Interest in pancreatic neuroendocrine tumors (pNETs) has grown since the recent approval of targeted agents for advanced disease, as was evident by the attendance at several sessions during the European Society for Medical Oncology (ESMO) 2012 Congress in Vienna, Austria.1
Kjell Öberg, MD, of Uppsala University in Sweden, noted, “These tumors are steadily increasing, compared with other malignant neoplasms. It’s not a rare disease any longer, and we don’t know why. Partly, it’s better awareness among physicians. This room at ESMO is filled. And also, better diagnostic methods and treatment opportunities.”
“Still, there is usually a delay of 4 to 5 years from first symptom to diagnosis, and 50% of patients present with metastatic disease. They have an indolent course, but median overall survival [OS] is only 33 months, and that is not very impressive,” he said.
The good news, added Tim Meyer, MD, of University College London in the United Kingdom, “is that with pNETs we are now in the luxurious position of having lots of treatments. The question now is, which is best?”
Prior to May 2011, options were limited. For patient with hormonal symptoms, octreotide LAR could be beneficial, and for oncologic control streptozocin-based chemotherapy was indicated. Upon disease progression, patients went on to investigational agents or regional therapy; no approved therapies were available.
But identification of somatic mutations in the mTOR pathway in pNET formed the scientific rationale for testing mTOR inhibitors in this disease. The 410-patient RADIANT-3 trial demonstrated that everolimus could effectively prolong remission, from a median progression-free survival (PFS) of 4.6 months with best supportive care alone to 11.0 months with everolimus, representing a 65% reduction in risk (P <.0001).
An understanding of the role of the angiogenesis pathway in pNETs also led to the development of sunitinib for this malignancy. The phase 3 trial showed median PFS increased from 5.5 months with placebo to 11.4 months with sunitinib, which was a 58% reduction in risk; this did not reach statistical significance due to early termination of the study and truncated enrollment.
“We have clear and convincing evidence that everolimus and sunitinib are effective in improving PFS,” Meyer told attendees.
James C. Yao, MD, of the University of Texas MD Anderson Cancer Center, Houston, added, “Both everolimus and sunitinib result in about 6 months of PFS benefit, but neither study was designed to evaluate overall survival.” He explained that because these tumors are rare, and patients live for years, clinical trials with an OS end point are not feasible, and an OS might not be formally demonstrated.
“Nonetheless, we actually do have improved survival,” he suggested. “When we only had streptozocin, median OS was 16 to 24 months. With the newer drugs, we are pushing OS to 3 years and beyond.”
He added that while the drugs have almost equivalent PFS benefit, everolimus has activity in controlling hormonal output from pNETs. “It is the most active agent I have seen for controlling hypoglycemia in patients with insulinoma,” he noted, “and it may reduce gastrin and glucagon as well.”
Algorithm for Managing Patients
Yao said he approaches the initial management of pNETs by considering the disease burden (ie, the percentage of liver involvement), the aggressiveness of the tumor (ie, Ki67 levels, tumor grade), and the primary site of the tumor.
“If I have a patient with low-volume, very low-grade disease, I think that surveillance or a somatostatin analogue is reasonable. For the opposite, a patient with 50% liver involvement and a high Ki67, chemotherapy may be the best starting point. For the intermediate patient, targeted therapy is a good choice,” he maintained.
To decide whether to treat with everolimus or sunitinib, Yao said, “There has been no head-to-head comparison. Practically speaking, most pNET patients will receive both agents at some time, but there are some factors to help you decide.”
He believes that everolimus is the preferred choice for the patient with a functional tumor or a high risk of bleeding, such as patients with a primary tumor at the tail of the pancreas and those with gastric varices. Everolimus also is preferred for patients with coronary artery disease, congestive heart failure, or uncontrolled hypertension. Sunitinib would be favored for patients with severe lung disease and uncontrolled diabetes, he said.
- Öberg K, Meyer T. NETs and endocrine tumors. Presented at: European Society for Medical Oncology 2012 Congress; September 29, 2012; Vienna, Austria. Proffered paper session.