PRRT has become a common treatment consideration for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in the second and later lines of therapy. However, PRRT is not without risks, and patients should be well informed of both the risks and benefits of therapy to allow for optimal shared decision making.

When I am counseling patients with GEP-NETs, we talk about the risks, benefits, and goals of each treatment option. The goals when using PRRT are to delay tumor growth and shrink tumors. PRRT is often used in the second-line setting, immediately after progression on an SSA such as octreotide or lanreotide. In the NETTER-1 trial, there was an almost 20% chance of tumor shrinkage in patients with midgut NETs when using ¹⁷⁷Lu-dotatate.

Broadly speaking, PRRT is often very well tolerated, and patients on PRRT may have a good quality of life. However, there are certainly some patients for whom this treatment may not be right. For example, the intensity of PRRT may be too much treatment for very low-volume disease, and we can consider saving this treatment for later, if needed. Further, other patients who may not be good candidates for PRRT are those who are already considered to be too sick to receive treatment.

If I am thinking about using PRRT, the most common side effects that I discuss with patients include fatigue, anemia, leukopenia, and thrombocytopenia, all of which tend to be cumulative over time. We monitor blood counts monthly but typically do not see an effect until toward the end of therapy, and it can be prolonged in some patients. In NETTER-1, approximately 10% of patients on PRRT experienced some degree of hair loss. When something may affect how you look, I think that it is important to talk to patients about it. In addition, a serious but rare side effect of PRRT that receives a lot of press is the development of myelodysplastic syndromes (MDS) and leukemias. Based on prospective studies, they have been reported to occur in approximately 2% to 3% of patients who are given PRRT. Even though their occurrence is somewhat rare, we want to avoid serious long-term side effects that could also impact our ability to give future therapies, as patients with metastatic NETs may live for years.

Other agents that are commonly used in NETs, such as the alkylating agent temozolomide, which is often used for pancreatic NETs, are also associated with an approximate 2% to 3% risk of developing MDS or leukemia. We think that if patients with pancreatic NETs were to take both PRRT and temozolomide at some point in their lifetimes, the rates of MDS and leukemia may be higher. The challenge is that we do not really have great biomarkers or other predictors that can tell us who may be predisposed to developing these severe side effects.

We commonly use liver-directed treatments, including embolization, chemoembolization, and radioembolization, with Yttrium-90 in patients with GEP-NETs. A common question that I get from patients is whether it is safe to receive double radiation to the liver (ie, to receive PRRT before or after receiving Yttrium-90 liver-directed treatment). In the context of side effects, it is not an absolute contraindication, but there is a theoretical risk. It has not been well studied, and the area is under investigation. I would say that the pendulum has swung away from using Yttrium-90 liver-directed therapies because we have better, higher-level evidence for using PRRT. It is not that we never use Yttrium-90, but we typically try to use PRRT first.