Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours

J. M. O’Sullivan1,+, R. A. Huddart1, A. R. Norman2, J. Nicholls3, D. P. Dearnaley1 and A. Horwich1

1 Academic Unit of Radiotherapy and Clinical Oncology, 2 Department of Computing and Information, 3 Bob Champion Research Unit, The Institute of Cancer Research, Royal Marsden NHS Trust, Sutton, UK

Received 12 April 2002; revised 28 June 2002; accepted 17 July 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Bleomycin pulmonary toxicity (BPT) has been known since the early clinical trials of bleomycin in the 1960s. Postulated risk factors include cumulative bleomycin dose, reduced glomerular filtration rate (GFR), raised creatinine, older age and supplemental oxygen exposure.

Patients and methods:

From our prospectively collected testicular cancer research database, we reviewed 835 patients treated at the Royal Marsden NHS Trust (Sutton, UK) with bleomycin-containing regimens for germ-cell tumours between January 1982 and December 1999, to identify those with BPT.

Results:

Fifty-seven (6.8%) patients had BPT, ranging from X-ray/CT (computed tomography) changes to dyspnoea. There were eight deaths (1% of patients treated) directly attributed to BPT. The median time from the start of bleomycin administration to documented lung toxicity was 4.2 months (range 1.2–8.2). On multivariate analysis, the factors independently predicting for increased risk of BPT were GFR <80 ml/min [hazard ratio (HR) 3.3], age >40 years (HR 2.3), stage IV disease at presentation (HR 2.6) and cumulative dose of bleomycin >300 000 IU (HR 3.5).

Conclusions:

Patients with poor renal function are at high risk of BPT, especially if they are aged >40 years, have stage IV disease at presentation or receive >300 000 IU of bleomycin. In such cases alternative drug regimens or dose restriction should be considered.

Key words: bleomycin, germ-cell tumours, glomerular filtration rate, pulmonary toxicity


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Bleomycin is a polypeptide antibiotic antineoplastic agent, which has been used clinically since the early 1970s. The drug is poorly absorbed by mouth and is usually given intravenously where it is <1% bound to plasma proteins. Between 50% and 70% of the drug is excreted unchanged by the kidneys. The half-life is 2–5 h in patients with normal renal function, but this can increase to 30 h in patients with reduced glomerular filtration rates (GFRs) [1]. Bleomycin is an attractive addition to combination chemotherapy regimens because of its broad activity and low myelotoxicity. The drug has been used for many years in the treatment of germ-cell tumours (GCTs) [2]. Bleomycin pulmonary toxicity (BPT) has been known since the early clinical trials in the 1960s [3]. Pulmonary toxicity is predominantly fibrotic and would appear to be immune mediated by macrophages and lymphocytes secreting tumour necrosis factor [46]. Bleomycin may induce reactive oxygen radicals by forming a complex with Fe3+. This theory of toxicity is supported by evidence of iron chelators reducing the pulmonary toxicity of bleomycin in animal models [7]. Hypersensitivity to bleomycin has also been recognised, but this is less common and more treatable than fibrosis [8]. Bleomycin hypersensitivity is not dose dependent and usually occurs within hours of administration.

A number of risk factors for developing BPT have emerged from various clinical trials. However, few reports have had sufficient statistical power to detect significant trends. Most studies describe case reports or retrospective studies with small numbers of events. Risk factors described include cumulative dose, low GFR, older age, supplemental oxygen exposure, bolus drug delivery (as opposed to continuous infusion), extent of lung metastases and prior lung disease [2, 9, 10]. Of these, cumulative dose and reduced renal function are the most well established risk factors. At doses between 100 000 and 450 000 IU toxicity is sporadic, while at doses above this range the incidence rises steeply [9, 11]. Cigarette smoking has been suggested as a risk factor for BPT [1214]; however, patient numbers are small. Other suggested factors include dose rate, combination with other drugs e.g. cisplatin, and the use of growth factors [9, 15, 16].

Because 85% of metastatic GCTs are cured, and given that the majority of patients are young adults, the risk of treatment toxicity is a major determinant of the choice of treatment schedules [17]. Studies investigating omission of bleomycin from the treatment of GCTs have shown reduced efficacy, unless there is a compensatory increase in the dose or number of courses of platinum containing chemotherapy [1820]. In poor-prognosis patients treated with a BEP regimen (bleomycin, etoposide and cisplatin), it is possible for ifosfamide to replace bleomycin (VIP schedule), with a similar efficacy but a higher rate of haematological toxicity [21].

Important considerations for BPT are the lack of a predictive test of clinically significant lung toxicity, and that the efficacy of treatments for the condition is uncertain. It would appear that standard lung function tests are not of use in predicting clinically significant toxicity [22]. Also, it is unclear whether routine chest X-rays (CXR) predict for serious toxicity. Attempts have been made to quantify the extent of lung damage [23]; however, there is as yet no agreed scoring system.

We undertook this study to more clearly define features that might predict BPT in a large patient cohort with a known denominator.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study design
We examined the prospectively collected germ-cell cancer research database for all male GCT patients registered at the Royal Marsden NHS Trust (RMT) (Sutton, UK) between January 1982 and December 1999. All GCT patients treated without bleomycin were excluded from the analysis: only patients who received bleomycin at the RMT were included in this study.

Chemotherapy for GCTs has evolved over the study period. Cisplatin, vinblastine and bleomycin (PVB) was used initially and subsequently BEP has become the standard management [24]. Other regimens have also been used depending on prognostic information; histology; patient characteristics; and various Medical Research Council, European Organisation for Research and Treatment of Cancer (EORTC), and in-house clinical trials carried out during the period examined. Bleomycin, etoposide and carboplatin (CEB) [25] and (C)BOP–BEP (carboplatin, bleomycin, vincristine and cisplatin–BEP) [26] have been used in clinical trials for patients with low-risk and intermediate/high-risk tumours, respectively. The majority of protocols involved administration of three doses of 30 000 IU of bleomycin per cycle for 3–4 cycles (i.e. total dose = 270 000–360 000 IU). At the RMT, bleomycin is given as a bolus injection for most regimens (Table 1)


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Table 1. Chemotherapy regimens
 
Our primary end point was to identify cases of BPT entered on the database. As there are no agreed criteria to define BPT, we identified all cases of lung toxicity ranging from fibrosis changes, consistent with BPT, noted on CXR or thoracic computed tomography (CT) scan, to dyspnoea requiring treatment with steroids. We also documented cases where BPT was the primary cause of death, this being the only end point of definite clinical significance as any other BPT is potentially short-lived [27].

We performed uni- and multivariate analyses assessing the following factors: age at time of bleomycin administration (as both a continuous and categorised variable); stage of disease at presentation; histology; highest recorded serum creatinine before treatment; GFR prior to bleomycin (continuous and split above and below 80 ml/min); {alpha}-fetoprotein and ß-human chorionic gonadotrophin levels at presentation; cumulative bleomycin dose (as a continuous variable and split above and below 300 000 IU); history of major surgery following bleomycin; haemoglobin level before bleomycin; and chemotherapy schedule. Risk factors were categorised by identifying inflection points on hazard ratio (HR) distribution graphs and translating this information into clinically useful categories.

The GFR was measured by 51Cr-EDTA clearance studies. History of major surgery following bleomycin was used as a surrogate identifier of supplemental oxygen use, which had been previously cited as a risk factor [28]. However, in our unit, it has long been the practice to use low oxygen concentrations during operative procedures after bleomycin containing chemotherapy.

Unfortunately, data on smoking habits were available only for a small proportion of patients (10%) and we have therefore not analysed this factor.

Statistics
Factors predicting BPT and mortality were examined using HRs generated from univariate and multivariate stepwise logistic regression analysis, 95% confidence intervals (CIs) of the HRs were also calculated [29]. We considered P values <0.05 to be statistically significant. Predictive models were created using data from the logistic regression analysis. Actuarial survival and freedom from toxicity were calculated using the method of Kaplan and Meier [30].


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eight hundred and thirty-five patients (mean age 29 years; 95% CI 12.6–46.4; inter-quartile range 24–36) were identified as having received bleomycin-containing regimens for GCTs between January 1982 and December 1999 at the RMT. The median follow-up for these patients was 7.4 years (range 0.7–19). Patient characteristics are shown in Table 2. As expected in a group treated with bleomycin, the majority of patients had nonseminoma (85%), 14% had seminoma; the remaining 1% were unclassified, usually because treatment was commenced before a biopsy or orchidectomy was performed. Most patients were either stage II (35%) or stage IV (33%). There were 143 deaths in the cohort and actuarial survival at 10 years was 83%. Of the deaths, 92 (64%) were due to the tumour, 19 (13%) were due to treatment toxicity, five (3%) were post-operative deaths, 11 (8%) were due to second malignancies and 16 (12%) were due to unrelated causes. Fifty patients (6%) had major surgery as defined by thoracotomy or laparotomy following bleomycin.


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Table 2. Patient characteristics
 
Fifty-seven patients (6.8%) had BPT. Of these, 35 (61%) were diagnosed by identification of changes consistent with BPT on CXR and/or CT scan alone. When the possibility of BPT was raised on a radiology report, the films were subsequently reviewed at our radiology review/revision meeting. An entry on the database of ‘BPT’ was not made without confirmation at the the review meeting. Twenty-two patients (39%) had a diagnosis of BPT based on clinical findings. Of these patients, all but one had CXR findings consistent with BPT. All 22 patients with clinically significant BPT were treated with steroids. The median time from first bleomycin administration to lung toxicity was 4.2 months (range 1.2–8.2). Eight patients (1% of total cohort, 14% of BPT) died of BPT. Post mortems were carried out on six of these eight patients, confirming the diagnosis in all six cases. There was a median time of 3 months (range 1.4–3.7) from the first bleomycin administration to death (Table 2). The 5-year actuarial freedom from BPT rate was 93%.

In univariate analysis of BPT, GFR <80 ml/min before chemotherapy (HR 3.3; 95% CI 1.4–8.0), stage IV disease (HR 2.6; 95% CI 1.5–4.4), age >40 years (HR 2.3; 95% CI 1.2–4.1) and cumulative dose of bleomycin >300 000 IU (HR 3.5; 95% CI 2–6) were significantly associated with an increased risk of lung toxicity. On multivariate analysis all four factors retained statistical significance (Table 3). When analysed by univariate analysis as continuous variables, age and creatinine clearance at the first bleomycin dose were not statistically significantly associated with increased risk of BPT (P = 0.4 and 0.2, respectively). The cumulative dose of bleomycin when analysed as a continuous variable, however, did have a significant association with the risk of BPT (HR 1.005; 95% CI 1.003–1.007).


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Table 3. Statistical analysis of bleomycin pulmonary toxicity
 
Using data from the multivariate analysis we constructed a model for risk prediction (Figure 1). The risk of BPT with combinations of risk factors was calculated using the median probability of toxicity with each permutation of combinations. The range of probabilities for each category of risk factors was 5.3–11.4% (one risk factor), 11.5–32% (two risk factors) and 32.5–52% (three risk factors). The combinations predicting the highest probabilities of BPT were GFR <80 ml/min and bleomycin dose >300 000 IU in the two risk factors group, and GFR <80 ml/min, bleomycin dose >300 000 IU and age >40 years in the three risk factors group. The model illustrated in Figure 1 provides a useful guide to when dose restriction or omission of bleomycin should be considered. Using the chart to cross reference risk factors present before bleomycin treatment gives the approximate probability of a patient experiencing BPT.



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Figure 1. Probability (%) of bleomycin pulmonary toxicity according to combinations of risk factors. A, age >40 years at first bleomycin dose; B, stage IV disease at first bleomycin dose; C, glomerular filtration rate <80 ml/min at first bleomycin dose; D, cumulative bleomycin dose >300 000 IU.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study comprised an analysis of BPT in a large cohort of patients with GCTs. A pulmonary toxicity rate of 6.8% (57/835) was identified in patients treated with bleomycin. Fourteen per cent (8/57) of patients with BPT [1% (8/835) of the total cohort] had fatal BPT. The probability of BPT when none of the risk factors was present was 2.5%. A potential limitation of the study is the lack of an agreed definition of BPT. This paper describes risk factors present before treatment with bleomycin and does not address the issue of reassessment of patient suitability during a course of therapy. It is also likely that radiological evidence of BPT is under-reported.

Bleomycin is excreted renally, with 70% of the dose excreted within the first 24 h. It is therefore not surprising that altered renal function accounted for the largest HR. When excretion is compromised by low GFR, the drug half-life is increased, leading to longer exposure of the lungs [1]. Renal function in this group of patients can be compromised in a number of ways, principally by renal damage from cisplatin, or by obstruction secondary to an abdominal tumour. It is therefore important that renal function is closely monitored in patients receiving bleomycin, especially when cisplatin is being used or when there is ureteric obstruction. Increased risk of BPT when renal function is compromised has previously been identified by a number of studies [3133].

In our study, cumulative doses of bleomycin >300 000 IU predicted for an increased risk of BPT (HR 4.3; 95% CI 2.2–8.2). The probability of BPT with a bleomycin dose >300 000 IU as the only risk factor was 8.5%. As often as possible the cumulative bleomycin dose was kept to a maximum of 270 000 IU. However, many of the protocols used over the time period of this study involved cumulative doses of up to 360 000 IU, especially in cases where bleomycin was used for salvage or in poor-prognosis disease. High cumulative doses of bleomycin have been shown to put patients at higher risk of pulmonary toxicity. Doses >550 000 IU have been associated with a BPT incidence of 17%, while the incidence was seen to drop to 5% when the dose was <450 000 IU. Fatal BPT occurred in 10% of those receiving >550 000 IU of bleomycin [3].

We showed that age >40 years increased the risk of BPT (HR 2.2; 95% CI 1.1–4.4). This is consistent with findings from other studies that show increasing risk of lung toxicity with increasing age [3, 27]. This may be due to reduced GFR or decreased ability to repair pulmonary tissue damage, with increasing age. In the GCT population, most patients are young adults. The oldest patient to receive bleomycin in our study was aged 64 years; the median age at chemotherapy was 29 years. It is therefore important to consider the possible effects of aging on a patient’s ability to tolerate bleomycin.

Stage IV disease may be associated with increased risk of BPT for a number of reasons. Total drug dose and treatment intensity may be increased, and there may be decreased renal function secondary to para-aortic metastases compressing the ureters. There may also be a higher risk of toxicity in patients with diffuse lung metastases.

More than 60% of patients with fatal BPT received intensive induction chemotherapy with (C)BOP–BEP. This schedule has been previously described by ourselves [34, 35]. When first used by our group, cumulative bleomycin doses of 450 000 IU were used, resulting in BPT in 16 (38%) patients treated and fatality in two cases. The standard dose was therefore changed to 345 000 IU resulting in a lower rate of BPT. In this study, the use of (C)BOP–BEP approached statistical significance for prediction of fatal BPT (HR 5.3; 95% CI 1.0–27.6). In the period analysed for this study, we identified 198 patients treated with (C)BOP–BEP, of whom 36 (18%) received the higher bleomycin dose schedule (450 000 IU) and 162 (82%) received 345 000 IU. There were 8/36 (22%) cases of BPT in the high-dose cohort, three of which were fatal; and 11/162 (7%) cases in the lower-dose group, of which two were fatal.

A history of major surgery after bleomycin was not predictive of increased risk of BPT. This may be because major surgery is a poor surrogate for supplemental oxygen exposure, or because the effect is not great. Clearly, a history of previous bleomycin exposure is a major consideration when a patient is being considered for general anaesthesia, particularly with regard to the concentrations of oxygen used [36]. Pretreatment haemoglobin levels were also not associated with altered risk of BPT.

Asymptomatic bleomycin toxicity identified radiologically may not be of major clinical importance. The changes on CXRs can be minimal and potentially reversible. Most centres would not actively treat asymptomatic lung changes. It is therefore difficult to alter practice on the basis of rates of asymptomatic lung toxicity. However, a crude mortality rate of 1% is clinically significant, and patients should have this risk explained, especially if renal function is compromised.


    Acknowledgements
 
This work was undertaken in the Royal Marsden NHS Trust, which received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. This work was supported by the Institute of Cancer Research, the Bob Champion Cancer Trust and Cancer Research UK.


    Footnotes
 
+ Correspondence to: Dr J. M. O’Sullivan, Unit of Academic Radiotherapy and Clinical Oncology, Institute of Cancer Research, Royal Marsden NHS Trust, Sutton, Surrey SM2 5PT, UK. Tel: +44-20-8642-6011; Fax: +44-20-8661-3142; E-mail: drjoeosullivan{at}ireland.com Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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