Colorectal Cancer: A New Paradigm

Author: Guido R. Zanni, PhD

Recently, the FDA approved several new agents for the third most common cancer in men and women in the United States: colorectal cancer (CRC).1 Historically, chemotherapy for CRC was limited to combination leucovorin and fluorouracil. The FDA approved irinotecan in 1996 and oxaliplatin in 2002 and later approved 3 biologics. These advances are welcomed, because someone dies from CRC every 9 minutes.1 CRC incidence begins to rise around age 40 and increases markedly after age 50. About 92% of CRCs are diagnosed in people aged 50 years or older, with 12.5% of cases diagnosed after age 85.1,2 Approximately 40% of people diagnosed with CRC will die within 5 years, but diagnosis before metastases occur improves survival chances substantially. Unfortunately, 20% of CRC patients are diagnosed in late stages.2 Most patients eventually develop liver metastases.3 The Table lists risk factors for CRC among Americans. Men tend to develop CRC slightly more often than women.2 The disease affects all ethnic groups, and people who emigrate from countries where CRC is uncommon eventually develop CRC at rates similar to those of native-born Americans?probably due to the Western diet.4 Most oncologists consider CRC completely preventable with lifestyle modification. Additionally, CRC-related mortality has been reduced by 40% to 50% in individuals who take aspirin and other NSAIDs regularly.5-7

Polyps: A Strong Role
Up to 90% of CRCs arise from adeno-matous polyps. Between 15% and 30% of people in the United States develop polyps; about 30% of these polyps are benign. Adenomatous (premalignant) polyps with diameters of at least 2 cm have a 50% chance of becoming malignant. Polyp removal significantly reduces the incidence of CRC.8-10 Approximately 70% of CRCs are nonhereditary and about 20% are familial. Patients with familial adeno-matous polyposis (FAP) can develop thousands of polyps before age 30 and inevitably develop CRC early (average age, 44 years). Colectomy is an appropriate prevention strategy. About 3% to 5% of all CRC is hereditary nonpolyposis colon cancer (HNPCC) caused by gene mutations. Nonpolyposis does not mean that the cancer does not emanate from polyps; it distinguishes HNPCC from FAP. Polyps do not develop earlier in people with HNPCC, but these polyps are aggressive.8-10

Screening and Diagnosis
In CRC, routine screening and polyp removal are key. The American Cancer Society recommends screening adults over age 50 and screening those at high risk earlier. Currently, colonoscopy is the gold standard.

Previous CRC increases the risk for a new primary tumor more than fourfold, so regular screening is a lifelong requirement. In addition, inflammatory bowel disease increases risk and screening requirements.11-13 Unfortunately, many Americans are not screened appropriately.

CRC is staged, using an evaluation system based on primary tumor, regional nodes, and metastasis. Patients presenting with the same stage of CRC can have different survival statistics. Accurate staging guides treatment and dramatically improves survival.

Treatment
Surgery, a common intervention, is curative in up to 80% of early cases, but overall survival among patients with advanced colon cancer, even after surgical resection, is as low as 15%. Surgery and adjuvant chemotherapy are common treatments for patients with stage III disease. Combination chemotherapy is given for metastatic disease when possible. Chemotherapy with radiation is given before or after surgery in most patients with stage II or III rectal (but not colon) cancer. Survival differs markedly, and clinicians must tailor patient-specific strategies.14 Fortunately, the National Comprehensive Cancer Network (NCCN) has created treatment guidelines for CRC, available at www.nccn.org/professionals/ physician_gls/PDF/colon.pdf. NCCN suggests triaging patients into those with liver metastases, those with lung metastases, and those with more disseminated disease. For patients presenting with liver metastases, for example, clinicians can select among several pathways: chemotherapy with a biologic, then possibly primary tumor removal and liver resection; or colectomy followed by neo-adjuvant chemotherapy and then liver resection.15

Drug and Biologic Options
Each patient?s situation is assessed in the light of available treatment options and regimen sequences. The goal is creating an early plan that extends survival and minimizes drug- or administration route?related side effects.15 Typical regimens include the following:

FOLFOX regimens may cause less nausea, vomiting, diarrhea, febrile neutrope-nia, and dehydration, but more sensory neuropathy and neutropenia, than the others, but they are effective and comparatively safe. When oral capecitabine is substituted for fluorouracil, severe diarrhea is more likely. An irinotecan/oxali-platin regimen is an appropriate alternative for fluorouracil-intolerant individuals.

Enter the Biologics
Bevacizumab
Today, targeted therapies in combination with cytotoxic agents often are used for advanced, recurrent, or metastatic disease. Bevacizumab is an antibody directed against vascular endothelial growth factor, a soluble protein instrumental in angiogenesis.16 Bevacizumab has marginal activity when it is given alone.17 Adding bevacizumab to irinote-can + bolus fluorouracil and leucovorin resulted in a significant and clinically meaningful improvement in survival (20.3 vs 15.6 months).18 Response rate, time of progression, and progression-free and overall survival also improved when bevacizumab every 2 weeks was added to FOLFOX.19 Clinicians must monitor bevacizumab patients for bleeding, which often starts as mild epistaxis. Proteinuria and hypertension are possible. Wound-healing complication (dehiscence) also is possible. Thus, patients receiving bevacizu-mab-containing regimens must be beva-cizumab-free for at least 6 weeks before and after surgery.

Risk of arterial thromboembolism is a concern, particularly for the elderly with histories of cardiovascular accident, myocardial infarction, transient ischemic attacks, or angina. Bevacizumab is rarely associated with reversible posterior leukoencephalopathy, a condition similar to malignant hypertension or eclampsia during pregnancy. Life-threatening gastrointestinal perforation secondary to bevacizumab also is a rare risk.19

Cetuximab
Cetuximab is a monoclonal antibody that specifically blocks epidural growth factor receptor (EGFR). Cetuximab has been found to improve response when used alone (unlike bevacizumab) and in combination with irinotecan in metastat-ic CRC refractory to irinotecan.20 With EGFR-targeted therapies, skin toxicity may be a surrogate for effectiveness. Pronounced acneiform rash may predict robust response. Infusion reactions are possible, and the most common adverse events include hypomagnesemia, weight loss, gastrointestinal disturbances, anemia, asthenia, headache, insomnia, depression, cough, and dyspnea.21 Cetuximab and bevacizumab have different biologic targets and toxicity profiles. One trial has shown that, in combination with irinotecan, concurrent use of these biologics can improve response in patients with metastatic CRC.22

Panitumumab
The FDA approved panitumumab in September 2006. Panitumumab binds to the EGFR on normal and tumor cells, competitively inhibiting ligand binding and causing cell death. Unlike cetuximab, a chimeric antibody, panitumumab is fully human?which may create less risk of infusion reactions and allergy. It, too, is associated with acneiform rash and significant dermatologic toxicity, itching, and rash. Hypomagnesemia is common, as are gastrointestinal complaints, fatigue, and vision changes.23

End Note
For CRC patients, toxicity can be significant and burdensome. Researchers are investigating ?stop-and-go? approaches to improve quality of life?giving patients either therapy holidays or less intensive therapy after response until disease progresses. One strategy drops oxaliplatin after a defined period of time, reintroducing it at disease progression.24 Early studies indicate that this strategy is safe, effective, and sometimes cost-reducing.

The NCCN guidelines offer choices for advanced metastatic CRC, especially for patients who are intolerant of intensive therapy. Clinicians will need to balance toxicity concerns with cost and potential benefits.

Dr. Zanni is a psychologist and health-systems consultant based in Alexandria, Va.

References

1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43-66.

2. American Cancer Society. Cancer Facts & Figures 2006. Atlanta, Ga: American Cancer Society; 2006.

3. Penna C, Nordlinger B. Colorectal metastasis (liver and lung). Surg Clin North Am. 2002;82:1075-1090, x-xi.

4. Kuriki K, Tajima K. The increasing incidence of colorectal cancer and the preventive strategy in Japan. Asian Pac J Cancer Prev. 2006;7:495-501.

5. Arber N, Eagle CJ, Spicak J, et al; PreSAP Trial Investigators. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355:885-895.

6. Phillips RK, Wallace MH, Lynch PM, et al; FAP Study Group. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut. 2002;50:857-860.

7. Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000;342:1946-1952.

8. Ahsan H, Neugut AI, Garbowski GC, et al. Family history of colorectal adenomatous polyps and increased risk for colorectal cancer. Ann Intern Med. 1998;128:900-905.

9. Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med. 1998;338:1481-1487.

10. Wijnen JT, Vasen HF, Khan PM, et al. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med. 1998;339:511-518.

11. Giardiello FM, Brensinger JD, Petersen GM, et al. The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med. 1997;336:823-827.

12. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525-532.

13. Kinzler KW, Vogelstein B. Landscaping the cancer terrain. Science. 1998;280:1036-1037.

14. AJCC Cancer Staging Handbook. 6th ed. New York, NY: Springer-Verlag; 2002.

15. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Colorectal Cancer. Available at: www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed March 29, 2007.

16. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669-676.

17. Hochster HS, Hart LL, Ramanathan RK, et al. Results of the TREE-2 cohort: Safety, tolerability, and efficacy of bevacizumab added to three oxaliplatin/fluoropyrimidine regimens as first-line treatment of metastatic colorectal cancer. Proc Am Soc Clin Oncol. 2006;24 [abstract 244].

18. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342.

19. Avastin Complete Prescribing Information. South San Francisco, Calif: Genentech; February 2004. Available at: www.gene.com/gene/products/information/oncology/avastin/insert.jsp. Accessed November 6, 2006.

20. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337-345.

21. Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 2006;55:657-670.

22. Saltz LB, Lenz H-J, Hochster H, et al. Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. J Clin Oncol (Meeting Abstracts). 2005;23(suppl):248S [abstract 3508].

23. Vectibix Complete Prescribing Information. Thousand Oaks, Calif: Amgen Inc; September 27, 2006. Available at: www.amgen.com/pdfs/products/vectibix_pi.pdf.

24. De Gramont A, Cervantes A, Andre T, et al. OPTIMOX study: FOLFOX 7/LV5FU2 compared to FOLFOX 4 in patients with advanced colorectal cancer. J Clin Oncol. (Meeting Abstracts) 2004;22(14S) [abstract 3525].