Combination chemotherapy with gemcitabine with isolated lung perfusion for the treatment of pulmonary metastases.
OBJECTIVE
Isolated lung perfusion is an experimental technique for the treatment of lung metastases. Single-agent isolated lung perfusion does not result in complete remission. We studied the in vivo and in vitro efficacy of combinations of gemcitabine, cisplatin, and melphalan.


METHODS
In vitro, using the sulforhodamine B assay, CC531s cells were incubated with cisplatin, gemcitabine, or melphalan or with a combination of these drugs. One drug was added at concentrations causing 25% growth inhibition, whereas the second drug was added at variable concentrations. In vivo, left pulmonary metastases were induced in Wag/Rij rats by means of intravenous injection of CC531s adenocarcinoma cells. At day 7, rats underwent left isolated lung perfusion with gemcitabine (n = 7), cisplatin (n = 9), melphalan (n = 7), gemcitabine-cisplatin (n = 6), melphalan-gemcitabine (n = 6), and cisplatin-melphalan (n = 7). Death by means of metastatic disease was the end point. Survival and differences in survival were assessed by using Kaplan-Meier and log-rank testing.


RESULTS
In vitro synergistic activity was observed for melphalan-gemcitabine, whereas other combinations showed additive or antagonistic activity. In vivo treated rats lived longer compared with control animals ( P < .0001). In isolated lung perfusion melphalan resulted in longer survival compared with gemcitabine ( P = .0016) and cisplatin ( P = .046). Isolated lung perfusion with melphalan-gemcitabine resulted in 67% survival of the rats after 90 days versus 0% in other groups.


CONCLUSIONS
Isolated lung perfusion monotherapy or combination therapy with gemcitabine, cisplatin, or melphalan resulted in significantly longer survival compared with that seen in control animals. Isolated lung perfusion combination therapy with melphalan-gemcitabine resulted in the best survival either in vitro or in vivo.
Van Putte
Bart P
BP
Departments of Thoracic and Vascular Surgery, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium.
Hendriks
Jeroen M H
JM
Romijn
Sander
S
Pauwels
Bea
B
Vermorken
Jan B
JB
Van Schil
Paul E Y
PE
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D010478:Chemotherapy, Cancer, Regional Perfusion; D002945:Cisplatin / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003841:Deoxycytidine; D002945:Cisplatin; D008558:Melphalan; D000093542:Gemcitabine