This information is about two chemotherapy treatments for non-Hodgkin lymphoma, called ICE and R-ICE. The information describes the drugs, how they are given and some of the possible side effects. This information is only about the use of ICE chemotherapy for non-Hodgkin lymphoma; however, it can be given in different ways to treat other types of cancer.

If you have any questions you can ask your doctor or nurse at the hospital where you are having your treatment, or speak to one of our cancer support service nurses.

ICE is named after the initials of the chemotherapy drugs used, which are ifosfamide, carboplatin and etoposide.

R-ICE also includes the monoclonal antibody drug rituximab (Mabthera®).

Rituximab

Rituximab belongs to a group of drugs known as monoclonal antibodies. It is used to treat several different types of B-cell non-Hodgkin lymphoma.

Monoclonal antibodies are used to try to destroy some types of cancer cells while causing little harm to normal cells. They are designed to recognise certain proteins that are found on the surface of some cancer cells. The monoclonal antibody recognises the protein and locks into it (like a key in a lock). This may then trigger the body’s immune system to attack the cancer cells and can sometimes cause the cells to destroy themselves.

Rituximab locks onto a protein called CD20, which is found on the surface of most of the abnormal white blood cells (B-cell lymphocytes) that occur in some types of non-Hodgkin lymphoma. It is also present on the surface of one of the main types of normal B-cell lymphocytes. Rituximab acts by attacking both abnormal (malignant) and normal B-cell lymphocytes. However, the body can quickly replace any normal white blood cells that are damaged.

ICE and R-ICE treatment can usually be given to you during a short stay in hospital. You will need to have a blood test before you start treatment – either on the same day or a few days before. You will also be seen by a doctor, specialist nurse or pharmacist. If the results of your blood test are normal, the pharmacy will prepare your chemotherapy drugs. This may take a couple of hours.

ICE and R-ICE chemotherapy is usually given through a thin plastic tube that is inserted under the skin and into a vein near the collarbone (central line), or passed through a vein in your arm (PICC line). Your doctor or nurse will explain more about this to you.

If you do not have a line, the nurse will put a thin, flexible tube (cannula) into a vein in your hand or arm. You may find this uncomfortable, or a little painful, but it should not take long.

You will be given some anti-sickness (anti-emetic) drugs. These are usually given by injection through the central line, PICC line or cannula, which is connected to a drip (infusion). Some anti-sickness medicines are given as tablets.

The chemotherapy drugs are then given separately, as infusions into your line or cannula:

• ifosfamide (a colourless fluid)
• carboplatin (a colourless fluid)
• etoposide (a colourless fluid).

If you are being treated with R-ICE, the rituximab (a clear fluid in a drip bag) is given as an infusion into your cannula or line. The first dose of rituximab is given slowly over a few hours, as some people can have an allergic reaction to it (see section on possible side effects). If you have a reaction, the drip can be stopped and started again more slowly, when symptoms have calmed down. You should be able to have your second and subsequent doses of rituximab more quickly.

Ifosfamide can irritate the bladder lining and cause bleeding. To help prevent this, a drug called mesna (Uromitexan®) is given. The mesna can be mixed with the ifosfamide, or given shortly after the ifosfamide, as a separate drip (infusion). Sometimes mesna may be given as tablets instead, which you can take at home. It is very important that you take the tablets exactly as they are prescribed.

Once treatment has finished you can go home. If you have a cannula it will be removed and you will be given a supply of anti-sickness drugs to take with you. It is important to take these as directed, even if you are not feeling sick, as some anti-sickness drugs are much better at preventing sickness than at stopping it once it starts.

Your doctor may use the word ‘regimen’ (e.g. the ICE regimen) when talking about your chemotherapy. This means the whole plan or schedule of your particular chemotherapy treatment. ICE and R-ICE chemotherapy can be given in slightly different ways. The following are descriptions of three commonly used schedules. You can ask your doctor or nurse to tell you whether it is one of these regimens that you will be having. If it is not, they can explain your regimen to you.

Schedule A

R-ICE chemotherapy is given in cycles that are repeated, usually three times, to make up a course of treatment.

Two days before you start your first cycle, you will be given a drip (infusion) of rituximab. On the first day of the cycle, you will be given another infusion of rituximab. Two days later (day 3) you will be given a short infusion of etoposide. On the next day (day 4), the etoposide will be repeated. You will also be given an infusion of carboplatin and start a 24-hour infusion of ifosfamide and mesna that have been mixed together. On the fifth day of the cycle, you will finish the ifosfamide and mesna infusion and be given etoposide for a third time. After this, you can go home.

Two days later (day 7 of the cycle) you will start daily injections of a drug called G-CSF (granulocyte-colony stimulating factor). This is a type of protein that stimulates the bone marrow to produce more white blood cells. The injections are given under the skin (subcutaneously). The G-CSF injections are given for eight days (days 7–14). This completes one cycle of your treatment. Each cycle lasts for 14 days.

On the next day you will start your next cycle of treatment, starting from day one again. The same drugs will be given to you again, except for the initial infusion of rituximab which is only given before the first cycle. Usually three cycles of treatment are given.

Schedule B

On the first day of ICE chemotherapy, you will be given all three chemotherapy drugs (ifosfamide, carboplatin and etoposide). The infusions of carboplatin and etoposide are both given over about an hour, and the ifosfamide lasts for about six hours.

On the next day (day 2), you will be given three more infusions of ifosfamide, each lasting six hours, and an infusion of etoposide, which will last for an hour. You will also be given a six-hour infusion of mesna. After this you will have a rest period, with no chemotherapy, for the next 19 days. This completes a cycle of your treatment. Each cycle lasts for 21 days (three weeks).

Following the rest period, three weeks after you started, you will be given the same drugs again, beginning your next cycle of your treatment. Usually three cycles of treatment are given over 2–3 months. This makes up a course of treatment.

If you are following this schedule and also being given rituximab (R-ICE), you will be given an infusion of rituximab on the first day of each cycle.

Schedule C

On the first day of ICE chemotherapy, you will be given an infusion of etoposide for an hour. On the next day (day 2) the etoposide will be repeated. You will also be given a 60-minute infusion of carboplatin and start a 24-hour infusion of ifosfamide and mesna.

On the following day (day 3) you will be given a third infusion of etoposide, again over about an hour. You will finish your 24-hour infusion of ifosfamide with mesna and be given a 12-hour infusion of mesna on its own. After this you will have a rest period with no chemotherapy for 25 days. This completes a cycle of your treatment. Each cycle lasts for 21 days (three weeks).

You will then have a rest period of one week. After the rest period (four weeks after you started) the same drugs will be given to you again, beginning the next cycle of your treatment. Usually 2–4 cycles of treatment are given over 2–4 months. This makes up a course of treatment.

If you are following this schedule but also being given rituximab (R-ICE), you will be given an infusion of rituximab on the first day of each cycle.

Each person’s reaction to chemotherapy is different. Some people have very few side effects, while others may experience more. The side effects described in this information will not affect everyone who is having ICE or R-ICE chemotherapy. We have outlined the most common side effects, so that you can be aware of them if they occur. However, we have not included those that are rare and therefore unlikely to affect you. If you notice any effects that you think may be due to the drug, but which are not listed here, please let your nurse or doctor know.

Feeling sick (nausea) and being sick (vomiting) There are now very effective anti-sickness (anti-emetic) drugs to prevent or reduce nausea and vomiting. If the sickness is not controlled, or continues, tell your doctor. They can prescribe other drugs, which may be more effective.

Some anti-sickness drugs can cause constipation. Let your doctor or nurse know if this is a problem.

Lowered resistance to infection The chemotherapy can reduce the production of white blood cells by the bone marrow, making you more prone to infection. This effect can begin seven days after treatment has been given, and your resistance to infection usually reaches its lowest point 10–14 days after chemotherapy. Your blood cells will then increase steadily, and will usually have returned to normal levels before your next cycle of chemotherapy is due.

Contact your doctor, or the hospital, straightaway if:

• your temperature goes above 38ºC (100.5ºF)
• you suddenly feel unwell (even with a normal temperature).

You will have a blood test before having more chemotherapy to make sure that your number of white blood cells has returned to normal. Occasionally, it may be necessary to delay treatment if your number of blood cells (blood count) is still low.

You may be given injections of a drug called G-CSF (granulocyte-colony stimulating factor), which is a protein that can help boost the number of white blood cells that your bone marrow produces. It is given as an injection under the skin (subcutaneously).

Bruising or bleeding ICE and R-ICE chemotherapy can reduce the production of platelets, which help the blood to clot. Let your doctor know if you have any unexplained bruising or bleeding, such as nosebleeds, blood spots or rashes on the skin, and bleeding gums.

Anaemia (low number of red blood cells) While having treatment with ICE or R-ICE chemotherapy you may become anaemic. This may make you feel tired and breathless. Let your doctor or nurse know if you experience these problems.

Tiredness Many people feel extremely tired (fatigued) during chemotherapy, particularly towards the end of treatment. This is a very common side effect and it is important to try to get as much rest as you need.

Hair loss may be total. Hair usually starts to fall out about 3–4 weeks after you first have chemotherapy. You may also experience thinning and loss of eyelashes, eyebrows and other body hair. Hair loss is temporary and all your hair will start to regrow once treatment is finished.

Irritation of the bladder It is important to try to drink plenty of fluids to prevent any irritation. While you are having the chemotherapy you will be encouraged to pass urine every 3–4 hours during the day, and last thing at night. Your urine may be measured and tested for the presence of blood. If there is blood in your urine, you will be given further doses of mesna.

Loss of appetite A dietitian or specialist nurse at your hospital can give advice and tips on boosting appetite, coping with eating difficulties and maintaining weight.

Your liver may be temporarily affected Ifosfamide may cause changes in the way that your liver works. Your liver will return to normal when treatment has finished. This is very unlikely to cause you any harm, but your doctor will monitor this carefully. Samples of your blood will be taken from time to time to check your liver function.

Skin changes Ifosfamide can cause a rash, which may be itchy. Your doctor can prescribe medicine to help with this. Your skin may darken, due to excess production of pigment. This usually returns to normal a few months after treatment has finished.

Diarrhoea This can usually be easily controlled with medicine, but tell your doctor if it is severe or continues. It is important to drink plenty of fluids if you have diarrhoea.

Effect on kidneys Your kidneys may be temporarily affected. This is unlikely to cause any symptoms. Your kidney function may be checked by your doctor, using blood or urine tests.

Sore mouth and taste change Your mouth may become sore or you may notice small ulcers during this treatment. Drinking plenty of fluids, and cleaning your teeth regularly and gently with a soft toothbrush, can help to reduce the risk of this happening. Tell your nurse or doctor if you have a sore mouth or ulcer, as special mouthwashes and medicines which prevent or clear any mouth infection can be prescribed.

You may notice that your food tastes different. Normal taste will usually come back after the treatment finishes.

Confusion, lethargy, sleepiness and loss of balance These are very rare side effects of ifosfamide and only occur with high-dose treatment. If you notice any of these effects it is important to tell your doctor.

While etoposide is being given, it can cause pain at the place where the injection is given, or along the vein. If you feel pain, tell your doctor or nurse.

Very rarely, etoposide may cause a second cancer, usually a type of acute leukaemia, to develop years later. Your nurse or doctor can discuss this with you.

Risk of blood clots Cancer can increase your risk of developing a blood clot (thrombosis), and having chemotherapy may increase this risk further. A blood clot may cause symptoms such as pain, redness and swelling in a leg, or breathlessness and chest pain. Blood clots can be very serious, so it is important to tell your doctor straightaway if you have any of these symptoms. However, most clots can usually be successfully treated by using drugs which thin the blood. Your doctor or nurse can give you more information.

Other medicines Some medicines can be harmful to take when you are having chemotherapy. Always tell your doctor about any medicine you are taking. This includes any that you may have bought from a pharmacy or supermarket, and any herbal or complementary therapies.

Fertility Your ability to become pregnant or father a child may be affected by this treatment. It is important to discuss fertility with your doctor before starting treatment.

Contraception It is not advisable to become pregnant or father a child while taking this treatment, as it may harm the developing foetus. It is important to use effective contraception whilst taking this drug, and for some time afterwards. Again, discuss this with your doctor.

Loss of periods Due to the effect of chemotherapy on the ovaries, women may find that their periods become irregular and may eventually stop. In younger women this may be temporary, but if you are closer to your menopause it may be permanent. This will result in menopausal symptoms such as hot flushes, sweats and vaginal dryness.

This section is based on our ICE and R-ICE chemotherapy factsheet which has been compiled using information from a number of reliable sources, including:

• Martindale: The Complete Drug Reference (35th edition). Eds Sweetman et al. Pharmaceutical Press, 2007.
• British National Formulary (54th edition). British Medical Association and Royal Pharmaceutical Society of Great Britain, September 2007.
• The Chemotherapy Source Book (3rd edition). Eds Perry, Lippincott Williams and Wilkins, 2001.

For further references, please see general bibliography.