___________________________________________________________________________ Colorectal Cancer
Multimodality Therapy Multimodality therapy has been the standard of care for patients with locally advanced rectal cancer since 1990, when the National Cancer Institute recommended adjuvant therapy for stage II and III disease [205]. This was based on findings of 33% to 55% reduction in local recurrence and significant prolongation in disease-free survival. Although the National Cancer Institute recommended adjuvant therapy, subsequent findings have shown superior efficacy, lower toxicity, and better long-term outcomes with neoadjuvant therapy. The Institute now recommends neoadjuvant therapy as the preferred treatment option for patients with stages II or III disease [205; 258; 259; 260]. Preoperative radiation therapy is more effective because well-oxygenated tissue responds better to irradiation; postoperative tissue is relatively hypoxic from surgery and may be more resistant to radiation therapy. Also, postoperative complications may delay initiating adjuvant therapy [261]. Neoadjuvant Chemoradiation Therapy As stated, neoadjuvant chemoradiation therapy is the preferred treatment option for patients with stage II or III disease, although adjuvant chemoradiation therapy remains an acceptable option [205]. Preoperative chemoradiation therapy is the standard of care for patients with clinically staged T3–T4 or node-positive disease (stages II/III) with benefits found in multiple trials, including [205]: • Tumor regression and downstaging • Improved tumor resectability • Higher rates of local control • Improved toxicity profile of chemoradiation therapy • Higher rates of sphincter preservation The most common neoadjuvant regimens for locally advanced tumors of the mid and lower third of the rectum are [261; 262; 263]: • Short-course radiation therapy with 5 Gy daily for five days, followed by surgery within one week. This approach results in a lower rate of grade 3/4 acute toxicity and better compliance. It is more commonly used when tumor regression and downsizing would not improve resection or sphincter preservation. • Long-course chemoradiation therapy using 45 to 50.4 Gy over 5 to 6 weeks with concurrent administration of 5-FU, followed by surgery 8 to 12 weeks later. Tumor regression and downsizing is more likely, making sphincter-preserving surgical procedures more feasible. When followed by proper surgical approach and execution, both regimens provide excellent local control for locally advanced tumors. Combined neoadjuvant radiation therapy and surgery may result in substantial long-term morbidity, including chronic bowel, sphincter, and sexual dysfunction, making careful selection of patients with greatest
potential benefit from radiation therapy essential [264; 265]. Neoadjuvant radiation therapy or chemoradiation therapy should not be used in low-risk operable rectal cancer [238]. Adjuvant Therapy Compared with adjuvant chemoradiation therapy, preoperative chemoradiation therapy is preferred because it decreases local recurrence and adverse effects. However, the evidence demonstrates that compared to observation alone or radiation therapy alone following surgery, adjuvant chemoradiation therapy improves survival and reduces local recurrence rates in patients with resected stage II or III rectal cancer who have not received preoperative radiation therapy [230; 258]. Many patients do not benefit from conventional 5-FU therapy, and introduction of newer chemotherapy regimens and biologic agents in colon cancer have prompted efforts to enhance survival benefits by optimizing radiation sensitization and chemotherapeutic selection and delivery. The NCCN now recommends m(modified)FOLFOX, CAPEOX, FOLFIRINOX, or mFOLFIRINOX as adjuvant chemotherapy in stage II/III rectal cancer. This comes with the caveat that conclusive data in rectal cancer are lacking, with recommendation for use in rectal cancer based solely on extrapolation of colon cancer data [230]. The merit of adding oxaliplatin to adjuvant 5-FU/ leucovorin in stage II/III rectal cancer is the subject of ongoing debate due to issues with acute toxicity [205]. Radiotherapy Toxicity The greater toxicity concerns with pelvic irradiation of rectal cancer involve potential late-onset morbidity. Relative to patients receiving surgical resection alone, those with additional radiation therapy treatment have shown increased risks of chronic bowel problems, sphincter dysfunction, sexual dysfunction, and elevated risk of surgical morbidity [258]. The improved local tumor control with neoadjuvant radiation therapy should be weighed against greater risks for acute toxicity (e.g., pelvic or perineal wound infection) and chronic/ late-onset toxicity (e.g., stool frequency and incontinence problems, pelvic fractures, worsening sexual function). The frequency of these adverse effects found in patients receiving radiation therapy plus surgery versus surgery-only includes fecal incontinence in 62% vs. 38%, and urinary incontinence requiring pad wearing in 56% vs. 33%, respectively [258]. CHEMOTHERAPY AGENTS AND REGIMENS USED IN ADVANCED COLON AND RECTAL CANCER Chemotherapy is the primary therapeutic modality for stage IV, metastatic, and recurrent colorectal cancer and the first treatment option for unresectable or metastatic tumors. Metastases develop in at least 50% of patients with colorectal cancer, and most metastatic tumors are unresectable. Management of metastatic colorectal cancer involves a continuum of care with sequential use of a variety of active agents in combination or as single agents. The choice of therapy
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