Colorectal Cancer: Pharmacologic Management

Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the United States.¹ Colorectal cancer is an umbrella term that refers to cancer of both the colon and the rectum. According to the American Cancer Society, approximately 46,050 new cases of rectal cancer and 106,970 new cases of colon cancer are projected to be diagnosed in 2023, with as many as 52,550 deaths from combined colorectal cancers anticipated.¹

Individuals with colorectal cancer do not always experience symptoms. The symptoms that do emerge usually include rectal bleeding and other gastrointestinal-related manifestations. Individuals with undiagnosed colorectal cancer may also experience fatigue and unexplained weight loss.² Because of blood loss through the gastrointestinal tract, anemia can also be the first sign of illness.

Adenocarcinomas, which are tumors that arise from the mucosal lining of the colon or rectum, account for the majority of colorectal cancers. They usually begin as small, surgically removable polyps. Although these polyps are not usually cancerous, they can become malignant if left untreated. Colorectal cancers can also be carcinoid tumors, gastrointestinal stromal tumors, lymphomas, and sarcomas.³ 

This article will review pharmacotherapeutic recommendations for both colon and rectal cancers as advised by the National Comprehensive Cancer Network (NCCN),^4,5 the National Cancer Institute ^6,7 and the American Cancer Society.⁸

Colorectal Cancer: Treatment and Management

Treatment recommendations for colorectal cancers depend highly on the pathologic stage of the illness. Broadly, staging for colorectal cancer is based on 3 criteria: 

• Tumor size and how much it has spread into the surrounding muscle and tissue (T),
• The number of lymph nodes the tumor has invaded (N), and 
• Whether the tumor has metastasized (M) to organs far from the original tumor site.

Because staging for colon and rectal cancers are similar, the two will be presented together; however, any discrepancies between the two will be discussed.^6-7

The T categories for colon and rectal cancers start at Tis for a tumor that is in situ, or contained to the original site of occurrence. T1 tumors have started to invade the surrounding smooth muscle of the colon or rectum but have not yet spread through the muscle wall. T2 tumors have spread through the muscle wall, and T3 tumors have started to spread into the surrounding tissues of the colon or rectum. Tumors of the T4a category have spread to the peritoneum, whereas tumors of the T4b category have spread or attached to other surrounding organs.

The N categories start with N0, which indicates that no lymph nodes have been affected. N1a refers to 1 lymph node having a tumor greater than .2 mm in diameter. When 2 to 3 lymph nodes are positive, this is qualified as N1b, and no positive lymph nodes with deposits in the surrounding tissue is considered N1c. N2a denotes 4 to 6 positive lymph nodes, and N2b denotes more than 7 positive lymph nodes.

Metastasis categories in colorectal cancer are defined in the following manner:  M0, no metastasis; M1a, metastasis to 1 distant organ; M1b, metastasis to at least 2 distant organs; and M1c, metastasis to the surface of the peritoneum. ^6-7

Staging of Colorectal Cancer

Staging of colorectal cancer is based on the combination of the aforementioned T, N, and M categories. The stage of the cancer determines the proper course of treatment.

• Stage 0: Tumor is contained to either the colon or the rectum. No lymph nodes have been affected, and there is no metastasis. Grading is Tis, N0, M0.
• Stage I: Tumor has spread into the surrounding smooth muscle. No lymph nodes have been affected, and there is no metastasis. Grading is T1-T2, N0, M0.
• Stage II: Tumor has spread into the surrounding organs. No lymph nodes have been affected, and there is no metastasis. Grading is T3-4, N0, M0.
• Stage III: Tumor has spread and has invaded the surrounding lymph nodes. There is no metastasis. Grading is T1-4a, N1-N2c, M0.
• Stage IV :Tumor may or may not have spread to surrounding tissues or lymph nodes, but the cancer has metastasized. Grading is Tis-T4b, N0-N2b, M1a-c.^6-7

Therapies for Colorectal Cancer

A variety of therapies are approved for colon and rectal cancers. While early stages of the disease can usually be fully addressed surgically, there are circumstances in which pharmacotherapies should be administered as early as stage I. 

Neoadjuvant therapies refer to pharmacotherapies given prior to a surgical procedure. These treatments are usually given in conjunction with radiation therapy. Adjuvant therapies are therapies administered following surgery. Therapy recommendations can depend on the patient’s genotype.

For treatment of colorectal cancer, pharmacologic management falls into 3 categories: chemotherapy, immunotherapy, and targeted therapy. 

Chemotherapy for Colorectal Cancer

Chemotherapeutic agents target fast-growing cells by damaging their DNA and forcing them to go into apoptosis, or programmed cell death. Chemotherapy for colon and rectal cancer can be given either as swallowable pills or as a systemic, intravenous infusion.⁸ 

The following are chemotherapeutic agents approved by the US Food and Drug Administration (FDA) for colorectal cancers⁹:

• Capecitabine
• Fluorouracil 
• Irinotecan hydrochloride
• Oxaliplatin
• Trifluridine and tipiracil hydrochloride

Immunotherapy for Colorectal Cancer

Immunotherapy typically involves activating the immune system in a way that alerts it to start killing cancer cells. In many cancers, tumor cells express certain surface proteins that allow them to trick the immune system into ignoring them. The immunotherapies recommended for colorectal cancer work by blocking either the programmed death-1/programmed death-1 ligand-1 (PD-1/PD-L1) binding interaction or the CTLA-4 receptor.  Both strategies result in T-cells of the immune system being able to attack tumors.¹⁰ 

Approved immunotherapies for colorectal cancers are primarily recommended for individuals who have genes with deficient mismatch repair (dMMR), because they have been found to respond better to these treatments.¹¹

Immunotherapy is usually delivered to the patient via intravenous infusion. The following are FDA-approved immunotherapies for colorectal cancers⁹:

• Ipilimumab 
• Nivolumab 
• Pembrolizumab

Targeted Therapy for Colorectal Cancer

Targeted therapy is designed to destroy cancer cells by acting on specific genetic and molecular pathways.¹² The following are FDA-approved targeted therapies for colorectal cancer⁹:

• Bevacizumab
• Cetuximab
• Panitumumab
• Ramucirumab
• Regorafenib
• Tucatinib
• Ziv-aflibercept

Of the approved targeted therapies, bevacizumab, ramucirumab, and ziv-aflibercept work by blocking the vascular endothelial growth factor (VEGF) ligand-receptor interaction. This is a binding interaction that tumors use to spread. Cetuximab and panitumumab block the epidermal growth factor receptor (EGFR) ligand-binding interaction. This pathway can also be involved in cancer growth. It is not an effective therapy for individuals with mutations in the KRAS, NRAF, or BRAF genes. Lastly, some cancer cells express human epidermal growth factor receptor 2 (HER2), which promotes excessive growth, and regorafenib and tucatinib target this pathway.

Combination Therapy for Colorectal Cancer

For colon and rectal cancers, many of the pharmacotherapeutic best practices involve combinations of therapies. In many cases, combination therapies involve a treatment regimen of chemotherapy drugs with immunotherapies or targeted therapies. The following are FDA-approved combination therapies for colorectal cancer:

• CAPOX: capecitabine and oxaliplatin
• FOLFIRI: leucovorin calcium, fluorouracil, and irinotecan hydrochloride
• FOLFIRI-bevacizumab
• FOLFIRI-cetuximab
• FOLFOX: leucovorin calcium, fluorouracil, and oxaliplatin
• FU-LV: leucovorin calcium and fluorouracil
• XELIRI: capecitabine and irinotecan hydrochloride

Notably, although there are other pharmacotherapies used for colorectal cancer, these are off-label use. Only FDA-approved treatments will be reviewed here. Mention will be made if treatment recommendations differ between colon and rectal cancer; otherwise, recommendations should be assumed to be for both cancer types.

Table 1. Management Guidelines for Chemotherapy for Colorectal Cancer

Drug	Dosage	Administration	Treatment Duration	Recommended Use
Capecitabine	1250 mg/m2 of body surface area taken 2 times daily	Oral tablets	Every 3 wk for 6 mo	Adjuvant treatment for specific tumors; see combination therapies; stages I-III
Fluorouracil	225 mg/m2 daily over 24 h on days 1-5 or 1-7 of each wk	IV infusion	For 5 wk during RT or for 6 mo during adjuvant treatment	Adjuvant treatment for nonadvanced disease; usually stages I-III
Irinotecan hydrochloride	125 mg/m2 on days 1, 8, 15, and 22;350 mg/m2 on day 1	IV infusion over 90 min	First regimen is followed by a 2-wk break; every 2 wk until disease worsens or toxicity is intolerable	Systemic treatment for stage IV advanced metastatic disease
Oxaliplatin	See CAPOX, FOLFIRI, and FOLFOX in Table 4	See CAPOX, FOLFIRI, and FOLFOX in Table 4	See CAPOX, FOLFIRI, and FOLFOX in Table 4	Adjuvant treatment for stage III colon cancer; systemic treatment for colon and rectal cancers in stage IV metastatic disease; only given as combination chemotherapy treatment
Trifluridine and tipiracil hydrochloride	35 mg/m2 2 times daily on days 1- 5 and days 8-12 of a 28-d cycle	Oral tablets	Until disease worsens or toxicity is intolerable	Systemic treatment for advanced stage IV; used after patient has already received combination chemotherapy treatment

IV= intravenous; RT = radiation therapy.

From FDA-approved prescribing information.^13-17

Table 2. Management Guidelines for Immunotherapy for Colorectal Cancer

Drug	Dosage	Administration	Treatment Duration	Recommended Use
Ipilimumab	1 mg/kg	IV infusion over 30 min immediately after nivolumab treatment	Every 3 wk for 4 doses then just nivolumab	Systemic treatment for advanced stage IV; tumors that are MSI-H or dMMR; for patients who have already received combination chemotherapy
Nivolumab	240 mg every 2 wk or 480 mg every 4 wk; in regimen with ipilimumab 1 mg/kg until end of ipilimumab treatment and then back to standard dosing	IV infusion	Every 2 wk or 4 wk; with ipilimumab every 3 wk for 4 doses and then standard dosing until disease worsens or toxicity is intolerable	Systemic treatment for advanced stage IV; tumors that are MSI-H or dMMR; for patients who have already received combination chemotherapy
Pembrolizumab	200 mg every 3 wk  or 400 mg every 6 wk	IV infusion	Until disease worsens or toxicity is intolerable up to 24 mo	Systemic treatment for advanced stage IV; tumors that are MSI-H or dMMR

IV = intravenous; MSI-H = microsatellite instability-high; dMMR = mismatch repair deficient.

From FDA-approved prescribing information.^18-20

Table 3. Management Guidelines for Targeted Therapy for Colorectal Cancer

Drug	Dosage	Administration	Treatment Duration	Recommended Use
Bevacizumab	With FOLFOX, 10 mg/kg every 2 wk; with FOLFIRI,  5 mg/kg every 2 wk or 7.5 mg/kg every 3 wk	IV infusion for 90 min for the first treatment, 60 min for the second treatment, and 30 min for all subsequent treatments	Until disease worsens or toxicity is intolerable up to 96 wk	Advanced metastatic disease stage IV
Cetuximab	400 mg/m2 for first dose and 250 mg/m2 for subsequent doses	IV infusion over 120 min for first dose and 60 min for subsequent doses	Until disease worsens or toxicity is intolerable	Advanced metastatic disease stage IV; only for individuals who have wild-type RAS and EGFR genes and used in combination with FOLFIRI or irinotecan; can be for BRAF V600E mutation in combination with encorafenib
Panitumumab	6 mg/kg	IV infusion over 60 min for first dose and 30-60 min for subsequent doses; larger doses can be administered over 90 min	Until disease worsens or toxicity is intolerable	Advanced metastatic disease stage IV; only for individuals who have wild-type KRAS and NRAS genes
Ramucirumab	8 mg/kg	IV infusion over 60 min for first dose and 30 min for subsequent doses; infusion is prior to FOLFIRI	Until disease worsens or toxicity is intolerable	Advanced metastatic disease stage IV
Regorafenib	160 mg daily for the first 21 d of a 28-d cycle	Oral tablets	Until disease worsens or toxicity is intolerable	Advanced metastatic disease stage IV
Tucatinib	300 mg twice daily	Oral tables	Until disease worsens or toxicity is intolerable	Inoperable tumor; advanced metastatic disease stage IV
Ziv-aflibercept	4 mg/kg every 2 wk	IV infusion for 1 h		Advanced metastatic disease stage IV has progressed and patient has passed another combined chemotherapy; recommended with FOLFIRI

IV = intravenous.

From FDA-approved prescribing information.^21-27

Table 4. Management Guidelines for Combination Therapy for Colorectal Cancer

Drug Combination	Dosage	Administration	Treatment Duration	Recommended Use
CAPOX	Oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily for 14 d	Oxaliplatin via IV infusion and capecitabine via oral tablets	Every 3 wk for 3 mo	Neoadjuvant treatment in stage II colon cancer and stages III and IV rectal cancer; adjuvant treatment in stages II and III colon and rectal cancers; systemic treatment of stage IV colon and rectal cancer
FOLFIRI	Irinotecan 180 mg/m2 and leucovorin calcium 400 mg/m2 on day 1; fluorouracil 400 mg/m2 on day 1 and 1200 mg/m2/d on days 2 and 3	Irinotecan and leucovorin calcium over 30-90 min IV infusion; day 1 fluorouracil via IV bolus and days 2-3 IV infusion for 46-48 h	Every 2 wk for 6 mo	Stage IV systemic treatment of colon and rectal cancer
FOLFIRI-bevacizumab	FOLFIRI regimen with bevacizumab 5 mg/kg on day 1	FOLFIRI administration with IV infusion of bevacizumab	Every 2 wk for 6 mo	Stage IV systemic treatment of colon and rectal cancer; only for populations without mutations in KRAS/NRAS/BRAF genes
FOLFIRI-cetuximab	FOLFIRI regimen with 500 mg/m2 of cetuximab on day 1	FOLFIRI administration with IV infusion of cetuximab over 2 h	Every 2 wk for 6 mo	Stage IV systemic treatment of colon and rectal cancer; only for populations without mutations in KRAS/NRAS/BRAF genes
FOLFOX	Oxaliplatin 85 mg/m2 and leucovorin calcium 400 mg/m2 on day 1; fluorouracil 400 mg/m2 on day 1 and 1200 mg/m2/d on days 2 and 3	Oxaliplatin and leucovorin calcium via IV infusion; day 1 fluorouracil via IV bolus and days 2-3 IV infusion for 46-48 h	Every 2 wk for 6 mo	Neoadjuvant treatment in stage II colon cancer and stages III and IV rectal cancer; adjuvant treatment in stages II and III colon and rectal cancers; systemic treatment of stage IV colon and rectal cancer

IV = intravenous.

From NCCN Guidelines for colon and rectal cancers.^4,5

Monitoring Side Effects of Colorectal Cancer Treatment

Monitoring side effects is a crucial part of medication management in cancer treatment. Each class of drug tends to have relatively similar side effect profiles.

Chemotherapy

Because chemotherapeutic agents are targeting cells that are growing rapidly, many other cells in the body can also be affected. Common symptoms include skin, hair, and nail irritation; gastrointestinal disturbances; and overall fatigue. As chemotherapy is usually not recommended in pregnant or lactating patients, specific guidelines on when family planning events can occur following treatment are provided. Oftentimes, side effect profiles are more severe in geriatric populations.

Table 5. Side Effect Profiles for Chemotherapy for Colorectal Cancer

Drug	Most Common Adverse Events	Side Effects Necessitating Treatment Discontinuation or Modification	Drug-Drug Interactions	Special Populations
Capecitabine	Hand and foot syndrome (palmar-plantar erythrodysesthesia), vomiting, abdominal pain, nausea, fatigue, increased bilirubin levels	Pathologic blood clotting, DPD deficiency, kidney failure, hand and foot syndrome, increased bilirubin levels, decreased neutrophils	Anticoagulants; phenytoin; leucovorin can increase toxicity of fluorouracil in combination therapy; CYP2C9 substrates; allopurinol should be avoided	Not recommended in pregnant or lactating individuals; greater chance for adverse events in geriatric population; individuals with kidney disease should receive lower dose
Fluorouracil	Low DPD, cardiotoxicity, ammonia-induced swelling of the brain, neurologic toxicity, diarrhea, hand and foot syndrome, mouth inflammation, myelosuppression, increased risk of elevated INR with anticoagulants	Low DPD, cardiotoxicity, ammonia-induced swelling of the brain, neurologic toxicity, diarrhea, hand and foot syndrome, mouth inflammation, myelosuppression, increased risk of elevated INR with anticoagulants	Anticoagulants and CYP2C9 substrates	Could cause harm to fetus; breastfeeding is not recommended; infertility is possible for both male and female patients so contraception is recommended for sexually active individuals; female patients should refrain from getting pregnant for 3 mo following treatment
Irinotecan hydrochloride	Abdominal pain, nausea, vomiting, diarrhea, constipation, anorexia, neutrophil deficiency, decreased leukocytes and lymphocytes, anemia, weakness, fever, weight loss, hair loss	Diarrhea, reduced bone marrow activity and blood cell count, severe allergic reaction, kidney disease, lung disease, liver disease	CYP3A4 inducers and inhibitors	Could cause harm to fetus; breastfeeding is not recommended until 7 d after final dose of treatment; infertility is possible for both male and female patients so contraception is recommended for sexually active individuals; female patients should refrain from getting pregnant for 6 mo following treatment; greater risk of diarrhea in geriatric population; not recommended for individuals with kidney or liver disease; individuals with certain UGT1A1 mutations have an increased risk of neutrophil deficiency
Oxaliplatin	Peripheral nerve damage, decreased neutrophils, low platelet count, anemia, nausea, increased transaminases and alkaline phosphatase levels, diarrhea, vomiting, fatigue, mouth ulcers	Peripheral nerve damage, decreased neutrophils, PRES, lung toxicity, hemorrhage, liver toxicity, rhabdomyolysis, increased QT interval	Drugs that extend QT interval; drugs that are toxic to the kidneys; anticoagulants increase risk of hemorrhage	Could cause harm to fetus; breastfeeding is not recommended until 3 mo after final dose of treatment; infertility is possible for both male and female patients; contraception is recommended for sexually active female patients for 9 mo after treatment and for male patients for 6 mo after treatment; higher risk of diarrhea and decreased neutrophils in geriatric population; reduced dose recommended for individuals with kidney disease
Trifluridine and tipiracil hydrochloride	Anemia, neutrophil deficiency, fatigue, nausea, platelet deficiency, reduced hunger, diarrhea, vomiting, fever	Severe myelosuppression	None indicated	Could cause harm to fetus; breastfeeding is not recommended until 1 d after final dose of treatment; infertility is possible for both male and female patients; contraception is recommended for sexually active female patients for 6 mo after treatment and for male patients for 3 mo after treatment; decreased neutrophils and platelet count and increased incidence of anemia in geriatric population; reduced dose recommended for individuals with kidney disease; not recommended for individuals with moderate to severe liver disease

DPD= dihydropyrimidine dehydrogenase; INR = international normalized ratio; PRES = posterior reversible encephalopathy syndrome.

From FDA-approved prescribing information.^13-17

Immunotherapy

Side effects of immunotherapy often involve immune-mediated reactions. These can include inflammation of certain organ systems, dermatitis or rash, and extensive symptoms of malaise. Immunotherapy is not recommended for pregnant or breastfeeding individuals, and wait times are recommended between completing treatment and conceiving.

Table 6. Side Effect Profiles for Immunotherapy for Colorectal Cancer

Drug	Most Common Adverse Events	Side Effects Necessitating Treatment Discontinuation or Modification	Drug-Drug Interactions	Special Populations
Ipilimumab	Fatigue, rash, itchy skin (pruritus), diarrhea nausea, muscle pain (myalgia), fever, cough, reduced hunger, vomiting, abdominal discomfort, difficulty breathing, upper respiratory tract infection, joint pain, headache, underactive thyroid, constipation, weight loss, dizziness	Hepatitis, rash, pituitary inflammation, adrenal insufficiency, overactive thyroid, underactive thyroid, thyroiditis, type 1 diabetes, lung inflammation, kidney dysfunction, colitis	None indicated	Could cause harm to fetus; breastfeeding is not recommended until 3 mo after final dose of treatment; contraception is recommended for sexually active female patients for 3 mo after treatment
Nivolumab	Fatigue, rash, itchy skin, muscle pain, diarrhea, nausea, constipation, labored breathing, cough, weakness, reduced hunger, back pain, joint pain, upper respiratory tract infection, fever, headache, abdominal discomfort, vomiting, UTI	Lung inflammation, colitis, hepatitis, adrenal insufficiency,  inflammation of the pituitary gland, thyroiditis, overactive thyroid, underactive thyroid, type 1 diabetes, kidney dysfunction, rash, infusion reactions, reactions to stem cell transplantation	None indicated	Could cause harm to fetus; breastfeeding is not recommended until 5 mo after discontinuation of use
Pembrolizumab	Fatigue, musculoskeletal discomfort, itchy skin, rash, nausea, reduced hunger, high blood sugar, anemia, reduced lymphocytes, hypoalbuminemia, low serum sodium levels, elevated alkaline phosphatase levels, elevated creatinine levels, reduced phosphate levels, elevated AST levels, elevated serum potassium levels, low serum calcium levels	Lung inflammation, colitis, hepatitis, adrenal insufficiency, inflammation of the pituitary gland, thyroiditis, overactive thyroid, underactive thyroid, type 1 diabetes, kidney dysfunction, rash, infusion reactions, reactions to stem cell transplantation	None indicated	Could cause harm to fetus; breastfeeding is not recommended until 4 mo after discontinuation of use

UTI = urinary tract infection; AST =aspartate aminotransferase.

From FDA-approved prescribing information.^18-20

Targeted Therapy

Targeted therapy often is associated with severe adverse reactions. Targeted therapy is not recommended for pregnant or breastfeeding patients. There are generally more side effect risks associated with targeted therapy when used in the geriatric population. Some targeted therapies may cause infertility in male and female patients.

Table 7. Side Effect Profiles for Targeted Therapy for Colorectal Cancer

Drug	Most Common Adverse Events	Side Effects Necessitating Treatment Discontinuation or Modification	Drug-Drug Interactions	Special Populations
Bevacizumab	Nose bleed (epistaxis), headache, hypertension, congestion, proteinuria, taste alterations, dry skin, hemorrhage, excessive tear production, back pain, skin shedding	Perforations in GI tract, slow wound healing, hemorrhage, arterial thrombotic events, venous thromboembolism, hypertension, PRES, kidney injury, infusion reactions, congestive heart failure	None indicated	Breastfeeding is not recommended during treatment or until 6 mo after last dose; pregnancy risk; female  patients are advised to use contraception for 6 mo after final dose; risk of infertility in female patients; increased prevalence of arterial thrombotic events in geriatric population
Cetuximab	Rash, itchy skin, nail changes, headache, diarrhea, infection, fatigue, abdominal discomfort, reduced hunger, joint pain	Infusion reactions, lung toxicity, severe rash	None indicated	Breastfeeding is not recommended during treatment or until 2 mo after last dose; pregnancy risk; female patients are advised to use contraception for 2 mo after final dose; risk of infertility in female patients
Panitumumab	Rash, fingernail infection, fatigue, nausea, diarrhea	Skin toxicity, tumor progression, infusion reactions, lung toxicity, eye toxicity	None indicated	Breastfeeding is not recommended during treatment or until 2 mo after last dose; pregnancy risk; female patients are advised to use contraception for 2 mo after final dose; risk of infertility in female patients; increased risk of adverse events in geriatric population
Ramucirumab	Diarrhea, decreased neutrophils, reduced hunger, nose bleed, stomatitis (oral mucositis)	Hemorrhage, GI perforations, slow wound healing, arterial thrombotic events, hypertension, infusion-related reactions, PRES	None indicated	Breastfeeding is not recommended during treatment or until 2 mo after last dose; pregnancy risk; female patients are advised to use contraception for 3 mo after final dose; risk of infertility in female patients
Regorafenib	GI and abdominal discomfort, hand and foot syndrome, weakness, fatigue, diarrhea, reduced hunger, hypertension, infection, hoarse voice, high serum bilirubin, fever, mouth inflammation, weight loss, rash, nausea	Liver toxicity, infections, hemorrhage, GI perforations, skin toxicity, hypertension, cardiac ischemia, RPLS, slow wound healing	Strong CYP3A4 inducers and inhibitors; BCRP substrates	Breastfeeding is not recommended during treatment or until 2 mo after last dose; pregnancy risk; female and male patients are advised to use contraception for 2 mo after final dose; risk of infertility in female and male patients; increased risk in geriatric population
Tucatinib	Fatigue, abdominal discomfort, infusion reactions, nausea diarrhea, rash, fever	Diarrhea, liver toxicity	Strong CYP3A4 and moderate CYP2C8 inducers; CYP2C8 inhibitors; CYP3A substrates; P-gp substrates	Breastfeeding is not recommended during treatment or until 1 wk after last dose; pregnancy risk; female and male patients are advised to use contraception until 1 wk after final dose; risk of infertility in female and male patients; geriatric population may have increased risk of adverse GI events; not recommended for patients with liver dysfunction
Ziv-aflibercept	Reduced leukocytes, diarrhea, reduced neutrophils, proteinuria, increase AST, mouth sore, fatigue, low platelets, increased ALT, hypertension, weight loss, reduced hunger, nose bleed, abdominal discomfort, hoarse voice, elevated serum creatinine, headache	Hemorrhage, GI perforations, slow wound healing, hypertension, arterial thrombotic events, new fistula, low neutrophils, proteinuria, diarrhea, RPLS	None indicated	Breastfeeding is not recommended during treatment or until 1 mo after last dose; pregnancy risk; female patients are advised to use contraception until 1 mo after final dose; risk of infertility in female and male patients; geriatric population may have increased risk of adverse GI events

ALT = alanine transaminase; AST = aspartate aminotransferase; GI = gastrointestinal; PRES = posterior reversible encephalopathy syndrome; P-gp = P-glycoprotein; RPLS = reversible posterior leukoencephalopathy syndrome.

From FDA-approved prescribing information.^21-27

Treatment Guidelines

The American Cancer Society and the NCCN provide the following recommendations for treatment of colon and rectal cancers based on stage.

Stage 0 

For both colon and rectal cancers, stage 0 tumors are exclusively treated by surgically removing the tumor. No pharmacologic therapies are recommended.^28,29

Stage I 

At this stage, colorectal cancers typically have grown into the mucosal lining of the colon or rectum. These tumors are predominantly treated surgically in colon cancer. However, in rectal cancer, if the tumor is high risk, adjuvant treatment may be recommended. If the tumor is T2 or T1 and high risk, treatment with capecitabine/ fluorouracil combined with radiation is recommended.^28,29

Stage II

Once the cancer has spread into the lymph nodes, chemotherapy, surgery, and radiation are all options for treatment. For colon cancer, surgery may still be the only recommendation. For rectal cancer, chemoradiation with capecitabine/fluorouracil is preferred. Following surgery, CAPOX/FOLFOX treatment regimens are recommended for rectal cancer.^28,29

Colon Cancer⁴

• If the tumor can be fully removed, then surgical excision should be done first
• Patients with T3, N0, M0 colon cancer with no high-risk features can receive FU-LV/capecitabine as adjuvant therapy 
• Patients with T3, N0, M0 colon cancer with high-risk features or T4, N0, M0 colon cancer can receive FU-LV/capecitabine or CAPOX/FOLFOX as adjuvant therapy

Rectal Cancer⁵

• For T3-4, N0, M0 rectal cancer, either radiation with capecitabine/fluorouracil followed by chemotherapy with CAPOX/FOLFOX as adjuvant therapy is recommended
• T3-4, N0, M0 rectal cancer can also be treated with CAPOX or FOLFOX as adjuvant therapy followed by chemoradiation with capecitabine/fluorouracil
• T3-4, N0, M0 rectal cancer can also be treated with CAPOX or FOLFOX as adjuvant therapy followed by observation

Stage III

During treatment of colon cancer at this stage, there is greater focus on removing remaining cancerous cells following surgery. In colon cancer, CAPOX/FOLFOX chemotherapy regimens are preferred as adjuvant therapies. In rectal cancer, chemoradiation is administered before surgery, and surgery is followed by adjuvant CAPOX, FOLFOX, or FU-LV.^28,29

Colon Cancer⁴

• For T1-4, N1-2, M0 (high risk and low risk stage III tumors) colon cancer, CAPOX/FOLFOX adjuvant therapy is recommended

Rectal Cancer⁵

• For T1-4, N1-2, M0 rectal cancer, chemoradiation with capecitabine or fluorouracil followed by chemotherapy with CAPOX/FOLFOX as adjuvant therapy is recommended
• T1-4, N1-2, M0 rectal cancer can also be treated with CAPOX/FOLFOX as adjuvant therapy followed by radiation with capecitabine/fluorouracil
• T1-4, N1-2, M0 rectal cancer can also be treated with CAPOX/FOLFOX as adjuvant therapy followed by observation
• T3, N1-2 M0; T1–2, N1–2, M0; T4, N2-2 and inoperable rectal cancer can be treated with radiation with capecitabine/fluorouracil followed by chemotherapy with CAPOX/FOLFOX as neoadjuvant therapy
• T3, N1-2 M0; T1–2, N1–2, M0; T4, N2-2 and inoperable rectal cancer can be treated CAPOX/ FOLFOX followed by chemoradiation with capecitabine/fluorouracil neoadjuvant therapy

Stage IV

Because stage IV tumors have spread to distant organs, surgery is usually not recommended. Any surgery that is performed is done to relieve symptoms and improve the patient’s quality of life. Systemic chemotherapy is recommended in this setting. Genetic testing may be useful prior to this stage to see if the patient is eligible for FDA-approved targeted therapies.^28,29 Recommendations for metastatic colon and rectal cancers are the same.

• M1 colon or rectal cancer with metastasis to the liver or lung that can be removed should receive adjuvant CAPOX or FOLFOX 
• M1 colon or rectal cancer with metastasis to the liver or lung that cannot be removed should receive systemic FOLFIRI/FOLFOX with bevacizumab, or FOLFIRI /FOLFOX with panitumumab or cetuximab if the patient is eligible based on genotype
• Other M1 colon or rectal cancer metastasis (that may or may not need additional surgery) should receive systemic therapy
  • If intensive therapy is recommended, the advised treatment is systemic CAPOX/FOLFOX with and without bevacizumab (or panitumumab/cetuximab, if eligible)
  • If intensive therapy is not recommended, the advised treatment is FU-LV or capecitabine with and without bevacizumab
• For subsequent treatment, if oxaliplatin-based therapy has previously been used without irinotecan, FOLFIRI/irinotecan are recommended with and without bevacizumab
• For subsequent treatment, if oxaliplatin-based therapy has not been previously used and irinotecan has been used, CAPOX or FOLFOX is recommended with and without bevacizumab, panitumumab, or cetuximab^4,5

Recurrent

In locally recurrent colon or rectal cancer, tumors are usually surgically removed followed by treatment with adjuvant chemotherapy. Distant recurrent tumors are treated more similarly to metastatic disease. ^28,29

References

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2. Colorectal cancer signs and symptoms. American Cancer Society. Updated June 29, 2020. Accessed May 3, 2023. https://www.cancer.org/cancer/types/colon-rectal-cancer/detection-diagnosis-staging/signs-and-symptoms.html

3. What is colorectal cancer? American Cancer Society. Updated June 29, 2020. Accessed May 3, 2023. https://www.cancer.org/cancer/types/colon-rectal-cancer/about/what-is-colorectal-cancer.html

4. NCCN Clinical practice guidelines in oncology (NCCN Guidelines^Ⓡ), colon cancer. National Comprehensive Cancer Network. Updated April 25, 2023. Accessed May 2, 2023. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf

5. NCCN Clinical practice guidelines in oncology (NCCN Guidelines^Ⓡ), rectal cancer. National Comprehensive Cancer Network. Updated April 25, 2023. Accessed May 2, 2023. https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf

6. Colon cancer treatment (PDQ®)–health professional version. National Cancer Institute. Updated January 20, 2023. Accessed May 2, 2023 https://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq#_74

7. Rectal cancer treatment (PDQ®)–health professional version. National Cancer Institute. Updated February 16, 2023. Accessed May 2, 2023 https://www.cancer.gov/types/colorectal/hp/rectal-treatment-pdq

8. Chemotherapies for colorectal cancer. American Cancer Society. Updated June 29, 2020. Accessed May 3, 2023. https://www.cancer.org/cancer/types/colon-rectal-cancer/treating/chemotherapy.html

9. Drugs approved for colon and rectal cancer. National Cancer Institute. Updated January 23, 2023. Accessed May 2, 2023 https://www.cancer.gov/about-cancer/treatment/drugs/colorectal

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25. Stivarga. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2020. Accessed May 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=824f19c9-0546-4a8a-8d8f-c4055c04f7c7&audience=consumer

26. Tukysa. Prescribing information. Seagen Inc; 2023. Accessed May 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f27eb1b9-b7fc-424e-988f-84dd7bb195a3&audience=consumer

27. Zaltrap. Prescribing information. Sanofi-aventis U.S. LLC; 2012. Updated November 25, 2020. Accessed May 4, 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6725df6-50ee-4b0a-b900-d02ba634395d&audience=consumer

28.  Colon cancer treatment, by stage. American Cancer Society. Updated January 26, 2023. Accessed May 4, 2023. https://www.cancer.org/cancer/types/colon-rectal-cancer/treating/by-stage-colon.html

29.  Rectal cancer treatment, by stage. American Cancer Society. Updated June 29, 2020. Accessed May 4, 2023. https://www.cancer.org/cancer/types/colon-rectal-cancer/treating/by-stage-rectum.html

Author Bio

Hannah Actor-Engel, PhD earned a Bachelor of Science degree in Neural Science at New York University, and she received her PhD in Neuroscience at the University of Colorado. She is a multidisciplinary neuroscientist who is passionate about scientific communication and improving global health through biomedical research.