Debating Best First-Line Treatment in Well-Differentiated G3 NENs

High-grade (G3) neuroendocrine neoplasms (NENs), which mainly occur in the pancreas, include both well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinoma. Traditionally, the treatment approach for high-grade NENs is platinum-based chemotherapy. However, there are limitations to the treatment, and not all patients respond well.

During a session at the North American Neuroendocrine Tumor Society annual meeting October 4-6 in Seattle, Washington, panelists debated whether newer targeted agents should be considered for first-line treatment in well-differentiated G3 NETs, and if the standard of care—cytotoxic therapy—should still play a role in first-line treatment.

“We’ve increasingly recognized that this is a very heterogenous group of neoplasms and that for patients with Ki-67 proliferation indexes of less than 55%, platinum-based therapy does not work particularly well,” said Jennifer Chan, MD, MPH, senior physician, clinical director, Program in Carcinoid and Neuroendocrine Tumors, Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School. Other limitations of platinum-based chemotherapy include: non-pancreatic NETs have less response to cytotoxic chemotherapy and no biomarkers exist to predict who will respond to the chemotherapy.

So, that begs the question: what method of treatment should be used as first-line therapy in this patient population? According to Chan, a growing body of evidence points to peptide receptor radionuclide therapy (PRRT) as first-line treatment.

Chan cited a study presented at the European Neuroendocrine Tumor Society 2018 conference¹, which evaluated PRRT in patients with G3 NENs. Halfdan Sorbye, MD, professor in the department of oncology, Haukeland University Hospital, Bergen, Norway, presented results of 149 patients, 46% of whom had well-differentiated disease and the majority (85%) had a Ki-67 index of less than 55%. Some received PRRT as first line, and some received PRRT in later lines. Of those who had data on response to treatment, 42% had either complete or partial response, and 38% had stable disease. The progression-free survival (PFS) was 19 months and overall survival was 44 months.

In another PRRT study of 28 patients², 20 had a Ki-67 index of less than 55% and 20 received radiosensitizing chemotherapy. Of the patients with a Ki-67 index of less than 55%, partial response was 35%, PFS was 12 months, and 45% of patients had stable disease after 3 months of treatment.

Chan also highlighted targeting agents everolimus and sunitinib, although the role of the agents is not well-established.

Despite the growing evidence of PRRT, and although not all patients respond to platinum-based chemotherapy, there is a role for cytotoxic therapy in the first-line treatment of G3 NENs, said Diane Reidy-Lagunes, MD, medical oncologist, Memorial Sloane Kettering Cancer Center (MSKCC). She highlighted 2 main points: not all cytotoxic therapies are the same and timing of the treatment is a critical factor.

Referring back to Sorbye’s trial, Reidy-Lagunes noted that the platinum-based chemotherapy used in the trial was platinum plus etoposide and that other cytotoxic therapies should be considered.

“So, importantly, what others are there? In particular, we know alkylating agents, such as temozolomide, are very active in these diseases,” she explained.

Even within platinum-based therapies, there are variations that invoke different responses. At MSKCC, patients with G3 pancreatic NETs are also treated with FOLFOX and GEMOX, oxaliplatin platinum-based regimens. Within the hospital’s database, patients with Ki-67 indexes less than 55% had a 26% response rate to platinum-based regimens. Those that responded tended to have an oxaliplatin platinum-based regimen, rather than a platinum etoposide-based regimen.

Closing up the session, Reidy-Lagunes argued that cytotoxic therapy should be used in poorly differentiated high-grade NENs and in well-differentiated NETs when a quick response rate is needed. Alkylating agents, in particular, should be considered first in high tumor burden and when tumor shrinkage is the goal.

References

1. Skovgaard D, Fazio N, Granberg D, et al. Peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic grade 3 neuroendocrine neoplasms: a retrospective international multicenter study. European Neuroendocrine Tumor Society. https://www.enets.org/peptide-receptor-radionuclide-therapy-prrt-in-gastroenteropancreatic-grade-3-neuroendocrine-neoplasms-a-retrospective-international-multicenter-study.html. Accessed October 5, 2018.

2. Thang S, Lung M, Kong G, et al. Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN)-a single-institution retrospective analysis [published online September 12, 2017]. Eur J Nucl Med Mol Imaging. doi: 10.1007/s00259-017-3821-2.