A randomized phase III study of 72 h infusional versus bolus bleomycin in BEP (bleomycin, etoposide and cisplatin) chemotherapy to treat IGCCCG good prognosis metastatic germ cell tumours (TE-3).
BACKGROUND
Bleomycin is an integral part of combination chemotherapy in germ cell tumours. Pulmonary toxicity often necessitates drug cessation and death occurs in 1%-2% of patients. A continuous infusion of bleomycin might reduce lung toxicity when compared with the conventional weekly boluses given as part of standard BEP chemotherapy.


METHODS
A phase 3 trial was conducted based on 212 men with IGCCCG good prognosis metastatic germ cell tumours with 1 : 1 randomization. They were stratified for age, smoking history and renal function. Patients received either conventional BEP with weekly bleomycin (30 000 units/week i.v. bolus) or as a 90 000 unit infusion on day 1 over 72 h. The primary endpoint was CT assessed lung toxicity, secondary endpoints included progression-free survival (PFS), changes in lung function testing and quality of life. Repeated measures mixed effects model was used to analyse the data.


RESULTS
CT assessed lung toxicity for the infusional and conventional arm patients were respectively 80% versus 62% at the end of treatment and 54% versus 51% at 1-year post-treatment. There was no significant difference between the two arms for CT assessed lung toxicity (estimated regression coefficient = 1.4, 95% CI: -0.36, 3.16). Older patients had higher toxicity (coefficient = 4.81, 95% CI: 3.04, 6.58). Lung toxicity increased after 1 cycle and peaked at end of treatment (P ≤ 0.002) and then declined. Lung function testing did not predict for subsequent lung damage. The median follow-up was 2.5 years. Two-year PFS rate (infusional: 93%, conventional: 94%; hazard ratio =0.91, 95% CI: 0.33, 2.52) was similar. Cough (P = 0.002) but not shortness of breath (P ≥ 0.09) was associated with bleomycin toxicity.


CONCLUSIONS
Infusional bleomycin has no advantage over standard administration. It supports abandoning routine pulmonary function testing, instead the presence of cough should be sought and the early use of CT scanning of the chest to evaluate potential lung toxicity is preferred.
Centre for Experimental Cancer Medicine, Barts Cancer Institute, QMUL, London.
J
J
Shamash
Centre for Experimental Cancer Medicine, Barts Cancer Institute, QMUL, London.
S-J
SJ
Sarker
Academic Unit of Radiotherapy & Oncology, Institute of Cancer Research, London.
R
R
Huddart
Department of Oncology, University College London Hospitals, London.
S
S
Harland
Department of Oncology, Huddersfield Royal Infirmary, Huddersfield.
J K
JK
Joffe
Department of Oncology, Addenbrookes' Hospital, Cambridge.
D
D
Mazhar
Cancer Centre, Lancashire Teaching Hospitals, Preston.
A
A
Birtle
The Beatson West of Scotland Cancer Centre, Glasgow.
J
J
White
Centre for Experimental Cancer Medicine, Barts Cancer Institute, QMUL, London.
K
K
Chowdhury
Centre for Experimental Cancer Medicine, Barts Cancer Institute, QMUL, London.
P
P
Wilson
Centre for Experimental Cancer Medicine, Barts Cancer Institute, QMUL, London.
M R
MR
Marshall
School of Medicine, University of Dundee, Dundee, UK.
S
S
Vinnicombe
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D008168:Lung / Q000000981:diagnostic imaging / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D055815:Young Adult
D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin
bleomycin; germ cell tumour; infusion; lung