DPD Deficiency and Managing Oxaliplatin Toxicities

Heather Greene

Hi Kevin. I’d like to spend this conversation discussing a few things we don’t see often but can be very serious for the patient when they occur. What can you tell me about DPD (or dihydropyrimidine dehydrogenase) deficiency?

Kevin Krise

I read an article about a woman who was diagnosed with cancer and then had a severe reaction after being treated with 5-fluorouracil (5-FU).¹ She was later found to have DPD deficiency. The point of the news story was, "Why didn't they test for this?" DPD deficiency is rare, but it's important for advanced practice providers and anybody who's treating patients with 5-FU or irinotecan to always keep this possibility in the back of our minds.

Heather Greene

DPD deficiency is something that you may see just once or twice in your whole career, really. Regarding the question of why we don't test, the NCCN doesn’t recommend routine testing.² In reviewing the literature, were you able to find the actual incidence of DPD?

Kevin Krise

The one piece of data I was able to find stated that 3% to 5% of adult patients with cancer have at least partial DPD deficiency.³ Our smaller subset of adult patients with colorectal cancer is not teased out in that data. Have you seen any patients in your practice with DPD deficiency?

Heather Greene

I had to think about this for a while, but I can say that in 20 years I've seen only 2 cases that I know for certain had DPD deficiency. It's important to recognize that a lot of times this diagnosis is made clinically initially. DPD is an enzyme that metabolizes 5-FU and capecitabine. So, if you don't have that enzyme, 5-FU will stick around a lot longer and can lead to severe and sometimes life-threatening side effects, including diarrhea, mucositis, and myelosuppression.

These toxicities usually develop more rapidly than in a patient that can normally metabolize 5-FU which of course is the crux of colorectal cancer treatments. So, if you have a patient with severe diarrhea, myelosuppression, or mucositis, within a day or two of starting their 5-FU, it's important to quickly recognize that the patient will likely require hospitalization and administration of uridine triacetate, the antidote. Uridine triacetate must be given within 96 hours of getting 5-FU,⁴ which means you may not be able to wait for the genotype testing to come back.

Kevin Krise

I think I’ve had just a handful of patients with DPD deficiency. One patient I saw many years was in the adjuvant setting, and they got very sick with a life-threatening toxicity. You have to have that difficult discussion with the patient that the risks of the adjuvant therapy likely outweigh the benefits of it. That can be really tough for a patient to wrap their head around. It’s obviously a risk, but this patient was really sick and potentially not going to survive. So, we had to stop the adjuvant treatment.

Heather Greene

Like we said, NCCN doesn’t recommend routine testing, but in this situation, understanding her genotype, if she’s homozygous, can tell us that that patient should never receive 5-FU again. How does that differ with your patients who have UGT1A1 polymorphisms? How is that different in terms of the ability to treat with irinotecan in that setting?

Kevin Krise

It’s important for APPs to have a low threshold when a patient presents with severe diarrhea or myelosuppression after receiving an irinotecan-based therapy. By low threshold, I mean seeing the toxicities that are present and realizing testing and a dose-reduction of irinotecan may be in order.

The difference between DPD deficiency with the 5-fluorouracil-based therapy and then the UGT1A1 is that we can often continue treatment with irinotecan, but at markedly reduced doses, and successfully treat them and manage their toxicity. Have you had that same experience?

Heather Greene

I recently saw a patient in the clinic of another physician. The physician incidentally found UGT1A1*28. The patient had asymptomatic hyperbilirubinemia, known as Gilbert's syndrome. But in preparation for treating her with irinotecan, that physician did UGT1A1 testing.

The patient had UGT1A120 polymorphism, but she was getting her 60th cycle of irinotecan. She had a 25% dose reduction in the irinotecan, mainly for neutropenia, and she's doing excellent. So, we just had to make some clinical adjustments.

Kevin Krise

So, while it’s not the most common thing that we see as APPs working in the colorectal GI malignancy setting, it’s an important possibility to keep in the back of our mind. We don't want to miss this and predispose our patients to more life-threatening problematic outcomes.

Heather Greene

Absolutely. Moving on to another treatment, just like 5-FU can be integral to treating colorectal cancer, it’s the same with oxaliplatin. Anybody who spends a day in a colorectal cancer clinic knows that oxaliplatin has a lot of toxicities, too. How do you balance the benefits of oxaliplatin with the toxicities that we see there?

Kevin Krise

It's vital for us to have very detailed conversations with the patient about what exactly they’re experiencing. While every patient describes their experience a bit differently, our focus is if the treatment is causing pain. Is it causing interference with function? We don't want to push these patients too far with oxaliplatin and then have debilitating outcomes. We need to pay attention to what they’re experiencing and then make dose adjustments as needed. We don’t want to get to a point where there is permanent damage from peripheral neuropathy. The trickier part of this is when we're in the adjuvant setting and we're trying to be as aggressive as possible, give them as much oxaliplatin as possible, and have to face the difficult decision of when to dose reduce or omit the treatment.

What has been your experience?

Heather Greene

I work with a physician who's very in tune to the toxicities associated with oxaliplatin. In our practice and congruent with NCCN guidelines, we rarely give more than 8 cycles of FOLFOX or FOLFIRINOX. We can always reintroduce the oxaliplatin with progression going forward, but that helps stave off a lot of those toxicities when you're trying to balance quality of life with quantity of life.

Kevin Krise

Unlike diabetic neuropathy where some of the neuropathic pain medications, anticonvulsants like pregabalin and gabapentin, are helpful, we don’t see those as beneficial to our patients when we push oxaliplatin and they get chemotherapy-induced peripheral neuropathy. It's a fascinating area, and I know of a study right now that’s using oxaliplatin concurrently with therapy to see if that can help.⁵ Any gains will be good to see because peripheral neuropathy is one of the biggest limiting factors. It’s hard to tell a patient that they need to be dose-reduced or taken off a medication when they want to continue treatment and do everything they can to get better. So, if there's a way that we could prevent or treat symptoms related to oxaliplatin, it would be really helpful.

Heather Greene

Yes, it would be. We know so much more now than we used to, back when everybody got 6 months of oxaliplatin in an adjuvant setting. Now, we try to minimize symptoms and make sure only those patients who are at highest risk get more than 3 or 4 months of oxaliplatin in the adjuvant setting, therefore limiting toxicity if they become metastatic in the future. We don’t want to add fuel to the fire there.

Kevin Krise

Absolutely. Thanks for such a great discussion, Heather.

Heather Greene

I’ve really enjoyed these conversations and getting your perspective on these important issues we face as APPs.