Difficulties in running a phase III trial to investigate the optimal management of patients with low-risk neutropenic fever


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Ernest Marshall2, Neil Steven1, Lucinda Billingham1, Cassandra Brookes1, Helen Innes2, Julie Joseph1

1University of Birmingham, UK, 2Clatterbridge Centre for Oncology, Wirral, UK

Abstract

Background

Although neutropenic fever is a potentially life-threatening complication of chemotherapy, low-risk patients are easily defined and safely treated in hospital with oral combination antibiotics. Early hospital discharge has potential quality of life benefits reducing costs and nosocomial infections, however, evidence is lacking supporting safety and efficacy.

Method

The ORANGE trial (ORal Antibiotics for Neutropenic sepsis Giving Early hospital discharge: CRUK/06/017, RefC1810/A4818) opened in August 2007, recruiting patients with solid tumours/lymphoma presenting with neutropenic fever defined as low-risk using the MASCC index. Patients received oral co-amoxiclav/ciprofloxacin at presentation. After a minimum of 24 hours inpatient therapy, clinically stable patients were randomised to standard inpatient care (fever resolution and neutrophil recovery) or immediate discharge with telephone follow-up.

Results

ORANGE closed early in April 2009 due to poor recruitment (27 patients registered and 12 randomised). Recruitment of investigator sites and patients was extremely difficult (34 hospitals and 5 hospital trusts declined participating). Most centres could not comply with clinical trials governance due to local admission pathways, often to off-site units or A&E, or could not comply with baseline MASCC risk assessment. Other reasons for decline included early discharge already in place or conflicting local antibiotic protocols, reducing ciprofloxacin usage due to suspected risk of Clostridium difficile infection.

Conclusion

Recently NCEPOD and NCAG reports highlighted poor care in UK neutropenic fever management, recognizing the value of clinical trials in this area. ORANGE identified complex local care pathways and lack of awareness of MASCC risk assessment. Local antibiotic policies conflict with neutropenic fever evidence base. Finally, ORANGE highlights complexities in managing trial governance requirements in acute oncology.