The French 5-FU cancer chemotherapy scandal: from inaction to indifference of the authorities. The importance of strong, determined action by citizens.
ANNETTE LEXA, Toxicologist
FEBRUARY 5, 2025
For the Canadian case, click here
Every year in France, hundreds or even thousands of cancer patients die, not because of their disease, but because of an anticancer drug, 5-Fluorouracil (5-FU), which proved toxic for them due to an enzymatic deficiency in DPD (Dihydropyrimidine dehydrogenase). A simple pre-therapeutic blood test could prevent these tragedies; unfortunately, it’s Russian roulette since not all oncologists do it.
Roselyne’s case, France
Roselyne has breast cancer that has metastasized to bone and liver. She was given oral CAPECITABINE MYLAN. CAPECITABINE MYLAN is a long-standing anticancer agent, widely prescribed mainly for advanced metastatic digestive adenocarcinoma, colorectal cancer, and relapsed breast or squamous cell adenocarcinoma of the upper aerodigestive tract and esophagus. It is used in 45% of chemotherapy protocols, often in consolidation.
80,000 patients (fluorouracil) and 30,000 (capecitabine) are treated every year in France*. However, this drug is responsible for 20-25% of severe to grave grade 3-4 irreversible polyvisceral toxicities and 2% of fatal toxicities. Deficiencies in the enzyme responsible for 5FU metabolism vary from partial to total. Capecitabine is a long-standing, well-known drug that brings an average survival rate of 10 months to patients with metastatic cancers.
*Capecitabine is a prodrug of 5-FU and has the same cellular mechanism as 5-FU.
A week after the start of treatment, the first symptoms appeared: mucositis and red cheeks. On the morning of Saturday, September 10, Roselyne called the cancer center to describe her first symptoms. She was told that the resident on duty could not see her. Faced with this refusal, Roselyne and her family went to the CHU emergency room. The doctor came to see her at reception. The family handed over the medical information leaflet. After going through it quickly, the doctor tells her there’s nothing wrong and advises her to rinse her mouth with degasified Coca-Cola and go to the Maison Médicale if she wants a prescription. At the Maison Médicale, she was told not to stop the treatment but to halve it, which was not what the leaflet recommended. Over the weekend, her condition worsens. The skin on her legs began to necrose, and swallowing caused her unbearable pain. On Monday, the family finally managed to contact the oncologist, but he refused to see Roselyne on the pretext that she had an appointment with him nine days later. He asks her to send him photos of her legs. He makes a remote diagnosis of toxidermia and advises her to stop treatment, indicating that he will prescribe another type of chemotherapy at the scheduled appointment.
The leaflet indicates :
-This drug should not be taken in cases of known deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD) involved in uracil and thymine metabolism.
– Contact your doctor immediately in the event of sudden onset of the following side effects: nausea, diarrhea, inflammation, pain and bleeding in the digestive tract and mouth, bone marrow depression (a decrease in certain types of white blood cells that can only be detected by a blood test).
– Stop taking CAPECITABINE MYLAN immediately and contact your doctor if any of the following symptoms occur: diarrhea, vomiting, nausea, stomatitis (mouth ulcers, pain, and swelling of the throat), hand-foot skin reaction (redness, tingling, purplish spots on the skin, redness of the palms) and facial edema, frequent urination, incontinence, etc.
Over the following days, symptoms worsened: facial edema, diarrhea, polyuria, abnormal sensation of thirst, urge to urinate, very damaged vaginal mucosa, numerous mouth ulcers and a significantly damaged mouth, hyponatremia, and high blood sugar. She was admitted to the CHU emergency department, where her type 2 diabetes was identified as the cause.
Transferred to intensive care, it took another three days before a late blood test finally revealed that Roselyne was in aplasia and septic shock. The oncologist testified that CAPECITABINE was to blame but that these symptoms should pass within three weeks. Within days, Roselyne developed septicemia, fell into a coma, and died. We are in 2016.
Two days before her mother’s death, her daughter Audrey had searched the Internet and discovered an identical case in Canada. The article stated that a small percentage of patients have an enzyme deficiency, DPD, which prevents them from eliminating fluoropyrimidine-based chemotherapies such as 5-FU or capecitabine.
The family brought the documents they had found on the subject to the intensive care unit two days before death. Contrary to the healthcare team, who had refused to look for the cause, focusing instead, in vain, solely on the effects, Audrey had found the cause – DPD deficiency. Unfortunately, it was too late.
A post-mortem DPD genotyping sample confirmed that Roselyne was homozygous and therefore totally DPD-deficient, meaning that she was unable to degrade 5-FU, which accumulates in the body and leads to the necrosis and death of all the body’s rapidly dividing cells (digestive and vaginal mucosa, white blood cells in the bone marrow, skin), leading to severe internal hydro-electrolytic imbalance (kidney and heart damage) and total immune collapse, culminating in death.
Roselyne had no chance of survival from the moment she took her first CAPECITABINE tablets.
This fatal risk is even more unacceptable given that, before starting treatment, she could have been prescribed the screening test that exists, which is simple, inexpensive, and accessible when the patient is informed in an informed manner. This did not happen.
Current scientific data show that :
-Hematological toxicity is present in 10% of patients.
-Hand-foot syndrome in 15-37% of patients
-Severe diarrhea in 15% of patients
-Neutropenia (infectious risk) in 39% of patients
These are all serious to fatal, acute, early-onset, and irreversible toxicities, requiring at the very least immediate treatment and sustained medical follow-up to mitigate the visceral damage, at least in the case of partial DPD-deficient heterozygotes.
The family then petitioned the Administrative Court to determine whether fault or negligence existed. The family was never informed of the existence of this genetic deficiency nor the existence of two possible tests, phenotyping (€40) or genotyping (€200). Some oncologists felt offering it to those who could afford it was discriminatory. Worse still, the family tried to raise the alarm but was confronted with the ignorance of a large part of the medical profession about the cytotoxicity of this drug. Moreover, the family had to contend with the difficulty of accessing medical records and the omerta surrounding the issue.
A family that will fight…
…for the sake of the common good, above and beyond the pain of the disease and the loss of a loved one…
Roselyne’s family has set up an association, the Association of 5FU Victims, AV5FU (https://www.association-victimes-5-fu.com), and has succeeded in gaining recognition for the usefulness of testing for this deficiency, which makes it possible to predict grave to fatal toxicity.
In April 2019, the ANSM issued rules requiring mandatory testing for DPD deficiency. The test is now reimbursed, even if it is far from being systematically offered.
In 2023, the Alliance nationale des associations victimes des produits de santé (ANAVIPS), of which the AV5FU is a member, reports that compliance with the obligation is still imperfect. In the case of the Centre Hospitalier de Saint-Quentin, for example, compliance is only 21%, while for the remaining 79%, it’s Russian roulette.
Open letter to Dr. Christelle Ratignier-Carbonneil, Director General of ANSM, to the Directors General of ARS, and to Thomas Audige, Chief Inspector of IGAS, Marseille, January 13, 2023
At the national level, knowing the test’s prescription rate is difficult. For patients treated with capecitabine but not reimbursed for a uracilemia test recorded in the SNDS**, it is impossible to tell whether a test was performed in a hospital. In addition, as 5-fluorouracil treatment is exclusively hospital-based, part of the hospital package (GHS), and not reimbursed as an extra charge, it is impossible to identify patients treated with fluorouracil in the SNDS. Difficult to monitor when you don’t want to know…
**The SNDS stands for Système National des Données de Santé (National Health Data System); the data it contains are used, among other things, for surveillance, monitoring, and health safety; it is fed by health insurance data, hospital data, medical causes of death (CépiDC database), etc…
For 2021, out of 19,787 patients who began treatment with capecitabine, 11,714 had at least one DPD screening test reimbursed (i.e., performed in a private medical biology laboratory). Of these 11,714 patients, 10,876 had at least one reimbursed test before initiating capecitabine. In comparison, for the remaining 838 patients (out of 11,714 = 7.2%), the uracilemia test (date estimated based on the reimbursement of the procedure) was performed either on the day of the dispensation of capecitabine or after dispensation. The number of patients not correctly tested is 19,787 – 10,876 = 8911, i.e. 8911 / 19,787 = 45%.
For 2022, out of 19,349 patients who started treatment with capecitabine, 10,913 patients had at least one reimbursed DPD screening test (i.e., performed in a private medical biology laboratory). Of these 10,913 patients, 10,115 had at least one test reimbursed before initiating capecitabine. In comparison, for the remaining 798 patients (out of 10,913 = 7.3%), the uracilemia test (based on procedure reimbursement) was carried out either on the day of capecitabine dispensing or after dispensing. The number of patients not correctly tested is 19,349 – 10,115 = 9234, i.e. 9234 / 19,349 = 47.7%.
Since then, the ANSM has stopped releasing figures, but according to them, all is well: (see here two letters).
The three levels of safety put in place by ANSM, i.e., verification of the test result when prescribing and dispensing chemotherapy and alerting by LAPs (Prescription Assistance Software), were ineffective for 79% of patients treated. The ANSM will respond in 2024, pledging to send emails to ARS (Agences Régionales de Santé) to ensure compliance with the 5FU pre-prescription test.
The severe dysfunctions (ANSM, ARS, prescribing physicians, hospital pharmacovigilance departments) testify at best to a kind of carelessness and, at worst, to serious negligence.
All patients affected by severe cancer in France have the right to be informed of the existence of this test before being prescribed and administered 5FU.
For further information:
The Canadian case
Thanks to many documents on the Canadian case received from Renée Pellerin, we have been able to write the following synthesis.
Renée Pellerin is an investigative journalist and author of the book ” Conspiracy of Hope ” and kindly allowed us to publish excerpts from her work.
Summary C.Bour
The context:
In 2018, a patient was given capecitabine without first being tested for dihydropyrimidine dehydrogenase (DPD) deficiency.
The gentleman developed vomiting, rash, and diarrhea after chemotherapy for colon cancer. The hospital failed to provide uridine triacetate (an antidote for 5FU poisoning) on time, and the patient died. The patient’s widow filed a wrongful death lawsuit against Oregon Health Sciences University (OHSU). She helped found a nonprofit organization called Advocates for Universal DPD/DPYD Testing ( AUDT ) that advocates for DPD deficiency testing in patients receiving fluoropyrimidines (5FU and capecitabine).
The National Comprehensive Cancer Network (NCCN) clinical practice guidelines, and even ASCO (American Society of Clinical Oncologists), still do not require screening for DPD genetic variants before fluoropyrimidine-based chemotherapy and even oppose mandatory screening.
The NCCN is a network of 33 cancer centers in the United States. It is an authoritative organization of experts in the field of cancer which promotes cancer care and research. The NCCN publishes treatment guidelines written by various committees, such as the Colon Cancer Panel. The NCCN argues that while dose adjustment of fluoropyrimidines based on DPD genotype has been shown to reduce toxicity to patients, it is uncertain, the organization says, that dose reductions would not result in lower efficacy. It also claims that 96% of patients treated with uridine triacetate (the antidote to 5FU toxicity) survived and had rapid reversal of severe cardiac and neurological toxicity.
The US Food and Drug Administration (FDA)* package inserts for capecitabine and fluorouracil (FU) acknowledge that patients with dihydropyrimidine dehydrogenase (DPD) protein deficiency are at increased risk of life-threatening toxicity.
* The FDA is an agency of the US Department of Health and Human Services that ensures the safety, efficacy, and security of drugs, vaccines, and medical devices.
Daniel Hertz, a professor of pharmacology (Michigan), has been very active in the US AUDT group lobbying the FDA to require systematic testing.
Now, the FDA has softened its position and proposes a surprising scenario in which patients with authenticated DPD deficiency should discuss it with their physician.
However, the European Medicines Agency and the French National Agency for the Safety of Medicines and Health Products (ANSM), after a fierce struggle by a citizens’ association (see the article above), have approved guidelines for preemptive screening for DPD in patients treated with fluoropyrimidines.
Test variants and effectiveness
DPD deficiency is the partial or complete loss of DPD enzyme function. Several variants of the enzyme have been studied in clinical studies of 5-FU toxicity, and these genetic variants do not all alter DPD enzyme activity to the same extent, nor do they cause toxicity of the same magnitude.
Several studies and meta-analyses have analyzed the association between specific variants and the prediction of fluoropyrimidine toxicity and have identified 4 main variants that pose a risk for the patient to express this toxicity. These four variants have reproducibly shown a significant association with an elevated risk of severe 5-FU toxicity.
Many methods have been used to identify patients with DPD deficiency.
Genetic testing is currently the most promising for individualizing the deficiency and adjusting the 5-FU dose according to the form and severity of the deficiency without altering survival in those with deficiencies requiring a reduction or adjustment of the 5-FU dose during their cancer treatment, as various studies have shown.
Guidelines
In 2023, the Ontario Health Cancer Care OntarioAction (an agency created by the Ontario government with a mandate to connect and coordinate the health care system in the province of Ontario for the best possible care) issued guidelines.
This organization makes several recommendations:
1- Patients on fluoropyrimidine-based treatments should be informed of DPD deficiency, the available tests to detect the deficiency, and the potential risks associated with fluoropyrimidine treatment if a deficiency is proven. It is important to note that with universal access to DPD testing, the risks should be minimized.
2- Prospective DPD genotyping should be included in planning fluoropyrimidine-based therapies.
3- Before initiating fluoropyrimidine-based treatments, patients should be screened for the presence of one of the 4 clinically relevant DPD variants.
4- Initial dose adjustments for fluoropyrimidine treatments should be made according to the identified DPD genotype as part of an informed discussion with patients based on risks and benefits. In subsequent cycles, the dose should be readjusted according to patient tolerance to reduce toxicity and optimize treatment efficacy.
Guidelines for implementing DPD testing are as follows:
• Patients who may be candidates for fluoropyrimidine therapy should be identified at the first visit (e.g., first meeting with an oncologist), and testing should be performed as early as possible.
• Successful implementation will require integration of DPD testing into a standard pre-chemotherapy check-up.
• Genetic testing results should lead to an initial treatment plan that also includes other risk factors for toxicity, as well as patient characteristics and values; treatment plans should be tailored to consider patient tolerance.
Screening for DPD deficiency, the organization recalls, has been recommended by several regulatory bodies, including the European Medicines Agency (EMA) and the National Institute of Excellence in Health and Social Services (INESSS), and has been adopted as a standard of care in Quebec, the Netherlands, France, Italy, and Belgium.
CONCLUSION
The Ontario Health Cancer Care Ontario Action concludes that screening tests not only improve patient safety and potential outcomes but also reduce healthcare and costs associated with treatment-related adverse events.
Clearly, in Canada and France, determined citizen initiatives have been needed to advance the safety of patients treated with 5FU.
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