Development Of Pulmonary Toxicity Research Articles

Effect of Bleomycin Administration on the Development of Pulmonary Toxicity in Patients With Metastatic Germ Cell Tumors Receiving First-Line Chemotherapy: A Meta-Analysis of Randomized Studies.

Limited information is available about the effect of bleomycin administration on the development of pulmonary toxicity in metastatic germ cell tumors (GCT). A literature search was conducted to identify randomized trials of first-line chemotherapy for GCT. We conducted univariate and multivariate analyses using random effects models to evaluate the predictive role of bleomycin administration in the development of all Grade and Grade 3 to 4 (G3-4) pulmonary toxicity. The results were adjusted for length of follow-up, prognostic risk group, year of treatment, presence of lung metastases, and primary mediastinal GCT. Fifty-three study arms of 25 phase II and III trials encompassing 6498 patients were selected: 40 that used bleomycin (n= 5093) and 13 that did not (n=1405). The pooled probability of all-Grade pulmonary toxicity in the bleomycin and nonbleomycin arms was 11.7% (95% confidence interval [CI], 8.4%-16.0%) and 1.7% (95% CI, 0.7%-4.2%), respectively. Univariate analysis indicated that bleomycin administration was associated with the incidence of all-Grade (odds ratio [OR], 7.57; 95% CI, 2.84-20.18; Wald test P< .001) and G3-4 pulmonary toxicity (OR, 5.19; 95% CI, 1.57-17.16; P= .007). Multivariate analysis showed a significant association of bleomycin administration with the incidence of all-Grade pulmonary toxicity (OR, 4.14; 95% CI, 1.36-12.59; P= .012) and a trend toward significance for G3-4 toxicity (OR, 2.24; 95% CI, 0.91-5.51; P= .080). We quantified the bleomycin-associated effect on the development of pulmonary toxicity in patients with GCT who received first-line chemotherapy. This information might be useful for planning clinical trials aimed at reducing chemotherapy as well as to inform patients in the clinic.

Paclitaxel-induced pneumonitis in patients with breast cancer: case series and review of the literature

Doxorubicin plus cyclophosphamide followed by paclitaxel is a common adjuvant treatment for high-risk breast cancer. It has been associated with pulmonary toxicity in several case reports. We describe three patients in whom interstitial pneumonitis developed immediately after the first paclitaxel exposure and worsened clinically over time. All reported dyspnoea, fever and progressive respiratory distress. Imaging revealed diffuse bilateral pulmonary infiltrates. Other causes of respiratory failure were excluded with laboratory work-up, imaging, biopsy studies and results of antibiotic treatment. The respiratory decline was reversed only after administration of high-dose steroids, an empirical treatment previously reported to be beneficial in similar cases. Although chemotherapy using concomitant or sequential drugs may make identification of the toxic agent difficult, we noted a clear temporal relationship between exposure to paclitaxel and the development of pulmonary toxicity. Furthermore, according to the available literature, it is less likely that a respiratory decline would be caused by either cyclophosphamide or trastuzumab. In conclusion, clinicians should be aware of the potentially life-threatening risk of pulmonary toxicity following paclitaxel treatment. If paclitaxel is halted early and the patient has good lung reserve, pulmonary toxicity can be reversed with high-dose steroid administration.

25 Impact of bleomycin (BLM) administration on the development of pulmonary toxicity in advanced germ cell tumours (GCT) receiving first-line chemotherapy (CT): A meta-analysis of randomized studies

25 Impact of bleomycin (BLM) administration on the development of pulmonary toxicity in advanced germ cell tumours (GCT) receiving first-line chemotherapy (CT): A meta-analysis of randomized studies

Impact of bleomycin (BLM) administration on the development of pulmonary toxicity in advanced germ cell tumors (GCT) receiving first-line chemotherapy (CT): A meta-analysis of randomized studies.

482 Background: Little is known about the impact of BLM administration on the development of pulmonary toxicity (PT) in patients (pts) with advanced GCT. This information is critical to further enhance the successful delivery of effective and safe CT in these pts. Methods: Literature was searched for randomized trials of 1st-line CT ( ≥ 3 cycles) for GCT. Descriptive statistics were used to summarize data, dichotomized by BLM-containing vs non containing CT. Univariable and multivariable analyses by random effect models evaluated the predictive role of BLM administration on the development of all grade and G3-4 PT, adjusted for the length of follow-up (FUP, continuous), time-frame of treatment ( ≤ 1997 versus &gt; 1997) % of pts with lung metastases (LM), % of primary mediastinal GCT (PMGCT), IGCCCG risk group. Results: 53 arms of 26 phase II and III trials totalling 6,498 pts were selected: 40 with BLM (n = 5,093) and 13 without BLM (n = 1,405). Median % of pts with LM was 44% (range 22-84%) and 31% (19-79%) in BLM-containing and non containing arms (Wilcoxon test p = 0.505). Median % of PMGCT was 15% (range 0-48%) and 2% (0-13%), respectively (p = 0.146). Median BLM total dose and No. of administrations were 360mg (range 120-375) and 12 (2-24). Median FUP was 52 and 53 months, respectively. The pooled probability of all grade PT was 11.7% (95% CI: 8.4-16.0%) and 1.7% (95% CI: 0.7-4.2%) in BLM-containing and non containing arms. Univariably, BLM administration was associated with the incidence of both all grade (odds ratio [OR]: 7.57, 95%CI: 2.84-20.18, Wald test p &lt; 0.001) and G3-4 PT (OR: 5.19, 95%CI: 1.57-17.16, p = 0.007). Multivariably, BLM administration was significantly associated with the incidence of all grade PT (OR: 4.14, 95%CI: 1.36-12.59, p = 0.012) and trended to significance for G3-4 toxicity (OR: 2.24, 95%CI: 0.91-5.51, p = 0.080). Conclusions: In this meta-analysis, BLM administration was significantly associated with the development of PT in pts with GCT. The quantification of the magnitude of incidence of PT provided here might be useful to optimize the delivery of non-PEB CT in the 1st-line setting.

Amiodarone-induced Acute Respiratory Distress Syndrome Developed after Increasing Dosage of Amiodarone

Amiodarone is a highly effective antiarrhythmic agent. It is commonly used to treat ventricular and supraventricular arrhythmias. However, amiodarone has been found to be associated with a variety of adverse effects. Amiodarone causes toxicity to organs such as lung, gastrointestinal tract, liver, eye, thyroid gland, skin, and neuromuscular system. Among these side effects, pulmonary toxicity is one of the most serious ones. The prevalence of amiodarone-induced pulmonary toxicity is not known precisely, but recent studies have reported that incidence rates range from 1% to 13%. The risk factors associated with the development of pulmonary toxicity are age, duration of treatment, cumulative dosage, history of cardiothoracic surgery, and use of high oxygen mixture. Amiodarone use has been rarely related to development of acute respiratory distress syndrome (ARDS), which is often in association with surgery or pulmonary angiography. We experienced a case of amiodarone-induced ARDS which developed after an increase of amiodarone dosage.

Fatal interstitial lung disease associated with high erlotinib and metabolite levels. A case report and a review of the literature

IntroductionErlotinib is an agent in the class of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Although this class of agents is considered to be relatively safe, the most serious, but rare, adverse reaction is drug-associated interstitial lung disease (ILD). This potentially fatal adverse reaction has been often described with gefitinib, but has been less well described for erlotinib. We here describe a case report of fatal interstitial lung disease in a Caucasian man associated with erlotinib and high erlotinib and metabolite plasma levels and discuss it in the context of all documented cases of erlotinib associated ILD. MethodsOur case was described and for the literature review a Pubmed and Google Scholar search was conducted for cases of erlotinib associated ILD. The retrieved publications were screened for relevant literature. ResultsBesides our case, a total of 19 cases of erlotinib-associated ILD were found. Eleven out 19 cases had a fatal outcome and in only one case erlotinib plasma concentrations were measured and found to be high. ConclusionErlotinib-associated ILD is a rare, serious and often fatal adverse reaction. Most likely, the cause for erlotinib-associated ILD is multifactorial and high drug levels may be present in patients without serious adverse reactions. However, considering the pharmacology of EGFR inhibitors, high drug and metabolite levels may play a role and future studies are warranted to identify risk factors and to investigate the role of elevated levels of erlotinib and its metabolites in the development of pulmonary toxicity.

Impact on Pulmonary Function of Pre-Transplant Radiotherapy in Hodgkin Lymphoma Patients Undergoing Autologous Stem Cell Transplant (ASCT).

For patients (pts) with Hodgkin lymphoma (HL) undergoing initial treatment with chemotherapy, often in conjunction with radiation therapy (RT), the rate of relapse ranges from 10 to 15 % in favorable prognosis stage I-II disease to 30 to 40 % in advanced disease. Patients with poor prognosis after first relapse, those with a second relapse, and pts with progressive disease are candidates for high dose chemotherapy followed by ASCT. A noted risk factor in HL patients following ASCT is development of pulmonary toxicity. The effect of prior conditioning regimens and RT on lung function has been implicated. Scant data is available regarding whether proximity of RT to time of transplant increases the risk for development of subsequent pulmonary toxicity. To address this question we retrospectively reviewed 172 sequential HL patients with pre-and post-transplant pulmonary function data who underwent ASCT at the Cleveland Clinic between 1985 and 2008 using a prospectively maintained, IRB approved, database. Bu/Cy/VP was the preparative regimen in 83% of pts (n=142), BCNU/Cy/VP in 13% of pts (n=22), and Melphalan in 4% of pts (n=7). The post-transplant change in pulmonary function (percent predicted DLCO and FEV1) in pts who received RT prior to ASCT was compared to those who did not receive RT. The timing of the RT was also examined. Statistical analysis was performed using the Wilcoxon rank sum test. 67 pts (39%) received pre-transplant RT at a median of 14.1 months prior to ASCT; 10 pts received RT ≤6 months prior to ASCT, 50 pts received RT >6 months before, and timing was unknown for seven pts. Overall, pts experienced a median 3.2% decline in DLCO (range 53.7% decline to 137.5% improvement) and a 2.9% decline in FEV1 (range 71.8% decline to 33.3% improvement) following transplant. The decline in DLCO and/or FEV1 was significant (>25%) in 16% of patients. The change in DLCO post-ASCT was not significantly different between pts who did or did not receive pre-transplant RT (median declines of 2.7% vs. 3.7%, respectively, p=1.0). There was, however, a significant difference with respect to FEV1. Pts who had prior RT experienced a median 6.4% decline in FEV1 following ASCT compared to a median 1.1% decline in pts who did not have prior RT (p=.03). The proportion of pts in whom the decline in FEV1 was significant however was similar in the two groups (7% vs. 6% respectively, p=1.0). Pts treated with pre-transplant RT within 6 months of ASCT tended to have greater declines in both DLCO and FEV1 following ASCT than patients not treated with RT (median declines: DLCO: 8.8% versus 0%; FEV1: 7.7% versus 4.8%, respectively); however the differences were not significant (p=.25 and .98, respectively).Conclusions: Pts treated with RT prior to ASCT experience a greater decline in FEV1 post-transplant than RT-naïve patients. The decline, however, is not generally of clinical significance, and the proportion of pts with clinically significant impairment of pulmonary function is similar in the two groups.

Transient Pulmonary Infiltrates Possibly Induced by Quinine Sulfate

Quinine sulfate, which has been available for many years, has not been implicated definitively in the development of pulmonary toxicity. A variety of adverse effects, however, have been reported with quinine administration. A 45-year-old woman with longstanding rheumatoid arthritis experienced wheezing, severe anxiety, breathlessness, cough, orthopnea, mild fever, chills, and pleuritic chest discomfort after taking a single dose of quinine for nocturnal leg cramps. Radiographic imaging demonstrated diffuse, bilateral pulmonary infiltrates suggestive of pulmonary edema. No cause other than acute quinine ingestion could be identified despite thorough cardiac and infectious disease evaluations. Clinicians should be aware of a possible association between quinine sulfate and pulmonary toxicity.

N‐acetyl‐L‐cysteine inhibits bleomycin‐induced interleukin‐8 secretion by bronchial epithelial cells

Bleomycin (BLM) has proven effective for the treatment of cancers, but the most serious dose-limiting side-effect is the development of pulmonary toxicity. Although the precise mechanism in the pathogenesis of BLM-induced lung injury has not been determined, oxygen radicals and neutrophils are indicated to play a key role in it. Interleukin-8 (IL-8) is thought to be an important mediator of the pathogenesis of acute lung injury. The IL-8 production from bronchial epithelial cell line, BEAS-2B cells was measured by enzyme-linked immunosorbent assays for IL-8. The concentrations of IL-8 were reportedly elevated in BLM-induced lung injury, suggesting the involvement of IL-8 in the pathogenesis of BLM-induced lung injury. In the present study, we showed that BLM induced the expression of IL-8 protein and mRNA in BEAS-2B cells, and N-acetyl-L-cysteine (NAC) inhibited IL-8 expression. In addition, the structurally unrelated antioxidant, pyrrolidine dithiocarbamate (PDTC) also effectively inhibited BLM-induced IL-8 production. These results suggest that anti-oxidant-sensitive mechanism might be involved in the inhibition of IL-8 secretion by BLM-stimulated bronchial epithelial cells and that NAC might be useful for the treatment of BLM-induced lung injury.

Disease-modifying antirheumatic drugs.

Disease-modifying antirheumatic drug (DMARD) therapy is now clearly accepted as the primary treatment for rheumatoid arthritis, with an increasing emphasis on use of combination therapy. Data on combination therapy have highlighted the difficulties in performing these studies and the large number of patients required to produce meaningful results. Combination studies have focused on use of rapidly decreasing high-dose steroids as a part of the combination and emphasize the importance of using patients with early rheumatoid arthritis. Even with relatively aggressive use of DMARDs, the majority of patients develop erosions. Adverse reactions to DMARDs continue to concern clinicians, although evaluation of the frequency of these events has led to a reappraisal of previously accepted monitoring strategies in some cases. For example, it may not be cost-effective to subject patients on antimalarials to regular review by an ophthalmologist because of the low frequency of serious eye defects. Studies have also identified risk factors for the development of pulmonary toxicity in association with methotrexate. That DMARDs are effective in treating rheumatoid arthritis is beyond question-just how effective they are and what combinations of DMARDs will show improved efficacy will provide data for the next annual review.

AMIODARONE-INDUCED PULMONARY TOXICITY IN FISCHER RATS: RELEASE OF TUMOR NECROSIS FACTOR ALPHA AND TRANSFORMING GROWTH FACTOR BETA BY PULMONARY ALVEOLAR MACROPHAGES

Amiodarone is an antiarrhythmic drug with numerous side effects, the most serious being the development of pulmonary toxicity. We have previously reported that a single intratra cheal instillation of amiodarone to Fischer 344 rats results in pulmonary fibrosis within 6 wk of treatment. Presently, the mechanism of amiodarone-induced pulmonary toxicity is unknown. Cytokines that stimulate fibroblast proliferation and/or collagen production may play a role in amiodarone-induced pulmonary toxicity. To investigate this possibility, female rats were given a single intratracheal instillation of amiodarone (6.25 mg/kg), its metabolite desethylamiodarone (5 mg/kg), or vehicle (sterile water). At I, 2, 3, or 6 wk after treatment the lungs were lavaged and the recovered cells were counted and identi fied. The alveolar macrophages were isolated by attachment to plastic petri dishes, cul tured overnight, and the spent media collected for tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β) analyses. Desethylamiodarone treatment resulted in a neutrophilic alveolitis, but the levels of TNF-α and TGF-β were not signifi cantly different from control animals. In contrast, amiodarone treatment resulted in a lym phocytic alveolitis and significantly higher amounts of TNF-α were observed at 3 and 6 wk after treatment. A trend toward higher levels of TCF-β was also noted in the amio-darone-treated group at wk 1-3 but the values were not significantly different from those of controls. In conclusion, the release of TNF-α may play a role in the development of amiodarone-induced pulmonary toxicity.

AMIODARONE-INDUCED PULMONARY TOXICITY IN FISCHER RATS: RELEASE OF TUMOR NECROSIS FACTOR ALPHA AND TRANSFORMING GROWTH FACTOR BETA BY PULMONARY ALVEOLAR MACROPHAGES

Abstract Amiodarone is an antiarrhythmic drug with numerous side effects, the most serious being the development of pulmonary toxicity. We have previously reported that a single intratra cheal instillation of amiodarone to Fischer 344 rats results in pulmonary fibrosis within 6 wk of treatment. Presently, the mechanism of amiodarone-induced pulmonary toxicity is unknown. Cytokines that stimulate fibroblast proliferation and/or collagen production may play a role in amiodarone-induced pulmonary toxicity. To investigate this possibility, female rats were given a single intratracheal instillation of amiodarone (6.25 mg/kg), its metabolite desethylamiodarone (5 mg/kg), or vehicle (sterile water). At I, 2, 3, or 6 wk after treatment the lungs were lavaged and the recovered cells were counted and identi fied. The alveolar macrophages were isolated by attachment to plastic petri dishes, cul tured overnight, and the spent media collected for tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β) analyses. Desethylamiodarone treatment resulted in a neutrophilic alveolitis, but the levels of TNF-α and TGF-β were not signifi cantly different from control animals. In contrast, amiodarone treatment resulted in a lym phocytic alveolitis and significantly higher amounts of TNF-α were observed at 3 and 6 wk after treatment. A trend toward higher levels of TCF-β was also noted in the amio-darone-treated group at wk 1-3 but the values were not significantly different from those of controls. In conclusion, the release of TNF-α may play a role in the development of amiodarone-induced pulmonary toxicity.

Amiodarone-induced pulmonary fibrosis in Fischer 344 rats

Amiodarone is a potent antiarrhythmic agent with a number of side-effects, the most serious being the development of pulmonary toxicity. The purpose of the study was to determine if a single intratracheal instillation of amiodarone would induce pulmonary fibrosis and associated functional changes in rats. Female Fischer 344 rats were given a single intratracheal instillation of 200 μl containing 1.25 mg amiodarone ( n = 9) while the control group received an equivalent volume of sterile water ( n = 8). After 6 weeks, pulmonary function tests, lung hydroxyproline measurements and lung histology were performed. The amiodarone-treated animals showed a significant reduction in the coefficient of diffusion ( kCO) and a significant increase in lung hydroxyproline levels as compared to the control group. The treated group had abnormal histology including areas of septal thickening with cellular infiltration of the interstitial and alveolar spaces, whereas the control group had normal histology. These observations suggest that the intratracheal instillation route of amiodarone treatment produces a fibrotic response in rats that can be measured physiologically, biochemically and histologically. This model may aid in the elucidation of the mechanism of amiodarone-induced pulmonary toxicity (AIPT)./ABS.

Resistance of the hamster to amiodarone-induced pulmonary toxicity following repeated intraperitoneal administration

Amiodarone is an effective antidysrhythmic agent, restricted in use by the development of pulmonary toxicity. Several in vivo animal models have been used to study amiodarone-induced pulmonary toxicity. Intratracheal administration of amiodarone to the hamster has been used as a model for the critical amiodarone-induced pulmonary fibrosis (AIPF). In order to investigate the cellular mechanism of human AIPF, which occurs following oral or intravenous administration, an animal model of AIPF resulting from systemic administration of the drug would appear to be preferable. We have evaluated pulmonary toxicity following repeated intraperitoneal amiodarone administration to the hamster. Intraperitoneal treatment of hamsters for 1, 4, or 7 weeks with amiodarone (100 mg/kg/day) did not lead to pulmonary toxicity based on wet lung weight, hydroxyproline content, or histological examination. Furthermore, when comparing 1- and 7-week treatment groups, there was no pulmonary accumulation of either amiodarone or desethylamiodarone beyond levels found at 1 week. Therefore, failure to develop pulmonary toxicity may be due to an inability to accumulate sufficient amiodarone and/or desethylamiodarone. Intratracheal administration of amiodarone to rodents remains the only in vivo animal model for studying the mechanism(s) of AIPF.

Pulmonary Accumulation of Amiodarone andN-desethylamiodarone: Relationship to the Development of Pulmonary Toxicity

To investigate the relationship between the amount of amiodarone and the major metabolite N-desethylamiodarone found in the lung with the development of toxicity, Fischer 344 and Wistar rats were given 175 mg/kg/day of drug by gavage. After 1, 3, 6, and 12 wk of drug feeding, both stains were examined for histologic evidence of pulmonary inflammation and for changes in lavage cell counts and differentials. The amounts of amiodarone and N-desethylamiodarone in the lungs were determined using high performance liquid chromatography. We found that in drug-fed Wistar rats the lavage differentials were unchanged, lavage cell counts were decreased compared with those in control rats, and the lungs appeared normal except for some foamy macrophages. Wistar rats also had low levels of amiodarone and metabolite in both lung tissue and cells. In contrast, Fischer rats had an increase in lavage lymphocytes, neutrophils, and macrophages compared with that in control rats and abnormal lung histologies. Also, there was much more drug and metabolite in the lungs than the amounts found in Wistar rats. Because Fischer rats had more metabolite than amiodarone in the lung and the reverse was true in Wistar rats, the in vitro cytotoxicity of amiodarone and N-desethylamiodarone were compared. We found that N-desethylamiodarone was significantly more cytotoxic than amiodarone to both fibroblasts and endothelial cells. We conclude that there is a relationship between the amounts of drug and metabolite in the lung and the development of pulmonary inflammation, and that N-desethylamiodarone may be more cytotoxic than amiodarone.

Amiodarone-induced pulmonary toxicity in rats: Biochemical and pharmacological characteristics

Treatment of humans with the antiarrhythmic drug, amiodarone (AD), may result in the development of pulmonary toxicity. To characterize this response, male Fischer 344 rats were treated with AD for 1, 3, 9, and 16 weeks. AD induces a twofold increase in the level of pulmonary phospholipid after 3 weeks of treatment. Continued administration results in only a small increase above this level. All classes of phospholipids are elevated; phosphatidylcholine displays the largest increase, both quantitatively and as a relative increase over the control level. Both AD and its principal metabolite, desethylAD, are sequestered in the lungs following AD treatment. The relative levels are similar at all time points except 16 weeks, where the relative amount of AD is decreased. After 3 weeks of AD, female 344 rats show the same increase in pulmonary phospholipid as males. While similar levels of desethylAD are sequestered in the lungs of both sexes, AD levels are much lower in female lungs. Evidence is presented to suggest that desethylAD may play an important role in the induction of the phospholipidosis. The activity of Na +,K +-ATPase in the lungs is inhibited by 75% after 9 weeks of AD while the activity of the acid hydrolase, β- N-acetylglucosaminidase is increased significantly at this time point. All biochemical changes are reversible with values returning to control levels 2 weeks after termination of a 3-week AD treatment protocol. Measurable levels of AD and desethylAD are present in lung tissue after 5 weeks of recovery.

Prospective Evaluation of Amiodarone Pulmonary Toxicity

Reports of pulmonary infiltrates in patients taking amiodarone, initiated the study of 69 patients for pulmonary toxicity using serial chest roentgenograms (CXRs), pulmonary function tests (PFTs), and symptoms before and during therapy. Mean PFTs did not significantly change from their baseline normal values, but 10 percent of patients had a greater than or equal to 15 percent fall in total lung capacity, and 28 percent a greater than or equal to 15 percent fall in diffusion capacity (DCO) following treatment. Initial abnormalities in pulmonary function or CXR were predictive of risk of developing pulmonary toxicity. Degree of exposure to amiodarone (dose plus duration) correlated only weakly with development of pulmonary toxicity, which could occur in patients taking relatively small doses of the drug. Pulmonary complications of amiodarone are common, in most cases reversible, and often confused with congestive heart failure or pneumonia. Patients should be evaluated before treatment by assessing symptoms, CXRs, and DCO. Patients with initial abnormalities in these parameters, particularly both CXR and DCO abnormalities, should be considered for alternative therapy.

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.