Key Points

• Retinoblastoma is a disease in which malignant (cancer) cells form in the tissues of the retina.
• Children with a family history of retinoblastoma should have eye exams to check for retinoblastoma.
• Retinoblastoma occurs in heritable and nonheritable forms.
• A child who has heritable retinoblastoma has an increased risk of trilateral retinoblastoma and other cancers.
• Genetic testing can determine whether a child has the heritable or nonheritable form of retinoblastoma.
• Signs and symptoms of retinoblastoma include "white pupil" and eyes that appear to be looking in different directions (crossed eyes).
• Tests that examine the retina are used to diagnose retinoblastoma.
• Certain factors affect prognosis (chance of recovery) and treatment options.

Retinoblastoma is a disease in which malignant (cancer) cells form in the tissues of the retina.

The retina is made of nerve tissue that lines the inside wall of the back of the eye. It receives light and converts the light into signals that travel down the optic nerve to the brain. The brain decodes the signals so that you can see the image.

Retinoblastoma may be in one eye (unilateral) or in both eyes (bilateral). Cavitary retinoblastoma is a rare type of retinoblastoma in which cavities (hollow spaces) form within the tumor.

Although retinoblastoma may occur at any age, it occurs most often in children younger than 2 years.

Children with a family history of retinoblastoma should have eye exams to check for retinoblastoma.

A child with a family history of retinoblastoma should have regular eye exams beginning early in life to check for retinoblastoma, unless it is known that the child does not have the RB1 gene change. Early diagnosis of retinoblastoma may mean the child will need less intense treatment.

Talk with your child’s doctor about the type of eye exam, how often eye exams are done, and at what age eye exams to check for retinoblastoma can stop.

Retinoblastoma occurs in heritable and nonheritable forms.

A child is thought to have the heritable (inherited) form of retinoblastoma when there is a certain mutation (change) in the RB1 gene. The mutation in the RB1 gene may be passed from the parent to the child, or it may occur in the egg or sperm before conception or soon after conception.

Other factors that suggest the child may have the heritable form of retinoblastoma include the following:

• There is a family history of retinoblastoma.
• There is more than one tumor in the eye.
• There is a tumor in both eyes.

After heritable retinoblastoma has been diagnosed and treated, new tumors may continue to form for a few years. Regular eye exams to check for new tumors are usually done every 2 to 4 months for at least 28 months.

Most cases of retinoblastoma are the nonheritable form. Nonheritable retinoblastoma is not passed down from parents. This type of retinoblastoma is caused by mutations in the RB1 gene that occur by chance after a child is born. Nonheritable retinoblastoma usually occurs in one eye.

A child who has heritable retinoblastoma has an increased risk of trilateral retinoblastoma and other cancers.

A child with heritable retinoblastoma has an increased risk of a pineal tumor in the brain. When retinoblastoma and a brain tumor occur at the same time, it is called trilateral retinoblastoma. The brain tumor is usually diagnosed between 20 and 36 months of age. Regular screening using MRI (magnetic resonance imaging) may be done for a child thought to have heritable retinoblastoma or for a child with retinoblastoma in one eye and a family history of the disease. CT (computerized tomography) scans are usually not used for routine screening in order to avoid exposing the child to ionizing radiation.

Heritable retinoblastoma also increases the child's risk of other types of cancer such as lung cancer, bladder cancer, or melanoma in later years. Regular follow-up exams are important.

Genetic testing can determine whether a child has the heritable or nonheritable form of retinoblastoma.

It is not always clear from the family medical history whether a condition is inherited. Certain families may benefit from genetic counseling and genetic testing. Genetic counselors and other specially trained health professionals can help parents understand the following:

• Their family medical history.
• Their options for RB1 gene testing.
• The risk of retinoblastoma for the child and the child's brothers or sisters.
• The risks and benefits of learning genetic information.

Genetic counselors can also help people cope with their genetic testing results, including how to discuss the results with family members.

Once it is known that the child has heritable retinoblastoma, other family members can be screened for the RB1 mutation. For one specific mutation, the risk of retinoblastoma in a sibling may depend partly on whether the mutation is inherited from the mother or from the father.

Retinoblastoma is a rare type of eye cancer that usually develops in early childhood, typically before the age of 5. This form of cancer develops in the retina, which is the specialized light-sensitive tissue at the back of the eye that detects light and color.

In children with retinoblastoma, the disease often affects only one eye. However, one out of three children with retinoblastoma develops cancer in both eyes. The most common first sign of retinoblastoma is a visible whiteness in the pupil called "cat's eye reflex" or leukocoria. This unusual whiteness is particularly noticeable in dim light or in photographs taken with a flash. Other signs and symptoms of retinoblastoma include crossed eyes or eyes that do not point in the same direction (strabismus), which can cause squinting; a change in the color of the colored part of the eye (iris); redness, soreness, or swelling of the eyelids; and blindness or poor vision in the affected eye or eyes.

Retinoblastoma is often curable when it is diagnosed early. However, if it is not treated promptly, this cancer can spread beyond the eye to other parts of the body. This advanced form of retinoblastoma can be life-threatening.

When retinoblastoma is associated with a genetic change (mutation) that occurs in all of the body's cells, it is known as hereditary (or germinal) retinoblastoma. People with this form of retinoblastoma typically develop cancer in both eyes and also have an increased risk of developing several other cancers outside the eye. Specifically, they are more likely to develop a cancer of the pineal gland in the brain (pineoblastoma), a type of bone cancer known as osteosarcoma, cancers of soft tissues (such as muscle) called soft tissue sarcomas, and an aggressive form of skin cancer called melanoma.

Retinoblastoma is diagnosed in 250 to 350 children per year in the United States. It accounts for about 4 percent of all cancers in children younger than 15 years.

At a glance: Retinoblastoma

• Symptoms: Pupil that looks white in bright light or flash photos, crossed eyes, eye swelling, teary eyes, eye pain

• Diagnosis: Dilated eye exam, ultrasound of the eye

• Treatment: Chemotherapy, laser treatment, radiation, cryotherapy (freeze treatment), surgery to remove the eye (enucleation)

What is retinoblastoma?

Retinoblastoma is a rare eye cancer that forms in the retina (the light-sensitive tissue at the back of the eye). Retinoblastoma is most common in children younger than age 5 — but in rare cases it can develop in older children and adults. It can affect 1 eye or both eyes.

Retinoblastoma can cause blindness and can also be life-threatening. But early diagnosis and treatment can help prevent vision loss and stop the cancer from spreading. That’s why it’s important to call your child’s doctor right away if you notice signs of retinoblastoma.

What are the signs of retinoblastoma?

The most common sign of retinoblastoma is a white pupil (the round black opening in the center of the eye) when a light shines into the eye. Parents often notice this sign when they take a photo of their child using a flash.

Other signs and symptoms of retinoblastoma include:

• Crossed eyes or 1 eye that drifts in a different direction
• Eye pain, swelling, or redness
• Watery or teary eyes
• Poor vision

If your child has poor vision from retinoblastoma, you may notice that they fall down more often, bump into things, or have trouble moving around the house. They may also bring objects close to their face to see them better.

It’s important to call your child’s doctor right away if you notice any of these signs.

Is my child at risk for retinoblastoma?

Any child can develop retinoblastoma, but children are at higher risk for retinoblastoma if another family member had it. If you or someone in your family had retinoblastoma, getting genetic testing done can tell you if you have the type that can be passed down.

If you have a family history of retinoblastoma, talk with your child’s doctor about their risk. Children at higher risk need regular eye exams to check for early signs of cancer.

What causes retinoblastoma?

Retinoblastoma happens when changes in a gene cause retina cells to grow into a tumor. Most of the time, these gene changes happen by chance — but sometimes the changed gene is inherited (passed down) from a parent.

When retinoblastoma is inherited, it’s likely to affect both eyes.

How will the eye doctor check for retinoblastoma?

An eye doctor can check for retinoblastoma as part of a dilated eye exam. They may also do other tests to help them see inside and around the eye, like retinal photos, ultrasounds, and MRI scans.

If your child is diagnosed with retinoblastoma, they may need other tests — like genetic testing to see if they have the inherited type of the disease. If they do, their other eye could be at risk of developing retinoblastoma too.

What's the treatment for retinoblastoma?

Retinoblastoma treatment depends on the size of the tumor and whether or not the cancer has spread outside of the eye. Treatment options include chemotherapy, cryotherapy (freeze treatment), laser therapy, radiation, and surgery. A specialist called a pediatric oncologist can help find the right treatment plan for your child.

Retinoblastoma can cause blindness and even death if it’s not treated in time — but it’s curable when doctors catch it before it spreads outside of the eye and quickly start treatment. That’s why it’s so important to tell your child’s doctor right away if you notice signs of retinoblastoma.

Mutations in the RB1 gene are responsible for most cases of retinoblastoma. RB1 is a tumor suppressor gene, which means that it normally regulates cell growth and stops cells from dividing too rapidly or in an uncontrolled way. Most mutations in the RB1 gene prevent it from making any functional protein, so cells are unable to regulate cell division effectively. As a result, certain cells in the retina can divide uncontrollably to form a cancerous tumor. Some studies suggest that additional genetic changes can influence the development of retinoblastoma; these changes may help explain variations in the development and growth of retinoblastoma and other types of tumors in different people.

A small percentage of retinoblastomas are caused by deletions in the region of chromosome 13 that contains the RB1 gene. Because these chromosomal changes involve several genes in addition to RB1, affected children usually also have intellectual disability, slow growth, and distinctive facial features (such as prominent eyebrows, a short nose with a broad nasal bridge, and ear abnormalities).

Normal Function

The RB1 gene provides instructions for making a protein called pRB. This protein acts as a tumor suppressor, which means that it regulates cell growth and keeps cells from dividing too fast or in an uncontrolled way. Under certain conditions, pRB stops other proteins from triggering DNA replication, the process by which DNA makes a copy of itself. Because DNA replication must occur before a cell can divide, tight regulation of this process controls cell division and helps prevent the growth of tumors. Additionally, pRB interacts with other proteins to influence cell survival, the self-destruction of cells (apoptosis), and the process by which cells mature to carry out special functions (differentiation).

Health Conditions Related to Genetic Changes

Retinoblastoma

Hundreds of mutations in the RB1 gene have been identified in people with retinoblastoma, a rare type of eye cancer that typically affects young children. This cancer develops in the retina, which is the specialized light-sensitive tissue at the back of the eye that detects light and color. Researchers estimate that 40 percent of all retinoblastomas are germinal, which means that RB1 mutations occur in all of the body's cells and can be passed to the next generation. The other 60 percent are non-germinal, which means that RB1 mutations occur only in the eye and cannot be passed to the next generation.

In germinal retinoblastoma, an RB1 mutation is present in all of the body's cells. For retinoblastoma to develop, the other copy of the RB1 gene also must be mutated or lost. This second mutation typically occurs early in life in retinal cells. Cells with two altered copies of the RB1 gene produce no functional pRB and are unable to regulate cell division effectively. As a result, retinal cells lacking functional pRB can divide uncontrollably to form cancerous tumors. Some studies suggest that additional genetic changes can influence the development of retinoblastoma; these changes may help explain variations in the development and growth of tumors in different people.

In people with germinal retinoblastoma, RB1 mutations increase the risk of several other cancers outside the eye. Specifically, these people are more likely to develop a cancer of the pineal gland in the brain (pinealoma), a type of bone cancer known as osteosarcoma, cancers of soft tissues such as muscle, and an aggressive form of skin cancer called melanoma.

Non-germinal retinoblastoma occurs in people with no history of the disorder in their family. Affected individuals are born with two normal copies of the RB1 gene. Then, usually in early childhood, both copies of the gene in retinal cells acquire mutations or are lost. These non-inherited genetic changes are known as somatic mutations. Somatic mutations in both copies of the RB1 gene prevent the cells from producing any functional pRB. The loss of this protein allows retinal cells to grow and divide without control or order, leading to the development of a cancerous tumor.

Bladder cancer

Somatic RB1 gene mutations have been identified in people with bladder cancer. These changes prevent pRB from regulating cell division effectively, leading to uncontrolled growth and division of affected cells and tumor formation.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Lung cancer

Somatic mutations in the RB1 gene have also been found in lung cancer. As in other forms of cancer, these genetic changes make the pRB protein ineffective, and cells can grow and divide without control, forming a tumor.

Other cancers

Somatic mutations in the RB1 gene are associated with many other types of cancer. In addition to the cancers listed above, changes in the RB1 gene have been reported in some cases of breast cancer, melanoma, and a bone cancer known as osteosarcoma. Somatic RB1 mutations have also been identified in some leukemias, which are cancers of blood-forming cells. Somatic RB1 mutations in cancer cells inactivate pRB so it can no longer regulate cell division effectively.

Other Names for This Gene

• p105-Rb
• PP110
• PPP1R130
• RB
• RB1 gene
• RB_HUMAN
• retinoblastoma 1
• Retinoblastoma 1 (including osteosarcoma)
• Retinoblastoma-1
• Retinoblastoma-associated protein

Genomic Location

Researchers estimate that one-third of all retinoblastomas are hereditary, which means that RB1 gene mutations are present in all of the body's cells, including reproductive cells (sperm or eggs). People with hereditary retinoblastoma may have a family history of the disease, and they are at risk of passing on the mutated RB1 gene to the next generation. The other two-thirds of retinoblastomas are non-hereditary, which means that RB1 gene mutations are present only in cells of the eye and cannot be passed to the next generation.

In hereditary retinoblastoma, mutations in the RB1 gene appear to be inherited in an autosomal dominant pattern. Autosomal dominant inheritance means that one copy of the altered gene in each cell is sufficient to increase the risk of cancer. A person with hereditary retinoblastoma may inherit an altered copy of the RB1 gene from one parent, or the altered gene may be the result of a new mutation that occurs in an egg or sperm cell or just after fertilization. For retinoblastoma to develop, a mutation involving the other copy of the RB1 gene must occur in retinal cells during the person's lifetime. This second mutation usually occurs in childhood, typically leading to the development of retinoblastoma in both eyes.

In the non-hereditary form of retinoblastoma, typically only one eye is affected and there is no family history of the disease. Affected individuals are born with two normal copies of the RB1 gene. Then, usually in early childhood, both copies of the RB1 gene in certain retinal cells acquire mutations. People with non-hereditary retinoblastoma are not at risk of passing these RB1 gene mutations to their children. However, without genetic testing it can be difficult to tell whether a person with retinoblastoma in one eye has the hereditary or the non-hereditary form of the disease.

Signs and symptoms of retinoblastoma include "white pupil" and eyes that appear to be looking in different directions (crossed eyes).

These and other signs and symptoms may be caused by retinoblastoma or by other conditions. Check with a doctor if your child has any of the following:

• Pupil of the eye that appears white instead of red when light shines into it. This may be seen in flash photographs of the child.

• Eyes that appear to be looking in different directions (crossed eyes).
• Pain or redness in the eye.
• Infection around the eye.
• Eyeball that is larger than normal.
• Colored part of the eye and pupil look cloudy.

Tests that examine the retina are used to diagnose retinoblastoma.

The following tests and procedures may be used:

• Physical exam and health history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken. The doctor will ask if there is a family history of retinoblastoma.
• Eye exam with dilated pupil: An exam of the eye in which the pupil is dilated (opened wider) with medicated eye drops to allow the doctor to look through the lens and pupil to the retina. The inside of the eye, including the retina and the optic nerve, is examined with a light. In young children, this exam may be done under anesthesia.

  There are several types of eye exams that are done with the pupil dilated:

  • Ophthalmoscopy: An exam of the inside of the back of the eye to check the retina and optic nerve using a small magnifying lens and a light.
  • Fluorescein angiography: A procedure to look at blood vessels and the flow of blood inside the eye. An orange fluorescent dye called fluorescein is injected into a blood vessel in the arm and goes into the bloodstream. As the dye travels through blood vessels of the eye, a special camera takes pictures of the retina and choroid to find any blood vessels that are blocked or leaking.
  • Electroretinography: An eye test that uses light and small electrodes to study the retina (the light-detecting part of the eye). This test measures and records the faint electrical signals given off by the cells in the retina when exposed to different types and amounts of light. It can be used to assess the function of the retina during and after treatment.
• RB1 gene test: A laboratory test in which a sample of blood or tissue is tested for a change in the RB1 gene.
• Ultrasound exam of the eye: A procedure in which high-energy sound waves (ultrasound) are bounced off the internal tissues of the eye to make echoes. Eye drops are used to numb the eye and a small probe that sends and receives sound waves is placed gently on the surface of the eye. The echoes make a picture of the inside of the eye and the distance from the cornea to the retina is measured. The picture, called a sonogram, shows on the screen of the ultrasound monitor. The picture can be printed to be looked at later.
• MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the eye. This procedure is also called nuclear magnetic resonance imaging (NMRI).

Retinoblastoma can usually be diagnosed without a biopsy.

When retinoblastoma is in one eye, it sometimes forms in the other eye. Exams of the unaffected eye are done until it is known that the retinoblastoma is the nonheritable form.

KEY POINTS

• After retinoblastoma has been diagnosed, tests are done to find out if cancer cells have spread within the eye or to other parts of the body.
• The International Retinoblastoma Staging System (IRSS) may be used for staging retinoblastoma.
  • Stage 0
  • Stage I
  • Stage II
  • Stage III
  • Stage IV
• There are three ways that cancer spreads in the body.
• Cancer may spread from where it began to other parts of the body.
• Treatment for retinoblastoma depends on whether it is intraocular (within the eye) or extraocular (outside the eye).
  • Intraocular retinoblastoma
  • Extraocular retinoblastoma (metastatic)
• Treatment for retinoblastoma also depends on whether the cancer has progressed or recurred.

After retinoblastoma has been diagnosed, tests are done to find out if cancer cells have spread within the eye or to other parts of the body.

The process used to find out if cancer has spread within the eye or to other parts of the body is called staging. The information gathered from the staging process determines whether retinoblastoma is only in the eye (intraocular) or has spread outside the eye (extraocular). It is important to know the stage in order to plan treatment. The results of the tests and procedures used to diagnose cancer are often also used to stage the disease.

The following tests and procedures may be used in the staging process:

• MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the brain. This procedure is also called nuclear magnetic resonance imaging (NMRI).
• Bone scan: A procedure to check if there are rapidly dividing cells, such as cancer cells, in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones with cancer and is detected by a scanner that also takes a picture of the body. Areas of bone with cancer show up brighter in the picture because they take up more radioactive material than normal bone cells do.

• Bone marrow aspiration and biopsy: The removal of bone marrow and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow under a microscope to look for signs of cancer. A bone marrow aspiration and biopsy is done if the doctor thinks the cancer has spread outside of the eye.

• Lumbar puncture: A procedure used to collect cerebrospinal fluid (CSF) from the spinal column. This is done by placing a needle between two bones in the spine and into the CSF around the spinal cord and removing a sample of the fluid. The sample of CSF is checked under a microscope for signs that the cancer has spread to the brain and spinal cord and sometimes it is also checked for a tumor marker called ganglioside GD2. This procedure is also called an LP or spinal tap.

The International Retinoblastoma Staging System (IRSS) may be used for staging retinoblastoma.

There are several staging systems for retinoblastoma. The IRSS stages are based on how much cancer remains after surgery to remove the tumor and whether the cancer has spread.

Stage 0

The tumor is in the eye only. The eye has not been removed and the tumor was treated without surgery.

Stage I

The tumor is in the eye only. The eye has been removed and no cancer cells remain.

Stage II

The tumor is in the eye only. The eye has been removed and cancer cells remain that can be seen only with a microscope.

Stage III

Stage III is divided into stage IIIa and stage IIIb:

• In stage IIIa, cancer has spread from the eye to tissues around the eye socket.
• In stage IIIb, cancer has spread from the eye to lymph nodes near the ear or in the neck.

Stage IV

Stage IV is divided into stage IVa and stage IVb:

• In stage IVa, cancer has spread to one or more parts of the body, such as the bone or liver.
• In stage IVb, cancer has spread to the brain or spinal cord. It also may have spread to other parts of the body.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

• Tissue. The cancer spreads from where it began by growing into nearby areas.
• Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
• Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

• Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
• Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if retinoblastoma spreads to the bone, the cancer cells in the bone are actually retinoblastoma cells. The disease is metastatic retinoblastoma, not bone cancer.

Treatment for retinoblastoma depends on whether it is intraocular (within the eye) or extraocular (outside the eye).

Intraocular retinoblastoma

In intraocular retinoblastoma, cancer is found in one or both eyes and may be in the retina only or may also be in other parts of the eye such as the choroid, ciliary body, or part of the optic nerve. Cancer has not spread to tissues around the outside of the eye or to other parts of the body.

Extraocular retinoblastoma (metastatic)

In extraocular retinoblastoma, cancer has spread beyond the eye. It may be found in tissues around the eye (orbital retinoblastoma), or it may have spread to the central nervous system (brain and spinal cord) or to other parts of the body such as the liver, bone, bone marrow, or lymph nodes.

Treatment for retinoblastoma also depends on whether the cancer has progressed or recurred.

Progressive retinoblastoma is cancer that continues to grow, spread or get worse. Progressive disease may be a sign that the cancer has become refractory to treatment.

Recurrent retinoblastoma is cancer that has recurred (come back) after it has been treated. The cancer may recur in the eye, in tissues around the eye, or in other places in the body, such as the liver, bone, bone marrow, or lymph nodes.

Treatment Option Overview

KEY POINTS

• There are different types of treatment for patients with retinoblastoma.
• Children with retinoblastoma should have their treatment planned by a team of health care providers who are experts in treating cancer in children.
• Six types of standard treatment are used:
  • Cryotherapy
  • Thermotherapy
  • Chemotherapy
  • Radiation therapy
  • High-dose chemotherapy with stem cell rescue
  • Surgery (enucleation)
• New types of treatment are being tested in clinical trials.
  • Targeted therapy
• Treatment for retinoblastoma may cause side effects.
• Patients may want to think about taking part in a clinical trial.
• Patients can enter clinical trials before, during, or after starting their cancer treatment.
• Follow-up tests may be needed.

There are different types of treatment for patients with retinoblastoma.

Different types of treatment are available for patients with retinoblastoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment.

Because cancer in children is rare, taking part in a clinical trial should be considered. Some clinical trials are open only to patients who have not started treatment.

Children with retinoblastoma should have their treatment planned by a team of health care providers who are experts in treating cancer in children.

The goals of treatment are to save the child's life, to save vision and the eye, and to prevent serious side effects. Treatment will be overseen by a pediatric oncologist, a doctor who specializes in treating children with cancer. The pediatric oncologist works with other health care providers who are experts in treating children with eye cancer and who specialize in certain areas of medicine. These may include a pediatric ophthalmologist (children's eye doctor) who has a lot of experience in treating retinoblastoma and the following specialists:

• Pediatric surgeon.
• Radiation oncologist.
• Pediatrician.
• Pediatric nurse specialist.
• Rehabilitation specialist.
• Social worker.
• Geneticist or genetic counselor.

Six types of standard treatment are used:

Cryotherapy

Cryotherapy is the use of extreme cold to destroy abnormal tissue. A small metal probe is cooled below freezing and placed on the surface of the eye near the tumor, which freezes and kills cancer cells. Cryotherapy is usually used to treat small retinoblastoma tumors that are located toward the front of the eye. This type of treatment is also called cryosurgery.

Thermotherapy

Thermotherapy is the use of heat to destroy cancer cells. Thermotherapy may be given using a laser beam aimed through the dilated pupil or onto the outside of the eyeball. Thermotherapy may be used alone for small tumors or combined with chemotherapy for larger tumors. This treatment is a type of laser therapy.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. The way the chemotherapy is given depends on the stage of the cancer and where the cancer is in the body.

There are different types of chemotherapy:

• Systemic chemotherapy: When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body. Systemic chemotherapy is given to shrink the tumor (chemoreduction) and avoid surgery to remove the eye. After chemoreduction, other treatments may include radiation therapy, cryotherapy, laser therapy, or regional chemotherapy. However, extraorbital disease requires intensive chemotherapy and may include consolidation with high-dose chemotherapy and autologous stem cell transplantation with or without radiation therapy.

  Systemic chemotherapy may also be given to kill any cancer cells that are left after the initial treatment or to kill cancer cells that are outside the eye. Treatment given after the initial treatment, to lower the risk that the cancer will come back, is called adjuvant therapy.

• Regional chemotherapy: When chemotherapy is placed directly into the cerebrospinal fluid (intrathecal chemotherapy), an organ (such as the eye), or a body cavity, the drugs mainly affect cancer cells in those areas. Several types of regional chemotherapy are used to treat retinoblastoma.
  • Ophthalmic artery infusion chemotherapy: Ophthalmic artery infusion chemotherapy carries anticancer drugs directly to the eye. A catheter is put into an artery that leads to the eye and the anticancer drug is given through the catheter. After the drug is given, a small balloon may be inserted into the artery to block it and keep most of the anticancer drug trapped near the tumor. This type of chemotherapy may be given as the initial treatment when the tumor is in the eye only or when the tumor has not responded to other types of treatment. Ophthalmic artery infusion chemotherapy is given at special retinoblastoma treatment centers.
  • Intravitreal chemotherapy: Intravitreal chemotherapy is the injection of anticancer drugs directly into the vitreous humor (jelly-like substance) inside of the eye. It is used to treat cancer that has spread to the vitreous humor and has not responded to treatment or has come back after treatment.
  • Intrathecal chemotherapy: Intrathecal chemotherapy is the injection of anticancer drugs directly into the cerebrospinal fluid (CSF). It is used to treat cancer that has spread to the brain.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy:

• External-beam radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.

  Certain ways of giving radiation therapy can help keep radiation from damaging nearby healthy tissue. These types of radiation therapy include the following:

  • Intensity-modulated radiation therapy (IMRT): IMRT is a type of 3-dimensional (3-D) external radiation therapy that uses a computer to make pictures of the size and shape of the tumor. Thin beams of radiation of different intensities (strengths) are aimed at the tumor from many angles.
  • Proton beam radiation therapy: Proton beam radiation therapy is a type of high-energy, external radiation therapy that uses streams of protons (tiny particles with a positive charge) to kill tumor cells. This type of treatment can lower the amount of radiation damage to healthy tissue near a tumor.
• Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. Certain ways of giving radiation therapy can help keep radiation from damaging nearby healthy tissue. This type of internal radiation therapy may include the following:
  • Plaque radiotherapy: Radioactive seeds are attached to one side of a disk, called a plaque, and placed directly on the outside wall of the eye near the tumor. The side of the plaque with the seeds on it faces the eyeball, aiming radiation at the tumor. The plaque helps protect other nearby tissue from the radiation.

Whether internal or external radiation therapy is given depends on the stage of the cancer being treated, where it is found in the body, and how the cancer responded to other treatments.

High-dose chemotherapy with stem cell rescue

High doses of chemotherapy are given to kill cancer cells. Healthy cells, including blood-forming cells, are also destroyed by the cancer treatment. Stem cell rescue is a treatment to replace the blood-forming cells. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient and are frozen and stored. After the patient completes chemotherapy, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells. Extraorbital disease requires intensive chemotherapy and may include consolidation with high-dose chemotherapy and autologous stem cell transplantation with or without radiation therapy.

Surgery (enucleation)

Enucleation is surgery to remove the eye and part of the optic nerve. A sample of the eye tissue that is removed will be checked under a microscope to see if there are any signs that the cancer is likely to spread to other parts of the body. This should be done by an experienced pathologist, who is familiar with retinoblastoma and other diseases of the eye. Enucleation is done if there is little or no chance that vision can be saved and when the tumor is large, did not respond to treatment, or comes back after treatment. The patient will be fitted for an artificial eye.

Close follow-up is needed for 2 years or more to check for signs of recurrence in the area around the affected eye and to check the other eye.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. Targeted therapies usually cause less harm to normal cells than chemotherapy or radiation therapy do.

• Oncolytic virus therapy: This treatment uses a virus that infects and breaks down cancer cells but not normal cells. An oncolytic adenovirus targeting the RB1 gene is injected into the tumor and may have anticancer effects in retinoblastoma. Targeted therapy is being studied for the treatment of retinoblastoma that has progressed or red.

Treatment for retinoblastoma may cause side effects.

For information about side effects that begin during treatment for cancer, see our Side Effects page.

Side effects from cancer treatment that begin after treatment and continue for months or years are called late effects. Late effects of treatment for retinoblastoma may include the following:

• Physical problems such as seeing or hearing problems.
• If the eye is removed, there may be changes in the shape and size of the bone around the eye until an artificial eye is fitted. This is most likely to occur in children aged younger than 3 years.
• Changes in mood, feelings, thinking, learning, or memory.
• Second cancers (new types of cancer), such as lung and bladder cancers, osteosarcoma, soft tissue sarcoma, or melanoma.

The following risk factors may increase the risk of having a second cancer:

• Having the heritable form of retinoblastoma.
• Past treatment with radiation therapy, especially before age 1 year.
• Having already had a previous second cancer.

It is important to talk with your child's doctors about the effects cancer treatment can have on your child. Regular follow-up by health professionals who are experts in diagnosing and treating late effects is important.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your child's condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

In retinoblastoma, new tumors may form for a few years after treatment. Regular eye exams are done to check for tumors in both eyes. Children with the heritable form of retinoblastoma will also have imaging tests to check whether cancer has spread to the brain.

Treatment of Unilateral, Bilateral, and Cavitary Retinoblastoma

If it is likely that the eye can be saved, treatment may include the following:

• Systemic chemotherapy or ophthalmic artery infusion chemotherapy, with or without intravitreal chemotherapy, to shrink the tumor. This may be followed by one or more of the following:
  • Cryotherapy.
  • Thermotherapy.
  • Plaque radiotherapy.
• External-beam radiation therapy for bilateral intraocular retinoblastoma that does not respond to other treatments.

If the tumor is large and it is not likely that the eye can be saved, treatment may include the following:

• Surgery (enucleation). After surgery, systemic chemotherapy may be given to lower the risk that the cancer will spread to other parts of the body.

When retinoblastoma is in both eyes, the treatment for each eye may be different, depending on the size of the tumor and whether it is likely that the eye can be saved. The dose of systemic chemotherapy is usually based on the eye that has more cancer.

Patients with cavitary retinoblastoma respond well to treatment and have favorable long-term outcomes, similar to patients with noncavitary retinoblastoma.

Treatment of Extraocular Retinoblastoma

Treatment of extraocular retinoblastoma (cancer has spread to the area around the eye) may include the following:

• Systemic chemotherapy and external-beam radiation therapy.
• Enucleation.
• Systemic chemotherapy followed by surgery (enucleation). External-beam radiation therapy and more chemotherapy may be given after surgery.

Treatment for extraocular retinoblastoma (cancer has spread to the brain) may include the following:

• Systemic or intrathecal chemotherapy and external-beam radiation therapy to the brain and spinal cord.
• Chemotherapy followed by high-dose chemotherapy with stem cell rescue with or without radiation therapy.

It is not clear whether treatment with chemotherapy, radiation therapy, or high-dose chemotherapy with stem cell rescue helps patients with extraocular retinoblastoma live longer.

For trilateral retinoblastoma (retinoblastoma and a brain tumor that occur at the same time), treatment may include the following:

• Systemic chemotherapy followed by surgery and high-dose chemotherapy with stem cell rescue.
• Systemic chemotherapy followed by surgery and external-beam radiation therapy.

For retinoblastoma that has spread to other parts of the body, but not the brain, treatment may include the following:

• Systemic chemotherapy followed by high-dose chemotherapy with stem cell rescue and external-beam radiation therapy.

Treatment of Progressive or Recurrent Retinoblastoma

Treatment of progressive or recurrent intraocular retinoblastoma may include the following:

• External-beam radiation therapy or plaque radiotherapy.
• Cryotherapy.
• Thermotherapy.
• Systemic chemotherapy or ophthalmic artery infusion chemotherapy.
• Intravitreal chemotherapy.
• Surgery (enucleation).
• A clinical trial of targeted therapy with an oncolytic virus that targets the RB1 gene and is injected into the tumor.
• A clinical trial that checks a sample of the patient's tumor for certain gene changes. The type of targeted therapy that will be given to the patient depends on the type of gene change.

Treatment of progressive or recurrent extraocular retinoblastoma may include the following:

• Systemic chemotherapy and external-beam radiation therapy for retinoblastoma that comes back after surgery to remove the eye.
• Systemic chemotherapy followed by high-dose chemotherapy with stem cell rescue and external-beam radiation therapy.
• A clinical trial that checks a sample of the patient's tumor for certain gene changes. The type of targeted therapy that will be given to the patient depends on the type of gene change.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on the following:

• Whether the cancer is in one or both eyes.
• The size and number of tumors.
• Whether the tumor has spread to the area around the eye, to the brain, or to other parts of the body.
• The age of the child.
• How likely it is that vision can be saved in one or both eyes.
• Whether a second type of cancer has formed.
• Whether the cancer is newly diagnosed or has recurred (come back).