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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 3  |  Page : 466-470

Pulmonary toxicity following bleomycin use: A single-center experience


Department of Medical and Pediatric Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India

Date of Web Publication31-Aug-2017

Correspondence Address:
Irappa Madabhavi
Department of Medical and Pediatric Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.204887

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 > Abstract 

Background: Bleomycin-induced pulmonary (BIP) toxicity is a notorious entity and cropped up in roughly 10% of cases. The aim of the study is to evaluate BIP at our tertiary care cancer center.
Patients and Methods: This is a retrospective, analytical study conducted at a tertiary care center from January 1998 to December 2012. Records of all the patients who were offered bleomycin chemotherapy as an integral part of adriamycin, bleomycin, vinblastine, and dacarbazine or bleomycin, etoposide, and cisplatin regimen in Hodgkin disease (HD) or germ cell tumor (GCT) were studied for the study inclusion criteria. Twenty-two patients treated with bleomycin who had respiratory symptoms and/or abnormal high-resolution computed tomography (HRCT) findings, suggestive of bleomycin-induced lung injury were included in this study.
Results and Statistical Analysis: A total of 22 patients met the inclusion criteria for the study cohort. Of 22 patients, 8 were of HD and 14 were of GCT (nonseminomatous GCT [NSGCT] = 10 and seminomatous GCT = 4). Of 22 patients, 14 had symptoms of nonproductive cough, dyspnea and showed HRCT findings of ground glass opacities, diffuse alveolar damage, extensive reticular markings, traction bronchiectasis, and/or nodular densities. Two patients had fever and pleuritic pain. Eight patients were asymptomatic. Symptomatic patients were treated with prednisone at the dose of 0.75–1 mg/kg 4–8 weeks then gradually tapered. Four patients required noninvasive ventilatory support and managed with oxygen, nebulization, and antibiotics. Two patients required mechanical ventilatory support (HD = 1 and NSGCT = 1) and developed multiorgan failure subsequently succumbed to death.
Conclusion: BIP is noteworthy lung toxicity as subsequent mortality ranges from 10% to 20% and shrinks survival rate in patients with highly curable malignant conditions. Physicians should be vigilant concerning this impending side effect.

Keywords: Bleomycin, bleomycin-induced pulmonary toxicity, germ cell tumor, Hodgkin disease


How to cite this article:
Madabhavi I, Modi G, Patel A, Anand A, Panchal H, Parikh S. Pulmonary toxicity following bleomycin use: A single-center experience. J Can Res Ther 2017;13:466-70

How to cite this URL:
Madabhavi I, Modi G, Patel A, Anand A, Panchal H, Parikh S. Pulmonary toxicity following bleomycin use: A single-center experience. J Can Res Ther [serial online] 2017 [cited 2020 May 27];13:466-70. Available from: http://www.cancerjournal.net/text.asp?2017/13/3/466/204887


 > Introduction Top


The myriad newer targeted agent has refurbished the oncology treatment since the last decade; however, some older chemotherapeutic agents such as bleomycin have upheld its place in the treatment of germ cell tumors (GCTs) and Hodgkin's disease/lymphoma (HD). Bleomycin-induced pulmonary (BIP) toxicity is the foremost drawback which is life menacing and may occur in up to 10% of cases. Oxidative damage inflammatory cytokines, lower level of enzyme bleomycin hydrolase (BH), and genetic susceptibility are the chief factors for pathogenesis.[1],[2] The aim of the study is to evaluate BIP at our tertiary care cancer center. Approximately 2%–3% is the mortality from all patients treated with bleomycin, and it is 10%–20% among who develop BIP.[3]


 > Patients and Methods Top


This is a retrospective, analytical study conducted at a tertiary care center from January 1998 to December 2012. This study was permitted by our Institutional Review Board and written informed consent was taken from all the eligible patients. Records of all the patients who were offered bleomycin chemotherapy as an integral part of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or bleomycin, etoposide, and cisplatin (BEP) regimen in HD or GCT were studied for the study inclusion criteria. Twenty-two patients met the inclusion criteria for this study. Data regarding age, sex, symptoms, signs, and laboratory parameters were extracted from the medical record department of our center and entered it into Microsoft Excel sheet.

Inclusion criteria

  • All the patients who are treated with bleomycin and had respiratory symptoms such as nonproductive cough, dyspnea, fever, and pleuritic pain
  • All patients who have abnormal high-resolution computed tomography (HRCT) findings suggestive of bleomycin-induced lung injury, such as ground glass opacities, diffuse alveolar damage, air space consolidation, extensive reticular markings, traction bronchiectasis, and/or nodular densities were included in the study.


Exclusion criteria

All patients treated with bleomycin who had not respiratory symptoms without any abnormal HRCT finding were excluded from the study.


 > Results and Statistical Analysis Top


A total of 22 patients met the inclusion criteria for the study cohort. The clinical profile, general characteristics, indication of bleomycin, cumulative dose of bleomycin, and treatment outcomes are described in [Table 1].
Table 1: Clinical profile and outcomes of study population

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Indications of bleomycin the study population

Of 22 patients, 8 were of HD and 14 were of GCT (nonseminomatous GCT [NSGCT] =10 and seminomatous GCT = 4). The dose of bleomycin used in HD was in the range of 80–160 U and in GCT was in the range of 270–360 U.

Diagnosis of bleomycin-induced lung injury

  1. a.Asymptomatic patients (n = 8): While evaluating the patients for their disease status at the end of the completion of chemotherapy found to have HRCT findings suggestive of bleomycin-induced lung injury (BIP), all these patients were kept under regular surveillance for their disease status and lung injury with 6 monthly imaging. No treatment was given to above patients as they were asymptomatic for the same
  2. b.Symptomatic patients (n = 14): Of 22 patients, 14 had symptoms of nonproductive cough, dyspnea. Two patients had fever and pleuritic pain. All these 14 patients were subjected to HRCT and found to have ground glass Wopacities (n = 10), diffuse alveolar damage associated with air space consolidation (n = 4), extensive reticular markings (n = 3), traction bronchiectasis (n = 2), and/or nodular densities (n = 2).


Treatment and outcomes of bleomycin-induced pulmonary

All the 14 patients were treated with prednisone at the dose of 0.75–1 mg/kg 4–8 weeks which then gradually tapered over an additional 4–6 months, in accordance with the patient's condition and clinical response. All the patients were regularly monitored for the side effects of the steroid therapy. Depending on the clinical and radiological severity of the BIP, all the patients who are requiring extra medications such as antibiotics, oxygen therapy, nebulization with steroids, beta agonists, and anticholinergics, inotropic agents such as dopamine and dobutamine.

Of 14 patients, eight patients did not require any supportive treatment. Four patients required noninvasive ventilatory support and managed with oxygen, nebulization, and antibiotics. Two patients required mechanical ventilatory support (HD = 1, NSGCT = 1) and developed multiorgan failure subsequently succumbed to death. The NSGCT patient was a chronic smoker with a history of pulmonary tuberculosis developed acute respiratory distress syndrome and was managed in the intensive unit with mechanical ventilation, broad-spectrum antibiotics, dopamine and noradrenaline infusion and subsequently expired owing to multiorgan failure. The HD patient had older age and comorbid conditions such as previous chest radiotherapy (RT) and history of chronic smoking (25 pack years). He developed sepsis with septic shock which was managed in the intensive unit with mechanical ventilation, broad-spectrum antibiotics and subsequently expired owing to multiorgan failure.

Monitoring and follow-up

All the patients were monitored with 3 monthly history and physical examination for their respiratory symptoms. HRCT thorax was done in all the patients at 6 months interval, and 20 patients had normal imaging after 18 months of follow-up. Two patients computed tomography (CT) images showed some fibrotic changes after 2 years of follow-up. All the patients are under regular surveillance at our center.

Pulmonary function tests

All the 22 patients had normal baseline pulmonary function tests (PFTs) before starting any chemotherapy to the study group. Moreover, we have not done any follow-up PFT after the treatment completion.


 > Discussion Top


Bleomycin was first isolated from the fungus Streptomyces verticillus before 50 years, and it is an antibiotic agent with antitumor activity. Bleomycin is a cell cycle-specific (mainly act on G2 and M phases) chemotherapeutic agent.[4] It is the essential part of ABVD and BEP regimens which are used in HD and GCT, respectively. After binding with iron, bleomycin forms free radicals which are responsible for DNA breaks, subsequently guide to cell death.[5] It is rapidly inactivated in liver and kidneys by the enzyme BH, following administered as intravenous route with terminal half-life of approximately 3 h. Bleomycin primarily eliminated chiefly through the kidneys (50%–70%).

The skin and lungs are the two most important targets of bleomycin toxicity as both the organs have the lowest levels of the enzyme BH which converts drug into nontoxic molecules. While skin toxicities are nonlife-threatening and managed safely, the foremost drawback is pulmonary toxicity, which is life menacing and may occur in up to 10% of cases. Some issues are unreciprocated concerning pathogenesis of bleomycin-induced lung toxicity but mainly owing to lower level of enzyme BH, genetic susceptibility, and oxidative damage.[1] Inflammatory cytokines such as interleukin-1, macrophage inflammatory protein-1, platelet-derived growth factor, and transforming growth factor beta) are also culprit.[6] On naked eye, lungs affected with bleomycin show fibrosis and subpleural lung damage. Moreover, microscopic examination shows destruction of type I pneumocytes, proliferation of type II pneumocytes, neutrophilic alveolitis, mononuclear cell infiltration, fibroblast proliferation, and fibrosis.[7]

The most common abnormalities associated with BIP toxicity are a reduced carbon monoxide diffusion capacity (DLCO) and a restrictive ventilatory defect, so baseline PFT is mandatory before starting bleomycin.[8] DLCO is significantly decrease (14%–20%) after adding bleomycin to cisplatin and etoposide (P+E) regimen compared toP+E regimen alone (0%–2%).[9] Although decreasing DLCO is the most sensitive indicator of pulmonary response to bleomycin, it could not differentiate patients with BIP from those without. The total lung capacity (TLC) is more specific pointer of BIP as its reduction correlated with the development of pulmonary symptoms and imaging changes.[10]

Pulmonary toxicity is evident as a subacute or chronic interstitial pneumonitis which is subsequently complicated by progressive interstitial fibrosis and death.[11] Bronchiolitis obliterans with organizing pneumonia and eosinophilic hypersensitivity are two discrete pulmonary syndromes allied to use of bleomycin.[12] BIP manifests clinically as a nonproductive cough, dyspnea, and infrequently with fever and pleuritic pain. On chest X-ray, erratic reticulonodular infiltrates are seen particularly in the lower lobes and subpleural areas. Pneumonia due to Pneumocystis jiroveci should put as differential diagnosis, and empirical treatment of former is recommended.[13]

[Table 1] shows description of various predisposing factors (including drug factors, patient's factors, and using concomitant therapy) that increase BIP. The cumulative dose for the development of BIP is more than 400 U; however, BIP may occur at doses <50 U. Concomitant use of other chemotherapeutic agents (mainly cisplatin) leads to increase frequency of BIP. The rate of BIP is lower if more than 4-week interval is maintained between chemotherapy and chest radiotherapy.[14] Animal studies showed that concomitant treatment with granulocyte colony-stimulating factor leads to increase incidence of BIP.[15]

The most efficient approach to avert pulmonary toxicity is to avoid cumulative toxicity of bleomycin with taking care of keeping efficacy. In good prognosis metastatic GCT, plummeting total dose of bleomycin from 360 to 270 mg would not diminish its efficacy.[16] However, physicians should vigilant regarding this life-threatening toxicity in patient with high-risk features and not falter to desist it from combination regimen. In addition, etoposide, ifosfamide, and cisplatin regimen has simulating efficacy compared to BEP regimen, nevertheless increased myelosuppression. The total cumulative dose of bleomycin in HD is 120 mg/m2. BIP can be lowered using alternative regimens such as mechlorethamine, vincristine, procarbazine, and prednisone regimen and etoposide, vinblastine, and doxorubicin regimen.[17],[18] Thoracic radiation can be avoided using positron emission tomography-CT to evaluate treatment response in early-stage disease.[19]

Bleomycin is advised to stop in all patients with documented or stoutly assumed BIP. Radiological diagnosis of BIP in asymptomatic patients does not warrant any treatment as unprompted resolution radiological findings may occur. Glucocorticoids should be held in reserve for patients with symptomatic lung toxicity. The dose of prednisone is 0.75–1 mg/kg 4–8 weeks which then gradually tapered over an additional 4–6 months, in accordance with the patient's condition and clinical response. More than half of patients are responded for short tenure improvement although symptoms may relapse when therapy is tapered.[20] Clinical improvement occurs most likely within weeks in patients with significant inflammatory component. Clinical improvement occurs most likely within weeks in patients with significant inflammatory component. The probability of absolute resurgence is less if diagnosis of BIP is belated or fibrosis occurs.[21] Apart from corticosteroid, one case reported using imatinib mesylate and got completely cured in patients with HD who developed severe BIP, following an ABVD regimen.[22] Other agents with promising results are nilotinib, gefitinib, montelukast, sirolimus, and pravastatin.

Limitations of the study

Ideally, PFTs should have been done; however, as our study is retrospective in nature, we have diagnosed BIP mainly based on clinical and HRCT findings as accidental findings while patient being under follow-up at our institute. Moreover, we have not done PFTs in the follow-up of the Hodgkin's and GCT patients.


 > Conclusion Top


BIP is noteworthy lung toxicity as subsequent mortality ranges from 10% to 20% and shrinks survival rate in patients with highly curable malignant conditions. Physicians should be vigilant concerning this impending side effect. The closest differential diagnosis of BIP is interstitial lung disease and sometime exigent to differentiate.

High yielding facts

  • BIP toxicity crop up in up to 10% patients can be life menacing if not diagnosed early and culprit drug promptly discontinued
  • Physicians should be vigilant concerning this fatal toxicity and avoid bleomycin in the presence of high-risk factors. Baseline PFT is must before starting treatment. Although DLCO is highly sensitive test, it is less specific as compared to TLC
  • It is clinically evidently by nonproductive cough, dyspnea, hypoxia, and bibasilar rales with reticulonodular pattern on chest imaging. Fever is infrequently associated that can be differentiated from pneumonia from P. jiroveci
  • The main treatment is to avoid in high-risk patients and be cautious regarding cumulative dose. Asymptomatic patients do not require any treatment, and steroid should be spared in symptomatic patients. The mortality rate is 10%–20% in patients who develop BIP.


Acknowledgment

We acknowledge all the patients and their caregivers along with our enthusiastic nursing staff.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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7.
White DA, Kris MG, Stover DE. Bronchoalveolar lavage cell populations in bleomycin lung toxicity. Thorax 1987;42:551-2.  Back to cited text no. 7
    
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9.
de Wit R, Stoter G, Kaye SB, Sleijfer DT, Jones WG, ten Bokkel Huinink WW, et al. Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: A randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. J Clin Oncol 1997;15:1837-43.  Back to cited text no. 9
    
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Wolkowicz J, Sturgeon J, Rawji M, Chan CK. Bleomycin-induced pulmonary function abnormalities. Chest 1992;101:97-101.  Back to cited text no. 10
    
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Santrach PJ, Askin FB, Wells RJ, Azizkhan RG, Merten DF. Nodular form of bleomycin-related pulmonary injury in patients with osteogenic sarcoma. Cancer 1989;64:806-11.  Back to cited text no. 12
    
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Bollée G, Sarfati C, Thiéry G, Bergeron A, de Miranda S, Menotti J, et al. Clinical picture of Pneumocystis jiroveci pneumonia in cancer patients. Chest 2007;132:1305-10.  Back to cited text no. 13
    
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Danson S, Blackhall F, Hulse P, Ranson M. Interstitial lung disease in lung cancer: Separating disease progression from treatment effects. Drug Saf 2005;28:103-13.  Back to cited text no. 14
    
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Saxman SB, Nichols CR, Einhorn LH. Pulmonary toxicity in patients with advanced-stage germ cell tumors receiving bleomycin with and without granulocyte colony stimulating factor. Chest 1997;111:657-60.  Back to cited text no. 15
    
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Einhorn LH, Williams SD, Loehrer PJ, Birch R, Drasga R, Omura G, et al. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: A Southeastern Cancer Study Group protocol. J Clin Oncol 1989;7:387-91.  Back to cited text no. 16
    
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Fyfe AJ, McKay P. Toxicities associated with bleomycin. J R Coll Physicians Edinb 2010;40:213-5.  Back to cited text no. 21
    
22.
Carnevale-Schianca F, Gallo S, Rota-Scalabrini D, Sangiolo D, Fizzotti M, Caravelli D, et al. Complete resolution of life-threatening bleomycin-induced pneumonitis after treatment with imatinib mesylate in a patient with Hodgkin's lymphoma: Hope for severe chemotherapy-induced toxicity? J Clin Oncol 2011;29:e691-3.  Back to cited text no. 22
    



 
 
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