combination trials of edatrexate with paclitaxel or cisplatin in patients with advanced non-small...
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CARBOPLATIN(C) AND VINORF.LBINE(V) IN METASTATIC(M) NON SMALL CELL LUNG CANCER(NSCLC). PRELIMINARY RESULTS. C.Santomagglo, A.Righi; oE.Tuccl,Y.Pepl; ^R.Algerl, A.Andrel. Pneumology Dept, Florence; ORadiotherapy Dept, University, Slena; ^Medlclne I Dept, Grosseto. Italy. With the am to improve the therapeutic index of
the combination of V and Cisplatln, we substituted C for the parent compound. Up to September 1993, thirty-four consecutive untreated patients (pts) affected by M-NSCLC were enrolled and are fully evaluable. M/F ratlo was 28/6, median age (63 years), median PS 1; histology was adenocarclnoma in 18 pts, epidermoid ln 13, adenosquamous in 2, and undifferentiated in 1. Sites of metastasis: lung 15, bone 13, liver 8, lymph nodes i,, and adrenal 4. Treatment: C 350 mg/sqm i.v. on d 1,V 25 mg/sqm i.v. on d 1 and 8. Cycles repeated every 4 weeks. We observed 13 PR (38X), 13 NC, 8 PD. No CR was achieved. Median time to progression was b months. Toxicity was mild, on the whole. In 142 cycles
administered no grade > 2 toxicity 'was observed, but 3 cases of grade 3 anemia. If further experiences will confirm this results, c-v should strongly considered for chemotherapy of M-NSCLC pts, where achievement of a good quality of life is a primary goal of treatment.
EFFECT OF GEMClTARINE ON RENAL FUNCTIONS lN NON- SMALLCELLLUNGCANCEROVSCLC).
HJM Grwn', JA Gietemal, S Meijel, RI Goedkoop’, EF Smit’. ’ Department of Pulmonary diseases, ’ Department of Nephrology, University Hospital, Groningen, The Netherlands ’ Medical Department, Eli Lilly, Nieuwegein, The Netherlands
R&al side-effects of gemcitabine seen in phase I studies were elevations of serum creatinine, proteinuria and erythrocyturia. We studied in 12 untreated patients (pts) with NSCLC with normal baseline renal functions the effects of gemcitabine on glomemlar and tubular functions. Gemcitabine was given as weekly infusions of 1250 mg/n? x3 weeks with one week rest. Serum creatinine was measured weekly and creatinine clearance every 3 weeks. Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured simultaneously in supine position with l%cdium tbalamate and “‘I-hippuran, respectively. Tubular damage was measured by excretion of tubular enzymes. Lactic dehydrogenase, alkaline phosphatase, gammaglutamyltransferase were measured with standard technics. B?_- microglobuline and albumen were measured with nephelomeuic technic and radiounmune assay respectively. Pts characteristics: median age 60 y’s (range 43-70). median weight 77 kg (range 53-101). median number of cmuses 4.5 (l-6). Serum creatinine and creatinine clearance measured in 24 hours urine did not change during 6 ccwrses of treatment. Only 1 of the 12 pts developed mild proteimuia (> 150 mg/24 h). In 2 of the 12 pts erythrocyturia was noticed, explained by cystitis and urolithiasis.The mean (*se) ERPF and GFR before and after the first infusion of gemcitabine was 412+37 and 411*37 ml/min and 103k7 and 103 i7 ml/min (n=9). After 2, 3 and 6 courses of gemcitabine no significant change in ERPF and GFR were noticed. Tubular enzymes also did not change during 6 courses. B2-microglobulin and albumen measured in the urine showed more variation but did not change significantly. All urological and ncphrologxzd toxicities were WHO grade 1 or less. In conclusion, we did not observed acute or late renal toxicity during gemcitabine treatment
COMBINATTON TRIALS OF EDATREXATE WTIH PACUTAXEL OR ClSPlATtN IN PATIENTS WtlH ADVANCED NON-SMALL CELL LUNG CANCER JR Rigas, DG Ptister, VA Miller, LB Tyson, TV Spfess, MG Kris Memorial Sloan-Kettering Cancer Center, New York, NY 10021 USA
Edatrexate (EIX) has demonstrated antitumor activity in non-small cell lung cancer (NSCLC). Both cisptatfn (DDP) and paclitaxel (PTX) have in vitro synergy wtth EDC The non-overlapping toxicities, dfffering mechanisms of action, in v&o synergy and antitumor activity in NSCLC make combinations of these agents attractive for study. We conducted two phase I trials of 2 drug combinations of ETX wfth PTX or DDP in NSCLC patients (pts). Thirty-seven pts wtth IIIB or IV NSCLC received either escalating doses of ETX (40,60,60, 100, 120 mg/m2) days 1, 15 with PTX 13.5 mg/m2 days 2, 16 infused over 3 hours, escalating doses of PTX (175, 210, 260 mg/mz) with ETX 120 mg/m’, escalating doses of ETX (40, 60 mg/my weekly wtth DDP 120 mg/m2 day 2 every 28 days or escalating doses of ElX (40, 50,60,70 mg/mz) days I, 15 with DDP 60 mg/mz days 2, 16. Characteristics: men 22; median age 64 (range 27-72); Karnofsky performance status 80-90 (27pts), 60-70 (IOpts); prior irradiation in 16 and prior chemotherapy in 16. Preliminary results:
Combinations (mdm2) n No prior Rx Prii Rx
ETX (40-120) + PTX (135)
ETX (120) + PTX (175-210)
ETX (40-50) + DDP (120)
ETX (40-70) + DDP (60)
12 l/l 3111
12 4l7 115
9 2’6 (3m
For ETX/PlX, leukopenia and neuropathy were noted white ETX/DDP produced leukopenia, thrombocytopenia, mucositfs, vomiting and neuropathy. Conclusions: mC with PTX or DDP demonstrate activity in NSCLC. Dose escalation continues for both trials. Phase II studies and the development of a 3 drug combination are planned. Supported by HHS CA-06826.
STUDY OFTHECOMBtNATlON MIC (MITOMYCIN, IFOSFAMIDEAND CISFIATIN) IN UNRESECTABLE OR ADVANCED NSCLC AS STANDARD TREATMENT. A MULTICENTRIC STUDY. A Artelf’), JM Vicent, C Vadell, J Herrero, J Cassinallot’), C Camps, A Berrocal. I Martfnt’), A Ant&r-Tones(*). Hospital Miguel Servet (‘1 and the Spanish Lung Cancer Group.
&j~&6.- Between D&91 to Sept/93, 88 consecutive patients tP) diagnosed of unresectable or advanced NSCLC have been treated with mitomvcin-C 6 mglm’, lfosfamide 3 9/m* and Cisplatin 50 mglm’ to evaluate its activitv and toxicity as standard treatment.
Patients.- 88 P have been enrolled (male 94%. median age 59 t41-80): Histology: squamous 52 (59%). adenoca 20 (22%). undii. 16 (19%); ECOG 0. 13P (14%): 1, 47P t54%), 2. 28P (32%); Stage illa, 8P (9%), Illb, 43P (49%). IV, 37P (42%); metastatic sites: lung 16, adrenal 14. bone 10, CNS 3, other 10.
&J&&- 87 P were evaluable. Objective responses were seen in 18 P (20.7%) (CR 1, PR 17). 90% of responses were reached with 4 courses or less. According to stage, response rates were llla 25%, lllb l&6%, IV 5%. No differences according to ECOG status or age ( < 50,50-70, < 70~). Thoracic RT (mean dose 46Gy) was delivered to 23P and holocranial t42Gv) to the 3 P with CNS involvement. Grade 3 (WHO) toxicitv appeared in 31 P (35%) l9ranulocvtopenia 11, gastrointestinal 14, anemia 3, thrombocytopenia 1, CNS 1, urological 1); Grade 4 in 12 P (13.6%) tgranulocvtopenia 8, gastrointestinal 4). Progression has already occurred in 66 P (75%) (local 40%, distant 37%. both 23%). Median Time to progression was 22.5 w. and median Survival 31~ (7.5m).
Conclusions.- MIC combination with the present schedule is a moderately effective regimen in non selected patients with NSCLC, but much less than previously reported (Cullen et al, Br J Cancer 1986 58:359). Toxicitv is mild and manageable. Response rate was low and survival was in the usual range. Steoe was the main predictor for response. Advanced age did not limit its administration nor reduce efficacy. Based in our results, we can’t consider this schedule as standard and studies have to be continued.