Colon Cancer

Primary Tumor (T)
TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
Tis = Carcinoma in situ: intraepithelial or invasion of lamina propria.
T1 = Tumor invades submucosa.
T2 = Tumor invades muscularis propria.
T3 = Tumor invades through the muscularis propria into pericolorectal tissues.
T4a = Tumor penetrates to the surface of the visceral peritoneum.
T4b = Tumor directly invades or is adherent to other organs or structures.

Note: A satellite peritumoral nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2), or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive nodes in the N category, whereas discontinuous spread or venous invasion should be classified and counted in the site-specific factor category Tumor Deposits.

Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or mucosal lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa.

Direct invasion in T4 (T4a and T4b) includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (e.g., invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (i.e., respectively, a tumor on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina).

Tumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be pT1–4a depending on the anatomical depth of wall invasion. The V and L classifications should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN site-specific factor should be used for perineural invasion.

Regional Lymph Nodes (N)
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Metastases in 1–3 regional lymph nodes.
N1a = Metastasis in 1 regional lymph node.
N1b = Metastases in 2–3 regional lymph nodes.
N1c = Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis.
N2 = Metastases in ≥4 regional lymph nodes.
N2a = Metastases in 4–6 regional lymph nodes.
N2b = Metastases in ≥7 regional lymph nodes.

Distant Metastases (M)
M0 = No distant metastasis.
M1a = Metastasis confined to 1 organ or site (e.g., liver, lung, ovary, nonregional node).
M1b = Metastases in >1 organ/site or the peritoneum.

AJCC Stage Groupings

Dukes B is a composite of better (T3, N0, M0) and worse (T4, N0, M0) prognostic groups,
as is Dukes C (any T, N1, M0 and any T, N2, M0).

MAC is the modified Astler-Coller classification.

Colorectal Cancer - Treatment Options

(Updated 08/2017)

Treatment overview
In cancer care, different types of doctors often work together to create a patient’s overall treatment plan that usually includes or combines different types of treatments. This is called a multidisciplinary team. For colorectal cancer, this generally includes a surgeon, medical oncologist, radiation oncologist, and a gastroenterologist. Cancer care teams include a variety of other health care professionals, such as physician assistants, oncology nurses, social workers, pharmacists, counselors, dietitians, and others.

Descriptions of the most common treatment options for colorectal cancer are listed below, followed by a brief outline of treatment options listed by stage. Treatment options and recommendations depend on several factors, including the type and stage of cancer, possible side effects, and the patient’s preferences and overall health. Your care plan may also include treatment for symptoms and side effects, an important part of cancer care.

Studies have shown that these various treatment approaches provide similar benefits regardless of the patient’s age. However, older patients may have unique treatment challenges. In order to tailor the treatment to each patient, all treatment decisions should consider such factors as:
• The patient’s other medical conditions
• The patient’s overall health
• Potential side effects of the treatment plan
• Other medications that the patient already takes
• The patient’s nutritional status and social support
(More information on the specific effects of surgery, chemotherapy, and radiation therapy on older patients can be found in this article in another section of Cancer.Net. )

Surgery

Surgery is the removal of the tumor and some surrounding healthy tissue during an operation. This is the most common treatment for colorectal cancer and is often called surgical resection. Part of the healthy colon or rectum and nearby lymph nodes will also be removed.

In addition to surgical resection, surgical options for colorectal cancer include:
• Laparoscopic surgery. Some patients may be able to have laparoscopic colorectal cancer surgery. With this technique, several viewing scopes are passed into the abdomen while a patient is under anesthesia. Anesthesia is medicine that blocks the awareness of pain. The incisions are smaller and the recovery time is often shorter than with standard colon surgery. Laparoscopic surgery is as effective as conventional colon surgery in removing the cancer. Surgeons who perform laparoscopic surgery have been specially trained in that technique.

• Colostomy for rectal cancer. Less often, a person with rectal cancer may need to have a colostomy. This is a surgical opening, or stoma, through which the colon is connected to the abdominal surface to provide a pathway for waste to exit the body. This waste is collected in a pouch worn by the patient. Sometimes, the colostomy is only temporary to allow the rectum to heal, but it may be permanent. With modern surgical techniques and the use of radiation therapy and chemotherapy before surgery when needed, most people who receive treatment for rectal cancer do not need a permanent colostomy. Learn more about colostomies.

• Radiofrequency ablation (RFA) or cryoablation. Some patients may be able to have surgery on the liver or lungs to remove tumors that have spread to those organs. Other ways include using energy in the form of radiofrequency waves to heat the tumors, called RFA, or to freeze the tumor, called cryoablation. Not all liver or lung tumors can be treated with one of these approaches. RFA can be done through the skin or during surgery. While this can help avoid removing parts of the liver and lung tissue that might be removed in a regular surgery, there is also a chance that parts of tumor will be left behind.

Side effects of surgery
In general, the side effects of surgery include pain and tenderness in the area of the operation. The operation may also cause constipation or diarrhea, which usually goes away after a while. People who have a colostomy may have irritation around the stoma. If you need to have a colostomy, the doctor, nurse, or an enterostomal therapist, who is a specialist in colostomy management, can teach you how to clean the area and prevent infection.

Many people need to retrain their bowel after surgery, which may take some time and assistance. You should talk with your doctor if you do not regain good control of bowel function.

Radiation therapy

Radiation therapy is the use of high-energy x-rays to destroy cancer cells. It is commonly used for treating rectal cancer because this tumor tends to recur near where it originally started.

• External-beam radiation therapy. External-beam radiation therapy uses a machine to deliver x-rays to where the cancer is located. Radiation treatment is usually given 5 days a week for several weeks. It may be given in the doctor's office or at the hospital.
        • Stereotactic radiation therapy. Stereotactic radiation therapy is a type of external-bean radiation therapy that may be used if a tumor has spread to the liver or lungs. This type of radiation therapy delivers a large, precise radiation dose to a small area. This technique can help avoid removing parts of the liver and lung tissue that might be removed during surgery. However, not all cancers that have spread to the liver or lungs can be treated in this way.

• Other types of radiation therapy. For some people, specialized radiation therapy techniques, such as intraoperative radiation therapy or brachytherapy, may help get rid of small areas of cancer that could not be removed with surgery.
        • Intraoperative radiation therapy. Intraoperative radiation therapy uses a high, single dose of radiation therapy given during surgery.
        • Brachytherapy. Brachytherapy is the use of radioactive "seeds" placed inside the body. In 1 type of brachytherapy with a product called SIR-Spheres, tiny amounts of a radioactive substance called yttrium-90 are injected into the liver to treat colorectal cancer that has spread to the liver when surgery is not an option. While limited information is available about how effective this approach is, some studies suggest that it may help slow the growth of cancer cells.

• Radiation therapy for rectal cancer. For rectal cancer, radiation therapy may be used before surgery, called neoadjuvant therapy, to shrink the tumor so that it is easier to remove. It may also be used after surgery to destroy any remaining cancer cells. Both approaches have worked to treat this disease. Chemotherapy is often given at the same time as radiation therapy, called chemoradiation therapy, to increase the effectiveness of the radiation therapy. Chemoradiation therapy is often used in rectal cancer before surgery to avoid colostomy or reduce the chance that the cancer will recur. One study found that chemoradiation therapy before surgery worked better and caused fewer side effects than the same radiation therapy and chemotherapy given after surgery. The main benefits included a lower rate of the cancer coming back in the area where it started, fewer patients who needed permanent colostomies, and fewer problems with scarring of the bowel where the radiation therapy was given.

Side effects of radiation therapy
Side effects from radiation therapy may include fatigue, mild skin reactions, upset stomach, and loose bowel movements. It may also cause bloody stools from bleeding through the rectum or blockage of the bowel. Most side effects go away soon after treatment is finished.

Sexual problems, as well as infertility (the inability to have a child) in both men and women, may occur after radiation therapy to the pelvis. Before treatment begins, talk with your doctor about the possible sexual and fertility-related side effects of your treatment and the available options for preserving fertility.

Chemotherapy

Chemotherapy is the use of drugs to destroy cancer cells, usually by ending the cancer cells’ ability to grow and divide.

Chemotherapy may be given after surgery to eliminate any remaining cancer cells. For some people with rectal cancer, the doctor will give chemotherapy and radiation therapy before surgery to reduce the size of a rectal tumor and reduce the chance of the cancer returning.

Types of chemotherapy for colorectal cancer
Currently, several drugs are approved by the U.S. Food and Drug Administration (FDA) to treat colorectal cancer in the United States. Your doctor may recommend 1 or more of them at different times during treatment. Sometimes these are combined with targeted therapy drugs (see “Targeted therapy” below).
• Capecitabine (Xeloda)
• Fluorouracil (5-FU, Adrucil)
• Irinotecan (Camptosar)
• Oxaliplatin (Eloxatin)
• Trifluridine/tipiracil (TAS-102, Lonsurf)

Some common treatment regimens using these drugs include:
• 5-FU
• 5-FU with leucovorin (Wellcovorin), a vitamin that improves the effectiveness of 5-FU
• Capecitabine, an oral form of 5-FU
• FOLFOX: 5-FU with leucovorin and oxaliplatin
• FOLFIRI: 5-FU with leucovorin and irinotecan
• Irinotecan alone
• XELIRI/CAPIRI: Capecitabine with irinotecan
• XELOX/CAPEOX: Capecitabine with oxaliplatin
• Any of the above with 1 of the following targeted therapies (see below): cetuximab, bevacizumab, or panitumumab. In addition, FOLFIRI may be combined with either of these targeted therapies (see below): ziv-aflibercept or ramucirumab

Side effects of chemotherapy
Chemotherapy may cause vomiting, nausea, diarrhea, neuropathy, or mouth sores. However, medications to prevent these side effects are available. Because of the way drugs are given, these side effects are less severe than they have been in the past for most patients. In addition, patients may be unusually tired, and there is an increased risk of infection. Neuropathy, tingling or numbness in feet or hands, may also occur with some drugs. Significant hair loss is an uncommon side effect with many of the drugs used to treat colorectal cancer, except irinotecan.

If side effects are particularly difficult, the dose of the drug may be lowered or a treatment session may be postponed. If you are receiving chemotherapy, you should talk with your health care team about when to call your doctor about side effects. Read more about managing side effects. The side effects from chemotherapy usually go away after treatment is finished.

Targeted therapy

(Updated 10/2017)
Targeted therapy is a treatment that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of cancer cells while limiting damage to healthy cells.

Recent studies show that not all tumors have the same targets. To find the most effective treatment, your doctor may run tests to identify the genes, proteins, and other factors in your tumor. This helps doctors better match each patient with the most effective treatment whenever possible. In addition, many research studies are taking place now to find out more about specific molecular targets and new treatments directed at them. These drugs are becoming more important in the treatment of colorectal cancer.

Studies have shown that older patients are able to benefit from targeted therapies, similar to younger patients. In addition, the expected side effects are usually manageable in both older and younger patients.

Types of targeted therapy
For colorectal cancer, the following targeted therapies may be options.

• Anti-angiogenesis therapy. Anti-angiogenesis therapy is a type of targeted therapy. It is focused on stopping angiogenesis, which is the process of making new blood vessels. Because a tumor needs the nutrients delivered by blood vessels to grow and spread, the goal of anti-angiogenesis therapies is to “starve” the tumor.
        • Bevacizumab (Avastin). When bevacizumab is given with chemotherapy, it increases the length of time patients with advanced colorectal cancer live. In 2004, the FDA approved bevacizumab along with chemotherapy as the first treatment, or first-line treatment, for advanced colorectal cancer. Recent studies have shown it is also effective as second-line therapy along with chemotherapy. A similar drug called bevacizumab-awwb (Mvasi) received FDA approval in 2017.
        • Regorafenib (Stivarga). This drug was approved in 2012 for patients with metastatic colorectal cancer who have already received certain types of chemotherapy and other targeted therapies.
        • Ziv-aflibercept (Zaltrap) and ramucirumab (Cyramza). Either of these drugs can be combined with FOLFIRI chemotherapy as a second-line treatment for metastatic colorectal cancer.

• Epidermal growth factor receptor (EGFR) inhibitors. An EGFR inhibitor is a type of targeted therapy. Researchers have found that drugs that block EGFR may be effective for stopping or slowing the growth of colorectal cancer.
        • Cetuximab (Erbitux). Cetuximab is an antibody made from mouse cells that still has some of the mouse structure.
        • Panitumumab (Vectibix). Panitumumab is made entirely from human proteins and is less likely to cause an allergic reaction than cetuximab.

Recent studies show that cetuximab and panitumumab do not work as well for tumors that have specific mutations, or changes, to a gene called RAS. ASCO recommends that all patients with metastatic colorectal cancer who may receive anti-EFGR therapy, such as cetuximab and panitumumab, have their tumors tested for RAS gene mutations. If a patient’s tumor has a mutated form of the RAS gene, ASCO recommends against the use of EFGR inhibitors. Furthermore, the FDA now recommends that both cetuximab and panitumumab only be given to patients with a tumor with non-mutated, sometimes called wild-type, RAS genes.

• Checkpoint inhibitors (immunotherapy). Immunotherapy is a way to boost the body's natural defenses to fight the cancer.
        •Pembrolizumab (Keytruda). Pembrolizumab is a humanized antibody that targets PD-1, a receptor on tumor cells, preventing the tumor cells from hiding from the immune system. A humanized antibody combines a human antibody with a small part of a mouse or rat antibody. The mouse or rat part binds to the target, and the human part makes it less likely to be destroyed by the body's immune system. Pembrolizumab is FDA approved for treating metastatic colorectal cancers that have a molecular feature called microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).
        •Nivolumab (Opdivo). Nivolumab is a checkpoint inhibitor that has received FDA approval to treat patients who are 12 or older and have MSI-H or dMMR metastatic colorectal cancer that has grown or spread after treatment with chemotherapy with a fluoropyrimidine (such as capecitabine and fluorouracil), oxaliplatin, and irinotecan.

Your tumor may also be tested for other molecular markers, including BRAF, HER2 overexpression, and others. These markers do not have FDA-approved targeted therapies yet, but there may be opportunities in clinical trials that are studying these molecular changes.

Side effects of targeted therapies
The side effects of targeted treatments can include a rash to the face and upper body, which can be prevented or reduced with various treatments. Find out more about skin reactions to targeted therapies.

Getting care for symptoms and side effects
Cancer and its treatment often cause side effects. In addition to treatments intended to slow, stop, or eliminate the cancer, an important part of cancer care is relieving a person’s symptoms and side effects. This approach is called palliative or supportive care, and it includes supporting the patient with his or her physical, emotional, and social needs.

Palliative care is any treatment that focuses on reducing symptoms, improving quality of life, and supporting patients and their families. Any person, regardless of age or type and stage of cancer, may receive palliative care. It works best when palliative care is started as early as needed in the cancer treatment process. People often receive treatment for the cancer at the same time that they receive treatment to ease side effects. In fact, patients who receive both at the same time often have less severe symptoms, better quality of life, and report they are more satisfied with treatment.

Palliative treatments vary widely and often include medication, nutritional changes, relaxation techniques, emotional support, and other therapies. You may also receive palliative treatments similar to those meant to eliminate the cancer, such as chemotherapy, surgery, or radiation therapy. Talk with your doctor about the goals of each treatment in the treatment plan.

Before treatment begins, talk with your health care team about the possible side effects of your specific treatment plan and palliative care options. During and after treatment, be sure to tell your doctor or another health care team member if you are experiencing a problem so it can be addressed as quickly as possible. Learn more about palliative care.

Treatment options by stage

In general, stages 0, I, II, and III are often curable with surgery. However, many patients with stage III colorectal cancer, and some with stage II, receive chemotherapy after surgery to increase the chance of eliminating the disease. Patients with stage II and III rectal cancer will also receive radiation therapy with chemotherapy either before or after surgery. Stage IV is not often curable, but it is treatable, and the growth of the cancer and the symptoms of the disease can be managed. Clinical trials are also a treatment option for each stage.

Stage 0 colorectal cancer
The usual treatment is a polypectomy, or removal of a polyp, during a colonoscopy. There is no additional surgery unless the polyp cannot be fully removed.

Stage I colorectal cancer
Surgical removal of the tumor and lymph nodes is usually the only treatment needed.

Stage II colorectal cancer
Surgery is often the first treatment. Patients with stage II colorectal cancer should talk with their doctor about whether more treatment is needed after surgery because some patients receive adjuvant chemotherapy. Adjuvant chemotherapy is treatment after surgery aimed at trying to destroy any remaining cancer cells. However, cure rates for surgery alone are quite good, and there are few benefits of additional treatment for people with this stage of colorectal cancer. Learn more about adjuvant therapy for stage II colorectal cancer. A clinical trial is also an option after surgery.

For patients with stage II rectal cancer, radiation therapy is usually given in combination with chemotherapy, either before or after surgery. Additional chemotherapy may be given after surgery as well.

Stage III colorectal cancer
Treatment usually involves surgical removal of the tumor fo llowed by adjuvant chemotherapy. A clinical trial may also an option. For patients with rectal cancer, radiation therapy may be used along with chemotherapy before or after surgery, along with adjuvant chemotherapy.

Metastatic (stage IV) colorectal cancer
If cancer spreads to another part in the body from where it started, doctors call it metastatic cancer. Colorectal cancer can spread to distant organs, such as the liver, lungs, the tissue called the peritoneum that lines the abdomen, or a woman’s ovaries. If this happens, it is a good idea to talk with doctors who have experience treating this stage of cancer. Doctors can have different opinions about the best standard treatment plan. Also, clinical trials might be an option.

Your treatment plan may include a combination of surgery, radiation therapy, immunotherapy, and chemotherapy, which can be used to slow the spread of the disease and often temporarily shrink a cancerous tumor. Palliative care will also be important to help relieve symptoms and side effects.

At this stage, surgery to remove the portion of the colon where the cancer started usually cannot cure the cancer, but it can help relieve blockage of the colon or other problems related to the cancer. Surgery may also be used to remove parts of other organs that contain cancer, called resection, and can cure some people if a limited amount of cancer spreads to a single organ, such as the liver or a lung.

In colorectal cancer, if the cancer has spread only to the liver and if surgery is possible—either before or after chemotherapy—there is a chance of complete cure. Even when curing the cancer is not possible, surgery may add months or even years to a person’s life. Determining who can benefit from surgery for cancer that has spread to the liver is often a complicated process that involves doctors of multiple specialties working together to plan the best treatment option.

For most patients, a diagnosis of metastatic cancer is very stressful and, at times, difficult to bear. Patients and their families are encouraged to talk about the way they are feeling with doctors, nurses, social workers, or other members of the health care team. It may also be helpful to talk with other patients, including through a support group.

Neoadjuvant therapy for resectable metastatic disease

Neoadjuvant therapy for resectable metastatic disease is usually administered for approximately 2-3 months, limiting the development of hepatotoxicity.
Regimens for adjuvant and neoadjuvant therapy are similar:
• mFOLFOX6
• FOLFIRI:
Irinotecan 180 mg/m2 IV over 30-90 min on day 1 plus
leucovorin 400 mg/m2 IV infusion to match duration of irinotecan infusion on day 1 plus
5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2 days (total 2400 mg/m2 over 46-48 hours) continuous infusion;
Repeat every 2 wk
• CapeOx with or without bevacizumab:
Oxaliplatin 130 mg/m2 over 2 h on day 1
capecitabine 1000 mg/m2 PO BID for 14 d;
bevacizumab 7.5 mg/kg IV on day 1
Repeat every 3 wk
• mFOLFOX6 plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 min on day 1
Repeat every 2 wk for four to six cycles with reevaluation for maintenance therapy
• FOLFIRI plus bevacizumab: Bevacizumab 5 mg/kg over 30-90 min on day 1
Repeat every 2 wk for 4-6 cycles
• mFOLFOX6 plus cetuximab (only for pan-RAS wild-type tumors): Cetuximab 400 mg/m2 loading dose over 2 h on day 1, then cetuximab 250 mg/m2 weekly
Repeat every 2 wk for 4-6 cycles
• FOLFIRI plus cetuximab (only for pan-RAS wild-type tumors): Cetuximab 400 mg/m2 loading dose over 2 hours on day 1, then cetuximab 250 mg/m2 over 1 hour weekly
Repeat every 2 wk for 4-6 cycles
• FOLFOXIRI:
Irinotecan 165 mg/m 2 over 60 minutes then
oxaliplatin 85 mg/m 2 plus
leucovorin 400 mg/m 2 concurrently over 120 minutes then
5-FU 1600 mg/m 2/day for 2 days (total 3200 mg/m 2 over 48 hours);
Repeat every 2 wk for 4-6 cycles
• FOLFOXIRI plus bevacizumab: Bevacizumab 5 mg/kg IV over 30-90 min plus FOLFOXIRI
Repeat every 2 wk for 4-6 cycles

Summary of guiding principles in the treatment of metastatic colorectal cancer

• Differentiating M1a (metastatic disease at one organ site) from M1b (metastasis at more than one organ site) is important, in view of the curative potential of M1a disease.
• It is reasonable to leave the primary therapy in place when starting treatment for metastatic disease, if the patient has no urgent complication such as obstruction or uncontrolled bleeding.
• A multidisciplinary approach is necessary to deal with the complicated issue of potentially resectable or marginally resectable metastatic disease.
• Patients who receive bevacizumab-containing neoadjuvant therapy must not undergo surgery until at least 6-8 weeks afterward, in order to minimize perioperative complications.
• With FOLFOXIRI, a lower dose of infusional 5-FU at 2400 mg/m2 should be considered in North American patients. This regimen has the advantage of increased response rate, R0 resection margin of metastatic disease, progression-free survival, and overall survival compared with FOLFIRI and should be used selectively in patients with good performance status, particularly when the goal is to render the patient cancer free with neoadjuvant therapy. The same is true if bevacizumab is to be added.

• The selection of oxaliplatin or irinotecan as part of the cytotoxic backbone upfront in metastatic disease is based primarily on toxicity profile.
• Bevacizumab, when used as first-line and second-line therapy and works with irinotecan- and oxaliplatin-based therapy, improves survival.
• Bevacizumab, when added to fluorouracil-based combination chemotherapy, results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.
• Bevacizumab, when added to IFL (irinotecan, fluorouracil, and leucovorin), significantly improves the response rate, overall survival, and progression-free survival.

• Interruption in therapy is not ideal for patients; some form of maintenance therapy is preferred after a stable disease state is obtained.
• Single-agent maintenance bevacizumab may be a feasible option for patients receiving bevacizumab + CapeOx as induction therapy.

• Anti-EGFR antibody therapy should be given only to patients with pan-RAS and BRAF V600E wild-type tumors.
• Anti-EGFR antibody therapy and bevacizumab should not be combined, due to increased toxicity.

• All patients with metastatic disease should have pan-RAS testing and BRAF V600E mutation testing. Data suggest that even in the setting of KRAS wild-type tumors, BRAF mutation abrogates the effect of anti-EGFR antibody therapy; it is, however, prognostic of a worse outcome.
• Patients with stage IV disease should be tested for MSI-H.
Consider pembrolizumab or nivolumab for unresectable or metastatic colon cancer that has tested positive for MSI-H or dMMR, and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan.

Chemotherapy for advanced or metastatic disease

In patients with metastatic colon cancer, testing of the tumor for KRAS mutations at exons 2, 3, and 4; NRAS mutations at exons 2, 3, and 4 (ie, pan-RAS or all-RAS testing) and BRAF V600E mutation should guide the decision whether to use biologic agents that target epidermal growth factor receptor (EGFR). Patients with wild-type pan-RAS and no BRAF V600E typically respond to anti-EGFR therapy.

Stage IV:
Chemotherapy for advanced or metastatic disease includes the use of multiple drugs as single agents or as combination regimens, as follows:
• Patients with right sided tumors are less likely to respond to EGFR therapy with cetuximab or panitumumab.
• BRAF V600E mutation makes response to anti-EGFR therapy less likely.

• Choice of initial therapy for advanced disease is based on goals of treatment, location of tumor, mutational profile, toxicity profile of the drugs, and patient's performance status.
• mFOLFOX6, FOLFIRI, CapeOx, FOLFOXIRI, capecitabine, and infusional 5FU/LV with or without targeted agents are all considered appropriate first-line agents.
• For patients who are not candidates for intensive therapy, single-agent 5FU/LV, capecitabine, irinotecan, cetuximab or panitumumab, and nivolumab or pembrolizumab, can be used in the appropriate setting.

First-line chemotherapy for bevacizumab candidates:
mFOLFOX6 plus bevacizumab
FOLFIRI plus bevacizumab
FOLFOXIRI plus bevacizumab
CAPEOX plus bevacizumab
Capecitabine plus bevacizumab
DeGramont regimen plus bevacizumab (in patients not able to undergo treatment with oxaliplatin or irinotecan):
Bevacizumab 5 mg/kg over 30-90 min on day 1 plus
leucovorin 400 mg/m2 IV over 2 h on day 1 plus
5-FU bolus 400 mg/m2, then 1200 mg/m2/day for 2 days (total 2400 mg/m2 over 46-48 h) continuous infusion;
Repeat every 2 wk for 4-6 cycles with reevaluation for maintenance therapy
5-FU and leucovorin (Roswell Park) with bevacizumab (in patients unable to undergo treatment with oxaliplatin or irinotecan):
Bevacizumab 5 mg/kg over 30-90 min on day 1 plus
leucovorin 500 mg/m2 over 2 h plus
5-FU 500 mg/m2 bolus every 2 wk for 4-6 cycles with reevaluation for maintenance therapy

First-line chemotherapy for patients who are not candidates for bevacizumab:
mFOLFOX6
mFOLFOX7: Oxaliplatin 85 mg/m2 IV over 2 h on day 1 plus leucovorin 400 mg/m2 IV over 2 h on day 1 plus 5-FU 1200mg/m2/day (total 2400 mg/m2 over 46-48 hours) continuous infusion; repeat every 2 wk
FOLFIRI
FOLFOXIRI
Capecitabine: Capecitabine 850-1250 mg/m2 PO BID on days 1-14; repeat cycle every 21 d until progression
Roswell Park regimen: Leucovorin 500 mg/m2 IV weekly for 6 wk over 2 h followed by 5-FU 500 mg/m2 IV bolus weekly for 6 wk; repeat cycle every 8 wk
CapeOx
mFOLFOX6 plus cetuximab (only for pan-RAS and BRAF V600E wild-type tumors): Cetuximab 500 mg/mg/m2 IV over 2 h every 2 weeks or cetuximab 400 mg/m2 loading dose on day 1, then cetuximab 250 mg/m2 weekly plus oxaliplatin 85 mg/m2 IV over 2 h on day 1 plus leucovorin 400 mg/m2 IV over 2 h on day 1 plus 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2-d (total 2400 mg/m2 over 46 h) continuous infusion; repeat every 2 wk
FOLFIRI plus cetuximab (only for pan-RAS and BRAF V600E wild-type tumors): Cetuximab 500 mg/m2 IV over 2 hr every 2 weeks or cetuximab 400 mg/m2 loading dose over 2 h on day 1, then cetuximab 250 mg/m2 over 1 h weekly plus irinotecan 180 mg/m2 IV over 30-90 min on day 1 plus leucovorin 400 mg/m2 IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2-d (total 2400 mg/m2 over 46 h) continuous infusion; repeat every 2 wk
FOLFOX plus panitumumab (only for pan-RAS and BRAF V600E wild-type tumors): Panitumumab 6 mg/kg IV infusion over 1 h on day 1, then oxaliplatin 85 mg/m2 IV infusion on day 1, then leucovorin 400 mg/m2 IV infusion, plus 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2 d (total 2400 mg/m2 over 46-48 h) continuous infusion; repeat every 2 wk
FOLFOX4 plus panitumumab (only for pan-RAS and BRAF V600E wild-type tumors): Panitumumab 6 mg/kg IV infusion over 1 h on day 1, then oxaliplatin 85 mg/m2 IV infusion on day 1 then leucovorin 200 mg/m2 (or equivalent) IV infusion plus 5-FU 400 mg/m2 IV bolus and 600 mg/m2 22-hour continuous infusion on days 1 and 2
FOLFIRI plus panitumumab (only for pan-RAS and BRAF V600E wild-type tumors): Panitumumab 6 mg/kg IV infusion over 1 h on day 1 plus irinotecan 180 mg/m2 IV over 30-90 min on day 1 plus leucovorin 400 mg/m2 IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2-d (total 2400 mg/m2 over 46 h) continuous infusion; repeat every 2 wk
Referral for clinical trial

Second-line chemotherapy for metastatic disease:
Subsequent therapy primarily depends on the initial therapy—oxaliplatin vs irinotecan based, as follows:
Bevacizumab is indicated for second-line treatment in patients whose disease has progressed on a first-line bevacizumab-containing regimen; use bevacizumab in combination with a fluoropyrimidine (eg, 5-FU, capecitabine) plus irinotecan or oxaliplatin-based chemotherapy; bevacizumab dose is either 5 mg/kg IV q2 wk or 7.5 mg/kg IV q3 wk for continuation
Ziv-aflibercept and ramucirumab are effective only in combination with FOLFIRI, in patients that have not previously received treatment with FOLFIRI.
Cetuximab and panitumumab (anti-EGFR) can also be used as single agents for patients who cannot tolerate chemotherapy.

For patients with previous oxaliplatin-based therapy as first-line treatment (ie, FOLFOX, CapeOx, CapeOx plus bevacizumab or FOLFOX plus bevacizumab), one of the following regimens can be used:
FOLFIRI
FOLFIRI + Bevacizumab or ziv-aflibercept or ramucirumab: Irinotecan 180 mg/m2 IV over 30-90 min on day 1 plus leucovorin 400 mg/m2 IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m2 IV bolus on day 1, then 1200 mg/m2/day for 2-d (total 2400 mg/m2 over 46 h) continuous infusion plus bevacizumab 5mg/kg iv on day 1 or ziv-aflibercept 4mg/kg iv over 60 mins on day 1 or ramucirumab 8mg/kg iv over 60 mins on day 1, repeat every 2 wk
FOLFIRI plus cetuximab or panitumumab (only for pan-RAS and BRAF V600E wild-type tumors): Cetuximab 400 mg/m 2 loading dose IV over 2 h on day 1, then cetuximab 250 mg/m 2 IV over 1 h weekly or panitumumab 6 mg/kg IV over 60 mins on day 1 plus irinotecan 180 mg/m 2 IV over 30-90 min on day 1 plus leucovorin 400 mg/m 2 IV infusion to match duration of irinotecan infusion on day 1 plus 5-FU 400 mg/m 2 IV bolus on day 1, then 1200 mg/m 2/day for 2-d (total 2400 mg/m 2 over 46-48 h) continuous infusion; repeat every 2 wk for 4-6 cycles, then reevaluate
Irinotecan plus cetuximab or panitumumab (only for pan-RAS and BRAF V600E wild-type tumors): Irinotecan 180 mg/m2 IV over 30-90 min on day 1 plus cetuximab 400 mg/m2 loading dose over 2 h on day 1, then cetuximab 250 mg/m2 over 1 h weekly or panitumumab 6 mg/kg iv over 60 min on day 1; repeat every 2 wk

For patients who had irinotecan therapy as first-line treatment (ie, FOLFIRI plus bevacizumab), the following regimens can be used:
mFOLFOX6
CapeOx
FOLFOX plus bevacizumab
CapeOx plus bevacizumab
mFOLFOX6 plus cetuximab or panitumumab (only for pan-RAS and BRAF V600E wild-type tumors)
Irinotecan plus cetuximab or panitumumab (only for pan-RAS and BRAF V600E wild-type tumors, and if anti-EGFR therapy was not used in combination with FOLFIRI)
Cetuximab 500 mg/m2 IV over 2 h every 2 weeks or cetuximab 400 mg/m2 IV over 2 h on day 1, then 250 mg/m2 IV over 1 h weekly with reevaluation after 8 wk
Panitumumab 6 mg/kg over 60-90 min every 2 wk with reevaluation after 8 wk
Pembrolizumab 200 mg IV q3wk, in adults with unresectable or metastatic colon cancer that has tested positive for MSI-H or deficient mismatch repair (dMMR) and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan
Nivolumab 240 mg IV q2wk, for unresectable or metastatic colon cancer that has tested positive for MSI-H or dMMR and has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
Referral for clinical trial

Third-line chemotherapy for metastatic disease:
Panitumumab 6 mg/kg over 60-90 min every 2 wk only for pan-RAS and BRAF V600E wild-type tumors, with reevaluation after 8 wk
Any regimen incorporating an EGFR antibody for patients with pan- RAS wild-type disease, using a cytotoxic backbone not previously tried
Regorafenib 160 mg PO qd for first 21 days of each 28-day cycle
First cycle: Regorafenib 80 mg PO qd on days 1-7, then 120 mg qd on days 8-14, then 160 mg PO qd on days 15-21 of each 28-day cycle; for subsequent cycles give 160 mg qd on days 1-21; monitor hepatic function before and during treatment and interrupt, reduce, or discontinue drug accordingly
Tipiracil/trifluridine 35 mg/m2 PO BID on days 1-5 and days 8-12 of each 28-day cycle; not to exceed 80 mg/dose; for use in patients previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti–vascular endothelial growth factor (VEGF) biological therapy, and (if pan- RAS wild-type), an anti-EGFR therapy
Pembrolizumab 200 mg IV q3wk over 30 min, for adults with unresectable or metastatic colon cancer that has tested positive for MSI-H or dMMR and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan
Nivolumab 240 mg IV q2wk over 30 min, for unresectable or metastatic colon cancer that has tested positive for MSI-H or dMMR and has progressed following treatment with a fluoropyrimidine (eg, 5-FU, capecitabine), oxaliplatin, and irinotecan
Nivolumab 3 mg/kg IV over 30 min, followed by ipilimumab 1 mg/kg IV over 30 min on the same day; repeat combination q3Weeks for up to 4 doses, THEN administer nivolumab 250 mg IV q2Weeks until disease progression or unacceptable toxicity.
Referral for clinical trial

Xelox (CAPOX)

For the first- and second-line treatment of advanced colorectal cancer
Capecitabine (Xeloda) 1,000 mg/m2 PO twice daily (approximately 12 hours apart) within 30 minutes after a meal on the evening of day 1 through the morning of day 15 in combination with oxaliplatin (130 mg/m2 IV on day 1), repeated every 3 weeks.
In a phase III trial of 2,034 patients, capecitabine/oxaliplatin (XELOX) with or without bevacizumab was compared with fluorouracil/leucovorin/oxaliplatin (FOLFOX4) with or without bevacizumab in a 2-by-2 factorial design. XELOX was found to be noninferior to FOLFOX4 for the first line treatment of metastatic colorectal cancer (8 months vs. 8.5 months, HR 1.04; 97.5% CI, 0.93 to 1.16).
In the safety analysis of 1,304 patients, grade 3 or 4 adverse reactions observed more frequently with XELOX included diarrhea (grade 3, 19%; grade 4: 1%) and hand-foot syndrome (grade 3, 6%), while FOLFOX4 produced more neutropenia (grade 3, 27%; grade 4, 16%).
A meta-analysis of this trial and 5 additional trials was performed concurrently with this study. No difference in progression-free survival or overall survival was observed between capecitabine/oxaliplatin combinations and fluorouracil/leucovorin/oxaliplatin combinations in patients with metastatic colorectal cancer.
Additional trials have shown efficacy for XELOX in the treatment of both previously treated and previously untreated patients with advanced colorectal cancer.

Capecitabine (Xeloda) + Oxaliplatin Q3W TOI
*Oxaliplatin IV 130 mg/m2 IV infusion over 2 hours Admix fluid: Dextrose 5 % In Water Volume: 250 mL Instructions: Not compatible with NS.
*Capecitabine Oral 1000 mg/m2 BID, (day 1, evening, to day 15, morning). Take with water and within 30 minutes of the end of a meal.
PREMEDICATIONS
Ondansetron IV 16 mg intravenously once.
Dexamethasone IV Dexamethasone 10 mg IV over 20 minutes. Admix fluid: 0.9 % Sodium Chloride Volume: 50 mL.

For the adjuvant treatment of stage III (Dukes C) colon cancer in combination with oxaliplatin (XELOX or CapeOX)†.
Repeated every 3 weeks for a total of 8 cycles.
In a phase III clinical trial, 1,886 patients with resected stage III colon cancer were randomized to receive oxaliplatin/capecitabine (XELOX) or 5-fluorouracil/leucovorin. After a median follow-up of 57 months, the addition of oxaliplatin to capecitabine produced a significant improvement in the primary endpoint, disease-free survival (HR 0.8; p = 0.0045). Disease-free survival at 3 years was 70.9% with XELOX vs. 66.5% with 5-FU/leucovorin. Overall survival was not significantly different between the arms (HR 0.87; p = 0.1486). Grade 3 or 4 neurosensory toxicity, vomiting, hand-foot syndrome, and thrombocytopenia occurred more frequently in the XELOX arm (p < 0.05); neutropenia, febrile neutropenia, and stomatitis occurred more frequently with 5-FU/leucovorin (p < 0.05).]

MOST COMMON SIDE EFFECTS OF CAPOX
Nausea, Vomiting, Diarrhea
Handfoot Syndrome
Neuropathy

For the treatment of unresectable advanced or metastatic biliary tract cancer†.
Multiple dosage regimens have been studied.
Capecitabine 1,250 mg/m2 PO twice daily on days 1 to 14, followed by a 7-day rest period, given in combination with cisplatin 60 mg/m2 IV over 1 hour on day 1, repeated every 21 days until disease progression or unacceptable toxicity.
In a phase II trial of 38 patients, capecitabine/cisplatin produced an overall response rate of 21.4%. Grade III or IV neutropenia occurred in 20% of patients
Another regimen is capecitabine 650 mg/m2 PO twice daily on days 1 to 14, followed by a 7-day rest period, given in combination with gemcitabine 1,000 mg/m2 IV over 30 minutes on days 1 and 8, repeated every 21 days. In phase II trials, this dosage produced an ORR of 29% to 31%.
Another phase II trial of 43 patients studied capecitabine 1,000 mg/m2 PO twice daily on days 1 to 14, followed by a 7-day rest period, given in combination with cisplatin 60 mg/m2 IV on day 1 and epirubicin 50 mg/m2 IV on day 1, repeated every 21 days until disease progression or unacceptable toxicity.

1) For the first-line or second-line treatment of metastatic colorectal cancer
bevacizumab in combination with 5-fluorouracil, leucovorin, and irinotecan (IFL plus bevacizumab).

2) For the first-line treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC)
cetuximab in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin).
NOTE: In clinical trials, response rates did not correlate with either the percentage of EGFR positive cells or the intensity of EGFR expression. EGFR expression status and the absence of a Ras mutation should be determined by an FDA approved test prior to starting therapy
(http://www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/ucm301431.htm)

NCCN preferred: bevacizumab + irinotecan
Cancer Chemother Pharmacol. 2017 Mar;79(3):579-585. doi: 10.1007/s00280-017-3255-3. Epub 2017 Feb 17.
https://www.ncbi.nlm.nih.gov/pubmed/28213683
Phase II study of bevacizumab and irinotecan as second-line therapy for patients with metastatic colorectal cancer previously treated with fluoropyrimidines, oxaliplatin, and bevacizumab.
Abstract
PURPOSE:
Fluorouracil and folinic acid with irinotecan (FOLFIRI) plus bevacizumab (BV) is widely used as second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, oxaliplatin, and BV. FOLFIRI requires a CV catheter and an infusion pump, which are inconvenient for patients. Sufficient data are not available for characterizing the effectiveness of fluoropyrimidines beyond first disease progression. In this study, we evaluated the efficacy and safety of irinotecan (CPT-11) plus BV as second-line therapy.
METHODS:
Patients with mCRC previously treated with at least four courses of a fluoropyrimidine, oxaliplatin, and BV were designated to receive 150 mg/m2 of CPT-11 and 10 mg/kg of BV every 2 weeks as second-line therapy. The primary endpoint was progression-free survival (PFS), and secondary endpoints included response rate (RR), overall survival (OS), and adverse events.
RESULTS:
Thirty patients from six institutes were enrolled from March 2011 to January 2014. The median PFS was 5.7 months (95% CI 4.2-7.3 months), and the RR was 6.7% (range 0.8-22.1%). Grades 3-4 adverse events included leucopenia (36.7%), neutropenia (50%), thrombocytopenia (26.7%), anemia (30%), diarrhea (3.3%), anorexia (6.7%), and hypertension (3.3%). Relative dose intensities were 94.5 and 96.3% for CPT-11 and BV, respectively. The median OS was 11.8 months (6.3 months-not reached).
CONCLUSIONS:
Administration of CPT-11 plus BV to patients with mCRC achieved comparable efficacies with relatively lower toxicities compared with the results of previous studies using FOLFIRI plus BV as second-line therapy. The dose intensity of CPT-11 was judged as satisfactory.

Adjuvant Treatment

Adjuvant therapy may confer a survival advantage in some patients with resected colon cancer (eg, those with stage III or high-risk stage II disease).
However, adjuvant treatment, especially with regimens containing oxaliplatin, is associated with considerable toxicity (notably chemotherapy-induced peripheral neuropathy), and not all patients derive benefit.
Consideration of disease stage and pathologic features, microsatellite instability (MSI) status, possible efficacy and toxicity profiles associated with treatment choice, and patient age, comorbidities, and preferences aid in decision-making regarding the use of adjuvant therapy for patients with colon cancer.

The IDEA collaboration investigated whether a shortened duration of adjuvant therapy would be a feasible way to avoid or lessen toxicities associated with oxaliplatin-containing adjuvant therapy in some patients with locoregional colon cancer, without impairing oncologic outcomes.

The data were sufficient to warrant division of stage III colon cancer into a low-risk (T1–3, N1) and a high-risk group (T4, N1–2 or Any T, N2)

For the low-risk group, the recommended duration of adjuvant therapy is 3 months if CapeOX is chosen, because noninferiority for DFS was proven in IDEA and patients should be spared the increased toxicity, cost, and inconvenience of longer therapy.
If FOLFOX is chosen for these patients, then 3 to 6 months of FOLFOX is recommended. The panel believes the shorter duration can be considered to reduce toxicity, cost, and inconvenience, but noninferiority could not be proven for 3 versus 6 months of FOLFOX in this subset.

For patients with high-risk stage III colon cancer, 3 to 6 months of adjuvant therapy is recommended if CapeOX is chosen; noninferiority of the shorter duration was not proven in this subset of patients, but the panel believes the shorter duration can be considered to minimize toxicity, cost, and inconvenience. Furthermore, DFS with 3 months of therapy was noninferior to DFS with 6 months for the entire cohort (Tany, N1–2) who received CapeOX (HR, 0.95; 95% CI, 0.85–1.06).
Finally, FOLFOX, if chosen, should be given for a full 6 months in the high-risk group because 3 months was shown to be inferior to 6 months for DFS.

The panel then discussed some concerns about the dosing of capecitabine in CapeOX, which they believe is critical if the decision is to give 3 months of CapeOX. Many oncologists, especially in the United States, routinely reduce the starting dose of capecitabine, but the panel strongly believes that the starting dose used in IDEA8 (1,000 mg/m2 twice daily) should be used because it is the only validated dose. The panel also discussed that, in practice, oxaliplatin is dropped from FOLFOX and CapeOX after 6 to 10 doses to reduce the risk of severe neurotoxicity. Therefore, it may be reasonable to complete 3 months of CapeOX for patients with high-risk stage III colon cancer and then drop oxaliplatin and continue capecitabine. However, the panel was divided on whether to recommend this approach.

The NCCN Guidelines list FOLFOX and CapeOX as equally preferred options without strongly recommending one over the other. Efficacy is similar, FOLFOX is less expensive for US patients, and CapeOX is more convenient for most patients (especially 3 months of CapeOX vs 6 months of FOLFOX). Both regimens are preferred over the other options for adjuvant treatment of patients with stage III colon cancer—6 months of either capecitabine or 5-FU/leucovorin—which are generally only recommended for patients with stage III colon cancer if they cannot tolerate oxaliplatin.

** Addition of Oxaliplatin has not been proved to be benefit in pts age 70 & older.

Despite the large number of patients in IDEA, the results were not as definitive as the panel would require for these new recommendations to be listed as category 1. Therefore, these shorter durations are included in the guidelines as category 2A recommendations. The 6-month durations of FOLFOX or CapeOX for patients with stage III colon cancer remain as category 1 recommendations based on older trials.

Note: Oxaliplatin is associated with cumulative dose‐dependent neurotoxicity
• Debilitating for many patients, both short‐ and long‐term
        Nerve damage (e.g. numbness, tingling, pain) can persist long after discontinuation of therapy, sometimes permanently
        Dose reductions and early discontinuation of therapy are common
• Shorter duration of treatment without loss of efficacy would be of benefit to patients and health care resources

Treatment of RAS Wild-Type/BRAF Mutation–Positive Metastatic CRC

Although survival for patients with advanced CRC has improved dramatically over the past decades, the most recently reported 5-year survival rate for patients with stage IV CRC was only 14%. Moreover, patients with BRAF-mutated mCRC have a particularly poor prognosis. BRAF V600E mutations are present in approximately 8% of mCRC cases and are associated with a more aggressive biology, shorter OS, and decreased response to chemotherapy compared with BRAF wild-type tumors. Thus, additional treatment options are still needed in mCRC, especially for the BRAF mutation–positive subset of patients.

Vemurafenib selectively inhibits the V600E-mutated form of the BRAF kinase.
However, vemurafenib monotherapy has shown limited activity in mCRC. Preclinical data suggest that BRAF V600E inhibition alone is ineffective because feedback activation of EGFR occurs. Therefore, blockage of EGFR and BRAF V600E together has been speculated to be more effective than BRAF V600E inhibition alone.
However, vemurafenib in combination with cetuximab- or panitumumab-based therapy has been ineffective in early clinical trials. Results from preclinical and early clinical studies suggest that the addition of irinotecan to BRAF and EGFR inhibition may improve antitumor activity.
The combination of vemurafenib, cetuximab, and irinotecan was thus tested in patients with BRAF V600E–mutated mCRC in the phase II SWOG S1406 trial.

The panel felt that the data from SWOG S1406 were strong enough to warrant the addition of vemurafenib/cetuximab/irinotecan for patients with BRAF V600E–mutated mCRC at this time.
In general, the panel believes that panitumumab and cetuximab are interchangeable.
They do not believe that dabrafenib and vemurafenib are interchangeable.
The panel declined to add dabrafenib/(cetuximab or panitumumab)/irinotecan to the continuum of care for patients with BRAF-mutant mCRC.
With the addition of vemurafenib/(cetuximab or panitumumab)/irinotecan to the mCRC continuum of care, the BRAF status of the tumor is now another factor that must be considered when choosing therapies for patients with mCRC.

The panel further notes that BRAF and RAS mutations are mutually exclusive. Therefore, although the guidelines only indicate that the new regimens are for “BRAF V600E mutation–positive” disease, these patients' tumors contain wild-type RAS.

In mCRC, data from the SWOG S1406 trial has led to new treatment options specifically for patients with BRAF V600E–mutated tumors. These patients have derived little benefit from EGFR-targeted agents in the past and have had poor prognoses. The addition of an inhibitor of the specific BRAF mutation provides additional treatment options that include EGFR inhibitors and gives these patients a chance for delayed disease progression.

Principles of Pathologic Review and Biomarker Testing

Treatment Options for unresectable metachronous metastasis

I.
• No previous chemotherapy
• Previous 5 FU/LV or Capecitabine
• Previous adjuvant CAPEOX/FOLFOX >12 months
Recommendation:
Systemic chemotherapy with CAPEOX/FOLFOX
Re-evaluate for resectability every 2 months.

• Previous adjuvant CAPEOX/FOLFOX within 12 months
Recommendation:
• FOLFIRI/Irinotecan ± anti-angiogenetic agents (bevacizumab**, ramucirumab, or ziv-aflibercept); OR
• FOLFIRI/Irinotecan ± anti-EGFR (cetuximab or panitumumab)- WT KRAS/NRAS*** only; OR
• Irinotecan + cetuximab/panitumumab + vemurafenib (BRAF V600E mutation positive***); OR
• nivolumab or pembrolizumab (dMMR/MSI-H only)
Re-evaluate for resectability every 2 months.

II.
Patients are re-evaluated every 2 months.
If the tumor remains unresectable, then continue the drug therapy.
If the tumor converts to resectability, then surgery can be done and followed by observation or adjuvant therapy (Chemotherapy ± Biologic therapy).
Hepatic artery infusion ± 5FU/LV (Categoer 2B) is also an option.

** bevacizumab is the preferred anti-angiogenic agents based on toxicity &/or cost.
*** BRAF V600E mutation makes response to cetuximab or panitumumab highly unlikely.

Systemic Therapy for Advanced or Metastatic Colon Cancer

1^st line: Oxaliplatin-based therapy if not previously given - e.g., FOLFOX, CapeOX
2^nd line: Irinotecan-based therapy
• FOLFIRI or Irinotecan; OR
• FOLFIRI/Irinotecan + anti-angiogenetic agents (bevacizumab**, ramucirumab, or ziv-aflibercept); OR
• FOLFIRI/Irinotecan + anti-EGFR (cetuximab or panitumumab)- WT KRAS/NRAS*** only; OR
• Irinotecan + cetuximab/panitumumab + vemurafenib (BRAF V600E mutation positive***); OR
• nivolumab or pembrolizumab (dMMR/MSI-H only)
3^rd line:
• regorafenib; OR
• Trifluridin + tipiracil; OR
• nivolumab or pembrolizumab (dMMR/MSI-H only) OR
• Best supportive Care

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE

SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE

Patient appropriate for intensive therapy

Oxaliplatin-based therapy --> Progression -->COL-D2
CAPEOX ± bevacizuma
FOLFOX ± bevacizumab
FOLFOX + (cetuximab or panitumumab) = (KRAS/NRAS/BRAF WT and left-sided tumors only)

Irinotecan-based therapy --> Progression -->COL-D3
FOLFIRI ± bevacizumab -->COL-D3
FOLFIRI + (cetuximab or panitumumab) = (KRAS/NRAS/BRAF WT and left-sided tumors only)

Oxaliplatin and Irinotecan-based therapy --> Progression -->COL-D4
FOLFOXIRI ± bevacizumab

Patient not appropriate for intensive therapy

Infusional 5-FU + leucovorin ± bevacizumabd
Capecitabine ± bevacizumab
(Cetuximab or panitumumab) (category 2B) = (KRAS/NRAS/BRAF WT and left-sided tumors only)
(Nivolumab or pembrolizumab) = (dMMR/MSI-H only)
Nivolumab + ipilimumab = (dMMR/MSI-H only) (category 2B)
(Trastuzumabl + [pertuzumab or lapatinib]) = (HER2-amplified and RAS WT)

Previous oxaliplatin-based therapy

FOLFIRI or irinotecan
+ (bevacizumabd, [preferred] or
+ ziv-aflibercept or
+ ramucirumab

OR
(FOLFIRI or irinotecan) + (cetuximab or panitumumab) = (KRAS/NRAS/BRAF WT only)
(Dabrafenib + trametinib) + (cetuximab or panitumumab) = (BRAF V600E mutation positive)
Encorafenib + (cetuximab or panitumumab) ± binimetinib = (BRAF V600E mutation positive)

OR
[Nivolumab ± ipilimumab] or pembrolizumab = (dMMR/MSI-H only)
(Trastuzumabl + [pertuzumab or lapatinib]) = (HER2-amplified and RAS WT)

Third-line include:
Regorafenib
Trifluridine + tipiracil

Previous irinotecan-based therapy

FOLFOX or CAPEOX
FOLFOX + bevacizumabd
CAPEOX + bevacizumab
FOLFOX + (cetuximab or panitumumab) = (KRAS/NRAS/BRAF WT only)

OR

Irinotecan + (cetuximab orpanitumumab) = (KRAS/NRAS/BRAF WT only)
(Dabrafenib + trametinib) + (cetuximab or panitumumab) = (BRAF V600E mutation positive)
Encorafenib + (cetuximab or panitumumab) ± binimetinib = (BRAF V600E mutation positive)

OR


[Nivolumab ± ipilimumab] or Pembrolizumab = dMMR/MSI-H only
Trastuzumabl + [pertuzumab or lapatinib] = (HER2-amplified and RAS WT)

Third-line include:
Regorafenib
Trifluridine + tipiracil