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Originally published as JCO Early Release 10.1200/JCO.2004.01.948 on March 8 2004 © 2004 American Society of Clinical Oncology.
Follow-Up for Patients With Colorectal Cancer After Curative-Intent Primary Treatment
1 Saint Louis University, St Louis, MO The introduction of effective anesthetics in the mid-nineteenth century permitted the rapid development of surgery, which remains the primary form of therapy for colorectal cancer. Some patients were rendered grossly disease-free by surgery, creating a population at risk for recurrence for the first time in history. A few decades later, surgical salvage of relapse was attempted and, in a few instances, patients were cured. This provided a rationale for trying to diagnose recurrence early, while resection was still feasible. It was known at that time that individuals with one cancer were unusually likely to develop another, particularly in the same tissue as the index lesion. This provided further justification for patient follow-up, but post-treatment surveillance strategies evolved unevenly and largely without clinical trials to demonstrate effectiveness. Efforts to diagnose and treat recurrent colorectal cancer reached a peak with planned "second-look" laparotomy for patients with various intra-abdominal cancers judged to be at high risk for local-regional relapse.1 Over half of these patients had node-positive colorectal cancer and nearly 50% of them had relapse documented at exploration. Most importantly, some patients were rendered tumor-free at operation, and a few of these were long-term disease-free survivors. The very high morbidity and mortality rates (to say nothing of the costs) associated with this strategy soon became apparent, but the introduction of modern diagnostic tools such as computed tomography (CT) and carcino-embryonic antigen (CEA) measurement now permit clinicians to select patients for salvage attempts much more precisely. Many of the wealthier nations of the world are now able to provide access to modern medicine to all or most of their citizens, with concomitant increases in the duration and quality of life. A by-product of the increase in the average life span has been a large increase in the total number of people afflicted with colorectal cancer, as the incidence of the disease increases with age. Costs of care also have risen dramatically, and therein lies one of the conundrums of modern clinical practice: how to use costly resources wisely. In an attempt to rationalize care, the concept of the randomized trial was introduced in the mid-twentieth century. The results of one million randomized trials have been published since then,2 but very few have dealt with follow-up of patients with colorectal carcinoma. This poses an important problem because there are many patients at risk and the costs of diagnosis (and treatment, if needed) are high.3 The American Cancer Society predicts that, in the United States in 2004, 146,900 people will be diagnosed with colorectal cancer and that 56,730 will die of this disease.4 Approximately 75% of all newly diagnosed cases receive curative-intent treatment and usually enter a surveillance scheme. There are many diagnostic modalities to employ during surveillance, but the quality of evidence underlying such schemes is poor. This is not surprising, as a recent analysis by the Institute of Medicine of the US National Academy of Sciences estimated that the quality of scientific evidence supporting health services in general is strong for only approximately 4% of patient care, modest for approximately 45%, and weak or absent for the remainder.5 The Institute of Medicine recognized that the level of agreement among doctors may be quite high even if the level of evidence-based support is low. However, in the case of colorectal carcinoma, the actual practice of clinicians who follow patients after curative-intent primary treatment does not even meet the criterion of general consensus. For example, in a survey of members of the American Society of Colon and Rectal Surgeons, we found that 31% of surgeons request CT at least once during the first postoperative year after colon cancer surgery, while 53% do not employ CT at all. Similarly, 5% monitor CEA levels monthly during the first postoperative year, while 4% never check CEA levels.6 Why is it important to rationalize follow-up strategies? To minimize overuse, underuse, and misuse of medical resources, which has been identified by the Institute of Medicine as a large, costly problem.7 The optimal level of follow-up would maximize patient welfare at the least cost. Patients are harmed if a strategy is too intensive, because they are unnecessarily exposed to hazards such as radiation, undergo uncomfortable endoscopy and blood tests, and incur treatment and opportunity costs, among other risks. If high-intensity surveillance testing provides no improvement in duration of life or quality of life, society is also harmed by the waste of resources. If the strategy is not intensive enough, patients who relapse and are potential candidates for effective salvage treatment may die needlessly. Society is also harmed in this case because the costs to social programs (such as Medicare and Social Security) of treating incurable colorectal carcinoma are typically quite high, so ill wage-earners are unable to work, their quality of life decreases, their children grow up without a parent, and other difficult-to-quantify ripple effects take place. In this issue of the Journal of Clinical Oncology, Chau et al8 at the Royal Marsden Hospital (Surrey, UK) address the surveillance dilemma. They evaluated the effectiveness of a rational, standardized schedule of serum CEA measurements and CT in a well-maintained registry of patients after conventional curative-intent excision plus adjuvant chemotherapy in a group selected to be at rather high risk for relapse. Their patients were followed for a median of 5.6 years after completion of therapy. The main aim of the randomized trial was not to evaluate these follow-up strategies; the current report describes a secondary analysis of registry data. Unfortunately, the authors grouped patients with recurrence of the index lesion and those with second primaries. This weakens the conclusions, because test parameters such as sensitivity and specificity for CT and CEA monitoring are not the same for these two types of adverse events. Chau et al mention the multitude of previous efforts to introduce rationality into surveillance practices for patients with colorectal cancer. Under some circumstances, casual inspection of registries can be very convincing. An example often cited is the introduction of penicillin into clinical use, which immediately and dramatically altered practice. The utility of cancer patient follow-up is much harder to judge. Proposals to carry out intensive surveillance now depend for justification on the results of costly, and often risky, surgery. Perhaps if there were much more effective medicines for relapsed colorectal carcinoma, surveillance would not need to be very stringent. The carefully worded and nuanced report of the Royal Marsden Hospital group provides support for the use of two diagnostic modalities in patients with colorectal cancer at relatively high risk for recurrence. Recurrences were observed frequently, as expected. Many were detected by development of symptoms and others were detected through follow-up testing. The authors also mention, appropriately, the considerable body of evidence suggesting that CEA monitoring alone has little or no value. They provide evidence that patients with relapses detected before development of symptoms had a better chance of long-term disease-free survival than symptomatic patients with relapses detected through work-up of symptoms. They conclude that surveillance CT and CEA testing are valuable components of postoperative follow-up in stage II and III colorectal cancer. Precise terminology is one of the essential problems with reports of this sort. The term "value" is often used in an informal sense, but it has acquired a somewhat different, more precise meaning in the realm of quantitative outcomes research and economic analysis. It is indisputable that individual patients derive value—in the conventional sense of the term—by detection and treatment of recurrent colorectal cancer, but it is not at all clear whether populations of patients derive value from a high-intensity surveillance strategy rather than a low-intensity one. Determining an optimal strategy for this population has proved to be devilishly difficult. What amount of dollars is society willing to expend per year of additional life attributable to follow-up? In wealthy nations, that number is probably about $50,000 to $100,000 per quality-adjusted life year.9 The authors do not address this point. Indeed, they cannot, because the experimental design precludes it. For most patients in poor nations and for those without access to care in wealthy ones, of course, these calculations have little relevance, adding an additional layer of complexity to the issue. What is to be done for those with few resources? Another limitation of this article is that patients at low risk for recurrence were not evaluated, although these patients commonly enter a surveillance program and the scanty available evidence suggests that the intensity of surveillance is not markedly affected by the initial tumor-node-metastasis system stage.10 Although the authors describe the use of CT and serum CEA monitoring, they do not mention whether other tests were employed routinely. Perhaps none were, given the protocol-dictated follow-up scheme. However, evidence about the actual practice of colorectal surgeons is available,6 suggesting that many other tests are used, although their specificity and sensitivity are often quite poor. Motivations underlying the current practice of surveillance for patients with colorectal carcinoma are numerous. One of the most important is detection of recurrence of the index lesion at a time when salvage treatment may be possible. This is the focus of the report by Chau et al. Little mention is made of the worthwhile enterprise of searching for a second colorectal cancer in patients who have had less than a total proctocolectomy and who develop new primary carcinomas at the rate of 0.3% to 0.4% per patient per year.11 Patients with new primary cancers have a rather good chance of being cured since these tumors tend to be detected at an earlier stage than the index lesion. Unfortunately, in the absence of excellent quality evidence, the motivations of individual practitioners in designing follow-up strategies may involve nonmedical considerations such as maintenance of rapport with referring doctors and avoidance of lawsuits.12 Chau et al8 recognize that their report is hypothesis-generating and they call for properly controlled trials on the topic. The generation of high-quality evidence to the practice of cancer patient follow-up is an important priority for the medical community, although trials are expensive to mount and take a long time to complete. Two trials of high-intensity versus low-intensity follow-up for breast cancer have been carried out, indicating that they are feasible.13,14 Both employed a randomized two-arm design with a sample size of about 1,500 patients. The same size is likely to be necessary for trials of colorectal cancer patient follow-up; one such trial is in progress at present (Gruppo Italiano di Lavoro per la Diagnosi Anticipata [GILDA]). Information in several languages about this international trial is available on the internet (http://crc.marionegri.it/protocols) and additional participants are welcome. Information about GILDA is available in abstract form only; it is hypothesized that the results of high-intensity and low-intensity strategies will be equivalent.15 This trial is likely to provide what the analysis of Chau et al cannot, which is direct evidence to answer the question of what constitutes optimal surveillance for patients after primary therapy, based on an adequately powered trial. This should define, for the first time, a standard around which future trials can be designed. Clinical trials of alternative strategies for cancer patient follow-up are not currently regarded as being high-priority investigations by pertinent funding agencies. However, until funding is provided for such trials, practice will continue to rest on relatively low-quality evidence. Further efforts to generate high-quality evidence are warranted. Certainly, the current practice is quite variable and very expensive. We urge the American Society of Clinical Oncology and other organizations concerned with improvement in cancer patient care to become active advocates for the funding of investigations in this area. The more successful our initial therapy for cancer patients becomes, the more survivors will enter follow-up programs. This holds true for most neoplasms, not just colorectal cancer. The opportunities to improve patient management after primary therapy are numerous. Trials will be able to address big questions, since so few have been done so far, and improvements in the quality of patient care will surely result. They are important both to society and to individual patients. Previous research has estimated that the economic returns on such investments exceed the expenditures by one to two orders of magnitude.16 Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Gilbertsen VA, Wangensteen OH: A summary of thirteen years' experience with the second look program. Surg Gynecol Obstet 114:438-442, 1962[Medline]
2. Ault A: Clinical research. Climbing a medical Everest. Science 300:2024-2025, 2003
3. Virgo KS, Vernava AM, Longo WE, et al: Cost of patient follow-up after potentially curative colon cancer treatment. JAMA 273:1837-1841, 1995
4. Jemal A, Tiwari RC, Murray T, et al: Cancer Statistics, 2004. CA Cancer J Clin 54:8-29, 2004 5. Lohr K: Guidelines for clinical practice: What they are and why they count. J Law Med Ethics 23:49-56, 1995[Medline] 6. Vernava AM 3rd, Longo WE, Virgo KS, et al: Current follow-up strategies after resection of colon cancer: Results of a survey of ASCRS members. Dis Colon Rectum 37:573-583, 1994[CrossRef][Medline]
7. Chassin MR, Galvin RW: The urgent need to improve health care quality: Institute of Medicine National Roundtable on Health Care Quality. JAMA 280:1000-1005, 1998
8. Chau I, Allen MJ, Cunningham D, et al: The Value of Routine Serum Carcino-Embryonic Antigen Measurement and Computed Tomography in the Surveillance of Patients After Adjuvant Chemotherapy for Colorectal Cancer. J Clin Oncol 22:1420-1429, 2004
9. Earle CC, Chapman RH, Baker CS, et al: Systematic overview of cost-utility assessments in oncology. J Clin Oncol 18:3302-3317, 2000 10. Johnson FE, Longo WE, Vernava AM, et al: How tumor stage affects surgeons' surveillance strategies after colon cancer surgery. Cancer 76:1325-1329, 1995[CrossRef][Medline]
11. Green RJ, Metlay JP, Propert K, et al: Surveillance for second primary colorectal cancer after adjuvant chemotherapy: An analysis of Intergroup 0089. Ann Intern Med 136:261-269, 2002 12. Johnson FE, Virgo KS, Clemente MF, et al: How tumor stage affects surgeons' surveillance strategies after surgery for carcinoma of the upper aerodigestive tract. Cancer 82:1932-1937, 1998[CrossRef][Medline]
13. Impact of follow-up testing on survival and health-related quality of life in breast cancer patients: A multicenter randomized controlled trial. The GIVIO Investigators. JAMA 271:1587-1592, 1994
14. Rosselli Del Turco M, Palli D, Cariddi A, et al: Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA 271:1593-1597, 1994 15. Johnson FE, Virgo KS, Longo WE, et al: Colorectal cancer patient follow-up after curative-intent surgery. Proc Am Soc Clin Oncol 22:297, 2003 (abstr 1194) 16. Phelps CE, Parente ST: Priority setting in medical technology and medical practice assessment. Med Care 28:703-723, 1990[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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