads to anxiety, financial burden, and seldom changes disease outcomes. In that circumstance, waiting for signs or symptoms, rather than detecting early disease manifestations is defensible, albeit somewhat paternalistic. Arguably, we spare patients the knowledge that they have a lethal disease and can husband scarce resources.2 However, for many discerning patients and physicians, particularly with respect to colorectal cancer, this minimalist approach has never been intellectually satisfying. Physical examination virtually never discerns early hepatic, lung, or anastomotic recurrence and carcinoembryonic antigen (CEA) is only elevated in 60% of patients with recurrence. Waiting for signs and symptoms seems contrary to instincts in life and medicine that early detection and prompt disease management is best. Also, despite the suspicion that tumor cells are embolic to many sites, some colorectal cancer patients develop a single or a few metastases, some amenable to curative surgical resection. Fong reported that a subset of 1,001 patients at Memorial Sloan-Kettering Cancer Center with a single liver metastasis resected had cure rates as high as 60%.3 Other series have noted that lung lesions, as well as recurrence at the site of colonic anastamosis and second primary tumors, were potentially curable.4,5 With more effective chemotherapy and biologic therapies for colorectal cancer, the potential for cure with medical therapy alone, a singularly elusive end point in the past, may have come within reach. In the North Center Cancer Treatment Group N9741 study, patients with advanced colorectal cancer were randomly assigned to folinic acid, fluorouracil (FU), and oxaliplatin (FOLFOX), irinotecan, FU, and leucovorin (IFL), or irinotecan and oxaliplatin (IROX).6 Approximately 11% of patients treated with FOLFOX, of whom only a minority underwent resection, are alive at 4 years, suggesting that patients with metastatic disease may be long-term survivors with chemotherapy alone (unpublished data). These combined advances in diagnostics and treatments suggest early detection of recurrence could translate into a second chance for cure for some patients faced with recurrent or metastatic cancer. In 2000, the American Society of Clinical Oncology (ASCO) convened experts to make evidence-based recommendations on follow-up.7 Their conclusion was that periodic clinical evaluations with CEA testing and colonoscopy were justifiable, but that other testing added little additional benefit. Despite this recommendation, we all have anecdotal triumphs in our practices of relapsed patients cured when recurrent disease was extirpated, and want more such happy endings and the best and most efficient way to turn anecdotes into standard practice. Randomized trials of more intensive versus less intensive follow-ups have been hard to conduct, forcing decisions based on retrospective reviews and meta-analyses. Additionally, the continuous improvement in diagnostic and treatment technology suggests the need for reassessment of best strategies. In this setting, Rodriguez-Moranto et al report the results of their randomized trial of two different follow-up strategies in this issue. Their study enrolled 259 stage II or III colorectal cancer patients from three hospitals in Catalonia.8 Their simple strategy included medical history, physical examination, CBC, liver function tests, and CEA. Their intensive strategy included the simple strategy methods plus abdominal computed tomography (CT) or ultrasound imaging, chest x-ray, and colonoscopy. Work-up for signs or symptoms of recurrent disease was comparable in both study arms. After a median follow-up of 4 years from diagnosis, there is no significant survival difference between the two strategies (hazard ratio [HR] = 0.87, P = .62). In subset analysis, the 76 intensive strategy patients with stage II colon cancer (HR = 0.34, P = .045) and the 29 with rectal cancer (HR = 0.09, P = .03) had a survival advantage over the simple strategy stage II groups. In those patients with recurrence on the intensive strategy 51% (18 of 35) were amenable to resection compared to 29% (10 of 34) in the simple strategy. The Rodriguez-Moranto et al study has strengths and weaknesses, some of which are acknowledged in their discussion. By conducting the study in three institutions, the authors limited the number of participating radiologists, gastroenterologists, medical oncologists, and surgeons. The ineligibility rate was minimal and no patients were lost to follow-up. The analysis is carefully done and clearly articulated. The authors and the Catalan government deserve applause for conducting and funding this study. Attempts by the GI intergroup in the United States to construct a similar study have never led to a successful trial. This study has its limitations. Because of modest sample size and progress in therapy a relatively small number of recurrences occurred in 69 of 259 patients. The inclusion of both colon and rectal cancer patients perhaps obfuscates rather than clarifies. The study began in 1997, long before the 2000 ASCO guidelines. Consequently, the simple strategy deviated from the ASCO guidelines by obtaining CBCs and liver function tests, and not getting a colonoscopy 3 years postoperatively. Colonoscopy proved to be the best test for discerning resectable recurrences and new primary tumors, and ideally should have been a part of both study arms. It is thus difficult to apply these data to the current United States standard of care. It seems likely, had both arms included follow-up colonoscopy, there would have been no survival differences between the strategies even in subset analysis. The use of abdominal CT in rectal cancer patients and ultrasound in colon cancer patients introduces another potential confounding variable. It also would have been valuable for the authors to separately report among the 28 local recurrences how many were anastomotic recurrences rather than second primaries. Consequently, this study is more provocative than definitive, and perhaps is most valuable for framing questions for the future. Since more resectable recurrences came to light via imaging after 2 years, trials could consider concentrating resources in the interval between 2 and 5 years postoperatively. These data suggest that the need to focus on different strategies in rectal than in colon cancer and in stage II than in stage III patients. Our assumption has been that stage II disease is stage III disease caught earlier. However, it is plausible that tumors diagnosed without lymph node invasion inherently differ and are more likely to spread in a confined, potentially resectable manner. How does this study advance our knowledge of the natural history of disease and help us better manage our patients? It would seem that both the minimalists and the frequent testers could declare the results of this study as a victory for their side. The minimalists would conclude that a simple strategy remains the best strategy. Those of us who favor more extensive testing might conclude that for stage II and rectal cancer patients this report justifies more resources spent on intensive follow-up. In truth, it seems that we still lack definitive evidence on which to base a clinical guideline despite the frequency that we confront this issue. Hints from this study should help us to frame additional trials that will help resolve this highly relevant surveillance debacle. Clearly, there is sufficient evidence to serially follow CEAs and to perform repeat colonoscopy at regular intervals as articulated by the ASCO guidelines. No study published to date, including this one, provides definitive data quantifying the relative value of imaging by CT, magnetic resonance imaging, or positron emission tomography scans as a means to prolong median survival. Meanwhile, I admit to routinely recommending three annual surveillance body CT scans to my stages II and III colorectal cancer patients between years 2 and 4 of follow-up, while hoping for better evidence to confirm my own prejudice that these expended resources have utility. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Author Contributions
REFERENCES 1. Sargent D, for the Adjuvant Colon Cancer Endpoints (ACCENT) Group: Endpoints for colon adjuvant clinical trials (CACT): Recommendations based on individual patient data (IPD) from 20898 patients (pts) and 18 randomized trials. Amer Soc Clin Oncol 23:248s, 2005 2. Pfister DG, Benson AB III, Somerfield MR: Surveillance strategies after curative treatment for colorectal cancer. N Engl J Med 350:2375-2382, 2004 3. Fong Y, Fortner J, Sun RL, et al: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann Surg 230:309-318, 1999[CrossRef][Medline] 4. Goldberg RM, Fleming TR, Tangen CM, et al: Surgery for recurrent colon cancer: Strategies for identifying resectable recurrence and success rates after resection. Ann Intern Med 129:27-35, 1998 5. Tepper JE, O'Connell M, Hollis D, et al: Analysis of surgical salvage after failure of primary therapy in rectal cancer: Results from intergroup study 0114. J Clin Oncol 21:3623-3628, 2003 6. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 7. Desch CE, Benson AB III, Smith TJ, et al: Recommended colorectal cancer surveillance guidelines by the American Society of Clinical Oncology. J Clin Oncol 17:1312-1318, 1999 8. Rodriguez-Moranta F, Salo J, Arcusa A, et al: Efficacy of postoperative surveillance in patients with colorectal cancer operated on for cure: A prospective, multicenter randomized controlled trial. J Clin Oncol 24:386-393, 2006
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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