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Special Focus: Pediatric Neuro-Oncology |
The Preston Robert Tisch Brain Tumor Center (S.G., J.A.Q., D.A.R., J.J.V., A.D., M.A.W., J.M.K., A.H.F., H.S.F.) and the Departments of Pediatrics (S.G., D.A.R., H.S.F.), Biostatistics and Bioinformatics (J.E.H.), Medicine (J.A.Q., J.J.V.), and Surgery (S.G., J.A.Q., D.A.R., J.J.V., A.H.F., H.S.F.), Duke University Medical Center, Durham, NC 27710; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104 (M.J.F., P.C.P.); and the Departments of Pediatrics and Neurology, New York University Medical Center, New York, NY 10016 (J.C.A.); USA
2 Please address correspondence to Sridharan Gururangan, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Box 3624, Durham, NC 27710, USA (gurur002{at}mc.duke.edu).
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Key Words: low-grade glioma • phase II trial • responses • temozolomide
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Introduction |
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Temozolomide (TMZ) (Temodar; Schering-Plough Corporation, Kenilworth, N.J.) is an imidazole tetrazinone and an orally active alkylating agent that has been shown to be efficacious in preclinical models of various CNS tumor xenografts, including malignant glioma (Friedman et al., 2000). The drug is particularly useful in patients with brain tumors due to its excellent penetration into the CNS and almost 100% bioavailability and linear pharmacokinetics after oral administration (Ostermann et al., 2004). Phase I studies in adults and children with recurrent brain tumors have shown that the drug has an excellent safety profile (Brada et al., 1999; Nicholson et al., 1998).
We therefore performed a phase II trial of TMZ in adults and children with recurrent LGG to assess the efficacy of the drug in these patients. The data regarding responses in adults with recurrent LGG have been reported previously and included five children who also are included in the present report (Quinn et al., 2003). We now describe the responses and disease stabilization rates and toxicities after treatment with oral TMZ in children with recurrent or progressive LGG treated on this study.
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Materials and Methods |
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Eligibility criteria for this study (Quinn et al., 2003) included histologically confirmed recurrent or progressive primary LGG (optic pathway glioma [OPG], pilocytic astrocytoma [PA], fibrillary astrocytoma [FA], oligodendroglioma [OG], or oligoastrocytoma [OA]). Patients with OPG did not require biopsy confirmation of disease. In these patients, additional eligibility criteria included progressive loss of vision as shown by ophthalmologic examination, increase in proptosis of 3 mm, and increase in diameter of the optic nerve of > 2 mm on neuroimaging or an increase in the distribution of tumor involving the optic tract or radiations using T1- or T2-weighted imaging on MRI of the brain. Subjects had to be between 4 and 18 years old, have a Lansky or Karnofsky status of 
70%, and have a life expectancy of more than 12 weeks. An interval of at least three weeks from prior surgical resection and six weeks from prior radiotherapy or chemotherapy was required unless there was unequivocal evidence of tumor progression after any of these treatments. Required evidence of adequate organ function included absolute neutrophil count (ANC) of 1,500/mm3, platelet count 100,000/mm3, hemoglobin 10 g/dl, blood urea nitrogen (BUN) and serum creatinine < 1.5x the upper limit of institutional normal (ULN), serum bilirubin < 1.5x ULN, and liver enzymes (alkaline phosphatase, serum glutamic oxalacetic transaminase/prothrombin time) < 2.5x ULN. Signed informed consent by a patient or parent/guardian as approved by the local institutional review board was required.
Exclusion criteria included active infection, prior malignancies, pregnancy, and lactation.
Treatment Plan and Modifications
TMZ was administered orally to patients in a fasting state, once a day for five consecutive days (days 1-5) at a starting dose of 200 mg/m2 per day. Treatment cycles were repeated every 28 days after the first daily dose of TMZ from the previous cycle. The next cycle of treatment was not given until the ANC was 1,500/mm3 and platelets were 100,000/mm3. As previously reported, dose modifications were made for grade 3-4 myelosuppression or nonhematologic toxicity (Quinn et al., 2003).
Required Observations Before, During, and After Protocol Therapy
Observations and laboratory tests obtained at baseline (within three days of starting treatment) included height, weight, body surface area, complete physical examination (including neuroophthalmologic examination in patients with OPGs), complete blood count with differential, electrolytes, BUN, liver function tests, MRI scan of brain with and without contrast, chest X-ray, and electrocardiogram. Subsequently, height, weight, physical examination, complete blood count with differential, electrolytes, BUN, creatinine, and liver function tests were obtained prior to each cycle, with MRI scan of the brain every eight weeks. In patients with optic pathway tumors and impaired vision, the frequency of ophthalmologic examinations was determined by the ophthalmologist but was usually every three to four months. Criteria for assessment of response are indicated in Table 1.
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Statistical Considerations
The statistical design for this study was previously reported from our center (Quinn et al., 2003). A two-stage design was used for this trial. We assessed the response rate to TMZ within each of the five histologic strata (PA, nonbiopsied OPG, FA, OG, or OA) after every two cycles of chemotherapy. If disease control (complete response [CR], partial response [PR], minimal response [MR], or stable disease [SD]) was not achieved in the first nine patients, we could infer with 95% confidence that the actual rate of response was less than 30% and the study would be closed to further accrual. Otherwise, a total of 25 evaluable patients would be enrolled in each stratum. With this number of patients, the disease control rate could be estimated with a standard error of 10% or less. Exact binomial CIs were computed for response rates. We expected to accrue six to eight patients per stratum per year, with the study completing in approximately three years. However, in contrast to the process with adult patients on this study (Quinn et al., 2003), accrual in children with recurrent LGG occurred mainly to the PA and OPG strata, as expected. Owing to slow accrual and opening of a competing national protocol for children with LGG using TMZ, it was decided to close the study after accrual of at least 25 patients with either OPG or PA.
Additional analysis was performed on collected data and included estimation of interval of disease control in patients with objective responses or SD (from date of enrollment in the study to date of disease progression or last follow-up), overall survival (OS), and progression-free survival (PFS). The latter two parameters were calculated by the Kaplan-Meier product-limit method using GraphPad Prism for Windows (version 4.00; GraphPad Software, San Diego, Calif.) for all patients and those with OPG/PA. PFS was determined from the date of study entry to date of disease progression, death from any cause, or last follow-up. OS was calculated from the time of study entry until death from any cause or last follow-up.
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Results |
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Responses to TMZ in Patients with OPG/PA
Details of prior therapy, toxicity, response, and final outcome for the 30 patients included in this study are given in Table 3. The 26 patients with OPG/PA received a median of nine cycles (range, 2-12 cycles) of TMZ. The best objective response observed after at least two cycles of treatment included PR in three patients (11%; 95% CI, 3%-30%; patients 5, 15, 17) and MR in one (4%; 95% CI, 0%-21%; patient 19). Stable disease (SD) was found in 11 patients (42%; 95% CI, 24%-63%), and progressive disease (PD) in 11 patients (42%; 95% CI, 24%-63%).
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Two patients with initial PR to TMZ (patients 5 and 15) had PD 13 and 8 months, respectively, after the initial response. Patient 5 (with neurofibromatosis type 1 [NF-1] and OPG) had a PR to TMZ after two cycles of treatment. However, eight months later, she developed significant decrease in visual acuity on a neuroophthalmologic examination even though MRI scan of her brain revealed SD. Patient 15 with a tectal plate PA had a PR to TMZ initially after eight months of treatment but was taken off therapy for noncompliance. Patients 2, 10, and 12, who completed therapy with SD, had PD 2, 24, and 29 months after coming off study.
The overall disease stabilization rate (PR + MR + SD) on study was 14 of 26 patients (54%; 95% CI, 34%-73%); disease control lasted a median of 34 months (range, 10-47 months) from beginning of treatment. Sixteen patients had PD either on or off treatment at a median of nine months (range, 2-29 months) after enrollment in the study. Patient 6, who had an initial diagnosis of PA by biopsy and who had PD on this study, was given focal radiotherapy as salvage therapy. A second biopsy on a subsequent recurrence revealed elements of atypical teratoid/rhabdoid tumor confirmed by immunohistochemical and genetic analysis (Allen et al., 2006). Patients 13, 14, and 15 were taken off study because of contracting Lyme disease, prolonged neutropenia, and poor compliance, respectively.
Responses in Patients with FA
The four patients with FA received a median of 12 cycles of TMZ (range, 2-12 cycles). Patient 29 had SD that lasted 29 months. The other three patients (patients 27, 28, and 30) had PD 12, 2, and 7 months, respectively, after enrollment in the study.
Disease Stabilization Based on Prior Therapy
Nineteen patients had received prior radiotherapy and/or chemotherapy (seven patients had received alkylator-based therapy), and 11 had either no prior therapy or surgery alone prior to enrollment in the study (Table 3). Twelve (52%) of 23 patients who had no prior therapy, only surgery, or only carboplatin-based regimens had disease stabilization (PR + SD + MR), compared with only two (28%) of seven patients who had received prior alkylator therapy (procarbazine regimen, or thioguanine, procarbazine, chloroethyl cyclohexylnitrosourea [lomustine], and vincristine [TPCV] regimen) as part of their chemotherapy (Table 3).
PFS and OS for All Patients
With a median follow-up of 38 months (range, 3-77 months), three patients have died of PD. The two-year PFS and OS were 51% (95% CI, 34%-69%) and 97% (95% CI, 90%-100%), respectively. The corresponding four-year PFS and OS were 17% (95% CI, 1%-33%) and 71% (95% CI, 43%-100%), respectively.
PFS and OS for Patients with OPG/PA
The two-year PFS and OS for the 26 patients with OPG and PA were 49% (95% CI, 30%-67%) and 96% (95% CI, 89%-100%), respectively (Fig. 1). The corresponding four-year PFS and OS were 31% (95% CI, 9%-51%) and 84% (95% CI, 69%-100%), respectively.
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The two-year PFS for the 14 patients with OPG/PA who had disease stabilization (PR, MR, or SD) after TMZ therapy was 73% (95% CI, 51%-96%). The corresponding four-year PFS was 61% (95% CI, 33%-89%).
Toxicity Related to TMZ Therapy
Toxic effects related to TMZ in this study were typically myelosuppression and fatigue (Table 3). Only patient 14 was taken off study due to prolonged neutropenia after therapy; the neutropenia ultimately resolved, and the patient was able to start on TPCV chemotherapy. Patient 15 had hemorrhage into the tumor that was associated with shrinkage of tumor but was not related to thrombocytopenia. Patient 13 was taken off study after nine cycles of treatment due to a diagnosis of Lyme disease. There were no toxicity-related deaths.
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Discussion |
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An objective response (PR + MR) of only 12% was observed in these children, in contrast to results for adults with progressive LGG treated on the same study (Table 4; Quinn et al., 2003). Adult patients with LGG (pre-dominantly FA, OG, or OA) have been reported to have higher rates of objective response (10%-60%), disease stabilization (>85%), seizure control, and quality of life (Brada et al., 2003; Hoang-Xuan et al., 2004; Pace et al., 2003; Quinn et al., 2003). In contrast to these reports, most patients (63%) in our study had disease progression on other chemotherapy regimens, including alkylators, prior to receiving TMZ, and this might explain the lower rates of observed objective responses. Only two of seven patients who had prior alkylator exposure experienced SD after TMZ treatment, compared with findings of PR or SD in 12 of 23 patients who had no prior therapy, surgery only, or a nonalkylator-based chemotherapy. Hence, it is likely that suboptimal responses in our study might be due to drug resistance caused by prior alkylator exposure, possibly related to overexpression of alkylguanine alkyl transferase (AGT).
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Bobola et al. (2005) observed elevated levels of AGT in LGG cell lines. The dose of TMZ that was lethal in 10% of these cell lines was about fourfold higher than the mean plasma concentration of TMZ that is clinically achievable (100 µmol/L). Prior exposure of these cell lines to O6-benzylguanine (O-6BG), an inhibitor of AGT, for 18-20 h restored sensitivity of these tumor cells to TMZ, suggesting that AGT overexpression was the predominant cause for initial TMZ resistance in these cell lines and possibly in the 46% of our patients who had PD during treatment. In contrast, Kuo et al. (2003), in a retrospective single-institution study, observed favorable responses in 13 children with progressive LGG treated with oral TMZ given either on a five-day schedule (150 mg/m2 per day, n = 4) or a prolonged 42-day schedule (75 mg/m2 per day, n = 9). PR was observed in four patients and SD in six patients. It should be noted, however, that nine patients in this study had no prior therapy except surgery or radiotherapy before treatment with TMZ. Also, it is likely that the prolonged schedule of TMZ might have had a better effect on tumor shrinkage due to increased AGT depletion in the tumor (Tolcher et al., 2003).
As expected, myelosuppression (mostly grade 2-4 thrombocytopenia) was the most common toxicity observed in our study, and the incidence was similar to what has been previously reported in the literature (Brada et al., 2003; Hoang-Xuan et al., 2004; Kuo et al., 2003; Pace et al., 2003; Quinn et al., 2003). Only one patient had prolonged neutropenia requiring discontinuation of TMZ. Myelosuppression from TMZ can be variable, and its severity depends on the level of AGT expression in the progenitor cells of the marrow, with low levels of AGT in CD34+ cells causing more severe myelosuppression, especially neutropenia and thrombocytopenia (Gerson, 2002). It has also been observed that low AGT expression in CD34+ cells in the marrow could predispose such patients treated with TMZ to a higher risk of developing secondary leukemia (Gerson, 2002).
Four (13.3%) of the 30 patients in our study had NF-1, and, as would be expected, all of them had OPG. NF-1 patients were enrolled on the study based on visual deterioration and/or change in the size of previously discovered optic pathway tumors. We did not exclude patients with NF-1 from this trial, although concerns have been raised regarding the long-term complications of using a DNA-methylating agent in such patients with an inherent genetic predisposition to tumors, especially leukemias. There have been recent reports of secondary acute leukemias after a short latency period following TMZ in adult patients who received TMZ concurrently with radiotherapy (De Vita et al., 2005). With follow-up periods of 24-48 months, none of our patients with NF-1 has had any undue ill effects from TMZ exposure.
Although disease stabilization after TMZ therapy in our patients with recurrent LGG lasted a median of 34 months, the PFS was only 17% at four years after enrollment for all patients and 31% for those with OPG/PA (see Fig. 1). Only nine patients (30%) have had SD and not required other modalities of treatment since completing TMZ therapy. Eighteen patients have undergone salvage chemotherapy, and nine of these patients have also required salvage radiotherapy after PD on or after TMZ treatment (Table 3). These results compare unfavorably with those obtained using carboplatin or TPCV-based regimens (Table 4; Gururangan et al., 2002; Packer et al., 1997; Prados et al., 1997). Therefore, further refinements are required in the chemotherapy of children with progressive LGG. On the basis of preclinical data confirming high AGT expression in LGG (especially PA) and the low rates of clinical objective responses, it might be prudent to consider alternative strategies of treatment that circumvent drug resistance.
O-6BG is a potent and irreversible inactivator of AGT in normal and tumor cells by serving as an alternative highly selective substrate for AGT (Friedman et al., 2002). A single intravenous dose of O-6BG (120 mg/m2) can deplete tumor cells of AGT for up to 24 h and can potentiate the cytotoxic effects of alkylating agents, including TMZ and nitrosoureas (Friedman et al., 2002; Warren et al., 2005). In a recently published phase I study of the use of oral TMZ plus O-6BG in children with recurrent brain tumors, complete response was seen in one patient with PA (after 12 cycles) and SD in two patients with OPG (Warren et al., 2005). Also, AGT depletion can be achieved by using a prolonged schedule of oral TMZ (Kuo et al., 2003; Tolcher et al., 2003). Future trials using TMZ in children with recurrent LGG should incorporate such novel strategies to improve disease control.
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Footnotes |
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3 Abbreviations used are as follows: AGT, alkylguanine alkyl transferase; ANC, absolute neutrophil count; BUN, blood urea nitrogen; FA, fibrillary astrocytoma; LGG, low-grade glioma; MR, minimal response; NF-1, neurofibromatosis type 1; OA, oligoastrocytoma; O-6BG, O6-benzylguanine; OG, oligodendroglioma; OPG, optic pathway glioma; OS, overall survival; PA, pilocytic astrocytoma; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TMZ, temozolomide; TPCV, thioguanine, procarbazine, chloroethyl cyclohexylnitrosourea (lomustine), and vincristine; ULN, upper limit of institutional normal.
Received for publication July 26, 2006. Accepted for publication October 12, 2006.
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