684 685

PHASE II STUDY OF CONCURRENT ClSPLATlN(CDDP)-VlNDESINE(VDS)

CHEMOTHERAPY(CT) PLUS TWICE-DAILY THORACIC RADIOTHERAPY

(TRT) FOR LOCALLY ADVANCED NO-MALL CELL LUNGCANCER (NSCLC). T. Matsumoto,Y. Nishiwaki, T. Tamura, N. Saijo, M. Shimoyama. Japan Clinical Oncology Group (JCOG) Lung Cancer Study Group East ., supported by a Grant-in-Aid from the Ministry of Health and Welfare. Japan.

,To determine the effectiveness and the toxicity of concurrent full-dose CT (CDDP/VDS) and twice-daily TRT for locally advanced NSCLC, a phase II study was conducted using CDDP (80 mglm’ day 1) and VDS (3 mg/m2 day 1, 8) at 4 week intervals,being repeated for 2 or 3 courses, and twice-daily TRT (1.5 Gy, 6 hours apart) starling on day 2 to a total of 51 Gy in 34 fractions during 3.3 weeks. TRTcould be extended up to 80 Gy in 40 fractions during 4 weekscriteria for eligibility were unresectable stage IIIA or Ill6 disease with measurable or evaluable lesion, PS (ECOG) O-1, less than 75 years of age and no prior treatment. Between May 1992 and Aprill993,61 cases were accrued; 49 male & 12 female ; median age 61 (range: 37-75) ; PS O/1=20/41 ; adeno/squamous cell / large cell=30/26/5 ; stage IIIA I Ill6 =13/48.Two courses of CTwere given to 92% of cases , with 56% receiving three courses. All but one Pt received 51 Gy or more of TRT, and 59% of them received 54-60 Gy

TRT was interrupted due to toxicity in 56% of cases with 1 to 19 days (median ; 2 days). Grade 3 and 4 of leukopenia, thrombocytopenia.and anemia were observed in 90% , 8% and 31% respectively. Grade 3 of esophagitis was observed in13%. There were 2 treatment-related deaths, one due to hemoptysis and the other due to neutropenia induced sepsis.

One patient had a complete response (CR), 40 partial response (PR), 11 no change (NC), and the overall response rate was 67.2% (95% confidence limits; 54.0.78.7%). Concurrent CDDPNDS plus twice-daily (1 SGyx 21 day) TRT could be administered with acceptable toxicity.This combined modality achieved a response rate of 67.2% in 61 cases with locally advanced NSCLC. MST has not been reached with an estimated 1 -year survival of 64%.

686

CONCURRENT CHRMORADIATION FOR STAGE III NON-SMALL CELL LUNG CANCER (NSCLC): FROM CISPLATIN ALONE TO CISPLATIN + ETOPOSIDE. F. Rebool, Y. Brewer, P. Vincent, B. Chawet, C. F&x Faure, M. Taolelle. Department of Thoracic Oncology. Clinique Sainte Catherine. BP 846. Avignon 84082 France.

Due to poor local contml and early distant metastasis, standard radiotherapy (RT) alone demonstratea a low curat& potential in Stage IIl NSCLC with l- and 2- year survival around 45% and 13% respecdvely. The purpose of this study was to improve upon these results through early integration of mncomitant chemotherapy with sucndard fractionation RT. Since July 1989, we have treated 146 patients @ts) with Stage IlI inoperable NSCLC (favorable CALGB criteria) with concomitant chemoradiation. In the first study, 73 pts received concomitant cisplatin at a dose of 20 mgkqmQ4 hr over 5 days for 2 cycles during w&s 2 and 6 of RT. Complete response rate was 66% at 6-weeks following completion of therapy, as determined by CT-scan, 6baroptic bronchoscopy and biopsy at the initial tumor site. Grade 3-4 toxicities were less than 10%. With a median follow-up of 27 months, actuarial sorvival at 1. 2 and 3 veam is 48.2%. 27.5% and 25% resmecdvelv. Disease-frx suvival is 2i% at 2 ani 3 years. Two-&u suvival appears substan&lly improved over standard radiotherapy alone, mainly due to better local control. However, there is no significant impact on one-year and median survivals, mainly because of a high incidence of distant metastasis during the tirst year. Therefore, we initiated in Feb. 1992, a second study in which etoposide at 50 mglsqmld for 5 days was added to the same dose of cisplatin for 4 cycles. Etoposide was chosen becaose of its potential synergy with cisplatin and radiation. The first 2 cycles of chemotherapy were delivered during weeks 1 and 5 of RT and were followed by hvo additional cycles at weeks 8 and 11. Seventy three pts have beeo enrolled and 40 have now surscient follow-up for an interim analysis. Complete response rate is 65%. With a median follow-up of 15.5 months, overall swival is 70.8% at 12 months with a disease-free survival of 58.6% at 15 months. F’m$ected survival is 45% at 2 years. Grade 3-4 toxicities were mainly hematologic (18%). These results appear to be substantially better than in the iirst study with a 22.6% improvement in l-year sowival and a 24.7% improvement in disease-free suvival at 15 months. At 15 months, median survival has not been reached whereas it was 11.4 months in the first study. These resolts could be related to a signhicaot reduction in the rate of early distant metastasis while sostalnina a hieh level of local control. Thev mav iustifv a Phase IIl randomititdal. - -

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AN ONGOING RANDOMIZED STUDY DF NEO-ADJUVANT WEMOTHERA- PY IN RESECTABLE NON SMALL CELL lU@!J CAlWCtI lNSCLC1 A. D+rre, 6. Milleron, D. Mere. 6. Lebeeu. Cl. Chwteng. P. Jmoulet. N. Peiilet. E. Ouoix. H. Jenicet. J.N. Lembrd. S. Qouve. J.M. We&et. E. Lemeri6.G. Miech, J.L. Sk. S. Coetmeur. ZkOOg See&n. FRANCE. Neo-ejduvant chemotherepy INAC) ie e promising rtretegic concept in the treatment of NSCLC. Phase II studies shown that NAC was feasible with high level of response rate end eccepteble morbidity. In 1991, we initiated, e randomized study to compere two treetment strategies : one induced by primery surgery (group 1). one induced by primary chemotherepy followed by surgery (group 2). The eligibility criteria ere es follows : histologically proved NSCLC, resectable. untreated, stages I (except TlNO) II snd Illa. Patients have to be aged < 75, with PS < 2. They are randomized in 2 groups. In group I, surgery is performed immediately after rendomizetion. In group II, 2 cycles of Mitomycin IM : 6 mg/mz/dl), lfosfemide (I : 1.5 glm’ldl-3), Cisplatin (P : 30 mglm’ldl-3) ere performed before surgery (day l-3 end 22-24). If there is en objective response, 2 more cycles will be performed efter surgery. In both groups, if the disewe is cleesifiid es T3 or N2 on surgical specimen, e rediotherepy will be performed. Since June 91, 168 patients have been randomized : 89 in group 1, and 79 in group 2. 130 have completed sll assigned treetment, 71 end 59 respectively. In group 1, 66 underwent thorecotomy (4 patients were ineligible), end in group 2, 51 (4 patients were ineligible, 1 patient refused treatment, 1 patient died of arterial embolisms, 1 patient died of neutropenie infection end 1 patient had e sub-clavicular progression). In group 1, surgery wee complete in 56 (85 %I, incomplete in 5 end exploratory in 5. In group 2, surgery wee complete in 43 (84 %), incomplete in 4 end exploratory in 4. The 1 * cycle of NAC wee done at full doses in ail eligible ceeee, except in 2 oases (patient’s refusal) and the 2” cycle was performed St reduced doses in 12 cases and not done in 7 cases. Surgery was performed at the right time (6* or 7* week), in 39 ceses (79 %). At the present time, (I NAC protocol csn be conducted. Surgery is feasible after 2 cycles of e MIP chemotherapy. The progression rate after 2 cycles wee low and did not prevent surgery.

687

CONCURRENT DAILY CHEMOTHERAPY WITH BYPERFRACTIONATED THORACIC IRRADIATION IN STAGE III NSCLC -PRELIMINARY RESULTS OF A PILOT STUDY. C Lo&in, D Logan, I Aref, 0 Agboola, A Crepeau, P Cross, WK Evans, A Gimxl, D Gravenor, L Grimaxl, K Reid, H Sachs, F Shawji, D Stewart, S Tadros, E Tomiak, M Howard and G Goss.

The use of multiple daily fractions (MDF) potentially decreases late tissue toxicity and overcomes accelerated clonogen repopulation, suggesting a therapeutic benefit over conventional fmctioMtion. Both in vitro aad in viva data have documented the radiosensitizing effect of cisplatin. The feasibility of combing MDF with daily cisplatin was tested in a pilot study at the Ottawa Regional Cancer Centre (ORCC).

Twenty-four patients (14 male & 10 female) were entered on this study, to ascertain the feasibility of delivering concurrent daily cisplatin with hypmfmcdoaated thoracic irradiation, followed by adjuvant combination chemotherapy (cisplatin and vinblastine) in stage Ill non-small cell lung cancer. Patient characteristics: median age 60.8 yrs.(range 35-77 years); median ECGG performance status 1 (range O-2), TNM stage - T,N, - 3 pts., T,N, - 2 pts., T,N, _ 5 pts., T& - 5 pts., T,N,, - 1 pt., T,N, - 6 pts., T,N, - 2 pts. Chemtierapy consisted of cisplatin 3 mg/m’ daily (4 pts.), 5 mg/m’ daily (1 pt.) aad 6mg/m2 daily (19 pts.), with weekly vinblastine 2mg/m’ (9 pts.) Hyperliactionated thoracic irradiation delivered 60 Gy in 40 fractions over 4 weeks at 1.5 Gy b.i.d., minimum 6 hours apart. Three-four weeks post concurenf chemo-irradiation 3 cycles of cisplatin 75-8OmgJm’ and vinblastine 6-8mglm’ were given q 21 days. Toxicity: there was no significant pulmonary, renal or neurological toxicity during concurrent chemo-kdiion and hem&ok&al toxicity was minimal (median WBC 4.5) The major toxicity was esophagitis RTOG grade 0 (6 pts.), grade 1 (5 pm.), grade 2 (8 pts.) and grade 3 (4 pts.) One instance of esophageal perforation occurred following dilatation for a non regimen related stricture. The patient fully recovered

Response rates and a detailed analysis of toxicity will be presented.