Some chemotherapy has been used for decades. It is familiar, effective, and still a foundational part of cancer treatment. But what happens when a patient's body is genetically different in a way that changes how that drug is processed?
For some people, that difference can turn a standard dose of chemotherapy into a dangerously high exposure.
On this episode of The Patient From Hell, host Samira Daswani welcomes back Dr. Gabriel A. Brooks, a medical oncologist specializing in gastrointestinal cancers at Dartmouth Cancer Center, for a conversation about DPD deficiency, DPYD genetic testing, and the growing role of pharmacogenomics in cancer care. Dr. Brooks explains why a genetic difference that many patients may never know they have can put them at higher risk for severe, and in some cases fatal, toxicity from two widely used chemotherapy drugs: fluorouracil, also known as 5-FU, and capecitabine.
The episode also explores how patient advocates helped push this issue into the regulatory spotlight, why the United States took longer than Europe to embrace pre-treatment testing, and what patients can ask their oncology team before starting treatment.
Episode Highlights
- What DPD deficiency actually means: The DPYD gene provides instructions for the enzyme dihydropyrimidine dehydrogenase, or DPD, which helps the body break down fluorouracil. Certain DPYD variants can reduce DPD activity and increase the risk of serious toxicity.
- Why the dose can matter differently from patient to patient: A dose that is appropriate for most patients may result in excessive exposure in someone with reduced DPD activity.
- The warning signs of severe toxicity: Dr. Brooks discusses unusually severe diarrhea, mucositis, low blood counts, infection risk, fatigue, nausea, and other symptoms that can signal a serious reaction.
- Why genetic testing matters before treatment: DPYD testing can identify genetic variants associated with increased risk before a patient receives fluorouracil or capecitabine. The FDA now recommends testing for relevant DPYD genetic variants before treatment with these drugs unless immediate treatment is necessary.
- How patient advocacy changed the conversation: Dr. Brooks describes working alongside advocates and families affected by severe chemotherapy toxicity who pushed regulators and medical organizations to take the issue more seriously.
- The questions patients can ask: Before starting fluorouracil or capecitabine, patients can ask whether DPYD testing has been performed and whether the treatment plan accounts for the result.
About Dr. Gabriel Brooks
Dr. Gabriel A. Brooks, MD, is a medical oncologist at Dartmouth Cancer Center whose clinical focus includes gastrointestinal cancers, including colorectal, pancreatic, and hepatobiliary cancers. He is an Associate Professor of Medicine and an Associate Professor of The Dartmouth Institute at the Geisel School of Medicine at Dartmouth. His research includes improving cancer care delivery and developing approaches to make treatment more individualized and safer for patients.
Dr. Brooks became interested in DPD deficiency after caring for a patient early in his oncology fellowship who became critically ill after receiving chemotherapy that included fluorouracil and ultimately died. The experience led him to investigate why some patients experience unexpectedly severe toxicity and eventually to become involved in advocacy surrounding DPYD testing.
What Is DPD Deficiency?
At the center of this episode is a gene called DPYD, which encodes the enzyme dihydropyrimidine dehydrogenase (DPD).
DPD plays an important role in metabolizing fluorouracil. Capecitabine is an oral prodrug that is converted in the body into fluorouracil. When someone has certain genetic variants that reduce DPD activity, the body may not process these medications normally, increasing exposure and the risk of severe adverse reactions.
Dr. Brooks explains that this is fundamentally a pharmacogenomics issue: the genetics of the patient can affect how their body responds to a medication.
That matters because fluorouracil and capecitabine are used across multiple cancer types, including colorectal, rectal, stomach, esophageal, pancreatic, breast, and head and neck cancers.
When Chemotherapy Toxicity Is More Than "Normal"
Cancer treatment often comes with side effects. But Dr. Brooks makes an important distinction during the conversation: not every toxicity should simply be accepted as an unavoidable part of chemotherapy.
Severe diarrhea can cause dehydration. Severe mucositis can make it difficult or impossible to eat. Low white blood cell counts can increase the risk of serious infection, while other blood-count abnormalities can lead to additional complications.
One particularly important point he makes is that severe toxicity from fluorouracil can have a recognizable pattern. Diarrhea may appear early, while some blood-count abnormalities can take ten days or more to develop.
Rather than waiting for severe toxicity to appear, Dr. Brooks argues for identifying patients at increased risk beforehand whenever there is time to test.
The FDA Changes the Conversation
The regulatory landscape has changed significantly in the United States.
The FDA updated the labeling for capecitabine in October 2025 and for fluorouracil in February 2026 to emphasize the risks associated with DPD deficiency. The current FDA communication states that healthcare providers should discuss DPD deficiency with patients and test for DPYD genetic variants before initiating treatment with capecitabine or fluorouracil unless immediate treatment is necessary.
The FDA also notes that patients with complete DPD deficiency are at increased risk for acute, early-onset, serious and potentially fatal toxicity, and that patients with partial DPD activity can also face increased risk.
For Dr. Brooks, this represents a significant shift toward using genetic information before treatment rather than learning about a patient's susceptibility only after a serious reaction occurs.
Why Did It Take So Long?
DPD deficiency has been studied for decades, but widespread implementation of testing in the United States has lagged behind other parts of the world.
As Dr. Brooks describes it, one reason was familiarity. Fluorouracil has been used since the 1950s, and clinicians have extensive experience managing its side effects. That familiarity can make it easy to view toxicity as simply part of chemotherapy rather than distinguishing between unavoidable toxicity and toxicity that may be preventable.
Europe moved earlier. The European Union recommended pre-treatment DPD deficiency screening in 2020, while the United States continued to debate testing, implementation, and how best to interpret different genetic results.
The FDA's more recent labeling changes mark another step toward making DPYD testing part of routine treatment discussions.
The Patient Advocates Behind the Change
One of the most compelling parts of the episode is the story of the patient advocates who helped bring attention to the issue.
Dr. Brooks describes connecting with families whose loved ones had experienced severe or fatal toxicity from fluorouracil or capecitabine. Those advocates eventually organized around the issue through Advocates for Universal DPD/DPYD Testing, petitioning regulators, engaging with organizations that develop clinical guidelines, and sharing their experiences publicly.
The advocacy was not driven by an abstract policy question. It came from families who wanted to prevent other patients from experiencing the same outcome.
The FDA's labeling changes have made this issue more visible, but implementation remains an important part of the story. Regulatory language does not automatically translate into identical practice at every cancer center overnight.
What Should Patients Ask Before Starting Chemotherapy?
Dr. Brooks believes patients should not have to be responsible for knowing every pharmacogenomic consideration before treatment. But he also offers a straightforward question patients can bring to their oncology appointment:
"Do I need to be tested for DPD deficiency or have a DPYD gene test before starting this treatment?"
That question becomes particularly relevant when the treatment plan includes fluorouracil or capecitabine.
Testing generally looks for genetic variants in a patient's germline DNA, meaning inherited DNA rather than DNA from the tumor. Dr. Brooks explains that DPYD testing is increasingly incorporated into some pharmacogenomic panels, and because a person's germline result does not change over time, the test generally does not need to be repeated.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) also maintains clinical guidance on using DPYD genotype information to help guide fluoropyrimidine treatment.
A Bigger Question About Personalized Cancer Care
The conversation about DPD deficiency ultimately points toward a much bigger shift in oncology: personalizing treatment based not only on the cancer, but also on the patient receiving the treatment.
Precision medicine is often discussed in terms of finding mutations or biomarkers inside a tumor. DPYD testing represents a different side of personalization. The question is not only, "What is happening in the cancer?" It is also, "How will this particular patient's body process the treatment?"
For Dr. Brooks, that distinction matters because the goal is not simply to treat cancer aggressively. It is to treat patients as safely and effectively as possible.
Pull Quote
"If something's avoidable, we should seek to avoid it."
— Dr. Gabriel Brooks
Resources
FDA: DPD Deficiency and Fluorouracil / Capecitabine
The FDA's current safety communication explains the risks associated with DPD deficiency and the recommendation to discuss and test for relevant DPYD variants before treatment.
CPIC: DPYD Guidelines
Clinical guidance on using DPYD genotype information to help guide fluoropyrimidine treatment.
Advocates for Universal DPD/DPYD Testing
A patient and clinician advocacy organization focused on increasing awareness and access to DPD/DPYD testing.
Dr. Gabriel A. Brooks — Dartmouth Health
Learn more about Dr. Brooks's clinical and research work in gastrointestinal oncology and cancer care delivery.
Listen to The Patient From Hell
The Patient From Hell is hosted by Samira Daswani, cancer survivor, entrepreneur, and founder of Manta Cares. Through candid conversations with patients, physicians, researchers, and healthcare leaders, the show explores the realities of cancer care while giving patients practical information to help them navigate difficult decisions.
Listen and watch through Manta Cares, YouTube, Spotify, and Apple Podcasts.
Disclaimer
This podcast and accompanying article are intended for general informational and educational purposes only and do not constitute medical advice, diagnosis, treatment, or professional healthcare services. The information discussed should not be used as a substitute for advice from a qualified healthcare professional. Treatment decisions should always be made in consultation with your oncology team and based on your individual medical circumstances.
