Questions Remain Regarding Combinations and Sequencing in pNETs

Pamela L. Kunz, MD

The treatment of pancreatic NETs (pNETs) now includes four FDA-approved agents: streptozotocin, everolimus, sunitinib, and lanreotide. While some of these agents have been approved for years, researchers are now focusing on the most appropriate way to combine and sequence them. To gain insight into the unanswered questions surrounding the treatment of pNETs, OncLive interviewed Pamela L. Kunz, MD, Assistant Professor of Medicine/Oncology at Stanford University.

What are some of the biggest unanswered questions regarding the treatment of pNETs today?

Some of the biggest unanswered questions are focused on how and when to use these FDA-approved agents: when to start treatment, in what order, and how to combine them.

I think the next generation of trials will be looking at combination therapies and sequencing. In the United States, we will be looking at how to combine somatostatin analogues and cytotoxic chemotherapies with biologic therapies. Can we combine temozolomide with something else? Will the combination be synergistic or is it just additive? And, do somatostatin analogues need to be a backbone to all therapies?

Some of our colleagues in Europe are looking at the sequencing question and whether it is better to start with cytotoxic chemotherapy or a biologic such as everolimus or sunitinib (SEQTOR study).

Additionally, in other solid tumors and hematologic malignancies, immunotherapies have generated considerable enthusiam. In gastrointestinal cancers including NETs, this area has not been well studied, but will likely be in the next 5-10 years.

What is the role of surgery and radiotherapy? Are the roles changing?

A traditional definition of ‘resectable’ for pNETs is similar to that of pancreatic adenocarcinoma. Surgery still plays a role for patients with pNETs — it is the mainstay of treatment for those with localized disease. In some cases for patients with limited metastatic disease — but there have been some shifts regarding timing. Now that we have more effective systemic treatment options for patients with metastatic disease, I think we are reserving surgery for later in the disease course. In addition, given the tumor shrinkage rates we see with agents like temozolomide and capecitabine, neoadjuvant chemotherapy is being considered in some settings.

Regarding radiotherapy, standard external beam radiotherapy plays little role in the routine management of NETs except in the palliative setting. However, I think peptide receptor radionuclide therapy (PPRT), the use of radiolabelled somatostatin analogues, is an area of ongoing and future studies. PRRT is widely available in Europe, though there have not been any rigorous prospective randomized clinical trials. The ongoing NETTER-1 study is evaluating high-dose octreotide versus PRRT in patients with small intestine NETs. I am really hopeful that that same question would be asked for patients with pNETs in a randomized clinical trial. The question would still remain, though, as to where PRRT fits into the treatment algorithm for patients with NETs — we know less about PRRT and its long-term side effects.

You mentioned liver metastases. What are the challenges for an oncologist in this area?

The liver, for many of these patients, poses the riskiest disease site. Liver metastases can cause liver dysfunction, biliary obstructions and infections, and pain. If we can resect liver lesions, shrink them, or use liver-directed therapies to control them, I think these patients will see benefit. There are a number of local therapies we use commonly for patients with NETs: hepatic artery-directed therapies (like chemoembolization and radioembolization) and ablation therapies. The patients for whom I would not consider regional therapies are patients who have extensive extrahepatic disease. For these patients, systemic therapy is most appropriate.