This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clarke, K. Articles by Kaye, A. H. Search for Related Content PubMed PubMed Citation Articles by Clarke, K. Articles by Kaye, A. H.

KRN8602 (MX2-Hydrochloride): An Active New Agent for the Treatment of Recurrent High-Grade Glioma

From the Centre for Developmental Cancer Therapeutics, Parkville, Victoria (affiliates: Ludwig Institute Oncology Unit, Austin & Repatriation Medical Centre; Melbourne Tumor Biology Branch, Ludwig Institute for Cancer Research; Department of Clinical Haematology and Medical Oncology, Royal Melbourne Hospital; and Department of Neurosurgery, University of Melbourne, Melbourne); Department of Medical Oncology, Sydney Cancer Centre, Sydney; St Vincent's Hospital, Darlinghurst; Department of Medical Oncology, Sir Charles Gardiner Hospital, Nedlands; and Institute of Drug Technology/Biomedicus, Victoria, Australia.

Address reprint requests to R. Basser, MBBS, Centre for Developmental Cancer Therapeutics, c/o Post Office, Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia; email basser{at}licre.ludwig.edu.au

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To assess the efficacy and toxicity of KRN8602 when administered as an intravenous bolus to patients with recurrent high-grade malignant glioma.

PATIENTS AND METHODS: Patients with recurrent or persistent anaplastic astrocytoma or glioblastoma multiforme who had not received recent chemotherapy or radiotherapy and were of good performance status (Eastern Cooperative Oncology Group score 2) were treated with an intravenous bolus of 40 mg/m² KRN8602 every 28 days. Tumor responses were assessed radiologically and clinically after every second cycle of therapy. Treatment was continued until documented progression or a total of six cycles.

RESULTS: A median of three cycles (range, one to six cycles) of KRN8602 was administered to 55 patients, 49 of whom received at least two cycles and were, therefore, assessable for response. The overall response rate (disease stabilization or better) was 43% (95% confidence interval, 29% to 58%). There were three complete responses, one partial response, seven minor responses, and 10 patients with stable disease. The median time to progression was 2 months (range, 1.5 to 37 months) and overall survival was 11 months (range, 1.5 to 40 months). Neutropenia was the most common toxicity, although it was generally of brief duration, and there were only seven episodes of febrile neutropenia in 176 cycles delivered. Nonhematologic toxicity was mostly gastrointestinal (nausea and vomiting, diarrhea) and events were grade 2 or lower except for a single episode of grade 3 vomiting.

CONCLUSION: KRN8602 is an active new agent with minimal toxicity in the treatment of relapsed or refractory high-grade glioma. Further studies with KRN8602 in combination with other cytotoxics and in adjuvant treatment of gliomas are warranted.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
NEARLY ALL PATIENTS with newly diagnosed high-grade cerebral glioma experience relapse of their cancer after initial surgery,¹ despite the use of adjuvant radiotherapy² and chemotherapy.^3,4 Salvage therapy for recurrent high-grade glioma has made little impact on survival, and most patients will die from their disease within 4 to 12 months of relapse.¹ Novel agents and approaches are required.

KRN8602 is the HCl salt of MX2 (3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin), a morpholino anthracycline that has been shown to be more potent than its daunorubicin derivative and has minimal acute and subacute cardiotoxicity in animal models.^5,6 Several features of this drug suggest that it may be useful for the treatment of intracranial malignancies, including increased lipophilicity⁵ and the ability to cross the blood-brain barrier.^7,8 KRN8602 has been shown to have activity against glioma cells in vitro at lower concentrations than either doxorubicin or nitrosoureas.⁹ In addition, growth of C6 glioma cells inoculated intracerebrally into nude mice can be inhibited by intravenous injection of KRN8602.⁹

This report describes the results of a multicenter phase II study of KRN8602 in patients with recurrent high-grade malignant glioma.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility
Patients with recurrent or persistent high-grade glioma whose initial pathologic diagnosis was glioblastoma multiforme (GM) or anaplastic astrocytoma (AA) were eligible. Initial histology results were reviewed by each institute using World Health Organization criteria.¹⁰ Biopsy was not mandatory at the time of recurrence. Eligible patients had measurable disease on magnetic resonance imaging, although computed tomography scan was used in one patient. Difficulties in distinguishing radiation necrosis from tumor recurrence are well documented^11,12; to minimize this possibility, only patients with contrast-enhancing lesions were included in the study. In all cases, there was evidence of relapse or progression of tumor compared with previous scans. In addition, the pretreatment scan could not be performed in the interval between 3 days and 3 months after surgery to avoid surgically induced contrast enhancement of residual tumor.¹³ Patients may have received prior chemotherapy, but not within the previous 12 weeks, and patients were permitted prior radiotherapy providing it had been given at least 4 months beforehand.

Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (ECOG 3 was permitted if due to focal neurologic impairment), absolute neutrophil count (ANC) greater than 1.5 x 10⁹/L, platelet count greater than 100 x 10⁹/L, hemoglobin greater than 10 g/dL, serum creatinine less than 0.2 mmol/L, bilirubin less than two times the upper limit of normal, and ALT and AST less than three times the upper limit of normal. Patients were required to have normal cardiac function as measured on resting nuclear gated heart pool scan and no history of myocardial infarction within the previous 6 months, current history of angina, or other major coexisting medical problem. Written informed consent as to the investigational nature of the treatment was obtained from all patients, and the protocol was approved by the institutional ethics committee.

Study Design
This was a multicenter, open-label, nonrandomized phase II study. Monitoring consisted of a full blood examination on days 10 and 20 after KRN8602 administration and liver and renal function tests at the end of each treatment cycle. Additional blood counts were taken as clinically indicated. Toxicity was assessed according to World Health Organization criteria at each visit. A repeat gated heart pool scan was performed after the third and sixth cycles where applicable or when a patient was removed from study. Disease status was reassessed clinically each cycle and radiologically after every second cycle.

Chemotherapy
KRN8602 (MX2 HCl) was supplied by the pharmaceutical division of Kirin Brewery Co LTD, Tokyo, Japan. Each vial of sterile lipophilised powder was reconstituted with 2 to 10 mL of distilled water. The drug was administered intravenously over 1 minute with 5% dextrose solution. Ondansetron (8 mg) and dexamethasone (20 mg) were given intravenously immediately before administration of KRN8602, and patients were supplied with oral ondansetron (8 mg) to be taken 4 and 8 hours after treatment.

Treatment was repeated every 28 days. The dose of KRN8602 was reduced by 25% in the subsequent cycle in the event of grade 3 nonhematologic toxicity (excluding alopecia, nausea, pain, and febrile neutropenia [temperature 38.2°C with ANC less than 1.0 [times] 10⁹/L]), grade 4 thrombocytopenia, prolonged (> 48 hours) grade 3 thrombocytopenia, and delayed hematologic recovery. Treatment delay of up to 4 weeks was allowed for recovery of ANC to greater than 1.5 x 10⁹/L and platelet count to greater than 100 x 10⁹/L. If recovery had not occurred by this time, then the patient was removed from study. Dose modifications were allowed on two occasions (to 50% of initial starting dose). If further dose reduction was required after this, then the patient was removed from study.

Evaluation of Treatment Response
A minimum of two cycles of KRN8602 was required to evaluate for a response. Patients were evaluated radiologically at the end of every second cycle of KRN8602 using the same radiologic modality (computed tomography or magnetic resonance imaging) throughout the study. All scans were reviewed by a central radiologist. Measurement of response was based on the product of the two largest perpendicular diameters of the contrast-enhancing lesion or, if multiple lesions were present, the sum of the products of the perpendicular lesions. Cystic changes were not included in the measurement of a lesion. Complete response (CR) was defined as complete resolution of all symptoms, signs, and radiologic evidence of tumor, partial response (PR) was defined as a 50% or greater decrease in total tumor load, and minor response (MR) was defined as 25% to 49% greater decrease in total tumor load. In the case of multiple lesions in patients with PR or MR, no progression (> 25%) of any individual lesion or appearance of new lesion was allowed. Stable disease (SD) was defined as no increase of greater than 25% in size of one or more measurable lesions nor reduction in tumor size of 50%. If a response was noted by the above criteria, then the scan was repeated at an interval of not less than 4 weeks to confirm response, and only responses durable for this time were recorded. To be included as CR, PR, MR, or SD, patients had to be neurologically stable and on a stable or reduced dose of corticosteroid.

Patients were removed from study if disease progression was documented, as evidenced by a 25% or greater increase in size of one or more lesions, the appearance of new lesions, or a significant worsening of symptoms. Providing no adverse events or study-limiting toxicities had occurred during treatment, patients with SD continued for a maximum of six cycles. Time to tumor progression was defined as the interval from the first day of KRN8602 infusion until tumor progression was documented radiologically or, if the patient died without a repeat scan, to the first date of known clinical deterioration. Survival was defined as the time from the first day of drug infusion to the time of death.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Fifty-five patients, 33 male and 22 female, were treated at five institutions from December 1994 to July 1997. One patient was enrolled but did not receive chemotherapy because of rapid deterioration in general health. The median age was 47 years (range, 15 to 73 years). Thirty-seven patients had GM, 15 had AA, and three had anaplastic oligodendrogliomas (OD). Tumor location, including multicentric tumors, were frontal (n = 20), temporal (n = 16), parietal (n = 8), occipital (n = 5), tempero-parietal (n = 5), fronto-parietal (n = 2), internal capsule (n = 2), and other (brainstem/optic chiasm, n = 6). Only one patient had tumor confined to the brainstem.

Fifty-four patients had previous debulking surgery, and 33 had multiple excisions for recurrent disease. KRN8602 was administered before surgery in one patient, whereas it was given to four patients after surgery for residual disease. The remaining patients (n = 50) received KRN8602 because of radiographic tumor progression. Forty-nine patients had received prior adjuvant radiotherapy and 11 had received prior chemotherapy consisting of carboplatin plus etoposide (n = 6), nitrosoureas alone (n = 3), vincristine plus procarbazine and lomustine (n = 1), or low-dose KRN8602 as part of previous phase I study (n = 1). The median time from initial diagnosis of glioma to enrollment on study was 26 months (range, 14 to 38 months).

A total of 176 cycles of KRN8602 were administered, and each patient received a median of three cycles (range, one to six cycles). Eleven patients completed six cycles. All patients were taking antiepileptic medications for the prevention of seizures at the time of enrollment on the study, which continued until at least the end of treatment.

Response and Survival
Forty-nine patients received at least two cycles of KRN8602 and were, therefore, assessable for response. Four patients had rapidly progressive disease during the first cycle of treatment, and one was withdrawn from study after a stroke occurred after one dose. The characteristics of patients who were assessable for response are listed in Table 1.

The overall response rate (SD or better) was 43% (95% confidence interval [CI] 29% to 58%) (Table 2). Three patients (two with GM and one with AA) had a CR. The patients with CR were 27, 32, and 40 years of age, and the times from initial diagnosis to treatment with KRN8602 were 60, 160, and 12 months, respectively. The times from diagnosis of high-grade glioma were 60, 1, and 2 months, respectively. At the time of last analysis, two of these patients (one each with GM and AA) remained in CR of 37 months' duration after five and six cycles of treatment, respectively. The patient with GM did not receive all six planned cycles of treatment due to prolonged thrombocytopenia after cycle 5. In the third patient, a CR was first noted after two cycles of KRN8602, but progressive disease occurred 1 month after the sixth cycle. A 35-year-old patient with anaplastic astrocytoma had a PR that persisted for 38 months after completion of the sixth cycle of treatment. The patient was initially diagnosed with anaplastic astrocytoma 96 months before commencing treatment and had also had two surgical resections and prior radiotherapy. All responders had a performance status of ECOG 1 or 2. Each patient had received two prior surgical resections of tumor. Three of the responding patients had received prior radiotherapy. All patients were concurrently taking phenytoin at the time of commencing the study. Seven patients (four with GM, two with AA, and one with OD) had an MR, whereas 10 patients (four with GM, three with AA, and three with mixed histology) had SD for at least 8 weeks.

The median time to tumor progression (TTP) was 2 months (range, 1.5 to 38 months) for the 49 assessable patients (2 months [range, 1.5 to 37 months] for GM, 3.5 months [range, 2 to 38 months] for AA and OD). The median survival was 11 months (range, 1.5 to 40 months), with 1- and 2-year survival probabilities of 47% (95% CI, 31% to 60%) and 16% (95% CI, 6% to 27%), respectively. For patients with GM, the median survival was 7 months (range, 1.5 to 37 months), with 1- and 2-year survivals of 37% (95% CI, 20% to 56%) and 10% (95% CI, 2% to 27%), respectively. For patients with AA or OD, the median survival was 14 months (range, 3 to 40 months), and 1- and 2-year survivals were 67% (95% CI, 41% to 87%) and 28% (95% CI, 10% to 54%), respectively. At last analysis 15 patients were alive, including six who progressed on or after KRN8602 and subsequently received other therapy, including surgery (n = 2) or alternative chemotherapy (n = 4). Forty-one patients died from disease progression.

Toxicity
Fifty-five patients received at least one cycle of KRN8602 and were assessable for toxicity. Neutropenia was the most common hematologic toxicity (Table 3). Twenty-seven patients had a total of 58 episodes of grade 4 neutropenia (33% of treatment cycles). In 22 patients, the initial episode of grade 4 neutropenia occurred in the first cycle, and there was no cumulative increase in WBC toxicity with further cycles. Nine patients required modification of KRN8602 dose due to neutropenia; three of these underwent dose reduction on two occasions. One patient was withdrawn from study after the fifth cycle because of prolonged neutropenia. Despite the high incidence of neutropenia, there were only seven episodes of febrile neutropenia. Hematologic toxicity was not greater in the 11 patients who had previously received chemotherapy (P > .1).

There were four episodes of grade 3/4 thrombocytopenia, and three patients received prophylactic platelet transfusions. One patient was withdrawn from study due to prolonged thrombocytopenia. There were no bleeding episodes. Five patients received RBC transfusions for anemia.

Mild ( grade 2) nausea and vomiting was the most common nonhematologic toxicity, occurring in 51% of treatment cycles (Table 4). Other nonhematologic toxicities were generally mild and self-limiting.

One patient had received one cycle of KRN8602 10 mg/m² on a phase 1 study¹⁴ six months before participating in the current trial. He received two cycles of chemotherapy with only minor ( grade 1) toxicity and ceased treatment because of progressive disease.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this study, 40 mg/m² of KRN8602 administered as a short intravenous bolus every 28 days produced an overall response rate (SD or better) of 43% in patients with high-grade recurrent malignant glioma. Patients who responded tended to be younger than those who did not, but there was no significant difference in the age of the groups. Although age has been reported to be a prognostic factor for survival in high-grade glioma,^15,16 no differences were found between responders and nonresponders in the number of surgical resections, prior radiotherapy, or chemotherapy. However, this is not surprising, as the inclusion criteria in this study resulted in patients with a uniformly poor prognosis being treated.

The level of activity observed in the current study compares favorably with cytotoxic agents currently used for relapsed glioma. The nitrosoureas (carmustine and lomustine), procarbazine, and carboplatin have been associated with single-agent response rates of 20% to 40%.¹⁷ Several new drugs have also been shown recently to be active. Paclitaxel was reported to give response rates of 35%¹⁸ to 55%,¹⁹ whereas temozolomide, an orally active derivative of procarbazine, was associated with responses in 27% of patients.²⁰ In studies of single agents, the time to progression has generally been only a few months and the overall survival less than 12 months,¹⁷ and this was also observed in the current study.

Although anthracyclines are effective against a wide range of tumor types, they have not been previously used to treat gliomas because of their inability to penetrate the blood-brain barrier. This is due to a high molecular weight and low lipid solubility. KRN8602, a morpholino derivative of daunorubicin, was reported in preclinical studies to be 40-fold more potent than the parent compound⁵ and to possess in vitro activity against a variety of pleiotropic drug-resistant cell lines.^5,21 Most importantly, it was found to be lipophilic and, therefore, able to penetrate the blood-brain barrier.^5,8,22 KRN8602 and its metabolites were detected in the brain tissue of rats after intravenous injection.^22,23 In addition, KRN8602 was shown to concentrate in implanted intracerebral tumors relative to normal brain and to inhibit the growth of glioma cells inoculated intracerebrally into mice.⁹ The passage of KRN8602 across the blood-brain barrier and increased potency compared with other anthracyclines is likely to account for the activity seen in this study.

The short time to progression and overall survival in patients with recurrent high-grade gliomas make the use of cytotoxic agents with substantial toxicity undesirable. In a prior phase I study of KRN8602 in patients with advanced malignancy, we found the dose-limiting toxicity to be neutropenia.^14,24 Nonhematologic toxicity was minimal, the most common being nausea and vomiting. In contrast to other anthracyclines, alopecia and mucositis were infrequent and mild. The maximum-tolerated dose of KRN8602 was determined to be 40 mg/m².¹⁴ Although KRN8602 was scheduled at 21-day cycles in the phase I study, prolonged neutropenia necessitated treatment delay in 40% of cycles. Therefore, the intercycle treatment interval for the current study was lengthened to 28 days. The administration of as many as six cycles of KRN8602 in the current trial was well tolerated; toxicity was not cumulative with successive cycles and rarely led to discontinuation of treatment.

Consistent with the predictions of the previous phase I study, the main toxicity of KRN8602 when administered in the absence of granulocyte colony-stimulating factor (G-CSF) was neutropenia. Although cases of grade 3 and 4 neutropenia were common, the period of severe neutropenia tended to be brief, and only seven of 176 treatment cycles were complicated by fever. Neutropenia did necessitate dose delay and reduction in nine patients. Three had a dose reduction on two occasions to a final dose of 50% of the starting dose, with one patient later being withdrawn from the study due to prolonged neutropenia. It is interesting to note that one patient who was withdrawn from the study due to persistent prolonged neutropenia achieved a PR. The addition of G-CSF in subsequent cycles to patients requiring dose reduction could have been considered; however, neutropenia was usually of brief duration and uncomplicated. Furthermore, although the maintenance of dose-intensity of anthracyclines has been shown to be important in other malignancies,^25,26 there are no data for such an effect in patients with high-grade gliomas. Thrombocytopenia was uncommon and only severe (grade 3 or 4) in four cycles.

Gastrointestinal effects, such as nausea and vomiting, mucositis, and diarrhea, were the most frequent nonhematologic toxicities and were usually mild. It is noteworthy that gastrointestinal side effects only became limiting in the phase I study of KRN8602 with escalation of doses to 70 mg/m² or higher with G-CSF support.¹⁴ We have not observed CNS toxicity attributable to KRN8602 in either the phase I or current study.

Although KRN8602 seems to be as active as currently used agents and is associated with minimal toxicity, further progress is urgently required in the treatment of recurrent high-grade gliomas. Chemotherapy regimens using multiple drugs may be more effective than single agents, but the survival with such an approach is still dismal.^17,27-29 However, greater benefit from new active agents may result from their administration after surgery and radiotherapy in newly diagnosed gliomas. A meta-analysis that included more than 3,000 patients showed that adjuvant nitrosourea-based regimens improve survival in GM and AA,³⁰ and several recent studies suggest that multiple agents might be superior to carmustine alone.^4,31 Trials investigating the role of KRN8602 in combination with other active agents and in the adjuvant setting are warranted.

	ACKNOWLEDGMENTS

 
Supported by a grant from the Pharmaceutical Division of Kirin Brewery Co, Ltd, Tokyo, Japan.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Burger PC, Vogel FS, Green SB, et al: Glioblastoma multiforme and anaplastic astrocytoma: Pathologic criteria and prognostic implications. Cancer56:1106-1111, 1985[Medline]

2. Walker MD, Green SB, Byar DP, et al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med303:1323-1329, 1980[Abstract]

3. Walker MD, Alexander E Jr, Hunt WE: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: A cooperative clinical trial. J Neurosurg49:333-343, 1978[Medline]

4. Levin VA, Silver P, Hannigan J, et al: Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys18:321-324, 1990[Medline]

5. Watanabe M, Komeshima N, Naito M, et al: Cellular pharmacology of MX2, a new morpholino anthracycline, in human pleiotropic drug-resistant cells. Cancer Res51:157-161, 1991[Abstract/Free Full Text]

6. Sato Y, Eddy L, Hochstein P: Comparative cardiotoxicity of doxorubicin and a morpholino anthracycline derivative (KRN8602). Biochem Pharmacol42:2283-2287, 1991[Medline]

7. Izumoto S, Arita N, Hayakawa T, et al: Effect of MX2, a new morpholino anthracycline, against experimental brain tumors. Anticancer Res10:735-739, 1990[Medline]

8. Kabuto M, Kubota T, Kobayashi H, et al: The antitumor effect of MX2, a new morpholino anthracycline, against malignant glioma cell lines and its subcellular distribution. Neurosurgery37:471-477, 1995[Medline]

9. Kabuto M, Kaye AH, Hill JS, et al: Antitumour effect of MX2, a new morpholino anthracycline against C6 glioma cells and its cytotoxic effect in combination with photodynamic therapy. J Clin Neuroscience1:47-52, 1994

10. Kleihues P, Burger PC, Scheithauer BW: The new WHO classification of brain tumours. Brain Pathol3:255-268, 1993[Medline]

11. Castel JC, Caille JM: Imaging of irradiated brain tumours: Value of magnetic resonance imaging. J Neuroradiol16:81-132, 1989[Medline]

12. Dooms GC, Hecht S, Brant-Zawadzki M, et al: Brain radiation lesions: MR imaging. Radiology158:149-155, 1986[Abstract/Free Full Text]

13. Albert FK, Forsting M, Sartor K, et al: Early postoperative magnetic resonance imaging after resection of malignant glioma: Objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery34:45-61, 1994[Medline]

14. Clarke K, Basser RL, Maher D, et al: Phase I and pharmacokinetic study of KRN8602 alone and with filgrastim in patients with advanced cancer. J Clin Oncol16:2181-2187, 1998[Abstract]

15. Rajan B, Ross G, Lim CC, et al: Survival of patients with recurrent glioma as a measure of treatment efficacy: Prognostic factors following nitrosurea chemotherapy. Eur J Cancer 30A:1809-1815, 1994

16. Huncharek M, Muscat J: Treatment of recurrent high grade astrocytoma: Results of a systematic review of 1,415 patients. Anticancer Res18:1303-1311, 1998[Medline]

17. Brandes AA, Fiorentino MV: The role of chemotherapy in recurrent malignant gliomas: An overview. Cancer Invest14:551-559, 1996[Medline]

18. Prados MD, Schold SC, Spence AM, et al: Phase II study of paclitaxel in patients with recurrent malignant glioma. J Clin Oncol14:2316-2321, 1996[Abstract]

19. Chamberlain MC, Kormanik P: Salvage chemotherapy with paclitaxel for recurrent primary brain tumors. J Clin Oncol13:2066-2071, 1995[Abstract/Free Full Text]

20. Newlands ES, O'Reilly SM, Glaser MG, et al: The Charing Cross Hospital experience with temozolomide in patients with gliomas. Eur J Cancer 32A:2236-2241, 1996

21. Coley HM, Twentyman PR, Workman P: 9-Alkyl, morpholinyl anthracyclines in the circumvention of multidrug resistance [see comments]. Eur J Cancer26:665-667, 1990

22. Watanabe M, Komeshima N, Nakajima S, et al: MX2, a morpholino anthracycline, as a new antitumor agent against drug-sensitive and multidrug-resistant human and murine tumor cells. Cancer Res48:6653-6657, 1988[Abstract/Free Full Text]

23. Umezawa H, Nakajima S, Kawai H, et al: New morpholino anthracyclines, MX, MX2, and MY5. J Antibiot40:1058-1061, 1987[Medline]

24. Morgan DJ, Hill JS, Clarke K, et al: Pharmacokinetics and pharmacodynamics of MX2 hydrochloride in patients with advanced malignant disease. Cancer Chemother Pharmacol40:202-208, 1997[Medline]

25. Focan C, Andrien JM, Closon MTet al: Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: A prospective randomized trial. J Clin Oncol11:1253-1263, 1993[Abstract/Free Full Text]

26. Wood WC, Budman DR, Korzus AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med330:1253-1259, 1994[Abstract/Free Full Text]

27. Jeremic B, Grujicic D, Jevremovic S, et al: Carboplatin and etoposide chemotherapy regimen for recurrent malignant glioma: A phase II study. J Clin Oncol10:1074-1077, 1992[Abstract]

28. Levin VA, Edwards MS, Wright DC: Modified procarbazine, CCNU and vincristine combination (PCV 3) in the treatment of malignant brain tumors. Cancer Treat Rep64:237-241, 1980[Medline]

29. Sanson M, Ameri A, Monjour A, et al: Treatment of recurrent malignant supratentorial gliomas with ifosfamide, carboplatin and etoposide: A phase II study. Eur J Cancer 32A:2229-2235, 1996

30. Fine HA, Dear KBG, Loeffler JS, et al: Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer71:2585-2597, 1993[Medline]

31. Hildebrand J, Sahmoud T, Mignolet F, et al: Adjuvant therapy with dibromodulcitol and BCNU increases survival of adults with malignant gliomas: EORTC Brain Tumor Group. Neurology44:1479-1483, 1994[Abstract/Free Full Text]

Submitted August 18, 1998; accepted March 19, 1999.

This article has been cited by other articles:

				G. Minotti, P. Menna, E. Salvatorelli, G. Cairo, and L. Gianni Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity Pharmacol. Rev., June 1, 2004; 56(2): 185 - 229. [Abstract] [Full Text] [PDF]

				S. L. Chua, M. A. Rosenthal, S. S. Wong, D. M. Ashley, A.-m. Woods, A. Dowling, and L. M. Cher Phase 2 study of temozolomide and Caelyx in patients with recurrent glioblastoma multiforme Neuro-oncol, January 1, 2004; 6(1): 38 - 43. [Abstract] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clarke, K. Articles by Kaye, A. H. Search for Related Content PubMed PubMed Citation Articles by Clarke, K. Articles by Kaye, A. H.