INTRODUCTION

Does detection of any polyp at computed tomographic colonography (CTC) justify colonoscopy? Or is there a minimum polyp size below which patients do not need to be referred for endoscopic polypectomy, and what is that size—1 cm, 6 mm, or something else? How clinicians approach this issue has enormous practical implications for implementation of CTC, since about 10% of persons having CTC can be expected to have a "lesion" (polyp or stool) 1 cm or larger, while about 35% will have one of 6 mm or larger.

Polyp Size and Cancer Risk

There is no disagreement among clinicians that lesions 1 cm or larger should prompt work up. While data are limited, the rate that such lesions grow to become clinical cancer is roughly 1% per year, based on a follow-up study in the pre-colonoscopy era in which patients with lesions over 1 cm on barium enema were followed over time (¹). This rate may overestimate risk for 1 cm lesions because in this study many lesions were larger than 1 cm and may have already been cancer when follow-up was begun. On the other hand, the rate may underestimate risk to the extent that "length–time bias" causes slower-growing tumors to be selected preferentially for entry into such a study. In any case, most clinicians would likely agree that 1 cm lesions should be worked up.

For very small lesions, at the other end of the size spectrum, few clinicians would likely argue that colonoscopy is justified because diminutive polyps, under 6 mm, are so common (being present in 30–50% of population, in the United States, above age 50 yr, according to autopsy studies) that the overwhelming majority cannot possibly represent an important near-term health threat.

The main area of controversy involves whether the threshold for work up should be 1 cm or 6 mm or something in between. The rationale to work up 6–9 mm lesions is, as discussed in a recent "white paper," (²) that about 1% of polyps in the 6–9 mm range could be expected to contain "invasive cancer," while 4% would contain high-grade dysplasia (²). While the label of "cancer" (and perhaps "dysplasia") is understandably worrisome to many people, the critical question is not what a lesion looks like and is labeled (i.e., cancer, dysplasia, or something else) but rather how it will behave: "What is its natural history to become untreatable cancer and over what period of time (i.e., before a next examination in a program of screening)?" Getting data to answer this question is difficult for obvious reasons. A report from Norway suggests that 1 cm lesions do not have an ominous short-term natural history (³), but such follow-up data are limited. Another way to think of the situation is that labels like cancer or dysplasia may have connotations that do not reflect actual clinical behavior. In the field of breast cancer screening, for example, questions have been raised about whether the clinical significance and natural history of ductal carcinoma in situ (DCIS) is ominous enough to warrant the aggressive treatment that the lesion often receives. Similarly, lesions labeled prostate cancer, particularly with low Gleason grades, are common and may have a benign natural history; yet prostate cancer is often treated aggressively. At the biological level, some lesions labeled cancer may not behave like cancer at all; Folkman has termed such lesions "cancer without disease" (⁴). The point is that just because a lesion has an ominous-sounding name does not mean that it is clinically important.

How these issues are deliberated has important practical implications both for current practice and for future research and technical development of CTC.

For current practice, clinicians will need to decide, as CTC becomes implemented, what threshold lesion size should prompt a work up. While a strong case can be made to use a threshold of 1 cm as long as a follow-up examination will be done (at which time many "lesions" may not have grown or may even disappear because they were stool or artifact), some people may be uncomfortable living with "any" type of uncertainty, even if very small.

Other Factors Affecting Decision Making

More important than a decision about current practice is to conduct the research and development that may address current uncertainties. For example, it would not be difficult to conduct a follow-up study to assess natural history of lesions of various sizes. Separately, technical improvements in CTC could make a strategy of "watchful waiting" attractive; in particular, development of a laxative-free prep could make CTC popular both in screening and in follow-up (^5,6). While other technical challenges confront CTC, including the cost of hardware and software and the radiation exposure of a test repeated over time; these challenges will likely be addressed in ways that make CTC increasingly attractive.

Stepping back from the data involved in decisions about threshold size, it is instructive to consider forces in the "larger environment" that tend to make decisions aggressive for both screening and treatment. Sometimes those forces seem to be saying, "Cancer must not be 'missed,' at almost any cost." One motivation to be aggressive is that consequences of "missed" cancer can include an unhappy patient, an unhappy doctor, and a potential legal liability. At the same time, there has to be some point of "diminishing returns" beyond which we must accept that some cancers will be missed. As a profession, we must consider what that point is and when forces to be aggressive and to "not miss anything" may become extreme, perhaps leading to suboptimal decision-making (^7,8).

The strength of forces to be aggressive is poignantly illustrated in decision making about prostate cancer screening. The benefit of prostate cancer screening is at best uncertain (i.e., there are no randomized controlled clinical trials (RCTs) demonstrating mortality reduction from screening and treatment), while harms from screening and treatment, such as impotence and incontinence, are well documented and common. In a situation with uncertain benefit and well-known and frequent harms, one might expect patients and doctors to be cautious about screening and treatment. Yet prostate cancer screening is commonly done, and patients and physicians receive almost no "negative feedback" following a decision to be aggressive (⁷). If a physician believes, as some do, that prostate cancer screening and treatment cause net harm to a patient, it still may be tempting for a physician to recommend screening because such a recommendation almost always results in positive feedback. If a screening test is negative, the patient is relieved; if positive, the patient is grateful that the lesion was caught "early" (⁷). Even when a decision for aggressive treatment leaves patients impotent and incontinent, 90% are pleased with the decision and would do it again (⁹). CRC screening is of course different because there is evidence of efficacy and because the harms of screening and treatment are much less than for prostate cancer. Nevertheless, the example illustrates the strength of forces to be aggressive and shows how such forces can operate independently of evidence of benefit. In other words, doctors and patients could experience positive feedback from a decision to not miss anything even if benefit were nonexistent. Recognizing that such forces exist may help professional organizations and clinicians make better policy and clinical decisions.

Picking a Threshold Size for Watchful Waiting

Returning to the question of "threshold" size, it is important to realize that in cancer screening lesions are sometimes followed over time, and the idea of watchful waiting is not new. Some breast lesions found at mammography are followed over time, while lung lesions discovered at spiral CT may similarly be watched before a diagnostic procedure is done. Further, natural history does not always turn out to be bad. It is instructive to consider that 15 yr ago, when the National Polyp Study (NPS) was being initiated, persons who had had colon polyps were considered to be "polyp-formers" with such a high risk of subsequent CRC that post-polypectomy surveillance was recommended as often as every 3 or 2 yr or even yearly (¹⁰). The NPS was designed to compare "non-aggressive" follow-up colonoscopy—3 yrs after polypectomy—versus aggressive follow-up, at 1 yr (¹¹). When the number of significant neoplasms occurring in follow-up was so small that a meaningful comparison between groups could not be done, the two groups were combined and compared to "historical" controls (¹¹). These and other data (^11,12) demonstrated that natural history was much less ominous than had been believed, providing the basis for substantial modification of recommendations for post-polypectomy surveillance (^13,14). We need to similarly learn about the natural history of lesions that may be discovered at CTC.

The Future

A strong case can be made to use 1 cm as the threshold for work up of lesions found at CTC. In the long run, the decision about which threshold to use now is less important than continuing the technical development of CTC to improve its accuracy, availability, cost, and convenience (e.g., no laxative prep), as well as to learn about natural history of various lesions, so that CTC technology may be maximally applied to benefit patients.

References

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