Cyclophosphamide (also known as cytoxan) is an alkylator agent, meaning it has a molecular structure that binds to DNA and creates a "cross-link" that blocks replication of the DNA. It is available in an oral form but is usually given intravenously (through a small piece of tubing inserted into the patient's vein), either in a peripheral (arm) vein or a central line using a Hickman catheter, Broviac catheter, or a port-a-cath. Cyclophosfamide is used with vincristine and doxorubicin.

One of Cyclophosfamide's breakdown products in the body causes a burn to the lining of the bladder, which can lead to bleeding into the urine, called hemorrhagic cystitis. This can be prevented by aggressive hydration and receiving a second protective drug called Mesna. Mesna can be given IV or by mouth and should be taken for approximately twelve hours after a high dose of cyclophosphamide. Because cyclophosphamide kills some of the dividing cells in the bone marrow, it suppresses blood counts: low white blood cells make the immune system weak, low red blood cells (anemia) causes fatigue and short-windedness and can be treated with blood transfusions, and low platelets can increase bruising and bleeding and can be treated with transfusions.

Cyclophosphamide usually causes nausea and vomiting; medicines to prevent and treat this should be given with the dose. It also causes reversible hair loss. In high cumulative doses, it can cause sterility. Men interested in preserving fertility should consider sperm banking before therapy begins. Methods to preserve fertility in females are experimental; women with concerns should discuss this issue with their treating physician before therapy begins.

Doxorubicin is one of the most active chemotherapies against many types of sarcomas. Indeed, the first line treatment for Ewing’s sarcoma often consists of cycles of vincristine, doxorubicin, and cyclophosfamide alternated with cycles of etoposide and ifosfamide.

Doxorubicin (also known as adriamycin) is in a class of chemotherapy drugs known as anthracyclines. It acts mainly by sticking in between DNA base pairs and obstructing replication of the genetic material, thereby inhibiting tumor growth. It is an orange colored clear fluid, given intravenously (through a small piece of tubing inserted into the patient's vein), either in a peripheral (arm) vein or a central line using a Hickman catheter, Broviac catheter, or a port-a-cath. It can be given over a variety of time frames, from 15 minutes to 72 hours.

Because doxorubicin is a vesicant (meaning it can cause severe tissue damage if it leaks out of the vein), it is strongly recommended that it be given in a central line. If given in a peripheral vein using a temporary IV, it must be given carefully by trained oncology nurses. During infusion patients may experience nausea, and, rarely, heart arrhythmias. Doxorubicin has a moderate to high incidence of nausea and patients should be well pre-medicated with anti-nausea medications. It causes hair loss, reddish discoloration of urine, and darkening of the skin and nails.

Doxorubicin causes suppression of blood counts: low white blood cells make the immune system weak, low red blood cells (anemia) causes fatigue and short-windedness and can be treated with blood transfusions, and low platelets can increase bruising and bleeding and can be treated with transfusions. Doxorubicin also causes mucositis, which is inflammation and ulceration of the lining of the mouth, throat, and rectum. It can be severe enough to impact ability to eat, and predispose to rectal infections. Supportive care includes good mouth care (soft toothbrushes and special prescription mouthwashes), stool softeners to avoid rectal tears, and pain medications as needed. Several other medicines are being looked at to treat mucositis; some advocate the use of glutamine, an essential amino acid, available by prescription or at health food stores, to speed mucosal healing.

The most concerning toxicity is cardiotoxicity, or heart damage, usually in the form of congestive heart failure. This is a condition of weakening of the heart muscles, resulting in shortness of breath, swelling of feet and lower legs, fast or irregular heartbeat. The incidence increases with total doses of drug received; it is uncommon with less than 300 mg/m2 and most common in those who get more than 550 mg/m2. Most Ewing’s protocols give in the range of 375 mg/m2 total dose. This cardiotoxicity is monitored for by studies of the heart function such as an echocardiogram (a sonogram that pictures the heart while contracting) or a MUGA (a nuclear medicine scan that quantitates heart contractile strength). These studies should be done while on therapy and then at intervals off therapy. The cardiotoxicity usually occurs within 1-6 months of chemotherapy, but can occur late.

Ongoing studies are looking at very late effects; for example, "What happens when someone who got doxorubicin when they were age 10 gets coronary artery disease at age 55?" Young women who have received doxorubicin should remind their doctor to monitor them carefully during pregnancy, as pregnancy puts an extra strain on the heart. A drug called Dexrazoxane is available that appears to protect the heart from anthracycline toxicity. Because it is not proven that it does not also protect the tumor, it is not recommended that it be given unless the patient is receiving significantly more than 300 mg/m2, or on a clinical trial. Doxil is a formulation of doxorubicin that is released more slowly in the body and therefore has different side effects. It may be as effective as standard doxorubicin in the treatment of sarcoma. It has not been used as primary therapy for Ewing’s but might be considered in recurrent or metastatic cases.

Ifosfamide is an alkylator agent, meaning it has a molecular structure that binds to DNA and creates a "cross-link" that blocks replication of the DNA. It is not available orally, so is given IV over 1-24 hours. Ifosfamide is usually used in alternating cycles with etoposide.

Ifosfamide has all the potential side effects of cyclophosphamide and a few other unique side effects. It can cause kidney damage, either resulting in poor function (as measured by a blood creatinine level or a functional study such as a nuclear glomerular filtration rate) or a problem called Fanconi’s syndrome, in which the kidneys do not properly regulate electrolytes. This is diagnosed by looking at the level of electrolytes (magnesium, phosphorus, bicarbonate, potassium, glucose). It can be temporary or permanent; oral replacement of "washed-out" electrolytes may be necessary.

Because some of ifosfamide’s breakdown products cross into the brain, it can cause neurologic symptoms: encephalopathy (confusion, sleepiness, hallucination), or rarely seizure and coma. These symptoms almost always resolve with discontinuation of the drug. Patients who have mild to moderate symptoms can usually continue to receive the drug; symptoms are lessened if the Ifosfamide is given slower (over 24 hours) and other sedating drugs are avoided.

Vincristine is a "mitotic inhibitor." Mitosis is the process of cell division in which each new cell receives the same amount of DNA as the parent cell. Drugs that block this process are called "mitotic inhibitors" or "antimitotic drugs." Vincristine and other chemotherapeutic agents are given through a small piece of tubing inserted into the patient’s vein either in a peripheral vein (e.g., a temporary IV in the arm) or a central vein via a Hickman catheter, Broviac catheter, or a port-a-cath (also known as a "port"). A port is a device surgically inserted under the skin into a large vein in the chest for long-term use to administer drugs and nutrients and to take blood samples.

Vincristine is a clear solution (i.e., it looks like water) that is injected into the patient over 2 to 5 minutes. Because vincristine is a vesicant (meaning it can cause severe tissue damage if it leaks out of the vein) if given in a peripheral vein, it must be given carefully by trained nurses. Vincristine can be given by itself on an out-patient basis; however, some centers suggest hospital admission when it is given with cyclophosfamide and doxorubicin. The most common dose is 2mg/m2 up to a maximum dose of 2 mg. The specific amount given is usually based on a patient's height and weight.

Vincristine has no immediate toxicities but can cause jaw pain, constipation, foot or leg numbness, pain or weakness (i.e., neuropathy). The pain is treated with Tylenol or stronger pain medicine. The constipation is treated with stool softeners or laxatives. The extremity neuropathy sometimes requires holding or reducing doses of the drug. Rarer side effects are mild suppression of blood counts, hair loss or seizures. There is not a maximum number of times that vincristine can be given to an individual, but too many doses over a given interval (such as when given weekly for more than 6 to 8 weeks) is likely to cause the side effects mentioned above, requiring "time-off" the vincristine.