From a historical perspective, 5-fluorouracil (5-FU) is widely recognized to have been one of the most useful and widely used antineoplastic drugs in cancer management, having previously been an essential component of standard therapeutic regimens for cancers of the breast and ovary, as well as all malignancies involving the gastrointestinal tract. Even today, 5-FU remains a standard drug in the treatment of advanced colorectal cancers, both as adjuvant therapy in the "curative" setting and as a strategy to extend survival and palliate symptoms in the management of metastatic disease.
The side effect profile of 5-FU has been well established, and includes bone marrow suppression, mucositis, stomatitis, diarrhea, emesis, "hand-foot syndrome," and neurologic (cerebellar ataxia, somnolence, seizures) as well as cardiac (angina, myocardial ischemia) effects.
A somewhat poorly defined group of patients appears to have a very high risk of experiencing severe life-threatening toxicity following administration of this agent.[1,2] Defining this population has been made more complex by virtue of the fact that 5-FU is commonly administered as a component of a combination chemotherapy regimen (eg, with leucovorin, oxaliplatin, and/or irinotecan in patients with colorectal cancer,) which makes it more difficult to appreciate the specific contributions of each individual drug.
The basic pharmacology and mechanism of 5-FU cytotoxicity are well understood: the drug inhibits tumor-associated thymidylate synthase (TS) and subsequently results in the failure of the malignant cell population to replicate. Of note, one important mechanism of cancer cell resistance to 5-FU results from an ability to overcome the drug’s inhibitory effects on TS; consequently, overexpression of TS is associated with an inferior response and survival.[3] However, there remains no solid evidence that results of pre-therapy testing for TS expression should be used to influence treatment decisions or can be used to favorably affect outcomes.
The enzyme dihydropyrimidine dehydrogenase (DPD) is responsible for the metabolism of 5-FU and more than 80% of the agent is rapidly metabolized to a nontoxic metabolite following drug delivery. It has been hypothesized that genetic control of 5-FU metabolism as well as the inherent biological control of TS may substantially influence both the toxicity experienced and the overall clinical effectiveness of the agent.
More than 25 years ago, a genetic defect with autosomal recessive inheritance that resulted in severe deficiency in DPD activity was initially documented. The presence of this mutation in a patient receiving 5-FU therapy was found to result in a profound delay in the elimination of the biologically active agent and in the production of severe toxicity, particularly febrile neutropenia, thrombocytopenia, anemia, mucositis, stomatitis, diarrhea, emesis, maculopapular rash, and neurologic effects.[1,2] Since that time, a number of genetic variants of this defect have been identified, with some resulting in partial and others complete deficiency of DPD.
DPD deficiency is thought to also result in severe toxicity in patients taking the 5-FU prodrug capecitabine, which is used in the treatment of breast and gastrointestinal cancers, even though there are few data on this issue specific to the drug.
While the potential clinical relevance of this genetic abnormality on the risk of serious 5-FU is clear, its actual prevalence within the population is quite low at < 1.5%.[1] Some reports have suggested a higher incidence of DPD abnormalities -- to approximately 3% -- if genetic defects that produce a more moderate impact are included.[2]
There are no reasonably specific clinical features (eg, age, sex, ethnicity, etc) that are known to substantially increase the statistical likelihood that DPD deficiency will be identified if a routine screening strategy were implemented within a specific population. As a result, one would potentially need to argue that all patients receiving 5-FU-based chemotherapy are at risk for the presence of DPD deficiency -- a conclusion that almost certainly would not be considered an acceptably cost-effective approach to disease management.[4]
In addition, it remains uncertain how patients with a pre-therapy identification of DPD deficiency should be managed. For example, if such an individual has an advanced colorectal cancer, should treatment with 5-FU be withheld? Should the dose be reduced? If yes, given the absence of any objective data in this area, should the dose reduction be 25%, 50%, or some other rather arbitrary percentage?
More important, will such a preventative approach actually be effective in eliminating the recognized excessive risk for the development of life-threatening side effects? Or will a strategy that substantially modifies an evidence-based anti-neoplastic regimen known to be highly clinically active in this setting actually result in a major reduction or perhaps even elimination of any therapeutic benefits associated with the administration of this agent? Unfortunately, the answers to these highly clinically relevant questions remain unknown.
To make matters even more complex, available evidence indicates that not all patients with a demonstrated genetic defect experience excessive side effects following exposure to 5-FU-containing chemotherapy. And, conversely, even within the population of patients who experience serious side effects following treatment with 5-FU, a subsequently documented DPD deficiency is only found in a minority of individuals.
At this time, based on the low population-based incidence of DPD deficiency as well as on the uncertainty regarding how patients with this specific genetic defect should ultimately be managed, it is difficult to suggest that routine testing for DPD deficiency should be considered a component of standard oncologic management associated with the administration of 5-FU-based therapy.
That being said, for the individual patient who experiences unexpected severe side effects, it is not unreasonable to obtain such an analysis for the purpose of understanding why this specific outcome developed in this patient.
The side effect profile of 5-FU has been well established, and includes bone marrow suppression, mucositis, stomatitis, diarrhea, emesis, "hand-foot syndrome," and neurologic (cerebellar ataxia, somnolence, seizures) as well as cardiac (angina, myocardial ischemia) effects.
A somewhat poorly defined group of patients appears to have a very high risk of experiencing severe life-threatening toxicity following administration of this agent.[1,2] Defining this population has been made more complex by virtue of the fact that 5-FU is commonly administered as a component of a combination chemotherapy regimen (eg, with leucovorin, oxaliplatin, and/or irinotecan in patients with colorectal cancer,) which makes it more difficult to appreciate the specific contributions of each individual drug.
The basic pharmacology and mechanism of 5-FU cytotoxicity are well understood: the drug inhibits tumor-associated thymidylate synthase (TS) and subsequently results in the failure of the malignant cell population to replicate. Of note, one important mechanism of cancer cell resistance to 5-FU results from an ability to overcome the drug’s inhibitory effects on TS; consequently, overexpression of TS is associated with an inferior response and survival.[3] However, there remains no solid evidence that results of pre-therapy testing for TS expression should be used to influence treatment decisions or can be used to favorably affect outcomes.
The enzyme dihydropyrimidine dehydrogenase (DPD) is responsible for the metabolism of 5-FU and more than 80% of the agent is rapidly metabolized to a nontoxic metabolite following drug delivery. It has been hypothesized that genetic control of 5-FU metabolism as well as the inherent biological control of TS may substantially influence both the toxicity experienced and the overall clinical effectiveness of the agent.
More than 25 years ago, a genetic defect with autosomal recessive inheritance that resulted in severe deficiency in DPD activity was initially documented. The presence of this mutation in a patient receiving 5-FU therapy was found to result in a profound delay in the elimination of the biologically active agent and in the production of severe toxicity, particularly febrile neutropenia, thrombocytopenia, anemia, mucositis, stomatitis, diarrhea, emesis, maculopapular rash, and neurologic effects.[1,2] Since that time, a number of genetic variants of this defect have been identified, with some resulting in partial and others complete deficiency of DPD.
DPD deficiency is thought to also result in severe toxicity in patients taking the 5-FU prodrug capecitabine, which is used in the treatment of breast and gastrointestinal cancers, even though there are few data on this issue specific to the drug.
Is There Value in Screening for DPD Deficiency?
The clinical relevance of DPD deficiency was highlighted in a report that found patients taking 5-FU experienced a 55% risk of experiencing severe (grade 4) neutropenia vs only 13% in individuals with normal DPD activity.[1]While the potential clinical relevance of this genetic abnormality on the risk of serious 5-FU is clear, its actual prevalence within the population is quite low at < 1.5%.[1] Some reports have suggested a higher incidence of DPD abnormalities -- to approximately 3% -- if genetic defects that produce a more moderate impact are included.[2]
There are no reasonably specific clinical features (eg, age, sex, ethnicity, etc) that are known to substantially increase the statistical likelihood that DPD deficiency will be identified if a routine screening strategy were implemented within a specific population. As a result, one would potentially need to argue that all patients receiving 5-FU-based chemotherapy are at risk for the presence of DPD deficiency -- a conclusion that almost certainly would not be considered an acceptably cost-effective approach to disease management.[4]
In addition, it remains uncertain how patients with a pre-therapy identification of DPD deficiency should be managed. For example, if such an individual has an advanced colorectal cancer, should treatment with 5-FU be withheld? Should the dose be reduced? If yes, given the absence of any objective data in this area, should the dose reduction be 25%, 50%, or some other rather arbitrary percentage?
More important, will such a preventative approach actually be effective in eliminating the recognized excessive risk for the development of life-threatening side effects? Or will a strategy that substantially modifies an evidence-based anti-neoplastic regimen known to be highly clinically active in this setting actually result in a major reduction or perhaps even elimination of any therapeutic benefits associated with the administration of this agent? Unfortunately, the answers to these highly clinically relevant questions remain unknown.
To make matters even more complex, available evidence indicates that not all patients with a demonstrated genetic defect experience excessive side effects following exposure to 5-FU-containing chemotherapy. And, conversely, even within the population of patients who experience serious side effects following treatment with 5-FU, a subsequently documented DPD deficiency is only found in a minority of individuals.
At this time, based on the low population-based incidence of DPD deficiency as well as on the uncertainty regarding how patients with this specific genetic defect should ultimately be managed, it is difficult to suggest that routine testing for DPD deficiency should be considered a component of standard oncologic management associated with the administration of 5-FU-based therapy.
That being said, for the individual patient who experiences unexpected severe side effects, it is not unreasonable to obtain such an analysis for the purpose of understanding why this specific outcome developed in this patient.
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