Treatment

Non-Hodgkin's Lymphoma

Adults

Non-Hodgkin’s lymphoma (NHL) often responds very well to modern treatments. This does not mean that it is always curable, but it does mean that treatment can often provide long cancer-free periods, reduced symptoms and improved quality of life for many patients. Certain types of NHL often remain dormant for long periods of time and require little or no treatment, while other types of NHL require immediate treatment. Response to treatment depends on the type of NHL and stage/grade of the disease.

Treatment, Side Effects and Medications

Types of treatment

There are six main treatment types of NHL, used on their own or in combination. These treatment types include:

• Surgery
• Radiation
• Chemotherapy
• Biologic therapies
• Transplantation
• Watchful waiting (also called watch and wait).

Each type of treatment is described in further detail in the sections and Web pages that follow.

Surgery

Surgery may be an option for many cancers, if the cancer appears localized (confined to one area). During surgery the cancerous area may be removed along with any surrounding tissue that might contain cancer cells. At times your surgeon may not be able to determine how much of an area has to be removed until the surgery is in progress.

Radiation

Radiation is used in specific areas to destroy cancer cells so they will not continue to spread. Unlike chemotherapy, which is a systemic (affects the whole body) therapy, radiation therapy is a localized therapy meaning that it only treats the area of the body where the cancer is located. Radiation treatment is frequently used in addition to surgery or chemotherapy, and is usually applied in lymphoma through external high-energy ray beam or radioactive isotopes. Not all types of lymphoma respond to radiation treatment, therefore it will be up to your healthcare professional to determine if radiation is appropriate in your situation.

External radiation treatment is similar to having an x-ray. The treatment appointment usually lasts several minutes, and in lymphoma a complete course of treatment is typically five days a week for four to five weeks in an outpatient setting depending on the cancer size, type and location.

As with all treatments, side effects vary from patient to patient and depend upon the part of the body treated and the amount of radiation used.

How does radiation therapy work?

Radiation therapy (also called radiation or radiotherapy) uses high-energy x-rays to kill cancer cells. The x-rays cause damage to the cell’s DNA (the genetic material of the cell) which makes it impossible for the cancer cell to repair itself, ultimately causing the cell to die. The radiation does not decipher between cancerous and non-cancerous cells and, therefore, healthy cells in the area will be killed off as well. Care is always taken to plan the treatment properly and ensure that other areas of the body are affected as little as possible. Normal cells affected by the radiation have a greater capacity to heal themselves than the lymphoma cells.

How is radiation therapy given?

A radiation field is the area of the body marked to receive the radiation therapy. To clearly outline the radiation field the skin is marked with tiny ink dots called tattoos. This ensures that the appropriate area is targeted for the radiation and that the exact same area is treated each time. Radiation is usually confined to lymph nodes or the area immediately surrounding the lymph nodes. The radiation field is different in each person and depends on many factors including the type of lymphoma and the extent of the disease. Healthy areas are shielded from the radiation with lead shields similar to the ones you wear at the dentist when receiving an x-ray. Lead blocks the path of any stray radiation beams and prevents them from affecting the DNA of normal cells. 

 

Radiation Fields

At the beginning of your treatment you may attend a session called planning. You will be in a room with a technician, a nurse and one or two doctors. Other than the fact that there will be no radioactive source in the room, the planning session will be very similar to what will happen when you receive your radiation therapy. For this reason it is often called a simulation.

Prior to the radiation treatment, you will be carefully positioned on a treatment table, with the parts of the body not being treated protected. You must lie completely still during the treatment. Often a mould is created or certain props such as pillows or rolled blankets are used to minimize movement. Above the treatment table is the large machine which delivers the radiation. The actual treatment lasts only for a few minutes and causes no pain or discomfort.

Radiation therapy is most often given on an outpatient basis. You may have to visit the hospital as many as five times per week during a course of radiation therapy. The total dose deemed appropriate for you is divided up and given over a period of one to six weeks. Each dose of radiation is called a fraction and the radiation oncologist prescribes a total number of fractions for your specific treatment.

What are the side effects of radiation therapy?

Although the radiation treatments are painless, there may be some associated side effects. The side effects are usually limited to the area of the body receiving the radiation and may vary based on the targeted site. The most common side effects are listed here followed by helpful coping suggestions.

Targeted Area	Possible Side Effects
Head and neck (areas affected can include the scalp, mouth and throat)	Hair loss (on the scalp or anywhere the radiation is targeted) Loss of appetite and taste Dry mouth Throat irritation Skin reactions
Chest (areas affected can include the esophagus and breasts)	Difficulty swallowing
Abdomen	Nausea Diarrhea

Hair Loss

What is it?

Hair loss from radiation is not like the general hair loss that occurs with chemotherapy. It involves only a patch of hair loss that occurs depending on the area of the body that receives the radiation. If the radiation was targeted at the head, a patch of hair loss may occur on the head. If the radiation was targeted at a specific lymph node in the groin area, there may be a loss of hair in the groin region. The hair loss is usually temporary; however, with high doses of radiation it may be permanent.

What can I do?

Here are some tips for minimizing and coping with hair loss:

• Pat your hair dry rather than rubbing it vigorously with a towel.
• Avoid hair dryers, curling or straightening irons.
• Avoid dying your hair or using other chemicals.
• Wear a hat when exposed to the sun, as areas of hair loss are very susceptible to sun damage.
• Consider wearing a hat, wig, scarf, turban or head wrap if it makes you feel better.
• You may require special shampoos or soaps. You can ask your radiation oncologist if these would be helpful for you.

Loss of Appetite and Taste

What is it?

Following radiation therapy you may find that foods you previously enjoyed no longer appeal to you. You may also not feel as hungry as you normally do.

What can I do?

It is very important to try to eat to keep your energy up and nutrition status optimal. It may help to eat smaller, more frequent meals throughout the day. You may find your appetite and taste improve if you can avoid strong odours and food preparation, and eat cold food instead of hot. Even though food is unappetizing, it is still very important to stay hydrated by consuming fluids, and trying to eat healthy foods to stay strong.

Dry Mouth and Throat Irritation

What is it?

After radiation therapy in the area of the mouth, saliva production may be decreased and patients may experience a dry mouth, also called xerostomia. Throat irritation may also occur from the decreased saliva or direct effects from radiation to that area.

What can I do?

Drink lots of fluids to keep your mouth as moist as possible. Saliva is important for fighting cavities so it may be necessary to use extra oral hygiene such as brushing your teeth after each meal and flossing (use caution with flossing if your blood cell counts are low). Your doctor may recommend you visit your dentist prior to receiving radiation treatments. Warm, gentle mouthwashes (non-alcohol based) may help refresh the area and decrease irritation. Eating foods that are more easily digested (soft foods or liquid dietary supplements) may be easier on your throat. Eating smaller meals and avoiding acidic foods like citrus fruits and citrus juices may also help.

For more information on this topic, please see this article.

Skin Reactions

What is it?

The area of skin that was exposed to the radiation may become red, irritated, itchy and flaky. Moist areas like the mouth may be more severely affected and may require treatment. It often looks and feels as though the area is sunburned and the skin may begin peeling. The skin reactions are usually short-lived and diminish over a few weeks.

What can I do?

It is important to protect these areas of skin from further damage. They should not be exposed to the sun, and should always be protected with sunscreen, even once the radiation therapy has finished. During treatment, your doctor may prescribe an alcohol-free, fragrance-free lotion or cream to apply to the affected area.

Difficulty Swallowing

What is it?

You may experience difficulty swallowing due to a dry mouth, or because the radiation has affected the esophagus which is involved in swallowing.

What can I do?

Staying hydrated and keeping the tissues in your mouth and throat as moist as possible may help. Eating softer, more digestible foods will cause less pain on swallowing and are easier to move through the digestive system. Healthy shakes and nutritious soups are good choices. Eating smaller meals more frequently may help ease the irritation.

Nausea

What is it?

Radiation therapy targeted towards the abdomen can sometimes cause nausea (the urge to vomit). The nausea may occur after the first radiation treatment.

What can I do?

Not eating in the few hours prior to your radiation treatment may help. Scheduling your treatments towards the end of the day may be helpful, so if you do feel nauseous, you can deal with it at home. Your doctor may prescribe an antiemetic (a drug that prevents vomiting) or antinauseant (a drug that prevents nausea) to be taken prior to the radiation treatment. If you experience nausea, the following are some ways to keep it under control:

• Consume mostly liquids leading up to your radiation treatment, including soups such as broths or consommés (avoid milk-based soups).
• Avoid foods that are too hot, cold, sweet or spicy, especially right before your treatment.
• Eat smaller meals more frequently throughout the day instead of three large meals.
• Get plenty of fresh air and try to avoid strong or unpleasant odours.
• Take the medication prescribed by your doctor.
• If you do experience vomiting, be sure to stay hydrated (see the tips in the Diarrhea section).

Diarrhea

What is it?

Frequent and watery bowel movements.

What can I do?

The most important consequence of diarrhea is dehydration (a loss of body fluids). To avoid dehydration, the following tips may be useful:

• Drink plenty of water throughout the day.
• Avoid milk products as they may worsen diarrhea.
• Pay attention to the signs of dehydration: dry mouth or skin, decreased urination, and dizziness or lightheadedness upon standing.
• Take the medications your doctor recommends for controlling your diarrhea.

Are there long-term side effects with radiation therapy?

It is possible for radiation to cause long-term side effects. The following table outlines the possible consequences of radiation given to different areas of the body. It is important to discuss these risks with your doctor if you feel concerned.

Treatment Area	Possible Long-Term Effect	What You Can Do
Pelvis or groin	Infertility	Ensure that the testes/ovaries are shielded from radiation if they are not the target of the treatment. If you have not yet had children, talk to your doctor about the risks associated with having children after radiation therapy.
Chest and breasts	Breast cancer	Long-term breast cancer screening is very important.
Skin	Skin cancer	Long-term skin cancer screening is very important. Protect your skin from the sun by using sunscreen and minimizing exposure.
Neck	Thyroid cancer	Discuss the risks with your doctor and have your thyroid checked on a regular basis.

Chemotherapy

Chemotherapy is the use of powerful anticancer drugs that are carried through the body in the bloodstream. It works by preventing lymphoma cells from multiplying and by removing or reducing the number of cancerous cells in the body. Chemotherapy may be taken by mouth or injected into a vein, and is often chosen when cancer is present in different parts of the body. Often, a combination of drugs is prescribed to improve the chances for success. After a round of chemotherapy drugs are administered, the patient will undergo a recovery period. This cycle allows the body to rest. Then another round of drugs is administered. The total course for chemotherapy may range from three to nine months. Depending on the type of cancer, chemotherapy may be effective after surgery in preventing the cancer from returning. Depending on the type of cancer and its stage, chemotherapy may be used as a cure, to prevent spreading, slow growth, kill cancerous cells that may have spread to other parts of the body, or relieve symptoms.

As with all treatments, side effects vary from patient to patient and depend upon the degree and duration of treatment. Ask your doctor for more information on managing chemotherapy-related side effects.

How does chemotherapy work?

Chemotherapy is a systemic therapy (affecting the whole body) that targets and kills rapidly dividing cells in the body, such as cancer cells. There are normal cells in the body which are rapidly dividing as well, and chemotherapy may damage these healthy cells. This is why chemotherapy can have side effects including hair loss, diarrhea, nausea and vomiting. Not all patients experience side effects from chemotherapy; if side effects do occur they can often be mild and treated effectively. Ask you doctor for more information on managing chemotherapy-related side effects.

Chemotherapy drugs work on the premise that cancer cells are always dividing and that normal cells, even those that have a fast turnover rate, are most often found in the resting (non-dividing) state in the body, dividing only when necessary. Chemotherapy tries to exploit this difference between normal and cancerous cells, aiming to preferentially attack tumour cells as they divide.

 

How chemotherapy works

What are the different types of chemotherapy?

There are many different ways of attacking rapidly dividing cells and hence, many different types of chemotherapy. Some types of chemotherapy drugs interact with receptors on the surface of cancer cells, some damage cell structures necessary for cell division and some directly target the cancer cell’s DNA, the genetic material of the cell.

Because these are all different ways of achieving the same result—death of the cancer cells—chemotherapy drugs are often given in combination in order to attack the lymphoma cells from all possible angles to increase the odds of achieving remission.

Chemotherapy combinations are often known by the initials of the names of the drugs in the combination. Two of the most common combinations used in NHL are called CHOP and CVP. CHOP is a combination of four drugs, namely, three chemotherapy medications and one steroid medication:

• Cyclophosphamide
• Doxorubicin (also called Hydroxydaunorubicin)
• Vincristine (also called Oncovin)
• Prednisone (the steroid medication).

CVP is a combination of two chemotherapy drugs and a steroid:

• Cyclophosphamide
• Vincristine (also called Oncovin)
• Prednisone (the steroid medication).

Steroid medications are included in these regimens as they are effective therapies for lymphoma and can quickly get NHL symptoms under control.

The type of chemotherapy a patient with NHL receives depends on a number of variables, including:

• The type of NHL
• The grade of NHL (whether the NHL is indolent or aggressive)
• The stage of NHL
• Whether it’s the first NHL treatment for the patient or if the NHL has relapsed following prior therapy
• The symptoms the patient is experiencing
• The overall health of the patient including age, medical history and vitality (often referred to as the performance status of the patient)
• The recommendations of the medical oncologist
• The choice and participation of the patient in the treatment decision process.

How is chemotherapy given?

Each dose of chemotherapy kills only a percentage of cancer cells. Chemotherapy is, therefore, often given in multiple treatments in order to destroy as many cancer cells as possible. Treatments are scheduled as frequently as possible to minimize the growth of the tumour and achieve the best possible outcome.

Chemotherapy is often given in cycles where the treatment is given for a period of time (e.g., every three weeks) followed by a rest period where no treatment is given. The rest period allows the healthy cells to recover. Together each period of treatment and rest is called a chemotherapy cycle. A full course of chemotherapy (the number of chemotherapy cycles given in total, e.g., six cycles) often takes several months. Most chemotherapy treatments can be given in an outpatient clinic, so patients can go home the same day.

Chemotherapy may be given in different forms: pills, injections or intravenous administration (administered directly into the bloodstream over a period of time through a needle). If you are going to be receiving multiple cycles of intravenous chemotherapy, your doctor may recommend having a venous catheter inserted. A venous catheter is a device, usually a flexible tube that is inserted into a vein for easier administration of intravenous drugs. A central line is a more permanent catheter that is usually inserted into a vein at the top of the chest. Both central lines and venous catheters can be left in place so you will not require a new needle with each intravenous treatment. As well, both central lines and venous catheters may be used to transfuse blood products into a patient or to easily remove blood for blood tests.

A cancer is often defined as chemosensitive or chemoresistant. Chemosensitive means that the tumour is responsive to chemotherapy and the chemotherapy treatment is effective in killing the cancer cells, whereas chemoresistant means that the tumour does not respond to chemotherapy and an alternate treatment is required.

Can the dose be reduced if I have a lot of side effects?

It is very important to try to maintain the highest tolerable dose during chemotherapy treatment. Studies have shown that reducing the dose or delaying chemotherapy treatments until side effects subside may decrease the likelihood of cure and the chances for long-term survival in some types of lymphomas. It is important for you as a patient to understand that changing the regimen to reduce short-term side effects may actually be harmful in the long run. However, your present quality of life is valuable as well, and you need to decide whether the side effects are tolerable or not. It is important to make this decision in an informed way and understand the potential consequences of your choice.

What are the side effects of chemotherapy?

Many people are frightened by the side effects of chemotherapy. However, it is important to understand that:

• Not all patients who receive chemotherapy experience side effects;
• Side effects are not always severe, they can be mild;
• Different chemotherapy drugs have different side effects;
• Doctors are familiar with chemotherapy side effects and can treat them so they are less severe and, sometimes, even prevent them from happening altogether.

Many of the side effects caused by chemotherapy are due to the effect the medications have on the healthy, non-cancerous cells of the body. The following table outlines the most common cell types affected as a result of chemotherapy, as well as the resulting side effects.

Cells Affected	Associated Side Effects
Cells of the digestive system including the mouth, esophagus, stomach and intestines	Mouth sores Sore throat Diarrhea Nausea Vomiting Changes in taste Loss of appetite
Cells of the skin and hair	Hair loss
Cells of the bone marrow; red blood cells, white blood cells and platelets	Decreased blood cell production (myelosuppression), including: Anemia (decrease in red blood cells) Neutropenia (decrease in white blood cells) Thrombocytopenia (decrease in platelets)

Mouth Sores and Sore Throat

What is it?

Mouth sores occur when the inside of your mouth becomes red, sore and irritated. It is often called mucositis. Your throat may also be sore. Infections of the mouth and throat may occur. If you have a persistently sore mouth or throat you should tell your doctor.

What can I do?

There are a number of things you and your doctor can do to prevent and treat mouth sores:

• Clean your teeth gently after each meal with a soft, nonabrasive toothbrush.
• Use lip moisturizer to avoid dry, irritated lips.
• Avoid mouthwashes that contain alcohol.
• Avoid citrus fruits, citrus juices and spicy foods.
• Rinse your mouth frequently with a salt and water combination or club soda (an easy-to-use salt and water combination).
• Eat softer foods so they are easier on the moist tissues of your mouth.
• Avoid flossing your teeth if your blood cell counts are low.

Diarrhea

What is it?

Frequent and watery bowel movements.

What can I do?

The most important consequence of diarrhea is dehydration (loss of body fluids). To avoid dehydration, the following tips may be useful:

• Drink plenty of water throughout the day.
• Avoid milk products as they may worsen your diarrhea.
• Pay attention to the signs of dehydration: dry mouth or skin, decreased urination, and dizziness or lightheadedness upon standing.
• Take the medications your doctor recommends for controlling diarrhea.

Nausea and Vomiting

What is it?

Chemotherapy can often be associated with both nausea (the urge to vomit) and vomiting. Nausea most commonly occurs on the day you receive the chemotherapy but can also occur in the few days following treatment.

What can I do?

Your doctor may prescribe an antiemetic (a drug that prevents vomiting) or an antinauseant (a drug that prevents nausea) to take before you begin chemotherapy. This can often prevent both the nausea and vomiting from occurring. If you do experience these symptoms, the following are ways to control them:

• Consume mostly liquids for the first one to two days after your chemotherapy treatment (returning to solid foods once the feeling has subsided); soups are a good choice including broths or consommés; however, avoid milk-based soups.
• Avoid foods that are too hot, sweet or spicy.
• Eat smaller meals more frequently throughout the day instead of three large meals.
• Get plenty of fresh air and try to avoid strong or unpleasant odours.
• If you do experience vomiting, be sure to stay hydrated (see the tips in the diarrhea section).
• Take the antiemetic/antinauseant medication prescribed by your doctor.

Changes in Taste

What is it?

Chemotherapy can often alter the taste of foods. Familiar foods can taste different (called dysgeusia) or food flavours can taste less intense than normal (hypogeusia). Taste changes are usually temporary and disappear once your chemotherapy treatment is completed.

What can I do?

Certain foods may be more appealing than others; if foods are not appetizing they may need to be avoided for a period of time and then gradually re-introduced. Keeping your mouth fresh and clean and frequently rinsed may help.

Loss of Appetite

What is it?

Loss of appetite is a common side effect of chemotherapy. It may be a result of other symptoms, such as nausea, vomiting or taste alterations.

What can I do?

It may help to eat smaller, more frequent meals throughout the day. You may find this symptom improves if strong odours are avoided, if you avoid food preparation and if you eat cold food instead of hot. Even though food is unappetizing, it is still very important to stay hydrated by consuming fluids and trying to eat healthy foods to stay strong.

Hair Loss

What is it?

Hair loss, also called alopecia, is a common side effect of chemotherapy and can affect the hair of the scalp, eyebrows, eyelashes, arms, legs and pelvic region. It affects different people in different ways. Some people may lose all their hair and some may only experience thinning of their hair. Hair loss or thinning usually begins gradually, within two to three weeks of your first chemotherapy treatment. This can be a very distressing side effect for patients. However, not everyone experiences hair loss and most people have a normal amount of hair within six months after their final chemotherapy treatment.

What can I do?

Here are some tips for minimizing and coping with hair loss:

• Pat your head dry rather than rubbing it vigorously with a towel.
• Avoid hair dryers, curling or straightening irons.
• Avoid dying your hair or using other chemicals.
• Wear a hat when exposed to the sun as areas of hair loss are very susceptible to sun damage.
• Consider wearing a hat, wig, scarf, turban or head wrap if it makes you feel better.

Decreased Blood Cell Production

What is it?

Blood cells, including red blood cells, white bloods cells and platelets, are continually being produced in the bone marrow. Because these cells are always dividing, they are also targeted by chemotherapy and, therefore, the number of all blood cells can be reduced. This is called myelosuppression. There are different types of myelosuppression depending on which blood cell is affected. They are anemia, neutropenia and thrombocytopenia.

Anemia is the term used to describe a decrease in the number of red blood cells, the oxygen carrying cells in the blood. Anemia can often cause patients to feel tired and lethargic and may require treatment if severe. Sometimes patients are prescribed injections to help stimulate the growth and production of red blood cells and decrease the side effects of anemia. Occasionally, blood transfusions are required for more severe anemia, especially when the bone marrow has been affected by the lymphoma.

Neutropenia occurs when there is a decrease in the number of neutrophils, a certain type of white blood cell. Neutrophils are very important for fighting infection. When there are too few, patients are more at risk for developing serious infections. If the neutropenia is severe, the chemotherapy may have to be delayed or the dosage reduced, as the risk of infection is serious. Sometimes patients with neutropenia are prescribed antibiotics to help fight off any possible infections. Injections may also be required on a routine basis to stimulate the growth and production of white blood cells and decrease the side effects of neutropenia.

Thrombocytopenia is the term used to describe a decrease in the number of platelets, cells that are very important for blood clotting. If platelet counts are low, a patient may experience increased bruising or excessive bleeding from cuts, nosebleeds and bleeding gums. Treatment may be needed if the thrombocytopenia is severe, with the usual treatment being a blood transfusion. Avoidance of blood-thinning medications (e.g., aspirin or anti-inflammatory drugs) may also be recommended.

What can I do?

The most important thing you can do is be alert for signs of myelosuppression. Signs of anemia include fatigue and lethargy. Signs of neutropenia include symptoms like fever, sore throat, rash, diarrhea, or redness, pain or swelling around a wound. Signs of thrombocytopenia include easy bruising or prolonged bleeding. If you notice these symptoms, inform your doctor immediately so appropriate action can be taken.

Fatigue

What is it?

Fatigue, or tiredness, is a common side effect of chemotherapy and usually goes away shortly after the treatment is complete. Severe fatigue can be a symptom of anemia and should be mentioned to your doctor. Fatigue is usually due to the strong chemotherapy medications and their effects on your body. It can also be due to the cumulative effects of many chemotherapy cycles, even those involving weaker chemotherapy drugs.

What can I do?

Some ideas about handling fatigue include:

• Keeping a diary to help you keep track of the times of day when you feel most tired. This can help you plan activities according to how you are feeling, that is to say rest when you need to and use the time when you’re not tired to go about your daily activities;
• Asking friends and family for help;
• Exercising when you have the energy and as long as your doctor says it’s all right to do so. Yoga, stretching and short walks can increase your energy and improve your overall vitality. Start slowly and build up your endurance to a comfortable range;
• Getting the rest and sleep you need while receiving chemotherapy. It may be important to take time off work and adjust your daily schedule to accommodate for rest and recuperation. Try not to rest more than necessary, as this can sometimes make you feel even more fatigued.

Biologic Therapies

Biologic therapy (also called biologic response modifier therapy or immunotherapy) uses the body’s immune system to fight the cancer or reduce some of the side effects of other cancer treatments. This may be done by helping to repair healthy cells damaged by the cancer thus helping these healthy cells to control the cancer, or by interfering with cancer cell growth. Terms such as interferons, interleukins, and tumour necrosis factor all refer to biologic therapy and more than one type may be used alone or in combination with chemotherapy or radiation treatment.

Types of biologic therapies include:

• Monoclonal antibody therapy
• Radioimmunotherapy
• Interferons
• Vaccines (under clinical investigation)
• Anti-angiogenesis therapies (under clinical investigation)
• Gene therapies (under clinical investigation).

Monoclonal Antibodies

Monoclonal antibodies are becoming increasingly available and can be effective in fighting very specific types of cancer. A healthy body normally produces antibodies to fight infection. Medical research has allowed us to now duplicate these antibodies in laboratories; however, instead of attacking germs, these monoclonal antibodies can be programmed to attack lymphoma cells.

The word monoclonal comes from the terms mono (meaning one) and clonal (meaning a clone of). Thus monoclonal antibodies mean antibodies that are all clones of a single cell and they are all identical. This is important because when the body sends them out to hunt for cancer cells they all behave the same way.

Monoclonal Antibody Therapy

The development of monoclonal antibodies has been one of the most significant advances in the treatment of NHL. Monoclonal antibodies are a more specific therapy than chemotherapy, meaning that they are directed at a target that is primarily located on tumour cells, as opposed to normal body cells. Not only does this make for very effective cancer treatment, it also greatly minimizes the side effects, as normal cells are minimally affected. A monoclonal antibody can be compared to a guided missile that identifies an exact target and kills it.

Monoclonal antibodies come in various different types. Currently in Canada, rituximab (Rituxan^®), ibritumomab tiuxetan (Zevalin^®) and tositumomab (Bexxar^®) are monoclonal antibodies approved to treat NHL. Others are under investigation.

Rituximab, for example, is a chimeric antibody which means it is part mouse and part human antibody. Murine monoclonal antibodies are fully mouse derived. Humanized antibodies are ones that were part mouse to start with, but have been fully converted to human. Then there are fully human antibodies which were entirely human from the start. There is also research being done into primatized (ape) antibodies.

How do monoclonal antibodies work?

All cells have certain protein markers on their surface called antigens. Monoclonal antibodies are specifically manufactured in a laboratory to recognize one type of antigen. For NHL, the monoclonal antibodies are specifically targeted to antigens found on lymphocytes, the normal body cell that lymphomas are derived from. The attachment of the monoclonal antibody to its target antigen triggers the cell to destroy itself and signals to the body’s immune system to attack and kill the cancer cell.

The most common antigen that they seek is called CD20. CD20 is found on most lymphoma B-cells and on many normal B-cells as well. This makes it an ideal target for an antibody based treatment. However there is also a lot of research happening using monoclonal antibodies that target the CD22, CD30, CD40, CD52 and CD80 antigens.

Rituximab

Rituximab is a monoclonal antibody that tightly attaches itself to the CD20 antigen on the surface of B-cells, the cancerous cell in many types of NHL. The CD20 antigen is also present on the surface of healthy, non-cancerous B-cells, which means that rituximab will also attach to and facilitate the destruction of these cells. However, normal B-cells, like all blood cells, are produced in the bone marrow from stem cells, and the stem cells do not have the CD20 antigen, meaning that they are not affected by monoclonal antibodies and are not destroyed. Stem cells can then replenish the store of healthy B-cells in the body. So although during treatment with rituximab the number of mature, normal B-cells is temporarily reduced, their levels return to normal once the treatment is completed.

Rituximab is a commonly used treatment for patients with either indolent or aggressive NHL. It is used on its own or in combination with chemotherapy and has been shown to increase the length of remission in indolent (slow-growing) NHL. It can also increase a patient’s chance of cure in aggressive (fast-growing) NHL.

Monoclonal antibodies can also be combined with radiation therapy which delivers a dose of radiation directly to the lymphoma cell. These are called radioimmunotherapies and are discussed in the section titled Radioimmunotherapy.

 

Monoclonal antibody therapy

How is the monoclonal antibody rituximab given?

Rituximab is given intravenously and can be given alone or in combination with chemotherapy, often increasing the effectiveness of chemotherapy treatments. Medications to prevent side effects are given prior to the monoclonal antibody treatment. If side effects occur the treatment can be given at a slower infusion rate or stopped until the side effects pass.

When given on its own rituximab is usually given as four weekly treatments over a 22-day period. When given in combination with chemotherapy, one dose of rituximab is administered with each cycle of treatment.

Rituximab Maintenance Therapy

Prolonged treatment with rituximab, called rituximab maintenance therapy, is used to treat patients with follicular NHL who have responded to their initial treatment. This means that patients who have received treatment for follicular lymphoma and have achieved remission (complete or partial remission) may benefit from prolonged administration with rituximab (generally administered every three months for a period of two years). Rituximab maintenance therapy has been shown to sustain the response obtained from the initial therapy and may improve survival for patients with follicular lymphoma. Ask your doctor for more information about rituximab maintenance therapy. Here is one study on the topic.

Phase III study showed first-line maintenance use of MabThera doubles likelihood of people with follicular lymphoma living without their disease worsening

Rituximab funding by province

The following links explain the funding policies for Rituximab treatment by province.

British Columbia Rituxan funding guidelines

Ontario Rituxan funding guidelines

Are there side effects from rituximab monoclonal antibody therapy?

Unlike the side effects associated with chemotherapy and radiation, most of the side effects from rituximab treatment are minor and short-lived, lasting only during the actual treatment and for a few hours afterwards. The chances of experiencing side effects also decrease with each treatment received because the patient adjusts to the treatment and, as treatment continues, there are fewer lymphoma cells to kill. The most common side effects are flu-like symptoms including fever, chills and sweating. Less common side effects include nausea, vomiting, rashes, fatigue, headache, wheezing, infection, and a sensation of tongue or throat swelling. Patients are monitored throughout the treatment session for signs of allergic reactions including itching, rashes, wheezing and swelling. If these symptoms occur, the treatment is slowed down or stopped for a short time until the symptoms subside. Antihistamines (e.g., Benadryl) and acetaminophen are commonly given before treatment to avoid allergic reactions.

Radioimmunotherapy

Radioimmunotherapy uses both radiation therapy and monoclonal antibody therapy to fight lymphoma. A radioactive molecule (a molecule that emits radiation and is capable of killing cancer cells) is attached to a monoclonal antibody so that the radiation is delivered specifically to lymphoma cells. It uses the effective targeting mechanism of the monoclonal antibody and the cancer-killing effect of radiation. This has the benefit of delivering deadly radiation to the cells near the antibody even if there is no antibody attached to it.

Two radioimmunotherapy agents are currently available in Canada for the treatment of NHL. These agents, called ibritumomab tiuxetan (Zevalin^®) and tositumomab (Bexxar^®), target the CD20 antigen on B-cells. They are commonly given to patients with relapsed indolent NHL who are no longer responding to conventional chemotherapy or monoclonal antibody treatment with rituximab.

How does radioimmunotherapy work?

Radioimmunotherapy uses monoclonal antibodies that have radioactive materials attached to them. These radioactive monoclonal antibodies circulate in the body until they find their target—the CD20 antigen of the B-cell (a protein found specifically on B-cells)—and attach themselves there. Once attached, the radiation kills the cancerous B-cell as well as any other lymphoma cells that are nearby.

How are radioimmunotherapies given?

Radioimmunotherapies are administered intravenously in the nuclear medicine clinic at the hospital under the supervision of a doctor who is specially trained and experienced with the safe use and handling of radioisotopes. A nurse or technician will assist the doctor and stay with you during treatment.

Other treatment team members may include:

• Treatment team hematologist: A doctor who specializes in diseases of the blood, like NHL.
• Oncologist: A doctor who specializes in treating cancer.
• Oncology nurse: A specialist who will teach you about treatment and assist with your care.
• Nuclear medicine physician: A doctor trained in radiation therapy who will decide your individual dose of the radioactive part of treatment. The nuclear medicine physician may also serve as the radiation safety officer for the treatment centre.
• Nuclear medicine technologist: A specialist who assists the nuclear medicine physician. This person may administer the radioactive part of therapy and perform the imaging procedures.
• Radiation oncologist: A doctor who uses radiation to treat cancer.
• Hospital pharmacist: A pharmacy specialist who may prepare the non-radioactive part of treatment.
• Radiopharmacist: The specialist who prepares the radioactive antibody.
• Radiation safety officer: An official at the hospital or treatment centre who knows the rules for using radioactive substances. This person will also decide if you will be able to go home right after treatment.

What are the benefits of using radioimmunotherapy to treat NHL?

Possible benefits of radioimmunotherapy for NHL include:

• Enhanced antitumour activity that may result from the targeted delivery of radioactive particles to the surface of cancer cells. This activity is in addition to other mechanisms of action that the monoclonal antibody may possess, such as interactions with the immune system and the induction of apoptosis;
• Radiolabelled monoclonal antibodies can deliver radiation to neighbouring cells in a tumour through a cross-fire effect. This may kill adjacent tumour cells that are antigen negative (i.e., to which the monoclonal antibodies cannot bind) or to which the monoclonal antibodies have not penetrated.

What side effects are associated with radioimmunotherapy?

There are some side effects from radioimmunotherapy that you may want to discuss with your doctor. These include anemia (low red blood cell counts), thrombocytopenia (low platelet counts) and immunosuppression (decreased immune function, a condition which could leave you at increased risk of infection). Other common side effects include chills, fever, nausea and throat irritation. As with any radiation treatment, there are increased long-term risks of certain cancers.

It may be necessary to speak with a doctor about safety precautions following radioimmunotherapy, as a small amount of radiation may be present in the body, i.e., in the blood and urine, for a short period after treatment. These precautions may include washing hands thoroughly after urination and using a condom during sexual intercourse. Flushing the toilet twice after going to the washroom is also a good idea.

Your cancer care team can determine if radioimmunotherapy is the right treatment for you.

Who is a candidate for radioimmunotherapy?

Your doctor will consider many factors to determine if you are a candidate for treatment. These include the specific type of lymphoma that you have as well as several considerations that are important to help minimize potential risks of therapy. Factors such as what kind of lymphoma therapy you have received before, the percentage of lymphoma cells in your bone marrow, your blood cell counts and possible allergies or sensitivities that you may have to any component of the regimen are all important in the decision process.

Ibritumomab Tiuxetan (Zevalin^®)

How is ibritumomab tiuxetan administered?

The ibritumomab tiuxetan regimen, consisting of two pre-doses of rituximab followed by one dose of ibritumomab tiuxetan, is delivered over the course of eight days. Since imaging scans are not required to determine the right dose for you, ibritumomab tiuxetan treatment is completed in only two hospital visits on an outpatient basis.

On the first day, you will first receive an intravenous infusion of rituximab, which takes a few hours. Rituximab is given to allow ibritumomab tiuxetan to improve targeting of cancer cells.

On the eighth day after the initial visit, you will return for a second infusion of rituximab, followed by ibritumomab tiuxetan, which is administered by an intravenous infusion that is completed in about 10 minutes. A nurse or technician will stay with you during treatment.

What precautions are necessary after receiving ibritumomab tiuxetan?

You should speak with your physician about safety precautions and any questions or concerns that you may have. Ibritumomab tiuxetan emits pure beta radiation, which does not penetrate outside the body. In addition, following treatment you will need to follow minimal radiation safety precautions. A small amount of radiation may be present for approximately up to one week following treatment in the blood and urine. Therefore, it is advisable to observe safety precautions for up to one week after treatment.

Typically, isolation is not required, and it is not necessary to avoid contact with family, friends or co-workers during this time. There is no special radiation protection required in your home or workplace. You can usually return to work and your normal activities following treatment, and there are no restrictions for travelling. Your physician will provide additional instructions and recommendations.

Safety precautions to be followed for seven days:

• Wash your hands thoroughly after using the bathroom.
• Use a condom during sexual intercourse to avoid transfer of bodily fluids. Men who have been given ibritumomab tiuxetan and who could become fathers must use reliable contraception during and for a year after stopping treatment.
• Pregnancy precautions: Women should use reliable contraception. Pregnancy should be ruled out before you start treatment and should be avoided during treatment and for a year after treatment.
• Breastfeeding women: Talk to your doctor before starting breastfeeding and after the end of treatment, as antibodies are excreted in human milk.

What side effects are associated with ibritumomab tiuxetan?

Because the ibritumomab tiuxetan regimen involves the administration of rituximab, side effects of rituximab and ibritumomab tiuxetan need to be discussed. The most common side effects reported by patients during treatment with ibritumomab tiuxetan are mild flu-like symptoms, similar to those reported with rituximab. These temporary side effects include weakness, abdominal and back pain, shortness of breath, chills, fever, throat irritation, increased cough, headache, nausea, vomiting, dizziness and rash.

It is important that you report to your physician immediately all symptoms experienced while receiving rituximab or ibritumomab tiuxetan, as it is possible that there may be indications of potentially more serious side effects. In rare cases, severe allergic reactions to rituximab have occurred.

Tositumomab (Bexxar^®)

How does tositumomab work?

Tositumomab is considered a dual-action treatment for NHL because it attacks cancer cells in two ways, providing both radiation therapy and biologic therapy in a single treatment. The biologic therapy action is provided by the monoclonal antibody called tositumomab. Tositumomab seeks out and attaches to the CD20 antigen on the surface of NHL cells. The radiation therapy action of tositumomab comes from a radioactive substance, called an isotope, which is attached to the monoclonal antibody. The isotope is iodine-131.

First, tositumomab, with iodine-131 attached to it, finds and binds to lymphoma cells. The monoclonal antibody causes your body’s natural defences to attack the cancer cells. When tositumomab binds to the cancer cells, iodine-131 releases radiation that kills the attached cells as well as other cells nearby.

The monoclonal antibody tositumomab attaches itself to the CD20 antigen. Tositumomab is designed to fit with the CD20 antigen, like a key fits a lock. This type of targeted treatment brings the cell-killing power of radiation from iodine-131 to the NHL tumour. Because the isotope is attached to tositumomab, it delivers radiation directly to cancer cells.

What happens during treatment?

Tositumomab is administered in a hospital or treatment centre for four visits over one to two weeks. It is usually given on an outpatient basis. However, depending on the total amount of radiation delivered, the radiation safety regulations in your province/hospital, and your individual home situation, it may be necessary to admit you to the hospital for two to three days.

Tositumomab is given in two steps. The first step is called the dosimetric step, and the second is called the therapeutic step. In the dosimetric step, your nuclear medicine physician or radiation oncologist determines the amount of radiation that is right for you. It involves three visits to the hospital or treatment centre.

How is tositumomab administered?

Before you are given any part of tositumomab therapy, your treatment team will give you medicine to help control some of the side effects of tositumomab that may occur with the infusions. Those medicines are called premedications, and they will include:

• Acetaminophen (e.g., Tylenol^®) to control fever;
• Diphenhydramine (e.g., Benadryl^®) to help with allergic reactions or flu-like symptoms.

Next, you will be given a dose of tositumomab without any radiation. This will be an intravenous infusion that will take approximately one hour. You will then be given the dosimetric dose, which is tositumomab plus a small amount of iodine-131. This infusion will take about 20 minutes. After you receive the dosimetric dose, your nuclear medicine team will take a scan with a gamma camera. This will be completed before you urinate, so be sure to urinate before the first infusion is started. The scan should take less than 10 minutes.

Your nuclear medicine team will use this information to determine how fast the radioactive substance leaves your body (the rate is different for every person). At the same time, the nuclear medicine physician or radiation oncologist will take a camera image to observe where the radioactivity is going in your body.

During infusions, your treatment team will monitor your blood pressure, heart rate, breathing, and temperature. If changes occur, your treatment team may decide to slow down or stop the infusion. Tositumomab may cause reactions because it contains proteins not usually found in your body. After you complete treatment and go home, be sure to call your oncologist or hematologist if any side effects get worse, or if you have any new side effects from the tositumomab treatment.

Protecting your thyroid

Your thyroid gland produces chemicals your body needs to function properly. To do so, your thyroid absorbs iodine from your blood stream. Because the isotope in tositumomab is a radioactive form of iodine, it’s important to protect your thyroid from absorbing it. Your doctor will give you a thyroid protection medication in pill or liquid form. You must take the first dose 24 hours before your first visit. You will not be able to be treated with tositumomab if you fail to start taking the thyroid protection medication 24 hours prior to the time you are scheduled for treatment. Also, you must keep taking the thyroid protection medication daily during treatment and for two weeks after the last day of treatment. After treatment with tositumomab, you should have your doctor monitor your thyroid function once per year. This requires a simple blood test.

What side effects are associated with tositumomab?

• Pregnant women should not receive tositumomab. Nursing mothers receiving tositumomab should discontinue breastfeeding.
• Use effective contraceptive methods during treatment and for 12 months afterward.

Radiation safety

While the iodine-131 in tositumomab is in your body, you will be emitting radiation. Iodine is removed from your body by the kidneys, so most of the radioactivity leaves the body through urine over approximately a week. The healthcare professionals in the nuclear medicine department of the hospital or treatment centre where you’ll be treated with tositumomab are very familiar with iodine-131 and have been trained in radiation safety procedures. They will explain to you the simple instructions that you need to follow after your tositumomab treatment to reduce the risk of radiation exposure to others.

There are three things to remember to help limit the amount of radiation others can receive from you after you’ve been treated with tositumomab:

1. Distance: The farther away you are from other people, the less radiation they will receive from you;
2. Time: The amount of radiation people around you are exposed to depends on the length of time they are near you;
3. Hygiene: Some hygiene (personal care) measures will help make sure the people around you are exposed to as little radiation as possible.

Interferons

Interferon is a protein molecule that is naturally produced by the body’s immune system to help fight infection and kill cancer cells in the body. A synthetic form of interferon has been produced and is used to treat certain kinds of NHL. It is thought that interferon kills tumour cells directly and signals to the rest of the immune system to do the same. Interferon can be given as a maintenance therapy to prolong the remission of patients previously treated with chemotherapy.

Flu-like symptoms are the most common side effects from interferon treatment. They include low-grade fever, fatigue, weakness, and muscle and joint aches. Staying well hydrated often helps with these side effects, as do non-prescription pain medications if recommended by your doctor. Interferon therapy can sometimes cause severe depression. Tell your doctor if you are feeling depressed. Less common side effects with interferon therapy include loss of appetite, aversion to food and a decrease in thyroid function. Due to the large number of associated side effects and the array of newer treatment options, interferon is rarely used in the management of NHL. This therapy is used however to treat T-cell lymphomas (review the section on T-cell Lymphomas for more information).

Vaccines

We are all familiar with standard vaccines for diseases such as polio and tetanus. Vaccines work by injecting an inactive portion of a disease molecule, too weak to cause the disease but strong enough to stimulate antibody production. Upon future exposure to the same disease, the body will be ready to mount a strong attack against it.

Vaccines are currently being studied as a potential treatment for lymphoma but are not yet approved for use. These vaccines are custom-made from each person’s unique tumour. A small amount of a patient’s tumour is taken from a lymph node, modified to make it look like a foreign invader (so the patient’s immune system will attack it), and reinjected back into the patient to stimulate antibody production and an immune response. The idea is that the immune system will then attack the tumour and break it down.

It is not yet known how effective these vaccines will be, but they do look promising. A major goal of cancer treatment is the development of therapies that are less toxic than chemotherapy.

Anti-angiogenesis Therapy

Angiogenesis means the development of new blood vessels. Many cancers are able to stimulate angiogenesis causing new blood vessels to form to supply energy and nutrition to the growing tumour. Anti-angiogenesis therapies work to stop the development of new blood vessels and destroy existing abnormal vessels surrounding tumours. The goal is to cut off the fuel supply to growing tumours and facilitate tumour cell death. Anti-angiogenesis therapies are currently under investigation in the therapy of lymphoma.

Gene Therapy

The main goal of gene therapy is to alter the genetic structure of cancer cells so they can no longer grow, or so they can be recognized by the body’s immune system and destroyed. Other kinds of gene therapies may be able to make cancer cells more vulnerable to chemotherapy and normal cells less vulnerable. This could increase the effectiveness of the chemotherapy but decrease the toxic side effects. Gene therapies are still under investigation but hold promise for future cancer treatments.

Bone Marrow Transplants and Stem-cell Transplants

At times, very advanced and nonresponsive lymphomas may be treated using a bone marrow transplant (marrow is the soft tissue in the center of large bones that produces white and red blood cells and platelets) or stem-cell transplantation (the cells that develop blood).

Transplants fall into three basic donor categories:

A syngeneic transplant is when the cells are donated by an identical twin. Allogeneic is when the donor’s basic cell is almost identical to the patient’s as with a close relative (brother or sister). Rarely is the basic cell type matched by an unrelated relative. Autologous is when the patient’s own stem cells are removed from his or her bone marrow or bloodstream. With types of NHL that have spread to the bloodstream or bone marrow, it may be difficult to obtain uncontaminated cells or cells that can be used, even after treating them in a laboratory to remove or kill the NHL cells.

Marrow or cell transplantation is done to replace healthy cells that have been destroyed by cancer treatment. Bone marrow or stem cells that have been removed from a donor are carefully frozen and stored while the patient receives high-dose chemotherapy and sometimes whole-body radiation treatment. This process kills all or most normal stem and bone marrow, while destroying cancer cells. This leaves them defenseless against infection and unable to form blood. After therapy, the frozen marrow or cells are thawed and put back in the body. During the recovery period, all of the body’s systems must be carefully monitored for rejection, infection and the need for any supportive treatments.

How do stem-cell transplants work?

Stem cells, because they divide rapidly, can be killed off by chemotherapy and radiation therapy. Therefore, the doses of chemotherapy and radiation therapy used to treat lymphoma are limited due to the risk of damaging these stem cells. Patients with lymphomas that are difficult to treat or resistant to standard therapy may benefit from chemotherapy or radiation therapy given in very high doses (myeloablative therapy). However, this can potentially destroy all the stem-cells in the bone marrow and leave the patient at very high risk for infection. To combat this problem, the patient receives a bone marrow or a stem-cell transplant. This means that they receive stem cells (either their own stem cells that were stored prior to myeloablative therapy or stem cells from a donor) to replenish their bone marrow which had previously been destroyed by the high-dose therapy.

What is the difference between a bone marrow transplant and a stem-cell transplant?

There are two different types of transplants: bone marrow transplants and peripheral blood stem-cell transplants (PBSCTs). The difference between the two depends on where the stem cells are taken from. In bone marrow transplants, the stem cells are taken from the bone marrow. In PBSCTs, the stem cells are taken from the circulating blood. PBSCTs are now more commonly performed than bone marrow transplants, as the procedure is easier and the body is able to regenerate new stem cells faster.

How are transplants performed?

Four steps are involved in a bone marrow transplant or PBSCT:

1. Harvesting stem cells or bone marrow: Harvesting is the procedure by which the bone marrow or stem cells are obtained in preparation for the transplant. In a bone marrow transplant, the stem cells are withdrawn from the bone marrow under general anesthesia by inserting a needle into a bone in the pelvic region, called the iliac crest. This bone marrow is then filtered and stored until the day of the transplant. In a PBSCT, stem cells are taken from the bloodstream, a far easier and more commonly used procedure. The stem cells are separated from other components of the blood in a process called apheresis, with the rest of the blood being returned to the patient.
2. Processing/preserving the stem cells or bone marrow: Stem cells or bone marrow harvested from the patient (autologous transplant) are generally preserved and stored in a freezer until ready for use. Stem cells or bone marrow derived from a donor (allogeneic transplant) are usually collected immediately before use and not stored for any length of time.
3. Administering myeloablative therapy: High-dose chemotherapy, with or without myeloablative radiation therapy, is then administered to the patient to destroy the cancerous cells, as well as the healthy cells in the bone marrow.
4. Reinfusing harvested stem cells or bone marrow: The harvested stem cells or bone marrow (obtained from either the patient’s own healthy cells or from a donor) are then transplanted intravenously into the bloodstream of the patient. The stem cells travel through the body to the bone marrow where they settle and implant themselves. These stem cells slowly begin to produce new, healthy blood cells. Eventually, they will produce enough healthy cells to repopulate the whole bone marrow, replenishing all blood and immune cells. Before the immune system is able to regenerate, the patient is at an increased risk of infection and must be closely monitored. The patient may also be susceptible to bleeding complications.

 

Autologous transplant

Allogeneic transplant

Watchful Waiting (Also Called Watch and Wait)

Many patients who are diagnosed with indolent (slow-growing) NHL have no symptoms or other risk factors that require immediate treatment. These patients are closely monitored using a watchful waiting or watch and wait approach. They have regular visits with their doctor, including laboratory tests and tumour imaging (such as CT scans), but they do not receive treatment unless the cancer progresses or symptoms appear.

Watchful waiting may initially cause distress to patients as it may seem a risky or passive approach to a serious disease. However, studies have demonstrated that the results are no different between those patients with indolent NHL who receive treatment immediately and those who wait until treatment is required. The benefit of watchful waiting is that it delays the side effects of cancer therapies, which can often be significant.

The watchful waiting approach does not mean nothing is done, the process is still an active one. Patients are seen regularly by their doctors and are very closely monitored for signs of disease progression. Patients in the watchful waiting category should be observant about the presence of disease symptoms, most notably the presence of B symptoms which may indicate that active treatment should begin. B symptoms include fever, night sweats and unexplained weight loss.

Most watchful waiting patients do go on to need active treatment for their NHL. However, some patients with indolent lymphomas never require treatment. If treatment is required, it typically begins about 18 months after the start of the watchful waiting approach.

What will be the outcome of my treatment?

Nobody can answer this question on an individual basis. There are too many factors that come into play. However the International Prognostic Index does give statistically valid estimates of which patients are most likely to relapse, and which patients are less likely to relapse.

The International Prognostic Index for Aggressive Lymphoma (IPI)
The International Prognostic Index for Follicular Lymphoma (FLIPI)

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