Targeted therapies for patients with advanced NSCLC harboring wild-type EGFR: what's new and what's enough / 癌症

Historically, non-small cell lung cancer (NSCLC) is divided into squamous and nonsquamous subtypes based on histologic features. With a growing number of oncogenic drivers being identified in squamous and nonsquamous NSCLC, this malignancy has been recently divided into several distinct subtypes according to the specific molecular alterations. This new paradigm has substantially highlighted the treatment of advanced NSCLC, shifting it from standard chemotherapy according to specific histologic subtypes to targeted therapy according to specific oncogenic drivers. The application of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in NSCLC patients harboring activating EGFR mutations has been a representative model of precise medicine in the treatment of NSCLC. As the role of EGFR-TKIs in routine management of patients with advanced NSCLC has been well established, this review provides an overview of alternative targeted therapy in the treatment of NSCLC, including EGFR-TKIs for patients with wild-type EGFR NSCLC, as well as other targeted agents either clinical available or in early- to late-stage development.

Effect of Wnt signaling suppression on gefitinib in non small cell lung cancer cell lines / 中华病理学杂志

<p><b>OBJECTIVE</b>To explore the effect of Wnt signaling suppression on proliferation of non small cell lung cancer to gefitinib, and its related mechanisms.</p><p><b>METHODS</b>PC9 and PC9/AB2 cells of both gefitinib sensitive and resistant were treated with different concentrations of gefitinib, and the proliferation index was measured using CCK8 kit. The members of Wnt signaling pathway were detected by Western blot. Dual luciferase reportor gene assay (TOP Flash) was used to document the transcriptional level of β-catenin. β-catenin siRNA was transfected into PC9/AB2 cells to suppress the Wnt signaling transcription, followed by treatment with different concentrations of gefitinib. Western blot was then used to detect the expression of EGFR and its downstream signaling after inhibit the expression of β-catenin.</p><p><b>RESULTS</b>Treating with different concentrations of gefitinib, the resistance of PC9/AB2 cells to gefitinib was significantly increased (P < 0.05). The members of Wnt signaling expressed at higher level in PC9/AB2 cells than in PC9 cells (t = 24.590, P = 0.000). TOP Flash examination showed that the endogenous transcriptional activity of Wnt signaling was higher in PC9/AB2 cell than that in PC9 cell (t = 4.983, P = 0.008). Compared with the negative control group, apoptotic rate and sensitivity to gefitinib significantly increased in interfered group (P < 0.05). The expression of p-ERK1/2 significantly decreased after Wnt signaling suppression, although other proteins showed no significant alterations.</p><p><b>CONCLUSION</b>Suppressing the activity of Wnt signaling can partly reverse the celluar resistance to gefitinib in non small cell lung cancer.</p>

Serum cytokine levels in patients with advanced non-small cell lung cancer: correlation with clinical outcome of erlotinib treatment / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Serum expression of cytokines may provide information about the clinical outcome of advanced non-small cell lung cancer (NSCLC) patients. This study aimed to investigate the relationship between serum cytokine levels and the clinical outcome of erlotinib treatment in a second or third line setting in patients with advanced NSCLC.</p><p><b>METHODS</b>A total of 162 patients with advanced NSCLC who received erlotinib as either second or third line therapy were enrolled in this study. Blood samples were collected before the initiation of erlotinib treatment, and the levels of IL-1, IL- 2R, IL-6, and tumor necrosis factor (TNF)-α were assessed by enzyme-linked immunosorbent assay (ELISA). Cutoff points were defined as the median levels of IL-1 (low (≥26.5 pg/ml) and high (>26.5 pg/ml)), IL-2R (low ( = 115 pmol/L) and high (>15 pmol/L)), IL-6 (low (≤49.5 pg/ml) and high (>49.5 pg/ml)), and TNF-α (low (≤48.5 pg/ml) and high (>48.5 pg/ml)). Kaplan-Meier analysis was used to estimate the survival time, and Cox regression analyses were used to correlate cytokines and baseline clinical characteristics with clinical outcomes, including time to progression (TTP) and overall survival (OS).</p><p><b>RESULTS</b>Between January 2007 and May 2011, 162 patients were enrolled. Their median age was 58 years. In this group, 109 were males and 53 were females, 74 were former or current smokers and 88 were non-smokers. A total of 122 patients had adenocarcinoma, 27 had squamous cell carcinoma, and 13 had tumors with other types of histology. And 139 patients had an Eastern cooperative oncology group (ECOG) performance status of 0-1, while 23 scored at 2-3. Expression of IL-1, IL-2R, and IL-6 was not significantly associated with age, gender, ECOG performance status, smoking status, or histology and stage of tumor. Only TNF-α was associated with smoking status (P = 0.045). Survival analysis showed that patients with low levels of either IL-6 or TNF-α had a statistically longer TTP and OS than patients with high expression (P < 0.05). These cytokines remained significant upon multivariate analysis (P < 0.05).</p><p><b>CONCLUSION</b>IL-6 or TNF-α may serve as potential predictive biomarker for the efficacy of erlotinib.</p>

Outcomes of chemotherapy in patients with EGFR mutation-negative non-small cell lung cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy of chemotherapy for patients with EGFR (exon 19 and 21) mutation-negative non-small cell lung cancer (NSCLC).</p><p><b>METHODS</b>One hundred and forty NSCLC patients with negative EGFR mutation (90 cases) or EGFR mutation (50 cases) underwent gemcitabine or vinorelbine plus cisplatin or carboplatin chemotherapy.</p><p><b>RESULTS</b>In the EGFR mutation-negative patients, there were PR in 26 cases, SD in 48 cases, PD in 16 cases, the disease control rate was 82.2%. In the patients with EGFR mutation, there were PR in 14 cases, SD in 23 cases, PD in 13 cases, the disease control rate was 74.0%. The difference of disease control rates in the two groups was not significant (P = 0.250). The progression free survival (PFS) of EGFR mutation-negative patients was 4.2 months (95%CI 3.8-4.6) vs. 4.0 months (95%CI 3.6-4.4) in patients with EGFR mutation, with a significant difference (P = 0.021). The overall survival (OS) of EGFR mutation-negative patients was 9.2 months (95%CI 8.4-10.0) vs. 7.8 months (95%CI, 6.9-8.7) of patients with EGFR mutation (P = 0.028).</p><p><b>CONCLUSIONS</b>Chemotherapy can prolong the PFS and OS of EGFR mutation-negative patients. However, only the extension of OS has practical significance.</p>

Survival without common toxicity criteria grade 3/4 toxicity following second-line treatment with pemetrexed for nonsquamous non-small cell lung cancer in Chinese patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The efficacy of pemetrexed in the second-line treatment of Chinese patients with advanced non-small cell lung cancer (NSCLC) has been shown to be similar to that of docetaxel in a recent study; additionally, pemetrexed was associated with much better safety and toxicity profiles. Here, the survival without common toxicity criteria grade 3/4 toxicity (SWT) data from a post hoc analysis of this recent prospective NSCLC study in Chinese patients is reported. This post hoc analysis differs from the main study; it focuses on the nonsquamous population to align with the current approval for pemetrexed in China.</p><p><b>METHODS</b>A total of 154 patients with nonsquamous NSCLC received either pemetrexed (500 mg/m(2) intravenously (IV)) or docetaxel (75 mg/m(2) IV) on day 1 of 21-day cycles. SWT was analyzed using Kaplan-Meier and univariate Cox methods.</p><p><b>RESULTS</b>Patients treated with pemetrexed had a longer median SWT than patients treated with docetaxel (7.4 months versus 1.2 months; unadjusted hazard ratio = 0.59, 95% confidence interval (CI): 0.41-0.84; P = 0.003). At 12 and 18 months, the SWT event-free probability for pemetrexed patients (18 months: 24.5%, 95%CI 13.9%-36.6%, vs. 12.3%, 95% CI 4.8%-23.6%) was greater than that for docexatel patients (12 months: 37.3%, 95% CI 26.5%-48.0%, vs. 23.3%, 95% CI 14.4-33.4). The progression-free survival without common toxicity criteria grade 3/4 toxicity (PFS-WT) was also statistically significantly longer for patients treated with pemetrexed than patients treated with docetaxel (1.9 months vs. 1.1 months, P = 0.002).</p><p><b>CONCLUSIONS</b>Chinese patients with nonsquamous NSCLC disease treated with pemetrexed had improved SWT beyond 6 months than those receiving docetaxel. This analysis supports a benefit-to-risk profile that favors pemetrexed over docetaxel in the second-line treatment of Chinese nonsquamous NSCLC patients.</p>

Clinical characteristics and diagnosis of pulmonary mucosa-associated lymphoid tissue-derived (MALT) lymphoma: a retrospective analysis of 29 cases / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the clinical manifestations and radiological characteristics, diagnostic methods and outcomes of pulmonary mucosa-associated lymphoid tissue-derived(MALT) lymphoma.</p><p><b>METHODS</b>A retrospective review of clinical, radiological and follow-up data of 29 pulmonary MALT lymphoma cases at Shanghai Pulmonary Hospital affiliated to Tong Ji University from January 2002 to June 2010 was performed.</p><p><b>RESULTS</b>Among these patients, there were 19(65.5%) males and 10 (34.5%) females aged from 27 to 73 (median 53) years old. Common clinical manifestations were cough (51.7%), fever (20.7%), apnea (17.2%), chest pain (17.2%), fatigue (13.8%) and weight loss (13.8%), while 9(31.0%) cases had no symptoms at diagnosis. The characteristics of the chest CT showed that 22 (75.9%) of the cases had patch infiltration or consolidation of the lung, 7(24.1%) of the cases had mass, and 15 (51.7%) unilateral and 14(48.3%) bilateral lesions. Their diagnosis duration varied between 0.5 and 96 months. 18(62.1%) cases were confirmed by surgery (15 open lung and 7 video-assisted thoracic surgery, VAST), 4 (13.8%) by percutaneous lung biopsy, 5 (17.2%) by bronchoscopic biopsy, and 2 (6.9%) by peripheral lymph node biopsy. The treatment methods included surgery, combined chemotherapy, radiotherapy and Chinese herbal medicine. The 1- and 3-year-survival rates were 92.3% and 87.4%, respectively.</p><p><b>CONCLUSIONS</b>Pulmonary MALT lymphoma is atypical in clinical manifestations and radiological characteristics, and easy to be misdiagnosed. Local diseases are mainly treated by operation while extensive diseases receive combined chemotherapy. A proper diagnosis is mainly based on pathological biopsy. Patients with MALT lymphoma have a favorable outcome. Poor prognosis may be connected with poor performance status and long diagnosis duration.</p>

Correlation analysis between cytokines levels in serum and bronchoalveolar lavage fluid, blood T cell subsets and pneumoconiosis severity / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To analyze the correlation between the pneumoconiosis severity and the cytokines levels in serum and bronchoalveolar lavage fluid (BALF) or blood T cell subsets.</p><p><b>METHODS</b>The subjects were divided into five groups: control group (6 cases), group exposed to dusts (6 cases) and 3 pneumoconiosis groups (36 in stage I, 12 in stage II and 10 in stage III). ELISA was used to detect IL-6, sIL-2R and TNF-α levels in serum and BALF. The subsets of blood T cells were classified by flow cytometer.</p><p><b>RESULTS</b>As compared with control group and group exposed to dusts, the levels of serum IL-6 and sIL-2R in patients with II or III stages significantly increased, which were positively correlated with pneumoconiosis stages (r(1) = 0.74, r(2) = 0.81, P < 0.05). The level of serum TNF-α significantly decreased in patients with III stages, as compared with control group and group exposed to dusts. There was a negative correlation between serum TNF-α level and pneumoconiosis severity (r = -0.58, P < 0.05). There was a positive correlation between the levels of IL-6, sIL-2R and TNF-α in BALF and the levels of IL-6, sIL-2R and TNF-α in serum (r(1) = 0.77, r(2) = 0.96 and r(3) = 0.88, P < 0.05). The proportion of CD(4)(+)T cells and the ratio of CD(4)(+)/CD(8)(+) decreased dramatically in patients with II and III stages. But there was no correlation between these values and disease severity.</p><p><b>CONCLUSION</b>The immune function in Th cell was inhibited. The levels of IL-6, sIL-2R and TNF-α in serum and BALF were associated with the severity of pneumoconiosis.</p>

Efficacy and safety of Erlotinib in the treatment for advanced non-small cell lung cancer in Chinese patients / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To observe the efficacy and the adverse effects of erlotinib in the treatment for advanced non-small cell lung cancer (NSCLC) in Chinese patients.</p><p><b>METHODS</b>From November 2005 to March 2009, a total of 519 patients with unresectable, local advanced, relapsed or metastatic NSCLC were enrolled in the trial. All the patients were treated with erlotinib 150 mg/day until disease progression or intolerable toxicity or for other reasons. The response rate, time to disease progression, overall survival and toxicity were analyzed.</p><p><b>RESULTS</b>Of these 519 patients, 1 case had complete response, 127 cases had partial response and 263 cases had stable disease, resulting in an overall response rate (CR + PR) of 26.7%, disease stable rate of 54.9% and disease control rate (CR + PR + SD) of 81.6%. The median time to progression was 6.44 months and median overall survival was 15.37 months. The major erlotinib treatment-related adverse events (AE) were mild (CTC AE 1/2), only 3 cases had severe adverse effect, 1 case had interstitial lung disease and died of respiratory failure.</p><p><b>CONCLUSION</b>The study presents excellent response rates, time to progression and overall survival of erlotinib treatment for advanced NSCLC in Chinese patients, and its adverse events are tolerable.</p>

Mutations in exon 19 of EGFR gene in non-small cell lung cancer from Chinese patients / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the mutations in exon 19 of epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer from Chinese patients.</p><p><b>METHODS</b>Genomic DNA was extracted from 72 lung cancer tissues. Then the exon 19 of EGFR gene was amplified by nested PCR and sequenced.</p><p><b>RESULTS</b>In 13 tumor tissues, multi-nucleotide in-frame deletion mutations at the exon 19 of EGFR gene, had been detected. There were 4 mutation types. The mutation rate was 18.1%. The mutations were all heterozygous. There was association of the exon 19 mutation of EGFR gene with adenocarcinoma, female patients and non-smokers.</p><p><b>CONCLUSION</b>There were multi-nucleotide in-frame deletion mutations in exon 19 of EGFR gene. Mutations of the exon 19 of EGFR gene were higher in female, non-smoking and adenocarcinoma patients.</p>

Impact of erlotinib treatment on symptoms and quality of life in patients with advanced non-small-cell lung cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the impact of erlotinib as a second or third line treatment on the symptoms and quality of life (QOL) in patients with advanced non-small cell lung cancer (NSCLC).</p><p><b>METHODS</b>Fifty patients with stage III b and IV NSCLC, treated previously with at least one regimen of platinum-based chemotherapy, received 150 mg of erlotinib orally, once a day till disease progression. QOL was assessed by European Organization for Research and Treatment of Cancer QLQ-C30 and the lung cancer module (QLQ-LC13). The primary end points for QOL analysis were time to deterioration of three common lung cancer symptoms: cough, dyspnea and pain.</p><p><b>RESULTS</b>Among 47 evaluable cases, there were partial remission (PR) in 18 cases, stable disease (SD) in 21 cases, and progressive disease (PD) in 8 cases. After two cycles of treatment, the mean scores of global QOL and all 5 functioning scales except the cognitive function increased significantly (P < 0.05). Mean scores of major general symptoms, hypodynamia and anorexia, and disease-related symptoms alleviated significantly. Both response rates of five functioning and global QOL were more than 44% after erlotinib treatment. Response rates of major general symptoms and disease-related symptoms varied from 14% to 76%. Patients with complete or partial response likely had improvement in the QOL response (P < 0.05), and the time to major symptom deterioration in those were significantly longer (P < 0.001) than that in patients with stable or even progressive disease.</p><p><b>CONCLUSION</b>Erlotinib is effective to improve not only survival, but also tumor-related symptoms and quality of life in patients with advanced NSCLC previously treated with cisplatin-contained regimens. The improvement in the quality of life is positively correlated with objective tumor response.</p>

Sensitivity of two cell lines with acquired resistance to gefitinib to several chemotherapeutic drugs / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To explore the sensitivity of tumor cell lines with acquired resistance to gefitinib to several chemotherapeutic drugs and provide preclinical basis of available chemotherapy regimens after failure of molecular targeted therapy.</p><p><b>METHODS</b>Human lung adenocarcinoma cell lines PC9 and PC9/G with acquired resistance to gefitinib were cultured in vitro. The sensitivity to chemotherapeutic drugs and inhibition rate of cell proliferation was determined by MTT assay. Effects of drugs on apoptosis and expression of P-170 were determined by flow cytometry. Difference of gene expression profile between PC9 and PC9/G cells was analyzed by DNA microarray. Western blot was used to test the expression of Akt, phospho-Akt and integrin beta1.</p><p><b>RESULTS</b>The resistance index of PC9/G cells to cisplatin was about 5.4-fold compared with that of PC9 cells. LY294002 may significantly elevate the sensitivity of PC9/G cells to cisplatin (P < 0.05). PC9/G cells were more sensitive to docetaxel than PC9 cells. No significant difference of sensitivity to pemetrexed was found between these two cell lines. Expression level of P-170 in PC9/G cells was lower than that in PC9 cells. In PC9/G cells, the expression of integrin beta1 and DNA healing gene was high and expression of gene during mitosis was low. The level of expression of Akt, phospho-Akt and integrin beta1 in PC9/G cells was higher than that in PC9 cells.</p><p><b>CONCLUSION</b>In PC9/G cells, a cell line with acquired resistance to gefitinib, over-expression of PI3K, integrin and DNA restoration gene and continuous activation of PI3K is found to be correlated with resistance to cisplatin. Docetaxel or pemetrexed is a more reasonable choice than cisplatin for treatment of NSCLC patients who failed to respond to EGFR-TKI.</p>

Gefitinib in the treatment of refractory non-small cell lung cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To observe the efficacy, median survival time, time to progression, quality of life and adverse effect of gefitinib (IRESSA) in the treatment for refractory advanced non-small cell lung cancer (NSCLC).</p><p><b>METHODS</b>Forty-one patients with stage III b to IV NSCLC who had previously treated with 2-7 cycles of platinum-based chemotherapy were enrolled into the study, 85.4% of the patients had received second line chemotherapy. The regimen was oral intake of gefitinib 250 mg once daily until the disease progression or intolerable toxic reaction occurred. The patients were required to receive tumor assessment before the treatment, one month, two months and every three months after IRESSA administration.</p><p><b>RESULTS</b>All 41 patients were evaluable for therapeutic effect. Partial response rate (PR), stable disease (SD) and progression of disease (PD) was 43.9% (18/41), 34.1% (14/41) and 22.0% (9/41), respectively. No complete regression was observed. The overall response rate was 43.9% (18/41) with a rate of 42.1% in the male and 45.5% in the female (P > 0.05). The disease control rate (PR + SD) was 78.0% (32/41). Twenty-two of the 41 patients (53.7%, 22/41) were still alive with MST of 10.1 months when the follow-up ended in Nov. 2006. TP and MST of dead patients was 2.7 and 5.0 months, respectively. The rate of symptom improvement was 78% for all patients with MST of 13.3 months for PR patients. The performance status (Karnofsky) was improved (20 +/- 5) after 28-day treatment. III-IV degree toxicity was not observed.</p><p><b>CONCLUSION</b>IRESSA is effective and safe for the advanced NSCLC patients with poor performance status who previously failed in the second or third line chemotherapy.</p>

Detection of epidermal growth factor receptor mutations in non-small cell lung cancer by real-time PCR using TaqMan-MGB probes / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate mutations of EGFR TK gene in non-small cell lung cancer (NSCLC) and the diagnostic value of the mutations assayed by real-time PCR using TaqMan-MGB probes.</p><p><b>METHODS</b>Tyrosine kinase genes of EGFR (exons 18, 19 and 21) were amplified by PCR technology, and sequenced and analyzed by Chromas software in 80 NSCLC patients. Based on the results of sequencing, TaqMan-MGB probes were designed and used to detect the mutations of EGFR by real-time PCR. The results of detected mutations were compared between real-time PCR and direct sequencing. The sensitivity and specificity of real-time PCR using TaqMan-MGB probes were analyzed by adding different number of PC-9 cells (exon 19 deleted EGFR) into A549 cells (Wild-type EGFR).</p><p><b>RESULTS</b>Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in 21 of 80 NSCLC patients with an incidence rate of 26.3%. In-frame deletions of exon 19 occurred in 13 patients and point mutation occurred in codon 858 (exon 21) in 8 patients. Real-time PCR with the TaqMan MGB probes could detect all the mutations of EGFR found by sequencing. The sensitivity and specificity of the detection of EGFR mutations were both 100%. Real-time PCR with TagMan MGB probes could detect EGFR mutation in as rare as 50 EGFR mutant cells and in a proportion of 10% of mutant cells in a cell population. The mutations were significantly higher in the adenocarcinoma than in non-adenocarcinoma (16/38 vs. 5/42, chi2 = 9.702, P <0.01), in the female patients than in the male patients (14/29 vs. 7/51, chi2 = 11.4, P <0.01) and in non-smokers than in smokers (16/40 vs. 5/40, chi2 = 7.812, P < 0.01). The mutations were not related to patients'age, TNM staging, etc.</p><p><b>CONCLUSION</b>Somatic mutations of EGFR gene develop in NSCLC and are more common in female, non-smoker and adenocarcinoma patients. Real-time PCR using TaqMan-MGB, which can be used to detect the EGFR gene mutations, is easy to operate and deserves widespread application.</p>

Immunotherapeutic effect of recombinant EGFR phage vaccine on tumors / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To construct a recombined phage vaccine and to evaluate the efficiency of this phage vaccine against EGFR-positive tumors.</p><p><b>METHODS</b>T7 phage display system was used to display five fragments of the extracellular domain of chicken EGFR. The EGFR was expressed as a fused protein on the surface of the T7 phage 10B capsid protein. The EGFR expression of the phage vaccine was verified by Western-blot analysis. Anti-EGFR antibody was detected by ELISA. Splenic lymphocytes of the immunized mice were separated and used to determine the immunotoxic effect against A431 cells. The phage vaccines were injected into C57 mice 4 times before Lewis lung cancer cells inoculation. Tumor volume was recorded to evaluate the anti-tumor effect of each vaccine.</p><p><b>RESULTS</b>Five phage vaccines inserted with the chicken EGFR gene were successfully constructed. Western blot assay showed that the extracellular domain of chicken EGFR proteins were displayed on the surface of the phage. Specific antibody was induced in the immunized mice, compared with the control group. Splenic lymphocytes of the immunized mice were shown to be immunotoxic against A431 cells. The killing rates of the experimental groups were higher than that of control group (P < 0.001, t-Student test). The highest killing rate was (45.74 +/- 7.21)%. The tumor growth was inhibited in the experimental groups compared with those of control groups (P < 0.05 in C1, C2, C3, C4 groups, P > 0.05 in C5 group).</p><p><b>CONCLUSION</b>Our results demonstrated that recombined EGFR phage vaccines may be used to induce therapeutic anti-tumor immunity against EGFR-positive tumors.</p>

Efficacy of calf spleen extraction injection combined chemotherapy in the treatment of advanced nonsmall cell lung cancer / 中国癌症杂志

Background and purpose:The occurrence and development of lung cancer are closely correlated with the immune function in the human body.The patients with malignant tumors have shown a disorder of immune function,especially in terms of loss of cellular immune function.The purpose of this study was to investigate the possible auxiliary effect of sipulin in the treatment of advanced non-small-cell lung cancer(NSCLC).methods: Ninety-three patients were randomly divided into two groups:sipulin group:sipulin plus docetaxel+cisplatin;control group:only administered docetaxel+cisplatin.The leukocyte,haemoglobin and platelet,toxicity of digestive tract,body weight,Karnofsky status and efficacy of those patients were evaluated before and after therapy,respectively.Results: Overall response rates were 46.67% and 30.23%(P=0.023)in sipulin group and control group,respectively.The median survival time was 10.1months versus 8.3 months(P=0.035)in sipulin group and control group,respectively.The 1-year survival rate for sipulin group and control group was 52.9% versus 39.4%(P=0.038),respectively.The clinical efficacy and the frequence of leukocyte reduction were better in sipulin group than in control group,the quality of life and clinical symptom of the patients in sipulin group were improved more significantly than those in control group (P