title: A study to investigate dose escalation of doxorubicin in ABVD chemotherapy for Hodgkin lymphoma incorporating biomarkers of response and toxicity.
abstract: BACKGROUND
  Myelotoxicity during initial cycles of chemotherapy for Hodgkin lymphoma is associated with better outcome, supporting the concept of individualised dosing based on pharmacodynamic end points to optimise results. This study was performed to identify the maximum tolerated dose (MTD) of doxorubicin within cycles 1-3 ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Circulating biomarkers of response (nucleosomal DNA, nDNA) and epithelial toxicity (Cytokeratin 18, CK18) were also measured.
  
  
  METHODS
  Dose escalation of doxorubicin in cycles 1-3 ABVD supported by pegfilgrastim was performed on a six-patient cohort basis (35, 45 and 55 mg m(-2)) with doxorubicin reduced to 25 mg m(-2) or omitted in cycles 4-6 to maintain cumulative exposure of 103-130% standard ABVD. BVD was given at standard doses throughout. Six additional subjects were recruited at the MTD.
  
  
  RESULTS
  Twenty-four subjects were recruited. Dose-limiting toxicities (DLTs) of grade 3 neuropathy, pneumonitis, palmar-plantar erythema and neutropenic infection were observed at 55 mg m(-2), so 45 mg m(-2) was declared the MTD. In patients who subsequently experienced DLT at any time, large increases in CK18 were seen on day 3 of cycle 1 ABVD.
  
  
  CONCLUSIONS
  Escalated ABVD incorporating doxorubicin at 45 mg m(-2) in cycles 1-3 can be delivered safely with pegfilgrastim support. Circulating cell death biomarkers may assist in the development of future individualised dosing strategies.
authors.affiliation: Departments of Medical and Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Gibb
authors.forename: A
authors.initials: A
authors.lastname: Greystoke
authors.forename: M
authors.initials: M
authors.lastname: Ranson
authors.forename: K
authors.initials: K
authors.lastname: Linton
authors.forename: S
authors.initials: S
authors.lastname: Neeson
authors.forename: G
authors.initials: G
authors.lastname: Hampson
authors.forename: T
authors.initials: T
authors.lastname: Illidge
authors.forename: E
authors.initials: E
authors.lastname: Smith
authors.forename: C
authors.initials: C
authors.lastname: Dive
authors.forename: A
authors.initials: A
authors.lastname: Pettitt
authors.forename: A
authors.initials: A
authors.lastname: Lister
authors.forename: P
authors.initials: P
authors.lastname: Johnson
authors.forename: J
authors.initials: J
authors.lastname: Radford
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D054316:Biomarkers, Pharmacological / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects; D015331:Cohort Studies; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
chemical_list: D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D001761:Bleomycin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin