Colorectal Cancer

Colorectal cancer is one of the major cancer types for which new immune-based cancer treatments are currently in development. This page features information on colorectal cancer and immunotherapy clinical trials for colorectal cancer patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based cancer treatments to people with colorectal cancer.

Colorectal cancer is the third most common type of cancer among both men and women in the United States. The name may refer to colon cancer or rectal cancer, which share many of the same disease characteristics. In 2013, it is projected that there will be 102,480 new cases of colon cancer and 40,340 new cases of rectal cancer in the U.S. Approximately 50,830 deaths are expected in the U.S. and 600,000 worldwide. There is urgent need of new therapeutic strategies, and CRI scientists are working hard to develop immunological treatments that improve the prognosis of patients suffering from this disease.

Colorectal cancer begins in the innermost lining of the colon or rectum. It can spread deeper into the colon or rectum wall or, in the case of advanced cancer, into other organs and lymph nodes. Over 95% of colorectal cancers are adenocarcinomas, a type of tumor that originates in the mucus-producing glands of the colon or rectum.

Urgent Need: Colorectal cancer comprises 9% of all cancer-related deaths, making it the fourth-deadliest cancer in the world. It is estimated that 1 in every 20 people will develop colorectal cancer at some point in their lives. Overall death and incidence rates among men and women have been declining for the past 20 years, thanks largely to screening tests that help detect early-stage cancer and pre-cancerous polyps. Among adults under 50, however, incidence has been rising by 1.7% annually since 1992.

Incidence and Mortality: The 1- and 5- and 10-year survival rates for colorectal cancer are 83%, 64%, and 58%, respectively. However, due to underuse of screening tests, only 39% of colorectal cancers are diagnosed at an early, localized stage, when the 5-year survival rate is 90%. At the locally advanced stage, when the cancer has invaded nearby organs or lymph nodes, the 5-year survival rate is 69%. If the cancer has advanced to the distant stage, invading organs far from the original site of the cancer, the 5-year survival rate drops to only 12%.

Risk Factors: Lifestyle-related risk factors include physical inactivity, obesity, high intake of processed or red meat, long-term smoking, alcohol consumption, and a diet lacking in vegetables and fruits. Personal or family history of colorectal cancer (and/or polyps), and a personal history of type 2 diabetes, chronic inflammatory bowel disease or genetic disease such as Lynch syndrome or familial adenomatous polyposis, have also been associated with increased risk.

Colorectal Cancer Treatment

The most common treatment for colorectal cancer is surgery. In the case of localized tumors, surgery may completely eliminate the cancer. When the cancer has invaded the bowel wall deeply or the lymph nodes, chemotherapy (sometimes in combination with radiation therapy) is administered before or after surgery. For patients whose cancer has recurred or has spread to the liver or lung, surgical resection, if feasible, is the only potentially curative treatment. According to the National Cancer Institute (NCI), surgery is curative in 25% to 40% of highly selected patients who develop resectable metastases in the liver and/or lung.

Standard first-line chemotherapy for metastatic colon cancer can consist of one of two regimens: FOLFOX (5-FU, leucovorin, and oxaliplatin) or FOLFIRI (5-FU, leucovorin, and irinotecan). Adding bevacizumab (Avastin), a monoclonal antibody that helps cut off the nutrient supply to the tumor by suppressing blood vessel growth (anti-angiogenesis), may also help improve survival when included with either treatment regimen. Cetuximab (Erbitux), a monoclonal antibody against the epidermal growth factor receptor (EGFR), has also been shown to improve survival when administered with multi-agent chemotherapy; this agent, however, is only effective in patients whose tumors lack a KRAS mutation.

Panitumumab (Vectibix), another anti-EGFR monoclonal antibody, has also been approved for patients who have become refractory to chemotherapy. Its effects on survival have been consistent with those achieved with cetuximab. In September 2012, the FDA also approved regorafenib (Stivarga®), an oral drug that targets multiple tyrosine kinases, for patients who progressed on prior therapy.

Approximately 50% of colon cancer patients will be diagnosed with liver metastases. This may occur either at the time of initial diagnosis or as a result of disease recurrence. Only a small proportion of patients with liver metastases are candidates for surgery, and other techniques and systemic treatments provide some alternative options. In some cases, metastases can be made resectable after the administration of chemotherapy.

When Are Clinical Trials Recommended?

For colon cancer, clinical trials may be appropriate or encouraged in the following cases:

• For all stage IV or recurrent colorectal cancer
• For patients with stage IIa or III colorectal cancer following surgery (i.e., in the adjuvant setting)

Go to our Clinical Trial Finder to find clinical trials of immunotherapies for colorectal cancer that are currently enrolling patients.

Colorectal Cancer Immunotherapy: Promising Directions and CRI Contributions

Immunotherapy as a potentially promising approach for treatment of colorectal cancer is based on several lines of evidence. The earliest came from a landmark study in 1998 by Haruo Ohtani, M.D., who demonstrated that the presence and location of CD8+ killer T cells within the tumor microenvironment (aka “tumor-infiltrating lymphocytes,” or TILs) correlated with colon cancer outcomes. Specifically, he showed that the accumulation of CD8+ T cells within the tumor correlated with and could predict improved patient survival, whereas accumulation of the same cells in the tumor periphery did not. These studies helped to establish the importance of TILs as prognostic factors in human cancer, and laid the foundation for many studies into the role of TILs as prognostic indicators in other cancers. This and other studies also provided early evidence that immunotherapies that can induce or enhance optimal immunologic conditions within colorectal cancers may hold promise for extending the lives of colorectal cancer patients.

Studies to characterize immunological parameters that can aid prognosis have recently led to the development of a new tool, the Immunoscore, by Jérôme Galon, Ph.D., which provides a novel way of classifying tumors that works better than the current staging system in predicting rate of relapse and survival in colorectal cancer patients. The traditional tumor staging system (TNM classification) provides limited prognostic information, and does not predict response to therapy. The Immunoscore, as an addition to TNM staging, may provide an essential prognostic and potentially predictive tool that can facilititate clinical decision-making, including rational stratification of patient treatment. An international task force, involving investigators in more than 20 countries, is now under way to validate the Immunoscore, the results of which may lead to the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). A recent paper, on which CRI CEO Jill O’Donnell-Tormey, Ph.D., is a co-author, discusses these efforts in more detail. (Access the Paper)

Other studies by CRI scientists that are shedding light on the understanding and treatment of colorectal cancer include:

• Research by Dirk Jäger, M.D., a member of the CRI/Ludwig Cancer Vaccine Collaborative (CVC) at the University of Heidelberg in Germany, is also working to elucidate how immune parameters correlate with prognosis in colorectal cancer. In 2011, he published a study demonstrating that T cell infiltrates at the invasive margin of liver metastases from colorectal cancer predicted response versus no response to chemotherapy, and represented the strongest independent prognostic factor in metastatic colorectal cancer. With his colleagues, he has established a platform that allows him to assess and monitor the complex interplay of different immune cell subsets with tumor cells and other cells in the tumor microenvironment. These studies will not only provide important prognostic clues for patients with colorectal cancer, but also open up new avenues for immune invention based on a better understanding of the immunological milieu in and around colorectal tumors and colorectal cancer metastases.

• Chronic inflammation is a key contributor to the development of colon cancer, and several clinical and epidemiological studies have shown that patients diagnosed with inflammatory bowel diseases (IBD), such as Crohn’s disease or ulcerative colitis, have an increased incidence of colorectal cancer. Several CRI-funded investigators are exploring inflammatory pathways and how they contribute to colon cancer development. In one study, CRI postdoctoral fellow Eran Elinav, M.D., Ph.D., at Yale University, along with former CRI predoctoral scholar Till Strowig, Ph.D., showed that deficiencies in caspase-1, an enzyme involved in the activation and maturation of inflammatory immune molecules, resulted in enhanced tumor formation in a colitis-associated colorectal cancer model. They further showed that caspase-1 plays a role in colorectal cancer development by regulating colonic cell proliferation in early stages of injury-induced tumor formation and cell death in advanced tumors, shedding new light on inflammation-initiated tumor formation, as well as offering new strategies to prevent or inhibit colon cancer development.

• Timothy Eitas, Ph.D., a CRI postdoctoral fellow at the University of North Carolina, Chapel Hill, is also exploring the role of inflammation in colorectal cancer. In his CRI-funded project, Dr. Eitas is studying a protein called NLRX1 and its role in mediating the production of inflammatory molecules called cytokines in ulcerative colitis and colitis-associated cancer. To date, Dr. Eitas’s research has shown that NLRX1 functions to protect against worse clinical outcomes in a model of colitis-associated cancer. In models lacking NLRX1, innate immune cells called macrophages produce higher levels of IL-6, a signaling molecule that has a central role in colorectal cancer development. He has also elucidated several downstream effects of IL-6 production in the progression of colitis-associated colon cancer, each of which may offer novel immunological and molecular targets for colorectal cancer treatment.

• Cancer-testis (CT) antigens have been a large focus of therapeutic vaccine approaches, but colorectal cancer and other gastrointestinal cancers very infrequently express CT antigens. CRI researchers are employing several strategies to overcome this limitation, including new approaches to try to increase expression of CT antigens in colorectal cancer. In one approach, CRI postdoctoral fellow Jeffrey Chou, M.D., Ph.D., at Fred Hutchinson Cancer Research Center, is using the chemotherapy decitabine to enhance the expression of the NY-ESO-1 antigen in colorectal cancer cells to test if it can enhance immune recognition of colorectal cancer.

• In another approach, investigators continue to look for other targets that may be expressed by colorectal cancer cells and may be promising for anti-cancer immunotherapy. In 2010, an international study involving several CRI researchers showed that NY-CO-58/KIF2C (also known as MCAK), first identified as a tumor antigen through the CRI/Ludwig Cancer Antigen Discovery Collaborative, is significantly overexpressed in colorectal cancers and was able to induce spontaneous CD4+ T cell responses, suggesting that its potential as an anti-colorectal cancer target is worth further exploration. (Access the PDF)

• Strategies to target immune checkpoints to enhance anti-cancer immunity, similar to anti-CTLA-4 therapy for melanoma, are showing promise in the treatment of colorectal cancer. In a phase I trial of a monoclonal antibody targeting the PD-1 molecule, researchers at the Johns Hopkins University School of Medicine, including CRI SAC member Drew M. Pardoll, M.D., Ph.D., achieved a complete durable response in a patient with metastatic colorectal cancer, a result that is particularly encouraging given that CRC is not typically considered a promising candidate for immune-based therapies [1].

• Results from a phase II trial testing another anti-PD-1 antibody, CT-011, in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer are expected in the first quarter of 2013 (NCT00890305). Note: In January 2013, Teva Pharmaceuticals ended its collaboration with CureTech on the development of the CT-011 antibody. The future of this development program is unclear [2].

Sources: National Cancer Institute Physician Data Query (PDQ), American Cancer Society Facts & Figures 2012, GLOBOCAN 2008, National Comprehensive Cancer Network (NCCN) Guidelines for Patients, ClinicalTrials.gov, CRI grantee progress reports and other documents