PRRT Effective and Safe as Salvage Therapy for GEP and Bronchial NETs

Wouter van der Zwan, MD

Tumor response rates after initial treatment with peptide receptor radionuclide therapy (PRRT) have proven clinical benefit; however, complete response is uncommon. It is more likely than not that residual tumors will develop and progress again, and retreatment with extra cycles of PRRT as salvage therapy can be considered when safer and more efficient alternatives are not available.

At the 10th Annual North American Neuroendocrine Tumor Society (NANETS) Symposium, efficacy, progression-free survival (PFS), overall survival (OS), and toxicity data were presented regarding a cohort of patients with bronchial and gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) who had been treated with salvage PRRT with 177-Lu[Dota⁰,Tyr³]octreotate.¹

Study author Wouter van der Zwan, MD, research physician within the PRRT team at the Department of Nuclear Medicine of the Erasmus University Medical Center in the Netherlands explained that somatostatin receptors on the cell membranes are frequently expressed in the slowly-growing bronchial and GEP NETs. These receptors end up being an ideal target for therapy with Lutetium-177-labeled somatostatin analogues. Per the results of the study, outcomes regarding PFS and OS are comparable to that of somatostatin analogs, chemotherapy, or targeted therapies.

While 177-Lu[Dota⁰,Tyr³]octreotate is most frequently used in a neoadjuvant setting, it may also be used in adjuvant setting after surgery. Data shows that retreatment with additional cycles of 177-Lu[Dota⁰,Tyr³]octreotate does not lead to serious hematological or nephrotoxic side-effects, however, the reported tumor response rate was lower compared with initial treatment when the drug is used as a salvage therapy.

In a cohort of a study conducted by researchers at the PRRT Treatment Center Rotterdam from the Erasmus University Medical Center, 33 eligible patients with progressive disease after an initial radiologic or clinical response were treated with 2 additional cycles with an intended dose of 14.8 GBq of 177-Lu[Dota⁰,Tyr&sup3;]octreotate.2 Responses were evaluated using Southwest Oncology Group criteria, including minor response (tumor size reduction of &ge;25% and <50%).

After a median follow-up time of 16 months (range, 1-40), the intended cumulative dose was not achieved in 4 patients, 2 of whom had progressive disease. The other 2 suffered from long-lasting thrombocytopenia. Hematologic adverse events (AEs) of grade 3 was observed in 4 patients, and a grade 4 hematologic AE was observed in another. No kidney failure or myelodysplastic syndrome was observed in any patients, and 8 patients experienced renewed tumor regression (2 partial remissions, 6 minor responses). Eight patients were reported to have stable disease. The median time to progression was 17 months.

Patients with pancreatic NETs and GEP NETs experienced similar treatment effects, however, no patients enrolled in the study developed serious delayed adverse events (AEs), and it was concluded that the majority of patients tolerated additional cycles well. Reported effects among some in the study included weight loss and bone metastases, but neither responses were statistically significant.

It was frequently assumed that additional cycles with 177-Lu[Dota⁰,Tyr&sup3;]octreotate could potentially have exhibited antitumor effects; however, effects were less than for the regular cycles. This may be the result of a worse clinical condition, more extensive tumor burden, or changed tumor characteristics. Additionally, antitumor effects could potentially remain less favorable than with initial treatments because the administered activity for the additional therapy is approximately half that of regular treatments, which would lead to lower levels of radiation being delivered to the tumors.

Of 14 patients who were re-re-treated with PRRT,1 Van der Zwan said that the median PFS was 14 months (n = 12; 95% CI, 9.8-18.2) and the median OS was 29 months (n = 14; 95% CI, 4.6-53.4). Across the entire treatment period from initial treatment to salvage therapy, the OS was 77 months (95% CI, 63.1-91).

Following salvage therapy, grade 3/4 bone marrow toxicity was experienced in 7.1% of patients. No grade 3/4 nephrotoxicity was observed that was related to PRRT.

The decision to administer an intended dose of 2 cycles was made to try to avoid long-term side effects in patients, and it was concluded by the study&rsquo;s authors that the drug, when used as a salvage therapy, can be both effective and safe.

References

1. van der Zwan W, Brabander T, Kam B, et al. PFS and OS after salvage peptide receptor radionuclide therapy (PRRT) with 177-Lu[Dota⁰,Tyr&sup3;]octreotate in patients with gastroenteropancreatic or bronchial neuroendocrine tumours (GEP-NETs) — The Rotterdam Cohort. Presented at: 10th Annual NANETS Symposium; October 19-21, 2017; Philadelphia, PA. Abstract 284.2. van Essen M, Krenning EP, Kam BLR, et al. Salvage therapy with 177Lu-Octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumors.J Nucl Med. 2010;51(3):383-390. doi: 10.2967/jnumed.109.068957.