Colorectal Cancer

The three papers contained in this supplement to ONCOLOGY were designed to serve as practical "keep on the shelf" references for the current management of metastatic colon cancer and screening and management of patients at high risk of colon cancer.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death in United States. For nearly 50 years, fluorouracil has been the only anticancer drug proven to benefit patients with metastatic CRC (mCRC), and it continues to be the backbone on which most treatment regimens are built. In the past 10 years, development of the topoisomerase I inhibitor irinotecan (Camptosar), the third-generation platinum analog oxaliplatin (Eloxatin), and the oral fluoropyrimidine capecitabine (Xeloda) advanced mCRC treatment and opened up an era of combination chemotherapy. More recently, monoclonal antibodies such as bevacizumab (Avastin), cetuximab (Erbitux), and panitumumab (Vectibix) have become available for use in mCRC treatment in combination with cytotoxic agents and as monotherapies. The addition of these targeted agents to the mCRC treatment armamentarium has resulted in more therapeutic options and improved treatment outcomes for the patients. The prospect of mCRC treatment is ever promising as more targeted agents such as vatalanib are being introduced and as intelligent combination regimens are being designed based upon a better understanding of pharmacokinetics. In this article we review various treatment options, including cytotoxic and targeted agents, currently available for patients with mCRC.

Advances in molecular genetics have evolved at such a fast pace that physicians may be bewildered about their clinical translation into patient care. However, genetic counselors, particularly those trained in cancer genetics, have been extremely helpful. The challenge to the physician, however, calls for an understanding of the natural history of hereditary cancer syndromes, which is often reflected in the pedigree. Pedigree/family history information must be compiled in sufficient detail to arrive at the most likely hereditary cancer syndrome diagnosis so that the molecular geneticist can search for the mutation. Finally, the challenge to the clinician is melding this into an accurate diagnosis, in order to provide highly targeted screening and management for high-risk patients. This article is an attempt to crystallize all of these issues in a format that will help physicians—particularly those in the oncology community—to meet this challenge effectively.

Traditional therapeutic concepts and treatment regimens for colorectal cancer are currently changing with the demonstration of the efficacy of biologic agents in this disease setting. The addition of the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) to conventional chemotherapy in the first- and second-line settings has shown a survival benefit; this outcome has helped to rapidly change the standard of care. Other targeted agents, such as anti-epidermal growth factor receptor (EGFR) antibodies, have shown proof of efficacy in colorectal cancer as well. The molecular targeted therapies are associated with toxicity profiles that are distinctly different from those seen with conventional chemotherapy. A notable difference is the absence of high risk for myelosuppression, diarrhea, or alopecia, which are common side effects of cytotoxic chemotherapy. This article will explore the toxicities associated with targeted therapies in detail in an attempt to provide assistance to the practicing oncologist in detecting and managing these side effects in their patients. In particular, the article will focus on the side effects associated with the three currently approved targeted drugs: the anti-VEGF monoclonal antibody bevacizumab and the anti-EGFR monoclonal antibodies cetuximab (Erbitux) and panitumumab (Vectibix).

Results from Oncolytics Biotech's phase I trial of Reolysin, its oncolytic reovirus, show stable disease in 7 of 32 patients with advanced or metastatic solid tumors refractory to standard therapy or for which no curative standard therapy exists. Dr. Timothy Yap of The Institute of Cancer Research, Sutton, UK, presented the study at the 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

Clinicians need to develop treatment strategies for subpopulations of patients with colorectal cancer, according to Richard Goldberg, MD, professor of medicine and division chief of hematology-oncology, University of North Carolina School of Medicine, Chapel Hill. He spoke at the 2006 Gastrointestinal Oncology Conference, sponsored by the International Society of Gastrointestinal Oncology.

A study published in the December issue of Gastroenterology has shown that medium-sized polyps found in the colon with flexible sigmoidoscopy and subsequently evaluated by full colonoscopy are associated with a significant number of advanced adenomas and cancers.

In clinical trials of panitumumab (Vectibix), 8% to 13% of patients with refractory colorectal cancer achieved a partial tumor response with the drug, according to data from five studies reviewed at the 2006 Gastrointestinal Oncology Conference. The meeting was sponsored by the International Society of Gastrointestinal Oncology.

Industry and government need to form a new alliance to more efficiently conduct clinical trials, Howard Hochster, MD, professor of medicine, New York University Medical Center, said at the 2006 Gastrointestinal Oncology Conference, sponsored by the International Society of Gastrointestinal Oncology.

Two of the hottest targets in colorectal cancer are spurring "lots of enthusiasm," Lee M. Ellis, MD, professor of surgical oncology and cancer biology, The University of Texas M.D. Anderson Cancer Center, said at the 2006 Gastrointestinal Oncology Conference, sponsored by the International Society of Gastrointestinal Oncology. The two targets, c-Src and urokinase plasminogen activator receptor (uPAR), both play key roles in tumor metastases and migration.

An innovative cancer agent called PHA-739358, which inhibits one of the aurora proteins, has shown indications of potential benefit in 7 of 36 patients (19.4%) with advanced or metastatic solid tumors who participated in a phase I dosing and toxicity study, Dutch researchers reported at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics

Sirtex is supporting a phase I trial of its SIR-Sphere microspheres as first-line therapy of liver metastases in patients with colorectal cancer in combination with chemotherapy (the FOLFOX-6 and FOLFIRI regimens). The principal investigator is Seza Gulec, MD, director of the Goshen Cancer Institute's Hepatic Oncology Program in Goshen, Indiana, where the trial is being conducted.

Roche announced that a large, international phase III study (NO16966) enrolling 2,035 previously untreated metastatic colorectal cancer patients met both of its primary endpoints.

Colorectal cancer is the second most common cause of cancer death in the United States. It is estimated that about 55,000 patients will die this year due to advanced colorectal cancer. These grim statistics persist despite a marked increase in the rate of screening colonoscopies and improvements in adjuvant chemotherapy. Successful chemoprevention strategies may reduce the risk of new colorectal cancers, thus decreasing related overall morbidity and mortality.

Adding the targeted antibody cetuximab (Erbitux) to standard cytotoxic chemotherapy as first-line treatment for patients with advanced colorectal cancer improves response rates, two groups of researchers said at the 31st Congress of the European Society for Medical Oncology (ESMO).

A phase III trial has shown that XELOX is as effective as FOLFOX4 in patients with metastatic colorectal cancer, and that adding the targeted agent bevacizumab (Avastin) to either regimen improves progressionfree survival (PFS).

The science supporting molecularly targeted therapies for the treatment of patients with solid tumors continues to evolve. Nurses are challenged to understand cell signaling, molecular targeting, and the mechanism of action of targeted agents. Two cell signal transduction pathways regulate the development, proliferation, and metastasis of solid tumors: the human epidermal growth factor (HER) receptor pathway and the vascular endothelial growth factor (VEGF) receptor pathway. Several novel pharmacologic agents with distinct indications and methods of administration target the HER and VEGF molecular pathways.

a brief overview of the dosing and administration guidelines for the various targeted therapy agents discussed in this supplement to the ONCOLOGY Nurse Edition. Please consult the manufacturer's package insert for more information.

The number of negative lymph nodes identified during surgical resection of stage III colorectal cancer predicts long-term survival independently of the number of positive nodes identified, new data show

The US Food and Drug Administration (FDA) has approved Amgen's Vectibix (panitumumab) for the treatment of patients with colorectal cancer that has metastasized following standard chemotherapy.

MediGene AG has announced that the interim analysis of a phase I/II trial of its oncolytic herpes simplex virus NV1020 has shown efficacy for the treatment of liver metastases in patients with colorectal cancer. Therefore, the trial will continue as scheduled, with the maximum dosage of the virus. The agent is delivered to the liver at weekly intervals through the hepatic artery. All patients receiving the maximum dosage demonstrated either disease stabilization or a clear regression of liver metastases, the company said in a press release, adding that some patients showed regressing metastases in other organs as well.

A new bioengineered protein that targets two apoptosis receptors produced one dramatic tumor regression and stopped tumor growth in several cases of disease stabilization in 60% of the advanced cancer patients treated in a phase I dose-finding trial

A polymorphism that reduces the hepatic metabolism of irinotecan (Camptosar) and that is present in about half of patients with colorectal cancer affects their odds of response to and toxicity from regimens containing this agent

Following priority review, the US Food and Drug Administration (FDA) has approved Amgen Inc's panitumumab (Vectibix) for the treatment of advanced colon cancer.

Colorectal cancer is the second leading cause of cancer-related death (after lung/bronchus cancer) in the United States.[1] In 2002, a total of 139,534 adults in the United States had colorectal cancer diagnosed, and 56,603 died. The US Preventive Services Task Force and other national organizations recommend that adults aged ≥ 50 years be screened for colorectal cancer with one or more of the following tests: fecal occult blood testing (FOBT) every year, sigmoidoscopy or double-contrast barium enema every 5 years, or colonoscopy every 10 years.

Cetuximab (Erbitux), a chimeric antiepidermal growth factor receptor monoclonal antibody currently used to treat metastatic colorectal cancer, is in clinical development for several other solid tumors. Although cutaneous manifestations are the most common toxicities associated with cetuximab, they are rarely life-threatening. Cetuximab-related infusion reactions are less common, but they may become severe and cause fatal outcomes if not managed appropriately. Little about the specific etiology of these events is known; however, an overview of infusion reactions observed with other compounds may shed some light and help characterize cetuximab-related reactions. For physicians administering cetuximab, familiarity with acute reaction treatment protocols and preparedness to identify and manage symptoms promptly and effectively are most important to minimize potential risks.

For metastatic colorectal cancer, the benefits of maintenance therapy with 5-FU/leucovorin appear questionable, according to results of the OPTIMOX2 study

Chemotherapy may render some liver metastases of colorectal cancer no longer visible by preoperative CT and ultrasound imaging (see also article on page 21), but viable cancer cells are still present in about four in five of these sites.

In patients with resectable rectal cancer, routine short-course preoperative radiotherapy results in a significant reduction in local recurrence and improved disease-free survival, compared with a selective postoperative approach.

Colorectal cancers that do not express epidermal growth factor receptor (EGFR) may still have overactivation of the EGFR signaling pathway, new data show. In addition, activation of the signaling pathway in the primary tumor is not a reliable indicator of its activation in metastases.