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A STRATEGY TO EVALUATE A NOVEL RADIOSENSITISER; A PHASE I TRIAL OF TAXOL AND CONCOMITANT TIIORACIC RADIATION IN NON-SMALL CELL LUNG CANCER P. Kirkbride*, D. Payne’, E. Eisenbau&, ??F’rincess Margaret Hospital Toronm and the +National Cancer Institute of Canada Clinical Trials Group @UC CTGh Kingston

Tissue ctdture studies have shcwn Tax01 blocks and/or prolongs cells in G2 or M in the phases of the cell cycle and this pmpetty is probably responsible for the observed anti-tumottr activity. It is well known that these ate the most tadiosetisitive phases of the cell cycle, and merefore Taxd could ftmction as a cell cycle selective radiosensitiser. In vitro sNdies suggest that the effect of radiation may be enhanced by a factor between 1.5-2.0.

To assess the clinical significance of these findings, the NCIC CTG appraised several shategies before emkxking on a Phase I study to evaluate Tax01 and conatnwtt radiotherapy in locally advanced non small ceU lung cancer. The relative maits of the different zqtwcba to dose exaladon of radiation and/or dtug, and the virNe.s of the chosen scheme will be presented.

Patients with Stage 38 non small cell lung cancer will be entered into the protocol. All patients will receive radical &iarion therapy to a dose of 6000 &y in 30 fractions. Tbe initial dose of Tax01 will be 45 mg/m2 given by IV infusion on Day 1, Escalation of treatment will be fust by increasing the number of Tax01 treannents over the course and then by increasing the dose of Tax01 in each treament. 3 patients will entered at each dose level and daN will be avaikae for at least 3 patients for 4 weeks at the completion of treament before. the next dose will be opened. If dose limiting toxicity (DLTI is seen at a given level a further 3 patients will be enrolled. Once 2 patients experience DLT that dose will be cc&de& &at maximum Nlemted dose. The results of this trial will allow a dose level to be defined for future Phase II Studies of Taxol and concurrent tbempy.

A PHASE 1-H STUDY OF DAILY CARBOPLATIN AND SIMULTANEOUS ACCELERATED, HYPERFRACTIONATED CHEST IRRADIATION FOLLOWED BY CARBOPLATIN IN PATIENTS WITH REGIONALLY INOPERABLE NON- SMALL CELL LUNG CANCER (NSCLC). K. Kelly, P.A. Bunn, Jr., M. Hazuka, A. Turrisi. Univ. of Colorado. Denver, CO, and Univ. of Michigan, Ann Arbor, Ml.

Several phase III trials have demonstrated the superiority of radiotherapy (RT) plus cisplatin-based chemotherapy versus radiotherapy alone for the trearment of moperable Stage IIIA and IIIB NSCLC. However, the optimal combinatmn regimen has not been defined. Recent studies utilizing accelerated, hyperfractionation radiotherapy demonstrated higher complete response rates, better local control, and better survival without substantial toxicity when compared to standard daily fractionation. Although the combination trials have used cisplatin as a radiosensitizer, carboplatin (CBDCA) also possess this property without the toxicities of cisplatin. Based on these findings, this pilot phase I-II dose escalating trial was initiated as follows PTS. CBDCA DOSE ROUTE DAYS NOTES TOTALRT. IO Group 1 25mgim’ IV Days 1-5 60 mins. 6000 IO Group 11 30mgim’ IV x 4 weeks prmr to 6000 IO Group III 35mg/m2 IV ” daily 6000 IO Grouo IV MTD IV ” AM RT. 6600 IO Grouu V MTD IV II 7200 The dose of carboolatin is escalated fust. once the maximallv tolerated dose (MTD) is determiied, the radiotherapy dose will be escalate; to determine if more than 60 Gy of chest irradiation can be gwen with the MTD of carboplatin. All patients will receive carboplatin 350mgim’ x 4 cycles as consolidation.

Fifteen patients (pts) have been enrolled. Thirteen patients are evaluable. One pt went off study on day 3 for personal reasons and the other pt developed an unrelated perforated bowel during week 2. Both patients were enrolled in level 2. Toxicities during the induction phase on level 1 included: grade 4 esophagitis _ 1 pt*, grade 3 esophagitis - 2 pts, and grade 3 oral candidiasis - lpt”. During the consolidation phase. grade 4 diarrhea - I pt, grade 3 thrombocytopenia - I pt’, and grade 3 anemia - I pt, (*same patient). Toxicities during the induction phase of level 2: grade 4 esophagitis - lpt, grade 3 thrombocytopenia - Ipt Hyper- fractionation XRT plus daily carboplatin is feasible and well tolerated. The results with 50 pts will be presented.

PILOT STUDY OF ALTERNATING RADIOTHERAPY AND CHEMOTHERAPY IN INOPERABLE NON SMALL CELL LUNG CANCER (NSCLC). G. Arcangeli (l),B. Saracino (2) M. Rinaldi (2), F. Angelini (11, L. D'Angelo (1) (1) S. M. Goretti Hosp., Latina and (2) Regina Elena National Cancer Institute, Rome, Italy.

Between 1988 and 1991, 35 patients with inoperable, locally advanced NSCLC, were treated by alternate radiotherapy and chemotherapy. Radiotherapy was given as three 180 ~GY fractions on day 1, 2 and 3; 20, 21 and 22; 48 and 49, for a total dose of 5940 cGy. A two drugs combination of CDDP (60 mg/mq for 1 day) and Etoposide (90 mg/mq for 3 consecutive days) was given from day 10 to 12, 37 to 39, and 65 to 67. The median follow-up was 56 months (range: 43 to 69). Toxicity was acceptable in all but 5 patients. One died for sepsis, and 4 disconti- nued the treatment because of hematologic or cardiac toxicity. Response was evaluated in 30 patients: clinical C.R., P.R., and no change or progression was observed in 5 (16.5%), 20 (67%) and 5 (16.5%) patients, respectively. The median survival of all 35 patients was 11 months. The median survival of the 30 patients who received the complete treatment was 14 months. Three patients (10%) are long term survivors (range: 48 to 68 months). The median time to local progression, independently from the type of early clinical response, was 13 months, with 38% of patients remaining free from local progression. The median time to systemic progression was 18 months with only 37% patients remaining free from systemic progression.

RTOG 3808 ECOG 4588, PRELItINARY ANALYSIS OF A PHASE III TRIAL IN REGIONALLY ADVANCED UNRESECTABLE NON-SMALL CELL LUNG CANCER. W Sause, C Scott, S Taylor, 0 Johnson, R Livingston, R Komaki, B Emami, \d Curran, R Byhdrdt, G Fisher, A Turrisi. LDS Hospital, SLC, UT; RTOG Headquarters Phil, PA; Rush Presbyterean Med Ctr, Chicago, IL; Vander- bilt Clinic, Nashville, TN; U/i/ash Hospital, Seattle, WA; Mallinckrodt Inst, St.Louis, MO; Fox Chase Cancer Ctr, Phil PA; Zablocki VA Hosp, Hilwaukee. WI; London Req Cancer Ctr, Ontario, Univ/Michigan Medical Ctr, Ann Arbor, Ml.

All patients with Stage II, IIIA, III6 non-small cell lung cancer who were deemed surgical1 unresectable were potential candidates. Patients were required to have Karnof- sky performance status (KPS) of greater than 60 and weight loss less than 5%. Randomized treatment consisted of 60 Gy or irradiation delivered at 2.0 ?y ner fraction vs. induc- tion chemotherapy consistinn of Cisnlatin 100 mg/m2 days 1 and 29 with Vinblastine 5 mq/m? weekly for 5 weeks followed by 60 Gy at 2 Gy per fraction starting on day 50. 490 patients were reoistered on trial of which 452 were pro- perly entered and eligible. 95% of patients were Stage IIIA and Ills. Greater than 2/3 of patients had KPS of more than 80. Toxicity was acceptable with 4 acute treatment-related deaths. One year and median survival were as follows: chew therapy plus radiation therapy-60%, 13.8 rnos, hyperfraction- ated radiation therapy-514, 12.3 mo5. and standard radia- tion therapy-46%. 11 .4 mos. The chemotherapy and radiation therapy arm was statistically superior, ioq rank p=O.O3. In selected patients with surgically unresectable non-small I ung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated irradiation or standard radiation therapy alone yielding a statistically signifi- cant short term survival advantage.