American Cancer Society
Find Support and Treatment: http://www.cancer.org/treatment/index
Guide to Cancer Drugs, specifically 5-FU: http://www.cancer.org/treatment/treatmentsandsideeffects/guidetocancerdrugs/fluorouracil
This page encourages you to discuss conditions with your doctor before starting treatment and here is what is said about DPD deficiency:
"If you have ever been told you have a dihydropyrimidine dehydrogenase (DPD) deficiency. DPD is an enzyme the body uses to process this drug. This inborn genetic abnormality can cause extreme side effects if you use 5-FU (even on your skin) or capecitabine. DPD deficiency can be present without symptoms, so you may not know you have it until you get one of these drugs or are tested for it."
This page also lists possible side effects for which you should be alert and not bashful about discussing with your doctor at the first sign of trouble. If you think your reaction is not normal, do not ignore the problem.
Colon Cancer Alliance www.ccalliance.org
Enter 5-FU into the website's global search tool to find info on topics Chemotherapy and Biologics (here it identifies the drugs and the side effects but it does not discuss the probability of severe toxic reactions), Treatment Side Effects (no grading of the toxic effects), and Personal Stories among other related topics.
Live Strong www.livestrong.org
Good support organization to help prepare for treatment but lacks specifics for dealing with individual treatment regimens such as 5-FU.
"Our mission is to provide financial support for the Prettitore Family and to raise awareness of DPD deficiency while striving to make patient testing for DPD Deficiency a requirement prior to 5-FU based chemotherapy treatments."
US Food and Drug Administration (FDA)
The FDA publishes label warnings for drugs used in chemotherapy treatments.
The package insert the FDA requires for Fluorouracil Intravenous use contains the following information:
Warning (Box Warning)
"It is recommended that fluorouracil be given only by or under the supervision
of a qualified physician who is experienced in cancer chemotherapy and who
is well versed in the use of potent antimetabolites. Because of the possibility
of severe toxic reactions, it is recommended that patients be hospitalized at
least during the initial course of therapy.
"Fluorouracil therapy is contraindicated for patients in a poor nutritional state, those
with depressed bone marrow function, those with potentially serious infections or
those with a known hypersensitivity to fluorouracil.
WARNINGS (see boxed WARNING)
THE DAILY DOSE OF FLUOROURACIL IS NOT TO EXCEED 800 MG. IT IS
RECOMMENDED THAT PATIENTS BE HOSPITALIZED DURING THEIR FIRST
COURSE OF TREATMENT.
"Fluorouracil should be used with extreme caution in poor risk patients with a history
of high-dose pelvic irradiation or previous use of alkylating agents, those who have
a widespread involvement of bone marrow by metastatic tumors or those with
impaired hepatic or renal function.
"Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and
neurotoxicity) associated with 5-fluorouracil has been attributed to deficiency of
dihydropyrimidine dehydrogenase activity (emphasis added here). A few patients have been rechallenged with 5-fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and
progressed with worse morbidity. Absence of this catabolic enzyme appears to
result in prolonged clearance of 5-fluorouracil.
"Pregnancy: Teratogenic Effects – Pregnancy Category D. Fluorouracil may cause
fetal harm when administered to a pregnant woman. Fluorouracil has been shown
to be teratogenic in laboratory animals. Fluorouracil exhibited maximum
teratogenicity when given to mice as single intraperitoneal injections of 10 to 40
mg/kg on day 10 or 12 of gestation. Similarly, intraperitoneal doses of 12 to 37
mg/kg given to rats between days 9 and 12 of gestation and intramuscular doses of
3 to 9 mg given to hamsters between days 8 and 11 of gestation were teratogenic.
Malformations included cleft palates, skeletal defects and deformed appendages,
paws and tails. The dosages which were teratogenic in animals are 1 to 3 times the
maximum recommended human therapeutic dose. In monkeys, divided doses of 40
mg/kg given between days 20 and 24 of gestation were not teratogenic.
"There are no adequate and well-controlled studies with fluorouracil in pregnant
women. While there is no evidence of teratogenicity in humans due to fluorouracil,
it should be kept in mind that other drugs which inhibit DNA synthesis (e.g.,
methotrexate and aminopterin) have been reported to be teratogenic in humans.
Women of childbearing potential should be advised to avoid becoming pregnant. If
the drug is used during pregnancy, or if the patient becomes pregnant while taking
the drug, the patient should be told of the potential hazard to the fetus. Fluorouracil
should be used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
"Combination Therapy: Any form of therapy which adds to the stress of the patient,
interferes with nutrition or depresses bone marrow function will increase the
toxicity of fluorouracil.
"General: Fluorouracil is a highly toxic drug with a narrow margin of safety.
Therefore, patients should be carefully supervised, since therapeutic response is
unlikely to occur without some evidence of toxicity. Severe hematological toxicity,
gastrointestinal hemorrhage and even death may result from the use of fluorouracil
despite meticulous selection of patients and careful adjustment of dosage. Although
severe toxicity is more likely in poor risk patients, fatalities may be encountered
occasionally even in patients in relatively good condition.
Therapy is to be discontinued promptly whenever one of the following signs of
Stomatitis or esophagopharyngitis, at the first visible sign.
Leukopenia (WBC under 3500) or a rapidly falling white blood count.
Diarrhea, frequent bowel movements or watery stools.
Gastrointestinal ulceration and bleeding.
Thrombocytopenia (platelets under 100,000).
Hemorrhage from any site.
"The administration of 5-fluorouracil has been associated with the occurrence of
palmar-plantar erythrodysesthesia syndrome, also known as hand-foot syndrome.
This syndrome has been characterized as a tingling sensation of hands and feet
which progress over the next few days to pain when holding objects or walking. The
palms and soles became symmetrically swollen and erythematous with tenderness
of the distal phalanges, possibly accompanied by desquamation. Interruption of
therapy is followed by gradual resolution over 5 to 7 days. Although pyridoxine has
been reported to ameliorate the palmar-plantar erythrodysesthesia syndrome, its
safety and effectiveness has not been established."
The package insert the FDA requires for Xeloda use contains the following information:
Contraindications (in other words, not to be used when the following conditions are known)
• "Dihydropyrimidine dehydrogenase (DPD) deficiency
• Severe Renal Impairment
Warnings and Precautions
• "Diarrhea: May be severe. Interrupt XELODA treatment immediately until diarrhea resolves or decreases to grade 1. Recommend standard antidiarrheal treatments.
• Coagulopathy: May result in bleeding, death. Monitor anticoagulant response (e.g., INR) and adjust anticoagulant dose accordingly.
• Cardiotoxicity: Common in patients with a prior history of coronary artery disease.
• Pregnancy: Can cause fetal harm. Advise women of the potential risk to the fetus.
• Hand-and-Foot Syndrome (Grade 2 or 3): Interrupt XELODA treatment until the event resolves or decreases in intensity.
• Hyperbilirubinemia (Grade 2 to 4): Interrupt XELODA treatment immediately until the hyperbilirubinemia resolves or decreases in intensity.
• Hematologic: Do not treat patients with neutrophil counts <1.5 x 109/L or thrombocyte counts <100 x 109/L. If grade 3-4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves.
"Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported."
National Comprehensive Cancer Network (NCCN) http://www.nccn.org/professionals/physician_gls/f_guidelines.asp
This site contains guidelines oncologists rely upon to detect and treat all forms of cancer. The guidelines for treating colon, rectal, anal, breast, head/neck cancers do not contain warnings concerning the risk of treating DPD deficient patients with 5-FU -- see also Petitions.