Colorectal Cancer

Nearly 150,000 people will be diagnosed with colorectal cancer in the United States in 2006. The impact of this diagnosis will be felt by countless family members, coworkers, and friends. Although screening tests for colorectal cancer have been available and encouraged by medical associations such as the American Cancer Society (ACS) and others, public awareness and compliance has been dismal.

The liver is a frequent site of metastatic colorectal disease. Over the past 20 years, improvements in systemic chemotherapy and surgical techniques have improved the survival of patients with hepatic metastases. For 4 decades, fluorouracil and leucovorin were the only drugs available to treat metastatic colorectal cancer, but several new drugs and a variety of novel regimens are now available. Further improvements in results have been seen with the delivery of chemotherapy via the hepatic artery. Surgical resection of liver metastases has been encouraged when possible, and recent advances in surgery such as portal vein embolization, have made liver resection a possibility for more patients. This review considers the timing and sequence of chemotherapy and surgery in this setting, as well as the roles of cryoablation, radiofrequency ablation, and radiation therapy.

The liver is a frequent site of metastatic colorectal disease. Over the past 20 years, improvements in systemic chemotherapy and surgical techniques have improved the survival of patients with hepatic metastases. For 4 decades, fluorouracil and leucovorin were the only drugs available to treat metastatic colorectal cancer, but several new drugs and a variety of novel regimens are now available. Further improvements in results have been seen with the delivery of chemotherapy via the hepatic artery. Surgical resection of liver metastases has been encouraged when possible, and recent advances in surgery such as portal vein embolization, have made liver resection a possibility for more patients. This review considers the timing and sequence of chemotherapy and surgery in this setting, as well as the roles of cryoablation, radiofrequency ablation, and radiation therapy.

Amgen announced interim results from two phase II studies of panitumumab, an investigational fully human monoclonal antibody that targets the epidermal growth factor receptor (EGFR). Results from both studies suggest that the antitumor activity of panitumumab was independent of tumor EGFR expression levels in patients with metastatic colorectal cancer who have failed standard chemotherapy.

The liver is a frequent site of metastatic colorectal disease. Over the past 20 years, improvements in systemic chemotherapy and surgical techniques have improved the survival of patients with hepatic metastases. For 4 decades, fluorouracil and leucovorin were the only drugs available to treat metastatic colorectal cancer, but several new drugs and a variety of novel regimens are now available. Further improvements in results have been seen with the delivery of chemotherapy via the hepatic artery. Surgical resection of liver metastases has been encouraged when possible, and recent advances in surgery such as portal vein embolization, have made liver resection a possibility for more patients. This review considers the timing and sequence of chemotherapy and surgery in this setting, as well as the roles of cryoablation, radiofrequency ablation, and radiation therapy.

In a phase III study, patients with untreated metastatic colon cancer had significantly higher response rates when cetuximab (Erbitux) was added to their chemotherapy, compared with chemotherapy alone (FOLFIRI or FOLFOX)

FOLFIRI can be given intermittently in advanced previously untreated colorectal cancer, with survival rates and toxicity similar to continuous FOLFIRI

Percutaneous radiofrequency ablation (RFA) of lung metastases of colorectal cancer may be a useful treatment option in patients who are not candidates for surgery, but the benefit varies with the size of the metastases

A phase I trial finds that the combination of cetuximab (Erbitux) and gefitinib (Iressa) produces responses in patients with advanced solid cancers expressing the epidermal growth factor receptor (EGFR)—especially colorectal cancer.

Current evidence suggests that colonoscopy screening can reduce mortality from colorectal cancer—if these procedures are performed in a high-quality manner, David A. Lieberman, MD, said at the 2006 Gastrointestinal Cancers Symposium.

People with hereditary nonpolyposis colorectal cancer (HNPCC), are willing to consider the pros and cons of prophylactic subtotal colectomy to manage their disorder, but still have strong concerns about the procedure

Increasing patient comfort may translate into higher screening rates for colon cancer, researchers said at Digestive Disease Week 2006. A new colonoscopy system promises a gentler procedure (abstract 719) and an alternative sedation method allows a quicker recovery time (abstract 645).

Avastin (bevacizumab, Genentech), in combination with FOLFOX4-oxaliplatin (Eloxatin)/5-FU/leucovorin—has received FDA approval for the second-line treatment of metastatic colorectal cancer.

In trials of first-line chemotherapy for metastatic colorectal cancer, gains in progression-free survival (PFS) are a good surrogate endpoint for gains in overall survival (OS), according to results of a study presented by Patricia A. Tang, MD, at the 2006 Gastrointestinal Cancers Symposium (abstract 226).

Genentech Inc, recently announced that the US Food and Drug Administration (FDA) approved bevacizumab (Avastin) in combination with intravenous fluorouracil (5-FU)-based chemotherapy for second-line metastatic colorectal cancer.

A small molecule that inhibits the insulin-like growth factor 1 receptor (IGF-1R) has blocked the development of human colorectal tumors in mice, according to researchers from OSI Pharmaceuticals, Melville, New York.

An increasing body of evidence suggests that geriatric patients can benefit from and tolerate standard chemotherapy similarly to younger patients in the settings of both early- and advanced-stage colorectal cancer. Assessment of this unique population requires more comprehensive evaluation in addition to routine history, physical examination, and laboratory tests. Specific considerations of their physiologic functional changes will help physicians better manage these patients. Ongoing studies are now designed to better understand the decision-making process, safety profile, and efficacy of various treatment regimens in geriatric patients.

Panitumumab, a new targeted treatment for advanced colorectal cancer, plus best supportive care extended progression-free survival (PFS) significantly, compared with best supportive care alone, Marc Peeters, MD, PhD, of Ghent University Hospital, Belgium, said at the 97th Annual Meeting of the American Association for Cancer Research (AACR) (abstract CP-1). FDA has granted the drug fast-track status, and it could be approved for use by the fall of this year.

A blood-based DNA test to detect colorectal cancer has the potential to increase screening rates and the number of tumors found at an early stage, according to researchers at Epigenomics, Inc. the Seattle-based molecular diagnostics company that is developing the test (see graphic on page 1).

Two large randomized trials have shown that the COX-2 inhibitor celecoxib (Celebrex) significantly reduces the recurrence of colorectal adenomas, according to data presented at the 97th Annual Meeting of the American Association of Cancer Research. However, the trials also found a significantly increased risk of serious cardiovascular (CV) events—strokes and heart attacks—among trial participants taking the drug. Celecoxib researchers and other experts at the meeting emphasized that more needs to be known about how and why celecoxib raises CV risk before it can be recommended for prevention of colorectal cancer.

Carcinoembryonic antigen (CEA) monitoring in patients with stage I-IV colorectal cancer has been, and remains, a controversial issue in oncology practice. Recommendations vary from bimonthly monitoring to no monitoring in the surveillance setting (for stage I-III disease). In the metastatic setting, there are no clear guidelines for CEA follow-up, although continued monitoring in such patients is common in the oncology community. This manuscript reviews the accuracy of CEA testing, its value as a prognostic indicator, and its role in surveillance and response assessment. The limitations of the test in the adjuvant and metastatic settings are illustrated through several case reports from the Colorectal Oncology Clinic at Roswell Park Cancer Institute. Guidelines for CEA monitoring are provided, based on a detailed literature review and institutional experience.

Carcinoembryonic antigen (CEA) monitoring in patients with stage I-IV colorectal cancer has been, and remains, a controversial issue in oncology practice. Recommendations vary from bimonthly monitoring to no monitoring in the surveillance setting (for stage I-III disease). In the metastatic setting, there are no clear guidelines for CEA follow-up, although continued monitoring in such patients is common in the oncology community. This manuscript reviews the accuracy of CEA testing, its value as a prognostic indicator, and its role in surveillance and response assessment. The limitations of the test in the adjuvant and metastatic settings are illustrated through several case reports from the Colorectal Oncology Clinic at Roswell Park Cancer Institute. Guidelines for CEA monitoring are provided, based on a detailed literature review and institutional experience.

Carcinoembryonic antigen (CEA) monitoring in patients with stage I-IV colorectal cancer has been, and remains, a controversial issue in oncology practice. Recommendations vary from bimonthly monitoring to no monitoring in the surveillance setting (for stage I-III disease). In the metastatic setting, there are no clear guidelines for CEA follow-up, although continued monitoring in such patients is common in the oncology community. This manuscript reviews the accuracy of CEA testing, its value as a prognostic indicator, and its role in surveillance and response assessment. The limitations of the test in the adjuvant and metastatic settings are illustrated through several case reports from the Colorectal Oncology Clinic at Roswell Park Cancer Institute. Guidelines for CEA monitoring are provided, based on a detailed literature review and institutional experience.

During the 1980s, the only drug routinely used to treat colorectal carcinoma was single-agent fluorouracil (5-FU), a drug that had shown no proven benefit in the adjuvant setting. Since then, significant improvements in the overall management of colorectal cancer have been made. This review will compare today's standard of care for adjuvant colorectal carcinoma to that practiced 20 years ago. The authors examine key questions asked about adjuvant therapy and the answers that ultimately changed clinical practice standards and improved overall survival for patients diagnosed with this disease. In addition, this review explores whether 5-FU should be given as part of a multidrug regimen and which route of administration is best when this drug is given. Further, the authors delve into both the use of locally directed therapies to the liver or peritoneum to improve outcomes and the selection of patients to receive adjuvant chemotherapy. Finally, a look to the future shows monoclonal antibodies to be an avenue of great promise in fighting colorectal cancer.

Anti-EGFR (epidermal growth factor receptor) therapies, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, demonstrate activity in a variety of tumor types. While both inhibit the EGFR pathway, they act via different mechanisms.

Since initial characterization over 40 years ago, strong preclinical and clinical data have clearly established the epidermal growth factor receptor (EGFR) as a worthy molecular target for intervention in cancer therapy. The receptor is expressed, overexpressed, or mutated in many human tumors, including head and neck, colorectal, pancreatic, non-small-cell lung, ovarian, esophageal, gastric, breast, prostate, bladder, and renal cancers. Experiments in several model systems have confirmed that EGFR signaling is involved in regulating several key biologic processes, including cell proliferation, epithelial development, organogenesis, apoptosis, angiogenesis, and differentiation. Furthermore, EGFR function has been shown to be altered and/or dysregulated in a variety of spontaneous tumors.

Overexpression of the epidermal growth factor receptor (EGFR) is correlated with poor prognosis in many human cancers. Two main classes of anticancer agents affect the EGFR: those targeting the extracellular ligand-binding domain and those that block the intracellular tyrosine kinase (TK) domain. Cetuximab (Erbitux) is a mouse/human chimeric monoclonal antibody that targets the ligand-binding domain of the EGFR, whereas erlotinib (Tarceva) and gefitinib (Iressa) are small-molecule TK inhibitors. Common toxicities of agents targeting the EGFR differ from those associated with traditional chemotherapy. Given the common pathway through which these agents work, some adverse events are similar. Many patients treated with these agents develop an acne-like rash on the face and upper body, most likely related to keratinocyte alterations and hair follicle proliferation and maturation. Although clinical manifestation of this reaction closely resembles acne vulgaris, the histology is more similar to infectious folliculitis. Other adverse events appear to be related to a drug class or individual agent. For example, interstitial lung disease is a rare but potentially fatal reaction that has been reported with gefitinib. Hypomagnesemia reported in association with cetuximab may be related to EGFR blockade in the kidney. Anaphylactic or anaphylactoid infusion reactions are also seen with cetuximab, as with other monoclonal antibodies.

Colon cancer remains one of the most common human malignancies, with an annual global incidence of slightly less than 1 million patients per year.

During the 1980s, the only drug routinely used to treat colorectal carcinoma was single-agent fluorouracil (5-FU), a drug that had shown no proven benefit in the adjuvant setting. Since then, significant improvements in the overall management of colorectal cancer have been made. This review will compare today's standard of care for adjuvant colorectal carcinoma to that practiced 20 years ago. The authors examine key questions asked about adjuvant therapy and the answers that ultimately changed clinical practice standards and improved overall survival for patients diagnosed with this disease. In addition, this review explores whether 5-FU should be given as part of a multidrug regimen and which route of administration is best when this drug is given. Further, the authors delve into both the use of locally directed therapies to the liver or peritoneum to improve outcomes and the selection of patients to receive adjuvant chemotherapy. Finally, a look to the future shows monoclonal antibodies to be an avenue of great promise in fighting colorectal cancer.

Surveillance screening for colon and breast cancer appears to diminish 5 years after the original diagnosis.