Earlier PRRT in Neuroendocrine Tumors: Treatment Selection and the Pharmacist’s Role

Peptide receptor radionuclide therapy (PRRT) is entering earlier treatment discussions for patients with neuroendocrine tumors (NETs), but selecting an appropriate candidate requires more than a pathology report. Disease pace and somatostatin receptor expression help inform whether treatment is appropriate, while coordination between treatment centers and local oncology teams remains essential throughout care.

In recognition of NET Cancer Day, Pharmacy Times spoke with Thomas Hope, MD, professor of radiology and director of theranostics at the University of California, San Francisco, about treatment selection following NETTER-2 and the practical considerations surrounding lutetium Lu 177 dotatate (Lutathera; Novartis). Hope discusses pharmacists’ roles in coordinating somatostatin analog (SSA) schedules, ensuring access to kidney-protective amino acid infusions, and supporting laboratory monitoring. He also shares his approach to radiation safety counseling and highlights the growing need for radiopharmacists.

Pharmacy Times: After NETTER-2, which patients with newly diagnosed, advanced, well-differentiated grade 2 or 3 gastroenteropancreatic neuroendocrine tumors would you consider for first-line lutetium Lu 177 dotatate? What would lead you to choose another treatment first?

Hope: In most neuroendocrine tumor patients, we probably would not use lutetium-based PRRT as a first-line therapy. We often want to understand the pace of disease and see how the patient is doing before making that decision. Additionally, surgery and targeted therapies such as liver-directed therapies are used earlier in the course of disease.

Nonetheless, there is a subset of patients we would consider for first-line PRRT, particularly those with higher-volume disease who are experiencing symptoms and may benefit from a more aggressive first-line systemic therapy rather than starting with somatostatin analogs (SSAs) or targeted treatments. For example, we might consider this in patients with higher-grade tumors, such as those with a Ki-67 in the 20s or 30s.

But that's not always a guarantee. Pathology is not always right, and the pace of disease, or how quickly the tumor is progressing, is much more important than the pathology itself.

Another consideration, particularly in pancreatic neuroendocrine tumors with higher-volume disease, is chemotherapy. CAPTEM, a combination of capecitabine and temozolomide, is an equally effective therapy as PRRT. Based on the available prospective studies, CAPTEM and PRRT have demonstrated similar response rates and progression-free survival, although treatment selection depends on the individual patient.

Many physicians may choose CAPTEM first simply because they can get treatment started faster. There is also an ongoing discussion about whether giving CAPTEM before PRRT, rather than starting with PRRT, could increase the risk of myelodysplastic syndrome. We don't yet know the answer to that question.

I think the broader importance of NETTER-2 is that it brings PRRT earlier into the treatment discussion, particularly among community oncologists who may be less familiar with neuroendocrine tumors. That doesn't necessarily mean we should start every patient on PRRT immediately. Rather, it means we should be thinking about it earlier instead of waiting until a patient has gone through numerous lines of therapy, when it may be too late.

Pharmacy Times: If some lesions show strong uptake on somatostatin receptor PET but others show little or none, how does that affect whether you recommend radioligand therapy?

Hope: If you look at the inclusion criteria for trials like NETTER-1, NETTER-2, and ACTION-1, they all require measurable disease to have uptake greater than the background liver.

Heterogeneous uptake, particularly when some lesions have uptake lower than or equivalent to the liver, can be a problem. Those lesions will not receive a sufficient radiation dose to effectively treat the cancer, meaning PRRT would primarily target the lesions with higher uptake.

Generally speaking, low-uptake lesions would be an exclusion criterion when considering a patient for PRRT.

However, there are circumstances where we might still consider PRRT. For example, if a patient has a liver lesion with low uptake that can be treated with liver-directed therapy, while the majority of their disease maintains high uptake, we could consider combining the two approaches.

Pharmacy Times: What are the most common treatment-day problems pharmacists can help prevent when coordinating somatostatin analog timing, antiemetic premedication, and the kidney-protective amino acid infusion?

Hope: One important area where pharmacists can play a role is ensuring the availability of the kidney-protective amino acid infusion. Years ago, there were limited options for compounded amino acids, so we used a formulation called Aminosyn II, which contains 17 amino acids. Patients frequently experienced nausea and vomiting, requiring extensive antiemetic premedication that often left them somnolent.

We worked closely with our pharmacists to get a manufacturer qualified to compound amino acids, which helped our patients dramatically. For centers looking to offer PRRT, ensuring access to the appropriate amino acid formulation is an important consideration.

Another important factor is coordinating the timing of somatostatin analogs (SSAs) with PRRT. The prescribing information recommends a 4-week interval between long-acting SSA administration and PRRT, so careful coordination of treatment schedules is important.

More broadly, as radiopharmaceuticals begin to play a larger and larger role in oncologic care, ensuring these drugs arrive on time is critical. Unlike conventional chemotherapy drugs, radiopharmaceuticals decay over time and have a limited window in which they can be administered. With PRRT and other radioligand therapies, that window may be 48 hours, 24 hours or even less, depending on when the drug is manufactured.

Delays, including flight disruptions, can become problematic and potentially cause patients to miss treatment. That's why having multiple manufacturing sites around the country and redundant supply chains is critically important.

As more manufacturers enter the field, we can build a more resilient supply chain. Increased competition will also encourage manufacturers to deliver drugs reliably, ensuring patients receive the treatments they need when they need them.

Pharmacy Times: Which changes in blood counts or kidney function between cycles should prompt a pharmacist to flag a possible treatment delay, especially when labs are drawn outside the treating center?

Hope: It's important to distinguish between changes in kidney function and bone marrow function, as they respond differently to PRRT.

Acute changes in kidney function during PRRT are relatively uncommon. If a patient's creatinine rises, indicating worsening renal function, my first concern would not necessarily be toxicity from PRRT. Instead, I would look for other potential causes, such as an obstruction in the kidneys or ureters that prevents urine from draining properly, or a prerenal issue, such as dehydration or cardiac problems that reduce blood flow to the kidneys.

That said, patients with impaired renal function may be at greater risk of kidney injury from PRRT. Kidney toxicity typically develops years after treatment rather than during the course of therapy.

Bone marrow is a different story. Red blood cells, white blood cells and platelets are continuously being produced in the bone marrow, making these cells particularly sensitive to radiation. As a result, PRRT can cause blood counts to decline, including platelet counts, red and white blood cell counts, and absolute neutrophil counts (ANC).

That's why we check labs before each treatment cycle. PRRT cycles are 8 weeks apart, and we check blood counts midway between treatments, around 4 weeks after each cycle, when counts generally reach their lowest point, or nadir.

Checking at that 4-week mark gives us time to assess whether blood counts are recovering, determine if additional testing is needed and decide whether the next treatment should be delayed to allow for recovery.

Ultimately, monitoring these changes between cycles is critical to determining whether a patient can safely proceed with their next dose.

Pharmacy Times: Which at-home radiation safety instructions are most often misunderstood, and how do you tailor counseling for patients who live with young children or someone who is pregnant?

Hope: When I counsel patients on radiation safety, I use what I call the "rule of threes." For three days after treatment, patients should sit when using the toilet, flush twice and wash their hands with soap and water. They should also maintain a distance of at least three feet from others and sleep in separate beds for three days.

One common issue is that patients sometimes receive radiation safety instructions intended for other treatments, such as radioactive iodine (I-131) therapy for thyroid cancer. Iodine is excreted through saliva, so those patients may receive specific guidance about sharing utensils or washing dishes. Those same precautions are not relevant to PRRT, and it's important that patients receive instructions specific to their treatment.

Another common misunderstanding is the relative risk of radiation exposure. We're talking about very low amounts of radioactivity. For example, if I stood three feet away from a patient for 10 hours on the day of treatment, when they're most radioactive, I would receive approximately the equivalent of one chest X-ray. That's a level of exposure comparable to radiation we encounter in everyday life, such as during air travel.

That doesn't mean we shouldn't take precautions. We follow the ALARA principle, which stands for "as low as reasonably achievable." The goal is to minimize unnecessary radiation exposure, even when the potential risks are very small.

I take a more cautious approach when patients live with young children. Even if the risk is extremely low, we want to do everything reasonably possible to minimize their exposure. In those situations, I extend the three-day precautions to seven days.

That doesn't mean patients need to completely isolate themselves from their children. They can still spend time together in the same room while maintaining an appropriate distance. What we want to avoid is prolonged close contact, such as having a child sit on their lap or reading a book together in close proximity.

The key is helping patients understand the actual level of risk while giving them practical precautions that allow them to safely return home after treatment.

Pharmacy Times: After the final cycle, what should pharmacists help put in place when patients return to their local oncology team so delayed toxicities such as persistent cytopenias are caught?

Hope: One of the most important considerations is coordinating the timing of somatostatin analogs (SSAs) and ensuring continuity of care. SSAs are typically administered locally, while PRRT is often administered at a specialized treatment center. It's important to coordinate these schedules and clearly communicate which team is responsible for each aspect of the patient's care, including whether and when SSA treatment should continue.

Ongoing laboratory monitoring is also important, particularly to assess blood counts following the final treatment cycle. The frequency of monitoring depends on the patient's results.

For example, if a patient's hemoglobin is 13 and their platelet count is 138,000 4 weeks after their fourth cycle, I generally wouldn't be too concerned. Bone marrow toxicity typically occurs within the first several weeks after treatment, rather than presenting as a delayed decline in blood counts.

If blood counts look good 4 weeks after the final cycle, patients can generally return to a standard monitoring schedule of approximately every three months. However, if counts remain low, more frequent testing may be necessary to track their recovery.

Ultimately, coordination between the treating center and the patient's local oncology team is critical. The treating physician or nurse should communicate the patient's treatment plan, laboratory results and follow-up needs to the local provider to ensure continuity of care.

Pharmacy Times: Do you have any additional comments?

Hope: One area that deserves more attention is the growing need for radiopharmacists. Unlike traditional pharmacists, radiopharmacists play a critical role in the production and preparation of radiopharmaceuticals, particularly those used in imaging. They're involved in cyclotron facilities and are essential to the broader radiopharmaceutical supply chain.

As radiopharmaceutical therapy and imaging continue to expand, we're in desperate need of more radiopharmacists. It's a critical role and we need to encourage people to join the field.