This site is intended for healthcare professionals Medscape Colon Cancer Treatment & Management TREATMENT Approach Considerations Surgery is the only curative modality for localized colon cancer (stage |-IIl). Surgical resection potentially provides the only curative option for patients with limited metastatic disease in liver and/or lung (stage IV disease), but the proper use of elective colon resections in nonobstructed patients with stage IV disease is a source of continuing debate. Adjuvant chemotherapy is standard for patients with stage III disease. Its use in stage | disease is controversial, with ongoing studies seeking to confirm which markers might identify patients who would benefit. At present, the role of radiation therapy is limited to palliative therapy for selected metastatic sites such as bone or brain metastases. Chemotherapy rather than surgery has been the standard management for patients with metastatic colorectal cancer. Biologic agents have assumed a major role in the treatment of metastatic cases, with selection increasingly guided by genetic analysis of the tumor. The proper use of elective colon/rectal resections in nonobstructed patients with stage IV disease is a source of continuing debate. For more information, see Colon Cancer Treatment Protocols. Surgical Care Surgery is the only curative modality for localized colon cancer (stage I-III) and potentially provides the only curative option for patients with limited metastatic disease in liver and/or lung (stage |V disease). The general principles for all operations include removal of the primary tumor with adequate margins including areas of lymphatic drainage. Standard colectomies for adenocarcinoma of the colon are depicted in the image below.Botore After colectomy Standard colectomies for adenocarcinoma of the colon. For lesions in the cecum and right colon, a right hemicolectomy is indicated. During a right hemicolectomy, the ileocolic, right colic, and right branch of the middle colic vessels are divided and removed, Care must be taken to identify the right ureter, the ovarian or testicular vessels, and the duodenum. If the omentum is attached to the tumor, it should be removed en bloc with the specimen. For lesions in the proximal or middle transverse colon, an extended right hemicolectomy can be performed, In this procedure, the ileocolic, right colic, and middle colic vessels are divided and the specimen is removed with its mesentery. For lesions in the splenic flexure and left colon, a left hemicolectomy is indicated. The left branch of the middle colic vessels, the inferior mesenteric vein, and the left colic vessels along with their mesenteries are included with the specimen For sigmoid colon lesions, a sigmoid colectomy is appropriate. The inferior mesenteric artery is divided at its origin, and dissection proceeds toward the pelvis until adequate margins are obtained. Care must be taken during dissection to identify the left ureter and the left ovarian or testicular vessels. Total abdominal colectomy with ileorectal anastomosis may be required for patients with any of the following + Hereditary nonpolyposis colon cancer syndrome (HNPCC) + Attenuated familial adenomatous polyposis (FAP) + Metachronous cancers in separate colon segments Total abdominal colectomy may also be indicated for some patients with acute malignant colon obstructions in whom the status of the proximal bowel is unknown. Laparoscopic surgeryThe advent of laparoscopy has revolutionized the surgical approach to colonic resections for cancers. Large prospective randomized trials have found no significant differences between open and laparoscopic colectomy with regard to intraoperative or postoperative complications, perioperative mortality rates, readmission or reoperation rates, or rate of surgical wound recurrence. Oncologic outcomes (cause-specific survival, disease recurrence, number of lymph nodes harvested) are likewise comparable. [62. 63, 64, 65, 66, 67) For example, the Clinical Outcomes of Surgical Therapy Study Group trial found no significant differences between laparoscopic-assisted colectomy (LAC) or open colectomy in terms of 5-year disease-free survival rate (69% versus 68% in the LAC and open colectomy groups, respectively) or overall survival (76% versus 75%). '§3] in a study by Lacy et al with median followup of 95 months, LAC was more effective than open colectomy, although the tendency toward higher cancer-related and overall survival did not reach statistical significance. 64) Metastatic colorectal cancer Chemotherapy rather than surgery has been the standard management for patients with metastatic colorectal cancer. The proper use of elective colon/rectal resections in nonobstructed patients with stage IV disease is a source of continuing debate. Medical oncologists properly note the major drawbacks to palliative resection, such as loss of performance status and risks of surgical complications that potentially lead to delay in chemotherapy. However, surgeons understand that elective operations have lower morbidity than emergent operations on patients who are receiving chemotherapy. There is a trend toward nonsurgical management of patients with asymptomatic, surgically incurable colorectal cancer, with studies showing that fewer than 10% of these patients subsequently require surgery for obstruction or perforation, [88 89] A review by Venderbosch et al found that resection of the primary tumor appears to improve survival in patients with stage IV colorectal cancer, but these researchers concluded that prospective studies are warranted, given the potential bias of those results. [70] Curative-intent resections of liver metastases have significantly improved long-term survival, with acceptable postoperative morbidity, including in older patients. !7"] A study by Brouquet et al found that resection of colorectal liver metastases after a second-line chemotherapy regimen was safe and provided a modest hope for definitive cure, making this approach viable in patients with advanced colorectal liver metastases. !72] Hepatic arterial infusion (HA) of chemotherapeutic agents such as floxuridine (FUDR) is a consideration following partial hepatectomy. A study by House et al found that adjuvant HAI-FUDR combined with modern systemic chemotherapy resulted in improved survival compared with adjuvant chemotherapy alone. |73) During the past decade, colonic stents have introduced an effective method of palliation for obstruction in patients with unresectable liver metastasis. However, a study by van Hooft et al found that colonic stenting has no decisive clinical advantages compared with emergency surgery. Although it may be used as an alternative treatment in undefined sets of patients, concerns about tumor spread caused by perforations remains. [74] AblationAlthough resection is the only potentially curative treatment for patients with colon metastases, other therapeutic options for those who are not surgical candidates include thermal ablation techniques Cryotherapy uses probes to freeze tumors and surrounding hepatic parenchyma. It requires. laparotomy and can potentially results in significant morbidity, including liver cracking, thrombocytopenia, and disseminated intravascular coagulation (DIC). Radiofrequency ablation (RFA) uses probes that heat liver tumors and the surrounding margin of tissue to create coagulation necrosis. RFA can be performed percutaneously, laparoscopically, or through an open approach. Although RFA has minimal morbidity, local recurrence is a significant problem and correlates with tumor size. Adjuvant Therapy The standard chemotherapy for patients with stage III and some patients with stage II colon cancer for the last two decades consisted of 5-fluorouracil in combination with adjuncts such as levamisole and leucovorin. [2: 3 4] This approach has been tested in several large randomized trials and has been shown to reduce individual 5-year risk of cancer recurrence and death by about 30%. In an observational study of 1291 patients with stage III colon cancer, adjuvant chemotherapy reduced the risk of distant recurrence after surgery by about half. Elderly patients benefited to a similar degree as younger patients. (7°: 761 Overall, 56% of the study participants received adjuvant chemotherapy, 31% developed distant metastases, and 37% were 75 years of age or older. In the total population, the use of adjuvant chemotherapy was associated with a significantly reduced risk of distant recurrence. In separate analyses of patients <75 years of age and those 275 years of age, the effect of adjuvant chemotherapy on recurrence risk was similar in both age groups, with hazard ratios of 0.50 and 0.57, respectively. [75, 761 ‘Two large randomized trials (MOSAIC and NASBP-C06) investigated the addition of oxaliplatin to fluorouracil (FOLFOX4 and FLOX, respectively) and demonstrated a significant improvement in 3-year disease-free survival for patients with stage II colon cancer. The addition of irinotecan to fluorouracil in the same patient population provided no benefit based on the results from two large randomized trials (CALGB 89803 and PETACC 3). Another randomized study, XACT, demonstrated noninferiority of capecitabine (Xeloda) compared with fluorouracilleucovorin as adjuvant therapy for patients with stage Ill colon cancer. A large trial comparing capecitabine plus oxaliplatin (XELOX) versus FOLFOX has completed accrual, but survival data have not yet been reported. Although information on results of adjuvant therapy in stage I and Il colon cancer is limited, analysis of a data set assembled by the Adjuvant Colon Cancer Endpoints group showed that adjuvant chemotherapy provides a significant disease-free survival benefit because it reduces the recurrence rate. The benefit was particularly evident within the first 2 years of adjuvant therapy but some benefit extended to years 3-4, [771 Adjuvant therapy in stage Il colon cancer The role of adjuvant chemotherapy for stage Il colon cancer is controversial. Surgery alone is usually curative for stage Il colon cancer, but approximately 20-30% of these patients develop tumor recurrence and ultimately die of metastatic disease. The American Society of Clinical Oncology doesnot recommend the routine use of adjuvant chemotherapy for patients with stage Il colon cancer, and instead recommends encouraging these patients to participate in clinical trials. {781 Alarge European trial (QUASAR) demonstrated small but significant benefit (3.6%) in terms of absolute 5-year survival rate for those patients who received fluorouracil/leucovorin versus those in the control group. 41 In contrast, a study by O'Connor et al found that in Medicare patients with stage Iicolon cancer, with or without poor prognostic features, overall survival was not substantially improved by adjuvant chemotherapy. [79] Ongoing adjuvant trials are investigating additional risk stratification of stage II colon cancer based on clinicopathological and molecular markers. For example, the ECOG 5202 trial is comparing two forms of adjuvant therapy (oxaliplatin, leucovorin, and fluorouracil with or without bevacizumab) in high-risk patients, with low-risk patients undergoing observation only. In this trial, high-risk patients are defined as those with microsatellite stability (MSS) or low-frequency microsatellite instability (MSI-L) and loss of heterozygosity at 18q. Low-risk patients are those with MSS or MSI-L and retention of 18q, or high-frequency MSI with or without loss of heterozygosity at 18q. Chemotherapy for Metastatic Disease Combination regimens provide improved efficacy and prolonged progression-free survival (PFS) in patients with metastatic colon cancer. The advent of new classes of active drugs and biologics for colorectal cancer has pushed the expected survival for patients with metastatic disease from 12 months two decades ago to about 22 months currently. Ina phase III multicenter trial in patients with advanced colorectal carcinoma refractory to fluorouracil, overall survival did not significantly differ between patients treated with fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) (n=246) compared with irinotecan (n=245); however, FOLFOX 4 improved response rate (RR) and time to progression (TTP) compared with irinotecan (P=0.0009 for each RR and TTP). FOLFOX4 was associated with more neutropenia and paresthesias. [8] Although many patients with colorectal cancer are elderly, exclusion of these patients from randomized controlled trials has impeded the creation of evidence-based guidelines for this population. A study by Seymour et al demonstrated that elderly and frail patients with untreated metastatic colorectal cancer can participate in a randomized controlled trial. Study patients, who were considered unfit for full-dose chemotherapy, underwent a comprehensive health assessment and were started on chemotherapy at 80% of standard doses. [81] In September 2015, the FDA approved tipiracil/trfuridine (Lonsurf) for metastatic colorectal cancer. Efficacy and safety were evaluated in the phase I! RECOURSE trial, an international, randomized, double-blind study involving 800 patients with previously treated metastatic colorectal cancer. Patients had received chemotherapy with a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and—for patients with KRAS wild-type tumors—cetuximab or panitumumab. The primary efficacy end point of the study was median overall survival, which was 7.1 months with tipiracil{rifluridine vs 5.3 months with placebo (P <0.001). The secondary end point was progression-free survival, which was 2 months with tipiracil/trifluridine vs 1.7 months with placebo, (®2] Biologic Agents Biologic agents used in the treatment of colon cancer include monoclonal antibodies against vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), as well as a kinase inhibitor and a decoy receptor for VEGF. Such agents include the following:Bevacizumab (Avastin) Cetuximab (Erbitux) Panitumumab (Vectibix) Regorafenib (Stivarga) Ziv-aflibercept (Zaltrap) Bevacizumab Bevacizumab is a humanized monoclonal antibody to VEGF. It was the first anti-angiogenesis drug to be approved in clinical practice and its first indication was for metastatic colorectal cancer. Approval was based on a pivotal trial that demonstrated improved progression-free survival (PFS) and overall survival (OS) when bevacizumab was added to chemotherapy with irinotecan, 5-fluorouracil, and leucovorin (IFL). Bevacizumab, in combination with fluorouracil-based chemotherapy, is indicated for first- and second- line treatment of metastatic colorectal carcinoma. Bevacizumab is also approved for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen. Approval for continuation treatment was based on a study that showed maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy. The risk of death was reduced by 19% for those who received bevacizumab in combination with standard chemotherapy in both the first- and second-line compared with those who received chemotherapy alone (hazard ratio [HR]=0.81, P=0.0057). PFS improved by 32% (HR=0.68, P < 0.0001). [831 A pooled analysis of cohorts of older patients (aged 65 years or older) from two randomized clinical trials concluded that adding bevacizumab to fluorouracil-based chemotherapy for first-line treatment of metastatic colorectal cancer improved OS and PFS in older patients as it does in younger patients, without increased risks of treatment in the older age group. Median OS improved from 14.3 months to 19.3 months with the addition of bevacizumab, while median PFS improved from 6.2 months to 9.2 months, [®4) Results from the randomized CAIRO3 trial appear to show that, compared with observation, maintenance therapy with capecitabine (Xeloda) and bevacizumab significantly delayed disease progression in 568 previously untreated patients with stable (or better) metastatic colorectal cancer after six cycles of induction therapy with capecitabine, oxaliplatin, and bevacizumab (CAPOX-B). [85 86] Patients in both groups were treated with CAPOX-B at first progression until second progression. Ata median follow-up of 48 months, CAPOX-B was restarted in 48% of those in the maintenance treatment group and 61% of patients in the observation group. '85: 6] Median second progression after randomization occurred at 11.7 months in the maintenance group and 8.5 months in the observation group, and median first progression after randomization occurred at 8.5 months in the maintenance group compared with 4.1 months in the observation group. !®61 Ina study by Tebbult et al, bevacizumab was found to be associated with a modestly increased risk of arterial thromboembolism (ATE). However, safety was not significantly worse in older patients or those with a history of ATE or other vascular risk factors. [87] Despite its role in the therapy of metastatic colon cancer, bevacizumab did not significantly prolong disease-free survival in patients with stage II and Il colon cancer, when added to adjuvant chemotherapy (mFOLFOX6) in a randomized trial (NASBP C-08). '88 CetuximabCetuximab is a chimeric monoclonal antibody against EGFR that is approved for treatment of KRAS mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer. Cetuximab may be used as monotherapy or in combination with irinotecan (Camptosar) in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin therapy. '89) Additionally, cetuximab is approved as combination therapy with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin), [90 911 KRAS mutations, which are present in about 40% of colon adenocarcinomas, affect sensitivity to anti- EGFR treatment. [3] The addition of anti-EGFR antibody treatment to standard chemotherapy regimens for patients with advanced colorectal cancer improves progression-free survival for those with wild-type KRAS status, but not those with mutant KRAS, [921 The CRYSTAL trial, a large international trial exploring the benefit of adding cetuximab to first-line chemotherapy with FOLFIRI, documented that only patients with wild-type KRAS derived clinical benefit from cetuximab. In patients with mutant KRAS, adding cetuximab to chemotherapy provided no clinical benefit and resulted only in unnecessary toxicity. Based on these results, testing for KRAS mutation was added to the cetuximab indication by the European Medicines Agency (EMA). The US Food and Drug Administration (FDA) approved the use of cetuximab in combination with FOLFIRI for firsttine treatment of patients with wild-type KRAS- metastatic colorectal cancer, as determined by FDA-approved tests, in July 2012. Panitumumab Panitumumab is a fully human monoclonal antibody against EGFR. This agent was originally approved as monotherapy for patients with EGFR-expressing metastatic colorectal cancer in whom combination chemotherapy with regimens containing fluoropyrimidine, oxaliplatin, and irinotecan had failed or was not tolerated. In May 2014, the FDA approved panitumumab for first-line treatment of patients with wild-type KRAS (exon 2) metastatic colorectal carcinoma in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX=4). !95] Approval was based on results from the PRIME trial. [94] The PRIME trial, a phase Ill study, showed that patients with wild-type KRAS tumors achieved statistically significant improvement in PFS with panitumumab and FOLFOX4 versus FOLFOX<4 alone (9.6 versus 8.0 months, P=0.02) and a nonsignificant improvement in OS versus FOLFOX<4 alone (23.9 versus 19.7 months, P =0.07). In contrast, patients with mutant KRAS had significantly reduced PFS with panitumumab-FOLFOX4. [41 Thus, panitumumab becomes an option, or an alternative to cetuximab, for patients who have tumors with wild-type KRAS. [95: 961 However, Hecht et al reported that adding panitumumab to bevacizumab and chemotherapy (oxaliplatin- and irinotecan-based) as first-line treatment of metastatic colorectal cancer resulted in increased toxicity and decreased PFS. [97] Ina randomized study of first-line treatment of metastatic colorectal cancer, Bokemeyer et al concluded that the overall response rate for cetuximab plus FOLFOX-4 was higher than with FOLFOX-4 alone. However, a statistically significant increase was seen only in patients with KRAS wild-type tumors, for whom the addition of cetuximab increased chance of response and lowered the risk of disease progression. [98 Douillard and colleagues reported that in addition to KRAS mutations in exon 2, additional RAS mutations (KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15) are associated with inferior PFS and OS with panitumumab-FOLFOX<4 treatment. [29] Other mutations that involve some of thekinases downstream from KRAS (such as BRAF and P/3K) are being investigated and may result in even more selective methods to identify patients that may benefit from EGFR inhibition. Ramucirumab The FDA approved ramucirumab for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer that has progressed on a firstine bevacizumab-, oxaliplatin- and fluoropyrimidine-containing regimen. The approval was based on the phase III RAISE trial, in which the ramucirumab-FOLFIRI combination improved overall survival and progression-free survival (13.3 months, 5.7 months) compared with placebo-FOLFIRI (11.7 months, 4.5 months) (P = 0.023 and < 0.001, respectively). [10] Regorafenib Regorafenib, a kinase inhibitor, was approved in September 2012. It is indicated for patients with metastatic colorectal cancer who have been previously treated with fiuoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; anti-VEGF therapy (eg, bevacizumab, ziv-aflibercept); and, if KRAS wild type, anti-EGFR therapy (eg, cetuximab, panitumumab), [101] Approval was based on a multicenter trial (n=760) that randomized patients at a 2:1 ratio to receive regorafenib in addition to best supportive care or placebo plus best supportive care. Statistically significant benefit in OS and PFS was observed for regorafenib over placebo in patients with metastatic colon cancer in whom all approved standard therapies had failed, [102] Ziv-aflibercept Ziv-aflibercept is a fusion protein that acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor (PIGF). This agent was approved for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin- containing fluoropyrimidine-based regimen. [1931 A phase Il trial by Van Cutsem and colleagues in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen found that the addition of ziv-aflibercept fluorouracil, leucovorin, and irinotecan (FOLFIRI) improves survival. Median survival time was 13.5 months with Ziv-aflibercept plus FOLFIRI versus 12.06 months with FOLFIRI alone (P = 0.0032); PFS was 6.90 versus 4.67 months, respectively (P < 0.0001). [104] Radiation Therapy Although radiation therapy remains a standard modality for patients with rectal cancer, it has only a limited role in colon cancer. Radiation therapy is not used in the adjuvant setting, and in metastatic settings it is used only for palliative therapy in selected metastatic sites such as bone or brain metastases. Newer, more selective ways of administering radiation therapy, such as stereotactic radiotherapy (CyberKnife) and tomotherapy, are currently being investigated. In the future, these techniques may extend the indications for radiotherapy in the management of colon cancer. A prospective, multicenter, randomized phase II study by Hendlisz et al showed that the addition of radioembolization with yttrium-90 significantly improved time to liver progression and median time to tumor progression in patients with unresectable, chemotherapy-refractory, liver-limited metastatic colorectal cancer. The study compared treatment with fluorouracil alone with fluorouracil plus yttrium-90 resin, which was injected into the hepatic artery. !°51 The US Food and Drug Administration (FDA) has approved yltrium-90 resin microspheres (SIR-Spheres) for the treatment of unresectable metastatic liver tumors from primary colorectal cancer in combination with adjuvant intra-hepatic artery chemotherapy with floxuridine. HER2-positive disease In a phase 2 proof-of-concept study, 27 heavily pretreated patients with HER2-positive metastatic colon cancer showed good response to a therapy regimen that is commonly used to treat HER2- positive breast cancer and does not include a chemotherapy backbone. The 27 patients in the study were identified through screening of 914 patients with KRAS exon 2 (codons 12 & 13) wild-type metastatic colorectal cancer, {708 107) Most of the patients had extensive metastatic disease and distal colon tumors, Almost 75% had received at least four prior treatment regimens and had spent a median total time of 20 months on previous treatments. Patients were treated with a combination of trastuzumab and lapatinib. At 1 year, 12 of the 27 patients (45%) were stil alive, At a median follow-up of 94 weeks, one patient (4%) had achieved a complete response, seven (26%) had achieved a partial response, and disease had stabilized in 12 patients (44%, [198, 107] Consultations Colorectal cancer, especially early stage disease, can be cured surgically. Following diagnosis and staging, obtaining surgical consultation for the possibility of resection may be appropriate. After surgery, the stage of the tumor may be advanced depending on the operative findings (eg, lymph node involvement, palpable liver masses, peritoneal spread) In the care of patients with colorectal cancer and isolated liver metastases, consider surgical consultation for possible resection. In some cases, resection of previously unresectable liver metastases may become feasible after cytoreduction with neoadjuvant chemotherapy. Therefore, ongoing involvement of the surgical oncologist is very important in patient care, even if the tumor is not considered resectable at the time of diagnosis. In patients with advanced disease, palliative surgery may be helpful in cases of bleeding or obstruction. Gastroenterology (Gl) consultation is critical for screening of high-risk individuals (ie, patients with a family history of colorectal cancer or polyposis syndromes) and those individuals who are found to be inappropriately iron deficient or to have occult blood on screening fecal examination. A colonoscopy or sigmoidoscopy is necessary to visualize the colon endoscopically, to obtain biopsies, or to resect polyps. GI consultation may also be necessary in the management of advanced disease. The advent of colorectal stents allows a nonsurgical management of impending obstruction in patients who present with unresectable, metastatic disease. GI consultation is necessary in the follow-up of patients after surgical resection and adjuvant chemotherapy. Patients must be screened for recurrent disease in the colon by colonoscopic examination at 1 year after surgery and then every 3 years. Long-Term MonitoringPooled analysis from several large adjuvant trials showed that 85% of colon cancer recurrences occur within 3 years after resection of primary tumor, with 95% occurring within 5 years. Therefore, patients with resected colon cancer (stage I! and Ill) should undergo regular surveillance for at least 5 years following resection. !1°8] Recommendations for post-treatment surveillance, from the European Society for Medical Oncology (ESMO), [95] the American Society for Clinical Oncology (ASCO), 198) and the National Comprehensive Cancer Network (NCCN) !"19l are compared in Table 2, below. Table 2. Surveillance recommendations for stage I! and II! colon cancer (Open Table in a new window) Parameter Organization ESMO [JSMO|(2013) ASCO (2013) ore) Every 3- Rey oe MO Every3-6 6 mo for for Sy, then — mofor3y, 2y, then History and physical exam every -12 Tg ates moat4andS notosy mo to 5 y y Every 3-6 mo Every > for 3, then p Every3mo 2, then CEA evey6-12 fey? Noe mo at 4 and 5 evary 8 y y Every 6-12 Chest CT* moforfirsts fYey TY evens y Att y, then every5y, Atty, 3 aly 4 after 4 dictated by, then Colonoscopy** ov oy a Sy thefindings every 5 on the yif thereafter previous negative colonoscopy Every 6- 12mo for up to Every 6-12 By; Abdominal CT mo for first 3 Every ty scans to y x include chest and pelvisESMO = European Society of Medical Oncology; JSMO = Japanese Society of Medical Oncology; ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network; CEA = carcinoembryonic antigen; CT = computed tomography * For patients at high risk for recurrence (eg, lymphatic or venous invasion, or poorly differentiated tumors). “Colonoscopy should be performed 3-6 mo postoperatively if preoperative colonoscopy was not done, due to an obstructing lesion; otherwise, colonoscopy in 4 y; if abnormal, repeat in 1 year; if no advanced adenoma (ie, villous polyp, polyp > 1 cm, or high-grade dysplasia), repeat in 3 y, then every 5 y. Followup should be guided by the patient's presumed risk of recurrence and functional status. Testing at the more frequent end of the range should be considered for patients at high risk, Patients with severe comorbid conditions that make them ineligible for surgery or systemic therapy should not undergo surveillance testing. !198 Cancer Care Ontario published guidelines for the follow-up care of survivors of stages Il and III colorectal cancer, and these were endorsed by the American Society of Clinical Oncology. The recommendations include the following [11, 108] * Surveillance is especially important in the initial 2-4 years following treatment, when most recurrences occur + Patients should be followed for 5 years, and regular reviews of medical history, physical examination, and carcinoembryonic antigen testing should be performed every 3-6 months + Annual computed tomography (CT) scanning of the abdomen and chest should be performed for 3 years * Pelvic CT scanning should be performed in patients with rectal cancer annually for 3-5 years * In patients who have not received pelvic radiation, a rectosigmoidoscopy should be performed every 6 months for 2-5 years + Asurveillance colonoscopy should be performed approximately 1 year after initial surgery + Patients should be counseled to maintain a healthy body weight, be physically active, and follow ahealthy diet Prevention Colorectal cancer prevention strategies fall into three categories:+ Screening (see Workup) + Lifestyle measures + Pharmacologic prevention Lifestyle measures Abundant epidemiologic literature suggests an association of risk for developing colorectal cancer with dietary habits, environmental exposures, and level of physical activity. For example, a prospective cohort study in the general population of two Danish cities concluded that if all participants had followed recommendations for five lifestyle factors (physical activity, waist circumference, smoking, alcohol intake, and diet), 23% of colorectal cancer cases might have been prevented. [112] There is also evidence that diet and physical activity affect the risk for recurrence of colon cancer. A prospective observational study involving patients with stage III colon cancer from the CALGB 89803 adjuvant chemotherapy trial demonstrated adverse effect with regards to risk for recurrence and increased mortality for patients following a "Western" diet (high intake of red meat, refined grains, fat, and sweets) versus a "prudent" diet (high intake of fruits and vegetables, poultry, and fish). [10] In another observational study from the same cohort of patients, patients were prospectively monitored and physical activity was recorded. The study concluded that physical activity reduces the risk of recurrence and mortality in patients with resected stage Ill colon cancer. {131 Morikawa et al reported that in patients with colorectal cancer that tested negative for cadherin- associated protein B 1 (CTNNB1 or B-catenin), high physical activity (=18 metabolic equivalent task [MET] hours/week) after diagnosis was associated with significantly better cancer-specific survival. No association between physical activity and survival was seen in CTNNB1-positive cases. [""4] In a study by Campbell et al, recreational physical activity before and after colorectal cancer diagnosis was associated with lower mortality. These researchers determined that 6 hours or more of sitting per day was associated with an increase in mortality compared with sitting 3 hours or less per day. The findings suggest that increasing physical activity helps reduce mortality in patients with colorectal cancer. 271 Pharmacologic prevention Pharmacologic prevention is based on the understanding of colorectal carcinogenesis and the availability of pharmacologic agents that are effective yet minimally toxic. The efficacy of these agents is usually first tested in high-risk populations. Celecoxib (Celebrex), a selective cyclooxygenase-2 inhibitor, was first tested in patients with familial adenomatous polyposis (FAP). Celecoxib was effective in decreasing the number and size of polyps on serial colonoscopies, which was the primary surrogate endpoint for this trial. {5 The drug was approved for FAP patients, although it remains to be seen whether this intervention translates to reduced cancer incidence and prolonged survival. Enthusiasm for cyclooxygenase-2 inhibitors as chemopreventive agents has dampened because of a high incidence of cardiovascular toxicity in trial patients, which led to the removal of rofecoxib from the market. Other nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac and nonselective cyclooxygenase inhibitors, have been tested in lower-risk populations. Aspirin use has been shown to be effective in both primary prevention of colorectal cancer (at doses of 300 mg or more daily for about 5 years !"16] ) and secondary prevention (at doses ranging from 81to 325 mg daily [117] ) of colorectal adenomas. The decrease in colon cancer risk with aspirin use may vary among population subgroups. However, body mass index, physical activity, and plasma C- peptide levels were shown to not have a significant impact on aspirin’s effect on colon cancer risk. (118) Examination of questionnaire data collected from the Nurses’ Health Study and the Health Professionals Follow-up Study showed regular aspirin use was associated with lower risk of BRAF — wild-type colorectal cancer (multivariable hazard ratio [HR], 0.73) but not with BRAF -mutated cancer risk (multivariable HR, 1.03). Status of tumor PTGS2 expression or PIK3CA or KRAS mutation had no effect on this association. [119] A 2013 study showed that low-dose aspirin taken every other day lowers the risk for colorectal cancer in middle-aged women. Nearly 40,000 women aged 45 and older were randomized to low-dose aspirin (100 mg) or placebo every other day for roughly 10 years; 84% were followed for an additional 7 years after treatment ended. At followup, colorectal cancer risk was lower in the aspirin group, mostly owing to a reduction in proximal colon cancer; this reduction in risk emerged after 10 years, (120) Some trials focused on combined inhibition of polyamine production and cyclooxygenase inhibition. A report from a large randomized trial of a combination of sulindac and dimethylformamine (DMFO), an inhibitor of omithine decarboxylase (ODC), described a dramatic effect of this combination in reducing polyp recurrence in patients with prior history of colon polyps. Confirmatory trials are ongoing. !121] Guidelines What to Read Next on Medscape Related Conditions and Diseases Colorectal Cancer Guidelines Colorectal Cancer and KRAS/BRAF Hereditary Colorectal Cancer Quiz: How Much Do You Know About Colorectal Cancer? Pediatric Colorectal Tumors Quiz: Do You Know the Risk Factors, Diagnostic Tests, and Treatment for Pancreatic Cancer? 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