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Journal of Clinical Oncology, Vol 19, Issue 4 (February), 2001: 1111-1117
© 2001 American Society for Clinical Oncology

Phase I Study of Topotecan Plus Cranial Radiation for Glioblastoma Multiforme: Results of Radiation Therapy Oncology Group Trial 9507

By Barbara J. Fisher, C. Scott, D. R. Macdonald, C. Coughlin, W. J. Curran

From the Departments of Radiation Oncology and Medical Oncology, London Regional Cancer Center, and Departments of Oncology and Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada; Radiation Oncology Headquarters, Philadelphia, PA; Dartmouth-Hitchcock Medical Center, Department of Radiation Oncology, Lahey-Hitchcock Medical Center, Lebanon, NH; and Department of Radiation Oncology, TJ University Hospital Bodine Center for Cancer Treatment, Philadelphia, PA.

Address reprint requests to Barbara Fisher, MD, London Regional Cancer Center, 790 Commissioners Road East, London, Ontario, Canada N6A 4L6.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: A phase I trial was conducted by the Radiation Therapy Oncology Group (RTOG) to determine the maximum-tolerated dose of topotecan that could be safely combined with standard cranial radiation for glioblastoma multiforme. A secondary objective was to document the acute and late toxicities of this combination of chemotherapy and radiation.

PATIENTS AND METHODS: Forty-seven patients with histologically confirmed glioblastoma multiforme were entered onto this phase I trial. Three cycles of topotecan were administered at 21-day intervals commencing at day 1 of cranial radiotherapy (60 Gy/30 fractions). Each cycle consisted of daily 30-minute intravenous (IV) infusions for 5 days. The dose of topotecan was escalated in three-dose increments from 0.5 mg/m2/d to 1.0 mg/m2/d to 1.5 mg/m2/d in different patient groups.

RESULTS: The majority of patients were over age 50. Three dose levels of topotecan were tested. Fifteen patients accrued to level 1 (topotecan dose 0.5 mg/m2/d). No grade 4 toxicities were seen. Sixteen patients accrued to level 2 (topotecan dose 1.0 mg/m2/d), five of whom had brief episodes of grade 4 neutropenia. Seventeen patients accrued to level 3 (1.5 mg/m2/d). Six of these patients had brief episodes of grade 4 neutropenia and four developed grade 3 thrombocytopenia. No serious nonhematologic or late toxicities were seen. Median survival for all patients was 9.7 months. There was no apparent difference in survival by topotecan dose schedule.

CONCLUSION: Toxicity was acceptable at an IV topotecan dose of 1.5 mg/m2/d administered daily for 5 days every 21 days for three cycles. A phase II trial has been performed using this dose of topotecan.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
NITROSUREAS, THE main chemotherapeutic agents used in the treatment of malignant gliomas, have demonstrated only modest antitumor activity.1-3 These drugs are associated with delayed and cumulative myelosuppression and are therefore usually delivered at 6 to 8 weekly intervals. In theory, such long drug-free periods may limit the efficacy of nitrosureas. Agents, such as topotecan, that produce less myelosuppression and can be administered on a more frequent basis may help to alleviate this problem, thereby making effective combination chemotherapy of brain tumors a more realistic goal. Topotecan has been considered a promising chemotherapeutic agent for the treatment of brain tumors for a number of reasons: its novel mode of action, its antitumor activity against other solid tumors,4-9 and its ability to penetrate the blood-brain barrier.10 Topotecan has demonstrated preclinical and clinical activity against a wide range of tumor types8 in addition to a variety of pediatric and adult CNS tumors. Friedman et al11 reported significant tumor regression and growth delay against xenografts derived from ependymomas, pediatric and adult high-grade gliomas, and medulloblastomas.

Camptothecin analogs, such as topotecan and irinotecan, are believed to exert their cytotoxic and radiosensitizing effects through the inhibition of the nuclear enzyme, topoisomerase I.5,12 This enzyme functions to induce transient single-strand breaks in the DNA matrix so that the DNA strands rotate around each other ahead of the replication fork and reseal. The rejoining step of this breakage-reunion reaction leaves the enzyme covalently bound to DNA resulting in single-strand DNA breaks.6,7 Camptothecins inhibit topoisomerase I-induced DNA damage repair leading to the conversion of repairable nonlethal DNA lesions into irreparable, lethal ones. This radiosensitization seems to be schedule-dependent, S phase-specific, cell line-dependent, and not strictly related to drug cytotoxicity.13

A number of studies have demonstrated the radiosensitizing properties of topotecan in vitro14-16 and in vivo.16 Boothman et al reported that post-treatment exposure to camptothecins enhanced the lethal effects of radiation on radioresistant human malignant melanoma cells. Boscia et al studied topotecan-induced radiosensitization in cisplatin-resistant cell lines both in vitro and in vivo. Kim et al17 noted that the potentiation of radiation response by topotecan in murine fibrosarcoma (in isogenic BA:B/C mice) model was dependent on drug dose and time sequence of topotecan and radiation. This radiosensitizing effect was maximal when topotecan was administered 2 to 4 hours preradiation. Various reports have indicated a dose enhancement ratio of 2.0 or more. Lamond et al18 reported potentiation of radiation lethality by topotecan in a D54 human glioma cell line. The dose enhancement ratio was 3.2 at 10% survival.

The maximally tolerated dose (MTD) of topotecan administered as a single agent in studies of recurrent glioblastoma has been reported to be 1.5 mg/m2/d given as a 30-minute infusion daily for 5 days separated by 21-day intervals.9,19,20 In all three trials, myelosuppression, principally neutropenia, was the dose-limiting factor. Nadir neutrophil counts occurred on days 8 to 11 and were of brief duration. Other toxic effects seen during these trials included mild to moderate nausea/vomiting, occasional anorexia, hair loss, fatigue, occasional diarrhea, skin rash, fever, dysuria, and occasional elevations in bilirubin or transaminases. No serious nonhematologic toxicity was documented. Several patients in these phase I trials experienced objective tumor regressions.

The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) completed a phase II trial of topotecan in recurrent malignant glioma among adults21 using a dose of 1.5 mg/m2 intravenously daily for 3 days repeated every 3 weeks. There were two objective responses (one patient experienced a complete response that lasted 9 days until his death from neutropenic sepsis and one patient sustained a partial response that is ongoing at more than 24 months), 21 patients with stable disease, and eight with progressive disease. The median progression-free survival time was 3.3 months, and median overall survival was 6.6 months. The principal toxicity was myelosuppression, specifically neutropenia. The degree of hematologic toxicity may have been slightly greater in those who had received prior chemotherapy (mainly nitrosureas) than in chemotherapy-naive patients. Twenty-five of 31 patients experienced grade 3 or 4 neutropenia (< 1.0 x 109/L). The median granulocyte nadir was 0.3 x 109 /L. Only nine patients experienced grade 3 or 4 thrombocytopenia, and one patient developed grade 3 anemia. Despite this, infection was uncommon (four of 31 patients), and only 12 of 109 cycles administered were associated with dose reductions related to prior toxicity. Nonhematologic toxicity was uncommon. No excessive scalp reactions were noted, and no neurologic toxicity (such as leukoencephalopathy) occurred to suggest that topotecan chemotherapy increased the toxicity of prior radiation. Although the objective response rate (6.5%) was low, 68% had stable disease, suggesting perhaps that topotecan has some activity in malignant glioma. The Pediatric Oncology Group22 conducted a phase II study of topotecan administered by 72-hour infusion at three weekly intervals in children with progressive or recurrent CNS tumors. There were no complete or partial responses; however, 20 of the 88 subjects had stable disease, including five of 13 glioblastomas. This combination of stable disease and tolerable toxicity suggests that further investigation of this drug in combination with radiation therapy is warranted.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Objectives
The objective of this phase I study was to determine whether this MTD of topotecan could be combined with standard cranial radiation therapy for glioblastoma multiforme. A secondary objective was to document the acute and delayed treatment-related toxicities of this combination.

Patient Selection
Eligible patients were 18 years of age or older with histologically confirmed supratentorial glioblastoma multiforme or gliosarcoma and had not received prior radiotherapy to the head or neck, prior chemotherapy, or prior radiosensitizer therapy. Informed consent was required. Other eligibility criteria included the following: Karnofsky performance status (KPS) score >= 50, neurologic functional status of 0 to 2 (level of function falls within the range from "no neurologic symptoms, fully active at home/work with no assistance," to "moderate neurologic symptoms, fully active at home/work but requiring assistance"), adequate bone marrow reserve (hemoglobin >= 10 g/dL, absolute neutrophil count >= 1,500/mm3, platelet count >= 100,000/mm3), normal renal function (blood urea nitrogen [BUN] <= 25 mg/dL and serum creatinine <= 1.5 mg/dL), and normal hepatic function (bilirubin <= 1.5 mg/dL and ALT or AST <= two times the upper limit of normal for the institution). The dose of corticosteroid had to remain stable for at least 1 week before study entry. All patients underwent a complete history and physical examination, a preoperative and postoperative computed tomography (CT) or magnetic resonance imaging (MRI) scan, complete blood count with differential, serum biochemistry, minimental status examination, and chest radiograph before study entry.

Treatment
Topotecan was supplied by the National Cancer Institute, Bethesda, MD, in vials containing 5 mg of topotecan base, 20 mg of mannitol, and 25 mg of tartaric acid. The lyophilized powder was reconstituted with 2 mL of sterile water for injection before dilution with 0.9% sodium chloride or 5% dextrose, and pH was to be adjusted to 3.0. The drug was administered intravenously by 30-minute infusion 0 to 2 hours before radiotherapy on days 0 to 5, 22 to 26, and 43 to 47. The level 1 dose of topotecan was 0.5 mg/m2/d administered five times per week every 21 days for a total of three cycles. The dose of topotecan was escalated from 0.5 mg/m2/d (level 1) to 1.0 mg/m2/d (level 2) to 1.5 mg/m2/d (level 3).

Radiation treatment was delivered with megavoltage machines of photon energies >= 4 MEV. The patients were treated with a head-holding device that was transparent to x-rays to ensure adequate immobilization during therapy and also to ensure reproducibility. The treatment volume for both the initial volume and the boost volume were based on the preoperative CT/MRI scans. For the first 46 Gy/23 fractions, the initial treatment volume consisted of the contrast-enhancing lesion and surrounding edema demonstrated on the CT/MRI plus a 2.0-cm margin. If no surrounding edema was present, the initial treatment volume included the contrast-enhancing lesion plus a 2.5-cm margin. After 46 Gy, the treatment volume was reduced to include the contrast-enhancing lesion (without edema) on the preoperative CT/MRI scan plus a 2.5-cm margin. The radiation dose was 60 Gy/30 fractions/6 weeks prescribed at the isocenter. CT- or MRI-guided treatment planning and isodose distributions including a composite plan were required. The inhomogeneity across the target volume was to be kept within 10% of the dose at the center of the volume. Portal imaging films were taken weekly. Radiation was initiated between 30 minutes and 2 hours after topotecan infusion. Figure 1 illustrates the treatment schema for this patients in this study.



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  		Fig 1. Treatment schema for Radiation Therapy Oncology Group 9507. Level 1: topotecan 0.5 mg/m2/d x 5 days/cycle; level 2: topotecan 1.0 mg/m2/d x 5 days/cycle; level 3: topotecan 1.5 mg/m2/d x 5 days/cycle.

 
Assessments
Complete blood cell counts were performed weekly during treatment until 3 weeks after completion of the third cycle of topotecan. Neurologic examination, serum chemistry (SMA12), anticonvulsant levels, minimental status, and toxicity evaluations were performed at each topotecan cycle and at every follow-up appointment (every 3 months for 1 year, every 4 months for the second year, and then every 6 months for the next 3 years). CT or MRI scans with and without contrast were performed at 3 monthly intervals following radiation and repeated at the time of neurologic deterioration.

Dose-Limiting Toxicities and Dose Reductions
Dose-limiting toxicity (DLT) was defined as grade 3 to 5 nonhematologic toxicity not acutely controlled by palliative measures or any grade 4 to 5 hematologic toxicity lasting longer than 7 days. For such patients, topotecan was withheld until resolution of the toxicity. Topotecan administration could be reinstituted, if medically appropriate, at 75% of the previous dose. If topotecan was withheld a second time because of drug-related toxicity, drug administration was discontinued.

If on day 1 of any topotecan cycle the absolute granulocyte count was less than 1.5 x 109/L, or if platelet count was less than 100 x 109/L, then drug administration was delayed until recovery of the granulocyte count to a level >= 1.5 x 109/L and platelet count to a level >= 100 x 109/L.

Statistical Methods
To be assessable, a patient must have been analyzable for toxicity at week 21. Once treatment results became available at week 21 for 10 cases, these 10 cases were reviewed with respect to unacceptable toxicity. If there were no fatal toxicities and no patients with unacceptable toxicity, the dose of topotecan was escalated to the next level. If two of the first 10 patients had unacceptable toxicity, accrual was to continue until five additional cases were evaluated. If fewer than three of these patients had unacceptable toxicity, then the dose could be escalated. If there were three or more of the first 10 patients in a cohort or four or more of the 15 patients in a cohort with unacceptable toxicity, then the previous topotecan dose level would be accepted as the maximally tolerated dose.

The median survival of glioma patients is known to be strongly affected by pretreatment prognostic factors such as age, neurologic function, extent of surgical resection, and KPS. Survival was assessed using the recursive partitioning analysis (RPA) technique described by Curran et al.23 Recursive partitioning uses a nonparametric statistical technique to create a model which predicts the survival outcome of glioma patients by stratifying them into one of six prognostic classes. Study patients could then be "staged" according to this model and individual survival compared to a matched standard population as predicted by the model.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Demographics
Forty-seven patients were enrolled. Pretreatment characteristics for each of the topotecan dose levels are described in Table 3. The majority of patients were 50 years of age or older. Median KPS score was 70 to 80. Twenty-four percent had biopsies, 26% had gross total resections, and the remainder underwent subtotal resections. All forty-seven patients were assessable for acute toxicity. Thirty-six patients, 12 at each of the three topotecan dose levels, were assessable for late toxicity. Acute toxicities for each of the topotecan dose levels are detailed in Table 1 and late toxicities in Table 2. The maximum toxicity reported per patient at the bottom of these tables refers to the maximum number of toxic events of that grade that occurred at a given dose of topotecan in a single patient.


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  		Table 3. Pretreatment Characteristics
 

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  		Table 1. Acute Toxicities (within 90 days from start of RT)
 

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  		Table 2. Late Toxicities (after 90 days from start of RT)
 
Hematologic Toxicity
Complete blood counts were drawn weekly after cycle 1 of chemotherapy throughout radiotherapy until 3 weeks after the administration of cycle 3. Hematologic toxicity increased as the dose of topotecan increased. Level 1 (topotecan 0.5 mg/m2/d) accrued 15 patients and no grade 4 toxicities were seen. One grade 3 neutropenia occurred. Level 2 (1.0 mg/m2/d) accrued 17 patients, five of whom had brief grade 4 neutropenia and one of whom experienced grade 4 leukopenia lasting less than 7 days. There were nine grade 3 hematologic toxicities. Level 3 (1.5 mg/m2/d) accrued 17 patients, eight of whom had brief grade 4 neutropenia lasting less than 7 days and one of whom had grade 4 leukopenia. There were 14 grade 3 hematologic toxicities. None of the grade 3 or 4 neutropenias were associated with fever. Only one patient experienced a break in radiation treatment because of hematologic toxicity. This patient missed one treatment because of grade 4 neutropenia.

There were no late (after 90 days from start of radiation) grade 4 hematologic toxicities. At level 3 there was one grade 3 neutropenia and one grade 4 leukopenia.

Other Toxicities
No serious nonhematologic acute or late toxicities were seen. At dose level 3, there were the following grade 1 toxicities: five cases of nausea/vomiting, seven skin reactions, one pulmonary toxicity, six hepatic toxicities, one fever, three cases of diarrhea/or constipation, 13 neurologic sequelae (mild headache and lethargy), and nine other toxicities. Grade 2 toxicities were as follows: four cases of nausea/vomiting, one hearing loss, four skin reactions, one pulmonary toxicity, one hepatic toxicity, one fever, six neurologic sequelae (moderate headache and lethargy), one case of diarrhea, and seven other toxicities. Grade 3 toxicities, consisting of severe headaches, occurred in three patients, one at a topotecan dose level of 0.5 mg/m2/d and two at topotecan dose level of 1.5 mg/m2/d (Table 1). The acute neurologic toxicities seen in this study were similar to those seen in historical controls.

There were no late grade 3 or 4 nonhematologic toxicities for levels 1, 2, or 3. At level 3 there were six grade 1 toxicities (one nausea/vomiting, two skin toxicities, one diarrhea, and two other toxicities) and three grade 2 toxicities (two skin and one other). There were no late neurologic toxicities.

Survival
Thirty-seven percent of patients were alive after 1 year. Median survival time for all patients was 9.7 months. Median survivals were 10.2, 11.4, and 8.8 months for topotecan dose levels 1, 2, and 3, respectively, but this difference was not statistically significant (P = .22). Survival time, as determined by RPA, is detailed in Table 4. The expected median survival times for RPA classes III, IV, V, and VI were 17.9, 11.1, 8.9, and 4.6 months, respectively. The corresponding median survival times for RPA classes III to VI in RTOG 9507 were 12.8, 8.8, 7.1, and 1.0 months.


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  		Table 4. Survival Time as Determined by RPA Class
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Topotecan seems to be a promising agent with which to conduct clinical trials involving patients with CNS malignancies either as a single agent11 or in combination with radiation treatment.18 Friedman et al24 have reported the results of 63 patients with newly diagnosed or recurrent malignant glioma treated with topotecan. Partial responses were observed in two of the 14 assessable patients with newly diagnosed glioblastoma (GBM), none of the 28 recurrent GBMs, one of the eight newly diagnosed anaplastic astrocytomas (AA), and three of the 10 recurrent AA. Four patients with recurrent AA and seven patients with recurrent GBM demonstrated stable disease (range, 8 to 52 weeks; median, 21 weeks) indicating that the drug has modest activity alone. RTOG 9507 determined that administration of topotecan on a 3-weekly basis at a dose of 1.5 mg/m2/d during cranial radiotherapy was well tolerated. The principal toxicity of this regimen is myelosuppression.

Tumor response rates are often documented in phase I studies of chemotherapeutic drugs used as single agents. However, in phase I chemoradiation studies, response rates are difficult to analyze in a meaningful way because radiation itself can induce tumor responses of varying degrees. Without a comparison group treated with radiation alone, it would be impossible to determine whether the response rate documented in this study was higher than, lower than, or equivalent to that which would have been produced with radiation. Curran et al23 have attempted to circumvent this problem by developing the recursive partitioning analysis model as a method of providing a matched historical control group with which to compare treatment outcome. Using this model, study patients can be compared with a prognostically similar patient group treated with standard chemoradiation. Tumor response is indirectly assessed in terms of median survival rather than tumor shrinkage.

There are a number of reasons why the survival rate of the study population in RTOG 9507 may have been lower than the RPA model predicted for a matched population of historical control patients. First of all, the sample size in this phase I study was relatively small. Second, the majority of the patients in RTOG 9507 did not receive the MTD of topotecan. It is possible that administration of submaximal doses of topotecan might actually impede radiation response. Third, only 20% of the patients in RTOG 9507 were in the relatively prognostically favorable class III, in which survival benefit would be easier to determine.

In this study, topotecan was infused over 30 minutes, 1/2 hour to 2 hours before radiotherapy, weekly every 3 weeks. More frequent administration of this drug might be associated with higher response rates than cyclical bolus injection. The Children’s Cancer Group25,26 has attempted to maximize the number of intermittent injections of topotecan by infusing the drug over 30-minute intervals daily for 33 treatment days in their phase I studies with brainstem glioma patients. Although Danks et al27 reported that intermittent exposure to topotecan allowed for maximal cytotoxicity in comparison with continuous infusion, theoretically at least, there are a number of reasons why continuous infusion might prove to be superior to bolus injection as method of administration. Continuous infusion provides constant exposure to the drug, potentially maximizing cytotoxicity, radiosensitization, and CSF penetration. The cytotoxicity of camptothecins is dependent on the formation of topoisomerase I-DNA complexes during the S phase of the cell cycle. Continuous infusion also permits a greater number of tumor cells to enter S phase when the drug is present, thus increasing cell kill. Maximal radiosensitization by topoisomerase I inhibitors occurs during, or immediately following, radiation.14,15,18 Continuous infusion of topotecan assures that drug is always present at the time of radiotherapy. Peak CSF penetration is also a time-dependent phenomenon. Blaney et al10 examined the plasma and CSF pharmacokinetics of topotecan in nonhuman primates and found that peak CSF concentrations of topotecan occurred 30 minutes after injection. Administration of the drug more than 30 minutes before radiotherapy would allow for decay of these peak drug CSF levels.

It is possible that other camptothecin analogs may prove to be superior to topotecan as radiosensitizers. CPT-11 (irinotecan) is a topoisomerase I inhibitor that has demonstrated activity in malignant glioma.28 Coggins et al29 reported that CPT-11 enhanced the activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in human malignant glioma xenografts. Friedman et al30 conducted a phase I trial of CPT-11 and BCNU for patients with recurrent malignant glioma. One partial response was seen in the first six patients. Toxicity was mild. The study continues to accrue patients. Friedman et al28 also described the results of a study of 60 patients with progressive or recurrent malignant glioma treated with CPT-11. Nine patients (15%) had confirmed partial responses and 33 patients (55%) achieved stable disease lasting longer than two courses. Principal toxicities observed during the study consisted primarily of gastrointestinal upset and infrequent neutropenia. Hare et al31 tested over 40 drugs against pediatric and adult CNS tumor xenografts and determined that irinotecan was the most active agent tested. To date, no studies of irinotecan combined with radiation in the treatment of malignant glioma have been reported.

In conclusion, we have determined that topotecan administered at a dose of 1.5 mg/m2/d for 5 days every 3 weeks for three cycles is well tolerated in combination with standard cranial radiation for glioblastoma multiforme. It is associated with moderate myelosuppression but no serious nonhematologic toxicity. A phase II trial using this regimen has been completed.


   ACKNOWLEDGMENTS
 
Supported by National Cancer Institute–Radiation Therapy Oncology Group grant.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Walker MD, Green SB, Byar DP, et al: Randomized comparisons of radiotherapy and nitrosureas for the treatment of malignant glioma after surgery. N Engl J Med 303: 1323-1329, 1980[Abstract]

2. EORTC Brain Tumor Group: Effect of CCNU on survival rate of objective remission and duration of free interval in patients with malignant brain glioma-final evaluation. Eur J Cancer 14: 851-856, 1978

3. Kornblith PL, Walker M: Chemotherapy for malignant glioma. J Neurosurg 68:1-17, 1088

4. Hertzberg RP, Caraga MJ, Hecht SM: On the mechanism of topoisomerase I inhibition by Camptothecin: Evidence for binding to an enzyme-DNA complex. Biochemistry 28: 4629-4638, 1989[Medline]

5. SmithKline Beecham Pharmaceuticals Investigator Brochure: Topotecan SK&F 104864-A, 1994

6. Lock RB, Ross WE: DNA Topoisomerases in cancer therapy. Anticancer Drug Des 2: 151-164, 1987[Medline]

7. Eng WK, Faucetter L, Johnson RK, et al: Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol:34:755-760, 1988

8. Heron JF: Topotecan: An oncologist’s view. Oncologist 3: 390-402, 1998[Abstract/Free Full Text]

9. Verweij J, Lund B, Beynen J, et al: Clinical studies with topotecan: The EORTC experience. Proc 7th NCI-EORTC symposium on new drugs in cancer therapy. Ann Oncol 3:118, 1992 (suppl 1)

10. Blaney SM, Cole DE, Balis FM, et al: Plasma and cerebrospinal fluid pharmokinetic study of topotecan in nonhuman primates. Cancer Res 53: 725-727, 1993[Abstract/Free Full Text]

11. Friedman HS, Houghton PJ, Schold SC, et al: Activity of 9-dimethylaminoethyl-10-hydroxycamptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol 34: 171-174, 1983

12. National Cancer Institute: Annual Report to the Food and Drug Administration: Topotecan HCL (NSC 609 699) IND 34494. Bethesda, MD, National Cancer Institute, June 1991

13. Chen AY, Choy H, Rothenbery ML: DNA topoisomerase I-targeting drugs as radiation sensitizers. Oncology (Huntingt) 13: 39-46, 1990 (suppl 10)

14. Boothman DA, Wang M, Schea RA, et al: Posttreatment exposure to camptothecin enhances the lethal effects of x-rays on radioresistant human malignant melanoma cells. Int J Radiat Oncol Biol Phys 24: 939-948, 1992[Medline]

15. Mattern MR, Hofmann GA, McCabe FL, et al: Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864). Cancer Res 51: 5813-5816, 1991[Abstract/Free Full Text]

16. Boscia RE, Korbut T, Holden SA, et al: Interaction of topoisomerase I inhibitors with radiation in cisdiamminedichlorplatinum (II)-sensitive and resistant cells in vitro and in the FsallC fibrosarcoma in vivo. Int J Cancer 53: 118-123, 1993[Medline]

17. Kim JG, Kim SH, Kolozsvary A, et al: Potentiation of radiation response in human carcinoma cells in vitro by topotecan, an inhibitor of DNA topoisomerase I. Int J Radiat Oncol Biol Phys 22: 515-518, 1992[Medline]

18. Lamond JP, Mehta MP, Boothman DA: The potential of topoisomerase I inhibitors in the treatment of CNS malignancies: Report of a synergistic effect between topotecan and radiation. J Neurooncol 30: 1-6, 1996[Medline]

19. Sirotti MN, Saltz L, Yound C, et al: Phase I and clinical pharmacologic study of intravenous topotecan. Proc Am Soc Clin Oncol 10: 104, 1991 (abstr)

20. Rowinsky E, Gochow L, Hendricks C, et al: Phase I and pharmacologic study of topotecan (SK&F 104864): A novel topoisomerase I inhibitor. J Clin Oncol 10: 647-656, 1992[Abstract/Free Full Text]

21. Macdonald D, Cairncross JG, Stewart D, et al: Phase II trials of topotecan in patients with recurrent malignant glioma: National Cancer Institute of Canada Clinical Trials Group. Ann Oncol 7: 205-207, 1996[Abstract/Free Full Text]

22. Kadota R, Stewart C, Hown M, et al: Topotecan for the treatment of recurrent or progressive central nervous system tumors: A Pediatric Oncology Group phase II study. J Neurooncol 43: 43-47, 1999[Medline]

23. Curran W, Scott C, Horton J, et al: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85: 704-710, 1993[Abstract/Free Full Text]

24. Friedman HS, Kerby T, Fields S, et al: Topotecan treatment of adults with primary malignant glioma: The Brain Tumor Center at Duke. Cancer 85: 1160-1165, 1999[Medline]

25. Snaghavi S, Krailo M, Needle M, et al: Topotecan, as a radiosensitizer, for brainstem glioma (BSG) of childhood: First report of CCG 0952, a phase I study. Proc Am Soc Ther Radiat Oncolo 42: 357A2260, 1998 (abstr)

26. Needle M, Mehta M, Krailo M, et al: Phase I study of topotecan as a radiosensitizer prior to daily involved field irradiation in children with intrinsic pontine glioma: A Children’s Cancer Group Study. Proc Am Soc Clin Oncol 18: 558a, 1999 (abstr)

27. Danks M, Pawlik C, Whipple D, et al: Intermittent exposure of medulloblastoma to topotecan produces growth inhibition equivalent to continuous exposure. Clin Cancer Res 3: 1731-1738, 1997[Abstract]

28. Friedman HS, Castellino RC, Elion GB, et al: Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts. Cancer Chemother Pharmacol 45: 345-349, 2000[Medline]

29. Coggins CA, Elion GB, Houghton PJ, et al: Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents. Cancer Chemother Pharmacol 41: 485-490, 1998[Medline]

30. Friedman HS, Petros WP, Friedman AH, et al: Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 17: 1516-1525, 1999[Abstract/Free Full Text]

31. Hare CB, Elion GB, Houghton PJ, et al: Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol 39: 187-191, 1997[Medline]

Submitted May 10, 2000; accepted October 23, 2000.


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R. Stupp, M. E. Hegi, M. J. van den Bent, W. P. Mason, M. Weller, R. O. Mirimanoff, J. G. Cairncross, and on behalf of the European Organisation for Researc
Changing paradigms--an update on the multidisciplinary management of malignant glioma.
Oncologist, February 1, 2006; 11(2): 165 - 180.
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S. Ostermann, C. Csajka, T. Buclin, S. Leyvraz, F. Lejeune, L. A. Decosterd, and R. Stupp
Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Temozolomide in Malignant Glioma Patients
Clin. Cancer Res., June 1, 2004; 10(11): 3728 - 3736.
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E. T. Wong and A. Berkenblit
The Role of Topotecan in the Treatment of Brain Metastases
Oncologist, February 1, 2004; 9(1): 68 - 79.
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A. Chakravarti, A. Chakladar, M. A. Delaney, D. E. Latham, and J. S. Loeffler
The Epidermal Growth Factor Receptor Pathway Mediates Resistance to Sequential Administration of Radiation and Chemotherapy in Primary Human Glioblastoma Cells in a RAS-dependent Manner
Cancer Res., August 1, 2002; 62(15): 4307 - 4315.
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R. Stupp, P.-Y. Dietrich, S. O. Kraljevic, A. Pica, I. Maillard, P. Maeder, R. Meuli, R. Janzer, G. Pizzolato, R. Miralbell, et al.
Promising Survival for Patients With Newly Diagnosed Glioblastoma Multiforme Treated With Concomitant Radiation Plus Temozolomide Followed by Adjuvant Temozolomide
J. Clin. Oncol., March 1, 2002; 20(5): 1375 - 1382.
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