Systemic Therapy for Advanced Pancreatic Neuroendocrine Tumors: An Update

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1 Focused Review 777 Systemic Therapy for Advanced Pancreatic Neuroendocrine Tumors: An Update Diane L. Reidy-Lagunes, MD, MS Abstract Well-differentiated neuroendocrine tumors (NETs) can be subdivided into carcinoid and pancreatic NETs (pancnets). Although these tumors share many morphologic and clinical characteristics, carcinoid tumors appear to be far less sensitive to therapeutic agents than pancnets, and recent advances approved for pancnets have not been submitted for FDA approval in patients with carcinoid tumors. Treatment options for patients with advanced pancnets are multidisciplinary and include surgical resection, liver-directed therapies, and systemic therapies. Cytotoxic therapies, such as temozolomide, fluorouracil, oxaliplatin, and streptozocin-based chemotherapy regimens, are active against some pancnets, and can play a role in the palliation of patients with advanced disease and symptoms related to tumor bulk. Two therapies were recently approved for progressive well-differentiated pancnets: sunitinib and everolimus. Both agents showed improved progression-free survival in patients with progressive pancnets, but can also result in nontrivial toxicities, and therefore should only be considered in patients with progressing and advanced or symptomatic disease. This article discusses these recent trials and provides an update of systemic treatment options in patients with well-differentiated pancnets. (JNCCN 2012;10: ) Well-differentiated neuroendocrine tumors (NETs) can be subdivided into carcinoid and pancreatic NETs (pancnets). Although these tumors share many morphologic and clinical characteristics, carcinoid tumors seem to be far less sensitive to therapeutic agents than pancnets, and recent advances approved for pancnets have not been submitted for FDA approval in patients From the Division of Solid Tumor Oncology, Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan- Kettering Cancer Center, and Weill College of Medicine, Cornell University, New York, New York. Submitted November 25, 2011; accepted for publication February 13, Dr. Reidy-Lagunes has disclosed that she serves on the advisory board for Novartis and Pfizer Inc. Correspondence: Diane L. Reidy-Lagunes, MD, MS, Memorial Sloan- Kettering Cancer Center, 1275 York Avenue, Room H-1004, New York, NY reidyd@mskcc.org with carcinoid tumors. Treatment options for patients with advanced pancnets are multidisciplinary and include surgical resection, liver-directed therapies, and systemic therapies. Cytotoxic therapies, such as temozolomide, fluorouracil, oxaliplatin, and streptozocinbased chemotherapy regimens, are active against some pancnets, and can play a role in the palliation of patients with advanced disease and symptoms related to tumor bulk. For the first time in 30 years, 2 therapies were recently approved for progressive well-differentiated pancnets 1,2 : sunitinib, an orally administered, multitargeted receptor kinase inhibitor, and everolimus, a mammalian target of rapamycin (mtor) inhibitor. 1 Both agents showed improved progression-free survival in patients with progressive pancnets, but can also result in nontrivial toxicities, and therefore should only be considered in patients with progressing and advanced or symptomatic disease. This article discusses these recent trials and provides an update of systemic treatment options in patients with well-differentiated pancnets. Well-differentiated NETs are rare neoplasms arising from the diffuse neuroendocrine cell system. panc- NETs, formally known as islet cell carcinomas, are tumors that develop from the endocrine tissues of the pancreas (i.e., islets of Langerhans), and carcinoid tumors are NETs that develop anywhere else outside the pancreas (mostly typically in the aerodigestive tract). This family of well-differentiated neoplasms is morphologically and clinically distinct from high-grade neuroendocrine carcinoma. This latter entity has an aggressive clinical behavior similar to small cell lung cancer and is generally managed with platinum-based chemotherapy. 3 Approximately 30% of pancnets are hormonesecreting (also known as functional tumors). 4 Functional pancnets can secrete a variety of hormones, leading to different clinical syndromes, and include insulinoma, gastrinoma, glucagonoma, vasoactive intestinal polypeptide (VIPoma), and other rare functioning tumors.

2 778 Reidy-Lagunes Often these syndromes can be effectively managed with somatostatin analogs (e.g., octreotide or a similar drug approved for use in Europe; lanreotide) or antitumor agents, which are discussed later. mtor inhibitors may be particularly effective in treating metastatic insulinomas, because a side effect of all mtor inhibitors is hyperglycemia. 5 The management and treatment of patients with pancnets pose a significant challenge because of the heterogeneous clinical presentations and varying degree of aggressiveness. For example, patients with large-volume, functional tumors may require medical therapies in addition to antitumor treatments to control their symptoms. In contrast, patients with low-volume, non hormone secreting (i.e., nonfunctioning) tumors are often completely asymptomatic and can be followed expectantly for months and sometimes years. An understanding of the patient s symptoms and tumor biology is critical to individualize management for these uncommon tumors. Typical indications for therapy are either 1) pain or symptoms caused by tumor bulk, 2) symptoms caused by uncontrolled hormone secretion, or 3) clinically significant tumor burden or disease progression under observation. 6 Grade of tumor (e.g., low- vs. intermediate-grade) can aid in treatment decisions but currently does not drive therapeutic management. Pathology Well-differentiated pancnets exhibit diverse clinical outcomes, which can be stratified based on certain histopathologic features. As with most tumors, although advanced tumor stage is indicative of an unfavorable prognosis, prediction of clinical outcome based on traditional histopathology alone has been unsatisfactory. In recent studies, however, the tumor grade (or the percentage of cells that stain for the proliferative marker Ki-67) has been correlated with survival (Table 1). 7,8 A recent hypothetical proposal of TMN classification provides a simple and practical system for patient stratification for all NETs. 9 Separate TNM staging systems are used for pancnets 10 (as opposed to carcinoids), because these do not arise in the luminal gut. Included in the TNM classification is an additional grading system: G1 (i.e., low-grade), G2 (i.e., intermediate-grade), and G3 (i.e., high-grade). The issue of functionality of NETs (i.e., whether the NET secretes a hormone) also impacts the nomenclature for pancnets. The biology of most functioning pancnets is still defined by the grade and stage of the tumor (although the clinical consequences of the hormone hypersecretion can be significant). This grading system is not considered or incorporated in many older clinical trials, thus making interpretation of the data extremely difficult. More recent trials stratify or mandate tumor grade. Genetics pancnets can occur both sporadically and in patients with various inherited disorders. 4,11 They occur in 80% to 100% of patients with multiple endocrine neoplasia type I (MEN1); in 10% to 17% of patients with von Hippel-Lindau syndrome (VHL); up to 10% of patients with von Recklinghausen s disease (neurofibromatostis-1); and occasionally in patients with tuberous sclerosis. 11 Each of these is an autosomal dominant disorder. 11 Of these disorders, MEN1 is the most frequent in patients with pancnets. 11,12 MEN1 is caused by mutations in the chromosome 11q13 region, resulting in alterations in the Menin gene, which encodes for a 610 amino acid nuclear protein, menin, which has important effects on transcriptional regulation, genomic stability, cell division, and cell cycle control. 11 Large studies validating molecular markers for pancnets that are useful in the prediction of response are unavailable. Recently, Jiao et al. 13 determined the exomic sequences of 10 nonfamilial pancnets and then screened the most commonly mutated genes in 58 additional pancnets. Fifteen percent of patients had mutations in genes from the mtor pathway (specifically tuberous sclerosis complex 2, a tumor suppressor gene (TSC2), and mutations in the catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA), along with 43% in DAXX and ATRX and 44% in MEN1 genes. 13 In patients who had all of these mutations (MEN1, DAXX, and ATRX) the median overall survival was 10 years. 13 In contrast, 60% of patients who lacked these mutations died within 5 years of diagnosis. These genetic mutations could potentially be used to stratify treatment for patients, and are currently being investigated.

3 779 Systemic Therapy for Advanced pancnets Table 1 European Neuroendocrine Tumor Society and WHO Grading of Neuroendocrine Tumors Low-grade (G1), well-differentiated < 2 mitoses/10 hpf and < 3% Ki-67 index Intermediate-grade (G2), well-differentiated 2 20 mitoses/10 hpf or 3% 20% Ki-67 index High-grade (G3), poorly differentiated > 20 mitoses/10 hpf or > 20% Abbreviations: hpf, high-power field. Treatment Targeted Therapy Role of Somatostatin Analogs: More than 90% of well-differentiated NETs have high concentrations of somatostatin receptors, and can be imaged using octreotide labeled with indium 111 (somatostatin scintigraphy; indium-111 pentetreotide [OctreoScan, Mallinckrodt Inc., St. Louis, Missouri]) Somatostatin scintigraphy negative tumors seem to correlate with a poorer prognosis. 17 In general, patients with Octreoscan-negative tumors should not be placed on somatostatin analogs, although rare case reports have shown these rare patients achieving tumor stability with octreotide therapy. 18 Somatostatin analog therapy (i.e., octreotide ) is highly useful for the treatment of these hormone-related pancnet symptoms, particularly VIPomas and glucagonomas. 19 Among patients with insulinoma, somatostatin analogs should be initiated with caution, because they may result in transient worsening of hypoglycemia. In addition, somatostatin analogs have been long assumed to have moderate antiproliferative effects on tumor growth. The first randomized data supporting this hypothesis was provided by the PROMID study. In this trial, 85 patients with metastatic midgut carcinoid tumors were randomly assigned to receive either octreotide long-acting release (LAR) at 30 mg intramuscularly monthly, or placebo. The median time to tumor progression was 14.3 months in the octreotide arm compared with 6 months in the placebo group. 20 As would be expected in this small trial, no difference was seen in overall survival. Whether the improvement in progression-free survival would also be seen in pancnets and other carcinoid tumors (e.g., outside the small bowel) is not directly known from the PROMID study; however, most feel that extrapolation of PROMID observations to other well-differentiated NETs is reasonable. 6 Sunitinib: Angiogenesis has been shown to play a crucial role in the development of pancnets in humans. 21 Well-differentiated NETs seem to express higher levels of hypoxia-inducible factor-1α, vascular endothelial growth factor (VEGF), and microvessel density than poorly differentiated NETs. 21 The highly vascular nature of well-differentiated NETs led to initial interest in angiogenesis inhibitors as a treatment modality in this disease and the phase II trials showed promising antitumor activity in panc- NETs. 22,23 These positive results led to a randomized phase III study in progressive pancnets 22 in which 171 patients were randomly assigned to receive either 37.5 mg daily of sunitinib or a placebo. The dosage was administered at 37.5 mg daily (as opposed to the 50-mg dose in the phase II study) because of the increased rate of grade 3 fatigue discussed previously. 2 The study was stopped prematurely by the independent Data Monitoring Committee before the first preplanned interim efficacy analysis, because of increased number of deaths and a higher adverse rate in the placebo arm. The median progression-free survival was significantly longer with sunitinib (11.4 vs. 5.5 months). 2 The sunitinib arm showed 8 objective responses (an overall response rate of 9.3% vs. none in the placebo group), 2 of which were described as complete. The size, location, and number of lesions involved in the complete response were unclear, which could have strengthened this finding. The most common adverse events associated with sunitinib included diarrhea (59%), nausea (45%), asthenia (34%), vomiting (34%), fatigue (32%), anorexia (22%), stomatitis (22%), dysgeusia (20%), and epistaxis (20%). Hand-foot syndrome and hypertension of any grade occurred in 23% and 26% of patients receiving sunitinib, respectively. The most common grade 3 or 4 adverse events in this group were neutropenia (12%) and hypertension (10%). Importantly, information regarding the duration of each of these toxicities has not been reported, and this information would be clinically relevant. For example, grade 2 hand-foot syndrome would have a very different impact on a patient if it lasted for 3 days versus if it lasted for 3 weeks. Despite these side effects, no differences were seen in the quality-of-life index with sunitinib.

4 780 Reidy-Lagunes Everolimus: mtor is a serine-threonine kinase that has a central role in regulating cellular function and mediates downstream signaling from several signaling pathways that have been implicated as critical pathways in NET growth. In a phase II trial, 36 heavily pretreated patients with disease progression (21 carcinoid, 15 pancnet) were treated with 25 mg intravenous weekly doses of the mtor inhibitor temsirolimus, with an overall response rate of 6%. 24 Median time to tumor progression was 6.0 months, and the study was considered negative because it did not meet its primary end point of objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST). This finding is in contrast to that of a phase II trial in another mtor inhibitor, everolimus (also known as RAD001), showing promising activity, with a progression-free survival of 16.7 months in patients receiving 10 mg of everolimus daily plus octreotide LAR. Response rate in this cohort was only 4%, suggesting that progression-free survival may be a better surrogate for evaluation than objective response rate for these tumors. 25 The promising everolimus phase II results led to the RADIANT-3 phase III study evaluating everolimus at 10 mg/d monotherapy (n = 207) plus best supportive care (n = 203) in 410 patients with progressive pancnets. This trial showed a significant 2.4-fold improvement in median progression-free survival (11.0 vs. 4.6 months; hazard ratio, 0.35; 95% CI, ; P <.001). The side effects associated with everolimus consisted of stomatitis (64%), rash (49%), diarrhea (34%), fatigue (31%), and infections predominantly of the upper respiratory tract (23%). 1 As with the sunitinib trial, the duration of each of these toxicities is unclear, which is important to know in patients on chronic therapy. The most common grade 3 or 4 drug-related adverse events were stomatitis (7%), anemia (6%), and hyperglycemia (5%). These clinical data illustrate unequivocal antitumor activity of sunitinib and everolimus. However, the patients enrolled in this trial had progressive disease. Patients with advanced NETs often have indolent disease and can be followed expectantly sometimes for months or even years without treatment. For this reason, immediate intervention at diagnosis of an asymptomatic patient with a hormonally nonfunctional pancnet is rarely indicated. Rather, careful evaluation of each individual patient with an initial interval of observation and assessment can help define who needs treatment sooner versus who is likely to do well without treatment for a more extended period. However, all therapies and interventions carry risks and side effects. The side effect profiles of sunitinib and everolimus are predictable but can impair the quality of life, and therefore must be considered. Even mild to moderate side effects can have a serious impact on a patient s sense of wellbeing. Chemotherapy for the Treatment of pancnets Currently, conventional chemotherapy has no clearly defined role in the treatment of metastatic NETs. Most clinicians advocate the use of cytotoxic chemotherapy in patients with high tumor burden with symptoms or disease progression. Furthermore, what cytotoxic chemotherapies should be used and in what order is also unclear. For example, whether a patient treated with temozolomide-based therapy would benefit from streptozocin on progression and/ or vice versa is unknown (Table 2). Again, panc- NETs seem to be more responsive than carcinoid tumors with chemotherapy playing a very narrow role in carcinoid tumors. ECOG performed one of the first randomized studies of chemotherapy in pancnets, in which 105 patients received either streptozocin plus doxorubicin, streptozocin plus fluorouracil, or chlorozotocin alone. 26 The reported response rate was 69% for the streptozocin and doxorubicin combination. These older studies reported loosely defined responses, assessed through physical examination, hormone markers, and liver spleen scans. Recent studies with more stringent criteria, defining response rate based on RECIST, report values from 16% to 39%. 26,27 A retrospective review examined objective tumor response rates and duration of progression-free survival in 84 patients with locally advanced or metastatic pancnets treated with the combination of fluorouracil, streptozocin, and adriamycin. 28 The overall response rate was 39%, as measured based on RECIST criteria, with one patient reportedly experiencing a complete response. Median time between the first cycle of chemotherapy and tumor response was 3.9 months, suggesting that pancnets might respond slowly to chemotherapy. 28 Dacarbazine and the sister oral compound temozolomide are alkylating agents that may be active in patients with pancnets. In an ECOG phase II

5 781 Systemic Therapy for Advanced pancnets Table 2 Systemic Therapies for Pancreatic Neuroendocrine Tumors Systemic Therapy Clinical Trial Response Rate (%) Other Results Everolimus 1 Phase III RCT 6 Progression-free survival: 11.5 mo Sunitinib 2 Phase III RCT 9 Progression-free survival: 11.5 mo T + Capecitabine 22 Phase II 70 Progression-free survival: 18 mo CAPEOX 25 Phase II 27 Response duration: 12 mo GEMOX 24 Phase II 17 Progression-free survival: 7 mo DTIC 20,a Multi-institutional phase II 34 Response duration: 10 mo TTh 21 Phase II 45 Response duration: 13.5 mo STZ + DOX 19,a Multi-institutional RCT 69 Response duration: 20 mo STZ + 5-FU 19,a Multi-institutional RCT 45 Response duration: 7 mo CLZ 19,a Multi-institutional RCT 30 Response duration: 7 mo 5-FU + STZ + DOX 18,a Retrospective 39 Progression-free survival: 18 mo Abbreviations: 5-FU, 5-fluorouracil; CAPEOX, capecitabine and oxaliplatin; CLZ, chlorozotocin; DOX, doxorubicin; DTIC, dacarbazine; GEMOX, gemcitabine and oxaliplatin; RCT, randomized controlled trial; STZ, streptozotocin; T, temozolomide; TTh, temozolomide and thalidomide. a Older studies in which fewer objective criteria were used to define response. study of dacarbazine, 14 of the 42 patients (33%) with pancnets were reported to have had a partial or complete response. 29 In another study that used modern response criteria, Kulke et al. 30 tested the combination of temozolomide and thalidomide in 29 patients with metastatic NETs in a phase II study. Patients received temozolomide at a dose of 150 mg/m 2 for 7 days every 2 weeks plus daily thalidomide (dose range, mg). The overall response rate was approximately 25% (45% for pancnets, 7% for carcinoids), again suggesting that pancnets are more sensitive than carcinoid tumors. 30 Grade 3/4 lymphopenia was noted in 70% of patients, with 10% developing opportunistic infections, a known side effect of temozolomide. A retrospective review showed that temozolomide was active in approximately 14% of patients, whereas a single phase II thalidomide study of 18 patients with NETs (13 carcinoid, 5 pancnet) showed no antitumor activity. 31,32 These findings suggest that the active drug in this combination is likely to be temozolomide. However, whether a meaningful difference exists between the activity of temozolomide and dacarbazine is difficult to determine because no trials have compared these agents. Recently, in a retrospective evaluation of the efficacy of capecitabine and temozolomide in 30 patients with metastatic pancnets, Strosberg et al. 33 found that 21 (70%) experienced an objective response rate, with a median progression-free survival of 18 months. Only 4 patients (12%) experienced grade 3 or 4 adverse events (fatigue, 3%; elevated liver enzymes, 3%; and thrombocytopenia, 6%). The dependence of temozolomide responsiveness on deficient methyl-guanine methyl transferase (MGMT) expression may explain the lack of benefit from this drug in some NETs and in carcinoids in particular. Kulke et al. 34 retrospectively assessed 76 patients receiving temozolomide-based treatments. A radiographic response (defined using RECIST criteria) was seen in approximately 33% of patients with pancnets (11/35 patients), but in 0% (0/38) of those with carcinoid tumors (P <.001). In 21 available specimens, complete absence of MGMT expression seemed to define patients with pancnets who would experience significant benefit from temozolomide (5/8 pancnets and 0/13 carcinoid tumors). Although these data are compelling, routine assay of MGMT expression to select patients for temozolomide therapy is not yet a standard approach. Platinum-based therapies have also shown promising activity in small phase II pancnet studies. A study with gemcitabine and oxaliplatin reported a response rate of 17% and treatment duration of 7 months. 35 Similarly, a study with capecitabine plus oxaliplatin reported a 27% response rate in 11 pancnets; duration of response was approximately 1 year. 36 More recently, 2 reports from the San Francisco area showed activity with a fluorouracil, oxaliplatin, and bevacizumab combination. The first by

6 782 Reidy-Lagunes Bergsland et al. 37 reported a 50% response rate in 12 patients with progressive pancnets who received short-term infusional 5-fluorouracil plus leucovorin (FOLFOX) and bevacizumab. The second report by Kunz et al. 38 used capecitabine in combination with oxaliplatin plus bevacizumab for 4 cycles and reported a response rate of 19% (3/16). Conclusions Well-differentiated NETs pose a significant challenge because of the tumor heterogeneity and varying degree of aggressiveness. An understanding of tumor signaling mechanisms has led to promising agents that target clinically significant pathways, and these agents have now been FDA-approved. In patients with progressive or symptomatic disease, treatment is indicated. Sunitinib and everolimus are targeted therapies that have shown promising results in pancnets and are now FDA-approved. Both agents significantly improved progression-free survival in phase III randomized trials and result in significant tumor stabilization, but objective response rates are low. Side effects are manageable and predictable but can be persistent and must be considered before initiating therapy. Cytotoxic chemotherapy can increase response rates but may result in significant toxicities. Almost all the reported cytotoxic chemotherapy trials are nonrandomized, with small patient cohorts making the results difficult to interpret. A crucial challenge will be to select the optimal therapy based on identification of patients who are most likely to benefit from treatment and biomarkers that allow this to be achieved while also serving as indicators of efficacy. Ongoing clinical trials also focus on combining targeted agents to improve outcome, but with combinations that appear tolerable (e.g., the VEGF inhibitor bevacizumab plus an mtor inhibitor). 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