PCV For Brain Tumors: Abstracts
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1. Perry JR, Brown MT, Gockerman JP, "Acute leukemia following treatment of malignant glioma" J Neurooncol 1998 Oct;40(1):39-46 PMID: 9874184, UI: 99089580, Division of Neurology, Duke University Medical Center, Durham, NC, USA.

We report two patients with acute myeloid leukemia (AML) following therapy for malignant glioma; one was a young women treated heavily with alkylating agents for glioblastoma and the other a young man treated with high doses of procarbazine, lomustine, and vincristine (PCV) for anaplastic astrocytoma.

We found 26 other examples of therapy related leukemia in adult and pediatric brain tumor patients. Including our two, there were 12 patients with malignant glioma; median interval from treatment to diagnosis of AML was 31 months. Nine adult malignant glioma patients all received nitrosoureas, some as the sole form of chemotherapy. No definite cases occurred after radiotherapy alone. Based upon analogy with other cancers, the cumulative dose of chemotherapy, especially alkylating agents, is the major risk factor for development of secondary AML. Agents implicated include carmustine (BCNU), lomustine (CCNU), and procarbazine.

Conventional radiotherapy appears not to confer additional risk. Progressive macrocytosis, early dose reductions for thrombocytopenia, and refractory anemia may provide early diagnostic clues. Current glioma therapy is leukemogenic but the number of patients who survive the interval required to induce AML is small; nevertheless, the identification of chemosensitive types of glioma, and subgroups of patients who derive the most benefit from chemotherapy, may result in increasing numbers of patients at risk of long term complications.

If regimens such as PCV continue to prove valuable in neurooncology the risk of leukemia will require integration into the clinical decision process. A search for more effective therapy with minimal mutagenicity remains critical.



2. Environmental Health Information Service, Report on Carcinogens 1998 Summary "Reasonably Anticipated to be a Human Carcinogen Eighth Report on Carcinogens" http://ntp-server.niehs.nih.gov/Main_pages/NTP_8RoC_pg.html http://ehis.niehs.nih.gov/ (27 Jan 99)
PROCARBAZINE HYDROCHLORIDE
CAS No. 366-70-1
First Listed in the Second Annual Report on Carcinogens
3D Structure
CARCINOGENICITY
There is sufficient evidence for the carcinogenicity of procarbazine hydrochloride in experimental animals (NCI 19, 1979; IARC V.26, 1981; IARC S.4, 1982; IARC S.7, 1987). The generic name procarbazine is used interchangeably with procarbazine hydrochloride in the literature, and since only procarbazine hydrochloride is produced, it was assumed to be procarbazine hydrochloride under study. When administered by repeated intraperitoneal injection, procarbazine hydrochloride induced olfactory neuroblastomas, adenocarcinomas of the mammary gland, and malignant lymphomas, lymphocytic type, in rats of both sexes, and olfactory neuroblastomas in mice of both sexes and uterine adenocarcinomas in female mice. When administered by gavage, the compound induced leukemia and benign tumors of the lung in mice of both sexes and adenocarcinomas or carcinomas of the mammary gland in female rats but not in male rats. When administered by repeated intravenous injections, the compound induced three renal sarcomas and two intra-abdominal spindle cell sarcomas in male rats. Male and female monkeys, including Rhesus, cynomolgus and African green monkeys, were given procarbazine hydrochloride by subcutaneous, intravenous, and oral routes. Rhesus monkeys developed acute myelogenous leukemia. Cynomolgus monkeys had leukemia or lymphoma, and multiple hemangiosarcomas. The rarity of neoplasms, and in particular leukemias (none in control monkeys in that colony), strongly suggests that procarbazine induced the tumors.

An IARC Working Group reported that there were no adequate data available to evaluate the carcinogenicity of procarbazine hydrochloride in humans as no epidemiologic study of procarbazine as a single agent was available. In various combinations with other chemotherapeutic agents given for Hodgkin's disease, procarbazine use has repeatedly been shown to lead to the appearance of acute nonlymphocytic leukemia. These combinations usually also include nitrogen mustard, an alkylating agent which is also a potent animal carcinogen, and these many observations do not permit conclusions about the independent effect of either drug.

PROPERTIES Procarbazine hydrochloride is a white-to-pale yellow crystalline powder with a slight odor. It is soluble but unstable in water and aqueous solutions. When heated to decomposition, it emits very toxic fumes of nitrogen oxides (NOx). It is available in the United States as a USP grade containing 98.5%-100.5% active ingredient. USE

Procarbazine hydrochloride is used in human medicine as an antineoplastic agent. It is used in combination with other antineoplastic agents to treat Hodgkin's disease and is also used to treat malignant melanoma, non-Hodgkin's lymphoma, and small-cell carcinomas of the lung (IARC V.26, 1981). FDA approved its use in 1969, indicating that the drug should be used as an adjunct to standard therapy.

PRODUCTION The USITC identified two U.S. producers of procarbazine hydrochloride in 1988, but no production data were reported (USITC, 1989). The USITC reported that two U.S. companies produced an unknown quantity of procarbazine hydrochloride in 1986 (USITC, 1987). No other production, import, or export data were available. The 1979 TSCA Inventory reported no production data for procarbazine or its hydrochloride (TSCA, 1979).

EXPOSURE The primary routes of potential human exposure to procarbazine hydrochloride are ingestion, inhalation, and dermal contact. For patients receiving the drug, the usual initial dose of procarbazine hydrochloride is 2-4 mg/kg body weight daily given orally in divided doses for 1 week, then 4-6 mg/kg body weight daily, until signs of bone marrow depression occur. After bone marrow recovery, treatment is resumed at a dose level of 1-2 mg/kg body weight per day (IARC V.26, 1981). Potential occupational exposure to procarbazine hydrochloride could occur during the manufacture, formulation, and packaging of the drug. The National Occupational Exposure Survey (1981-1983) indicated that 1,329 workers, including 289 women, potentially were exposed to procarbazine hydrochloride (NIOSH, 1984). This estimate was derived from observations of the actual use of the compound (89% of total observations) and of tradename products known to contain the compound (11%). Health professionals (e.g., physicians, nurses, pharmacists) are potentially exposed to the pharmaceuticals during preparation, administration, and cleanup. In 1980, the National Prescription Audit reported 1.5 million prescriptions dispensed for procarbazine hydrochloride. Some of the metabolites of procarbazine are both carcinostatic and carcinogenic.

REGULATIONS Procarbazine hydrochloride is used primarily as a pharmaceutical and is produced in low quantities relative to other chemicals; therefore, it is of little regulatory concern to EPA. However, there may be a small pollution problem relative to hospital wastes. Procarbazine hydrochloride is approved as a prescription drug for treatment of Hodgkin's disease and for patients nonresponsive to other cancer treatments. It is subject to FDA prescription drug labeling requirements under the Food, Drug, and Cosmetic Act (FD&CA). OSHA regulates procarbazine hydrochloride under the Hazard Communication Standard and as a chemical hazard in laboratories.



3.. Environmental Health Information Service, Report on Carcinogens 1998 Summary, "Known to be a Human Carcinogen Eighth Report on Carcinogens" http://ntp-server.niehs.nih.gov/Main_pages/NTP_8RoC_pg.html http://ehis.niehs.nih.gov/ (27 Jan 99)

Report On Carcinogens
1998 Summary
Known to be a Human Carcinogen Eighth Report on Carcinogens 1-(2-CHLOROETHYL)-3-(4-METHYLCYCLOHEXYL)-1-NITROSOUREA (MeCCNU) CAS No. 13909-09-6
First Listed in the Sixth Annual Report on Carcinogens
3D Structure

CARCINOGENICITY There is limited evidence for the carcinogenicity of 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU) in experimental animals (IARC S.7, 1987). Data on MeCCNU were included in a report in which a large number of cancer chemotherapeutic agents were tested for carcinogenicity by repeated intraperitoneal injection in rats and mice (Weisburger, 1977). The compound increased the incidence of tumors in rats and slightly increased the incidence of leukemia and lymphosarcomas in female mice. When administered by intravenous injection, MeCCNU induced lung tumors in rats. An IARC Working Group reported that there is sufficient evidence for the carcinogenicity of MeCCNU in humans (IARC S.7, 1987). Adjuvant treatment with the compound has been evaluated in 3,633 patients with gastrointestinal cancer treated in nine randomized trials. Among 2,067 patients treated with the compound, 14 cases of acute nonlymphocytic leukemia occurred, whereas one occurred among 1,566 patients treated with other therapies. Cumulative risk was not affected by concomitant radiotherapy or immunotherapy. A subsequent report described a strong dose-response relationship, giving a relative risk of almost fortyfold among patients who had received the highest dose.

PROPERTIES MeCCNU is a powder stable in pure form and in solution at slightly acid pH, and readily decomposes in strong acid and alkaline solution (Safety Data Sheet, Division of Safety, National Institutes of Health, 1986). It is very slightly soluble in water, soluble in absolute ethanol, lipids, and nonpolar, organic solvents. Conditions contributing to instability are acid, alkali and elevated temperatures. There is very little information in the literature concerning the chemical and physical properties of MeCNNU. There is much more voluminous information on 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), which is chemically and physically similar to MeCCNU. MeCCNU is likely to be inactivated under conditions of fire. Hazardous decomposition products under conditions of fire are likely to include hydrochloric acid and nitrogen oxides. The formation of 2-chloroethanol, acetaldehyde, vinyl chloride, and cyclohexylamine in varying amounts has been reported for the aqueous hydrolysis of CCNU. The same products are probably formed from MeCCNU (except that MeCCNU would give 4-methylcyclohexylamine) and may also be decomposition products on ignition. USE MeCCNU has been used to treat malignant melanoma and cancer of the brain, lung, and digestive tract (Boice et al., 1983). MeCCNU is an experimental tumorigen.

PRODUCTION No production figures for MeCCNU are available.

EXPOSURE The National Occupational Exposure Survey (1983) estimated that 229 total workers, including 82 women, were potentially occupationally exposed to MeCCNU (RTECS, 1990).

REGULATIONS OSHA regulates MeCCNU as a chemical hazard in laboratories under the Hazard



Arch Neurol 1976 Nov;33(11):739-44 Single-agent chemotherapy of brain tumors. A five-year review. Wilson CB, Gutin P, Boldrey EB, Drafts D, Levin VA, Enot KJ

Identification of effective single chemotherapeutic agents for brain tumors must precede the rational use of multiple drug combinations. In phase 2 trials beginning in 1968, 158 patients with intrinsic brain tumors (mostly recurrent malignant astrocytomas) were considered evaluable. The larger trials with more effective drugs produced these results: carmustine (BCNU) response rate, 47%, with median duration of nine months; lomustine (CCNU), 44%, with median duration of six months; procarbazine hydrochloride, 52%, with median duration six months; carmustine and vincristine sulfate combined, 44%, with median duration of only four months; and BIC (5-[3,3-bis(2-chloroethyl)-1-triazeno]imidazole-4-carboxamide), 38%, with median duration of five months. Administration of glucocorticoids was not found to bias the frequency of response. Forty-seven patients, 26 of whom had responded to the initial drug, received a second drug. Among 26 patients who were evaluable, only four responded to the second drug. PMID: 185991, UI: 77044132



4.. Sanderson PA, Kuwabara T, Cogan DG, "Optic neuropathy presumably caused by vincristine therapy." Am J Ophthalmol 1976 Feb;81(2):146-50 PMID: 1251878, UI: 76133933

A 36-year-old man with Hodgkin's disease developed symmetric optic neuropathy after treatment with nitrogen mustard, vincristine, procarbazine, and prednisone. Histopathologic sections of the eyes showed loss of ganglion cells in the macular region and atrophy of the corresponding fibers in the optic nerve. Vincristine is presumed to have been the cause of the optic neuropathy because of its recognized neurotoxicity and its temporal relation to the onset of the visual complaint. PMID: 1251878, UI: 76133933



5.. Gutin PH, Wilson CB, Kumar AR, et al., "Phase II study of procarbazine, CCNU, and vincristine combination chemotherapy in the treatment of malignant brain tumors." Cancer 1975 May;35(5):1398-404 PMID: 1122488, UI: 75129136

Forty-eight patients with primary or metastatic malignant tumors of the central nervous system (CNS) were treated with combination chemotherapy, consisting or procarbazine (100 mg/m2 X 14 days), CCNU (75 mg/m2), and vincristine (1.4 mg/m2 X 2, 1 week apart) (PCV) every 4 weeks. Most patients had undergone initial resection of primary tumors, postoperative radiotherapy, and a post irradiation interval of 3 months or more. Other patients harbored unbiopsied, newly-discovered primary or metastatic tumors. All patients were deteriorating neurologically when treatment began. Overall response rate for PCV combination therapy was 44%, no better than results obtained with single agent procarbazine or BCNU, the most effective drugs used alone in previous brain tumor chemotherapy PMID: 1122488, UI: 75129136



6.. Sandberg-Wollheim M, Malmstrom P, Stromblad LG, et al., "A randomized study of chemotherapy with procarbazine, vincristine, and lomustine with and without radiation therapy for astrocytoma grades 3 and/or 4." Cancer; VOL 68, ISS 1, 1991, P22-9 TOXBIB/91/266221;PMID: 2049748, UI: 91266221 Department of Neurology, University Hospital, Lund, Sweden.

The authors undertook a controlled, prospective, randomized study of 171 patients with supratentorial astrocytoma grades 3 and/or 4 (classified according to Kernohan). All patients were given chemotherapy consisting of procarbazine, vincristine, and lomustine (CCNU) (PVC). Half of the patients received whole-brain irradiation (RT) to a dose of 5800 cGy in the tumor-bearing hemisphere and 5000 cGy in the contralateral hemisphere. After diagnosis of progressive tumor growth, patients received individual treatment. The endpoint of the study was time to progression, but cases were followed until the patients died. Median time to progression (MTP) for the whole randomized population was 21 weeks. Median survival time (MST) was 53 weeks; 18% of patients survived for 2 years or longer. Survival analysis showed that patients less than 50 years of age treated with PVC plus RT had significantly longer MTP (81 weeks) and MST (124 weeks) than all other patients. For patients less than 50 years of age treated with PVC alone, MTP was 21 weeks and MST was 66 weeks. For patients more than 50 years of age treated with PVC plus RT, MTP was 23 weeks and MST was 51 weeks; in the PVC group, MTP was 17 weeks and MST was 39 weeks. Age, Karnofsky index, areas of Grade 2, and absence of extensive necrosis in the tumor were significant prognostic factors in the univariate analyses. Patients less than 50 years of age treated with PVC plus RT had significantly longer survival (P = 0.037) when correcting for these factors in a multi-variate analysis.



7.. Postma TJ, van Groeningen CJ, et al., "Neurotoxicity of combination chemotherapy with procarbazine, CCNU and vincristine (PCV) for recurrent glioma." J Neurooncol 1998 May;38(1):69-75 PMID: 9540059, UI: 98200881 Department of Neurology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.

In cerebral glioma combination chemotherapy with procabazine, CCNU and vincristine (PCV) is used as adjuvant therapy in cases of recurrence. Standard PCV is usually well tolerated, but intensive PCV (CCNU 130 mg/m2 on day 1, procarbazine 75 mg/m2 on day 8-21, vincristine 1.4 mg/m2 on day 8 and 29; 6 courses every 6 weeks) is less well tolerated. We observed central neurotoxic side effects (focal neurological deficit, cognitive disturbances, slowing of EEG background activity, atrophy on cerebral MR) in combination with hematological and hepatic toxicity in four of 26 PCV treated patients with recurrent glioma. Prolonged myelo-suppression and/or ongoing (partial reversible in two patients) neurological deficit still influence daily life in three of four patients months after discontinuation of chemotherapy. Despite the fact that all four patients used anticonvulsants and have been treated with radiotherapy in the past, we have the strong impression that central neurotoxic side effects are related to intensive PCV therapy. We advocate to use the standard PCV regimen in patients with recurrent glioma, because of this potential toxicity and the lack of evidence that intensive PCV leads to better tumor control than standard PCV in cerebral glioma.



8.. Bouffet E, Mornex F, Jouvet A, Thiesse P, Mertens P, Helfre S, Sindou M, Bret P, "Assessment of procarbazine, vincristine and lomustine association (PCV protocol) in oligodendroglioma and mixed glioma." Bull Cancer 1997 Oct;84(10):951-6, PMID: 9435796, UI: 98098085 Departement de neurooncologie, Centre Leon-Berard, Lyon, France.

Effective chemotherapy using PCV (procarbazine, lomustine and vincristine) has been documented in anaplastic oligodendrogliomas and oligoastrocytomas. A pilot study using PCV was conducted for relapsing patients with anaplastic oligodendrogliomas and oligoastrocytomas. Preliminary results are reported. Fourteen patients were enrolled. All received at least two courses of PCV and were evaluable for response. Eleven patients (78%) responded to chemotherapy with complete responses in 2 patients. Response was more obvious regarding contrast enhanced areas than volumes changes (11 responses versus 7). A story of seizure was the main clinical prognostic factor for response. All toxicities were manageable and no treatment related death occurred. Chemotherapy is an effective treatment in aggressive oligodendrogliomas. Further studies must assess the role of chemotherapy in the multidisciplinary management of oligodendroglioma. PMID: 9435796, UI: 98098085



9.. Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, et al., "Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas." J Natl Cancer Inst 1998 Oct 7;90(19):1473-9, PMID: 9776413, UI: 98447308 Department of Medical and Experimental Oncology, London Regional Cancer Centre, Ontario, Canada.

BACKGROUND/METHODS: Gliomas are common malignant neoplasms of the central nervous system. Among the major subtypes of gliomas, oligodendrogliomas are distinguished by their remarkable sensitivity to chemotherapy, with approximately two thirds of anaplastic (malignant) oligodendrogliomas responding dramatically to combination treatment with procarbazine, lomustine, and vincristine (termed PCV). Unfortunately, no clinical or pathologic feature of these tumors allows accurate prediction of their response to chemotherapy. Anaplastic oligodendrogliomas also are distinguished by a unique constellation of molecular genetic alterations, including coincident loss of chromosomal arms 1p and 19q in 50%-70% of tumors. We have hypothesized that these or other specific genetic changes might predict the response to chemotherapy and prognosis in patients with anaplastic oligodendrogliomas. Therefore, we have analyzed molecular genetic alterations involving chromosomes 1p, 10q, and 19q and the TP53 (on chromosome 17p) and CDKN2A (on chromosome 9p) genes, in addition to clinicopathologic features in 39 patients with anaplastic oligodendrogliomas for whom chemotherapeutic response and survival could be assessed.

RESULTS/CONCLUSIONS: Allelic loss (or loss of heterozygosity) of chromosome 1p is a statistically significant predictor of chemosensitivity, and combined loss involving chromosomes 1p and 19q is statistically significantly associated with both chemosensitivity and longer recurrence-free survival after chemotherapy. Moreover, in both univariate and multivariate analyses, losses involving both chromosomes 1p and 19q were strongly associated with longer overall survival, whereas CDKN2A gene deletions and ring enhancement (i.e., contrast enhancement forming a rim around the tumor) on neuroimaging were associated with a significantly worse prognosis. The inverse relationship between CDKN2A gene deletions and losses of chromosomes 1p and 19q further implies that these differential clinical behaviors reflect two independent genetic subtypes of anaplastic oligodendroglioma. These results suggest that molecular genetic analysis may aid therapeutic decisions and predict outcome in patients with anaplastic oligodendrogliomas. PMID: 9776413, UI: 98447308



10.. Kim L, Hochberg FH, Thornton AF, et al., "Procarbazine, lomustine, and vincristine (PCV) chemotherapy for grade III and grade IV oligoastrocytomas." J Neurosurg 1996 Oct;85(4):602-7, PMID: 8814163, UI: 96409181
Brain Tumor Center (Department of Medical Neuro-Oncology, Radiation Therapy, and Neurosurgical Oncology, Boston, Massachusetts, USA.

The authors provided procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy to 32 patients whose tumors contained varying mixtures of oligodendroglial and astrocytic cells. Twenty-five patients had oligodendroglioma-astrocytoma (oligoastrocytoma) with a histological Grade of III (19 patients) or IV (six patients); seven had anaplastic oligodendroglioma. The PCV therapy was administered every 6 weeks for a total of at least 124 cycles. The median duration of follow-up review from the start of chemotherapy was 19.3 months. Nineteen patients were treated before receiving radiation therapy and 12 after receiving it (one patient received concurrent radiotherapy and chemotherapy). Grade 3 or 4 hematological toxicity was experienced by nine (31%) of 29 patients. Ten patients had delayed treatment due to treatment-related toxicities (34.5%). Ninety-one percent of the 32 patients responded to the therapy. These included 10 patients with a complete response and 19 with a partial response. The median time to progression was 15.4 months for all patients and 23.2 months for those with Grade III tumors. The median time to progression for patients with Grade III oligoastrocytomas was 13.8 months; for those with Grade IV oligoastrocytoma it was 12.4 months and for those with anaplastic oligodendrogliomas it was 63.4 months (p = 0.0348). These patients survived a median of 49.8 months, 16 months, and 76 or more months, respectively, from the start of chemotherapy (p = 0.0154). The PCV therapy provides durable responses in patients with Grade III or IV oligoastrocytomas.
PMID: 8814163, UI: 96409181



11.. Peterson K, Paleologos N, Forsyth P, Macdonald DR, Cairncross JG, "Salvage chemotherapy for oligodendroglioma" J Neurosurg 1996 Oct;85(4):597-601,
Department of Neurology, University of Minnesota, Minneapolis, USA.

The authors present their experience with salvage chemotherapy for oligodendroglioma, an uncommon brain tumor that responds predictably to PCV (procarbazine, lomustine (CCNU), and vincristine) when given as initial therapy. The authors reviewed the records of patients with oligodendrogliomas who received a second, third, or fourth cytotoxic regimen prescribed to combat tumor recurrence documented by computerized tomography or magnetic resonance imaging following an initial chemotherapy program. Initial regimens were prescribed at various time points: as neoadjuvant therapy prior to radiotherapy, as adjuvant therapy in conjunction with radiotherapy, or at recurrence following radiotherapy. Response criteria were based on measurable changes in tumor size following published guidelines. Twenty-three patients (14 men and nine women) aged 25 to 58 years (median 36 years) received 33 salvage regimens. When non-PCV chemotherapy had been the prior regimen, seven (88%) of eight patients responded to salvage chemotherapy, all seven (100%) responding to PCV. Administration of PCV was effective after regimens of carmustine and CCNU but was ineffective after prior administration of PCV. When PCV had been given any time previously, only four (19%) of 21 patients responded to salvage chemotherapy; however, four (40%) of 10 patients who received etoposide (VP-16)/cisplatin (CDDP) responded. Despite the small number of patients, two noteworthy trends emerge from these data: first, PCV is a highly effective salvage treatment when used at tumor recurrence following non-PCV chemotherapy regimens, and second, the synergistic combination of VP-16 and CDDP may exert substantial anti-oligodendroglioma activity, and it warrants further evaluation.



12.. Glass J, Hochberg FH, Gruber ML, Louis DN, Smith D, Rattner B,"The treatment of oligodendrogliomas and mixed oligodendroglioma-astrocytomas with PCV chemotherapy." J Neurosurg 1992 May;76(5):741-5, PMID: 1564535, UI: 92226817
Department of Neurology, Massachusetts General Hospital, Boston.

Malignant oligodendrogliomas have been shown to be responsive to chemotherapy. The authors administered systemic chemotherapy to seven patients with oligodendroglioma or anaplastic oligodendroglioma, and to 14 with mixed oligodendroglioma-astrocytoma. Fourteen patients underwent chemotherapy before and seven after irradiation. The PCV (procarbazine, methyl-1-(2-chloroethyl)-1-nitrosourea (CCNU), and vincristine) chemotherapy was administered every 6 weeks (42-day cycles) for two to five cycles as follows: CCNU, 110 mg/sq m on Day 1; procarbazine, 60 mg/sq m/day on Days 8 to 21; and vincristine, 1.4 mg/sq m/day on Days 8 and 29. Complete or partial (greater than 50% reduction in tumor mass) responses at 20 to 100+ weeks after treatment were noted in 11 (79%) of the 14 patients treated before irradiation, including two with anaplastic oligodendroglioma and nine with mixed tumors. Complete responses were seen in two patients, one with anaplastic oligodendroglioma and one with a mixed tumor. Partial responses were seen in three of seven patients treated after radiotherapy. Stabilization of tumor growth followed PCV chemotherapy in four patients (two treated before and two after radiotherapy). Tumor growth progressed in two patients during therapy despite an initial response and in two patientsdespite therapy. The authors conclude that mixed oligodendroglial tumors aswell as anaplastic oligodendrogliomas are responsive to PCV chemotherapy.PMID: 1564535, UI: 92226817 ----------------------------------------------------------- 13.. Jeremic B, Jovanovic D, Djuric LJ, Jevremovic S, Mijatovic LJ, et al., "Advantage of post-radiotherapy chemotherapy with CCNU, procarbazine, and vincristine (mPCV) over chemotherapy with VM-26 and CCNU for malignant gliomas." J Chemother 1992 Apr;4(2):123-6, PMID: 1321239, UI: 92333357
Department of Oncology, University Hospital, Kragujevac, Yugoslavia.

Between 1981 and 1987, 133 patients with anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) were treated with surgery and post-operative radiotherapy. 36 AA and 31 GBM patients were treated with adjuvant chemotherapy consisting of CCNU 100 mg/m2 day 1, procarbazine 60 mg/m2 days 1-14, and vincristine 1.4 mg/m2 (max. 2 mg) days 1 and 8, every 6 weeks which we called a "modified PCV" (mPCV) regimen. 37 AA and 29 GBM patients were treated with adjuvant chemotherapy consisting of VM-26 75 mg/m2 days 1 and 2, and CCNU 60 mg/m2 days 3 and 4, every 6 weeks. Prognostic covariates such as patient's age, Karnofsky performance status score and the extent of surgery were balanced between the two treatment groups. The time to tumor progression and survival time for both regimens show that mPCV produces a two-fold increase in these factors at the 50th and 25th percentile for AA patients, but not for GBM patients, although there are more long-term GBM survivors with mPCV than with the VM-26 + CCNU regimen.



14. Levin VA, Silver P, Hannigan J, Wara WM, Gutin PH, Davis RL, Wilson CB, et al., "Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, 6G61 final report." Int J Radiat Oncol Biol Phys 1990 Feb;18(2):321-4, PMID: 2154418, UI: 90153593
Department of Neurological Surgery, University of California-San Francisco Medical School 94143.

Data from Northern California Oncology Group protocol 6G61, which was closed in February 1983, were reanalyzed in December 1988. The protocol called for a randomized trial that compared the effects of following 60 Gy radiation/oral hydroxyurea treatment with either carmustine (BCNU) or the combination of procarbazine, lomustine (CCNU), and vincristine (PCV) for two histologic strata: glioblastoma multiforme and other anaplastic gliomas. PCV produced longer survival and time to tumor progression than BCNU for both histologic groups, although the difference was statistically significant only for the anaplastic gliomas. With PCV treatment, time to progression and survival doubled for anaplastic glioma patients in the 50th and 25th percentiles.



15. Repetto L, Grimaldi A, Ardizzoni A, Sertoli MR, Rosso R, "Metastatic malignant melanoma treated with procarbazine, vincristine and lomustine (POC)." Chemioterapia 1987 Feb;6(1):63-5,PMID: 3829137, UI: 87159595

Fourteen consecutive melanoma patients with evaluable metastatic disease were treated with combination chemotherapy including procarbazine, vincristine and lomustine (POC). All but two patients had been previously treated with single agent chemotherapy (dacarbazine 11 patients, melphalan plus hyperthermia 1 patient). One transient partial response and 4 stable disease were noted. Median overall survival was 5 months. In our experience POC seems unlikely to improve the response rate compared with other chemotherapy combinations. Patient characteristics can partially explain the contrasting results reported in the literature. 16. Bremer AM, Nguyen TQ, Balsys R, "Therapeutic benefits of combination chemotherapy with vincristine, BCNU, and procarbazine on recurrent cystic craniopharyngioma. A case report." J Neurooncol 1984;2(1):47-51,

The authors report a case of recurrent cystic craniopharyngioma managed with chemotherapy. The patient refused adamantly the alternative therapy methods, such as surgery and radiotherapy, initially offered. Eight courses of chemotherapy with vincristine (2 mg/M2, i.v.) on day 1,1,3-bis(2-chloroethyl)-1-nitrosourea (100 mg/M2, i.v.) on day 2, and procarbazine (50 mg, b.i.d., p.o.) on days 3 to 21 were administered at 6 week intervals. The effectiveness of this treatment modality has been evaluated by the unequivocal neurological improvement and by the decreases in size of the cyst using serial computerized tomography. Toxocities were mild and chiefly hematological.



17. Brufman G, Halpern J, Sulkes A, Catane R, Biran S, "Procarbazine, CCNU and vincristine (PCV) combination chemotherapy for brain tumors." Oncology 1984;41(4):239-41,

12 patients with brain tumors were treated with a combination of procarbazine, CCNU (bis-2-chloroethyl-3-cyclohexyl-1-nitrosourea) and vincristine. 3 of 8 patients (37.5%) with primary brain tumors responded to chemotherapy, with a mean duration of 9.3 months. The mean survival of responders was 11.7 months, versus 3.6 months for nonresponders. 4 patients with metastatic brain tumors were also treated with the same combination chemotherapy; only 1, suffering from a lymphoma of the brain, responded partially.



18. Genot JY, Krulik M, Poisson M, van Efferterre R, et al., "Two cases of acute leukemia following treatment of malignant glioma." Cancer 1983 Jul 15;52(2):222-6,

Two female patients, 42 and 30 years old, respectively, died of acute nonlymphocytic leukemia 43 and 38 months, respectively, after a subsequent treatment: chemotherapy for one and irradiation and chemotherapy for the other, following excision of a malignant glioma. At the time of death, both seemed to be in complete remission of their brain tumor. Both had been treated with procarbazine and nitrosoureas. The latter were responsible for severe myelosuppressive episodes and seem to have played an essential role in the induction of the leukemia. In one case, a myelodysplasia was observed before the onset of the AL and the diagnosis of refractory anemia with excess of blasts seemed warranted. Secondary acute leukemias are rare in the evolution of malignant gliomas and the usefulness of subsequent radiochemotherapy cannot be questioned at the present time. The risks involved in this therapy are minor when compared to the short-term fatal prognosis of this type of tumor. 19. Avellanosa AM, West CR, Tsukada Y, et al., "Chemotherapy of nonirradiated malignant gliomas. Phase II: study of the combination of methyl-CCNU, vincristine, and procarbazine." Cancer 1979 Sep;44(3):839-46,

Twenty-eight adult patients with nonirradiated malignant gliomas of the brain were administered a combination of methyl-CCNU (130 mg/m2, p.o., day 1), vincristine (2 mg/m2, i.v., day 1) and procarbazine (100 mg/m2, p.o., days 2 to 15) (MVP), scheduled to be given at successive 6 week intervals. Nineteen (67.9%) were not responsive to MVP and 9 (32.1%) were. Of 16 who had previous partial resection of their tumors, 8 (50%) responded to MVP and 8 (50%) did not. Of 12 who had previous biopsy, only 1 (8.3%) responded. Overall 1-year survival rate for the 28 patients was 28.6%. Major side effects of MVP were leukopenia, thrombocytopenia, pulmonary emboli, and thrombophlebitis, detected mainly during the first 20 to 24 weeks of treatment.



20. Hildebrand J, "A review of studies of the EORTC brain tumor group." Cancer Treat Rep 1981;65 Suppl 2:89-94,

The results of three randomized trials performed by the EORTC Brain Tumor Group in patients with histologically proven brain gliomas are presented. CCNU (130 mg/m2 every 6 weeks) in combination with dexamethazone (4-20 mg daily) prolonged total survival compared to a group of patients treated only with corticosteroids. CCNU (130 mg/m2 every 6 weeks) either alone or one day after VM-26 (100 mg/m2) produced an objective remission in less than 30% of treated patients. However, the two treatment modalities did not prolong the interval between surgical removal of the tumor and relapse (recurrence). None of 12 patients with signs of brain tumor recurrence previously treated with VM-26 plus CCNU responded to procarbazine (3-week courses of 150 mg/m2/day).



21. Crafts DC, Levin VA, Edwards MS, Pischer TL, Wilson CB "Chemotherapy of recurrent medulloblastoma with combined procarbazine, CCNU, and vincristine." J Neurosurg 1978 Oct;49(4):589-92,

Seventeen patients with recurrent medulloblastoma were treated with a combination of three drugs: procarbazine, CCNU, and vincristine (PCV). Tumor recurrence was documented at varying periods following surgery and radiotherapy. Among 16 evaluable patients, ten showed a response to PCV on the basis of subjective neurological improvement and a decrease in tumor size by radiological criteria. Five patients were designated as having stable disease on the basis of no change in neurological status and tumor size. One patient showed uninterrupted progression of disease. The median time to progression for all patients was 45 weeks. Significnat myelotoxicity, exacerbated by prior spinal irradiation, compromised therapy.

After an initial response, it was often necessary to reduce the higher doses of CCNU and procarbazine that caused concomitant bone-marrow toxicity; as a consequence of the lowered doses, tumor progression was then frequently observed. The authors conclude that PCV is an effective form of palliative therapy for recurrent medulloblastoma. 22. Buge A, Poisson M, Pouillart P, "A study of the use of sequential chemotherapy in 176 cases of glioblastoma." Rev Neurol (Paris) 1978 May;134(5):369-77.

Sequential administration of VM 26 and CCNU has been used in France for the treatment of glioblastoma since 1973. Results have shown that this association can cause a remission lasting, on average, from seven to eight months after starting chemotherapy. It seems that, adding Adriamycin to this sequential therapy does not increase its efficiency. On the other side, dosage and the interval between cycles of chemotherapy appear to be a determining factor in the activity, but the limits are very narrow. Therapy is either ineffective or has doubtful efficiency in about one third of patients, and even when prolonged clinical remission is obtained, cessation of therapy, usually due to a persistent thrombopenia is followed by progression of the tumour in the following months. The large amount of research being made in the field of cellular kinetics and pharcacology will, hopefully, lead to improvement in results.



23. Beisler JA, Peng GW, Driscoll JS, "Potential antitumor agents: procarbazine analogs and other methylhydrazine derivatives." J Pharm Sci 1977 Jun;66(6):849-52,

With the objective of developing new antitumor agents, two groups of hydrazine compounds, having structural features in common with the antitumor agents procarbazine and 1-acetyl-2-picolinoylhydrazine, were synthesized. The L-1210 leukemia system was used to evaluate compounds of both groups. The aliphatic procarbazines also were screened for antitumor activity as bis(benzyloxycarbonyl) derivatives and as derivatives having a phthalazine nucleus. No L-1210 antitumor activity was exhibited by these compounds.



24. Cairncross G, Macdonald D, Ludwin S, et al., "Chemotherapy for anaplastic oligodendroglioma." J Clin Oncol 1994 Oct;12(10):2013-21,
Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada.

PURPOSE: To examine the rate and duration of response of anaplastic oligodendrogliomas to a dose-escalated combination chemotherapy regimen consisting of procarbazine, lomustine (CCNU), and vincristine (PCV) and to evaluate the side effects of this treatment.

METHODS: In this single-arm multicentered phase II study, patients with measurable, newly diagnosed or recurrent, contrast-enhancing anaplastic oligodendrogliomas were treated with up to six cycles of PCV. Central pathology and radiology review were mandatory, and rigorous response criteria based on imaging were used.

RESULTS: Thirty-three patients entered the trial; nine were excluded subsequently, seven due to ineligible pathology. Eighteen of 24 eligible patients (75%) responded, nine completely (38%), four had stable disease (SD), and two progressed during the first cycle of PCV. Responses were observed in nine of 10 patients (90%) with a preexisting low-grade oligodendroglioma and 10 of 15 (67%) with necrotic tumors, called glioblastoma multiforme by some. Previously irradiated patients were as likely to respond to PCV as those newly diagnosed (11 of 15 [73%] v seven of nine [78%]). The median time to progression will be at least 25.2 months for complete responders, and was 14.2 months for partial responders and 6.8 months for stable patients. Four ineligible patients also responded to PCV; all had gliomas with oligodendroglial differentiation. All responders,or ineligible, were stable or improved neurologically, but nine of 22 (41%) experienced a decline in Eastern Cooperative Oncology Group (ECOG) performance status of one grade while on PCV. Adverse events on treatment included a death from Pneumocystis pneumonia, a severe reversible encephalopathy due to procarbazine, an intratumoral hemorrhage, and a subdural hematoma. All other acute toxicities were anticipated and manageable.

CONCLUSION: Anaplastic oligodendrogliomas are chemosensitive brain cancers. Patients with these tumors respond predictably, durably, and often completely to PCV, and many tolerate a dose-escalated formulation. Cooperative group and randomized trials will be necessary to explore fully the role of chemotherapy in the treatment of aggressive oligodendrogliomas.



25. Newton HB, Bromberg J, Junck L, Page MA, Greenberg HS, "Comparison between BCNU and procarbazine chemotherapy for treatment of gliomas." J Neurooncol 1993 Mar;15(3):257-63,
Department of Neurology, University of Michigan.

We compared sequential single-agent BCNU and procarbazine (PCB) chemotherapy in 31 patients with gliomas [grade IV (10), grade III (15), grade II (6)]. Patients had failed surgical biopsy +/- resection and radiation therapy. All patients were treated initially with BCNU 150-300 mg/m2 by intra-arterial or intravenous route every 6 weeks. After CT evidence of tumor progression, all patients received PCB 150 mg/m2/day for 28 days every 8 weeks. Patient responses to BCNU were CR (0), PR (7), SD (12), progression (12), and to PCB CR (2), PR (9), SD (6), and progression (14). Kaplan-Meier estimates of median time to failure for all patients were shorter for BCNU, 5.0 months (range 1.5-20), than for PCB, 6.0 months (range 2-50+). There was a statistically significant difference (Mantel-Cox test, p = 0.02) in the distribution of time to disease progression between the two drugs, especially for grade III tumors (p = 0.02). The cumulative proportion of patients without disease progression at 6 months was 26% while on BCNU, compared to 48% while on PCB; at 12 months the cumulative proportions were 3% for BCNU compared to 35% for PCB. Although there was no formal washout period between administration of the two drugs, no carryover effect was evident. These data provide further evidence that PCB has significant activity against malignant glioma and may, in fact, be more effective than BCNU.



26. Coyle T, Bushunow P, Winfield J, Wright J, Graziano S. "Hypersensitivity reactions to procarbazine with mechlorethamine, vincristine, and procarbazine chemotherapy in the treatment of glioma." Cancer 1992 May 15;69(10):2532-40, PMID: 1568176, UI: 92233357
Department of Medicine, State University of New York Health Science Center, Syracuse.

The authors report the clinical features of hypersensitivity reactions believed to result from procarbazine in eight patients treated with mechlorethamine, vincristine, and procarbazine (MOP) for high-grade glioma. There was one instance of hypersensitivity in 7 patients treated for recurrent disease and seven instances in 16 patients treated with an adjuvant protocol using MOP directly after surgery. Maculopapular rash was seen in seven of eight, fever was seen in four of eight, and reversible abnormal liver function test results were seen in three of four patients. Pulmonary toxic effects were seen in five of eight patients and consisted of isolated interstitial pneumonitis in one, fever and infiltrate after rechallenge with procarbazine after previous rash in two, and cough accompanying rash in two. The toxic effects were mild to moderate in six patients but severe to life threatening in the two who were rechallenged after development of rash. The observed incidence of rash during adjuvant therapy was higher than that previously found by the authors for recurrent disease, and it appears to be higher than has been reported in Hodgkin's disease, lymphoma, and other solid tumors. The findings by the authors suggest that a high index of suspicion be kept for hypersensitivity reactions to procarbazine when treating primary brain tumors and that, contrary to the experience in other settings, procarbazine be stopped if rash develops.



27. Newton HB, Junck L, Bromberg J, Page MA, Greenberg HS, "Procarbazine chemotherapy in the treatment of recurrent malignant astrocytomas after radiation and nitrosourea failure." Neurology 1990 Nov;40(11):1743-6,
Department of Neurology, University of Michigan Hospitals, Ann Horbor 48109-0316.

The Brain Tumor Study Group has shown procarbazine (PCB) to be as effective an adjuvant treatment as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We treated 35 patients with recurrent malignant astrocytomas after radiation and nitrosourea failure with successive courses of PCB 150 mg/m2/d for 28 days every 8 weeks. After 2 courses, 2 patients had complete responses, 7 had partial responses, 11 had stable disease, and 15 had progression. Significantly more patients receiving PCB had complete or partial responses or stable disease than a similar group of patients in a previous trial who received intra-arterial (IA) cisplatin (DDP). There is a significant advantage in time to disease progression for those receiving PCB compared with those receiving IA diaziquone (AZQ). Our results suggest that PCB is a more effective 2nd agent than IA DDP or AZQ following radiation and nitrosourea failure.



28. Rodriguez LA, Prados M, Silver P, Levin VA, "Reevaluation of procarbazine for the treatment of recurrent malignant" Cancer 1989 Dec 15;64(12):2420-3
Department of Neurosurgery, University of California-San Francisco.

Ninety-nine patients with primary recurrent malignant tumors of the central nervous system were treated with procarbazine as a single agent. Procarbazine was not given as a specified protocol, but for patients who were ineligible or refused other protocols. All patients had been treated previously with radiotherapy and 96 patients had also received previous chemotherapy. Twenty-five patients were treated at the first progression of their tumor, 47 were treated at the second progression, and 27 were treated at the third progression of their tumor. For the aggregate, the response plus stabilization rate was 27% for glioblastoma multiforme with median time to tumor progression of 30 weeks, and 28% for other anaplastic gliomas with a median time to tumor progression of 49 weeks. With respect to the percent of patients who responded or stabilized to treatment, these results are inferior to those reported previously for patients treated with procarbazine at recurrence. With respect to duration of response and stabilization, the data are comparable.



29. Sposto R, Ertel IJ, Jenkin RD, Boesel CP, et al., "The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial." J Neurooncol 1989 Jul;7(2):165-77,
University of Southern California School of Medicine, Los Angeles.

Fifty-eight patients with high-grade astrocytoma were treated by members of the Childrens Cancer Study Group in a prospective randomized trial designed to study the effectiveness of chemotherapy as an adjuvant to standard surgical treatment and radiotherapy. Following surgical therapy, patients were assigned randomly to radiotherapy with or without chemotherapy consisting of chloroethyl-cyclohexyl nitrosourea, vincristine, and prednisone. Treatment with chemotherapy prolonged survival and event-free survival. Five-year event-free survival was 46% for patients in the radiotherapy and chemotherapy group, and 18% for patients in the radiotherapy-alone group. Five-year survival was similarly improved. The differences in outcome due to treatment were statistically significant after correcting for imbalances in important prognostic factors (event-free survival, p = 0.026; survival, p = 0.067). The presence of mitoses or necrosis in the tumor specimen was associated with poorer outcome. Patients whose initial surgery was limited to biopsy, and patients with basal ganglia lesions, also had significantly worse outcome. Chemotherapy administered at the time of recurrence in a small number of patients did not produce any long-term survivors. This study is to our knowledge the only randomized trial to investigate effectiveness of chemotherapy in the treatment of high-grade astrocytoma in children.



30. Hildebrand J, "A review of studies of the EORTC brain tumor group." Cancer Treat Rep 1981;65 Suppl 2:89-94, PMID: 7049364, UI: 82259060

The results of three randomized trials performed by the EORTC Brain Tumor Group in patients with histologically proven brain gliomas are presented. CCNU (130 mg/m2 every 6 weeks) in combination with dexamethazone (4-20 mg daily) prolonged total survival compared to a group of patients treated only with corticosteroids. CCNU (130 mg/m2 every 6 weeks) either alone or one day after VM-26 (100 mg/m2) produced an objective remission in less than 30% of treated patients. However, the two treatment modalities did not prolong the interval between surgical removal of the tumor and relapse (recurrence). None of 12 patients with signs of brain tumor recurrence previously treated with VM-26 plus CCNU responded to procarbazine (3-week courses of 150 mg/m2/day).



31. Wilson CB, Gutin P, Boldrey EB, Drafts D, Levin VA, Enot KJ, "Single-agent chemotherapy of brain tumors. A five-year review." Arch Neurol 1976 Nov;33(11):739-44, PMID: 185991, UI: 77044132

Identification of effective single chemotherapeutic agents for brain tumors must precede the rational use of multiple drug combinations. In phase 2 trials beginning in 1968, 158 patients with intrinsic brain tumors (mostly recurrent malignant astrocytomas) were considered evaluable. The larger trials with more effective drugs produced these results: carmustine (BCNU) response rate, 47%, with median duration of nine months; lomustine (CCNU), 44%, with median duration of six months; procarbazine hydrochloride, 52%, with median duration six months; carmustine and vincristine sulfate combined, 44%, with median duration of only four months; and BIC (5-[3,3-bis(2-chloroethyl)-1-triazeno]imidazole-4-carboxamide), 38%, with median duration of five months. Administration of glucocorticoids was not found to bias the frequency of response. Forty-seven patients, 26 of whom had responded to the initial drug, received a second drug. Among 26 patients who were evaluable, only four responded to the second drug.



32. Gutin PH, Wilson CB, Kumar AR, Boldrey EB, et al., "Phase II study of procarbazine, CCNU, and vincristine combination chemotherapy in the treatment of malignant brain tumors." Cancer 1975 May;35(5):1398-404,

Forty-eight patients with primary or metastatic malignant tumors of the central nervous system (CNS) were treated with combination chemotherapy, consisting or procarbazine (100 mg/m2 X 14 days), CCNU (75 mg/m2), and vincristine (1.4 mg/m2 X 2, 1 week apart) (PCV) every 4 weeks. Most patients had undergone initial resection of primary tumors, postoperative radiotherapy, and a post irradiation interval of 3 months or more. Other patients harbored unbiopsied, newly-discovered primary or metastatic tumors. All patients were deteriorating neurologically when treatment began. Overall response rate for PCV combination therapy was 44%, no better than results obtained with single agent procarbazine or BCNU, the most effective drugs used alone in previous brain tumor chemotherapy studies.



33. Kim L; Hochberg FH; Thornton AF; Harsh, "Procarbazine, lomustine, and vincristine (PCV) chemotherapy for grade III and grade IV oligoastrocytomas." J Neurosurg; VOL 85, ISS 4, 1996, P602-7, TOXBIB/96/409181;
Brain Tumor Center (Department of Medical Neuro-Oncology, Radiation Therapy, and Neurosurgical Oncology, Boston, Massachusetts, USA.

The authors provided procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy to 32 patients whose tumors contained varying mixtures of oligodendroglial and astrocytic cells. Twenty-five patients had oligodendroglioma-astrocytoma (oligoastrocytoma) with a histological Grade of III (19 patients) or IV (six patients); seven had anaplastic oligodendroglioma. The PCV therapy was administered every 6 weeks for a total of at least 124 cycles. The median duration of follow-up review from the start of chemotherapy was 19.3 months. Nineteen patients were treated before receiving radiation therapy and 12 after receiving it (one patient received concurrent radiotherapy and chemotherapy). Grade 3 or 4 hematological toxicity was experienced by nine (31%) of 29 patients. Ten patients had delayed treatment due to treatment-related toxicities (34.5%). Ninety-one percent of the 32 patients responded to the therapy. These included 10 patients with a complete response and 19 with a partial response. The median time to progression was 15.4 months for all patients and 23.2 months for those with Grade III tumors. The median time to progression for patients with Grade III oligoastrocytomas was 13.8 months; for those with Grade IV oligoastrocytoma it was 12.4 months and for those with anaplastic oligodendrogliomas it was 63.4 months (p = 0.0348). These patients survived a median of 49.8 months, 16 months, and 76 or more months, respectively, from the start of chemotherapy (p = 0.0154). The PCV therapy provides durable responses in patients with Grade III or IV oligoastrocytomas.



34. Levin VA; Silver P; Hannigan J; Wara WM. 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 Phys; VOL 18, ISS 2, 1990, P321-4,
Department of Neurological Surgery, University of California-San Francisco Medical School 94143.

Data from Northern California Oncology Group protocol 6G61, which was closed in February 1983, were reanalyzed in December 1988. The protocol called for a randomized trial that compared the effects of following 60 Gy radiation/oral hydroxyurea treatment with either carmustine (BCNU) or the combination of procarbazine, lomustine (CCNU), and vincristine (PCV) for two histologic strata: glioblastoma multiforme and other anaplastic gliomas. PCV produced longer survival and time to tumor progression than BCNU for both histologic groups, although the difference was statistically significant only for the anaplastic gliomas. With PCV treatment, time to progression and survival doubled for anaplastic glioma patients in the 50th and 25th percentiles.



35. Eyre HJ; Eltringham JR; Gehan EA; Vogel FS, et al., "Randomized comparisons of radiotherapy and carmustine versus procarbazine versus dacarbazine for the treatment of malignant gliomas following surgery." Cancer Treat Rep; VOL 70, ISS 9, 1986, P1085-90,

Between 1977 and 1981, the Southwest Oncology Group entered 278 patients on a randomized study (SWOG 7703) to compare the effect of three different chemotherapeutic agents given in combination with radiotherapy (6000 rads over 7 weeks) following surgery for malignant gliomas. The chemotherapy regimens were: carmustine (BCNU)--80 mg/m2 iv daily X 3 every 6 weeks; procarbazine (PCB)--100 mg/m2 orally; or dacarbazine (DTIC)--175 mg/m2 iv daily X 5 every 4 weeks. Patients were stratified according to age, and degree of resection, with no differences identified between groups. The response rates (complete plus partial) for BCNU and DTIC were significantly better than for PCB [BCNU, 39%; PCB, 13%; and DTIC, 38% (P less than 0.01)]. The response duration and survival were somewhat better in patients treated with BCNU and DTIC, but compared to patients treated with PCB, the difference was not statistically significant. Median survival times were: BCNU, 45 weeks; PCB, 31 weeks; and DTIC, 49 weeks (P greater than 0.3). There were six toxic deaths with BCNU and four with PCB, most of which were due to infection associated with leukopenia. The high toxicity and minimal benefit of chemotherapy added to radiotherapy compared to historical results with radiotherapy alone suggest that combined treatment may not be indicated for some patients.



36. Shapiro WR; Green SB; Burger PC; Mahaley MS Jr., et al., "Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma." J Neurosurg; VOL 71, ISS 1, 1989, P1-9, TOXBIB/89/293204
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.

Within 3 weeks of definitive surgery, 571 adult patients with histologically confirmed, supratentorial malignant gliomas were randomly assigned to receive one of three chemotherapy regimens: BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) alone, alternating courses (every 8 weeks) of BCNU and procarbazine, or BCNU plus hydroxyurea alternating with procarbazine plus VM-26 (epipodophyllotoxin). Patients accrued in 1980 and 1981 were to receive 6020 rads of whole-brain radiotherapy concurrent with the first course of chemotherapy. Patients accrued in 1982 and 1983 were randomly assigned to receive either whole-brain irradiation as above, or 4300 rads of whole-brain radiotherapy plus 1720 rads coned down to to the tumor volume. The data were analyzed for the total randomized population and separately for the 510 patients, termed the "Valid Study Group (VSG)," who met protocol eligibility specifications (including central pathology review), 80% of whom had glioblastoma multiforme. The median survival times from time of randomization for the three chemotherapy groups of the VSG ranged from 11.3 to 13.8 months, and 29% to 37% of the patients survived for 18 months (life-table estimate); the differences between these groups were not statistically significant. Survival differences between the radiotherapy groups were small and not statistically significant. It is concluded that, for malignant glioma, giving part of the radiotherapy by coned-down boost is as effective as full whole-brain irradiation, and that multiple-drug chemotherapy as outlined in this protocol conferred no significant survival advantage over BCNU alone.



37. Pfefferbaum B; Pack R; van Eys J, "Monoamine oxidase inhibitor toxicity." J Am Acad Child Adolesc Psychiatry; VOL 28, ISS 6, 1989, P9545,

Monoamine oxidase inhibitor (MAOI) drugs are used in the treatment of depressive and anxiety disorders in adults. MAOIs are also used in high doses for the treatment of lymphomas and of central nervous system (CNS) tumors in children. Toxic effects resulted when procarbazine, a drug of this class, was used in treating a child with a CNS tumor. Psychotic reaction in the child may have been triggered by any of several factors, but arguments are for an organic cause. The implication of the MAOI procarbazine must be seriously considered. The case highlights potential serious problems associated with MAOIs and the interaction of this agent with other drugs.



38. Eyre HJ; Quagliana JM; Eltringham JR; Frank J., et al., "Randomized comparisons of radiotherapy and CCNU versus radiotherapy, CCNU plus procarbazine for the treatment of malignant gliomas following surgery." J Neurooncol; VOL 1, ISS 3, 1983, P171-7,

One hundred and fifteen eligible patients with histologically verified malignant gliomas (astrocytoma grade III-IV) were randomized to receive either radiotherapy 6 000 rads/7 week plus CCNU 130 mg/M2 every 6 weeks (treatment 1) or radiotherapy 6 000 rads/7 weeks plus CCNU 75 mg/M2 day 1 plus procarbazine 100 Mg/m2 days 1-14 every 6 weeks (treatment 2) within 4 weeks following surgical resection. The response rates showed no statistically significant differences between treatment 1 CR/PR - 24/17% and treatment 2 CR/PR - 14/14% (P-value = 0.31). The median survival was also not significantly different: 55 and 50 weeks for treatments 1 and 2, respectively. The most important prognostic parameter identified was age with younger patients showing higher response rates and longer survival. Patients` performance status was also a useful prognostic parameter for response and survival. Neither the extent of surgical resection nor the tumor grade correlated significantly with the outcome. Further studies are needed to identify active chemotherapeutic agents for the treatment of brain tumors.



39. Seiler RW; Bernasconi S; Berchtold W; Feldges A, et al., "AdJuvant chemotherapy with procarbazine, vincristine and prednisone for medulloblastomas." Helv Paediatr Acta; VOL 36, ISS 3, 1981, P249-54,

The survival of 20 children with medulloblastoma who received adJuvant chemotherapy with procarbazine, vincristine and prednisone after resection and craniospinal irradiation is compared with the preliminary results of the Children`s Cancer Study Group (CCSG) and the international Society of Pediatric Oncology (SIOP) medulloblastoma studies. Survival with the chemotherapy used in the SPOG study was not superior to the survival of children who received craniospinal irradiation only.



40. Silvani A; Salmaggi A; Pozzi A; Fariselli L., et al., "Effectiveness of early chemotherapy treatment in anaplastic astrocytoma patients." Tumori; VOL 81, ISS 6, 1995, P424-8, TOXBIB/96/397574
Istituto Nazionale Neurologico C. Besta, Milan, Italy.

There are limited data in the literature concerning chemotherapy trials for the treatment of anaplastic astrocytomas. Forty-one anaplastic astrocytoma patients, operated on during the period 1988 to 1993 at the Neurological institute of Milan, received 4-5 cycles of chemotherapy (BCNU + cisplatin), subsequently radiotherapy (median dose 56.5 Gy), and finally a second-line chemotherapy protocol at recurrence (procarbazine, vincristine, lomustine). The aim of the study was to evaluate the effectiveness of the planned protocol, considering the time to tumor progression and the survival time. The group of anaplastic astrocytoma patients was compared with a homogeneous group of 39 anaplastic astrocytoma patients treated only with radiotherapy after surgery. The median time to tumor progression of patients on the protocol was 24.5 months. The median survival time for anaplastic astrocytoma patients treated with our scheduled protocol or only with radiotherapy was 38.8 and 21 months, respectively. However, our data need to be confirmed by large randomized clinical studies.



41. Physicians' Desk Reference, 48th ed.(1994):654-5 "CeeNU"



42. Physicians' Desk Reference, 48th ed.(1994):1253-5 "Oncovin"



43. Physicians' Desk Reference, 48th ed.(1994):1941-2 "Matulane



44. CTEP, Division of Cancer Treatment and Diagnosis (DCTD), NCI "Cancer Therapy Evaluation program ctep.info.nih.gov(8 Dec 98)



45. U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Center for Drug Evaluation and Research, Office of information Technology, Division of Data Management and Services, "Approved Drug Products with Therapeutic Equivalence Evaluations" Electronic Orange Book cder www.fda.gov (20 Jan 99)


46. CTEP, Developing Cancer Therapies, "FDA Approved Anti-Cancer Drugs"; http://ctep.info.nih.gov/handbook/HandBookText/fda_agen.htm (20 Jan 99)


47. Tong, Theodore G., "Foods to Avoid on MAO Inhibitors", Revised by DRUGDEX
Editorial Staff 1/94(DC2763)
http://www.lycaeum.org/drugs/plants/maoi/maoi.foods.html (20 Jan 99)


48. Mahan, L. Kathleen, Krause's food, nutrition, and diet therapy 9th ed.(1996)392-3 "Monamine OXidase Inhibitors"


49. Lehmann DF, Hurteau TE, Newman N, Coyle TE, "Anticonvulsant usage is associated with an increased risk of procarbazine hypersensitivity reactions in patients with brain tumors." Clin Pharmacol Ther 1997 Aug;62(2):225-9,
Department of Medicine, School of Medicine, State University of New York Health Science Center at Syracuse 13210, USA.

BACKGROUND: Procarbazine usage in brain tumors has a high incidence of hypersensitivity reactions compared with its use in other malignancies. Procarbazine oxidation to a reactive intermediate is enhanced by phenobarbital. Patients with primary brain tumors would have a preferential exposure to anticonvulsants compared to patients with other malignancies.

OBJECTIVE: To determine whether anticonvulsant exposure is associated with procarbazine hypersensitivity reactions in patients with primary brain tumors.

METHODS: This retrospective cohort study included 83 patients with primary brain tumors who were treated with procarbazine between 1981 and 1996 at a university hospital-based regional oncology center. Data were extracted by chart review. The data collected included age, sex, race, tumor type, smoking, alcohol usage, and all concomitant medications, as well as creatinine, aspartate aminotransferase, total bilirubin, and anticonvulsant serum levels. Anticonvulsant exposure was determined by the presence of detectable serum levels. Cases of procarbazine hypersensitivity reactions were identified through a review of progress notes.

RESULTS: There were 20 patients with procarbazine hypersensitivity reactions. A significant association between the exposure to anticonvulsants and the development of procarbazine hypersensitivity reactions was found (p = 0.05). In addition, there was a significant dose-response association between the development of procarbazine hypersensitivity and the presence of therapeutic anticonvulsant serum levels (p = 0.03).

CONCLUSIONS: Concomitant exposure to anticonvulsants is associated with procarbazine hypersensitivity reactions, possibly though a reactive intermediate generated by CYP3A isoform induction. All patients in this cohort received enzyme-inducing anticonvulsants. New anticonvulsants devoid of this property are available. These data support trials that use these newer agents for the prophylaxis of seizures in patients with brain tumors who are to receive procarbazine.



50. Supplement to the Manual of Clinical Dietetics, The American Dietetic Association, (1996) "Tyramine-Controlled Diet"


51. Gundersen S, Lote K, Watne K, "A retrospective study of the value of chemotheraphy as adjuvant therapy to surgery and radiotherapy in grade 3 and 4 gliomas." Eur J Cancer 1998 Sept;34(10):1565-9,
Department of Medical Oncology and Radiotherapy, Norwegian Radium Hospital, Montebello, Oslo, Norway.

The aim of this retrospective study was to evaluate the effect of adjuvant chemotherapy among patients less than 55 years of age with anaplastic gliomas (historical grade 3, n = 85) with four cycles 4 weeks apart of 160 mg carmustine (BCNU) infused into the internal carotid artery, combined with vincristine 2 mg and procarbazine 50 mg x 3 for 1 week (i.a.BCNU-PV) versus no adjuvant chemotherapy. In glioblastomas (histological grade 4, n = 257) the same chemotherapy was evaluated versus two cycles 4 weeks apart of 160 mg lomustine (CCNU) orally instead of BCNU, combined with vincristine and procarbazine (PCV) versus no chemotherapy. All patients in both groups received radiotherapy.

Among glioblastoma patients less than 55 years of age there was a significant (P = 0.03), but moderately increased survival in the i.a.BCNU-PV group versus the two other arms that did not differ from each other. This difference could be explained by an uneven distribution of prognostic factors, especially age group (less than 50 years versus 50-54 years) in favour of the i.a.BCNU-PV group.

In anaplastic gliomas, the median survival in the i.a.BCNU-PV group was 80 months versus 25 months for the no chemotherapy arm (P = 0.004). No significant differences in the distribution of prognostic factors were found between the two therapy arms. We suggest that the role of adjuvant chemotherapy in glioblastomas is unclear, while i.a.BCNU-PV as adjuvant chemotherapy among patients less than 55 years of age and with anaplastic gliomas increased survival markedly.



52. Fernandex CV, Esau R, Hamilton D, et. al., "Intrathecal vincristine: an analysis of reasons for recurrent fatal chemotherapeutic error with recommendations for prevention." J Pediatr Hematol Oncol 1998 Nov-Dec;20(6):587-90,
Department of Pediatrics, British Columbia's Children's Hospital, Vancouver, Canada.

PURPOSE: Accidental intrathecal vincristine instillation is usually a fatal error. The authors report an analysis of a patient and suggest means with which to reduce such errors.

PATIENTS AND METHODS: A 7-year-old girl with recurrent acute lymphoblastic leukemia was inadvertently injected intrathecally with 1.5 mg vincristine. A detailed analysis of the events leading to this error and a review of all reported cases in the English literature were undertaken.

RESULTS: Reasons for errors reported by us and other institutions included mistaking vincristine for an intended intrathecal drug, assuming vincristine was an additional drug to be injected, not checking physician orders, mistaken route of administration, and mislabeling of syringes.

CONCLUSION: Intrathecal injection of vincristine may be the end-result of a series of systems errors. Protocol recommendations to reduce the likelihood of this error are presented.




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