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ARTICLE IN PRESSNCH-1694; No. of Pages 11

Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx

Revisiting bleomycin from pathophysiology to safe clinical use

Marios Froudarakis a,1, Eleftheria Hatzimichael b,c,d,∗,1, Lydia Kyriazopoulou b,Konstantinos Lagos b, Periklis Pappas e, Andreas Tzakos f, Vasilis Karavasilis g,

Danai Daliani h, Christos Papandreou h, Evangelos Briasoulis b,c

a Department of Pulmonology, Democritus University of Thrace, Greeceb Department of Haematology, University Hospital of Ioannina, Greece

c Cancer Biobank Center, University of Ioannina, Greeced Computational Medicine Center, Jefferson Medical College, Thomas Jefferson University, USA

e Department of Pharmacology, University of Ioannina, Greecef Department of Chemistry, University of Ioannina, Greece

g Medical School Aristotle University of Thessaloniki, Greeceh Department of Medical Oncology, University of Thessaly, Greece

Accepted 12 December 2012

ontents

. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.1. Molecular pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.2. Clinical pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Pathophysiology of bleomycin-induced lung injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Incidence and risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Treatment of bleomycin lung injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Guidelines of safe clinical use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007.1. Hodgkin Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007.2. Testicular germ cell tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

bstract

Bleomycin is a key component of curative chemotherapy regimens employed in the treatment of curable cancers, such as Hodgkin lym-homa (HL) and testicular germ-cell tumours (GCT), yet its use may cause bleomycin-induced lung injury (BILI), which is associated withignificant morbidity and a mortality rate of 1–3%. Diagnosis of BILI is one of exclusion and physicians involved in the care of HL and GCT

te towards the identification of molecular predictors of bleomycin toxicity

atients should be alerted. Pharmacogenomic studies could contribu

Please cite this article in press as: Froudarakis M, et al. Revisiting bleomycin from pathophysiology to safe clinical use. Crit RevOncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2012.12.003

∗ Corresponding author at: Academic Department of Haematology, University Hospital of Ioannina, St. Niarchou Av, 45110 Ioannina, Greece.el.: +30 2651099615; fax: +30 2651099615.

E-mail addresses: ehatzim@cc.uoi.gr, eleftheria.chatzimichail@jefferson.edu (E. Hatzimichael).1 These authors contributed equally.

040-8428/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.critrevonc.2012.12.003

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ARTICLE IN PRESSNCH-1694; No. of Pages 11

M. Froudarakis et al. / Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx

n the aim to optimize individual use of bleomycin. We review all existing data on bleomycin’s most recent integrated chemical biology,olecular pharmacology and mature clinical data and provide guidelines for its safe clinical use.

2012 Elsevier Ireland Ltd. All rights reserved.

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eywords: Bleomycin; Hodgkin’s Lymphoma; Testicular germ-cell tumour

. Introduction

Bleomycin is a key component of chemotherapy com-only employed in the treatment of Hodgkin lymphoma (HL)

nd testicular germ-cell tumours (GCT), the most highly cur-ble cancers [1,2]. Nevertheless, bleomycin can cause severeife-threatening lung injury, which ranges from hypersen-itivity pneumonitis and bronchiolitis obliterans organizingneumonia (BOOP) to acute interstitial pneumonia and pro-ressive pulmonary fibrosis [3]. Pulmonary toxicity is anown side effect of cancer chemotherapy [4], but a 1–4%eath rate of bleomycin is judged unacceptable for patientsith curable cancers [5,6]. Toxic effects of bleomycin areenerally attributed to formation of free radicals [7] and organpecificity is driven by the bleomycin catalysing hydrolase,hich is absent in lung and skin tissue, rendering these organsulnerable to toxicity [8].

. Pharmacology

.1. Molecular pharmacology

Bleomycin sulphates are water-soluble glycopeptide prod-cts of the actinobacterium Streptomyces verticillus [9]. Drugormulations consist of a mixture of bleomycin analogues thatiffer in their cationic C-terminal amine. The chemical for-ulas used are primarily bleomycin A2 and B2 as illustrated

n Fig. 1A. The crystal structures of bleomycin B2 and A2eveal important interactions with DNA and cellular proteinsFig. 1B).

Cytotoxic activity of bleomycin is through oxidation ofeoxyribose of thymidylate and other nucleotides, whichroduce single-strand and double-strand breaks in DNA,hromosomal aberrations, gaps, fragments and transloca-ions [10]. Bleomycin is deactivated by bleomycin hydrolaseBLMH), which is found predominantly in the liver, spleen,one marrow, and intestine, but is poorly expressed in skinnd lung, which relates to cutaneous effects and lung injury11].

Resistance of tumours to bleomycin has been linked toigh levels of hydrolase activity [12], but increased proteininding, decreased cellular uptake, drug inactivation by thiolsnd adaptation to oxidative stress and enhanced capacity toNA repair may also participate [13].

Please cite this article in press as: Froudarakis M, et al. Revisiting bOncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2012.12.0

.2. Clinical pharmacology

Oral bioavailability of bleomycin is poor. On intravenousdministration it has a terminal half-life of approximately

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injury; Therapeutics; Safe clinical use; Toxicity

0 min, which increases exponentially as the creatininelearance decreases [14]. In patients with a normal renalunction approximately 65% of an administered dose isxcreted in the urine as active bleomycin within therst 24 h [8], while renal dysfunction leads to signifi-antly increased drug exposure [14]. Bleomycin poorlyrosses the blood–brain barrier, however it does cross thelacenta [15].

. Pathophysiology of bleomycin-induced lung injury

Cytokines and free radicals are key effectors of BILInd are related to low levels of BLMH in lung, particu-arly in type II pneumocytes [3,16]. This feature rendersung cells vulnerable to toxic effects of bleomycin at mito-is [17]. On molecular level, bleomycin binds to DNA usingron ions as cofactor, and in the presence of oxygen gener-tes hydroxyl radicals, which causes DNA breaks and leadso cell apoptosis of both epithelial and endothelial cells inung [18].

Acute inflammation is central to development of BILI.nflammatory exudate consists mainly of mononuclearacrophages, lymphocytes and neutrophils [19] (Fig. 2).leomycin stimulates alveolar macrophages to secrete

nflammatory cytokines such as tumour necrosis factorTNF), interleukin (IL)-1, IL-18 [20], IL-22 and IL-17a [21]nd endothelial cells to secrete IL-6 [22,23]. Cytokines acti-ate lymphocytes and upregulate the expression of adhesionolecules on endothelial cells facilitating inflammatory cells

o adhere to the endothelium, influx into the interstitium andamage endothelial cells through the Fas–FasL pathway [24].ibroblasts are activated early in BILI through stimulationf fibronectin, which is produced by damaged endothelialells or stimulation by cytokines, such as TNF, plateleterived growth factor (PDGF) and transforming growth fac-or � (TGF�) [25]. Continued exposure of lung to bleomycinan lead to increasing collagen synthesis and depositionf various matrix proteins including collagens, elastin, androteoglycans [26]. Moreover, bleomycin-activated alveo-ar macrophages stimulate the synthesis of hyaluronan, aonnective tissue molecule that is seen in fibrotic lungs17]. T lymphocytes are also involved in the inflamma-

leomycin from pathophysiology to safe clinical use. Crit Rev03

uring Th1 inflammation (e.g., IFN-�) or Th2 inflamma-ion (e.g., IL-13) that modulate the expression of growthactor activity through the STAT family of transcriptionactors [27].

Please cite this article in press as: Froudarakis M, et al. Revisiting bleomycin from pathophysiology to safe clinical use. Crit RevOncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2012.12.003

ARTICLE IN PRESSONCH-1694; No. of Pages 11

M. Froudarakis et al. / Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx 3

Fig. 1. (A) Chemical structures of bleomycin A2 and bleomycin B2. (B) Structure of bleomycin A2 and bleomycin B2 in associated protein/DNA complexes. (A)Crystal structure of DNA-bound Co(III)·bleomycin B2 (pdbid: 2R2S [87]). The N-terminal fragment of Moloney murine leukaemia virus reverse transcriptaseand a 7.5-bp oligonucleotide duplex are shown as ribbon, bleomycin B2 is shown as balls and sticks. (B) Bleomycin B2 from (A) is shown as sticks. (C)Structure of the copper (II)-bound bleomycin A2 complexed with the bleomycin-binding protein from bleomycin-producing Streptomyces verticillus (pdbid:1JIF)[88]. The bleomycin-binding protein is shown as ribbons and bleomycin A2 as balls and sticks. (D) Bleomycin A2 from (C) is shown as sticks.

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4 M. Froudarakis et al. / Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx

Fig. 2. Schematic illustration of BILI pathophysiology. Existing data implicate free radicals, DNA breaks, pneumocyte and endothelial cell damage, cytokineproduction, activation of inflammation and fibroblasts, fibrous exudation into the alveoli, fibrin formation and interstitial fibrosis in pathophysiology bleomycin-induced lung injury. Symbols and abbreviations: green granules: surfactant; light blue cytoplasm: lack of bleomycin hydrolase; brown lines: fibrin; red lines endingi -I, typeP

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. Incidence and risk factors

Pulmonary toxicity is reported to occur in up to 46%f patients treated with bleomycin-containing chemotherapyith a mortality rate approaching 1–3% [28–31].A number of risk factors have been identified in several

linical studies. Those are cumulative dose, old age, reducedenal function, supplemental oxygen exposure, cigarettemoking and route of drug delivery (intravenous or intra-uscular administration) [3]. Cumulative dose and reduced

enal function are the best recognized. Additional risk fac-ors include administration rate (bolus versus continuousnfusion), combination with nephrotoxic drugs, e.g., cis-latin, and the use of growth factors [5]. More recently,harmacogenetic studies have associated single nucleotideolymorphisms in the bleomycin hydrolase gene with drugctivity and toxicity [32,33].

A linear association between total dose and severityf BILI has early been found in animals and in humans31,34]. The incidence of BILI increases from 3% in patientseceiving a cumulative dose of <300 IU of bleomycin, to0% in patients treated with a cumulative dose of >500 IU5,35]. However large inter-patient variability has been noted

Please cite this article in press as: Froudarakis M, et al. Revisiting bOncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2012.12.0

3]. Fatal BILI has been described in patients treated with100 IU of bleomycin, while others receiving >500 IU didot develop any pulmonary toxicity [36,37]. In another study

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I pneumocyte; PuC-II, type II pneumocyte; N/M, neutrophil/macrophage;

o difference in the cumulative dose of bleomycin was foundetween patients who died of BILI and those who did not38]. Generally, cumulative doses above 400 IU are associ-ted with increased risk for BILI, although significant lungnjury can occur with lower doses [3,37,39,40].

Patients’ age is also an established risk factor for theevelopment of BILI. Patients older than 70 years have anncreased susceptibility to develop BILI [41,42]. A Scottishtudy found that the occurrence of fatal BILI increased withach decade after the age of 30 years [38] and in a study of41 patients with HL, BILI was present in 33% of patientslder than 40 years and in 11% of patients below 40 years ofge [6].

Declining of renal function leads to increased exposureo bleomycin [14,15]. A number of clinical studies havevidenced that increased bleomycin lung toxicity is clearlyssociated with decline in renal function to the point that renalysfunction is a strong predictor of bleomycin lung damage5,43,44].

Tobacco smoking, oxygen supplementation during anaes-hesia and the use of granulocyte colony stimulating factorG-CSF) are less defined risk factors. Smoking history haseen suggested as a possible risk factor for developing BILI

leomycin from pathophysiology to safe clinical use. Crit Rev03

45,46]. Administration of high oxygen concentrations inatients undergoing surgery after exposure to bleomycin haseen inculpated for potentiating BILI [47], which is also

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in Oncology/Hematology xxx (2013) xxx–xxx 5

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Fig. 3. High resolution CT of a young female patient with Hodgkin Lym-phoma who developed BILI post 5 cycles of ABVD. (A) High-resolution CTscan image through lung bases that shows extensive ground-glass opacity(arrow) involving both lower lobes, with coarse and fine interlobular intersti-tial thickening (arrowheads). Irregular linear bands of fibrosis (thick arrow)and traction bronchiectasis (open arrowhead) are also seen. The patient haddeveloped progressive dyspnoea, a low grade fever and had diffuse finerales on auscultation. (B) Resolution of pulmonary infiltrates and symptomsf

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M. Froudarakis et al. / Critical Reviews

upported by animal studies [48], but this has been questionedy other investigators [38,49].

Regarding co-treatments, brentuximab vedotinAdcetrisTM), a CD30 directed antibody–drug conju-ate which recently gained FDA approval for treatmentf patients with refractory HL, was found to increaseulmonary toxicity of bleomycin [50]. The contributionf G-CSF and chest irradiation in promoting bleomycinssociated lung injury is debated [51–55].

In the field of pharmacogenomics, De Haas et al. found thathe homozygous variant G/G of BLMH gene SNP rs1050565c.1327A>G) is associated with reduced survival and higherrevalence of early relapses in GCT patients treated withleomycin-containing chemotherapy but failed to find differ-nces in the development of bleomycin-induced pulmonaryoxicity based on the BLMH genotype [33].

. Diagnosis

Diagnosis of BILI is one of exclusion, due to lack of spe-ific symptoms, findings and tests (Table 1). BILI is suspectedn the presence of a constellation of signs and/or symptoms,maging features and lung function tests in patients treatedith intravenous bleomycin [3]. The earliest symptom is dys-noea and the earliest sign is fine rales. Pleural effusion orneumothorax findings may also exist [3,56–59]. The moref lung parenchyma is involved the higher the impact isn symptoms and respiratory function with acute respira-ory failure and acute respiratory distress syndrome (ARDS)eveloping in severe cases [3,56].

Pulmonary function tests are altered at the early stages,ith diffusion lung capacity of carbon monoxide (DLCO)eing the most sensitive indicator [60]. Although the declinef DLCO lacks specificity for bleomycin and/or associa-ion with symptoms, a decrease of DLCO of >40% of there-treatment value is commonly accepted as a warningign urging interruption of bleomycin administration [60].

decrease of lung volumes, such as total lung capacity and

Please cite this article in press as: Froudarakis M, et al. Revisiting bOncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2012.12.0

decrease of vital capacity (VC) and forced expiratory vol-me at 1 s (FEV1), define a typical restrictive syndrome in

able 1atient’s symptoms and signs with bleomycin lung toxicity.

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atients with BILI and is associated with respiratory alkalosisnd decrease of pO2 and pCO2 [52,61].

Chest radiography may show bilateral consolidation withombined alveolar and interstitial infiltrates. Patchy infil-rates may also be present unilaterally. A pleural reaction isometimes present [3,56]. High-resolution chest tomographyHRCT; Fig. 3) is the gold standard test to evaluate both alve-lar and interstitial findings [62]. Fiberoptic bronchoscopyith broncho-alveolar lavage (BAL) does not offer diagnostic

dvantages, but it can rule out other causes [63].

. Treatment of bleomycin lung injury

Steroids (prednisone 1 mg/kg/day) are the treatment ofhoice after exclusion of infectious causes [3]. BOOP or

leomycin from pathophysiology to safe clinical use. Crit Rev03

ypersensitivity pneumonitis respond well to steroid therapy,hich is not the case for interstitial pneumonia. However,

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n some cases, even after initial efficacy of steroid therapy,atients may relapse after tapering [57].

Targeted drugs developed on other indications emergeow as novel therapies for the treatment of BILI. Thehronic myeloid leukaemia drugs imatinib and nilotinib,ith activity against BCR-ABL, seem to offer therapeu-

ic potentials against BILI because of their inhibitoryctivity against the PDGF receptor. These drugs testedn mouse models were found to attenuate the extent ofung injury and fibrosis and to diminish inflammatory cellsnd levels of IL-6, IL-1beta, TNF-alpha, TGF-beta1 andDGFR-beta, with nilotinib being more potent [64–66].

clinical case report showed also impressive resolutionf life-threatening bleomycin-induced pneumonitis withmatinib [67].

. Guidelines of safe clinical use

.1. Hodgkin Lymphoma

Both gold standard chemotherapy regimens for HL,BVD and BEACOPP incorporate bleomycin in combi-ations [68]. Therefore sensible use of bleomycin is ofppermost importance to provide most efficient and less toxicherapy per patient [69].

Taking into consideration known risk factors and accumu-ated clinical evidence it is suggested that:

atients receiving bleomycin should be questioned for dys-nea, and have careful physical examination of thorax andhest radiography at each cycle. Reported dyspnea com-ined with fine rales is an alert for BILI. Wherever available

monthly monitoring of DLCO is advised on the intent toiscontinue bleomycin if DLCO drops below 35% of pretreat-ent value [70].

All patients should have renal function assessment beforehe initiation of bleomycin and before each consecutive cyclef chemotherapy. Bleomycin dose should be adjusted to0–40% of normal dose in cases creatinine clearance dropselow 50 mL/min [71].

Regarding co-treatments, bleomycin must not be givenn combination with brentuximab vedotin [50]. G-CSFhould be used with caution and only after an episode ofebrile neutropenia, or in order to avoid treatment delays.adiotherapy should be withheld for a minimum of foureeks post bleomycin administration to avoid pulmono-

oxic synergy. Finally for HL patients on surgery whoad recently been given bleomycin, careful fluid balancend avoidance of high O2 concentrations inhalation isecommended.

Please cite this article in press as: Froudarakis M, et al. Revisiting bOncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2012.12.0

.2. Testicular germ cell tumours

GCTs represent the most common solid cancers in youngen with an increasing incidence [72]. Therapy optimization

cr

ology/Hematology xxx (2013) xxx–xxx

or metastatic GCTs by means of more efficient platinum regi-ens, patient risk categorization and reduced toxicity and

uration of therapy, when appropriate, has lead to approxi-ately 90% cure rate [73,74].Although the use of bleomycin is not questioned in

atients with intermediate or poor prognosis metastaticCTs, it has been the field of controlled randomized stud-

es in patients with good-risk GCTs, mainly due to concernsf pulmonary toxicity [38,75–79]. Several clinical researchroups have worked on this issue but differences in the crite-ia for pulmonary toxicity, for discontinuation of bleomycinand cisplatin) therapy and the reporting requirements makeomparisons difficult. Rates of reported pulmonary toxicityary from 5% to more than 50%, and mortality rates of 0–4%38,78–80].

In the US, the Memorial Sloan-Kettering Cancer CenterMSKCC) Group suggests that four cycles of etoposide andisplatin (4EP) are equivalent to three cycles of bleomycin,toposide and cisplatin (3BEP) and should be considereds another standard regimen for the treatment of good-risketastatic GCT [81]. Similarly the Indiana Group suggests

BEP for good-risk patients and retains 4EP for patients olderhan 50, heavy smokers, or those with serum creatinine higherhan 2 mg/dl [82].

In Europe, an EORTC group study compared EP to BEPor good-prognosis GCT patients showed that 3BEP is suf-cient for good-prognosis GCTs. Moreover, acute BILI wasore frequent in patients treated with 4 versus 3 cycles

f therapy (20% versus 14%) [83]. In another study theenito-Urinary Group of the French Federation of Cancerenters (GETUG) suggests that 3BE500P is the treatmentf choice for patients with good-risk metastatic nonsemino-atous GCT and 4E500P should only be used if there is a

ontraindication for bleomycin [77]. Again, the Australiannd New Zealand Germ Cell Trials Group found that threeycles of dose-intense BEP (30 kU bleomycin on days 1, 8,nd 15; 100 mg/m2 etoposide on days 1–5; and 20 mg/m2

isplatin on days 1–5, repeated every 21 days; 3B90E500P)utperforms four cycles of standard BEP (4B30E360P) byerms of survival and toxicity despite higher total bleomycinose [84].

Finally, the M.D. Anderson Cancer Center (MDACC)roup suggests that bleomycin should i. be suspended uponuspicious symptoms and/or signs or when there is a greaterhan 10% decline in FVC or more than 20% decline in

LCO and ii. be held at first cycle in patients with high vol-me lung metastases plus dyspnoea at presentation and/orO2 < 80 mmHg or both to decrease ARDS rate at treatmenttart [85,86].

. Conclusions

leomycin from pathophysiology to safe clinical use. Crit Rev03

Bleomycin-containing regimens remain the standard ofare for HL and for patients with intermediate and poor-isk GCTs. Those patients need close medical monitoring

ARTICLE IN PRESSONCH-1694; No. of Pages 11

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M. Froudarakis et al. / Critical Reviews

or early diagnosis of lung toxicity to prevent morbiditynd mortality. Although no category 1 recommendationsxist, the following are generally accepted guidelines in thisetting:

consider all risk factors for BILI when treating patientswith HL or GCT;maintain dose-intensity/density in parallel with efforts tominimize potentially lethal BILI;

carefully assess for symptoms or signs suggestive of pul-monary toxicity, perform DLCO/FVC tests;discontinue bleomycin in case of clinical or radiographicsigns of pulmonary toxicity and/or if significant declinesin DLCO;

restrict the total bleomycin dose to less than 400 IU; consider omitting bleomycin at first cycle in the rare case of

high volume choriocarcinoma, extensive lung metastases,hemoptysis or hypoxemia;

limit as much as possible the inhaled oxygen concentration(<30%);

cease smoking (lifelong); monitor the fluid balances to minimize the risk for clini-

cally significant lung toxicity; consider substituting 4EP for 3BEP in good-risk metastatic

GCTs for patients with higher risk for bleomycin toxic-ity (i.e., smokers, advanced age, renal insufficiency notamenable to correction before initiation of treatment, priorradiation therapy);

efforts are currently undertaken to develop phar-macogenomic predictors of bleomycin toxicity bystudying variants of the gene that encodes bleomycinhydrolase.

onflict of interest statement

The authors have no conflict of interest.

cknowledgements

Eleftheria Hatzimichael is funded as a scholar by the Hel-enic Society of Haematology Foundation (January 2012 toanuary 2013).

The authors would like to thank Dr. S.J. Theodorou forroviding the images of the High Resolution Computedomography.

ReviewersGeorge Patrinos, PhD, Assistant Professor of Pharma-

Please cite this article in press as: Froudarakis M, et al. Revisiting bOncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2012.12.0

ogenomics, Pharmacy School, University of Patras, Greece.Pierre Fournel, MD, Department of Medical Oncology,

nstitut de Cancérologie de la Loire, Saint-Priest en Jarez,rance.

[

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eferences

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iographies

Marios Froudarakis, MD, PhD, is Associate Professorf Pulmonary Medicine at the Democritus University ofhrace Medical School, Greece. He has done his graduate andost-graduate medical studies in Saint-Etienne France. He isurrently the Vice-Director of the Department of Pulmonaryedicine and Head of the Interventional Pulmonology Unit.e is an Expert in Interventional Pulmonology, giving a greatumber of lectures worldwide and receiving every year inhe average five fellows from different countries for train-ng and research. He is member of the European Respiratoryociety, the American College of Chest Physicians and theuropean Association of Bronchology and Interventionalulmonology. He organizes every year the European Respi-atory Society Course on Medical Thoracoscopy. He has apecific interest for lung cancer and pleural disease. He hasver 70 publications in indexed medical journals that haveeceived over 800 citations.

Eleftheria Hatzimichael, MD, PhD, is a Haematologist

leomycin from pathophysiology to safe clinical use. Crit Rev03

nd the Clinical and Translational Research Leader of theepartment of Haematology, University Hospital of Ioan-ina. She graduated from the School of Medicine, Universityf Ioannina in 1998 and was trained in Haematology at

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t. Bartholomew’s Hospital, Barts and the London Trust,ondon, UK and the University Hospital of Ioannina,reece. She is currently a Visiting Scientist at the Computa-

ional Medicine Centre, Thomas Jefferson University havingeceived a one-year fellowship from the Hellenic Society ofaematology Foundation in order to work in the field of non-

oding human genome. She is co-investigator in more than0 phase II–III clinical trials, has served as a reviewer in 8ournals and is in the Editorial Board of 1 international scien-ific journal. She has over 55 papers in peer-reviewed journalshat have received 380 citations. Full list of publications atttp://publicationslist.org/eleftheria.hatzimichael.

Lydia Kyriazopoulou, MD, is a graduate of the Medicalchool of Aristotle University of Thessaloniki (1998) and is

Specialist Haematologist since 2008, trained at “AHEPA”ospital of Thessaloniki. She has previously worked at thelood Bank of the General Hospital of Katerini for one yearnd has research experience from a six-month stay in theepartment of Hematology, Hammersmith Hospital, Impe-

ial College London, London, UK with a scholarship of theellenic Society of Hematology Foundation. Since 2009 she

s a consultant Haematologist in the Department of Haema-ology, University Hospital of Ioannina.

Konstantinos G. Lagos, MD, graduated from the Schoolf Medicine, University of Ioannina, Greece, and was

Research Fellow of the Outpatient Clinic of Lipidsetabolism and Hypertension of the University Hospital of

oannina from 2005 to 2009. Currently he is Haematologyrainee in the Department of Hematology in the Univer-ity Hospital of Ioannina, Greece. His research interestsnclude clinical trials in haematological malignancies, lipidsetabolism and metabolic syndrome.

Periklis Pappas, PhD, is Assistant Professor at theepartment of Pharmacology at the Medical School of theniversity of Ioannina since 2007, after a Lecturing periodf 6 years. In 2006 he worked for a sabbatical year at the Uni-ersity of Eastern Finland on the pharmacodynamic role ofuclear receptors on the regulation of ALDH1A7. Dr. Pap-as participated in more than 10 funded research projectsnd he was the PI for 3 grants. He has published 34 papersn PubMed (H-factor: 10). His expertise include: (i) Molec-lar Pharmacology and Toxicology: xenobiotic metabolism,harmacodynamics of angiogenesis, AhR polymorphism, (ii)europharmacology: chemical carcinogens and CNS, drugs

nd CNS (behaviour, disulfiram, antihistamines, NSAIDs)sing HPLC analysis of biogenic amines in various parts ofhe brain, (iii) Pharmacokinetics: medicinal products, clinicalrials of phase I and II, and (iv) Evaluation of in vitro drugytotoxicity using primary cell cultures and cell lines.

Andreas Tzakos, PhD, studied Chemistry at the Univer-

Please cite this article in press as: Froudarakis M, et al. Revisiting bOncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2012.12.0

ity of Ioannina (1995–1999). During his MSc (2002) andhD (2004) studies at the University of Ioannina he per-ormed several long-term scientific visits in Internationalesearch labs working on the application of multidimensional

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ology/Hematology xxx (2013) xxx–xxx

MR and other biophysical techniques in biomolecularystems. After postdoctoral research in structural and molec-lar biology at the MRC Laboratory of Molecular Biology,ambridge, UK, he is currently (since 2009) a Lecturerf Organic Chemistry at the University of Ioannina. Heas served as a reviewer in seven International Journalsnd is in the Editorial Board of three International scien-ific Journals. His current interests are directed in decodinghe molecular mechanisms, which underlie cancer develop-

ent using multidisciplinary approaches at the interfaces ofhemistry, biology and medicine. He has over 35 publica-ions in International Journals. Full list of publications atttp://www.chem.uoi.gr/?q=el/node/102.

Vasilios Karavasilis, MD, PhD, is currently a Lecturern Medicine/Oncology at the Aristotle University of Thes-aloniki and honorary Consultant Medical Oncologist atapageorgiou General Hospital of Thessaloniki. Part of his

raining in Medical Oncology was done at the Royal Mars-en Hospital, UK where he spent a considerable amount ofime at the drug development unit, testing novel drugs. Heas several publications in the field of early phase dugs andranslational research. His current research activities includeung, urological and GI malignancies.

Danai D. Daliani, MD, is Medical Oncologist. Sheeceived her medical degree from the Medical School ofhe University of Athens (1987). After the mandatory ruralervice in her country, she was trained in Internal Medicinet Columbia University – Roosevelt Hospital New York,Y (1990–1993) and Medical Oncology – Hematology at

he University of Texas – M.D. Anderson Cancer Center1993–1997), where she also served as Assistant Profes-or in the Genitourinary Medical Oncology Department1997–2003) focusing her clinical research on novel treat-ents for GU malignancies. Upon her return to Greece,

he served the National Health System as Consultant at theedical Oncology Department of the University Hospital

f Larissa until August 2011. Since September 2011, she isirecting the Medical Oncology Department at Euroclinicf Athens. She is ABIM certified in Internal Medicine andedical Oncology and a member of the American Soci-

ty of Clinical Oncology, American Association for Canceresearch, European Society of Medical Oncology and Asso-iation of Medical Oncologists of Hellas.

Christos Papandreou, MD, PhD, is a Professor ofedicine-Oncology at the University of Thessaly and Direc-

or of the Department of Medical Oncology at the Universityospital of Larissa, Greece. He received his MD and his PhD

rom the University of Athens, School of Medicine. He wasrained in Internal Medicine at the State University of Nework, Downstate Medical Center (S.U.N.Y.-D.M.C.) and heubsequently completed his clinical fellowship in Medical

leomycin from pathophysiology to safe clinical use. Crit Rev03

ncology at S.U.N.Y. and Memorial Sloan-Kettering Can-er Center, New York, NY. He also did a research fellowshipt the Molecular Hematology – Virology Laboratory at the

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.U.N.Y. and at the Laboratory of Mammalian Cell Transfor-ation Sloan-Kettering Institute for Cancer Research at Nework. He is board-certified in Internal Medicine and Medi-al Oncology. He was appointed as an Instructor in medicinet the Cornell University Medical College and as an assis-ant Attending at Memorial Sloan-Kettering Cancer Centern New York. Subsequently he served as Assistant Professort the University of Texas M.D. Anderson Cancer Center.e has a strong background in translational research involv-

ng the Neuropeptide-Peptidase axis in Prostate cancer, theFkappa B/Proteasome axis in Prostate, Colon, Lung and

Please cite this article in press as: Froudarakis M, et al. Revisiting bOncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2012.12.0

varian Cancers.

Evangelos Briasoulis, MD, PhD, is an Associate Pro-essor of Oncology at the University of Ioannina Medical

1rh

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chool, Greece. He is the Head of the Academic Depart-ent of Hematology, Ioannina University Hospital, Greece

since 2010) and Director of the Cancer Biobank Centerf the University of Ioannina, which is a member of theuropean Biobanking and Biomolecular Resources Research

nfrastructure. He has a strong research background andxpertise in experimental therapeutics, early developmentf anticancer drugs and cancer molecular biomarkers. Hisurrent research interests are metronomic chemotherapy, epi-enetic and microRNA biomarkers and clinical trials inaematological disorders and blood cancers. He has over

leomycin from pathophysiology to safe clinical use. Crit Rev03

50 publications in indexed medical journals that haveeceived over 2700 citations. Full list of publications atttp://publicationslist.org/evangelos-briasoulis.