Accomplishments in 2008 in the Management of Gastrointestinal Neuroendocrine Tumors

SUMMARY

1. Overview of the Disease Process

   1. Incidence

   2. Prognostic Factors

2. General Therapy Standards

3. Accomplishments and Lack of Accomplishments During the Year

   1. Somatostatin Analogs

   2. Peptide Receptor–Targeted Therapy

   3. Selective Internal Radiotherapy (SIRT)

   4. Cytotoxic Therapies: Temozolomide

   5. VEGF Pathway Inhibitors

   6. mTOR Inhibitors

   7. Development of Biomarkers

4. What Needs to be Done (Application of the Accomplishments)

5. Controversies and Disagreements

   1. Histologic Classification and Staging of Neuroendocrine Tumors

   2. Clinical Trial Design and End Points

6. Future Directions

I. OVERVIEW OF THE DISEASE PROCESS

I-A. Incidence

The annual incidence of clinically relevant carcinoid tumors has previously been estimated to be 1 to 2 per 100,000 population per year.¹ A recent study, however, suggested that the annual incidence of carcinoid tumors may be higher. In an analysis of the Surveillance, Epidemiology, and End Results (SEER) database, the estimated annual incidence of carcinoid tumors was 5.25 per 100,000 population, and the limited duration prevalence in the United States was estimated to exceed 100,000 individuals.² These increases in diagnosed incidence and prevalence are likely attributable, in part, to an increasing awareness of and improved diagnostic strategies for neuroendocrine tumors (NETs).

I-B. Prognostic Factors

Currently, traditional clinicopathologic features remain the primary validated predictors of prognosis in neuroendocrine tumors. The SEER database utilized a general staging system in which patients are divided into “localized,” “regional,” or “distant” metastatic disease.³ The World Health Organization has further defined neuroendocrine tumors according to stage, degree of differentiation, tumor site of origin, and proliferative index, as measured by Ki-67 staining.⁴ A lack of molecular and genetic prognostic factors has been an impediment to determining the best approach for neuroendocrine tumor patients therapeutically, particularly in light of the promise of novel therapies targeting specific molecular pathways. The identification of molecular and genetic prognostic factors for neuroendocrine tumor patients was noted as a key research priority at a National Cancer Institute summit meeting in September 2007.⁵

Similarly, risk factors for neuroendocrine tumors remain poorly understood. A number of rare inherited syndromes associated with neuroendocrine tumors have been identified, and include multiple endocrine neoplasia type 1 (MEN1), von Hippel–Lindau (VHL), and tuberous sclerosis syndromes.⁶ These syndromes, however, account for fewer than 5% of all diagnosed neuroendocrine tumor cases. Risk factors for “sporadic” neuroendocrine tumors are only beginning to be identified. In recent case control studies, diabetes, smoking, and having a first-degree relative with cancer were identified as modest risk factors for neuroendocrine tumors.^7,8

II. GENERAL THERAPY STANDARDS

The carcinoid syndrome, as well as other hormonal syndromes associated with neuroendocrine tumors, can often be well controlled with somatostatin analogs. The long-acting depot form of the somatostatin analog octreotide is commonly used in the United States and is administered as an intragluteal injection. Lanreotide, another somatostatin analog, appears to be similar to octreotide in its clinical efficacy for carcinoid syndrome, and can be self-administered as a long-acting subcutaneneous injection.⁹ Hepatic-directed therapy, including hepatic resection, hepatic arterial embolization, and ablative therapies are commonly used as palliative techniques in patients with hepatic-predominant disease. Although carcinoid and pancreatic neuroendocrine tumors appear histologically similar, there is increasing evidence that pancreatic neuroendocrine tumors are more responsive to chemotherapy than are carcinoid tumors. Streptozocin is an approved treatment for patients with well or moderately differentiated pancreatic neuroendocrine tumors; traditional streptozocin-based regimens used for pancreatic neuroendocrine tumors include streptozocin/5-fluorouracil, streptozocin/doxorubicin, or a three-drug combination of streptozocin/doxorubicin/5-fluorouracil.¹⁰ The widespread use of streptozocin, however, has been limited by concerns regarding its potential for toxicity.

III. ACCOMPLISHMENTS AND LACK OF ACCOMPLISHMENTS DURING THE YEAR

III-A. Somatostatin Analogs

Novel somatostatin analogs that are more broadly targeted and have higher affinities for somatostatin receptors have recently been developed. The potential cytostatic effect of these agents has also been a topic of increasing interest.

• Pasireotide (SOM230) is a multi-ligand somatostatin analog that has exhibited high binding affinity to sst1, sst2, sst3, and sst5.¹¹ In a phase II trial, 44 patients with metastatic carcinoid tumors whose symptoms of diarrhea and flushing were inadequately controlled by octreotide LAR received pasireotide 300 μg subcutaneously twice per day, escalated to a maximum dose of 1,200 μg twice per day every 3 days until symptom control was achieved. Control of symptoms was achieved in 11 of 44 patients (25%).¹² Pasireotide is currently being compared with high-dose octreotide in patients with carcinoid syndrome refractory to standard-dose octreotide (Table 1).

• In a randomized study, 85 patients with unresectable or metastatic midgut neuroendocrine tumors were randomized to receive treatment with octreotide LAR or placebo. Patients randomized to the octreotide arm had a significantly longer progression-free survival duration (14.3 vs. 6 months; P = .0037), which led to early termination of the study.¹³ A randomized trial evaluating the effect of lanreotide vs. placebo on progression-free survival is ongoing (Table 1).

Table 1:

Ongoing or recently completed randomized trials in neuroendocrine tumors

Sponsor (NCT Trial No.)	Experimental Arm	Control Arm	Tumor Type
SWOG (NCT00569127)	Bevacizumab + octreotide LAR	IFN-α-2b + octreotide LAR	Carcinoid
Novartis (NCT 00412061)	Everolimus+ octreotide LAR	Octreotide LAR	Carcinoid
Novartis (NCT 00690430)	Pasireotide	High-dose octreotide	Refractory carcinoid syndrome
Ipsen (NCT 00353496)	Lanreotide autogel	Placebo	Carcinoid or pancreatic NET
Pfizer (NCT 00428597)	Sunitinib	Placebo	Pancreatic NET*
Novartis (NCT 00510068)	Everolimus	Placebo	Pancreatic NET

^*Accrual stopped early for efficacy

Abbreviations: NET = neuroendocrine tumor; SWOG = Southwest Oncology Group

III-B. Peptide Receptor–Targeted Therapy

The high rate of somatostatin receptor expression in neuroendocrine tumors provides the rationale for use of radionuclide therapy for patients with inoperable or metastatic disease. The available radiolabeled somatostatin analogs differ from one another in their affinity for the various somatostatin receptor subtypes and in the radionuclides to which they are conjugated. The most frequently used radionuclides for targeted radiotherapy have included indium (¹¹¹In), yttrium (⁹⁰Y), and lutecium (¹⁷⁷Lu), which differ from one another in terms of emitted particles, particle energy, and tissue penetration.¹⁴

• [¹⁷⁷Lu-DOTA, Tyr³]octreotate has been used in the treatment of 504 patients with neuroendocrine tumors strongly expressing somatostatin receptors. Efficacy results, reported for 310 of the 504 patients, suggest an overall tumor response rate of up to 30%.¹⁵

III-C. Selective Internal Radiotherapy (SIRT)

Hepatic arterial embolization is an accepted palliative treatment for patients with advanced neuroendocrine tumors and hepaticpredominant disease. Both bland embolization and chemoembolization have been explored. More recently, radioembolization has also shown promise.

• In a retrospective series of 148 neuroendocrine tumor patients treated with ⁹⁰Y microspheres, partial or complete responses were observed in 63% of patients, with only mild associated toxicity.¹⁶

• Partial radiologic responses were observed in 50% of patients in a prospective study, in which 32 patients were treated with ⁹⁰Y microspheres.¹⁷

III-D. Cytotoxic Therapies: Temozolomide

Temozolomide is an orally available cytotoxic alkylating agent with a mechanism of action similar to that of streptozocin and dacarbazine. Recent prospective and retrospective studies have suggested that temozolomide-based regimens may be similar in efficacy to streptozocin-based regimens in pancreatic neuroendocrine tumors.¹⁸

• In the largest of the retrospective series, 18/53 (34%) patients with pancreatic neuroendocrine tumors, but only 1/44 (2%) patients with carcinoid tumors (P < .001), experienced a partial or complete response to temozolomide-based therapy.¹⁸

• The cytotoxic effect of temozolomide has been attributed to its ability to induce DNA methylation at the O–6 position of guanine. The sensitivity of tumor cells to alkylating agents, including temozolomide, has been associated with decreased levels of the DNA repair enzyme, O6-methylguanine DNA methyltransferase (MGMT), which, through its ability to restore DNA to its normal form, can prevent chemotherapy-induced cell death.¹⁹ MGMT deficiency appears to be more common in pancreatic neuroendocrine tumors than in carcinoid tumors; potentially explaining the greater sensitivity of pancreatic neuroendocrine tumors to treatment with the alkylating agents streptozocin or temozolomide, and raising the possibility of using MGMT expression as a predictive marker in future studies of these tumors.¹⁸

III-E. VEGF Pathway Inhibitors

Neuroendocrine tumors are highly vascular, and overexpression of vascular endothelial growth factor (VEGF) has been observed in both midgut carcinoid tumors and in pancreatic endocrine tumors.²⁰ Therapies targeting VEGF (bevacizumab) and VEGF receptor (sorafenib, sunitinib) have recently been evaluated in the phase II setting in patients with advanced neuroendocrine tumors (Table 2).

Table 2:

Phase II trials of novel “targeted” agents in neuroendocrine tumors

Agent	Molecular Target(s)	No. Patients	Tumor	Tumor Response Rate (%)	Reference
Imatinib	PDGFR-α, -β; KIT; Bcr-Abl	27	Carcinoid	4	Yao et al, 200734
Bevacizumab + octreotide	VEGF	22	Carcinoid	18	Yao et al, 200821
Sunitinib	VEGFR, PDGFR, C-Kit, RET, FLT3	41	Carcinoid	2	Kulke et al, 200823
		66	Pancreatic endocrine	16
Sorafenib	VEGFR, B-Raf	50	Carcinoid	7	Hobday et al, 200722
		43	Pancreatic endocrine	11
Gefitinib	EGFR	40	Carcinoid	3	Hobday et al, 200635
		31	Pancreatic endocrine	6
Temsirolimus	mTOR	21	Carcinoid	5	Duran et al, 200625
		15	Pancreatic endocrine	7
Everolimus (RAD001) + octreotide	mTOR	30	Carcinoid	17	Yao et al, 200826
		30	Pancreatic endocrine	27

Abbreviations: EGFR = epidermal growth factor receptor; mTOR = mammalian target of rapamycin; PDGFR = platelet-derived growth factor receptor; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor

• In a phase II trial, 44 patients with advanced or metastatic carcinoid tumors who were receiving a stable dose of octreotide were randomly assigned to treatment with bevacizumab or pegylated inferon-alpha 2b (IFN-α-2b).²¹ Four of 22 (18%) bevacizumabtreated patients achieved confirmed radiographic partial responses compared with none of the patients treated with pegylated IFN-α-2b. After 18 weeks, 95% of bevacizumab-treated patients remained progression-free compared with 68% of IFN-α-2b–treated patients. These encouraging results have led to the development of an ongoing study, led by the Southwest Oncology Group, in which patients are randomized to receive either IFN-α-2b or bevacizumab in addition to octreotide, with a primary end point of progression-free survival (Table 1).

• The small-molecule tyrosine kinase inhibitor sorafenib was evaluated in 50 patients with carcinoid and 43 patients with pancreatic neuroendocrine tumors. In a preliminary analysis, responses were observed in 7% of the carcinoid patients and 11% of the pancreatic NET patients.²²

• In a phase II study, 109 patients with advanced neuroendocrine tumors received repeated 6-week treatment cycles of sunitinib, administered orally at 50 mg once daily for 4 weeks, followed by 2 weeks off treatment.²³ Partial responses were observed in 2% of the carcinoid cohort and 16% of the pancreatic neuroendocrine cohort. An international randomized phase III study to confirm the activity of sunitinib in pancreatic neuroendocrine tumors has recently been stopped early, after preliminary results demonstrated that treatment with sunitinib was associated with a median progression-free survival of 11.1 months, as compared with 5.5 months in the placebo arm.²⁴ Detailed results of this trial have not yet been published.

III-F. mTOR Inhibitors

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that participates in the regulation of cell growth, proliferation, and apoptosis through modulation of the cell cycle. mTOR also mediates downstream signaling from a number of pathways, including the VEGF and insulin-like growth factor signaling implicated in neuroendocrine tumor growth. Two rapamycin derivatives have been evaluated recently in neuroendocrine tumors: temsirolimus and everolimus (RAD001) (Table 2).

• In an initial multicenter study, 37 patients with advanced progressive neuroendocrine tumors were treated with weekly intravenous temsirolimus. The intent-to-treat response rate for the cohort was 5.6%. Outcomes were similar between patients with carcinoid and pancreatic neuroendocrine tumors.²⁵

• In a second phase II study, 30 patients with carcinoid tumors and 30 with pancreatic neuroendocrine tumors were treated with a combination of the mTOR inhibitor everolimus, 5–10 mg/day, and depot octreotide (30 mg every 4 weeks). The overall tumor response rate in evaluable patients was 17% in carcinoid and 27% in pancreatic neuroendocrine tumor patients.²⁶ Evaluation of the activity and safety of everolimus in patients with neuroendocrine tumors is ongoing.

III-G. Development of Biomarkers

Recent advances in genomic technology, together with the development of neuroendocrine tumor cell lines, offer the potential for the discovery of novel biomarkers and treatment targets in neuroendocrine tumors. Several studies have demonstrated the feasibility of this approach, although definitive diagnostic and prognostic biomarkers have not yet been identified using these approaches.

• Characteristic allelic imbalances have been observed in both carcinoid and pancreatic neuroendocrine tumors using single nucleotide polymorphism analysis. Of these, loss of chromosome 18 appears to be a characteristic feature of small bowel carcinoid tumors.^27–29

• Preliminary studies have suggested that gene expression profiling may be a useful tool in differentiating indolent from aggressive neuroendocrine tumors and in identifying novel treatment targets.³⁰

• Neuroendocrine tumor cell lines have recently been developed, and, if validated, may further speed the development of novel “targeted” therapies for this disease.^31–33

IV. WHAT NEEDS TO BE DONE (APPLICATION OF THE ACCOMPLISHMENTS)

Several studies are ongoing to confirm the activity of agents that have demonstrated promising activity in the phase II setting, including phase III randomized trials of bevacizumab, sunitinib, and everolimus. Peptide receptor–targeted radiotherapy has yet to be explored in the randomized setting; however, the approach appears promising and the development of somatostatin analogs with even higher affinity for different somatostatin receptor subtypes has the potential to further enhance therapeutic efficacy. Similarly, the antitumor effects of “cold” somatostatin analogs warrant confirmation in a second phase IIl randomized trial.

V. CONTROVERSIES AND DISAGREEMENTS

V-A. Histologic Classification and Staging of Neuroendocrine Tumors

Neuroendocrine tumors comprise a wide spectrum of histologies; there is little disagreement that the clinical course of indolent, “well differentiated” neuroendocrine tumors is far different from that of their more aggressive “poorly differentiated” counterparts. There remains widespread disagreement and inconsistency in pathology reporting with regard to use of mitotic index, proliferative index (Ki-67), and other reporting criteria, posing an obstacle to the development of consistent inclusion criteria for clinical trials, as well as interpretation of clinical trial results. Lack of a consistent histologic and classification scheme also poses difficulties in the interpretation of retrospective data in epidemiology studies.

V-B. Clinical Trial Design and End Points

The relatively unique association of neuroendocrine tumors with clinical syndromes related to hormonal secretion has created a need for agents that target hormonal hypersecretion. Somatostatin analogs have had a clear impact in this area; however, there is currently no accepted standard trial design or criterion to rapidly and easily assess efficacy of novel agents in this setting. The indolent nature of many neuroendocrine tumors creates a challenge in assessing the efficacy of novel drugs in the phase II setting, particularly given the apparent cytostatic (rather than cytotoxic) effect of many new agents. Wide variability in the requirement for or interpretation of “progressive disease” prior to study entry makes it difficult to interpret disease stabilization during treatment in single-arm studies.

VI. FUTURE DIRECTIONS

Recent epidemiologic data suggest that neuroendocrine tumors are both more common and more prevalent than initially thought. Despite early concerns regarding the ability to accrue patients and complete large randomized trials, ongoing or recently completed studies of bevacizumab, sunitinib, octreotide, lanreotide, and everolimus have demonstrated the feasibility of rigorously evaluating novel antitumor therapies for this disease. The development of standardized histologic and staging criteria, together with a more standardized approach to evaluating novel agents in early-phase studies, should speed the identification of promising agents worthy of evaluation in the randomized setting. Therapies targeting hormonal symptoms are of equal importance given their potential effects on patient quality of life; well-designed clinical trials and clearly defined efficacy criteria will be critical in accelerating the development of these agents. Finally, rapid progress in technologies for molecular profiling, and early indications of activity associated with “targeted” therapies, offer the very real possibility of identifying new treatment targets and biomarkers predictive of risk, prognosis, and efficacy in gastrointestinal neuroendocrine tumors.