Verapamil increases the survival of patients with anthracycline-resistant metastatic breast carcinoma.
BACKGROUND
Verapamil (VER), a potent calcium channel blocker, has been found to overcome P-gp-mediated multi-drug resistance (MDR) and to increase sensitivity to cytotoxic anticancer drugs in refractory myeloma and non-Hodgkin lymphoma. The value of VER for treating solid tumors is still a matter for debate.


METHODS
We performed a prospective study in 99 patients with anthracycline-resistant metastatic breast carcinoma (MBC), to assess the clinical effect of oral VER given in association with chemotherapy. Instead of retreating patients with anthracycline, we used a partially noncross-resistant regimen (VF), combining vindesine (VDS) and 5-fluorouracil given as a continuous infusion (5-FU CI). Patients were randomly assigned to two cohorts. One cohort (47 patients) was treated in 28-day cycles, each involving the administration of VDS (3 mg/m2 i.v. bolus on days 1 and 10) and 5-FU CI, (400 mg/m2/day i.v. from day 1 to day 10). The other cohort (52 patients) received the same VDS and 5-FU treatment and an additional oral VER treatment (240 mg/day divided in 2 doses), from day 1 to day 28 of each cycle. Patients were treated until progression.


RESULTS
The treatment was well tolerated and no side effects that could be attributed to VER were detected. Patients treated with VER had longer overall survival (OS) (median OS: 323 vs. 209 days, P = 0.036) and a higher response rate (27% vs. 11%, P = 0.04) than those not given VER. Progression-free survival (PFS) was also longer but the difference was not statistically significant (median PFS: 4.6 and 2.7 months for the VER and non-VER groups respectively, P = 0.6).


CONCLUSIONS
This clinical trial demonstrates that a chemosensitizer, such as VER, can increase the survival of MBC patients with acquired anthracycline resistance.
Belpomme
D
D
Oncology Department, H pital Boucicaut, Paris, France. artac.cerc@bcc.ap-hop-paris.fr
Gauthier
S
S
Pujade-Lauraine
E
E
Facchini
T
T
Goudier
M J
MJ
Krakowski
I
I
Netter-Pinon
G
G
Frenay
M
M
Gousset
C
C
Marié
F N
FN
Benmiloud
M
M
Sturtz
F
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D015993:Life Tables; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D011446:Prospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D014700:Verapamil / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014751:Vindesine / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D002121:Calcium Channel Blockers; D009363:Neoplasm Proteins; D014700:Verapamil; D014751:Vindesine; D005472:Fluorouracil