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Departments of Surgery, Medicine, and Pediatrics [H. S. F.] and Department of Pathology [T. K.], Duke University, Durham, North Carolina 27710, and Division of Oncology, Newcastle General Hospital, Newcastle Upon Tyne, NE4 6BE United Kingdom [H. C.]
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ABSTRACT |
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 Top ABSTRACT IntroductionBackgroundMechanism of ActionMechanisms of ResistanceReducing Resistance to...Clinical Experience with...Phase 2 and 3...Overcoming ResistanceSummary and ConclusionsREFERENCES |
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Temozolomide, a p.o. imidazotetrazine second-generation alkylating agent, is the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. In vitro, temozolomide has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma. In clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. Temozolomide has recently been approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. Predictable bioavailability and minimal toxicity make temozolomide a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types. An overview of the mechanism of action of temozolomide and a summary of results from clinical trials in malignant glioma are presented here.
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Introduction |
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TopABSTRACTIntroductionBackgroundMechanism of ActionMechanisms of ResistanceReducing Resistance to...Clinical Experience with...Phase 2 and 3...Overcoming ResistanceSummary and ConclusionsREFERENCES |
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Interest in temozolomide as an antitumor agent derives from its broad-spectrum antitumor activity in tumor models in mice (3) . In vitro, temozolomide has demonstrated schedule-dependent antitumor activity against a variety of malignancies, including glioma, metastatic melanoma, and other difficult-to-treat cancers (3, 4, 5) . In preclinical studies, temozolomide demonstrated distribution to all tissues, including penetration into the CNS; relatively low toxicity compared with its parent compound, mitozolomide; and antitumor activity against a broad range of tumor types, including glioma, melanoma, mesothelioma, sarcoma, lymphoma, leukemia, and carcinoma of the colon and ovary (3, 4, 5, 6, 7, 8) . Its demonstrated ability to cross the blood-brain barrier is of special interest with respect to its activity in CNS tumors (9) .
In Phase 1 and 2 clinical studies conducted by the CRC (London, United Kingdom), temozolomide was absorbed rapidly, exhibited 100% p.o. bioavailability within 1–2 h of administration, and demonstrated antineoplastic activity in recurrent high-grade glioma, melanoma, and mycosis fungoides (10, 11, 12, 13) . Results of these trials showed that when temozolomide is administered p.o. once daily for 5 days in a 4-week cycle, it is well tolerated, producing mild-to-moderate toxicity that is both predictable and easily managed. The results also confirmed the ability of temozolomide to penetrate the CNS and indicated that temozolomide has considerable potential in treating gliomas and improving the QOL of patients with glioma (12, 13, 14) . Additional Phase 1 studies have confirmed these results and have extended these observations to pediatric patients (15 , 16) .
Temozolomide has been evaluated in a number of Phase 2 and 3 clinical trials for the treatment of glioblastoma multiforme, anaplastic astrocytoma, and malignant metastatic melanoma—malignancies for which there are no satisfactory therapies. On the basis of the results of these studies, temozolomide has been approved in the European Union for the treatment of patients with glioblastoma multiforme showing progression or recurrence after standard therapy. Recently, temozolomide received accelerated approval from the FDA for treatment of adult patients with anaplastic astrocytoma who have relapsed after treatment that included a nitrosurea drug (BCNU or CCNU) and procarbazine. Studies are under way to evaluate the combination of temozolomide with other chemotherapeutic agents and biochemotherapy in the treatment of malignant glioma and metastatic melanoma, respectively. This article reviews the mechanism of action of temozolomide as an anticancer agent and summarizes the most recent clinical studies of temozolomide for the treatment of malignant gliomas.
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Background |
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TopABSTRACTIntroductionBackgroundMechanism of ActionMechanisms of ResistanceReducing Resistance to...Clinical Experience with...Phase 2 and 3...Overcoming ResistanceSummary and ConclusionsREFERENCES |
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Temozolomide, a 3-methyl derivative of mitozolomide, was less toxic than mitozolomide and exhibited comparable antitumor activity against various murine tumors (3) . Additional characteristics that justified its further development for clinical evaluation in patients with cancer included wide tissue distribution with penetration into the intact mouse brain (25) , 100% bioavailability after p.o. dosing, and no requirement for enzymatic conversion to the potent antitumor metabolite MTIC.
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Mechanism of Action |
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TopABSTRACTIntroductionBackgroundMechanism of ActionMechanisms of ResistanceReducing Resistance to...Clinical Experience with...Phase 2 and 3...Overcoming ResistanceSummary and ConclusionsREFERENCES |
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. The initial
proposal was that this effect of water was catalyzed in the close
environment of the major groove of DNA (26
, 27)
, but
confirming this mechanism has been difficult, and it is known that
temozolomide converts readily to MTIC in free solution in the absence
of DNA (2)
. MTIC degrades to the methyldiazonium cation,
which transfers the methyl group to DNA and to the final degradation
product, AIC, which is excreted via the kidneys (28
, 29)
.
The methyldiazonium cation can also react with RNA and with soluble and
cellular protein (23)
. However, the methylation of RNA and
the methylation or carbamoylation of protein do not appear to have any
known significant role in the antitumor activity of temozolomide.
Additional studies are required to clarify the role of these targets in
the biochemical mechanism of action of temozolomide.
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Among the lesions produced in DNA after treatment of cells with temozolomide, the most common is methylation at the N7 position of guanine, followed by methylation at the O3 position of adenine and the O6 position of guanine (29) . Although both the N7-methylguanine and O3-methyladenine adducts probably contribute to the antitumor activity of temozolomide in some if not all sensitive cells, their role is controversial (30, 31, 32) . The O6-MG adduct (which accounts for 5% of the total adducts formed by temozolomide; Ref. 29 ) probably plays a critical role in the antitumor activity of the agent. This is supported by the correlation between the sensitivity of tumor cell lines to temozolomide and the activity of the DNA repair protein O6-alkylguanine alkyltransferase, which specifically removes alkyl groups at the O6 position of guanine. Cell lines that have low levels of AGT are sensitive to the cytotoxicity of temozolomide, whereas cell lines that have high levels of this repair protein are much more resistant to it (33, 34, 35) . This correlation has also been observed in human glioblastoma xenograft models (4 , 5 , 8) . The preferential alkylation of guanine and adenine and the correlation of sensitivity to the drug with the ability to repair the O6-alkylguanine lesion also have been seen with triazine, DTIC, and the nitrosourea alkylating agents BCNU and CCNU (35, 36, 37) .
The cytotoxic mechanism of temozolomide appears to be related to the failure of the DNA MMR system to find a complementary base for methylated guanine. This system involves the formation of a complex of proteins that recognize, bind to, and remove methylated guanine (38, 39, 40) . The proposed hypothesis is that when this repair process is targeted to the DNA strand opposite the O6-MG, it cannot find a correct partner, thus resulting in long-lived nicks in the DNA (41) . These nicks accumulate and persist into the subsequent cell cycle, where they ultimately inhibit initiation of replication in the daughter cells, blocking the cell cycle at the G2-M boundary (41, 42, 43, 44) . In both murine (42) and human (45) leukemia cells, sensitivity to temozolomide correlates with increased fragmentation of DNA and apoptotic cell death. In addition to causing cell death, there is evidence from preclinical studies that DNA adducts formed by temozolomide and the subsequent alteration of specific genes and their cognate protein products may reduce the metastatic potential of tumor cells by altering the immunogenicity of the tumor cells (46, 47, 48) . It has also been postulated that temozolomide-induced DNA damage and subsequent cell-cycle arrest may reduce the metastatic properties of some tumor cells (49, 50, 51) .
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Mechanisms of Resistance |
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TopABSTRACTIntroductionBackgroundMechanism of ActionMechanisms of ResistanceReducing Resistance to...Clinical Experience with...Phase 2 and 3...Overcoming ResistanceSummary and ConclusionsREFERENCES |
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MMR Pathway.
Although AGT is clearly important in the resistance of cells to
temozolomide, some cell lines that express low levels of AGT are
nevertheless resistant, which indicates that other mechanisms for
resistance may be involved (60
, 61)
. A deficiency in the
MMR pathway resulting from mutations in any one or more of the five or
six protein complexes that recognize and repair DNA can render cells
tolerant to methylation and to the cytotoxic effects of temozolomide.
This deficiency in the MMR pathway results in a failure to recognize
and repair the O6-MG adducts produced by
temozolomide and other methylating agents (33
, 62
, 63)
.
DNA replication continues past the O6-MG adducts
without cell cycle arrest or apoptosis. Resistance in tumor cells that
are deficient in MMR is unrelated to the level of AGT and is,
therefore, unaffected by AGT inhibitors.
PARP.
Another possible mechanism of resistance for temozolomide is the base
excision repair pathway. Studies have shown that treatment of human
tumor cells with temozolomide induced an increase in the activity of
PARP, which is believed to be involved in nucleotide excision repair
(64
, 65)
, and the inhibition of PARP has been reported to
enhance the cytotoxicity of methylating agents (66, 67, 68)
.
Several studies with inhibitors of PARP and with cell lines deficient
in either MMR or excision repair have indicated a role of the repair of
N7-methylguanine and
O3-methyladenine adducts in the
resistance to the antitumor activity of temozolomide and other
alkylating agents (30
, 33
, 66
, 67)
. However, the
importance of these adducts in the antitumor activity of the drug may
be secondary to that of the O6-MG adduct, except
in those tumors that are deficient in base excision repair (31
, 32
, 69)
.
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Reducing Resistance to Temozolomide |
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TopABSTRACTIntroductionBackgroundMechanism of ActionMechanisms of ResistanceReducing Resistance to...Clinical Experience with...Phase 2 and 3...Overcoming ResistanceSummary and ConclusionsREFERENCES |
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O6-BG.
O6-BG is a low-molecular-weight substrate for AGT
and a potent inhibitor of AGT-mediated resistance to DNA damage by
chloroethylnitrosoureas and methylating agents (36
, 70
, 71)
. Evidence from preclinical studies suggests a role for
O6-BG in increasing the therapeutic index of
temozolomide. Pretreatment with O6-BG enhances
the activity of temozolomide in vitro and in vivo
in tumor cells that have high levels of AGT but has little effect on
tumor cells that have low or undetectable levels of AGT (8
, 33
, 34 , 56
, 72)
. However, in vivo enhancement of
temozolomide activity by O6-BG has been observed
in a human glioma xenograft derived from a low-AGT-producing cell line
that is refractory to O6-BG enhancement of
temozolomide activity in vitro (73)
, which
suggests that some in vivo metabolic interaction with
O6-BG enhanced the activity of temozolomide. In
these studies, extended treatments with O6-BG are
more effective than single treatments (56
, 73)
. In a human
melanoma xenograft model, a combination of O6-BG
and temozolomide, given on a 5-day schedule, resulted in a greater
antitumor effect than did an equitoxic dose of temozolomide
(8)
. The combination of temozolomide and
O6-BG also resulted in a delay of tumor growth
equivalent to that produced by a 3-fold greater dose of temozolomide on
the same 5-day schedule.
Other studies have shown that bone marrow cells are low in AGT activity, and AGT depletion with O6-BG substantially increased the sensitivity of these cells to O6-alkylating agents including BCNU and temozolomide (74, 75, 76) . It is, thus, possible that hematological toxicity may limit the doses of O6-BG and other inhibitors of DNA repair used in clinical practice. A study of the effect of O6-BG pretreatment on the toxic and clastogenic effects of temozolomide on murine hematopoietic cells in vivo has confirmed potentiation of bone marrow cell sensitivity (75) . An increase in the frequency of formation of micronuclei in the bone marrow of mice pretreated with O6-BG observed in this study also suggests the possibility of an increased incidence of secondary leukemias.
Attempts to reduce the toxicity produced by this combination have focused on protection of normal hemopoietic tissue by transducing hematopoietic progenitor cells with O6-BG-resistant methyltransferase genes (77 , 78 , 79) . Expression of a double-mutant form of AGT in murine bone marrow cells significantly reduced the toxicity produced by temozolomide given in combination with O6-BG and led to a reduction in the frequency of combined O6-BG/temozolomide-induced micronuclei in the bone marrow (78) . Although transducing hematopoietic progenitor cells with O6-BG-resistant methyltransferase genes protects committed murine hemopoietic progenitors against the toxicity of O6-alkylating agents, a similar effect is not observed with primitive, multipotent spleen colony-forming cells (76) . In a recent study, Chinnasamy et al. (76) showed that transduction of primitive, multipotent spleen colony-forming cells with a double mutant of AGT did not result in a significant protection against the toxicity produced by combination of BCNU and O6-BG. These results indicate that the protective effect afforded by transducing hematopoietic progenitor cells with O6-BG-resistant methyltransferase genes may be highly specific to the cytotoxic agent and the cell type involved (76) . Thus, further investigation is needed to define the potential clinical benefit of this type of protective genetic therapy.
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Clinical Experience with Temozolomide in Malignant Gliomas |
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TopABSTRACTIntroductionBackgroundMechanism of ActionMechanisms of ResistanceReducing Resistance to...Clinical Experience with...Phase 2 and 3...Overcoming ResistanceSummary and ConclusionsREFERENCES |
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On the basis of the schedule-dependent antitumor activity observed with temozolomide in preclinical studies (3) , an additional 42 patients were given a single p.o. dose of temozolomide started at 150 mg/m2 and escalated to 240 mg/m2 for 5 days in a 4-week cycle if no major myelosuppression was detected. In this population, the DLT of temozolomide was mild-to-moderate myelosuppression (neutropenia and thrombocytopenia), which was both predictable and easily controlled. The MTD was 200 mg/m2 per day (10) . As a result, the recommended dosage for Phase 2 studies was 150 mg/m2 for the first course and, in the absence of any major myelosuppression, escalation to 200 mg/m2 for subsequent courses. Nonhematological toxicity, mainly nausea and vomiting, was mild and controlled with standard antiemetic agents. No drug-related adverse CNS effects or alopecia occurred with temozolomide (10) .
Subsequent Phase 1 studies have been conducted to evaluate the safety of a machine-filled capsule preparation of temozolomide, which differed from the hand-filled preparation used in the initial CRC Phase 1 study (80 , 81, 82, 83, 84) .
These studies have confirmed the safety, tolerability, and PK of temozolomide reported by Newlands et al. (10) .
Safety.
Consistent with the results of a Phase 1 study, hematological toxicity,
specifically thrombocytopenia and neutropenia, was dose limiting.
Neutropenia or thrombocytopenia typically appeared 21–28 days after
the first dose of each cycle and recovered to grade 1 myelosuppression
within 7–14 days. Grade 4 toxicity occurred at cumulative p.o. dosages
of more than 1000 mg/m2 over 5 days, but little
other significant toxicity was seen. Grades 3 or 4 myelosuppression
generally occurred in fewer than 10% of patients studied.
Prior treatment with chemotherapy, radiation, or both has a significant effect on the MTD of temozolomide (83) . Hammond et al. (80) evaluated the effect of prior myelosuppressive therapy on toxicity and PK profile of temozolomide in 24 advanced cancer patients who were stratified according to prior exposure to chemotherapy and radiation. Patients in either category received a dosage of 100 mg/m2/day temozolomide for 5 days, which was escalated to 150 and 200 mg/m2/day in the absence of myelosuppression (80) . The MTD for temozolomide was established as 150 mg/m2/day. Another similar Phase 1 study, reported by the National Cancer Institute, evaluated the safety of temozolomide in patients who were stratified on the basis of prior exposure to nitrosourea (83) . The MTD for patients with prior exposure to nitrosourea was 150 mg/m2/day, and the MTD for patients without such prior exposure was 250 mg/m2/day. An evaluation of the PK of temozolomide showed that clearance from the plasma was significantly less in patients with prior exposure to nitrosourea than it was in patients without such prior exposure (83) . This may have contributed to the lower dosage of temozolomide that was tolerated by these patients and had a notable effect on the dosing recommendation for these patients.
The results of these studies indicate that a dosage of 200
mg/m2 of temozolomide given on a 5-day schedule
repeated every 28 days is appropriate for patients who are not
pretreated with radiation, chemotherapy, or both. Patients who are
pretreated with chemotherapy receive a lower starting dosage of
temozolomide (i.e., 150 mg/m2), which
can be escalated to 200 mg/m2 in subsequent
courses in the absence of grade 3 or 4 myelosuppression
(80)
. A summary of the administration schedule for
temozolomide and the MTD that was observed in several completed Phase 1
trials is presented in Table 1
.
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Pediatric Patients.
Phase 1 studies of temozolomide were expanded to include pediatric
cancer patients (16)
. In a Phase 1 study conducted to
define the multiple-dose PK of temozolomide, 20 patients between 3 and
17 years old were given temozolomide over a dosage range of 100–240
mg/m2/day (15)
. Patients were
stratified according to prior craniospinal irradiation or nitrosourea
therapy. The MTD was 200 mg/m2 for patients who
had not received prior craniospinal irradiation or nitrosourea therapy
but was not defined for children with prior craniospinal irradiation
because of the small number of patients. Temozolomide was absorbed
rapidly, had an AUC that increased in a dosage-related manner, and
showed no evidence of accumulation. The plasma half-life, whole-body
clearance, and volume of distribution were independent of dosage (Table 3)
. Compared with adult patients treated
with 200 mg/m2/day, children seemed to have a
higher AUC (48.7 versus 34.5 µg·h/ml), most likely
because children have a larger ratio of body surface area to volume
(15)
. Despite higher concentrations at dosages equivalent
to those used in adult patients, the bone marrow function in pediatric
patients appears to allow greater exposure to the drug before bone
marrow DLT develops.
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Phase 2 and 3 Clinical Experience |
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TopABSTRACTIntroductionBackgroundMechanism of ActionMechanisms of ResistanceReducing Resistance to...Clinical Experience with...Phase 2 and 3...Overcoming ResistanceSummary and ConclusionsREFERENCES |
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Similar results were reported in a multicenter Phase 2 study conducted by the CRC that evaluated temozolomide in patients diagnosed with anaplastic astrocytoma, glioblastoma multiforme (grade 4), and unclassified high-grade astrocytoma (grades 3–4; 13 ). In this study, objective responses, measured by improvement in neurological status, were seen in 11 (11%) of 103 patients who received temozolomide; 5 of these patients had improvement on CT or magnetic resonance imaging scans (13) . An additional 47% of the patients in the study had stable disease. The median survival of all patients with measurable response was 5.8 months, and 22% of the patients had no neurological or radiological evidence of progressive disease at 6 months. The results of this study further confirmed the activity of temozolomide in patients with recurrent and progressive high-grade glioma.
Recently, three open-label, multi-institutional studies have evaluated
the use of temozolomide in 525 patients with malignant glioma. These
studies represent the largest evaluation of a single agent in patients
with recurrent malignant gliomas that were rigorously controlled with
strict prospectively defined criteria for assessment of tumor response,
central review of histology, and validated instruments to assess
health-related QOL. The first two trials evaluated the safety,
efficacy, and health-related QOL effects of temozolomide in patients
with glioblastoma multiforme at first relapse and were as follows:
(a) a pivotal multicenter Phase 2 study that compared the
PFS at 6 months and the safety in patients treated with temozolomide
with those in patients treated with procarbazine (91)
; and
(b) a second supportive trial in patients with glioblastoma multiforme
to further examine the efficacy and health-related QOL aspects of
temozolomide. In the pivotal Phase 2 study, 225 patients were
randomized to receive either temozolomide (n = 112) or
procarbazine (n = 113; Ref. 91
). The
treatment arms were similar with respect to baseline disease
characteristics and prior therapies. Objective responses (PR or stable
disease) were seen in 46% of patients treated with temozolomide and in
33% of patients treated with procarbazine, with PRs occurring in 5%
of patients in both groups (91)
. Patients treated with
temozolomide had significantly better 6-month PFS and overall survival
than those treated with procarbazine (21% in the temozolomide group
versus 9% in the procarbazine group; P =
0.008). Median PFS was also better for temozolomide compared with
procarbazine (2.89 months for temozolomide versus 1.97
months for procarbazine; hazard ratio of 1.47; P =
0.0063; Ref. 91
. A difference in PFS in favor of
temozolomide was observed as early as 1 month after randomization, and
the difference was maintained for several months (Fig. 2)
. Similar findings were observed in the
confirmatory single-arm study that evaluated temozolomide in 138
glioblastoma multiforme patients. In this study, treatment with
temozolomide resulted in a PFS of 19% (95% CI, 12–26%; Table 5
). These studies formed the basis for
the approval of temozolomide in the European Union for the treatment of
patients with glioblastoma multiforme showing progression or recurrence
after standard therapy.
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. The median overall survival was 13.6
months, and the 6- and 12-month survival rates based on Kaplan-Meier
estimates were 75% (95% CI, 69–83%) and 56% (95% CI, 50–66%),
respectively (92)
. Central review of gadolinium-enhanced
magnetic resonance imaging scans revealed a 35% objective response
rate for the intent-to-treat population. When the stable disease
population was included, the overall tumor response was 61%
(92)
. In this study, maintenance of PFS and objective
response were associated with health-related QOL benefits independent
of steroid use. This study documents the efficacy, safety, and QOL
benefits of temozolomide in patients with recurrent anaplastic
astrocytoma. On the basis of these results, temozolomide received
accelerated approval from the FDA for treatment of adult patients with
anaplastic astrocytoma who have relapsed after treatment that included
a nitrosurea drug (BCNU or CCNU) and procarbazine.
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Malignant Metastatic Melanoma.
The efficacy of temozolomide was evaluated in a study of patients with
advanced metastatic melanoma, including patients with brain metastases
(11)
. Fifty-six patients were given p.o. temozolomide 150
mg/m2 once daily for 5 days. If grade 2 or
greater myelosuppression did not occur by day 22, subsequent 5-day
courses (200 mg/m2/day) were administered at
28-day intervals. Among the 56 patients (49 with evaluable lesions),
CRs occurred in 3, all with lung metastases only, and PRs occurred in
9, which yielded a response rate of 21%. Stable disease was observed
in an additional eight patients. The mean duration of response was 6
months (range, 2.5–18 months), and the median survival times were 14.5
months in responding patients and 4.5 months in nonresponders.
Leukopenia was the major toxicity; five cases of grade 4 leukopenia,
two cases of grade 4 thrombocytopenia, and no other grade 4 toxic
effects occurred in the 55 evaluable patients over 217 courses of
treatment. These results confirmed the safety and efficacy of
temozolomide in malignant metastatic melanoma that were observed in the
Phase 1 study (11)
.
A second Phase 2 trial in advanced malignant melanoma evaluated the relationship between pretreatment AGT levels in biopsies of cutaneous tumors and involved lymph nodes and clinical response to treatment with temozolomide (94) . Among the 50 evaluable patients, there were 3 CRs and 4 PRs for an overall response rate of 14%. Stable disease was observed in an additional six patients. Lymphocytopenia was the major toxicity, however, with only eight and nine cases of grade 3 or higher neutropenia and thrombocytopenia, respectively. Analysis of the pretreatment AGT levels and clinical response to temozolomide in 33 patients revealed that pretreatment levels of AGT are not predictive of response to temozolomide in melanoma (94) .
Recently, a Phase 3 trial compared the overall survival, PFS, objective response, and safety of temozolomide and DTIC in 305 patients with advanced metastatic melanoma (95) . This study also assessed the health-related QOL and PK of both drugs and their metabolite, MTIC. In this study, patients were randomized to receive either p.o. temozolomide at a starting dose of 200 mg/m2/day for 5 days every 28 days or i.v. DTIC at a starting dose of 250 mg/m2/day for 5 days every 21 days. Median survival in the intent-to-treat population was similar for patients treated with temozolomide or DTIC (7.7 and 6.4 months for temozolomide and DTIC, respectively; a hazard ratio of 1.18), Median PFS was significantly longer for temozolomide (1.9 months) versus DTIC (1.5 months; P = 0.012; hazard ratio = 1.37; CI, 1.07–1.75; Ref. 95 ). Temozolomide was associated with health-related QOL benefit, with more temozolomide-related patients demonstrating an improvement or maintenance in physical functioning at week 12 compared with those treated with DTIC. PK analysis revealed that systemic exposure (AUC) to the parent drug and the active metabolite MTIC was higher after p.o. temozolomide compared with i.v. DTIC. These results indicate that temozolomide demonstrates efficacy equal to that of DTIC against advanced metastatic melanoma.
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Overcoming Resistance |
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TopABSTRACTIntroductionBackgroundMechanism of ActionMechanisms of ResistanceReducing Resistance to...Clinical Experience with...Phase 2 and 3...Overcoming ResistanceSummary and ConclusionsREFERENCES |
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Combination with Cisplatin.
Preclinical evidence indicates that cisplatin enhances the antitumor
activity of temozolomide (96)
. On the basis of these data
and complementary toxicity profiles, a Phase 1 trial of the combination
was conducted in 15 patients with advanced cancer (97)
. In
this study, cohorts of three patients received temozolomide daily for 5
days together with cisplatin on day 1 for 4 weeks at the following
temozolomide (mg/m2/day) and cisplatin
(mg/m2) dose levels: 100/75; 120/75; 200/75; and
200/100. The DLT observed at the highest temozolomide/cisplatin dose
level was myelosuppression (neutropenia and thrombocytopenia) and
vomiting. The MTDs established in this trial were 200
mg/m2/day for temozolomide and 75
mg/m2 for cisplatin. This combination did not
alter the PK or the MTD of temozolomide. The principal nonhematological
toxicities consisted of nausea, vomiting, and hearing loss. PR was
achieved in 2 of the 14 evaluable patients, one with untreated
non-small cell lung cancer and the other with squamous cell carcinoma.
Combination with BCNU.
In a Phase 1 study evaluating the combination of BCNU (75
mg/m2) given before or after a 5-day course of
temozolomide, no differences between the regimens were seen in the PK
of temozolomide or the toxicity of the drugs at the doses used
(98)
. One patient with glioblastoma had a PR that has been
maintained for 1 year, and two other patients (one with osteosarcoma
and one with uterine carcinosarcoma) have had minor responses. This
study is continuing so that the MTD for this combination can be
established (98)
.
Combination with IFN-
-2b.
Both temozolomide and IFN--2b have demonstrated antitumor activity
against melanoma. IFN--2b is approved in the United States for
postsurgical adjuvant treatment of melanoma with high-risk metastases.
It is approved in some European countries for use as monotherapy for
the palliative treatment of melanoma. In a Phase 1 study to determine
the MTD and DLT, patients with histologically confirmed, surgically
incurable metastatic melanoma were treated with 5-day courses of p.o.
temozolomide in dosages of 100 or 200 mg/m2/day
with continuous s.c. injections of IFN--2b three times a week at
escalating doses starting at 5 mU/m2
(99)
. In the cohort treated with 1000
mg/m2 of temozolomide and 5
mU/m2 of IFN--2b, two patients developed
dose-limiting thrombocytopenia, and one patient developed grade 4
neutropenia. When higher doses of IFN--2b (7.5 and 10.0
mU/m2) were combined with 150
mg/m2 of temozolomide, grade 4 hematological
toxicity was observed in one of six and one of three patients,
respectively. No DLT occurred in patients treated with 750
mg/m2 of temozolomide plus 5
mU/m2 of IFN--2b. The MTD was determined as
temozolomide 150 mg/m2 and IFN--2b 7.5
mU/m2 (99)
. Antitumor responses were
seen in 3 of 12 patients, and stable disease in 4 of 12 patients. These
results indicate that this combination when administered at the MTD is
well tolerated, and the antitumor activity observed provides the basis
for additional studies.
Continuous Dosing Schedule.
Because AGT levels may recover within the 24-h interval between
individual temozolomide doses in each 5-day cycle, dosing more
frequently than once a day for 5 days may improve the response to
treatment. A Phase 1 study of 24 patients with recurrent tumors, 17 of
which were malignant gliomas (81)
, examined continuous
dosing of temozolomide over a 6- to 7-week period with dosages ranging
from 50 to 100 mg/m2/day. This schedule produced
a higher cumulative dose of drug than the indicated 5-day schedule and
increased the AUC by a factor of 2.1 without producing any
hematological DLT. No major toxicity was observed at the dosage level
of 75 mg/m2/day (81)
. Objective
responses were reported in patients with high-grade glioma and
melanoma, and the overall response rate for the prolonged schedule was
33%. Seven (41%) of 17 glioma patients demonstrated tumor responses.
Six of the 17 glioma patients maintained stable disease
(81)
.
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Summary and Conclusions |
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TopABSTRACTIntroductionBackgroundMechanism of ActionMechanisms of ResistanceReducing Resistance to...Clinical Experience with...Phase 2 and 3...Overcoming ResistanceSummary and ConclusionsREFERENCES |
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Unique characteristics of stability and solubility allow temozolomide to be absorbed readily and distributed to all tissues with approximately 100% bioavailability after p.o. administration. Thus, temozolomide does not require hepatic metabolism for activation and is capable of penetrating the blood-brain barrier. Temozolomide demonstrates dose-linear PK, is cleared rapidly, and does not accumulate with repeat dosing. Its PK yields little intrasubject or intersubject variability, which is manifested by its predictable clinical tolerance and mild side-effect profile.
Little success has been seen with BCNU, CCNU, or procarbazine used as single-agents or in combination chemotherapy for the treatment of high-grade gliomas; surgery and radiation therapy remain the first-line treatments (87 , 100) . These agents are severely cytotoxic or poorly tolerated, and resistance develops rapidly, which limits the minimal benefits offered by treatment with these drugs (87) . Preliminary clinical studies conducted by the CRC demonstrated that temozolomide has meaningful efficacy and an acceptable safety profile in the treatment of patients with malignant glioma. The results have been confirmed in three open-label multi-institutional studies that represent the largest evaluation of a single agent in patients with recurrent malignant gliomas, using strict prospectively defined criteria for the assessment of tumor response, central review of histology, and validated instruments to assess health-related QOL. Temozolomide has also demonstrated activity in patients with newly diagnosed glioma. The tolerability and ease of administration of temozolomide have particular clinical value for the treatment of pediatric glioma, for which chemotherapy is often the primary modality (87) .
Although advanced melanoma is relatively resistant to therapy, several
biological response modifiers and cytotoxic agents have been reported
to produce objective responses including DTIC, IFN--2b, and
interleukin 2 (101)
. The objective response rate for DTIC
is 15–20%, and it produces a limited number of durable responses.
Although various combination regimens of chemotherapy (e.g.,
DTIC, tamoxifen) and cytokines (e.g., interleukin 2,
IFN--2b) have increased the rates of remission and improved response
rates as much as 50%, no single agent has improved survival rates
compared with those obtained with DTIC alone in patients with
metastatic malignant disease (101)
. Additionally, the
chemotherapeutic regimens used to treat metastatic malignant disease
are ineffective in brain metastases. Thus, for long-term control of
metastatic melanoma to be achieved, agents that are effective against
CNS metastases must be used. Temozolomide demonstrates comparable
activity to that of DTIC against advanced malignant melanoma and may
offer an alternative choice to DTIC because of its ability to penetrate
the blood-brain barrier.
In summary, the unique pharmacological profile of temozolomide, its
availability as an oral agent, and its documented safety and efficacy
supports its potential in the treatment of malignant glioma and
malignant melanoma. Future studies will focus on various types of
combination therapy, dose intensification, and dose-finding trials with
new dosing schedules. Many tumors including sarcoma, colon, lung, and
prostate are resistant to standard chemotherapy, and synergistic or
additive activity exhibited by temozolomide in combination with other
chemotherapeutic agents (e.g., BCNU, cisplatin) or
biologicalresponse modifiers (e.g., IFN--2b) has
been documented in many of these chemoresistant tumor types.
Furthermore, the potential for more predictable toxicity, increased
antitumor activity, and activity in CNS metastasis may lead to improved
therapeutic index and health-related QOL.
Studies are ongoing in recurrent glioma to explore the standard 5-day temozolomide schedule with other cytotoxic agents including 6-thioguanine (Gliadel; BCNU) wafer as well as cis-retinoic acid. Studies in malignant metastatic melanoma are currently exploring the use of the standard 5-day temozolomide schedule in combination with biochemotherapy regimens. Finally, additional Phase 2 studies are planned to explore the antitumor activity of the standard 5-day temozolomide schedule in combination with antimicrotubule agent taxanes (e.g., paclitaxel, docetaxel); topoisomerase I and II inhibitors (e.g., antitumor antibiotics, camptothecin, topotecan); and the angiogenesis inhibitor, thalidomide.
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FOOTNOTES |
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1 Supported by a grant from Schering-Plow Research
Institute, Kenilworth, New Jersey. 
2 To whom requests for reprints should be
addressed, at Duke Medical Center, Box 3624, Durham, NC 27710. Phone:
(919) 684-5301; Fax: (919) 681-1697.
3 Abbreviations used: MTIC,
5-(3-methyltriazen-1-yl)imidazole-4-carboximide; DTIC,
5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide, or dacarbazine;
CNS, central nervous system; CRC, Cancer Research Campaign; BCNU,
carmustine; AIC, 5-aminoimidazole-4-carboxamide; O6-MG,
O6-methylguanine; AGT, alkylguanine
alkyltransferase; CCNU, lomustine; PARP, poly(ADP)-ribose polymerase;
O6-BG, O6-benzylguanine; AUC,
area under the concentration-time curve; MTD, maximum tolerated
dose/dosage; CT, computerized tomography; PK, pharmacokinetic(s); CR,
complete response; PR, partial response; QOL, quality of life. FDA,
United States Food and Drug Administration; MMR, mismatch repair; DLT,
dose-limiting toxicity; PFS, progression-free survival; CI, confidence
interval.
Received 4/15/99; revised 3/29/00; accepted 3/30/00.
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REFERENCES |
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TopABSTRACTIntroductionBackgroundMechanism of ActionMechanisms of ResistanceReducing Resistance to...Clinical Experience with...Phase 2 and 3...Overcoming ResistanceSummary and ConclusionsREFERENCES |
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-6 integrin phosphorylation. Eur. J. Cancer, 31A: 746-754, 1995.[CrossRef]
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