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Chapter: Basic & Clinical Pharmacology : Cancer Chemotherapy

Gastrointestinal Cancers

Colorectal cancer (CRC) is the most common type of gastrointestinal malignancy.


Colorectal cancer (CRC) is the most common type of gastrointestinal malignancy. Nearly 145,000 new cases are diagnosed each year in the USA; worldwide, nearly one million cases are diagnosed each year. At the time of initial presentation, only about 40–45% of patients are potentially curable with surgery. Patients presenting with high-risk stage II disease and stage III disease are candidates for adjuvant chemotherapy with an oxaliplatin-based regimen in com-bination with 5-FU plus leucovorin (FOLFOX or FLOX) or with oral capecitabine (XELOX) and are generally treated for 6 months following surgical resection. Treatment with this combination regi-men reduces the recurrence rate after surgery by 35% and clearly improves overall patient survival compared with surgery alone.

Significant advances have been made over the past 10 years with respect to treatment of metastatic CRC. There are four active cytotoxic agents—5-FU, the oral fluoropyrimidine capecitabine, oxaliplatin, and irinotecan; and three active biologic agents—the anti-VEGF antibody bevacizumab and the anti-EGFR antibodies cetuximab and panitumumab. In general, a fluoropyrimidine with either intravenous 5-FU or oral capecitabine serves as the main foundation of cytotoxic chemotherapy regimens. Recent clinical studies have shown that FOLFOX/FOLFIRI regimens in combi-nation with the anti-VEGF antibody bevacizumab or with the anti-EGFR antibody cetuximab result in significantly improved clinical efficacy with no worsening of the toxicities normally observed with chemotherapy. In order for patients to derive maxi-mal benefit, they should be treated with each of these active agents in a continuum of care approach. Using this strategy, median survivals now are in the 24–28 month range, and in some cases, approach 3 years. One of the main challenges facing clinicians at present is to begin to identify which patients would benefit from these various cytotoxic and biologic agents as well as identify those who might experience increased toxicity.

The incidence of gastric cancer, esophageal cancer, and pancre-atic 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 (pacli-taxel or docetaxel) also exhibit clinical activity. Response rates in the 40–50% range are now being reported. Recent studies have shown that the addition of the biologic agent trastuzumab to cis-platin-containing chemotherapy regimens provides significant clinical benefit in gastric cancer patients whose tumors overexpress the HER-2/ neu receptor. In addition, neoadjuvant approaches with combination chemotherapy and radiation therapy prior to surgery appear to have promise in selected patients.

Although gemcitabine is approved for use as a single agent in metastatic pancreatic cancer, the overall response rate is less than 10%, with complete responses being quite rare. Intense efforts con-tinue to be placed on incorporating gemcitabine into various com-bination regimens and on identifying novel agents that target signal transduction pathways thought to be critical for the growth of pan-creatic cancer. One such agent is the small molecule inhibitor erlo-tinib, which targets the EGFR-associated tyrosine kinase. This agent is now approved for use in combination with gemcitabine in locally advanced or metastatic pancreatic cancer although the improvement in clinical benefit is relatively small. There is also evidence to sup-port the use of adjuvant chemotherapy with either single-agent gemcitabine or 5-FU/leucovorin in patients with early-stage pancre-atic cancer who have undergone successful surgical resection.

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Basic & Clinical Pharmacology : Cancer Chemotherapy : Gastrointestinal Cancers |

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