a) CASE REPORT: Rhabdomyolysis confirmed by rechallenge occurred in a 26-year-old man receiving dacarbazine and interferon alfa-2B for metastatic melanoma. On day 4 of the first cycle of combination therapy, symptoms of myalgia arose, followed by weight gain of 12 kilograms, acute renal failure and rhabdomyolysis (creatine kinase 1000-fold above normal). He recovered with supportive care and began a second cycle of the same drugs 4 months later. Myalgia, emesis, thoracic pain and rhabdomyolysis of cardiac muscle ensued and progressed to shock. Despite recovering from this second episode, the patient succumbed to tumor cachexia 8 months later (Hauschild et al, 2001).

a) CASE REPORT: A 56-year-old man developed insulin-dependent diabetes mellitus after the first course of chemotherapy with dacarbazine, mitomycin, doxorubicin, cisplatin, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Concomitant medications included dexamethasone and ondansetron. The patient had no family or personal history of diabetes, and had received chemotherapy to treat metastatic leiomyosarcoma. Post-treatment symptoms included continual vomiting, limited caloric intake, polyuria, and polydypsia. Five days after chemotherapy, the patient became orthostatic and dehydrated, and was hospitalized with diabetic ketoacidosis. The condition was managed with hydration and insulin, and the patient continued to use daily NPH insulin for the next 2 months. A second chemotherapy cycle was administered without complications, but further cycles were precluded by tumor progression. While a definitive mechanism was never determined, the authors essentially ruled out corticosteroid-induced diabetes mellitus because of the persistent hyperglycemia, implicating one or more of the chemotherapeutic agents or GM-CSF (Dispenzieri & Loprinzi, 1997).

a) Several cases of a flu-like syndrome with fever, aches, and malaise have occurred during dacarbazine therapy. Symptoms usually occur after single large doses approximately 7 days after treatment, and symptoms may last from 7 to 21 days and occur with successive treatments (Prod Info dacarbazine intravenous injection powder for solution, 2014; Gerner et al, 1973; Gerner & Moore, 1973; Foley et al, 1973; Nathanson et al, 1971).

a) Anaphylactic shock has been described during dacarbazine therapy (Prod Info dacarbazine intravenous injection powder for solution, 2014; Abhyankar et al, 1988).
b) CASE REPORT: A 3-year-old child with neuroblastoma received 2 days of intravenous dacarbazine 25 mg/m(2) as a 1-hour infusion with cyclophosphamide and vincristine as part of a chemotherapy protocol. A 5-day regimen was scheduled but the drug was discontinued prematurely due to sweating during the second course of therapy. On rechallenge 2 weeks later at a lower dose, 5 mL of a 2 mg/dL solution, the patient developed respiratory distress, cyanosis, hypotension, and facial erythema. Resuscitation was successful with epinephrine and corticosteroids (Abhyankar et al, 1988).

a) Listed as: Dacarbazine
b) Carcinogen Rating: 2B

a) Orthostatic hypotension has been reported in several patients receiving dacarbazine therapy (Samson et al, 1976; Kokoschka, 1978).

a) Seizure activity has occurred during dacarbazine therapy (Gams & Carpenter, 1974; Nathanson et al, 1971).
b) CASE REPORTS: Seizure activity was reported in 3 patients receiving intravenous dacarbazine 625 mg/m(2) on days 1 and 5 every 3 weeks (2 to 5 courses) in combination with adriamycin. Two patients were treated for malignant melanoma and 1 for soft-tissue sarcoma. The first patient experienced episodic twitching and transient paralysis of the left arm as well as balance difficulties at the beginning of the third course of therapy. Brain scan revealed a left parietal-parasagittal lesion. The patient was administered phenytoin 100 mg three times daily and cranial irradiation but continued to experience focal seizure activity. The second patient exhibited a general grand mal seizure following the second course of therapy. Lumbar puncture, brain scan and EEG revealed no CNS metastases. Phenytoin 100 mg four times daily, cranial irradiation, and phenobarbital 32 mg four times daily controlled seizures, but the patient died 2 weeks later. In case 3, the patient exhibited focal seizures beginning in the right arm which progressed to grand mal seizures upon initiating the second course of therapy. Brain scan revealed lesions in the area of the left central sulcus and below the post-central gyrus. Phenytoin 100 mg three times daily controlled seizures, but the patient deteriorated progressively over the next 2 weeks and died. Patients with central nervous system disease may be candidates for serious CNS side effects during dacarbazine therapy (Gams & Carpenter, 1974).

a) CASE REPORT: Severe dementia developed in a 46-year-old man receiving dacarbazine for metastatic melanoma. The patient received 500 mg daily for 5 days a month (2 cycles), then 700 mg daily for 5 days (2 cycles). The patient experienced severe nausea followed by confusion and depression after 3 months of treatment. The patient refused further treatment after 4 cycles of therapy. His memory deteriorated over the next year, and left hemiparesis developed. No response was seen with vitamin B therapy, and intellectual function continued to deteriorate. The patient died 8 months later secondary to myocardial infarction. Mild dilation of the ventricles with some frontal cortical atrophy was observed with nonspecific subarachnoid fibrosis. The authors stressed that extreme caution should be utilized with dacarbazine in patients with preexisting cerebral disease or other neurological abnormalities (Paterson & McPherson, 1977).

a) Generalized weakness, polyneuropathy, blurred vision and headache have been reported in a small number of patients receiving dacarbazine therapy (Kleeberg & Schreml, 1976; Gottlieb, 1974; Nathanson et al, 1971).

a) Facial paresthesia has been noted with dacarbazine therapy (Prod Info dacarbazine intravenous injection powder for solution, 2014).

a) Nausea and vomiting are the most frequently observed toxic effects of dacarbazine and occur in over 90% of patients treated with initial doses (Prod Info dacarbazine intravenous injection powder for solution, 2014; Didolkar et al, 1986; Kleeberg & Schreml, 1976; Finkelstein et al, 1972; Gottlieb, 1974; Gerner et al, 1973; Gerner & Moore, 1973). Vomiting typically lasts 1 to 12 hours (Prod Info dacarbazine intravenous injection powder for solution, 2014).
b) Diarrhea is an infrequent occurrence during dacarbazine therapy (Kokron et al, 1978; Kokron et al, 1978; Kessinger et al, 1977; Gerner et al, 1973).

a) Stomatitis is an infrequent occurrence during dacarbazine therapy (Gottlieb, 1974; Gerner et al, 1973).

a) Anorexia is a frequently occurring toxic effect of dacarbazine, and usually occurs coexistent with nausea and vomiting (Prod Info dacarbazine intravenous injection powder for solution, 2014; Gerner et al, 1973).

a) Elevations in alanine aminotransferase (ALT, SGPT), aspartate aminotransferase (AST, SGOT), and lactic dehydrogenase (LDH) have occurred during dacarbazine therapy (Didolkar et al, 1986; Sutherland & Krementz, 1981; Gerner et al, 1973; Gerner & Moore, 1973; Finkelstein et al, 1972; Nathanson et al, 1971) and one case of jaundice has been observed (Finkelstein et al, 1972).
b) Three case reports of hepatic injury in nurses following years of handling cytostatic drugs (dacarbazine, bleomycin, vincristine, cyclophosphamide, doxorubicin, and methotrexate) were described. All patients had neurological symptoms associated with elevated serum alanine aminotransferase and alkaline phosphatase levels, and liver biopsy revealed portal hepatitis with piecemeal necrosis in one, and hepatic fibrosis and fat accumulation in the others (Sotaniemi et al, 1983). Handling of cytostatic agents may insidiously produce hepatic damage and possibly irreversible fibrosis.
c) HEPATIC VENO-OCCLUSIVE DISEASE

a) Leukopenia and thrombocytopenia are the severe toxic effects of dacarbazine therapy (Prod Info dacarbazine intravenous injection powder for solution, 2014; Didolkar et al, 1986; Sutherland & Krementz, 1981; Kleeberg & Schreml, 1976; Gutterman et al, 1974; Ahmann et al, 1972; Nathanson et al, 1971). Combination dacarbazine and methyl-CCNU therapy has resulted in death secondary to leukopenia and thrombocytopenia (Costanza et al, 1977; Ahmann et al, 1976).
b) Leukopenia and/or thrombocytopenia occurred in 17 of 115 patients receiving 2 mg/kg/day and in 29 of 115 patients receiving 4.5 mg/kg/day intravenously (Nathanson et al, 1971).
c) Anemia has also been reported during dacarbazine therapy (Prod Info dacarbazine intravenous injection powder for solution, 2014; Finkelstein et al, 1972). Anemia and thrombocytopenia were reported in all 20 children (3 to 13 years of age) receiving dacarbazine for acute lymphocytic or acute undifferentiated leukemia (Finkelstein et al, 1972).
d) Anemia was described in 6 of 16 patients receiving 200 mg/m(2)/day over 3 days (maximum 6 courses of 3 days) in patients with metastatic melanoma, stage III (Kleeberg & Schreml, 1976).
e) Acute internal bleeding has occurred in at least one patient receiving dacarbazine therapy for disseminated malignant melanoma (Ahmann et al, 1972).
f) During a clinical efficacy trial involving 39 patients who underwent 40 vascular isolation and hyperthermic perfusions with dacarbazine for malignant melanoma, leukopenia (leukocyte count less than 4000/mm(3)) and thrombocytopenia (platelet count less than 100,000/mm(3)) occurred in 14 of the 40 instances. In all patients, significant leukopenia and thrombocytopenia occurred following dacarbazine administration of doses greater than 3000 mg (Didolkar et al, 1986).

a) Intravascular hemolysis was reported in 4 of 20 patients (20%) who received dacarbazine 750 mg/m(2) IV on day 1 every 28 days as one arm of a clinical efficacy trial. The other patient group, who received dacarbazine 200 mg/m(2) IV days 1 through 5 every 28 days, did not develop hemolysis. The authors speculate that the hemolysis may be due to the high peak concentrations of dacarbazine related to the 1-day dosage regimen (Rajkumar et al, 2000).

a) Alopecia may occur in patients receiving dacarbazine alone or in combination with other chemotherapeutic agents (Prod Info dacarbazine intravenous injection powder for solution, 2014; Ahmann et al, 1976; Gottlieb et al, 1972).

a) CASE REPORT: A 44-year-old woman developed radiation recall dermatitis 10 days after her first dose of dacarbazine and 3 months after radiation therapy for metastases of malignant melanoma. The patient had a post-radiotherapy skin reaction at the site of treatment (right supraclavicular fossa and upper right back) which resolved within 2 weeks of completion of radiotherapy. Following radiotherapy, the patient developed subcutaneous and splenic metastases, and recurrence in the right supraclavicular fossa. Dacarbazine 800 mg/m(2) was administered and she developed severe burning pain and erythema over the right shoulder. Pain and erythema persisted and 5 days later it was noted that the erythematous area over the right shoulder and a smaller circular area on the back corresponded to radiotherapy fields. Symptoms completely resolved within 2 days of treatment with prednisolone (30 mg daily for 5 days). The patient received 3 additional doses of dacarbazine with pretreatment with prednisolone (30 mg/day for 5 days starting 1 day prior to dacarbazine). Recall dermatitis did not recur (Kennedy & McAleer, 2001).

a) A fatal case of erythema multiforme resulted after administration of a triple-drug chemotherapy regimen of dacarbazine, vincristine, and actinomycin D (Hall et al, 1979).

a) Hyperpigmentation has been reported with dacarbazine therapy (Nixon et al, 1981).

a) Facial flushing has been noted with dacarbazine therapy (Prod Info dacarbazine intravenous injection powder for solution, 2014).

a) Photosensitivity reactions may rarely occur with dacarbazine therapy (Prod Info dacarbazine intravenous injection powder for solution, 2014).

a) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.