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Table of Contents
CASE REPORT
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 103-106

Beware of bleomycin toxicity: Fertility preservation for dysgerminoma


Department of Obstetrics and Gynaecology, JIPMER, Puducherry, India

Date of Web Publication22-Feb-2019

Correspondence Address:
Paapa Dasari
Department of Obstetrics and Gynaecology, WCH, JIPMER, Puducherry
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tofj.tofj_6_18

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  Abstract 


An 18-year-old female who underwent fertility preservation surgery for dysgerminoma Stage IIa received adjuvant chemotherapy and bleomycin, etoposide and cisplatin of four cycles. She presented with cough and breathlessness after 45 days of the last cycle of chemotherapy. She was tachypneic and had decreased SpO2 and was managed by supportive therapy. Her X-ray chest revealed bilateral ground-glass nodular opacity and computed tomography thorax showed evidence of pulmonary fibrosis in the form of intra- and inter-lobular septal fibrosis with surrounding ground-glass opacity. She ultimately died after 5 days of admission due to respiratory failure. Her body weight was 37 kg and she received standard dose of bleomycin and the cumulative dose was 360 U. Bleomycin dose recommendation is not per kg bodyweight, and the complication of pulmonary fibrosis could have been prevented if the dosage schedule as per bodyweight (0.25–0.5 U/kg) is advocated.

Keywords: Adolescent girl, bleomycin, dysgerminoma, mortality, pulmonary fibrosis


How to cite this article:
Ali AM, Dasari P. Beware of bleomycin toxicity: Fertility preservation for dysgerminoma. Onco Fertil J 2018;1:103-6

How to cite this URL:
Ali AM, Dasari P. Beware of bleomycin toxicity: Fertility preservation for dysgerminoma. Onco Fertil J [serial online] 2018 [cited 2019 May 21];1:103-6. Available from: http://www.tofjonline.org/text.asp?2018/1/2/103/252691




  Introduction Top


Fertility preservation in adolescents and young women is the recommended strategy in the current era. Fertility preservation needs to be undertaken without compromising the life of the patient. Stage Ia is treated only with surgery and followed up with clinical and radiological surveillance (ultrasonography/magnetic resonance imaging) in addition to tumor markers for 2 years. Chemotherapy is indicated if stage of the disease is advanced (Ic and IIa) in addition to cytoreductive surgery. The recommended chemotherapeutic regimen is bleomycin, etoposide and cisplatin (BEP) for 3–4 cycles, and multidisciplinary approach including fertility services is recommended especially for teenage and young adults.[1]

Bleomycin is a commonly used chemotherapeutic agent for germ cell tumors, lymphomas, cervical cancer, squamous cell tumors of head and neck. It is reported that up to 10% of patients receiving bleomycin develop life-threatening pulmonary toxicity such as subacute pulmonary fibrosis, hypersensitivity pneumonitis, and organizing pneumonia. Bleomycin-induced pneumonitis (BIP) may occur in 20%–40% and mortality of 3% is reported.[2] Pneumonitis if not treated in time progresses to fibrosis. Mortality due to BIP ranges from 2% to 10% and it increases to 33% in mechanically ventilated patients.[3] The risk factors for toxicity include age >40 years, renal disease, smoking, and a cumulative dose of >300 units.[4] There are no recommendations for dose adjustment in young or adolescent girls, and the administration of standard dose leads to toxicity and death. Hence, this case is reported.


  Case Report Top


An 18-year-old female was admitted to the intensive care unit with breathlessness, dry nonproductive cough, and tachypnea, which had increased for the past 2 days. She was a known case of dysgerminoma stage IIA and underwent right salphingo-ovariotomy and received four cycles of BEP, with the last cycle administered 45 days ago. She developed dermatological and gastrointestinal side effects and pancytopenia during the 3rd and 4th cycles and received specific management in the ICU by multidisciplinary team and was discharged at request. She had responded to chemotherapy partially, and her lactate dehydrogenase came down to 279 U/L from the initial value of 1571 U/L after four cycles.

Her initial contrast-enhanced computed tomography (CT) showed 14 cm × 7.8 cm × 13.2 cm abdominopelvic mass arising from the right ovary extending to the right flank. It had central nonenhancing necrotic areas in the superior part, and there was no calcification. There was minimal free fluid in pelvis and few small volume (largest 6 mm) upper para-aortic lymphnodes were present. The left ovary measured 4.2 cm × 2.6 cm. At laparotomy, uterus, left ovary, and both fallopian tubes were normal. The right ovarian mass was 15 cm × 10 cm, and there were no adhesions and no breach in the capsule. Right ovariotomy and omental biopsy and peritoneal biopsy were done. Other intra-abdominal organs were normal. Cytology of ascitic fluid was negative for malignant cells. Histopathological examination was reported as dysgerminoma with fallopian tube surface implant and pathological staging was pT2aNxMx.).

On admission, she was conscious, oriented, and was tachypneic with respiratory rate of 40–60/min and had tachycardia of 120/min. On auscultation, crepitation were heard bilaterally – right more than left. Her SpO2 in room air was 65%–75% and with oxygen SpO2 was maintained at 88%. Her blood pressure was 90/60 mmHg. Her chest X-ray revealed bilateral diffuse ground-glass nodular opacity [Figure 1].
Figure 1: Chest X-ray showing bilateral ground-glass nodular opacities

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She was started on empirical antibiotic treatment with ceftriaxone and co-trimoxazole. Her CT findings revealed bilateral subplural inter- and intra-lobular septal thickening and surrounding ground-glass opacification with diagnosis of pulmonary fibrosis. [Figure 2] shows apical lung fibrosis and [Figure 3] shows mid zonal lung fibrosis. The diagnosis of bleomycin-induced lung injury was confirmed by medical oncologists and pulmonologists, and she was started on prednisolone and montelukast. Her condition deteriorated over the next 4 days due to respiratory failure which worsened. On the 5th day, she sustained cardiac arrest from which she could not be revived.
Figure 2: Computed tomography – Thorax axial view shows apical fibrotic patches of lungs

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Figure 3: Computed tomography – Thorax axial view midzone shows fibrotic patches of lungs

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  Discussion Top


Germ cell tumors (GCTs) account for 2%–3% of all malignancies, and dysgerminoma is the most common GCT. Majority (75%) present in adolescent and young adults. The standard chemotherapy regimen for GCT is BEP 3–4 cycles with doses as shown in [Table 1].[5],[6]
Table 1: Bleomycin, etoposide, and cisplatin regimen

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Bleomycin is an important component of BEP regimen given weekly IV in 30 units (days 1, 8, and 15) in 3–4 cycles up to a cumulative doses of 270–360 U which might cause the feared and sometimes fatal BIP.[4] Bleomycin causes endothelial damage of the lung vasculature mediated through cytokines and free radicals, which leads to subsequent infiltration of inflammatory cells and fibrosis. The effects are shown in [Figure 4].
Figure 4: Mechanism of Bleomycin action

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Clinical symptoms of toxicity are nonproductive cough, progressive dyspnea, and tachypnea with fine crackles on auscultation. Symptoms usually occur 1–6 months after completion of chemotherapy.[5] Identification of patients with bleomycin pulmonary toxicity is difficult because of nonspecific symptoms, and a normal X-ray chest does not exclude bleomycin pulmonary toxicity (BPT). Dermatological effects are most frequent and occur in as high as 50% and there were experienced by this patient and were promptly managed.

In BEP regimen, bleomycin is given in a standard dose of 30 U and not as per kg body weight or body surface area. This patient received 360 U over four cycles as per the standard dose protocol and as advised by medical oncologists.[6] The recommended dose as per the drug schedule is 0.25–0.5 unit/kg.[7] This patient with initial body weight of 37 kg required approximately 18.5 units at a dose of 0.5 units/kg. Hence, this may be the reason for the development of pulmonary fibrosis in this adolescent girl. It could have been prevented by predicting the possibility of toxicity.

Toxicity can be avoided by performing serial monitoring of diffusion lung capacity of carbon dioxide (DLCO) forced vital capacity and stopping bleomycin administration when DLCO declines by >40%.[8]

O'Sullivan et al. concluded that that there are three main factors predicting the highest probability of bleomycin-induced pulmonary fibrosis. These are glomerular filtration rate <80 ml, cumulative dose of >300 units, and age >40 years.[9] Mortality in GCTs is usually related to the stage of the disease and there is no mortality attributed to therapy when a 3-day regimen of BEP was advocated in a large series reported by Taiwainese Gynaecological oncology group.[10]

There is no specific treatment for BPT. Steroids are recommended for symptomatic patients (prednisolone 1 mg/kg for 4–8 weeks). Risk or benefit between permissive hypoxemia versus the potential toxic effects of oxygen predisposed by bleomycin should be carefully considered. In severe hypoxemia, supplemental oxygen is sparingly used to maintain oxygen saturation.[4]


  Conclusion Top


Prevention of bleomycin-induced toxicity is important to reduce the morbidity and mortality. Chemotherapeutic regimens should be tailor made for each patient depending on the body weight rather than a fixed dose to avoid the serious side effects.

Precautions need to be taken to prevent bleomycin toxicity as there is no specific treatment and mortality is high once lung injury develops.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Management of Female Malignant Ovarian Germ Cell Tumours-RCOG (Scientific Impact Paper No. 52). Available from: https://www.rcog.org.uk/en/guidelines-research-services/guidelines/sip52/. [Last accessed on 2016 Nov 25].  Back to cited text no. 1
    
2.
Vaidya PJ, Sandeepa HS, Singh T, Susheel Kumar SK, Bhargava R, Ramakrishnan G, et al. Combined prednisolone and pirfenidone in bleomycin-induced lung disease. J Cancer Res Ther 2016;12:1198-202.  Back to cited text no. 2
    
3.
Besteiro B, Elankumaran P. Bleomycin lung injury. A case report and review of the literature. J Anest Intensive Care Med 2017;3:1-4.  Back to cited text no. 3
    
4.
Stein ME, Zidan J, Charas T, Gershuny A, Ben-Yosef R. Bleomycin-induced pneumonitis in three patients treated with chemotherapy for primary advanced seminoma. J BUON 2015;20:928-32.  Back to cited text no. 4
    
5.
Calzas Rodríguez J, Carmen Juarez Morales MD, Casero MA. Death by bleomycin pulmonary toxicity in ovarian dysgerminoma with pathologic complete response to chemotherapy. A case report. Respir Med Case Rep 2016;18:48-50.  Back to cited text no. 5
    
6.
BEP: Bleomycin / Etoposide / Cisplatin in Germ Cell Tumours. Available from: http://www.londoncanceralliance.nhs.uk/.../Urology_Germ_cell_BEP_5day_protocol_v3.1... [Last accessed on 2010 May 19].  Back to cited text no. 6
    
7.
Bleomycin Dosing, Indications, Interactions, Adverse Effects, and More. Available from: https://www.reference.medscape.com/drug/bleomycin-342113.  Back to cited text no. 7
    
8.
Shippee BM, Bates JS, Richards KL. The role of screening and monitoring for bleomycin pulmonary toxicity. J Oncol Pharm Pract 2016;22:308-12.  Back to cited text no. 8
    
9.
Reinert T, Baldotto CS, Nunes FA, et al. J Cancer Res 2013;2013:480608. [doi: 10.1155/2013/480608].  Back to cited text no. 9
    
10.
Chen CA, Lin H, Weng CS, Wen KC, Lu CH, Chou HH, et al. Outcome of 3-day bleomycin, etoposide and cisplatin chemotherapeutic regimen for patients with malignant ovarian germ cell tumours: A Taiwanese Gynecologic Oncology Group study. Eur J Cancer 2014;50:3161-7.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1]



 

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