PCV - Temozolomide
Neupogen

MGH Brain Tumor Center
Cox 315
617.724.8770

http://brain.mgh.harvard.edu/
© 2000 MGH Brain Tumor Center

This booklet is intended to give brain tumor patients and their families a better understanding of chemotherapy treatments. This information can give the patient more control over the disease and its treatment. Topics which are covered include:

	the rationale for chemotherapy
	common side effects of chemotherapy and ways to minimize them
	when to call the doctor or nurse
	specific information about PCV chemotherapy and
	temozolomide chemotherapy

Types of therapies for gliomas

There are three standard types of treatment for patients with high-grade gliomas: surgery, radiation therapy, and chemo-therapy. Clinical research centers such as the MGH Brain Tumor Center also offer investigational treatments.

Because high-grade gliomas have a tendency to grow rapidly, treatment must be started as soon after surgery as is feasible. Generally, this means that patients should be undergoing either radiation therapy or chemotherapy within 2 to 4 weeks after surgery.

While radiation and chemotherapy are helpful in controlling high-grade gliomas, at present it is not possible to cure most of these tumors. The two major reasons for this are that: 1) tumor cells infiltrate into surrounding brain and thus cannot be completely removed by the surgeon, and 2) that most types of glioma cells are somewhat resistant to radiation and chemotherapy.

Therefore, the goals of brain tumor treatments are to:

	remove as many tumor cells as possible (with surgery)
	kill as many of the cells left behind after surgery as possible (with radiation and chemotherapy)
	put remaining tumor cells into a nondividing, quiescent state for as long as possible (with radiation and chemotherapy)

With these treatments, the growth of high-grade gliomas can usually be controlled for a period of time. However, the tumor cells may start to grow again. Patients receive aggressive initial treatment in order to delay this regrowth as long as possible. Careful surveillance with serial MRI or CT scans is a crucial part of medical care, because tumor regrowth requires alteration of current treatment, or, for patients in the observation phase, restarting treatment.

Surgery and radiation therapy

The first step in therapy is maximal reasonable removal of tumor tissue. There is great variability in the amount of tumor that can be safely removed from the brain of a patient. The variability is based mainly on the location of the tumor. An MRI scan is usually obtained within 3 days after tumor removal. This "post-op" MRI serves as a baseline for future comparison.

Radiation therapy is an important part of the treatment of high-grade gliomas. In typical situations, patients begin radiation treatments within 2 to 4 weeks after tumor resection. Treatments are given daily, Monday through Friday, for 4 to 6 weeks. Each treatment takes only a few minutes. An MRI is usually obtained about 2 to 4 weeks after the end of radiation therapy in order to judge the effect of treatment. Most of the time this scan will show no change from the post-operative MRI, which is good. Some shrinkage is even better. Growth during radiation therapy is an unwanted sign of an aggressive tumor.

Rationale for chemotherapy

Chemotherapy is helpful in controlling high-grade gliomas. As noted above, the goal of chemotherapy is to kill as many of the tumor cells as possible, and to put remaining tumor cells into a nondividing, sleeping state for as long as possible. Most chemotherapy agents are designed to attack tumor cells in a way that impairs their ability to divide and give rise to additional tumor cells. Some newer drugs under investigation attempt to attack other aspects of tumors, such as formation of new blood vessels.

Many different chemotherapy drugs are available. Neuro-oncologists are skilled at tailoring treatments for individual patients. For most tumors radiation is given prior to chemotherapy, however, chemotherapy may be administered prior to radiation therapy for patients whose tumors contain a component of oligodendroglioma.

Chemotherapy for patients with glioblastoma multiforme occasionally raises an important question as to timing. Specifically, although chemotherapy is beneficial, it is not known whether the timing of administration after radiation is important, particularly for older patients. Some centers in the United States now save chemotherapy until there is evidence that the tumor is growing after radiation therapy in these older patients. This may mean that months could elapse between the end of radiation treatment and the beginning of chemotherapy, allowing the patient to recover strength. Other specialists prefer to give chemotherapy immediately after radiation therapy and to give different chemotherapy when the tumor starts to grow again. This decision has to made on a patient-by-patient basis.

Clinical trials

In addition to standard chemotherapy, major research centers conduct studies of new drugs. It is usually advisable to enter a research study if possible, both for reasons of potential personal benefit as well as for the benefit of others in the future. Neuro-oncologists and nurses will provide detailed information about clinical trials.

The MGH Brain Tumor Center conducts studies of many new agents. Most of these studies are performed by groups of research hospitals in the United States, and some others are set up in conjunction with pharmaceutical companies. The MGH Brain Tumor Center is a founding member of the National Cancer Institute (NCI) sponsored cooperative clinical trials group called New Approaches to Brain Tumor Therapy (NABTT).

The terminology used in chemotherapy trials can be confusing. There is a short glossary of these terms at the end of this booklet. A list of sites on the world wide web that discuss chemotherapy trials is also provided at the end of the booklet.

Side effects of chemotherapy

Although chemotherapy is intended to target dividing tumor cells, there are normal cells in the body which are also dividing. These normal cells can also be temporarily affected by chemotherapy, thus producing side effects. In addition, chemotherapy can produce nausea or vomiting by a direct effect on the vomiting center in the brain. Specific side effects of chemotherapy are discussed below.

Due to significant advances in medical science, chemotherapy is much easier to tolerate today than even a few years ago. A neuro-oncologist or nurse practitioner will discuss the potential side effects of chemotherapy prior to beginning the treatments. After all questions have been answered, a consent form must be signed.

The bone marrow produces blood cells that circulate in the arteries, veins and capillaries. There are white blood cells which fight infection, red blood cells which carry oxygen, and platelets which prevent bleeding.

White blood cell counts and platelet counts drop transiently after each dose of most types of chemotherapy. The lowest point (called the ‘nadir’) could increase the risk for serious infection (low white blood cells) or bleeding (low platelets). Low red blood cell count (anemia) is not common with most types of chemotherapy. These changes are measured by performing a CBC (complete blood count). Most of the time patients do not have symptoms related to the presence of low blood counts.

A CBC is taken within 24 - 48 hours before administration of chemotherapy; the results will help the doctor and nurse decide if it is safe to give the chemotherapy.

Patients and their families need to be vigilant about signs of infection and bleeding while on chemotherapy. Good oral hygiene and handwashing can help prevent infections.

Common signs of infection include fever (oral temperature over 100.0 degrees F), chills, sore throat, shortness of breath, new cough, abdominal pain, and pain or burning with urination.

Common signs of bleeding include easy bruising of the skin, tiny spots of hemorrhage under the skin (petechia), nose bleeds, and bleeding of the gums with brushing.

NOTE: Call the doctor or nurse promptly if any of these signs occur while on chemotherapy.

Treatment of infections in patients with low white blood counts includes administration of antibiotics by vein in the hospital, and injections of Neupogen (G-CSF, a white blood cell growth factor; see the end of the booklet regarding instruction for administration of Neupogen at home). Low platelet counts are treated with platelet transfusions.

Many chemotherapy agents can cause nausea and vomiting for one to several days following treatment. Antinausea medicines (antiemetics) such as Zofran and Kytril can reduce or eliminate these symptoms. Antinausea medications are usually given 30 minutes to one hour prior to administration of chemotherapy. Patients should keep a small supply of these medications at home in case symptoms persist. Specific instructions about recommended use of antinausea agents will be given for each chemotherapy regimen. It is usually a good idea to eat light meals around the day of chemotherapy.

The cells which produce sperm in men are frequently destroyed by chemotherapy. This can cause sterility, and therefore may make it impossible to father a child. Many men decide to bank sperm prior to chemotherapy. This should be discussed with the doctor before starting chemotherapy.

Most chemotherapy drugs can be harmful to a fetus, and therefore it is crucial to not become pregnant while receiving chemotherapy. Women of child-bearing years need to use a reliable birth control method for the entire time they are undergoing chemotherapy, including the rest periods. Men should use a condom when having sexual relations for 3 days after chemotherapy to protect their spouses from exposure to the drug.

Damage to the kidneys, liver and other organs is rare. There are some unique risks with individual drugs, and these will be reviewed in detail prior to their administration. Chemotherapy patients should avoid overexposure to sun light. Wear protective clothing (brimmed hat, shirt sleeves) and use suntan lotion.

When receiving chemotherapy, and for 3 days after, careful attention should be paid to hand washing after urination, since many chemotherapy drugs are removed from the body in the urine. If family members help with personal care of the patient, they should wear latex gloves when handling urine or vomitus for 3 days after chemotherapy. Clothing soiled with urine, vomit, or feces should be washed separately in hot soapy water.

Women who have menstrual cycles and have not gone through menopause will probably notice a change in their cycle. The bleeding may lessen, become spotty or stop completely. The time between cycles may also change. The menstrual cycle usually changes after one or two complete cycles (42 - 84 days) of chemotherapy. Some women whose menstrual cycles stop undergo menopause, with or without symptoms. Women who are closer to the age of menopause occasionally do not resume menstruating once chemotherapy stops.

When to call the doctor

The doctor or nurse should be called in the following situations:

	signs of infection—fever, chills, pain on urinating, unusual headache, stiff neck, sore throat, or abdominal pain
	signs of possible bleeding—unusual bruising, tiny red spots on the skin, severe headache, unusual abdominal pain, bright red blood from the nose or rectum
	severe nausea and vomiting which is not relieved by the anti-nausea medicine, or if the anti-nausea medicine is repeatedly vomited and there is a concern for dehydration
	development of a skin rash
	development of constipation which is not relieved by usual methods
	decrease in urine output despite drinking usual amounts of fluids.

	CCNU pills day 1
	vincristine injection day 8 and day 29
	procarbazine pills days 8 through 21 (every day for 2 weeks)

Specific Information About Each Drug

Instructions: Take the antinausea medication (for example, Zofran 8 mg pill) 30 to 60 minutes prior to bedtime. Then take the CCNU immediately before going to bed. (For example: if usual bed time is at 11 PM, take the anti-nausea medicine at 10 PM and the CCNU at 11 PM.)

CCNU comes in capsule form and is taken by mouth on day 1 of the chemotherapy cycle. The dose is determined by a formula using height and weight. Several capsules are needed to make up the full dose.

The most common side effect of CCNU is nausea and vomiting. In order to prevent or minimize this, an antinausea drug will be prescribed (see above).

CCNU causes a drop in number of white blood cells and platelets, with the lowest point occurring around 4 – 6 weeks.

The chemotherapy agents in the PCV regimen usually do not cause hair loss. CCNU can cause stiffening of the lungs, but this is rare at the dose of CCNU used in this regimen. Other possible side effects of CCNU which are not common, include sensitive gums, sores in the mouth, and fatigue. Many years after taking CCNU there is a very small risk of a second cancer such as leukemia.

Instructions: Vincristine is given at the hospital by placing a small needle in a vein which is connected to a bag of saline by tubing. The vincristine is in a syringe which is then connected to the tubing and injected by the nurse. The injection only takes a few minutes.

The major side effect of vincristine is to damage nerves in the hands and feet or in other parts of the body. This type or nerve injury is usually a reversible after about six weeks. Typical symptoms of this nerve injury include tingling or numbness of the fingertips and/or toes, an achy jaw and constipation. Tingling or numbness can make it difficult to use buttons or zippers. A diet high in fiber, with plenty of fresh fruits or fruit juices and vegetables will help prevent constipation. Maintaining an active physical program, when possible, will also help prevent constipation.

Nausea and vomiting are so rare with vincristine that anti-nausea medicine does not need to be taken. Vincristine does not affect the blood counts.

Instructions: Procarbazine is taken at bedtime, as with the CCNU (see above), with the anti-nausea pill an hour before. Procarbazine is usually taken as two capsules each night from day 8 through day 21 of each cycle (14 days).

The major side effects of procarbazine are fatigue and loss of appetite, nausea and vomiting, and a decrease in blood counts. The nausea usually occurs with the first three doses (days 8-10), and then disappears for the following 11 days. However, if nausea and vomiting are persistent, the antinausea medicine may be continued for the entire 14 days. A prescription for antinausea medicine (Zofran, Kytril, or compazine) will be provided along with the prescription for the procarbazine.

There are certain foods containing large amounts of tyramine which should be avoided while taking procarbazine. Headaches, nausea, an increase in blood pressure, and a rapid pulse may occur if large amounts of these foods are consumed while on procarbazine. If a restricted food is eaten by mistake, the risk of side effects is very low, and a doctor should be notified only if symptoms develop.

The foods to avoid are:

Aged Meats Cream Raisins

Alcohol Fava beans Sour cream

Avocado Game Soy sauce

Bananas Licorice Yeast extracts

Canned figs Liver Yogurt

Aged Cheeses Meat extracts

Chocolate Meat tenderizers

Also avoid over-the-counter cold medicines while taking procarbazine (decongestants are the main offenders), and reduce the amount of coffee consumed. In fact, it is a good idea to speak with a doctor or nurse prior to starting any new medication while on procarbazine.

Some patients develop a rash while taking procarbazine. This is a form of allergic reaction, and can usually be managed with antihistamines. Call the doctor or nurse prior to taking the next dose of procarbazine if a rash appears while taking procarbazine.

Temozolomide (Temodar)

	Temodar pills days 1, 2, 3, 4, and 5
	Rest period days 6 - 28

Specific Information About Temozolomide

Temozolomide

Instructions:

	eat nothing after midnight prior to each day of chemo-therapy. Temozolomide must be taken on an empty stomach.
	upon arising in the morning, take Zofran 8mg with sips of water
	take temozolomide 30 minutes after the Zofran
	wait one hour and then eat a light breakfast and take other usual medications
	keep a written record of each dose
	obtain a CBC on days 1, 21, and 28

Temozolomide comes in capsule form. The dose is calculated using height and weight. Usually more than one capsule will be needed to make up the full dose. The capsules may be of different strengths.

The most common side effect of temozolomide is nausea, fatigue, and constipation. In order to prevent or minimize this an antinausea drug will be prescribed. Take the antinausea medication (for example, Zofran 8 mg pill) on an empty stomach upon arising each day of chemotherapy. Senekot and Colace are useful to treat constipation.

Temozolomide causes a drop in the white blood count and platelet counts. This typically reaches a low point about 21 days after starting the chemotherapy pills (day 21).

Temozolomide rarely causes hair loss. Other uncommon, but possible, side effects of temozolomide include sores in the mouth.

Neupogen (G-CSF, filgastrim)

Syringes. 3cc syringe with 5/8th inch, 25 gauge needle attached.

Alcohol wipes

	do not shake the vial. If there are frothy bubbles on the surface of the liquid in the vial, allow the vial to sit undisturbed for a few minutes until the bubbles disappear.
	use aseptic technique. Clean the top of the vial with an alcohol wipe, and then wipe a small area of skin at the site of the injection. Sites include top of the upper thighs, abdomen, and back of the upper arm.
	take care to avoid accidental needle sticks push the syringe needle into the vial, turn the vial upside down, and withdraw the entire volume (1 cc) of liquid into the syringe. Remove the syringe, point it upright and carefully expel any air.
	gently pinch the region of skin just cleaned into a large fold with the fingers of one hand, and then stick the needle all the way into the fold with a quick push.
	inject the Neupogen quickly. Remove the needle. Release the skin fold.
	dispose of used materials in a safe manner. All materials (vials of drug, syringes, alcohol wipes, etc.) are designed for single use only. Dispose of syringes in a safe place (for instance, use an empty coffee can or Chlorox bottle, and then place inside a regular trash bag for disposal).

	keep a positive mental attitude
	eat a healthy diet, including plenty of fresh fruits, fruit juices and vegetables to prevent constipation
	drink adequate fluids-- at least 2 quarts a day unless the doctor has recommended a restricted fluid intake. Juices are preferable to plain water
	get some form of exercise-- even a little is better than none. However, avoid exhaustion
	avoid sun exposure. Where a brimmed hat, long sleeves, and use suntan lotion
	be alert to signs of infection or bleeding
	use good handwashing after toileting
	perform good mouth care and personal care
	use anti-nausea medicines as directed. It is easier to prevent nausea and vomiting than to stop it once it starts.
	keep all questions and notes in a permanent notebook

Advice about seizures

Seizures may occur in patients with brain tumors. Seizures can have many different manifestations, but common types are twitching of the face, arm or leg without complete loss of consciousness, and total body shaking with complete loss of consciousness. Following a seizure the patient may be sleepy or confused and there may be increased weakness.

Most seizures are brief and self-limited. If a seizure lasts for 2 minutes or less and the patient returns to normal quickly, make a telephone call to the neuro-oncologist at the Brain Tumor Center (617-724-8770) for instructions (for example, to check the blood level of a seizure medication). If the seizure lasts for more than 3 minutes or if a second seizure occurs shortly after the first, it is usually necessary to call for medical help by dialing 911. Have the doctor at the Emergency Room call the Brain Tumor Center for advice.

In patients with brain tumors, the following activities should be discussed with a neuro-oncologist: driving, operating heavy equipment, swimming, any potentially dangerous activity.

In the event of a seizure, several things are important:

	remain calm and call for help
	protect the patient from sharp objects or dangerous situations during the seizure
	do not put anything in the patient’s mouth. Patients do not suffocate during seizures.
	if vomiting occurs, turn the patient up on their side to minimize the risk of aspiration.

Follow-up tests

An MRI or CT scan is obtained at regular intervals in order to see how the tumor is responding to chemotherapy. Scans are usually obtained after every second cycle (i.e., just prior to the start of cycles 3 and 5, etc.). If new problems arise, it is sometimes necessary to have a scan earlier than these scheduled intervals.

Side-effects of common medications

Decadron: Decadron (dexamethasone) is very useful to reduce swelling around the tumor. It also has many side effects, but these are usually less important than the benefit from taking Decadron. However, it is always a major goal find the smallest dose that is helpful. Side effects include: euphoria, with excessive feeling of well-being and insomnia; increased appetite, especially for sweets; weight gain with fat deposition in the cheeks; high blood sugar, particularly in diabetics; high blood pressure; muscle weakness in the legs (this affects the ability to climb stairs and arise from chairs); stomach ulcers (an acid blocking drug is usually given to combat this); and increased risk of infection (patients on Decadron for more than 2 months should ask about prophylactic Bactrim).

Dilantin: Dilantin (phenytoin) is a common medication taken to prevent seizures. The major side effects of Dilantin are toxic blood levels (too high), and rash. Dilantin toxicity causes clumsiness while walking, much like that of alcohol intoxication. Dilantin rashes are very common and can be dangerous so that the patient must switch to a different medication for seizure control. (Note: changing a seizure medication requires consultation with a neurologist or neuro-oncologist). Some patients experience fatigue with Dilantin, but this symptom is more commonly due to the tumor and its treatment.

Tegretol: Tegretol (carbamazepine) is a common anti-seizure medication. It may cause a rash, may lower the white blood counts, and may cause double vision when levels become toxic.

Depakote: Depakote (valproic acid) is another common anti-seizure medication. The most frequent side effect is a mild tremor in the hands. A rash is much rarer than with Dilantin. This medication is very harmful to the human fetus and should not be taken by pregnant women.

Services of the MGH Brain Tumor Center

Brain Tumor Support Group

The Brain Tumor Support Group meets in the Brain Tumor Center on the 1st and 3rd Tuesdays of the month from 12:00-2:00 PM. The group offers an opportunity for patients and family members to learn about the issues that concern them most, have support provided, as well as an opportunity to meet others living with similar experiences. For more information call (617) 726-7851or (617) 726-1061.

Clinical social workers help patients and their family members find solutions to many problems-- from daily crises to life's most difficult situations. This is accomplished through counseling, active problem solving and direct connection with the network of community and hospital resources. Insurance pre-approval or physician referral are not necessary. The Brain Tumor Center’s social worker can be reached directly at (617) 724-5828.

Physical and occupational therapists assess functional status and provide treatment aimed at maximizing independence and functional capacity. Physical therapists prescribe individualized exercises to address strength, balance, endurance, and pain, and may recommend adaptive equipment. Occupational therapists give instruction in the use of assistive devices, adaptive techniques and hand splints to increase independence in day-to-day tasks. Call (617) 724-6575.

Patients can receive therapy for problems with speech articulation, language, short term memory, and attention. Steps to Success is an intensive 6 week group program for patients with cognitive and language deficits who are returning to work. Referrals are made at (617) 724-0762.

An oncologic psychiatry consultation can be valuable for patients with problems such as clinical depression or anxiety. Referrals are made by calling (617) 726-2405.

Neuropsychological testing can be useful to determine the nature and severity of cognitive problems such as memory loss. Testing can also serve as a valuable baseline for the future. Referrals can be made at (617) 726-3647.

Short glossary of terms used in clinical trials

New chemotherapy agents are evaluated in carefully designed, standard format "trials".

Phase I trial. A small trial, typically with 10 to 12 patients, designed to test the toxicity of various doses of a new agent.

Phase II trial. Larger trial involving more patients to assess whether a new agent from the Phase I level can effectively treat a tumor.

Phase III trial. Very large trial designed to compare how the new agent, from the Phase II level, compares to the best currently available agent(s).

Neoadjuvant trial. Chemotherapy agent is administered after biopsy or surgery, but prior to irradiation.

Adjuvant trial. Agent is administered immediately after surgery and irradiation.

Recurrent (salvage) trial. Agent is administered at the time of tumor progression or recurrence.

MRI scans are used to measure whether the tumor is responding to the new treatment.

Complete response. All radiographic signs of tumor (on MRI or CT) have disappeared.

Partial response. The tumor has been reduced in size by 50% or more, as measured by MRI or CT.

Stable disease. No change in tumor size between two radiographic studies.

Progressive disease. Increase in size of tumor between two studies.

World wide web sites with information about brain tumors

MGH Brain Tumor Center - http://brain.mgh.harvard.edu/

American Brain Tumor Association - http://www.abta.org/

American Cancer Society - http://www.cancer.org

Brain Tumor Clinical Trials - http://www.virtualtrials.com

Brain Tumor Foundation of Canada - http://www.btfc.org

National Brain Tumor Foundation - http://www.braintumor.org

National Cancer Institute - http://cancernet@icicc.nci.nih.gov

New Approaches to Brain Tumor Therapy - http://www.nabtt.org

The Brain Tumor Society - http://www.nabtt.org

Notes to the physicians of patients on PCV

The recommended doses of PCV agents are as follows:

	CCNU 110 mg/m2 p.o. on day 1
	vincristine 1.4 mg/m2 (maximum dose of 2 mg) i.v. on days 8 and 29
	procarbazine 60 mg/m2/day (maximum dose of 100 mg/day) p.o. days 8-21

Zofran (ondansetron) 8 mg orally is excellent for control of CCNU-induced nausea. Compazine 10 mg orally for the first three nights of procarbazine is usually sufficient to control nausea, although some patients do better with ondansetron. Prior to initiation of each cycle, CBC values should be: absolute neutrophil count of 1,500 or greater and platelet count of 100,000. Twenty-five percent dose reduction of CCNU is commonly required to avoid prolonged delays between cycles.

Chemotherapy should be administered by physicians who are trained in medical oncology. The doses of drugs in this booklet are intended as a general guide. The MGH Brain Tumor Center does not take responsibility for medical decisions made by physicians outside the Center.

Notes to the physicians of patients on temozolomide

	The recommended dose of temozolomide is:
	Cycle 1
	temozolomide 150 mg/m2 daily x 5 days (i.e., days 1-5) every 28 days
	check CBC on day 21 (nadir) and d28.