Stages of Colon Cancer

Understand the stages of colon cancer and how Texas Oncology provides personalized treatment, early detection, and advanced care across Texas.

Stages I-III Stage IV

Stage I-III Colon Cancer

The treatment of early stage colon cancer consists of surgery followed by systemic adjuvant chemotherapy in individuals at risk of cancer recurrence.^1,2,3,4

Following surgical removal of colon cancer, the cancer is classified as:

Stage I colon cancer is confined to the lining of the colon, does not penetrate the wall of the colon into the abdominal cavity, and has not spread to any adjacent organs or local lymph nodes. Approximately 90% of patients are cured with surgery alone and will not experience a cancer recurrence.³
Stage II colon cancer has penetrated the wall of the colon into the abdominal cavity but does not invade any of the local lymph nodes – 25-40% of stage II patients will experience recurrence following surgery and systemic adjuvant therapy is recommended for some patients to reduce this risk.³
Stage III colon cancer has penetrated the wall of the colon into the abdominal cavity and invaded any of the local lymph nodes. Half of patients will experience recurrence following surgery and systemic adjuvant therapy is recommended to most patients to reduce this risk.³

The following is a general overview of the treatment of stage I – 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 commonly recommended for some patients with stage II and most patients with stage III colon cancer. The goal of systemic adjuvant therapy is to reduce the risk of colon cancer recurrence.^{1,2,3,4,5,6,7}

Stage II Colon Cancer

Adjuvant chemotherapy may delay cancer progression and prolong survival in some but not all patients with stage II colon cancer. Characteristics that may indicate a higher risk of recurrence in stage II cancer include the following:^3,4

High grade cells on pathologic exam.
Less than 12 lymph nodes sampled during surgery.
Perforation or obstruction of the colon due to cancer.
Stage IIB tumors (tumor has extended beyond the wall of the colon).

OncotypeDX Testing

The OncotypeDX test that may help determine prognosis for patients with stage II colon cancer. 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.⁴

Stage III Colon Cancer

Systemic adjuvant chemotherapy is administered to patients with stage III colon cancer because it reduces the risk of cancer recurrence and improves survival.^3,4,5,6,7

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.⁵

Adjuvant Chemotherapy Regimens for Colon Cancer

FOLFOX (LV/5-fluorouracil + Eloxatin (oxaliplatin)
CAPEOX (Xeloda (capecitabine) + Eloxatin
Xeloda

The overall health of the patient must 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 order to reduce neuropathy, a significant and troublesome side effect of Eloxatin The American Society of Clinical Oncology released guidelines that states that patients with clinically low-risk stage II-III colon cancer should have the option of receiving 3 months of adjuvant Eloxatin-based chemotherapy instead of 6 months.

Resulting recommendations of therapy duration apply to patients with completely resected stage III colon cancer who are being offered adjuvant chemotherapy with Eloxatin 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.^8,9

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 confirm 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.^{10,11,12,13,14,15}

Strategies to Improve Treatment

Genetic Mutations

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. Doctors will increasingly use genomic testing to help better identify who will benefit from adjuvant therapy.

References

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.

2 ascopubs.org/doi/abs/10.1200/JCO.2017.35.4_suppl.710

3 Journal of Clinical Oncology (online April 15, 2019; doi:10.1200/JCO.19.00281).

4 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.

5 Andre T, Boni C, Mounedji-Boudiaf, et al. Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer. New England Journal of Medicine. 2004;350:2343-2351.

6 Twelves C, Wong A, Nowacki M, et al. Capecitabine as Adjuvant Treatment for Stage III Colon Cancer. New England Journal of Medicine. 2005; 352:2696-2704.

7 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.

8 Grothey, A. et al. (2018) Duration of Adjuvant Chemotherapy for Stage III Colon Cancer. The New England Journal of Medicine.

9 Iveson, T. et al. (2018) 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial.

10 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.

11 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.

12 abstracts.asco.org/199/AbstView_199_194502.html

13 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.

14 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.

15 Nelson H, Sargent D, Wie H, et al. A Comparison of Laparoscopically Assisted and Open Colectomy for Colon Cancer. New England Journal of Medicine 2004;350:2050-2059.

Stage IV-Metastatic Colon Cancer

Colon cancer is classified as stage IV or metastatic when the cancer has spread to distant locations in the body and cannot be primarily treated with surgery; this may include the liver, lungs, bones, distant lymph nodes or other sites.

Patients diagnosed with stage IV colon cancer have an increasing number of treatment options as a result of genomic testing and the development of precision cancer medicines. Some patients may be cured of their cancer, and others can derive significant long-term survival benefit with appropriate sequencing of treatment based on their cancers genomic profile.¹

Initial – First Line Treatment of Metastatic Colon Cancer

Treatment of advanced colon cancer may consist of chemotherapy, precision cancer medicines, and immunotherapy or some combination that is often determined by genomic – biomarker testing of the cancer.

Fluorouracil chemotherapy (5-FU) has been the standard treatment for stage IV colon cancer and is typically administered with leucovorin (LV), a drug that is similar in structure and function to the essential vitamin folic acid.

The addition of other drugs to 5-FU/LV and an oral alternative has been found to provide additional benefit to 5-FU alone and standard chemotherapy treatment for advanced colon cancer now includes any of the following regimens for individuals that do not have a cancer driving mutation or targetable biomarker.

FOLFOX (LV/5-fluorouracil + Eloxatin (oxaliplatin)
CAPEOX (Xeloda (capecitabine) + Eloxatin)
FOLFIRI (LV/5-fluorouracil + Camptosar (irinotecan)
FOLFOXIRI (LV/5-fluorouracil + Camptosar + Eloxatin)

These treatment regimens typically paired with Avastin^® (bevacizumab) are the standard initial treatment for most patients and improve survival particularly for the treatment of left sided colon cancers. FOLFOXIRI + Avastin has been estimated to double the 5-year overall survival rate when compared to FOLFIRI + Avastin.²

Colon Cancer Mutations Targeted by Precision Cancer Medicines

Genetic Mutations: Not all colon cancer cells are alike. They may differ from one another based on what genes have mutations. Molecular testing should be performed to test for genetic mutations or the proteins they produce on ALL patients. By testing an individual’s colon cancer for specific unique genomic- biomarkers doctors can offer a personalized treatment approach utilizing precision medicines. Colon cancer mutations are being identified and new medicines developed to target these mutations on an ongoing basis.

Individuals with the following biomarkers may have their colon cancer treated differently using targeted precision cancer medicines – other biomarkers are being identified on an ongoing basis.

Epidermal growth factor receptor (EGFR) occurs in ~ 10% of colon cancers.^4,5,6

BRAFV600: Patients with mutant BRAF genes generally have a poorer prognosis but may benefit from treatment with precision cancer medicines.^3,21

Microsatellite Instability High (MSI-H): MSI-H is a DNA abnormality found in about 15% of colon cancers.Keytruda, and Opdivo have both been demonstrated to improve treatment of individuals with MSI-High disease.^7,8

HER 2: Human epidermal growth factor receptor 2 (HER2) targeted therapies can dramatically improve outcomes HER2 + colon cancers and all colo-rectal cancers should be tested for HER 2.⁹

NTRK:neurotrophic tropomyosin receptor kinases (NTRKs genes, which encode for TRKs can become abnormally fused to other genes, resulting in growth signals that can lead to cancer and be targeted with specific medications.

Treatment of Colon Cancer That Has Metastasized to a Single Site

Many individuals with CRC involving the liver or other sites erroneously conclude that they have no treatment options other than systemic therapy. Stage IV colon cancer commonly spreads to the liver or the lungs and patients who have cancer that has spread to one or two treatable sites are candidates for additional local treatment directed at the metastases.^11,12 Clinical trials have demonstrated that the combination of systemic therapy and surgery for liver metastases further improves treatment outcomes.^16,17,18 When it’s possible to completely surgically remove all liver metastases, surgery is a preferred treatment.

Although surgery offers some patients the chance for a cure a majority of patients with liver metastases are not candidates for surgery because of the size or location of their tumors or their general health.

If the tumors cannot be removed surgically there are several other therapeutic options for the treatment of liver metastases, and isolated areas of cancer in other organs. The type of directed therapy used is determined by the size of the cancer, the number of metastases, and the location of the cancer within the liver or other organs.

The use of minimally invasive techniques such as ablation, embolization, and radioembolization allows the delivery of radiation therapy or chemotherapy directly to the liver tumor(s). Other therapies include radiofrequency ablation (RFA) which uses heat to kill cancer cells, cryotherapy (use of cold to kill cancer cells), delivery of chemotherapy directly to the liver, and radiation.^{10,12,13,14,15,16,17,18,19}

SIR-Spheres Y-90 resin microspheres are a medical device used in an interventional radiology procedure known as selective internal radiation therapy (SIRT), or radioembolization, which targets high doses of radiation directly to liver tumors. The treatment consists of tens of millions of radioactive Y-90 coated resin particles, each no bigger in diameter than a human hair. SIR-Spheres Y-90 are injected into the hepatic artery, which is the main blood supply to the liver via a catheter inserted into the femoral artery through an incision in the groin. The Y-90 resin microspheres become lodged in the smaller blood vessels that surround cancer in the liver, where they deliver a high dose of radiation to the cancer, while sparing healthy liver tissue.^13,15

Patients need to understand that many advanced treatment options are only be available at cancer centers specializing in the treatment of colon and rectal cancers and patients should consider getting an opinion at one of these centers.

Maintenance Therapy

Maintenance therapy may improve survival for patients with metastatic colorectal cancer as compared with re-introduction of chemotherapy at the time of disease progression.²⁰ Maintenance therapy refers to therapy that is used following initial systemic therapy, when a patient’s cancer is stable and not exhibiting signs of progression.

Treatment of Recurrent Metastatic Colon Cancer

When colon cancer has returned following initial treatment with surgery, radiation therapy, and/or chemotherapy or has stopped responding to treatment, it is said to be recurrent or relapsed.

Patients with recurrent colon cancer can be broadly divided into two groups:

Those with isolated recurrence of cancer that can be surgically removed or treated with a directed therapy with the goal of cure.
Those with more widespread cancer.

Most patients with recurrent colon cancer have previously been treated and the recurrent cancer has typically become resistant to whatever treatment regimen was initially used. Testing for specific genomic abnormalities of an individual cancer is essential to determine optimal treatment for recurrent disease. Many patients survive for years after developing recurrent cancer as a result of precision cancer medicines being developed to target the specific genomic abnormalities. In addition, participation in a clinical trial if available should be considered.

Many individuals will not have a specific mutation identified that can be targeted. Treatment of these individuals consists of chemotherapy medications not previously used or participation in a clinical trial.^22,23,24,25

Medications Commonly Used to Treat Recurrent Colon Cancer

5-Flourouracil
Xeloda (Capecitabine)
Camptosar (Irinotecan)
Eloxatin (Oxaliplatin)
Avastin (Bevacizumab)
Erbitux (Cetuximab)
Cyramza (Ramucirumab
Vectibix (Panitumumab)
Stivarga (Regorafenib)
Lonsurf (TAS-102)

Strategies to Improve Treatment

The major research focus in advanced colon cancer is the identification of additional cancer driving mutations as targets for precision cancer medicines and the development of immunotherapy treatment strategies.

References

1 Venook A, Niedzwiecki D, lenz H-J, et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).J Clin Oncol 32:5s, 2014 (suppl; abstr LBA3)

2 Cremolini C, Loupakis F, Masi G, et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (mCRC): Updated survival results of the phase III TRIBE trial by the GONO group. J Clin Oncol. 33, 2015 (suppl 3; abstr 657).

3 abstracts.asco.org/199/AbstView_199_194502.html

4 Cunningham D, Humblet Y, Siena S, et al. Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer. New England Journal of Medicine 2004;351:337-345.

5 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.

6 http://investors.amgen.com/phoenix.zhtml?c=61656&p=irol-newsArticle&ID=1934128

7 https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm560167.htm

8 https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569366.htm

9 Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncology. Published online April 20, 2016.

10 Alsina J, Choti MA. Liver-directed therapies in colorectal cancer. Seminars in Oncology. 2011;38:651-567.

11 American Cancer Society. Colorectal Cancer Facts & Figures 2017-2019. Atlanta: American Cancer Society, 2017.

12 Cho M, Gong J and Fakih M.The state of regional therapy in the management of metastatic colorectal cancer to the liver. Expert Review of Anticancer Therapy, 2016; 16(2): 229–245.

13 van Hazel GA, Heinemann V, Sharma NK et al. SIRFLOX: Randomized Phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2016; 34: 1723–1731.

14 Kennedy AS, Ball D, Cohen SJ et al.Multicenter evaluation of the safety and efficacy of radioembolization in patients with unresectable colorectal liver metastases selected as candidates for 90Y resin microspheres. Journal of Gastrointestinal Oncology. 2015; 6: 134–142.

15 SIR-Spheres^® microspheres (Yttrium-90 Microspheres) Product Information. Available at: http://www.sirtex.com/us/clinicians/package-insert/.

16 Wei A, Greig P, Grant D, et al. Survival After Hepatic Resection for Colorectal Metastases: A 10-Year Experience. Annals of Surgical Oncology. 2006; 13:668-676.

17 Portier G, Elias D, Bouche O, et al. Multicenter Randomized Trial of Adjuvant Fluorouracil and Folinic Acid Compared With Surgery Alone After Resection of Colorectal Liver Metastases: FFCD ACHBTH AURC 9002 Trial. Journal of Clinical Oncology. 2006; 24: 4976-4982.

18 Capussotti L, Muratore A, Mulas MM, Massucco P, Aglietta M. Neoadjuvant Chemotherapy and Resection for Initially Irresectable Colorectal Liver Metastases. British Journal of Surgery. 2006;93:1001-1006.

19 Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III Trial Comparing Protracted Intravenous Fluorouracil Infusion Alone or With Yttrium-90 Resin Microspheres Radioembolization for Liver-Limited Metastatic Colorectal Cancer Refractory to Standard Chemotherapy. Journal of Clinical Oncology. 2010;28:3687-94.

20 Maindrault-Goebel F, et al. Final Results of OPTIMOX2, a Large Randomized Phase II Study of Maintenance Therapy or Chemotherapy-Free (CFI) after FOLFOX in Patients with Metastatic Colorectal Cancer (MRC): A GERCOR Study. Proceedings from the 2007 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #4013.

21 J Clin Oncol. 2019 March 20. Epub ahead of print).

22 Grothey A, Sobrero AF, Siena S et al. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. Paper presented at: 2012 Gastrointestinal Cancers Symposium; January 19-21, 2012; San Francisco, CA. Abstract LBA385.

23 FDA approves new treatment for advanced colorectal cancer. [FDA News Release]. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm321271.htm

24 Argiles G, et al. Abstract O-026. Presented at: ESMO World Congress on Gastrointestinal Cancer; July 3-6, 2019; Barcelona, Spain.

25 Lancet Oncol. 2019 Jun 28. Epub ahead of publication