Carcinoid and neuroendocrine tumors: building on success.

Published Ahead of Print on April 27, 2015 as 10.1200/JCO.2014.60.2532 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.60.2532

JOURNAL OF CLINICAL ONCOLOGY

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Carcinoid and Neuroendocrine Tumors: Building on Success Pamela L. Kunz Stanford Cancer Center, Stanford, CA. Published online ahead of print at www.jco.org on April 27, 2015. Author’s disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Pamela L. Kunz, MD, Stanford University School of Medicine, Stanford Cancer Center, 875 Blake Wilbur Dr, Stanford, CA 943055826; e-mail: [email protected].

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We have come a long way in our understanding and treatment of neuroendocrine tumors since the term “karzinoide” was coined in 1907. Neuroendocrine tumors are a group of biologically and clinically heterogeneous neoplasms that most commonly originate in the lungs, GI tract, and pancreas. The selection of initial and subsequent therapies requires careful consideration of both tumor and treatment characteristics. With recent advances, we now have more tools for the diagnosis and treatment of our patients. This comprehensive review article summarizes recent advances in the field of neuroendocrine tumors and places them into context for best management practices. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology

© 2015 by American Society of Clinical Oncology 0732-183X/15/3399-1/$20.00

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INTRODUCTION

We have come a long way in the understanding and treatment of carcinoid and neuroendocrine tumors (NETs) since Dr Siegfried Oberndorfer coined the term “karzinoide” in 1907. In fact, the previously neglected field of NET research has seen a renaissance in recent years, with increasing numbers of clinical trials, publications and US Food and Drug Administration (FDA) –approved agents. NETs are now recognized as true neoplasms with characteristic neuroendocrine differentiation, they can arise in various anatomic locations, and they may be associated with symptoms caused by peptide release. The annual incidence of NETs in the United States ranges between two and five per 100,000 patients, and recent analyses have indicated an increase in NET incidence in the United States and elsewhere.1-4 Although the incidence of NETs is rare, NETs are more prevalent than gastric and pancreas adenocarcinomas combined because of the indolent nature of the disease. Population-based studies suggest that median overall survival (OS) for metastatic pancreatic and small bowel NETs is 24 and 56 months, respectively.2 NETs are therefore a greater public health problem than previously appreciated, and high-quality research in the field is imperative. In 2009, the NET Taskforce of the National Cancer Institute (NCI) GI Steering Committee convened a planning meeting for clinical trials to identify key unmet needs and formulate future priorities for the field.5 Select key recommendations from this meeting are listed in Table 1. In the short interval since this meeting, many recommendations have

been implemented and met; others are being addressed in ongoing studies. In particular, as we have learned more about the heterogeneous clinical outcomes and biology of NETs, it has been increasingly apparent that we must separate NETs into pancreatic and nonpancreatic subgroups for the purposes of clinical trial eligibility and standard treatment. Also, since the American Joint Committee on Cancer (AJCC) incorporated NET staging into the seventh edition of the AJCC Cancer Staging Manual, clinical trial designs have been standardized, and clinical trials addressing carcinoid syndrome, advanced carcinoid tumors, and pancreatic NETs have been conducted. The treatment of NETs requires a coordinated multidisciplinary approach. The management of localized NETs primarily involves surgical resection followed by clinical surveillance. However, the treatment approach for patients with unresectable and/or metastatic disease may involve a combination of surgical resection, systemic therapy, and liver-directed therapies with the goal of alleviating symptoms of peptide release and controlling tumor growth. Several completed and ongoing studies are evaluating somatostatin analogs (SSAs), vascular endothelial growth factor (VEGF) pathway inhibitors, mammalian target of rapamycin (mTOR) inhibitors, cytotoxic chemotherapy, and peptide receptor radionuclide therapy (PRRT). In addition to these expanding treatment options, the field has also seen advances in classification, biology, diagnostics, and staging. We now have more tools but we need to better understand how to use them optimally for our patients. This article will review the © 2015 by American Society of Clinical Oncology

Information downloaded from jco.ascopubs.org and provided by at Fudan University on May 3, 2015 from 61.129.42.15 Copyright © 2015 American Society of Clinical Oncology. All rights reserved.

Copyright 2015 by American Society of Clinical Oncology

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Table 1. Select Key Recommendations from the NCI NET Taskforce Clinical Trials Planning Meeting Classification of NETs Carcinoid tumors and pancreatic NETs should be examined separately in clinical trials. Stratification of carcinoid tumors by primary site should be considered in larger, randomized studies. The American Joint Committee on Cancer staging system for NETs should be used as the staging standard in clinical trials. A formal assessment of grade or differentiation should be required for clinical trial enrollment; well-differentiated and poorly differentiated NETs should be studied separately. Evaluation of therapeutic agents for carcinoid syndrome Refractory carcinoid syndrome is an unmet medical need. The successful clinical development of new agents for this indication has proven challenging because of difficulty in selecting appropriate entry criteria and clinical trial end points. Hepatic-directed therapy Hepatic artery embolization is commonly performed in patients with unresectable hepatic-predominant disease. A variety of techniques, including bland embolization, chemoembolization, and radioembolization, are currently used but have never been compared in a controlled setting. Randomized phase II trials exploring the relative efficacy and toxicity of these techniques are recommended. Peptide receptor radiotherapy Randomized phase III studies comparing peptide receptor radiotherapy to standard systemic therapy are warranted. Clinical trials of novel systemic agents for advanced NETs Study design and end points Overall survival is not a practical end point for most advanced NET studies. PFS is recommended as the primary end point for phase III studies as well as for phase II studies in which a delay in progression is expected in the absence of significant radiologically defined tumor responses. Randomized phase II studies that require disease progression before study entry and use PFS as a primary end point should be used to screen novel agents in NETs. Incorporation of biomarkers Serial measurements of plasma chromogranin A should be incorporated into prospective clinical trials. Assessment of tumoral O6-methylguanine DNA methyltransferase expression is warranted in future studies of alkylating agents. Specific recommendations for ongoing and future studies Advanced carcinoid tumors Randomized studies of tyrosine kinase inhibitors targeting VEGFR should be considered in patients with advanced carcinoid tumors. Advanced pancreatic NETs In contrast to carcinoid tumors, there is now substantial evidence that pancreatic NETs are sensitive to alkylating agents. Randomized studies assessing the relative efficacy of streptozocin or temozolomide and assessing the efficacy of temozolomide alone or a temozolomide-based doublet are warranted. NOTE. Modified with permission.5 Abbreviations: NCI, National Cancer Institute; NET, neuroendocrine tumor; PFS, progression-free survival; VEGFR, vascular endothelial growth factor receptor.

recent advances in the field and discuss recommendations on current best management practices. PATHOLOGIC AND CLINICAL CLASSIFICATION SYSTEMS

Historically, there has been much debate about the confusing and inconsistent nomenclature and classification of NETs. The heterogeneous nature of the disease is inherently complicated. In fact, there are more than 20 International Classification of Diseases for Oncology (3rd Edition) histology codes for NETs. Factors such as anatomic site, histology, grade, differentiation, and hormone secretion are key con2

© 2015 by American Society of Clinical Oncology

tributors to a patient’s clinical course and outcome. The inconsistencies in classification systems have hampered clinical trial design, epidemiologic studies, and patient care. The WHO histologic classification of neuroendocrine neoplasms of the GI system6 and lung7 incorporates clinical, molecular, and histopathologic features of these tumors (Table 2). Given the complexity of pathology reporting for NETs, guidelines for the minimum required data elements for pathology reporting were published in 2010.8 These minimum data elements include tumor characteristics, histology, immunohistochemical markers for NETs (synaptophysin, chromogranin), tumor grade, mitotic rate, and Ki-67 index. NETs are also classified by various clinical classifications systems, for example, by embryologic origin (foregut, midgut, hindgut), anatomic site of origin (lung, pancreas, GI tract), and secretion of various peptides and neuroamines (insulin, gastrin, glucagon, vasoactive intestinal peptide, somatostatin [SST]). In particular, the anatomic site of origin (defined as pancreatic v nonpancreatic) is now recognized as a key determinant of treatment selection. Those that actively secrete hormones and cause clinical symptoms are referred to as functional, of which carcinoid syndrome is the classic example. For purposes of clinical management, features of both the histologic and clinical classification systems are considered.

NET GENETICS AND BIOLOGY

It has been recognized that 15% to 20% of NETs are part of inherited genetic syndromes, including multiple endocrine neoplasia type 1 and type 2 (MEN1 and MEN2), von Hippel-Lindau syndrome, neurofibromatosis type 1, and tuberous sclerosis complex. Yet these clinical syndromes were appreciated long before the inherited basis of these syndromes was discovered, for example, MEN-1 in 1997.9 Some of the earliest discoveries in NET biology involve SST and its G-protein-coupled membrane receptors (SSTR1-5). All five SSTRs have been identified throughout the CNS, the GI tract, and endocrine and exocrine glands. The physiologic effects of SST are largely inhibitory: it reduces GI motility and gallbladder contraction, inhibits secretion of most GI hormones, and reduces blood flow in the GI tract.10 Synthetic SST analogs bind mainly to SSTR2 and include octreotide, lanreotide, and pasireotide. More recently, we have made some progress in understanding the molecular biology of NETs. Jiao et al11 examined the exomic sequences in 68 sporadic pancreatic NETs and found that the most frequently mutated genes were MEN-1 (44%), DAXX/ATRX(43%), and genes in the mTOR pathway (15%). In a study of small intestine NETs (SI-NETs), Banck et al11a analyzed 48 SI-NETs by exome sequencing and detected a low rate of somatic single nucleotide variants with an average of 0.1 per 106 nucleotides, suggesting that SI-NETs are mutationally quiescent. However, several recurrent somatic copy number alterations were discovered in cancer-related pathways, including PI3K/Akt/mTOR, tumor growth factor ␤ (through alterations in SMAD genes), and SRC. Francis et al11b also examined somatic mutations in SI-NETs and identified recurrent mutations and deletions in CDKN1B. Future studies are needed to confirm these findings, examine epigenetics alternations, and determine prognostic and predictive biomarkers in NETs. JOURNAL OF CLINICAL ONCOLOGY


Carcinoid and Neuroendocrine Tumors: Building on Success

Table 2. WHO Grading Systems for GI and Pulmonary NETs Lung and Thymus NETs7 Differentiation Well-differentiated

Poorly differentiated

Grade

Nomenclature

GEP NETs7

Proliferative Rate

NET

Proliferative Rate

G1 (low grade)

Typical carcinoid

⬍ 2 mitoses/10 hpf AND no necrosis

NET

G2 (intermediate grade)

Atypical carcinoid

2-10 mitoses/10 hpf OR necrosis

NET

G3 (high grade)

Small-cell carcinoma; large-cell neuroendocrine carcinoma

⬎ 10 mitoses/10 hpf

Neuroendocrine carcinoma small-cell type; neuroendocrine carcinoma large-cell type

⬍ 2 mitoses/10 hpf AND ⬍ 3% Ki-67 index 2-20 mitoses/10 hpf OR 3%-20% Ki67 index ⬎ 20 mitoses/10 hpf OR ⬎ 20% Ki-67 index

Abbreviations: GEP, gastroenteropancreatic; hpf, high-powered field; NET, neuroendocrine tumor.

DIAGNOSTICS AND STAGING

The diagnostic approach to patients with NETs is outlined in the National Comprehensive Cancer Network Neuroendocrine Tumor Guidelines12 and the North American Neuroendocrine Tumor Society guidelines.13 In general, multiphasic computed tomography or magnetic resonance imaging scans are recommended for initial evaluation and surveillance. SST scintigraphy is not recommended for routine surveillance, but rather as being appropriate for answering specific clinical questions. Biochemical evaluation of serum and urine peptides is recommended as clinically indicated, depending on the primary site and associated symptoms. Another important advance in recent years is the addition of NET staging to the seventh edition of the AJCC Cancer Staging Manual.14 The TNM staging for NETs of the GI tract and pancreas was modeled after their adenocarcinoma counterparts. Recent single-institution15-17 and population-based studies18 have evaluated the prognostic validity of these new NET staging systems with mixed results. TREATMENT

An understanding of key tumor characteristics balanced with an understanding of adverse effects of treatment and outcome measures should inform the selection of initial and subsequent treatment strategies (Table 3). TREATMENT FOR SYMPTOMS OF HORMONE EXCESS For patients with functional tumors, SSAs are the mainstay of treatment to control symptoms of hormone excess. Octreotide was the first synthetic SSA developed in the 1980s. It shows high affinity toward SSTR2 and has higher potency and a longer half-life compared with naturally occurring SST. The short-acting formulation can be given by continuous infusion or as a subcutaneous injection two to three times per day. A long-acting formulation, octreotide LAR, was developed in the 1990s and is typically administered at 20 to 30 mg as a once-per-month intramuscular injection. It is recommended to continue initial short-acting formulation coverage for about 2 to 3 weeks until steady-state levels of octreotide LAR are achieved. Dose www.jco.org

and frequency of both short- and long-acting SSAs may be further increased for symptom control as needed.19 Lanreotide has similar SSTR binding affinity to octreotide and is available in two formulations: sustained-release lanreotide given as an intramuscular injection once every 2 weeks and prolonged-release lanreotide given as a deep subcutaneous injection once every 4 weeks. Short-acting octreotide and sustained-release lanreotide were shown to be equally effective in controlling carcinoid syndrome.20 Lanreotide is approved in Europe and the United States for treatment of acromegaly. Pasireotide has a high affinity to SSTR subtypes 1, 2, 3, and 5 and displays a 30- to 40-fold higher affinity for SSTR1 and SSTR5 than octreotide or lanreotide.21 Given its broader binding affinity, it has been hypothesized to have a greater inhibitory effect than octreotide.22 A phase III study of pasireotide LAR versus octreotide LAR in patients with symptomatic metastatic NETs demonstrated equal efficacy of these drugs in controlling symptoms of hormone secretion.23 Pasireotide is approved in Europe and the United States for Cushing disease. The most commonly encountered adverse effects of SSAs include nausea, abdominal cramps, diarrhea, steatorrhea, flatulence, hyperglycemia and cholelithiasis/biliary sludging, and injection site pain. It has been recommended that cholecystectomy be performed prophylactically in patients with NETs being given or considering SSA therapy. Pasireotide, compared with the other SSAs, has higher rates of

Table 3. Tumor and Treatment Characteristics That Have an Impact on Treatment Selection Characteristic Tumor Extent of disease

Pace of growth Primary site Grade Hormone status Treatment Adverse effects Outcome measures

Parameter Localized v metastatic/unresectable; widely metastatic v liver dominant; low v high volume Stable v progressive Pancreatic v nonpancreatic Low grade (well differentiated) v high grade (poorly differentiated) Functional v nonfunctional Mild v severe Delayed progression v tumor shrinkage



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Locoregional/ resectable

Grade

Extent

Diagnosed with NET

Metastatic/unresectable

Poorly differentiated

Well differentiated

Extent

Pace

Asymptomatic or stable disease

Systemic treatment if widespread

Primary site Treatment characteristics

Progressive and/or symptomatic

Surgery

Platinum/ etoposide

Observe, SSA

Hepatic artery embolization if liver-dominant disease

Pancreatic NET

Nonpancreatic NET

SSA, everolimus, sunitinib, cytotoxic chemotherapy

SSA, IFN

Fig 1. Algorithm for approaching tumor control in neuroendocrine tumors (NETs). IFN, interferon; SSA, somatostatin analog.

hyperglycemia. Finally, SSAs should be used with caution in patients with insulinomas because they have the potential to worsen hypoglycemia by suppressing glucagon secretion. Telotristat, a tryptophan hydroxylase inhibitor in the serotonin synthesis pathway, is being investigated for control of hormonerelated symptoms. Early-phase clinical trials have been promising24 and phase III trials are ongoing (NCT01677910; TELESTAR [Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome]; and NCT02063659; TELECAST [Telotristat Etiprate for Carcinoid Syndrome Therapy]).

tients with bulky, rapidly progressive, and/or symptomatic pancreatic NETs, cytotoxic chemotherapy may yield greater tumor shrinkage than SSAs or molecularly targeted agents. For patients with liver-dominant metastatic disease, hepatic artery embolization (bland embolization, chemoembolization, and radioembolization) is an additional consideration. Although we are now fortunate to have several treatment options for our patients, the optimal sequence of these treatments is unknown. Tables 4 and 5 summarize key completed and ongoing clinical trials for tumor control.

TREATMENT FOR CONTROL OF TUMOR GROWTH An algorithm for approaching tumor control in NETs is outlined in Figure 1 and takes into consideration tumor characteristics with adverse effects of treatment and outcome measures. Extent of disease is the first consideration. For localized tumors, surgical resection is the mainstay of treatment with a curative intent. For unresectable or metastatic disease, treatment selection is next guided by degree of differentiation. Expectant management may be considered in some patients with advanced well-differentiated NETs, particularly those with low-volume, nonprogressive, or asymptomatic disease. For select patients with metastatic welldifferentiated NETs, cytoreductive surgery may also be considered. For patients with well-differentiated, symptomatic and/or progressive disease, systemic therapies are often the first line of treatment. Selection of systemic treatment is further determined by primary site: pancreatic versus nonpancreatic. These patient subgroups are treated differently because of underlying differences in biology, response rates, and prognosis. Recent randomized studies of octreotide LAR,25 lanreotide,26 everolimus,27 and sunitinib28 in well-differentiated NETs have demonstrated prolongation of progression-free survival (PFS) compared with placebo. For pa-

Treatment of Poorly Differentiated Neuroendocrine Carcinomas Poorly differentiated neuroendocrine carcinomas (NECs) can arise in any primary anatomic site yet have a predictably aggressive clinical course. First-line therapy is traditionally platinum with etoposide.32,33 This choice is based on the small-cell lung cancer literature; however, high-quality, prospective data specific to poorly differentiated NECs is lacking. These tumors often have a rapid response to platinum-based cytotoxic chemotherapy, but the duration of this response is usually short-lived. The NORDIC NEC study (Predictive and Prognostic Factors for Treatment and Survival in 305 Patients With Advanced Gastrointestinal Neuroendocrine Carcinoma [WHO G3]) retrospectively evaluated 252 patients with NECs who were treated with cisplatin-etoposide (n ⫽ 129) or carboplatin-etoposide (n ⫽ 67) in the palliative setting. Both regimens had similar response rates (31%), median PFS (4 months), and OS (11 months). Patients with a lower proliferative rate (Ki-67 ⬍ 55%) had a lower response rate (RR) to chemotherapy (15% v 42%) but a better OS (14 v 10 months) compared with patients with a Ki-67 ⱖ 55%.34 Some retrospective studies suggest

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Table 4. Key Completed Randomized Clinical Trials in NETs

Trial Name Somatostatin analogs Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients With Metastatic Neuroendocrine Midgut Tumors (PROMID) Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors (CLARINET)ⴱ Biologics Efficacy and Safety of Everolimus (RAD001) Compared to Placebo in Patients With Advanced Neuroendocrine Tumors A Study of Sunitinib Compared to Placebo for Patients With Advanced Pancreatic Islet Cell Tumorsⴱ Cytotoxics Cytotoxic chemotherapy Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndromeⴱ Streptozocin-Doxorubicin, StreptozocinFlurouracil, or Chorozotocin in the Treatment of Advanced Islet-Cell Carcinoma

Reference

Tumor Type

Study Arm

No. of Patients

TTP or PFS (months)

OS (months)

RR (%) 2 0

Rinke 200925 Arnold 201360

Midgut

Octreotide Placebo

42 43

14.3 6.0

Not reached 84

Caplin 201426

pNET, midgut, hindgut, unknown

Lanreotide

101

18.0

Placebo

103

Not reached

Not reached Not reached

207 203

11.0 4.6

Not reached 36.6

5 2

Not reported Not reported

Yao et al27

Pancreatic NET

Everolimus Placebo

Raymond et al28

Pancreatic NET

Sunitinib Placebo

86 85

11.4 5.5

30.5 24.4

9 0

Moertel et al29

Carcinoid and pancreatic NET

Streptozocin/ fluorouracil Streptozocin/ cyclophosphamide Streptozocin/ doxorubicin Streptozocin/ fluorouracil Chlorozotocin

42

Not reported

Not reported

33

Moertel et al30

Pancreatic NET

47 38

26 20

26.4

69

34

6.9

16.8

45

33

6.9

16.8

30

Abbreviations: NET, neuroendocrine tumor; OS, overall survival; PFS, progression-free survival; RR, response rate; TTP, time to progression. ⴱ Registration trial leading to US Food and Drug Administration approval.

that temozolomide and capecitabine may be active in poorly differentiated NECs.35 To further evaluate this combination, an NCI cooperative group trial is in development to evaluate the combination of capecitabine and temozolomide versus cisplatin and etoposide in these poorly differentiated NECs (EA2142). Treatment of Well-Differentiated NETs SSAs. SSAs have long been used to control symptoms of hormone excess in patients with NETs, and only recently have they been appreciated as antiproliferative agents for patients with welldifferentiated metastatic disease. Possible mechanisms for the antiproliferative activity of SSAs include antimitotic activity leading to cell cycle arrest36 and inhibition of growth factors such as growth hormone, insulin-like growth factor-1, insulin, gastrin, and epidermal growth factor.37 The first clinical trial to demonstrate prolonged time to tumor progression (TTP) of SSAs in NETs was the PROMID (Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients With Metastatic Neuroendocrine Midgut Tumors) study.25 In this phase III trial, 85 patients with well-differentiated metastatic midgut NETs were randomly assigned to receive 30 mg octreotide LAR once per month via intramuscular injection versus placebo. Octreotide significantly improved TTP when compared with placebo (14.3 v 6 months; hazard ratio [HR], 0.34; 95% CI, 0.20 to 0.59; P ⬍ .001); there was no difference in median OS. Although this study did not have a www.jco.org

formal impact on the FDA label for octreotide LAR, octreotide was widely adopted for controlling tumor growth in patients with metastatic midgut NETs. The CLARINET (Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors) study was a phase III study of lanreotide in patients with advanced, nonfunctioning, SSTRpositive well-differentiated NETs. Patients were randomly assigned to receive lanreotide 120 mg via a deep subcutaneous injection every 28 days versus placebo. In 205 enrolled patients, lanreotide significantly improved PFS when compared with placebo (18.0 months v median not reached; HR, 0.47; 95% CI, 0.30 to 0.73; P ⬍ .001); there was no difference in median OS.26 In contrast to PROMID, this study included patients with grade 1 or 2 tumors (Ki-67 ⬍ 10%), larger liver tumor volume, and stable disease at baseline. Lanreotide was granted FDA approval in December 2014 for advanced gastroenteropancreatic NETs. Although PROMID evaluated octreotide LAR in midgut NETs and CLARINET studied lanreotide in pancreatic, midgut, hindgut, and unknown primary NETs, the PFS benefit in those trials was thought to be an SSA class effect. The recommended SSA doses for tumor control are octreotide LAR 20 to 30 mg via intramuscular injection once per month and lanreotide 120 mg via deep subcutaneous injection once per month. In contrast to dosing for hormone control, a 2-week overlap with short-acting octreotide is not required. There are little high-level data to support the routine use of above-standard doses of SSAs for tumor control. © 2015 by American Society of Clinical Oncology


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Table 5. Key Active Clinical Trials in NETs

Phase GI and lung NETs III

III

II

III

Pancreatic NETs II

II

III

Trial Acronym

Trial Name

SWOG 0518

Octreotide Acetate and Recombinant Interferon Alfa2b or Bevacizumab in Treating Patients With Metastatic or Locally Advanced, High-Risk Neuroendocrine Tumor RADIANT-4 Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors (GI or Lung Origin) A021202 Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors NETTER-1 A Study Comparing Treatment With 177Lu-DOTA0-Tyr3Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours

NCT No.

Status

Tumor Type

Primary End Point

NCT00569127 Accrual complete

Octreotide LAR ⫹ interferon-␣ v octreotide LAR ⫹ bevacizumab

GI and lung NETs

400

PFS

NCT01524783 Accrual complete

Everolimus v placebo

GI and lung NETs

302

PFS

NCT01841736 Ongoing

Pazopanib v placebo

GI and lung NETs

150

PFS

NCT01578239 Ongoing

High-dose octreotide LAR v PRRT

Midgut

280

PFS

Everolimus ⫹ Pancreatic NET octreotide LAR with or without bevacizumab

138

PFS

Temozolomide v temozolomide ⫹ capecitabine

Pancreatic NET

145

PFS

Everolimus followed by Pancreatic NET streptozocinfluorouracil v streptozocinfluorouracil followed by everolimus

180

PFS

112

PFS

Everolimus and Octreotide NCT01229943 Accrual Acetate With or Without complete Bevacizumab in Treating Patients With Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors That Cannot Be Removed by Surgery ECOG 2211 Temozolomide With or Without NCT01824875 Ongoing Capecitabine in Treating Patients With Advanced Pancreatic Neuroendocrine Tumors SEQTOR Efficacy and Safety of Everolimus NCT02246127 Ongoing and (STZ-5FU) Given One Upfront the Other Upon Progression in Advanced pNET CALGB 80701

Poorly differentiated NECs II EA2142

Regimen

No. of Patients

Randomized Phase II Study of Pending Cisplatin and Etoposide Versus Temozolomide and Capecitabine in Patients with Advanced G3 Non-Small Cell Gastroenteropancreatic Neuroendocrine Carcinomas

Opening spring Cisplatin ⫹ etoposide v GI NECs 2015 temozolomide ⫹ capecitabine

Abbreviations: CALGB, Cancer and Leukemia Group B; DFS, disease-free survival; ECOG, Eastern Cooperative Oncology Group; NEC; neuroendocrine carcinoma; NET, neuroendocrine tumor; PFS, progression-free survival; PRRT, peptide receptor radionuclide therapy; SWOG, Southwest Oncology Group.

Radiolabeled SSAs. PRRT with radiolabeled SSAs is a promising systemic treatment modality for patients with inoperable or metastatic NETs. The radiolabeled SSAs bind to SST receptors and cause a localized antitumor effect.38 Although PRRT has been used for treatment of metastatic SSTR-positive NETs in Europe since the 1990s, it is not approved by the FDA, given lack of prospective, randomized data. In 2008, Kwekkeboom et al39 reported a large retrospective analysis of 500 patients treated with [177Lu-DOTA0,Tyr3]octreotate. Complete and partial tumor remissions occurred in 2% and 28% of the patients, respectively, and minor tumor response (decrease in size ⬎ 25% and ⬍ 50%) occurred in 16% of the patients. Median TTP 6


was 40 months, and median OS was 46 months. Serious delayed toxicities occurred in a minority of patients and included renal insufficiency (two patients), liver toxicity (three patients), and myelodysplastic syndrome (four patients).39 The first phase III clinical trial of PRRT, NETTER-1 (NCT01578239; A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours), is now underway. It compares [177Lu-DOTA0,Tyr3]octreotate to high-dose octreotide LAR (60 mg once per month) in patients with inoperable, SSTR-positive, metastatic midgut NETs. In addition, JOURNAL OF CLINICAL ONCOLOGY



novel radiolabeled SST antagonists are being developed for both imaging and treatment.40 Biologics. Biologic therapies, including inhibitors of signaling pathways that target VEGF and mTOR, have met with recent success in the treatment of NETs. Yet we often forget that interferon (IFN) was a biologic therapy ahead of its time. It was studied extensively for the treatment of NETs as a single agent and in combination with SSAs.41-43 However, its routine use is limited by toxicity. In Southwest Oncology Group (SWOG) 0518 (Octreotide Acetate and Recombinant Interferon Alfa-2b or Bevacizumab in Treating Patients With Metastatic or Locally Advanced, High-Risk Neuroendocrine Tumor), a phase II clinical trial in poor prognosis carcinoid, IFN-␣ was selected as the control arm in a trial of octreotide LAR plus IFN-␣ versus octreotide LAR plus bevacizumab. The study has completed accrual, and results are pending.44 RADIANT-2 (Everolimus and Octreotide in Patients With Advanced Carcinoid Tumor) was a randomized phase III study of everolimus, an mTOR inhibitor, in advanced NETs.45 In all, 429 patients with well-differentiated, functional, progressive lung, GI, or pancreatic NETs were randomly assigned to receive everolimus 10 mg orally once per day or placebo; both arms also received intramuscular octreotide LAR 30 mg once per month. Crossover was allowed at time of progression. Median PFS, as determined by central review, favored the everolimus arm at 16.4 versus 11.3 months (HR, 0.77; 95% CI, 0.59 to 1.00; P ⫽ .026). Median PFS as determined by local review also favored the everolimus arm at 12.0 versus 8.6 months (HR, 0.78; 95% CI, 0.62 to 0.98; P ⫽ .018). However, the primary end point of central PFS missed statistical significance by a narrow margin (prespecified P ⱕ .0246). This difference in PFS between central and local radiology review was determined to be from informative censoring (when dropout or censoring occurs at different rates as a result of bias) and confounded the statistical analysis. The finding of informative censoring in this study raises important issues for future NET trial design. In particular, imaging and interpretation of hypervascular NET lesions is challenging and lacks standard guidelines. The ongoing study of pazopanib versus placebo in nonpancreatic NETs (NCT01841736; A021202; Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors) aims to address this issue in a correlative analysis of imaging characteristics. In addition, imaging of NETs has been declared a priority by the American College of Radiology Imaging Network, and efforts to bank images from patients on all NCIsponsored clinical trials is underway. Given that RADIANT-2 was officially a negative study, RADIANT-4 (Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors [GI or Lung Origin]) was designed as a follow-up in an effort to clarify clinical activity of everolimus in welldifferentiated NETs of GI or lung origin; crossover was not allowed. The study has completed accrual and results are pending. RADIANT-3 (Efficacy and Safety of Everolimus [RAD001] Compared to Placebo in Patients With Advanced Neuroendocrine Tumors) was a randomized phase III study that evaluated everolimus in advanced pancreatic NETs (Table 4).27 In that study, 410 patients with low- or intermediate-grade, progressive, advanced pancreatic NETs were randomly assigned to receive everolimus 10 mg orally once per day or placebo. Median PFS was 11.0 months with everolimus compared with 4.6 months with placebo (HR, 0.35; 95% CI, 0.27 to www.jco.org

0.45; P ⬍ .001). On the basis of that trial, everolimus was FDAapproved for treatment of advanced pancreatic NETs in 2011. Sunitinib, an oral VEGF tyrosine kinase inhibitor, was evaluated in a phase III study of 171 patients with advanced, well-differentiated, progressive pancreatic NETs.28 Patients were randomly assigned to receive sunitinib 37.5 mg orally once per day or placebo. The study was discontinued early after an independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo arm and a difference in PFS that favored the sunitinib arm. PFS was 11.4 months in the sunitinib arm compared with 5.5 months in the placebo arm (HR, 0.42; 95% CI, 0.26 to 0.66; P ⬍ .001). This trial led to the FDA approval of sunitinib for advanced pancreatic NETs in 2011. Although direct cross-trial comparison is considered taboo from a statistics standpoint, it is hard to ignore the strikingly similar results of the sunitinib and everolimus (RADIANT-3) studies in pancreatic NETs. Despite different mechanisms of action, the median PFS for the experimental and placebo arms in both trials were almost identical, approximately 11 and 5 months, respectively. In addition, both studies demonstrated low RRs and failed to demonstrate an OS survival benefit, due in part to the cross-over study design. Reasons for these similarities are not entirely clear but may speak more to the underlying biology than the treatment. Cytotoxics. Recently published guidelines from the European Neuroendocrine Tumor Society,47-49 the North American Neuroendocrine Tumor Society,13 and the National Comprehensive Cancer Network12 recommend cytotoxic chemotherapy for patients with well-differentiated pancreatic NETs who have bulky, rapidly progressive, and/or symptomatic disease. Chemotherapy is recommended in this setting over molecularly targeted therapies and SSAs because of higher objective response rates and therefore better symptom control by reduction in tumor bulk. Chemotherapy may also be administered to patients with progressive well-differentiated, nonpancreatic NETs in whom there are no other treatment options; however, there has been a lack of objective radiologic responses, PFS, and OS benefit in this patient population. Early NET clinical trials studied the alkylating agent streptozocin and eventually led to its approval by the FDA for treatment of pancreatic NETs in 1982.29,30 The patient populations studied in the early trials were heterogeneous and included both pancreatic and nonpancreatic NETs. These trials also used nonstandard clinical and radiographic response criteria and cannot easily be compared with modern trials. The clinical activity of streptozocin has since been confirmed in several prospective single-arm and randomized clinical trials, albeit with less robust data than that reported in the earlier studies.50,51 Widespread use of streptozocin in the United States has been limited by toxicities and drug availability. Temozolomide is an oral alkylating agent that serves as a prodrug to dacarbazine. In contrast to streptozocin and dacarbazine, temozolomide has a more favorable adverse effect profile and has demonstrated promising activity in pancreatic NETs. It has been studied as a single agent and in combination in many small studies.52-55 The combination of temozolomide and capecitabine has shown the most promising antitumor activity in advanced pancreatic NETs in retrospective and small prospective trials. In a retrospective study evaluating the combination in 30 patients with pancreatic NETs, an RR of 70% was noted with a median PFS of 18 months.56 Recently, a small © 2015 by American Society of Clinical Oncology


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prospective, single-arm phase II trial of temozolomide and capecitabine was presented at the 2014 American Society of Clinical Oncology GI Cancers Symposium that reported an RR of 36% in pancreatic NETs with a median PFS of more than 20 months.57 That study deserves mention because it is the first prospective trial to study temozolomide-capecitabine combination therapy in advanced NETs. However, it is limited by its small sample size, short follow-up, limited available data on clinical responses, and nonstandard eligibility criteria because it included patients with pituitary adenomas (a benign condition not generally included in cancer clinical trials). Because the activity of temozolomide alone and in combination with capecitabine is promising, an ongoing US Intergroup trial is formally evaluating this combination in a prospective randomized clinical trial (NCT01824875; Temozolomide With or Without Capecitabine in Treating Patients With Advanced Pancreatic Neuroendocrine Tumors; Table 5). Other therapies. Liver-directed intra-arterial therapies, including transarterial bland embolization, transarterial chemoembolization, and selective internal radiotherapy with yttrium-90 (90Y) microspheres, are indicated in patients with liver-predominant metastatic disease and relatively low tumor burden. Few prospective randomized trials have been conducted to evaluate and compare these techniques, and little is known about their relative efficacy. BUILDING ON SUCCESS AND THINKING TOWARD THE FUTURE

We have made rapid progress in our understanding of NET epidemiology, classification, biology, diagnostics, and treatment. In fact, many of the recommendations from the 2009 NCI NET Taskforce clinical trials planning meeting have already been met. Clinical outcomes and an evolving understanding of NET biology have taught us to be splitters not lumpers because we now design trials separately for pancreatic REFERENCES 1. Lawrence B, Gustafsson BI, Chan A, et al: The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 40:1-18, 2011 2. Yao JC, Hassan M, Phan A, et al: One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26:3063-3072, 2008 3. Garcia-Carbonero R, Capdevila J, CrespoHerrero G, et al: Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): Results from the National Cancer Registry of Spain (RGETNE). Ann Oncol 21:1794-1803, 2010 4. Mocellin S, Nitti D: Gastrointestinal carcinoid: Epidemiological and survival evidence from a large population-based study (n ⫽ 25 531). Ann Oncol 24:3040-3044, 2013 5. Kulke MH, Siu LL, Tepper JE, et al: Future directions in the treatment of neuroendocrine tumors: Consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin Oncol 29:934-943, 2011 6. Bosman FT, Carneiro F, Hruban RH, et al: (eds): WHO Classification of Tumours of the Digestive System (ed 4). Lyon, France, International Agency for Research on Cancer, 2010 8


versus nonpancreatic and well versus poorly differentiated NETs. Treatment paradigms have followed suit. We have also learned that clinical trial success in NETs cannot be defined by the FDA gold standard of an OS benefit because most patients have an indolent disease course and live to receive multiple sequential therapies; PFS is the preferred primary end point in this disease. The therapeutic options for patients with advanced NETs are now abundant. This wealth of options has created a new challenge of navigating a complex treatment landscape. The choice of treatment must be tailored to the patient, with special attention to extent of disease, pace of growth, primary site, grade, and hormone status, and treatment characteristics. Yet, with challenge comes opportunity. We must design trials that address the next generation of NET priorities— combinations of systemic therapies, comparison of hepatic artery embolization techniques, sequence of existing therapies, and trials enriched for biomarker-selected patients. Several ongoing studies are poised to answer some of these key questions (Table 5). Other priorities include further refinement of histologic classification for NECs, development of NET imaging and tumor assessment guidelines, and assessment of predictive and prognostic biomarkers. Finally, we must better examine quality of life, patient-reported outcomes, and survivorship. These patient-centric issues are especially important in an indolent disease for which patients may have years of treatment-related adverse effects and the emotional stress of a chronic cancer diagnosis. With shrinking resources, it is imperative that we design smarter trials—trials that are designed to deliver the greatest benefit to patients.58 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at www.jco.org.

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Pamela L. Kunz

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Carcinoid and Neuroendocrine Tumors: Building on Success The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Pamela L. Kunz Stock or Other Ownership: Guardant Health Consulting or Advisory Role: Ipsen, Guardant Health, Novartis


Research Funding: Advanced Accelerator Applications, Genentech/Roche, Merck, Lexicon Pharmaceuticals, Merrimack Pharmaceuticals, Oxigene



Gastroenteropancreatic neuroendocrine (carcinoid) tumors in children.

Expert consensus for the management of advanced or metastatic pancreatic neuroendocrine and carcinoid tumors.

Savings From ACOs-Building on Early Success.

Prospective evaluation and treatment of familial carcinoid small intestine neuroendocrine tumors (SI-NETs).

Update on pancreatic neuroendocrine tumors.

[Neuroendocrine tumors].

Bronchoplastic procedures for carcinoid tumors.

Carcinoid tumors of the testis.

Update on management of midgut neuroendocrine tumors.

A guide to midgut neuroendocrine tumours (NETs) and carcinoid syndrome.

Building on success with new fields to conquer.

Bronchial carcinoid tumors in children and adolescents.

Pulmonary Neuroendocrine Tumors.

[Pulmonary neuroendocrine tumors].

Pancreatic neuroendocrine tumors.

Prognostic impact of p16 and p21 on gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine tumors of the bronchopulmonary system (typical and atypical carcinoid tumors): current strategies in diagnosis and treatment. Conclusions of an expert meeting February 2011 in Weimar, Germany.

Nonfunctional pancreatic neuroendocrine tumors.

Bronchial neuroendocrine (carcinoid) tumor causing unilateral left-sided carcinoid heart disease.

Management of ampullary carcinoid tumors with pancreaticoduodenectomy.

Anorectal carcinoid tumors. Is aggressive surgery warranted?

Postoperative surveillance of small appendiceal carcinoid tumors.

Silencing of UCHL1 by CpG promoter hyper-methylation is associated with metastatic gastroenteropancreatic well-differentiated neuroendocrine (carcinoid) tumors.

Biochemical prognostic indicators for pancreatic neuroendocrine tumors and small bowel neuroendocrine tumors.