The risk to patients comes in two forms: 1) the chemotherapy agent and 2) the resistance of oncologists to change treatment practices because of the belief that the condition that puts patients at risk is a “rare” genetic condition.

 

The Chemotherapy Agent: Fluorouracil

 

Fluoropyrimidine Drugs  (i.e., 5-FU (Fluorouracil™),  oral capecitane-( Xeloda™) have been the primary chemotherapy agent used for many years to effectively treat patients with colon, rectal, and anal cancer, and in some cases for patients with breast, and head/neck cancer.  This class of compounds  is used in combinational regimens with other cytotoxics known as: LV-5FU2, FOLFOX4, FOLFOX6, FOLFIRI (digestive cancers),  TPF (Head and Neck Cancers), FEC 100 (Breast Cancers).  Capecitabine can be given either alone or as part of combinational therapy (CAPOX, XELIRI).  Though used for many years, medical journals increasingly point out the risk of its use and are urging care in the administration of fluoropyrimidine drugs (see Research).

Severe toxic reactions affect between 10%-40% of patients and lead to at least 500-1000 deaths in the USA (see Research, Caudle et al., Zhu et al.). Toxic reactions, or adverse events, are graded on a scale of 0, no adverse reaction, to 5, death.  Grade 3 is a severe toxic reaction and a Grade 4 is a life threatening reaction; hospitalization is typical in either Grade 3 or 4 reactions.  Severe side effects may include stomatitis, mucositis, diarrhea, neutropenia, cardiotoxicity and neurotoxicity.  Grade4 neutropenia with sepsis (whole body inflammation caused by infection) is the most frequent cause of treatment-related deaths with fluoropyrimidine  drugs.

Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at a high risk of suffering these severe toxic reactions. In the liver, the DPD enzyme is necessary for the body to metabolize 5-FU into inactive metabolites and keep it from destroying healthy cells.  Normally, more than 90% of the injected dose of 5-FU is rapidly cleared in the liver by DPD, and only a small amount of drug will act as a cytotoxics.  As a consequence, and although variable depending on the regimens, standard dosing of fluoropyrimidine drugs is normally elevated (e.g., 600 mg/m²/d for 5-FU, and 1250 mg/m²/d for capecitabine) because it takes into account that 90% of the dose is normally deactivated in the body.   

In most cases, people will not know they suffer this DPD deficiency unless specifically tested, and deficient patients treated with standard dosage may face overexposure to the drug and subsequent severe/lethal toxicities.

 

There is an antidote for instances where an error in dosage is detected immediately; however, there is no antidote to help the effects of “over dosing” experienced by patients with deficient DPD levels.   It is therefore imperative that you discuss with your doctor how to manage your risk of exposure to 5-FU before your first chemotherapy treatment.

 

Standard Oncological Practice: 5-FU, No Pre-Screening to Detect At Risk Patients

 

The National Comprehensive Cancer Network (NCCN) provides guidelines widely used for the detection and treatment of cancer (see Resources ).  The NCCN holds that "impaired dihydropyrimidine dehydrogenase (DPD) activity is a rare occurrence” (see Petitions).   It, therefore, has not moved to prescribe pre-screening of patients or to reduce the initial dosage of patients. Unfortunately many oncologists hold this same belief and this puts patients at risk.

 

In addition, genetic tests are generally not part of pre-screening because they cannot reliably predict all the patients at risk.  That is in part because science needs to identify more of the genetic conditions that contribute to DPD deficiency AND because non-genetics factors (e.g. drug to drug interactions and circadian variations) also contribute to compromised DPD activity (see Research, Ciccolini et al./Gamelin et al.).  Screening DPD deficiency on a sole genetic basis is considered as an underpowered strategy today, because the number of patients displaying some known genetic polymorphism is far less than the number of patients displaying severe toxicities upon 5-FU administration, and that epigenetics or non-genetics factors may be unaddressed.

 

“Functional” tests that detect DPD activity level are used successfully in France to drastically reduce toxicities and fatalities associated with 5-FU or capecitabine  treatments (see Research) but these tests are not yet widely adopted in the USA (see Resources).

 

Reduce Your Risk

 

Talk with your doctor about the risk of your chemotherapy and how you may reduce it.  Ask your doctor to test your DPD activity level before your first treatment. If that type of test is unavailable to your doctor, ask to start with a lower initial dose of 5-FU which the doctor can adjust after monitoring the effects of the drug on you (see Research, Caudle et al. ; Diasio et al., and see Hope).

 

When you have this conversation with your doctor, not only will you be looking out for your health, you will serve to increase awareness of this risk and help shape the future of health care for patients -- pay it forward.