Procarbazine, CCNU and Vincristine, Also known as PCV

Each drug will be reviewed separately, then the combination will be reviewed, then we present our thoughts. Procarbazine | CCNU | Vincristine | PCV | Our thoughts

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PROCARBAZINE REVIEW

Proprietary Name: Mutulane

Other Names: Procarbazine, Mutulane, Ibenzmethyzine hydrochloride, matulane, MBH, MIH hydrochloride, Nutulan, Nathulane, Natunalar, NCI-CO1810, Procarbazin (German), Procarbazine hydrochloride(USAN), PCB hydrochloride(44,45)

Active Ingredient: Procarbazine Hydrochloride(43,44,45)

Dosage Form: Oral Capsule, ivory that contains 50Mg procarbazine as the hydrochloride, bottles of 100.(43,44,45)

FDA Approved: 1969 for Hodgkins, made by: Sigma - Tau(46)

Classification: Synthetic, Antineoplastic(44,45)

Description: Matulane is a potent antineoplastic drug, a hydrazine derivative antineoplastic agent, hydrochloride. Chemically, procarbazine hydrochloride is N-isopropl-alpha-(2-methylhydrazino)-P-toluamide monohydrochloride.(43)

Clinical Actions: The exact mode of cytotoxic actons of procarbazine is not clearly defined; some evidence is that the drug may act by inhibition of protein, RNA and DNY synthesis. Procarbazine is primarily metabolized in the liver and kidneys; it appears to auto oxidized to the azo derivative with the release of hydrogen peroxide. The azo derivative isomerizes to the hydrazone and following hydrolysis splits into a benzylaldehyde derivative and methylhydrazine. The methylhydrazine is further degrated to CO2 and CH4 and possibly hydrazine, whereas the aldehyde is oxidized to acid which is excreted in the urine. Procarbazine is rapidly and completely absorbed following oral administration, maximum peak plasma concentrations are reached within 60 minutes; approximately 70% is excreted in the urine within 24 hours following administration. Further, procarbazine crosses the blood brain barrier and equilibrates between plasma and cerebrospinal fluid after oral administration.(43)

Dosage: Dosages vary depending upon whether Procarbazine is being used as a combination drug with other anticancer drugs or as a single therapeutic agent or as a single High Dose therapeutic agent. A suggested guideline per the PDR for Procarbazine as a single agent is 100mg 2x daily for 14 days. However, dosages may vary and so may treatment cycles. All dosages are based on the patient's weight, age, and other various factors.(43)

Precautions: In that

Foods that must be avoided as follows:

• All Cheeses
• Smoked or picked fish
• Nonfresh meats
• Livers
• Wines
• Broad Beans
• Banana Peels
• Meat Extracts
• Yeast Extracts/Brewers Yeast (bread ok)
• Dry sausage
• Sauerkraut
• Beer and Al (nonalcoholic varieties included)
• (Check frozen, canned foods for yeast extracts and protein extracts and be
• sure that all foods are fresh, check expiration dates, avoid left overs and
• be be cautious in restaurants)

Precautions: Undue toxicity may occur if Procarbazine is used in patients with impairment of renal and/or hepatic function.(43)
Cessation of procarbazine may be necessitated should any of the below occur as follows:
Central nervous system signs or symptoms such as paresthesias, neuropathies or confusion. Leukopenia (white blood count under 4000), thrombocytopenia(platelets under 100,000), hypersensitivity reaction, ulceraction or persistant spot of soreness around the oral cavility, diarrhea or loose stools, hemorrhage or bleeding tendencies. Pregnancy: Procarbazine can cause fetal harm.(43)

Drug Interactions: Foods containing high levels of tyramine, OTC drugs such as antihistamines or sympathomimetics. All prescription drugs should be evaluated by the physician. Other drugs that should be avoided are barbiturates, narcotics, hypotensive agents or phenothiazines, ethyl alcohol.
No cross resistance with steriods, radiotherapy or other chemotherapeutic agents have been demonstrated.(43)

Frequent Adverse Reactions: The most frequent occurring reactions are leukopenia, anemia, and thombopenia. The most commonly reported side effects are nausea and vomiting.(43)

Possible Adverse Reactions:43

• Carcinogenesis: The International Agency for Research on Cancer (IARC) considers that there is sufficient evidence for the human carcinogenicity of procarbazine when it is given in combination with other antineoplastic agents but that there is inadequate evidence of carcinogenicity of procarbazine when given as a single agent.(43,2,1) The Environmental Health Information Services (EHIS), reports MeCCNU, Case No. 12909-09-6, as Known to be a human carcinogen.(41)
• Neurological: Convulsions, coma, neuropathy, ataxia, paresthesia, nystagmus, reflexes, falling, foot drop, headache, and dizziness.
• Cardiovascular: Hypotension, syncope and tachycardia.
• Ophthalmic: Retinal hemorrhage, papilledema, inability to focus, photophobia and diplopia.
• Hematologic: Pancytopenia; eosinophilia; hemolytic anemia; bleeding tendencies such as petechiae, epistaxis, purpura and hemoptysis.
• Gastrointestinal: Hepatic dysfunction, jaundice, diarrhea, constipation,dysphagia, anorexia, abdominal pain, stomatis, hematemesis, and dry mouth.
• Respiratory: Pneumonitis, pleural effusion and cough.
• Cardiovascular: Hypotension, tachycardia and syncope.
• Dermatologic: Herpes, dermatitis, pruritus, alopecia, hyperpigmentation, rash, urticaria and flushing.
• Genitourinary: Hematuria, urinary frequency, and nocturia.
• Musculoskeletal: Pain, including myalgia and arthralgia; and tremors.
• Psychiatric: Hallucinations, depression, apprehension, nervousness, confusion, and nightmares.
• Endocrine Adverse Reactions: Gynecomastia in prepubertal and early pubertal boys.
• Mutagenesis and Impairment of fertility: Procarbazine has been shown to be mutagenic in a variety of bacterial and mammalian tests. Procarbazine has not been adequately studied for its effects on peri and postnatal development. It might be expected that compounds that inhibit DNA, RNA and protein synthesis might have adverse effects on peri and postnatal development.
• Additional Miscellaneous Adverse Reactions: Intercurrent infections, hearing loss, pyrexia, diaphoresis, slurred speech, lethargy, weakness, fatigue, edema, insominia, chills, hoarseness and drowsiness.

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CCNU REVIEW

Proprietary Name: CEENU

Other Names: Lomustine, CCNU, Belustine, Cecenu, CeeNU, Chloroethylcyclohexylnitrosourea, CiNu, Lomustine(USAN), 1-Nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl(44,45)

Active Ingredient: Lomustine(41,44,45)

Dosage Form: Oral Capsule, available in 10mg, 40mg and 100 mgs.(41)

FDA Approved: 1977, Brain Tumors and Hodgkin's Disease, NSC# 79037, Bristol Myers Squibb(41,46)

Classification: Synthetic Alkylating Agent(41,44,45)

Description: Lomustine (CCNU)) Capsules is one of the nitrosoureas used in treating certain neoplastic diseases. It is 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.(41)

Clinical Actions: It is generally agreed that CCNU alkylates DNA and RNA, it is not cross resistant with other alkylators, as with other nitrosoureas; it may also inhibit several ky enzymatic processes by carbamoylation of amino acids in proteins. Approximately half of the radioactivity is excreted in the form of degradation products within 24 hours after administration. The half life of the metabolities range from 16 hours to 2 days and tissue levels are comparable to plasma levels in approximately 15 minutes after intravenous administration. CCNU crosses the blood brain barrier.(41)

Dosage: Dosages may vary depending upon whether CCNU is being used as a single agent or in a combination in addition to other chemotherapeutic agents. As a single agent in previously untreated patients, the recommended dosages per the PDR, is 130mg as a single oral dose every 6 weeks.

Frequent Adverse Reactions: The most common and severe toxic side effects are bone marrow suppression, thrombocytopenia and leukopenia, which may contribute to bleeding and infections. Bone marrow toxicity is cumulative and thus dosage adjustments must be considered on the basis of the Nadir blood counts from prior dose.(41)

Possible Adverse Reactions:

• Carcinogenesis: CCNU (nitrosoureas) is carcinogenic. The EHIS in the Report on Carcinogens lists CCNU as a known carcinogens.(3,41) Additional studies involving Alkylating agents such as BCNU, CCNU and combination PCV; by the Division of Neurology, Duke University Medical Center, reported two patients with acute myeloid leukemia (AML) following an alkylating agent and the other treated with PCV. They also reported 26 other examples of therapy related leukemia in adult and pediatric brain tumor patients, the median interval from treatment to diagnosis of acute myeloid leukemia was 31 months. No definitive cases occurred after radiotherapy alone. (1)
• Pregnancy: CCNU can cause fetal harm.(41)
• Hematologic: Anemia also occurs, however less frequent and severe than thrombocytopenia or leukopenia.(41)
• Pulmonary: Toxicity appears to be dose related with cumulative doses usually greater than 1100 mg; however, pulmonary toxicity has been reported rarely with CCNU.(41)
• Gastrointestinal: Nausea and vomiting may occur; however prior administration of antiemetic is effective. Further nausea and vomiting can be reduced if CCNU is administered to a fasting patient.(41)
• Renal: Renal failure has been reported in patients who have received large cumulative doses. Kidney damage has also been reported on lower total dosages.(41)
• Additional toxicities: Stomatitis, alopecia, optic atrophy and blindness have been reported infrequently. Disorientation, lethargy, ataxia and dysarthria has also been reported; however, the relationship to medication in these patients is unclear.(41)

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VINCRISTINE REVIEW

Proprietary Name: Vincristine Sulfate PFS(44,45)

Other Brand Names: Oncovin marketed by Eli Lilly & Company; and Vincristine Sulfate marketed by Faulding.(44,45,46)

Other Names: Kyocristine, Leurocristine sulfate, Leurocristine sulfate (1:1) Lilly 37231, LCR, NSC 67574, NSC67674, Onkovin, Vincaleukoblastine, 2Vincrisul, VCR sulfate(44,45,46)

Active Ingredient: Vincristine Sulfate(46)

Dosage Form: Injection, Intravenous (42,44,45)

FDA Approved: 1963 on label, Ewing's Sarcoma, Rhabdomyosarcoma, Wilm's Tumor, Neuroblastoma, Hodgkin's Lymphomas, Leukemia. NSC# 67574, Oncovin, Eli Lilly (44,45,46)

Classification: Plant Alkaloids (46) Description: Vincaleukoblastine, 22-oxo- , sulfate (1:1) (salt). Vincristine is the salt of an alkaloid obtained from a common flowering herb, the perwinkle plant.

Clinical Actions: The clinical actions of Vincristine remain under investigation; however the actions have been related to the inhibition of microtobule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase state. The liver is the major excretory organ. Most of an intravenous dose of Vincristine is escreted into the bile after rapid tissue binding. Vincristine does not appear to cross the blood brain barrier.(42)

Drug Interactions: Vincristine has been reported to reduce blood levels of antiseizure medications and to increase seizure activity; therefore, dosage adjustment should be based on blood level monitoring. the cause of such interaction is not clear; however, the interaction may result from reduced absorption of phenytoin and an increase in the rate of its metabolism and elimination.(42)

Warning: Vincristine must be given intravenously and NOT intrathecally.(42,52)

Frequent Adverse Reactions: The most common adverse reaction is hair loss. Leukopenia, neuritic pain and constipation occur but usually for less than 7 days. Other adverse reactions that may persist during treatment are sensory loss, paresthesia, difficulty in walking, loss of deep tendon reflexes and muscle wasting. Most symptoms will usually disappear after the sixth week of discontinuance of treatment; however some neuromuscular side effects may continue for prolonged periods of time for some patients.

Possible Adverse Reactions:

• Carcinogenesis: Vincristine is not listed as a known carcinogenic as a single treatment agent; however, when given in combination with other anticancer drugs known to be carcinogenic have developed second malignancies.(42)
• Pregnancy: Vincristine can cause fetal harm when given to a pregnant woman.(42)
• Hematologic: Anemia, Leukopenia and thrombocytopenia; however serious bone marrow depression is NOT usually a major dose limiting event.(42)
• Pulmonary: Shortness of breath and severe bronchospasm have been reported; however, most frequently when used in combination with mitomycin-c.(42)
• Gastrointestinal: Constipation, abdominal cramps, weight loss, nausea, vomiting, oral ulceration, diarrhea, paralytic ileus(which mimics the surgical abdomen), intestinal necrosis, intestinal perforation and anorexia. Constipation may be related to upper colon impaction; however all cases have responded to high enemas and laxatives. Routinely prophylactic regimen against constipation is recommended for all patients taking vincristine.(42)
• Neurologic: Often there is a sequence to the development of neuromuscular side effects. Initially, only sensory impairment paresthesia may be encountered; however with continued treatment, neuritic pain and later motor difficulties may occur. There have not been any reported agents that can reverse the neuromuscular manifistations that could/may accompany treatment with Vincristine.(42) Loss of deep tendon reflexes, foot drop, ataxia, paralysis, cranial nerve manifestations, paralysis of muscless controlled by cranial motor nerves; extraocular and laryngeal muscles are those most commonly involved. Jaw pain, pharyngeal pain, parotid gland pain, back pain, limb pain and myalgias.
• Convulsions followed by coma have been reported in pediatric patients.
• Transient cortical blindness and optic atrophy with blindness have been reported.
• Partial or total deafness which may be temporary or permanent and difficulties with balance, including dizziness, nystagmus and vertigo have occurred.(42)

Additional Possible Side Effects: Rash, Alopecia, fever and headaches.(42)

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PCV CHEMOTHERAPY:

Discussion of past clinical trials, And its effectiveness in the treatment Of Malignant Glioma (Brain Cancer)

There is a huge amount of clinical trial data available for review of the effectiveness of PCV chemotherapy in the treatment of malignant glioma. The trials which this essay seeks to highlight, necessarily focus on the benefits of PCV as it has been demonstrated in the treatment of Grade 3 and 4 malignancies. These include anaplastic astrocytoma, glioblastoma multiforme and malignant oligodendroglioma. PCV therapy has been found to especially benefit oligodendroglioma patients.

One draw back these researchers encountered was in identification of results specifically for each type of malignancy. This was because many studies were conducted under the heading of mixed glioma, whereby the results for anaplastic astrocytoma and glioblastoma muliforme were not always clearly separated.

CLEARLY, STUDIES HAVE SHOWN THAT MALIGNANT OLIGODENDROGLIOMA HAS A HISTORY OF RESPONDING TO TREATMENT WITH PCV CHEMOTHERAPY.

We have chosen seven clinical trials to use for discussion of the possible benefits of PCV chemotherapy in treating malignant brain cancer. These trials help to reveal useful information about what has been observed in the past from PCV treatment(s) of malignant brain cancer. Some of these will focus attention on the benefits recorded for PCV versus another common first-line brain cancer treatment called BCNU. Some of these will examine the results of studies of treatment with procarbazine (PCB)only.

Clinical Trial # 1: In this single-arm multicentered phase II study dated 1994, patients with measurable, newly diagnosed or recurrent , contrast-enhancing anaplastic oligodendroglioma were treated up to six cycles of PCV. Of 33 patients enetered into the trial, nine were subsequently excluded for ineligible pathologies. Of the remaining 24 patients, the following results were noted:

18/24 patients responded to the treatment (75%)
9/24 patients responded completely (38%)
5/24 patients responded partially (21%)
4/24 patients had stable disease (16%)

Median time to progression for complete responders was 25.2 months.
Median time to progression for partial responders was 14.2 months
Median time to progression for stable patients was 6.8 months

Previously irradiated patients were as likely to respond as those newly diagnosed.
11/15 irradiated patients (73%)
7/9 newly diagnosed (78%)

Adverse events on treatment included a death from Pneumocystis pneumonia, a severe reversible encephalopathy due to procarbazine, an intratumoral hemorrahage 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.(24)

Clinical Trial #2 In this trial dated 1989, a total of 99 patients with primary recurrent malignant tumors of the central nervous system were treated with procarbazine as a single agent. All patients had been previously treated with radiotherapy, and 96 patients had also received a previous chemotherapy.

25/99 were treated at their first progression of tumor
47/99 were treated at their second progression of tumor
24/99 were treated at their third progression of tumor
Response plus stabilization for gliobasltoma was 27% with median time to progression of 30 weeks.
Response plus stabilization for other anaplastic gliomas was 28% with median time to progression of 49 weeks.

CONCLUSION: 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.(28)

Clinical Trial # 3

In this trial dated 1993, researchers compared sequential single-agent BCNU and procarbazine (PCB) chemotherapy in 31 patients with gliomas [grade IV (10), grade III (15) and grade II (6)]. Patients had failed surgical biopsy/resection and radiation therapy.(25)

Patient responses to BCNU were CR(0), PR(7), SD(12) and progression (12).
Patient responses to PCB were CR(2), PR(9), SD(6) and progression (14).
Kaplan-Meier estimates of median time to failure were shorter for BCNU, 5.0 months (range 1.5 to 20 months) than for PCB, 6.0 months (range 2 to 50 months).
The cumulative proportion of patients without disease progression at 6 months was 26% while on BCNU, compared to 48% while on PCB.
The cumulative proportion of patients without disease progression at 12 months was 3% for BCNU compared to 35% for PCB.

CONCLUSION: These data provide further evidence that Procarbazine (PCB) has significant activity against malignant glioma and may, in fact, be more effective than BCNU.(25)

Clinical Trial # 4
In this trial dated 1979, there were 28 patients with nonirradiated malignant gliomas. They were administered PCV chemotherapy on a schedule at successive 6-week intervals.(19)

9/28 patients responded to treatment (32%)
19/28 patients did not respond to treatment (68%)
Overall 1-year survival rate for the 28 patients was 29%.
Major side effects of the PCV treatment were leukopenia, thrombocytopenia, pulmonary emboli and thrombophlebitis, detected mainly during the first 20 to 24 weeks.(19)

CONCLUSION: None was given, just the data.

Clinical Trial # 5

In this randomized trial dated 1991, a study was made of treatment with PCV chemotherapy for patients with and without previous radiation therapy for astrocytoma grades 3 and/or 4.

The researchers undertook a controlled, prospective randomized study of 171 patients. All patients were given PCV chemotherapy. Half of the patients received whole brain radiation to a dose of 5800 cGy in the tumor-bearing hemisphere and 5000 cGy in the contralateral hemisphere. After diagnosis of progressive tumor, patients then received individual treatment.

The endpoint of the study was time to progression, but cases were followed until the patients died.(6)

Median time to progression (MTP) for whole population was 21 weeks.
Median survival time (MST) for whole population was 53 weeks.
18% of patients survived for 2 years or longer.
Survival analysis showed that patients under age 50, who had both PCV chemotherapy plus radiation therapy had significantly longer MTP and MST.
Less than 50 yrs old, PCV + Rad, MTP was 81 weeks and MST was 124 weeks.
Less than 50 yrs old, PCV only, MTP was 21 weeks and MST was 66 weeks.
Greater than 50 yrs old, PCV + Rad, MTP was 23 weeks and MST was 51 weeks.
Greater than 50 yrs old, PCV only, MTP was 17 weeks and MST 39 weeks.

CONCLUSION: Patients less than 50 years old treated with PCV plus Radiation Therapy had significantly longer survival when correcting for these factors in a multi-variate analysis.(6)

Clinical Trial # 6

In this trial dated 1996, the researchers provided PCV chemotherapy to 32 patients whose tumors contained varying mixtures of oligodendroglial and astrocytic cells. 25 patients had oligodendroglioma-astrocytoma. Of those 25 patients, 19 had a histological grade III and six had Grade IV. Another seven patients had anaplastic oligodendroglioma. The PCV therapy was administered every six weeks, up to a total of 124 cycles. 19 patients were treated before radiation treatment, one concurrently, and 12 patients after receiving radiation treatment.(10)

29/32 patients responded to the treatment (91%)
9/29 patients experienced hematological toxicity (31%)
10/29 patients had delayed treatments due to treatment induced toxicities (35%)
10/29 patients had complete responses
19/29 patients had partial responses
The median time to progression (MTP) for all patients was 15.4 months
The MTP for oligoastrocytoma Grade III tumors was 13.8 months
The MTP for oligoastrocytoma Grade IV tumors was 12.4 months
The MTP for anaplastic oligodendroglioma tumors was 63.4 months
The median survival time (MST) from the start of PCV chemotherapy
The MST for oligoastrocytoma Grade III tumors was 49.8 months
The MST for oligoastrocytoma Grade IV tumors was 16.0 months
The MST for anaplastic oligodendroglioma tumors was 76.0 months

CONCLUSION: The PCV therapy provides durable responses in patients with Grade III and Grade IV oligoastrocytomas.(10)

Clinical Trial # 7

In this trial dated 1990, researchers provided procarbazine (PCB) chemotherapy to 35 patients with recurrent malignant astrocytomas, after treatment with BCNU and radiation had failed. The treatment of PCB was given in successive courses for 28 days every eight weeks.(27)

After two courses: 2/35 had complete responses (6%) 7/35 had partial responses (20%) 11/35 had stable disease (31%) 15/35 had progression (43%)

Significantly more patients had responses or stable disease than a similar group of patients in a previous trial who received intra-arterial cisplatin (DDP). There also was a significant advantage in time to disease progression for those receiving PCB compared with those receiving IA diaziquone (AZQ).

CONCLUSION: Results show that PCB is a more effective 2nd agent than IA DDP or AZQ following failure of treatment with BCNU and radiation.(27)

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CONCLUSION OF THE WRITERS OF THIS ARTICLE

Editor's Note: the authors are not MDs, so take this as ideas for you to discuss with your doctor!

Our research and review of available information on PCV chemotherapy lead us to the following conclusions about PCV as a treatment for malignant glioma.

1. PCV appears to be superior to BCNU as a first-line treatment of malignant glioma.
2. PCV has remarkable results in bettering prognosis for malignant oligodendroglioma.
3. PCV has demonstrated results of slowing down the progression of tumor and increasing the average survival time in patients that take the treatment for anaplastic astrocytoma and glioblastoma multiforme.
4. Beneficial results of PCV are less for glioblastoma than for anaplastic astrocytoma.
5. Combining PCV treatment with radiation treatment has demonstrated results of slowing down progression of tumor and increasing average survival treatment in malignant glioma for those patients that respond to the treatment combination.
6. Treatment with only procarbazine (PCB) chemotheraapy has also demonstrated beneficial results of slowing down progression of tumor and increasing average survival time for those patients that respond.
7. There are health risks involved with taking PCV treatment (and PCB) that the patient and his primary caregivers should be aware of beforehand. The benefits in our opinion are worth the risks.
8. Diet is an important part of optimization of PCV chemotherapy.

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This page was created on 09/03/2016 and last updated on 04/21/2019