Unresectable Pancreatic Neuroendocrine Tumors Research Articles

Pathological complete response of initially unresectable multiple liver metastases achieved using combined peptide receptor radionuclide therapy and somatostatin analogs following pancreatic neuroendocrine tumor resection: a case report

BackgroundPeptide receptor radionuclide therapy (PRRT) serves as a novel and effective treatment option for somatostatin receptor-positive unresectable liver metastases of pancreatic neuroendocrine tumors (PNETs). However, there are few reported cases of surgical resection for initially unresectable liver metastases of PNET that were converted to resectable after PRRT. Here we report a case where PRRT and somatostatin analogs (SSAs) led to a pathological complete response of initially unresectable multiple liver metastases following PNET resection.Case presentationA 52-year-old man underwent pylorus-preserving pancreaticoduodenectomy for PNET at age 40 and subsequent hepatectomies for resectable liver metastases at 44 and 47 years of age. At age 48, a follow-up examination revealed unresectable multiple liver metastases, and PRRT with 177Lu-DOTATATE therapy was initiated. After four cycles of PRRT, most liver metastases diminished according to imaging studies, and the remaining two hepatic lesions continued to shrink with additional lanreotide. Conversion surgery for liver metastases was successfully performed, revealing no viable tumor cells in tissue specimens. Seventeen months after surgery, imaging showed no detectable residual tumor or recurrence. We present a review of the relevant literature that highlights the significance of our findings.ConclusionsThis rare case highlights the pathological complete response of initially unresectable multiple liver metastases achieved by PRRT and SSAs following PNET resection, suggesting their potential as a multimodality treatment option for unresectable PNET.

Apoptosis-related factors are relevant to progression of pancreatic neuroendocrine tumors

BackgroundMultidisciplinary therapy centered on antitumor drugs is indicated in patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, the criteria for selection of optimal therapeutic agents is controversial. The aim of this study was to assess the malignancy of PanNET for optimal therapeutic drug selection.MethodsForty-seven patients with PanNET who underwent surgery were reviewed retrospectively, and immunohistochemical characteristics, including expression of GLUT1, SSTR2a, SSTR5, Survivin, X-chromosome-linked inhibitor of apoptosis protein (XIAP), and Caspase3 in the resected specimens, were investigated. Relapse-free survival (RFS) and overall survival (OS) were evaluated with regard to the characteristics using the Kaplan–Meier method and compared with the log-rank test.ResultsGLUT1 expression showed significant correlation with sex (p = 0.036) and mitotic rate (p = 0.048). Survivin and XIAP expression showed significant correlation with T-stage (p = 0.014 and 0.009), p-Stage (p = 0.028 and 0.045), and mitotic rate (p = 0.023 and 0.007). XIAP expression also significantly influenced OS (p = 0.044).ConclusionsSurvivin and XIAP correlated with grade of malignancy, and expression of XIAP in particular was associated with a poor prognosis. Expression of these proteins may be a useful indicator to select optimal therapeutic agents in PanNET.

Analysis of polymorphisms in EGF, EGFR and HER2 genes in pancreatic neuroendocrine tumors (PNETs)

ObjectivesPancreatic neuroendocrine tumors (NETs) are rare and account for about 7% of all cancers occurring in the pancreas. The epidermal growth factor family of receptors and their ligands play an important role in the growth and progression of tumors but their role in PNET development remains unknown. We hypothesized that functional single nucleotide polymorphisms (SNPs) in the EGF, EGFR, and HER2 genes might affect individual susceptibility to PNETs development and invasion like it was shown for various other tumors. MethodsWe genotyped 68 patients with unresectable PNETs and 300 controls to evaluate the association between EGF, EGFR, and HER2 polymorphisms and susceptibility to PNETs and presence of metastases. ResultsGenotype analysis of three SNPs EGF +61A/G (rs4444903), EGFR +1562 G/A (rs11543848), and HER2 +1963 A/G (rs1136201) showed that carriers of EGFR +1562 AG genotype and AA/AG EGF +61/HER2 +1963 genotype combination are at risk of developing PNET. Furthermore, EGFR +1562 AA genotype could be associated with the susceptibility to insulinoma development. ConclusionsOur results suggest involvement of EGFR signaling pathway in etiology of PNET development.

P-155 Efficacy of somatostatin analogues in the treatment of metastatic and unresectable pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumours represent 1.3% of primary pancreatic tumours. Evidence for the use of somatostatin analogues for pNET is solid in favour of lanreotide, while the potential benefit of octreotide remains unclear beyond symptom control.

Optimal strategy of systemic treatment for unresectable pancreatic neuroendocrine tumors based upon opinion of Japanese experts

Background/objectivesA number of therapeutic agents have been reported to be clinically useful for the management of the patients with unresectable pancreatic neuroendocrine tumors (PanNETs) including somatostatin analogues, molecular-targeted agents and cytotoxic agents. However, the optimal strategy for selection among those treatment modalities above in these patients has remained unexplored. MethodsJapanese experts for PanNET discussed and determined the optimal treatment strategies according to the results of previously reported studies. ResultsThe tumor volume of liver metastases and the Ki-67 labeling index were unanimously accepted as indicators of the tumor burden and tumor aggressiveness, respectively, which are two most clinically pivotal factors for determining the strategy of systemic treatment for unresectable PanNETs. In addition, for those with a relatively small tumor burden and slow disease progression, somatostatin analogues were selected as the first-line treatment agents. For those with a relatively large tumor burden and rapid tumor progression, cytotoxic agents were selected, possibly aiming at tumor shrinkage. For those of intermediate tumor volume and/or growth rate, molecular-targeted agents were selected as the first choice. Based on this strategy discussed among the experts, we tentatively prepared a MAP for proposing optimal treatment strategy and examined its validity in some patients with unresectable PanNETs. Results validated the usefulness of this MAP proposed for patients harbouring unresectable PanNETs. ConclusionWe herein propose a tentative MAP for optimal treatment selection for the patients harbouring unresectable PanNETs. Further large scale studies are, however, warranted to validate the usefulness of this MAP proposed in this study.

A patient with a pancreatic neuroendocrine tumor and multiple liver metastases achieved a long-term partial response to third-line streptozocin treatment.

The Japanese guideline for gastroenteropancreatic neuroendocrine tumor treatment recommends everolimus or sunitinib as first-line treatment for unresectable pancreatic neuroendocrine tumors (PNETs). Streptozocin (STZ) is recommended as an alternative. We encountered a patient with PNET who had multiple liver metastases and who showed a remarkable response to third-line STZ. The patient was a 50-year-old man with a pancreatic head tumor 32mm in diameter. We planned to perform subtotal stomach-preserving pancreaticoduodenectomy, but abandoned resecting the pancreas during the surgery upon discovering a small liver tumor 3mm in diameter, examination of frozen sections of which revealed a poorly differentiated adenocarcinoma. However, the final pathological examination revealed that the liver nodule was a PNET; hence, we completed the subtotal stomach-preserving pancreaticoduodenectomy 5weeks after the first laparotomy. The patient received no adjuvant chemotherapy after surgery. Twenty-one months later, we discovered 20 scattered liver metastases via computed tomography; these were considered unresectable. Therefore, we administered everolimus for 7months, but the patient developed interstitial pneumonia and experienced metastatic progression. Subsequent sunitinib administration for 6months was ineffective. Finally, we chose STZ (1000mg/m2, weekly) as a third-line treatment, which produced a partial response for 10months. The patient remains alive 38months after the detection of recurrence. As the order in which anti-cancer drugs should be administered to treat PNET has not been determined, additional predictors of their therapeutic efficacy should be investigated.

Grading by the Ki-67 Labeling Index of Endoscopic Ultrasound-Guided Fine Needle Aspiration Biopsy Specimens of Pancreatic Neuroendocrine Tumors Can Be Underestimated.

There is an increasing need for grading with small endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) specimens for the proper diagnosis and therapy selection of patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, our understanding of EUS-FNAB specimen grading is limited compared with surgically resected specimens. We retrospectively determined Ki-67 labeling index (LI) of 33 matched EUS-FNAB and surgically resected PanNETs with digital image analyzer. Pairwise grades between the matched biopsy and surgically resected PanNET specimens were compared. The mean Ki-67 LI was higher in surgically resected PanNET specimens (5.5%) than in biopsy specimens (3.2%; P = 0.022). There was moderate agreement between the Ki-67 LI grades when individually evaluated matched biopsy and resected specimen pairs were compared (κ value = 0.62; P < 0.0001). However, discordance was noted in 6 cases (18%), and all of them were either grade 2 or 3 in resected PanNETs. Although Ki-67 LI grading of EUS-FNAB specimens may be concordant with that of matched surgically resected specimens in a large proportion of the PanNET cases, Ki-67 LI grading of EUS-FNAB specimens should be carefully applied in clinical practice because of the possibility of grading underestimation with grade 2 to 3 PanNET cases.

Erratum to liver transplantation for unresectable pancreatic neuroendocrine tumors with liver metastases in an era of transplant oncology.

[This corrects the article DOI: 10.21037/gs.2017.12.11.].

Liver transplantation for unresectable pancreatic neuroendocrine tumors with liver metastases in an era of transplant oncology.

Patients with pancreatic neuroendocrine tumors (pNETs) very often present with a metastatic disease at the first diagnosis. Liver transplantation (LT) for unresectable pNET with liver metastases (pNETLM) has been described to prolong survival in highly selected patients, although outcomes were worse than those of patients who underwent LT for gastrointestinal NETLM (GI-NETLM). In this review, several proposed criteria are described with their rationale and controversies. Most of the data used to establish these criteria do not reflect the recent improvements of non-surgical treatments that has changed the landscape of treatment for pNETs, including the development of peptide receptor radionuclide therapy and molecular-targeted agents (sunitinib and everolimus). Properly designed studies are necessary to define the role of down-staging and bridging therapy prior to LT incorporating systemic chemotherapy using these molecular-targeted agents. Also, given the indolent nature of low or intermediate grade pNETs, the best endpoint to compare the efficacy of each treatment option for patients with pNETLM has yet to be determined. Lastly, the definition of "unresectable" remains ambiguous. The indication of the conventional technique of two-staged liver resection with portal vein embolization or the new technique of associating liver partition and portal vein ligation for staged hepatectomy to expand the resectability of wide-spread metastatic liver tumors has been controversial. In an era of transplant oncology, LT should be the last resort for patients who are considered unresectable and otherwise untreatable after an exhaustive multidisciplinary team discussion by all experts in the field. In conclusion, although its long-term outcomes have been promising, the role of LT for unresectable pNETLM as a curative or palliative treatment remains unclear. A well-designed randomized control study is required to elucidate the clinical impact of LT for pNETLM.

Efficacy of radiotherapy for primary tumor in patients with unresectable pancreatic neuroendocrine tumors.

Detailed information regarding the clinical efficacy of radiotherapy (RT) for primary tumor in patients with unresectable pancreatic neuroendocrine tumors (pNETs) is unknown. We therefore performed a retrospective study to evaluate the efficacy and safety of RT for primary pancreatic tumors in patients with pNETs. We investigated 11 patients with pNETs who received RT to the primary site between January 1997 and June 2015. Seven patients had Grade 2 neuroendocrine tumors (NET-G2) and four had neuroendocrine carcinoma (NEC) according to the 2010 WHO histopathological classification. The tumor response and control rates were 27.2% and 100%, respectively (3: partial response, 8: stable disease). Among patients with NET-G2 tumors, the response rate was 28.5% (2/7 patients) and symptomatic improvement was noted in 33.3% of the patients (1/3 patients). The response rate for patients with NEC were 25% (1/4), one NEC patients with symptoms exhibited symptomatic improvement. The median overall survival and median progression-free survival were 35.9 months and 5.5 months, respectively. Grade 3 diarrhea as an acute toxicity and Grade 3 gastrointestinal hemorrhage as a late toxicity were observed. RT to the primary cancer site in patients with pNETs was an effective modality for local disease control and the treated patients had good outcomes. If metastatic tumors are under control, RT to the primary site may be beneficial for patients with pNETs.

Impact of Therapy Sequence with Alkylating Agents and MGMT Status in Patients with Advanced Neuroendocrine Tumors.

Alkylating chemotherapeutics with either a streptozotocin-(STZ) or temozolomide-(TEM) backbone are routinely used in patients with progressive and unresectable pancreatic neuroendocrine tumors (PNET). In addition, dacarbazine (DTIC) was described as an alternative alkylating therapy option for PNETs. The optimal treatment sequence with alkylating compounds and a potential use of O6-methylguanine-DNA methyltransferase (MGMT) level as predictive biomarker have not yet been sufficiently elucidated. The aim of our study was the evaluation of therapy sequence with either STZ-based treatment followed by DTIC (group A) or the inverse schedule with upfront DTIC (group B) and to correlate MGMT status with clinicopathological characteristics and response to therapy. We retrospectively analyzed 28 patients with neuroendocrine tumors (NET) who were treated with STZ-based therapy and DTIC. Additionally, in a second group MGMT immunohistochemistry was performed from primary and metastatic tumor sites. For statistical evaluation Kaplan-Meier analysis, Cox regression methods and Fisher's exact test were used. There was no difference of objective response and disease control between either STZ-based therapy followed by DTIC treatment (group A) after progression or the reverse sequence (group B). Median time to progression (TTP) was estimated to be 21 months in both arms. First-line STZ-based chemotherapy was not superior to first-line DTIC treatment (16 vs. 13 months; p=0.8). MGMT status did not correlate with clinicopathological characteristics or response to therapy with these alkylating agents. Upfront chemotherapy with either STZ-based treatment or DTIC monotherapy showed similar efficacy and median TTP rates. In this study, MGMT protein expression assessed by immunohistochemistry did not play an important role as a predictive marker for alkylating agents.

AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas

Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well.

IS2-4 - Current Status and Perspective of Chemotherapy for Unresectable Pancreatic Neuroendocrine Carcinoma

Cisplatin plus etoposide (EP regimen) or cisplatin plus irinotecan (IP regimen) has been widely used for the treatment of unresectable neuroendocrine carcinoma, according to the guidelines for the treatment of small cell lung cancer. The response rate and median survival time were 12%-67% and 5.8-19 months for the EP regimen and 39%-83% and 10.1-14 months for the IP regimen according to previous reports, which were all retrospective analyses. The treatment efficacy of both regimens was favorable, and both regimens have been acknowledged as de facto standard regimens for unresectable neuroendocrine carcinoma. At present, a phase III trial of EP vs. IP has been planned for unresectable neuroendocrine carcinoma originating from gastrointestinal cancer and hepatobiliary and pancreatic cancer by the Japan Clinical Oncology Group (JCOG1213).In patients who were refractory or intolerant to these regimens, there are no standard regimens for use as subsequent treatments to the EP or IP regimens for unresectable neuroendocrine carcinoma. Everolimus, which is an mTOR inhibitor, has been established as a standard therapy for unresectable pancreatic neuroendocrine tumors because a significantly favorable progression-free survival was shown in a phase III trial of evelorimus vs. a placebo for aggressively progressive pancreatic neuroendocrine tumors (G1 or G2 tumors). In a subgroup analysis of this trial, everolimus showed a tendency toward a greater prolongation of progression-free survival in patients with G2 tumors than in patients with G1 tumors. In addition, the overexpression of mTOR has been reported in patients with neuroendocrine carcinoma. Therefore, everolimus is likely to be effective against neuroendocrine carcinoma. A multicenter phase II trial (NECTOR trial) is underway to elucidate the efficacy and safety of everolimus in patients with pancreatic neuroendocrine carcinoma who are refractory or intolerant to the EP or IP regimen.

Emerging therapies and latest development in the treatment of unresectable pancreatic neuroendocrine tumors: an update for clinicians

Pancreatic neuroendocrine tumors (pNETs) differ in their clinical behavior, presentation and prognosis based on their initial histological features and disease stage. While small resectable tumors can be treated surgically, metastatic and locally advanced disease carries a significant mortality and treatment options have been limited in terms of their efficacy. Streptozocin-based regimens were the only agents available before but recent advances have improved the armamentarium to treat pNETs. Newer chemotherapeutic agents such as temozolomide, somatostatin analogs and targeted therapies including everolimus and sunitinib are now available to treat these tumors. Several combination regimens with targeted therapies and newer agents such as pazopanib are being developed and tested in ongoing trials.

Pancreatic Neuroendocrine Tumors: Signal Pathways and Targeted Therapies

Pancreatic neuroendocrine tumors (PNETs) are rare but are well understood to cover a broad spectrum of clinical presentation, tumor biology and prognosis. More than 60% of PNETs are diagnosed at advanced disease stage and are ineligible for surgical resection. Prior to 2011, streptozocin was the only approved agent for unresectable advanced PNETs. In recent years, breakthroughs in signal pathway research have led to the identification of new therapeutic targets and agents directed at the molecular level. In 2011, two new targeted therapeutic agents, sunitinib and everolimus, were approved by the Food and Drug Administration (FDA). Sunitinib is an inhibitor of multiple tyrosine kinases, and everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway. This review discusses the major signaling pathways that are frequently mutated or deregulated in PNETs, and the implications of molecular alterations for PNET therapy. Biologic therapy through targeting relevant pathways represents a promising approach in the therapy of advanced and unresectable PNETs.

PCN61 Cost-Effectiveness of Sunitinib + Best Supportive Care for the Treatment of Unresectable Pancreatic Neuroendocrine Tumors in Mexico

Patients with non-resectable pancreatic Neuroendocrine Tumors (NET) have very few therapeutic alternatives. Sunitinib had showed a substantial clinical benefit in this group of patients, however there are few economic studies pursuing to estimate its economic consequences. The objective of this study was to estimate the cost-effectiveness of sunitinib in the treatment of well-differentiated non-resectable pancreatic NET, from the perspective of the Social Security Mexican Institute (IMSS). A three health states Markov model (pre-progression, post-progression, death; 2-week cycles) was used to estimate the health and economic consequences of sunitinib 37.5/day+ best supportive care (BSC) regarding placebo+ BSC along a ten-years horizon (discount rate: 5%). Effectiveness measures were overall: survival (OS), progression-free survival (PFS) and quality adjusted life years gained (QALY). Resource utilization (BSC, adverse events management, medical follow up) was estimated through a Delphi Panel with Mexican oncologists (n=10). Unit costs of medication and medical resources were obtained from institutional sources. Deterministic and probabilistic sensitivity analyses were developed and acceptability curves were constructed. Sunitinib+BSC gained additional 0.49 years of PFS, 1.18 years of OS and 0.70 QALYs against placebo+BSC. Sunitinib+BSC increased medical direct costs (2011 US$) per patient in $20,854 (around two-fold the cost of placebo+BSC: $18,082), which was driven by acquisition costs of sunitinib and medical follow up before progression (due to the noted clinical benefit in sunitinib's patients). ICER's were $42,157, $17,662 and $29,808 per progression-free year, life-year and QALY gained, respectively, which remained robust through ±25% changes in main parameters. At willingness to pay higher than $40,000, $21,800 and $37,200 sunitinib+BSC becomes the most efficient alternative in regards to PFS, OS and QALYs, respectively. At IMSS, sunitinib+BSC would provide substantial clinical benefits to patients suffering unresectable pancreatic NET, although the latter would increase medical costs of treatment and clinical follow up.

Safety and Efficacy of Sunitinib in Patients with Unresectable Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (PNETs) are becoming increasingly common, with the majority of patients presenting with either lymph node involvement or metastatic disease, thus requiring systemic therapy. Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth rather than by simply interfering with rapidly dividing cells (eg, with traditional chemotherapy). In this review article, pharmacologic inhibition of multiple targets including vascular endothelial growth factor receptor (VEGF-R), platelet-derived growth factor receptor (PDGF-R), stem cell factor receptor (c-KIT-R), FML-like tyrosine kinase-3 receptor (FLT3-R), colony stimulating factor 1 receptor (CSF1-R), and glial cell-line derived neurotrophic factor receptor (RET-R) with sunitinib in patients with unresectable PNETs is discussed. Phase III data indicate that additional treatment with sunitinib can improve prognosis in these patients.

Updated overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) of sunitinib (SU) versus placebo (PBO) for patients (Pts) with advanced unresectable pancreatic neuroendocrine tumors (NET).

4008 Background: In a double-blind phase 3 trial, SU improved PFS vs PBO (11.4 vs 5.5 months; HR 0.418, 95% CI 0.263, 0.662; p=0.0001) and was well tolerated in pts with advanced well-differentiated, unresectable NET that had progressed in ≤12 months (NEJM, Feb 2011). Initial OS showed a benefit for SU over PBO, but median OS was not reached (NR). Here we report updated results of median OS and also PFS assessed by BICR to correct for potential unblinding due to identifiable adverse events (AE). Methods: Pts were randomized 1:1 to SU 37.5 mg as a continuous daily dose or PBO, each with best supportive care. Primary endpoint was PFS; secondary endpoint was OS. Median OS and HR were estimated using Kaplan-Meier (K-M) methods and Cox proportional hazards models. Baseline and on-study CT/MRI scans were evaluated by a 2-reader, 2-time point lock, followed by a sequential locked-read, batch-mode paradigm by blinded, third-party radiologists. Results: 171 pts were randomized (SU, n=86; PBO, n=85) from 6/2007 to 4/2009. The trial ended early when an independent data monitoring committee noted efficacy favoring SU and more serious AEs and deaths with PBO. The study was unblinded at closure, and pts were offered open-label SU. At study end, there were 9 and 21 deaths in SU and PBO arms, respectively; HR of 0.409 (95% CI 0.187, 0.894; p=0.0204) favoring SU. By 6/2010, there were 34 and 39 deaths, respectively; median OS was 30.5 (95% CI 20.6, NR) and 24.4 (95% CI: 16.3, NR) months, respectively. The HR of 0.737 (95% CI 0.465, 1.168; p=0.1926) continued to favor SU; a K-M plot showed early/persistent separation of curves. For BICR analysis, scans were collected for 170 (99.4%) pts, with 160 (93.6%) having complete scan sets/time points. Median PFS by BICR was 12.6 vs 5.8 months for SU and PBO (HR 0.315 [95% CI 0.181, 0.546; p=0.000015]). Conclusions: SU led to a 6.1-month improvement in median OS vs PBO, and BICR analysis confirmed the investigator-assessed PFS benefit of SU. These updated results support the robustness of the initial findings and the clinical benefit of treatment with sunitinib.