Association of p53 codon 72 polymorphism and MDM2 SNP309 with clinical outcome of advanced nonsmall cell lung cancer

BACKGROUND: The purpose of the study was to investigate whether polymorphisms of p53 codon 72 (Arg72Pro) and MDM2 SNP309 (309T>G) affect p53 expression and the clinical outcome of patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: A total of 148 NSCLC patients, previously enrolled in 2 different prospective clinical trials, were genotyped for the p53 Arg72Pro and MDM2 309T>G polymorphisms. Immunohistochemical staining of p53 protein was performed on 61 tumor samples. Genotypes were correlated with p53 expression, clinicopathologic factors, tumor response, and survival. Multivariate logistic or Cox regression analyses were used to adjust for possible confounding variables. RESULTS: The distribution of sex, age, performance status, stage, tumor histology, and smoking habit was not significantly different among polymorphism variants. However, a significant association was observed between p53 Arg72Pro polymorphism and primary resistance to chemotherapy. Patients with the Pro/Pro variant were more likely to be resistant to first-line chemotherapy, especially the irinotecan plus cisplatin regimen, than those with Arg/Arg or Arg/Pro variants (60% vs 27%, P = .014). In multivariate analysis, the Pro/Pro genotype was strongly predictive for shorter progression-free survival (PFS) (hazard ratio [HR] = 1.952, P = .01). The p53 overexpression was associated with MDM2 SNP309. The TT genotype showed more p53 overexpression than TG or GG genotypes (P = .036). In multivariate analysis, the MDM2 TT genotype was independently predictive for longer survival (HR = 1.742, P = .032). CONCLUSIONS: The p53 72Pro/Pro variant was predictive for primary resistance to chemotherapy and shorter progression-free survival. The MDM2 SNP309 was associated with less p53 overexpression and prognostic for worse survival. Genotyping these polymorphisms may be useful for predicting the clinical outcome of advanced NSCLC.     

晚期非小细胞肺癌对铂类药物的化疗敏感性与p53和p73基因多态的关系

目的探讨细胞凋亡相关基因p53和p73的遗传多态,与晚期非小细胞肺癌（NSCLC）对铂类药物化疗敏感性的关系。方法以聚合酶链反应（PCR）-限制性片段长度多态性（RFLP）和突变扩增阻抑系统（ARMS）分析方法,对165例以顺铂（DDP）或卡铂（CBP）为主进行化疗的晚期NSCLC患者,进行p53第72密码子Arg→Pro多态,和p73第2外显子G4C14-A4T14多态的检测,2～3个疗程后进行效果评价。以非条件Logistic回归模型比较不同基因型与化疗疗效的关系。结果携带p53 72Pro等位基因患者的化疗敏感性,是携带p53 72Arg／Arg基因型患者的2、46倍（95％CI,1．11～5．45,P=0．026）;而携带至少1个p73突变等位基因（A4T14）的患者,其化疗敏感性是携带p73 G4C14／G4C14基因型患者的2．22倍（95％讲,1．14～4、30,P=0．019）。2个多态位点合并分析结果显示,同时携带p53和p73野生基因型的患者,化疗有效率为7．7％;而携带1个、2个和≥3个p53和p73变异等位基因的患者,化疗有效率分别为34．8％、42．2％和40、7％。结论p53和p73基因遗传多态与晚期NSCLC患者对以铂类药物为主的化疗敏感性有关。     

MDM2 and p53 polymorphisms are associated with the development of hepatocellular carcinoma in patients with chronic hepatitis B virus infection

A single-nucleotide polymorphism (SNP) in the promoter region of MDM2, SNP 309, is associated with hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus infection. The effect of p53 codon 72 polymorphism Arg72Pro on HCC risk remains inconsistent. This study evaluated the association of MDM2 and p53 polymorphisms with the presence and early onset of HCC in Korean patients with chronic hepatitis B virus (HBV) infection. In total, 583 consecutive patients with chronic HBV infection were classified according to the presence (n = 287) or absence (n = 296) of HCC. The MDM2 SNP 309 and p53 Arg72Pro were genotyped using restriction fragment length polymorphism method. The MDM2 G/G and p53 Pro/Pro genotypes were more frequent in HCC group than in non-HCC group (P < 0.001 and P = 0.004, respectively). Multivariate analysis for the presence of HCC revealed that the odds ratio (OR) for MDM2 G/G over T/T was 4.89 (P < 0.001) and that of p53 Pro/Pro over Arg/Arg was 3.03 (P = 0.006). Combined MDM2 G/G and p53 Pro/Pro had a synergistic effect on HCC risk, with an OR of 20.78 (P < 0.001). The mean age of tumor onset in patients with MDM2 G/G genotype was 50.9 years compared with 55.1 with T/T genotype (P = 0.018) and that with p53 Pro/Pro was 49.7 years compared with 52.9 with Arg/Arg (P = 0.040). Thus, MDM2 SNP 309 and p53 Arg72Pro are associated with the early development of HCC in Korean patients with chronic HBV infection.     

A radiomics prognostic scoring system for predicting progression-free survival in patients with stage IV non-small cell lung cancer treated with platinum-based chemotherapy

ObjectiveTo develop and validate a radiomics prognostic scoring system (RPSS) for prediction of progression-free survival (PFS) in patients with stage IV non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy.MethodsIn this retrospective study, four independent cohorts of stage IV NSCLC patients treated with platinum-based chemotherapy were included for model construction and validation (Discovery: n=159; Internal validation: n=156; External validation: n=81, Mutation validation: n=64). First, a total of 1,182 three-dimensional radiomics features were extracted from pre-treatment computed tomography (CT) images of each patient. Then, a radiomics signature was constructed using the least absolute shrinkage and selection operator method (LASSO) penalized Cox regression analysis. Finally, an individualized prognostic scoring system incorporating radiomics signature and clinicopathologic risk factors was proposed for PFS prediction.ResultsThe established radiomics signature consisting of 16 features showed good discrimination for classifying patients with high-risk and low-risk progression to chemotherapy in all cohorts (All P<0.05). On the multivariable analysis, independent factors for PFS were radiomics signature, performance status (PS), and N stage, which were all selected into construction of RPSS. The RPSS showed significant prognostic performance for predicting PFS in discovery [C-index: 0.772, 95% confidence interval (95% CI): 0.765−0.779], internal validation (C-index: 0.738, 95% CI: 0.730−0.746), external validation (C-index: 0.750, 95% CI: 0.734−0.765), and mutation validation (C-index: 0.739, 95% CI: 0.720−0.758). Decision curve analysis revealed that RPSS significantly outperformed the clinicopathologic-based model in terms of clinical usefulness (All P<0.05).ConclusionsThis study established a radiomics prognostic scoring system as RPSS that can be conveniently used to achieve individualized prediction of PFS probability for stage IV NSCLC patients treated with platinum-based chemotherapy, which holds promise for guiding personalized pre-therapy of stage IV NSCLC.     

Shenqi fuzheng,an injection concocted from chinese medicinal herbs,combined with platinum-based chemotherapy for advanced non-small cell lung cancer: a systematic review

Background

Platinum-based chemotherapy has been a standard therapy for advanced non-small cell lung cancer (NSCLC), but it has high toxicity. In China, Shenqi Fuzheng, a newly developed injection concocted from Chinese medicinal herbs has been reported that may increase efficacy and reduce toxicity when combined with platinum-based chemotherapy, but little is known about it outside of China. The aim of this study was to systematically review the existing clinical evidence on Shenqi Fuzheng Injection(SFI) combined with platinum-based chemotherapy for advanced NSCLC.

Methods

Pubmed, Cochrane Library, EMBASE, CNKI, and CBM search were organized for all documents published, in English and Chinese, until April 2010. The randomized controlled clinical trials were selected based on specific criteria, in which a SFI plus platinum-based chemotherapy treatment group was compared with a platinum-based chemotherapy control group for patients with advanced NSCLC. The quality of studies was assessed by modified Jadad''s scale, and Revman 4.2 software was used for data syntheses and analyses.

Results

Twenty nine studies were included in this review based on our selection criteria. Of them, ten studies were of high quality and the rest were of low quality, according to the modified Jadad scale. The meta-analysis showed there was a statistically significant higher tumor response (RR, 1.19; 95% CI, 1.07 to 1.32; P = 0.001) and performance status ((RR, 1.57; 95% CI, 1.45 to 1.70; P < 0.00001); but lower severe toxicity for WBC (RR, 0.37; 95% CI, 0.29 to 0.47; P < 0.00001), PLT (RR, 0.33; 95% CI, 0.21 to 0.52; P < 0.00001), HB (RR, 0.44; 95% CI, 0.30 to 0.66; P < 0.0001) and nausea and vomiting (RR, 0.32; 95% CI, 0.22 to 0.47; P < 0.00001), when the SFI plus platinum-based chemotherapy treatment group was compared with the platinum-based chemotherapy control group. Sensitivity analysis was restricted to studies with the high quality, and the result was similar when the studies with low quality were excluded. Asymmetry was observed in a funnel plot analysis, and Egger''s test also indicated an evidence of publication bias (P = 0.016).

Conclusions

SFI intervention appears to be useful to increase efficacy and reduce toxicity when combined with platinum-based chemotherapy for advanced NSCLC, although this result needs to be further verified by more high-quality trials.     

Risk of MDM2 SNP309 alone or in combination with the p53 codon 72 polymorphism in acute myeloid leukemia

A single nucleotide polymorphism (SNP) in the promoter of MDM2 gene, SNP309 T > G (a T–G exchange at nucleotide 309 in the first intron), can increase the expression level of MDM2, thereby causing an impairment of p53 tumor suppressor activity. A G–C exchange at p53 codon 72 polymorphism results in a substitution of proline (Pro) for arginine (Arg) in the transactivation domain, which was shown to alter the primary structure of the p53 protein. Both polymorphisms have been implicated in cancer. To investigate whether that MDM2 SNP309 and p53 codon 72 polymorphism should be at least partially responsible for genetic susceptibility to acute myeloid leukemia (AML), both polymorphisms were determined in a case–control study consisting of 231 AML patients and 128 normal individuals. The MDM2 SNP309G allele was associated with increased risk of AML. Furthermore, the p53 codon 72 and MDM2 SNP309 polymorphisms did not associate with age of onset and any other clinical parameters studied. When the p53 and MDM2 polymorphisms were combined, no multiplicative joint effect between the MDM2 GG and p53 Pro/Pro genotypes exists in the risk of developing AML. These results suggest that the MDM2 SNP309 homozygous GG genotype may be a genetic susceptibility factor in the pathogenesis of AML.     

MDM2 promoter SNP309 is associated with an increased susceptibility to chronic lymphocytic leukemia and correlates with MDM2 mRNA expression in Chinese patients with CLL

A single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM2 leading to increased expression of MDM2 and attenuated function of p53 has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. The MDM2 SNP309 genotypes in 173 CLL patients and 260 healthy controls were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, which was confirmed by direct DNA sequencing. Compared with the T/T genotype, the SNP309 G/G genotype instead of T/G heterozygote was associated with a significantly increased risk of CLL (OR = 2.84; 95% CI 1.61-5.03; p < 0.001). Age at onset of CLL was similar irrespective of MDM2 status. MDM2 mRNA expression within CLL of G/G genotype was significantly higher than that in T/G (p = 0.009) and T/T genotypes (p < 0.001). Excluding patients with p53 deletions or mutations enhanced the significance of the findings (G/G vs. T/T, p < 0.001; G/G vs. T/G p = 0.001), which prompted us to study the role of the polymorphism in p53 wild-type individuals. In the p53 wild-type groups, survival analysis showed that the patients with MDM2 SNP309 G/G and T/G genotypes both had significantly shorter treatment-free survival (TFS) than SNP309 T/T genotype. Notably, univariate and multivariate analyses showed that MDM2 SNP309 genotypes were associated with TFS. These data show that MDM2 309G polymorphisms contribute to the risk of developing CLL. The unfavorable MDM2 SNP309 G/G genotype was associated with an increase of MDM2 mRNA expression. MDM2 SNP309 was found to be associated with TFS in p53 wild-type Chinese CLL populations.     

Interaction of P53 Arg72Pro and MDM2 T309G polymorphisms and their associations with risk of gastric cardia cancer

The P53 tumor suppressor pathway plays an important role in cancer development. The auto-regulatory feedback mechanism of the P53 and MDM2 expression is critical in keeping proper tumor suppressor function of this pathway. This study examined the effect of P53 Arg72Pro variants on transactivation of polymorphic MDM2 promoter (T309G) and their associations with risk of developing gastric cardia adenocarcinoma (GCA) in a Chinese population. Luciferase assays consistently showed a significantly higher activity of the MDM2 309G promoter compared with the MDM2 309T promoter. In cells co-transfected with variant P53 cDNAs, P53-72Pro displayed a significantly higher ability to activate the MDM2 promoter than P53-72Arg. Genotype analyses in 500 GCA patients and 1000 controls showed that significantly increased risk for developing GCA was associated with the MDM2 309G and the P53 72Pro allele compared with the MDM2 309T and the P53 72Arg allele in an allele dose-dependent manner. A joint effect between the MDM2 and P53 polymorphisms in intensifying GCA risk was detected, with the odds ratio (OR) for the presence of both MDM2 390GG and P53 72Pro/Pro genotypes being 5.05 [95% confidence interval (CI), 2.50-10.20]. These results suggest that the P53 72Pro and MDM2 309G polymorphisms contribute to the risk of developing GCA.     

Clinical implications of the MDM2 SNP309 and p53 Arg72Pro polymorphisms in transitional cell carcinoma of the bladder

Recent studies have shown that functional polymorphisms at the MDM2 SNP309 T/G and p53 Arg72Pro may be associated with cancer susceptibility. However, the role of these polymorphisms on the risk of transitional cell carcinoma of the bladder (TCCB) and clinical outcome remains unknown. SNP309 and p53 Arg72Pro polymorphisms were genotyped in 227 patients and 266 control subjects. The association between each polymorphism, TCCB risk and clinical outcome was evaluated by using a logistic regression model, a Kaplan-Meier curve with the log-rank test, or a Cox proportional hazard model. No significant associations between the polymorphisms and TCCB risk were found. On the MDM2 SNP309, the TT patients with superficial TCCB tended to have a longer recurrence-free survival than the TG or GG patients after transurethral resection (P=0.074). On the p53 Arg72Pro, the Pro/Pro patients with superficial TCCB had a significantly lower risk for recurrence than the Arg/Pro or Arg/Arg patients [Hazard ratio (HR), 0.364; 95% confidence interval (CI), 0.14-0.93]. In contrast, the Pro/Pro patients following radical cystectomy showed a significantly poorer survival and a higher risk of disease-specific death than the Arg/Pro + Arg/Arg patients (HR, 2.76; 95% CI, 1.11-6.84). MDM2 SNP309 and p53 Arg72Pro polymorphisms might influence the clinical outcome of TCCB in a distinctive way between superficial TCCB and invasive TCCB. The results may reflect marked differences in the genetic background between superficial and an invasive type of TCCB.     

Role of the MDM2 Promoter Polymorphism (-309T>G) in Acute Myeloid Leukemia Development

Background: The human homologue of the mouse double minute 2 (MDM2) gene is a negative regulator ofTp53. MDM2-309T>G a functional promoter polymorphism was found to be associated with overexpressionthereby attenuation of Tp53 stress response and increased cancer susceptibility. We have planned to evaluate thepossible role of MDM2-309T>G polymorphism with risk and response to chemotherapy in AML. Materials andMethods: A total of 223 de novo AML cases and 304 age and sex matched healthy controls were genotyped for theMDM2-309T>G polymorphism through the tetra-primer amplification refractory mutation system (ARMS)-PCRmethod. In order to assess the functional relationship of -309T>G SNP with MDM2 expression level, we quantifiedMDM2 mRNA in 30 primary AML blood samples through quantitative RT-PCR. Both the (-309T>G) genotypesand the MDM2 expression were correlated with disease free survival (DFS) rates among patients who haveachieved complete remission (CR) after first induction chemotherapy. Results: MDM2-309T>G polymorphismwas significantly associated with AML development (p<0.0001). The presence of either GG genotype or G alleleat MDM2-309 confered 1.79 (95% CI: 1.12-2.86; p<0.001) and 1.46 fold (95%CI: 1.14-1.86; p= 0.003) increasedAML risk. Survival analysis revealed that CR+ve cases with GG genotype had significantly increased DFS rates(16months, p=0.05) compared to CR+ve TT (11 months) and TG (9 months) genotype groups. Further, MDM2expression was also found to be significantly elevated in GG genotype patients (p=0.0039) and among CR+vecases (p=0.0036). Conclusions: The MDM2-309T>G polymorphism might be involved in AML development andalso serve as a good prognostic indicator.     

Significant Association of the MDM2 T309G Polymorphism with Breast Cancer Risk in a Turkish Population

Background: Breast cancer is a leading cause of death in women worldwide. Genetic polymorphisms have beenreported to be important etiological factors. Murine double minute 2 (MDM2) T309G interacts with p53 and mutationsin p53 are present in approximately 50% of all cancers. However, it has been reported that effect of the polymorphismon breast cancer risk may vary in different populations. Here, we therefore investigated whether there is an associationbetween MDM2 T309G (rs2279744) polymorphism and breast cancer in a Turkish population. Materials and Methods:We analysed 110 patients with breast cancer and 138 matched? controls. For genotyping, polymerase chain reactionand restriction length fragment polymorphism methods were used. Results: A significant difference was observedbetween case and control groups with regard to the distribution of the MDM2 T309G polymorphism (p<0.05). Therewas a significantly higher frequency of the TT genotype in the control group (p=0.028; OR, 2.42; 95% CI, 1.09-5.37).However, we did not find any relationships among tumor grade and metastasis status and this polymorphism. Conclusion:This study indicates that the MDM2 T309G polymorphism GG genotype and the TG+GG combination may be riskfactors for breast cancer in our Turkish population.     

MDM2 SNP309 modifies the prognostic significance of the p53 mutational status in patients with ovarian cancer

A single nucleotide polymorphism (SNP309) of MDM2 causes elevated MDM2 levels and an attenuation of p53 function. The aim of the present study was to examine the clinical relevance of the MDM2 SNP309 in ovarian cancer.MDM2 SNP309 genotype was analyzed in 198 patients with primary ovarian cancer. MDM2 expression was investigated using immunohistochemistry. A functional yeast-based assay and subsequent sequencing were performed to determine p53 mutational status. Of the patients, 44.4% (88 of 198) exhibited the common variant (T/T), 40.9% (81 of 198) the heterozygous variant (T/G) and 14.7% (29 of 198) the homozygous variant (G/G) MDM2 SNP309 genotype. MDM2 SNP309 was not associated with p53 mutational status, MDM2 expression, clinicopathological parameters or prognosis. In patients with the T allele (T/T and T/G genotype), p53 wild type carcinomas were associated with significantly improved recurrence-free (p<0.001) and overall survival (p<0.001) as compared to p53 mutant carcinomas. In contrast, p53 mutational status did not possess prognostic relevance in G/G carriers. A possible functional impairment of the p53 pathway caused by the G/G genotype of the MDM2 SNP309 may modify the association between p53 mutational status and prognosis in ovarian cancer.     

Genetic polymorphisms of MDM2, cumulative cigarette smoking and nonsmall cell lung cancer risk

Abnormalities of the tumor suppressor TP53 pathway are critical in the development of many cancers since it regulates cell cycle components and apoptosis. Murine double minute-2 (MDM2) protein is a central node in the p53 pathway and a direct negative regulator of p53. The MDM2 SNP309 (rs2279744) polymorphism increases MDM2 RNA and protein levels, attenuating the p53 pathway. The MDM2 SNP309 polymorphism was investigated in 1,787 Caucasian nonsmall cell lung cancer (NSCLC) patients and 1,360 healthy controls. Cases and controls were analyzed for associations with genotype and adjusted for age, gender, histology and smoking history. There were no overall associations between the MDM2 genotypes and risk of lung cancer (adjusted odds ratios [AORs] = 0.82 [95% confidence interval [CI] = 0.6-1.1] for the T/G genotype and AOR = 1.32 [95% CI = 0.9-2.0] for the G/G genotype). A statistically significant interaction (p = 0.01) was found between smoking and MDM2 genotypes. Consistent with this interaction, stratified analysis by pack-years of smoking demonstrated that the AORs of G/G vs. T/T were 1.56 (1.0-2.7), 1.46 (1.0-2.2), 0.80 (0.5-1.3) and 0.63 (0.4-1.1), respectively, for never, mild (<30 pack-years), moderate (30-57 pack-years) and heavy smokers (>or=58 pack-years). In conclusion, a strong gene-smoking interaction was observed between the MDM2 SNP309 and NSCLC risk.     

MDM2 SNP309T>G polymorphism and risk of hepatocellular carcinoma: A case–control analysis in a Moroccan population

Background: The Murine double minute 2 (MDM2) gene encodes a negative regulator of the p53 tumor suppressor protein. A single nucleotide polymorphism (SNP) in the MDM2 promoter (a T to G exchange at nucleotide 309) has been reported to produce accelerated tumor formation. The aim of this study was to investigate whether this functional SNP is associated with an enhanced risk of liver tumorigenesis in Moroccan patients. Methods: The study consisted in the comparison of 96 hepatocellular carcinomas (HCC) cases and 222 controls without HCC matched for age, gender and ethnicity. PCR–RFLP and sequencing methods were used to determine the genotype at the MDM2 SNP309T>G locus. Results: Overall, our results indicate that the GG genotype of SNP309 is significantly associated with an increased risk of HCC (odds ratio, OR = 2.60, 95% CI, 1.08–6.28). Interestingly, despite a wide range of confidence interval, there is a trend associating the GG genotype with a high risk of HCC in males (OR = 3.31; 95% CI, 0.93–11.82) and in HCV-infected patients (OR = 3.7; 95% CI, 0.82–16.45). By contrast, no association between age at diagnosis and MDM2 SNP309 genotypes was observed in HCC patients (P = 0.610). Conclusion: Our findings suggest that the MDM2 309T>G polymorphism is an important modulator of hepatocellular carcinoma development in Moroccan patients.     

rs9904341多态性与肺癌易感性和铂类药物化疗敏感性的相关性

[目的]探讨survivin基因启动子区rs9904341位点多态性与肺癌发生风险和晚期非小细胞肺癌(NSCLC)患者铂类药物化疗疗效的关系。[方法]通过聚合酶链反应—限制性酶切片断多态性方法(PCR-RFLP)检测289例健康对照组和289例肺癌患者的rs9904341多态性的基因型;其中130例晚期NSCLC仅接受铂类药物化疗,分析经2个周期化疗后的疗效及基因型与铂类药物化疗疗效和生存期的关系。[结果]基因型CC、CG、GG在肺癌组的分布频率分别为29.07%、47.05%、23.87%,在对照组的分布频率分别为20.42%、51.9%、27.68%,两组无显著性差异(P=0.053)。肺癌组中C等位基因和CC基因型的分布均显著高于对照组(P<0.05)。rs9904341多态性与晚期NSCLC患者铂类药物化疗有效率无显著相关性,但与临床受益率相关,GG基因型携带者的临床受益率是CC基因型者的2.06倍(95%CI:0.71～5.97,P=0.184)。对289例肺癌患者生存分析显示,CC基因型肺癌患者较CG+GG基因型预后差(95%CI:1.11～2.6,P=0.015)。[结论]rs9904341多态性与肺癌的发病风险、预后及晚期NSCLC患者铂类药物化疗临床受益率相关。     

Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer.

The role of chemotherapy in the palliation of patients with advanced stage (IIIB and IV non-small-cell lung cancer (NSCLC) remains controversial. We have carried out a chemotherapy study emphasising symptom relief, a topic not normally discussed in previous similar studies. A total of 120 patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) were treated with a moderate-dose palliative chemotherapy regimen consisting of mitomycin C 8 mg m-2 i.v. on day 1 (alternate courses), vinblastine 6 mg m-2 i.v. on day 1 and cisplatin 50 mg m-2 i.v. on day 1 (MVP), repeating every 21 days for a maximum of six courses. Thirty-eight of 118 assessable patients (32%) achieved an objective response. Patients with locally advanced disease (stage IIIB) had a significantly better response rate (52%) than those with metastatic disease (25%) (P < 0.01). In 76 out of 110 (69%) patients, with tumour-related symptoms including 24 out of 31 patients (78%) with locally advanced disease, symptoms completely disappeared or substantially improved. In only 15 patients (14%) did symptoms progress during treatment. Symptomatic improvement was achieved after one course of chemotherapy in 61% and after two courses in 96% of responding patients. The schedule was well tolerated. Only 19% developed WHO grade 3/4 nausea/vomiting, and only 3% developed significant alopecia. Other toxicities were minimal. MVP is a pragmatic inexpensive chemotherapy regimen that offers useful symptom palliation in patients with advanced NSCLC and merits a 1-2 course therapeutic trial in such patients. The schedule should also be assessed as primary (neoadjuvant) chemotherapy before radical radiotherapy for locally advanced NSCLC in a randomised trial.