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Abstract No 7166
Authors
Abstract
Background: From January 2000 to August 2002, fourty-six chemo- and radiotherapy naïve patients (pts) with pathologically confirmed mediastinoscopy proven stage IIIa/N2 NSCLC were treated with induction Docetaxel and Cisplatin within a 2-stage phase II trial. Based on institutional policy, pts were registered for the EORTC 08941 trial comparing surgical resection with radical radiotherapy after chemotherapy (Splinter, 2000). Methods: Docetaxel was given at a dose of 85 mg/m² on day 1 as a 1-hour infusion with premedication, followed by Cisplatin at a dose of 40 mg/m²/day given on day 1 and 2. Courses were repeated every 21 days and a maximum of 3 courses were given. Responses were evaluated according to the RECIST criteria. Results: Of the 46 patients registered, about 2/3rd (65.2 %) had a performance status of 0/1 and most of the patients were male (80.4 %). Median age was 60 years (range 27-74), and in the majority of patients the histological subtypes were squamous (43.5%) and adeno (34.8 %). The reported hematological grade 3/4 toxicities were as follows:leucopenia (21 pts), neutropenia (30 pts); there was no grade 3/4 thrombocytopenia or anemia. Eight cases of febrile neutropenia were reported of which one resulted in early death. Other common non-hematological toxicities CTC grade 3/4 were: nausea (8 pts), vomiting (6 pts), fatigue (5 pts) and dyspnoe (5 pts). 39/46 pts (84.8 %) reached the end of treatment as defined by the protocol, 6 pts (13 %) stopped due to toxicity and one pt due to protocol violation before reaching 3 cycles. Considering eligible pts (n=40), a total of 18 responses ( 1 CR and 17 PR) have been reported (RR 45 %; 95 % CI: 29.3 % - 61.5 %). The median survival of all pts was 16.7 months (95 % CI: 12.2 % – 21.7 %), and the 1- year-survival rate was 64.6 % (95 % CI: 50.1 – 79.0). Conclusion: As a result of this international multi-center phase II trial the combination of Docetaxel and Cisplatin seems to be a tolerable and effective regimen for induction chemotherapy of stage IIIa/N2 NSCLC.
Abstract No 618
Authors
Abstract Background: Whilst evidence suggests that baseline health related quality of life (HRQOL) scores predict survival in metastatic cancer patients, few trials have examined prognostic HRQOL factors in non-metastatic cancer patients. In this international phase III randomized controlled trial (RCT), we address these issues and retrospectively explore if baseline HRQOL scores predict survival in locally advanced breast cancer (LABC) patients. Methods: 435 LABC patients were enrolled over a period of three years randomized to receive in arm A: F (500 mg/m2 IV d1, 8 q 28 d x 6), E (60 mg/m2 IV d1, 8) and C (75 mg/m2 p.o. d1-14) versus E (120 mg/m2 IV d 1), C (830 mg/m2 IV d 1) and G-CSF (5 ug/kg/d s.c. d 2-13) q 14 d x 6 in arm B. HRQOL was assessed using the EORTC QLQ-C30 with baseline assessments being conducted before randomization. The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap re-sampling technique was used to assess the stability of the outcomes. In this prognostic factor analysis, 359 (82.5%) of the 435 patients had a HRQOL assessment available at baseline and were then evaluated. Age, TNM stage, ER status as well as pre-selected HRQOL variables from the EORTC QLQ-C30 were analyzed for prognostic factor analyses in predicting overall survival (OS). Results: Diagnosis of inflammatory breast cancer (T4d, any N, M0) significantly predicted poor survival with a hazard ratio (HR) 1.375 (95% CI 1.027 – 1.840, p=0.0323). However, no HRQOL scores at baseline showed up as prognostic indicators of OS, either in the univariate or multivariate analysis. A confirmatory analysis using a model-averaging technique, based on repeated forward Cox PH model-building on bootstrap generated data-sets were applied and confirmed the previous results. Conclusions: This is the first HRQOL prognostic factor analysis (PFA) study in LABC, and overall one of the largest HRQOL PFA using a robust methodology carried out in a homogenous cancer population. Our results indicate that HRQOL scores have no prognostic value in LABC patients.
Abstract No 3620
Authors
Abstract
Background: A survival benefit has been demonstrated with adjuvant systemic (syst) chemotherapy (CT) using 5FU in patients (pts) with colon cancer. Administration of regional CT during one week is easier, but past studies have only shown a trend towards a benefit. The aim of this multicenter, intergroup study was to evaluate the efficacy of short term (1 week) regional chemotherapy in combination with long term (6 mo) systemic CT and to compare systemic 5 FU + Levamisol (FU+L) to 5 FU + folinic acid (FU+FA) in patients with stage II and III (Astler B2 and C) colorectal cancer. Methods: 1857 pts were randomized during surgery to one of 4 treatment arms (2 by 2 design) and, as per protocol, eligibility (stage II or III colon or rectum adenocarcinoma) was confirmed by pathology in 1501 pts as follows: A - Regional (reg) CT + syst FU+L, n = 380. B - Reg CT + syst FU+FA, n =368. C - syst FU+L only, n = 374. D - syst FU-FA only, n =379. Regional CT was either intraperitoneal (3600 mg/m2 in 6 days) or intraportal (3500 mg/m2 in 7 days). Results: Median follow up was 6.8 years. Tolerance was good. 79.7 % pts received full dose of reg CT, and 74.3 % full dose of syst CT. Overall survival at 5 years was 72.3% vs 72.0% in pts with or without regional CT (HR = 0.96, logrank p=0.68) and 72.3% vs 71.9% in pts with FU + FA vs FU + L (HR = 0.98, logrank p=0.81). Disease free survival at 5 years was 63.9% in pts who received regional CT and 61.4% in pts who did not receive regional CT (HR = 0.94, p=0.43) and 64.0% vs 61.8% in pts with FU + FA vs FU + L (HR = 0.92, logrank p=0.32). The data do not show any treatment differences according to stage (II vs III) or tumor location (colon vs rectum). Conclusions: 1 – combining regional and systemic adjuvant CT does not improve the efficacy of systemic chemotherapy. 2 – folinic acid when combined with systemic adjuvant 5 FU is not superior to levamisole.
Abstract No 4117
Authors
Abstract
Background: Tolerability and activity of 5-day (d) infusional FU-oxaliplatin were improved with Chrono as compared with Cst in colorectal cancer pts(Lévi et al, Lancet 1997). CDDP addition to FU tended to prolong Progression-Free Survival (PFS) in pancreatic cancer pts(Ducreux et al, Ann Oncol 2002). Methods: A factorial design tested the relative effects of CDDP addition (100 mg/m²/course, c) to FU (c1/c2/c3 : 5/6/6.5 g/m²) and Cst vs Chrono (FU : 10 pm-10 am, peak at 4 am ; CDDP : 10 am-10 pm, peak at 4 pm) 5 d q21d. Pts with advanced (25) or M (82) histologically-proven pancreatic cancer were registered in 15 centers. CTC toxicity was assessed q10 d and response q 3c. Survival was the main endpoint. Results: Characteristics : CDDP no/yes, 55/52 pts ; Chrono no/yes, 54/53 pts; median age, 63 y; WHO PS 0/1/2, 35/52/20 pts; M sites 0/1/2+, 16/51/36 pts. CDDP increased median PFS from 2.1 months (mo.) [95% CL, 1.9-2.3] to 3.2 mo. [2.5-5.0] and median survival from 5.4 mo. [3.9-8.4] to 8.3 mo. [5.7-11.9]. Median survival (mo.) was 6.1 on Cst and 6.7 on Chrono (NS). CDDP addition reduced the risk of P by 44% (Log rank, p = 0.005) and that of death by 20% (p = 0.26). CDDP significantly increased grade 3-4 toxicity per patient : neutropenia (58 vs 6%), thrombopenia (38 vs 2%), anemia (25 vs 12%). The dose intensities of FU and CDDP were higher with Chrono (p = 0.03). Despite this, Chrono decreased the incidence of grade 3-4 mucositis (8 vs 27%, p = 0.01), anorexia (10 vs 23%) and diarrhea (2 vs 10%). Conclusions: CDDP addition to FU near maximum tolerated doses prolonged PFS in pancreatic cancer pts, with a trend toward improved survival. Chrono ameliorated non haematological tolerability and allowed to administer higher DIs. Chrono FU should be combined with a less toxic Pt complex to concurrently improve antitumor efficacy and tolerability in M pancreatic cancer. Support : NCI, ARC (grant 9033), ARTBC, hôp. P Brousse, Villejuif (F).
Abstract No 6528
Authors
Abstract
Background: Late toxicity has become an important factor influencing the management in survivors of childhood cancer and Hodgkin lymphoma. Although, significant proportions of patients with aggressive non-Hodgkin's lymphoma (NHL) become long-term survivors, a systematic analysis on late non-malignant toxicity in these patients is lacking. An EORTC database of these patients, consistently treated with CHOP-like regimens since 1980, offered the possibility to explore late complications in detail. Methods: Using detailed questionnaires, late complications (>2 years after start therapy) of 757 patients (90%) with a median follow-up of 9.4 (2.1-20.4) years were scored. The cumulative incidences of complications were computed in a competing risk model by Gray (death being the competing event) to avoid bias caused by the high percentage of NHL-related deaths. Risk factors were estimated in a Cox proportional-hazards model, but also evaluated with the Gray-test. Results: Late non-neoplastic complications were found in 46% of the patients, see Table. Conclusions: Half of the patients with aggressive NHL experience late non-neoplastic, mainly cardiovascular or gonadal, complications. Regulation of hypertension and quitting smoking after treatment may preserve a better quality of life.
Late complications % cumulative incidence at 15 years
(n=patients analyzed) Significant risk factors
Cardiac complications 20% (n=697) Age>50, smoking
Large arterial vessel occlusion 7% (n=686) Age>50, hypertension
Hypertension 8% (n=689) Radiotherapy abdomen age>50, smoking, salvage
Gastro-intestinal ulcers or perforations 6% (n=683) Hypertension, salvage, RT abdomen
Lung fibrosis 6% (n=683) Smoking, bleomycin, RT mediastinum
Renal insufficiency 11% (n=682) Salvage, hypertension, cisplatin
ASCT, radiotherapy, MOPP
Disabling neuropathy 13% (n=689) Salvage, cisplatin
Hypothyroidism 5% (n=652) Radiotherapy neck, gender
Male Infertility 18% (n=193) MOPP, cisplatin
Female infertility (<40 years) 29% (n=62) ASCT, salvage
Abstract No 9015
Authors
Abstract
Background: Based on our phase II results, RHT is considered a promising neoadjuvant treatment strategy for HR-STS and is being evaluated in a prospective RCT (phase III). We are now reporting the results of the first interim analysis after recruitment of 146 patients (pts) with HR-STS (tumors ≥ 5 cm, grade 2 or 3, extracompartmental, and deep). Methods: Between July/97 and Nov/01 all pts have been randomised to receive four pre- and post-operative cycles EIA (etoposide: 250 mg/m²; ifosfamide: 6 g/m²; adriamycin: 50 mg/m²) either combined with RHT (74) or EIA alone (72). Pts were stratified by extremity (E=64) vs non-extremity (Non-E=82), and by primary (S1=65) vs recurrent (S2=29) vs previously inadequate (R1/R2) resected (S3=52) tumors. Results: At Nov/03 224 pts of planned 340 pts (170 pts per arm) have been randomized. For 141 pts entering the protocol treatment, 95% (preoperative) and 89% (postoperative) of prescribed EIA cycles could begiven. 80% (preoperative) an 66% (postoperative) of the planned numbers of RHT applications were performed. Hematological toxicity (grade 3/4) was seen in 17 pts consisting primarily of leucopenia (13) and thrombopenia (4). In 102 pts evaluable (not evaluable S3=33 or other=11) for response after completion of 4 EIA with or without RHT, objective response rate was 28% (2 CR; 27 PR). In addition, 7 pts showed MR (7%), 57 pts SD (56%) and 9 pts PD (6%). Of 135 assessable pts, 33% received no surgery (32 pts S3/R1 and 13 pts other reasons), but 61% received conservative resection (83) and 5% were amputated (7) with 10% histopathological complete necrosis (9). At median follow-up of 36 months (cut-off 4/03) the 3–year local progression free rate (LPFR), distant progression free rate (DPFR), and overall survival (OS) for E are 86.6% (95% CI: 77.3-96.0%), 78.1% (95% CI:67.0-89.1%) and 77.3%(95%CI:65.8-88.7%) andfor Non-E are 40.9%(95% CI:28.1-53.7%), 54.9%(95% CI:40.3-69.5%) and 41.5% (95% CI:28.9-54.0) repectively. Conclusions: The neoadjuvant EIA regimen with or without RHT is feasible and tolerable in the majority of pts. While this is a preliminary report, the estimated 3-year LPFR, DPFR and OS in local-advanced HR-STS pts are encouraging. The second interim analysis is planned for 247 pts.
Abstract No 4504
Authors
Abstract
Background:In 1992, as radical prostatectomy was more frequently applied to clinical T1-2N0M0 prostate cancer, the EORTC has undertaken a randomized trial of immediate post-operative treatment versus wait-and-see policy, for patients with high risk factors of local relapse on pathological specimen. We present the first efficacy results of this study. Methods:Eligible patients were ≤75 years old, WHO performance status (PS) 0-1, had T0-3N0M0 PC preoperatively and ≥1 pathological risk factor of: capsule invasion, positive surgical margins, invasion of seminal vesicles. P-XRT was 60Gy conventional external radiation delivered over 6 weeks. The trial was powered to detect a hazard ratio (HR) of 0.77 with 80% power with two-sided α=0.05 with regard to clinical or biological progression-free survival. Results:1005 pts were accrued by end 2001 (P-XRT: 503, Px: 502). Median age was 65.4 years, PS 0 in 93.8%, median pre- and post-operative PSA 12.3 and 0.2 ng/ml, respectively. All but 41pts on P-XRT were irradiated with median dose 60Gy (range: 50-74). The trial was reviewed by an IDMC in December 2003, after a median follow-up of 5 years and early disclosure of the trial results was recommended. Biochemical PFS (time to twice confirmed PSA increase over nadir or first clinical failure or death) at 5 years was 72.2% (CI: 67.7-76.8) on P-XRT and 51.8% (CI: 46.8-56.8), HR=0.52 (CI: 0.42-0.64), P<0.0001. Clinical PFS was improved from 74.8% to 83.3% at 5 years (HR=0.68, CI: 0.52-0.89, P=0.004). The incidence of loco-regional failure was significantly decreased (P<0.0001). Further follow-up is needed to assess the impact on distant metastases and overall survival. P-XRT is associated with an increased risk of immediate and late grade 1-2 side effects. Grade 3 side effect rates so far were less than 5% in both groups. Conclusions:Post-operative radiotherapy results in improved biochemical and clinical PFS. This benefit is to be weighed against the treatment side effects. Further follow-up is needed to assess the impact on overall survival.
Abstract No 9004
Authors
Abstract
Background: The EORTC-ISG-AGITG trial in which 946 GIST patients (pts) were randomized to receive 400 or 800 mg of Imatinib daily has shown an increased progression free survival in pts randomized to the HD arm. Pts randomized to LD could cross-over to HD upon progression (PD). The present analysis aims at evaluating the feasibility, safety and efficacy of this policy. Methods: End-points include the fraction of pts on LD with PD who crossed over, the cumulative incidence of subsequent dose reductions (with treatment discontinuation as competing risk), inter-pt comparison of toxicities observed at LD and HD (Mc Nemar paired test), objective responses and time to second PD after cross-over (Kaplan-Meier estimate). Results: Of the 473 patients randomized to LD, 220 patients had PD as of 7/12/03. Of the 206 patients with f/u information, 143 pts (69%) crossed to HD (41% of the 44 pts with prior dose reduction on LD and 77% of the remaining 162 pts with PD not requiring a dose reduction on LD). The cumulative incidence of subsequent dose reduction after cross-over was 31% after one year, and 2 pts discontinued therapy due to toxicity. Anemia and fatigue increased after cross-over, while leucopenia and neutropenia were less severe than during the initial LD treatment. Excluding 29 pts who crossed-over before (11 pts) or > 60 days after (18 pts) radiologically documented PD and the 17 pts not yet reassessed, 2 confirmed partial responses, 30 stable disease (20+ to 592+ days), and 65 pts with PD were recorded in 97 evaluable pts. In all, 89% of pts discontinued protocol therapy for PD. However, after 1 year, 26% of the pts were still progression free (median time to PD: 78 days compared to 203 days prior to cross over. Conclusions: Cross-over to HD Imatinib is feasible in most GIST pts who progress on LD therapy. Despite increased fatigue and anemia, dose reduction is only required in 31% of pts within a year. Dose increase leads to further therapeutic activity.
Abstract No 1501
Authors
Abstract
Background: Autocrine activation of PDGFα&β receptors yields strong mitogenic effects and activates tumor angiogenesis in malignant gliomas. Preclinical data showed tumor growth inhibition of ras and v-sis transformed BALB/c, 3T3U87 and U343 human glioma xenografts in mice using imatinib mesylate. Methods: To assess the antitumor activity (measured by response and 6-month PFS) and the safety of imatinib mesylate (Glivec) in patients (pts) with histologically proven, CT-scan or MRI documented measurable recurrent glioblastoma, stable/decreasing doses of steroids, no more than one prior chemotherapy regimen, and no surgery or radiotherapy within 3 months prior to enrollment were entered. Imatinib mesylate was given until tumor progression at the daily dose of 600mg (group A) and 800mg (group B) in two cohorts of pts. A Fleming one sample/one stage testing procedure was used. Results: A total of 51 pts (M/F: 26/25; median age: 54, range: 27-68; PS 0/1/2: 18/26/7) were entered. 33 pts had been exposed to chemotherapy, 50 to radiotherapy, and 45 had prior resection. 19 pts were entered in group A (70 cycles) and 32 in group B (113 cycles). Grade 3-4 neutropenia was reported in 5 pts (1 in group A and 4 in group B) and was associated with fever in 3 pts. Dose reduction:5 pts (4 in group A, 1 in group B); dose interruption: 21 pts (11 in group A, 10 in group B) pts. Grade 3-4 non hematological toxicity consisted of edema (1 pt), skin rash (2 pts), and reversible ALT elevation (4 pts). One patient presented an intratumoral hemorrhage associated with a documented tumor progression (considered not related to treatment). Three pts (2 in group A and 1 in group B) experienced confirmed partial responses that lasted 10, 10, and 12+ months. Responses slowly occurred after 3, 6 and 7 months of drug exposure. Prolonged >6-months tumor stabilizations were reported in 5 pts (1 in group A and 4 in group B). Conclusion: Imatinib mesylate as single agent displays promising antitumor activity and good safety profile in patients with recurrent glioblastoma. This study is currently extended to patients with malignant oligodendroglioma and anaplastic astrocytoma.
Abstract No 3526
Authors
Abstract
Background: The tolerability and anticancer activity of a 5-day (d) infusion of 5-fluorouracil (FU), leucovorin (LV) and oxaliplatin (l-OHP) were improved with chronomodulated (CM) delivery as compared with constant rate infusion in metastatic colorectal cancer (MCC) (Lévi, Lancet Oncology, 2, 2001). We investigated whether FFL4-10 - schedule (sch) B - (Berthault et al. JCO 1996) improves survival as compared with FOLFOX2 - sch A - (De Gramont et al. EJC 1997) in MCC patients (pts). Methods:554 pts had to be randomized to receive either sch at the same dose levels (g/m²) per course (c) q14 d: FU (c1, 3 ;c2, 3.4; c3 : 3.6; LV, 1.2 ; l-OHP, 0.1 . For sch A, l-OHP was infused for 2 h at daytime ( d1), LV for 2 h (d1, d2) and FU for 22 h (d1, d2). For sch B, FU-LV and l-OHP were infused daily from 10 pm to 10 am (peak at 4 am) and from 10 am to 10 pm (peak at 4 pm) using a programmable pump. Pts were evaluated q14 d for toxicity and q4 c for response. The primary endpoint was Overall Survival (OS), 430 events being required. Results: 564 pts (sch A/B : 282/282 pts) from 36 centers with median follow-up >3 years; sch A/B %pts: women, 40.1/40.4; Colon primary, 59.9/58.5; PS 0/1/2, 49.3/40.4/9.2 vs 47.5/40.4/11.7; single M site, 50.7/50; synchronous M, 73/74.1; adjuvant chemo, 16.7/19.1. N of courses : sch A/B: 2916/2783. Toxic deaths : 1/2. OS (Hazard Ratio=0.94, 95% CI:0.73-1.21) and Progression Free Survival (PFS) (HR=1.01, 95% CI: 0.81-1.26) did not differ significantly. Conclusions: This is the first trial that has compared the two most active treatment schedules as 1st line chemotherapy of MCC. No difference in OS and PFS were observed with a median survival > 18 months in both regimens and a different but low toxicity profile (<7 % of courses). Supported in part by an educational grant from SANOFI-SYNTHELABO.
Table
FOLFOX2 (sch A) CM FFL4-10 (sch B) p-value
% neutropenia gr 3-4 per pt (per c) 25.0 (6.5) 7.0 (2.5) <0.001 (<0.001)
% diarrhea gr 3-4 per pt (per c) 10.8 (1.2) 28.3 (5.1) <0.001 (<0.001)
% mucositis gr 3-4 per pt (per c) 6.8 (0.8) 13.8 (1.9) 0.002 (<0.001)
% sensory neuropathy (per pt) 26.6 26.0 0.87
% ORR (%best response),based on extramural review 45.3 (52.8) 42.2 (51.1) 0.45 (0.67)
Median PFS (months) [95% CL] 8.3 [7.9-9.3] 8.3 [7.4-9.4] 0.88(Logrank)
Median survival(months) [95% CL] 18.7 [17.7-21.0] 19.6 [18.2-21.2] 0.53(Logrank)
Abstract No 9599
Authors
Abstract
Background:In the EORTC 26981-22981/NCIC CE3 phase III trial, 573 pts with newly diagnosed GBM were randomized to receive radiotherapy (RT) or RT plus Temozolomide (results separately reported). In this analysis we evaluate clinical parameters as prognostic factors for survival. Methods:The Cox Proportional Hazard model was used to assess factors related to patients’ characteristics (age, gender, WHO Performance Status (PS), Mini Mental State Examination (MMSE)), disease history (extent of resection, time between surgery and start of radiotherapy, administration of corticosteroids, baseline haematological and non-haematological toxicity status), tumor location (hemisphere and lobe). These factors were first screened by univariate technique and the hemisphere was the only variable that did not pass the 10% significance level.Results: In the multivariate analysis, poorer prognosis was associated with the extent of surgery (biopsy worse than partial or complete debulking) (p<0.0001), greater age (p=0.016), male gender (p=0.013), lower MMSE Score (p<0.0001), the administration of corticosteroids (p=0.012), tumor location in the frontal lobe (p=0.002) or tumor on more than one lobe (p=0.02). The time between surgery and start of radiotherapy, the baseline haematological and non-haematological toxicity status and the WHO PS status were not retained. Gender seems related to overall survival but probably because the proportion of male patients with a tumor on more than one lobe was significantly higher (p<0.0001).Conclusions: This analysis confirms the extent of surgery and age as major prognostic factors. MMSE has a better correlation to survival than WHO PS. The model will be validated with the bootstrap technique and on an independent data set. The results should be taken into consideration for future EORTC glioma trials.
Abstract No 5531
Authors
Abstract
Background: In 1986, the EORTC HNCCG initiated a randomized phase III trial to assess whether LP using ICT followed by radiation therapy (XRT) was as safe as the conventional treatment: total laryngectomy with partial pharyngectomy (TLP), radical neck dissection (RND) and postop XRT. Preliminary results were published in 1996; this updated analysis has been carried with a median follow-up of 10 years. Methods: 202 patients (pts) candidates for TLP + RND + XRT were randomly assigned to receive in the surgery arm (arm 1) this treatment or in the ICT arm (arm 2) up to 3 cycles of CDDP (100mg/m² day 1) and 5FU (1000 mg/m² days 1-5) followed in case of complete response by XRT or by TPL + RND + XRT in the other cases. The endpoints were survival (OS and PFS) and LP defined as a functional larynx free of disease (larynx in place without tracheotomy, feeding tube or gastrostomy, and without evidence of local disease). Results: this final analysis was carried out on 194 eligible pts (arm 1: 94, arm 2: 100). There were 92 males (98%) in arm 1 and 94 (94%) in arm 2. Stage II, III and IV respectively numbered 6, 51 and 37 in arm 1 and 7, 59 and 34 in arm 2. Postop courses and quality of surgical resections did not differ between both arms (ie. initial surgery in arm 1or surgery after ICT in arm 2) as well as tolerance to XRTwhatever its schedule. Ultimate disease control, including successful salvage surgeries after XRT, was not significantly different between both arms. As of December 2003, 14 % of pts in arm 1 and 17 % of pts in arm 2 were still alive. The hypopharynx SCC evolution was the cause of death in 43 pts in arm 1 and in 41 pts in arm 2. The 5-yr.OS was 33 % in arm 1 and 38 % in arm 2, the 10-yr. OS was respectively 14 % and 13 %. The 5-yr. PFS was 26 % in arm 1 and 32 % in arm 2, the 10-yr. PFS was respectively 8.5 % and 11 %. In arm 2 survival with a functional larynx in place was 22 % at 5 years and 9 % at 10 years. Conclusions: this final analysis has confirmed the preliminary results. This LP strategy provided similar survival curves as compared with conventional treatment and allowed 2/3 of the survivors to retain their larynx.
Abstract No 515
Authors
Abstract No 5003
Authors
Abstract
Background: Adding anthracyclin to conventional platinum based chemotherapy of ovarian cancer has been found to improve survival. The aim of the present study was to evaluate the effect on survival of adding epirubicin to the standard treatment with carboplatin and paclitaxel. Methods: Between March 1999 and August 2001, 887 patients were randomized to receive 6-9 cycles of paclitaxel (175 mg/m2, 3 h iv) followed by carboplatin (AUC 5, Calvert formula) with or without epirubicin (75 mg/m2 iv prior to paclitaxel) on a 3-weekly schedule. The primary endpoint was progression-free survival and 542 progression events were required to detect a hazard ratio of 0.786 or less. Results: Patient characteristics were similar across the treatment arms. Residual disease less than 1 cm at surgery with no measurable disease before chemotherapy was reported in 328 patients (37%), with 159 in the TEC and 169 in the TC arm. A total of 63 patients had to be withdrawn from the study, 20 were ineligible, 32 due to hypersensitivity reaction to paclitaxel during the first or second course and 11 withdraw informed consent, leaving 824 patients for the survival analysis. The median follow up is 30 months for patients still alive. Progressive disease has been reported for 573 patients and 326 have died. In the total group of patients, the median time to progression was 17.2 months in the TEC arm and 16.3 in the TC arm (p=0.99) . In the group with residual tumor of 1 cm or less, the median time to progression was 24.7 months in the TEC arm and 24.4 months in the TC arm (p=0.94). In patients with more than 1 cm of residual tumor, the median time to progression in the TEC arm was 14.6 months and 13.8 months in the TC arm (p=0.75). The median overall survival has not yet been reached. Conclusions: The addition of epirubicin to the standard carboplatin and paclitaxel treatment did not improve progression free survival. The evaluation of effect on long term survival awaits further follow up.
Abstract No 5005
Authors
J. Pfisterer, M. Plante, I. Vergote, A. Du Bois, U. Wagner, H. Hirte, A. J. Lacave, A. Stähle, R. Kimmig, E. Eisenhauer; AGO OVAR, Kiel, Germany; NCIC CTG, Quebec City, PQ, Canada; EORTC GCG, Leuven, Belgium; AGO OVAR, Wiesbaden, Germany; AGO OVAR, Tübingen, Germany; NCIC CTG, Hamilton, ON, Canada; EORTC GCG, Oviedo, Spain; AGO OVAR, Karlsruhe, Germany; AGO OVAR, München, Germany; NCIC CTG, Kingston, ON, Canada
Abstract
Background: Most patients (pts) with OVCA relapse. ICON 4 - AGO OVAR 2.2 results suggest combination C-based therapy may be superior to single agent C. GC is a feasible less neurotoxic regimen and thus of interest to evaluate in this setting. Methods: In this phase III trial pts with platinum sensitive recurrent OVCA (≥ 6 months after the end of primary therapy) were randomized to receive C (AUC 4 d1) plus G (1000 mg/m² d1 and 8) or C (AUC 5 d1) every 3 weeks. The primary objective compared progression free survival (PFS) in both arms. Secondary objectives were response rate (RR) and duration, overall survival (OS), toxicity and quality of life (QoL). Results: From 09/99 and 04/02, 356 pts (178 GC, 178 C) were randomized. Both study arms were well balanced for baseline disease characteristics. Median number of cycles was 6 for GC (0-10) and C (0-9). The weekly dose intensity was 98.2% for C (C arm) and 96.2% for C and 75.6% (92.8% for d 1 and 63.4% for d8) for G (GC arm). Grade 3/4 hematologic toxicities were significant higher in the GC arm (anemia 27.4% of pts. vs. 8.0%, neutropenia 70.3% vs. 12.0%, thrombocytopenia 34.9% vs. 11.4%). G-CSF or GM-CSF was more often used in GC (23.6% of pts. vs. 10.1%) as well as red cell transfusions (37.1% vs. 14.6%). Clinical sequelae were similar between arms: febrile neutropenia (1.1% GC vs. 0% C) and infections (0.6% for both arms). Grade 3/4 non-hematologic toxicities were infrequent in both arms (< 5%), especially for sensory neuropathy (1.1% GC vs. 1.7% C). Overall RR for GC was 47.2% (95% CI: 39.9-54.5%) and 30.9% (95% CI: 24.1-37.7) for C (p= 0.0016). GC pts reported significantly faster palliation of abdominal symptoms as well as significantly improved global QoL. With a median follow up of 13 months, median PFS was 8.6 mo (95%CI: 8.0-9.7) for GC and 5.8 mo (95% CI: 5.2-7.1) for C (HR 0.72 [95% CI: 0.57-0.90], p= 0.0038, e= 311). OS data are immature and this study was not powered to detect differences in OS. Conclusion: The combination of G plus C improves PFS and QoL in platinum sensitive recurrent OVCA patients with acceptable toxicity.
Abstract No 3504
Authors
Abstract
Background: This trial evaluates the addition of CT to preop RT, and the value of postop CT for improving survival in T3-T4 resectable rectal cancer. Eligibility : age < 80 y and WHO PS < 2. Arm 1: preopRT 45 Gy in 5 weeks (w). Arm 2 : preopRT + two 5 day CT courses ( 5-FU 350 mg/m2/d ; LV : 20 mg/m2/d ), the 1st and 5th w of RT. Arm 3 : preopRT + four postop CT courses. Arm 4 : preopRT-CT + postop CT. We analyzed the pathological response. Methods: 1011 pts entered the trial : group 1-no preop CT (arms 1+3) : 505 pts ; group 2- preop CT (arms 2+4) : 506 pts. Patients/tumour (T) : median age 63.2 y ; male/female 73.1 %/27.9 % ; T distance from anal verge : <5 cm : 49.1% ; 6-10 cm : 43.7 % ; >10 cm : 6.46 % ; NA : 0,8 % ; T stage : T3 : 89.5 % ; T4 : 10 %. NA : 0.5 %. A resection was performed in 476 pts (94.3 %) and 473 pts (99.5 %) in Group 1 and 2 respectively. Results: Group 1 vs Group 2 : Median tumour length (mm) : 30 vs 25 (p = <0.0001). Extension into rectal wall : T0 : 5.3 % vs 14 % (p = >0.0001) ; PT0-2 : 42.9 % vs 58.1 % (p = < 0.0001). Median depth invasion beyond muscularis propria (mm) : 3 vs 2 (p = 0.061). Veinous (V) invasion 13.9 % vs 9.1 % (p = 0.021). Perineural (N) invasion 14.3 % vs 7.6 % (p = 0.001). Lymphatic (L) invasion 17.4 % vs 11.4 % (p = 0.008). Nodal invasion : 26.9 % vs 20.9 % (p = 0.031). Conclusions: The addition of 5-FU-LV to preopRT significantly reduced tumor size and pTN stage, and significant decreased LVN invasion rates. Longer follow-up is needed to assess the true impact on local control and survival. Supported in part by a grant from the French Research Ministry (PHRC 1992) and by NCI grants 2U10-CA11488-22 through 5U10-CA11488-32.
Abstract No 7020
Authors
Abstract
Background: Attempts to maintain the response to initial therapy have been unsuccessful in SCLC. BEC2 is a murine IgG2b antibody that elicits antiidiotypic response to GD3, a glycosphingolipid overexpressed on membranes of SCLC and other tumors derived from the neural crest. In a pilot study (Grant et al. Clin Cancer Res 1999) long-term survivors were reported in SCLC patients vaccinated with BEC2/BCG. Methods: LD-SCLC patients in response after 4-6 cycles of multi-agent chemotherapy and thoracic irradiation were eligible. PCI was recommended in complete responders. Patients were randomized to observation or to 5 BEC2 (Merck KGaA and ImClone Systems Inc.) vaccinations (2.5 mg by 8 intradermal injections) with BCG, given on week 0, 2, 4, 6 and 10. A total of 376 deaths were required to detect a 40% increase in median survival in the V arm using a 2-sided α of 5% and a 90% power. The protocol was amended after 55% of inclusions to allow patients with a PPD positive test, when this was found to be safe (Klimek et al, ASCO 2000).Results: From April 1998 to October 2002 515 patients were randomized to observation (O, n=258) or vaccination (V, n=257). Arms were well balanced; 38% female, Karnofsky PS >80% in 94%, PPD positive in 11%, complete response to initial therapy in 49%, sequential chemotherapy-thoracic irradiation in 40%; 62% received PCI. The most frequent treatment related side effect was local reaction at the injection sites (95% of patients, grade 3 in 35%). Lethargy was observed in 37% (grade 3 in 3%). Six toxic deaths have been reported, 4 in the O arm (1 radiation pneumonitis and 3 pancytopenia) and 2 in the V arm (2 radiation pneumonitis). So far 71% of patients have progressed and 72% have died. There was no difference in survival (median 16.3 vs 14.3 months, p=0.3) or progression-free survival (median 6.6 vs 5.7 months, p=0.2) between O and V arms. Conclusions: Vaccination with BEC2/BCG does not provide any survival advantage in limited disease SCLC patients after a major response to induction chemo-radiation.
Abstract No 7021
Authors
Abstract No 4551
Authors
Abstract
Background: Surrogate endpoints are needed to shorten the duration of Phase III clinical trials in advanced prostate cancer. Prostate-specific antigen (PSA) is the most studied biomarker in prostate cancer. This study attempts to validate PSA endpoints as surrogates for overall survival (OS). Methods: Individual data from 2161 patients with advanced prostate cancer treated in studies comparing bicalutamide (‘Casodex’), either as monotherapy or in combination with an LHRHa, with castration were used in a meta-analytical approach to surrogate endpoint validation. PSA response, several definitions of time to PSA progression and longitudinal PSA measurements were considered. Results: The analyses confirmed the known association between the PSA endpoints and OS at the individual patient level (biomarker association). However, when comparing patients treated with bicalutamide-based treatment or castration, the effect of hormonal intervention on the PSA endpoint did not predict the effect on OS with a high degree of precision. The association between intervention on any PSA endpoint and OS, measured by the determination coefficient R2 (ranging from 0.10-0.66 for PSA progression, to 0.69 for the whole PSA profile) was generally low. Conclusions: It is a common misconception that a correlation at the individual level between PSA and OS is enough to demonstrate surrogacy. To demonstrate true surrogacy, a high correlation between the treatment effect on the surrogate and the treatment effect on the true endpoint needs to be established across groups of patients treated with two alternative interventions. The level of association observed in this study between the treatment effect on PSA endpoints and that observed on OS was in general low, showing that in Phase III clinical trials of hormonal treatments in advanced prostate cancer, treatment effects on OS cannot be predicted from observed treatment effects on PSA endpoints with a high degree of precision. This study indicates that PSA is unlikely to be a useful surrogate for OS in advanced prostate cancer. ‘Casodex’ is a trademark of the AstraZeneca group of companies
Abstract No 2
Authors
Abstract
Background:
Standard therapy of GBM after biopsy or resection is RT. TMZ, a novel methylating agent demonstrated some activity against recurrent glioma. In a phase II trial we observed a potential survival advantage by adding TMZ concomitantly and adjuvant to RT (Stupp et al. JCO 2002). In this randomized trial we tested this novel regimen against RT. Methods: Patients (pts) age 18-70 years with histologically proven newly diagnosed GBM (WHO grade IV) were eligible. Pts were randomized between standard RT (60 Gy in 30 daily fractions of 2 Gy) versus the same RT and concomitant (TMZ 75 mg/m2/d, daily up to 42 days) followed by up to 6 cycles of adjuvant TMZ (150-200 mg/m2, daily x 5d, q28 d). Survival (intent to treat) was the primary endpoint aiming at a 30% improvement (log-rank). Pathology was centrally reviewed. Results: Five hundred and seventy-three pts from 85 centers were randomized. Median follow-up is 2 years, 436 patients have died. Median time between histological diagnosis and treatment start was 5 weeks. RT was delivered as prescribed in 93% of pts. Concomitant TMZ was administered without interruption in 76%, temporarily interrupted in 11% and prematurely discontinued in 12%. Adjuvant TMZ was given to 76% of pts, 36% completed all 6 cycles for a total of 924 cycles. The increase in median survival is 3 months. The log-rank test is significant with a p-value of < .0001. The hazard ratio is 0.62 (95% c.i. 0.51-0.75). Grade 3/4 hematotoxicity was observed in 7% of pts during concomitant TMZ/RT treatment, and in 16% (5.2% of cycles) of the adjuvant TMZ. Patients continue to be followed to evaluate long term effects of treatment.
RT (n=286) RT/TMZ (n=287) p-value
Age, median (range) [years] 56.6 (23.1-70.8) 55.7 (19-70.5) NS
Tumor resection 70% 68% NS
WHO PS : 0 / 1 / 2 39% / 49% / 12% 39% / 48% / 13% NS
Steroids at baseline 75% 67% p=0.041
Progr.-free surv. (95% c.i.) 5.0 mo (4.2-5.5) 7.2 mo (5.8-8.3) p< .0001
Median survival (95% c.i.) 12 mo (11.2-13.2) 15 mo (13.6-16.8) p< .0001
2-year survival (95% c.i.) 8% (4-12%) 26% (20-32%) p< .0001
Conclusions: Concomitant and adjuvant TMZ chemotherapy significantly improves PFS and overall survival in GBM pts. This treatment is safe and well tolerated.
Abstract No 4517
Authors
Abstract
Background: Adjuvant radiotherapy is effective treatment for stage I seminoma, but is associated with a late risk of 2nd cancers. The MRC has undertaken two trials to reduce adjuvant radiation dose (TE18: 30Gy vs 20Gy) and volume (TE10: PA strip vs dog-leg field) without loss of effectiveness. Following reports that 1 course of carboplatin (C) may be equivalent to radiation (R) this large randomised trial was undertaken to compare these approaches; we present the initial results of this study. Methods: The primary randomisation was between R and 1 course of C AUCx7; R dose was optionally decided by randomisation between 20 Gy/10f and 30 Gy/15f prior to results of TE18, or centre choice of schedule. The trial was powered to exclude absolute differences in the 2 year relapse rates of >3%. Results: From June 96 to March 01 1447 patients (pts) were randomised (ratio 3:5) between C and R. Pt characteristics were well balanced: mean age 38 years, 14% had elevated HCG and 10% had previous ipsilateral inguinal operations. Of pts randomised to R 13% had dogleg field and 87% PA strip. Median follow up (FU) is now 3 years and over 90% of patients have at least 2 years FU. Relapse-free survival rates for R vs C (95%CI) are 97.2% (95.9, 98.1) v 98.1% (96.6, 98.9) at 2 years and 96.6% (95.2, 97.6) v 95.4% (93.3, 96.9) at 3 years; HR 1.39 (90% CI: 0.92, 2.11) p=0.195; the 90% CI excludes an increase in relapse rates in the C arm of more than 3% at 2 years and of more than 4% at 3 years. Pattern of relapse varied, sites being the PA nodes only in 70% (C) v 7% (R), and pelvis relapse in 4% (C) vs 28%(R). Second germ cell tumours (GCTs) have been reported in 1 pt allocated C and 7 allocated R, non-GCTs 2 C vs 4 R. No disease or treatment related deaths have been reported after C and only 1 after R; non-cancer deaths 1 (C) vs 2 (R). Conclusions: With a median FU of 3 years, an absolute increase in relapse rate in the C arm of more than 3% at 2 years can be excluded reliably, early data on 2nd malignancies favours the C group and to date there have been no disease or treatment related deaths. Further FU is needed to confirm that these results are maintained beyond 3 years.
Abstract No 5508
Authors
Abstract
Background: Data from 5 phase II studies support the notion that T may add to the efficacy of PF in LA-SCCHN (Posner et al. ASCO 20: 203b, 2001). Based on our phase I-II experience with TPF (Schrijvers et al. Ann Oncol 15: 638, 2004), we undertook a phase III trial comparing TPF with PF in such patients (pts). Methods: Eligible pts included nonresectable LA-SCCHN (excluding nasopharynx, nasal & paranasal cavities), measurable disease, adequate organ function, WHO performance status (PS) 0-1, age 18-70 yrs, signed informed consent. Stratification included primary tumor site and institution. Treatment arms were: Arm 1 (PF): P 100 mg/m2 day (d) 1, then F 1000 mg/m2 CI d1-5 q 21 d; Arm 2 (TPF): T 75 mg/m2 d1, P 75 mg/m2 d1, then 5-FU 750 mg/m2 CI d1-5 q 21 d. Planned treatment included 4 cycles unless progression (PD), unacceptable toxicity or pt refusal. Thereafter (interval 4-7 wks), all pts received protocol defined radiotherapy (RT: conventional, accelerated/ hyperfractionated) unless PD after cycle 1 or 2. Surgery before RT (neck dissection) or 3 months (mo) after RT (residual disease) was permitted. The planned sample size of 348 pts and 260 events had 85% power to detect a hazard ratio (HR) of 0.67 (median 10 vs 15 mo) for the primary endpoint of progression-free survival (PFS), using a 5% 2-sided test. Results: 358 pts were accrued (181 to PF and 177 to TPF). Pt/tumor characteristics (age, sex, PS, primary site, T&N stage) were well balanced. After a median follow-up of 32 mo, TPF demonstrated significantly superior PFS (HR 0.72; [95% CI 0.56;0.91]; p=0.006), overall survival (HR 0.73; [95% CI 0.57; 0.94]; p=0.016) and response rate (RR: 67.8% vs 53.6%; p=0.007), while the PF arm showed greater grade 3-4 nausea (7.3% vs 0.6%), vomiting (5.0% vs 0.6%) and stomatitis (11.2% vs 4.6%) and more toxic deaths (5.5% vs 2.3%). Conclusions: TPF (→RT) is superior to PF (→RT) in terms of RR, PFS, OS and is better tolerated.
Abstract No: 523
Authors
Abstract
Background: The prognostic impact of invasion factors uPA and PAI-1 in primary breast cancer has been demonstrated at the highest level of evidence by the prospective clinical Chemo N0 trial and a large pooled analysis. Recent results also suggested a predictive impact of these factors. Methods: In order to validate the predictive impact of uPA and PAI-1 in primary breast cancer, a pooled analysis was performed on 18 observational data sets (n=8,377) provided by members of the EORTC Receptor and Biomarker Group. uPA and PAI-1 were determined in primary tumor tissue extracts using ELISAs and ranked by center. Decisions to administer adjuvant therapy did not utilize uPA/PAI-1. Median follow-up was 79 months. Results: Time-varying survival analysis stratified by center showed that adjuvant chemotherapy (CT) was associated with an enhanced benefit (HR 0.60, CI 0.41-0.87) in patients with high uPA/PAI-1, particularly for preventing relapses during the first 3 years – in addition to its benefit in the cohort as a whole. In the 0-3 node subgroup, the enhanced benefit was also strong (HR 0.51, CI 0.31-0.85). No interaction between adjuvant endocrine therapy (ET) and uPA/PAI-1 was found in Cox analysis. However, a low-risk subgroup of N0, hormone-receptor positive, low uPA/PAI-1 patients receiving ET was identified with 10-year OS and DFS of about 92 %. Conclusions: A strong and independent predictive impact of uPA and PAI-1 regarding adjuvant chemotherapy in breast cancer was validated in this pooled analysis. However, we did not see evidence for a subgroup defined by uPA and PAI-1 for which adjuvant endocrine therapy should not be given. Our data suggest that all patients with high uPA/PAI-1 – regardless of their nodal status – should receive adjuvant chemotherapy. Moreover, in patients where the decision between endocrine and chemo-endocrine therapy is clinically open, uPA and PAI-1 could provide decisive evidence.