Medically reviewed by C.H. Weaver M.D. 2/2019
Following surgical removal of colon cancer, the cancer is classified as stage III if the final pathology report shows that the cancer has penetrated the wall of the colon into the abdominal cavity and invaded any of the local lymph nodes, but cannot be detected in other locations in the body. Stage III adenocarcinoma of the colon is a common and curable cancer.
Despite undergoing complete surgical removal of the cancer half of patients with stage III colon carcinoma experience recurrence of their cancer because some cancer cells had spread outside the colon and were not removed by surgery. Additional treatment is needed to eliminate these cancer cells.
The following is a general overview of the diagnosis and treatment of stage III colon cancer. The information on this Web site is intended to help educate you about treatment options and to facilitate a shared decision-making process with your treating physician.
Systemic Adjuvant Therapy
The delivery of systemic treatment following local treatment with surgery is referred to as “adjuvant” therapy and may include chemotherapy or precision cancer medicines. Systemic adjuvant chemotherapy is administered to patients with stage III colon cancer because it reduces the risk of cancer recurrence and improves survival. Since the 1980’s, the mainstay of chemotherapy treatment has been 5-flourouracil (5-FU) and leucovorin (LV), which is very well tolerated by most patients. Adding Eloxatin® (oxaliplatin) to 5-FU/LV improves (FOLFOX) survival rates by 5-10%
Xeloda® (capecitabine) is a form of the chemotherapy drug 5-FU that is administered orally as a pill, rather than into a vein and appears to work as well as 5-FU/LV with fewer side effects. In addition, oral administration is more convenient since it requires fewer clinic visits—patients receiving Xeloda will make a minimum of eight trips to their clinic, whereas those on 5-FU may make up to 30 trips.(1,2)
Chemotherapy Regimens for Stage III Colon Cancer
- FOLFOX (LV/5-fluorouracil + Eloxatin (oxaliplatin)
- CAPEOX (Xeloda (capecitabine) + Eloxatin)
The overall health of the patient must also be considered when weighing the risks and benefits of adjuvant therapy. Patients with fewer other health problems (such as diabetes, obesity or heart disease) will better tolerate adjuvant chemotherapy.
In 2019 The American Society of Clinical Oncology (ASCO) released a new guideline that states that patients with clinically low-risk stage III colon cancer should have the option of receiving 3 months of adjuvant oxaliplatin-based chemotherapy.
An expert panel of 15 individuals convened and conducted a systematic review of relevant studies – including pooled data from the six randomized International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration, which compared 3 months vs 6 months of adjuvant therapy in patients with completely resected colon cancer.
Resulting recommendations of therapy duration apply to patients with completely resected stage III colon cancer who are being offered adjuvant chemotherapy with oxaliplatin and a fluoropyrimidine.
For patients at a high risk of recurrence (T4 and/or N2), adjuvant chemotherapy should be offered for a duration of 6 months.
For patients at a low risk of recurrence (T1, T2, or T3 and N1), either 6 months of adjuvant chemotherapy or a shorter duration of 3 months may be offered on the basis of a potential reduction in adverse events and no significant difference in disease-free survival with the 3-month regimen.
Furthermore, the panel recommends a shared decision-making approach on a case-by-case basis in determining duration of therapy. Decision-makers should take into account patient characteristics, values and preferences, and other factors including a discussion of the potential for benefit and risks of harm associated with treatment duration, the guideline states.(2)
Oncotype DX Testing
A newer test that may help guide treatment decisions for patients with stage colon cancer is the OncotypeDX colon cancer test. This estimates the risk of cancer recurrence by evaluating the activity of certain genes in a sample of tumor tissue. Risk of recurrence can vary among patients with colon cancer, and use of the Oncotype DX test in combination with other markers of risk may help to individualize treatment decisions.(3)
Treatment of the Older Individuals
A large percentage of patients with colon cancer are 65 years or older. Sometimes elderly patients and/or their physicians may believe that treatment will be more toxic for elderly patients than it is for their younger counterparts. Due to this perceived intolerability of therapy, elderly patients often do not receive optimal treatment. The results of several clinical trials however confirms that elderly patients with colon cancer who are in otherwise good health tolerate chemotherapy as well as younger patients and experience improved survival from its use.(1)
Although combination chemotherapy regimens have demonstrated effectiveness, some elderly patients or their physicians may be reluctant to use these regimens because of concern about adverse treatment effects in older patients.
In order to describe the safety and efficacy of FOLFOX4 in elderly colorectal cancer patients, researchers combined information from four clinical trials. These trials included a total of 3,742 patients, 614 of whom were age 70 or older. One of the trials enrolled patients with Stage II or Stage III colorectal cancer, two studies enrolled patients with metastatic colorectal cancer, and one study enrolled patients who had experienced cancer progression during initial treatment.
- Patients age 70 or older were more likely than younger patients to experience low levels of white blood cells (neutropenia) or platelets (thrombocytopenia). Grade 3 or 4 neutropenia developed in 43% of younger patients and 49% of older patients. Grade 3 or 4 thrombocytopenia developed in 2% of younger patients and 5% of older patients.
- The overall frequency of serious adverse effects of treatment was similar in the two age groups (63% in younger patients and 67% in older patients).
- The benefits of FOLFOX4 on response to treatment and survival were also similar in the two age groups.
The researchers conclude that the FOLFOX4 chemotherapy regimen remains safe and effective when used in selected elderly patients with colorectal cancer. The researchers note that judicious use of FOLFOX4 “should be considered without regard to patient age, although scant data are available for patients older than 80 years.”(4)
Patients older than age 75 represent a large number of those who are diagnosed each year with colorectal cancer; however there is little data to support adjuvant chemotherapy in this population because older people are often excluded from clinical trials.
To evaluate the effectiveness of adjuvant chemotherapy in this patient population, researchers performed a retrospective analysis of data from four sources: the Surveillance, Epidemiology, and End Results (SEER) database and the New York State Cancer Registry (NYSCR), both of which are linked to Medicare programs and the NCCN Outcomes Database and the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS).
The study included data from 5,489 patients aged 75 or older with stage III colorectal cancer diagnosed between 2004 and 2007. The patients were categorized into two groups: chemotherapy or no chemotherapy. Those who underwent chemotherapy were further categorized to determine whether their chemotherapy included Eloxatin® (oxaliplatin).
The results of the analysis indicated that the use of chemotherapy declined with age and comorbidity. Patients who received chemotherapy had significantly better survival than those who did not. In fact, the researchers found that the survival benefit was equal to that seen in clinical trials of younger patients. Chemotherapy that included Eloxatin appeared to be associated with a trend toward lower mortality in two of the four data sets.
The researchers concluded that patients aged 75 and older with stage III colorectal cancer may experience a survival benefit with adjuvant chemotherapy. They suggest that adjuvant therapy in this older patient population is worth considering, depending on individual health characteristics.(5)
Strategies to Improve Treatment
The progress that has been made in the treatment of colon cancer has resulted from patient participation in clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of stage III colon cancer.
Systemic Adjuvant Therapy
Several new chemotherapy and biological drugs demonstrate promising activity for the treatment of colon cancer. Clinical research is ongoing to develop new multi-drug treatment regimens that incorporate new anti-cancer therapies for use as adjuvant treatment.4,5 Clinical trials are ongoing evaluating new combinations of chemotherapy alone or with precision cancer medicines.
Precision Cancer Medicines
The purpose of precision cancer medicine is not to categorize or classify cancers solely by site of origin, but to define the genomic alterations in the cancer’s DNA that are driving that specific cancer. Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Not all colon cancer cells are alike. They may differ from one another based on what genes have mutations. Molecular testing is performed to test for certain genetic mutations or the proteins they produce because the results can help select treatment including newer precision cancer medicines designed to attack specific colon cancer cells with specific genetic mutations.
- EGFR: The epidermal growth factor receptor (EGFR) is involved in cellular growth and replication. Some colon cancers produce too much EGFR and this leads to more rapid growth of the cancer. Some medicines specifically target EGFR and the spread of cancer can be reduced or delayed.6,7
- The RAS Genes: KRAS and NRAS are a family of proteins found in cells that when mutated promote cancer cell growth. An estimated 40–50% of colorectal cancers contain these genes. Some colon cancer treatments don’t work if the RAS gene is abnormal. If cancer has a KRAS or NRAS mutation drugs that inhibit cancer cell growth and survival by targeting a protein known as the EGFR are ineffective. Cancers lacking these genetic mutations are referred to as “wild type”.
- BRAF: BRAF is also a gene that signals cells to divide. Patients with mutant BRAF genes generally have a poorer prognosis (chance of survival and worse side effects) but may benefit from treatment with a precision cancer medicine.
- PIK3CA: While somewhat new, a growing number of clinicians are testing for mutant PIK3CA genes; particularly in patients who have early-stage colorectal cancer. There is some suggestion that aspirin use may help decrease the risk of recurrent colorectal cancer in patients with early stage disease and PIK3CA mutation.
- Microsatellite Instability High (MSI-H) MSI-H is a DNA abnormality found in about 15% of colon cancers. It is most often found in tumors associated with genetic syndromes like Lynch syndrome but can also occur sporadically. MSI-H is what “happens” when the genes that regulate DNA function don’t work correctly. These DNA regulating genes, known as Mismatch Repair Genes (MMR), work like genetic “spell checkers.” When problems occur in these spell-checking MMR genes, it means that areas of DNA start to become unstable. A high frequency of instability is called MSI-H. Patients with MSI-H tumors may respond differently to certain treatment. It is important to test colon cancers for this trait because it can help determine if the colorectal cancer is related to an inherited family syndrome.
Targeting “Wild type” KRAS & RAS
Erbitux® (cetuximab) and Vectibix (panitumumab) are a type of precision cancer medicine called a monoclonal antibody that works by binding to EGFR which is involved in cellular growth and replication,. By targeting EGFR the spread of cancer can be reduced or delayed. Both Vectibix and Erbitux can be combined with chemotherapy to improve outcomes in patients that test positive for EGFR and do not have a RAS mutations.6,7,8
Avastin® (bevacizumab): Avastin is type of targeted therapy that slows or prevents the growth of new blood vessels, a process called angiogenesis. Cancer cells require food, oxygen, and proteins in order to grow and spread. New blood vessels are necessary to deliver these essential components of cellular growth. Avastin starves cancer cells by inhibiting angiogenesis. Avastin has been shown to improve outcomes among patients with metastatic colon cancer,9 and is being studied among patients with earlier-stage colon cancer as well.
Advances in Surgery for Colon Cancer
Surgical removal of cancer remains an integral part of the treatment strategy for patients with stage III colon cancer however few patients are cured with surgery alone. Conventional surgery involves opening the pelvis and/or abdomen to gain access to the large intestine. As with any surgery, there are risks associated with removing cancer, including infection, blood loss, and other possible complications of surgery.
Clinical trials have shown that a less invasive surgical technique, called laparoscopic surgery, may be more tolerable than and similarly effective as conventional surgery. Laparoscopic surgery involves the placement of small probes into the area of surgery. The probes contain cameras and instruments for removing the cancer. The surgeon performs the surgery through the probes while watching his or her movements captured by the camera and projected on a large screen. This type of procedure prevents the need for large surgical incisions, and may be associated with fewer complications, especially infections (abdominal infections, urinary tract infections and pneumonia). In addition, patients undergoing laparoscopic surgery generally experience less discomfort post-operatively and have a quicker recovery time (return to normal activities).10,11,12
When choosing between open and laparoscopic abdominal surgery, patients and their doctors must weigh the potential short-term benefits of laparoscopic surgery with a possible small increase in cancer recurrence that may be associated with laparoscopic resection. Patients may choose based on their own health and the expertise and recommendations of their surgeon.
1 D Sargent, R Goldberg, J MacDonald, et al. Adjuvant Chemotherapy for Colon Cancer (CC) Is Beneficial Without Significantly Increased Toxicity in Elderly Patients (Pts): Results from a 3351 Pt Meta -Analysis. Proceedings from the 36th annual meeting of the American Society of Clinical Oncology. Blood. 2000;19: Abstract #933.
Journal of Clinical Oncology (online April 15, 2019; doi:10.1200/JCO.19.00281).
3 O’Connell M, Lee M, Lopatin M et al. Validation of the 12-gene colon cancer recurrence score (RS) in NSABP C07 as a predictor of recurrence in stage II and III colon cancer patients treated with 5FU/LV (FU) and 5FU/LV+oxaliplatin (FU+Ox). Paper presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012;Chicago,IL. Abstract 3512.
Goldberg RM, Tabah-Risch I, Bleiberg H et al. Pooled Analysis of Safety and Efficacy of Oxaliplatin Plus Fluorouracil/Leucovorin Administered Bimonthly in Elderly Patients with Colorectal Cancer. Journal of Clinical Oncology. 2006;24:4085-4091.
Sanoff HK, Carpenter WR, Stürmer T, et al. Effect of adjuvant chemotherapy on survival of patients with stage III colon cancer diagnosed after age 75 years. Journal of Clinical Oncology. 2012; 30(21): 2624-2634.
7 Hriesik C, Ramanathan R, Hughes S. Update for Surgeons: recent and noteworthy changes in therapeutic regimens for cancer of the colon and rectum. Journal of the American College of Surgeons2007; 205: 468-478.
8 Taieb J, Puig PL, Bedenne L. Cetuximab plus FOLFOX-4 for fully resected stage III colon carcinoma: scientific background and the ongoing PETACC-8 trial. Expert Reviews of Anticancer Therapy.2008;8(2):183-9.
10 Mirza MS, Longman RJ, Farrokhyar F, et al. Long-term outcomes for laparoscopic versus open resection of nonmetastatic colorectal cancer. Journal of Laparoendoscopic Advances in Surgical Technique2008;18(5):679-685.
11 Bilimoria KY, Bentrem DJ, Merkow RP, et al. Laparoscopic-assisted vs. Open Colectomy for Cancer: Comparison of Short-term Outcomes from 121 Hospitals. Journal of Gastrointestinal Surgery [early online publication]. June, 2008.