Journal of Oncology Pharmacy Practice

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Incidence, outcome and predictors of bleomycin pulmonary toxicity in a university hospital in Oman Bushra M Ahmed and Ibrahim S Al-Zakwani J Oncol Pharm Pract 2013 19: 3 originally published online 13 April 2012 DOI: 10.1177/1078155212444649 The online version of this article can be found at: http://opp.sagepub.com/content/19/1/3

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Journal of

Oncology Pharmacy Practice

Original Article

Incidence, outcome and predictors of bleomycin pulmonary toxicity in a university hospital in Oman

J Oncol Pharm Practice 19(1) 3–7 ! The Author(s) 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155212444649 opp.sagepub.com

Bushra M Ahmed Department of Pharmacy, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman

Ibrahim S Al-Zakwani Department of Pharmacy, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman; Department of Pharmacology & Clinical Pharmacy, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman; Gulf Health Research, Muscat, Oman

Abstract Objectives: To determine the incidence and predictors of bleomycin pulmonary toxicity in a university hospital in Oman. Methods: This retrospective chart review consisted of 46 patients treated with bleomycin-containing regimes at Sultan Qaboos University Hospital in Oman between January 2007 and December 2010. Data regarding patient age, chemotherapy protocol, cumulative bleomycin dose, smoking history, renal function and concurrent use of granulocyte colony stimulating factor (GCSF) were collected from the hospital’s electronic database. Analyses were performed using univariate statistical techniques. Results: Of the 46 patients, 22% (n ¼ 10) experienced bleomycin pulmonary toxicity. There was an overall mortality of 4.3% (n ¼ 2; N ¼ 46), with significantly more deaths in the bleomycin pulmonary toxicity group compared to the cohort that did not have bleomycin pulmonary toxicity (20% versus 0%; p ¼ 0.043). The bleomycin pulmonary toxicity group was significantly older compared to the cohort that did not have bleomycin pulmonary toxicity (48 versus 34 years; p ¼ 0.017). Furthermore, adriamycin, bleomycin, vinblastine, dacarbazine, as front-line chemotherapy, was found to have a trend towards increased risk of bleomycin pulmonary toxicity (90% versus 56%; p ¼ 0.067; power ¼ 31%). There did not seem to be significant differences in bleomycin dose (143 versus 149 units; p ¼ 0.727), smoking status (10% versus 14%; p ¼ 1.000) and systolic blood pressure (133 versus 131 mmHg; p ¼ 0.746) between the two study groups. Conclusion: This study confirms a relatively high incidence of bleomycin pulmonary toxicity in a tertiary hospital in Oman. Older patients were significantly more likely to suffer bleomycin pulmonary toxicity compared to younger patients.

Keywords Bleomycin, pulmonary toxicity, Oman

germ cell tumors; as well as for both Hodgkin and nonHodgkin lymphoma.1

Introduction Bleomycin is a polypeptide antibiotic that has been used in cancer chemotherapy for over 20 years. It is an attractive addition to combination chemotherapy regimens because of its broad activity and low myelotoxicity.1 It is also commonly used as part of cytostatic treatment for several tumor types such as squamous cell carcinoma of the head and neck, cervix and esophagus;

Corresponding author: Bushra M Ahmed, Department of Pharmacy, Sultan Qaboos University Hospital, Sultan Qaboos University, P.O. Box 38, Al-Khodh, Muscat, PC-123, Sultanate of Oman. Email: [email protected]


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Journal of Oncology Pharmacy Practice 19(1)

However, bleomycin is sometimes associated with significant side effects.2 Bleomycin-induced toxicity occurs predominantly in the lungs and the skin due to the lack of the bleomycin hydrolase in these organs.2 Administration side effects such as fever, chills and sometimes hypotension are well known.1 Other side effects include dermal hyperpigmentation and fibrosis, stomatitis and fatigue,1 while pulmonary toxicity is the most feared and dose-limiting side effect of bleomycin.2 In addition, several distinct pulmonary syndromes have been associated with the use of bleomycin, such as bronchiolitis obliterans with organizing pneumonia (BOOP), eosinophilic hypersensitivity and interstitial pneumonitis.1 Bleomycin-induced lung toxicity has been reported to occur in 2–46% of patients, depending on criteria used and the presence of risk factors and mortality occurs in about 1–2% of treated patients.2 The clinical picture of bleomycin pulmonary toxicity (BPT) is usually non-specific. Dyspnea is present in 70–90% of the cases usually with chest discomfort and may be associated with non-productive cough. Moreover, fever and tachypnoea are usually present. Pulmonary function test may show a restrictive pattern with a low diffusing capacity for carbon monoxide (DLCO). In practice, the time course of onset of clinical manifestations may suggest BPT as it usually develops sub acutely between one and six months after treatment with bleomycin.2 A number of risk factors for the development of BPT have been reported in the literature including cumulative doses of >450 total units, low glomerular filtration rate (GFR; 40 years),3 supplemental oxygen exposure,3 bolus drug delivery (as opposed to continuous infusion),1 combination therapy with cyclophosphamide or granulocyte-colony stimulating factor,5 extent of lung metastases, prior lung disease and history of smoking.1 Little is known about incidence, outcome and predictors of BPT in the Gulf region. Furthermore, practice patterns and patients characteristics in this part of the World may differ significantly from those observed in the West. In addition, anecdotal reports have also suggested an increased number of BPT cases in the recent years compared to the past. Hence, the aim of this study was to determine the incidence, outcome and predictors of BPT in patients treated at Sultan Qaboos University Hospital in Oman over a 4-year period between 2007 and 2010.

Methods A retrospective case-notes review was performed of all cases of cancers treated with bleomycin-containing chemotherapy regimens at Sultan Qaboos University Hospital (SQUH), Oman, during the 4-year period between January 2007 and December 2010. SQUH is

one of the two centers that use bleomycin in the country. Inclusion criteria included all patients who received at least one dose of bleomycin at SQUH during this period.1 As per the internal recommended guidelines at SQUH, bleomycin is administered as a slow IV push over 10 min. Test dose is not routinely given unless a patient has previously developed sensitivity and is re-challenged with bleomycin. However, due to the possibility of an acute reaction, only physicians are allowed to administer IV chemotherapy. Cases were identified by review of the chemotherapy drug records for inpatients as all patients receiving bleomycin-containing chemotherapy for various types of cancers were treated as in-patients for the first few days of each cycle. As there are no internationally accepted guidelines for the diagnosis of BPT, the criteria used was based on the presence of pulmonary symptoms with DLCO reduced by 30–35% from the patient’s baseline, bilateral interstitial infiltrates on chest x-ray or computed tomography scan and the absence of infection. BPT was classified as fatal BPT when the primary cause of death is respiratory failure with no other identifiable pathology. Data collected for patients included previously described risk factors for BPT. Each case was reviewed with respect to the total bleomycin dose received by the patient, age at diagnosis, treatment with radiotherapy before or during chemotherapy, previous lung disease, smoking history and the lowest GFR of any cycle at the time of treatment with bleomycin. Measurement of the GFR had been performed by using the modification of diet in renal disease (MDRD) equation for measurement of creatinine clearance. Mortality, and its association with BPT, was based on the documentation in the electronic patient record (EPR).

Statistical analysis Descriptive statistics were used to describe the data. For categorical variables, frequencies and percentages were reported. Differences between the two groups (BPT; yes/no) were analyzed using Pearson’s 2 tests (or Fisher’s exact tests for cells 90 ml/min. The demographic and clinical characteristics of the study cohort are listed in Table 1. The overall mean age of the cohort was 37 17 years ranging from 14 to 69 years. The BPT group was, however, significantly older compared to the cohort that did not have BPT (48 versus 34 years; p ¼ 0.017). The observed rate of BPT was 41% (7 of 17 patients) and 10% (3 of 29 patients) in patients >40 years old and patients less than 40 years old, respectively. There were a total of 43% (n ¼ 20) female patients. There did not seem to be a significant difference in bleomycin dose (143 versus 149 units; p ¼ 0.727), smoking status (10% versus 14%; p ¼ 1.000) and systolic blood pressure (133 versus 131 mmHg; p ¼ 0.746) in the two study groups. It appeared that GFR was not a significant predictor of BPT, however, this statement should be interpreted with caution due to low study power (14% instead of the usual of at least 80%). In all, 67% (n ¼ 31) of patients had a diagnosis of Hodgkin’s lymphoma (HL). Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) was the major intervention in our study (n ¼ 29; 63%). The front-line chemotherapy (ABVD) had a tendency of an increased risk of BPT compared

to other chemotherapy regimens (90% versus 56%; p ¼ 0.067; power ¼ 31%). In addition, the BPT group had a higher proportion of patients using GCSF than the non-BPT cohort (60% versus 53%; p ¼ 0.685; power ¼ 3%). When the data was analyzed for each year separately, it was noted that most of the cases were in 2008 and 2009, where approximately 37% of patients on bleomycin developed BPT. However, in 2007, no case of BPT was observed while there was only one case that was observed in 2010 (Table 2).

Discussion This retrospective study demonstrates for the first time the incidence of BPT in a tertiary hospital in Oman. A pulmonary toxicity rate of 22% (10/46) was identified in patients treated with bleomycin. In all, 20% (2/10) of patients with BPT [4.3% (2/46) of the total cohort] had fatal BPT. Martin et al. reported a relatively similar incidence of 18% (25/141) and mortality rate of 4.2% (6/141) in HL patients treated with bleomycin-containing regimens.6 Age seems to play a significant role in the development of BPT. In our study, the rate of BPT was increased by a factor of 4 in patients’ 40 years old compared with younger patients (41% versus 10%, respectively). Martin et al. reported a similar age effect presented as higher rate of pulmonary toxicity in patients 40 years old compared with younger patients (33% versus 11%, respectively).6 Age in association with BPT also had an impact on mortality, as the two patients who died in this study were >40 years

Table 1. Demographic and clinical characteristics. Characteristic

All (N ¼ 46)

BPT (n ¼ 10; 22%)

No BPT (n ¼ 36; 78%)

p Value

Age, mean SD, years Female gender, n (%) Bleo dose, mean SD, mg Smoking, n (%) SBP, mean SD, mmHg GFR, ml/min, n (%) >90 80–90 30–59 400 mg have been shown to put patients at higher risk for developing BPT.2 However, the maximum dose used in this study was 252 units with a mean dose of 148 units. This is significantly lower than the dose associated with higher rates of toxicity. As a result, no significant differences were found in this study between BPT and non-BPT patients in terms of cumulative bleomycin dose. Simpson et al. described 180 patients with germ cell tumours treated with bleomycin and they did not find a significant difference in the cumulative dose between patients who died from BPT and patients who did not.7 This was also in line with findings from the study by Martin et al. where bleomycin dose did not significantly increase the risk of BPT in patients with HL.6 BPT was reported even with low doses of bleomycin. Iacovino et al. described two cases of fatal BPT in patients who received 100 and 165 units of bleomycin.8 Bechard et al. reported a case of fatal BLT after 20 units of bleomycin.9 In our study, BPT developed after cumulative doses ranging between 90 and 216 units. During treatment with ABVD, pulmonary toxicity was seen anytime between the second and the sixth chemotherapy cycle (2–6 months) while one patient developed BPT after the third dose of the first cycle while being treated with BEP protocol. Real et al. suggested that a hypersensitivity response to bleomycin may be sometimes confused with BPT especially in patients who received low doses of bleomycin.10 However, there are no criteria to differentiate these conditions from each other where the radiologic and functional pulmonary changes will be similar.10 Considering patients’ renal function and BPT, although it has been suggested that high creatinine level is the most important risk factor for predicting BPT, this conclusion could not be proven in this study due to limited number of patients with GFR < 80 ml/min. Of the three patients with impaired renal function in our study, one patient who was 66 years old and had a calculated GFR of 44 ml/min had developed the pulmonary toxicity after a

ABVD-R

BEACOP

cumulative dose of 216 units. The other two patients aged 58 and 59 years with GFR levels of 35 and 18 ml/ min, respectively, received very small doses of bleomycin of 26 units and 10 units, respectively. (Treatment was stopped or continued abroad). Similarly, six patients had a history of smoking in our study, hence its association with BPT could not be elucidated. With regard to front line chemotherapy as a risk factor for BPT, it was shown that ABVD had a tendency of higher rate of pulmonary toxicity compared to MOPP/AVD in the treatment of HL. In this study, 22% of ABVD-patients developed BPT compared to 4% of MOPP/AVD-patients.6 Another cohort study of 60 HL patients treated with ABVD showed that 37% of patients had a declined pulmonary function, where bleomycin was discontinued in 23% of patients and 1% had fatal BPT.11 In our study, of the 29 patients who were treated with ABVD chemotherapy, 31% (9/29) developed BPT. Out of these, two had already completed their treatment protocol when BPT was diagnosed, 21% (6/29) had to discontinue bleomycin from further chemotherapy cycles and 3% (1/29) had fatal BPT. In comparison, only 6% (1/17) of patients on non-ABVD regimens developed BPT. However, due to small sample size, a significant


Ahmed and Al-Zakwani

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difference could not be observed between BPT and non-BPT patients treated with different chemotherapy protocols. Table 3 outlines all the chemotherapy protocols used in the current study. The concomitant administration of GCSF with bleomycin-containing chemotherapy was not found to increase risk of BPT in our study. This finding was also observed by Bastion and Coiffier in 278 patients treated with bleomycin GCSF and no pulmonary complications occurred in the study group.12 Moreover, in a two-group study, 29 patients received bleomycin + GCSF and 57 patients received only bleomycin. No difference in BPT between the two groups was observed (p ¼ 1.000).13 It has been observed by the treating oncologists that the incidence of BPT has increased in recent years compared to the past. We analyzed the data for four consecutive years from 2007 to 2010. It was found that the main cases of BPT had occurred in 2008 and 2009. No obvious reason was found for this finding as bleomycin brand has not been changed in the hospital over the 4-year study period, as well as the method of aseptic preparation and the laminar flow cabinet. Bearing in mind that the overall incidence of toxicity was comparable to previous studies,3,4,6–13 this finding may be coincidental. This study has some limitations including its type, being retrospective might lead to bias. In addition, its small sample size might affect detection of some clinically significant meaningful predictors for BPT. However, the study outcome might provide meaningful information in pooled meta-analysis.

Conclusion BPT contributed to significant co-morbidity and mortality. Knowledge about the incidence of this condition in our institution and the risk factors associated with it will allow physicians to be more vigilant including providing regular screening for BPT. As a value-added benefit, employing a specialized chemotherapy pharmacist to check the appropriateness of therapy as well as any dosage modification necessary, e.g. in renal impairment, is warranted. In fact, at the writing of this manuscript, the Hospital Administration had approved a grade for such a service. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Acknowledgement We thank the medicine information centre for their kind support. Also, a special thanks goes to Dr Ikram Burney, Senior Oncology Consultant at SQUH, and Ph. Mafiana Rose, Oncology Clinical Pharmacist, for their valuable advice.

References 1. Sleijfer S. Bleomycin-induced pneumonitis. Chest 2001; 120: 617–624. 2. Gillian TD, Bleomycin-induced lung injury. http:// www.uptodate.com/contents/bleomycin-induced-lunginjury?source¼search_result&selectedTitle¼1%7E150 (2010, accessed 9 July 2011). 3. Azambuja E, Fleck JF, Batista RG, et al. Bleomycin-lung toxicity: who are the patients with increased risk? Pulm Pharmacol Ther 2005; 18: 363–366. 4. O’Sullivan JM, Huddart RA, A. Norman AR, et al. Predicting the risk of bleomycin lung toxicity in patients with germ cell tumours. Ann Oncol 2003; 14: 91–96. 5. Ali A. Drug-induced pulmonary toxicity. http:// emedicine.medscape.com/article/1343451-overview (2011, accessed 9 July 2011). 6. Martin WG, Ristow KM, Habermann TM, et al. Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin’s Lymphoma. J Clin Oncol 2005; 23: 7614–7620. 7. Simpson AB, Paul J, Graham J, et al. Fatal bleomycin pulmonary toxicity in the west of Scotland 1991–1995: a review of patients with germ cell tumours. Br J Cancer 1998; 78: 1061–1066. 8. Iacovino JR, Leitner J, Abbas AK, et al. Fatal pulmonary reaction from low doses of bleomycin. JAMA 1976; 235: 1253–1255. 9. Bechard DE, Fairman RP, DeBlois, et al. Fatal pulmonary fibrosis from low-dose bleomycin therapy. South Med J 1987; 80: 646–649. 10. Real E, Roca MJ, Vinuales A, et al. Life threatening lung toxicity induced by low dose of bleomycin in a patient with Hodgkin’s disease. Haematologica 1999; 84: 667–668. 11. Hirsch A, Vander Els N, Straus DJ, et al. Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on pulmonary function and symptoms in early-stage Hodgkin’s disease. J Clin Oncol 1996; 14: 1297–1305. 12. Bastion Y and Coiffier B. Pulmonary toxicity of bleomycin: is G-CSF a risk factor? Lancet 1994; 344: 474. 13. Saxman SB, Nichols C and Einhorn LH. Pulmonary toxicity in patients with advanced-stage germ cell tumors receiving bleomycin with and without granulocyte colony stimulating factor. Chest 1997; 111: 657–660.
