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Frequency and risk factors of bleomycin-induced pulmonary toxicity in South Indian patients with germ-cell tumors


1 Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Gorimedu, Puducherry, India
2 Department of Radio Diagnosis, Jawaharlal Institute of Postgraduate Medical Education and Research, Gorimedu, Puducherry, India
3 Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Gorimedu, Puducherry, India
4 Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Gorimedu, Puducherry, India

Date of Submission19-May-2019
Date of Decision26-Nov-2019
Date of Acceptance12-Dec-2019
Date of Web Publication07-Jul-2020

Correspondence Address:
Kesavan Ramasamy,
Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Gorimedu, Puducherry
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_348_19

 > Abstract 


Aim: Bleomycin, etoposide, and cisplatin (BEP) regimen is the standard treatment for germ-cell tumors (GCTs). Bleomycin-induced pulmonary toxicity (BPT) is fatal and dose-limiting toxicity associated with this regimen. In this study, we aimed to identify the frequency and risk factors of BPT in South Indian GCT patients receiving BEP regimen.
Patients and Methods: The study was carried out in the Department of Medical Oncology, Regional Cancer Centre at a tertiary care hospital in South India. All the patients with GCT (testicular and ovarian) who were receiving BEP regimen from December 2014 to May 2018 were included in the study. BPT was defined as the presence of radiological features and/or clinical symptoms during or post-treatment.
Results: BPT was observed in 11 (27%) patients of 41 analyzed patients. Five (12%) patients developed BPT during treatment whereas six (15%) patients developed BPT post-treatment. Cumulative bleomycin dose ≥240 mg (relative risk 3.8, confidence interval: 1.2–12.2,P =0.02) was found to increase the risk of BPT. Three-year overall survival in patients with and without toxicity was 82% and 93%, respectively.
Conclusions: The frequency of BPT in the study population is 27%, and cumulative bleomycin dose ≥240 mg has been found to be associated with increased risk of developing BPT. BPT does not negatively impact survival outcome in GCT patients receiving BEP regimen.

Keywords: Bleomycin, etoposide, and cisplatin regimen, bleomycin-induced pulmonary toxicity, germ-cell tumor, risk factors



How to cite this URL:
Thakkar DN, Ramasamy K, Adithan S, Selvarajan S, Dubashi B. Frequency and risk factors of bleomycin-induced pulmonary toxicity in South Indian patients with germ-cell tumors. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 23]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=289132




 > Introduction Top


Germ-cell tumors (GCTs) are malignant neoplasms originating from the primordial germ cell, which occur most commonly in young adults. Since 1970s, bleomycin, etoposide, and cisplatin (BEP) regimen has been the standard treatment for GCTs as the 5-year survival rate in the favorable prognosis group is 91% with this regimen.[1] Minimizing toxicities with this regimen is of major interest as most commonly treated patients are young adults, and treatment response is high.[2] The most frequent toxicities are neutropenia, vomiting, nausea, and diarrhea.[3] The most frequent adverse reactions seen among-long term survivors are ototoxicity, peripheral neuropathy, lung toxicity, cardiovascular disease, and metabolic syndrome.[4] In this study, we have focused on bleomycin-induced pulmonary toxicity (BPT) that occurs in nearly 46% of patients receiving BEP regimen with the resultant mortality rate of 4%.[5]

Bleomycin is a glycopeptide antibiotic which is degraded by the enzyme bleomycin hydrolase. Skin and lung are the primary targets of bleomycin toxicity as they have a lower level of this enzyme. In patients with normal kidney function, the half-life of bleomycin is 2–5 h and about 70% of the drug is excreted renally. Impaired renal function is a risk factor for BPT as it increases the half-life of the drug.[6] Cumulative bleomycin dose >3 mg is a suggested risk factor but it has been shown that BPT can occur even at cumulative doses <100 mg.[7] The other postulated risk factors include presence of mediastinal mass, age >3 years, use of growth factors, and history of cigarette smoking.[6]

The incidence of BPT has been found to be varying in different parts of the world based on the ethnicity. As South Indian population is ethnically and genetically unique, the frequency of BPT could vary in these patients.[8],[9] In addition, there has been an observation by the clinicians that South Indians are more prone to this toxicity than North Indians. Hence, in this study, we aimed to identify the frequency and risk factors of BPT in South Indian GCT patients receiving BEP regimen. We also analyzed the influence of BPT on survival outcome.


 > Patients and Methods Top


The ethical approval was taken from the institutional ethics committee before starting the study. The study details were explained to the participants and written informed consent was obtained. The study was carried out in the Department of Medical Oncology, Regional Cancer Centre at a tertiary care hospital in South India, from December 2014 to May 2018. All GCT (testicular and ovarian) patients receiving BEP regimen during this period were included in the study. The GCT patients who did not receive bleomycin-based regimen were excluded. As computed tomography (CT) scan reports were important in diagnosing BPT, the patients with missing CT scan reports were also excluded. Testicular GCT patients were classified into good, intermediate, and poor prognosis groups using the International Germ Cell Consensus Classification.[10] The patients had received 3–4 cycles of BEP based on their prognostic factors, and each cycle was of 21 days (bleomycin 30 mg days 1, 8 and 15, etoposide 100 mg/m2 days 1–5, cisplatin 20 mg/m2 days 1–5). All the patients were followed up for 6 months after completion of treatment.

Diagnosis of bleomycin-induced pulmonary toxicity

BPT was defined as the presence of radiological features and/or clinical symptoms during or posttreatment in the absence of infection. For all the patients, high-resolution computed tomography (HRCT) scans (make: Siemens, SOMATOM Sensation 64 Slice CT Scanner) were done at regular intervals as part of treatment protocol (before starting the treatment, end treatment, and 6 months' posttreatment) to know the disease status which was used to monitor the patients for radiological signs of BPT. Dedicated HRCT thorax was only taken when BPT was suspected clinically during treatment or during follow-up period. The CT scan reports of pretreatment and after treatment were compared, and the findings were reported formally by the radiologist. The patients were interviewed after receiving each cycle and were asked if they had developed the symptoms such as cold, fever, dry cough, and dyspnea. In case of severe symptoms, bleomycin was stopped and the patient was started on steroids therapy after excluding infection.

Scan protocol

The patients were asked to lie in supine position and were instructed to hold breath during the scanning procedure. Helical acquisition protocol was used for scanning and slice thickness was kept 1mm. The images were viewed in soft tissue reconstruction and HRCT reconstruction with edge-enhancement algorithm.

Survival analysis and other toxicities of bleomycin, etoposide, and cisplatin regimen

The disease was considered refractory if serum markers such as human chorionic gonadotropin, alpha-fetoprotein, lactate dehydrogenase, and CA125 did not decline after the completion of chemotherapy. Early relapse was defined as reoccurrence of disease within 2 years post start of the chemotherapy after an initial response. Overall survival (OS) was defined as the time between start of the treatment to death or last date of follow-up. Data such as date of start of the treatment, last follow-up date, vital status at the last date of analysis, age, gender, stage, smoking history, presence of lung metastasis, preexisting lung disease, bleomycin dose, granulocyte-colony stimulating factor (G-CSF) administration, and the lowest glomerular filtration rate (GFR) value during the treatment were collected from patients' medical records.

Statistical analysis

Chi-square test was done to assess if parameters such as age, bleomycin dose, pretreatment lung metastasis, advanced stage, GFR, hemoglobin (Hb), and smoking history were associated with BPT. To test if there was a difference in OS in the presence of BPT, Kaplan–Meier curves were plotted, and statistical significance was checked using the log-rank test. All the statistical analyses were done using SPSS version 19 (Armonk, NY, USA: IBM Corp.).


 > Results Top


A total of 41 eligible patients were recruited for the study. Baseline characteristics of the study population have been described in [Table 1]. Twenty-six patients had testicular GCT while 15 had ovarian GCT. The median age was 28 years and mean bleomycin dose given was 193 ± 109 mg.
Table 1: Baseline characteristics of patients receiving bleomycin, etoposide, and cisplatin regimen

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BPT was observed in 11 (27%) patients. In 5 (12%) patients, bleomycin was omitted as they developed pulmonary toxicity during treatment and were continued on EP regimen. Two patients were asymptomatic with CT scan findings suggestive of inter- and intra-lobular septal thickening in the upper lobe in one patient and intralobular septal thickening and ground glass opacities in the subpleural region in the other. One patient had fever and cough with minimal fibrotic changes whereas other patient had cough with intralobular septal thickening and subpleural opacities. One 32-year-old seminoma patient with intermediate risk had severe cough and dyspnea. His radiological findings showed patchy areas of ground-glass opacities and consolidation changes in the subpleural region and peribronchovascular thickening in the right upper lobe [Figure 1]a. More than 75% of the lung volume showed ground-glass opacities which could be secondary to metastasis as the patient, later on, died due to refractory disease. Six (15%) patients developed BPT 2–6 months after completion of treatment. One patient had very subtle interlobular septal thickening immediately after chemotherapy which became prominent after 3 months [Figure 1]b. The details of 11 cases that developed BPT have been given in [Table 2].
Figure 1:(a) Case 4, CT scan taken after 3 cycles of bleomycin, etoposide, and cisplatin shows patchy areas of ground glass opacities and consolidation changes in the subpleural region. (b) Case 3, CT scan taken 3 months posttreatment shows inter and intralobular septal thickening

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Table 2: Clinical profile of patients who developed pulmonary toxicity

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Cumulative bleomycin dose ≥240 mg (relative risk 3.8, confidence interval [CI] 1.2–12.2, P = 0.02) was found to increase the risk of BPT by Chi-square test whereas age >3 years, smoking history, administration of G-CSF, GFR, lung metastasis, advanced stage, and Hb did not increase the risk to develop BPT [Table 3].
Table 3: Risk factors of bleomycin-induced pulmonary toxicity

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Influence of BPT on survival outcome

Of 26 testicular GCT patients, three died due to refractory disease and one patient had relapsed. Statistical analysis for OS according to prognostic factors was not possible as there were no events in one prognostic group. Of 15 ovarian GCT patients, seven had advanced stage disease of which one patient died. Statistical analysis for OS was not possible based on stage as there were no events in the early stage. Overall, 4 (9.7%) patients died and one patient relapsed of 41 analyzed patients and there was no mortality due to BPT. The patients with and without BPT had a mean OS time of 36 and 51 months, respectively. Three-year OS was 82% in BPT and 93% in non-BPT group. With log-rank testing, we found that BPT did not affect OS (P = 0.3, hazard ratio 2.4, CI: 0.3–16.8) in GCT patients [Figure 2].
Figure 2:Kaplan–Meier plot for OS according to bleomycin-induced pulmonary toxicity in germ-cell tumour patients receiving bleomycin, etoposide, and cisplatin regimen

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 > Discussion Top


Bleomycin is an effective component of the BEP regimen due to its low myelotoxicity and broad spectrum of action. Clinical trials have shown that for patients with good prognosis, 4 cycles of EP is as effective as 3 cycles of BEP while avoiding BPT. However, for patients with intermediate to poor risk, 4 cycles of BEP remain the standard treatment.[11] Thus, diagnosing BPT and identifying its risk factors becomes imperative. In this study for the first time, we have assessed the frequency of BPT in GCT patients of South Indian origin who were receiving BEP regimen and also identified the associated risk factors.

Eleven (27%) out of 41 patients developed BPT in this study. Five patients were asymptomatic but had CT scan findings suggestive of toxicity whereas six patients (15%) had respiratory symptoms and radiological signs of toxicity. One ovarian GCT patient had cough and fever during the treatment and bleomycin was terminated and was restarted on bleomycin as CT scan did not show any signs of toxicity. None of the patients required treatment with steroids and there was no mortality due to BPT. In 10 cases, radiologic pulmonary fibrosis involved <25% of the lung volume and in one case more than 75% of the lung volume showed ground-glass opacities which could be secondary to metastasis as patient later on died due to refractory disease. Most common radiological features involved inter- and intra-lobular septal thickening and patchy ground-glass opacities predominantly in the subpleural region. Five patients developed toxicity 2–3 months after receiving the first dose of bleomycin and six patients developed late toxicity which occurred 3–6 months after completion of chemotherapy. In most cases, radiological signs were persistent even after 1 or 2 years postcompletion of treatment.

In Mangalore, South India, the incidence of BPT was found to be 9.5% by Rajendran and Prasad in Hodgkin lymphoma patients receiving ABVD regimen.[12] The difference in incidence could be due to different criteria used as there are no standard guidelines for diagnosing BPT. Kwan et al. found the incidence of grade 2–5 BPT to be 8.5% in Canadian GCT patients using Common Terminology Criteria for Adverse Event criteria.[13] In Maruyama et al.'s study, 29% of the patients had developed BPT of 52 patients with symptomatic BPT observed in 4% of the patients.[14] Zhao et al. conducted a study in Chinese ovarian GCT patients. They graded BPT by pulmonary function tests and found that 49.2% of the patients had pulmonary dysfunction.[5] Thus, the incidence of BPT varies from population to population and based on the criteria used for diagnosis.

We also investigated the risk factors associated with BPT. Age >3 years, administration of G-CSF, and reduced GFR were found to increase the risk of BPT in some studies;[6] but, in our study, we did not find any association. In our study, patients who received cumulative bleomycin dose ≥240 mg had 3.8 times higher risk of developing BPT. In previous studies, cumulative dose >3–400 units has been described as a risk factor; on the contrary, some reports have found that pulmonary toxicity is not dose related and can even occur at a cumulative dose <100 units.[7] Exposure to O2 therapy which is a known risk factor of BPT was not recorded and is one of the limitations of the study.

In this study, we found that discontinuing bleomycin during treatment due to toxicity in five patients did not affect their survival outcome. Al-Jizani et al.'s study demonstrated that BPT does not adversely affect RFS (relapse-free survival) and OS but early diagnosis of BPT and discontinuation of bleomycin led to better survival outcome.[15] Sun et al., reported that neither discontinuation of bleomycin nor BPT negatively impacted survival outcomes and was in agreement with Al-Jizani et al.'s findings.[16]

Use of PFTs in predicting BPT has been controversial and has been questioned by many studies. Zhao et al., assessed the diagnostic value of PFTs and found that BPT could be sensitively diagnosed and graded using PFTs.[5] Whereas, Roncolato et al. reported that asymptomatic reductions in carbon monoxide diffusing capacity (DLCO) led to unnecessary omission or reduction of bleomycin in 50% of the patients and hence the use of PFTs in predicting BPT should be questioned.[17] McKeage et al. recruited 81 patients receiving bleomycin-based regimen and measured DLCO frequently during treatment and in addition to symptoms to diagnose clinically significant toxicity observed interstitial changes on X-ray. Of 81 recruited patients, 6 developed toxicity; however, only one patient had drop in DLCO and other five had normal DLCO. Twelve patients had abnormal DLCO but did not develop clinically significant toxicity and thus they reported that DLCO is a poor predictor of BPT.[18] One study also concluded that PFTs are not useful in detection of BPT and no reduction or omission should be made in asymptomatic patients based on reduction in PFT parameters. They also concluded that routine use of PFTs to diagnose BPT should be abandoned and to detect clinically significant BPT doing an early CT scan when patients are symptomatic is preferable.[19] In this study, we could not perform PFTs to monitor patients' lung function during and posttreatment as most of the patients found it difficult to perform the tests and also due to technical difficulties encountered while performing DLCO. In this study HRCT scans were used to diagnose BPT as X-rays appear nonspecific and have limited utility. Findings such as ground-glass opacities, inter-, and intra-lobular septal thickening are seen adequately only in HRCT scans. This is supported by Padley et al.'s and Bellamy et al.'s studies which reported that HRCT scans are more sensitive than X-rays in detecting BPT.[20],[21]

In the present study, we have analyzed a small cohort; so, the study is not powered enough to reveal the statistical significance of the risk factors associated with BPT. Hence, studies with a larger cohort are required to validate this finding. Pulmonary fibrosis is fatal and irreversible toxicity of bleomycin and so far pirfenidone (transforming growth factor beta inhibitor) and imatinib (tyrosine kinase inhibitor) have had very limited success in treating severe BPT.[22],[23] CT scans can detect subtle changes in lungs at the early stages which if bleomycin is continued could cause irreversible damage to lungs. Hence, doing an early CT scan when patients are symptomatic could be used as a warning sign to omit bleomycin and prevent subsequent irreversible pulmonary toxicity.


 > Conclusion Top


The frequency of BPT in the study population is 27% and cumulative bleomycin dose ≥240 mg has been found to be associated with increased risk of developing BPT. BPT does not negatively impact survival outcome in GCT patients receiving BEP regimen.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgments

We acknowledge Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) for providing intramural grant to support this work. We also acknowledge late Dr. Steven A. Dkhar, Professor of Pharmacology, JIPMER for his guidance in conducting this study.

Financial support and sponsorship

This study was financially supported by JIPMER (institute) intramural grant.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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de Haas EC, Zwart N, Meijer C, Nuver J, Boezen HM, Suurmeijer AJ, et al. Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer. J Clin Oncol 2008;26:1817-23.  Back to cited text no. 1
    
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Gershenson DM, Frazier AL. Conundrums in the management of malignant ovarian germ cell tumors: Toward lessening acute morbidity and late effects of treatment. Gynecol Oncol 2016;143:428-32.  Back to cited text no. 2
    
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Kawai K, Ando S, Hinotsu S, Oikawa T, Sekido N, Miyanaga N, et al. Completion and toxicity of induction chemotherapy for metastatic testicular cancer: An updated evaluation of Japanese patients. Jpn J Clin Oncol 2006;36:425-31.  Back to cited text no. 3
    
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Gil T, Sideris S, Aoun F, van Velthoven R, Sirtaine N, Paesmans M, et al. Testicular germ cell tumor: Short and long-term side effects of treatment among survivors. Mol Clin Oncol 2016;5:258-64.  Back to cited text no. 4
    
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Zhao Q, Cao D, Yu M, Yang J, Liu Y, Xiang Y, et al. Safety and efficacy of bleomycin/pingyangmycin-containing chemotherapy regimens for malignant germ cell tumor patients in the female genital system. Oncotarget 2017;8:15952-60.  Back to cited text no. 5
    
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O'Sullivan JM, Huddart RA, Norman AR, Nicholls J, Dearnaley DP, Horwich A. Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours. Ann Oncol 2003;14:91-6.  Back to cited text no. 6
    
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Thakkar DN, Kodidela S, Sandhiya S, Dubashi B, Dkhar SA. A polymorphism located near PMAIP1/Noxa gene influences susceptibility to Hodgkin lymphoma development in South India Asian Pac J Cancer Prev 2017;18:2477-83.  Back to cited text no. 8
    
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Kwan EM, Beck S, Amir E, Jewett MA, Sturgeon JF, Anson-Cartwright L, et al. Impact of granulocyte-colony stimulating factor on bleomycin-induced pneumonitis in chemotherapy-treated germ cell tumors. Clin Genitourin Cancer 2017. pii: S1558-7673 (17) 30267-7.  Back to cited text no. 13
    
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Maruyama Y, Sadahira T, Mitsui Y, Araki M, Wada K, Tanimoto R, et al. Prognostic impact of bleomycin pulmonary toxicity on the outcomes of patients with germ cell tumors. Med Oncol 2018;35:80.  Back to cited text no. 14
    
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Al-Jizani WA, Al-Mansour MM, Al-Fayea TM, Shafi RU, Kazkaz GA, Bayer AM, et al. Bleomycin pulmonary toxicity in adult Saudi patients with Hodgkin's lymphoma. Future Oncol 2015;11:2149-57.  Back to cited text no. 15
    
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Sun HL, Atenafu EG, Tsang R, Kukreti V, Marras TK, Crump M, et al. Bleomycin pulmonary toxicity does not adversely affect the outcome of patients with Hodgkin lymphoma. Leuk Lymphoma 2017;58:2607-14.  Back to cited text no. 16
    
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Roncolato FT, Chatfield M, Houghton B, Toner G, Stockler M, Thomson D, et al. The effect of pulmonary function testing on bleomycin dosing in germ cell tumours. Intern Med J 2016;46:893-8.  Back to cited text no. 17
    
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McKeage MJ, Evans BD, Atkinson C, Perez D, Forgeson GV, Dady PJ. Carbon monoxide diffusing capacity is a poor predictor of clinically significant bleomycin lung. New Zealand Clinical Oncology Group. J Clin Oncol 1990;8:779-83.  Back to cited text no. 18
    
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Shamash J, Sarker SJ, Huddart R, Harland S, Joffe JK, Mazhar D, et al. A randomized phase III study of 72h infusional versus bolus bleomycin in BEP (bleomycin, etoposide and cisplatin) chemotherapy to treat IGCCCG good prognosis metastatic germ cell tumours (TE-3). Ann Oncol 2017;28:1333-8.  Back to cited text no. 19
    
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Bendstrup E, Hyldgaard C, Agerbæk M, Andersen CU, Hilberg O. No effect of pirfenidone treatment in fulminant bleomycin-induced pneumonitis. Respir Med Case Rep 2014;12:47-9.  Back to cited text no. 22
    
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Banakh I, Lam A, Tiruvoipati R, Carney I, Botha J. Imatinib for bleomycin induced pulmonary toxicity: A case report and evidence-base review. Clin Case Rep 2016;4:486-90.  Back to cited text no. 23
    


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