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Review Article

The role of screening and monitoring for bleomycin pulmonary toxicity

J Oncol Pharm Practice 0(0) 1–5 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155215574294 opp.sagepub.com

Brittney M Shippee1, Jill S Bates2 and Kristy L Richards3,4

Abstract Bleomycin-induced pulmonary toxicity can have a significant impact on patient outcomes. However, no guidelines for ideal screening and monitoring are available. This paper reviews the literature to identify the best way to monitor and reduce patient risk for bleomycin pulmonary toxicity. We have created evidence-based guidelines to help healthcare professionals identify patient risk factors and provide appropriate assessment and monitoring for patients receiving bleomycin therapy.

Keywords Bleomycin, pulmonary toxicity, monitoring, risk factors

Background Bleomycin is a mainstay of treatment for a variety of highly curable diseases, such as Hodgkin lymphoma and testicular cancer. Hodgkin lymphoma and testicular cancer have a five-year overall survival rate of 85 and 95%, respectively.1 Unfortunately, bleomycin is associated with a dose-limiting pulmonary toxicity, which may occur in 2–42% of patients, with a mortality rate of 1–5%.2–4 Bleomycin exerts its cytotoxic effect by binding to DNA and producing single- and double-stranded DNA breaks through free radical formation in the presence of iron and oxygen.2,3 Bleomycin hydrolase, an endogenous human enzyme that deactivates bleomycin, is commonly found in the liver, spleen, intestines, and bone marrow. Variable concentrations of bleomycin hydrolase have also been found in human tumor tissue.5 Since bleomycin hydrolase is not found in the lungs and skin, toxicity is predominantly seen in these areas. In the lungs, free radicals and cytokines cause endothelial damage, stimulating a cascade of inflammatory markers, fibroblast activation, and collagen deposition. Interstitial pneumonitis, which can progress to pulmonary fibrosis, is the most common form of bleomycin pulmonary toxicity (BPT). Other manifestations include bronchiolitis obliterans organizing pneumonia and eosinophilic hypersensitivity.

BPT occurs gradually during treatment; however, development of BPT has been reported two years following treatment.6,7 Symptoms include a nonproductive cough and dyspnea on exertion (DOE). These can progress to dyspnea at rest, tachypnea, and cyanosis.2 It is important to be aware that patients with BPT can also be asymptomatic.8 Findings from a computerized tomography scan of the chest reveal bilateral consolidations combined with alveolar and interstitial infiltrates.2 Because many of these symptoms resemble other disease states, BPT is often a diagnosis of exclusion.2,7

Risk factors of BPT Risk factors for BPT include cumulative dose, reduced renal function, increased age, cigarette smoking, supplemental oxygen administration, scuba diving, use of 1

Department of Pharmacy, UAB Medicine, Birmingham, AL, USA Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, NC, USA 3 UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA 4 Division of Hematology/Oncology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 2

Corresponding author: Brittney M Shippee, Department of Pharmacy, UAB Medicine, JT 1728/ 619 19th Street South, Birmingham, AL 35249, USA. Email: [email protected]

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granulocyte colony stimulating factor (G-CSF), and mediastinal radiation.2,9–12 O’Sullivan et al. performed a retrospective study, aimed at defining features to predict BPT.10 Eight hundred and thirty-five patients with germ cell tumors were reviewed, with 57 (6.8%) being identified as having BPT. Patients who received cumulative bleomycin doses over 300 units were found to be at increased risk. Notably, there are reports of BPT occurring in patients who received cumulative doses less than 100 units.2 Additionally, patients with a GFR < 80 ml/min were at increased risk of BPT.10 Bleomycin undergoes renal elimination, with decreased renal function, the half-life can be delayed, resulting in increased bleomycin exposure. Patients  40 years of age were also at increased risk of BPT. While the exact mechanism is unknown, it is thought to be due to decreased radical scavenging and natural decline in renal function.2 Lower et al. investigated the link between cigarette smoking and BPT.11 Based upon radiographic changes in 32 patients, pulmonary fibrosis occurred in 55% of the 22 smokers and in 0 of the 10 lifetime nonsmokers. The identification of supplemental oxygen as a risk factor for BPT was identified following a prospective study.12 The study reported fatal postoperative respiratory distress in five patients who had previously received bleomycin. It described a second cohort of 12 patients who had an uneventful postoperative course. Comparing groups, the nonsurvivors received a higher mean fractional concentration of inspired oxygen (FIO2) (0.39 versus 0.24, p < 0.001) and less intraoperative crystalloids (3.87 ml/kg/h versus 5.96 ml/kg/h, p < 0.05). In a retrospective study including 77 patients with testicular cancer who underwent major surgery, the importance of preoperative pulmonary status, anesthesia time, FIO2, fluid balance, bleomycin dose, number of acute toxicity episodes, oxygen saturation problems, and pulmonary symptoms were examined.13 Postoperative oxygen saturation problems (prolonged intubation, pulmonary edema, dyspnea, tachypnea, or desaturation requiring diuresis) occurred in 19 patients. A multivariate analysis found the amount of blood transfused, preoperative forced vital capacity (FVC) and surgical time remained the most significant factors affecting postoperative morbidity and clinical outcome. The maintained average intraoperative FIO2 was 40% (median 36, range 21–60%) and was not found to be significant. Following the previous case reports, a theoretical risk of BPT induced by scuba diving was proposed.14 While no reports of scuba diving-induced BPT have been published, there are conflicting opinions regarding the safety of scuba diving following treatment.15 Some believe that scuba diving can be resumed 6–12 months following an uncomplicated 3–4 cycles of bleomycin,

etoposide, and cisplatin (BEP) and advise caution for those patients who develop clinical signs of pulmonary impairment during or following bleomycin. It is important to note that most recommendations regarding scuba diving are for patients with testicular cancer. van Hulst et al. created a practical algorithm to evaluate if patients treated with bleomycin were able to safely resume scuba diving.14 The algorithm consisted of a series of tests including, a physical exam, fitness test, chest X-ray (CXR), and pulmonary function tests (PFTs). Sixteen patients previously treated with bleomycin were evaluated using the algorithm. Eleven patients had testicular or germ cell cancer and five had Hodgkin lymphoma. Four patients (one testicular/germ cell and three Hodgkin lymphoma) were found unfit to scuba dive using the algorithm. All three of the Hodgkin lymphoma patients who were considered unfit had previously received radiation to the thorax.14 Since cytokines have a role in the development of BPT, it is hypothesized that the concurrent use of G-CSF, which elevates cytokine concentration, and bleomycin could increase the incidence of BPT.2 Several case reports have been published associating G-CSF use with the development of BPT.16 Results from a retrospective review of 141 patients with Hodgkin lymphoma found BPT occurring in 26% (19 of 74 patients) of patients receiving G-CSF compared to 9% (six of 67 patients) in patients who did not receive G-CSF.17 Comis et al. published one of the first studies to evaluate whether PFTs are a useful predictor of clinically apparent or subclinical BPT.8 The study included 11 male patients with germ cell tumors who received a three-drug regimen of vinblastine 0.2 mg/kg/day for two days, cisplatin 20 mg/m2/day for five days, and bleomycin 30 units weekly for 12 doses. PFTs, FVC, FEV1, and DLCO were performed at baseline and at one- to three-week intervals. Two patients received prior mediastinal radiation therapy and were analyzed separately. Bleomycin was discontinued if radiographic findings consistent with BPT developed, if the patient developed DOE during daily activities in the absence of anemia, or if fine crackling rales were found on routine weekly physical exam. In the group of nine patients who did not receive radiation therapy, an approximate 20% decrease in mean DLCO was found after a total of 60 units of bleomycin had been administered (p < 0.05). A linear decrease in DLCO was found with increasing doses of bleomycin. Interestingly, no significant changes in FVC values with increasing bleomycin dose were found. Upon completion of therapy, DLCO determinations at seven months post bleomycin were still significantly decreased from baseline values (p < 0.05).

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Two patients in this group developed BPT. Both developed abrupt decreases in both DLCO and FVC, which led to the discontinuation of bleomycin. The first patient had persistent disease after receiving three cycles of chemotherapy (total dose bleomycin 360 units) and was given an additional 30 units of bleomycin. At the time of bleomycin administration, the DLCO and FVC were 41 and 84% of their baseline values and the patient had no pulmonary symptoms or radiographic findings consistent with pulmonary toxicity. Within one month of administration, the patient died of respiratory failure. The second patient received the first 120 units of bleomycin at a reduced average dose of 13 units/week due to myelosuppression. During this time, a decrease in DLCO was initially seen, but returned to baseline after receiving a total of 150 units. When the bleomycin dose was increased to 30 units/week, a rapid decline in DLCO and FVC occurred at a rate of 10% of the initial value per week. One month after receiving the final bleomycin dose (total dose 270 units), the patient developed severe DOE, hypoxemia, and was found to have diffuse bilateral pulmonary infiltrates. The two patients who received prior radiation therapy were both found to have an abrupt decline in DLCO after receiving 90 and 30 units of bleomycin, respectively. The patient who received 90 units of bleomycin was found to have a persistently decreased DLCO at 60% of the predicted value throughout the 12-month observation period following therapy. The second patient received 30 units and within 10 days of administration, the DLCO decreased to 51% of the predicted value and diffuse bilateral pulmonary infiltrates developed within and outside of the radiation field. A prospective study conducted by Sleijfer et al. evaluated pulmonary function changes in 54 patients, with metastatic testicular cancer, who were randomized to receive BEP versus EP.18 The primary objective was to evaluate if changes in PFTs were a result of bleomycin specifically or other agents in the regimen. PFTs were performed at baseline and at three-week intervals. These included slow inspiratory vital capacity (VC), and the transfer factor of the lungs for carbon monoxide (DLCO), the diffusion capacity of the alveolo-capillary membrane (Dm), pulmonary capillary blood volume (Vc), and the transfer factor of the lungs for carbon monoxide per unit alveolar volume (KCO). BPT was defined as symptoms including dry cough, DOE, dyspnea at rest, tachypnea, fever, and cyanosis, and a CXR consisting of fine reticular bibasilar infiltrate, an alveolar interstitial bibasilar infiltrate, progressive lower lobe involvement, or lobar consolidation. If patients developed BPT, bleomycin was discontinued. Similar to the previous trial, changes in PFTs were not used to reduce or discontinue bleomycin dose.

During treatment a significant decline in DLCO was seen in both groups beginning at week 6 (p < 0.01). A significant difference in DLCO between groups was found only during week 12, when the decrease in the BEP group was most profound at approximately 20% (p < 0.01). The pulmonary capillary blood volume (Vc), a component of the DLCO, was not changed in the EP group, yet a significant decline of approximately 10% was seen in the BEP group starting at week 9 of therapy (p < 0.05). When assessing the change in VC between groups, no significant changes were seen in the EP group. The BEP group was found to have a significant increase in VC from the start of therapy to week 3 (p < 0.05). Following week 3, the VC started to decline, with an approximately 20% decline from baseline seen at week 12 in the BEP group (p < 0.01). No difference in Dm or KCO was seen between groups. Three patients in the BEP group developed BPT during the fourth cycle of therapy, so the final dose of bleomycin was omitted. When PFTs in these patients were compared to the rest of the BEP group, no significant differences were found. No patient in the EP group developed pulmonary symptoms. Martin et al. conducted a retrospective review of 141 patients with newly diagnosed Hodgkin lymphoma who received bleomycin-containing chemotherapy.17 Eighteen percent (n ¼ 25) of patients developed BPT. Patients in the BPT group had a significantly higher median age of 49 versus 29 years (p ¼ 0.0009). A higher proportion of patients in the BPT group received ABVD (88% versus 50%, p ¼ 0.002) as firstline therapy. Patients who developed BPT had a significantly lower five-year OS of 63% versus 90% when compared with the non-BPT group (p ¼ 0.001). Six patients died due to BPT, with the mortality from BPT in all patients being 4.2% (6 of 141). All deaths due to BPT were seen in patients over 40 years of age. When identifying patient-related risk factors within the cohort, a higher rate of BPT was seen in patients receiving G-CSF, compared to those who did not (26% versus 9%, p ¼ 0.006). The omission of bleomycin from therapy had no effect on five-year OS and PFS (p ¼ 0.396). The effect of PFTs on bleomycin dosing in metastatic germ cell tumors has also been evaluated in 30 patients enrolled in a phase II trial of accelerated BEP.19 Notable exclusion criteria included patients > 40 years of age and those who received previous radiation therapy. Patients with intermediate or poor prognosis received four cycles of accelerated BEP and bleomycin 30 units weekly for a maximum of 12 doses, while patients with good prognosis received three cycles and a maximum of nine bleomycin doses.19,20A clinical assessment, CXR, DLCO, and FVC were performed

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every two weeks. Bleomycin was omitted if there were unexplained changes on CXR consistent with bleomycin toxicity, unexplained clinical evidence (significant dyspnea, cough, or basal crepitations),  25% reduction in DLCO or FVC from baseline, or GFR < 35 ml/min. Eighty percent of the planned bleomycin doses were administered, while 20% of doses were omitted due to > 25% reduction in DLCO. All doses of bleomycin were held due to an asymptomatic decline in DLCO that lacked radiographic evidence. Although not statistically significant, patients with lung metastases were 2.5 times as likely to have a > 25% reduction in DLCO (50% versus 20%, p ¼ 0.15) and were four times as likely to receive < 2/3 of their planned doses (40% versus 10%, p ¼ 0.14). Survival data comparing outcomes between patients who had bleomycin doses omitted and those that received all doses were not addressed.

Discussion Bleomycin is a highly effective antineoplastic agent used for the treatment of Hodgkin lymphoma and testicular cancer; however, its dose-limiting pulmonary toxicity can have a significant impact on patient outcomes. The nonspecificity of BPT symptoms is problematic as patients are often misdiagnosed. A delay in diagnosis and treatment can have dire consequences, allowing BPT to progress to pulmonary fibrosis. A variety of patient risk factors for BPT have been identified, including cumulative bleomycin dose > 300 units, reduced renal function (CrCl < 80 ml/ min), age > 40 years, cigarette smoking, supplemental oxygen administration, scuba diving, G-CSF use, and mediastinal radiation.9–11 Cumulative dose, age, and reduced renal function are the most heavily identified risk factors in the literature.10 Supplemental oxygen use, scuba diving, and G-CSF continue to remain controversial risk factors for BPT. Due to the role of oxygen free radicals in the pathogenesis of BPT, the use of high FIO2 could be unsafe,2 but there is conflicting evidence associating risk for BPT with high perioperative FIO2.12,13 Due to this, some healthcare professionals do not believe that supplemental oxygen use is a BPT risk factor.15 However, larger studies are needed to justify removing restriction on high perioperative FIO2. The implication of scuba diving as a BPT risk factor is extrapolated from the supplemental oxygen data. In clinical practice, healthcare providers have allowed patients with testicular cancer to resume scuba diving 12 months following an uncomplicated course of bleomycin therapy.15 These patients should be closely monitored for pulmonary symptoms when scuba diving is resumed. If symptoms do occur, scuba diving should not be

reattempted.14 Data identifying G-CSF use as a BPT risk factor are continuing to become more compelling. When possible, G-CSF should be avoided in patients receiving bleomycin-containing regimens. The ideal method to monitor for BPT remains controversial,21 and pulmonary function testing can be physically demanding on patients. However, monitoring PFTs at baseline and every three weeks during bleomycin treatment is consistent throughout the literature,8,18,19 and Comis et al. found a dose-related fall in DLCO to be a predictive indicator in monitoring patients for BPT.8 The results of this study along with expert commentary were instrumental in implementing the widespread use of monitoring DLCO in patients receiving bleomycin and holding treatment if DLCO decreases 40–60% from baseline.2,8,22 Conversely, Houghton et al. found that 20% of bleomycin doses omitted in their study, due to a >25% reduction in DLCO, occurred in patients who lacked pulmonary symptoms or radiographic changes.19 Based on these findings, Houghton et al. suggested that using predefined thresholds for DLCO may be too aggressive and result in prematurely omitting bleomycin. Sleijfer et al. found that DLCO is not specific for BPT and can also reflect pulmonary affects from other antineoplastic agents such as etoposide and cisplatin.18 Vc and VC were shown to be more specific bleomycin-induced alterations of PFTs. Additional larger studies are needed to confirm the utility of using VC and VC compared to DLCO.

Summary Combining a thorough history and physical exam monitoring patients for signs and symptoms of BPT, identification of patient-risk factors, and PFT monitoring is the best way to monitor for and reduce patient risk of BPT. Prior to receiving each dose of bleomycin, patients should be clinically assessed for pulmonary signs and symptoms of BPT. If identified, bleomycin should be held until other possible underlying causes are ruled out. Caution should be taken when using bleomycin in the subset of patients with identified risk factors and the use of alternative regimens should be considered. Patients who are smokers should be counseled on the importance of smoking cessation and provided support. Additional studies are needed to define the impact of supplemental oxygen use and scuba diving on BPT risk. Until then, patients should be educated about the possible risk of supplemental oxygen use and BPT, particularly when seeking medical attention. Bleomycin alert bracelets are available; use of these can inform emergency providers of their bleomycin exposure and possibly prevent unnecessary oxygen exposure. Patients

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who had an uncomplicated course of bleomycin may resume scuba diving 12 months following completion of therapy. G-CSF use is becoming a well-defined BPT risk factor, while more supportive data continue to be published. Whenever possible, G-CSF should be excluded from bleomycin-containing regimens. PFTs at baseline and every three weeks during therapy should be performed. Bleomycin should be held in patients who have a linear decline in DLCO of 40–60% from baseline. While Vc and VC have been shown to be more specific for bleomycin-induced alterations in PFTs, larger studies are needed to confirm the utility of using these in place of DLCO. Following these evidence-based guidelines should continue to improve the risk assessment and mitigate the possibility of BPT development.

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Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of Interest

15. 16.

None declared. 17.

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The role of screening and monitoring for bleomycin pulmonary toxicity.

Bleomycin-induced pulmonary toxicity can have a significant impact on patient outcomes. However, no guidelines for ideal screening and monitoring are ...
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