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1. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 1 15 ADENOCARCINOMA OF THE COLON AND RECTUM Bruce M. Brenner, M.D., F.A.C.S., and David M. Ota, M.D., F.A.C.S. Colorectal cancer (CRC) remains a major public health problem in this pathway as well, including mutations in DCC, SMAD2, and throughout the world. In the United States, CRC is the third most SMAD4 on chromosome 18q and p53 on chromosome 17p; these frequently diagnosed cancer in both men and women and the sec- events are thought to occur at a later stage of tumor progression. ond most common fatal cancer (behind lung cancer).1 During Mutations in the K-ras oncogene occur at an intermediate stage. 2004, there were an estimated 106,000 cases of colon cancer and The accumulation of additional mutations (as yet poorly deﬁned) 41,000 cases of rectal cancer in the United States, resulting in allows metastases to develop. 57,000 total deaths.1 The cost of treating colorectal cancer in the Microsatellite instability (MSI) is an alternative pathway to United States is believed to be between 5.5 and 6.5 billion dollars genomic instability and subsequent colorectal carcinogenesis.This a year.2 Worldwide, the risk of death from CRC is highest in phenomenon arises from defects in mismatch repair genes, which developed countries and especially low in Asia and Africa.3 cause signiﬁcantly increased mutation rates in comparison with Data from the Surveillance, Epidemiology, and End Results those in normal cells. MSI in hereditary nonpolyposis colorectal (SEER) program indicate that the overall incidence of and mor- cancer (HNPCC) [see Risk Factors, below] is most commonly tality from CRC have been decreasing in the United States among attributable to germline mutations in the hMLH1 and hMSH2 both men and women,4 though they remain generally higher genes.10 MSI in sporadic CRC is most frequently associated with among men than among women. Overall, the incidence of and hypermethylation of the promoter region of the hMLH1 gene,11 mortality from CRC are highest among African Americans, some- which leads to inactivation of the gene and loss of expression of the what lower among European Americans, and lowest among hMLH1 protein. Native, Asian, and Hispanic Americans [see Table 1].5 Most CRCs still occur in the distal colon (beyond the splenic ﬂexure), but the incidence of proximal adenocarcinomas relative to that of distal Risk Factors adenocarcinomas has been increasing over the past 25 years [see A number of risk factors for CRC have been described, includ- Figure 1].6 The cause of this shift is not known. ing a family history of cancer or adenomatous polyps, familial CRC syndromes, inﬂammatory bowel disease (both ulcerative colitis and Crohn disease), and dietary and lifestyle factors.12,13 Genetics The vast majority of CRCs worldwide are sporadic—that is, they The development of CRC involves a progression from normal are not associated with known genetic syndromes. In the United mucosa through adenoma to carcinoma.7 A genetic model of colo- States, no more than 5% of CRCs are associated with known rectal carcinogenesis has been proposed that describes a sequence genetic syndromes. of key mutations driving the process of colorectal carcinogenesis In a meta-analysis of studies addressing CRC risk and family [see Figure 2].8 This process may involve the accumulation of history, the relative risk of CRC in those with an affected ﬁrst- mutations in both tumor suppressor genes and proto-oncogenes, degree relative was 2.25; this ﬁgure rose to 4.25 if more than one as well as epigenetic phenomena such as DNA hypermethylation relative was involved and to 3.87 if CRC was diagnosed before the or hypomethylation.9 The onset of genomic instability increases age of 45.14 The National Polyp Study found that the relative risk the mutation rate and accelerates this progression. Inactivation of of CRC was 1.78 in ﬁrst-degree relatives of patients with adeno- the adenomatous polyposis coli (APC) gene on chromosome 5q is matous polyps.15 In another study, the relative risk of CRC was thought to be one of the earliest mutations in sporadic cancers and 1.74 in ﬁrst-degree relatives of patients with adenomatous polyps is seen as a germline mutation in patients with familial polyposis and was especially high (4.36) in those diagnosed with polyps at [see 5:14 Hereditary Colorectal Cancer and Polyposis Syndromes]. or before the age of 50.16 Mutations in other tumor suppressor genes play an important role The most common of the genetic syndromes known to be asso- Table 1 Incidence and Mortality of CRC by Race and Sex5 Incidence (No./100,000) Mortality (No./100,000) Race Male Female Male Female White 64.1 46.2 25.3 17.5 African American 72.4 56.2 34.6 24.6 Asian/Pacific Islander 57.2 38.8 15.8 11.0 Native American 37.5 32.6 18.5 12.1 Hispanic 49.8 32.9 18.4 11.4
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 2 5.4% for patients with pancolitis and rises further with greater duration of disease.18 Despite the common misconception, Crohn disease may be associated with a similarly increased risk of CRC.19 Numerous lifestyle and dietary factors have been put forward as potential causes of increased CRC risk. Lower levels of physi- cal activity and increased body mass are associated with an increased risk of CRC in both men and women.20 The Western- Transverse Colon style diet, which is high in calories and fat and low in ﬁber, is asso- 13% (13%) ciated with high rates of CRC. There is evidence that increased dietary intake of calcium may confer some protection against the Ascending Descending development of CRC and adenomatous polyps. The Calcium Colon Colon Polyp Prevention Study, a large randomized trial done in the 12% (8%) 4% (6%) United States, reported a small but statistically signiﬁcant reduc- tion in the incidence of recurrent colorectal adenomas with dietary calcium supplementation.21 To date, the evidence from randomized trials has not shown dietary ﬁber supplementation to Sigmoid Colon have a similar effect. In Japan, where the incidence of CRC has 23% (25%) traditionally been low, CRC has become considerably more com- mon in the past few decades.22 This increased incidence is believed to be the result of post–World War II lifestyle changes Cecum (e.g., increased consumption of animal fat and decreased expen- 17% (15%) diture of energy) that mirror Western habits. Rectum 18% (21%) Screening Rectosigmoid Junction Early diagnosis of colorectal neoplasms at a presymptomatic 10% (10%) stage is important for improving survival. Polypectomy has con- sistently been shown to decrease the subsequent development of CRC: the National Polyp Study found that the incidence of CRC in patients who underwent colonoscopic polypectomy was as Figure 1 Shown are the relative frequencies of CRC for various much as 90% less than would otherwise have been expected.23 anatomic subsites of the colon in 1996. For comparative purposes, Identifying patients with early-stage disease that has not yet ﬁgures for 1976 are provided in parentheses. metastasized can prevent many CRC-related deaths. Early detec- tion of and screening for CRC have become important compo- nents of routine care and public health programs both in the ciated with CRC is HNPCC, which accounts for the majority of United States and abroad.The beneﬁts of screening for CRC are patients with familial CRC. MSI is the characteristic ﬁnding of especially substantial in patients who are at high risk for CRC HNPCC, though it is also present in approximately 15% of all (e.g., those with affected ﬁrst-degree relatives), but even average- sporadic CRCs. HNPCC can be diagnosed clinically on the basis risk patients derive some beneﬁt. of what are known as the Amsterdam Criteria.17 Polyposis syn- There is no ideal method of screening for CRC that is applica- dromes (e.g., familial polyposis and juvenile polyposis) account for ble to all patients. Physical examination is generally not helpful in the remainder of patients with familial CRC syndromes. HNPCC making the diagnosis; various investigative tests are used instead. and polyposis syndromes are discussed further elsewhere [see 5:14 Modalities commonly employed for CRC screening and early Hereditary Colorectal Cancer and Polyposis Syndromes]. detection include fecal occult blood testing (FOBT), double-con- As determined by a 2001 meta-analysis, the lifetime risk of trast barium enema (DCBE), ﬂexible sigmoidoscopy, and CRC for patients with ulcerative colitis is 3.7%, which increases to colonoscopy. Of these, only FOBT and sigmoidoscopy have been APC β-catenin K-ras DCC/SMAD4/SMAD2 p53 Other Changes? Normal Dysplastic Early Intermediate Late Carcinoma Metastasis Epithelium ACF Adenoma Adenoma Adenoma Genetic Instability Figure 2 Diagram illustrates genetic model of colorectal tumorigenesis.8
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 3 Clinical Evaluation Table 2 American Joint Committee on Cancer TNM Clinical Classification of Colorectal Cancer As a consequence of the use of screening modalities, patients with CRC are often asymptomatic at diagnosis. Some CRC patients present with occult GI bleeding and anemia. Many T0 No evidence of primary tumor patients do not exhibit symptoms until relatively late in the course Tis Carcinoma-in-situ, intraepithelial or invasion of lamina propria of the disease. The duration of symptoms, however, is not neces- T1 Tumor invades submucosa sarily associated with the stage of the tumor.35 Primary tumor (T) T2 Tumor invades muscularis propria The most common symptoms of CRC are bleeding per rectum, T3 Tumor invades through muscularis propria abdominal or back pain, and changes in bowel habits or stool cal- T4 Tumor invades other organs or perforates visceral iber. Other symptoms are fatigue, anorexia, weight loss, nausea, peritoneum and vomiting. Some patients present with acute bowel obstruction N0 No regional lymph node metastases or perforation. Regional N1 Metastases in 1 to 3 regional lymph nodes lymph nodes (N) N2 Metastases in 4 or more regional lymph nodes Staging and Prognosis Distant M0 No distant metastasis metastasis (M) Accurate staging of CRC is extremely important for determin- M1 Distant metastasis ing patient prognosis and assessing the need for adjuvant therapy. Traditionally, staging of CRC has been based on modiﬁcations of tested in randomized trials.24 It is clear, however, that these tests the Dukes classiﬁcation, which was initially developed as a prog- are less sensitive and speciﬁc than colonoscopy. There is evidence nostic tool for rectal cancer in the 1930s.36 Since this classiﬁcation that colonoscopy detects many CRCs in asymptomatic patients was ﬁrst implemented, it has undergone multiple modiﬁcations, of that would not be detected by sigmoidoscopy.25,26 Colonoscopy which the most widely used is the modiﬁed Astler-Coller system, has been shown to be a safe and effective method of CRC screen- initially introduced in the 1950s.37 Currently, the TNM classiﬁca- ing in asymptomatic, average-risk patients.27 tion, developed by the American Joint Committee on Cancer Newer screening modalities, such as virtual colonoscopy and (AJCC) and the International Union against Cancer (UICC), is stool DNA assays, are currently being developed and tested. the preferred staging system [see Tables 2 and 3].38 This system Virtual colonoscopy, which uses high-resolution computed tomo- takes into account the depth of penetration into the bowel wall (T) graphic scanning to image the colon, has been evaluated in at least [see Figure 3], the presence and number of involved mesenteric two multicenter trials in the United States, with varying nodes (N), and the presence of distant metastases (M). results.28,29 One of the studies reported a sensitivity and a speci- CLINICAL STAGING ﬁcity of 89% and 80%, respectively, for polyps larger than 6 mm and up to 94% and 96%, respectively, for polyps larger than 10 Clinical staging is based on the history and the physical exami- mm.28 The sensitivities were equivalent to those of optical nation, endoscopic ﬁndings, and biopsy results. If colonoscopy colonoscopy in this group of asymptomatic average-risk patients. cannot be completed, an air-contrast barium enema study should The second study, however, found that virtual colonoscopy had a be performed to evaluate the remainder of the colon. Additional sensitivity of only 39% for lesions larger than 6 mm and 55% for staging information may be obtained by means of imaging studies lesions larger than 10 mm.29 Given these divergent ﬁndings, it (e.g., roentgenography, CT, magnetic resonance imaging, and appears that there are issues related to equipment, software, and positron emission tomography [PET]). A chest x-ray is routinely training that remain to be addressed before virtual colonoscopy obtained to rule out metastases and prepare for operation. can be recommended as a routine screening modality. Another There is some debate regarding the utility of preoperative CT consideration is that patients with lesions detected by means of vir- scans in the management of primary colon cancer. The rationale tual colonoscopy must still undergo optical colonoscopy for treat- for obtaining these scans includes evaluation of potential metasta- ment or tissue diagnosis. Fecal DNA assays have been developed tic disease and assessment of the local extent of disease. In a 2002 to test for mutations in multiple genes known to be involved in study of preoperative CT in patients with intraperitoneal colon colorectal neoplasia and are currently being evaluated in clinical trials.30 These assays are not as sensitive as colonoscopy but may be useful in patients who are unable or unwilling to comply with Table 3 American Joint Committee on Cancer endoscopic screening.31 Staging of Colorectal Cancer Many groups have advocated CRC screening, and published guidelines are available from several organizations, including the Stage T N M American Cancer Society,32 the American Gastroenterologic Association,33 and the U.S. Preventive Services Task Force.34 All of Stage 0 Tis N0 M0 these guidelines recommend that screening begin at age 50 for Stage I T1, T2 N0 M0 average-risk patients. The recommended screening options are consistent among the various organizations and include (1) FOBT Stage IIA T3 N0 M0 yearly, (2) ﬂexible sigmoidoscopy every 5 years, (3) yearly FOBT Stage IIB T4 N0 M0 and ﬂexible sigmoidoscopy every 5 years, (4) DCBE every 5 years, and (5) colonoscopy every 10 years. In high-risk patients (e.g., Stage IIIA T1, T2 N1 M0 those with a family history of CRC), screening may begin at an Stage IIIB T3, T4 N1 M0 earlier age—generally, 10 years younger than the age of the affect- ed ﬁrst-degree relative. There are also speciﬁc intensive screening Stage IIIC Any T N2 M0 and follow-up regimens for patients with known or suspected Stage IV Any T Any N M1 familial cancer syndromes.
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 4 Astler-Coller Stage A B1 B2 C1 C2 D Mucosa (T1N0M0) (T2N0M0) (T3-4N0M0) (T2N1M0) (T3-4N1M0) (TXNXM1) Submucosa Muscularis Serosa Lymph Nodes Liver Lungs Distant Metastases Figure 3 Classiﬁcation of CRC takes into account depth of tumor penetration and involvement of lymph nodes. cancer, however, the results of the imaging changed management ical utility of most of these markers. As noted [see Risk Factors, in only 19% of patients, and CT had a sensitivity of only 78% for above], MSI is seen in as many as 15% of patients with sporadic all metastatic disease.39 Nonetheless, many surgeons routinely per- CRC. Patients with MSI typically have proximal, poorly differen- form staging CT in patients with primary colon cancer. PET is a tiated tumors with mucinous or signet-ring components, but they sensitive study, but its routine use for staging primary CRC is not usually exhibit improved overall survival.44 These patients may be generally recommended. PET may be considered for high-risk less sensitive to 5-ﬂuorouracil (5-FU)–based chemotherapy.45 patients in whom the detection of metastases would change initial The long arm of chromosome 18 (18q) harbors at least three management.40 candidate tumor suppressor genes, including DCC, SMAD2, and In cases of rectal cancer, locoregional staging may signiﬁcantly SMAD4. Deletions of chromosome 18q in CRC patients are asso- affect therapeutic decision making. Such staging includes deter- ciated with decreased survival. One study found that patients with mination of the depth of invasion of the rectal wall and the degree stage II cancers and 18q allelic loss had a prognosis similar to that of regional node involvement. Modalities commonly used include of patients with stage III disease.46 In addition, p53 mutations and CT, MRI, and endoscopic ultrasonography (EUS). In a 2004 overexpression are associated with poor outcomes in CRC.47 meta-analysis that examined the relative utility of each of these Thymidylate synthase is an enzyme active in DNA synthesis that studies in rectal cancer staging,41 EUS proved to be the most accu- is targeted by 5-FU and similar chemotherapeutic agents. Over- rate technique for evaluating muscularis propria involvement and expression of this enzyme is associated with a poor prognosis but perirectal tissue invasion. The various techniques were equally also with improved sensitivity to 5-FU–based chemotherapy.48 accurate in assessing lymph node involvement, with none of them All of these molecular alterations, as well as others (e.g., K-ras being highly sensitive. mutations and 5q deletions), are commonly observed in CRC patients, but further study is required to establish their real prog- PATHOLOGIC STAGING nostic signiﬁcance. Deﬁnitive pathologic staging is carried out after surgical explo- ration and examination of the resected specimen. The ﬁnal stage of the cancer is then determined on the basis of the TNM system [see Tables 2 and 3]. Survival is correlated with the stage of the 100 Survival Rate for Colon Cancer Cases (%) tumor [see Figures 4 and 5]. In the current (sixth) edition of the AJCC staging system,38 stage II is subdivided into stages IIA and 80 IIB, and stage III is subdivided into stages IIIA, IIIB, and IIIC on the basis of both the extent of wall penetration and the number of nodes involved. These changes were implemented as a result of 60 studies demonstrating differences in survival among these sub- groups [see Figure 6].42 40 Numerous other criteria have been evaluated as additional prognostic factors in CRC. The degree of lymphatic invasion and the extent of vascular invasion are important adjuncts to the TNM 20 staging system and are incorporated in the current schema.38 Certain histologic types, including signet-ring and mucinous car- cinomas, are associated with poor outcomes. The preoperative 0 serum carcinoembryonic antigen (CEA) level may be an indepen- Dx 1 2 3 4 5 dent prognostic factor that is predictive of resectability and the Time after Diagnosis (years) presence of distant metastases.43 Stage 0 Stage I Stage II MOLECULAR MARKERS Stage III Stage IV Overall Various molecular markers have been investigated with respect to prognosis and response to therapy in CRC patients. Unfortun- Figure 4 Shown are 5-year survival rates for cases of colon can- ately, there are conﬂicting data on the prognostic impact and clin- cer diagnosed in 1,735 U.S. hospitals in 1995 and 1996.
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 5 100 Surgical Staging Survival Rate for Rectal Cancer Cases (%) The selection of patients for adjuvant therapy relies heavily on 80 accurate staging. A signiﬁcant percentage of patients with early- stage node-negative disease present with recurrences or metas- tases; such a presentation implies that the patients had occult 60 metastatic disease at the time of operation. Surgical resection of CRC should include division of the appropriate mesenteric vessels 40 at their origins, along with resection of the regional nodes. Optimal staging of CRC patients, especially with regard to nodal status, remains controversial. One area of debate is the number of nodes 20 that must be examined to conﬁrm node-negativity. This number depends both on the surgeon’s technique (i.e., how many nodes were resected) and on the pathologist’s efforts to harvest nodes 0 from the specimen. Most groups recommend analysis of at least Dx 1 2 3 4 5 12 nodes to conﬁrm node-negativity.51 Time after Diagnosis (years) Because of the importance of nodal status, ultrastaging of har- vested nodes with techniques such as serial sectioning, immuno- Stage 0 Stage I Stage II histochemistry (IHC), and reverse transcriptase polymerase chain Stage III Stage IV Overall reaction (RT-PCR) has been proposed as a means of detecting micrometastases. All of these techniques may result in upstaging Figure 5 Shown are 5-year survival rates for cases of rectal can- of patients who are node negative on standard pathologic analysis, cer diagnosed in 1,683 U.S. hospitals in 1995 and 1996. which involves only bivalving the nodes and examining a limited number of sections. The prognostic impact of micrometastases Management of Colon Cancer that are detected only by IHC or RT-PCR and are not veriﬁed by hematoxylin-eosin staining remains unclear. It is impractical to SURGICAL THERAPY perform these assays on all nodes harvested; accordingly, the use Surgery with curative intent remains the mainstay of therapy for of lymphatic mapping to identify sentinel lymph nodes (SLNs) colon cancer [see Figure 7]. Complete R0 resection (leaving no has been proposed as a means of selecting a small number of gross or microscopic disease) with wide margins along the bowel nodes for further analysis. wall, coupled with regional lymphadenectomy, is the standard of SLN biopsy in the setting of CRC remains investigational. care.The major arterial vessels supplying the segment of the colon Lymphatic mapping may be done with either in vivo or ex vivo containing the tumor should be excised at their origins. A mini- injection of tracer dye. The dye rapidly diffuses through the lym- mum margin of 5 cm of normal bowel on each side of the tumor phatic vessels, and SLNs can be identiﬁed and marked in the is considered adequate. mesocolon within minutes. This procedure has been shown to be Extent of Resection feasible in a number of studies52; however, its sensitivity and false negative rates have been variable. In a 2004 multicenter trial, SLN The standard extent of resection for various colon cancers has biopsy with serial sectioning had a false negative rate of 54% in been deﬁned. For tumors of the cecum and the ascending colon, patients with node-positive colon cancer.53 In a large single-insti- a right hemicolectomy that includes the right branch of the mid- dle colic artery at its origin should be performed. For tumors of the hepatic ﬂexure, an extended right colectomy that includes the 100 entire middle colic artery is indicated. For tumors of the transverse Cumulative Survival Rate for Stage III colon, an extended right or left colectomy or a transverse colecto- my may be performed. For tumors of the splenic ﬂexure region, a 80 Colon Cancer Cases (%) left hemicolectomy is performed, and for sigmoid tumors, a sig- moid colectomy is performed. 60 In patients who have small or ﬂat tumors or who are undergo- ing resection after a polypectomy, intraoperative identiﬁcation of the tumor may be difﬁcult.This is especially true with laparoscop- 40 ic procedures, in which the bowel often cannot be palpated. If the lesion is in the cecum, the ileocecal valve and the appendiceal ori- ﬁce are visualized endoscopically, and localization of the tumor is 20 simple. If the lesion is at another location, endoscopic measure- ments of the distance from the anus or estimates of the location of 0 the tumor may be inaccurate. Endoscopic tattooing, a process in Dx 1 2 3 4 5 which an agent is injected into the bowel wall submucosally at or near the site of the lesion, has been employed to facilitate intraop- Time after Diagnosis (years) erative identiﬁcation of the tumor site. India ink is the agent most Stage IIIA Stage IIIB Stage IIIC commonly used for this purpose and generally yields excellent results.49 As an alternative, many institutions use a commercially Figure 6 Shown are 5-year survival rates for cases of stage III available sterile suspension of carbon particles, which is also very colon cancer diagnosed between 1987 and 1993, stratiﬁed accord- safe and effective.50 Intraoperative endoscopy is another option for ing to stage III subgroups established by 6th edition of AJCC locating these lesions. Staging Manual.38
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 6 Patient has invasive colon cancer Order investigative studies to stage and assess resectability of tumor: • Complete colonoscopy • CT of abdomen and pelvis • Chest x-ray or chest CT • CEA level Tumor is resectable Tumor is unresectable No metastases are present Metastases are present Patient is asymptomatic Patient is symptomatic Perform segmental colectomy Perform staged or concurrent Administer systemic chemotherapy Perform palliative resection, with regional lymphadenectomy. resection. or supportive care. stenting, or diversion. Administer systemic chemotherapy. Administer systemic chemotherapy. Tumor is stage III or Tumor is stage I or high-risk stage II low-risk stage II Tumor becomes Tumor remains Administer adjuvant unresectable resectable chemotherapy. Perform staged or Administer systemic concurrent resection of chemotherapy or primary tumor and supportive care. metastases. Follow up according to protocol. Figure 7 Algorithm outlines treatment of colon cancer. tution trial, both SLNs and non-SLNs were studied with serial been developed and are being tested in prospective, randomized sectioning and IHC in patients who were node negative on routine multicenter trials [see 5:34 Segmental Colon Resection]. Initially, there pathologic analysis54; 19.5% of patients were upstaged by the were concerns about port-site recurrences,57 but current data sug- combination of serial sectioning and IHC of SLNs. These results gest that these concerns are unfounded.58 With respect to com- imply that the main role of this technique may be in upstaging parative cost, data from a subset of patients in the European patients who are node negative on routine pathologic analysis. COlon cancer Laparoscopic or Open Resection (COLOR) trial Further study is required before the use of SLN techniques in the demonstrated that although the total cost to society from laparo- context of CRC becomes standard clinical practice. scopic colectomy is similar to that from open colectomy, the costs Occult metastatic disease may also be present in the peritoneal to the health care system are signiﬁcantly higher with the former.59 cavity or systemically in the blood or bone marrow at the time of The Clinical Outcomes of Surgical Therapy (COST) study group, operation. The presence of tumor cells in the peritoneum may be a large, randomized, multicenter trial conducted in the United detected by performing cytologic analysis of washings done at the States, found that laparoscopic-assisted colectomy conferred only time of operation. In one study, disseminated tumor cells were minimal (though statistically signiﬁcant) short-term quality-of-life identiﬁed in peritoneal washings or blood in 25% of patients, and beneﬁts when compared with open colectomy.60,61 Cancer-specif- their presence was found to be an independent prognostic factor ic outcomes (e.g., recurrence rates, wound recurrences, and over- for survival.55 In another study, patients with positive peritoneal all survival rates) were similar with the two approaches.61 The washings had signiﬁcantly higher rates of local recurrence and COST investigators concluded that laparoscopic colectomy is an peritoneal carcinomatosis but manifested no differences in sur- acceptable alternative to open colectomy. Recurrence and survival vival.56 Again, further study is required before these assays can be data from other large multicenter trials (e.g., the COLOR trial62) routinely used for staging CRC. are not yet available. Laparoscopic versus Open Colectomy Special Situations At present, open colectomy is the most widely accepted treat- Obstructing and perforated cancers Obstructing and per- ment of resectable colon cancer. Laparoscopic techniques have forated colon cancers are associated with a poor prognosis and
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 7 with increased surgical morbidity (as a consequence of the need for the basis of several phase III randomized trials designed to test the emergency surgery). Perforation can occur either via direct erosion hypothesis that postoperative systemic adjuvant chemotherapy of the tumor through the wall of the colon or secondary to obstruc- would signiﬁcantly improve survival in patients with resected but tion with resultant bowel distention proximal to the tumor. high-risk cancers. Multi-institutional, cooperative cancer group tri- Patients with perforated colon cancer are managed with emer- als were necessary to obtain populations large enough to test this gency laparotomy, washout, and resection of the primary lesion to hypothesis. The North Central Cancer Treatment Group prevent further soilage. A diverting stoma is usually indicated, with (NCCTG) initiated a randomized trial of postoperative systemic either a Hartmann pouch or a mucous ﬁstula constructed distally. adjuvant 5-FU plus levamisole for Dukes stage B and C (AJCC Select patients may be managed by means of primary anastomo- stage II and III) colon carcinomas.69 Patients were randomly sis, with or without a proximal diverting colostomy or ileostomy. assigned to receive either levamisole alone or 5-FU plus levamisole. Obstructing right-side cancers (up to the splenic ﬂexure) can Overall survival was signiﬁcantly improved in stage C patients usually be treated with resection and primary anastomosis. The treated with 5-FU plus levamisole. This was the ﬁrst randomized traditional emergency treatment of obstructing left-side colon can- trial to demonstrate the efﬁcacy of systemic adjuvant therapy. cers is a diverting colostomy, with or without resection of the The NCCTG trial led to second-generation trials of adjuvant lesion. In many such cases, the stoma is never taken down. Some therapy for patients with resected colon cancers. In one such surgeons advocate emergency treatment of these lesions with total study, patients with high-risk stage II or stage III colon cancer were abdominal colectomy and ileorectal anastomosis as a means of randomly assigned to receive either 5-FU plus leucovorin and lev- improving outcomes.63 Another treatment option is primary resec- amisole or 5-FU plus levamisole.70 Survival rates after 12 months tion and anastomosis, with or without on-table intestinal lavage. of adjuvant chemotherapy were no better than those after 6 Yet another option for managing obstructing left-side colon and months of chemotherapy; however, 5-FU plus levamisole proved rectal cancers is the use of colorectal stents with the aim of avoid- to be inferior to 5-FU plus leucovorin and levamisole with respect ing emergency surgery. Stents can serve as a bridge to deﬁnitive to survival. resection by decompressing the colon and thereby allowing subse- National Surgical Adjuvant Breast and Bowel Project (NSABP) quent bowel preparation. In patients with advanced disease, stents protocol C-04 randomly assigned Dukes stage B and C colon can- may also be employed for palliation as an alternative to surgical cer patients to receive (1) postoperative 5-FU plus leucovorin, (2) resection or a diverting stoma. 5-FU plus levamisole, or (3) 5-FU plus leucovorin and levami- sole.71 A slight improvement in 5-year disease-free survival was Synchronous primary colorectal cancers The incidence noted with 5-FU plus leucovorin, but overall 5-year survival did not of synchronous CRCs is reported to range from 3% to 5%64,65 but differ signiﬁcantly among the three treatment arms. Accordingly, may be as high as 11%.66 Stage for stage, there appear to be no dif- 5-FU plus leucovorin became the standard adjuvant regimen. ferences in survival between synchronous cancers and single pri- Intergroup Trial 0089 randomly assigned patients with high- mary cancers.67,68 Synchronous adenomatous polyps are present risk stage II and III disease to receive either 5-FU plus high-dose in as many as 35% of patients undergoing surgical treatment of leucovorin or 5-FU plus low-dose leucovorin. The investigators CRC.65,68 In one study, the presence of synchronous lesions made concluded that (1) the high-dose and low-dose regimens were the surgical procedure more extensive than was initially planned equivalent, (2) a regimen consisting of four cycles of 5-FU with for resection of the primary tumor in 11% of patients.65 high-dose weekly leucovorin was equivalent to the low-dose leu- Most synchronous polyps are identiﬁed on preoperative colo- covorin Mayo Clinic regimen, and (3) the addition of levamisole noscopy, and the colon can often be cleared of these lesions before to the 5-FU plus leucovorin regimen did not improve survival. operation. Management of adenomas not amenable to endoscop- These clinical trials have established 5-FU plus leucovorin as ic resection and management of synchronous cancers are more standard therapy for patients with high-risk stage II and stage III challenging. Each primary cancer must be managed surgically colon cancer.The next generation of clinical investigations should according to sound oncologic principles. One option is to perform provide data on the potential beneﬁts of augmenting this regimen multiple segmental resections with multiple anastomoses. Another with irinotecan or oxaliplatin in an adjuvant setting.72 is to perform an extended resection that encompasses all of the Routine use of systemic adjuvant therapy for stage II colon can- lesions or even total abdominal colectomy if needed.The presence cer remains controversial. Patients with stage II colon cancers, of a rectal cancer and a second synchronous lesion makes surgical including those at high risk (e.g., those who present with large treatment even more challenging, especially if sphincter preserva- bowel obstruction or perforation), are typically included in adju- tion and a low rectal or coloanal anastomosis are contemplated. vant chemotherapy trials. A meta-analysis of stage II patients included in NSABP colon cancer trials demonstrated that adju- ADJUVANT THERAPY vant chemotherapy did confer a survival beneﬁt at this disease Signiﬁcant progress in systemic adjuvant therapy for patients stage.73 This study was criticized, however, for having included undergoing resection of a colorectal adenocarcinoma has been patients from trials that lacked a surgery-only arm, as well as from made in the past 20 years, primarily through a series of phase III trials that employed outmoded chemotherapeutic regimens.74 randomized trials and the development of new drugs. The evolu- Another meta-analysis, which included only trials that compared tion of adjuvant therapies is likely to continue for the foreseeable 5-FU plus leucovorin with observation after curative resection in future, and surgeons will play a pivotal role as the primary stage II patients, found no statistically signiﬁcant survival beneﬁt entrance point for standard adjuvant therapy and new phase III with chemotherapy.75 A 2004 meta-analysis formulated recom- randomized trials. Surgeons’ awareness of past accomplishments, mendations on this controversial topic and provided a Web-based current study ﬁndings, and future phase III trials is crucial for tool for calculating risk.76 This report included data from seven improving the survival of potentially cured patients. randomized trials that compared surgery alone with surgery plus The 5-year survival rate after resection of colon cancer is inverse- chemotherapy. Patients with node-negative disease derived a ly correlated with the pathologic stage [see Figure 4].The diminish- much lower reduction in risk and no statistically signiﬁcant ing 5-year survival rates for stage II and III colon cancer became improvement in overall survival. The authors concluded that the
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 8 use of postoperative adjuvant chemotherapy for stage II colon can- Local excision Local excision—including transanal, trans- cer patients should be individualized on the basis of the estimated sphincteric, and transcoccygeal techniques, as well as transanal prognosis and the potential treatment beneﬁt. endoscopic microsurgery (TEM) [see 5:35 Procedures for Rectal In summary, postoperative systemic adjuvant therapy is the Cancer]—is another option for curative resection of low rectal can- standard of care in patients with stage III disease. In stage II colon cers with preservation of sphincter function. These procedures cancer patients who have undergone complete surgical resection, were initially implemented for local control in patients who were the relative risk of recurrence is small enough that adjuvant medically unﬁt for or unwilling to undergo major resections. chemotherapy yields relatively little beneﬁt in terms of survival. Transsphincteric and transcoccygeal resections have been associ- There is, however, a subgroup of patients who have recognized ated with an increased incidence of complications, including fecal prognostic factors that signiﬁcantly reduce survival and in whom ﬁstulas and incontinence, and have largely been abandoned now adjuvant therapy is therefore more likely to be beneﬁcial. These that other, better techniques are available. risk factors include (1) bowel obstruction, (2) colonic perforation, Local excision with curative intent is generally reserved for the (3) high-grade or lymphovascular invasion, and (4) the presence treatment of early-stage (T1–2N0) lesions. Selection of patients of fewer than 12 lymph nodes in the resected specimen. for these procedures is critical and is based on preoperative stag- ing and on the probability of harboring nodal metastases, which increases with the T stage. EUS has become an important staging Management of Rectal Cancer procedure in these patients, both for assessing the depth of tissue Rectal cancer presents special management issues with respect invasion and for detecting the presence of nodal disease. CT is to local recurrence after surgical resection.With cancer of the intra- generally performed to rule out distant metastases. Palliative pro- peritoneal colon, local recurrence is rare. With rectal cancer, how- cedures (e.g., fulguration and endocavitary irradiation) may also ever, surgical treatment alone results in recurrence rates of 16.2% be considered in patients who are unﬁt for major surgery. after low anterior resection (LAR) and 19.3% after abdominoper- Several criteria have been established to identify patients who ineal resection (APR).77 Higher stages are associated with higher may be candidates for transanal excision (TAE).81 Generally, the recurrence rates: 8.5% for Dukes stage A, 16.3% for stage B, and lesion must be no more than 4 cm in diameter, must encompass 26% for stage C.77 Multimodality management, including adjuvant no more than one third of the circumference of the rectum, and radiation therapy or chemotherapy (or both) in combination with must be less than 8 cm from the anal verge. With the advent of appropriate operative therapy, can reduce local recurrence rates TEM, these criteria have been expanded to include patients with higher lesions. Poorly differentiated tumors and the presence of signiﬁcantly. lymphovascular invasion may also be associated with increased SURGICAL THERAPY nodal involvement and higher recurrence rates. At least two prospective trials have reported their results with TAE.82,83 Local Extent of Resection recurrence rates ranged from 5% to 7% for T1 lesions treated with surgery alone. Results were not as promising for T2 lesions: local Sphincter preservation has become a major goal in the multi- recurrence rates ranged from 14% to 16%, even when adjuvant modality treatment of rectal cancer. Surgical procedures are cho- radiation or chemoradiation therapy was provided. sen and performed with this goal ﬁrmly in mind. The use of local excision in patients with more locally advanced disease is even more controversial. Such patients are at considerably Radical resection Traditionally, tumors of the rectum have greater risk for nodal metastases and thus for local recurrence even been treated with either LAR or APR [see Figure 8]; in numerous after adequate resection of the primary lesion. Traditionally, local series, APR rates of 60% or higher have been reported. Surgical excision in patients with locally advanced disease has been associat- techniques such as stapled or handsewn coloanal anastomoses [see ed with unacceptably high recurrence rates. Some authors advocate 5:29 Intestinal Anastomosis], when combined with total mesorectal combining chemoradiation therapy with local excision to manage excision (TME), have led to excellent cancer-related outcomes these patients. In a 2004 retrospective series, the results of local exci- without the need for permanent colostomy. The use of preopera- sion were comparable to those of radical resection in T3 patients tive chemoradiation therapy for tumor downstaging may also who had a good response to preoperative chemoradiation therapy reduce the need for APR.78 Technical details of surgical proce- and who refused or were medically unﬁt for major surgery.84 The dures for rectal cancer are discussed elsewhere [see 5:35 Procedures role of local excision in these patients remains poorly deﬁned. for Rectal Cancer]. Patients undergoing local resection must receive careful follow- The morbidity associated with radical rectal resection can be up, including digital examination, measurement of CEA levels, substantial. Anastomotic leakage rates vary widely, ranging from proctoscopy, and, possibly, transanal ultrasonography. A subset of less than 10% to more than 30% after resection with anastomosis. these patients with local-only recurrences who are medically ﬁt for Leaks can lead to substantial morbidity and mortality and can surgery may be candidates for resection. At present, few good data necessitate reoperation. Such concerns have prompted the use of are available on the results of salvage surgery for local recurrence temporary diverting ileostomies or colostomies in patients with after local excision of rectal cancer, but it is unlikely that outcomes low rectal anastomoses. Defunctioning stomas may be overused, are equivalent to those of initial radical resection.85 however, thereby increasing the cost of care in low-risk patients.79 Preoperative chemoradiation therapy has not been shown to Importance of Radial and Distal Resection Margins increase anastomotic leakage rates. Urinary and sexual dysfunc- There has been a great deal of debate about what constitutes tion are also fairly common after radical resection of rectal cancer. an adequate margin of resection in surgical treatment of rectal Autonomic nerve preservation in conjunction with TME may cancer.With respect to distal margins, 2 to 5 cm has traditional- improve the functional results of these procedures.80 The use of ly been considered to be the minimum necessary for curative local resection techniques (see below) is another means of reduc- resection. Growing interest in sphincter preservation has led ing surgical morbidity and mortality in rectal cancer patients. investigators to consider smaller distal margins (i.e., < 2 cm).
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 9 Patient has rectal cancer Order investigative studies to stage and assess resectability of tumor: • Complete colonoscopy • CT of abdomen and pelvis • Chest x-ray or chest CT • CEA level • Rectal ultrasonography, MRI, or both Tumor is resectable Tumor is unresectable (T4 or M1) Perform palliative stenting or diversion if tumor is obstructing. Administer chemotherapy, Tumor is early stage Tumor is locally advanced Tumor has metastasized, radiation therapy or both.. (T1–2 and N0 on (T3–4 or N1–2 on ultrasonography) but metastases are ultrasonography) resectable Administer adjuvant chemoradiation therapy preoperatively. Perform staged or concurrent resection of Perform low anterior resection or APR. primary tumor and Tumor becomes Tumor remains If patient is unfit for major operation, metastases. resectable unresectable consider TAE. Administer systemic Resect primary Administer Consider systemic chemotherapy. chemotherapy. tumor and systemic metastases. chemotherapy or supportive care. Patient is candidate for TAE Patient is not (e.g., lesion is low and small) candidate for TAE Perform transanal excision. Tumor is T1 Tumor is T2 with Tumor is T3–4 with clear clear margins and either is margins N1–2 or has Administer adjuvant positive margins chemoradiation therapy. Perform low anterior resection or APR with definitive pathologic staging. Tumor is T1–2 and Tumor is T3–4 or N0 with clear margins N1–2 or has positive margins Administer adjuvant chemoradiation therapy. Follow up according to protocol. Figure 8 Algorithm outlines treatment of rectal cancer. Studies have shown that clear margins smaller than 2 cm are not patients receiving adjuvant chemoradiation therapy.87,88 associated with higher local recurrence rates or reduced sur- The importance of radial margin involvement after rectal can- vival.86 Subsequent reports have suggested that even smaller his- cer resection was not recognized until comparatively recently.89 tologically negative margins (i.e., < 1 cm) may be adequate in Radial margins are assessed by means of serial slicing and evalua-
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 10 tion of multiple coronal sections of the tumor and the mesorec- T stage. Patients with T3 or T4 rectal cancer on ultrasonography tum.89 Involvement of radial margins is a predictor of both local would be eligible for preoperative treatment. recurrence and survival after potentially curative rectal cancer Two Swedish studies studied the role of preoperative radiation surgery90 and may be associated with an increased risk of distant therapy in treating rectal cancer. The ﬁrst demonstrated that a metastases.91 Radial margins smaller than 2 mm are associated short course of preoperative radiation therapy (2.5 Gy in 5 frac- with increased local recurrence rates.91 Adjuvant radiation therapy tions) was comparable to high-dose postoperative radiation thera- does not compensate for the adverse impact of positive margins on py (60 Gy over a period of 8 weeks).The local recurrence rate was local recurrence rates.92 signiﬁcantly lower with the short-course preoperative regimen (12% versus 21%), and there was no overall survival difference ADJUVANT THERAPY between the two regimens.103 In the second trial, patients received Adjuvant therapy for rectal cancer has focused both on locore- either a short course of preoperative radiation therapy or surgery gional control of disease and on treatment of systemic disease. alone.104 The local recurrence rate for preoperative therapy plus Several large studies have evaluated local recurrence of disease surgery was 11%, compared with 27% for surgery alone.The com- after surgical resection alone. Local failure rates of 30% to 40% for bined regimen also resulted in signiﬁcantly better 5-year survival T2N0 disease and 50% to 70% for node-positive disease strongly (58% versus 48%). suggested that postoperative adjuvant therapy was needed.93-95 In The question of the relative merits of preoperative and postoper- distinct contrast to these data, however, other series in which TME ative radiation therapy may be resolved by the ﬁndings from a 2004 was performed reported extremely low local recurrence rates with German trial that randomly assigned patients to receive either pre- surgery alone.96,97 operative or postoperative 5-FU plus radiation, followed by sys- A series of randomized trials were conducted to assess adjuvant temic 5-FU therapy.78 This study was limited to patients with local- therapy for rectal cancer. Initial studies reported a decrease in local ly advanced disease, including those who had T3 or T4 disease or recurrence rates with postoperative radiation therapy.98,99 In a were node positive on ultrasonography. TME was performed in all multi-institutional trial conducted by the NCCTG, the combina- patients and was done 6 weeks after treatment in patients receiving tion of 5-FU with radiation therapy led to improvements in local preoperative chemoradiation therapy.The primary end point of this control rates and in survival.100 These results were conﬁrmed in study was overall survival; secondary end points included disease- large intergroup trials, the results of which indicated that continu- free survival, local and distant control of disease, sphincter preser- ous infusion of 5-FU during radiation therapy resulted in signiﬁ- vation, toxicity of adjuvant therapy, surgical complications, and cantly better disease-free survival and overall survival than bolus quality of life. There was no difference between the preoperative infusion of 5-FU. group and the postoperative group with respect to 5-year survival, Simultaneously with the ongoing development of postoperative but the local recurrence rate was signiﬁcantly lower with the former locoregional adjuvant therapy for rectal cancer, interest in preoper- (6% versus 13%), as were both the short-term and the long-term ative therapy has been growing. Preoperative radiation therapy has toxicity of adjuvant therapy. Although overall, the rates of complete been associated with excellent local control of disease, sphincter (R0) resection and sphincter preservation were similar in the two preservation, and acceptable postoperative recovery. There is evi- groups, the APR rate was signiﬁcantly lower in patients determined dence that rectal adenocarcinoma is sensitive to preoperative radi- by the surgeon to require APR before randomization. ation therapy, with or without 5-FU. Pathologic complete response rates of 10% to 20% have been noted in resected rectal speci- mens101; pathologic complete response is associated with im- Special Considerations proved outcomes.102 SYNCHRONOUS METASTATIC (STAGE IV) DISEASE Perhaps the strongest reason to consider preoperative therapy for rectal cancer is its potential for inducing signiﬁcant tumor As many as 20% of CRC patients have metastatic disease at the regression before surgical resection. Such regression makes clear time of initial presentation. The need for surgical intervention in radial and distal margins easier to obtain. Moreover, tumor regres- this group of patients is not well deﬁned. Clearly, surgical resection sion with preoperative therapy may result in higher sphincter or diversion is indicated in patients who present with signiﬁcant preservation rates. In many published series, the APR rate in rec- bleeding, perforation, or obstruction. In asymptomatic patients tal cancer patients is between 40% and 60%; more aggressive pre- with unresectable metastatic disease, the role of surgical resection operative efforts to induce regression may give surgeons a better of the primary lesion remains controversial. In patients with chance to achieve sphincter preservation without compromising resectable metastatic disease (e.g., isolated liver or lung metas- local control of disease.101 tases), curative resection may be undertaken. There remains signiﬁcant controversy regarding the choice In a retrospective review of patients presenting with unre- between preoperative and postoperative radiation therapy for rectal sectable stage IV CRC, there was no difference in survival between cancer. An advantage of the postoperative approach is that the dis- those who were initially managed surgically and those who were ease is more accurately staged before adjuvant therapy begins, and initially managed nonoperatively.105 In the surgical group, the mor- thus, patients with early-stage disease are less likely to be overtreat- bidity rate was 30% and the mortality 5%. Only 9% of the non- ed.Two trials attempted to compare preoperative and postoperative operative patients subsequently required surgical intervention for radiation therapy for rectal cancer in an effort to determine their bowel obstruction. In another retrospective series, patients man- relative effects on local control, overall survival, and sphincter aged surgically had signiﬁcantly better overall survival than those preservation. Both studies were unsuccessful, however—probably managed nonoperatively but had a lesser tumor burden106; 29% of because of bias on the part of the treating physicians in favor of the nonoperative patients eventually required surgery for bowel either preoperative or postoperative radiation therapy—and were obstruction. When prognostic factors were evaluated in the surgi- closed because of slow accrual. At present, there is greater enthusi- cal arm of this series, the only factor associated with improved out- asm for preoperative therapy and pretreatment staging with tran- comes was a less than 25% extent of liver involvement. On the srectal ultrasonography, which is 90% accurate for determining the basis of these and other studies, asymptomatic patients with unre-
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 11 sectable metastatic CRC should be managed selectively: those with Systemic therapy may improve survival in some patients who have limited tumor burdens may beneﬁt from surgical treatment, unresectable recurrent lesions. whereas those with more extensive disease (especially extensive Various modalities are available for follow-up after surgical treat- liver involvement) may initially be managed nonoperatively. ment of CRC. The history and the physical examination continue Management of patients with synchronous resectable isolated to be useful, in that a signiﬁcant percentage of patients present with liver metastases continues to evolve. Many studies have docu- symptomatic recurrences. Measurement of serum CEA levels has mented improved survival after liver resection in patients with proved effective in detecting asymptomatic recurrences. Other metastatic disease that is conﬁned to the liver. Patients presenting studies, such as liver function tests (LFTs), complete blood count with synchronous lesions have a worse prognosis than those pre- (CBC), chest x-ray, and imaging studies (e.g., CT and ultrasonog- senting with metachronous lesions.107 Many of these patients have raphy), have not been consistently shown to detect asymptomatic been managed with staged resections of the primary cancers and resectable recurrences. One study that evaluated routine CEA the liver metastases. Several groups have reported that such com- measurement and CT scanning of the chest, the abdomen, and the bined procedures do not substantially increase surgical morbidity pelvis for follow-up of stage II and III CRC demonstrated that and mortality or compromise cancer survival.108,109 These com- both modalities were able to identify asymptomatic patients with bined procedures should be done only in carefully selected pa- resectable disease.116 Colonoscopy is valuable for detecting tients at specialized centers with signiﬁcant experience in resection metachronous cancers and polyps. of both CRC and liver tumors. Some authorities advocate so-called intensive follow-up. However, this term lacks a standard deﬁnition, and such follow-up PERITONEAL CARCINOMATOSIS has not been conclusively shown to be beneﬁcial. In a meta-analy- Peritoneal carcinomatosis develops in approximately 13% of all sis that compared an intensive follow-up regimen (including histo- CRC patients.110 The survival rate of patients who present with ry, physical examination, and CEA measurement) with no follow- peritoneal carcinomatosis from CRC is dismal. In patients with up, the former detected more candidates for curative re-resection stage IV CRC, the presence of carcinomatosis is associated with a and led to improvements in both overall survival and survival of signiﬁcant reduction in survival (from 18.1 months to 6.7 patients with recurrences.117 Two other meta-analyses have been months).111 Treatment has traditionally included systemic published that assessed the value of intensive follow-up of CRC chemotherapy, with surgery reserved for palliation of symptoms patients.118,119 Both of these meta-analyses included only random- such as bowel obstruction. Newer chemotherapy regimens that ized, controlled trials, and both documented a survival advantage include agents such as oxaliplatin may improve survival, but they with intensive follow-up. Some caution is required in interpreting certainly are not curative. these results, however, because the meta-analyses included trials Peritoneal carcinomatosis is often associated with hematogenous with vastly different follow-up regimens in their baseline and inten- metastases, but in some 25% of patients, the peritoneal cavity is the sive groups. only site of disease. Several groups have advocated the use of At present, the ideal follow-up regimen for CRC patients cytoreductive surgery and hyperthermic intraperitoneal chemo- remains to be determined. Intensive follow-up regimens obviously therapy (HIPEC) as a means of improving survival in these are more costly. Patients with stage I disease are at very low risk for patients.112 This treatment, however, is associated with signiﬁcant recurrence and therefore do not require intensive follow-up.120 morbidity and mortality.113 A randomized trial from the Nether- Patients with stage II and III disease are at signiﬁcantly higher risk lands that compared cytoreduction surgery plus HIPEC with sys- for recurrence and therefore need more speciﬁc cancer-related fol- temic chemotherapy plus palliative surgery found that patients in low-up, but how intensive such a follow-up regimen should be is the former group exhibited a statistically signiﬁcant improvement still a matter of debate. in median survival (22.3 months versus 12.6 months).114 Cyto- Several organizations, including the American Society of Clinical reductive surgery plus HIPEC seems to be a viable option for the Oncology,121 the National Comprehensive Cancer Net- treatment of peritoneal carcinomatosis. Patient selection for these work (NCCN),122,123 and the American Society of Colon and aggressive procedures remains a major issue, given the substantial Rectal Surgeons,124 have developed algorithms for postoperative morbidity and mortality associated with them. surveillance of CRC patients. Their recommendations generally apply to patients with stage II or III disease (and sometimes patients with T2 lesions) who are candidates for resection of recur- Follow-up and Management of Recurrent Colorectal rent disease.The recommendations vary somewhat among groups, Cancer but the following are generally agreed on: The goal of any CRC follow-up regimen should be to detect any 1. Measurement of CEA levels every 2 to 3 months for 2 years, recurrences or metachronous lesions that are potentially curable. then every 3 to 6 months for 3 years, then annually. In a large, multicenter trial, the incidence of second primary CRCs 2. Clinical examination every 3 to 6 months for 3 years, then in patients with resected stage II and III lesions was found to be annually. 1.5% at 5 years.115 Between 40% and 50% of patients experience 3. Colonoscopy perioperatively, then every 3 to 5 years if the relapses after potentially curative resection of CRC. Detection and patient remains free of polyps and cancer (the NCCN also rec- treatment of recurrent disease before symptom development may ommends colonoscopy 1 year after primary therapy). improve survival.The time to recurrence is critical, in that as many as 80% of recurrences occur within the ﬁrst 2 years and as many Imaging studies (e.g., CT and chest x-ray) are not routinely rec- as 90% within the ﬁrst 4 years. Patterns of recurrence should also ommended, nor are other blood tests (e.g., CBC and LFTs). be taken into account—for example, the markedly increased risk of A complete review of the treatment of recurrent CRC is beyond local recurrence in rectal cancer patients compared with that in the scope of this chapter.The primary aim of postoperative surveil- colon cancer patients. Even when recurrent CRC is detected, only lance is the detection of treatable recurrences or metastatic disease. a small percentage of patients are candidates for reoperation, and The most common sites of metastasis in CRC patients are the liver resection in these patients may not improve overall survival. and the peritoneal cavity. Surgery is the only potentially curative
© 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 5 Gastrointestinal Tract and Abdomen 15 Adenocarcinoma of the Colon and Rectum — 12 therapy for recurrent CRC. Only a select group of pa- these patients, treatment of such metastases has not been studied tients with isolated peritoneal, liver, or lung metastases are candi- as well as treatment of liver metastases. Some series have reported dates for surgical resection. As noted [see Special Considerations, 5-year survival rates higher than 40% after complete resection. Peritoneal Carcinomatosis, above], cytoreductive surgery and Patient selection remains a major issue. Several prognostic factors HIPEC improve survival in patients with peritoneal carcinomatosis that may predict poor outcomes have been identiﬁed, including (1) and may lead to long-term survival in a very select group of patients. a maximum tumor size greater than 3.75 cm, (2) a serum CEA Numerous studies have addressed the treatment of patients with level higher than 5 ng/ml, and (3) pulmonary or mediastinal lymph isolated liver metastases from CRC. Resection of isolated hepatic node involvement.128,129 Patients with both pulmonary and hepat- metastases has been reported to yield 5-year survival rates higher ic metastases may also be considered for surgical resection. than 30%, with acceptable surgical morbidity and mortality. Inves- Pelvic recurrences of rectal cancer present another difﬁcult man- tigators from the Memorial Sloan-Kettering Cancer Center devel- agement issue. These tumors may cause signiﬁcant pain and dis- oped a staging system known as the clinical score in an attempt to ability, and if they are not treated, survival is measured in months. predict which patients are likely to beneﬁt from aggressive surgical Radiation and chemotherapy provide symptomatic relief and yield resection.125 This system used ﬁve factors that were found to be a modest increase in survival. Surgery may provide excellent palli- independent predictors of poor outcome: (1) node-positive prima- ation and is potentially curative in patients who do not have distant ry disease, (2) a disease-free interval shorter than 12 months, (3) metastases. the presence of more than one hepatic tumor, (4) a maximum Multimodality therapy has been advocated as a means of hepatic tumor size exceeding 5 cm, and (5) a CEA level higher than improving the chances of cure. In one study, a 37% 5-year survival 200 ng/ml. Patients who met no more than two of these criteria rate was reported in patients who underwent multimodality thera- generally had good outcomes, whereas those who met three or py, including resection with negative margins.130 A subgroup of more were recommended for inclusion in adjuvant therapy trials. patients in whom complete resection was impossible underwent PET scanning has also been used to detect occult metastatic intraoperative radiation therapy; the 5-year survival in this sub- disease and thus to aid in the selection of patients for surgical group was 21%. Several predictors of poor outcomes were identi- resection. In one series, a 5-year overall survival of 58% was report- ﬁed, including incomplete resection, multiple points of tumor ﬁxa- ed after resection of CRC liver metastases in patients screened with tion, and symptomatic pain. In another series, hydronephrosis was PET.126 When combined with the clinical risk score, PET was associated with the presence of unresectable disease.131 Selection of found to be helpful only in patients with a score of 1 or higher.127 appropriate patients for curative surgery remains a major issue in Modalities for treating unresectable disease conﬁned to the liver the management of locally recurrent rectal cancer. include cryotherapy, radiofrequency (RF) ablation, hepatic artery Chemotherapy is the mainstay of palliative treatment for patients infusion of chemotherapeutic agents, and hepatic perfusion. Of with CRC and unresectable recurrent or metastatic disease. these, RF ablation is the one most commonly employed. It may be Combinations of 5-FU and leucovorin with newer agents such as performed via an open approach, percutaneously, or laparoscopi- irinotecan and oxaliplatin deﬁne the current standard. Patients in cally; it may also be combined with resection and with local or sys- whom these regimens fail may be considered for treatment with temic chemotherapy. The survival beneﬁt (if any) associated with other newer agents, including cetuximab, a monoclonal antibody use of these modalities has not been well established. against epidermal growth factor receptor, and bevacizumab, a Patients with isolated lung metastases from CRC may also ben- monoclonal antibody against the vascular endothelial growth fac- eﬁt from surgical resection. Because there are relatively few of tor receptor. References 1. Jemal A, Tiwari RC, Murray T, et al: Cancer sta- 8. Fearon ER, Vogelstein B: A genetic model for col- 15. Winawer SJ, Zauber AG, Gerdes H, et al: Risk of tistics, 2004. CA Cancer J Clin 54:8, 2004 orectal tumorigenesis. Cell 61:759, 1990 colorectal cancer in the families of patients with 2. Redaelli A, Cranor CW, Okano GJ, et al: 9. 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Le Marchand L, Zhao LP, Quiaoit F, et al: Family Cancer risk in patients with inﬂammatory bowel 6. Hawk ET, Limburg PJ, Viner JL: Epidemiology history and risk of colorectal cancer in the multi- disease: a population-based study. Cancer 91:854, and prevention of colorectal cancer. Surg Clin ethnic population of Hawaii. Am J Epidemiol 2001 North Am 82:905, 2002 144:1122, 1996 20. Le Marchand L, Wilkens LR, Kolonel LN, et al: 7. Muto T, Bussey HJ, Morson BC: The evolution of 14. Johns LE, Houlston RS: A systematic review and Associations of sedentary lifestyle, obesity, smok- cancer of the colon and rectum. Cancer 36:2251, meta-analysis of familial colorectal cancer risk. Am ing, alcohol use, and diabetes with the risk of col- 1975 J Gastroenterol 96:2992, 2001 orectal cancer. Cancer Res 57:4787, 1997