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rectal cancers It has long been controversial whether chemoradiation should be administered preoperatively ( neoadjuvant ) or postoperatively ( adjuvant ) Neoadjuvant therapy may decrease the size of the tumor before surgery (tumor downstaging), allowing more patients to undergo curative resection with sphincter preservation rather than abdominoperineal resection When initial imaging studies suggest stage I disease, surgery may be performed first, followed by postoperative chemoradiation in patients found at surgery to have more advanced (stage II or III) disease A recent, large, randomized controlled trial reported that preoperative therapy led to better patient treatment compliance, reduced local recurrence and toxicity, and a higher number of sphincterpreserving resections Therefore, preoperative chemoradiation increasingly is recommended for patients with distal rectal cancers that are determined to be stage II or III by endorectal ultrasound or MRI

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patients with Stage III disease Current studies are evaluating oral capecitabine in combination with oxaliplatin The role of combination adjuvant therapy of FOLFOX plus a biologic agent (bevacixumab, cetuximab, or panituxumab) also is under investigation 4 Stage IV (metastatic disease) Approximately 20% of patients have metastatic disease at the time of initial diagnosis, and another 30% eventually develop metastasis The long-term survival of these patients is only 5%, and the median survival is only 6 months in the absence of other treatment Resection of isolated (one to three) liver or lung metastases may result in long-term (over 5 years) survival in 35 55% of cases For those with unresectable hepatic metastases, local ablative techniques (cryosurgery, radiofrequency or microwave coagulation, embolization, hepatic intra-arterial chemotherapy) may provide long-term tumor control Approximately 20% of patients with metastatic disease respond to chemotherapy regimens containing intravenous 5-FU and folinic acid (leucovorin) or the oral 6-FU analog capecitabine, prolonging median survival to about 11 months However, the addition of either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI; IFL) to 5-FU and folinic acid provides further improvement in tumor response rate (40%) and median survival (15 20 months) Currently, FOLFOX and FOLFIRI are the preferred first-line treatment regimens for most patients with metastatic colorectal cancer Patients progressing with one regimen may respond to the alternative regimen, prolonging mean survival to > 20 months The role of oral capecitabine (instead of intravenous 5-FU) in combination with oxaliplatin or irinotecan is under investigation The most recent advance in the treatment of metastatic colon cancer is the development of the biologic agents, cetuximab, panitumumab, and bevacizumab The role of these agents is rapidly evolving Cetuximab and panitumumab are monoclonal antibodies to EGFR; bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) Combination therapy with bevacizumab and FOLFOX or FOLFIRI prolong mean survival 2 5 months compared with either regimen alone Therefore, many oncologists are now using one of these combinations for initial therapy of metastatic disease Bevacizumab may cause serious thromboembolic events (including stroke and myocardial infarction) in 5% of patients Cetuximab and panitumumab have modest efficacy when used as single agents for second-line therapy in patients whose disease has progressed on chemotherapeutic regiments containing 5-FU, irinotecan, or oxaliplatin The role of these agents in combination with FOLFOX and FOLFIRI is under investigation Similarly, the role of combination therapy of bevacizumab plus cetuximab or panitumumab with or without other agents requires further study.

Patients who have undergone resections for cure are followed closely to look for evidence of symptomatic or asymptomatic tumor recurrence that may be amenable to curative resection in a small number of patients The optimal cost-effective strategy is not clear Two randomized trials reported that intense follow-up with yearly colonoscopy, abdominal CT, and chest radiography did not improve overall outcome compared with most standard follow-up protocols Patients should be evaluated every 3 6 months for 3 5 years with history, physical examination, and CEA determinations Patients who had a complete preoperative colonoscopy should undergo another colonoscopy 1 year after surgical resection Patients who did not undergo full colonoscopy preoperatively should undergo colonoscopy within 3 6 months postoperatively to exclude other synchronous colorectal neoplasms and 1 year thereafter Thereafter, surveillance colonoscopy should be performed every 3 5 years to look for metachronous polyps or cancer Because of the high incidence of local tumor recurrence in patients with rectal cancer, sigmoidoscopy should be performed every 3 6 months for 3 years New onset of symptoms or a rising CEA warrants investigation with chest and abdominal CT to look for recurrent or metastatic disease that may be amenable to therapy For patients with a rising CEA with unrevealing CT imaging, a PET scan is more sensitive for the detection of occult metastatic disease

The stage of disease at presentation is the most important determinant of long-term survival: stage I, > 90%; stage II, 70 80%; stage III with fewer than four positive lymph nodes, 67%; stage III with more than four positive lymph nodes, 33%; and stage IV, 5 7% For each stage, rectal cancers have a worse prognosis For those patients whose disease progresses despite therapy, meticulous efforts at palliative care are essential (see 5)

FIGURE 2-8

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