VA Class:AN100

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Carmustine

Carmustine, a nitrosourea-derivative alkylating agent, is an antineoplastic agent.

Brain Tumors

Conventional Chemotherapy

Carmustine is used as an adjunct to radiation therapy following surgery for malignant glioma, such as glioblastoma multiforme and anaplastic astrocytoma.120,125 The addition of carmustine to radiation therapy has not been shown to increase survival time, but a trend toward a higher long-term survival rate (e.g., at 18 months) has been observed.126,127 Carmustine also has been used as adjuvant or salvage therapy for oligodendroglioma, a uniquely chemosensitive form of glioma.120,127,128

The benefit of adjuvant chemotherapy for the treatment of malignant gliomas has not been established.125,129 Although individual studies do not show a definitive benefit, analysis of pooled data130 from the reported results of several published randomized studies suggests that the use of adjuvant chemotherapy prolongs survival in adults with malignant gliomas. However, in a large randomized trial, the addition of lomustine, another nitrosourea, in combination with procarbazine and vincristine to radiation therapy did not prolong median survival or increase the survival rate in patients with high-grade astrocytoma.131

Compared with IV administration, intra-arterial administration of carmustine is associated with excessive toxicity, including blindness and fatal encephalopathy, and inferior survival.132

Intracranial Wafer Implant

Adjunctive Therapy at Primary Surgery

The intracranial carmustine wafer implant is used as an adjunct to surgery and radiation therapy for newly diagnosed high-grade malignant glioma.124,135

This indication is based mainly on the results of a randomized, double-blind, placebo-controlled trial of 240 patients with newly diagnosed malignant glioma, including glioblastoma multiforme (207 patients), anaplastic oligoastrocytoma (11 patients), anaplastic oligodendroglioma (11 patients), and anaplastic astrocytoma (2 patients), who were undergoing initial craniotomy for tumor resection.124,152 Treatment regimens consisted of surgery with implantation of either carmustine wafers or placebo wafers (typically 6-8 wafers), and most patients (77.5% in the carmustine wafer group and 81.7% in the placebo wafer group) received a standard course of radiation therapy (55-60 Gy) typically initiated at 3 weeks following surgery.124 Systemic chemotherapy was administered to 17 patients (14%) receiving the carmustine wafer and 12 patients (10%) receiving the placebo wafer; all 6 patients with anaplastic oligodendroglioma received chemotherapy within 30 days of surgical implantation of the carmustine wafer.124

At a minimum follow-up of 3 years, patients receiving the carmustine wafer implant had prolonged median survival (13.9 versus 11.6 months; hazard ratio: 0.73) compared with those receiving the placebo wafer implant.124,152 Subgroup analysis of patients with glioblastoma multiforme did not show any difference in survival for patients receiving the carmustine wafer implant versus the placebo wafer implant.124,152 Although intracranial hypertension (9 versus 2%) and CSF leak (5 versus 0.8%) occurred more frequently in patients receiving the carmustine wafer, the incidence of other adverse neurologic effects or any adverse effect occurring in at least 5% of patients did not differ between those receiving the carmustine wafer or the placebo wafer.124,152

Adjunctive Therapy at Surgery for Recurrent Disease

The intracranial carmustine wafer implant is used as an adjunct to surgery for the palliative treatment of recurrent glioblastoma multiforme in patients for whom surgical resection is indicated.120,124,135,137

This indication is based principally on a randomized, double-blind, placebo-controlled clinical trial of 222 patients undergoing surgical resection for gliomas that recurred following initial surgery and radiation therapy.124,133 Treatment regimens consisted of surgery with implantation of either carmustine wafers or placebo wafers (typically 7-8 wafers).124,133 Chemotherapy was withheld at least 4 weeks (6 weeks for nitrosoureas) prior to and 2 weeks after surgery.124 Among all patients with recurrent malignant glioma, patients receiving carmustine wafer implants had a similar median survival (32 versus 24 weeks) and a similar 6-month survival rate (60 versus 47%) as patients receiving placebo wafer implants.124 No survival benefit was evident in patients who had pathologic diagnoses other than glioblastoma multiforme at the time of surgery.124,133 Among those with glioblastoma multiforme, patients receiving carmustine wafer implants had a longer median survival (28 versus 20 weeks) and an increased 6-month survival rate after surgery (56 versus 36%) compared with those receiving placebo wafer implants.124,133

Safety and efficacy of the carmustine wafer compared with conventional chemotherapy with IV carmustine for the treatment of brain tumors has not been evaluated in randomized trials to date.134

Multiple Myeloma

Carmustine-containing regimens are used as an alternative for the palliative treatment of multiple myeloma.105,120,138

Analysis of pooled data139 from randomized studies showed no difference in survival for patients receiving combination chemotherapy versus melphalan and prednisone, a regimen of choice120,138 for multiple myeloma. In a randomized trial, no difference in survival was observed in patients receiving salvage therapy with VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone) or VAD (vincristine, doxorubicin, dexamethasone) for relapsed or refractory multiple myeloma following initial treatment with cyclophosphamide and prednisone.140

Hodgkin's Disease

Although carmustine is labeled for use in combination with other agents as secondary therapy for the treatment of refractory or relapsed Hodgkin's disease,105 combination regimens containing other agents currently are preferred as conventional chemotherapy for this cancer.120,141 The role of carmustine as a component of high-dose chemotherapy used as a preparatory regimen for bone marrow transplantation or peripheral blood stem cell transplantation in the treatment of refractory or relapsed Hodgkin's lymphoma is being investigated.141,142,143

Non-Hodgkin's Lymphoma

Although carmustine is labeled for use in combination with other agents as secondary therapy for the treatment of refractory or relapsed non-Hodgkin's lymphomas,105 combination regimens containing other agents currently are preferred as conventional chemotherapy for these cancers.120,144 The role of carmustine as a component of high-dose chemotherapy used as a preparatory regimen for bone marrow transplantation in the treatment of refractory or relapsed non-Hodgkin's lymphomas is being investigated.144,145

Melanoma

Although carmustine has been used alone114,116 or in combination therapy114,116,119 for the palliative treatment of metastatic melanoma†, low response rates and substantial toxicity have contributed to declining use of this agent.117,122 Response rates reported for carmustine appear to be lower than those reported for dacarbazine as a single agent, but randomized comparisons have not been done.114,116,122 Carmustine has been used in various combination regimens (e.g., carmustine, cisplatin, dacarbazine, and tamoxifen) for the treatment of metastatic melanoma.119 Although early studies reported high response rates for combination chemotherapy regimens for the treatment of metastatic melanoma, evidence from large, randomized trials has not established the superiority of combination regimens compared with dacarbazine alone.114,118,121 Dacarbazine monotherapy currently is a systemic treatment of choice for metastatic melanoma (see Uses: Melanoma in Dacarbazine 10:00 for an overview of therapy for melanoma).115,116,118,120,121,122 Although the nitrosoureas, such as carmustine, are lipid-soluble and can cross the blood-brain barrier, these agents appear to have no appreciable antitumor effect on cerebral metastases.116

Cutaneous T-cell Lymphoma

Carmustine is used topically† for the palliative treatment of cutaneous T-cell lymphoma (mycosis fungoides)†.120,123,149,150

Reconstitution and Administration

Carmustine is administered by IV infusion and intracranially as wafer implants.

Conventional Chemotherapy

Carmustine is administered by IV infusion. The drug is reconstituted by dissolving the contents of the vial labeled as containing 100 mg of carmustine with 3 mL of sterile dehydrated (absolute) alcohol, followed by addition of 27 mL of sterile water for injection. 105 The resultant solution contains 3.3 mg of carmustine per mL of 10% alcohol. This solution may be further diluted with 5% dextrose injection, and administered by IV infusion over a period of 1-2 hours; administration of carmustine over shorter periods of time may produce intense pain and burning at the injection site and along the vein. (See Cautions: Other Adverse Effects.) Carmustine also has been administered by intra-arterial† (into the carotid artery) route; however, such administration has been associated with ocular toxicity.105

The manufacturer recommends that protective gloves be used during handling of carmustine powder and preparation of solutions of the drug, since accidental exposure of the skin to the drug has resulted in transient burning and hyperpigmentation of the affected areas.105 If the lyophilized material or solutions of the drug come in contact with the skin or mucous membrane, the affected area should be washed immediately and thoroughly with soap and water.105

Diluted solutions of carmustine should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.105

Intracranial Wafer Implant

Carmustine wafers are implanted intracranially in the resection cavity following surgical resection of brain tumor.124

The manufacturer recommends that double surgical gloves be worn when handling intracranial carmustine wafers since exposure to carmustine can result in severe burning and hyperpigmentation of the skin.124 A surgical instrument dedicated to the handling of carmustine wafers should be used to implant the wafers.124 Any carmustine wafer or wafer remnant should be handled as a potentially cytotoxic material.124 The outside surface of the outer foil pouch containing the carmustine wafer is not sterile;124 the inner pouch is sterile, and the wafer should be placed into a designated sterile field following removal from the pouch.124

Dosage

Conventional Chemotherapy

The usual IV dosage of carmustine used as a single agent in previously untreated patients is 150-200 mg/m² administered every 6 weeks; this may be administered as a single dose or divided into daily injections such as 75-100 mg/m² on 2 successive days.105 If carmustine is administered in combination with other myelosuppressive drugs or to patients with compromised bone marrow function, dosage must be reduced accordingly.105 Subsequent dosage must be determined by the clinical and hematologic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects. Clinicians should consult published protocols for the dosage of carmustine and other chemotherapeutic agents and the method and sequence of administration. Because of the delayed and cumulative myelosuppressive effects, carmustine usually is given at intervals of at least 6 weeks.105 However, repeat courses of carmustine should not be administered until leukocyte and platelet counts have returned to acceptable levels (usually 4000/ mm³ and 100,000/ mm³, respectively).105 In addition, an adequate number of neutrophils should be present on the peripheral blood smear.105 The manufacturer suggests that dosage subsequent to the initial course of therapy may be adjusted according to the schedule in the table that follows; however, some clinicians believe the manufacturer's recommendations could result in overdosage, and advocate dosage reductions of 25% when platelet nadirs are 50,000-74,999/ mm³, 50% for nadirs of 25,000-49,999/ mm³, and 75% for nadirs less than 25,000/ mm³.

Topical Use for Cutaneous T-cell Lymphoma

In the treatment of cutaneous T-cell lymphoma (mycosis fungoides)†, carmustine has been applied topically† as an alcoholic solution or ointment; such dosage forms are not commercially available in the US.149,150 The drug is usually applied topically once daily.150 The usual topical dosage is 10 mg daily for 7-14 weeks (maximum: 17 weeks).149 If response is inadequate, a second course of topical therapy is administered after a rest interval of 6 weeks, using 20 mg daily for 4-8 weeks, as tolerated.149 Clinicians should consult specialized references for specific information and details on the preparation and use of topical carmustine for cutaneous T-cell lymphoma.149,150

Intracranial Wafer Implant

The carmustine wafer is implanted at the initial surgery for newly diagnosed high-grade malignant glioma.124 The carmustine wafer also is implanted during surgery for recurrent glioblastoma multiforme.124

In clinical trials of patients undergoing surgery and intracranial implantation of carmustine wafers for recurrent malignant glioma, chemotherapy was withheld for at least 4 weeks (6 weeks for nitrosoureas) prior to and 2 weeks after surgery;124 external beam radiation therapy was administered no sooner than 3 weeks after surgery.151

Following the resection of either newly diagnosed high-grade malignant glioma or recurrent glioblastoma multiforme and confirmation of tumor pathology, when hemostasis is obtained, up to 8 carmustine wafers are placed intracranially to cover as much of the resection cavity as possible.124 The manufacturer recommends the implantation of 8 wafers (each wafer containing 7.7 mg of carmustine with 8 wafers resulting in a total dose of 61.6 mg carmustine).124 If the size and shape of the cavity will not allow placement of 8 wafers, the maximum possible number of wafers should be used.124 Because there is no clinical experience with higher doses, no more than 8 wafers should be placed intracranially per surgical procedure.124

The wafers should be placed intracranially to cover as much of the resection cavity as possible, and slight overlapping of the wafers is permissible.124 Wafers broken in half may be used, but wafers broken in more than 2 pieces should be discarded.124 Oxidized regenerated cellulose (Surgicel^®) may be placed over the wafers to secure them against the surface of the resection cavity.124 Following placement of the wafers, the resection cavity should be irrigated and the dura closed in a watertight fashion to minimize the risk of CSF leak.124

Information on the adverse effects associated with use of the intracranial carmustine wafer is derived mainly from data for 240 patients with newly diagnosed malignant glioma or 222 patients with recurrent malignant glioma receiving either carmustine-wafer or placebo-wafer implants in 2 randomized trials.124 Unless otherwise specified, adverse effects occurred at a similar rate in patients receiving carmustine-wafer or placebo-wafer implants.124

Respiratory Effects

Pulmonary toxicity, including acute or delayed onset of pulmonary fibrosis causing death, has occurred in patients receiving systemic carmustine therapy.105 Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis occurring 9 days to 43 months following treatment has been reported in patients receiving carmustine or related nitrosoureas.105 Most reported cases of pulmonary toxicity have occurred in patients receiving prolonged carmustine therapy with total doses exceeding 1400 mg/m²; however, pulmonary fibrosis has occurred with lower total doses.105 Other risk factors include prior history of pulmonary disease and duration of carmustine therapy.105 Pulmonary toxicity occasionally has been rapidly progressive and/or fatal.105

In a study of 17 children (aged 1-16 years) receiving carmustine in cumulative doses ranging from 770-1800 mg/m² combined with cranial radiation therapy for intracranial tumors, 8 children (47%) died of delayed pulmonary fibrosis, including all of those who received initial treatment at less than 5 years of age (5 children).105 Onset of pulmonary fibrosis has been observed up to 17 years following carmustine therapy.105 Clinical findings include pulmonary hypoplasia with upper zone contraction on chest radiographs, and an unusual pattern of upper zone fibrosis on thoracic CT scans; no abnormal findings were observed on gallium scans.105 Late onset of reduction in pulmonary function was observed in all long-term survivors in the study.105 Carmustine-induced pulmonary fibrosis may be slowly progressive and cause death.105

Pulmonary embolism occurred in 8% of patients receiving the intracranial carmustine wafer implant at initial surgery for malignant glioma.124 Pneumonia was reported in 8%, and dyspnea in 3%, of patients.124

Pulmonary embolism was reported in 4-9% of patients with recurrent glioma receiving the intracranial carmustine wafer implant in a randomized trial.151 Aspiration pneumonia has been reported in 1% of patients receiving the carmustine wafer implant in clinical studies to date.124

Hematologic Effects

A serious and frequent adverse effect associated with systemic administration of carmustine is delayed hematologic toxicity, which is cumulative and usually occurs 4-6 weeks after administration of the drug.105 Thrombocytopenia is generally the most severe hematologic effect, appearing and subsiding earlier than other hematologic toxicities; however, both leukopenia and thrombocytopenia may be dose-limiting toxicities.105 Thrombocytopenia usually is evident at approximately 4 weeks and persists for about 1-2 weeks, and leukopenia usually is evident at approximately 5-6 weeks and persists for 1-2 weeks.105 Following repeated doses of carmustine, however, cumulative myelosuppression manifested as more depressed indices or as more prolonged suppression may occur.105 Anemia also occurs, but generally is less frequent and less severe than other hematologic toxicities.105

Anemia was reported in 4-9% of patients with recurrent glioma receiving the intracranial carmustine wafer implant in a randomized trial.151 Thrombocytopenia and leukocytosis each has been reported in 1% of patients receiving the carmustine wafer implant in clinical studies to date.124

Acute leukemia and bone marrow dysplasia have been reported in patients receiving long-term nitrosourea therapy,105,107,108 including some who received carmustine.107,108

Nervous System Effects

Among patients receiving the intracranial carmustine wafer implant at initial surgery for malignant glioma, the most common adverse nervous system effects were hemiplegia (41%), seizures (33%), headache (28%), confusion (23%), brain edema (23%), and aphasia (18%).124 Depression was reported in 16% of patients, and somnolence and speech disorder each occurred in 11% of patients.124 Intracranial hypertension occurred more frequently in patients receiving the carmustine wafer implant (9%) than in those receiving the placebo wafer implant (2%).124,152 Other adverse nervous system effects included amnesia in 9%; personality disorder in 8%; anxiety, facial paralysis, or neuropathy, in 7%; ataxia, hypesthesia, paresthesia, or abnormal thinking, in 6%; and abnormal gait, dizziness, grand mal seizure, hallucinations, insomnia, or tremor, in 5% of patients.124 Brain abscess or meningitis was reported in 5% of patients receiving the carmustine wafer and 6% of patients receiving the placebo wafer.124 Coma occurred in 4%, incoordination in 3%, and hypokinesia in 2%, of patients receiving the carmustine wafer implant.124

In randomized trials of patients with newly diagnosed or recurrent malignant glioma, adverse nervous system effects which may have been related to treatment with the intracranial carmustine wafer implant included seizures and brain edema.124 Among patients with newly diagnosed malignant glioma, seizures or grand mal seizures respectively occurred in about 33 or 5% of patients receiving the carmustine wafer and 38 or 4% of those receiving the placebo wafer.124 Within the first 5 days following wafer implantation, the incidence of seizures was 2.5% in the carmustine wafer-treated group and 4.2% in the placebo wafer-treated group.124 The time of onset of the first postoperative seizure did not differ between the groups.124 Among patients with recurrent disease, the incidence of postoperative seizures was 19% in both the placebo wafer- and carmustine wafer-treated groups; however, the first new or worsened seizure occurred sooner after craniotomy and occurred more frequently during the first 5 postoperative days in patients treated with the carmustine implant.124 The median time to onset of the first new or worsened seizure was 3.5 days in patients receiving carmustine wafers compared with 61 days in those receiving placebo wafers.124 About 54% of patients receiving carmustine wafers experienced the first new or worsened seizure within the first 5 postoperative days compared with 9% of those receiving placebo wafers.124

Among patients with newly diagnosed malignant glioma, brain edema occurred in 22.5% of patients receiving the carmustine wafer and 19.2% of patients receiving the placebo wafer in a randomized trial.124 Brain edema was reported in 4% of patients with recurrent malignant glioma treated with intracranial carmustine wafer implants in a randomized trial.124 Cases of intracerebral mass effect unresponsive to corticosteroids, including one case leading to brain herniation, have been reported in patients treated with carmustine wafers.124 Reoperation, sometimes involving removal of carmustine wafers or wafer remnants, has been necessary in some patients developing brain edema with mass effect due to tumor recurrence, intracranial infection, or necrosis.124 Formation of tumor bed cyst that was unresponsive to treatment with high-dose corticosteroids and required reoperation for drainage also has been reported following implantation of carmustine wafers.136

Pain occurred in 13% of patients receiving the intracranial carmustine wafer implant for newly diagnosed malignant glioma.124 Pain was reported in a greater number (7 versus 1%) of patients receiving intracranial carmustine wafer implants for recurrent malignant glioma in a randomized trial compared with those receiving placebo wafer implants.124

Common adverse nervous system effects occurring in patients undergoing intracranial implantation of the carmustine wafer for recurrent malignant glioma in a randomized trial include convulsion or hemiplegia in 19%, headache in 15%, somnolence in 14%, confusion in 10%, aphasia in 9%, stupor in 6%, intracranial hypertension in 4%, and meningitis or abscess in 4%.124 Other adverse nervous system effects reported in less than 4% but at least 1% of patients receiving the carmustine wafer implant for recurrent malignant glioma in clinical studies to date include hydrocephalus, depression, abnormal thinking, ataxia, dizziness, insomnia, monoplegia, coma, amnesia, diplopia, and paranoid reaction.124 Cerebral hemorrhage and cerebral infarct each was reported in less than 1% of patients receiving the carmustine wafer implant.124 In a small randomized study of patients receiving carmustine-wafer or placebo-wafer implants for the initial treatment of high-grade glioma, hemiparesis occurred in 38% of patients receiving the carmustine wafer.134

Headache also has been reported in patients receiving IV carmustine.105 Other effects reported in conjunction with systemic administration of carmustine but not definitely attributable to the drug include dizziness, loss of equilibrium, and ataxia.

In a randomized trial, encephalopathy, sometimes fatal, was reported in patients receiving intra-arterial carmustine.132

Local Effects

Healing abnormalities, including wound dehiscence; delayed wound healing; subdural, subgaleal, or wound effusions; and CSF leaks, were reported in 16% of patients receiving the intracranial carmustine wafer implant versus 12% of patients receiving the placebo wafer at initial surgery for malignant glioma.124 CSF leaks occurred in 5% of patients receiving the carmustine wafer versus 0.8% of those receiving the placebo wafer.124 Healing abnormalities occurred in 14% of patients receiving the intracranial carmustine wafer implant compared with 5% of those receiving the placebo wafer implant for recurrent malignant glioma in a randomized trial.124

Local burning pain at the site of injection or along the course of the vein and venospasm occur commonly in patients receiving IV carmustine, but true thrombosis and thrombophlebitis occur rarely.38,105 Rapid IV infusion of carmustine may produce intensive flushing of the skin and suffusion of the conjunctiva; these effects occur within 2 hours and may persist for 4 hours after administration of carmustine.105

Infectious Complications

Infection occurred in 18% of patients receiving the carmustine wafer and 20% of those receiving the placebo wafer for newly diagnosed malignant glioma in a randomized trial.124 Intracranial infection (abscess or meningitis) was reported in 5% of patients receiving the carmustine wafer and 6% of patients receiving the placebo wafer for newly diagnosed malignant glioma in a randomized trial.124 Intracranial infection (meningitis or abscess) occurred in 4% of patients receiving the intracranial carmustine wafer implant compared with 1% of those receiving the placebo wafer implant for recurrent malignant glioma in a randomized trial.124 Among patients with recurrent disease receiving the carmustine wafer implant, there were 2 cases of bacterial meningitis, one case of chemical meningitis, and one case of meningitis of unspecified type; a brain abscess was reported in a patient receiving the placebo wafer.151 Deep wound infection (i.e., infection of subgaleal space, bone, meninges, or neural parenchyma) was reported in 6% of patients receiving the carmustine-wafer or placebo-wafer implant for recurrent disease.151

Pneumonia occurred in 8% of patients receiving the carmustine wafer for newly diagnosed malignant glioma.124 Pneumonia and oral candidiasis (moniliasis) were reported in 4-9% of patients with recurrent glioma receiving the intracranial carmustine wafer implant in a randomized trial; these adverse effects were reported at a similar rate in patients receiving the placebo wafer implant.151 Sepsis has been reported in 1% of patients receiving the carmustine wafer implant in clinical studies to date.124

GI Effects

Nausea and vomiting occur frequently after IV administration of carmustine.105 These effects are dose related and generally occur within a few minutes to 2 hours and persist up to 6 hours after administration of the drug.105 Prior administration of antiemetics may diminish or prevent these effects.105 Other less frequently reported adverse effects of carmustine include diarrhea, esophagitis, anorexia, and dysphagia.

The most common adverse GI effects reported in patients receiving the intracranial carmustine wafer implant at initial surgery for malignant glioma were nausea (22%), vomiting (21%), and constipation (19%); abdominal pain occurred in 8%, and diarrhea occurred in 5%, of patients receiving the carmustine wafer.124 Nausea and vomiting occurred in 8% of patients with recurrent glioma receiving the intracranial carmustine wafer implant in a randomized trial.124 Other adverse GI effects reported in 1-2% of patients receiving the carmustine wafer implant in clinical studies to date include diarrhea, constipation, dysphagia, GI hemorrhage, and fecal incontinence.124

Hepatic Effects

Hepatotoxicity, reported in up to 26% of patients who receive carmustine, is generally mild and reversible, usually occurring when high doses of the drug are administered. Hepatotoxicity may be manifested by increases in serum transaminase, alkaline phosphatase, and bilirubin concentrations;105 jaundice, portal system encephalopathy, and at least 1 death have also been reported.

Abnormal results of liver function tests were reported in 1% of patients receiving the intracranial carmustine wafer implant at initial surgery for malignant glioma.124

Renal and Electrolyte Effects

A decrease in kidney size, progressive azotemia, and renal failure have occurred in patients who received large cumulative doses after prolonged therapy with carmustine and related nitrosoureas; renal damage has also occurred occasionally in patients receiving lower total doses.105

Hyponatremia was reported in 4-9% of patients with recurrent glioma receiving the intracranial carmustine wafer implant in a randomized trial.151 Hypokalemia has been reported in 1% of patients receiving the carmustine wafer implant in clinical studies to date.124

Ocular Effects

The manufacturer reports that ocular toxicity, including neuroretinitis, has occurred in patients receiving carmustine therapy, particularly when the drug was injected intra-arterially into the carotid artery.105 In a randomized trial, severe ocular toxicity, including progression of visual loss to blindness, was reported in patients receiving intra-arterial carmustine.132

Among patients receiving the intracranial carmustine wafer implant at initial surgery for malignant glioma, adverse ocular effects included conjunctival edema (7%), abnormal vision (6%), visual field defect (5%), unspecified eye disorder (3%), and diplopia (1%).124

Visual field defect and ocular pain have been reported in 2 and 1%, respectively, of patients receiving the intracranial carmustine wafer implant in clinical studies to date.124 Conjunctivitis was reported at a similar rate in patients with recurrent glioma receiving either carmustine-wafer or placebo-wafer implants in a randomized trial.133

Cardiovascular Effects

Chest pain,105 hypotension,105 and tachycardia105 have been reported in patients receiving IV carmustine.

Among patients receiving the intracranial carmustine wafer implant at initial surgery for malignant glioma, deep thrombophlebitis occurred in 10%, peripheral edema in 9%, and hemorrhage in 7% of patients.124 Chest pain occurred in 5% of patients receiving the carmustine wafer implant and none of the patients receiving the placebo wafer implant.124

Deep thrombophlebitis was reported in 4-9% of patients with recurrent glioma receiving the intracranial carmustine wafer implant in a randomized trial.151 Hypertension, edema, chest pain, and hypotension have been reported in 3, 2, 1, and 1%, respectively, of patients receiving the carmustine wafer implant in clinical studies to date.124

Genitourinary Effects

Among patients receiving the intracranial carmustine wafer implant at initial surgery for malignant glioma, urinary tract infection and urinary incontinence each occurred in 8% of patients.124

Urinary tract infection was reported in about 20% of patients with recurrent glioma receiving either the intracranial carmustine-wafer or placebo-wafer implant in a randomized trial.124 Urinary incontinence has been reported in 2% of patients receiving the carmustine wafer implant in clinical studies to date.124

Endocrine and Metabolic Effects

Diabetes mellitus occurred in 5%, and Cushing's syndrome occurred in 3%, of patients receiving the intracranial carmustine wafer implant at initial surgery for malignant glioma.124 Hyperglycemia has been reported in 3% of patients receiving the intracranial carmustine wafer implant in clinical studies to date.124

Dermatologic Effects

Accidental contact of the skin with reconstituted solutions of carmustine has produced transient hyperpigmentation of the affected area.105 Adverse dermatologic effects resulting from topical application† of carmustine for the treatment of mycosis fungoides† include moderate to severe dermatitis, tiny petechiae simulating hemosiderosis, hyperpigmentation, and telangiectasia.

Rash has been reported in 12% of patients with newly diagnosed malignant glioma and 5% of patients with recurrent glioma receiving the intracranial carmustine wafer implant in randomized trials.124 Alopecia occurred in 10% of patients receiving the intracranial carmustine wafer implant at initial surgery for malignant glioma.124

Musculoskeletal Effects

Back pain was reported in 7%, and myasthenia in 4%, of patients receiving the intracranial carmustine wafer at initial surgery for malignant glioma.124 Neck pain and back pain have been reported in 2 and 1%, respectively, of patients receiving the intracranial carmustine wafer implant in clinical studies to date.124

Other Adverse Effects

The most common adverse effect reported in patients receiving the intracranial carmustine wafer implant at initial surgery for malignant glioma in a randomized trial was aggravation reaction, which occurred in 82% of patients.124 As defined by COSTART, aggravation reaction refers to events involving progression of tumor or disease or general deterioration in condition, such as performance status or neurologic status.124 Asthenia or fever occurred in 22 or 18%, respectively, of patients receiving the carmustine wafer at initial surgery.124 Facial edema was reported in 6% of patients receiving the carmustine wafer.124 Other adverse effects occurring in patients receiving the intracranial carmustine wafer at initial surgery for malignant glioma include accidental injury (5%) and allergic reaction (2%).124

Fever has been reported in 12% of patients with recurrent glioma receiving the intracranial carmustine wafer implant in a randomized trial.124 Accidental injury and allergic reaction each has been reported in 1% of patients receiving the carmustine wafer implant in clinical studies to date.124 Allergic reaction also has been reported in patients receiving IV carmustine.105

Precautions and Contraindications

Conventional Chemotherapy

Carmustine is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. The drug must be used only under constant supervision by clinicians experienced in cancer chemotherapy.

Patients who receive myelosuppressive drugs experience an increased frequency of infections as well as possible hemorrhagic complications. Because these complications have caused fatalities, the patient should be instructed to notify the clinician if fever, sore throat, or unusual bleeding or bruising occurs. The patient's hematologic status must be carefully monitored, and blood counts performed weekly during and for at least 6 weeks after carmustine therapy. Carmustine should be administered with caution to patients with depressed platelet, leukocyte, or erythrocyte counts.

Pulmonary toxicity associated with carmustine therapy appears to be dose related, and patients receiving cumulative doses exceeding 1400 mg/m² are at substantially higher risk than patients receiving lower cumulative doses of the drug. Pulmonary function tests should be performed prior to initiation of and frequently during carmustine therapy. Patients with a baseline forced vital capacity (FVC) or pulmonary diffusion capacity for carbon monoxide (DL_CO) that is less than 70% of the predicted value are particularly at risk for carmustine-induced pulmonary toxicity.105 In addition, delayed onset of pulmonary fibrosis, frequently fatal, has occurred up to 17 years following carmustine therapy in children and adolescents.105 (See Cautions: Pulmonary Effects.)

Because carmustine may cause hepatic dysfunction, liver function should be monitored periodically in patients receiving the drug.105 The manufacturer recommends that renal function tests also be monitored periodically during carmustine therapy.105

Carmustine is contraindicated in patients who have demonstrated previous hypersensitivity to the drug.105

Intracranial Wafer Implant

Patients undergoing craniotomy for malignant glioma and intracranial implantation of carmustine wafers should be monitored closely for potential complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, and brain edema.124 Reoperation, sometimes involving removal of carmustine wafers or wafer remnants, may be necessary in patients developing brain edema with mass effect due to tumor recurrence, intracranial infection, or necrosis.124 Communication between the surgical resection cavity and the ventricular system could result in migration of carmustine wafers into the ventricular system, leading to obstructive hydrocephalus; any such communication larger than the diameter of a carmustine wafer should be closed prior to implantation of carmustine wafers.124

Imaging studies of the head (e.g., CT scan, MRI) may reveal enhancement in the brain tissue surrounding the resection cavity following intracranial implantation of carmustine wafers; this enhancement may represent edema and inflammation caused by carmustine wafer or tumor progression.124

The use of carmustine wafers is contraindicated in patients who have demonstrated a previous hypersensitivity to carmustine or any component of the implants.124

Pediatric Precautions

Safety and efficacy of carmustine in children have not been established.105 Fatal pulmonary fibrosis with delayed onset up to 17 years following treatment has been reported in children receiving IV carmustine therapy for brain tumors.105 Because of the extremely high risk of pulmonary toxicity frequently causing death, particularly in children younger than 5 years of age, the risks and benefits of carmustine therapy must be weighed carefully.105 (See Cautions: Pulmonary Effects.)

Safety and efficacy of intracranial carmustine wafer implants in children have not been established.105

Geriatric Precautions

Safety and efficacy of carmustine in geriatric patients have not been studied specifically to date.105,148 While clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.105,148 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.105,148

Because geriatric patients may have decreased renal function and because patients with renal impairment may be at increased risk of carmustine-induced toxicity, drug dosage should be titrated carefully and renal function should be monitored closely in patients in this age group.105,148

Mutagenicity and Carcinogenicity

In vitro tests have shown carmustine to be mutagenic, and both in vitro and in vivo tests have shown the drug to be clastogenic.124 Carmustine has been shown to be carcinogenic in rats and mice, and has been associated with a marked increase in the incidence of tumors, particularly subcutaneous and lung neoplasms, when administered to these animals in dosages approximately equivalent to or less than the usual human dosage.105,124 Nitrosourea therapy, such as carmustine therapy, has carcinogenic potential in humans, and the manufacturer states that acute leukemia and bone marrow dysplasia have been reported in patients receiving long-term therapy with nitrosourea derivatives.105

No mutagenicity or carcinogenicity studies have been performed with the carmustine wafer.124

Pregnancy, Fertility, and Lactation

Pregnancy

Carmustine may cause fetal harm when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite possible risks to the fetus.105,113 Carmustine has been shown to be teratogenic in rats and embryotoxic in rats and rabbits receiving dosages approximating the usual human dosage.105,124 There are no adequate and controlled studies to date using carmustine or carmustine wafer implants in pregnant women,105,124 and the drug should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.113 Women of childbearing potential should be advised to avoid becoming pregnant during carmustine therapy.105 When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.105,124

Fertility

Carmustine has been shown to affect fertility in male rats receiving the drug at dosages somewhat higher than the usual human dosage.105

Lactation

It is not known whether carmustine is distributed in milk.105 Because of the potential for serious adverse reactions to carmustine in nursing infants, nursing should be discontinued during systemic carmustine therapy.105

It is not known whether components of the carmustine wafer, including carmustine, carboxyphenoxypropane, or sebacic acid, are distributed in milk.124 Because of the potential for serious adverse reactions to carmustine in nursing infants, nursing should be discontinued in patients receiving carmustine wafer implants.124

Interactions of carmustine wafers with other drugs have not been formally studied.124 In clinical trials of patients undergoing surgery and intracranial implantation of carmustine wafers for recurrent malignant glioma, chemotherapy was withheld for at least 4 weeks (6 weeks for nitrosoureas) prior to and 2 weeks after surgery.124 The short-term or long-term toxicity of carmustine wafers used in conjunction with systemic chemotherapy has not been fully evaluated.124

Cimetidine

Cimetidine may potentiate the myelosuppressive effects (e.g., neutropenia, agranulocytosis) of myelosuppressive drugs (e.g., alkylating agents, antimetabolites) or therapies (e.g., radiation). Concomitant cimetidine therapy has been reported to potentiate the neutropenic and thrombocytopenic effect of carmustine alone or combined with radiation therapy.

Mitomycin

Qualitative and quantitative changes in tear films leading to damage of the corneal and conjunctival epithelium have been reported in patients receiving high doses of carmustine and mitomycin.146

Phenytoin

In patients receiving carmustine and phenytoin, serum concentrations of phenytoin may be decreased.147 In patients receiving carmustine therapy, serum concentrations of phenytoin should be monitored carefully and dosage adjustments made as necessary.147

Radiation Therapy

In clinical trials of patients undergoing surgery and intracranial implantation of carmustine wafers for recurrent malignant glioma, external beam radiation therapy was initiated no sooner than 3 weeks after surgery.151 In a randomized trial of patients receiving either carmustine wafers or placebo wafers at initial surgery for malignant glioma, most patients received a standard course of radiation therapy (55-60 Gy) initiated at 3 weeks following surgery.124 No short-term or long-term toxicity is known to result from the use of radiation therapy in conjunction with intracranial carmustine wafers.124

Acute Toxicity

There are no known antidotes for overdosage of IV carmustine.105

There is no clinical experience with intracranial implantation of more than 8 carmustine wafers per surgical procedure.124

Pharmacology

Although carmustine is believed to act by alkylation of DNA and RNA,105,124 the mechanism of action has not been completely elucidated and other effects such as carbamoylation105 and modification of cellular proteins may be involved. The overall result is thought to be the inhibition of both DNA and RNA synthesis. The manufacturer reports that cross-resistance between carmustine and lomustine has occurred.

The cytotoxic effect of the carmustine wafer is dependent on release of the drug to the tumor cavity in sufficient amounts to achieve concentrations that result in tumoricidal activity.124

Pharmacokinetics

Absorption

The absorption of the copolymer contained in carmustine wafers has not been evaluated in humans.124 Plasma concentrations of carmustine following intracranial implantation of the wafers have not been determined in humans, but in rabbits undergoing surgical implantation of wafers containing 3.85% carmustine, no detectable levels of carmustine were observed in plasma.124

Distribution

Following IV infusion of carmustine, the steady-state volume of distribution averaged 3.25 L/kg.124 Because of their high lipid solubility, carmustine and/or its metabolites readily cross the blood-brain barrier.105 Substantial CSF concentrations occur almost immediately after IV administration of carmustine, and CSF concentrations of radioactivity have been variously reported to range from 15-70% of concurrent plasma concentrations. Carmustine metabolites are distributed into milk, but in concentrations less than those in maternal plasma.

The carmustine implant is designed to deliver carmustine directly into the surgical cavity created upon resection of a brain tumor.124 The concentration of carmustine achieved in human brain tissue with intracranial implantation of the carmustine wafers has not been determined.124 The distribution of the copolymer contained in carmustine wafers has not been evaluated in humans.124 In rabbits undergoing surgical implantation of wafers containing 3.85% carmustine, no detectable concentrations of carmustine were observed in CSF.124

Elimination

After IV administration, carmustine is rapidly cleared from the plasma with no intact drug detectable after 15 minutes.105 In studies using ¹⁴C-labeled carmustine, prolonged concentrations of radioactivity were present in the plasma and tissue,105 probably as a result of protein binding and/or enterohepatic circulation of metabolites, and may be responsible for the delayed hematologic toxicity of carmustine. (See Cautions.) Following IV infusion of carmustine, the terminal plasma elimination half-life and clearance averaged 22 minutes and 56 mL/minute per kg, respectively.124

When the carmustine wafer is exposed to the aqueous environment of the resection cavity, hydrolysis of the anhydride bonds in the copolymer occurs, resulting in the release of carmustine and two monomers, carboxyphenoxypropane, and sebacic acid.124 The carmustine contained in the wafer diffuses into the surrounding brain tissue.124 The metabolism and excretion of the copolymer contained in carmustine wafers has not been evaluated in humans.124 Animal studies have shown that more than 70% of the copolymer degrades within 3 weeks following implantation of carmustine wafers into brain tissue;124 following hydrolysis of the copolymer, carboxyphenoxypropane is eliminated renally, while sebacic acid (an endogenous fatty acid) is metabolized in the liver and expired as carbon dioxide.124 In humans, wafer remnants have been observed on brain imaging scans or located during subsequent surgical procedures up to 8 months following intracranial implantation.124 Wafer remnants retrieved from 2 patients approximately 2-3 months after implantation were analyzed and found to consist mostly of water and monomeric components with minimal detectable amounts of carmustine.124

Carmustine is rapidly metabolized.105 The antineoplastic and toxic effects of carmustine are thought to be caused by active metabolites.105 One metabolite, an alkylating moiety thought to be chloroethyl carbonium ion, leads to the formation of DNA cross-links.124 The metabolites are slowly excreted in urine. Following IV administration of ¹⁴C-labeled carmustine, about 30% of the radioactivity is excreted within 24 hours38 and about 60-70% of the radioactivity is excreted within 96 hours.105,124 Some enterohepatic circulation is believed to occur. Less than 1% of the radioactivity is excreted in feces. About 6-10% of the radioactivity is excreted as respiratory carbon dioxide, and the fate of the remaining 20-30% of a dose has not been determined.105,124

Chemistry and Stability

Chemistry

Carmustine, a nitrosourea derivative, is generally considered to be an alkylating agent. The drug occurs as lyophilized yellow flakes or congealed mass.105 Carmustine is slightly soluble in water, freely soluble in alcohol, and highly soluble in lipids.

Carmustine also is commercially available as a component of a biodegradable polymer implant.124 The intracranial carmustine implant is a sterile, off-white to pale yellow wafer measuring approximately 1.45 cm in diameter and 1 mm in thickness that contains 7.7 mg of carmustine and 192.3 mg of polifeprosan 20.124 Carmustine is homogeneously distributed in the matrix of polifeprosan 20, a biodegradable polyanhydride copolymer consisting of poly[bis( p -carboxyphenoxy)propane and sebacic acid in a 20:80 molar ratio that is used to control the local delivery of carmustine.124

Stability

Carmustine lyophilized material decomposes to an oily liquid at temperatures of 30.5°C or warmer; the liquefied material appears as an oily film on vials of the drug. Vials of the lyophilized material that may not have been refrigerated adequately should be inspected to determine whether any decomposition has occurred by holding them up to a bright light.105 If the drug appears as dry flakes or as a dry, congealed mass, the vial of carmustine is suitable for use and should be refrigerated immediately if it is to be stored for later reconstitution.105 If an oily film is present inside the vial, the drug should be discarded.105 Carmustine powder must be refrigerated at 2-8°C.105 Both the powder and its solutions must be protected from light.105 When stored according to manufacturer recommendations, the contents of unopened vials of the drug remain stable for up to 3 years.105

Following reconstitution of the lyophilized material with dehydrated (absolute) alcohol and sterile water for injection as directed by the manufacturer, solutions of carmustine are clear and colorless to yellow in color.105 These solutions are stable in glass containers for 8 hours at 25°C when protected from light.101,105 Reconstituted carmustine solutions that are further diluted with 5% dextrose injection to a final concentration of 0.2 mg/mL in glass containers are stable for 8 hours when stored at 25°C and protected from light;105 however, carmustine powder contains no preservatives and the possibility of microbial contamination of reconstituted solutions must be considered. Some data indicate that solutions of carmustine in 5% dextrose injection in PVC containers are rapidly degraded; admixture of the drug in PVC containers should therefore be avoided.102 The manufacturer recommends that only glass containers be used for the administration of solutions of the drug.105 Carmustine is rapidly degraded in aqueous solutions at pH greater than 6,103 and it is recommended that the drug not be admixed with nor administered through a common tubing or site with solutions containing sodium bicarbonate.104

Carmustine wafers must be stored at a temperature of -20°C or less.124 The aluminum foil laminate pouches containing each carmustine wafer should not be opened until immediately prior to the implantation procedure.124 Unopened foil pouches may be kept at ambient room temperature for up to 6 hours at a time.124

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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