- Email: [email protected]
Where the dragon truly sleeps
EDITORIAL
Where the dragon truly sleeps The moment a person learns that he or she has cancer, that person’s view about life is altered. At some level, no matter what the histology, stage, or initial treatment success might be, a cancer survivor believes that deep within his or her cellular infrastructure lies a sleeping dragon capable of awakening in the future. That dragon may be unrecognized metachronous neoplasia, a genetic milieu that portends future carcinogenesis, or cancer cells inadvertently left from treatment that ‘‘got it all.’’ For someone diagnosed with colon and rectal cancer (CRC), the dragon awakens with disturbing frequency. One of our most important roles as treating physicians is to couple emotional support to the patient with science that provides the maximal chance for a cancer-free life. Empathy must coexist with a firm understanding of colon cancer genetics, cancer biology, cancer growth patterns, and the efficacy of our treatment. Based on these precepts, we recommend interventions that first try to eliminate existing cancer and then find treatable recurrences without subjecting patients to unnecessary discomfort and society to unnecessary costs. Successful application of these principles should be in concert with current overriding quality goals: ‘‘patient-centered, valuedriven care,’’1 the ‘‘triple aim’’ of the Institute for Healthcare Improvement,2 and the effort to avert an impending ‘‘perfect storm of overutilization.’’3 Patients who undergo ‘‘curative’’ surgery for CRC face a 20% to 30% risk of cancer-related death within 5 years of diagnosis. In trying to prevent death from recurrent cancer, gastroenterologists use the tool they know the best: colonoscopy. Unfortunately, there remains confusion about how often patients with CRC should be examined, and overuse of colonoscopy is common, as pointed out by Wang et al4 in this month’s Gastrointestinal Endoscopy. This article is the result of a study based in China that compared ‘‘intense colonoscopy surveillance’’ (ICS) (10 examinations over 5 years) with ‘‘routine colonoscopy surveillance’’ (RCS) (examinations at 6, 30, and 60 months after surgery) in 319 patients with CRC who had initial curative-intent surgery. Patients in the ICS arm were examined every 3 months for a year, every 6 months for 2 years, then annually to 5 years. The difference in mortality was not significant at 5 years: 77% of the patients in the ICS arm were alive (with 3 serious
Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2008.06.052
complications related to colonoscopy) compared with 73% of patients in the RCS arm (no complications). The only significant difference in outcomes between the 2 study arms was the number of asymptomatic recurrences found and the number of times a second surgery ‘‘for cure’’ was attempted. In both situations the ICS arm appeared to do better (see Table 54). Based on these findings, the investigators state: ‘‘These results clearly indicate that postoperative intensive colonoscopic surveillance plays an important role in the asymptomatic diagnosis and treatment of postoperative colorectal cancer in patients with an improved prognosis for these patients.’’4 I would suggest that differences relate to lead-time bias and had recommended surveillance
It is unreasonable to imagine that such diversity of molecular colorectal carcinogenesis would yield cancers that would be defeated with a single strategy for treatment and posttreatment surveillance.
intervals been followed, no differences in any outcome would be likely. The recent consensus guideline from the American Cancer Society and the U.S. Multi-Society Task Force on Colorectal Cancer recommends a clearing colonoscopy either before surgery or within 3 to 6 months if the CRC prevents a total colon examination. The next examinations should be performed at 1 and 3 years after surgery and then at 5-year intervals for life (perhaps modified if polyps or metachronous cancers are found).5 Wang et al4 found 5 of 13 recurrent cancers at the year-1 examination, an examination recommended by the guideline but not performed in this study (examinations were at 6 months and 30 months). What is evident from multiple studies and articulated clearly in the consensus document is that recurrent disease usually begins outside of the colon, and, when found by a luminal examination, it is often too late. Colonoscopy is useful in most patients, mainly to uncover metachronous neoplasia. Unfortunately, despite controlled trials, a large meta-analysis, and an evidence-based consensus guideline, colonoscopy continues to be overused in many patients.5-7 In thinking about this article, I came to 2 general conclusions. First, as a colonoscopist, I need to remember that ‘‘more’’ is not necessarily ‘‘better.’’ Whether we consider
616 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 3 : Part 2 of 2 : 2009
www.giejournal.org
Allen
Editorial
patients with CRC or patients who have had polypectomy, overuse of colonoscopy is a real problem that diverts scarce resources away from CRC screening and continues despite evidence-based guidelines that recommend less frequent examinations.8-10 Occasionally, unnecessary colonoscopy results in harm to our patients, as demonstrated by 3 major complications in the ICS arm of the study by Wang et al.4 Second, as a gastroenterologist, I need to bring more than colonoscopy to a complex disease like CRC. We are the physicians who best understand the totality of CRC from initial assessment of individual and population risk through all aspects of prevention to management of cancer itself. It is time that we took back the control of CRC as a disease. For us to be credible, however, we need more thought and less scope. Discovery of a new colon cancer often occurs during a typical gastroenterologist’s day of repeated 30-minute episodes composed of introducing oneself to gowned patients as sedation is administrated (3 minutes), colonoscopy (17 minutes), documentation (2 minutes), postprocedure conversations with patient and family (3 minutes), walking (1 minute), and the rest of life (4 minutes). Diagnosing a new cancer brings the day to a jarring halt and marks a watershed event for the patient. At this moment, a routine ‘‘screening’’ becomes a long-term commitment to a person who now needs a complex, multifaceted team to provide the maximal chance of survival. Upon hearing the diagnosis, the first question asked by the sedated patient is ‘‘Will I live?’’ If what the gastroenterologist offers is a recommendation to ‘‘see your primary physician’’ and ‘‘follow up with me for another colonoscopy in a year,’’ then we sell our specialty short and relegate the patient to ‘‘usual’’ (read disjointed) care. We need to bring more to the table. In reality, we can only answer the patient’s question accurately by defining critical predictive measures about a specific cancer that we then subject to multivariant analysis coupled with both objective (we wish) and subjective (we regret) Bayesian probability to classify it into a recognized pattern of clinical and biologic behaviors so we can define an effective treatment strategy, surveillance regimen, and prognosis. Currently, we predict the behavior of CRC by considering 5 criteria: molecular pathogenesis, histology, cancer stage, location, and the presence or absence of certain predictive markers. Failing to consider all characteristics will render conclusions about initial treatment and posttreatment surveillance mere guesswork, often to the detriment of patient care. This is another reason why scoping more does not help. CRC is a heterogeneous disease that does not follow a single pattern of growth. Two major molecular pathways have been defined, each with an increasing number of variants, as reviewed by Jass.11 The most common pathway is the classic loss of heterozygosity (LOH) pathway in which initiation appears to follow a point mutation within the tumor suppressor adenomatous polyposis coli (APC) gene. LOH cancers do not show variations within gene regions termed microsatellites and are thus microsatellite stable. This pathway www.giejournal.org
accounts for the majority of sporadic CRC (especially distal) plus cancers that develop within the familial adenomatous polyposis syndrome. A second pathway is characterized by variations in microsatellite regions (called microsatellite instable [MSI]). MSI cancers arise through 2 major pathways. Lynch syndrome cancers (also known as hereditary nonpolyposis colorectal cancer) are MSI positive, caused by inherited mutations within 1 of 6 recognized mismatch repair (MMR) genes. Lynch syndrome cancers tend to be proximal and develop rapidly through the precancerous polyp stage. A second MSI pathway (12% of all CRC) begins with a Braf mutation, which leads to development of nondysplastic sessile serrated adenomas (SSA) (usually seen as flat or sessile polyps in the proximal colon). Progression from nondysplastic SSA to the more worrisome dysplastic SSA is caused by epigenetic methylation of promoter genes near the hLMH1 MMR gene. SSAs in which the hMLH1 has been silenced by methylation are thought to progress rapidly into a MSI cancer. A final pathway (still not well defined) is the path followed by ‘‘flat adenomas,’’ first described by Muto et al,12 recently revisited by Soetikno et al13 and the subject of a 2008 international consensus conference.14 It is unreasonable to imagine that such diversity of molecular carcinogenesis would yield cancers that would be defeated with a single strategy for treatment and posttreatment surveillance. The basic histology of CRC is a second parameter to consider when designing CRC treatment and postsurgical management. There are known differences in growth rates, the presence of lymph-node involvement and causative molecular alterations based on differentiation of cancer cells, and host immune response as defined by pathologic analysis. Some15 advocate use of advanced techniques, such as MSI testing or immune-histochemical analysis, to look for MMR gene drop-out on tumors that display certain histology patterns or those derived from patients with ‘‘redflag’’ clinical characteristics (age, family history, etc).16 Because 2.2% of all CRC can be traced to Lynch syndrome tumors, even in the absence of obvious family pedigrees, advance analysis (which borders on gene testing) may become more common and will certainly alter treatment and surveillance recommendations.16 Cancer stage and location has long determined both surgical approaches and postsurgical therapy and surveillance. Cancer stage is the primary determinant of whether adjuvant chemotherapy is needed (a topic beyond the scope of most gastroenterologists and this editorial). Wang et al4 appropriately separated colon from rectal cancers. There are marked differences in behavior, metastatic spread, and rates of local recurrence between colon and rectal cancers, and these differences have generated different surveillance strategies within consensus guidelines.5 Even within the category of ‘‘colon’’ cancer, the expected anastomotic recurrence rates differ between right-sided and left-sided CRC. Postsurgical endoscopy is designed to identify recurrence of the primary cancer (rarely) in addition to
Volume 69, No. 3 : Part 2 of 2 : 2009 GASTROINTESTINAL ENDOSCOPY 617
Editorial
metachronous lesions. The former is vanishingly rare for patients who undergo a right hemicolectomy for a cecal cancer, unusual for patients who undergo sigmoid resection for CRC but more common for patients with rectal cancer. Risk stratification of CRC has been advanced by the use of key predictive markers, as reviewed by Mutch.17 The pantheon of such markers includes pathologic staging, immunologic microenvironment surrounding cancer cells, carcinoembryonic antigen, a cancer’s molecular profile (eg, kRas, p53, DCC, APC, and MSI), markers for targeted therapy (eg, VEGE, an angiogenesis marker), epidermal growth factor receptor (EGFR), and thymidylate synthase plus geneexpression profiles. There are hints (but no firm current data) that a combination of predictive markers may determine chemotherapy strategies or recurrence patterns. This is an area where gastroenterologists should stay tuned. It is time to ask the obvious question: Why, in an editorial about postsurgical colonoscopy, is the reader forced to consider molecular biology and EGFR? It is because the article by Wang et al4 is an interesting metaphor for events that are shaping our specialty. CRC is a life-changing disease with a complex cause, heterogeneous growth, variable recurrence pattern, and multiple treatment choices. To this disease, we (gastroenterologists) have brought a single tool: the colonoscope. Bringing a single tool to a multifaceted disease places our specialty at risk for becoming irrelevant, especially, as we have stated above, if less colonoscopy is better for our patients. For gastroenterologists to rely so heavily on colonoscopy to support our professional lives is as logical as relying on a luminal examination to detect an extraluminal cancer recurrence. Our future goal must be 2-fold. First, we should provide high-quality, safe, and appropriately timed colonoscopy. Second, we should establish ourselves as the recognized experts in comprehensive CRC care (both inside and outside of the colonic lumen). From a luminal standpoint, CRC screening and surveillance is still best accomplished by colonoscopy. Within all the noise concerning CTcolography or other substitutes for a direct examination, a key concept remains: colonoscopy prevents CRC deaths. The 20-year results from the National Polyp Study (NPS) were presented in a plenary session at the 2007 Digestive Disease Week (A. Zauber, PhD, personal communication, 2008). In the 48,743 patient-years now analyzed within the NPS, CRC deaths were reduced by 90% among 2602 patients who initially entered the study with at least 1 adenomatous polyp, and only 1 CRC death occurred among 773 patients with nonadenomatous polyps. Most mortality reduction was traced to the initial high-quality examination in which all visible polyps were removed (according to study protocol). If we can get our quality-control measures in order, perform examinations at the appropriate time, and follow the protocol of the NPS (remove all abnormally appearing lesions), then we will again demonstrate that no other single intervention can approach the level of CRC prevention offered by a single high-quality colonoscopy.
Allen
Wang et al4 provides us with an excellent study that reaffirms 10-year-old conclusions. Despite the assertion by the investigators that supports intensive colonoscopic surveillance, at the end of 5 years, the only outcome that matters (patient survival) did not improve with 3 times the number of colonoscopies. This tells me to remember that recurrent CRC usually occurs where the endoscope cannot see. We need to get our heads and minds out of the lumen of the colon and focus on where the dragon truly sleeps. DISCLOSURE The author disclosed no financial relationships relevant to this publication. John I. Allen, MD, MBA, AGAF, FACG Minnesota Gastroenterology Division of Gastroenterology Department of Medicine University of Minnesota School of Medicine Minneapolis, Minnesota, USA Abbreviations: APC, adenomatous polyposis coli; CRC, colon and rectal cancer; EGFR, epidermal growth factor receptor; ICS, intense colonoscopy surveillance; LOH, loss of heterozygosity; MMR, mismatch repair; MSI, microsatellite instable; NPS, National Polyp Study; RCS, routine colonoscopy surveillance; SSA, sessile serrated adenoma.
REFERENCES 1. Institute for Clinical Systems Improvement. Available at: http:// www.icsi.org. Accessed June 23, 2008. 2. Institute for Healthcare Improvement. The triple aim technical brief (6/ 28/07). Available at: http://www.ihi.org. Accessed June 23, 2008. 3. Emanuel EJ, Fuchs VR. The perfect storm of overutilization. JAMA 2008;299:2789-91. 4. Wang T, Cui Y, Huang WS, et al. The role of postoperative colonoscopic surveillance after radical surgery for colorectal cancer: a prospective, randomized clinical study. Gastrointest Endosc 2009;69:609-15. 5. Rex DK, Kahi CJ, Levin B, et al. Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2006;130:1865-71. 6. Shoemaker D, Black R, Giles L, et al. Yearly colonoscopy, liver CT and chest radiography do not influence 5 year survival of colorectal cancer patients. Gastroenterology 1998;114:7-14. 7. Jeffery GM, Hickey BE, Hider P. Follow up strategies for patients treated for nonmetastatic colorectal cancer. Cochrane Database Systematic Review 2002:CD002200. 8. Boolcharnd V, Olds G, Singh J, et al. Colorectal screening after polypectomy: a national survey study of primary physicians. Ann Intern Med 2006;145:654-9. 9. Mysliwiec PA, Brown ML, Klabunde CN, et al. Are physicians doing too much colonoscopy? Surveillance after polypectomy. Ann Intern Med 2004;141:264-71. 10. Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US MultiSociety Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology 2006;130:1872-85. 11. Jass JR. Colorectal cancer: a multipathway disease. Crit Rev Oncog 2006;12:273-87.
618 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 3 : Part 2 of 2 : 2009
www.giejournal.org
Allen
Editorial
12. Muto T, Kamiya J, Sawada T, et al. Small ‘‘flat adenoma’’ of the large bowel with special reference to its clinicopathologic features. Dis Colon Rectum 1985;28:847-51. 13. Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008;299: 1027-35. 14. Kudo S, Lambert R, Allen JI, et al. Nonpolypoid neoplastic lesions of the colorectal mucosa. Gastrointest Endosc 2008;68(Suppl):S3-47.
www.giejournal.org
15. Murphy P, Peterson G, Thibodeau S, et al. Genetic testing for colon cancer: joint statement of the American College of Medical Genetics and the American Socitey of Human Genetics. Genet Med 2000;2: 362-6. 16. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer) N Engl J Med 2005;352:1851-60. 17. Mutch MG. Molecular profiling and risk stratification of adenocarcinoma of the colon. J Surg Oncol 2007;96:693-703.
Volume 69, No. 3 : Part 2 of 2 : 2009 GASTROINTESTINAL ENDOSCOPY 619
Where the dragon truly sleeps The moment a person learns that he or she has cancer, that person’s view about life is altered. At some level, no matter what the histology, stage, or initial treatment success might be, a cancer survivor believes that deep within his or her cellular infrastructure lies a sleeping dragon capable of awakening in the future. That dragon may be unrecognized metachronous neoplasia, a genetic milieu that portends future carcinogenesis, or cancer cells inadvertently left from treatment that ‘‘got it all.’’ For someone diagnosed with colon and rectal cancer (CRC), the dragon awakens with disturbing frequency. One of our most important roles as treating physicians is to couple emotional support to the patient with science that provides the maximal chance for a cancer-free life. Empathy must coexist with a firm understanding of colon cancer genetics, cancer biology, cancer growth patterns, and the efficacy of our treatment. Based on these precepts, we recommend interventions that first try to eliminate existing cancer and then find treatable recurrences without subjecting patients to unnecessary discomfort and society to unnecessary costs. Successful application of these principles should be in concert with current overriding quality goals: ‘‘patient-centered, valuedriven care,’’1 the ‘‘triple aim’’ of the Institute for Healthcare Improvement,2 and the effort to avert an impending ‘‘perfect storm of overutilization.’’3 Patients who undergo ‘‘curative’’ surgery for CRC face a 20% to 30% risk of cancer-related death within 5 years of diagnosis. In trying to prevent death from recurrent cancer, gastroenterologists use the tool they know the best: colonoscopy. Unfortunately, there remains confusion about how often patients with CRC should be examined, and overuse of colonoscopy is common, as pointed out by Wang et al4 in this month’s Gastrointestinal Endoscopy. This article is the result of a study based in China that compared ‘‘intense colonoscopy surveillance’’ (ICS) (10 examinations over 5 years) with ‘‘routine colonoscopy surveillance’’ (RCS) (examinations at 6, 30, and 60 months after surgery) in 319 patients with CRC who had initial curative-intent surgery. Patients in the ICS arm were examined every 3 months for a year, every 6 months for 2 years, then annually to 5 years. The difference in mortality was not significant at 5 years: 77% of the patients in the ICS arm were alive (with 3 serious
Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2008.06.052
complications related to colonoscopy) compared with 73% of patients in the RCS arm (no complications). The only significant difference in outcomes between the 2 study arms was the number of asymptomatic recurrences found and the number of times a second surgery ‘‘for cure’’ was attempted. In both situations the ICS arm appeared to do better (see Table 54). Based on these findings, the investigators state: ‘‘These results clearly indicate that postoperative intensive colonoscopic surveillance plays an important role in the asymptomatic diagnosis and treatment of postoperative colorectal cancer in patients with an improved prognosis for these patients.’’4 I would suggest that differences relate to lead-time bias and had recommended surveillance
It is unreasonable to imagine that such diversity of molecular colorectal carcinogenesis would yield cancers that would be defeated with a single strategy for treatment and posttreatment surveillance.
intervals been followed, no differences in any outcome would be likely. The recent consensus guideline from the American Cancer Society and the U.S. Multi-Society Task Force on Colorectal Cancer recommends a clearing colonoscopy either before surgery or within 3 to 6 months if the CRC prevents a total colon examination. The next examinations should be performed at 1 and 3 years after surgery and then at 5-year intervals for life (perhaps modified if polyps or metachronous cancers are found).5 Wang et al4 found 5 of 13 recurrent cancers at the year-1 examination, an examination recommended by the guideline but not performed in this study (examinations were at 6 months and 30 months). What is evident from multiple studies and articulated clearly in the consensus document is that recurrent disease usually begins outside of the colon, and, when found by a luminal examination, it is often too late. Colonoscopy is useful in most patients, mainly to uncover metachronous neoplasia. Unfortunately, despite controlled trials, a large meta-analysis, and an evidence-based consensus guideline, colonoscopy continues to be overused in many patients.5-7 In thinking about this article, I came to 2 general conclusions. First, as a colonoscopist, I need to remember that ‘‘more’’ is not necessarily ‘‘better.’’ Whether we consider
616 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 3 : Part 2 of 2 : 2009
www.giejournal.org
Allen
Editorial
patients with CRC or patients who have had polypectomy, overuse of colonoscopy is a real problem that diverts scarce resources away from CRC screening and continues despite evidence-based guidelines that recommend less frequent examinations.8-10 Occasionally, unnecessary colonoscopy results in harm to our patients, as demonstrated by 3 major complications in the ICS arm of the study by Wang et al.4 Second, as a gastroenterologist, I need to bring more than colonoscopy to a complex disease like CRC. We are the physicians who best understand the totality of CRC from initial assessment of individual and population risk through all aspects of prevention to management of cancer itself. It is time that we took back the control of CRC as a disease. For us to be credible, however, we need more thought and less scope. Discovery of a new colon cancer often occurs during a typical gastroenterologist’s day of repeated 30-minute episodes composed of introducing oneself to gowned patients as sedation is administrated (3 minutes), colonoscopy (17 minutes), documentation (2 minutes), postprocedure conversations with patient and family (3 minutes), walking (1 minute), and the rest of life (4 minutes). Diagnosing a new cancer brings the day to a jarring halt and marks a watershed event for the patient. At this moment, a routine ‘‘screening’’ becomes a long-term commitment to a person who now needs a complex, multifaceted team to provide the maximal chance of survival. Upon hearing the diagnosis, the first question asked by the sedated patient is ‘‘Will I live?’’ If what the gastroenterologist offers is a recommendation to ‘‘see your primary physician’’ and ‘‘follow up with me for another colonoscopy in a year,’’ then we sell our specialty short and relegate the patient to ‘‘usual’’ (read disjointed) care. We need to bring more to the table. In reality, we can only answer the patient’s question accurately by defining critical predictive measures about a specific cancer that we then subject to multivariant analysis coupled with both objective (we wish) and subjective (we regret) Bayesian probability to classify it into a recognized pattern of clinical and biologic behaviors so we can define an effective treatment strategy, surveillance regimen, and prognosis. Currently, we predict the behavior of CRC by considering 5 criteria: molecular pathogenesis, histology, cancer stage, location, and the presence or absence of certain predictive markers. Failing to consider all characteristics will render conclusions about initial treatment and posttreatment surveillance mere guesswork, often to the detriment of patient care. This is another reason why scoping more does not help. CRC is a heterogeneous disease that does not follow a single pattern of growth. Two major molecular pathways have been defined, each with an increasing number of variants, as reviewed by Jass.11 The most common pathway is the classic loss of heterozygosity (LOH) pathway in which initiation appears to follow a point mutation within the tumor suppressor adenomatous polyposis coli (APC) gene. LOH cancers do not show variations within gene regions termed microsatellites and are thus microsatellite stable. This pathway www.giejournal.org
accounts for the majority of sporadic CRC (especially distal) plus cancers that develop within the familial adenomatous polyposis syndrome. A second pathway is characterized by variations in microsatellite regions (called microsatellite instable [MSI]). MSI cancers arise through 2 major pathways. Lynch syndrome cancers (also known as hereditary nonpolyposis colorectal cancer) are MSI positive, caused by inherited mutations within 1 of 6 recognized mismatch repair (MMR) genes. Lynch syndrome cancers tend to be proximal and develop rapidly through the precancerous polyp stage. A second MSI pathway (12% of all CRC) begins with a Braf mutation, which leads to development of nondysplastic sessile serrated adenomas (SSA) (usually seen as flat or sessile polyps in the proximal colon). Progression from nondysplastic SSA to the more worrisome dysplastic SSA is caused by epigenetic methylation of promoter genes near the hLMH1 MMR gene. SSAs in which the hMLH1 has been silenced by methylation are thought to progress rapidly into a MSI cancer. A final pathway (still not well defined) is the path followed by ‘‘flat adenomas,’’ first described by Muto et al,12 recently revisited by Soetikno et al13 and the subject of a 2008 international consensus conference.14 It is unreasonable to imagine that such diversity of molecular carcinogenesis would yield cancers that would be defeated with a single strategy for treatment and posttreatment surveillance. The basic histology of CRC is a second parameter to consider when designing CRC treatment and postsurgical management. There are known differences in growth rates, the presence of lymph-node involvement and causative molecular alterations based on differentiation of cancer cells, and host immune response as defined by pathologic analysis. Some15 advocate use of advanced techniques, such as MSI testing or immune-histochemical analysis, to look for MMR gene drop-out on tumors that display certain histology patterns or those derived from patients with ‘‘redflag’’ clinical characteristics (age, family history, etc).16 Because 2.2% of all CRC can be traced to Lynch syndrome tumors, even in the absence of obvious family pedigrees, advance analysis (which borders on gene testing) may become more common and will certainly alter treatment and surveillance recommendations.16 Cancer stage and location has long determined both surgical approaches and postsurgical therapy and surveillance. Cancer stage is the primary determinant of whether adjuvant chemotherapy is needed (a topic beyond the scope of most gastroenterologists and this editorial). Wang et al4 appropriately separated colon from rectal cancers. There are marked differences in behavior, metastatic spread, and rates of local recurrence between colon and rectal cancers, and these differences have generated different surveillance strategies within consensus guidelines.5 Even within the category of ‘‘colon’’ cancer, the expected anastomotic recurrence rates differ between right-sided and left-sided CRC. Postsurgical endoscopy is designed to identify recurrence of the primary cancer (rarely) in addition to
Volume 69, No. 3 : Part 2 of 2 : 2009 GASTROINTESTINAL ENDOSCOPY 617
Editorial
metachronous lesions. The former is vanishingly rare for patients who undergo a right hemicolectomy for a cecal cancer, unusual for patients who undergo sigmoid resection for CRC but more common for patients with rectal cancer. Risk stratification of CRC has been advanced by the use of key predictive markers, as reviewed by Mutch.17 The pantheon of such markers includes pathologic staging, immunologic microenvironment surrounding cancer cells, carcinoembryonic antigen, a cancer’s molecular profile (eg, kRas, p53, DCC, APC, and MSI), markers for targeted therapy (eg, VEGE, an angiogenesis marker), epidermal growth factor receptor (EGFR), and thymidylate synthase plus geneexpression profiles. There are hints (but no firm current data) that a combination of predictive markers may determine chemotherapy strategies or recurrence patterns. This is an area where gastroenterologists should stay tuned. It is time to ask the obvious question: Why, in an editorial about postsurgical colonoscopy, is the reader forced to consider molecular biology and EGFR? It is because the article by Wang et al4 is an interesting metaphor for events that are shaping our specialty. CRC is a life-changing disease with a complex cause, heterogeneous growth, variable recurrence pattern, and multiple treatment choices. To this disease, we (gastroenterologists) have brought a single tool: the colonoscope. Bringing a single tool to a multifaceted disease places our specialty at risk for becoming irrelevant, especially, as we have stated above, if less colonoscopy is better for our patients. For gastroenterologists to rely so heavily on colonoscopy to support our professional lives is as logical as relying on a luminal examination to detect an extraluminal cancer recurrence. Our future goal must be 2-fold. First, we should provide high-quality, safe, and appropriately timed colonoscopy. Second, we should establish ourselves as the recognized experts in comprehensive CRC care (both inside and outside of the colonic lumen). From a luminal standpoint, CRC screening and surveillance is still best accomplished by colonoscopy. Within all the noise concerning CTcolography or other substitutes for a direct examination, a key concept remains: colonoscopy prevents CRC deaths. The 20-year results from the National Polyp Study (NPS) were presented in a plenary session at the 2007 Digestive Disease Week (A. Zauber, PhD, personal communication, 2008). In the 48,743 patient-years now analyzed within the NPS, CRC deaths were reduced by 90% among 2602 patients who initially entered the study with at least 1 adenomatous polyp, and only 1 CRC death occurred among 773 patients with nonadenomatous polyps. Most mortality reduction was traced to the initial high-quality examination in which all visible polyps were removed (according to study protocol). If we can get our quality-control measures in order, perform examinations at the appropriate time, and follow the protocol of the NPS (remove all abnormally appearing lesions), then we will again demonstrate that no other single intervention can approach the level of CRC prevention offered by a single high-quality colonoscopy.
Allen
Wang et al4 provides us with an excellent study that reaffirms 10-year-old conclusions. Despite the assertion by the investigators that supports intensive colonoscopic surveillance, at the end of 5 years, the only outcome that matters (patient survival) did not improve with 3 times the number of colonoscopies. This tells me to remember that recurrent CRC usually occurs where the endoscope cannot see. We need to get our heads and minds out of the lumen of the colon and focus on where the dragon truly sleeps. DISCLOSURE The author disclosed no financial relationships relevant to this publication. John I. Allen, MD, MBA, AGAF, FACG Minnesota Gastroenterology Division of Gastroenterology Department of Medicine University of Minnesota School of Medicine Minneapolis, Minnesota, USA Abbreviations: APC, adenomatous polyposis coli; CRC, colon and rectal cancer; EGFR, epidermal growth factor receptor; ICS, intense colonoscopy surveillance; LOH, loss of heterozygosity; MMR, mismatch repair; MSI, microsatellite instable; NPS, National Polyp Study; RCS, routine colonoscopy surveillance; SSA, sessile serrated adenoma.
REFERENCES 1. Institute for Clinical Systems Improvement. Available at: http:// www.icsi.org. Accessed June 23, 2008. 2. Institute for Healthcare Improvement. The triple aim technical brief (6/ 28/07). Available at: http://www.ihi.org. Accessed June 23, 2008. 3. Emanuel EJ, Fuchs VR. The perfect storm of overutilization. JAMA 2008;299:2789-91. 4. Wang T, Cui Y, Huang WS, et al. The role of postoperative colonoscopic surveillance after radical surgery for colorectal cancer: a prospective, randomized clinical study. Gastrointest Endosc 2009;69:609-15. 5. Rex DK, Kahi CJ, Levin B, et al. Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2006;130:1865-71. 6. Shoemaker D, Black R, Giles L, et al. Yearly colonoscopy, liver CT and chest radiography do not influence 5 year survival of colorectal cancer patients. Gastroenterology 1998;114:7-14. 7. Jeffery GM, Hickey BE, Hider P. Follow up strategies for patients treated for nonmetastatic colorectal cancer. Cochrane Database Systematic Review 2002:CD002200. 8. Boolcharnd V, Olds G, Singh J, et al. Colorectal screening after polypectomy: a national survey study of primary physicians. Ann Intern Med 2006;145:654-9. 9. Mysliwiec PA, Brown ML, Klabunde CN, et al. Are physicians doing too much colonoscopy? Surveillance after polypectomy. Ann Intern Med 2004;141:264-71. 10. Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US MultiSociety Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology 2006;130:1872-85. 11. Jass JR. Colorectal cancer: a multipathway disease. Crit Rev Oncog 2006;12:273-87.
618 GASTROINTESTINAL ENDOSCOPY Volume 69, No. 3 : Part 2 of 2 : 2009
www.giejournal.org
Allen
Editorial
12. Muto T, Kamiya J, Sawada T, et al. Small ‘‘flat adenoma’’ of the large bowel with special reference to its clinicopathologic features. Dis Colon Rectum 1985;28:847-51. 13. Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA 2008;299: 1027-35. 14. Kudo S, Lambert R, Allen JI, et al. Nonpolypoid neoplastic lesions of the colorectal mucosa. Gastrointest Endosc 2008;68(Suppl):S3-47.
www.giejournal.org
15. Murphy P, Peterson G, Thibodeau S, et al. Genetic testing for colon cancer: joint statement of the American College of Medical Genetics and the American Socitey of Human Genetics. Genet Med 2000;2: 362-6. 16. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer) N Engl J Med 2005;352:1851-60. 17. Mutch MG. Molecular profiling and risk stratification of adenocarcinoma of the colon. J Surg Oncol 2007;96:693-703.
Volume 69, No. 3 : Part 2 of 2 : 2009 GASTROINTESTINAL ENDOSCOPY 619