I and II are en-zymes that alter the topologicstate of DNA through DNA strand
cleavage, strand passage, and religation. They participate in most aspects of
DNA metabolism and are therefore vital to the cell undergoing division.
Topoisomerases I and II are critical cellular targets for several antitumor
agents: camptothecin derivatives interact with topoisomerase I, and
anthracycline derivatives and epipodophyllotoxine derivatives with topoisomerase
Since the discovery of the parent compound 20(s)-camptothecin in
1966, several derivatives have been prepared. Two such agents, irinotecan
(CPT-11, Camptosar) and topotecan (Hycamtin), have been approved for medical use
in the United States.[4,5] Camptothecins are active agents in the treatment of
gastrointestinal malignancies, ovarian cancer, lung cancer, and myelodysplastic
syndrome, with activity also reported in other tumors such as brain and breast
malignancies. Irinotecan is currently the leading camptothecin used
worldwide. The most significant impact of irinotecan to date has been in the
management of metastatic colorectal cancer, but clinically relevant activity in
many other diseases has been documented as well.
Anthracyclines are antitumor antibiotics active against a wide
range of hematologic and solid cancers. Anthracyclines inhibit topoisomerase II
and are involved in oxidation/reduction reactions through the generation of free
radicals. Antiproliferative activity is thought to result from these and
other mechanisms. Since its introduction into clinical practice in the 1960s,
doxorubicin has been recognized as one of the most active antineoplastic agents
available, with a wide spectrum of antitumor efficacy. Epirubicin (Ellence)
hydrochloride is a synthetic derivative of daunorubicin (DaunoXome), the
prototype anthracycline. Epirubicin is the 4¢ epimer of doxorubicin; its
structure differs from that of doxorubicin only in the reorientation of a single
hydroxyl group at the 4¢ position. Epirubicin was identified through
screening a series of doxorubicin derivatives that could potentially improve
therapeutic index as compared with the parent compound.
Combination chemotherapy is important in the treatment of many
tumor types, as it can achieve additive or synergistic cytotoxic
activities.[9,10] The DNA topoisomerases I and II are targets of several
antineoplastic agents. Depletion of the target topoisomerase can be accompanied
with reciprocal changes in the other topoisomerases. Targeting both
topoisomerases I and II could therefore offer significant synergy. In
preclinical models, inhibition of topoisomerases I and II has resulted in
synergistic activity when such agents were administered sequentially in several
tumor types. While clinical data are limited, a phase I study with topotecan
(topoisomerase I inhibitor) followed sequentially with doxorubicin
(topoisomerase II inhibitor) showed that this combination can be given safely
with hematologic toxicity as the dose-limiting toxicity.
Both irinotecan and epirubicin play important roles in cancer
therapies today. Each has a broad spectrum of action with the additional
potential for clinical synergy. Except for bone marrow toxicity, the two agents
have few toxicities in common. The phase I study reported herein is exploring
the clinical potential of the combination of irinotecan (topoisomerase I
inhibitor) and epirubicin (topoisomerase II inhibitor) in patients with advanced
cancer. Only very preliminary data are available so far for this ongoing trial.
Study objectives are to determine the dose-limiting toxicity and
maximum tolerated dose of the combination of irinotecan and epirubicin when
administered in a day 1 and day 8, every-28-days cycle. Additional goals are to
determine the pharmacokinetics of each agent to assess potential drug
interactions, and to document any observed antitumor responses in the hopes of
focusing phase II efforts with this combination.
Extra care was taken due to the high probability of
myelosuppression, as was seen with similar combinations. The starting irinotecan
dose was 100 mg/m² on days 1 and 8 given every 28 days. This dose represents
less than 50% of the recommended phase II dose of 125 mg/m² weekly for 4 weeks
followed by a 2-week rest. In the literature, the recommended epirubicin dose is
135 mg/m² given every 3 weeks as a single agent or 60 mg/m² on days 1 and 8
every 4 weeks when used in a combination regimen. The starting epirubicin dose
in this phase I study was 40 mg/m² on days 1 and 8, which is 59% of the
single-dose epirubicin given every 3 weeks and 66% of the epirubicin dose when
given on days 1 and 8 every 4 weeks. Dose escalation is detailed in Table
Entry criteria included histologically documented incurable
malignancy, age of at least 18 years, anticipated survival of at least 8 weeks,
and Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Patients had to have adequate end organ function, including normal hepatic and
renal function. Also required were a white blood cell count above 3,000/µL, an
absolute neutrophil count above 1,500/µL, and a platelet count above
100,000/µL. Normal cardiac function, as measured by radionuclide ventriculogram
scan (ejection fraction greater than 50%), was also required.
Patients must have recovered from the reversible side effects of
previous therapy. Exclusion criteria included previous doxorubicin treatment of
more than 240 mg/m², severe anorexia or vomiting, significant recent weight
loss, pregnancy or lactation, serious intercurrent medical illnesses, history of
congestive heart failure, and concurrent immunotherapy or radiotherapy. All
patients provided written informed consent.
According to the original study plan, patients were to be
enrolled at dose level 1 with starting doses of irinotecan at 100 mg/m² and
epirubicin at 40 mg/m² (Table 1). One treatment cycle was 4 weeks, with study
drugs administered on days 1 and 8 with the subsequent 2 weeks off. Irinotecan
was to be given over 90 minutes and epirubicin was to be given over 5 minutes
intravenously. Using a typical phase I dose-escalation scheme, three patients
were to be treated in each cohort. If no dose-limiting toxicities were observed
in the first treatment cycle, an additional three patients would be started at
the next dose level. However, because significant myelosuppression was observed
in patients at the first dose level, the protocol was modified as shown in Table
Dose-limiting toxicity is defined as a treatment-related
toxicity severe enough to preclude additional therapy for that patient, and is
typically grade 3 or 4 toxicity. The maximum tolerated dose is defined as the
highest dose level that does not result in dose-limiting toxicities in two or
more of six patients treated at that level.
Blood samples are being obtained from all patients at
predetermined intervals on day 1 only. Samples will be analyzed to determine
clearance and half-life of both irinotecan and epirubicin. Specifically, this
analysis will help determine whether concurrent administration of the two
compounds results in any significant pharmacokinetic interactions.
All treatment is delivered on an outpatient basis. Patients are
evaluated on each day of treatment by physical examination and laboratory
studies including hematologic and chemistry panels. Tumor assessment is
conducted at baseline and again every 8 weeks (or two cycles). Repeat ejection
fraction is assessed after patients have received 450 to 500 mg/m² of
epirubicin. Patients who are tolerating the therapy reasonably well and gaining
clinical benefit (ie, stable or improving disease status) may continue on the
Four patients were accrued to the initial cohort. Their
characteristics are listed in Table 3. Two patients had to be replaced due to
rapid disease progression and two developed a dose-limiting toxicity. No
significant acute toxicities were observed, namely, no significant diarrhea or
nausea/vomiting. However, two of the four patients had myelosuppression as
dose-limiting toxicity. Both patients were re-treated at reduced doses and
currently remain on study. Toxicities are summarized in Table
4. One patient
with metastatic gallbladder cancer had a minor response accompanied by a 50%
decrease in carcinoembryonic antigen level. Another patient with metastatic
pancreatic cancer had stable disease and symptomatic improvement.
The combination of topoisomerase I and II inhibitors previously
has been shown to result in significant myelosuppression, and we have observed a
similar effect in early results of this trial. Once a maximum tolerated dose is
identified and the pharmacokinetic data analyzed, selected phase II studies will
be initiated in patients with gastric cancer and cholangiocarcinoma/bile duct
cancers. The day 1 and 8 schedule is convenient for patients and has resulted in
acceptable acute side effects. Although it is possible that alternative
schedules (such as every 14 days or every 21 days) may allow for higher dose
escalation, we suspect this will not be the case.
1. Cummings J, Smyth JF: DNA topoisomerase I and II as targets
for rational design of new anticancer drugs. Ann Oncol 4(7):533-543, 1993.
2. Malonne H, Atassi G: DNA topoisomerase targeting drugs:
mechanism of action and perspectives. Anticancer Drugs 8(9):811-822, 1997.
3. Wall ME, Wani MC, Natschke SM, Nicholas AW: Plant antitumor
agents. 22. Isolation of 11-hydroxycamptothecin from Camptotheca acuminata Decne:
Total synthesis and biological activity. J Med Chem 29(8):1553-1555, 1986.
4. Horowitz RW, Wadler S, Wiernik PH: A review of the clinical
experience with Irinotecan. Am J Ther 14(5/6):203-210, 1997.
5. Burris HA: Topotecan: Incorporating it into the treatment of
solid tumors. Oncologist 3(1):1-3, 1998.
6. Rothenberg ML: Topoisomerase I inhibitors: Review and update.
Ann Oncol 8(9):837-855, 1997.
7. Booser DJ, Hortobagyi GN: Anthracycline antibiotics in cancer
therapy. Drugs 47(2):223-258, 1994.
8. Camaggi CM, Comparsi R, Strocchi E, et al: Epirubicin and
doxorubicin comparative metabolism and pharmacokinetics: A cross-over study.
Cancer Chemother Pharmacol 21:221-228, 1988.
9. Jonsson E, Fridborg H, Nygren P, et al: Synergistic
interactions of combinations of topotecan with standard drugs in primary
cultures of human tumor cells from patients. Eur J Clin Pharmcol 54(7):509-514,
10. Eder JP, Chan V, Wong J, et al: Sequence effect of
irinotecan (CPT-11) and topoisomerase II inhibitors in vivo. Cancer Chemotherapy
Pharmacol 42(4):327-35, 1998.