ISOLATED LUNG PERFUSION WITH DOXORUBICIN REDUCES CARDIAC AND HOST TOXICITIES ASSOCIATED WITH SYSTEMIC ADMINISTRATION

Background. For patients with malignant neoplasms metastatic to lung, systemic chemotherapy in doses high enough to achieve significant surv ival improvement is often limited by host toxicity. Isolated single-lu ng perfusion offers the advantage of delivering high-dose organ-specif ic chemotherapy while minimizing systemic toxicity. We compared the ca rdiac and systemic toxicities associated with intravenous administrati on versus isolated single-lung perfusion with doxorubicin. Methods. Th irty-three male Fischer 344 rats weighing 275 to 300 g were randomized into three groups: normal control rats (n = 11), intravenous doxorubi cin (7 mg/kg) (n = 11), and isolated left lung perfusion with 320 mu g doxorubicin/mL (n = 11). Animals undergoing isolated single-lung perf usion were anesthetized with pentobarbital, intubated, and ventilated, and then had left thoracotomy with cannulation of the pulmonary arter y and a pulmonary venotomy; pulmonary artery and vein were clamped pro ximally. Animals were perfused for 10 minutes at a rate of 0.5 mL/min, followed by a 5 minute rinse with buffered hespan solution. Arterioto my and venotomy were repaired and circulation was restored. Daily weig hts were recorded. On day 24, cardiac output was determined in all gro ups by injection of radiolabeled chromium 51 microspheres. Results. An imals treated with 7 mg/kg intravenous doxorubicin had a significant w eight loss as compared with those treated with isolated lung perfusion (209.2 a 29.9 g versus 302.3 +/- 10.1 g; p < 0.01). Animals treated w ith isolated single-lung perfusion, after recovering from surgical str ess, resumed normal growth pattern. Significant cardiac toxicities wer e seen in intravenously treated animals; cardiac index (27.4 +/- 6.9 v ersus 39.4 +/- 6.3 mL . min(-1) . 100 g body weight(-1)) and heart wei ghts (0.56 +/- 0.04 versus 0.88 +/- 0.09 g) were reduced in the intrav enously treated group as compared with the group treated with isolated single-lung perfusion. In addition, severe hematologic toxicities are associated with intravenous doxorubicin administration. Conclusions. Intravenous administration of doxorubicin is associated with severe ho st toxicities, which include weight loss, decreased cardiac function, and hematologic toxicity. Isolated lung perfusion with high-dose doxor ubicin is well tolerated and is associated with minimal host toxicity.