P-551 A phase II randomized trial of weekly versus. 3-weekly docetaxel as second line treatment for non-small cell lung cancer

S230 P 548 El

Poster Session 4/Chemotherapy:

Prolonged infusion (PI) of gemcitabine (G) in combination with cisplatin (C) in patients with advanced non-small cell lung cancer (NSCLC): preliminary results of a dose-finding and pharmacokinetic (PK) study

Orazio Caffo’ , Samuela Binato”, Antonio Santo3, Monica Giovannini3, Antonio Lucenti4, Maurizio Centonzes, Marco Zaffaroni”, Massimo ZucchettiG, Giuseppe Cartei”, Enzo Galligioni4. ‘Medical Oncology Department - Santa Chiara Hospital, Trenfo, Italy; 2 Medical Oncology Department, Padova, Italy; 3 Medical Oncology Department, Verona, Italy; 4 Medical Oncology Department, Trenfo, Ha/y; sRadio/ogy Department, Trento, Italy; 6 Mario Negri Institute, Milano, lfaly

Background: The combination of G and C is one of the most frequently used treatments in advanced NSCLC. The antitumoral activity of G is mediated by di- and triphosphate derivates, whose intracellular concentration is dose rate dependent. Increased levels of active metabolite (dFdU) are achieved by prolonging infusion time while holding the dose rate fixed at IO mg/smq/min. We therefore designed a dose-finding and pk study to define the optimal dose of G in PI combined with C in patients with advanced NSCLC. Methods: G was administered at a fixed dose rate of IO mg/smq/min on days 1,8 and C (75 mg/sqm) on day 8, q 21 days, for a maximum of 6 cycles. G was escalated from 600 to 1200 mg/sqm, with a 100 mg/sqm dose escalation, up to the dose-limiting toxicity, with at least 3 pts at each dose level. Plasma levels of G and dFdU were determined by HPLC on samples obtained on days 1 and 8 of the first treatment course in at least 3 pts/cohort. QLQ30 and LC13 EORTC questionnaires were adopted for quality of life evaluation. Results: Twenty-two patients (median age 60 y, range 38-69 y) have been included so far in the study. All pts have been treated with at least 3 GC courses, up to the sixth dose level, and within these dose levels the maximum tolerated dose of G in PI was not reached. Major toxicities and responses after three courses of therapy are reported in the table. Preliminary pk data obtained at doses of 600-900 mglsqm show G plasma levels comprised in the range 15-22 WM. After a preliminary analysis quality of life seems to be not worsened by the treatment. Dose level 600 700 800 900 1000 1100

# courses 10 14 9 9 9 9

Vomiting (G3-4) 1

1

Neutropenia (G3-4)

# Evaluable pts (after 3 courses)

PR

SD

PD

4 5 3 3 3 3

2 1 2 2 2 1

1 2 1 1 1

1 2 1 1

1 2 2 2 2

NSCLC 2

patients who received a platin agent plus a “new” cytotoxic drug vs an older regimen (median 9.3 vs. 6.7 months, ~~0.026). Finally improved survival was also found for the group of patients who received second line chemotherapiy after 1997 compared to before 1997 (n=58, median 9.9 vs 4.1 months, p
P 550 Prolonged gemcitabine infusion (GMCpi) alone or in L-L.--! combination with cisplatin in advanced NSCLC patients with stable disease (SD) after two courses of chemotherapy (CT) containing gemcitabine 30-minutes infusion (GMC) Carmelo Tibaldi’, Francesca Russo2, llaria Bernardini3, Antonio Chella4, Giovanni Toma3, Fabrizio Tempestini5, Anna Maria Santolicandro3, Albert0 Ricchi*, Alfred0 Falcone3. ’Azienda USL 6 Livorno, Livorno, Italy; *AZ. USL 6 Livorno, Livorno, Ha/y; 3Az USL 6 Livorno, Livorno, Italy; 4 Dip. Cardiotoracico Univ. Piss, Piss, ha/y; s AZ USL 6 Livorno, Livorno, ltaly

Rationale: Aim of the study is to investigate, in advanced NSCLC patients pretreated with 30-minutes GMC infusion, if the prolonged GMC infusion (fix dose rate= 10 mg/sqm/min) is able to overcome the resistance to GMC and consequently to change SD to PR. Study design: Patients with advanced NSCLC were treated with 2 courses of CT according to the age as follows: elderly patients (age >70 yrs) Gemcitabine 1200 mg/sqm iv 30-min infusion on days 1,8 every 21 days; younger patients (age ~70 yrs) CDDP 80 mg/sqm on day 1 and Gemcitabine 1200 mg/sqm iv 30-min infusion on days I,8 every 21 days. Patients with SD after 2 cycles of CT were treated for further 2 courses with Gemcitabine 1200 mg/mq iv 120 minutes infusion (IO mg/sqm/min) on days. I,8 every 21 days alone in case of elderly patients, or in combination with Cisplatin 80 mg/sqm iv on day 1 in younger patients. Patients characteristics: Up to now 20 patients were enrolled, 17 males and 3 females: median age was 68 yrs (range 50-82). PS: 0=6, 1=6, 2=8; twelve pts were adenocarcinoma, 7 squamous, 1 other. Seven patients were treated with GMCpi and 13 patients with CDDP+GMCpi. Total number of cycles administered was 75; we observed the following G3-4 (WHO) hematological toxicity (% of courses):

GMC

Conclusion: G administered

as PI at a fixed dose rate of IO mg/smq/min does not seem to produce dose limiting toxicities up to the dose of 1100 mg/sqm. Pts’ accrual is ongoing at the last dose level. The final results of the present study will be available by the meeting time.

P 549

El

Progress in palliative chemotherapy modern chemotherapy regimens

for NSCLC? Effects of

Miklos Pless’ , Frank Waechter’ , Jakob R. Passweg2, Richard Herrmann’ ’ Medical Oncology University Hospital, Base/, Switzerlanfl 2 Hematology University Hospital, Base/, Switzerland

Background: Randomized prospective trials (RPT) suggest that newer chemotherapeutic agents (i.e. gemcitabine, one of the taxanes or vinorelbine) improve survival in NSCLC. The goal of this retrospective study was to analyze outcome of 230 consecutive patients with inoperable NSCLC in a single institution and to a) determine whether there was an improvement in outcome over time and b) if so, to analyze factors associated with this improvement. Methods: 230 documented patients with NSCLC at the Base1 University Hospital treated after 1990 were analyzed retrospectively. Breakpoints by year of treatment were determined using sequential Cox proportional hazards regression models and the Kaplan-Meier estimator. Multivariate analysis was used to determine which factors were associated with improved survival over time. Results: One- and 2-year survival of patients diagnosed after 1997 was significantly better than of those diagnosed prior to 1997. (40f 8% versus 19 f 9% and 23 f 7% vs 5 f 5% respectively, pI997 did not differ significantly in sex (70% male), age (median 60 years), stage, performance status, histology, weight loss, proportion with elevated LDH. of the factors analyzed, LDH, Albumin, Leukocytosis and performance status were significantly associated with survival. Further analysis showed that 1) patients treated with best supportive care only (n=31) had better survival after 1997 (median 5.7 vs 4.1 months, ~~0.025). 2) When comparing only patients who received palliative chemotherapy the cohort after 1997 had significantly improved survival (n=199, median 9.2 vs 6.9 months, p
Neutropenia Thrombocytopenia Anemia

G3

G4

1.3

1.3

1.3

1.3

~GMCpi G3 G4

~CDDP+GMC G3 G4

CDDP+GMCpi G3 G4

4.0 2.6 13

6.6 5.3 2.6

1.3 5.3

No G3-4 non- haematological toxicity was observed. Responses: up to now 14 patients are evaluable for response: 4/14 (28.5%) PR, 6/14 (42.8%) SD, 4/14 (28.5%) PD. All responses were reviewed by an independent radiologist. Conclusions: The Gemcitabine administered at the dose of 1200 mg/sqm iv 120 minutes infusion (IO mg/sqm/min) on days I,8 every 21 days alone or in combination with CDDP is well tolerated and seems to be able to change SD to PR in about 28% of the patients. Updated results will be presented at the meeting.

I P 551

A phase II randomized trial of weekly versus. 3-weekly docetaxel as second line treatment for non-small cell lung cancer

Chun-Minq Tsai’, Chao-Hua Chiu’, Gwo-Shu Wang*, Wei-Juin Su’, Yuh-Min Chen’ , Reury-Perng Perng*. ’ Section of Thoracic Oncology Chest Department, Taipei Veterans Genera/ Hospital, Taipei, Taiwan; e Chesf Deparfmenf, Taipei Veterans Genera/ Hospital, Taipei, Taiwan

Purpose: This phase II randomized

prospective study was designed to compare the toxicity profile, efficacy, and quality of life between weekly and classic 3-weekly schedules of taxotere in the treatment of previously treated NSCLC patients. Method: arm A: taxotere 66 mg/m’ day 1 and Arm B: taxotere 33 mg/m* days1 and 8, were given every three weeks. Dose might be escalated (lO%/cycle) when no Grade II toxicity occurred. Results: Fifty patients were randomized and forty-three patients are now available for analysis. Patients were required to have stage IV or IIIB measurable or evaluable disease who failed cisplatin-based front line chemotherapy with performance status 0, 1, or 2. Patient characteristics were similar in these two arms. The dose intensities were similar with the same median cy-

Poster Session I/Chemotherapy: cles (3) completed. ORRs were 13.6% and 28.6% in arm A and arm B, respectively, DCRs (CR+PR+SD) were 50% and 48%, respectively, and median time-to-progression were 11.3 and 12.7 weeks, respectively. Median survivals were 33.4 and 27.6 weeks, l-year survivals 45% and 28%, respectively. Arm A had significantly higher leukopenia and neutropenia, but with less compromised QoL. Patients in arm B received less salvage treatment after taxotere treatment. Conclusion: While weekly taxotere schedule shows higher ORR and less hematological toxicity, there is no advantage to 3-week schedule in terms of time-to-progression and survival, but more compromised QoL.

P 552 El

Paclitaxel, Gemcitabine, and Cisplatin in non-resectable, non-small cell lung cancer (NSCLC)

Jens B. Sorensen’, Lars Erik Stenbygaard*, Kell Osterlind3, Heine Hmi Hansen4 ’ Dept. of Oncology 5073, Copenhagen, Denmark; ‘Dept. Oncology Herlev Hospital, Copenhagen, Denmark, Copenhagen, Denmark; 3 Dept Oncology Herlev Hospital, Copenhagen, Denmark, Copenhagen, Denmark; 4 Dept. Oncology National University, Copenhagen, Denmark

Aim: To evaluate the activity of a new 3-drug chemotherapy

regimen in a phase II-study in NSCLC. Methods: Treatment was Paclitaxel 180 mg/mz and Cisplatin 100 mg/m’ day 1, and Gemcitabine 1000 mg/m’ day 1 and 8, every 3 weeks to pts. with previously untreated non-resectable NSCLC without brain metastases, performance status 2 or better, normal organ functions, and uni-or bi-dimentionally measurable disease. Results: Among 104 pts. treated there were 48 males (46%) and 56 females (54%) with stages IIIA, 1118,and IV in IO%, 49%, and 41%, respectively, and performance status O,l, and 2, in 41%, 45%, and 15%, respectively. Histology was squamous cell in 33%, adenocarcinoma in 52%, large cell in lo%, and adenosquamous or undifferentiated NSCLC in 6%. Median age was 57 years (range 42-70), and median no. of treatment courses was 6 (range 1-l 3). Hematologic toxicity was pronounced but short-lasting, with WHO grade IV neutropenia in 53 pts. (52%) and thrombocytopenia in 30 pts. (29%). Septicemia occurred in 15 pts. (14%) and bleeding episodes in 3 pts. (3%), with one toxic death (1%). No pts. had WHO grade IV nausea, while 27 (26%) had grade 3. Total response rate was 55% (partial responses 44 pts. (42%) and complete 13 pts. (13%)). Time to progression was in median 36 wks. (range 4-228~) and median survival 55 wks (range O-239+). Conclusions: This 3-drug regimen seems promising, with a substantial number of long lasting responses. Toxicity was especially hematological, which was however short-lasting and was manageable. This promissing regimen is currently under evaluation in a randomized trial comparing it to a 2-drug standard regimen.

P 553 El

Induction chemoterapy Gemcitabine(G)-Cisplatin(C) versus Etoposide(E)-Cisplatin(C) in IIIA/IIIB stages non small cell lung cancer (NSCLC) patients with intermittent radiotherapy

Saulius Cicenas, Terese Pipiriene-Zelviene, Arvydas Burneckis, Audrone Ciceniene. Vilnius University Oncology Institute, Vilnius, Lithuania

Objectives: To compare the response

rate, duration and toxicity of GC vs radiotherapy in chemonaive patients with IIIAIIIIB NSCLC. Patients and Methods: Pts with PS O-2, histologicaly confirmed advanced NSCLC, stage IIIA/B (mediastinoscopy in all pts for N2 disease). Arm A: G 1,250 mg/m* on days 1 and 8 plus C 70 mglm” on days 1; arm B: E 120 mg/m’ on days 1 and 2 plus C 70 mg/m’ on day 1 in 21-day cycle. Initial tumor response was performed after 2 cycles of chemotherapy. Patients with PR or CR received 42 Gy radiotherapy (RT) plus another 3 cycles of GC or EC. Pts with SD underwent radical radiation up to 70 Gy. In cases of PD or unaccaptable toxicity pts. went out of study. Second tumor response evaluation was performed after the 5-cycle for pts remaining on treatment. Results: So far, 58 pts, entered the study and received 2 cycles of chemotherapy. After 2 cycles in GC arm:2 (6,6%) CR, 20 (66,6%) PR, 8 (26,6%) had no response of whom 2 died of PD and 3 progressed and received 70 Gy RT. After 5 cycles of chemotherapy and 42 Gy of RT in the 17 responders, there were 5 CR and 12 PR. In EC arm, none CR was observed after 2 cycles of chemotherapy, 6 (21,4%) had PR, and 7 (25%) had SD of whom 2 died due to PD, while the others underwent RT. After 5 cycles of chemotherapy with 42 Gy of RT in the 15 responders, there were 4 pts with no change. Hematological toxicity: leukopenia 17 pts (56,6%) in GC 18 pts (64,2%) in EC. 1 SEA in GC. Neutropenia: 7 pts (23,3%) in GC, 10 pts (35,7%) in EC, trombocytopenia 10 pts (33,3%) in GC, 9 pts (28%) in EC. No febrile neutropenia. Conclusions: 1. It seems that GC regiment is superior to EC regiment in advanced NSCLC. A trend favouring the GC regimen regarding response rate and duration of response. 2. RR after two cycles of chemotherapy was 67.3% EC with intermittent

SCLC

S231

in GC arm and 46.4% in EC arm. 3. After five cycles of chemotherapy and radiation RR in GC arm was 67,3% and 21.4% in EC arm. Response duration in GC-13 mo and EC-6.5 mo.

THURSDAY, 14 AUGUST 2003

Chemotherapy:

I

P 554

SCLC

Raised serum urea predicts for early death in poor prognosis small cell lung cancer

Vanessa A. Potter’, Gulnaz Begum 2, Penella J. Wol13. ’ Dept Clinical Oncology Nottingham City Hospital, Nottingham NG.5 IPB and The Cancer Centre, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK 515 2TH, Birmingham, UK; ’ CRC Clinical Trials Unit, The Medical School, Edgbaston, Birmingham 615 2TT; Birmingham, UK; 3 Dept of Clinical Oncology Nottingham City Hospital, Nottingham, UK NG5 7PB, Noifingham, UK

Background: Studies have defined factors that predict for response to treatment and long term survival in small cell lung cancer (SCLC) and can be used to divide patients into different prognostic groups. This study set out to identify additional features predicting early death in poor prognosis SCLC patients receiving CAV chemotherapy. Methods: Patients with poor prognosis SCLC (defined by a Manchester score of 3 or more) seen at Nottingham City Hospital between 1998 and 2000 were identified. Pre-treatment variables were assessed using univariate and multivariate analysis to determine risk factors for early death. Results: 83 patients with poor prognosis SCLC were identified and data obtained for 46 who received CAV chemotherapy and 16 who received no chemotherapy. The median survival patients who received no chemotherapy was only 0.54 months, while the median survival of those who received CAV chemotherapy was 5.5 months, with 17% surviving 1 year. 33% of patients receiving CAV died during the first cycle of chemotherapy, 22% attributable to sepsis. Univariate analysis identified age over 65 (p=O.O04), raised urea (p= 0.001) and a raised neutrophil count (~~0.04) to be predictors of early death. Multivariate analysis showed a raised serum urea to be the most important predictor of early death - increasing the risk 13-fold (95% Cl = 2.8 - 64). Conclusions: In this population of patients with poor prognosis small cell lung cancer the risk of toxic death during the first cycle of chemotherapy was high (22%). A raised serum urea was found to be the most important independent predictor of early death.

I P 555

Weekly cisplatin-epirubicin-paclitaxel (PET) with G-CSF support in extensive stage SCLC. SICOG 9910 phase II study

Giuseppe Frasci’, Luigi Maiorino’, Pasquale Comella3, Dario Muci3, Nicola Panza4, Cosimo Brunetti4, Marina Licenziato3, Antonio Farris4, Enrico Barbato“, Giuseppe Comella3. ’ National Tumor lnstifute Of Naples, Nap/es, Nap/es; 2 NationalTumor lnsfituie c/o S/COG, Nap/es, /ta/y; 3 National Tumor lnsfitute c/o S/COG, Nap/es, Italy; 4 S/COG, Nap/es, Italy

Purpose: The present study was aimed at defining the antitumor activity of the cisplatin-epirubicin-paclitaxel (PET) weekly administration with G-CSF support in chemo-naive SCLC patients with extensive disease (ED-SCLC). Methods: Chemonaive ED-SCLC patients received cisplatin 30 mg/sqm, epirubicin 50 mg/sqm, paclitaxel 120 mg/sqm weekly, with G-CSF (5 microgr./kg days 3-5) support, for a maximum of 12 weeks. Results: Thirty-nine patients were treated, for a total of 348 cycles delivered. Eight complete responses (21%) and 22 partial responses (56%) were recorded, giving a 77% response rate [95% confidence interval, 61-89%]. At a 14-month (range, 7-28) median follow-up, 24 deaths have occurred. Median progression-free and overall survival were 7 months and 11 months, with Iyear and P-year projected probability of survival of 45% and 24%, respectively. No toxic deaths occurred. Grade 4 neutropenia and thrombocytopenia occurred in 4 and 1 patient, respectively. Only one case of neutropenic sepsis was recorded, while hemorragic thrombocytopenia was never observed. Diarrhea, emesis and fatigue were the main nonhematologic toxicities being severe in 3, 6 and 6 patients, respectively.. Conclusions: The weekly PET combination with G-CSF support represents a well tolerated therapeutic approach in chemo-naive ED-SCLC patients. Both response rate and median survival does not seem substantially better than those achievable with a standard approach. Further randomised trials with this approach are not warranted.