PREPARATIVE REGIMENS
BMT patients are given an enormous quantity and variety of medications during their treatment. Depending on the disease being treated, the type of BMT, and complications that arise, patients may take as many as 25 different medications in a single day while hospitalized.
This issue of BMT Newsletter is the first in a series on drugs used during a BMT. We'll examine their purpose and side effects, beginning with those used in preparative regimens.
What is a preparative regimen?
The preparative regimen (also called the conditioning regimen) is the high dose chemotherapy and/or radiation administered to patients during the 5 to 10 day period immediately preceding the BMT. Depending on the disease being treated, the preparative regimen may consist of one or more chemotherapy drugs and total body irradiation (TBI), or a combination of chemotherapy drugs without TBI. Many different preparative regimens are used today, and new ones are constantly being tested.
For patients with leukemia and other cancers, the preparative regimen is designed to kill as many diseased cells as possible without major damage to the patient's organs and tissues. Drugs used in the preparative regimen are often the same as those used in standard chemotherapy to treat the disease. The doses, however, are much higher and therefore more effective in killing the cancerous cells. The high-dose chemotherapy also destroys the bone marrow.
Thus, a bone marrow transplant is required even if the disease being treated has not affected the bone marrow. In allogeneic BMTs (those in which bone marrow from a donor is used), the preparative regimen must also include agents that suppress the patient's immune system. These "immunosuppressive" agents help prevent the patient's body from rejecting the donated bone marrow, a condition called graft rejection. TBI and/or drugs such as cyclophosphamide (Cytoxan, CY) are commonly used to prevent graft-rejection. In patients with leukemia, they may also be used because of an "anti-leukemic" effect they appear to confer on patients post-transplant.
Preparative regimens administered to patients with non-malignant diseases such as aplastic anemia or immune deficiency disorders are designed both to suppress the patient's immune system and to make space for new, healthy bone marrow. The doses of radiation and/or chemotherapy required to prepare these patients for transplant are usually lower than those used to treat BMT patients with malignant diseases.
No perfect preparative regimen exists for any disease treated by a BMT. Thus, two BMT centers may use different preparative regimens to treat the same disease. A single BMT center may also use two different regimens to treat patients with the same disease as part of a study to compare their effectiveness.
Total Body Irradiation (TBI)
Preparative regimens for leukemia often include total body irradiation (TBI). TBI is effective in suppressing the immune system, making space for new, healthy bone marrow, and killing diseased cells. It's used less frequently in preparative regimens for solid tumor cancers such as breast and ovarian cancer.
Total body irradiation is typically administered to patients in one or more sessions over a 1 to 7 day period. When TBI is administered over several days it is called fractionated TBI. When administered in more than one session each day, it's called hyperfractionated TBI.
While patients do not actually see or feel the radiation, many still find TBI therapy an unnerving experience. Patients must sit or lie still, sometimes in an awkward position, for 10 to 45 minutes while the radiation is being administered. This can be difficult, particularly if the patient is nauseated or sedated. Special stands or boxes used at some BMT centers to help patients remain immobile can be confining and make some patients feel anxious. Anticipation of nausea or vomiting following TBI may increase a patient's apprehension about TBI therapy. Pre-medication with sedatives can help reduce anxiety. Children are usually sedated before TBI sessions in an effort to minimize their movement.
It helps to visit the radiation center before TBI therapy begins to familiarize yourself with the equipment and to get your questions answered. Some centers provide patients with a "trial run" of TBI therapy so that patients know in advance what to expect.
High Dose Chemotherapy
High dose chemotherapy is part of most preparative regimens. The drugs are usually administered intravenously through a Hickman-type catheter over 2 to 4 days. The exception is busulfan, a drug that is only available in pill form. Depending on the drug(s) used, high dose chemotherapy may be included in the preparative regimen to kill cancerous cells, to prevent graft rejection, or both. Chemotherapy drugs commonly used in BMT preparative regimens are listed in the chart on page 2.
Side Effects
The high dose chemotherapy and TBI used in preparative regimens is toxic to normal tissues and organs, as well as diseased cells. Nausea, vomiting, diarrhea, mouth sores and temporary hair loss almost always occur to varying degrees regardless of which preparative regimen is used. Severe or long term damage to organs and tissues occurs less frequently.
Patients are often frightened and overwhelmed by the list of possible side effects associated with preparative regimens. It helps to remember that most side effects are temporary and completely reversible, and that severe or long term organ damage is the exception rather than the rule. Keep in mind that any discomfort associated with side effects can usually be prevented or relieved with medication.
Common Preparative Regimens
BUCY busulfan, cyclophosphamide
BCV carmustine, cyclophosphamide, etoposide
BEAM carmustine, etoposide,
cytosine arabinoside, melphalan
CY cyclophosphamide
TCC thiotepa, cyclophosphamide, carboplatin
BCC carmustine, cisplatin, cyclophosphamide
MVT mitoxantrone, etoposide, thiotepa
ICE ifosphamide, carboplatin, etoposide
TBI + CY total body irradiation, cyclophosphamide
TBI + BUCY total body irradiation, busulfan,
cyclophosphamide
TBI + CV total body irradiation, cyclophosphamide,
etoposide
TBI + VP16 total body irradiation, etoposide
TBI + ara-C total body irradiation, cytosine arabinoside
TBI + Melphalan total body irradiation, melphalan
Nausea, Vomiting & Diarrhea
Nausea and vomiting are common, following all preparative regimens. Drugs called "antiemetics" are used to treat nausea. ("Emesis" means vomiting; thus, "antiemetics" are drugs that prevent vomiting.) Antiemetics commonly used to treat nausea include lorazepan (Ativan), metoclopromide (Reglan), droperidol (Inapsine), dronabinol (Marinol), dexamethasone (Decadron), prochlorperazine (Compazine), diphenhydramine (Benadryl) and ondansetron (Zofran).
The feeling of nausea is usually controlled by the brain, not by the stomach. Antiemetics act on the central nervous system to counteract this side effect. Antiemetics can cause additional side effects such as anxiety, drowsiness and restlessness. Occasionally, muscle tightness, uncontrolled eye movement or shakiness can occur. These drugs reactions can be frightening, but are usually less serious than they appear. Lowering the dose of the antiemetic or administering an antihistamine such as Benadryl usually reduces or eliminates the problem.
Diarrhea following the preparative regimen is also common. Anti-diarrheal drugs such as lomotil "sedate" the nerves in the gastrointestinal area, slowing down muscle contractions and the diarrhea.
Common Side Effects of Preparative Regimens
- Immediate/Short Term
- nausea
- vomiting
- diarrhea
- sore jaw (inflamed salivary gland)*
- mild heartbeat irregularities
- Intermediate Term (1-2 weeks following
treatment)
- nausea
- vomiting
- diarrhea
- temporary hair loss
- mouth and throat sores
- skin irritation, darkening
- bladder irritation
- mild/moderate liver problems
- mild/moderate heartbeat irregularities
- mild/moderate breathing problems
- Long Term
- infertility
- cataracts*
- learning disabilities*
* usually associated with preparative regimens that include TBI
Mouth, Throat, Skin & Hair
Cancerous cells are abnormal cells that rapidly divide and increase in number.High dose chemotherapy and radiation target rapidly dividing cells. However, some normal cells such as those that line the mouth, throat and gut, as well as hair and skin cells, are also rapidly dividing cells. These cells can be irritated and temporarily damaged by high dose chemotherapy or radiation.
Mouth and throat discomfort (mucositis) typically appear 4 to 8 days following the preparative regimen. Topical anesthetics such as dyclone or intravenous narcotics are used to relieve this discomfort. Frequent brushing of the teeth and gums with a soft brush or sponge, and rinsing with a solution of saline helps prevent mouth infections.
Mucositis often makes eating difficult. Patients may be fed intravenously until the discomfort subsides. (Intravenous feeding is also used if the stomach is unable to absorb sufficient nutrients [malabsorption] as a result of temporary irritation caused by the preparative regimen.)
Temporary hair loss (alopecia) always occurs following the preparative regimen. Hair loss changes a patient's appearance and for some (particularly adolescents) can be very distressing. Scarves, hats or wigs can be used until the hair grows back. Some patients prefer to shave their heads or cut their hair very short before hair loss begins. Hair normally grows back within 3-6 months following the transplant.
Skin rash is common following preparative regimens that include TBI, busulfan, carmustine (BCNU) or thiotepa. Less often, hyperpigmentation_dark spots on the skin_occurs.
Bladder Irritation (hemorrhagic cystitis)
Bladder irritation, sometimes evidenced by bloody or painful urination, can occur following the preparative regimen, particularly those that include cyclophosphamide (Cytoxan, CY) or Ifosphamide. Increasing the rate of intravenous fluids, using a "foley catheter" to irrigate the bladder, and/or administering a drug called MESNA are techniques commonly used to prevent or treat this problem.
Liver, Lungs & Heart
Temporary organ damage often occurs following high dose chemotherapy and/or TBI. It's usually mild and completely reversible. Liver damage occurs in approximately 50 percent of patients following the preparative regimen. Symptoms include jaundice, significant weight gain due to fluid retention, and abnormal blood levels of liver enzymes and bilirubin (a pigment produced during the break up of red blood cells). "Resting" the liver, counteracting some of the symptoms and avoiding medications that aggravate the condition is the usual treatment until the liver heals itself.
Breathing irregularities can also occur following the preparative regimen. Ten to 20 percent of patients develop non-infectious pneumonia during the first four weeks post-transplant. In most cases, injury to the lungs is mild and temporary, but some patients do experience breathing problems long term.
Mild, temporary heartbeat irregularities (arrhythmia) or rapid heartbeat can occur following the preparative regimen, particularly those that include cyclophosphamide or carmustine. Severe or long term heart problems are rare.
Confusion & Anxiety
Confusion or altered thinking is an occasional, temporary side effect of the preparative regimen, or of drugs used to control certain side effects. These side effects can be frightening both to the patient and their loved ones if they occur. It helps to remember that these problems are temporary and reversible, and can usually be managed by changing the dosage or type of drug being administered.
Reproductive Organs
Damage to reproductive organs from high dose chemotherapy and/or radiation is common, and often results in long term infertility. Patient age, sex, stage of sexual maturity, and dosage of TBI and/or chemotherapy administered affect the likelihood of infertility post-BMT. Few patients who receive TBI pre-transplant regain fertility post-transplant.
Despite the frequency of infertility post-transplant, more than 60 children are known to have been born to former BMT patients. (See issue #8 of BMT Newsletter for options available to deal with infertility.)
Other Long-Term TBI Side Effects
Cataracts occur in approximately 20 percent of patients who undergo fractionated TBI. Cataracts can be surgically removed, usually in an outpatient setting.
Mild to moderate learning disabilities may occur in children who've undergone TBI. Younger children often experience delayed growth as well. Hormone therapy may be recommended to promote growth if this problem occurs.
Chemotherapeutic Drugs Commonly Used In Bone Marrow Transplantation
Generic Name Trade Name Abbreviation
Amsacrine Amsidyl m-AMSA
Busulfan Myleran BUS; BU
Carboplatin Paraplatin CPP; CB
Carmustine BiCNU BCNU
Cisplatin Platinol CDDP
Cyclophosphamide Cytoxan Neosar CTX; CY
Cytarabine
Hydrochloride Cytosar-U Ara-C
(Cytosine Arabinoside)
Etoposide VePesid VP-16;
VP-16-213
Ifosfamide Ifex IFX
Melphalan Alkeran L-PAM
Mitoxantrone Novantrone NOV
Mitomycin C Mutamycin MITO
Mechlorethamine
Hydrochloride Mustargen HN2
(Nitrogen Mustard)
Thiotepa Thiotepa TT
Total Body Irradiation TBI
Final Note
Anxiety about the possible side effects of the preparative regimen is normal. It helps to put the risk of developing each side effect into perspective, and to remember that most are temporary and completely reversible. Counselors and/or psychiatrists are available at most BMT centers to help patients cope with their anxiety. It pays to take advantage of their help.
Chemo
Drugs Commonly Used in PrepRegimens