Patient education: Colorectal cancer treatment; metastatic cancer (Beyond the Basics)

COLORECTAL CANCER OVERVIEW — Colon and rectal cancer are cancers that involve the lowest part of the digestive system: the large intestine and the rectum (figure 1). Despite early diagnosis and treatment, cancers involving the colon or rectum (colorectal cancer) can reappear at a later time, even if the cancer was entirely removed during the initial treatment. (See "Patient education: Colon and rectal cancer (Beyond the Basics)".)

Reappearance of the colorectal cancer after initial curative therapy is referred to as a recurrence or a relapse. A colorectal cancer recurrence can be either local (confined to the area where the cancer was initially diagnosed or nearby tissues) or at a distant site. When the recurrence develops at a site away from the colon or rectum, it is called a metastasis.

In other cases, a colorectal cancer has already spread to distant sites by the time it is diagnosed. This is referred to as metastatic (stage IV) colorectal cancer.

Cure is not possible for most patients with metastatic colorectal cancer, although some patients who have limited involvement of distant organs (particularly restricted to the liver and/or lung) can be cured with surgery. For others, chemotherapy is the most appropriate option. Chemotherapy does not cure metastatic colorectal cancer, but it can improve symptoms and prolong life. Sometimes both chemotherapy and surgery are recommended.

This article will discuss management of patients with metastatic colorectal cancer. Treatment for localized colon cancer and localized rectal cancer is discussed elsewhere. (See "Patient education: Colon and rectal cancer (Beyond the Basics)".)

More detailed information about colorectal cancer, written for health care providers, is available by subscription. (See 'Professional level information' below.)

CANCER CARE DURING THE COVID-19 PANDEMIC — COVID-19 stands for "coronavirus disease 2019." It is an infection caused by a virus called SARS-CoV-2. The virus first appeared in late 2019 and has since spread throughout the world. Getting vaccinated lowers the risk of severe illness; experts recommend COVID-19 vaccination for anyone with cancer or a history of cancer.

In some cases, if you live in an area with a lot of cases of COVID-19, your doctor might suggest rescheduling or delaying medical appointments. But this decision must be balanced against the importance of getting care to screen for, monitor, and treat cancer. Your doctor can talk to you about whether to make any changes to your appointment schedule. They can also advise you on what to do if you test positive or were exposed to the virus.

TREATMENT FOR RESECTABLE METASTATIC COLORECTAL CANCER — Sometimes surgery is an option for a person whose colorectal cancer has spread in a limited way outside of the intestine to an area such as the liver. Up to 30 percent of people may be cured if metastases in the liver can be completely removed (the medical term for this is "resected"). In order for surgery to be considered, there must be no evidence of cancer outside of the liver, and there must be an adequate amount of normal liver left behind after the resection to sustain life.

There is controversy and variability about what is considered "resectable" versus "nonresectable" metastatic disease in the liver. If at all possible, patients should request a consultation with an experienced liver surgeon or surgical oncologist (a surgeon with expertise in the treatment of cancer) before deciding on a treatment plan.

Chemotherapy may be recommended before surgery in some cases, even if the metastatic disease appears to be confined to the liver. This approach may help a person who is a borderline candidate for surgery (because of the size or location of the tumors) have successful surgery after the colorectal cancer metastases have been reduced in size by the chemotherapy.

If surgical removal of the liver metastases is successful, additional chemotherapy is often recommended after surgery. (See 'First-line chemotherapy for metastatic colorectal cancer' below.)

At some institutions, the chemotherapy is given directly into the liver (an approach called hepatic intra-arterial chemotherapy) with or without additional chemotherapy given into the veins (intravenous chemotherapy) [1]. However, it is unclear if this approach is better than intravenous chemotherapy alone; the most commonly used approach is intravenous chemotherapy.

Surgical treatment may also be considered for a patient with a limited amount of metastatic disease in the lung. The role of additional chemotherapy after surgical removal of lung metastases is not clear.

CHEMOTHERAPY FOR UNRESECTABLE COLORECTAL CANCER — As noted above, surgery is the only way to cure metastatic colorectal cancer. In most cases, surgery is not possible, and chemotherapy is recommended to reduce symptoms and prolong survival. Although chemotherapy provides meaningful improvements in survival, it is not possible to cure metastatic colorectal cancer with chemotherapy alone.

Continuum of care concept — With most types of incurable cancer (other than metastatic colorectal cancer), individual chemotherapy drugs or regimens are given continuously until the cancer stops responding to that drug or regimen, and then an entirely new regimen (termed "second-line therapy") may be tried.

The situation is different with metastatic colorectal cancer because there are many active drugs that can be combined in a number of ways. In addition, treatment-related side effects may be lessened by limiting the number of doses of certain drugs. Thus, instead of giving the first-line regimen until the tumor progresses, treatment is often individualized.

●Specific chemotherapy drugs may be given, stopped, and then restarted at a later time, sometimes in combination with other chemotherapy drugs.

●Periods of aggressive chemotherapy may be interspersed with periods of "maintenance" chemotherapy, allowing the patient to have the greatest possible quality of life while minimizing side effects.

This has been referred to as the "continuum of care" approach to treatment of metastatic colorectal cancer.

Conventional chemotherapy — The conventional chemotherapy drugs used to treat metastatic colorectal cancer include:

●Fluorouracil (FU), which is usually given into the vein with a second drug called leucovorin, which enhances its activity

●Orally active FU-like drugs, such as capecitabine (brand name: Xeloda)

●Oxaliplatin (brand name: Eloxatin), which is given intravenously

●Irinotecan (brand name: Camptosar), also given intravenously

●Trifluridine-tipiracil (brand name: Lonsurf), an oral agent that contains two components, trifluridine and tipiracil, each of which have different properties. In the United States, trifluridine-tipiracil is approved for the treatment of patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens as well as other targeted therapies.

These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment. (See 'Colorectal cancer chemotherapy side effects' below.)

Targeted therapy — Other drugs that are active against metastatic colorectal cancer work by a different mechanism. These are referred to as "targeted therapy agents" since they are either antibodies (a type of protein) or drugs that work to inhibit specific proteins that are important for the growth and/or survival of colon cancer cells.

Because targeted therapy agents do not directly interfere with rapidly dividing cells, they do not have the usual side effects of conventional chemotherapy. However, targeted chemotherapy has other unique side effects, which are described in detail below. (See 'Colorectal cancer chemotherapy side effects' below.)

Currently available targeted chemotherapy agents include:

●Bevacizumab (brand name: Avastin) – Bevacizumab binds to a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the development of a blood supply within a growing cancer; this blood supply is essential for the tumor to grow and spread. Bevacizumab enhances the antitumor effect of other chemotherapy drugs. Bevacizumab is not effective when given by itself, but is generally given in combination with other drugs, such as FU (or capecitabine), oxaliplatin, and irinotecan (see below).

●Ramucirumab (brand name: Cyramza) – Ramucirumab is a protein that binds to a receptor for VEGF (VEGFR2), thus targeting signaling through the same pathway that bevacizumab does. Like bevacizumab, ramucirumab enhances the antitumor effect of other chemotherapy drugs. In the United States, it is approved in combination with an irinotecan-based chemotherapy regimen for patients who have previously been treated with bevacizumab plus an oxaliplatin-containing regimen.

●Aflibercept (brand name: Zaltrap) – Intravenous aflibercept represents another method of interfering with a tumor's blood supply; it is a fusion protein that acts by "trapping" VEGF and preventing it from activating its receptors on the tumor cells. In the United States, aflibercept is approved, in combination with irinotecan-based chemotherapy, for patients whose tumors have progressed while receiving an oxaliplatin-containing chemotherapy regimen, with or without bevacizumab.

●Regorafenib (brand name: Stivarga) – Regorafenib is a pill form of a drug that blocks several VEGF receptors as well as other proteins referred to as kinases. In the United States, regorafenib is approved as a single agent for the treatment of patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens as well as other targeted therapies.

●Cetuximab (brand name: Erbitux) and panitumumab (brand name: Vectibix) – Cetuximab and panitumumab target a different protein, the epidermal growth factor receptor (EGFR).

Unlike bevacizumab, cetuximab and panitumumab are active when given alone or in combination with other drugs, like irinotecan.

However, these agents do not work for everyone. Their activity depends on whether or not the tumor has specific genetic abnormalities (a mutation in a set of genes called RAS genes or in a separate gene called BRAF V600E).

•If the tumor does not have a RAS or a BRAF V600E mutation, cetuximab and panitumumab might work (ie, they can be effective).

•If the tumor has a RAS or a BRAF V600E mutation, cetuximab and panitumumab do not work, even in combinations with standard chemotherapy agents.

•If the tumor has a BRAF but not a RAS mutation, cetuximab and panitumumab might work in combination with other drugs that specifically target the BRAF mutation and related molecules (for example, encorafenib). Combinations such as these are typically used for second-line rather than first-line therapy, meaning they are usually only tried when the initial regimen is no longer helpful.

●Larotrectinib (brand name: Vitrakvi) and entrectinib (brand name: Rozlytrek) are drugs called tropomyosin receptor kinase (TRK) inhibitors. They target a specific protein that is present in large amounts in people whose cancer has an abnormality resulting from two genes fusing together (called "TRK fusion-positive tumors"). These abnormalities are very rare.

Immunotherapy — Immunotherapy refers to drugs that stimulate or unleash your immune system to attack and kill the cancer cells.

There are several different types of immunotherapy. The most important types for advanced colorectal cancer are the immune checkpoint inhibitors nivolumab (brand name: Opdivo), pembrolizumab (brand name: Keytruda), and ipilimumab (brand name: Yervoy). They have important benefits for a small number of patients, notably the approximately 5 percent whose tumors have specific genetic alterations. (See 'Patients whose tumors have defective mismatch repair' below.)

Monitoring during treatment — A person's response to chemotherapy is monitored with periodic X-ray studies (such as computed tomography [CT] scans) usually every 8 to 12 weeks during therapy. In addition, blood levels of a tumor marker called carcinoembryonic antigen (CEA) are generally measured every one to three months during therapy. CEA levels are typically high in people with advanced colorectal cancer; persistently rising CEA levels could suggest that the disease is progressing, and a change in therapy might be warranted.

However, a rising CEA alone is not sufficient evidence to prompt a change in treatment. Disease progression should be confirmed with radiographic testing (eg, CT scan) or a biopsy before changing treatment.

FIRST-LINE CHEMOTHERAPY FOR METASTATIC COLORECTAL CANCER — Conventional chemotherapy drugs and targeted agents are generally used in combination for people with newly diagnosed, previously untreated metastatic colorectal cancer. Many different combinations have been developed and may be recommended for initial (first-line) treatment. The following sections will review the choices for the chemotherapy "backbone." Following this is a discussion of adding targeted chemotherapy agents, such as bevacizumab, to this backbone.

FOLFOX, FOLFIRI, FOLFOXIRI, and XELOX (CAPOX) — Several combination chemotherapy regimens may be considered for the initial treatment of metastatic colorectal cancer. Each of these regimens consists of two, three, or four drugs used together in a specific way:

●Oxaliplatin plus fluorouracil (FU) and leucovorin (referred to as FOLFOX)

●Irinotecan plus FU and leucovorin (referred to as FOLFIRI)

●Oxaliplatin plus irinotecan plus FU and leucovorin (referred to as FOLFOXIRI)

●Oxaliplatin plus capecitabine (referred to as XELOX or CAPOX)

With FOLFOX, FOLFIRI, and FOLFOXIRI, the oxaliplatin and/or irinotecan are typically given into a vein (intravenously) all at once on the first day of treatment (day 1). The leucovorin and FU are given intravenously, with the FU infused over a protracted period of time (46 hours). All three regimens require that patients have a central venous access catheter (often termed a "port"), which is surgically inserted into one of the large blood vessels in the chest, and a portable chemotherapy pump at home (referred to as a home infusion pump). This pump is actually very small, and it fits into a fanny pack that can be worn around the waist.

Both FOLFIRI and FOLFOX result in similar outcomes when used as first-line therapy [2,3]; the choice between them is often based on expected side effects. (See 'Colorectal cancer chemotherapy side effects' below.)

FOLFOXIRI is a more intense regimen than either FOLFOX or FOLFIRI; although it has a higher level of treatment response, it also has more severe side effects than either FOLFOX or FOLFIRI. Its use is generally limited to very healthy, relatively young individuals in good physical condition with few other medical problems.

With XELOX (or CAPOX), the oral drug capecitabine (brand name: Xeloda) is given along with intravenous oxaliplatin. This regimen is more convenient for the patient because it does not require a home infusion pump. At many institutions, the oxaliplatin is administered through a central venous line because it causes pain when administered into an arm vein, but some patients may be able to avoid a port.

XELOX/CAPOX is probably as effective as FOLFOX for first-line treatment. However, some side effects, including diarrhea and hand-foot syndrome (redness, tenderness, and peeling of the skin of the palms and soles of the feet), may be more pronounced with XELOX.

How long is the first-line regimen recommended? — The optimal duration of initial FOLFOX or XELOX is controversial.

●If a person is responding well and has no severe or bothersome side effects, it is reasonable to continue the regimen until the tumor progresses.

●Another acceptable approach is to give three or four months of FOLFOX or XELOX, and then switch to "maintenance chemotherapy" with FU plus leucovorin or capecitabine with or without bevacizumab. The oxaliplatin would be restarted at the time of disease progression. This approach has been shown to delay the development of oxaliplatin-related neuropathy.

●If a patient develops severe neuropathy during treatment with FOLFOX, XELOX, or FOLFOXIRI, oxaliplatin may need to be withdrawn, at least temporarily, to allow the neuropathy to resolve. During this time, maintenance chemotherapy with FU and leucovorin or capecitabine alone may be substituted, or a different chemotherapy regimen (eg, FOLFIRI) could be considered (see 'Second-line treatment of metastatic colorectal cancer' below). The risk associated with a complete break in chemotherapy in this setting is also addressed below. (See 'Can I take a break from chemotherapy?' below.)

The optimal duration of treatment with FOLFIRI is not clear. Patients who initially take FOLFIRI usually require a change in treatment because of disease progression, rather than side effects.

Can I take a break from chemotherapy? — As noted above, a temporary discontinuation of oxaliplatin could be considered after three to four months of FOLFOX or XELOX therapy if the colorectal cancer has responded to treatment, there are no cancer-related symptoms, and tumor growth is not interfering with the function of other organs (eg, liver failure, bowel obstruction). In many cases, continuation of at least some chemotherapy with FU and leucovorin (or capecitabine) with or without bevacizumab will be advised; this is known as "maintenance therapy." Alternatively, a temporary complete break from chemotherapy after the initial three to six months of treatment could also be considered. For people who elect to take a break, it is likely that cancer regrowth will happen sooner. However, because chemotherapy can be restarted at that time, treatment breaks do not have a long-term detrimental impact on survival.

If chemotherapy is stopped completely because of side effects or patient preference, close monitoring is recommended; this generally includes a computed tomography (CT) scan every two months. If the colorectal cancer begins to progress, chemotherapy is generally restarted.

Adding targeted agents — Adding bevacizumab (brand name: Avastin) to FOLFOX, XELOX/CAPOX, FOLFIRI, or FOLFOXIRI significantly increases the likelihood that the tumor will respond and prolongs survival compared with treatment without bevacizumab.

In many cases, bevacizumab is recommended as a component of the first-line treatment of metastatic colorectal cancer, along with FOLFIRI, FOLFOX, FOLFOXIRI, or XELOX/CAPOX. However, the benefits of adding bevacizumab to these chemotherapy regimens must be balanced against the potentially serious side effects that can occur with this drug (eg, bleeding, blood clots). (See 'Targeted therapy' above.)

Benefit has also been shown for adding one of the epidermal growth factor receptor (EGFR)-targeted agents (cetuximab or panitumumab) to first-line chemotherapy if your tumor does not have a RAS or a BRAF V600E mutation. Newer data from clinical trials suggest that the site where the original colorectal cancer was located (right sided [ascending and transverse colon] versus left sided [descending and sigmoid colon, rectum] (figure 1)) might influence the relative benefit of adding an anti-EGFR agent or bevacizumab to the first-line chemotherapy regimen, with cetuximab and panitumumab being more effective in patients with left-sided primary tumors.

Patients who cannot tolerate FOLFOX, XELOX (CAPOX), FOLFOXIRI, or FOLFIRI — If a person cannot tolerate an aggressive chemotherapy regimen like FOLFOX, XELOX (CAPOX), FOLFOXIRI, or FOLFIRI because of their age, physical condition, or other medical problems, there are a few options:

●Intravenous FU plus leucovorin, with or without bevacizumab is a reasonable and less toxic alternative, at least when the FU is infused over a protracted period of time (46 hours, termed short-term infusion).

●Another alternative is capecitabine (with or without bevacizumab), which is taken in pill form twice daily for 14 days, followed by a seven-day break. Capecitabine is about as effective as is intravenous FU plus leucovorin. People who are on a regimen that contains capecitabine should probably not take proton pump inhibitors (PPIs, medications that decrease the stomach's production of acid and are used to treat acid reflux or other digestive problems). PPIs may affect how well capecitabine works.

These regimens may be slightly less effective than FOLFOX or FOLFIRI, but they tend to be less toxic.

Patients whose tumors have defective mismatch repair — As noted above, immunotherapy drugs such as pembrolizumab or nivolumab, with or without ipilimumab have important benefits for a small number of people, notably the approximately 5 percent whose tumors have specific genetic alterations (doctors call this type of tumor "mismatch repair deficient" [dMMR] or "microsatellite instability high" [MSI-H]). Doctors who examine tumor tissue under a microscope are able to detect most mismatch repair deficient tumors by testing for specific proteins in the tissue.

Most of the data on benefits of immune checkpoint inhibitor immunotherapy come from studies in previously treated patients, after conventional chemotherapy has been unsuccessful. However, more recent data suggest that upfront pembrolizumab offers better outcomes than first-line oxaliplatin or irinotecan-based chemotherapy in people with dMMR/MSI-H tumors [4]. Pembrolizumab doubled the time to tumor progression while on therapy (average of 16 versus 8.2 months) and also had fewer side effects. Other immunotherapy drugs are also being studied for potential first-line use.

SECOND-LINE TREATMENT OF METASTATIC COLORECTAL CANCER — If the colorectal cancer continues to grow despite chemotherapy or it begins to enlarge after an initial response to the first-line chemotherapy regimen, a different chemotherapy combination may be tried, as long as the patient is well enough to tolerate additional therapy. The choice of second-line treatment typically depends on what was given originally and on the genetic makeup of your tumor. As examples:

●If you initially received FOLFOX or XELOX (CAPOX), your doctor may suggest a switch to FOLFIRI. If you initially received FOLFIRI, your doctor may suggest a switch to FOLFOX or CAPOX.

●If your tumor does not have a RAS or a BRAF V600E mutation, one of the epidermal growth factor receptor (EGFR)-targeted agents (cetuximab or panitumumab) may be added to one or more of the conventional chemotherapy agents, if these drugs were not used for initial therapy. (See 'Targeted therapy' above.)

●For patients with mismatch repair deficient (dMMR) metastatic colorectal cancer, treatment with one or more of the immune checkpoint inhibitors can be tried after conventional chemotherapy is no longer effective. (See 'Immunotherapy' above.)

●For patients with a BRAF V600E mutation, treatment with encorafenib and cetuximab can be tried after initial chemotherapy is no longer effective.

●For patients with a TRK fusion-positive cancer, a TRK inhibitor (larotrectinib or entrectinib) is an appropriate second-line treatment.

It is probably more important for the person to be exposed to all of the available chemotherapy drugs at some point during the course of treatment than to give the drugs in a specific order. This is because survival may be prolonged by second-line (as well as third-line) therapy.

COLORECTAL CANCER CHEMOTHERAPY SIDE EFFECTS — The side effects of colorectal cancer chemotherapy depend on the type, combination, and schedule of drugs used. The most common side effects of each agent are listed below, but it is important to review the entire range of potential side effects of all of the individual drugs in the chemotherapy regimen with the health care team.

●Fluorouracil (FU) and leucovorin – The most common side effects are diarrhea, mucositis (soreness in the mouth), and temporarily lowered blood counts. Side effects (including hair loss) tend to be less when FU is given as a short-term infusion over 48 hours rather than as a quick or "bolus" injection.

●Capecitabine – The most common side effect of capecitabine is hand-foot syndrome. Otherwise, oral FU-like drugs such as capecitabine have the same side effects as intravenous FU, although diarrhea and mucositis are somewhat less common. Side effects of capecitabine may be more common when it is given after a regimen including FU and leucovorin.

●Irinotecan – When given alone, irinotecan usually causes more diarrhea, lower blood counts, more fatigue, and more hair loss compared with FU. When irinotecan is combined with FU and leucovorin (FOLFIRI), the most common side effect is diarrhea. Patients should call their health care provider immediately if severe diarrhea develops.

●Oxaliplatin – Oxaliplatin can cause numbness and tingling of the hands and feet; this is more likely with longer durations of therapy. This drug routinely also causes an unusual sensitivity to cold temperatures. This can result in the sensation of spasms of the throat while inhaling cold air or ingesting cold liquids or foods. Patients should avoid drinking cold fluids, inhaling cold air, and exposing their hands and feet to cold, when possible, for several days after their oxaliplatin infusions.

●Bevacizumab, aflibercept, and ramucirumab – Bevacizumab, aflibercept, and ramucirumab all target vascular endothelial growth factor (VEGF), and they share many of the same side effects. Because there is a small risk that these agents can impair wound healing, surgery should be avoided for several weeks before and after treatment with any of these agents (if possible) to avoid this potential side effect.

Bevacizumab, aflibercept, and ramucirumab may also cause bleeding in the gastrointestinal tract or, uncommonly, a tear of the bowel during treatment. They can also increase blood pressure or cause protein to spill into the urine. Close monitoring is necessary to detect and treat these problems early.

There is an increased risk of blood clots for patients using bevacizumab, aflibercept, or ramucirumab in combination with FU-containing chemotherapy. Approximately 2 to 4 percent of patients have serious events such as strokes and heart attacks during therapy. The risk appears to be highest in patients with prior heart problems and in those over the age of 65. For this reason, use of these drugs may not be recommended for people over age 65 who have had a stroke, transient ischemic attack (TIA), or heart attack within the previous 6 to 12 months.

●Regorafenib – Like bevacizumab, aflibercept, and ramucirumab, regorafenib also targets the VEGF pathway and shares many of the same side effects, including bleeding or a tear of the bowel during treatment, and high blood pressure. Unlike bevacizumab, aflibercept, and ramucirumab, regorafenib is given by itself and not with other chemotherapy agents. Other reported side effects with regorafenib are fatigue, diarrhea, liver damage, and hand-foot syndrome, a condition in which there is soreness, redness, and peeling of the skin of the palms and soles of the feet.

●Cetuximab – Cetuximab can cause allergic reactions slightly more frequently than bevacizumab. If severe, treatment with cetuximab may need to be stopped. Patients will be closely monitored for allergic reactions during and after their treatment.

Other side effects include a skin rash that resembles acne, diarrhea, blood clots in the legs, and low blood levels of magnesium. Low magnesium levels can cause weakness, heart rhythm abnormalities, and lead to low levels of other components of the blood, such as potassium and calcium.

●Panitumumab – While panitumumab can also cause allergic reactions that, if severe, may require that treatment be stopped, the risk is much lower than with either cetuximab or bevacizumab.

Other side effects are similar to those seen with cetuximab including an acne-like skin rash, which may be severe; diarrhea; blood clots in the legs; and low blood levels of magnesium.

●Encorafenib – When encorafenib is combined with cetuximab the type, frequency, and severity of side effects associated with cetuximab are not worse. The addition of encorafenib does slightly increase the risk of visual blurring and weakening of the heart muscle.

●Trifluridine-tipiracil – The most common adverse effects are low blood counts, fatigue, nausea, and diarrhea. While frequent, gastrointestinal side effects are generally not severe.

●Nivolumab, pembrolizumab and ipilimumab – Checkpoint inhibitors like nivolumab and pembrolizumab can cause significant side effects. All three drugs can cause the body to develop an immune reaction against its own tissues. This can result in a wide range of side effects that occasionally (<5 percent of all treated patients) can be severe or life-threatening. The most important of these side effects include lung inflammation (causing difficulty breathing), rash or inflammation of the skin, hepatitis, inflammation of the kidneys causing decreased kidney function, colitis (causing diarrhea or bleeding), and inflammation of endocrine organs (pituitary, thyroid, or adrenal, leading to diminished hormone production).

●Larotrectinib and entrectinib – Both drugs can cause abnormal liver tests, and cause neurologic abnormalities including change in mental status, difficulty walking, and numbness. Neurologic side effects tend to be more frequent and more severe with entrectinib. Entrectinib can also cause heart failure and bone fractures. For these reasons, larotrectinib is usually preferred over entrectinib.

IMPORTANCE OF VITAMIN D — Low levels of vitamin D may be associated with worse outcomes in patients with metastatic colorectal cancer. The results of one trial comparing different chemotherapy regimens for metastatic colorectal cancer suggest that patients who had the highest blood levels of vitamin D survived longer than did those who had the lowest levels [5]. Given the benefits of vitamin D in terms of bone health and the possibility of better cancer-related outcomes in those with higher levels, health care providers may test serum vitamin D levels in patients with newly diagnosed metastatic colorectal cancer and provide supplementation to those with low levels. (See "Patient education: Vitamin D deficiency (Beyond the Basics)" and "Patient education: Calcium and vitamin D for bone health (Beyond the Basics)".)

CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

●www.cancer.gov/about-cancer/treatment/clinical-trials

●www.clinicaltrials.gov/

Videos addressing common questions about clinical trials are available from the American Society of Clinical Oncology.

WHERE TO GET MORE INFORMATION — Your health care provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our website (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for health care professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient education: Colon and rectal cancer (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient education: Colon and rectal cancer (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Clinical presentation, diagnosis, and staging of colorectal cancer
Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy
Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques
Surgical resection of pulmonary metastases: Outcomes by histology
Nonsurgical local treatment strategies for colorectal cancer liver metastases
Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach
Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy
Locoregional methods for management and palliation in patients who present with stage IV colorectal cancer
Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents
Cardiovascular toxicities of molecularly targeted antiangiogenic agents
Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors

The following organizations also provide reliable health information:

●American Society of Clinical Oncology

●National Comprehensive Cancer Network [6]

●National Cancer Institute

1-800-4-CANCER

●American Cancer Society

1-800-ACS-2345

●National Library of Medicine

●The American Gastroenterological Association

●The American College of Gastroenterology