Skip main navigation

Evidence behind clinical practice guidelines

Cancer chemotherapy has the potential for prolonging lives and regimes that include the fluoropyrimidines lead to improved overall survival rates
Laboratory worker in orange gloves analysing a sample
© University of East Anglia
We will consider the evidence behind clinical practice guidelines described on the PharmGKB pharmacogenomics knowledge resource website
Cancer chemotherapy has the potential for prolonging lives, and regimes that include the fluoropyrimidines lead to responses and improved overall survival for patients with many solid tumours including colorectal cancer.
However, the associated adverse effects can result in serious morbidity, or even mortality. Approximately one fifth of patients suffer from severe adverse events including gastrointestinal symptoms, mucositis/stomatitis, palmar-plantar syndrome, paraesthesia, cardiac toxicity, neutropenia, anaemia, thrombocytopenia and abnormal liver function tests.
If individuals with high susceptibility for adverse effects could be picked up early with predictive tests (biomarkers) appropriate risk mitigation strategies could be put in place, with the option of dose modification and/or the application of supportive therapeutics.
In ideal circumstances, any biomarker would reliably separate out two contrasting groups of patients; those likely to derive considerable benefit from chemotherapy (good tumour response with low risk of adverse effects) as opposed those with poor benefit: harm ratio (limited tumour response with high likelihood of serious harm).
In practice, patients usually have different patterns of clinical response; substantial beneficial tumour response linked to high levels of adverse effects, and vice versa, leading to uncertain clinical utility.
Glossary
Dihydydropyrimidine dehydrogenase (DPD)
This is a key metabolic enzyme that affects the pharmacokinetics of and toxicity of fluoropyrimidines including 5-fluorouracil (5-FU) and its oral prodrugs. Over 80% of 5-FU is catabolised by DPD into non-cytotoxic metabolites. The activity of DPD varies widely between patients. Treatment of patients with fluoropyrimidines is not recommended if they have complete DPD deficiency.
5-Fluorouracil (5-FU)
This is a fluoropyrimidine that has been used as a chemotherapeutic agent for more than five decades.
Capecitabine (CAP)
This is a pro-drug that is preferentially converted to 5-FU in tumour cells, it was designed for oral administration.
DPYD genotypes
DPYD is the gene that encodes DPD. It is highly polymorphic between individuals, with several functionally important and even catalytically inactive alleles described.
Positive predictive value (PPV)
If we consider the performance of a biomarker for a given phenotype; the PPV is the probability that a positive test means that the individual truly has the phenotype.
Negative predictive value (NPV)
If we consider the performance of a biomarker for a given phenotype; the NPV is the probability that a negative test means that the individual does not show the phenotype.
© University of East Anglia
This article is from the free online

Using Personalized Medicine and Pharmacogenetics

Created by
FutureLearn - Learning For Life

Our purpose is to transform access to education.

We offer a diverse selection of courses from leading universities and cultural institutions from around the world. These are delivered one step at a time, and are accessible on mobile, tablet and desktop, so you can fit learning around your life.

We believe learning should be an enjoyable, social experience, so our courses offer the opportunity to discuss what you’re learning with others as you go, helping you make fresh discoveries and form new ideas.
You can unlock new opportunities with unlimited access to hundreds of online short courses for a year by subscribing to our Unlimited package. Build your knowledge with top universities and organisations.

Learn more about how FutureLearn is transforming access to education