(Laurie Barclay, MD, March 2004)

Colorectal cancer, which represents about 15% of all cancers in the U.S., is cancer of the large intestine and rectum. Each year, approximately 130,000 to 148,000 people in the U.S. are diagnosed with colorectal cancer. The probability of developing colorectal cancer is slightly higher in women than in men, and overall lifetime prevalence is about 1 in 20.

About 5% of colorectal cancers are caused by genetic defects including hereditary polyposis syndromes, such as familial adenomatous polyposis (FAP) and Gardner’s syndrome; and hereditary non-polyposis colon cancer (HNPCC), such as Lynch I and Lynch II syndromes. Other risk factors include advancing age; high-fat, low-fiber diet; cancer of the ovary, uterus, or breast; prior colorectal cancer; family history of colorectal cancer in first-degree relatives; and ulcerative colitis.

Most colorectal cancers arise in the innermost layer of the sigmoid colon and grow slowly over several years, often beginning as small benign polyps. Removing these polyps before they develop malignant characteristics is effective in preventing colorectal cancer. Adenocarcinomas account for more than 95% of colorectal cancers, while carcinoid tumors, gastrointestinal stromal tumors, and lymphomas are much less common.

Because patients with colorectal cancer are often asymptomatic in the early stages, colonoscopy and tests for fecal occult blood are useful as regular screening procedures. According to experts at the Memorial Sloan-Kettering Cancer Center in New York, NY, regular screening could halve U.S. mortality from colorectal cancer, and it could prevent many cancers before they develop.

In later stages, symptoms may include rectal bleeding or melena; altered bowel habits lasting for more than a few days, including diarrhea, constipation, or narrowing of the stool; abdominal pain; a persistent urge to defecate; unexplained weight loss or fatigue; vomiting; and generalized weakness.

Tests used for diagnosis and staging may include colonoscopy or sigmoidoscopy with biopsy; computed tomography (CT) and magnetic resonance imaging (MRI) scans to detect distant metastases; chest X-ray to reveal lung metastases; and blood tests for CEA, a protein marker for colorectal cancer. Other tests may include positron-emission tomography (PET) scanning, preoperative angiography, or endorectal ultrasound to stage rectal cancer.

In stage 0, cancer is limited to the innermost lining of the colon or rectum. Stage I cancer involves more of the inner wall, whereas Stage II cancer has spread locally outside the colon or rectum but does not involve the lymph nodes. Stage III is characterized by lymph node metastases, and Stage IV by distant metastases to the liver, lungs, or other organs.

Depending on the stage, treatment options include surgery, radiation therapy, chemotherapy, and combination therapy. Surgery may be as noninvasive as polyp removal during colonoscopy, or as extensive as hemicolectomy.

Approved chemotherapy agents for colorectal cancer include 5-fluorouracil (5-FU), leucovorin, and capecitabine, as well as irinotecan, the first new drug for colorectal cancer in 40 years. This agent may shrink metastases refractory to other treatments.

In an international trial, irinotecan in combination with 5-FU and leucovorin (IFL) was more effective than standard chemotherapy as first-line treatment for advanced colorectal cancer, and it is now being tested in earlier stages of colorectal cancer. The FOLFOX regimen, consisting of oxaliplatin, 5-FU, and leucovorin, is similar in efficacy to IFL.

Recent strategies to optimize the efficacy of chemotherapy include preoparative chemoradiation therapy for rectal cancer, and an intrahepatic pump to deliver chemotherapy to liver metastases. In rectal cancer, combined modality therapy before surgery may reduce tumor size sufficiently to allow bowel reconstruction rather than permanent colostomy, with an overall cure rate of more than 70% and a local recurrence rate of 10%.

CenterWatch has identified a pipeline of 50 drugs in various stages of development for colorectal cancer, including chemotherapeutic agents, immunotherapy, and cell modulators.

Genentech has submitted a Biologics Licence Application (BLA) for Avastin (bevacizumab), a humanized antibody to vascular endothelial growth factor (VEGF). Its mechanism of action is to block angiogenesis, or the formation and growth of new blood vessels supplying the tumor.

Avastin is the first angiogenesis inhibitor to be proven effective in a randomized Phase III trial. In about 800 patients with newly diagnosed metastatic colon cancer who received Avastin along with IFL combination chemotherapy, median survival was significantly longer than in patients who received IFL with placebo (20.3 months vs. 15.6 months). The Avastin group also fared better in terms of median progression-free survival (10.6 months vs. 6.2 months) and proportion of patients with at least 50% reduction in tumor size (45% vs. 35%).

Adverse effects were similar in both groups except for medication-responsive hypertension and rare bowel perforation in the Avastin group. The National Cancer Institute (NCI) has temporarily suspended enrollment in a trial of Avastin plus 5-FU and leucovorin for patients with refractory locally advanced or metastatic colorectal cancer pending evidence of efficacy.

Novartis has completed Phase III testing of PTK 787, also a potent angiogenesis inhibitor. After oral administration, this drug blocks VEGF receptor tyrosine kinases, impairs VEGF-induced responses and slows tumor growth. Animal models suggest that in concentrations up to 1 microM, PTK 787 has no cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. It therefore should be well tolerated without effects on wound healing, on circulating blood cells, or on bone marrow recovery after conventional chemotherapy.

An immunotherapeutic approach to colorectal cancer is to use an autologous vaccine after tumor resection. Intracel has completed
Phase III testing of OncoVAX in patients diagnosed with TNM Stage II colon cancer. Using the patient's own surgically removed tumor, a specific OncoVAX is prepared for each patient after enzymatic treatment, freezing, and irradiation of the tumor cells to prevent them from growing into new tumors. Several weeks after surgery, the patient receives a series of four specific vaccinations, the first two of which contain Bacillus Calmette Guérin (BCG) as an immunogenic enhancer.

In a prospective, randomized, multicenter Phase III trial conducted in Amsterdam, OncoVAX significantly reduced the rate of tumor recurrences by 44% in patients with Stage II and III colon cancer at a median follow-up period of 5.3 years. Stage II patients had a 61% reduction in recurrences, as well as proportional increases in overall survival. Safety profile was extremely favorable. OncoVAX is commercially available in the Netherlands for Stage II patients, and Intracel is now preparing a BLA for FDA submission.

Another cancer vaccine is IGN101, in Phase III testing by Igencon. The vaccine antigen is a murine monoclonal antibody that structurally resembles EpCAM, an epithelial cell adhesion molecule that is usually overexpressed on epithelial cancer cells, and triggers an immune response to it. By selectively destroying residual tumor cells, this immune response may prevent or inhibit the formation of metastases.

In a Phase II clinical trial, IGN101 induced specific immunogenicity in patients with carcinoma likely to express EpCAM, even when patients were also receiving chemotherapy. A multicenter, placebo-controlled Phase III trial in metastatic colorectal cancer is scheduled to begin enrollment early this year.

Cetuximab, a highly specific chimerized monoclonal antibody that binds exclusively to epidermal growth factor receptor (EGFR), is in Phase III testing by ImClone Systems. When bound to EGFR, it blocks growth factors EGF and TGF-alpha from binding and from signalling the tumor cell to promote growth, survival and progression.

Also in Phase III testing is NeuTrexin, a MedImmune product which disrupts DNA, RNA, and protein synthesis. This formulation consists of trimetrexate glucuronate for injection with concurrent leucovorin protection.

Like OncoVAX and IGN101, Avicine (CTP-37) is also a therapeutic cancer vaccine. AVI BioPharma has completed Phase II testing of this hormone vaccine that elicits an immune response to human chorionic gonadotropin (hCG) peptide, a well-characterized tumor-associated antigen. The greater the hCG expression by cancer cells, the more aggressive the tumor, as hCG promotes angiogenesis and immunosuppression.

Avicine is a synthetic peptide composed of carboxy terminal 37 amino acids (CTP-37) of the beta-subunit of hCG conjugated to diphtheria toxoid. Although it effectively stimulates an immune response to hCG, it does not cross-react with similar glycoprotein hormones. Clinical studies using hCG vaccines in cancer indicate that an immune response to hCG plays a significant role in patient survival.

Still in earlier stages of development are agents representing a variety of novel strategies. Abgenix is in Phase II testing of ABX-EGF, a fully human monoclonal antibody generated using XenoMouse® technology. ABX-EGF targets the epidermal growth factor receptor (EGFr), which is over-expressed in colorectal and in many other cancers. In preclinical testing, ABX-EGF slows the growth of human tumors implanted in mice. Several clinical studies suggest that ABX-EGF is effective as a single agent with a good pharmacokinetic and tolerability profile.

ADVENTRX Pharmaceuticals is in Phase II development of CoFactor, a form of folate associated with increased levels of methylenetetrahydrofolate (MTHF). Clinical trials beginning late last year are pairing CoFactor with 5-FU in metastatic colorectal cancer. Earlier studies suggest that CoFactor enhances antitumor activity of 5-FU by inhibiting thymidylate synthase (TS), an enzyme vital to tumor cell growth. CoFactor’s mechanism of action is to bind TS to the active metabolite (FdUMP) of 5-FU, resulting in irreversible inhibition. When CoFactor stimulates cell division, 5-FU is taken up by cancer cells, and the irreversible inhibition results in cancer cell death.

Compared with current therapies, CoFactor plus 5-FU may more than double the time to tumor progression. In Swedish Phase I/II trials, gastrointestinal and breast cancer patients treated with CoFactor/5-FU had remissions that were twice as long as patients treated with 5-FU/leucovorin, with fewer adverse effects. Among patients failing therapy for advanced disease, 63% showed stabilization or response to CoFactor with 5-FU.

ADVENTRX suggests that CoFactor should greatly improve quality of life by allowing reduced dosage of 5-FU, removal of leucovorin, and elimination of toxicity caused by CPT-11 and oxaliplatin, and that CoFactor qualifies for the FDA fast track program.

Aroplatin, in Phase II testing by Antigenics, is a liposomal formulation of a third-generation platinum product similar to oxaliplatin. Like current platinum-based chemotherapeutics, Aroplatin has considerable antitumor activity, but it may have a different mechanism of action and may therefore be effective in cancers resistant to other platinum agents. Other differences may include reduced toxicity and increased bioavailability because of
liposome encapsulation.

Another approach to improved drug delivery is Xyotax (CT-2103), in Phase II development by Cell Therapeutics. This formulation consists of paclitaxel (Taxol) linked to a novel polyglutamate polymer that increases water solubility 80,000-fold, allowing better tolerability, shorter intravenous infusion time without routine premedication, higher dose delivery, and greater efficacy
in animal models. Unlike paclitaxel, Xyotax is engulfed by tumor cells instead of passively diffusing into them, bypassing a common mechanism of paclitaxel resistance associated with the multi-drug resistance pump in the cell membrane.

Genta and Pfizer are testing a novel biologic approach in Genasense (oblimersen)/Camptosar, now in Phase II development. Through antisense technology, this drug inhibits the production of Bcl-2, a cancer cell protein thought to contribute to drug resistance. Because Genasense facilitates programmed cell death or apoptosis, it is administered before anticancer therapy to potentiate the effects of chemotherapy, radiation, monoclonal antibodies or immunotherapy.

MediGene AG has an unusual strategy for colorectal cancer in its product NV1020, a modified herpes simplex type 1 virus (HSV) genetically engineered to replicate aggressively in cancer cells and to kill them while sparing normal cells. A Phase I clinical trial of NV1020 for liver metastases of colorectal cancer has been completed at Memorial Sloan Kettering Medical Center in New York, NY.

GenVec and National Cancer Institute are in Phase II testing of TNFerade, a gene-based product that delivers tumor necrosis factor-alpha (TNFa) gene directly into the tumor. This product is less toxic than TNFa, which is approved in Europe for the treatment of soft tissue sarcoma.

Rather than waiting to treat an established colorectal tumor, ILEX Oncology is developing Eflornithine (difluoromethylornithine or DFMO) as a chemopreventive drug targeting early stage epithelial cancers. This drug inhibits ornithine decarboxylase, an enzyme in the polyamine synthesis pathway that is elevated in most tumors and premalignant conditions. The National Cancer Institute is conducting randomized Phase II trials of Eflornithine in sporadic adenomatous polyposis.

Strategies for colorectal cancer run the gamut from improved delivery of standard chemotherapeutic agents to biological approaches including immunotherapy, monoclonal antibodies, antisense technology, genetic manipulation, and even use of modified viruses. Because colorectal cancer is often preceded by polyps or other premalignant lesions, chemoprevention may be another effective tactic.