Combining the chemotherapy streptozotocin with drugs that target the mTOR pathway may be an effective way to treat pancreatic neuroendocrine tumors (pNETs), according to findings presented at the 2015 North American Neuroendocrine Tumor Society symposium. Using the two types of drugs together was found to effectively target tumors in both 

Most pNETs are generally resistant to chemotherapy because they have a low proliferation rate and defects in their apoptotic pathway. Therapies that target the mTOR pathway have shown some benefit against pNETs, but their effect is limited.

Based on the literature, researchers have hypothesized that overactivation of the mTOR pathway could lead to resistance to streptozotocin, according to lead author Cécile Vercherat, PhD, a researcher at the Centre de Recherche en Cancérologie de Lyon (CRCL) in Lyon, France. Thus, she and her team decided to combine streptozotocin with a drug that inhibits mTOR.

In the current study, the investigators evaluated streptozotocin in combination with four different mTOR inhibitors: everolimus (Afinitor) and three experimental agents—MK2206, BKM120, and BEZ235.

Streptozotocin, a natural product that was originally developed as an antibiotic, has been used to treat pancreatic islet cell tumors since the 1980s. It is the standard first-line chemotherapy for pNETs that cannot be treated with surgery.

The FDA approved everolimus in 2011 to treat pNETs, but its effect is limited because the majority of patients develop resistance to the drug.

In the first part of the research, the investigators used the insulinoma cell lines INS-1E and MIN6 to evaluate cell viability, proliferation, and apoptosis when streptozotocin was combined with mTOR inhibitors. They found that all four combinations had a synergistic effect, leading to heterogeneous mTOR pathway inhibition and increased apoptosis.

Somewhat surprisingly, Vercherat said, they found that when insulinoma cell lines were treated with streptozotocin, there was a “transient but important activation of the mTOR pathway.”

The four combinations were also evaluated in animal models that were created by injecting tumor cells into the spleens of mice. This experimental model results in primary tumors that form on the spleen and tumor nodules that form in the liver.

The animals were divided into groups for treatment with a control and groups for the four different mTOR inhibitors, each combined with streptozotocin. All four experimental groups showed decreased tumor dissemination, which was measured by a reduction in the tumor surface, and a decrease in the mean tumor size in the liver nodules, although there were differences seen in the effectiveness of the different mTOR inhibitors.

Side effects, including hyperglycemia, were seen in the mice treated with BKM120, but the researchers were able to avoid this effect by decreasing the dose.

 suggested a synergistic effect between the two types of treatment. According to the researchers, the findings of their study suggest that the combination of mTOR inhibitors and streptozotocin should be evaluated in clinical trials.

	Vercherat C, Bourguillault F, Hervieu V, et al. mTOR pathway inhibition sensitizes insulinoma cells to streptozotocin induced apoptosis. Presented at: 2015 NANETS Symposium; October 15-17; Austin, TX. Abstract B14.

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Combining the chemotherapy streptozotocin with drugs that target the mTOR pathway may be an effective way to treat pancreatic neuroendocrine tumors.

Combining Chemo With mTOR Inhibitors Shows Promise in pNETS

Treatment with capecitabine and temozolomide (CAPTEM) is an effective therapy for patients with metastatic pancreatic neuroendocrine tumors (pNETs), but the efficacy of several predictive markers previously thought to determine which patients might respond to the regimen could not be validated, according to a presentation at the 2015 NANETS Symposium.

“In our study we tried to assess the role of potential predictors of response to temozolomide-based regimens in metastatic pNETs,” according to lead author Mauro Cives, MD, who presented the findings at the 2015 North American Neuroendocrine Tumor Society symposium. The markers the investigators evaluated were expression of MGMT, proliferative activity, and ALT activation.

Investigators looked at 143 patients with metastatic pNETs treated at Moffitt who had undergone therapy with CAPTEM and retrospectively evaluated them for radiographic response. “This is the largest reported cohort of pNET patients treated with temozolomide-based chemotherapy,” said Cives, a research associate in the Department of GI Oncology at the Moffitt Cancer Center and Research Institute in Tampa, Florida.

The investigators observed a partial response in 54% of patients, with 35% experiencing stable disease. The median progression-free survival time was 17 months (95% CI, 15-25 months), and 78% of patients had some degree of tumor shrinkage on waterfall plot analysis. Cives reported that median overall survival was 73.2 months (95% CI, 51.9-81.1 months). Thrombocytopenia was the most common grade 3/4 toxicity.

Researchers also aimed to determine whether biomarkers might be used to determine which patients with pNETs were more likely to respond to treatment with CAPTEM. Temozolomide is an alkylating agent that was developed as an oral alternative to dacarbazine. It is cytotoxic even to slow-growing cells such as neuroendocrine tumors, Cives noted, and acts by inducing DNA breaks.

Some small retrospective studies have linked the MGMT protein, which repairs DNA mismatch errors, to the therapeutic success of temozolomide treatment in cancer, with low levels corresponding to a better response. In addition, in one study, about half of all pNETs were found to be deficient in MGMT, which suggested that MGMT status might be a good biomarker for these tumors.

In the current study, immunohistochemistry (IHC) was used to retrospectively evaluate MGMT expression. Tissue was available for staining in 65 patients. The results of MGMT expression were correlated to patient response to treatment and Cives said that they failed to predict responses for CAPTEM for metastatic pNETS.

The investigators also evaluated tumor proliferation as a predictor of response, as measured by mitotic count, expression of Ki-67 based on IHC, and tumor grade. Here, too, the investigators found that proliferative activity did not predict response to treatment with CAPTEM, although they noted that proliferative activity did vary by time and location.

Finally, the investigators evaluated ALT activation as a prognostic factor for response to CAPTEM. ALT has also been evaluated as a prognostic marker in the past, but its predictive value is unknown. FISH was used to evaluate ALT activation in 128 specimens. When the research team correlated the results of FISH with the patient outcomes, they did not find it predictive of response to CAPTEM. However, they did find a high degree of correlation between loss of 

and ALT activation, suggesting that it may be a positive prognostic factor in the metastatic setting.

The investigators also evaluated the status of frequently altered genes in pNETS and correlated them to response to CAPTEM, but have not yet reported those findings.

	Cives M, Ghayouri M, Brelsford, et al. Identification of response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Presented at: 2015 NANETS Symposium; October 15-17; Austin, TX. Abstract C13.

The efficacy of several predictive markers previously thought to determine which patients might respond to temozolomide-based therapy could not be validated for patients with pancreatic neuroendocrine tumors.

Biomarker Needed for CAPTEM Regimen in Metastatic Pancreatic NETs

Full surgical resection (R0) of gastroenteropancreatic neuroendocrine tumors (NETs) is associated with a greater than 90% survival rate at five years, according to findings presented at the 2015 North American Neuroendocrine Tumor Society (NANETS) symposium. The rate of recurrence varied by tumor location and stage, but the majority of patients with all types of NETs who underwent full resection were still free of recurrence in the five-year time frame.

“The presence of metastatic disease does not seem as though it should deter attempts at R0 resection when it’s feasible,” according to lead author Katherine Van Loon, MD, MPH, a gastrointestinal cancer specialist at the University of California, San Francisco, Medical Center. She noted that there were differences in disease-free survival in patients who had NETs in the pancreas and small bowel depending on their stage at diagnosis, but a significant difference in overall survival was not detected.

Current NCCN guidelines recommend that patients with gastrointestinal NETs undergo complete resection of the primary tumor and metastases whenever possible, but until now, large multicenter studies looking at recurrence rates in patients who undergo this procedure have not be conducted.

The multicenter study reviewed 1125 patients who were treated at seven NCCN institutions between 2004 and 2012. It included patients 18 or older who had a new diagnosis of NET of the small bowel, pancreas, or colon/rectum, and who underwent complete resection for their primary tumor and any metastatic tumors. Of the 1125 total patients in the database diagnosed with GI NETs, 294 underwent R0 resection and were disease-free after surgery. The median follow-up time from surgery was 62.1 months.

The patients included in the analysis were 51% male and 88% Caucasian. The median age of patients in the study was 55 years, with a range from 20 to 90 years. Patients with colon/rectal NETs tended to be younger and healthier than patients with pancreas or small bowel tumors, Van Loon said.

Among patients with pancreatic NETs, 26% recurred. For patients with small bowel NETs, 18% recurred. For patients with colorectal NETs, 11% recurred. The overall recurrence rate was 21% (n = 61).

Van Loon noted in her presentation that for patients who were followed longer than the median of about five years, recurrences continued to happen after that five-year time point. She pointed out that NCCN guidelines recommend follow-up scans by multiphase CT and/or MRI every 6-12 months for up to ten years, but these guidelines are “notably, very vague.”

She also said that it’s “significant to note that close to 40% of patients in the first year following surgery underwent no imaging,” despite the fact that NCCN guidelines recommend that scans be performed 3-12 months after surgery.

“Surveillance practices were variable, suggesting a need for refinement of the guidelines,” Van Loon said.

The study also looked at the sites of recurrence for the 61 patients who had recurrences.

“The majority of recurrences that were reported were liver recurrences,” Van Loon said, but data were missing on the location of recurrence in many patients, resulting in one of the study’s limitations.

One notable finding was that only one patient had a recurrence in the lung.

“Thus, I would say that chest imaging as part of routine surveillance following R0 resection may be of limited utility,” she said.

Current NCCN guidelines do not include chest imaging, but the researchers wanted to investigate that recommendation.

Regarding future direction, Van Loon recommended that there be more inquiry into frequency, type, and location of recurrence following surgery. She also said that future research should follow patients for longer than five years, because studies have shown that liver recurrences can appear up to ten years later. That was not possible in the current study because the database was closed in 2012.

	Van Loon K, Zhang L, Creasman J, et al. Recurrence Patterns Following Surgical Resection of Gastroenteropancreatic Neuroendocrine Tumors: An Analysis from the NCCN Oncology Outcomes Database. Presented at: 2015 NANETS Symposium; October 15-17; Austin, TX. Abstract C42.

Full surgical resection of gastroenteropancreatic neuroendocrine tumors is associated with a greater than 90% survival rate at five years.

Julie Grisham

Articles

Combining Chemo With mTOR Inhibitors Shows Promise in pNETS

Biomarker Needed for CAPTEM Regimen in Metastatic Pancreatic NETs

Full Surgical Resection Should Be Performed Whenever Possible for Gastroenteropancreatic NETs