Significant advances have been made over the past 10 years with respect to treatment of metastatic CRC. Five active cytotoxic agents have been approved during this time period—5-FU, the oral fluoropyrimidine analogs capecitabine and TAS-102, oxaliplatin, and irinotecan. In addition, 5 novel biologic agents and one small molecule inhibitor have been approved, including the anti-VEGF antibody bevacizumab; the recombinant fusion protein ziv-aflibercept, which targets VEGF-A, VEGF-B, and PlGF; the anti-VEGF-R2 antibody ramucirumab, which inhibits binding of the VEGF ligands VEGF-A, VEGF-C, and VEGF-D; the two anti-EGFR antibodies cetuximab and panitumumab; and the small molecule TKI inhibitor regorafenib. In general, a fluoropyrimidine—either intravenous 5-FU or oral capecitabine—serves as the main foundation of cytotoxic chemotherapy regimens. Recent clinical studies have shown that in tumors with wild-type KRAS and NRAS, FOLFOX/FOLFIRI regimens in combination with the anti-VEGF antibody bevacizumab or with the anti-EGFR antibody cetuximab or panitumumab result in significantly improved clinical efficacy with no worsening of the toxicities normally observed with chemotherapy. In order for patients to derive maximal benefit, they should be treated with each of these active agents in a continuum of care approach. Regorafenib and TAS102 are approved for the chemo-refractory disease setting, but unfortunately, each drug is associated with significant toxicities and only limited clinical efficacy with very low overall response rates; median progression-free survival is about 2-months. Given all of the available treatment regimens, median overall survival for metastatic CRC is now in the 28to 30-month range and, in some cases, approaches or even exceeds 3 years.
The incidence of gastric cancer, esophageal cancer, and pancreatic cancer is much lower than for CRC, but these malignancies tend to be more aggressive and result in greater tumor-related symptoms. In most cases, they cannot be completely resected surgically, as most patients present with either locally advanced or metastatic disease at the time of their initial diagnosis. 5-FU-based chemotherapy, using either intravenous 5-FU or oral capecitabine, is generally considered the main backbone for regimens targeting gastroesophageal cancers. In addition, cisplatin-based regimens in combination with either irinotecan or one of the taxanes (paclitaxel or docetaxel) also exhibit clinical activity. Response rates in the 40–50% range are now being reported. The addition of the biologic agent trastuzumab to cisplatin-containing chemotherapy regimens provides significant clinical benefit in metastatic gastric cancer patients whose tumors overexpress the HER-2/neu receptor. At present, the optimal fluoropyrimidine backbone has not been established, and either infused 5-FU or oral capecitabine can be combined with cisplatin plus trastuzumab. For second-line therapy, the combination of ramucirumab plus paclitaxel is recommended for patients with a good performance status and favorable comorbidity profile. In patients who are unable to tolerate more intensive therapy, single-agent ramucirumab or paclitaxel monotherapy are more appropriate treatment options.