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A summary of the synergistic antitumor effect of irinotecan following temozolomide

administration
Sean Green, PharmD
October 13, 2013
Irinotecan is a camptothecan antineoplastic agent which exerts its effects through
inhibition of the topoisomerase I enzyme. By stabilizing the covalent bonds between DNA and
the replication fork, irinotecan is able to halt S-phase DNA replication and exert clinically
significant anti-tumor effects against a variety of neoplasms, including adult gastrointestinal,
lung, brain and gynecologic cancers; and pediatric rhabdomyosarcoma and neuroblastoma.
Separately, temozolomide, the prodrug of monomethyl triazenoimidazole carboxamide (MTIC),
has demonstrated activity against high-grade pediatric gliomas through its mechanism of O 6guanine methylation. While irinotecan is traditionally given as a single intravenous agent in
doses of 125 to 350mg/m2 every 1 to 3 weeks, and temozolomide is administered as 200 to
215mg/m2 orally (due to its excellent bioavailability) for 5 days in each 28 day cycle, recent
preclinical and human data have suggested a synergistic action between these two agents when
irinotecan is administered following temozolomide.
In 2000, VJ Patel and colleagues examined the combination of temozolomide and
irinotecan against a malignant glioma xenograft in mice. Since the two drugs had previously
been proven to be active against central nervous system malignancies in the past, they wished
to create a regimen, which could potentially have greater results. By administering 0.1 of the
10% lethal dose (LD10) of temozolomide on day 1 and 0.1 of the LD 10 of irinotecan on days 1
through 5 and 8 through 11, they found a response greater than the additive effects of the two
agents, even when irinotecan administration was delayed by 3 to 5 days. However, when the
experiment was reversed by giving 0.5 of the irinotecan LD 10 on day 1 followed by 0.1 of the LD10
of temozolomide at 3 hours, 5 hours and 5 days post-irinotecan, less activity was seen than with
either agent alone. Similar results were achieved by PJ Houghton et al, who assessed 5 days of
temozolomide followed by 5 days of irinotecan given in three 21-day cycles over eight weeks to
mice with neuroblastoma, rhabomyosarcoma and glioblastoma xenografts. Further more,
because lower doses of each individual agent were administered, the time dependent
synergistic administration seemed to reduce the amount of toxicity.
Finally, LM Wagner and his group conducted a Phase I trial of temozolomide and irinotecan
in 12 pediatric patients (age 1 to 23) with refractory solid tumors including Ewings sarcoma,
ependymoma, neuroblastoma, low-grade glioma, and Wilms tumor. All patients were given
100mg/m2 of oral (PO) temozolomide on days 1 through 5, followed by intravenous (IV)
inrinotecan at 10mg/m2/dose in 6 patients or 15mg/m2/dose in 6 patients on days 7 through 12
and days 14 through 19. Each cycle was 28 days in length. Two patients in the high-dose arm
experienced dose limiting toxicities, one with sepsis and the other with grade 4 diarrhea. No
patients in the lower-dose arm experienced major toxicity. Five patients, all with diagnoses of
Ewings sarcoma or neuroblastoma, showed a response with 1 complete response, 2 partial
responses and 2 minimal responses, while 7 patients had no response to therapy.
These results suggest not only synergy between irinotecan and temozolomide with timedependent administration, but also clinical activity against pediatric solid tumors. This preclinical
and Phase I data has paved the way for larger pilot studies and randomized trials to assess these
agents. Currently Childrens Oncology Group has two open trials, ACNS0821 and ANBL1121, to
evaluate the clinical utility of irinotecan/temozolomide combinations in recurrent/refractory
medulloblastoma and CNS PNET and neurolblastoma, respectively.

References:
1. Patel VJ, Elion GB, Houghton PJ. Clin Cancer Res 2000;6:4154-4157
2. Houghton PJ, Stewart CF, Cheshire PJ. Clin Cancer Res 2000;6:4110-4118
3. Wagner LM, Crews KR, Iacono LC. Clin Cancer Res 2004;10:840-848
4. Childrens Oncology Group Website. Protocols.
https://members.childrensoncologygroup.org/prot/protall.asp, Accessed 13 October 2013.