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Background In IPASS ( NCT00322452 ), progression-free survival (PFS, primary endpoint) was significantly longer with first-line gefitinib versus carboplatin/paclitaxel in never/light ex-smokers with advanced pulmonary adenocarcinoma in Asia, both in the overall intent-to-treat (ITT) population and in the EGFR mutation-positive subgroup. To further characterize the clinical relevance of these data, we investigated objective response rate (ORR) and health-related quality of life (HRQoL) in patients treated with gefitinib. Methods Objective response was assessed (RECIST) 6-weekly (previously reported). Post hoc assessments included median time to response, median duration of response and change in tumor size. The analysis of response population included those patients treated with gefitinib who responded ( n = 262 from ITT; n = 94 from EGFR mutation-positive subgroup). The percentage of patients with deterioration in HRQoL (Functional Assessment of Cancer Therapy-Lung [FACT-L], Trial Outcome Index [TOI]) and symptoms (Lung Cancer Subscale [LCS]) at 4 months post-randomization was analyzed according to progression status (EFQ population grouped by progressors/non-progressors in both treatment arms). The ORR (ITT) and incidence of skin rash/acne (evaluable-for-safety) were summarized. Results In patients whose tumors responded to gefitinib, median time to response was 6.1 weeks in the ITT population ( n = 262) and 6.0 weeks in the EGFR mutation-positive subgroup ( n = 94); median duration of response was 9.7 and 8.7 months in these groups, respectively. There was significant tumor shrinkage with gefitinib. A greater percentage of patients in the EFQ population whose tumors progressed experienced deterioration in HRQoL and symptoms at 4 months versus patients whose tumors did not progress (FACT-L 33.7% vs 16.3%; TOI 33.7% vs 13.2%; LCS 31.7% vs 15.5%). In the gefitinib arm of the EFS population, incidence of rash was 75.8% and 68.1% in EGFR mutation-positive and -negative subgroups, respectively (with ORR for the gefitinib arm of the ITT 71.2% vs 1.1%, respectively). Conclusions Patients whose tumors responded to first-line gefitinib experienced significant tumor shrinkage and a rapid, durable response. Deterioration in HRQoL and lung cancer symptoms at 4 months post-randomization was found to be associated with tumor progression, highlighting the role of patient-reported outcomes in the evaluation of advanced NSCLC disease. Rash was not supported as a predictive marker of response to gefitinib.

Aim: In the IRESSA Pan-Asia Study (IPASS), 1217 patients in East Asia with pulmonary adenocarcinoma who were never-smokers or ex/light-smokers received first-line gefitinib (250 mg/day) or carboplatin/paclitaxel (area under the curve 5/6; 200 mg/m2). Efficacy analyses were pre-planned in patients in China. Methods: In China, 372 patients (30.6% of the overall group) were randomized. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), objective response rate (ORR), health-related quality of life (HRQoL), symptom improvement, safety and tolerability. Results: For patients in China, PFS did not significantly differ from the overall IPASS population (interaction test P= 0.427). PFS was numerically longer (hazard ratio [HR] 0.79; 95% CI 0.62–1.01; P= 0.065; median PFS 6.8 months for both treatments) and ORR significantly higher (ORR 44.6 vs 29.8%; odds ratio 1.88; 95% CI 1.22–2.89; P= 0.004) for gefitinib than carboplatin/paclitaxel. OS (mature data) was similar for both treatments (HR 0.92; 95% CI 0.73–1.17; P= 0.511; median OS gefitinib 18.1 months vs 18.3 months carboplatin/paclitaxel). HRQoL improvement rates favored gefitinib; symptom improvement rates were similar for both treatments. Gefitinib had a more favorable tolerability profile than carboplatin/paclitaxel. Efficacy by epidermal growth factor receptor biomarker status (exploratory analyses) was difficult to interpret due to low patient numbers with known biomarker status. Conclusion: For the Chinese subgroup of IPASS, gefitinib demonstrated improved PFS and ORR, similar OS, higher HRQoL, similar symptom improvement rates and a more favorable tolerability profile than carboplatin/paclitaxel, generally consistent with the overall IPASS population.

Purpose The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. Patients and Methods In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. Results OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). Conclusion EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation–positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

This multicenter, non-interventional, prospective, observational study aimed to determine whether patients’ attitude to chemotherapy is an independent prognostic factor for survival in patients with advanced non-small cell lung cancer (NSCLC) who are treated with gemcitabine–platinum. Chemonaive patients (n = 1895) with stage IIIB or IV NSCLC not amenable to curative surgery or radiotherapy were treated with a combination of gemcitabine plus cisplatin/carboplatin and followed for a maximum of 18 months. Patients’ attitude to treatment was measured on a 5-point scale and responses were used to assign patients to one of the three need categories: A, maximum extension of survival with the acceptance of high toxicity (60.0% of patients); B, maximum extension of survival only if coupled with normal lifestyle (26.1%); C, relief of symptoms (13.8%). Median survival varied significantly among the need categories (A = 13.00 months, B = 15.70 months, C = 15.33 months; log-rank test P = 0.0415). Patient attitude to treatment (need categories) was not a significant prognostic factor for survival after adjusting for known prognostic factors (P = 0.0503). After adjusting for baseline differences, patients in this study had a significantly lower risk of death than patients in three randomized trials (hazard ratio 0.879; 95% confidence interval: 0.775, 0.998; P = 0.0458). In conclusion, in this observational study, patient attitude to chemotherapy was not an independent prognostic factor of survival.

Summary Background In the treatment of advanced cancer, a physician's ability to accurately identify a patient's attitude towards treatment is critical. This paper describes the extent of any differences observed between patient attitudes towards chemotherapy for advanced non-small cell lung cancer (NSCLC) as assessed by patients themselves versus their physicians. Patients and methods Patients with stage IIIB or IV NSCLC who received gemcitabine plus cisplatin or carboplatin were enrolled into this prospective observational study. Patients and their physicians completed questionnaires containing descriptions of seven patient-specific attitudes. A pre-defined algorithm was used to categorize patients into one of the three ‘need' categories based on the questionnaire responses: (A) "maximum extension of survival with acceptance of high toxicity", (B) "maximum extension of survival only if coupled with normal life style", and (C) "relief of symptoms". Each patient was categorized based on his own response, as well as his physician's response. Results A total of 1895 patients were enrolled from 19 countries across 3 continents. Data from 1884 patients were analysed. Based on patient versus physician responses, respectively, the distribution of patients was 60% versus 39% in need category A, 26% versus 33% in B, and 14% versus 29% in C. Patient self-assessed versus physician-assessed need category identification was aligned for 891 patients (47.3%): 541 (29%) in A, 218 (12%) in B, 132 (7%) in C. While there was slight agreement between the identification of ‘need' categories by physicians and patients (kappa=0.18, 95% CI: 0.15–0.21), physicians also tended to place patients further down the scale (towards C) than patients placed themselves ( P Conclusions Patients have varying needs from cancer chemotherapy and it may not always be correctly identified by the treating physician. Physicians may underestimate patient's desire for extended survival compared with symptom relief.

Objective: To analyze the clinical and pathologic features and the treatment outcomes of primary lymphoma of respiratory system (PLRS). Methods: The clinical manifestation, imaging changes, pathologic subtypes, treatment and overall survival of 11 patients with PLRS were analyzed retrospectively. Results: Of the 11 patients diagnosed with PLRS by histopathology, the tumor of 2 patients occurred in trachea and the other 9 in lung. Cough, dyspnea and fever were the most frequent symptoms. Mass or infiltrative changes could be found on the chest X-ray and/or CT scan. Two patients were diagnosed as having Hodgkin’s Lymphoma (HL) and 9 having non-Hodgkin’s Lymphoma (NHL), including 7 patients with low degree NHL [5 of them (55.6%) were mucosa-associated lymphoid tissue (MALT) lymphoma] and 2 with intermediate degree NHL. Of 10 patients undergoing exploratory thoracotomy and surgical treatment, 8 received adjuvant chemotherapy and 2 adjuvant of radiotherapy. The remaining patient was subjected to combined chemotherapy. Both of HL patients survived more than 5 years without clinical disease. The median survival of MALT lymphoma and other type of NHL was 39 months and 34 months respectively. Conclusion: Both the clinical manifestation and imaging changes are non-specific. The diagnosis was made through exploratory thoracotomy (10 cases) and fiber-optical bronchoscopy (1 case). MALT lymphoma is the most frequent pathologic subtype. Majority of patients are diagnosed and treated by surgical resection. The prognosis is acceptable.

The epidermal growth factor receptor (EGFR) signaling pathway is crucial for regulating tumorigenesis and cell survival and may be important in the development and progression of non-small cell lung cancer (NSCLC). We examined the impact of EGFR-tyrosine kinase inhibitors (TKIs) on progression-free survival (PFS) and overall survival (OS) in advanced NSCLC patients with and without EGFR mutations.Randomized trials that compared EGFR-TKIs monotherapy or combination EGFR-TKIs-chemotherapy with chemotherapy or placebo were included. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs for the EGFR mutation-positive (EGFRmut(+)) and EGFR mutation-negative (EGFRmut(-)) subgroups were calculated with the fixed-effects inverse variance weighted method. All statistical tests were two-sided.We included 23 eligible trials (13 front-line, 7 second-line, 3 maintenance; n = 14570). EGFR mutation status was known in 31% of patients. EGFR-TKIs treatment prolonged PFS in EGFRmut(+) patients, and EGFR mutation was predictive of PFS in all settings: The front-line hazard ratio for EGFRmut(+) was 0.43 (95% confidence interval [CI] = 0.38 to 0.49; P.001), and the front-line hazard ratio for EGFRmut(-) was 1.06 (95% CI = 0.94 to 1.19; P = .35; P interaction.001). The second-line hazard ratio for EGFRmut(+) was 0.34 (95% CI = 0.20 to 0.60; P.001), and the second-line hazard ratio for EGFRmut(-) was 1.23 (95% CI = 1.05 to 1.46; P = .01; P interaction.001). The maintenance hazard ratio for EGFRmut(+) was 0.15 (95% CI = 0.08 to 0.27; P.001), and the maintenance hazard ratio for EGFRmut(-) was 0.81 (95% CI = 0.68 to 0.97; P = .02; P interaction.001). EGFR-TKIs treatment had no impact on OS for EGFRmut(+) and EGFRmut(-) patients.EGFR-TKIs therapy statistically significantly delays disease progression in EGFRmut(+) patients but has no demonstrable impact on OS. EGFR mutation is a predictive biomarker of PFS benefit with EGFR-TKIs treatment in all settings. These findings support EGFR mutation assessment before initiation of treatment. EGFR-TKIs should be considered as front-line therapy in EGFRmut(+) advanced NSCLC patients.

Evaluation of health-related quality-of-life (HRQoL) and symptom improvement were preplanned secondary objectives for the overall population and posthoc analyses for epidermal growth factor receptor (EGFR) mutation-positive/negative subgroups in IPASS.HRQoL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) and Trial Outcome Index (TOI); symptom improvement by the Lung Cancer Subscale (LCS). Improvements defined as: 6 or more (FACT-L; TOI), 2 or more (LCS) points increase maintained for 21 or more days.Overall (n = 1151/1217 evaluable), HRQoL improvement rates were significantly greater with gefitinib versus carboplatin/paclitaxel; symptom improvement rates were similar for both treatments. Significantly more patients recorded improvements in HRQoL and symptoms with gefitinib in the EGFR mutation-positive subgroup (n = 259; FACT-L 70.2% versus 44.5%; odds ratio, 3.01 [95% confidence interval, 1.79-5.07]; p0.001; TOI 70.2% versus 38.3%; 3.96 [2.33-6.71]; p0.001; LCS 75.6% versus 53.9%; 2.70 [1.58-4.62]; p0.001), and with carboplatin/paclitaxel in the EGFR mutation-negative subgroup (n = 169; FACT-L 14.6% versus 36.3%; odds ratio, 0.31 [0.15-0.65]; p = 0.002; TOI 12.4% versus 28.8%; 0.35 [0.16-0.79]; p = 0.011; LCS 20.2% versus 47.5%; 0.28 [0.14-0.55]; p0.001). Median time-to-worsening (months) FACT-L score was longer with gefitinib versus carboplatin/paclitaxel for the overall population (8.3 versus 2.5) and EGFR mutation-positive subgroup (15.6 versus 3.0), and similar for both treatments in the EGFR mutation-negative subgroup (1.4 versus 1.4). Median time-to-improvement with gefitinib was 8 days in patients with EGFR mutation-positive tumors who improved.HRQoL and symptom endpoints were consistent with efficacy outcomes in IPASS and favored gefitinib in patients with EGFR mutation-positive tumors and carboplatin/paclitaxel in patients with EGFR mutation-negative tumors.

A nonrandom chromosomal translocation breakpoint, t(15;17)(q22;q21), is found in almost all patients with acute promyelocytic leukemia (APL). Most of these breakpoints occur within the second intron of the retinoic acid receptor-alpha (RARA) gene. We screened a cDNA library of APL and have identified and sequenced a cDNA transcribed from the t(15;17) translocation breakpoint. The 5' end of cDNA p1715 consists of 503 bp of the RARA exon II sequence. A 1.76-kb cDNA without homology to any known gene available in GenBank was found truncated downstream. This cDNA sequence was assigned to chromosome 15 by dot blot hybridization of the flow cytometry-sorted chromosomes. We designate this fusion cDNA RARA/myl, which is different from myl/RARA reported by de The et al. (H. de The, C. Chomienne, M. Lanotte, L. Degos, and A. Dejean, Nature (London) 347:558-561, 1990). This result demonstrates that the two different types of hybrid mRNA can be transcribed from this breakpoint. We screened a non-APL cDNA library and identified a 2.8-kb myl cDNA. This cDNA is able to encode a polypeptide with a molecular weight of 78,450. Alternative splicing of the myl gene which resulted in myl proteins with different C terminals was found. Southern blot analysis of the genomic DNA isolated from 17 APL patients by using the myl DNA probe demonstrated that the myl gene in 12 samples was rearranged. Northern (RNA) blot analysis of RARA gene expression in two APL RNA samples showed abnormal mRNA species of 4.2 and 3.2 kb in one patient and of 4.8 and 3.8 kb in another patient; these were in addition to the normal mRNA species of 3.7 and 2.7-kb. The myl DNA probe detected a 2.6-kb abnormal mRNA in addition to the normal mRNA species of 3.2, 4.2, and 5.5 kb. Using the polymerase chain reaction, we demonstrated that both RARA/myl and myl/RARA were coexpressed in samples from three different APL patients. From this study, we conclude that the t(15;17) translocation breakpoint results in the transcription of two different fusion transcripts which are expected to be translated into fusion proteins.

The retinoic acid receptor alpha (RAR alpha) and the myl gene are involved in the translocation breakpoint t(15;17)(q22;q21) in acute promyelocytic leukemia (APL). The majority of the breakpoint sites have been mapped within the second intron of the RAR alpha gene; however, the breakpoint sites on the myl gene are variable. Using primer sets derived from exon 2 or exon 3 of the RAR alpha gene and a primer derived from the myl cDNA, we were able to amplify the breakpoint sites of the fusion transcripts of all six APL RNA samples by the reverse transcriptase-polymerase chain reaction (RT-PCR). A DNA fragment of 290 bp (breakpoint A) was amplified using RNA samples from three patients, whereas two DNA fragments of 630 and 774 bp (breakpoint B) were amplified using RNA samples from the other three APL patients. DNA sequence analysis of the amplified fragments suggests that the APL breakpoints clustered within two different introns of the myl gene. Northern blot analysis demonstrated that fusion transcripts RAR alpha/myl and myl/RAR alpha of varying sizes were detected in patients with different breakpoint sites on the myl gene. In addition, we analyzed five APL samples in complete remission and detected t(15;17)- positive cells. We conclude that the t(15;17) breakpoints in APL can be amplified by PCR using a single primer set and that minimal residual disease can be demonstrated in APL using RT-PCR.

Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer.In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival.The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group.Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

To evaluate the efficacy of sequential administration of gefitinib and docetaxel in the second-line therapy for advanced non-small cell lung cancer (NSCLC).Eighty-two patients with advanced NSCLC who had received both gefitinib and docetaxel treatment were divided into 2 groups: Group A (n = 17) that were treated with gefitinib first and then crossed over to docetaxel treatment when progressive disease (PD) occurred as second-line treatment, and Group B (n = 65) that were treated with docetaxel first, and then crossed over to gefitinib treatment when PD occurred.The response rate of gefitinib in phase I (duration before crossover) was 27.7%, not significantly different from that in phase II (duration after crossover) (29.4%, P0.05). The response rate of docetaxel in phase I was 13.8%, not significantly different from that in phase II (5.9%, P0.05). Gefitinib showed an efficacy superior to docetaxel after adjusting the sequence of these two agents (28.0% vs 12.2%, chi2 = 5.46, P = 0.02). The time to progression (TTP) of gefitinib was 6.0 months, significantly longer than that of docetaxol (4.0 months, P = 0.00). Though no statistically significant survival difference was seen between these two groups, stratified analysis showed that the median survival time of the patients with the Eastern Cooperative Oncology Group (ECOG) = 2 in Group A was 13.0 months, significantly longer than that in Group B (6.0 months, P = 0.01). The adverse events (AEs), including skin rash and diarrhea were all generally tolerable. The incidence of AEs was similar in these two groups.Although no impact was found in the efficacy and survival between these two different sequential administration of gefitinib and docetaxel for patients with advanced NSCLC, but the patients with poor performance status may get longer survival if they receive treatment of gefitinib first crossed-over to docetaxel.

Purpose Genetic variations in EGFR may alter protein function and therefore the therapeutic efficacy of epidermal growth factor receptor inhibitors. This study investigated the association between polymorphisms in EGFR and clinical outcome in patients with advanced non-small-cell lung cancer (NSCLC) treated with Gefitinib. Methods A whole gene-based tag-SNP approach was used to determine the candidate SNPs in EGFR . Four tag SNPs, one CA simple sequence repeat (CA-SSR) in intron 1, one coding region SNP (R521K), and SNPs identified by resequencing in the tyrosine kinase domain of EGFR were selected to analyze their association with therapeutic outcome and survival in 84 advanced NSCLC patients treated with Gefitinib. Progression-free and overall survivals were computed by Cox model adjusted for clinical factors. Results We identified two EGFR polymorphisms, rs2293347 (D994D) and CA-SSR in intron 1, associated with clinical outcome of Gefitinib therapy. The response rate for the rs2293347GG or shorter CA repeat genotype was significantly higher than that for the rs2293347GA or AA or longer CA repeat genotype (71.2% versus 37.5%, P =0.0043 and 88.5% versus 48.3%, P =0.0005). The rs2293347GG genotype was also associated with longer progression-free survival compared with the rs2293347GA or AA genotype (11 months versus 3 months, P =0.0018). A combination of rs2293347GG and shorter CA repeat genotypes had more pronounced clinical benefit. Conclusion The D994D and CA-SSR polymorphisms in EGFR are potential predictors for clinical outcome in advanced NSCLC patients treated with Gefitinib.

To evaluate the efficacy and safety of subcutaneous injection of recombinant human interleukin-2 (Proleukin) in the treatment of metastatic renal cell carcinoma (RCC).Forty-one patients with pathologically confirmed metastatic RCC after radical nephrectomy were enrolled into this study. Two or four consecutive cycles of subcutaneous injection of rhLL-2 were given, with each cycle duration of five weeks consisting of 4 weeks of treatment and one week of rest. The rhLL-2 was injected twice daily subcutaneously at a dose of 9 MIU on D1-D5 during week one, then 9 MIU twice daily on D1-D2 and followed by 9 MIU daily on D3-D5 during week 2-4. Patients were evaluated after the second cycle of treatment. If an objective response or stable disease was observed, the patient would receive another two cycles of treeatment.Of the 41 patients, the overall objective response rate was 17.1% (95% confidence interval, 5.6% to 28.6%) with a complete response (CR) rate of 0.0% and partial response rate (PR) of 17.1%. However, nineteen patients (46.3%) still had a stable disease (SD), and 15 (36.6%) had progressed disease (PD). The disease control rate was 63.4% and the median time to progression (mTTP) was 6 months. The 1-year survival rate was 71.2% with a median overall survival (mOS) rate of 22.5 months. Among 36 PP population, the overall objective response rate was 19.4% (95% confidence interval, 6.5% to 32.3%) with CR rate of 0.0% and PR rate of 19.4%. Sixteen patients(44.4%) had stable disease, and 13 (36.1%) progressed disease. The disease control rate was 63.9%. The 1-year survival rate was 66.7% with a median time to progression of 6 months. The median overall survival (mOS) had not reached yet. The follow-up data showed that the long term survival of the patient who responsed to the IL-2 therapy can be prolonged. Severe toxicity (or = grade III) was rarely observed. Grade I or II toxicities such as fatigue (100.0%) and fever (82.9%) were frequently observed but reversible.Subcutaneous injection of recombinant human interleukin-2 may prolong the survival of patients with a metastatic renal cell carcinoma. This regimen is tolerable with rare severe toxicities.

To investigate the antitumor efficacy, time to tumor progression (TTP) and toxicity of gefitinib (Iressa, ZD1839)--a selective epidermal growth factor receptor tyrosine kinase inhibitor in the treatment of male patients with advanced non-small-cell lung cancer (NSCLC). Methods Fifty-nine male patients with stage IV NSCLC orally took Iressa 250 mg once daily until disease progression or intolerable toxicity ocurred. They were required to conduct tumor-evaluation before the treatment, one month after Iressa administration and then every other month.Of these 59 patients, no complete regression was observed, 23.7% had partial response (PR), and 16.9% stable disease (SD) with a disease control (PR + SD) rate of 40.7%, while 59.3% had progress of disease (PD). The median time to tumor progression (TTP) was 1.8 months, and the median survival was 8.5 months. Fifty-nine patients were followed up over one year, 35 over two year and 15 over three year, and the 1-, 2- and 3-year survival rates were 42.4%, 17.1% and 13.3%. The most common adverse effects were grade 1 or 2 skin reaction and diarrhea.Iressa is effective in antitumor for the male patients with advanced non-small-cell lung cancer, and can improve the survival for those responsing to gefitinib. The adverse effects are usually tolerable.

To evaluate the maximum tolerated dose and dose-limiting toxicity (DLT) of 10-hydroxy-camptothecin (10-HCPT) in HFL regimen for the treatment of advanced colorectal cancer (CRC).18 advanced CRC patients, 13 males and 3 females, aged 33 - 70, were randomly assigned to 6 groups to be treated with 10-HCPT 4, 6, 8, 10, 12, or 14 mg/m(2), and 5-fluoro-uracil (5-FU) 425 mg/m(2), and leucovorin (LV) 20 mg/m(2), all administered intravenously on days 1 - 5 with 4 weeks as one cycle. The efficacy and side-effect were evaluated.There were two patients with grade IV myelosuppression in the 10, 12, and 14 mg/m(2) groups each. The most dose-associated adverse reactions were myelosuppression and GI dysfunction. The DLT was myelosuppression, and the maximum tolerable dose of 10-HCPT is 10 mg/m(2) on days 1 - 5.HFL regimen is well tolerated in the patients with advanced CRC. The dosing regimen recommended in clinic trial is 8 mg/m(2).

To evaluate the efficacy, side-effects and quality of life in the advanced colorectal cancer patients treated by irinotecan plus fuorouracil and leucovorin with thalidomide or without thalidomide.Eligible patients were randomly assigned to the treatment group and control group in a 1:1 ratio. In the treatment group, 32 evaluable patients were treated with irinotecan 180 mg/m2 i. v. on day 2, fuorouracil 400 mg/m2 bolus on day 1, 2 at a dose of 1200 mg/m2 civ. for 43 hours; leucovorin 200 mg/m2 i. v. on day 1, 2; thalidomide 300 mg, orally on day 1 - 14, two weeks as a cycle. In the control group, the regimen was the same as in the treatment group except oral intake of thalidomide.The response rate was 28.1% in the treatment group vs. 15.2% in the control group (P = 0.2034) with a median TTP of 3.8 months vs. 2. 5 months (P = 0.1312). Furthermore, there was no statistically difference either between two groups regarding to adverse effects.Irinotecan plus fuorouracil and leucovorin without oral intake of thalidomide is as effective and tolerable as irinotecan plus fuorouracil and leucovorin combined with oral thalidomide for advanced colorectal cancer.

To evaluate the efficacy and adverse events of irinotecan (CPT-11) combined with cisplatin (DDP) in the treatment of patients with advanced non-small cell lung cancer (NSCLC).Of 36 NSCLC patients consisting of 23 males and 13 females with a medium age of 52 years included, there were 26 adenocarcinomas, 7 squamous cell carcinomas, 1 adeno-squamous cell carcinoma and 2 unclassified types; 13 stage III B and 23 stage IV; 24 chemonaive and 12 previously treated by chemotherapy with a medium Karnofsky status of 90. All patients had measurable or evaluable parameters. The regimen was administered as following: CPT-11 60 mg/m2, IV, D1, 8 and 15; DDP 80 mg/m2, IV, D1; every 28 days as a cycle.Totally, 97 cycles were carried out in these 36 patients with a medium cycles of 3. Of 35 evaluable patients, 22.9% (8/35) achieved partial response, 60.0% (21/35) had stable disease and 17.1% (6/35) progressive disease. The response rate was 29.2% (7/24) for chemonaive patients and 9.1% (1/11) for these previously treated. The 1-year survival rate was 45.4% with a medium time to tumor progression (TTP) of 199 days for the responders. The incidence rate of grade III/IV adverse events were: 16.7% for neutropenia, 13.9% alopecia, 5.6% diarrhea, 2.8% nausea and vomiting, respectively.Irinotecan plus cisplatin is effective with tolerable adverse events in treating patients with advanced non-small cell lung cancer, but further investigation trials are needed.

The purpose of this phase I/II study is to investigate the safety/toxicity profile of weekly administration of docetaxel in combination with cisplatin for the chemo-naive patients with advanced non-small cell lung cancer (NSCLC), and to evaluate the efficacy of this regime.In phase I trial, 15 patients were included. IV infusion of escalating doses of docetaxel consisting of four levels from 25 to 40 mg/m2 (25, 30, 35, 40 mg/m2) on D1, 8, 15 and cisplatin of 75 mg/m2 on D1 was administered. The regime was repeated every 4 weeks. Blood samples were obtained on D1, 15 in the first cycle to measure the PK. Dose limiting toxicity (DLT) was determined in cycle 1 and defined as any grade 3 non-hematologic toxicity which could not be reverted into grade less than grade 2 within 4 days or any grade 4 hematologic toxicity. Eighty-three patients completed their phase II study with administration of docetaxel at a dose of 35 mg/m2 based on the data of phase I trial.In the phase I trial, grade 3/4 neutropenia was mainly observed in patients who received docetaxel of 40 mg/m2 (level 4) with one patient suffering from an infection signifying dose limiting toxicity (DLT). Non-hematological toxicities including nausea/vomiting, alopecia, fluid retension and asthenia were tolerable. Based on these data, the maximum tolerence dose (MTD) did not reach the level of weekly giving docetaxel at a dose of 40 mg/m2 in combination with cisplatin 75 mg/m2 every 4 weeks. The pharmacokinetic/dynamics results There was no statistically significant difference between clearance value among the 4 dose levels of docetaxel from 25 to 40 mg/m2 when measured by Cmax and AUC. The pharmacokinetics of docetaxel was not influenced by the presence of co-administration of cisplatin when compared D1 with D15 as based on CmaxN, AUCN and CL. In the phase II trial, totally 83 patients received 216 cycles of chemotherapy. One CR (complete response) and 22 PR (partial response) were achieved with an objective response rate of 27.7% in this series and 30.7% in the evaluable patients. The 1-year survival was 48.6% with a median survival of 10.7 months (range: 3-34 months). Hematologic toxicities were the major side effects, though most were mild; grade III/IV neutropenia developed in 15%. The common non-hematologic toxicities were nausea, vomiting and asthenia.Weekly consecutive administration of docetaxel on D1, 8, 15 for 3 weeks plus cisplatin on D1 is tolerable and effective with minimal myelosuppression in chemo-naive patients with advanced NSCLC.

To evaluate the difference of efficacy, side-effects and quality of life in advanced non-small-cell lung cancer (NSCLC) patients treated with oxaliplatin plus vinorelbine or cisplatin plus vinorelbine.Eligible patients were randomly assigned to NL (oxaliplatin + vinorelbine) group and NP (cisplatin + vinorelbine) group in a 2:1 ratio. In the NL group, 70 evaluable cases were treated with oxaliplatin 130 mg/m(2) i.v. on day 2, and vinorelbine 25 mg/m(2) i.v. on days 1 and 8 in 21 days per cycle. In the NP group, 32 evaluable cases were treated with cisplatin 80 mg/m(2) i.v. divided to 2 - 3 days dosing, 21 days per cycle, and vinorelbine administered by the same way as in the NL group. The response rate, time to progression (TTP), one-year survival, side-effects and the quality of life were observed.The response rate was 35.7% vs. 43.8% (P = 0.4), median TTP was 4.7 months vs. 5.5 months (P = 0.6), one-year survival rate was 38.5% vs. 58.6% (P = 0.07) in the NL and NP groups, respectively. Grade I-II neuro-sensory toxicity occurred significantly more frequent in NL group than in NP group (68.4% vs. 36.4%, P = 0.0017). However, Grade I-II granulocytopenia was significantly less occurred in NL group than in NP group (49.4% vs. 70.6%, P = 0.037). There was no statistically difference between the two groups regarding quality of life.Due to good efficacy and tolerability, the NL regimen offered a new candidate for treating advanced NSCLC.

Gefitinib, a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been approved to be used in treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in many countries. This study, a multicenter clinical trial, was designed to evaluate the efficacy of gefitinib on Chinese patients with locally advanced or metastatic NSCLC after failure of previous chemotherapy, and explore its safety.A total of 159 pathologically-confirmed NSCLC patients were enrolled. Gefitinib was orally administered 250 mg once daily until disease progression or the occurrence of intolerable toxicity.The objective response rate was 27.0%; the disease control rate was 54.1%. The median progression-free survival time was 97 days; the median overall survival time was 10.0 months; the 1-year survival rate was 44%. The most common drug-related adverse events were rash (44.0%), pruritus (15.7%), and diarrhea (10.1%), and most of them were grade 1-2 events with no need of further treatment.Gefitinib is effective and safe in treating Chinese patients with locally advanced or metastatic NSCLC after failure of previous chemotherapy.

To evaluate the antitumor efficacy, time to tumor progression (TTP) and toxicity of Iressa (ZD1839)-a selective epidermal growth factor receptor tyrosine kinase inhibitor in advanced non-small-cell lung cancer (NSCLC) patients who have failed to respond previous chemotherapy.Fifty-two patients with grade IV NSCLC previously treated with chemotherapy (77.0% of patients after second line therapy) received 250 mg of Iressa orally once daily until disease progression or development of intolerable toxic reaction. They were required to receive tumor-evaluation before the treatment, one month after Iressa administration and every other month thereafter.Without complete regression being observed, partial response (PR) rate was 21.2% (11/52), stable disease (SD) 32.7% (17/52), disease control rate (PR + SD) 53.8%, progression of disease (PD) 46.2% (24/52); median time to tumor progression (TTP) was 3.5 month. Among them, 22 patients were followed up over one year and the 1-year survival rate was 31.8%. Symptomatic improvement rate was 52.9%. The most common adverse effects were skin reactions and diarrhea which were generally mild (grade 1 or 2). Only one patient withdrew from the trial because of grade III hepatic toxicity with increase in ALT and AST.Iressa has significant antitumor activity in advanced NSCLC patients who have previously failed in second or third line chemotherapy. It greatly alleviates tumor related symptoms. Adverse effects are generally tolerable. IRESSA is suitable for patients with poor performance status (ECOG2).

Paclitaxel was used in a phase II trial in combination with cisplatin for esophageal cancer. The anti-tumor response, toxicity and survival of the treated patients were evaluated.Thirty patients with advanced, unresectable, or complicated with metastasis were allotted, twenty-seven patients had no prior chemotherapy while 3 patients had received adjuvant chemotherapy. Patients were given paclitaxel 175 mg/m(2) by 3-hour infusion on D1, and cisplatin 40 mg/m(2) daily on D2 and D3. Granulocyte colony-stimulating factor (G-CSF) was not routinely administered unless the patient had neutropenia. Treatment was recycled every 21 days.Thirty patients (male/female, 28/2; median age 58) completed a median of 3 cycles and 27 patients were evaluable for response. Major objective responses were observed in 16 patients (59.3%; 95% confidence interval, 38.9% to 75.5%), including 5 complete responses (18.5%) and 11 partial responses (40.7%). The median time to tumor progression was 5.0 months (range, 1 to 23 months). The median actuarial survival was 9.7 months (range, 1 to 23 months). Twenty-eight patients were assessable for toxicity. The most common nonhematologic toxicity was alopecia. Grade 3 to 4 neutropenia was observed in 17.9% of the patients. Toxicity was manageable with dose attenuation and G-CSF support.The combination of paclitaxel and cisplatin can be considered as a main regimen in the treatment of advanced esophageal cancer.

A randomized, selfcross-over and placebo-controlled clinical trial has been taken to evaluated the curative efficacy of rhIL-11 (Mega) for thrombocytopenia in 29 cancer patients with severe myelosuppression induced by chemotherapy. Twenty-five micro g/kg of Mega or placebo was administered subcutaneously once daily starting 24 hours after the completion of chemotherapy, and continuing for 7 to 14 days or until the platelet count reached 300 x 10(9)/L. The results from those in 118 cases performed phase II clinical trial, showed that there were 29 cases with platelet count less than 50 x 10(9)/L in placebo cycle, but there was only 1 case in Mega cycle. The percentage of the patients with platelet count less than 50 x 10(9)/L in placebo cycle of placebo + Mega group was higher than that of Mega + placebo group. The nadir and platelet counts on day 21 after chemotherapy in Mega cycle were 2.04 and 1.43 times more than those in placebo cycle, respectively. The data show that Mega had significant thrombopoietic activity with a long lasting oction for the patients experienced severe myelosuppression. It significantly increases the likelyhood of avoiding thrombocytopenia in cancer patients undergoing chemotherapy and shortens the duration of thrombocytopenia.

8041^ Background: The IRESSA Pan Asia Study (IPASS) demonstrated superiority of G vs C/P for progression-free survival (PFS) in 1,217 chemonaïve, never/light ex-smokers with WHO PS 0–2, adenocarcinoma histology and stage IIIB/IV NSCLC. PFS favored C/P initially then G, likely driven by different outcomes according to EGFR mutation (M) status. Planned analyses of pts recruited in China are reported. Methods: 372 pts in China (31% of overall population) were randomized to G 250 mg/day (n=184) or C (AUC 5 or 6)/P (200 mg/m2) (n=188). Primary objective was to assess PFS in ITT population; a treatment by country interaction test (China vs other) was performed. Secondary endpoints were overall survival (OS), objective response rate (ORR, RECIST), QoL (FACT-L, TOI), symptom improvement (LCS) and tolerability. Results: PFS results for pts in China did not significantly differ from other pts (interaction test p=0.4265). G demonstrated numerically longer PFS vs C/P; effect was not constant over time, favoring C/P initially then G. Preliminary OS (28% maturity; follow-up ongoing) was similar for G and C/P. ORR was significantly higher with G (45%) than C/P (30%). QoL improvement rates were higher with G than C/P (FACT-L 44 vs 34%; TOI 45 vs 25%); symptom improvement rates were similar (LCS 48 vs 42%). G had a more favorable tolerability profile than C/P. Conclusions: For pts in China, efficacy and tolerability data were generally consistent with the overall population. G demonstrated improved efficacy (PFS and ORR), similar OS, higher QoL and similar symptom improvement rates and more favorable tolerability profile compared with C/P in chemonaïve, never/light ex-smokers with advanced NSCLC and adenocarcinoma histology. In IPASS, EGFR mutation status appeared to be a strong predictive biomarker for G efficacy compared with C/P. [Table: see text] [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .

8006^ Background: IPASS demonstrated overall superiority of first-line G vs C/P for progression-free survival (PFS) in never/light ex-smokers with stage IIIB/IV adenocarcinoma NSCLC in Asia. PFS favored CP initially and then G. Outcome was correlated with biomarkers (preplanned exploratory objective). Methods: 683 patients provided tissue samples. Analyses included primary endpoint PFS (Cox proportional hazards) and secondary endpoint objective response rate (ORR; logistic regression) by biomarker status. Results: EGFR mutation (M) status was evaluable in 437 pts by Amplification Refractory Mutation System (ARMS; 60% M+). M+ pts had significantly longer PFS and higher ORR and M- pts significantly shorter PFS and lower ORR with G than C/P. In M unknown pts PFS and ORR were similar to overall population. Post hoc analysis of overall survival favored G in M+ pts (31% maturity; HR 0.78; 95% CI 0.50–1.20) and C/P in M- pts (53% maturity; HR 1.38; 95% CI 0.92–2.90); differences were not statistically significant and follow-up is ongoing. EGFR gene-copy number was evaluable in 406 pts by fluorescence in situ hybridization (FISH; 61% FISH +). Similar PFS and ORR results to analyses by M status were observed, driven by the overlap in EGFR FISH and M status. EGFR protein expression (PE) was evaluable in 365 pts by immunohistochemistry (73% PE+). PFS outcomes did not differ statistically between PE+ and PE-. ORR favored G in both PE+ and - pts. Conclusions: EGFR M status was a strong predictive biomarker for the efficacy of G vs C/P in this clinically selected first-line setting. [Table: see text] No significant financial relationships to disclose. ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .

7148 Background: A physician’s ability to accurately identify a patient’s attitude toward treatment is critical. The primary objective of this study (B9E-AA-JHSH) was to evaluate patient attitudes as predictors of survival independently of currently known predictive variables, and secondarily, whether physician-assessed patient attitudes differed from patient-assessed attitudes. Methods: This was a non-interventional, prospective, observational study of patients from 19 countries of Asia, Central Eastern Europe, and Latin America. Eligible patients had stage IIIB/IV NSCLC not amenable to curative surgery/radiotherapy, gemcitabine and cis/carboplatin as part of treatment, and were chemonaive. Physicians and patients used a 7-item questionnaire to assign patient attitudes to 1 of 4 categories using a pre-defined algorithm: A = Cure; B = Maximum extension of survival with acceptance of high toxicity; C = Maximum extension of survival only if coupled with normal lifestyle; and D = Symptom relief. Enrolled patients were followed until 18 months from enrolment, death, or loss to follow up. Results: From Sept 2002 to Dec 2003, 1,985 patients were enrolled; the majority were male (73.4%), [Table: see text]

The local xenogeneic graft-vs-host reaction (XGVHR) is mediated by competent T lymphocytes. It was effectively used as a practical bioassay to assess the in vitro immunomodulatory effects of several drugs on cells derived from cancer patients. A modified version of the XGVHR model was recently developed primarily for preclinical evaluation of in vivo immunorestoration induced by experimental biological response modifiers (BRMs). A well-defined biological response modifier, cimetidine, was injected into Cytoxan-primed rats prior to their inoculation with xenogeneic human mononuclear cells. The cimetidine treatment induced a partial abrogation of the immunosuppressive effect of Cytoxan as manifested by a significant decline in the volume of the XGVHR from 115.23 +/- 15.72 mm3 (positive control) to 67.3 +/- 11.41 mm3 (P less than 0.01). This abrogation of Cytoxan-induced immunosuppression by cimetidine was incomplete since the XGVHR without Cytoxan (negative control, saline only) was still significantly lower (45.12 +/- 4.55 mm3; P less than 0.01). The effect of cimetidine injection in vivo appeared to be dose dependent and did not exhibit any nonspecific toxic effect to the mononuclear cell inoculum. These results indicate that the model can serve as a useful tool in the preclinical evaluation of newly developed immunorestorative biological response modifiers.