VA Class:AN300

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Dacarbazine

Dacarbazine, a synthetic analog of a naturally occurring purine precursor, is an antimetabolite antineoplastic agent.

Melanoma

Dacarbazine monotherapy currently is a systemic treatment of choice for metastatic melanoma.101,106,107,111,135,138 Although dacarbazine also has been used in various combination regimens† for the treatment of this disease,101,105,109,110,111,112,113,114,115,116,118,125,126,127,134,135,136,137 randomized trials currently have not shown that combination regimens are superior to dacarbazine alone,111,135 and the optimal regimen remains to be established.106,135,138

Overview

Localized melanoma is highly curable with surgical excision.105,106,107,108 In some patients with spread of melanoma to regional lymph nodes, wide surgical excision and removal of the involved lymph nodes may be curative.105,106,107,108 Adjuvant therapy with interferon alfa following resection of melanoma at high risk for recurrence has been shown to prolong disease-free but not overall survival, particularly in patients with node-positive disease.106,108,119,124,139 (See Uses: Melanoma in Interferon Alfa 10:00.) The role of adjuvant therapy following surgical resection of localized melanoma without nodal involvement has not been fully established, and eligible candidates should continue to be enrolled in clinical trials.106,107,108,119,121,122,123,138 Adjuvant therapy with conventional antineoplastic agents (e.g., dacarbazine, melphalan),105,107,128,131 nonspecific immunotherapy (e.g., BCG),107,129 or cell-based melanoma vaccine130 has not been shown to increase survival in patients with localized melanoma at high risk for recurrence, and inconclusive results have been reported with the use of levamisole, a nonspecific immunomodulating agent.107,132,133

Locally recurrent or in-transit metastatic melanoma of the extremities has been treated with surgical resection, local injection of lesions (e.g., BCG), or isolated limb perfusion (e.g., melphalan) (see Uses: Melanoma in Melphalan 10:00);105,106,108,131 for patients rendered free of disease following treatment, enrollment in a clinical trial for adjuvant therapy may be considered.108,119,138 Primary or recurrent disseminated (i.e., metastatic) melanoma generally is incurable, and palliative treatment may include surgery (e.g., regional lymphadenectomy, metastasectomy),105,106 radiation therapy,105,108 and/or systemic therapy with chemotherapy105,106,108 and/or biologic therapy.105,106,107,108 Surgical resection of isolated metastases may prolong disease-free or overall survival in some patients with metastatic or recurrent melanoma;105,106,107,108 for patients rendered free of disease following treatment, enrollment in a clinical trial for adjuvant therapy may be considered.108,119,138 Radiation therapy may provide symptomatic relief for brain, bone, and visceral metastases.105

Advanced melanoma is relatively resistant to systemic therapy,105,107 and combination chemotherapy regimens have not been shown to be superior to dacarbazine used as a single agent, the current standard of care to which all experimental therapies for metastatic melanoma should be compared.106,135,138 Palliative treatment with aldesleukin or interferon alfa provides durable remissions in about 5% of selected patients with advanced melanoma.105,138 (See Uses: Metastatic Melanoma in Aldesleukin 10:00 or Uses: Melanoma in Interferon Alfa 10:00.)The use of vaccines, monoclonal antibodies, and gene therapy also is being investigated in patients with metastatic melanoma.105,107 Because the prognosis for patients with advanced melanoma is poor, all patients should be considered for enrollment in clinical trials at the time of diagnosis.105,107,138

Metastatic Melanoma

Dacarbazine monotherapy is used for the palliative treatment of metastatic melanoma.101,105,106,107,108,111,135 Overall response rates of about 10-15% have been reported in patients receiving dacarbazine as a single agent in randomized trials;111,135 although durable complete responses have occurred in some patients (less than 5%),111,135 the duration of response usually is short (e.g., 3-6 months).105,106,107 Dacarbazine also has been used with other agents,105,106,107,108,111,135 but randomized trials currently have not shown that combination regimens are superior to dacarbazine alone in the treatment of metastatic melanoma.111,135 The use of dacarbazine-containing chemotherapy in combination with biologic therapy using aldesleukin and interferon alfa is being investigated for the treatment of metastatic melanoma;110,113,114,135,136,137 a large randomized trial is under way to investigate the comparative efficacy and toxicity of concurrent biochemotherapy with interferon alfa-2b, aldesleukin, cisplatin, vinblastine, and dacarbazine versus combination chemotherapy with cisplatin, vinblastine, and dacarbazine in patients with metastatic melanoma.137

In phase II, single-institution studies, some combination chemotherapy regimens (e.g., dacarbazine, carmustine, cisplatin, and tamoxifen) for metastatic melanoma showed higher response rates than those observed in other studies using single-agent therapy,105,135 but evidence from large, randomized trials has not shown combination therapy to be superior to dacarbazine alone.105,111,135 In a multicenter, phase III, randomized trial, toxicity was greater but response rate and survival time did not differ among patients receiving combination therapy with dacarbazine, carmustine, cisplatin, and tamoxifen versus dacarbazine alone.135

Evidence suggests that the addition of cisplatin to dacarbazine-containing regimens increases toxicity but does not improve survival.112 The addition of tamoxifen109,111,115,134 and/or interferon alfa111,125,126 to dacarbazine (used alone or in combination regimens) has not been shown to improve efficacy in patients with metastatic melanoma. Interpretation of the results from a randomized trial suggesting that the combination of dacarbazine and tamoxifen was superior to dacarbazine alone in patients with metastatic melanoma was limited by design flaws (e.g., small sample size, imbalance in prognostic factors),116,117 and other studies have not confirmed the benefit of tamoxifen.109,111,115,134 In a phase III, randomized trial, response rates, progression-free survival, or overall survival did not differ among patients receiving combination chemotherapy with dacarbazine, cisplatin, and carmustine, with or without tamoxifen.134 In another phase III, randomized trial, the addition of tamoxifen to combination therapy with dacarbazine, cisplatin, and carmustine did not improve response rates in patients with metastatic melanoma.115 In a large randomized trial, the addition of tamoxifen, with or without interferon, to dacarbazine did not increase the response rate, time to treatment failure, or duration of survival.111 Results from a small randomized trial suggested that the combination of dacarbazine and interferon alfa was superior to dacarbazine alone,127 but other studies did not confirm these findings.111,125,126 Although duration of response was prolonged with the addition of interferon alfa-2a to dacarbazine in patients with advanced melanoma, no difference was observed in objective response rate or overall survival.125 In a large randomized trial, the addition of interferon alfa, with or without tamoxifen, to dacarbazine did not increase the response rate, time to treatment failure, or duration of survival, but significantly increased toxicity.111

Further study is needed to establish the optimal regimen for the treatment of metastatic melanoma.105,107,138

Hodgkin's Disease

Dacarbazine is used in combination with other antineoplastic agents in the treatment of advanced Hodgkin's disease.100,101,102,103,104 Combination therapy for Hodgkin's disease is clearly superior to single-agent therapy.102,103,104 Various regimens have been used in combination therapy and comparative efficacy is continually being evaluated.102,103,104 Dacarbazine is often used with doxorubicin, bleomycin, and vinblastine (known as the ABVD regimen) for the treatment of patients with advanced Hodgkin's disease.101,102,103,104 The ABVD regimen also is used in an alternating schedule with the MOPP regimen (mechlorethamine, vincristine, procarbazine, and prednisone) for the treatment of advanced Hodgkin's disease.101,102,103,104

Other Uses

Dacarbazine has been used with some success alone or in conjunction with other antineoplastic agents in the treatment of soft-tissue sarcomas† (e.g., leiomyosarcoma, fibrosarcoma, rhabdomyosarcoma) and neuroblastomas†. Dacarbazine alone has reportedly been beneficial in the treatment of a few cases of malignant glucagonoma†.

Reconstitution and Administration

Dacarbazine is administered by IV injection or infusion. Care should be taken to avoid extravasation of the drug. (See Cautions: Local Effects.) The powder for injection is reconstituted by adding 19.7 mL of sterile water for injection to a vial labeled as containing 200 mg of the drug.100 The resultant solution contains 10 mg of dacarbazine per mL. Reconstituted solutions may be administered by IV push over a 1-minute period. Alternatively, the reconstituted solution may be further diluted with up to 250 mL of 5% dextrose or 0.9% sodium chloride injection and infused IV over a 15- to 30-minute period. The manufacturer's labeling should be consulted for information on reconstitution and further dilution of other strengths of the powder for injection.

Dosage

Dosage of dacarbazine must be based on 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 dacarbazine and other chemotherapeutic agents and the method and sequence of administration.

Because dacarbazine is considered an antineoplastic agent of high emetic risk, antiemetic therapy for the prevention of acute and delayed emesis is recommended.140 (See Cautions: GI Effects.)

Melanoma

For the treatment of metastatic melanoma, the manufacturer states that the recommended adult dosage of dacarbazine is 2-4.5 mg/kg daily for 10 days.100 It appears that the drug may be equally efficacious at the lower dosage. This regimen may be repeated at 4-week intervals.100 Alternatively, 250 mg/m² may be given daily for 5 days.100 This treatment course may be repeated every 3 weeks.100

In the treatment of melanoma, dacarbazine has also been administered by regional intra-arterial† infusion to increase the concentration of drug delivered directly into the tumor.

Hodgkin's Disease

For the treatment of Hodgkin's disease, the usual adult dosage of dacarbazine is 150 mg/m² daily for 5 days in combination with other antineoplastic agents; the regimen may be repeated every 4 weeks.100 Alternatively, a dacarbazine dose of 375 mg/m²is administered on the first day, in combination with other antineoplastic agents, and repeated every 15 days.100

GI Effects

GI symptoms of nausea, vomiting, and anorexia occur in over 90% of patients treated with dacarbazine.100 Because of its emetogenic potential, dacarbazine is classified as an antineoplastic agent of high emetic risk (i.e., incidence of emesis exceeds 90% if no antiemetic agents are administered).140 GI symptoms generally occur within 1 hour after the initial dose and may persist up to 12 hours. Rapid tolerance to adverse GI effects develops in most patients with symptoms subsiding after 1-2 days of treatment, suggesting that a CNS mechanism may be involved.100 Rarely, diarrhea, stomatitis, or intractable nausea and vomiting which necessitated discontinuance of dacarbazine therapy have occurred.

For the prevention of acute emesis, the American Society of Clinical Oncology (ASCO) currently recommends that a 3-drug antiemetic regimen consisting of a type 3 serotonin receptor antagonist, dexamethasone, and aprepitant be given before the administration of dacarbazine or other chemotherapy regimens with high emetic risk.140 (See Aprepitant 56:22.92.) Currently available selective 5-HT₃ receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron, or tropisetron [not commercially available in the US]) are comparably effective in preventing acute chemotherapy-induced nausea and vomiting.140 (For additional information, see the individual monographs for 5-HT₃ receptor antagonists in 56:22.20.)

For the prevention of delayed emesis, ASCO currently recommends a 2-drug regimen of dexamethasone and aprepitant following the administration of chemotherapy associated with high emetic risk, such as dacarbazine.140

Aggressive antiemetic therapy for the prevention of acute and delayed emesis during early courses of emetogenic chemotherapy is the best way to prevent anticipatory nausea and vomiting; behavioral therapy also may be useful.140 Although evidence is lacking, many clinicians also find benzodiazepines useful in the management of anticipatory emesis.140 For further discussion of the mechanism and management of emesis for antineoplastic agents of high emetic risk, see Emetogenic Effects in Cautions: GI Effects in Cisplatin 10:00.

Hematologic Effects

The predominant manifestations of hematologic toxicity produced by dacarbazine are leukopenia and thrombocytopenia. These effects generally appear 2-4 weeks after the last dose of the drug; rarely, deaths have occurred. The patient's hematologic status must be carefully monitored. (See Cautions: Precautions and Contraindications.) Eosinophilia has also been reported in one patient receiving the drug.

Hepatic Effects

Hepatotoxicity accompanied by hepatic vein thrombosis and potentially fatal hepatocellular necrosis has been reported in approximately 0.01% of in patients receiving dacarbazine therapy. Adverse hepatic effects have occurred more frequently when dacarbazine was administered concomitantly with other antineoplastic agents; however, these effects have also been reported in some patients receiving dacarbazine alone.

Local Effects

Administration of concentrated dacarbazine solutions may cause severe pain along the injected vein. For this reason, it has been recommended that the drug be diluted and administered by infusion. Extravasation of dacarbazine must be avoided as it may cause tissue damage and severe pain. Local pain, burning sensation, and irritation at the injection site may be relieved by local application of hot packs.

Other Adverse Effects

A flu-like syndrome, consisting of fever, myalgia, and malaise, may occur during or after treatment with dacarbazine. This flu-like syndrome, although infrequent, may recur with successive treatments.

Facial flushing and paresthesia have been reported occasionally, but appear to be transitory. Alopecia has also occurred. Rarely, transient elevations in serum alkaline phosphatase, AST (SGOT), ALT (SGPT), and BUN concentrations have been reported. CNS symptoms such as confusion, lethargy, blurred vision, seizures, and headache also have occurred during dacarbazine therapy. Dermatologic reactions, including erythematous, macular, papular, and/or urticarial rashes, have been reported infrequently, and photosensitivity reactions have occurred rarely.

Precautions and Contraindications

Dacarbazine should be used only under constant supervision by clinicians experienced in cancer chemotherapy. The drug can produce severe, possibly fatal, hematologic or hepatic toxicity and severe GI reactions, and should be administered to patients who are preferably hospitalized and receive frequent determinations of hematopoietic function. In the treatment of each patient, the clinician must carefully weigh the possibility of achieving therapeutic benefits against the risks of toxicity.

Leukocyte, erythrocyte, and platelet counts should be performed prior to and at regular intervals during dacarbazine therapy. Hematopoietic toxicity (generally a leukocyte count of less than 3000/mm³ and a platelet count of less than 100,000/mm³) may require temporary suspension or cessation of the drug.

Dacarbazine can cause anaphylactic reactions and is contraindicated in patients who have demonstrated hypersensitivity to the drug.

Carcinogenicity

Dacarbazine has carcinogenic effects in animals; however, the importance of these effects in humans has not been determined.

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date in humans, dacarbazine has been shown to be teratogenic in rats when given at dosages 20 times the usual human dosage. Dacarbazine should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

The effect of dacarbazine on fertility in humans is not known. Reproduction studies in male rats using dacarbazine dosages 10 times the usual human dosage have not revealed evidence of impaired fertility; however, in female rats receiving dacarbazine, fetal resorptions occurred more frequently than in rats receiving placebo.

Lactation

It is not known whether dacarbazine is distributed into milk. Because of the carcinogenic potential of dacarbazine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pharmacology

The precise mechanism(s) of action of dacarbazine has not been determined, but it appears that the drug exerts its cytotoxic effect by acting as an alkylating agent. Dacarbazine is probably not a cell cycle-phase specific agent; it exhibits no specific dose-response relationship or schedule dependency. The drug possesses minimal immunosuppressive activity.

Pharmacokinetics

Absorption

Dacarbazine is poorly absorbed from the GI tract. Peak plasma concentrations of about 8 mcg/mL are reached immediately following administration of dacarbazine 4.5 mg/kg by IV push.

Distribution

The volume of distribution of dacarbazine exceeds total body water content, suggesting localization in some body tissue, probably the liver. The drug is only slightly bound to plasma proteins. Dacarbazine crosses the blood-brain barrier to a limited extent; CSF concentrations are reported to be about 14% of plasma concentrations. It is not known if dacarbazine crosses the placenta or distributes into milk.

Elimination

Plasma concentrations of dacarbazine appear to decline in a biphasic manner. In individuals with normal renal function, the half-life in the initial phase (t_½α) averages 19 minutes and the half-life in the terminal phase (t_frac12;β) averages 5 hours. The manufacturer states that in one patient with renal and hepatic dysfunction, the t_½α was 55 minutes and the t_½β was 7.2 hours.

Dacarbazine is extensively metabolized. Dacarbazine is N-demethylated by liver microsomal enzymes to 5-(3-monomethyl-1-triazenyl)-1 H -imidazole-4-carboxamide (MIC) which spontaneously decomposes to form AIC plus an unidentified alkylating or methylating moiety. Small amounts of the drug may also be converted to the diazonium salt of AIC (Diazo-ICA), which undergoes spontaneous intramolecular coupling to form 2-azahypoxanthine. Some dacarbazine metabolites may contribute to the antineoplastic effect of the drug. Metabolism of dacarbazine may be enhanced by agents such as phenobarbital and phenytoin which induce liver microsomal enzymes.

Dacarbazine is excreted in the urine by tubular secretion; 30-46% of an administered dose is excreted in the urine within 6 hours. About half of the drug excreted is recovered as unchanged dacarbazine and half as AIC.

Chemistry and Stability

Chemistry

Dacarbazine, a synthetic analog of the naturally occurring purine precursor 5-amino-1 H -imidazole-4-carboxamide (AIC), is an antineoplastic agent. Dacarbazine occurs as a colorless to ivory-colored crystalline solid. The drug is slightly soluble in water and in alcohol. Protonated dacarbazine has a pK_a of 4.42. Commercially available dacarbazine powder for injection also contains anhydrous citric acid and mannitol. When reconstituted with sterile water for injection to a concentration of 10 mg/mL, dacarbazine solutions have a pH of 3-4.

Stability

Dacarbazine is sensitive to light and heat; elevated temperatures may cause a color change from ivory to pink which is indicative of some decomposition. Commercially available dacarbazine powder for injection must be protected from light and should be refrigerated at 2-8°C.100

Dacarbazine solutions containing 10 mg/mL in sterile water for injection are stable for up to 72 hours when stored at 4°C or up to 8 hours at room temperature. Solutions further diluted with up to 500 mL of 5% dextrose or 0.9% sodium chloride injection are stable for at least 24 hours when stored at 2-8°C or up to 8 hours at room temperature (under normal room light conditions). Dacarbazine solutions are physically incompatible with solutions of hydrocortisone sodium succinate.

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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