Recognizing Available Therapies and Treatment Differences Within Classes in Colorectal Cancer

Recognizing Available Therapies and Treatment Differences Within Classes in Colorectal Cancer David Bai, 2018 PharmD Candidate, and Michael R. Page, PharmD, RPh COLORECTAL CANCERS INCLUDE CANCERS of both the colon and rectum. Cancer cells may stay localized to the colon or rectum, or may grow into surrounding tissues and travel to other organs. Left untreated, cancer may lead to complications that affect normal body functions, eventually resulting in death. Colorectal cancer is the third leading cause of cancer-related deaths in women and the second in men in the United States, and is estimated to cause 50,260 deaths in this country in 2017 alone. 1 Optimizing treatments and creating treatment innovations for colorectal cancer remain important priorities for clinicians, researchers, and managed care professionals. Risk Factors for Colorectal Cancer Factors associated with an increased risk of developing colorectal cancer relate to age, ethnic background, and comorbidities. As in many other types of cancer, the probability of developing colorectal cancer increases with advancing age; individuals 50 years or older are at greater risk than those younger. Patients of certain ethnic backgrounds, including African American or Ashkenazi Jewish descent, may also be at increased risk. 2 Certain comorbidities and genetic conditions may increase the risk of developing colorectal cancer. These predisposing comorbidities include type 2 diabetes and inflammatory bowel diseases, including ulcerative colitis and Crohn s disease. 3 The genetic diseases associated with an increased risk of developing colorectal cancer include Lynch syndrome, familial adenomatous polyposis (FAP), Turcot syndrome, Peutz-Jehgers syndrome, and MUTYH-associated polyposis. 2,3 Modifiable lifestyle-related risk factors include obesity, lack of exercise, poor diet, tobacco use, and alcohol use. 4 Screening and Testing for Colorectal Cancer Screening and testing for colorectal cancer is key to early detection. In some cases, signs may be detected in an ordinary physical exam through palpation for abdominal masses or through a digital rectal exam. Other tests may include examination of stool for presence of blood, and evaluation of patients for laboratory abnormalities such as anemia, liver enzyme elevations, and certain tumor markers, which are detectable through a blood test. 5 Although results of the above tests may raise clinical suspicion of colorectal cancer, these tests alone are not sufficient to establish a diagnosis. For a definitive diagnosis, colonoscopy is required, which involves inserting a colonoscope into the rectum to examine intestinal tissue. During a colonoscopy, biopsies may be performed and tissues may be examined by a pathologist; polyps may also be resected to reduce the risk of progression to colon cancer. 5 Imaging tools may also be used to evaluate patients, including computed topography scanning, ultrasound, magnetic resonance imaging, chest X-ray, positron emission topography, and angiography. Angiography and use of a radioactive form of sugar may be used to determine the metabolic activity of cancer cells to further characterize tumors. Imaging tests may help identify whether or not tumors have spread to other locations in the body, including the lungs and brain. 5 Screening for colorectal cancer varies depending on a patient s risk of developing cancer. For the most patients, screening through colonoscopy should be performed starting at age 50, with repeat testing every 10 years. Alternative methods may include flexible sigmoidoscopy every 5 years or fecal immunochemical testing annually. 6 More frequent testing is required in patients with a greater risk of cancer due to presence of certain risk factors. For instance, patients with inflammatory bowel disease (IBD) require a colonoscopy within 8 years of receiving their IBD diagnosis. After testing, they will be categorized as low-risk or high-risk, requiring repeat testing every 2 to 3 years or every year, respectively. 7 Patients with certain genetic conditions, such as FAP and Lynch syndrome, require earlier and more frequent testing for colorectal cancer. For patients who have been definitively diagnosed with FAP via a genetic test, an annual colonoscopy is required beginning as early as age 10 years, and no later than age 15 years. Similarly, patients whose genetic test indicates Lynch syndrome may require an initial colonoscopy between the ages of 20 and 25» AJMC : Evidence-Based Oncology AUGUST 2017 13

TABLE 1. FDA-Approved Treatments for Colon Cancer 10-14 NONTARGETED THERAPY DRUG Capecitabine (Xeloda) 5-fluorouracil/leucovorin (Adrucil) Oxaliplatin (Eloxatin) Irinotecan (Camptosar) Trifluridine/Tipiracil (Lonsurf) Adjuvant treatment for colon cancer First-line monotherapy for colon cancer PACKAGE INSERT DRUG INDICATION Adenocarcinoma of the rectum or the colon Advanced colorectal cancer Adjuvant treatment for those who have stage III colon cancer and had a complete resection of the primary tumor First-line therapy with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum Patients whose colon/rectal cancer has progressed following 5-fluorouracil and leucovorin treatment Metastatic colorectal cancer for patients previously treated with fluoropyrimidine, irinotecan, oxaliplatin, VEGF, and, if RAS wild type, EGFR May work against KRAS mutation wild types years, or 2 to 5 years prior to reaching the age at diagnosis of the person in the family who was youngest when diagnosed with colorectal cancer (whichever is earlier). Afterwards, patients may require further screenings every 1 to 2 years. 8 Because family history is also a risk factor for colorectal cancer, patients with relatives who have developed colorectal cancer may require earlier screening than members of the general population. For patients with 1 or more first-degree relatives who developed colorectal cancer, regardless of age at diagnosis, a colonoscopy is recommended beginning at age 40, or 10 years prior to reaching the age at diagnosis of the person in the family who was youngest when diagnosed with colorectal cancer (whichever is earlier). Afterwards, colonoscopies should be repeated every 5 to 10 years. For patients with 1 or more second-degree relative aged less than 50 years at diagnosis, colonoscopies should begin at age 50 years and be repeated every 5 to 10 years. 7 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 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 Chemotherapy 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 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 14 AUGUST 2017 AJMC : Evidence-Based Oncology

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 5-Fluorouracil/Leucovorin 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 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 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 Because of their specificity, targeted therapies may be less toxic than traditional chemotherapeutic treatements. 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 Targeted Therapy Targeted therapies work against cancer by blocking or interfering with certain receptors or molecules that are involved in the growth, progression, or spread of cancer. Because of their specificity, targeted therapies may be less toxic than traditional chemotherapeutic treatments. Additionally, targeted therapies are generally used only in patients with specific genetic markers, a distinct subset.» AJMC : Evidence-Based Oncology AUGUST 2017 15

TABLE 2. FDA-Approved Targeted Therapies for Colon Cancer 21-26 TARGETED THERAPY DRUG Bevacizumab (Avastin) Cetuximab (Erbitux) Panitumumab (Vectibix) Ramucirumab (Cyramza) Regorafenib (Stivarga) Ziv-aflibercept (Zaltrap) PACKAGE INSERT DRUG INDICATION Metastatic colorectal cancer with intravenous 5-fluorouracil based chemotherapy for first-line or second-line treatment Metastatic colorectal cancer with fluoropyrimidine-, irinotecan-, or fluoropyrimidineoxaliplatin based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen Treatment of KRAS wild type, EGFR-expressing metastatic colorectal cancer: As a single agent after failure of both irinotecan- and oxaliplatin-based regimens or in patients who are intolerant to irinotecan In combination with FOLFIRI for first-line treatment In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy Treatment of wild-type RAS in metastatic colorectal cancer: In combination with FOLFOX for first-line treatment Monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy In combination with FOLFIRI for the treatment of metastatic colorectal cancer after prior therapy of bevacizumab, oxaliplatin, and fluoropyrimidine Metastatic colorectal cancer; previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vegf therapy, and, if KRAS wild type, an anti-egfr therapy In combination with FOLFIRI for metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen Below, we summarize available targeted therapies for colon cancer (see also Table 2). 21-26 Anti-EGFR Targeted Therapy EGFR, a cellular-signaling receptor, has an important role in cell development, proliferation, and differentiation. 27 Two EGFR-targeted therapies effectively used for colon cancer treatment are cetuximab and panitumumab, but only after a patient has been genetically tested for the KRAS mutation. These anti-egfr treatments are generally used only in patients with wild-type KRAS; they should be avoided by patients with KRAS-mutated cancers. 28 Cetuximab is a chimeric product with both murine and human portions of its sequence. 28 In a trial that compared the resection rates of chemotherapy alone versus the combination of cetuximab and chemotherapy in patients with metastatic colorectal cancer with unresectable liver metastases, cetuximab was shown to significantly improve rates of complete resection (25.7% with cetuximab/chemotherapy vs 7.4% with chemotherapy alone; P <.01). Not only was the resection rate in this trial improved, but a meta-analysis of 4 separate trials revealed that the addition of cetuximab or panitumumab to chemotherapy improved rates of complete resection by 11% to 18% (P =.04). 27 Two other trials, CRYSTAL and OPUS, have also demonstrated the benefits of cetuximab in the treatment of patients with metastatic colorectal cancer. In CRYSTAL, patients assigned to FOLFIRI and cetuximab compared with FOLFIRI alone demonstrated greater PFS (9.9 months vs 8.7 months; P =.02) and OS (23.5 months vs 20.0 months; P =.0093). In OPUS, response rates were higher in patients who received FOLFOX and cetuximab in combination compared with patients receiving FOLFOX alone (61% vs 37%; P =.011). 27 Panitumumab differs from cetuximab in that it is a fully human antibody. 28 PRIME was the major trial involved in the approval of panitumumab, and in the panitumumab and FOLFOX combination group versus the FOLFOX-only group, the addition of panitumumab resulted in both better PFS (10 months vs 8.6 months; P =.01) and OS (23.9 months vs 19.7 months; P =.17). 29 Anti-VEGF Targeted Therapy VEGF, an angiogenic factor, is another target for treatment of colorectal cancer. Signaling of VEGF stimulates the proliferation of endothelial cells and blood vessel growth. 9 One of these treatments is bevacizumab, a humanized anti-vegf monoclonal antibody that inhibits VEGF-A from binding to its receptors, thereby inhibiting angiogenesis. In patients with metastatic colorectal cancer, the addition of bevacizumab to an oxaliplatin-based regimen significantly improved PFS (9.4 months vs 8.0 months; P =.0023), but no improvement in OS was detected. In another trial, the addition of bevacizumab to a FOLFOX regimen was associated with an improvement in OS (12.9 months vs 10.8 months; P =.0011). 27 16 AUGUST 2017 AJMC : Evidence-Based Oncology

Other anti-vegf drugs include ziv-aflibercept, ramucirumab, and regorafenib. Ziv-aflibercept is a humanized recombinant fusion protein. Instead of binding to the VEGF receptor directly, this medication binds to VEGF itself, preventing VEGF from attaching to the receptor and initiating angiogenesis. In the VELOUR trial, OS improved for patients receiving ziv-aflibercept in combination with FOLFIRI versus those receiving FOLFIRI alone (13.5 months vs 12.1 months; P =.003). 27 Ramucirumab, too, prevents VEGF from binding to its associated receptors and promoting angiogenesis. In the phase III trial RAISE, improvement of OS was seen in patients who received ramucirumab in combination with FOLFIRI versus patients receiving FOLFIRI alone (13.3 months vs 11.7 months; P =.02). 27 Another medication, regorafenib, targets VEGF, but as a multi-kinase inhibitor, it has other modes of action as well, targeting a multitude of other receptors including BRAF. Two trials, CORRECT and CONCUR, demonstrated regorafenib s efficacy and safety of regorafenib. In the CORRECT trial, patients assigned to the treatment with regorafenib plus best supportive care had an OS of 6.4 months compared with 5.0 months for supportive care alone (P =.005). In another trial, CONCUR, conducted in Asian patients, use of regorafenib also significantly improved OS versus supportive care (8.8 months vs 6.3 months; P =.00016). 27 Conclusion While colorectal cancer remains in many cases a devastating form of cancer, in the United States and worldwide, current therapies and treatments have improved patient outcomes. Patients, medical providers, and managed care professionals should be aware of the risk factors, screening and testing guidelines, and available treatment options. 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