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Recognizing Patient Subtypes in Late-line Colorectal Cancer for Selection of Targeted Therapy
Hyunjee Song, 2018 PharmD Candidate, and Michael R. Page, PharmD, RPh
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Recognizing Available Therapies and Treatment Differences Within Classes in Colorectal Cancer
David Bai, 2018 PharmD Candidate, and Michael R. Page, PharmD, RPh
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Recognizing Available Therapies and Treatment Differences Within Classes in Colorectal Cancer

David Bai, 2018 PharmD Candidate, and Michael R. Page, PharmD, RPh
Treatments for Colon Cancer
Although colorectal cancer involves cancers of both the colon and rectum, we will focus in this article on available treatments for colon cancer. Treatment options for colon cancer, as for other cancers, include surgery, chemotherapy, targeted therapy, and radiation. Clinical trials also may be considered if none of the other therapies are appropriate for the patient.
Surgical Therapy
Surgery is an important treatment option for colon cancer, as surgical resection may successfully eliminate early-stage tumors. The types of surgery for colon cancer include colectomy, the most common for this disease, and it involves removing only the portion of the colon that contains cancer. Colostomy, another surgical option, results in the necessity of diverting stool from the large bowel directly to an abdominal opening. Lymphadenectomy is surgery that may be required if cancer has spread to the lymph nodes, while metastasectomy is often necessary if cancer has metastasized to other organs and must be removed.9
Radiation, a classic form of cancer treatment, involves the use of high-energy waves to damage DNA and either prevent replication or cause cell death. The form used most often is external beam radiation therapy; other options including intraoperative radiation therapy and brachytherapy. In brachytherapy procedures, radiation is delivered using radioactive devices implanted directly into tissue.9
Chemotherapeutic drugs are used to slow the spread of cancer by inhibiting cell replication. A chemotherapy regimen usually includes several medications. While less-intensive regimens of 5-fluorouracil/leucovorin or capecitabine/irinotecan may be used in selected patients, more-intensive chemotherapy regimens include folinic acid-fluororuracil-oxaliplatin (FOLFOX), folinic acid-fluorouracil-irinotecan (FOLFIRI), and capecitabine-oxaliplatin (CAPEOX).9 Table 1 contains a full list of medications approved for use in colon cancer and FDA-approved indications for each treatment.10-14
Capecitabine is an oral chemotherapeutic medication indicated for use as first-line monotherapy in patients with metastatic colon cancer or as an adjuvant therapy in treating colon cancer with or without other chemotherapeutic medications. Capecitabine works by converting itself to 5-fluorouracil in vivo through enzymes. Afterwards, 5-fluorouracil is metabolized into 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). FdUMP binds to thymidylate synthase to form a ternary complex. This inhibits the formation of thymidylate, a precursor of thymidine triphosphate, which is necessary for the synthesis of DNA. FUTP can be mistakenly incorporated in place of uridine triphosphate (UTP) during synthesis of RNA. This can interfere with RNA processing and protein synthesis.10 In a phase III clinical trial of patients with metastatic colorectal cancer, capecitabine demonstrated its noninferiority to 5-fluorouracil/leucovorin therapy on measures of overall survival (OS) and progression-free survival (PFS).15
The combination of 5-fluorouracil and leucovorin has been approved for use in multiple cancers including adenocarcinomas of the colon and rectum. Importantly, 5-fluorouracil is an infused treatment that has the same mechanism of action as oral capecitabine. In vivo, 5-fluorouracil forms FdUMP, which inhibits the formation of thymidylate, and FUTP, which is incorporated in place of UTP during the synthesis of RNA.11 Leucovorin is required when using 5-fluorouracil because it enhances the binding of 5-fluorouracil to an enzyme within cancer cells to enhance its duration of action.16 The efficacy of 5-fluorouracil in combination with leucovorin has been demonstrated in multiple trials for several types of cancer. However, in patients with advanced colorectal cancer, a clinical trial showed that the addition of leucovorin was associated with a significantly higher response rate than 5-fluorouracil alone (43% vs 10%, P = .001).17
Oxaliplatin is a platinum-based chemotherapeutic medication indicated for use in advanced colon cancer and as adjuvant treatment of stage III colon cancer among patients who have undergone complete resection of the primary tumor. Oxaliplatin works by forming intrastrand and interstrand crosslinks within DNA, which inhibit DNA replication and transcription.12 In the phase III MOSAIC trial, 5-fluorouracil/leucovorin was compared with FOLFOX. In this trial, among patients with stage II and III colon cancer, the probability of surviving 6 years was superior in the FOLFOX group compared with patients receiving 5-fluorouracil/leucovorin (72.9% vs 68.7%: P = .023). However, results between the 2 regimens were similar in patients with stage II colon cancer (86.9% with FOLFOX vs 86.8% with 5-fluorouracil/leucovorin, P = .986).18
Irinotecan is indicated for use in combination with 5-fluorouracil/leucovorin for those with metastatic colon cancer. It also is indicated as a single agent for patients whose disease has progressed following 5-fluorouracil/leucovorin therapy. Irinotecan works by binding to topoisomerase I-DNA complex and preventing the religation of these single-strand breaks.13 In a trial comparing 5-fluorouracil/leucovorin alone with 5-fluorouracil/leucovorin plus irinotecan, patients receiving the irinotecan-containing regimen showed superior outcomes in all primary outcomes tested. Response rates were higher in the irinotecan group compared with patients receiving 5-fluorouracil/leucovorin alone (50% vs 28%: P <.0001). Time to disease progression (7.0 vs 4.3 months; P = .004) and median survival (14.8 months vs 12.6 months; P = .042) were also significantly longer in patients receiving FOLFIRI.19
Trifluridine and Tipiracil (Lonsurf)
Lonsurf is the brand name of a chemotherapy agent that combines 2 drugs, trifluridine and tipiracil. It is used as third-line therapy for metastatic colorectal cancer for patients previously treated with fluoropyrimidine, irinotecan, oxaliplatin, and anti-VEGF therapy, and, if RAS wild type, anti-EGFR therapy. Lonsurf may also work against wild-type KRAS. Trifluridine is incorporated into DNA, interfering with DNA synthesis and cell replication. Tipiracil, a thymidine phosphorylase inhibitor, increases exposure of trifluridine.14 From these 2 mechanisms of actions, cancer cells are killed due to DNA damage. Lonsurf is a relatively new therapy, approved in 2015 after the results of the phase III RESOURCE trial were released. In this trial, Lonsurf was compared to best supportive care and found superior in PFS (2.0 months vs 1.7 months; P <.001) and OS (7.1 months vs 5.3 months; P <.001).20

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