2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Fig 1. PubMed publications and clinical trial postings by year for
pancreatic NETs.
receive everolimus 10 mg orally daily or placebo. The primary
endpoint was PFS; secondary endpoints were overall
survival (OS), response rate (RR), and safety. The median
PFS was 11.0 months with everolimus as compared to 4.6
months with placebo (hazard ratio [HR] 0.35; 95% CI 0.27 to
0.45; p � 0.001). The RR was 5% in the everolimus arm
compared to 2% in the placebo arm. Updated OS showed no
difference between arms; however, patients in the placebo
arm crossed over to treatment at progression, likely reducing
the chance of observing a survival difference (Table 1).
Another randomized study evaluated the efficacy of
sunitinib, an inhibitor of the VEGF pathway, in advanced
pancreatic NETs. One hundred seventy one patients with
advanced, well-differentiated, progressive pancreatic NETs
were randomly selected to receive sunitinib 37.5 mg orally
daily or placebo. 8 Primary endpoints were PFS; secondary
endpoints were RR, OS, and safety. The study was discontinued
before the preplanned interim efficacy analysis, 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. At the time of study closure, median 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 � 0.001).
KEY POINTS
● Surgical resection continues to be the mainstay of
treatment for patients with locoregional disease.
● Somatostatin analogs are indicated for patients experiencing
symptoms of hormone excess; there are
currently no prospective data to support the use of
somatostatin analogs as antitumor agents for pancreatic
neuroendocrine tumors.
● For patients with advanced disease, single-agent
everolimus and sunitinib have recently been shown to
improve progression-free survival.
● Temozolomide-based chemotherapy regimens are
emerging as an acceptable alternative to streptozocin;
prospective randomized studies are in
development.
272
RRs in the sunitinib and placebo arms were 9.3% and 0%,
respectively. A high proportion of patients in the placebo
arm received sunitinib at progression through a continuation
study, and although an early survival analysis appeared
to favor the sunitinib arm, this difference did not
remain significant with additional follow-up (Table 1).
Cytotoxic Chemotherapy
Patients with advanced pancreatic NETs currently have
few treatment options that yield objective radiographic
tumor regression. Recent studies evaluating everolimus 7
and sunitinib 8 in this patient population have demonstrated
prolongation of PFS compared to placebo, but overall tumor
RRs (by RECIST) with these agents are less than 10%.
Historical studies reporting the highest RRs include regimens
with cytotoxic chemotherapy. In an initial randomized
study of 106 patients, Moertel and colleagues reported
activity associated with the combination of streptozocin and
doxorubicin in patients with advanced islet-cell tumors
(Table 1). 9 The RR associated with this regimen was reported
to be 69%; however, because of the use of nonstandard
response criteria, the true objective radiologic RR was
likely much lower. Retrospective series have reported overall
RRs of 6% to 39% associated with streptozocin-based
regimens in pancreatic NETs. 10,11 Although clearly associated
with activity, the combination of streptozocin and
doxorubicin is also associated with considerable toxicity,
including myelosuppression, asthenia, and renal insufficiency,
precluding its routine use in this disease. Additionally,
recent issues with drug availability have made routine
use difficult.
Recent retrospective series and small, prospective phase
II studies suggest that temozolomide is similarly active but
less toxic than streptozocin-based therapy when treating
patients with pancreatic NETs. In a retrospective series of
36 patients treated with temozolomide monotherapy, tumor
regression was observed in 31% of bronchial carcinoid tumors
and 8% of pancreatic NETs. 12 In a series of 97 patients,
18 of 53 patients with pancreatic NETs (34%) achieved a
partial or complete response to temozolomide-based therapies.
13 A third retrospective series of 21 patients treated
with temozolomide monotherapy demonstrated responses in
25% of pancreatic NETs. 14
Temozolomide has also been investigated prospectively in
phase II studies of patients with NETs, though always in
combination with other agents. In an initial study, 29
patients with metastatic NETs were treated with a combination
of temozolomide, administered at a dose of 150 mg/m 2
Table 1. Studies Leading to FDA Approval of Agents in
Advanced Pancreatic NETs
Regimen
Number of
Patients
RR
(%)
TTP or PFS
(mo)
PAMELA L. KUNZ
OS
(mo) Reference
Strep/dox vs. 36 69 20 26.4 Moertel et al. 9
Strep/5FU vs. 33 45 6.9 16.8
Chlorotozocin 33 30 6.9 16.8
Everolimus vs. 207 5 11.0 NR Yao et al. 7
Placebo 203 2 4.6 36.6
Sunitinib vs. 86 9 11.4 30.5 Raymond et al. 8
Placebo 85 0 5.5 24.4
Abbreviations: mo, months; NET, pancreatic neuroendocrine tumor; NR, not
reached; OS, overall survival; PFS, progression-free survival; RR, response rate;
TTP, time to progression.