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A novel non-phorbol-ester-like tumor promoter, okadaic acid (OA) has been shown to be an inhibitor of protein phosphatase I and IIA and, thus, to cause an ‘apparent activation’ of protein kinase C (PKC). We prewously showed that cis-diamminedich1oroplaunum(Il) (CDDP)- rcsistanl cells, PC-9/CDDP, were cross-resistant to OA and that the cross-reSIstawe was not due to the increasedefllux ofOA. We hypothe- sized that the phosphorylation status of some cellular proteins might be important in CDDP-resistance. No significant difference in PKC achv- ity or lolaI protein phosphatasc activity measured in vilro was seen between PC-9 and PC-9/CDDP cells, nor in their sensitivily to inhibi- lion by OA, nor in the amount of phosphorylation of whole cells or TCA-insoluble material. By SDS-PAGE after incubation of intact cells with “P, we detected a marked increase, compared to PC-9 cells, m phosphorylauon of the nuclear proteins of MW 32 and 20 kDa m CDDP- resistant PC-9/CDDP cells with no apparent difference in protein contern. When phosphorylation of nuclear proteins observed in PC-9/ CDDP cells was analyzed by 2-dimensmnal SDS-PAGE, the 32.kDa protcm had a PI of about 4.5. The 32-kDa and 20-kDa bands were increased in a dose-dependent manner by CDDP treatment. On the other hand, no increase in phosphoryladon of these proteins was observed in parental PC-9 cells. These results demonstrate a marked difference in Ihe phosphorylation status of specific nuclear proteins between parental and CDDP-resistant cell lines. which may bc related to CDDP-resis- tancc.

Randomized study of cyclophosphamide, doxorubicin, and vin-

c&tine versus etoposide and cisplatin versus alternation of these

hvo regimens inextensive small-cell lung cancer: A phase III trial of

the Southeastern Cancer Study Group

RothBJ,JohnsonDH,EinhornLH,SchacterLP,ChemgNC,Cohen HI et al. Unwersity Hospiml, 926 Wm Michigan. Indianapolu.lN 46202. J Chn Oncol 1992;10:282-91.

Purpose: The tial was undertien to determine (1) Ihe relative efficacy/toxicity of two commonly used combination chemotherapy regimens in patients with extensive small-cell lung cancer (SCLC) and (2) whether the rapid alternation of these two regimens could provide superior therapeutic results compared with either regimen alone. Pa- tients and Methods: In this place III trial, 437 eligible patients were stratified by performance status (PS) and sex and were randomly assigned to receive either 12 weeks of cisplatm and etoposide (EP): I8 weeks ofcyclophosphamide, doxorubicin. and vmcristine (CAV); or I8 weeks of altemauon of these two regimens (CAV/EP). Results: There were no egmficant differences in treatment outcome for EP, CAV, or CAV/EP in terms of response rate (61%. 51%. 59%. respectively), complete response rate (lo%, 7%, 7%. respectively), or m&an sur- vival (8.6 months, 8.3 months, 8.1 months, respectively), with a non- statistically significant trend toward a longer median tune to progres- sion with alternating therapy (4.3 months, 4.0 months, 5.2 months, respecuvely). Crossover second- line chemotherapy given at progres- sion produced low response rates and short survival, regardless of the regimen used. Myelosuppression was the dose limiting toxicity for all patients, although the pattern and severhy differed among the treatment arms. Conclusions: The combination regimens EP and CAV can bc considered equivalently effecuve induction therapies in extenwc SCLC, and these two regimens are, to some degree, crossresistant. Alternating therapy provides no therapeutic advantage compared wilh the use of citherof these regimens alone and should not be considcrcd as standard treatment in this chmcal setting.

Prolonged administration of oral etoposide in non-small-cell lung

cancer: A phase II trial Waits TM, Johnson DH, Hainswortb JD, Hande KR, Thomas M, Greco FA. Division ofMedico Oncology. 1956 Vanderbilt Clinic. Nashdle, TN 37232.5536. J Clin Oncol 1992;10:292-6.

Purpose: The trial was undertaken to investigate the acuvity and toxicity of a prolonged schedule of oral etopostde in the treatment of advanced non- small-cell lung cancer (NSCLC). Patients and Methods: Between March 1989 and August 1990, 25 patients wtb advanced

NSCLC were treated with oral etoposide 50 mp/m2/d for 2 I consecuuve days,repeatedevery28 to 35 days. Themedianpatientagewas6Oyears (range, 38 IO 84 years); maIe:female ratio was 12: 13. Elghtpatlents had stage IIIB disease; I7 had stage IV. Seventy-six percent of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. No patient had received previous chemotherapy wth standard agents; nme patients had received previous or concurrent radiatmn therapy. Plasma etoposide concentrations were measured to estimate ctoposide bio- availability and kinetics. Results: Five of 22 patienls (23%: 95% confidence interval [CI], 10% to 43%) had partial re- sponses.Medianresponsedurationwas5 months(rangc,2to6monthsl. Four of five responders were female. Besides alopecia, which occurred in all patients, myelosuppression was the most common toxicity, but was mild or moderate in most patients. Median leukocyte nadir durmg course 1 was 3,2OO/pL: only four of 69 courses produced a leukocyte nadir less than l,OOO/pL. Severe tbrombocytopenia (< 75.OOO/pL) did not occur. Gastrointestinal toxicity was uncommon. Median peak etoposide concentration was 3.4 pg/mL. A mean serum etoposide concentration greater than 1 pg/mL was maintained for more than 13 hours; the plasma concenuation-ume curve (AUC) was esumated to be 90% of that predicted after an identical dose of etoposide given intn- venously. Conclusions: Etoposide given by this dose and schedule has moderate activity as first-line systemic therapy for advanced NSCLC. In previously untreated patlents, chronic oral etoposide IS well toler- ated, and incorporation into combination regunens should bc feasible. Etoposide bio-availability may be increased at lower oral doses.

Phase I-II study of high-dose epirnbicin in advanced non-small-cell

lung cancer

Feld R, Wicrzbicki R. Walde PLD. Shepherd FA, Evans WK. Gupta S et al. 500 Sherbourne SI. Toronm. Ont. M4X lK9. J Clin Oncol 1992:10:297-303.

Purpose: A phase I multicenter trial was performed to determme the maximum-tolerated dose (MTD) of epirubicin. given on 3 consecuwe days every 3 weeks to prevmusly untreated patients wtb advanced non- small-cell lungcancer(NSCLC).PalientsandMetbods: Afterappropri- ate staging and a baseline multiple-gated angiogram (MUGA) scan, at least four patients were entered at each dose level, starting at 35 mg/m’ ofepirubicin given intravenously (IV) daily for 3 days (105 mum”) and escalatmg by 5 mg/m2 per injection in each dose level (15 mg/m’ per course). Epirubicin was administered up to a maximum dose of 60 mg/ mz/dfor3days(l8Omg/m2).TheMTDwasdeterminedtobe55mglmi/ d for 3 days (165 mg/m’) after treating a total of 35 (33 assessable) patients. Nadir granulocyte counts and associated febrile episodes comprised the dose-limiting toxicity, but there were no treatment- related deaths. A phase II trial was performed using a dose of 50 mg/mz/ d for 3 days (I 50 mg/m2)evcry 3 weeks with no dose escalation, but with dose reduction for toxicity as required. A total of 30 patients were entered onto this phase of the study. Results: The major toxicity, as in the phase I trml, was neutropenia with five febrile eprsodes, again with no treatment-related deaths. An overall response ratcof 12 of 63 (19%) was noted in tbecombined patient population of the phase I-II trial, wth 95% confidence mlervals of 10% to 31%. When the response rate was analyzed by histology, only one of I7 (6%) patients with squamous histology, as compared wth I1 of 46 (24%) wth non-squamous histology, responded, but this did not reach statisncal signilicance (P = .I5). Conclusions: High-dose epirubicin is tolerable and is an active smgle agent in NSCLC. It should be combined with relatively nonmy- elosuppressive agents such as cispladn to try to obtain higher response rates and extend the survival m tlus disease.

A study of oral etoposide, infusional cisplatin, and infusional 5

fluorouracil for locally advanced or metastatic non-small-cell lung

cancer: A Mid-Atlantic oncology program study

RosenthalCJ, Wampler GL. Brereton HD, Ahlgren JD, Lokich JJ,Fryer JG et al. SUNY-Healrh Science Cenrer a Brooklyn, 450 Clarkson Awtue, Brooklyn, NY 21203. Am J Clin Oncol Cancer Chn Trials 1992;15:12-7.