2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

THERAPEUTIC OPTIONS FOR PANCREATIC NETS
for 7 days, every other week, and thalidomide at doses of
50 to 400 mg daily; this combination was associated with
objective tumor responses in 5 of 11 patients (45%). 15 A
subsequent phase II study evaluated the combination of
temozolomide and bevacizumab in the treatment of 34
patients with NETs (15 pancreatic, 19 carcinoid). 16 Patients
received 150 mg/m 2 /day of temozolomide orally for 7 days,
every other week, and 5 mg/kg of bevacizumab intravaneously
every other week. Because of anticipated lymphopenia,
patients also received prophylaxis with trimethoprim/
sulfamethoxazole (1 double strength tablet every Monday,
Wednesday, Friday). Objective tumor responses were observed
in 33% of patients with pancreatic NETs, but not in
patients with carcinoid tumors. In a third, prospective
study, a regimen of everolimus and temozolomide was associated
with an overall tumor RR of 35% for patients with
advanced pancreatic NETs. 17 Taken together, these prospective
and retrospective studies suggest that temozolomidebased
therapy is comparable to streptozocin-based regimens
and might reasonably be associated with an overall tumor
RR of 30% to 40% for patients with advanced pancreatic
NETs.
Interestingly, preclinical and early clinical evidence suggests
that capecitabine may be synergistic with temozolomide.
18,19 In a series of 17 patients with pancreatic NETs,
combination therapy with temozolomide and capecitabine
was associated with a tumor RR of 59%. 20 A recent singleinstitution
retrospective study by Strosberg and colleagues
reported RRs of 70% and median PFS of 18 months for 30
patients with advanced pancreatic NETs. 21 In this study,
temozolomide was administered at a dose of 200 mg/m 2
on days 10 to 14, and capecitabine was administered at a
dose of 750 mg/m 2 twice daily on days 1 to 14. The combination
and specific dosing schedules were well-tolerated,
with only four patients experiencing grade 3 or 4 adverse
events (anemia, thrombocytopenia, elevated aspartate aminotransferase,
and elevated alanine aminotranferease). The
most common grade 1 and 2 adverse events were fatigue,
nausea, myelosuppression, and hand-foot syndrome. Based
on this study, the combination of temozolomide and capecitabine
has become popular and commonly used in patients
with advanced pancreatic NETs.
Other Therapies for Advanced Disease
Hepatic metastases commonly occur in patients with
pancreatic NETs and adversely affect overall prognosis and
quality of life. Therapies directed at locoregional control of
hepatic disease may be necessary to decrease symptoms
associated with hormone excess. Surgery for hepatic metastases
should be considered whenever the metastases are
considered resectable and when there is no evidence of
extrahepatic disease. Thermal ablation or cryoablation may
be considered as an adjunct to surgery or in settings where
extrahepatic disease or comorbidities might favor a less
aggressive intervention. Selective catheterization of the
hepatic artery and embolization of vessels perfusing the
tumors can result in clinically significant responses. Embolization
options include bland embolization, chemoembolization,
and radioembolization. Retrospective studies report
benefit, though no prospective studies have been conducted.
22
Radiolabeled somatostatin analogs with therapeutic doses
of the radioactive isotope can also provide disease control in
patients with advanced disease and are used routinely in
Europe. 23 The most commonly used radionuclides are indium
( 111 I), yttrium ( 90 Y), and lutetium ( 177 Lu) and are only
available in Europe. The largest retrospective study of
patients with gastroenteropancreatic NETs demonstrated
clinical responses in 46% of patients at 3 months (complete
2%, partial 28%, and minor 16%) and stable disease in 36%;
the minority had progressive disease (20%). Median time to
progression (TTP) was 40 months; median OS was 128
months. The bone marrow and kidneys are the most important
dose-limiting organs in peptide receptor radionuclide
therapy. 24 Prospective randomized studies are needed to
confirm these observed benefits.
Ongoing and Future Directions
The renaissance of clinical research in the field of NETs
has only just begun. Ongoing and proposed studies are
poised to answer important questions.
First, do somatostatin analogs have antitumor activity in
pancreatic NETs? Though many physicians extrapolate the
findings from the PROMID study, 25 there is currently no
prospective data to support the use of somatostatin analogs
as antitumor agents for pancreatic NETs. An ongoing international
study was designed to answer this question by
randomly selecting patients with advanced nonfunctioning
pancreatic NETs to receive lanreotide autogel versus placebo
(CLARINET, NCT00353496). Primary endpoints are
TTP and death. The study opened in June 2006, and accrual
is ongoing.
Second, does the combination of two biologic agents improve
efficacy outcomes in pancreatic NETs? A CALGB
study (80701, NCT01229943) addresses this question and
randomly selects patients with advanced pancreatic NETs to
receive everolimus and octreotide long-acting release (LAR)
versus everolimus, bevacizumab, and octreotide LAR. The
primary endpoint is PFS. The study opened in October 2010,
and accrual is ongoing.
The development of thoughtful future studies is critical
in moving the field forward. In fact, a National Cancer
Institute Neuroendocrine Tumor Clinical Trials Planning
Meeting 26 held in 2009 identified key unmet needs, recommended
appropriate study endpoints and inclusion criteria,
and formulated priorities for future NET studies. The prospective
evaluation of single-agent temozolomide and a
comparision to temozolomide-based combinations for pancreatic
NETs was a key recommendation of this meeting.
ECOG 2211 is a proposed study in which patients with
advanced pancreatic NETs will be randomly selected to
receive temozolomide versus temozolomide and capecitabine.
The principal objective of the study will be to assess
whether the addition of capecitabine to temozolomide improves
RRs when compared to temozolomide alone. It is
anticipated that the superior arm will serve as a building
block in future studies.
Conclusion
The recent advances in the field of pancreatic NETs
are truly exciting. We now have additional agents in our
arsenal of therapeutic options for patients with this disease,
including everolimus and sunitinib, both of which have
been shown to prolong PFS. Given the increasing number
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