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Keywords:

  • everolimus;
  • neuroendocrine tumor;
  • carcinoid;
  • pheochromocytoma;
  • paraganglioma;
  • positron emission tomography

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

BACKGROUND:

The current study was conducted to evaluate the efficacy and safety of everolimus in the treatment of patients with nonfunctioning neuroendocrine tumors (NETs) or pheochromocytomas/paragangliomas.

METHODS:

Patients with histologically confirmed nonfunctioning NETs or pheochromocytomas/paragangliomas and with documented disease progression before study enrollment were eligible for the current study. Everolimus was administered daily at a dose of 10 mg for 4 weeks. Response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST; version 1.0) every 8 weeks. The primary endpoint was the 4-month progression-free survival rate (PFSR). The hypothesis of the current study was that the 4-month PFSR would increase from 50% to 65%. Safety was evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0).

RESULTS:

A total of 34 patients were enrolled. Of these, 27 patients had nonfunctioning NETs, 5 had pheochromocytomas, and 2 had paragangliomas. The 4-month PFSR was 78%. Partial response (PR) was observed in 3 patients. Twenty-eight patients had stable disease (SD) and 2 patients developed progressive disease (PD). The response rate (RR) and overall disease control rate (DCR) were 9.0% (95% confidence interval [95% CI], 0%-18.6%) and 93.9% (95% CI, 85.8%-100%), respectively. The PFS was 15.3 months (95% CI, 4.6 months-26.0 months). Of the patients with nonfunctioning NETs, 3 achieved a PR and 23 had SD (RR, 11.1%; DCR, 100%); the PFS was 17.1 months (95% CI, 11.1 months-23.0 months) and the 4-month PFSR was 90.0%. Twenty-one patients (80.8%) demonstrated tumor shrinkage. In 7 patients with pheochromocytomas/paragangliomas, 5 achieved SD, and 2 developed PD. The PFS was 3.8 months (95% CI, 0.5 months-7.0 months) and the 4-month PFSR was 42.9%. Four patients demonstrated tumor shrinkage. The major grade 3/4 adverse events were thrombocytopenia (14.7%), hyperglycemia (5.9%), stomatitis (5.9%), and anemia (5.9%).

CONCLUSIONS:

Everolimus was associated with high therapeutic efficacy and tolerability in patients with nonfunctioning NETs, and demonstrated modest efficacy in patients with pheochromocytomas/paragangliomas. Cancer 2012. © 2012 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

Neuroendocrine tumors (NETs) represent a heterogeneous group of tumors that are characterized by their ability to secrete peptides. This group includes gastrointestinal NETs, islet cell tumors, medullary thyroid carcinomas, small cell lung carcinomas, pheochromocytomas, paragangliomas, and Merkel cell carcinomas. Among these, the most common site of origin is the gastroenteropancreatic lesion. Although NETs are rare tumors, an analysis of the Surveillance, Epidemiology, and End Results (SEER) database has shown an increase of the incidence of NETs in the United States.1 Between 1975 and 2004, an approximate 5-fold increase was reported. It is interesting to note that the number of NETs in all sites has increased. The exact reasons for this are unknown but may include improved diagnostic techniques, cancer screenings being performed more frequently, and some environmental factors.2, 3

The biology of NETs is dependent on several factors, including the primary tumor site, degree of differentiation, and tumor grade.4, 5 NETs can be divided into functioning and nonfunctioning tumors based on whether they secrete hormones, which causes clinical symptoms. The management of NETs can vary according to histology, grade, extent of disease, and the involved sites. According to the World Health Organization (WHO) classification, grade 3 NETs are known to have an aggressive clinical course. The treatment strategy for these types of NETs has been similar to that of small cell lung cancer. In contrast, well-differentiated to moderately differentiated NETs (grade 1 or 2 according to the WHO classification) can be managed differently. Some cases of indolent, low-volume, asymptomatic, advanced NETs can be followed without treatment until there is evidence of disease progression or until symptoms develop. The treatment of patients with progressive disease (PD), disease-related symptoms, or a high disease burden varies according to tumor subtype. Patients with localized NETs primarily receive local treatments such as surgery. Surgical resection or hepatic artery embolization are also useful for hepatic metastases of NETs.6

With the advent of octreotide, an octapeptide that mimics natural somatostatin and is a potent inhibitor of growth hormones, glucagon, and insulin, the control of hormonal symptoms caused by functioning NETs has been greatly improved because the majority of NETs express somatostatin receptors.7 Octreotide long-acting release (LAR) has been shown to have antitumor effects as well as hormonal symptom control. In patients with advanced, well-differentiated carcinoid tumors occurring in the midgut, this drug has been shown to improve progression-free survival (PFS) compared with placebo, regardless of the functioning status of the tumors.8

However, to the best of our knowledge, aside from octreotide, no satisfactory systemic antitumor treatment options are available. The effect of cytotoxic chemotherapy on well-differentiated or moderately differentiated NETs has been minimal,9, 10 and immunomodulating agents have not been useful.11

Recently, new insights regarding the pathogenesis of NETs have come to light. The high expression of vascular endothelial growth factor (VEGF) and its receptor (VEGFR) in NETs has led to trials examining the effect of antiangiogenic agents on NETs. Sunitinib, a small-molecule tyrosine kinase inhibitor of VEGFR and platelet-derived growth factor receptor, has been found to improve PFS and overall survival in patients with well-differentiated pancreatic NETs compared with placebo in a phase 3 clinical trial.12

Another important pathway in NETs is the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway stimulates cell growth, proliferation, and angiogenesis. Autocrine activation of the mTOR signaling pathway, mediated through insulin-like growth factor 1, has been implicated in the proliferation of pancreatic NET cells.13 The effect of everolimus, an mTOR inhibitor, on low-grade or intermediate-grade pancreatic NETs was evaluated in a phase 3 trial (RAD001 in Advanced Neuroendocrine Tumors, Third Trial [RADIANT-3]). Everolimus significantly improved PFS compared with placebo.14 Everolimus, in combination with octreotide LAR, has also been studied in a phase 3 trial (RADIANT-2) of low-grade or intermediate-grade NET (carcinoid) with a history of secretory symptoms attributable to carcinoid syndrome.15 Compared with placebo plus octreotide LAR, everolimus plus octreotide LAR was found to improve PFS in patients with advanced NETs associated with carcinoid syndrome.

However, to the best of our knowledge there have only been rare reports that focused on the therapeutic efficacy of mTOR inhibitor monotherapy (without octreotide LAR) in the population of patients with only nonfunctioning NETs, including all primary sites throughout the body.

Pheochromocytomas and paragangliomas are rare NETs with an estimated prevalence of between 1:6500 and 1:2500. These lesions arise from adrenal chromaffin cells or similar types of cells in extraadrenal sympathetic and parasympathetic paraganglia.16 Nearly all pheochromocytomas and sympathetic extraadrenal paragangliomas as well as approximately 20% of head and neck paragangliomas produce, store, metabolize, and secrete catecholamines or their metabolites. Thus, pheochromocytomas and paragangliomas are found in approximately 0.05% to 0.1% of patients with sustained hypertension. Systemic treatment has rarely been reported in cases of malignant unresectable pheochromocytoma and paraganglioma.

The current study was conducted to evaluate the efficacy and safety of everolimus monotherapy (without octreotide LAR) for the treatment of nonfunctioning NETs regardless of tumor origin, especially pheochromocytomas and paragangliomas.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

The current study was a multicenter, single-arm, open-labeled phase 2 study. A total of 8 centers participated. The study was approved by the Institutional Review Boards of all participating centers and was registered with the United States National Library of Medicine (ClinicalTrials.gov) as NCT01152827.

Patient Eligibility Criteria

The following inclusion criteria were used for patient selection 1) histologically or cytologically confirmed nonfunctioning NETs, pheochromocytomas, or extraadrenal paragangliomas; 2) local, locally advanced, or metastatic disease documented as having demonstrated PD by a scan (computed tomography [CT], magnetic resonance imaging [MRI], or technetium [99mTc] sestamibi [MIBI]) taken 2 to 12 months before the baseline compared with a previous scan taken at any time in the past (PD had to have been documented according to Response Evaluation Criteria In Solid Tumors [RECIST] criteria); 3) lesions that were not amenable to surgery, radiotherapy, or combined modality therapy; 4) at least 1 measurable lesion (based on RECIST criteria [version 1.0]); 5) age > 18 years; 6) an Eastern Cooperative Oncology Group (ECOG) performance status of 0,1; and 7) adequate organ function (absolute neutrophil count [ANC] ≥ 1500 cells/μL; platelet count ≥ 100,000 cells/μL; hemoglobin ≥ 9.0 g/dL; serum creatinine ≤ 1.5 × the upper limit of normal [ULN]; serum bilirubin ≤ 1.5 × ULN; and aspartate aminotransferase [AST], alanine aminotransferase [ALT], and alkaline phosphatase ≤ 2.5 × ULN [if liver metastasis existed, ≤ 5 × ULN]). Written informed consent was obtained from all participants. Important exclusion criteria were 1) functioning NETs; 2) prior chemotherapy, radiotherapy, or surgery within 4 weeks before enrolling in the study except for palliative radiotherapy for the treatment of nontargeted lesions (within 2 weeks before entering the study); 3) intestinal obstructions or impending obstructions; 4) recent upper gastrointestinal bleeding; and 5) cardiac arrhythmia (grade ≥ 2), atrial fibrillation of any grade, or a QTc interval > 450 milliseconds for males or > 470 milliseconds for females.

Treatment

Everolimus was given at a dose of 10 mg daily without interruption. The cycles were repeated every 28 days. The cycles were delayed until the following criteria were satisfied: ANC > 1500 cells/μL, platelet count > 75,000 cells/μL, and nonhematologic toxicity related to the everolimus returning to baseline levels or ≤ grade 1. Treatment was discontinued for patients with PD, individuals who experienced unacceptable adverse events (AEs), or patients who withdrew their consent.

Dose Adjustments

Ten mg of everolimus per day was the starting dose for all patients entering the study. Lower dose levels were 5 mg daily and 5 mg every other day subsequently. Everolimus therapy was discontinued if a patient was unable to tolerate the drug at a dose of 5 mg every other day or if drug-related toxicity required treatment interruption for > 21 days. Everolimus administration was interrupted for patients with grade 3 hematologic or nonhematologic toxicities (based on the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], version 3.0) and resumed at 1 dose level lower after toxicity was reduced to grade 1 (except hyperlipidemia). Everolimus was permanently discontinued for patients who developed NCI CTCAE grade 4 toxicities, except for individuals with grade 4 neutropenia, in which case the toxicity was managed with treatment interruption and dose reduction. In addition, dose reduction was required for patients with grade 2 pneumonitis.

Assessment of Therapeutic Efficacy and Toxicity

Tumor responses were assessed every 8 weeks or earlier in patients with suspected PD based on the RECIST criteria. CT scans were performed at least 4 weeks after the first scan to confirm complete responses (CRs) and partial responses (PRs).

The primary endpoint for measuring treatment efficacy was the 4-month PFS rate (PFSR). PFS was defined as the time between the initiation of treatment and PD or death by any cause. Secondary endpoints for evaluating efficacy included response rates (RRs), disease control rates (DCRs), time needed to observe the responses, response duration, and overall survival rates. The duration of response was measured from the time that measurement criteria were met for a CR or PR (whichever was recorded first) until the first date that disease recurrence or PD was objectively documented. Overall survival was estimated from the date of the first treatment to patient death or the date of the last follow-up visit.

We also evaluated metabolic responses with 18F-fluorodeoxyglucose (FDG) positron emission tomography-CT (PET-CT) after 8 weeks of treatment if possible. PET response (also defined as the metabolic response) was measured at the same time point (after 8 weeks of treatment) as the CT scan according to the recommendations of the European Organization for Research and Treatment of Cancer (EORTC) PET Study Group.17 Complete resolution of FDG uptake within the tumor so that it was indistinguishable from surrounding normal tissue was considered to represent a metabolic CR. A metabolic PR was defined as a reduction of ≥ 25% in tumor FDG uptake. An increase in tumor standardized uptake values (SUVs) of ≥ 25% within the region of interest defined by the baseline scan, or the appearance of new FDG uptake in another region of the tumor, was classified as metabolic PD. Metabolic stable disease (SD) was classified as an increase in the tumor SUV of < 25% or a decrease of < 25%. Safety was assessed according to the NCI CTCAE.

Statistical Analysis

The main purpose of the current study was to assess the 4-month PFSR. The H0 (null hypothesis) predicted a 4-month PFSR of 50%, whereas the H1 (alternative hypothesis) predicted a 4-month PFSR of 65%, a type I error of 5% (1-sided), and 80.0% power. The rationale for this hypothesis was based on our previous study of patients with metastatic/recurrent NETs.5 The time-to-disease progression after first-line systemic treatment was 6.0 months (95% confidence interval [95% CI], 3.3 months-8.7 months) and that after second-line and third-line systemic treatment was 5.0 months (95% CI, 3.5 months-6.5 months) and 2.0 months (95% CI, 1.5 months-2.5 months), respectively. Because the majority of the patients who were eligible for the current study had a high probability of pretreatment with other kinds of systemic agents, we set the H0 as a 4-month PFSR of 50%. Because we expected that everolimus could improve the 4-month PFSR by 30%, we set the H1 as a 4-month PFSR of 65%. To test these hypotheses, 29 patients were required for the study. When we assumed a 15% dropout rate, we determined that a total of 33 patients needed to be enrolled.

Survival and all safety analyses were performed on the intention-to-treat population. The objective response was assessed on the per-protocol population. Follow-up began at the outset of treatment. The censoring event for responses was the start of PD. The censoring event for survival was death. Overall survival and PFS were analyzed using the Kaplan-Meier method. The survival results were expressed as the median value with the 95% CI.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

Patient Characteristics

A total of 34 patients were enrolled in the current study between February 2007 and August 2010. The data cutoff was April 2011. The baseline characteristics of the patients are shown in Table 1. The median age of the patients at the time of study entry was 56 years (range, 29 years-73 years). Twenty-one patients (61.8 %) were male. Fourteen patients had an ECOG performance status of 0. Twenty-seven patients (79.4%) had nonfunctioning NETs, 5 patients (14.7%) had pheochromocytomas, and 2 patients (5.9%) had paragangliomas. All patients had metastatic disease. There were 4 metastatic sites in 2 patients, and 3 metastatic sites in 6 patients.

Table 1. Patient Characteristics (N = 34)
CharacteristicsNo.Percentage
  1. Abbreviations: EGOG, Eastern Cooperative Oncology Group; NET, neuroendocrine tumor.

Age, yMedian(Range)
At the time of diagnosis 54(26-70)
At study entry56(29-73)
Gender  
Men2161.8%
Women1338.2%
Histology  
Nonfunctioning NET2779.4%
Pheochromocytoma514.7%
Paraganglioma25.9%
Differentiation  
Well-differentiated2882.4%
Moderately differentiated617.6%
Performance status  
ECOG 01441.2%
ECOG 12058.8%
Primary tumor site  
Colorectal2161.8%
Adrenal gland514.7%
Lung38.8%
Pancreas12.9%
Stomach12.9%
Neck12.9%
Mediastinum12.9%
Liver12.9%
Disease status  
Initially metastatic2573.5%
Recurrent926.5%
Organ involved  
Liver2058.8%
Lymph node926.5%
Bone38.8%
Pancreas514.7%
Colorectal2058.8%
Time since initial diagnosis  
≤6 mo617.6%
>6 mo to ≤2 y1544.1%
>2 y to ≤5 y1132.4%
>5 y25.9%
Previous treatment  
Cytotoxic chemotherapy2573.5%
Radiotherapy926.5%

The time elapsed since initial diagnosis to study entry ranged from 6 months to 2 years in 15 patients (44.1%) and from 2 years to 5 years in 11 patients (32.4%). No patient with a pheochromocytoma and paraganglioma received prior iodine-131 metaiodobenzylguanidine (MIBG) therapy.

Safety was assessed in 34 patients and the tumor response was evaluated in 33. Disease status evaluation was not performed in 1 patient because the patient refused further treatment (treatment duration was 1.1 months). The median follow-up time for all patients was 10.3 months (95% CI, 9.7 months-13.3 months).

A total of 308 cycles of treatment were delivered to patients at the time of the data cutoff. The median number of cycles delivered per patient was 5.5 cycles (range, 2 cycles to > 32 cycles).

Response to Treatment and Survival Rates

Among 33 the patients who were evaluated, objective responses were observed in 3 (0 CRs and 3 PRs), for an overall RR of 9.0% (95% CI, 0%-18.6%). Twenty-eight patients (84.8%) had SD. The overall DCR was 93.9% (95% CI, 85.8%-100%). PD was observed in 2 patients (6.0%) (Table 2). As shown in Figure 1 using a waterfall plot (Fig. 1), 25 patients (75.6%) demonstrated tumor shrinkage. The median PFS was 15.3 months (95% CI, 4.6 months-26.0 months) and the 4-month PFSR was 78% (Fig. 2). This exceeded the rate noted in our hypothesis, which stated that treatment with everolimus would increase the 4-month PFSR from 50% to 65%. At the time of the data cutoff, no deaths had occurred. The median duration of treatment was 6.2 months (range, 1.1 months to > 30.6 months).

thumbnail image

Figure 1. A waterfall plot demonstrating the maximum reduction in tumor size is shown in (A) all patients, (B) patients with nonfunctioning neuroendocrine tumors (NETs), and (C) patients with pheochromocytomas/paragangliomas. PD indicates progressive disease; PR, partial response; SD, stable disease. * Y axis indicates the percentage change in tumor volume.

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thumbnail image

Figure 2. Progression-free survival (PFS) is shown in all patients, patients with nonfunctioning neuroendocrine tumors (non functioning NET), and patients with pheochromocytomas/paragangliomas (pheo/para).

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Table 2. Therapeutic Efficacy of Everolimus in Patients With NETs or Pheochromocytomas/Paragangliomas
 All Populations (N = 34)Patients With Nonfunctioning NETs (N = 27)Patients With Pheochromocytomas/ Paragangliomas (N = 7 [5+2])
  1. Abbreviations: 95% CI, 95% confidence interval; CR, complete response, NA, not applicable; NETs, neuroendocrine tumors; PD, progressive disease; PFS, progression-free survival; PFSR, progression-free survival rate; PR, partial response; SD, stable disease.

No. of evaluated patientsN = 33N = 26N = 7
CR000
PR330
SD28235
PD202
Response rate9.0%11.5%0%
Disease control rate93.9%100%71.4%
Duration of response, mo6.4 (95% CI, 0.2-12.6)6.4 (95% CI, 0.2-12.6)NA
PFS, mo15.3 (95% CI, 4.6-26.0)17.1 (95% CI, 11.1-23.0)3.8 (95% CI, 0.5-7.0)
4-mo PFSR78.0%90.0%42.9%
12-mo PFSR50.7%64.0%14.3%
18-mo PFSR36.2%45.7%0.0%

Among the 27 patients with nonfunctioning NETs, 3 achieved a PR and the remaining patients had SD (RR, 11.5%; overall DCR, 100%) with a median PFS of 17.1 months (95% CI, 11.1 months-23.0 months) and a 4-month PFSR of 90.0%. Twenty-one patients (80.8%) demonstrated tumor shrinkage. The median duration of response was 6.4 months (95% CI, 0.2 months-12.6 months). The median duration of treatment was 6.7 months (range, 1.1 months to > 30.6 months).

In individuals with pheochromocytomas/paragangliomas, 5 patients achieved SD and 2 developed PD. The median PFS was 3.8 months (95% CI, 0.5 months-7.0 months) and the 4-month PFSR was 42.9%. A reduction in tumor volume was noted in 4 patients. The median duration of treatment was 3.8 months (range, 1.1 months-8.3 months).

Metabolic Response Evaluation

Baseline PET-CT was performed in 16 patients. The median SUV of these patients was 4.95 (range, 1.6-8.3). PET-CT was performed 8 weeks after treatment in 15 patients. The median SUV of the posttreatment PET-CT was 3.40 (range, 1.3-14.5). Both pretreatment and posttreatment PET-CT scans were performed in 14 patients. Among these patients, 5 (35.7%) had achieved a metabolic PR, 5 patients (35.7%) had metabolic SD, and 4 patients (28.6%) developed metabolic PD. Table 3 shows the detailed data for all 14 patients. The 8-week metabolic response was found to be highly correlated with the CT response. Among the patients demonstrating SD with CT, patients with metabolic PRs tended to have a longer PFS.

Table 3. Metabolic Response of the Patients
Patient ID No. (At Diagnosis)Pretreatment SUVPosttreatment SUVVariation, %aPET ResponsePFS, Months
  • Abbreviations: CT, computed tomography; ID, identification; NET, neuroendocrine tumor; PD, progressive disease; PET, positron emission tomography; PFS, progression-free survival; PR, partial response; SD, stable disease; SUV, standardized uptake value.

  • a

    Variation between the posttreatment SUV and the pretreatment SUV.

Patients with PR at the CT evaluation
1 (NET)3.31.3-59.1PR22.7
Patients with SD at the CT evaluation
2 (NET)8.35.1-38.7PR17.1
3 (NET)2.71.6-42.6PR19.0
4 (NET)5.22.6-50.0PR2.8
5 (NET)4.72.6-44.8PR28.9
6 (NET)1.61.60.0SD30.6
7 (NET)8.38.5+2.4SD3.3
8 (NET)5.75.70.0SD3.3
9 (NET)2.62.60.0SD6.8
10 (Pheochromocytoma)3.63.4-5.6SD8.3
11 (NET)6.014.5+141.7PD13.0
12 (Paraganglioma)2.63.7+42.3PD9.3
13 (NET)2.23.0+35.7PD7.7
Patients with PD at the CT evaluation
14 (Pheochromocytoma)7.69.6+26.3PD1.9

Safety

Hematologic and nonhematologic AEs are summarized in Table 4.

Table 4. Adverse Eventsa
EventAll Grades, No. of Patients (%)Grade 3/4, No. of Patients (%)
  • Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

  • a

    Toxicity grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).

Anemia 4 (11.8%)2 (5.9%)
Thrombocytopenia 5 (14.7%)5 (14.7%)
Rash10 (29.4%)0 (0%)
Diarrhea 9 (26.5%)1 (2.9%)
Anorexia 7 (20.6%)0 (0%)
Stomatitis 6 (17.6%)2 (5.9%)
Asthenia 8 (23.5%)1 (2.9%)
Nausea 4 (11.8%)0 (0%)
Edema 4 (11.8%)0 (0%)
Pruritis 2 (5.9%)0 (0%)
AST/ALT elevation 5 (14.7%)0 (0%)
Hyperglycemia 4 (11.8%)2 (5.9%)
Hypocalcemia 1 (2.9%)1 (2.9%)

The most common AEs (all grades) were rash (29.4%), diarrhea (26.5%), anorexia (20.6%), stomatitis (17.6%), and fatigue (17.6%). The major grade 3/4 AEs were thrombocytopenia (14.7%), hyperglycemia (5.9%), stomatitis (5.9%), and anemia (5.9%). There were no treatment-related deaths reported.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

Everolimus monotherapy was examined in patients with nonfunctioning NETs and pheochromocytomas/extraadrenal paragangliomas. The median PFS for all patients was 15.3 months and that for patients with nonfunctioning NETs was 17.1 months.

NETs represent a very heterogenous group of tumors and patients with progressive NETs have limited treatment options. Recently, in 2 phase 3 studies of patients with pancreatic NETs, sunitinib and everolimus improved PFS mainly via disease stabilization.12, 14 In the interim, there is the huge therapeutic challenge posed by NETs that originate from sites other than the pancreas. The combination of everolimus and octreotide has been tested in a phase 3 trial (RADIANT-2) of low-grade or intermediate-grade NETs (carcinoid) in patients with carcinoid syndrome.15 The functional status of NETs has been regarded as a prognostic factor. To the best of our knowledge, the current study is the first using mTOR inhibitor monotherapy (without octreotide) to focus only on patients with nonfunctioning NETs originating from all sites (colorectal, adrenal, lung, and stomach) along with pheochromocytomas and extraadrenal paragangliomas.

The RADIANT-2 trial enrolled patients with NETs originating from the small intestine (52%), lung (10.2%), colon (6.5%), pancreas (6.0%), liver (4.1%), and other sites. Except for pheochromocytomas and extraadrenal paragangliomas, the origin of the tumors is similar to the current study. However, all patients in the RADIANT-2 trial had a history of secretory symptoms (diarrhea or flushing) attributable to carcinoid syndrome and all patients in the current study had nonfunctioning tumors. In patients with functioning NETs, the PFS with placebo plus octreotide LAR was 11.3 months and the treatment benefit with everolimus plus octreotide LAR was recorded regardless of the primary tumor site.15

The PFS of 17.1 months for patients with nonfunctioning NETs who were treated with everolimus in the current study was good when compared with the PFS of 16.4 months for patients with functioning NETs who were treated with the combination of everolimus and octreotide.15 In the current study, none of the patients received the concomitant octreotide.

The incidence of pheochromocytoma/extraadrenal paraganglioma is very low, and the majority of cases are benign. However, some are clinically malignant. The incidence of malignant pheochromocytoma/extraadrenal paraganglioma ranges from 3% to 36%, depending on the genetic background and tumor localization. Some of these tumors are diagnosed as malignant at the time of initial presentation whereas others are diagnosed after surgical removal of the primary tumor, which initially was clinically benign, due to malignant transformation (in other words, cases of recurrent disease). Cases of malignant pheochromocytoma/extraadrenal paraganglioma are currently defined by the presence of metastases but not local invasion. To our knowledge, no large trial published to date has examined pheochromocytomas/extraadrenal paragangliomas because of the low incidence of these lesions.

The benefit of everolimus monotherapy was observed in the current study regardless of the origin of the primary tumor. However, patients with pheochromocytomas/extraadrenal paragangliomas were found to have a shorter PFS than those with nonfunctioning NETs. Among the 7 patients with pheochromocytomas/extraadrenal paragangliomas, 4 demonstrated a tumor volume reduction even though this was less than was noted in patients who achieved a PR. Of these 4 patients, 1 patient developed PD due to the appearance of a new lesion. Therefore, when taken together, it appears that everolimus has an effect on pheochromocytomas/extraadrenal paragangliomas.

In a recent report, the majority of patients with metastatic pheochromocytomas and sympathetic paragangliomas were found to not respond to cytotoxic chemotherapy, and the effect of chemotherapy on overall survival appeared to be small.18 Nevertheless, to our knowledge there have been very few studies published to date regarding targeted therapy for pheochromocytomas/extraadrenal paragangliomas. The studies that have been performed included a very small number of patients. For example, 1 study included only 4 patients who received everolimus whereas others included a very limited number of patients (or only 1 patient) who were treated with sunitinib.19-22 Therefore, the effect of everolimus on pheochromocytomas/extraadrenal paragangliomas should be investigated further.

Several mechanisms may influence the enhanced glucose uptake in cancer cells, including upregulation of glucose transporters and increases in hexokinase activity and the protein kinase B, also called Akt, which appears to play a key role in the control of glucose metabolism together with proteins that are involved in the signal cascade pathway, such as mTOR.23 Changes in tumor metabolism caused by the mTOR inhibitor have been examined using FDG-PET. It has been shown that decreases in tumor FDG uptake can be observed as early as 24 hours after the administration of a single dose of temsirolimus in a murine model of renal cell cancer.24 In addition, metabolic changes elicited by everolimus and noted on PET are closely linked with the antitumour activity of everolimus. FDG uptake measured by PET can be used as a surrogate marker to determine the optimal biological dose of an mTOR inhibitor in vivo soon after the initiation of therapy.25 In 1 pilot study, FDG-PET was found to be a valuable tool for evaluating the early pharmacodynamic effects of mTOR inhibition in patients with non-small cell lung cancer (NSCLC). However, the goal of this proof-of-principle study was to explore FDG-PET as a pharmacodynamic tool for everolimus therapy in patients with NSCLC rather than to evaluate early metabolic response as a predictor of outcome.26

In the current study, we evaluated the metabolic response after 8 weeks of treatment using FDG-PET, and analyzed the correlation between the metabolic response and morphologic responses assessed by RECIST. To do this, we followed the recommendations of the EORTC PET Study Group.17 The pretreatment SUV was relatively low compared with that of other common types of solid tumor, which reflected the less aggressive nature of NETs. Among the 14 patients who underwent pretreatment and posttreatment PET, 5 (35.7%) demonstrated a metabolic PR and 5 (35.7%) had metabolic SD. In addition, 4 patients (28.6%) developed metabolic PD. These results indicate that the 8-week metabolic response was highly correlated with the CT response. Furthermore, among the patients with a SD-CT response, patients with a PR-PET response had a tendency toward a longer PFS than those with SD-PET or PD-PET responses. This result suggests the possibility of metabolic response by FDG-PET as a candidate for predicting clinical outcome. However, the application of FDG-PET to daily practice in patients with NET should be considered with caution before it is validated in further prospective large-scale clinical trials.

In some cases of targeted agents, there are ethnic differences noted with regard to metabolism. Thus, differences in safety or even efficacy have been reported.27 The toxicities observed in the current study are similar to those noted in previous reports. However, the incidences of rashes of all grades and stomatitis were lower than those of the RADIANT-3 and RADIANT-2 trials.14, 15 In those trials, the incidences of stomatitis and rashes of all grades were 64% and 49%, respectively, in the RADIANT-3 trial and 62% and 37%, respectively, in the RADIANT-2 trial. In the current study, the incidences of stomatitis and rashes of all grades were 17.6% and 29.4%, respectively. Reported grade 3/4 stomatitis and rashes were similar in all 3 studies: 5.9% and 0%, respectively, in the current study; 7% and < 1%, respectively, in the RADIANT-3 trial; and 7% and 1%, respectively, in the RADIANT-2 trial. However, the incidence of grade 3/4 thrombocytopenia was higher in the patients in the current study (14.7%) compared with those in the RADIANT-3 trial (4%) and RADIANT-2 trial (5%). The incidence of hyperglycemia among patients in the current trial, RADIANT-3 trial, and RADIANT-2 trial was also similar. The increases in AST/ALT were somewhat higher among patients in the current study (all grades: 14.7%) compared with the RADIANT-3 and RADIANT-2 trials (< 10%). However, there were no patients with a grade 3/4 elevation in AST/ALT. Everolimus can reactivate patients with the hepatitis B or hepatitis C viruses. Thus, liver enzymes should be monitored carefully when using this compound, especially in areas in which the hepatitis B virus is endemic. The differences in incidence or grade between some adverse events observed in the current study and the RADIANT-3 and RADIANT-2 trials cannot be explained solely by ethnic differences. In a Japanese trial of everolimus monotherapy for the treatment of patients with advanced gastric cancer, the incidences of all grades of stomatitis and rashes were 73.6% and 45.3%, respectively.28 Further study is needed to clarify the reported differences in safety between study populations.

In the current study, we enrolled patients with nonfunctioning NETs to compare the results with those of the RADIANT-2 trial. Although the patients in the current study did not have the secretory symptoms, such as diarrhea or flushing, attributable to carcinoid syndrome, they may have had different symptoms such as pain, fatigue, and so on. Twenty patients (58.8%) had an ECOG performance status of 1 at the time of study entry. Therefore, the change in quality of life during the study period is important. We did not collect data regarding quality of life from patients using variable symptom questionnaires. However, we believe that this should be considered in future studies of NETs. The duration of follow-up was not sufficient to collect overall survival data. After the data cutoff, during posttreatment follow-up, 3 patients died (2 with pheochromocytomas and 1 with a NET). Two patients with pheochromocytomas whose best responses were both PD died after 3 months and 10 months off treatment, respectively. One patient with a nonfunctioning NET whose best response was SD died after 7 months off treatment.

We determined that everolimus is a promising and well-tolerated agent for the treatment of patients with nonfunctioning NETs regardless of the primary origin of the tumor. This drug demonstrated modest efficacy in patients with pheochromocytomas/paragangliomas. Early metabolic responses measured by 18F-FDG PET were found to be highly correlated with CT responses. The results of the current study support the further study of everolimus in patients with pheochromocytomas/paragangliomas and the incorporation of PET into NET studies.

FUNDING SUPPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES

Everolimus was kindly supplied by Novartis.

CONFLICT OF INTEREST DISCLOSURES

Dr. Bang has acted as a consultant and in an advisory role for Novartis, and has also received honoraria and research funding from Novartis. Dr. Oh has received honoraria from Novartis.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. REFERENCES
  • 1
    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. 2008; 26: 3063-3072.
  • 2
    Hauso O, Gustafsson BI, Kidd M, et al. Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer. 2008; 113: 2655-2664.
  • 3
    Modlin IM, Champaneria MC, Chan AK, Kidd M. A three-decade analysis of 3,911 small intestinal neuroendocrine tumors: the rapid pace of no progress. Am J Gastroenterol. 2007; 102: 1464-1473.
    Direct Link:
  • 4
    Kim SJ, Kim JW, Oh DY, et al. Clinical course of neuroendocrine tumors with different origins (the pancreas, gastrointestinal tract, and lung) [published online ahead of print June 8, 2011]. Am J Clin Oncol.
  • 5
    Kim SJ, Kim JW, Han SW, et al. Biological characteristics and treatment outcomes of metastatic or recurrent neuroendocrine tumors: tumor grade and metastatic site are important for treatment strategy. BMC Cancer. 2010; 10: 448.
  • 6
    Vogl TJ, Naguib NN, Zangos S, Eichler K, Hedayati A, Nour-Eldin NE. Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and thermal ablation. Eur J Radiol. 2009; 72: 517-528.
  • 7
    Reubi J, Kvols LK, Waser B, et al. Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res. 1990; 50: 5969-5977.
  • 8
    Rinke A, Muller HH, Schade-Brittinger C, et al; PROMID Study Group. 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: a report from the PROMID Study Group. J Clin Oncol. 2009; 27: 4656-4663.
  • 9
    Chan JA, Zhu AX, Stuart K, et al. Phase II study of pemetrexed in patients with advanced neuroendocrine tumors. Cancer Chemother Pharmacol. 2010; 66: 961-968.
  • 10
    Kulke MH, Kim H, Clark JW, et al. A Phase II trial of gemcitabine for metastatic neuroendocrine tumors. Cancer. 2004; 101: 934-939.
  • 11
    Stuart K, Levy DE, Anderson T, et al; Eastern Cooperative Oncology Group. Phase II study of interferon gamma in malignant carcinoid tumors (E9292): a trial of the Eastern Cooperative Oncology Group. Invest New Drugs. 2004; 22: 75-81.
  • 12
    Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364: 501-513.
  • 13
    von Wichert G, Jehle PM, Hoeflich A, et al. Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res. 2000; 60: 4573-4581.
  • 14
    Yao JC, Shah MH, Ito T, et al; RAD001 in Advanced Neuroendocrine Tumors Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011; 364: 514-523.
  • 15
    Pavel ME, Hainsworth JD, Baudin E, et al; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011; 378: 2005-2012.
  • 16
    Chen H, Sippel RS, O'Dorisio MS, et al; North American Neuroendocrine Tumor Society (NANETS). The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010; 39: 775-783.
  • 17
    Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer. 1999; 35: 1773-1782.
  • 18
    Ayala-Ramirez M, Feng L, Habra MA, et al. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience [published online ahead of print October 17, 2011]. Cancer. doi: 10.1002/cncr.26577.
  • 19
    Druce MR, Kaltsas GA, Fraenkel M, Gross DJ, Grossman AB. Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001). Horm Metab Res. 2009; 41: 697-702.
  • 20
    Santarpia L, Habra MA, Jimenez C. Malignant pheochromocytomas and paragangliomas: molecular signaling pathways and emerging therapies. Horm Metab Res. 2009; 41: 680-686.
  • 21
    Park KS, Lee JL, Ahn H, et al. Sunitinib, a novel therapy for anthracycline- and cisplatin-refractory malignant pheochromocytoma. Jpn J Clin Oncol. 2009; 39: 327-331.
  • 22
    Jimenez C, Cabanillas ME, Santarpia L, et al. Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau disease-related tumors. J Clin Endocrinol Metab. 2009; 94: 386-391.
  • 23
    Dimitrakopoulou-Strauss A, Hohenberger P, Strobel P, Marx A, Strauss LG. A recent application of fluoro-18-deoxyglucose positron emission tomography, treatment monitoring with a mammalian target of rapamycin inhibitor: an example of a patient with a desmoplastic small round cell tumor. Hell J Nucl Med. 2007; 10: 77-79.
  • 24
    Thomas GV, Tran C, Mellinghoff IK, et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med. 2006; 12: 122-127.
  • 25
    Cejka D, Kuntner C, Preusser M, et al. FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo. Br J Cancer. 2009; 100: 1739-1745.
  • 26
    Nogova L, Boellaard R, Kobe C, et al. Downregulation of 18F-FDG uptake in PET as an early pharmacodynamic effect in treatment of non-small cell lung cancer with the mTOR inhibitor everolimus. J Nucl Med. 2009; 50: 1815-1819.
  • 27
    Kim HS, Hong MH, Kim K, et al. Sunitinib for Asian patients with advanced renal cell carcinoma: a comparable efficacy with different toxicity profiles. Oncology. 2011; 80: 395-405.
  • 28
    Doi T, Muro K, Boku N, et al. Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol. 2010; 28: 1904-1910.