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cgi

American Journal of Clinical Oncology

Issue: Volume 22(2), April 1999, pp 168-171
Copyright: © 1999 Lippincott Williams & Wilkins, Inc.
Publication Type: [Articles]
ISSN: 0277-3732
Accession: 00000421-199904000-00012
Keywords: Brain tumors, 2-Chlorodeoxyadenosine, Chemotherapy, Recurrent gliomas, Clinical trial

[Articles]

Phase II North Central Cancer Treatment Group Study of

2-Chlorodeoxyadenosine in Patients With Recurrent Glioma
Rajkumar, S. Vincent M.D.; Burch, Patrick A. M.D.; Nair, Suresh M.D.; Dinapoli, Robert P. M.D.; Scheithauer, Bernd
M.D.; O'Fallon, Judith R. M.D.; Etzell, Paul S. M.D.; Leitch, John M. M.D.; Morton, Roscoe F. M.D.; Marks, Randolph
S. M.D.

Author Information
From the Mayo Clinic and Mayo Foundation (S.V.R., P.A.B., R.P.D., B.S., J.R.O., R.S.M.), Rochester,
Minnesota; the Geisinger Clinical Oncology Program (S.N.), Danville, Pennsylvania; Meritcare Hospital CCOP
(P.S.E., J.M.L.), Fargo, North Dakota; and the Iowa Oncology Research Association CCOP (R.F.M.), Des
Moines, Iowa, U.S.A.
Conducted as a North Central Cancer Treatment Group trial and supported in part by Public Health Service
grants CA-25224, CA-37404, CA-37417, CA-35101, CA-35113, CA-35103, CA-35195, CA-35269, and
CA-35448 from the National Cancer Institute, Department of Health and Human Services, Bethesda,
Maryland, U.S.A.
Address correspondence and reprint requests to Dr. Randolph S. Marks, Mayo Clinic, 200 First Street SW,
Rochester, MN 55905, U.S.A.
Abstract

There is no standard treatment for patients with recurrent gliomas, and their prognosis remains poor.
2-Chlorodeoxyadenosine is a purine analogue that has significant activity in many low-grade
lymphoproliferative disorders. The authors conducted a phase II study to determine the efficacy of
2-chlorodeoxyadenosine in patients with recurrent gliomas. Patients with a histologically confirmed
primary brain tumor with evidence of progression after radiation therapy were eligible. Protocol
treatment consisted of 2-chlorodeoxyadenosine 7.0 mg/m2 intravenously on days 1 through 5 every 28
days. For those with a history of prior nitrosourea therapy, the dose of 2-chlorodeoxyadenosine was
reduced to 5.6 mg/m2 on days 1 through 5. Treatment was continued until progression or a maximum of
12 cycles. Fifteen patients with recurrent astrocytomas or oligoastrocytomas of all grades were entered
in the study. Treatment was well tolerated. Major toxicities were myelosuppression and neurotoxicity. No
responses were seen. The authors conclude that although 2-chlorodeoxyadenosine is well tolerated, no
demonstrable activity in patients with recurrent gliomas was established.

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Standard therapy for patients with gliomas consists of surgery or radiation with or without subsequent
nitrosourea-based adjuvant chemotherapy.1,2 Nevertheless, most patients with gliomas experience
recurrent disease. No standard therapy exists for patients with recurrent gliomas. Several approaches,
including surgery, brachytherapy,3 radiosurgery,4 chemotherapy,5 and immunotherapy,6 have been tried,
but the survival and median response rates are poor. The prognosis for most patients with recurrent gliomas
remains dismal.

2-Chlorodeoxyadenosine is an adenosine deaminase-resistant purine analog that has been successfully

used in the treatment of several hematologic malignancies.7,8 It is the treatment of choice in hairy cell
leukemia, with complete response rates exceeding 80% after a single cycle of treatment.9,10 Activity has
been seen in several other malignancies, including chronic lymphocytic leukemia, low-grade lymphomas,
and acute leukemia.7,11 2-Chlorodeoxyadenosine has been studied in patients with recurrent gliomas
during phase I evaluation of this drug in patients with solid tumors. Two of seven patients with recurrent
gliomas responded to 2-chlorodeoxyadenosine in one phase 1 trial.12

2-Chlorodeoxyadenosine is phosphorylated to its active form, 2-chlorodeoxyadenosine triphosphate, by the

enzyme deoxycytidine kinase.13 Levels of this enzyme are higher in gliomas than in surrounding brain
tissue.14 There is also laboratory evidence that it inhibits the cell cycle of glioma cells grown in vitro.15
Given the lack of effective therapy in patients with recurrent gliomas, we proceeded with a phase II trial of
2-chlorodeoxyadenosine in this patient population. The dosage and schedule of 2-chlorodeoxyadenosine
was based on an earlier phase I study we conducted with this agent in patients with solid tumors.16

PATIENTS AND METHODS

Eligibility Criteria
All patients had histologic confirmation of astrocytoma, oligodendroglioma, mixed astrocytoma or
oligodendroglioma, or gliosarcoma (any grade) at initial diagnosis or recurrence. Evidence of tumor
progression after radiation therapy based on computed tomographic scanning or magnetic resonance
imaging was required. All patients had measurable or evaluable disease and were on a fixed dose of
corticosteroids (or no corticosteroids) for at least 1 week before baseline imaging studies. Patients had not
received radiation therapy for at least 1 month before study entry. One prior chemotherapy regimen was
permitted. Patients with an age less than 18 years, absolute neutrophil count less than 2,000/µl, platelet
count less than 130,000/µl, serum creatinine clearance more than 0.3 mg/dl above institutional normal
value, total bilirubin count more than 1.5 mg/dl above the upper limit of institutional normal value,
uncontrolled infection, pregnancy or lactation, Eastern Cooperative Oncology Group performance score of
3 or 4, or prior therapy with 2-chlorodeoxyadenosine were excluded from study participation. All patients
provided written informed consent before study enrollment.

Protocol Therapy
Protocol treatment consisted of 2-chlorodeoxyadenosine administered intravenously over 2 hours at a dose
of 7 mg/m2 daily for 5 consecutive days. Treatment was repeated every 28 days until progression or a
maximum of 12 cycles. For those with a history of prior nitrosourea therapy, the dose of
2-chlorodeoxyadenosine was reduced to 5.6 mg/m2 daily for 5 days.

Patient Evaluations

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Within 14 days before registration and initial treatment, each patient had a baseline evaluation consisting of
history, general physical examination, neurologic examination including the Folstein and Folstein minimental
status examination, complete blood count, and serum chemistries (electrolytes, calcium, aspartate
transaminase, alkaline phosphatase, bilirubin, and creatinine). All baseline evaluations were repeated before
retreatment. A computed tomography or magnetic resonance imaging scan of the head with contrast was
performed at baseline and repeated before the second, third, fifth, seventh, ninth, and twelfth cycles. A
baseline chest radiograph was performed and repeated as clinically indicated. Women with childbearing
potential also had a serum pregnancy test before initial treatment. The complete blood count was
performed weekly during treatment. After completion of treatment, baseline evaluations were repeated
every 3 months for 1 year, and every 6 months thereafter.

Assessment of Toxicity and Response

National Cancer Institute common toxicity criteria were used throughout. The 2-chlorodeoxyadenosine dose
was decreased 25% for nadir absolute neutrophil count 500/µl or less or platelet count less than 75,000/µl.
For grade 3-4 stomatitis or diarrhea, the dose of 2-chlorodeoxyadenosine was reduced by 20 % to 33%.
The 2-chlorodeoxyadenosine dose was decreased by 33% for grade 2 neurologic symptoms and
discontinued if higher degrees of neurotoxicity occurred. Treatment was delayed for absolute neutrophil
counts less than 2,000/µl or platelet counts less than 130,000/µl until marrow recovery. For a rise in serum
creatinine clearance more than 1.5 mg/dl above the upper limit of normal, the 2-chlorodeoxyadenosine
dose was decreased by 50%. Treatment was delayed until renal function improved if serum creatinine
clearance was more than 2 mg/dl above the upper limit of normal.

Assessment of response was based on computed tomography or magnetic resonance imaging scans and
by neurologic examination. To qualify for objective response, patients must have experienced tumor
reduction on computed tomography or magnetic resonance imaging evaluation while remaining
neurologically stable or improved and on a stable or decreased dose of corticosteroids. Complete response
was defined as disappearance of all visible tumor. Partial response was defined as 50% reduction in the
product of perpendicular diameters of the clearly demarcated contrast-enhancing mass. Patients with
tumors that were not bidimensionally measurable but were clearly evaluable for response to therapy were
considered to have a regression if there was unequivocal reduction in the size of contrast enhancement or
decrease in mass effect as agreed on independently by the primary physician and the quality control
physicians. Progression was indicated if there was a more than 25% increase in the product of
perpendicular diameters of the mass, unequivocal increase in the size of the contrast-enhancing lesion,
increase in the mass effect, or appearance of new lesions. Neurologic worsening, based on an overall
clinical evaluation, despite two sequential stable computed tomography or magnetic resonance imaging
scans also constituted progression.

RESULTS
From October 1993 through January 1994, 15 patients were entered in the study at eight participating North
Central Cancer Treatment Group institutions. Patient characteristics are detailed in Table 1. The median time
from diagnosis of primary brain tumor to recurrent disease and protocol entry was 26 months (range, 4-128
months). Eleven patients had received prior nitrosourea chemotherapy and hence received a lower dose of
2-chlorodeoxyadenosine as planned. An average of three cycles of 2-chlorodeoxyadenosine was
administered to each patient (range, 1-11 cycles).

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TABLE 1. Patient characteristics

Survival and Responses

No objective responses were seen. The best response was stable disease in 11 patients. Median time to
progression was 3 months. Median survival was 8 months. At the time of analysis, 13 of 15 patients have
died and the two surviving patients are both alive with progressive disease at 32 months of follow-up. One-
and 2-year survival rates were 33% and 13%, respectively.

Toxicity

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The toxicity profile of the patients is detailed in Table 2 and represents the most severe toxicity associated
with the study treatment for each patient. Treatment was generally well tolerated, and no grade 4 toxicity
was seen. No patient died of toxicity. Four patients discontinued treatment because of toxicity, all resulting
from prolonged thrombocytopenia. However, the degree of thrombocytopenia was mild, and only one
patient had grade 3 thrombocytopenia. Bleeding complications did not occur. Neurotoxicity led to motor
and sensory symptoms in three patients. Other toxicities were mild and did not exceed grade 2 severity.

TABLE 2. Toxicity profile

DISCUSSION
The survival of patients with recurrent gliomas is poor, and there is a need to identify new agents with
activity against these tumors. 2-Chlorodeoxyadenosine is a novel purine analogue of 2 deoxyadenosine, in
which a chlorine atom is substituted at the 2 position. This makes it resistant to degradation by the enzyme
adenosine deaminase. The active phosphorylated form of 2-chlorodeoxyadenosine competes with
adenosine triphosphate for incorporation into DNA.17 Such incorporation inhibits DNA synthesis and leads
to cell death, accounting for its antitumor activity. The enzyme that phosphorylates
2-chlorodeoxyadenosine to its active form is deoxycytidine kinase. Lymphoid tissue is rich in this enzyme
and the drug has shown significant activity in the treatment of several lymphoid malignancies.7,8

In this trial, we treated 15 patients with recurrent gliomas with 2-chlorodeoxyadenosine and found that this
agent had no activity with the dose administration schedule studied. Time to progression and survival were
poor. Although we used a schedule of 2-chlorodeoxyadenosine that is different from that used in the
treatment of hairy cell leukemia,9 we do not believe that the agent merits additional investigation in patients
with primary brain tumors.

Treatment was well tolerated. Similar to other studies with 2-chlorodeoxyadenosine, myelosuppression was
the most common toxicity noted.17 Neurotoxicity is an important adverse effect that has been reported
with all purine analogues. Four patients in our study had evidence of neurotoxicity, and toxicity was severe
in two patients.

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In summary, we found that 2-chlorodeoxyadenosine is generally well tolerated but does not have activity in
patients with recurrent gliomas on the treatment schedule studied. We do not recommend further testing of
this agent in glioma.

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Key Words: Brain tumors; 2-Chlorodeoxyadenosine; Chemotherapy; Recurrent gliomas; Clinical trial

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