Prediction of BCNU Pulmonary Toxicity in Patients with Malignant Gliomas

Aronin, Patricia A.; Mahaley, M. S.; Rudnick, Seth A.; Dudka, Lynn; Donohue, James F.; Selker, Robert G.; Moore, Pearl

doi:10.1056/nejm198007243030403

Cited by 180 publications

(40 citation statements)

References 6 publications

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“…Follow-up studies in another 10 patients showed a significant sub-clinical deterioration in lung function following chemotherapy (Table V). The clinical, radiological and histological features of 'early onset' lung fibrosis have previously been described with BCNU and other nitrosoureas (Bailey et al, 1978;Durant et al, 1979;Aronin et al, 1980;Sekler et al, 1980;Weiss et al, 1981); correlation is seen when cumulative dosage of BCNU > 1000mgm2 (Weiss et al, 1981). However, the two cases of interstitial pneumonitis in our study received a cumulative dosage of < 400 mg m-2 of fotemustine suggesting that the synergy between DTIC and fotemustine (as used in the schedule here) may be responsible for the acute pulmonary event, possibly related to greater cytotoxicity in normal lung cells following depletion of the endogenous ATase.…”

Section: Discussionmentioning

confidence: 90%

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Lee

Margison²,

Woodcock³

et al. 1993

Br J Cancer

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Summary There is increasing experimental evidence to suggest that expression of 06-alkylguanine-DNAalkyltransferase (ATase) is a major factor in resistance to dacarbazine (DTIC). We recently demonstrated a progressive ATase depletion in human peripheral lymphocytes with nadir levels occurring at 4-6 h after DTIC administration (Lee et al., 1991). Therefore in an attempt to improve the clinical response rate of DTIC, fotemustine was administered 4 h after DTIC administration; since in the case of fotemustine, ATase removes the chloroethyl lesions from the 06-position of guanine, thereby preventing the formation of the cytotoxic cross-links. Sixty patients with widely metastatic melanoma received DTIC at 400, 500 or 800 mg m-2 followed by fotemustine (100 mg m') at 4 h after DTIC administration. Treatment was repeated every 28 days with a total of 169 cycles of chemotherapy administered; 75, 57 and 37 treatment cycles with 400, 500 and 800mg m2 DTIC groups respectively. Eighteen of the 60 patients responded (with three complete response); response rates were linearly related to dose, being 24%, 30% and 40% in patients receiving 400, 500 and 800 mg m-2 of DTIC respectively and the overall response rate was 30%. Median survival was 3.6 months (range, 1-15 months) with no statistically significant difference between the different DTIC treatment groups (P = 0.67). Nine patients are alive at 5 to 26 months (median 10 months); three patients with no tumour and five patients with stable disease. A statistically significant relationship was seen between the development of severe haematological toxicity (WHO > 3) with increasing dosage of DTIC and significant subclinical pulmonary damage was seen in 11 patients where the lung function was monitored during the course of treatment. In conclusion, it appears that with this small group of patients, escalation of DTIC dosage might not significantly affect response rates but does increase haematological toxicity. The present study provides a framework for other studies in an attempt to modulate ATase-mediated drug resistance in tumour tissues but the associated toxicity will need careful monitoring.

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Section: Discussionmentioning

confidence: 90%

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Lee

Margison²,

Woodcock³

et al. 1993

Br J Cancer

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“…1,500 mg/m 2 . 87 Lung injury may even occur at lower doses in individuals who have previously received thoracic radiation. 86 Symptoms such as dyspnea, tachypnea, and nonproductive cough, may develop as early as 1 month after initiation of therapy.…”

Section: Hsct and Lung Injurymentioning

confidence: 99%

Pulmonary Outcomes in Survivors of Childhood Cancer

Huang

Hudson

Stokes

et al. 2011

Chest

138

137

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O ver the last 3 decades, therapeutic progress has resulted in a growing population of survivors of childhood cancer. In 2006, there were Ͼ 11 million cancer survivors in the United States, three times the number of survivors in 1971. 1 The 5-year survival rate for children diagnosed with cancer is approaching 85%, 2 and an estimated one in 570 individuals in the United States between the ages of 20 and 34 is a survivor of childhood cancer. 3 Unfortunately, increased survival rates are not without consequences. There is substantial evidence Background: The purpose of this article is to summarize the literature that documents the longterm impact of cancer treatment modalities on pulmonary function among survivors of cancer and to identify potential areas for further research. Methods: Systematic reviews of clinical trials, observational studies, case series, and review articles were conducted. Articles were limited to the studies that discussed pulmonary toxicity or late effects among pediatric cancer survivors and to follow-up investigations that were conducted a minimum of 2 years after completion of cancer-related treatment or 1 year after hematopoietic stem cell transplant. Results: Sixty publications (51 clinical studies/reports and nine reviews) published from January 1970 to June 2010 in PubMed met the inclusion criteria. Data showed an association between radiotherapy, alkylating agents, bleomycin, hematopoietic stem cell transplant, and thoracic surgery and pulmonary toxicity, as well as possible interactions among these modalities. Conclusions: Pulmonary toxicity is a common long-term complication of exposure to certain anticancer therapies in childhood and can vary from subclinical to life threatening. Pulmonary function and associated loss of optimal exercise capacity may have adverse effects on long-term quality of life in survivors. Lung function diminishes as a function of normal aging, and the effects of early lung injury from cancer therapy may compound these changes. The information presented in this review is designed to provide a stimulus to promote both observational and interventional research that expands our knowledge and aids in the design of interventions to prevent or ameliorate pulmonary late effects among survivors of childhood cancer. CHEST 2011; 140(4):881-901Abbreviations: ALL 5 acute lymphoblastic leukemia; BCNU 5 carmustine; CCNU 5 lomustine; D lco 5 diffusing capacity of the lung for carbon monoxide; GVHD 5 graft-vs-host disease; gy 5 gray; HL 5 Hodgkin's lymphoma; HSCT 5 hematopoietic stem cell transplant; NHL 5 non-Hodgkin's lymphoma; PFT 5 pulmonary function testing; TLC 5 total lung capacity

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“…Drug-induced pneumonitis has been a well-recognised complication of treatment with BCNU since the 1970s (Collis et al, 1991) and the risk rises steadily with increasing dose (Aronin et al, 1980). Other risk factors are pre-existing lung disease and smoking (Kreisman et al, 1992), although the former just failed to reach statistical significance in the current study.…”

Section: Prognostic Factorsmentioning

confidence: 56%

Idiopathic pneumonia syndrome after high-dose chemotherapy for relapsed Hodgkin's disease

Rubio

Hill²,

Milan³

et al. 1997

Br J Cancer

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(Goldstone et al, 1993). Rates of morbidity and mortality have improved with better supportive measures and administration of HDC at an earlier phase in the course of the disease, but procedure-related mortality remains in the region of 10-20% in most published series using autologous bone marrow transplantation (ABMT) Jones et al, 1990;Reece et al, 1991;Bierman et al, 1993). Approximately 50% of these fatalities will be as a consequence of idiopathic pneumonia syndrome (IPS). This presents with dyspnoea, pulmonary infiltrates and fever, and the differential diagnosis is between infection (often with an uncommon or unusual organism), pulmonary involvement with HD, intrapulmonary haemorrhage or druginduced pneumonitis (Clark et al, 1993). The latter is most frequently associated with high-dose BCNU (carmustine), which induces interstitial fibrosis in a dose-dependent manner. (Litam et al, 1981;Pecego et al, 1986;Weaver et al, 1993). The mechanism is poorly understood but thought to involve toxic metabolites that react with sulphydryl compounds (including glutathione) resulting in neutralization. Depletion of such compounds and inhibition of glutathione reductase in alveolar Received 19April 1995 Revised 11 October 1996 Accepted 14 October 1996 Correspondence to: D Cunningham macrophages is postulated to increase the risk of oxidant injury (Arrick et al, 1984;Clark et al, 1993).Pulmonary toxicity may occur 9 days to 12 years after starting BCNU (Durant et al, 1979) and may present with the sudden onset of dyspnoea and progress rapidly to death, or be more insidious with a fatal outcome within 2 years (Phillips et al, 1983). In a dosefinding study published in 1990 using cyclophosphamide, etoposide and BCNU (Wheeler et al, 1990) 450 mg m-2 of BCNU was the maximum tolerated dose, with a 5% mortality rate compared with 22% observed following a dose of 600 mg ni-2. Another study using the same regimen and 600 mg m-2 BCNU, published the following year, reported a 16% incidence of IPS and a 12% mortality rate (Reece et al, 1991). A more recent series (Weaver et al, 1993) reported no IPS in patients who received BCNU 300 mg m-2 a rate of 23% in patients who received 600 mg m-2.The aim of our study was to quantify the risk and time of onset of IPS at our own institution and determine the risk factors for its development and prognostic factors for outcome. PATIENTS AND METHODS Using

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Prediction of BCNU Pulmonary Toxicity in Patients with Malignant Gliomas

Cited by 180 publications

References 6 publications

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Pulmonary Outcomes in Survivors of Childhood Cancer

Idiopathic pneumonia syndrome after high-dose chemotherapy for relapsed Hodgkin's disease

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