Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study.
BACKGROUND
Previous phase 2 studies have shown antitumour activity with gemcitabine and oxaliplatin (GEMOX) in patients with advanced biliary-tract cancers (BTCs). In this phase 2 study, we assessed the efficacy and safety of combined bevacizumab with GEMOX (GEMOX-B) in patients with advanced BTCs, and investigated how changes in 18-fluorodeoxyglucose ([(18)F]FDG)-PET correlate with clinical outcome.


METHODS
Patients with advanced measurable BTCs were given the following treatment on days 1 and 15 of a 28-day cycle: bevacizumab 10 mg/kg, followed by gemcitabine 1000 mg/m(2) (10 mg/m(2) per min) and oxaliplatin 85 mg/m(2) (2-h infusion). [(18)F]FDG-PET scans were obtained at baseline and after completion of the second cycle. The primary endpoint was progression-free survival (PFS). Efficacy and safety analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00361231.


RESULTS
35 patients were enrolled and evaluable for efficacy and toxicity. Median PFS was 7.0 months (95% CI 5.3-10.3), and PFS at 6 months was 63% (47-79), which was below the targeted rate of 70%. Grade 3-4 toxic effects included neutropenia (n=7), raised alanine aminotransferase concentrations (n=5), peripheral neuropathy (n=5), and hypertension (n=5). [(18)F]FDG-PET scans showed a significant decrease in maximum standardised uptake value (SUV(max)) after two cycles of treatment (5.72 [SD 2.01] at baseline; 3.73 [SD 1.88] after two cycles; p<0.0001). These changes were more pronounced in patients with partial response or stable disease than those with progressive disease (24 patients, -2.80 [SD 1.95] vs five patients, 1.41 [SD 3.13]; p=0.009). Change in SUV(max) was a significant predictor of PFS (HR 1.35, 1.14-1.60, p=0.0006) and overall survival (1.25, 1.05-1.50, p=0.01).


CONCLUSIONS
GEMOX-B showed antitumour activity with tolerable safety in patients with advanced BTCs. Decreases in SUV(max) on [(18)F]FDG-PET scans after treatment were associated with disease control and increases in PFS and overall survival.


BACKGROUND
Genentech Oncology and Sanofi-Aventis.
Zhu
Andrew X
AX
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. azhu@partners.org
Meyerhardt
Jeffrey A
JA
Blaszkowsky
Lawrence S
LS
Kambadakone
Avinash R
AR
Muzikansky
Alona
A
Zheng
Hui
H
Clark
Jeffrey W
JW
Abrams
Thomas A
TA
Chan
Jennifer A
JA
Enzinger
Peter C
PC
Bhargava
Pankaj
P
Kwak
Eunice L
EL
Allen
Jill N
JN
Jain
Sanjay R
SR
Stuart
Keith
K
Horgan
Kerry
K
Sheehan
Susan
S
Fuchs
Charles S
CS
Ryan
David P
DP
Sahani
Dushyant V
DV
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D001661:Biliary Tract Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000401:mortality; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D016016:Proportional Hazards Models; D019275:Radiopharmaceuticals; D018570:Risk Assessment; D013997:Time Factors; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D019275:Radiopharmaceuticals; D003841:Deoxycytidine; D019788:Fluorodeoxyglucose F18; D000068258:Bevacizumab