By Danita Acquafredda and George Hunter
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.
