The main clinical challenge in treating pancreatic neuroendocrine tumors (NETs) is sequencing therapies. Once the tumor progresses after treatment with a somatostatin analogue, clinicians must decide whether to choose chemotherapy, peptide receptor radionuclide therapy (PRRT), or embolization. According to experts at the 2023 Great Debates & Updates in Gastrointestinal Malignancies, the choice comes down to chemotherapy for relatively aggressive disease, PRRT for strong somatostatin receptor expression, and hepatic arterial embolization for liver-dominant, relatively unaggressive disease.
Pancreatic NETs make up less than 2 percent of pancreatic cancers, but they tend to have a better prognosis than the more common type.
"Pancreatic NETs are unique in that their genomic profile has several characteristic mutations linked to key pathways. Other NETS are bland genomically in comparison," noted Arvind Dasari, MD, Associate Professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center. "Clinically, we have become more aggressive and prognosis has improved, but pancreatic NETs still lag behind small bowel and other sites. Unlike most other treatments for NETs where we use all available therapies, we need to know how to sequence therapies to decide which one to use first. In the future, we need treatment unique to pancreatic NETs related to drug development or to the biology of the tumor to replace other alkylating agents, such as chemotherapy and temozolomide."
Study Details
CompareNet is a Phase II, randomized, prospective trial of lutetium Lu-177 dotatate PRRT versus capecitabine/temozolomide in well-differentiated pancreatic NETs. This trial, currently recruiting, will be important to show the potential to assess long-term toxicity differences between these treatments, answer important real-world questions, and provide important data for future trial combinations and prospective data for well-differentiated, Grade 3 NETS, as well as important insight into the sequence question, Dasari noted.
The first prospective, multicenter, randomized trial of capecitabine and temozolomide versus temozolomide in advanced pancreatic NETs was the E2211 Phase II study. Objective responses were high in both arms, with a trend toward improvement from 34 percent to 40 percent with the combination. The study met its primary endpoint of progression-free survival (PFS) at the time of interim analysis, with median PFS improving to 22.7 months with the combination versus 14.4 months with temozolomide alone.
More adverse events were noted with the combination, including twice as many Grade 3/4 events (44%) than with temozolomide alone (22%). Temozolomide-associated toxicity was mostly cytopenias. Gastrointestinal toxicity was higher with capecitabine. Importantly, there was a trend of MGMT deficiency associated with PFS and overall survival (OS). MGMT loss is noted in 60 percent of all pancreatic NET patients.
"MGMT loss may predict loss of response to temozolomide. The results suggest the benefit of temozolomide may be limited to a subset of patients," Dasari said.
The randomized, controlled, NETTER-1 trial evaluated the efficacy and safety of lutetium-177 Lu dotatate versus octreotide long-acting repeatable in patients with advanced, progressive, somatostatin receptor-positive midgut NETs. About 80 percent of patients received intensive therapy. The overall response rate was 18 percent in the lutetium Lu-177 dotatate group versus 3 percent in controls. PFS improved from 23 months to 45 months with the experimental treatment. For patients with indolent tumors such as NETs, it is hard to show a survival benefit, but there was a strong trend in OS in favor of lutetium Lu-177 dotatate (48 months vs. 36 months, HR: 0.84), Dasari noted. Adverse events included minor nausea and vomiting. Cytopenias were not very common-about 10 percent Grade 3/4-but should be monitored, he said. Long-term toxicity showed a slight risk of myelodysplastic syndrome and leukemias.
Researchers are now looking for further iterations of PRRT. Alpha emitters have a shorter range, higher energy transfer, are more selective, and potentially have higher efficacy. Early data show some clinical efficacy and prospective trials are ongoing. PRRT is safe and effective, especially in pancreatic NETs, and data from prospective trials suggest PRRT may be more effective than other established therapies in pancreatic NETs.
"Early treatment with PRRT may be more effective and also allows for subsequent retreatment with PRRT. Ongoing trials will further improve outcomes with PRRT through combination therapies and with novel radioligands such as alpha emitters," said Heloisa Soares, MD, PhD, Medical Oncologist at the Huntsman Cancer Institute at the University of Utah. "In relatively aggressive disease, I favor chemotherapy. With strong somatostatin receptor expression, I prefer PRRT."
There have been selected studies of chemotherapy in pancreatic NETs. The European-based SEQTOR trial is a randomized, open-label, Phase III study that compared the efficacy and safety of everolimus followed by chemotherapy with streptozocin (STZ)-5FU upon progression or the reverse sequence in advanced progressive pancreatic NETs. There was no large difference in PFS at first treatment between the two groups. The response rate was higher with chemotherapy (30%) versus everolimus (11%). The results suggest that STZ-5FU should be the first option when tumor shrinkage is a priority, the authors stated.
The differences in safety profile may also inform treatment choice for selected patients. Toxicity was more pronounced with the chemotherapy arm.
"In the U.S., we tend to use temozolomide," Soares said. "Response rate in most studies is between 30 and 40 percent. I favor chemotherapy when patients are symptomatic and need to quickly relieve symptoms. When making a treatment decision, I take into account the grade-higher grade tumors benefit more; for volume of disease for symptomatic tumors, I give chemotherapy over PRRT; and for the need for response, if the need is urgent, I give chemotherapy. PRRT logistics and coordination of care take more than 1 month. Cytotoxic therapy can be provided in a few weeks."
Mark L. Fuerst is a contributing writer.