Bleomycin pulmonary toxicity: its relationship to renal dysfunction

Two hundred seventy-five patients who had received bleomycin were examined for evidence of pulmonary toxicity. Twenty-six patients were diagnosed as having bleomycin pulmonary toxicity and, of these, 20 (77%) were documented as having renal dysfunction without other features recognized to be associated with the development of pulmonary toxicity. In this study renal dysfunction was a most important factor in the development of bleomycin pulmonary toxicity. As bleomycin is often administered with nephrotoxic drugs, it is suggested that renal function should be checked prior to each administration of bleomycin. It is proposed that appropriate dose modifications could significantly reduce the morbidity and mortality associated with bleomycin administration.     

Bleomycin induced hyperpigmentation with yolk sac tumor

Hyperpigmentation is one of the cutaneous side effects of chemotherapautic agents, but it is usually accepted as a cosmetic problem. We report a child with yolk sac tumor who developed localized pigmentation after the first course of chemotherapy regimen that included cisplatin, etoposide and bleomycin. The hyperpigmentation was diffuse scattered, flagellate like and linear streaking which was thought to be mainly related to the skin toxicity of bleomycin.     

Low-dose bleomycin lung

A patient with retroperitoneal diffuse histiocytic lymphoma treated with combination chemotherapy developed breathlessness and fever after receiving 30 units of bleomycin. At this stage pulmonary function tests were impaired and gallium scanning showed diffuse uptake in both lungs although a chest X-ray film was normal. Bleomycin treatment was stopped but interstitial infiltrates appeared on subsequent chest X-ray films. Open lung biopsy showed histologic changes of bleomycin toxicity. After treatment with prednisone, the patient felt well and was shown to have a normal gallium scan and normal respiratory function studies.     

Low-dose bleomycin lung

A patient with retroperitoneal diffuse histiocytic lymphoma treated with combination chemotherapy developed breathlessness and fever after receiving 30 units of bleomycin. At this stage pulmonary function tests were impaired and gallium scanning showed diffuse uptake in both lungs although a chest X-ray film was normal. Bleomycin treatment was stopped but interstitial infiltrates appeared on subsequent chest X-ray films. Open lung biopsy showed histologic changes of bleomycin toxicity. After treatment with prednisone, the patient felt well and was shown to have a normal gallium scan ad normal respiratory function studies.     

Randomized study for the treatment of adult advanced Hodgkin's disease: Epirubicin,vinblastine, bleomycin,and dacarbazine (EVBD) versus mitoxantrone,vinblastine, bleomycin,and dacarbazine (MVBD)

Seventy patients with previously untreated advanced Hodgkin's disease and without bulky disease were entered in a prospective randomized clinical trial comparing epirubicin in combination with vinblastine, bleomycin, and dacarbazine (EVBD) with a regimen containing mitoxantrone, vinblastine, bleomycin, and dacarbazine (MVBD). Both groups were comparable for the variables of age, sex, stage, and presence of B symptoms and histology. Thirty-one (88%) of EVBD-treated patients achieved a pathologically documented complete remission (CR) compared to the 24 cases (68%) of the MVBD-treated group. After a median follow-up of 36 months, duration of CR is better in the EVBD-treated patients with an actuarial 5-year duration of CR of 80%, statistically different to the MVBD group: 53% (P < 0.01). Both regimens ahowed the same gastrointestinal toxicity, but the patients treated with the MVBD regimen shown most and severe hematological and cardiac toxicities. Also, biochemical alterations in hepatic test were observed in these patients. The alternative use of epirubicin in combination chemotherapy appears to be as effective in advanced Hodgkin's disease without bulky disease, with reduced clinical toxicity. Mitoxantrone containing regimen was not found to have an equivalent efficacy and clinical toxicity was most frequent and severe. We feld that mitoxantrone could be consider a second-line drug in the treatment of advanced Hodgkin's disease. © 1994 Wiley-Liss, Inc.     

Procarbazine-induced interstitial pneumonitis with a normal chest x-ray: a case report

Pulmonary toxicity due to cytotoxic drugs is well described in the literature. This is most commonly described in association with bleomycin, busulfan, and methotrexate. This report presents a case of interstitial pneumonitis with a normal chest x-ray that is most certainly due to procarbazine. In addition, the role of gallium-67 citrate scintigraphy in early diagnosis is discussed. This is especially important since discontinuation of the drug before radiographic manifestations of pulmonary toxicity become evident may prevent permanent pulmonary injury and its sequelae.     

Extensive pneumothorax, pneumomediastinum and surgical emphysema as a complication of bleomycin therapy

Bleomycin is a commonly used chemotherapeutic agent and one of the commonest cytotoxic drugs leading to pulmonary parenchymal damage. It generally leads to interstitial pneumonitis and fibrosis, hypersensitivity reactions and acute respiratory distress syndrome. We describe an 8-year-old boy who, following prolonged bleomycin therapy, demonstrated extensive air dissection and extrapulmonary air, an unusual and fatal complication.     

Cisplatin, bleomycin, and vinblastine combination therapy of testicular tumors: an analysis.

A combination regimen consisting of cisplatin, bleomycin, and vinblastine was evaluated in 86 patients with metastatic testicular tumors. Prior therapy included surgical resection of primary tumor (84 patients), radiotheapy (21 patients), chemotherapy (33 patients). Thirteen patients received prior bleomycin and vincristine or vinblastine. Of 80 evaluable patients 51 achieved complete response (CR) and 26 achieved partial response (PR), for an overall response rate 96.5%. There was no significant difference in response rates or survival with respect to prior therapy, sites of metastatic lesions, and tumor histology. The median survival time was not reached in an observation period of 44+ months. Sixty patients were alive 11+--44+ months, and 57 of these were free of disease. Thirty-two of the 60 patients (53%) had a survival time greater than 20 months. Toxicities included nephrotoxicity (18 patients) leukopenia, (69 patients), thrombocytopenia (nine patients), and anemia (56 patients). Bleomycin-induced pulmonary toxicity was fatal in one patient. Other toxicities included nausea and vomiting, stomatitis, fever, alopecia, and neurological effects.     

Cisplatin,bleomycin, and vinblastine combination therapy of testicular tumors: An analysis

A combination regimen consisting of cisplatin, bleomycin, and vinblastine was evaluated in 86 patients with metastatic testicular tumors. Prior therapy included surgical resection of primary tumor (84 patients), radiotherapy (21 patients), chemotherapy (33 patients). Thirteen patients received prior bleomycin and vincristine or vinblastine. Of 80 evaluable patients 51 achieved complete response (CR) and 26 achieved partial response (PR), for an overall response rate 96.5%. There was no significant difference in response rates or survival with respect to prior therapy, sites of metastatic lesions, and tumor histology. The median survival time was not reached in an observation period of 44+ months. Sixty patients were alive 11+–44+ months, and 57 of these were free of disease. Thirty-two of the 60 patients (53%) had a survival time greater than 20 months. Toxicities included nephrotoxicity (18 patients) leukopenia, (69 patients), thrombocytopenia (nine patients), and anemia (56 patients). Bleomycin-induced pulmonary toxicity was fatal in one patient. Other toxicities included nausea and vomiting, stomatitis, fever, alopecia, and neurological effects.     

First report of a vincristine dose-related Raynaud's phenomenon in an adolescent with malignant brain tumor

The authors report a case of a vincristine-induced, reproducible dose-related Raynaud's phenomenon. It occurred in a 14-year-old boy with a malignant brain tumor who received repeated vincristine injections. The authors describe how they handled this severe secondary Raynaud's phenomenon with acral cutaneous tissue necrosis. Reducing the dose of the vinca-alkaloid injections, together with an additional medication with a calcium-channel blocking agent, was a successful strategy in this patient. There are few case reports of secondary Raynaud's phenomenon in adult oncologic patients receiving certain anticancer drugs (including vincristine, bleomycin, and cisplatin), and to the authors' knowledge this kind of vincristine toxicity has not previously been described in either adults or children.     

Acute spontaneous pneumomediastinum in a child with Hodgkin's disease and pulmonary fibrosis

A case of acute spontaneous pneumomediastinum in a 13-year-old boy suffering from Hodgkin's disease and pulmonary fibrosis is reported. He was initially treated for Pneumocystis carinii but his respiratory function progressively deteriorated, and fibrosis secondary to bleomycin was suspected. The day before the admission to the Pediatric Intensive Care Unit the patient complained of anterior thoracic pain, and a chest x-ray revealed a left-sided small spontaneous pneumothorax and pneumomediastinum. Although air leak responded initially to conservative treatment, acute tension pneumomediastinum with cardiopulmonary decompensation recurred 6 days later, while the patient was on mechanical ventilation. Treatment with urgent evacuation of the accumulated air via subxiphoid drainage, using an old but ill-defined technique, resulted in complete resolution of pneumomediastinum and significant improvement of the hemodynamic condition.     

Treatment of refractory lymphoproliferative diseases with daily, low-dose vincristine, continuous infusion of bleomycin, and high-dose prednisone

Vincristine 0.25 mg/m2 by IV push and bleomycin 5 units daily by continuous infusion were given on days 1, 2, 3 and 4, together with prednisone 1,000 mg/m2 po in 4 divided doses either on days 1, 3, 5, and 7 (6 patients) or on days 1 and 3 (11 patients) to 17 patients with various lymphoproliferative diseases who had failed their previous treatment program. Fourteen were leukopenic and/or thrombocytopenic. Of 10 patients with non-Hodgkin's lymphoma 2 achieved complete remission and 5 a partial response. Both patients with Hodgkin's disease achieved partial response. A decrease in plasma M protein (median decrease 51%) was observed in 3/3 patients with multiple myeloma and 2/2 with Waldenstrom's macroglobulinemia. Decrease in tumor cell infiltration by 48%, 58% and 100% was observed in 3 patients (2 with macroglobulinemia and 1 with myeloma) in the bone marrow. Leukopenia of less than 3,600/mm3 and thrombocytopenia of less than 70,000/mm3 reverted to normal in 5/7 and 7/10 patients, respectively. Remission duration ranged from 4 to 35+ weeks (median 17 weeks). Three patients had severe GI bleeding. Psychosis controlled by phenothiazines was observed in one, and bleomycin toxicity (anaphylaxis, skin rash, and lung toxicity, one each) was observed in 3 patients. No severe neurotoxicity was observed.     

Bleomycin in combination chemotherapy of metastatic wilms tumor: A late recurrent case,refractory to conventional therapy

A patient with a late recurrence (13 years) of Wilms tumor is presented. After relapse with conventional chemotherapy, an objective partial remission was obtained with bleomycin, vinblastine, cyclophosphamide, and cis-platinum. Stable disease was noted when bleomycin was withheld. Bleomycin in this combination appeared to effect a good response, and further studies of chemotherapy of Wilms tumor should include bleomycin in combination with other active agents.     

Bleomycin in combination chemotherapy of metastatic Wilms tumor: a late recurrent case, refractory to conventional therapy.

A patient with a late recurrence (13 years) of Wilms tumor is presented. After relapse with conventional chemotherapy, an objective partial remission was obtained with bleomycin, vinblastine, cyclophosphamide, and cis-platinum. Stable disease was noted when bleomycin was withheld. Bleomycin in this combination appeared to effect a good response, and further studies of chemotherapy of Wilms tumor should include bleomycin in combination with other active agents.     

Does chemotherapy have a role in the management of craniopharyngioma?

Craniopharyngiomas are classified as histologically benign tumours that are usually treated by surgery alone or in combination with radiotherapy. However, the difficulty in managing recurrent tumours and the desire to try to avoid treatment-related morbidity from both surgery and irradiation has led to exploration of the role of chemotherapy in this tumour. In the majority of cases this has involved the application of intratumoral bleomycin in cystic craniopharyngiomas. This review reports the published experience of this type of local chemotherapy, including delivery, scheduling, outcomes and toxicity. In addition, the rarely reported use of systemic chemotherapy is discussed.     

Controversies in the Role of Radiotherapy in the Treatment of Pediatric Hodgkin Lymphoma

Hodgkin lymphoma in children is a highly curable malignancy with current approaches utilizing combined modality therapy and a risk-adapted approach. The combination of anthracyclines, bleomycin, and radiotherapy, as well as other alkylating agents, are significant risk factors for secondary malignancies and cardiopulmonary toxicity. Therefore, current strategies aim to optimize cure rates while minimizing late effects. The role of radiotherapy has been examined in recent pediatric trials, with varying results. However, they provide evidence, as a whole, for the omission of radiotherapy for a subgroup of patients, without compromising outcomes.     

Intratumoral therapy with bleomycin for cystic craniopharyngiomas in children

Surgical removal of cystic craniopharyngiomas in children is associated with significant operative morbidity and recurrence rates. The purpose of this study was to review our experience with a less invasive therapy, namely, intratumoral bleomycin, in the treatment of predominantly cystic craniopharyngiomas. All children with craniopharyngiomas treated at a tertiary care pediatric neurosurgical center since 1994, when bleomycin was first used, were reviewed retrospectively. Seven patients received intratumoral bleomycin therapy. Patients received 2-5 mg bleomycin per dose, 3 times per week, for 3-5 weeks as an initial course. Mean follow-up of these patients was 3 years. In 4 patients, treatment resulted in a significant decrease (>50%) in tumor size, which has remained stable. Two patients' tumors progressed and underwent resection, and 1 patient had surgical removal because of persistent headaches, although no growth of residual tumor had been noted. One patient developed peritumoral edema as a result of bleomycin therapy. Intratumoral bleomycin is a useful alternative therapy for cystic craniopharyngiomas, and may control tumor growth and delay potentially harmful resection and/or radiotherapy in young children.     

LEUCOVORIN AND MAXIMUM TOLERATED DOSE TOXICITY OF METHOTREXATE IN RATS

High-dose methotrexate (HD-MTX) is widely used in combination chemotherapy and can be handled without life-threatening toxicity in combination with leucovorin (LV) rescue. However, in an experimental animal modelfortesting of short-term HD-MTX effects in anesthetized rats, the authors previously demonstrated intolerable toxicity and death within a few hours in some animals. Serum levels were below levels routinely found in patients on HD-MTX treatment. This study was aimed at disclosure of possible mechanisms for acute toxicity of MTX in rats. The previously determined maximum tolerated dose of 5 g/kg MTX was used as the test dose. The animals that died showed sudden reduction in heart rate and blood pressure. LV, 1 g/kg infused immediately prior to MTX, changed MTX elimination kinetics, but did not change the acute toxicity. The data of this study together with additional evidence obtained in the experimental model, suggest that MTX acute toxicity may not be related to its antiproliferative effect, but rather to perturbation of endothelial cell and platelet function.     

Leucovorin and maximum tolerated dose toxicity of methotrexate in rats

High-dose methotrexate (HD-MTX) is widely used in combination chemotherapy and can be handled without life-threatening toxicity in combination with leucovorin (LV) rescue. However, in an experimental animal modelfortesting of short-term HD-MTX effects in anesthetized rats, the authors previously demonstrated intolerable toxicity and death within a few hours in some animals. Serum levels were below levels routinely found in patients on HD-MTX treatment. This study was aimed at disclosure of possible mechanisms for acute toxicity of MTX in rats. The previously determined maximum tolerated dose of 5 g/kg MTX was used as the test dose. The animals that died showed sudden reduction in heart rate and blood pressure. LV, 1 g/kg infused immediately prior to MTX, changed MTX elimination kinetics, but did not change the acute toxicity. The data of this study together with additional evidence obtained in the experimental model, suggest that MTX acute toxicity may not be related to its antiproliferative effect, but rather to perturbation of endothelial cell and platelet function.     

POG 8625: a randomized trial comparing chemotherapy with chemoradiotherapy for children and adolescents with Stages I, IIA, IIIA1 Hodgkin Disease: a report from the Children's Oncology Group

To determine if 6 courses of chemotherapy alone could achieve the same or better outcome than 4 courses of chemotherapy followed by radiation therapy (chemoradiotherapy) in pediatric and adolescent patients with Hodgkin disease. Children < or =21 years old with biopsy-proven, pathologically staged I, IIA, or IIIA1 Hodgkin disease were randomly assigned 6 courses of alternating nitrogen mustard, oncovin, prednisone, and procarbazine/doxorubicin, bleomycin, vinblastine, and dacarbazine (treatment 1) or 4 courses of alternating nitrogen mustard, oncovin, prednisone, and procarbazine/doxorubicin, bleomycin, vinblastine, and dacarbazine +2550 cGy involved-field radiotherapy (treatment 2). The complete response rate was 89%, with a complete response and partial response rate of 99.4%. There was no statistically significant difference in event-free survival (EFS) or overall survival between arms. The EFS for those who achieved an early complete response was significantly higher than for those who did not. For pediatric patients with asymptomatic low-stage and intermediate-stage Hodgkin disease, chemotherapy and chemoradiotherapy both resulted in 3-year EFS of approximately 90% and statistically indistinguishable 8-year EFS and overall survival, without significant long-term toxicity. Early response to therapy was associated with higher EFS, a concept that has led to the Children's Oncology Group paradigm of response-based risk-adapted therapy for pediatric Hodgkin disease.