洛铂联合多西他赛行肿瘤细胞减灭术加腹腔热灌注化疗治疗腹膜癌的临床观察

目的 分析洛铂联合多西他赛行肿瘤细胞减灭术（cytoreductive surgery, CRS）加腹腔热灌注化疗（hyperthermic intraperitoneal chemotherapy, HIPEC）治疗腹膜癌（peritoneal carcinoma, PC）的围手术期安全性及疗效。 方法 PC患者行CRS+HIPEC治疗,药物为洛铂50 mg/m2、多西他赛60 mg/m²,加入12 000 ml 0.9%氯化钠溶液加热至（43±0.5）℃持续灌注60 min。记录术后6天体温和心率变化、围手术期不良事件、血常规及血生化指标、术后患者恢复情况及生存结果。结果 90例PC患者行95次CRS+HIPEC,手术时间180~450 min (中位数485 min）;术后6天最高体温、心率分别为36.4℃~38.6℃（中位数37.5℃）、76~124 bpm（中位数100 bpm）,严重不良事件16例,包括围手术期死亡2例。中位生存期20.8月（95%CI: 13.1~25.8月）,1、3、5年生存率分别为75.6%、45.6%、43.3%。 结论 洛铂联合多西他赛进行CRS+HIPEC治疗PC安全性可接受,有助于延长患者生存期。     

Endoscopic Endonasal Dacryocystorhinostomy: Best Surgical Management for DCR

EEDCR is a highly rewarding Endoscopic procedure for management of dacryocystitis when epiphora does not respond to medications or repeated syringing of nasolacrimal duct. It is a simple, less time consuming, safe but skilful, highly satisfying surgery both for the patients as well as the surgeons. There is very big advantage of EEDCR, it is close 100% successful procedure, even if there is recurrence of epiphora it is again correctable fully with no residual affects. EEDCR is far more superior to External DCR/Laser DCR and there are definite reasons for it. A total number of 578 cases have been operated by me from April 1, 2005 to March 31, 2011, only very few reoccurrences were there and they were corrected easily so much so that it can be said that it is a close 100% successful procedure and best surgical management of DACRYOCYSTITIS up to date. The successful outcome was defined as symptomatic relief from epiphora and dacryocystitis and a patent nasolacrimal duct upon syringing at the end of procedure and on follow up of patient.     

参麦注射液对阿霉素所致大鼠心肌损伤保护作用的实验研究

目的　观察参麦注射液 (SMI)对阿霉素 (ADM )诱导大鼠心肌损伤的保护作用和抗氧化作用。方法　选用ADM诱导大鼠心肌损伤模型。SD大鼠 60只 ,随机分为 3个组 ,每组 2 0只 ,分别为正常组、治疗组、对照组。正常组 :实验第 1～ 9天注射生理盐水 ,每天 3ml/kg ,1次 /天。治疗组 :实验第 1～ 9天注射参麦注射液 ,每天 3ml/kg ,1次 /天 ,第 4天注射阿霉素 ,隔天 1次 ,连用 3次 ,用生理盐水配置成 1mg/ml,每次 3mg/kg。对照组实验 1～ 9天注射生理盐水 ,每天 3ml/kg ,1次 /天。第 4天注射阿霉素 ,以后隔天 1次 ,连用 3次 ,用生理盐水配置成 1mg/ml,每次 3mg/kg。到期测定血丙二醛 (MDA )含量和超氧化物歧化酶(SOD )活性 ,并进行心肌病理检查。结果　对照组MDA水平明显高于治疗组 ,对照组SOD水平则显著低于治疗组 ,即加用SMI可提高SOD活性 ,降低MDA含量。SMI能明显减轻大鼠心肌损伤 ,对照组与治疗组比较 ,治疗组心肌损伤明显减轻 ,治疗组与正常组比较无显著性差异。参麦注射液有抗氧化作用 ,与对照组比较 ,血SOD水平升高 ,MDA水平降低 ,心肌病理计分下降。结论参麦注射液有抗氧化作用和对阿霉素所引起的心脏毒性具有保护作用 ,为临床寻找有效的阿霉素所致心肌损伤保护药物提供良好的客观依据 ,值得临床推广应用     

Denosumab in patients with cancer and skeletal metastases: A systematic review and meta-analysis

Background

We conducted a systematic review of the literature to determine the efficacy and safety of denosumab in reducing skeletal-related events (SRE) in patients with bone metastases.

Methods

A literature search using MEDLINE, EMBASE, Web of Science and The Cochrane Collaboration Library identified relevant controlled clinical trials up-to-March 14, 2012. Two independent reviewers assessed studies for inclusion, according to predetermined criteria, and extracted relevant data. The primary outcomes of interest were SRE, time to first on-study SRE, and overall survival. Secondary outcomes included pain, quality of life, bone turnover markers (BTM), and adverse events.

Results

Six controlled trials including 6142 patients were analyzed. Compared to zoledronic acid, denosumab had lower incidence of SRE with a risk ratio (RR) of 0.84 (95% confidence intervals (CI) 0.80–0.88), delayed the onset of first on-study SRE (RR 0.83; 95% CI 0.75–0.90) and time to worsening of pain (RR 0.84; 95% CI 0.77–0.91). No difference was observed in overall survival with pooled hazard ratio of 0.98 (95% CI 0.90–1.0). For total adverse events, denosumab was similar to zoledronic acid (RR 0.97; 95% CI 0.89–1.0). No significant differences were observed in the frequency of osteonecrosis of the jaw (RR 1.4; 95% CI 0.92–2.1). Patients on denosumab had a greater risk of developing hypocalcemia (RR 1.9; 95% CI 1.6–2.3).

Conclusions

Denosumab was more effective than zoledronic acid in reducing the incidence of SRE, and delayed the time to SRE. No differences were found between denosumab and zoledronic acid in reducing overall mortality, or in the frequency of overall adverse events.     

体内诱导艾氏腹水瘤细胞的耐药性研究

肿瘤细胞耐药性的存在是临床化疗失败的主要原因之一。本实验在小鼠体内用阿霉素（ADR）诱导艾氏腹水瘤细胞（EHR）的耐药性，探讨细胞产生耐药性的机理。HPLC法测定细胞内药物浓度．结果表明耐药细胞─—EHR/ADR细胞内ADR积聚低于EHR细胞，而对ADR外排快于EHR细胞；异博定（VER）增加EHR／ADR细胞对ADR的摄取并阻滞其外排．而对EHR影响不大，揭示EHR／ADR细胞具有MDR特性。     

邻近腋窝的上皮样血管内皮瘤1例报道

We described a case of a 71-year-old woman with an epithelioid hemangioendothelioma (EHE) in her left axilla,a rare location which hasn't been reported yet. The patient suffered from numbness, pain and decreased muscle strength of her left upper extremity. Sonography revealed a hypoechoic mass surrounded the axillary artery and brachial artery. No obvious capsule was demonstrated. CT showed a soft-tissue mass with some calcifications and peripheral ring-like en-hancement. The MRI indicated a mass with mainly intermediate signal intensity on Tl-weighted imagine and intermediate signal intensity on T2-weighted imagine. The diagnosis was confirmed by histopathologic examination after surgery. There are some correlations of these imaging features with its histopathologic characters.     

Oxygen for relief of dyspnoea in mildly- or non-hypoxaemic patients with cancer: a systematic review and meta-analysis

The aim of this study was to determine the efficacy of palliative oxygen for relief of dyspnoea in cancer patients. MEDLINE and EMBASE were searched for randomised controlled trials, comparing oxygen and medical air in cancer patients not qualifying for home oxygen therapy. Abstracts were reviewed and studies were selected using Cochrane methodology. The included studies provided oxygen at rest or during a 6-min walk. The primary outcome was dyspnoea. Standardised mean differences (SMDs) were used to combine scores. Five studies were identified; one was excluded from meta-analysis due to data presentation. Individual patient data were obtained from the authors of the three of the four remaining studies (one each from England, Australia, and the United States). A total of 134 patients were included in the meta-analysis. Oxygen failed to improve dyspnoea in mildly- or non-hypoxaemic cancer patients (SMD=-0.09, 95% confidence interval -0.22 to 0.04; P=0.16). Results were stable to a sensitivity analysis, excluding studies requiring the use of imputed quantities. In this small meta-analysis, oxygen did not provide symptomatic benefit for cancer patients with refractory dyspnoea, who would not normally qualify for home oxygen therapy. Further study of the use of oxygen in this population is warranted given its widespread use.     

GF方案与TP方案一线治疗晚期非小细胞肺癌的临床对照研究

Objective  

The aim of the study was to evaluate the efficacies of initial gemcitabine plus cisplatin (GP) and paclitaxel plus cisplatin (TP) 1st-line chemotherapies for advanced non-small cell lung cancer (NSCLC) and observe their side effects.     

鼻咽癌患者放射性骨坏死引起的正电子显像假阳性结果1例及文献复习

目的:探讨鼻咽癌(NPC)患者放射性骨坏死(osteoradionecrosis,ORN)引起正电子假阳性结果的原因及避免因此引发诊断错误的方法。方法:回顾性分析1例放疗后的鼻咽癌患者,行鼻咽部MRI及正电子显像后,再行组织病理学检查,对三种结果进行分析、比较。结果:MRI及正电子显像均诊断患者颅底区域肿瘤复发,组织病理学结果则显示鼻咽部病灶为放射性骨坏死。因此正电子扫描结果为假阳性结果。结论:鼻咽癌患者放疗后所致的放射性骨坏死容易引起正电子显像假阳性结果并可能引发不必要的治疗,因此NPC患者的正电子图像,对于可能的局限性肿瘤复发诊断,应该非常慎重。     

Bortezomib-related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence

Background: Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM. Case presentation: A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with 4 cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. Discussion: CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. Conclusion: In the era of proteasome inhibitor (PtdIns)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.     

两种不同方案治疗晚期非小细胞肺癌的疗效比较(英文)

Objective: The aim of this study was to analyze and compare the recent efficacy and toxicity of a three-drug platinum-based regimen (A regimen): [cisplatin (DDP) + gemcitabine (GEM) + vinorelbine (NVB)] and a two-drug combination without a platinum drug (B regimen): GEM + NVB, which were used to treat 55 advanced non-small cell lung cancer (NSCLC) patients, in a bid to provide a guidance for clinical treatment. Methods: Twenty-four cases of advanced NSCLC (stage III-IV) patients were treated with A regimen ...     

Suppression of NAD(P)H-quinone oxidoreductase 1 enhanced the susceptibility of cholangiocarcinoma cells to chemotherapeutic agents

Background

Cholangiocarcinoma (CCA) is highly resistant to most of the known chemotherapeutic treatments. NAD(P)H-quinone oxidoreductase 1 (NQO1) is an antioxidant/detoxifying enzyme recently recognized as an important contributor to chemoresistance in some human cancers. However, the contribution of NQO1 to chemotherapy resistance in CCA is unknown.

Methods

Two CCA cell lines, KKU-100 and KKU-M214, with high and low NQO1 expression levels, respectively, were used to evaluate the sensitivity to chemotherapeutic agents; 5-fluorouracil (5-FU), doxorubicin (Doxo), and gemcitabine (Gem). NQO1 and/or p53 expression in KKU-100 cells were knocked down by siRNA. NQO1 was over-expressed in KKU-M214 cells by transfection with pCMV6-XL5-NQO1 expression vector. CCA cells with modulated NQO1 and/or p53 expression were treated with chemotherapeutic agents, and the cytotoxicity was assessed by SRB assay. The mechanism of enhanced chemosensitivity was evaluated by Western blot analysis.

Results

When NQO1 was knocked down, KKU-100 cells became more susceptible to all chemotherapeutic agents. Conversely, with over-expression of NQO1 made KKU-M214 cells more resistant to chemotherapeutic agents. Western blot analysis suggested that enhanced chemosensitivity was probably due to the activation of p53-mediated cell death. Enhanced susceptibility to chemotherapeutic agents by NQO1 silencing was abolished by knockdown of p53.

Conclusions

These results suggest that inhibition of NQO1 could enhance the susceptibility of CCA to an array of chemotherapeutic agents.     

Proficiency of DNA repair genes and microsatellite instability in operated colorectal cancer patients with clinical suspicion of lynch syndrome

Background

Lynch syndrome (LS) diagnosis is underestimated, and most of the patients remain undetected after colorectal resections. The study aims to assess the frequency of LS in patients undergoing surgical treatment for colorectal cancer (CRC).

Methods

A total of 458 CRC patients were operated from January 2005 to December 2008. Positive CRC family history (FH) was present in 118 (25.8%) patients. Histologic sections were reviewed for microsatellite instability (MSI) criteria (Bethesda guidelines), immunohistochemical (IHC) analysis for MLH1, MSH2, MSH6, PMS2 proteins, through the avidin-biotin-peroxidase complex, MSI (BAT-25, BAT-26, NR-21, NR-24 and MONO-27) and BRAF somatic mutation.

Results

Of the 118 patients with FH, 61 (51.69%) met at least one of the revised Bethesda criteria. IHC was abnormal in 8 (13.1%) and MSI in 12 patients (20%). BRAF was negative in all cases. MSI histopathological included: intratumoral lymphocytes (47.5%), expansive tumors (29.5%) mucinous component (27.8%) and Crohn’s like reaction in (14.7%). There was an association between the revised Bethesda criteria with: sex, mucinous histology and Crohn’s like reaction; MSI and IHC with PMS2 and MLH1. Revised Bethesda criteria 4 had 10.6 increased chances to display positive MSI. We have proposed a score to contribute as a practical tool in the diagnosis of LS.

Conclusions

The frequence of LS in resected CRC patients was 2.6%. The criterion 4 Revised Bethesda was associated more strongly with the presence of MSI.     

Marked radiosensitization of cells in culture to X ray by 5-chlorodeoxycytidine coadministered with tetrahydrouridine, and inhibitors of pyrimidine biosynthesis

Our approach to overcome the problem of rapid catabolism and general toxicity encountered with 5-halogenated analogues of deoxyuridine (5-bromo, chloro or iododeoxyuridine), which has limited their use as tumor radiosensitizers, is to utilize 5-chlorodeoxycytidine (CldC) with tetrahydrouridine (H4U). We propose that CldC, coadministered with H4U, is metabolized in the following manner: CldC----CldCMP----CldUMP---- ----CldUTP----DNA. All the enzymes of this pathway are elevated in many human malignant tumors and in HEp-2 cells. In X irradiation studies with HEp-2 cells, limited to 1 or 2 radiation doses, we have obtained 3.0 to 3.8 apparent dose enhancement ratios (these represent upper limits) when cells are preincubated with inhibitors of pyrimidine biosynthesis: N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorodeoxyuridine (FdU) or 5-fluorodeoxycytidine (FdC) + H4U. Optimum conditions for radiosensitization are: PALA (0.1 mg/ml) 18-20 hr prior to FdU (0.1 microM) or FdC (0.02 microM) + H4U (0.1 mM) followed 6 hr later by CldC (0.1-0.2 mM) + H4U (0.1 mM) for 56-68 hr. Viabilities of 10 +/- 4% to 15 +/- 1% (+/- S.E.) were obtained for drug-treated unirradiated cells. Enzymatic studies indicate that this toxicity may be tumor selective. CldC + H4U alone (at these concentrations) results in 20% substitution of CldU for thymidine in DNA (determined by HPLC analysis). Preliminary toxicity studies indicate that mice will tolerate treatment protocols involving a single dose of PALA (200 mg/kg) followed by a dose of FdU (50 mg/kg) and 3 cycles of CldC (500 mg/kg) + H4U (100 mg/kg) at 10 hour intervals, with marginal weight loss (4%). In this approach we seek to obtain preferential conversion of CldC to CldUTP at the tumor site by taking advantage of quantitative differences in enzyme levels between tumors and normal tissues.     

蛋白激酶C的下调与KBV200细胞多药耐药性的关系

目的　探讨蛋白激酶C (PKC)在肿瘤多药耐药 (MDR)中的作用。方法　3 2 P掺入法测定PKC的活性 ;Westernblot法检测KBV2 0 0细胞株PKC亚型的表达和亚细胞分布 ;实验组用十字孢碱 (SP)预孵育KBV2 0 0细胞 ;MTT法检测耐药株KBV2 0 0细胞的耐药性。结果　SP可下调膜组分和浆组分的PKC活性及总活性 ;使PKCα膜组分和浆组分的表达均降低 ,PKCβ的膜组分消失 ,浆组分PKCβ的表达稍增强 ,PKCε的膜组分和浆组分表达无变化 ;SP可降低VCR、ADR对KBV2 0 0细胞的IC50 值 (P <0 0 1)。结论　SP使KBV2 0 0细胞耐药性降低 ,可能与下调PKC有关。     

MNP和MVP方案治疗非小细胞肺癌的临床研究

目的　比较MNP和MVP方案治疗晚期非小细胞肺癌 (NSCLC)的疗效和不良反应。方法　 12 6例晚期NSCLC患者随机分为A和B组 ,A组采用MNP(丝裂霉素 去甲长春花碱 顺铂 )方案化疗。B组采用MVP(丝裂霉素 长春酰胺 顺铂 )方案化疗。至少连用 2个周期后评价疗效。结果　A组有效率为 5 4.0 % ( 3 4/63 ) ,B组有效率为 3 4.9% ( 2 2 /63 ) ,无显著性差异 (P>0 .0 5 ) ;其中对腺癌有效率A组为 44 .4% ( 16/3 6) ,B组为 3 3 .3 % ( 12 /3 6)。A组静脉炎发生率为 2 8.6% ( 14 /4 9) ,B组为 0 (P <0 .0 5 ) ,其它不良反应 2组无显著性差异。结论　MNP方案为治疗晚期NSCLC较为有效和安全的化疗方案     

细胞减灭术加腹腔热灌注化疗治疗卵巢癌腹膜转移癌的临床研究

目的 研究细胞减灭术（CRS）加腹腔热灌注化疗（HIPEC）治疗卵巢癌腹膜转移癌的疗效及安全性。方法 46例晚期（A组,FIGO Ⅲc/Ⅳ期,n=16和复发性,B组,n=30）卵巢癌腹膜癌患者接受了CRS+HIPEC治疗,分析其临床资料,主要终点指标为总生存期,次要指标为安全性。结果 A、B两组患者的中位总生存期（OS）分别为74.0月和57.5月（P=0.68）。腹膜癌指数（PCI）≤20（n=24）和＞20（n=22）的中位OS分别为76.6和38.5月（P=0.01）。CC 0~1分和CC 2~3分的中位OS分别为79.5和24.3月（P=0.00）。对复发性卵巢癌腹膜癌患者来说,铂类敏感型和耐药型患者的中位OS分别为6 5 . 3 和2 0 . 0 月（P=0.05）。无围手术期死亡病例,5例患者出现术后并发症。多因素分析显示,CC 0~1分、术后化疗≥6周期为改善生存的独立预后因素。结论 CRS+HIPEC可延长卵巢癌腹膜癌患者的总生存期,安全可行。     

Oxaliplatin-based hyperthermic intraperitoneal chemotherapy with single drug versus multiple drug treatment for colorectal cancer with peritoneal metastases: an observational cohort study

BackgroundLong-term survival for selected patients with peritoneal metastases (PM) from colorectal cancer (CRC) is possible when treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The objective of this study was to compare three different oxaliplatin-based (OX)-HIPEC regimens. Primary end-point was disease-free survival (DFS), and secondary endpoints, morbidity and overall survival (OS).MethodsThis is a retrospective study of all patients with colorectal PM treated with CRS and HIPEC between 2004 and 2015 from the prospectively maintained Uppsala HIPEC database. One hundred and thirty-three patients were identified. Three HIPEC regimens were included: OX-HIPEC, OX-HIPEC + post-operative intraperitoneal chemotherapy (EPIC) with 5-fluorouracil (5-FU), and oxaliplatin-irinotecan-based (OXIRI)-HIPEC. Multivariable Cox regression for DFS was performed.ResultsSixty-one patients received OX-HIPEC, 24 patients received OX-HIPEC + 5-FU EPIC, and 48 patients received OXIRI-HIPEC. The DFS for the OX-HIPEC group was 10.5 months, OX-HIPEC + EPIC 11.9 months, and OXIRI-HIPEC 13.4 months (OX-HIPEC vs. OXIRI HIPEC, P=0.049). The morbidity and OS did not differ between the groups. In the multivariable analysis, low peritoneal cancer index (PCI), absence of liver metastases, low completeness of cytoreduction (CC) score, and multiple drug (EPIC or OXIRI) HIPEC regimen were independent prognostic factors for DFS.ConclusionsThis study showed improved DFS with an intensification of HIPEC by adding irinotecan or EPIC compared to oxaliplatin alone without an increase in morbidity or mortality.     

Provasopressin expression by breast cancer cells: implications for growth and novel treatment strategies

Summary The arginine vasopressin (AVP) gene is expressed in certain cancers such as breast cancer, where it is believed to act as an autocrine growth factor. However, little is known about the regulation of the AVP protein precursor (proAVP) or AVP-mediated signaling in breast cancer and this study was undertaken to address some of the basic issues. The cultured cell lines examined (Mcf7, Skbr3, BT474, ZR75, Mcf10a) and human breast cancer tissue extract were found to express proAVP mRNA. Western analysis revealed multiple forms of proAVP protein were present in cell lysates, corresponding to those detected in human hypothalamus extracts. Monoclonal antibodies directed against different regions of proAVP bound to intact live Mcf7 and Skbr3 cells. Dexamethasone increased the amount of proAVP-associated glycopeptide (VAG) secreted by Skbr3 cells and a combination of dexamethasone, IBMX and 8br-cAMP increased cellular levels of VAG. Exogenous AVP (1, 10, and 100 nM) elevated phospho-ERK1/2 levels, and increased cell proliferation was observed in the presence of 10 nM AVP. Concurrent treatment with the V1a receptor antagonist SR49059 reduced the effects of AVP on proliferation in Mcf7 cells, and abolished it in Skbr3 cells. Results here show that proAVP components are found at the surface of Skbr3 and Mcf7 cells and are also secreted from these cells. In addition, they show that AVP promotes cancer cell growth, apparently through a V1-type receptor-mediated pathway and subsequent ERK1/2 activation. Thus, strategies for targeting proAVP should be examined for their effectiveness in diagnosing and treating breast cancer.     

NP与MNP方案治疗NSCLC近期疗效及毒性的对比分析

目的 :对比观察二药和三药联合化疗方案治疗非小细胞肺癌 (NSCLC)的近期疗效和毒性反应。方法 :6 2例初治的Ⅲb～Ⅳ期NSCLC ,随机分成A组 (去甲长春新碱 2 5mg/m2 静注第 1、8天 +顺铂 80mg/m2 静滴 ,分 2天 ,即NP方案 )、B组 (丝裂霉素 6mg/m2 静注第 1天 +去甲长春新碱 2 5mg/m2 静注第 1、8天 +顺铂 80mg/m2 静滴 ,分 2天 ,即MNP方案 )两组 ,分别化疗 2周期 ,每 4周为一周期。结果 :A组有效率为 33 3%、B组有效率为 37 9% (P >0 0 5 ) ;血小板降低A组为33 3% ,B组为 5 8 6 % (P <0 0 5 )。两组其余毒性反应无显著差异。结论 :二药联合可能比三药联合毒性低 ,而有效率无显著差异。