One death is too many – Especially when it can be prevented. The new MGB policy will benefit patients who are at risk of deadly toxicities from a widely prescribed chemotherapy.
According to Precision Medicine Online, an MGB spokesperson said that the Boston-based system will test patients for changes in the cell’s sequence (variants) that would limit the body’s ability to clear the chemotherapy drug capecitabine (Xeloda). MGB is making the testing available for all patients beginning with the chemotherapy – capecitabine. The spokesperson stated that being tested for DPYD outweighs any risks.
Could this death have been avoided?
Larry Milesky died on May 27, 2023, at the age of 73. The cause of death was a lethal overdose of the widely used chemotherapy drug Xeloda (capecitabine) with oxaliplatin. He was being treated at MGH for colorectal cancer, stage III, that had spread to his lymph nodes. His PET scans were clear.
Larry was the father of three children and worked as a radio marketing consultant. He and his wife Kerin Milesky had been married thirty-three years and enjoyed walking several miles each day.
About Relapse
About one-third of stage III patients with colorectal cancer and positive lymph nodes will have a relapse within five years after surgery. Yet, in certain circumstances, it is preventable.
Larry’s friends and family recounted his love of sports and their gathering at the beach every summer. He did not want chemotherapy as he was very concerned about its toxicity and the effect on his active lifestyle. His wife, Kerin Milesky said that after weighing the risks of toxicities versus the long-term survival benefits, her husband agreed to the oncologist’s plan.
But when they finally performed the DPYD tests and determined Larry had the DPD deficiency it was too late. The cancer had spread and was out of control.
Xeloda’s label indicates that there is no dose proven safe for patients who have a complete absence of DPD activity. Larry’s genotype had been a most studied variant, and he was at high risk of a fatal Xeloda overdose. Within days Larry was in excruciating pain. His oncologist decided to stop chemotherapy. There is an antidote for fluoropyrimidine overdoses manufactured by SERB Pharmaceuticals called Vistogard. It carries a wholesale price of $75,000.
BUT it will only work if given within four days after the last chemotherapy treatment. Larry was well beyond this point by the time Vistogard was given to him.
Over the course of the next few days Larry was in the MGH emergency room having difficulty breathing, an inability to swallow and a pain level of 10. The last 20 days of her husband’s life were a catastrophic decline according to Kerin. Larry went into septic shock, suffered from malnutrition and endured several infections and intubations. She said the chemotherapy burned him internally just as other families often describe the effects of 5-FU and Xeloda on loved ones who have DPD deficiencies.
When Larry’s wife heard about MGB’s change in policy she felt pleased that there has been at least one positive outcome from her husband’s death. It has been encouraging that MGB patients can now be prescreened for the DPD deficiency and be protected from illness and death”.
One in One Thousand . . .
It is estimated that 1 in 1000 patients have two copies of a variant in the DPYD gene resulting in the absence of the DPD enzyme responsible for metabolizing 5-FU and Xeloda. The CPIC, an international guidelines organization, advises reduction of starting doses of 5-FU or Xeloda by 50% in patients with partial DPYD deficiencies.
However, when attending to patients with an active score of zero, the CPIC advises patients to avoid 5-FU or Xeloda entirely.
The NCCN is highly influential in shaping oncology practices in the United States, yet it does not suggest that doctors should test all cancer patients for DPYD variants before prescribing fluoropyrimidines. Although the FDA has updated related chemotherapy labels warning of the risks for patients with reduced or absent DPD activity, the Agency advises patients to consider testing and encourages doctor/patient discussions.
Note that the US-based NCCN does not issue a recommendation that doctors test all cancer patients for DPYD variants.
In addition, the USFDA has updated labels of the chemotherapies warning of the risks to patients who have either reduced or are absent DPD activity but tells doctors to “consider” testing for genetic variants of DPYD before initiating 5-FU and Xeloda then have a discussion with patients. Therefore, the majority of US cancer centers do not screen patients for these variants. Their concern is that dose adjustments may reduce efficacy or that the testing may not identify patients experiencing other chemo toxicities.
As of 2014 doctors who have been supportive of DPYD testing or family members who lost loved ones because they discovered the deficiency too late have petitioned several NCCN committees at least six times only to be ignored. However, at cancer centers where DPD deficient patients have died, the petitioners have been more successful.
If Larry Milesky had known he had DYPD, considering how worried he had been about chemo side effects, his wife is positive that he would not have made the same decision.
Most groups of physicians at DFCI (Dana Farber Cancer Institute) are ordering testing but 100 percent adoption is not the ultimate goal. Physicians should also exercise their judgment. For example, some patients may be tolerant of fluoropyrimidines as a result of having previous treatment at other hospitals. Consideration must be given to the urgency of starting chemotherapy if delaying treatment for even a few days may not be appropriate.
