Phase II evaluation of dibromodulcitol in the treatment of recurrent medulloblastoma, ependymoma, and malignant astrocytoma

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✓ The authors have conducted a Phase II trial to evaluate orally administered dibromodulcitol in the treatment of 40 evaluable patients with recurrent medulloblastoma, ependymoma, and malignant astrocytoma. Ten of 20 patients harboring medulloblastoma responded to therapy with a median time to tumor progression (MTP) of 40 weeks, and four of 20 patients had no sign of progression of disease 4 years after treatment was begun. The MTP for all 12 patients with ependymoma was 30 weeks. Nine of these 12 patients had stabilization of their disease with an MTP of 67 weeks; three of these 12 patients had no signs of progression for 1 to 3 years after treatment was begun. Of six patients harboring supratentorial gliomas, none responded to dibromodulcitol. Two patients, one with a primitive neuroectodermal tumor and the other with a metastatic carcinoma of the breast, had stabilization of disease for more than 4 and 2 years, respectively.

Abstract

✓ The authors have conducted a Phase II trial to evaluate orally administered dibromodulcitol in the treatment of 40 evaluable patients with recurrent medulloblastoma, ependymoma, and malignant astrocytoma. Ten of 20 patients harboring medulloblastoma responded to therapy with a median time to tumor progression (MTP) of 40 weeks, and four of 20 patients had no sign of progression of disease 4 years after treatment was begun. The MTP for all 12 patients with ependymoma was 30 weeks. Nine of these 12 patients had stabilization of their disease with an MTP of 67 weeks; three of these 12 patients had no signs of progression for 1 to 3 years after treatment was begun. Of six patients harboring supratentorial gliomas, none responded to dibromodulcitol. Two patients, one with a primitive neuroectodermal tumor and the other with a metastatic carcinoma of the breast, had stabilization of disease for more than 4 and 2 years, respectively.

The halogenated hexitol, dibromodulcitol (DBD), is spontaneously hydrolyzed in situ to the diepoxide hexitol, dianhydrogalactitol (DAG).14 Dibromodulcitol crosses the blood-brain barrier readily18 and can achieve brain/plasma and cerebrospinal fluid (CSF)/plasma ratios of 1:1 or more.14 In clinical trials, DBD was found to be active against a variety of tumors,9,12 including adenocarcinoma of the breast,4,23 soft-tissue sarcomas,3,4,23 and melanoma,6 and it reduces the frequency of infiltration into the central nervous system (CNS) in children with acute lymphoblastic leukemia.24 With the exception of our preliminary report on the use of DBD to treat recurrent medulloblastoma20 and the recent report by Áfra, et al.,1 on the use of DBD adjuvant to radiation therapy in patients with primary malignant gliomas, to our knowledge there are no reports describing the efficacy of this drug against malignant brain tumors.

Because DBD is hydrolyzed to DAG in situ, it is not immediately obvious why administration of DBD would be preferred to DAG. In the United States, DBD is administered orally and DAG is administered intravenously. Because DBD is readily absorbed in the gastrointestinal tract and has a long plasma half-life, this difference in route of administration is important clinically.5 When administered in vitro, DAG produces cell kill only after extended periods of exposure.21,22 Thus, daily oral administration of DBD assures that relatively constant levels of DAG are present in situ for sufficiently long periods of time to kill tumor cells and to prevent the repair of cell damage caused by DAG.

Because of some variability in DBD absorption in patients, due to dietary and other factors, Bellet, et al.,6 treated metastatic melanoma patients with DBD doses sufficient to cause actual hematological toxicity. Patients were treated with daily doses of 100 mg/sq m until the white blood cell (WBC) count or platelet count fell to 50% of pretreatment levels; this level of myelotoxicity was tolerable but dose-limiting. In the study reported here, we used this same treatment protocol in a Phase II study of patients harboring recurrent primary malignant brain tumors who had failed to respond to previous therapies.

Clinical Material and Methods
Patient Selection

The 41 patients in the study group were followed from July, 1979, until January, 1984. The eligibility requirement for the study was a documented recurrence of a primary brain tumor or the presence of a metastatic tumor to the brain. Recurrence was documented by computerized tomography (CT) scans, radionuclide scans, and, in patients with spinal tumors, with myelography. All patients but one had been treated with radiation therapy, and most had been treated with chemotherapy. There were 20 patients with medulloblastoma, 12 with ependymoma, and nine with miscellaneous recurrent tumors.

Treatment Protocol

Dibromodulcitol was supplied in 50- and 100-mg tablets.* In the original study design, patients were to be treated daily with 150 mg/sq m if they had not previously received chemotherapy or craniospinal irradiation, or with 100 mg/sq m if they had been so treated. In the initial phase of the trial, DBD was administered orally either until the WBC or platelet count decreased to 50% of pretreatment levels or for 14 consecutive days, whichever occurred first. Because the 14-day schedule produced minimal toxicity in most patients, treatment time was increased up to 45 consecutive days in patients who could tolerate this schedule. Depending on the toxicity produced, courses of treatment were repeated after a 3-week respite, and were continued until progression was evident or until patients had been treated for 1 year. Dose reductions were based on the standard myelotoxicity criteria of the Northern California Oncology Group (Table 1). Dexa-methasone doses were kept at the lowest level consistent with good medical practice.

TABLE 1

Myelotoxicity levels caused by treatment with dibromodulcitol*

Blood Count (× 1000/cu mm)Toxicity LevelMedulloblastoma Cases (%)Ependymoma Cases (%)
leukocytes
 3.0–4.013033
 2.0–3.023033
 1.5–2.0350
 < 1.54100
platelets
 100–125108
 75–1002250
 50–7531016
 < 50458

Myelotoxicity levels are according to the criteria of the Northern California Oncology Group.

Evaluation Methods

Results of treatment were measured from the first treatment with DBD. Patients with brain tumors were evaluated every 7 or 8 weeks using our previously published criteria.19 Before each course of therapy, clinical status was determined by a neurological examination, and by CT and technetium-99m-diethylenetriaminepentaacetic acid (99mTc-DTPA) radionuclide brain scans. “Response” to treatment was defined as a definite improvement in the results of two of the three tests, “progression” as a definite worsening in the results of two of the three tests, and “stable disease” as no definite change in the results of two of the three tests, provided the dose of steroids was the same or lower.

Patients harboring spinal cord tumors were also evaluated with periodic myelography and/or spinal CT scans and cerebrospinal fluid (CSF) cytology, and CSF protein and polyamine levels were determined. Response and disease stability were defined as an improvement in neurological signs and symptoms, and in the myelogram and/or spinal cord CT scans, and by a reduction in CSF protein levels and resolution of abnormal CSF cytology.

Results

Of the 41 patients entered into the study, 40 who completed at least 25 days of treatment with DBD were evaluable. One patient was lost to follow-up study.

Medulloblastoma Cases

Clinical characteristics, dosage, and response to therapy for the 20 patients with recurrent medulloblastoma are listed in Table 2. Two of the 20 patients responded, eight had stabilization of their disease, and 10 continuted to deteriorate after one course of DBD. Kaplan-Meier plots15 show that the median time to tumor progression (MTP) was only 10 weeks for all 20 patients (Fig. 1). However, patients who responded to therapy or who were considered to have stable disease had an MTP of 40 weeks; four of the 20 patients had no signs of progression at 4 years.

TABLE 2

Results of treatment of medulloblastoma with dibromodulcitol (DBD)

Case No.Sex, Age (yrs)Karnofsky Performance Score*Site of RecurrencePrevious TreatmentDBD TreatmentTime to Progression (wks)
Average Dose (mg/sq m/day)Course Duration (days)Total Courses      
1M, 2390infratentorial, boneRT, P, HU, V110251D
2F, 970infratentorialRT, P, HU, MP64451D
3F, 2880infratentorialRT10014118 (S)
4M, 1480infratentorial, spinal cord, supratentorialRT, P, HU, MP, A, V6915456 (S)
5M, 1090supratentorialRT, HU, MP, A, M53167+214 (S)
6M, 980infratentorialRT, C, P, V73157+222 (S)
7M, 3350infratentorial, spinal cordRT, CP, BL, A, T, HU77451D
8M, 2390infratentorialRT, P, HU, MP, C, V6340338 (S)
9M, 1090infratentorialRT, C, P, V, A, M10013541 (R)
10M, 780infratentorialRT125271+ 15 (S)
11M, 2790infratentorialRT, HU, C, P, V110251D
12M, 470infratentorialRT83451D
13M, 690infratentorialRT, P, HU110351D
14M, 990infratentorialRT, P, HU110451D
15M, 890infratentorial, spinal cordRT, P, HU, C, P, V, A10033112 (S)
16M, 2290spinal cordRT6834343 (S)
17M, 380infratentorialC, V13520215 (R)
18M, 1190infratentorialRT, P, HU, T, M, MG, IMP85451D
19M, 21100infratentorialRT, P, HU100451D
20M, 1090infratentorialRT100451D

Score determined at start of DBD treatment.

RT = radiation therapy; P = procarbazine; HU = hydroxyurea; V = vincristine; MP = 6-mercaptopurine; A = intrathecal cytosine arabinoside; M = intrathecal methotrexate; C = CCNU; CP = cis-platinum; BL = bleomycin; T = intrathecal thiotepa; MG = MGBG (methylglyoxal bis(guanylhydrazone)); IMP = iodine-125 implant.

D = immediate deterioration; S = stable disease; R = responder.

Fig. 1.
Fig. 1.

Kaplan-Meier representation of the probability of freedom from tumor progression for all 20 medulloblastoma patients (solid line) and the subset of 10 patients who responded or stabilized after treatment with dibromoducitol (broken line). The ticks represent patients censored from evaluation because they have not yet failed therapy.

Four of the 10 patients who deteriorated after one course of DBD had been treated with chemotherapy after craniospinal irradiation. In two patients (Cases 5 and 6), CSF putrescine and protein content decreased to normal levels (from 700 to 200 pmol/ml and 420 to 254 pmol/ml for putrescine, respectively, and from 116 to 15 mg/dl and 394 to 20 mg/dl for protein, respectively). During treatment, CSF cytology was positive in only two patients. Both patients deteriorated after the first course of DBD because of growth of parenchymal lesions, not because of subarachnoid spread of tumor.

Ependymoma Cases

Twelve patients had recurrent ependymomas in the spinal cord, fourth ventricle, or cerebrum (Table 3). There were no true responders in this group. Nine of the 12 patients had stabilization of disease, and three deteriorated after one course of DBD. Kaplan-Meier plots show that the MTP for all 12 patients was 30 weeks (Fig. 2). The MTP for the nine patients with stable disease was 67 weeks; at 1 to 3 years after treatment, three patients had no evidence of progression. Cerebrospinal fluid cytology was negative in all patients, and putrescine and protein levels were of little use for evaluation.

TABLE 3

Results of treatment of recurrent ependymomas with dibromoducitol (DBD)

Case No.Sex, Age (yrs)Karnofsky Performance Score*Site of RecurrencePrevious TreatmentDBD TreatmentTime to Progression (wks)
Average Dose (mg/sq m/day)Course Duration (days)Total Courses      
21M, 2470spinal cordRT, B10634586 (S)
22F, 1690supratentorialRT, B, IMP10832229 (S)
23M, 3590spinal cordRT, B85451+ 12 (S)
24F, 890spinal cord, infratentorialRT, B13330126 (S)
25M, 2170supratentorialRT, B, FU, C, P121451D
26M, 3980infratentorialRT, B, P80455+ 172 (S)
27M, 1080infratentorialRT, B116381D
28F, 3070supratentorialRT10045223 (S)
29M, 4290infratentorialRT100455+82 (S)
30M, 390infratentorialRT94451D
31F, 3390spinal cordRT9845274 (S)
32F, 2390spinal cordRT83452+54 (S)

Score determined at start of DBD treatment.

RT = radiation therapy; B = BCNU; IMP = iodine-125 implant; FU = fluorouracil; C = CCNU; P = procarbazine.

D = immediate deterioration; S = stable disease.

Fig. 2.
Fig. 2.

Kaplan-Meier representation of the probability of freedom from tumor progression for all 12 ependymoma patients. The ticks represent patients censored from evaluation because they have not yet failed therapy.

Miscellaneous Tumors

Of the remaining eight evaluable patients, two had glioblastoma multiforme, three had anaplastic astrocytoma, and one each had primitive neuroectodermal tumor, brain-stem glioma, and metastatic adenocarcinoma of the breast (Table 4). No patient with a supratentorial malignant glioma responded or had disease stabilization. The patient with the brain-stem glioma stabilized initially but died 25 weeks after beginning DBD therapy, and the patient with the secondary tumor of the breast stabilized for 104 weeks before deteriorating. The patient with the primitive neuroectodermal tumor is alive with no evidence of active disease 4 years after beginning DBD therapy.

TABLE 4

Results of treatment of miscellaneous recurrent tumors with dibromoducitol (DBD)

Case No.Sex, Age (yrs)Tumor Type*Previous TreatmentDBD TreatmentTime to Progression (wks)
Average Dose (mg/sq m/day)Course Duration (days)Total Courses     
33M, 48AART, C, FU, HU, P, B, PC, CP, BL103451D
34F, 43AART, B, FU, C, P100271D
35M, 37AART, C, P, V83451D
36M, 47GMRT, B, FU, HU, MP103421D
37F, 57GMRT, P, B, FU103451D
38F, 54GMRT, HU, PC71451
39F, 14BSGRT, FU, C, HU, MP8336225 (S)
40M, 16PNRT, C, P, V, HU83373+212 (S)
41F, 38BCRT, B, FU, HU, MP115212104 (S)

AA = anaplastic astrocytoma; GM = glioblastoma multiforme; BSG = brain-stem glioma; PN = primitive neuroectodermal tumor; BC = breast adenocarcinoma.

RT = radiation therapy; C = CCNU; FU = fluorouracil; HU = hydroxyurea; P = procarbazine; B = BCNU; PC = PCNU (1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl); CP = cis-platinum; BL = bleomycin; V = vincristine.

D = immediate deterioration; S = stable disease. Case 38 was lost to follow-up review.

Toxicity

Values for leukocytes and platelets for patients with medulloblastoma and ependymoma are listed in Table 1. Because the majority of these patients had toxicity levels less than or equal to 2, it is probable that higher levels of DBD could have been tolerated.

Discussion

The results of this study show that, used as a single agent, orally administered DBD is only moderately effective against recurrent medulloblastoma and ependymoma, and is ineffective against recurrent supratentorial glioblastoma multiforme and other malignant astrocytomas. While the response of one patient with a metastatic breast carcinoma and of one patient with a primitive neuroectodermal tumor suggests that DBD might be useful for the treatment of these tumors, response in a larger group of patients must be determined to confirm these preliminary results.

The results of treatment of medulloblastoma with various combinations of chemotherapy and radiation therapy were reviewed recently.7,20 Procarbazine;16 high-dose cyclophosphamide;2 the combination of CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea), procarbazine, and vincristine (Oncovin) — the PCV combination;10 the multiple-drug combination protocol of vincristine, intravenous and intrathecal methotrexate, BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea), and dexamethasone;11 and MOPP (mechlorethamine, Oncovin, procarbazine, and prednisone)8 are all active against recurrent medulloblastoma, with a range of median times to progression or to relapse of 13 to 102 weeks. At our institution, the standard treatment for recurrent medulloblastoma has been PCV chemotherapy. Approximately 80% of our medulloblastoma patients who had not been treated extensively with chemotherapy before recurrence showed disease stabilization or improvement with MTP's of approximately 43 weeks.10,20 By comparison, of the 10 patients who responded or stabilized after treatment with DBD in this present study, six of whom had been treated extensively with chemotherapy before recurrence (Cases 4, 5, 6, 8, 9, and 15), half had disease stabilization or response with an MTP of 40 weeks. This result suggests that DBD might not be cross-resistant and therefore may be of value in combination chemotherapy with agents such as CCNU, procarbazine, and vincristine.

Ependymomas, even the recurrent type, are slow-growing tumors. Because of their location, they are difficult to evaluate in follow-up studies; evaluation of response or progression of spinal cord ependymomas can be especially difficult. Moreover, the only reports of stabilization of ependymomas after treatment with BCNU are anecdotal.17,25 In 75% of our ependymoma patients, DBD produced disease stabilization. While the MTP for all patients with ependymomas was 30 weeks (Fig. 2), the MTP for stable patients was 67 weeks, and three patients continue to be free of progression at 54, 82, and 172 weeks after initiation of DBD therapy. These results suggest that DBD should be evaluated further as an agent for the treatment of recurrent ependymoma.

The benefit of various forms of chemotherapy for the treatment of recurrent supratentorial gliomas is well documented.13,17,25 In our present study, DBD had no therapeutic effect in six patients with supratentorial gliomas and only a short-term effect in one patient with a brain-stem glioma. The lack of efficacy of DBD against gliomas has been reported before.12 The results obtained by Áfra, et al.,1 in a study of the effect of DBD used adjuvant to irradiation of malignant gliomas are probably not due to a direct anti-tumor effect of DBD but to a radiation-enhancing effect.

Based on the results of this study, we consider DBD to be active against medulloblastoma and ependymoma, and believe that it should be evaluated for use in combination protocols. Because we evaluated only one dose schedule in this study, others should be examined to determine if other schedules have an effect on the results of treatment.12 Dibromodulcitol is a valuable agent because it is easily administered and has virtually no acute side effects. Even though myelosuppression caused by DBD was dose-limiting, it was sufficiently attenuated so that most patients who had undergone irradiation of the spinal axis could tolerate DBD for an average of 31 ± 13 days (mean ± standard deviation) per course. Moreover, while the drug was less well tolerated than expected in patients treated with prior chemotherapy and irradiation to the spinal axis, several patients with medulloblastoma and ependymoma responded to DBD for periods of months to years.

Acknowledgments

We thank the physicians in Northern California, and especially at the Kaiser-Permanente Medical Centers of the Greater Bay Area, for referring patients to our service. We thank Irene Asturias for typing the manuscript in draft.

References

  • 1.

    Afra DKocsis BDobay Iet al: Combined radiotherapy and chemotherapy with dibromodulcitol and CCNU in the postoperative treatment of malignant gliomas. J Neurosurg 59:1061101983J Neurosurg 59:

  • 2.

    Allen JCHelson L: High-dose cyclophosphamide chemotherapy for recurrent CNS tumors in children. J Neurosurg 55:7497561981J Neurosurg 55:

  • 3.

    Andrews NCWeiss AJAnfield FJet al: Phase I study of dibromodulcitol (NSC-104800). Cancer Chemother Rep 55:61651971Cancer Chemother Rep 55:

  • 4.

    Andrews NCWeiss AJWilson Wet al: Phase II study of dibromodulcitol (NSC-104800). Cancer Chemother Rep 58:6536601974Cancer Chemother Rep 58:

  • 5.

    Belej MATroetel WMWeiss AJet al: The absorption and metabolism of dibromodulcitol in patients with advanced cancer. Clin Pharmacol Ther 13:5635721972Clin Pharmacol Ther 13:

  • 6.

    Bellet RECatalano RBMastrangelo MJet al: Positive phase II trial of dibromodulcitol in patients with metastatic melanoma refractory to DTIC and a nitrosourea. Cancer Treat Rep 62:209520991978Cancer Treat Rep 62:

  • 7.

    Berry MPJenkin RDTKeen CWet al: Radiation treatment for medulloblastoma. A 21-year review. J Neurosurg 55:43511981J Neurosurg 55:

  • 8.

    Cangir Avan Eys JBerry DHet al: Combination chemotherapy with MOPP in children with recurrent brain tumors. Med Pediatr Oncol 4:2532611978Med Pediatr Oncol 4:

  • 9.

    Chiuten DFRozencweig MVon Hoff DDet al: Clinical trials with the hexitol derivatives in the U.S. Cancer 47:4424511981Cancer 47:

  • 10.

    Crafts DCLevin VAEdwards MSBet al: Chemotherapy of recurrent medulloblastoma with combined procarbazine, CCNU, and vincristine. J Neurosurg 49:5895921978J Neurosurg 49:

  • 11.

    Duffner PKCohen METhomas PRMet al: Combination chemotherapy in recurrent medulloblastoma. Cancer 43:41451979Cancer 43:

  • 12.

    Eckhardt S: Ten-year international clinical experience with DBD in the treatment of malignant diseasesEckhardt S (ed): Dibromodulcitol. Budapest: Medicina Konyvkiado1982174188Dibromodulcitol.

  • 13.

    Edwards MSLevin VAWilson CB: Brain tumor chemotherapy: an evaluation of agents in current use for phase II and III trials. Cancer Treat Rep 64:117912051980Cancer Treat Rep 64:

  • 14.

    Horváth IPCsetényi JKerpel-Fronius Set al: Metabolism and pharmacokinetics of dibromodulcitol (DBD, NSC-104800) in man. I. Metabolites of DBD. Eur J Cancer Clin Oncol 15:3373441979Eur J Cancer Clin Oncol 15:

  • 15.

    Kaplan ELMeier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:4574811958J Am Stat Assoc 53:

  • 16.

    Kumar ARVRenaudin JWilson CBet al: Procarbazine hydrochloride in the treatment of brain tumors. Phase 2 study. J Neurosurg 40:3653711974J Neurosurg 40:

  • 17.

    Levin VA: Chemotherapy of recurrent brain tumorsPrestayko AWCrooke ST (eds): Nitrosoureas: Current Status and New Developments. New York: Academic Press1981159167Nitrosoureas: Current Status and New Developments.

  • 18.

    Levin VA: Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 23:6826841980Levin VA: Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 23:

  • 19.

    Levin VACrafts DCNorman DMet al: Criteria for evaluating patients undergoing chemotherapy for malignant brain tumors. J Neurosurg 47:3293351977J Neurosurg 47:

  • 20.

    Levin VAVestnys PSEdwards MSBet al: Improvement in survival produced by sequential therapies in the treatment of recurrent medulloblastoma. Cancer 51:136413701983Cancer 51:

  • 21.

    Levin VAWheeler KT: Chemotherapeutic approaches to brain tumors. Experimental observations with dianhydrogalactitol and dibromodulcitol. Cancer Chemother Pharmacol 8:1251311982Cancer Chemother Pharmacol 8:

  • 22.

    Nomura KHoshino TDeen DFet al: Perturbed cell kinetics of 9L rat brain tumor cells following dianhydrogalactitol. Cancer Treat Rep 62:205520611978Cancer Treat Rep 62:

  • 23.

    Sellei CEckhardt SHorváth IPet al: Clinical and pharmacologic experience with dibromodulcitol (NSC-104800), a new antitumor agent. Cancer Chemother Rep 53:3773841969Cancer Chemother Rep 53:

  • 24.

    Sitarz ALAlbo VMovassaghi Net al: Dibromodulcitol (NSC-104800) compared with cyclophosphamide (NSC-26271) as remission maintenance therapy in previously treated children with acute lymphoblastic leukemic or acute undifferentiated leukemia: possible effectiveness in reducing the incidence of central nervous system leukemia. Cancer Chemother Rep 59:9899941975Cancer Chemother Rep 59:

  • 25.

    Wilson CBGutin PBoldrey EBet al: Single-agent chemotherapy of brain tumors. A five-year review. Arch Neurol 33:7397441976Arch Neurol 33:

Dibromoducitol was supplied by the Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland.

This work was supported in part by NIH Program Project Grant CA 13525.

Article Information

Present address for Dr. Fulton: Neurology Unit, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada.

Address reprint requests to: Victor A. Levin, M.D., Brain Tumor Research Center, 783 HSW, University of California, San Francisco, California 94143.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Kaplan-Meier representation of the probability of freedom from tumor progression for all 20 medulloblastoma patients (solid line) and the subset of 10 patients who responded or stabilized after treatment with dibromoducitol (broken line). The ticks represent patients censored from evaluation because they have not yet failed therapy.

  • View in gallery

    Kaplan-Meier representation of the probability of freedom from tumor progression for all 12 ependymoma patients. The ticks represent patients censored from evaluation because they have not yet failed therapy.

References

1.

Afra DKocsis BDobay Iet al: Combined radiotherapy and chemotherapy with dibromodulcitol and CCNU in the postoperative treatment of malignant gliomas. J Neurosurg 59:1061101983J Neurosurg 59:

2.

Allen JCHelson L: High-dose cyclophosphamide chemotherapy for recurrent CNS tumors in children. J Neurosurg 55:7497561981J Neurosurg 55:

3.

Andrews NCWeiss AJAnfield FJet al: Phase I study of dibromodulcitol (NSC-104800). Cancer Chemother Rep 55:61651971Cancer Chemother Rep 55:

4.

Andrews NCWeiss AJWilson Wet al: Phase II study of dibromodulcitol (NSC-104800). Cancer Chemother Rep 58:6536601974Cancer Chemother Rep 58:

5.

Belej MATroetel WMWeiss AJet al: The absorption and metabolism of dibromodulcitol in patients with advanced cancer. Clin Pharmacol Ther 13:5635721972Clin Pharmacol Ther 13:

6.

Bellet RECatalano RBMastrangelo MJet al: Positive phase II trial of dibromodulcitol in patients with metastatic melanoma refractory to DTIC and a nitrosourea. Cancer Treat Rep 62:209520991978Cancer Treat Rep 62:

7.

Berry MPJenkin RDTKeen CWet al: Radiation treatment for medulloblastoma. A 21-year review. J Neurosurg 55:43511981J Neurosurg 55:

8.

Cangir Avan Eys JBerry DHet al: Combination chemotherapy with MOPP in children with recurrent brain tumors. Med Pediatr Oncol 4:2532611978Med Pediatr Oncol 4:

9.

Chiuten DFRozencweig MVon Hoff DDet al: Clinical trials with the hexitol derivatives in the U.S. Cancer 47:4424511981Cancer 47:

10.

Crafts DCLevin VAEdwards MSBet al: Chemotherapy of recurrent medulloblastoma with combined procarbazine, CCNU, and vincristine. J Neurosurg 49:5895921978J Neurosurg 49:

11.

Duffner PKCohen METhomas PRMet al: Combination chemotherapy in recurrent medulloblastoma. Cancer 43:41451979Cancer 43:

12.

Eckhardt S: Ten-year international clinical experience with DBD in the treatment of malignant diseasesEckhardt S (ed): Dibromodulcitol. Budapest: Medicina Konyvkiado1982174188Dibromodulcitol.

13.

Edwards MSLevin VAWilson CB: Brain tumor chemotherapy: an evaluation of agents in current use for phase II and III trials. Cancer Treat Rep 64:117912051980Cancer Treat Rep 64:

14.

Horváth IPCsetényi JKerpel-Fronius Set al: Metabolism and pharmacokinetics of dibromodulcitol (DBD, NSC-104800) in man. I. Metabolites of DBD. Eur J Cancer Clin Oncol 15:3373441979Eur J Cancer Clin Oncol 15:

15.

Kaplan ELMeier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:4574811958J Am Stat Assoc 53:

16.

Kumar ARVRenaudin JWilson CBet al: Procarbazine hydrochloride in the treatment of brain tumors. Phase 2 study. J Neurosurg 40:3653711974J Neurosurg 40:

17.

Levin VA: Chemotherapy of recurrent brain tumorsPrestayko AWCrooke ST (eds): Nitrosoureas: Current Status and New Developments. New York: Academic Press1981159167Nitrosoureas: Current Status and New Developments.

18.

Levin VA: Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 23:6826841980Levin VA: Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 23:

19.

Levin VACrafts DCNorman DMet al: Criteria for evaluating patients undergoing chemotherapy for malignant brain tumors. J Neurosurg 47:3293351977J Neurosurg 47:

20.

Levin VAVestnys PSEdwards MSBet al: Improvement in survival produced by sequential therapies in the treatment of recurrent medulloblastoma. Cancer 51:136413701983Cancer 51:

21.

Levin VAWheeler KT: Chemotherapeutic approaches to brain tumors. Experimental observations with dianhydrogalactitol and dibromodulcitol. Cancer Chemother Pharmacol 8:1251311982Cancer Chemother Pharmacol 8:

22.

Nomura KHoshino TDeen DFet al: Perturbed cell kinetics of 9L rat brain tumor cells following dianhydrogalactitol. Cancer Treat Rep 62:205520611978Cancer Treat Rep 62:

23.

Sellei CEckhardt SHorváth IPet al: Clinical and pharmacologic experience with dibromodulcitol (NSC-104800), a new antitumor agent. Cancer Chemother Rep 53:3773841969Cancer Chemother Rep 53:

24.

Sitarz ALAlbo VMovassaghi Net al: Dibromodulcitol (NSC-104800) compared with cyclophosphamide (NSC-26271) as remission maintenance therapy in previously treated children with acute lymphoblastic leukemic or acute undifferentiated leukemia: possible effectiveness in reducing the incidence of central nervous system leukemia. Cancer Chemother Rep 59:9899941975Cancer Chemother Rep 59:

25.

Wilson CBGutin PBoldrey EBet al: Single-agent chemotherapy of brain tumors. A five-year review. Arch Neurol 33:7397441976Arch Neurol 33:

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