___________________________________________________________________________ Colorectal Cancer
Diagnosis In general, the imaging appearances of liver metastases are non- specific, requiring biopsy specimens for histologic diagnosis. CT is the imaging modality of choice for evaluating hepatic metastases. CT permits better evaluation of the involvement of extrahepatic tissues, including the bones, bowel, lymph nodes, and mesentery. MRI may be superior to CT and PET scan for detection and characterization of small lesions [323]. Surgery Advances in chemotherapy have steadily improved survival in patients with colorectal cancer liver metastases, with trials now reporting a median survival of 20 months. However, with chemotherapy alone, five-year survival has been poor historically—less than 1%. This has been modestly improved in trials using FOLFOX and/or FOLFOXIRI, with five-year survival rates of 5% to 10% [300; 324]. Despite advances in chemotherapy, liver resection is the best option for achieving long-term survival and may be curative in stage IV disease con- fined to the liver [325; 326]. Resection of liver metastases with clear margins is associated with a 5-year survival rate of 45% and 10-year overall survival rate of 25% [285; 327; 328; 329]. Hepatic metastases are considered suitable for resection based
• Arm A: Fluoropyrimidine/oxaliplatin • Arm B: Fluoropyrimidine/oxaliplatin/cetuximab • Arm C: Intermittent fluoropyrimidine/oxaliplatin In patients receiving chemotherapy plus placebo versus cetuximab, the overall survival was 17.9 vs. 17.0 months and progression-free survival was 8.6 vs. 8.6 months. In patients treated continuously (arm A) versus intermittently (arm C), median survival was 15.8 vs. 14.4 months [315; 316]. None of these findings were statistically significant. In a separate study, patients with EGFR-expressing metastatic colorectal cancer were randomized to first-line FOLFOX-4 plus cetuximab or placebo. The participants did not differ in response rate or progression-free survival. However, in patients with KRAS wild-type tumors, the response rate was 61% vs. 37% and progression-free survival was 7.7 vs. 7.2 months. In contrast, patients with KRAS mutant tumors showed progression-free survival of 5.5 vs. 8.6 months [317]. Panitumumab Panitumumab is approved for use in patients with chemo- therapy-refractory metastatic colorectal cancer. In clinical trials, panitumumab as single agent or combination therapy demonstrated improvements in progression-free survival and overall survival comparable to cetuximab [318; 319; 320]. Regorafenib The safety and efficacy of regorafenib was evaluated by a single clinical trial of 760 patients with previously treated metastatic colorectal cancer. Participants were randomized to regorafenib or placebo plus best supportive care and showed a median overall survival of 6.4 vs. 5.0 months [321]. Second-Line Chemotherapy Second-line chemotherapy with irinotecan in patients treated with 5-FU/leucovorin as first-line therapy led to improved overall survival versus infusional 5-FU or supportive care [322]. Conversely, patients who progressed on irinotecan and 5-FU/ leucovorin and then received FOLFOX4 or 5-FU/leucovorin showed a median time-to-progression of 4.6 vs. 2.7 months [304]. Tucatinib plus trastuzumab had clinically meaningful anti-tumor activity and favorable tolerability. This combina- tion is the first FDA-approved anti-HER2-positive regimen for metastatic colorectal cancer [235]. TREATMENT OF LIVER METASTASES Approximately 15% to 25% of patients with colorectal cancer will present with liver metastases at diagnosis, and another 25% to 50% will develop metachronous hepatic metastasis after resection of the primary tumor. Only a small proportion of patients with hepatic metastases are candidates for surgical resection, but advances in tumor ablation techniques and regional and systemic chemotherapy administration have now expanded the treatment options [203].
on the following criteria [203]: • Limited number of lesions • Intrahepatic location of lesions • Lack of major vascular involvement • Absent or limited extra-hepatic metastases • Sufficient functional hepatic reserve
Cancer Care Ontario recommends that patients with extra- hepatic metastases limited to the lungs may be suitable for liver resection if all pulmonary metastases are eradicated [327]. Studies of patients with combined liver and lung resec- tion found three-year survival of 36% to 59%, and five-year survival of 9% to 74% [330]. The study showing 74% survival at five years calculated survival from the first metastasectomy instead of the more common second metastasectomy (usually the lungs). Median survival was 42 months when calculated from last metastasectomy [331]. Pooled data from all studies showed five-year survival of 30% [330]. Routine liver resection is not recommended in patients with portal nodal disease or non-pulmonary extra-hepatic metastases [327]. Liver resection is recommended in patients with initially unresectable liver metastases sufficiently downstaged by neo- adjuvant chemotherapy [203]. If complete resection has been achieved, adjuvant chemotherapy should be used; neoadjuvant chemotherapy in patients without extra-hepatic metastases led to complete resection in 15% to 36%, and the five-year survival in these patients (33% to 42%) is similar to survival in patients with liver metastases considered resectable without chemotherapy [203; 330]. Consensus is lacking on the best regimen to convert isolated liver metastases from unresectable to resectable [203].
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