Treatment combinations for pancreatic neuroendocrine tumors

Well-differentiated pancreatic neuroendocrine tumor

A new paper has recently been released in Digestion: International Journal of Gastroenterology that reviewed previously reported European trials. These trials specifically aimed at the treatment of advanced pancreatic neuroendocrine tumors outlined several combinations of chemotherapy drugs used to help with progression free survival (PFS). Pancreatic neuroendocrine tumors (PNETS) are still relatively rare in the umbrella of all gastroenteropancreatic tumors (GEP-NETS or just NETS) and certainly amongst pancreatic lesions in general. From an earlier study that compared data from the USA, Western Europe and Japan, it was discovered all NETS were on the rise, including PNETS.

PNETS On The Rise

Generally, PNET diagnosis in the USA was slightly higher than in Europe, with a higher male predominance in France, USA and Norway, but a female predominance in Italy. In the USA, from data collected in the SEER database, pancreatic NETs were more common in Whites and African Americans than in Asian Americans and American Indians. The most recent US study, showed an increase of incidence rates (IRs) from 0.17 in 1973–1977 to 0.43 in 2003–2007. There were major differences in how the IRs showed up in the database because how the disease was coded between pancreatic neuroendocrine tumor vs islet cell tumors. Generally speaking, since many PNETS are non-functional, they are not diagnosed until there was considerable progression in disease, about 60% – 905, in fact. That presents issues for a patients whose disease is rare and can be difficult to treat.

When Chemo is Considered for PNETS

There is still some controversy in terms of what are the best lines of treatment particularly when dealing with advanced PNETS. While surgery is still considered the best for improving long-term survival, when multiple unresectable metastases are present, systemic treatments are indicated. So, if you have a primary pancreatic tumor and other metastases on your liver or other distant sites such as your bones or other organs, surgery won’t work.

Ki-67 proliferation index, also known as just Ki-67, is a nuclear protein that is present in cellular proliferation. A higher Ki-67 rate indicates the faster your cancer cells are dividing and growing. Ki-67 is frequently used to help a doctor determine the best course of treatment for a patient.

Generally speaking, if you Ki-67 is less than 10%, Somatostatin analogues (SSA) such as Sandostatin-LAR and Lanreotide are prescribed. They can provide symptom relief, and in many cases, can keep disease stable. But, when a patient progresses under SSA or has a Ki-67 greater than 10%, systemic treatments are then indicated.

Therapies Described In Study

Three centers; Uppsala in Sweden, Berlin and Marburg in Germany, that were included in this paper, are all European Centers of Excellence. Each designed studies that focused on the use of several chemotherapy drugs, used in combination, for the treatment of advanced PNETS. The drugs they used in various combinations include streptozocin (STZ), temozolomide (TEM), dacarbazine (DTIC), and antimetabolites such as 5-fluorouracil (5-FU), and capecitabine (CAP). Anthracycline doxorubicine (Dox) has limited application due to its cardiotoxicity. Present practice includes a regimen of STZ and 5FU.  The Moertel protocol (used in Germany) and the Uppsala protocol (Sweden protocol), both commonly used in clinical practice are regiments that combine STZ with 5-FU. In either protocol, patients had response rates of 27% – 48% and disease control rates as high as 92%.

TEM therapy has a long tradition of use in glioblastoma and melanoma. Combined with CAP, it’s become an alternative to IV chemo and become quite popular. TEM alone, had marginal benefits for PNETS, but, combined with CAP in a regimen commonly known as CAPTEM, has has good response rates and tolerability, but, limited availability to data from trials. It is considered an alternative, but, not superior to 5-FU & STZ. Further studies are needed to clarify this, so the recommendations may change over time. As a side note, 5-FU works in a similarly to capecitabine.

Finally, DTIC has also been described as being studied also in triple combinations with 5-FU, and epirubicin or leucovorin, or as a monotherapy for advanced PNETS. It shares a similar metabolite to TEM, which has had success in the treatment of advanced PNETS. The enthusiasm to use it, however, has been low based on different schedules and dosages having severe toxicities.

Targeted therapies such as everolimus (Afinitor) and sutitinib (Sutent) were approved for use about five years ago. Patients achieved about 10% objective response with the median progression-free survival being 6 – 12 months. Both of these drugs are considered second and third line treatments after a patient has progressed using either chemo or somatostatin analogues. It is not described in what sequence these drugs should be used.

The SEQTOR trial is currently assessing the use of 5-FU & STZ followed by everolimus vs. the reverse order. This European study is being performed at multiple centers, so those results are still unknown. Further, there are no studies that describe comparing the efficacies of targeted therapies, chemotherapies or somatostatin analogue therapies.

The complex nature of advanced PNETS requires a multi-modal therapy that requires a multidisciplinary team consisting of surgeons, nuclear physicians, gastroenterologists, and oncologists. The lack of data comparing existing treatments is the largest challenge for clinicians, and future studies need to address comparison and sequence of all the described treatments.

The entire study, Role of Cytotoxic Chemo in Advanced Pancreatic Neuroendocrine Tumors, can be read in its entirety.