duration of 37 months.78 Despite the demonstrated
efficacy of streptozocin-based regimens, their po-
tential toxicity has precluded their more widespread
use in patients with advanced pancreatic NETs.
Recent prospective and retrospective studies have
suggested that oral temozolomide-based regimens
may be comparable in efficacy and more toler-
able than streptozocin-based regimens (Table 3).
In retrospective series, temozolomide-based thera-
py has been associated with overall response rates
of 8% to 70%.71,72,79 Temozolomide has been evalu-
ated prospectively in combination with thalidomide,
bevacizumab, or everolimus, with overall response
rates of 24% to 45%.75–77 Most recently, activity has
been observed with a regimen incorporating low-
dose, metronomic temozolomide.80 While temozolo-
mide-based therapy is clearly active in pancreatic
NET, neither the optimal dosing regimen for temo-
zolomide nor the relative activity of temozolomide
as a single agent or in combination with other thera-
peutic agents has been clearly established.
The cytotoxic effect of temozolomide has been
attributed to its ability to induce DNA methylation at
the O6 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). MGMT deficiency appears
to be more common in pancreatic NETs than in
carcinoid tumors, potentially explaining the greater
sensitivity of pancreatic NETs to treatment with the
alkylating agents streptozocin or temozolomide.71
MGMT expression potentially could be used as a
predictive marker in future studies of these tumors.
Table 3. Selected Trials of Cytotoxic Chemotherapy in Advanced Pancreatic Neuroendocrine Tumors
Chlorozotocin 33 30 17 mo* 18.0 mo
Fluorouracil + streptozocin 33 45 14 mo* 16. 8 mo Moertel et al, 199273
Doxorubicin + streptozocin 36 69 18 mo* 26.4 mo
Dacarbazine 50 34 NR 19. 3 mo Ramanathan et al,
Temozolomide + thalidomide 11 45 NR NR Kulke et al, 200675
Temozolomide + bevacizumab 15 33 14. 3 mo 41.7 Chan et al, 200676
Temozolomide + everolimus 24 35 NR NR Kulke et al, 201077
Streptozocin + doxorubicin +
84 39 18 mo 37 mo Kouvaraki et al,
Temozolomide (diverse regimens) 53 34 13.6 mo 35.3 mo Kulke et al, 200971
Temozolomide (single agent) 12 8 NR NR Ekeblad et al,
Temozolomide + capecitabine 30 70 18 NR Strosberg et al,
NR = not reported.
*Reported as duration of tumor regression.