Colorectal Cancer _ ___________________________________________________________________________
Stage IV colon cancer denotes distant metastatic disease, and therapeutic options for stage IV and recurrent disease include [201]: • Surgical resection of locally recurrent cancer • Surgical resection and anastomosis or bypass of obstructing or bleeding primary lesions in selected metastatic cases • Resection of liver metastases in selected metastatic patients (i.e., those for whom the five-year cure rate for resection of solitary or combination metastases exceeds 20%) or ablation in selected patients • Resection of isolated pulmonary or ovarian metastases in selected patients • Palliative radiation therapy • Palliative chemotherapy • Targeted therapy • Clinical trial enrollment As with colon cancer, surgical resection is the only potentially curative treatment for patients with locally recurrent, liver-only, or lung-only metastatic rectal cancer [201]. Patients with limited pulmonary metastasis and patients with both pulmonary and hepatic metastasis may also be considered for surgical resection, with five-year survival possible in highly selected patients [273; 274]. The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent [275]. Locally recurrent rectal cancer may be resectable, particularly after an inadequate prior operation. For patients with local recurrence alone after an initial attempted curative resection, aggressive local therapy with repeat low anterior resection and coloanal anastomosis, abdominoperineal resection, or posterior or total pelvic exenteration can lead to long-term disease-free survival [187; 276; 277]. The use of induction chemoradiation therapy for previously nonirradiated patients with locally advanced pelvic recurrence (i.e., pelvic side-wall, sacral, and/or adjacent organ involvement) may increase resectability and allow for sphincter preservation [263]. Intraoperative radiation therapy in patients who previously received external-beam radiation therapy may improve local control in patients with locally recurrent disease, with acceptable morbidity [278]. STAGE IV COLORECTAL CANCER WITH UNRESECTABLE OR MEDICALLY INOPERABLE METASTASES Pivotal studies have established the clinical use and/or FDA approval of chemotherapy and targeted therapy agents and regimens in metastatic colorectal cancer treatment. Unless stated otherwise, all outcomes are median values and all studies were randomized double-blinded with active or placebo control group. Outcomes are time-to-progression, progression-free survival, disease-free survival, and overall survival. Data from several studies suggest that there is little difference in clinical
outcomes when intensive therapy is given first-line versus when less intensive therapy is given first followed by more intensive combinations. Additionally, first-line combination therapy can be more toxic but not more effective [220; 279]. 5-FU When 5-FU was the only available chemotherapeutic option with colorectal cancer activity, trials in patients with locally advanced, unresectable, or metastatic disease showed partial response, prolonged time-to-progression of disease, and improved survival and quality of life compared with best supportive care only. Several trials analyzing the activity and toxicity of various 5-FU/leucovorin regimens found comparable results and median survival of roughly 12 months [280; 281; 282]. Capecitabine Randomized studies found capecitabine equivalent in efficacy to the 5-FU/leucovorin regimen [283; 284]. Other studies in metastatic colorectal cancer found non-inferiority between capecitabine/oxaliplatin (CAPOX) and 5-FU/oxaliplatin regimens as first-line therapy [285; 286]. Irinotecan and Oxaliplatin In patients with previously untreated metastatic colorectal cancer, adding irinotecan or oxaliplatin to 5-FU/leucovorin has led to improved treatment response, progression-free survival, and overall survival [287; 288; 289]. A comparison of FOLFOX4 against irinotecan, 5-FU, and leucovorin (IFL) showed progression-free survival of 8.7 vs. 6.9 months and overall survival of 19.5 vs. 15.0 months [290]. Comparisons of FOLFOX and FOLFIRI found identical progression-free survival and overall survival, although patients were allowed to cross over after progression. The toxicity profiles of the regimens differed [291; 292]. Patients randomized to FOLFIRI, modified IFL (mIFL), or capecitabine/irinotecan (CAPIRI) showed progression-free survival of 7.6 vs. 5.9 months with FOLFIRI vs. mIFL, and 7.6 vs. 5.8 months with FOLFIRI vs. CAPIRI. CAPIRI also led to the highest rates of grade 3 or greater nausea, vomiting, diarrhea, dehydration, and hand-foot syndrome [293]. FOLFOX and FOLFIRI are first-line treatments for patients with metastatic colorectal cancer, with FOLFIRI preferred when using irinotecan [293]. Oxaliplatin CAPOX was found comparable to 5-FU and oxaliplatin as an oxaliplatin-based regimen for first-line treatment of metastatic colorectal cancer [285; 286]. As second-line treatment following progression on irinotecan and 5-FU/leucovorin, patients randomized to FOLFOX4 or infusional 5-FU/leucovorin showed a median time-to-progression of 4.6 versus 2.7 months [294].
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