97

366 367

TREATMENT CHARACTERISTICS IN PATIENTS SURVIVING A PHASE I STUDY OF LIPOSOME-ENCAPSULATED FIVE TO 18+ YEARS. AN ANALYSIS OF 1714 CONSECUTIVE DOXORURICIN (D-99) AND GRANULOCYTE COLONY PATIENTS. STlMUUTIN6 FACTOR (G-CSF) IN PATLENTS WITH U. LASSBN, K. OSTBRLIND, M. HANSEN*, P. DOMBERNOW- ADVANCED SOLID TUMORS. s1 R Maxanet, R Sal&, A SKY* ??, B. BERGMN"', H.H. HANSEN. Department of Oncology, Rigshospitalet, Copen- hagen, Medical Department P, Bispebjerg Hospital*, Copenhagen, Department of Oncology, Herlev Univer- sity Hospital**, Denmark and Pulmonary Division, Renstrwnska Hospital, Gothenborg, Sweden***. A total of 1714 patients entered one of nine consecutive clinical trials with combination chemotherapy from 1973 to 1986. Sixty patients survived more than five years. Late relapses occurred in 15.0 % of the five year survivors and secondary malignancies in 20.0 %. Twenty-six patients are still alive and disease- free 5 to 18 years (at median 9.5 years) from initiation of treatment. Extensive stage disease, performance status > 2, liver and bone marrow metastases, elevated lactate dehydrogenase and alkaline phosphatase were all negative prognostic factors. Five-year survival was 3.5 % (4.8 % for limited-stage disease and 2.3 % for extensive stage disease). Ten-year survival was 1.8 % (limi- ted stage disease 2.5 % and extenive stage disease 1.2 %). Conclusion: Long-term survival can be achieved for both stages of small cell lung cancer. Long-term survivors continuously have considerably mortality due to late relapses, secondary malignancies, especially tobacco-related cancers, and other tobacco-related diseases. Tobacco prevention is therefore necessary and will on the long view save more lives, compared to present available therapy.

Skarln, D Gordon, A Eliis. Dana-Farbar Cancer tnstitute,, $va;d kl.sChool,kJton,hk%TtaLiposomecompny,Rineaton

Doxorubkinisoneofthamostactlve fhsmorhenpautiagant~in~ wide variety of matiis & a dose response curve is clinically evident However, toxicities lit doss eacaktii. Encapsulation of doxorubicin within liposomes ameliorates myocardiol L gastrointestinal toxicities in animals The maximum tolerated dose (MTD) of D-99 in phase 1/H human studies is 90 mg/m2/cycle. These studies indicate D-99 has a similar hematdogic toxicity profile but may have less cardiovasctdar & gastrointestinal toxicity than doxorubkin. In efforts to circumvent the dose limiting granulocytopenic toxicity of D-99 & further assess the non- hematologic toxicity, we describe the results of a phase I dose escalation trial of D-99 with G-CSF in patients (pts) with advanced sdid tumors. 27 pts not previously treated with an anthracycline were given escalating doses of D-99 (90-165 mg/mZ) & G-CSF every 21 days in cohorts of 3-5 pts. The dose limiting toxicity (DLT) of D99/G-CSF was 165 r&m2 as defined by grade 4 hwnatologic toxicity losting greater than 7 days (MTD 150 mg/m2). Mucositis(grade3)wasobservedathigherdceesbutwasnotdose limiting. Dccaskmal transient fever was observed within 12 hours of D-99 infusion. Seven pts were treated with >500 mg/m2 (total) of D-99 without cardiotoxicity. Pharmacokinetic studies are currently being analyzed. Of 14 avaluable pts with lung malignancies, 3/l 0 non-small cell lung cancer pts, l/2 small cell lung cancer pts, & 2/2 mesothekma pts had at least a partial msponse @SD%) to therapy. This phase I study demonstmtes that D-99 with G-CSF can be dose escalated (1.67X Lm) conventional doxorubicin) with acceptable non-hamatological toxicity. The responses observed in lung malignsncies are encouraging & need to be tested further in phase II studies.

Limi#ed Sanlpung Models of CPT-11 md SN-36 A. Karate, H. Nakaehima. Y. Saw&i, N. Yamamoto, M. Fukuda, J. Shiraishi, H. Arioka, F. Oahita, Y. Ohe, T. Tamura, K. Eguchi, T. Shiikai, N. Saiio National Cancer Center Hospital and Research Institute, Tokyo, Japan

We tried to eatabliih the limited sampling models (LSMs) of CPT-11 and its active metabolile. SN-36 in patients treated with cumbination chemotharapy using CF’T-II and VP-16. We have previously reported thal the principal toxicitiea awociated with this reg!men were dianhea and granulocytopenia (J Clm Oncolll:2030-2095,1663) and the large interpalienl vadabiiii existed in the pharmacokinetic paramelera of CPT-1 1 and SN-36 (Proc. AACR 34:360,1633). Training data eel of LSMs has been determined in 30 patients (pts). CPT-11 and VP-I 6 were administered de@ for 3 conaecutk days a1 escalating dose of Cm-1 1 I VP-16 from 40160, 80/60,60/80 to 60&O mgIsqm. Elood sample was obtained on days 1 and 3 before inlueion , 0.5, 1, 1.25, 1.5, 2.2.5hounafterthsetartofinfuaionand0.25.0.5,1,2,4,8.12,21.5hours after the end oi infusion. The concentrations of CPT-11 and SN-36 were evaluated with HPLC. LSMa was developed with stepwiaa and multiple regression analysis. Beaed on the training data set, optimal sampling points were detemined to be C4 and C6, where C4 and C6 were the concantra6ons al 4 and 6 hours atler infusion. The validity of LSMe were evaluated pmapeclively with a teal data set in 13 pis who received CPT-11 and VP-1 6 at dow of 60&O mgkqm. The LSMa of CPT-11 were proven to be highly predictive, with correlation awfFl&@ between prediied and actual AUCa ( day 1 : 0.84. day 3 : 0.97 ) , unbiased, with mean prediin emora ( day 1 : -1.4%.day3 :S.S%)and precise,wi!h maan squared predictionerro~(day 1 : 3.0 %, day 3 : 3.1 % ). But large interpatient variabilii in the AUC valuea of SN-36 prevented us to establish the LSM of SN-36. Severity of this regimen seems to depend on the AUC values of CPT-11 and SN-36. Furlher phammcoiogic studies are necessary lo establish an appropriate administration schedule of CPT-1 I.

AN EXPERIMENTAL STUDY ON THE LOCAL INJECTION OF

ADRIAMYCIN-ENCAPSULATED LIPOSOMES IN MEDIASTINAL

LYMPH NODES.

B.R. We, H.Takahashi, N.Kajiwara, M.Kinoshita. M. S&to,

K. Yoneyama, N. Kawate. C. Konaka, H. Kato. Department of

Surgery. Tokyo Medical College, Tokyo, Japan.

Liposomes as drug carrxrs in cancer chemotherapy IS recently

noted because of Its little toxicity and no antigeniaty.

Adriamycin-encapsulated liposomes (Lip-ADM) was produced

with pH gradient method. Injection of Lip-ADM (0.5 mg/kg) into

the subcarinal lymph node of dog, compared with the other two

administrated routes, intra-venous ( 2.0 mg/kg) and mtra-thoracic

( 1.0 mg/kg) were performed. The disposed dogs were sacrified at

the lst, the 2nd and the 3rd week. The following were considerated

: 1. the parmacokinestics of ADM, 2. the released curves of ADM

m media&ml lymph nodes, 3. histological examinations, and 4.

the antineoplastic concentration of released ADM corresponded

to the experimental antineoplastic effect of ADM in PC-9 (an

adenocarcinoma cell line of lung) by colony forming assay,

in-vitro. The results of this study showed : 1. tras-endoscopic

administration of Lip-ADM was possible, 2. high level accumu-

lation of Lip-ADM and continous released of free-ADM in

mediastinal lymph nodes were recognized, 3. high level antineo-

plastic concentration was recognized until the 3rd week. Also,

the study suggested that the local inlectmn of Lip- ADM, through the bronchial endoscope, would be recommended as a &mica1 mode of application.