Median Survival For Pts Research Articles

Clinical Characteristics and Outcome of Patients (pts) with F317L BCR-ABL Kinase Domain (KD) Mutation after Therapy with Tyrosine Kinase Inhibitors (TKIs).

Background. Point mutations of the Bcr-Abl KD are the most frequently identified mechanism of resistance in pts with CML who failed TKI. The setting for outgrowth of different mutations and their subsequent response to different TKIs varies significantly. For example, mutations in codon 317, which would be predicted to impair dasatinib binding, have been generated during in vitro mutagenesis with dasatinib but not nilotinib, and the F317L, in particular, has been reported following treatment with dasatinib.Aims. We assessed the incidence and pattern of development F317L mutations in pts with TKI-resistant CML at our institution and responses following change in therapy.Results. F317L mutation was detected in 20 patients: 12 occurred among 99 pts (12%) after imatinib failure who had KD mutation assessment, and 8 among 16 pts (50%) who developed new mutations on dasatinib therapy (among 77 treated) (p=0.001). Median age for all pts with F317L was 49 years (range, 34–66 years). Pts had received imatinib for a median of 23 months (mo) (range, 2–69). Best response to imatinib was complete hematologic response in 11 and cytogenetic response in 8 (5 complete, 2 partial, 1 minor). One pt did not respond. At the time the mutation was detected, 8 pts were in chronic (CP), 6 in accelerated (AP) and 6 in blast phase (BP). Patients with F317L-mutated tumors developing on imatinib or dasatinib had similar characteristics as those who had KD mutations at other sites or no mutation detected. Among pts with F317L at start of 2nd TKI, 3 received dasatinib and all 3 had transient hematologic responses (best response) (1 partial -PHR-, 2 complete -CHR-) lasting 4, 12 and 19 mo;.4 were treated with nilotinib and 3 responded (1 CHR, 1 major molecular response-MMR-,1 complete molecular response -CMR-); 2 had imatinib dose escalation after appearance of F317L and both had a sustained complete cytogenetic response (CCyR) for 24+ and 26+ months; one pt received stem cell transplant and is in CMR 20 months after transplant; one pt did not respond to a combination of imatinib and farnesyl transferase inhibitor; and one pt was lost of follow-up with no further therapy. Among pts who developed F317L while on dasatinib (n=8), 4 never responded and 4 had an initial response to dasatinib (1 CHR, 3 CCyR) lost after a median of 15 months (range, 3 to 26); one pf these was then treated with nilotinib and achieved an ongoing CCyR for 3+ months and 2 received bosutinib after failing both nilotinib and dasatinib, achieving a transient CHR lasting 6 and 9 months, respectively. After a median follow-up of 29 months from treatment failure and 25 months from the detection of F317L, 10 pts (50%) are alive (7 CP, 2 AP, 1 BP at F317L). Median survival of pts with F317L from mutation detection was 19 mo. Survival of pts with F317L was similar to those with other mutations or without mutation when survival was dated from the time of treatment failure (p=0.51) or from mutation detection (p=0.92).Conclusion. F317L occurs more frequently after dasatinib therapy paralleling the findings of in vitro studies. TKIs showing differential in vitro activity against this mutation (e.g. nilotinib or INNO-406) may represent good candidates for treatment failure associated with F317L-mutated tumors.

Glioma patterns of care in Victoria from 1998–2000

11521 Background: The management of Gliomas is complex and requires a multidisciplinary approach. The care of such patients (pts) may be variable. The State of Victoria has a population of approximately 4 million people and over 300 new glioma cases diagnosed annually. Methods: This was a retrospective cohort study conducted by surveying doctors involved in managing incident adult glioma cases identified from the population based Victorian Cancer Registry during 1998–2000. The survey was conducted in 2004–5 obtaining at least four years follow-up data on all pts. Results: 828 pts were considered eligible for this study. 264 pts (32%) were aged over 70 years and 92 (11%) were aged over 80 years. 105 (13%) did not have a histologic diagnosis and 473 (57%) had glioblastoma multiforme (GBM). Complete macroscopic resection was performed in 209 pts (25%). Of all pts with a glioma, 612 (74%) and 326 (54%) were referred at initial diagnosis for consideration of radiotherapy and chemotherapy respectively. In 473 pts with GBM, 406 (86%) and 147 (31%) pts were initially referred for consideration of radiotherapy and chemotherapy respectively. Only 39 pts(5%) were enrolled on a clinical trial. The median survival for pts with a GBM was 7.4 months with a 3% five-year survival. Conclusions: This is one of the largest ever-reported glioma management surveys. Much of the patient demographics and approach to treatment were expected and represent a reasonable “standard of care”. Importantly, this study emphasises the elderly nature of this patient population and identifies areas of concern including: absence of histologic diagnosis, lack of multi-disciplinary care and low clinical trial enrolment. No significant financial relationships to disclose.

Prospective trial of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with advanced non-transitional cell (non-TCC) carcinomas of the urothelial tract

4542 Background: Non-TCC’s account for 5–10% of urothelial tract tumors and are each characterized by unique demographics, risk factors, and patterns of spread. A unifying feature of these malignancies is their aggressive course and poor outcomes with standard chemotherapeutic regimens. Given the rarity of these tumors, no prospective data are available to guide management. Methods: Patients with unresectable/metastatic adenocarcinoma, squamous cell, small cell, sarcomatoid, and poorly differentiated carcinomas of the urothelial tract were eligible. Treatment consisted of: Paclitaxel 200 mg/m2 IV on day 1, cisplatin 70 mg/m2 IV on day 1, ifosfamide 1500 mg/m2 IV on days 1–3 + mesna. GCSF was administered with each cycle. Treatment was recycled every 3 weeks for a maximum of 6 cycles. The primary endpoint was the response rate. Results: Twenty patients (pts) were enrolled with the following histologic types: adenocarcinoma 11/20, squamous cell carcinoma 8/20, small cell carcinoma 1/20. Pts received a median of 4 cycles (range, 1–6). The grade 3–4 toxicities included neutropenia (6/20), anemia (9/20), thrombocytopenia (4/20), confusion (1/20), seizure (1/20), neuropathy (1/20), renal insufficiency (2/20), fatigue (2/20), and hyponatremia (1/20). Thirteen of the 20 pts have died. The median survival for pts with adenocarcinoma is 24 months (95% CI 9.6–32.4) and with squamous cell carcinoma is 8.4 months (95% CI 5.3-NR). Five pts achieved durable disease-free survival (1+, 2+, 4+, 6+, and 8+ years) after ITP ± surgical consolidation. Conclusions: ITP is an active regimen in pts with advanced non-TCC’s of the urothelial tract. To our knowledge, this is the first prospective study of a chemotherapeutic regimen in this patient population. [Table: see text] [Table: see text]

Long-term follow-up of a phase II randomized trial in advanced gastrointestinal stromal tumor (GIST) patients (pts) treated with imatinib mesylate

9528 Background: Imatinib achieves tumor control in most pts with advanced GIST, but the durability of remissions has not been well described. We now present an updated long-term analysis of a randomized phase II trial first presented in 2001, with a median follow-up of 52 months. Methods: 147 pts with unresectable or metastatic malignant GIST were randomized to treatment with daily dosing of imatinib, 400 or 600 mg po. Results: Two pts (1%) achieved a complete response, 98 (67%) achieved a partial response (PR), and 23 (16%) exhibited stable disease (SD) as their best response. Median time-to-response was 13 weeks (95% CI; 12–23 weeks), but one quarter of pts responded after 23 weeks. No significant response differences were seen between the two dose levels tested. The median duration of response was 27 months, and median overall survival was 58 months. Pts with SD or PR had similar 4-year survival rates (64% versus 62%). KIT and/or PDGFRA mutational analyses were obtained in 87% of patients, and the mutational status was highly significant in predicting outcome. GISTs harboring KIT mutations in exon 11, exon 9, and with no detectable mutations in KIT or PDGFRA demonstrated PR rates of 87%, 48%, and 0%, respectively. The median survival for pts with exon 11 KIT mutations has not yet been reached, and it was 45 months for those with exon 9 mutations. Conclusions: While late progression can be seen in GIST pts treated with imatinib, the majority of pts derive benefit. Survival in those achieving SD parallels those with PRs. Late responses are often seen in pts with initial SD, and responses in general are of lasting duration. In particular, pts with KIT mutations in exon 11 (the most common exon affected) have very high response rates and favorable long term survival. [Table: see text]

A phase II study for selection of clinical and molecular predictors for survival in patients (pts) with advanced NSCLC treated with erlotinib

17066 Background: The primary objective of the ongoing phase II study was to find clinical and molecular predictors for survival. Consequently, we prospectively examined gene and protein expression and EGFR mutation profiles of tumor cells, and clinical variables. Methods: Pts with advanced NSCLC (stage IIIb/IV) previously treated with platinum-based chemotherapy received 150mg/day erlotinib (Tarceva an EGFR tyrosine-kinase inhibitor) orally until disease progression. For molecular analyses, biopsies were taken from the primary lung tumor prior to erlotinib treatment. Pure tumor cells were isolated using laser-capture microdissection. For expression analysis, a microarray of 8793 genes (Human Focus Array, Affymetrix) was used. Data were analyzed using VSN method and significance analysis of microarrays. Results: In an interim analysis, clinical data were available for 36 of 43 so far included pts in the ongoing phase II study. For 36 pts, the tumor responses were: 1 CR (3%), 4 PR (11%), 11 SD (30%) and 19 PD (53%), and the median survival was 20 wks. Overall survival was significantly better in pts with rash than without rash: 9.2 vs 4.3 months. In a 14 months follow up, all of the responding pts survived while the median survival for pts with SD or PD was 11.4 and 4.0 months, respectively. Comparing gene expression profiles of tumors from 6 pts with a response or SD with those from 13 pts with tumor progression, we could not identify genes that were differentially expressed with sufficient significance. In 20 tumor samples evaluated for EGFR protein expression and mutation analysis, 19 expressed EGFR (IHC). A base exchange in exon 18 (2166G>A; A722A) and 20 (2547A>G; Q787Q) of the EGFR already described as a single nucleotide polymorphism was seen in 4 samples performing SSCP gel electrophoresis and sequencing. Conclusions: Rash, a side effect with erlotinib, was significantly associated with better survival. No activating EGFR mutations were found indicating that the response in 14% of pts is independent of mutations. For identification of genes predictive for response to erlotinib, a larger sample number is necessary. No significant financial relationships to disclose.

Mortality trends in colorectal cancer (CRC) and influencing factors

13527 Background: A decline in overall cancer death rate was observed in the early 1990s after more than six decades of increase in cancer mortality. Effective prevention, screening and early detection as well as improved treatment strategies may be influencing factors. The aim of this study is to compare the overall survival of patients (pts) with CRC in two different years using our prospective regularly updated register database. Methods: Patients diagnosed of CRC during 1996 and 2000 were included in the study. To analyse the relation between variables the exact Fisher test was used. Survival curves were constructed according to the Kaplan-Meier method and compared by log rank analysis. Analyses were performed using the SPSS package. Results: 289 pts in 1996 and 380 in 2000 were included. Demographic data and tumour characteristics were similar in both groups. 42% of pts in 1996 and 56% in 2000 had received chemotherapy (ChT) (p<0.05). In adjuvant setting, 41.8% of patients with stage II-III colon cancer received ChT in 1996 and 57.5% in 2000 (p=0.019). ChT schedules for advanced CRC included Oxaliplatin and Irinotecan in 23% of ChT in 1996 and in 68% in 2000 (p<0.005). The number of palliative ChT lines was significantly higher in 2000 (p<0.05). Radiotherapy was administered as part of rectal cancer therapy to 48% of pts 1996 and to 60% in 2000 (p=0.05). From those, preoperative radiotherapy was administered to 21% of pts in 1996 and to 66% in 2000 (p<0.05). 4.1% of all pts were lost of follow up. With a median follow up of 104.5 months (m) for 1996 and 56.3 m for 2000, the 5-year overall survival (OS) was 45% and 61.6% respectively (p<0.001). The 5-year disease free survival (DFS) of pts with radical surgery was 73% and 81% respectively (p=0.09). The median survival of pts with radical surgery that relapse during follow up was 13.4 m in 1996 and 17.6 m in 2000 (p<0.04). There were statistical significant differences in OS between 1996 and 2000 in tumour site, stage II-III cancer and males, not in females. DFS for stages II-III was better in 2000, but no significant differences were observed. Conclusions: A positive CRC mortality trend was observed. The influencing factors were related with the use of ChT as an adjuvant treatment and the addition of new drugs in colon cancer therapies as well as preoperative radiotherapy for rectal cancer. No significant financial relationships to disclose.

Intermittent chemotherapy in advanced unresectable colorectal cancer. An option for our patients?

3703 Background: Chemotherapy (CT) improves overall survival and quality of life in advanced unresectable colorectal cancer (auCRC) and CT has better outcome when administered early. Several schedules are active in auCRC, but optimal duration remains uncertain and general practice results in administering CT until progression, toxicity or patient’s decision. The purpose of this study is to identify which auCRC patients (pts) could benefit from stopping first line CT although no progressive disease has been observed without detriment in overall survival. Methods: all pts with CRC are prospectively recorded in our single institution-data base and are included in the same assistance protocol. 358 pts (224 M; 134 F) with auCRC have been analysed. Median age 61y (23,83);67% presented as auCRC at diagnosis and 33% appeared in the follow up; 46 pts had locoregional (LR) disease, 220 pts had distant metastasis (M) and 92 pts had LR + M. Number of metastatic sites: one, 64.7%; two, 26.3% and >two, 9%. All pts received CT. CT lines: Group 1, one line with 5FU: 150 pts (42%); group 2, one line with either CPT-11 or Oxaliplatin: 67 pts (19%); group 3, two or more lines: 141 pts (39%). CT was stopped between two lines for at least 3 months (m) in 80/148 pts (141 pts of group 3 + 7 pts of groups 1 and 2) with a median interval of 9 m (3–56). CT was stopped due to maintained response in 57/80 pts (71.3%), and 12 pts (15%) restarted the same CT scheme.Kaplan-Meier survival curves were compared with log rank test. We used X2 tests to determine association between continuous or intermittent CT with certain prognostic variables. Results: With a median follow-up of 24.7 m (3.5; 72.4), the median survival (MS) of all pts was 16.7m (14.7;18.6); MS of group 1: 12.5 m; MS of group 2: 14.5m; MS of group 3: 27.9m (p<0.0001). MS of initial auCRC: 13.3m; MS for progressive auCRC: 21.53m (p<0.01). MS of pts with continuous CT: 16.5 m; MS of pts that stopped CT for at least 3 months: 36.9m (p50y in the group of intermittent CT (p<0.05). Conclusions: there is a group of pts with auCRC that could benefit from interrupting CT and restarted CT when they progress even with the same schedule. Randomised trials are warranted in order to establish the optimal duration of CT in auCRC. No significant financial relationships to disclose.

2nd line chemotherapy for patients with malignant mesothelioma (MPM) pretreated with pemetrexed (PMTX) and platinum (P)

7331 Background: PMTX + P based Ctx is considered standard care for advanced MPM. Although substantial improvement has been achieved with this Ctx doublet, time to progression and overall survival remain short. 2nd line Ctx in pts pretreated on a PMTX based combination has not been evaluated. Methods: We analyzed 67 consecutive pts (54 m/ 13 f) pretreated with PMTX (500 mg/m2) +/-CDDP (75 mg/m2) or carboplatin (AUC 5) regarding 2nd line Ctx for MPM between 12/2002 and 11/2004. All pts were treated at the Ev. Johannes Hospital Bielefeld. Response and survival data of pts receiving 2nd line Ctx were evaluated. Survival was compared with those pts receiving best supportive care (BSC). Results: Out of 67 pts 52 did not receive any 2nd line Ctx. This was due to death from MPM during 1st line Ctx in 32 pts. There was no further need for 2nd line Ctx in 20/52 which were alive and in stable disease (SD) at the end of 11/2004. Three out of these 20 pts were in continuous SD without any further treatment after a median of 6 cycles of 1st line Ctx. 2nd line Ctx was given in 10/67 pts (9 m/1f; mean age 67 ys). This was gemcitabine (1000 mg/m2 d1,8,15 repeated d29) based in 9/10 pts. In one pt PMTX + carboplatin was reintroduced due to progression of MPM 6 months after the end of 1st line Ctx. SD in pts with 2nd line Ctx was observed in 2 pts, while 8 pts progressed on 2nd line Ctx. BSC was given in 5/67 pts (4 m/1 f; mean age 52 ys) following progression after end of 1st line Ctx. Death due to MPM was observed in 6/10 pts receiving 2nd line Ctx and in 3/5 pts with BSC. Median survival in pts receiving BSC was 5 months (range 2 to 15+). Similar survival was observed with 2nd line Ctx (5 months, range 1 to 16+). Final data on TTP and survival in pts receiving 2nd line Ctx for MPM will be presented at the meeting. Conclusions: 2nd line Ctx or BSC was administered in 22,3% of MPM pts failing or relapsing PMTX based 1st line Ctx. Efficacy of 2nd line Ctx was 20% with SD as best response. Our data underline the need for randomized trials evaluating 2nd line Ctx in PMTX pretreated MPM pts. No significant financial relationships to disclose.

EGFR mutations and pAKT expression as potential predictors of gefitinib efficacy in non-small cell lung cancer (NSCLC) patients (pts)

7077 Background: Activating mutations in exons 18–21 of the EGFR gene have been found in tumors from NSCLC pts that respond to gefitinib (GEF). The goal of this study was to assess EGFR mutations, as well as expression of EGFR and related molecules by immunohistochemistry (IHC) as predictors of GEF efficacy. Methods: A total of 143 consecutive pts were enrolled in the Expanded Access Trial; 7 pts died and 1 withdrew consent prior to starting treatment. Only pts with > 1 week of therapy were included for analysis. IHC was performed for 64 pts with evaluable tissue specimens. Tissue from 34 pts was analyzed for activating mutations by sequence analysis. Fisher’s Exact Test was used to evaluate associations. Results: 126 pts (64 female, 62 male; median age 68; 67 adenocarcinomas, 59 others) received GEF; median follow-up was 169 days. Overall response rate was 6.4% (1CR, 7PR), and 51 pts (40%) had stable disease (SD). Median Kaplan-Meier survival and progression-free interval (PFI) were 172 and 59 days, respectively. EGFR mutations were found in 9 of 34 tumors evaluated. None of the tumors from 9 pts with PD had mutations; 6/8 (75%) pts with CR or PR, and 3/14 (21%) pts with SD had detectable mutations. A significant association (p<.002) was observed between mutation and response. Median PFI for pts with and without EGFR mutations was 274 and 117 days, respectively (p<.05); no significant difference in survival was observed. Significant positive associations with response were also observed for EGFR (p<.02) and ErbB2 expression (p<.07). Median survival for pts with and without pAKT expression was 373 and 150 days, respectively (p<.02). Significant positive associations with pAKT expression were observed for EGFR (p<.02), ErbB2 (p<.003), pMAPk (p<.04), and IGF-1r (p<.06) expression. Conclusions: Defining molecular profiles predictive of GEF efficacy is still at an early stage. EGFR activating mutations, and detectable EGFR, pAKT, and ErbB2 expression may have predictive value for GEF response; pAKT may have predictive value for survival. Further investigation of molecular markers and mutations is warranted due to the clinical implications with respect to pts with NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, CTI, Genentech, GlaxoSmithKline, Lilly Oncology, Pfizer Abbott Laboratories, Amgen, AstraZeneca, Genentech, Lilly Oncology, Pfizer AstraZeneca, Bristol-Myers Squibb, CTI, Genentech, GlaxoSmithKline, Lilly Oncology, Pfizer AstraZeneca, Bristol-Myers Squibb, CTI, Genentech, GlaxoSmithKline, Lilly Oncology, Pfizer

Survival Based on Metaphase Versus Interphase Cells for 154 Patients with Newly Diagnosed Multiple Myeloma.

Background: Multiple myeloma (MM) has been studied by conventional cytogenetics and fluorescence in situ hybridization using DNA probes (FISH) on interphase nuclei and metaphase cells, but the relative clinical significance of proliferating (metaphase) versus non-proliferating (interphase) cells at diagnosis is poorly understood. We investigated a consecutive series of 154 patients (pts) with newly diagnosed untreated MM, and compared results for metaphase and interphase cells with survival.Methods: Bone marrow within 30 days of diagnosis was analyzed by standard cytogenetics. Leftover cells were stored at −70°C. Interphase and metaphase FISH was done using probes for IGH, FGFR3, CCND1, c-MAF, D13S319, LAMP1, p53 and D17Z1 to detect t(4;14), t(11;14), t(14;16) and chromosome 13 or 17 anomalies, respectively. We analyzed <10 metaphases and 200 unselected interphase nuclei for each FISH probe set for each pt. Survival rates were estimated using Kaplan-Meier and differences in survival curves compared using log-rank test.Results: 61 (39.6%) pts had abnormal metaphases by cytogenetics (43 pts) and/or FISH (46 pts): 12 (19.7%) had t(11;14) by cytogenetics (3 pts) and/or FISH (11 pts), 11 (18.0%) had t(4;14) by FISH but not cytogenetics, and 3 (4.9%) had t(14;16) by FISH but not cytogenetics. Metaphases with 13q- were seen in 30 pts (49.2%). Interphase FISH results were abnormal for 133 (86.3%) pts: mean percent neoplastic nuclei was 26.9 ± 21.6 (3.9 to 99.0). Mean percent plasma cells was 54.7 ± 24.6 (3.0 to 99.0). Each of the 61 pts with abnormal metaphases was also abnormal in interphase nuclei. Median survival for pts with ≥50% (20 pts) abnormal nuclei was 202 days vs. 1351 days for pts with <50% (134 pts) (p<0.001). Median survival for pts with abnormal metaphases (61 pts) was 587 days vs. 1404 days for pts with normal metaphases (93 pts) (p=0.002). Median survival was 381 days for 30 pts with 13q- metaphases compared with 1404 days for 38 pts with normal metaphases and 13q- interphase nuclei (p<0.001). Metaphase and interphase analysis along with other potential risk factors (hemoglobin <10, serum calcium ≥11, serum creatinine ≥2, plasma cell labeling index and percent bone marrow plasma cells) were evaluated by multivariate analysis using a stepwise selection in a Cox proportional hazards model. Only the observation of 13q- in metaphases or ≥50% abnormal interphase nuclei were significant predictors of survival.Conclusions: Analysis of metaphases at diagnosis is important to detect proliferating disease which is a strong indicator of poor prognosis. Metaphase FISH is a necessary adjunct to conventional cytogenetics to detect cryptic t(4;14) and t(14;16), and accurately detect prognostic chromosome anomalies such as 13q-. Observing a 13q- in metaphase cells is a strong predictor of survival compared with observing 13q- in only interphase nuclei. At diagnosis, analysis of interphase nuclei is efficient, identifies an abnormal clone in 86% of pts and defines a subset of patients with ≥50% nuclei that have a poor prognosis. Since analysis of metaphases gives better prognostic information, interphase FISH is not a substitution in the cytogenetic work up of patients with MM.

Clinical Characteristics and Outcome of a Large Series of Patients with Chronic Lymphocytic Leukemia (CLL) According to ZAP-70 Expression.

The prognosis of patients with CLL has been traditionally assessed by using clinical stages. Clinical stages, however, are a mere reflection of the biological diversity of CLL. In this regard, we and others have recently shown that ZAP-70 expression separates CLL into two clinical forms with different outcome. The aim of this study was to analyze the distribution of age, gender, and different prognostic parameters according to ZAP-70 expression in 222 pts with CLL (median age, 62 yrs; female/male: 89/133). ZAP-70 was determined by flow cytometry, a high expression being defined as >20% ZAP-70 positive CLL cells. Median follow-up of the series was 7.1 years. Clinical stages at diagnosis were: Binet stage A, 187 pts; B, 21 pts; and C, 14 pts. Rai Stage 0, 123 pts; I, 53 pts; II, 28 pts; III, 7 pts; and IV, 11 pts. Overall median survival was 13 years. Parameters associated with a high ZAP-70 expression were lymphocyte doubling time >12 mos., atypical morphology, bone marrow infiltration > 60%, increased serum LDH and timidin kinase, CD38 expression >20%, del(13q14), unmutated status of IgVH, and development of Richer syndrome. Interestingly, ZAP-70 expression distribution correlated with Rai's stage (0 vs. 1 to 4). Also, CD38 expression was able to separate two subpopulations with different survival among CLL cases with low ZAP-70 expression (median survival 18 yrs vs. 13 yrs), but not in pts. with ZAP-70>20%. About 50% of pts in Binet A progressed during the follow-up. Median time to progression for patients with high ZAP-70 expression was 3.3 years whereas it was not reached for patients with low ZAP-70 expression. Median survival of pts with low ZAP-70 expression was 16.3 years, whereas it was of 8.5 years in those with high ZAP-70 expression. In conclusion, ZAP-70 expression identifies a subgroup of patients with CLL with unfavorable prognostic factors related to the proliferation and progression of the disease.Prognostic Parameters according to ZAP-70 expressionVariableZAP-70 >20%ZAP-70 < 20%p=Median age60 yrs63 yrsGender (female)39%41%LDT < 12 mos42%23%0.009Atypical morphology54%12%0.000BM infiltration >60%50%33%0.03Increased LDH13%4%0.028Increased TK66%28%0.000CD38 > 20%67%32%0.000Del(13q14)38%55%0.027Unmutated IgVH88%11%0.000Richter Syndrome8%2%0.039Rai Stage > 053%37%0.039TTP (Binet A)3.3 yrsNR0.000Median Survival16.3 yrs8.5 yrs0.000

Post study docetaxel in non-small cell lung cancer (NSCLC) patients after discontinuation from a randomized phase III trial of pemetrexed versus docetaxel: An exploratory analysis

7135 Background: For NSCLC pts with good performance status, second-line treatment with chemotherapy improves survival. Routine administration of second-line chemotherapy has increased the percentage of pts receiving third-line therapy. In a recent multicenter, randomized, phase III comparison of pemetrexed versus docetaxel in previously treated pts with advanced NSCLC, survival time with pemetrexed therapy was similar to docetaxel (median 8.3 vs 7.9 months). Over 40% of pts in the study received third-line chemotherapy post study. Of those pts treated with pemetrexed, 32% received docetaxel post study. The aim of this exploratory analysis was to evaluate if the survival observed in the pemetrexed arm was due to a cross-over effect of post study chemotherapy with docetaxel as opposed to other post study chemotherapy agents. Methods: Survival analyses were performed using Kaplan-Meier method in 3 subsets of patients with respect to their post study treatment. Results: In total, 541 pts received either pemetrexed or docetaxel; 48% of pts in the pemetrexed arm and 39% of pts in the docetaxel arm received third line chemotherapy. In the pemetrexed arm, the median survival of pts who received post study docetaxel was 1 month less (9.6) than the median survival of pts who received other post study chemotherapy agents (10.6; p=.219). Conclusions: In the original study, overall survival was similar for both treatment arms. In this evaluation, these results provide no evidence that the overall survival observed in the pemetrexed arm with third-line post study docetaxel is different than that observed in the pts who received other third-line post study chemotherapy agents. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. Aventis; Eli Lilly & Co. Eli Lilly & Co. Eli Lilly & Co. Eli Lilly & Co.

Post study docetaxel in non-small cell lung cancer (NSCLC) patients after discontinuation from a randomized phase III trial of pemetrexed versus docetaxel: An exploratory analysis

7135 Background: For NSCLC pts with good performance status, second-line treatment with chemotherapy improves survival. Routine administration of second-line chemotherapy has increased the percentage of pts receiving third-line therapy. In a recent multicenter, randomized, phase III comparison of pemetrexed versus docetaxel in previously treated pts with advanced NSCLC, survival time with pemetrexed therapy was similar to docetaxel (median 8.3 vs 7.9 months). Over 40% of pts in the study received third-line chemotherapy post study. Of those pts treated with pemetrexed, 32% received docetaxel post study. The aim of this exploratory analysis was to evaluate if the survival observed in the pemetrexed arm was due to a cross-over effect of post study chemotherapy with docetaxel as opposed to other post study chemotherapy agents. Methods: Survival analyses were performed using Kaplan-Meier method in 3 subsets of patients with respect to their post study treatment. Results: In total, 541 pts received either pemetrexed or docetaxel; 48% of pts in the pemetrexed arm and 39% of pts in the docetaxel arm received third line chemotherapy. In the pemetrexed arm, the median survival of pts who received post study docetaxel was 1 month less (9.6) than the median survival of pts who received other post study chemotherapy agents (10.6; p=.219). Conclusions: In the original study, overall survival was similar for both treatment arms. In this evaluation, these results provide no evidence that the overall survival observed in the pemetrexed arm with third-line post study docetaxel is different than that observed in the pts who received other third-line post study chemotherapy agents. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. Aventis; Eli Lilly & Co. Eli Lilly & Co. Eli Lilly & Co. Eli Lilly & Co.

A pilot study of monoclonal antibody cG250 and low dose subcutaneous IL-2 in patients (pts) with advanced renal cell carcinoma (RCC)

2558 Background: The median survival of pts with metastatic RCC is 10 months. No therapy has been shown to improve the survival of these pts. cG250 is a chimeric monoclonal antibody (MoAb) that recognizes the CAIX/MN antigen. cG250 induces Ab-dependent cellular cytotoxicity (ADCC) responses in vitro that can be enhanced by IL-2. Our previous trial using cG250 alone showed it is safe, that tumor-specific targeting is high and that the T½ of cG250 in the circulation is long. We studied the effects of adding daily low-dose subcutaneous (sc) IL-2 to cG250 for treatment of clear cell RCC. Methods: The endpoints of the trial were toxicity; immunological effects (human anti-chimeric antibodies [HACA], ADCC, natural killer [NK] and lymphokine-activated killer cell [LAK] activity); cG250 biodistribution and pharmacokinetics (PK); and antitumor effects. Eligible pts had unresectable metastastic or locally advanced clear cell RCC with measurable or evaluable disease. Nine pts were treated as follows. cG250: 10 mg/m2/week (wk) x 6wk (1st and 5th doses trace-labeled with 131I). IL-2: 1.25x106 IU/m2/day x 6wk. Results: Treatment was generally well tolerated with no adverse events attributable to cG250. Two pts required 50% dose reduction of IL-2 due to toxicity. No HACA was detected. Labeled cG250 showed excellent targeting of tumor deposits. cG250 PK: T½α 22.96±12.53 hrs, T½β 135.20±46.90. IL-2 did not affect cG250 PK. ADCC and/or LAK cell activity was enhanced in some pts. No antitumor responses were observed. Conclusions: Weekly cG250 with daily low-dose sc IL-2 is well tolerated. IL-2 does not influence the PK or biodistribution of cG250 and does not increase HACA. Some pts showed enhanced ADCC or LAK activity. Other strategies for enhancing the antitumor effect of cG250 are being explored. No significant financial relationships to disclose.

Pharmacogenetic correlates of clinical benefit from gemcitabine and platinum in patients with advanced bladder cancer

3202 Background: The expression level of the DNA excision repair gene ERCC1 has been correlated with outcome in pts receiving platinum agents for a variety of malignancies. While ribonucleotide reductase (RRM1) levels have been associated with responsiveness to gemcitabine (G), deoxycytidine kinase (DOCK), cytidine deaminase (CD), and other enzymes may also be useful to predict response to G. Therefore, pharmacogenetic correlations were carried out in pts with transitional cell bladder cancer (BC). Methods: mRNA enzyme levels (MEL) of ERCC1, RRM1, DOCK, and CD were determined using quantitative realtime PCR (Taqman) in microdissected paraffin-embedded tumor from treatment-naïve patients with locally advanced or metastatic BC who received G and a platinum agent. The result was expressed as a ratio of the PCR product of each enzyme compared to the β-actin gene. Thresholds for chemotherapy (CT) resistance were determined using the bootstrap technique. Statistical correlations between MEL and clinical endpoints were performed using the Chi square method. Results: 50 consecutive pts with locally advanced or metastatic BC (41 M, 9 F) received G and cisplatin or carboplatin. Among 18 pts with metastatic disease, there were 6 PD, 3 SD, 5 PR, and 2 CR. The median survival for pts with SD, PR, and CR was 13.4 m (range 6.5–25.0); and for pts with PD, 7.6 m (range 3.3–13.5). Among 25 pts who received adjuvant post-operative therapy, 7 died of disease an average of 10.6 m from the start of CT. An additional 4 pts relapsed and are receiving treatment, while 14 remain disease free with a median F/U of 19 m. Among 4 pts with bladder sparing CT-XRT, 3 are alive and disease free and 1 has succumbed to disease with a median F/U of 23.6 m. Among 2 pts with neoadjuvant CT, downstaging occurred in both cases, and both are alive with a median F/U of 12.3 m. Correlations with MEL will be presented at the meeting. Conclusions: MEL may permit the identification pts with a high probability of benefit before CT and avoid ineffective CT when the enzyme profile indicates resistance. Prospective validation of these results would establish MEL for treatment selection in patients with BC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Response Genetics Response Genetics Response Genetics Eli Lilly

Pharmacogenetic correlates of clinical benefit from gemcitabine and platinum in patients with advanced bladder cancer

3202 Background: The expression level of the DNA excision repair gene ERCC1 has been correlated with outcome in pts receiving platinum agents for a variety of malignancies. While ribonucleotide reductase (RRM1) levels have been associated with responsiveness to gemcitabine (G), deoxycytidine kinase (DOCK), cytidine deaminase (CD), and other enzymes may also be useful to predict response to G. Therefore, pharmacogenetic correlations were carried out in pts with transitional cell bladder cancer (BC). Methods: mRNA enzyme levels (MEL) of ERCC1, RRM1, DOCK, and CD were determined using quantitative realtime PCR (Taqman) in microdissected paraffin-embedded tumor from treatment-naïve patients with locally advanced or metastatic BC who received G and a platinum agent. The result was expressed as a ratio of the PCR product of each enzyme compared to the β-actin gene. Thresholds for chemotherapy (CT) resistance were determined using the bootstrap technique. Statistical correlations between MEL and clinical endpoints were performed using the Chi square method. Results: 50 consecutive pts with locally advanced or metastatic BC (41 M, 9 F) received G and cisplatin or carboplatin. Among 18 pts with metastatic disease, there were 6 PD, 3 SD, 5 PR, and 2 CR. The median survival for pts with SD, PR, and CR was 13.4 m (range 6.5–25.0); and for pts with PD, 7.6 m (range 3.3–13.5). Among 25 pts who received adjuvant post-operative therapy, 7 died of disease an average of 10.6 m from the start of CT. An additional 4 pts relapsed and are receiving treatment, while 14 remain disease free with a median F/U of 19 m. Among 4 pts with bladder sparing CT-XRT, 3 are alive and disease free and 1 has succumbed to disease with a median F/U of 23.6 m. Among 2 pts with neoadjuvant CT, downstaging occurred in both cases, and both are alive with a median F/U of 12.3 m. Correlations with MEL will be presented at the meeting. Conclusions: MEL may permit the identification pts with a high probability of benefit before CT and avoid ineffective CT when the enzyme profile indicates resistance. Prospective validation of these results would establish MEL for treatment selection in patients with BC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Response Genetics Response Genetics Response Genetics Eli Lilly

Prognostic significance of aneuploidy in non-small cell lung cancer (NSCLC) patients (pts)

7319 Background: DNA content abnormalities assessed with flow cytometry are linked with a poor prognosis in many cancer types, including NSCLC. The aim of this study was to determine prognostic significance of aneuploidy assessed with conventional cytogenetic analysis in NSCLC. Methods: Study group included 89 consecutive NSCLC pts (15 females and 74 males, mean age of 61 years) who underewent pulmonary resection between April 1997 and July 1999. Pathologic stage distribution was as follows: I (27 pts), II (23 pts), III (36 pts) and IV (3 pts). 54 pts had sqaumous cell carcinoma, 22 -adenocarcinoma, 6 –large cell carcinoma and 7 –mixed NSCLC. Tumor ploidy was determined by karyotyping of primary tissue culture cells derived from postoperative specimens. G-banding with Wright stain and further analysis was performed according to recommendations of the International System of Human Cytogenetics Nomenclature. Results: Aneuplody was present in 33 tumors (37%), more frequently in adenocarcinoma (25 pts, 71%) than in squamous cell carcinoma (8 pts, 15%, p<0.001). No correlation of aneuploidy with grade (p=0.70), stage (p=0.29), age (p=0.69) and sex (p=1.00) was found. Median survival of pts with and without aneuploidy was 15 and 38 months, respectively (log rank; p=0.028). In the multivariate analysis, aneuploidy was the strongest adverse factor for survival (HR=1.92, 95% CI 1.11–3.32; p=0.020), followed by tumor stage (HR=1.59, 95% CI 0.92–2.74; p=0.094). Conclusion: NSCLC aneuploidy, as evaluated by conventional cytogenetic analysis, occurs more frequently in adenocarcinoma than in squamous cell carcinoma, and is an independent predictor of poor prognosis. No significant financial relationships to disclose.

Phase I/II study of exisulind (E) and vinorelbine (V) in elderly patients with advanced non-small cell lung cancer (NSCLC)

7272 Background: Exisulind (E) is an oral selective apoptotic antineoplastic drug that exerts its antitumor effect via the inhibition of tumor-related cGMP phosphodiesterase and activation of protein kinase G. E caused growth inhibition when used alone and with chemotherapy in multiple in vitro and in vivo tumor models. The aim of this study is to define the maximum tolerated dose (Phase I) and efficacy (Phase II) of V + E in elderly patients with IIIB/IV NSCLC. Methods: Patients (pts) were > 69 yrs of age. No prior chemotherapy was allowed. PS 0–1. Pts were entered on 3 dose levels of E (125 mg BID, 125 mg qAM and 250 mg qPM, and 250 mg BID) with V (25 mg/m2) given weekly in a 4 week cycle. Pts with clinical benefit (CR/PR/SD) after 6 cycles of V + E were allowed to continue on E alone Results: 14 pts were enrolled in the phase I portion of the study: 3 on dose level 1, 4 on dose level 2 and 7 on an expanded dose level 3. Median age of this group was 78 yrs (range 72–84). Dose limiting toxicities included grade (Gr) 3 constipation (1 pt) and Gr 3 diarrhea (1 pt), both at dose level 2, and Gr 4 neutropenic fever (1 pt) at dose level 3. The MTD of E was 125 mg BID. One PR was confirmed. 15 pts have been enrolled thus far in the phase II portion of the study (a total accrual of 30 pts is anticipated); median age is 77 yrs (range 71–81). Gr 3/4 treatment-related toxicities include neutropenia (5 pts; 2 with Gr 4), leukopenia (4 pts), anemia (1 pt), fatigue (3 pts), dyspnea (2 pts), and constipation (1 pt). 12 pts are evaluable for response: 2 PRs have been confirmed. The preliminary median survival for pts in the phase II portion of the study to date is 23 weeks (range 1 – 49+ weeks). Conclusions: E does not appear to worsen the toxicity of V in untreated elderly patients with advanced NSCLC. The phase II portion of this study is on-going. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Pathways, Inc.; OSI Pharmaceuticals, Inc.

A pilot study of monoclonal antibody cG250 and low dose subcutaneous IL-2 in patients (pts) with advanced renal cell carcinoma (RCC)

2558 Background: The median survival of pts with metastatic RCC is 10 months. No therapy has been shown to improve the survival of these pts. cG250 is a chimeric monoclonal antibody (MoAb) that recognizes the CAIX/MN antigen. cG250 induces Ab-dependent cellular cytotoxicity (ADCC) responses in vitro that can be enhanced by IL-2. Our previous trial using cG250 alone showed it is safe, that tumor-specific targeting is high and that the T½ of cG250 in the circulation is long. We studied the effects of adding daily low-dose subcutaneous (sc) IL-2 to cG250 for treatment of clear cell RCC. Methods: The endpoints of the trial were toxicity; immunological effects (human anti-chimeric antibodies [HACA], ADCC, natural killer [NK] and lymphokine-activated killer cell [LAK] activity); cG250 biodistribution and pharmacokinetics (PK); and antitumor effects. Eligible pts had unresectable metastastic or locally advanced clear cell RCC with measurable or evaluable disease. Nine pts were treated as follows. cG250: 10 mg/m2/week (wk) x 6wk (1st and 5th doses trace-labeled with 131I). IL-2: 1.25x106 IU/m2/day x 6wk. Results: Treatment was generally well tolerated with no adverse events attributable to cG250. Two pts required 50% dose reduction of IL-2 due to toxicity. No HACA was detected. Labeled cG250 showed excellent targeting of tumor deposits. cG250 PK: T½α 22.96±12.53 hrs, T½β 135.20±46.90. IL-2 did not affect cG250 PK. ADCC and/or LAK cell activity was enhanced in some pts. No antitumor responses were observed. Conclusions: Weekly cG250 with daily low-dose sc IL-2 is well tolerated. IL-2 does not influence the PK or biodistribution of cG250 and does not increase HACA. Some pts showed enhanced ADCC or LAK activity. Other strategies for enhancing the antitumor effect of cG250 are being explored. No significant financial relationships to disclose.

180. The role of surgery in management of limited disease (LD) small cell lung cancer (SCLC), a retrospective comparative study

To asses the role of surgery in SCLC we performed a retrospective analysis of survival in two groups of LD patients (pts) treated between 1982 and 1995. In one group (67 pts) complete resection was followed by chemotherapy, the other (67 pts) was treated with conventional nonsurgical management. In all operated pts the diagnosis of SCLC was established only after the examination of surgical specimen. The non-surgical group was selected using “pair-matched case-control” methodology out of 176 LD pts potentially suitable for surgery (i. e. no pleural effusion or other local advancement, no supraclavicular lymph node involvement, good PS) but treated with non-surgical approach. Total series included 109 males and 25 females, 20 T1 and 114 T2 disease, 51 N0, 43 N1 and 40 N2 disease. In the surgical group 23 pts received prophylactic cranial irradiation and in the non-surgical group 39 pts received thoracic irradiation. The most important prognostic factors were well balanced between both groups. Median survival in pts treated with and without surgery was 22 months and 11 months, respectively (p