TAX 326-2003 JCO

Randomized,Multinational,Phase III Study of Docetaxel Plus Platinum Combinations Versus Vinorelbine Plus Cisplatin for Advanced Non–Small-Cell Lung Cancer:The TAX326

Study Group

By Frank Fossella,Jose R.Pereira,Joachim von Pawel,Anna Pluzanska,Vera Gorbounova,Eckhard Kaukel,Karin V.Mattson, Rodryg Ramlau,Aleksandra Szcze?sna,Panagiotis Fidias,Michael Millward,and Chandra P.Belani

Purpose:To investigate whether docetaxel plus platinum regimens improve survival and affect quality of life(QoL)in advanced non–small-cell lung cancer(NSCLC)compared with vinorelbine plus cisplatin as?rst-line chemotherapy.

Patients and Methods:Patients(n?1,218)with stage IIIB to IV NSCLC were randomly assigned to receive docetaxel 75mg/m2and cisplatin75mg/m2every3weeks(DC); docetaxel75mg/m2and carboplatin area under the curve of 6mg/mL?min every3weeks(DCb);or vinorelbine25mg/ m2/wk and cisplatin100mg/m2every4weeks(VC). Results:Patients treated with DC had a median survival of11.3v10.1months for VC-treated patients(P?.044; hazard ratio,1.183[97.2%con?dence interval,0.989to 1.416]).The2-year survival rate was21%for DC-treated patients and14%for VC-treated patients.Overall response rate was31.6%for DC-treated patients v24.5%for VC-treated patients(P?.029).Median survival(9.4v9.9 months[for VC];P?.657;hazard ratio,1.048[97.2con?-dence interval,0.877to1.253])and response(23.9%)with DCb were similar to those results for VC.Neutropenia, thrombocytopenia,infection,and febrile neutropenia were similar with all three regimens.Grade3to4anemia, nausea,and vomiting were more common(P<.01)with VC than with DC or DCb.Patients treated with either docetaxel regimen had consistently improved QoL compared with VC-treated patients,who experienced deterioration in QoL. Conclusion:DC resulted in a more favorable overall re-sponse and survival rate than VC.Both DC and DCb were better tolerated and provided patients with consistently im-proved QoL compared with VC.These?ndings demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for?rst-line treatment of advanced or metastatic NSCLC.

J Clin Oncol21:3016-3024.?2003by American Society of Clinical Oncology.

N ON–SMALL-CELL LUNG cancer(NSCLC)accounts for approximately80%of all lung cancers,with1.2million new cases worldwide each year.1,2NSCLC resulted in more than 1million deaths worldwide in20012and is the leading cause of cancer-related mortality in both men and women(31%and25%, respectively).3Most patients present with locally advanced stage III or metastatic stage IV disease.A meta-analysis of52 randomized trials indicated an absolute1-year survival bene?t of 10%and a modest improvement in median survival of 1.5 months for patients treated with cisplatin-containing regimens, compared with best supportive care alone.4Although the current practice for treating patients with metastatic disease includes the addition of newer generation agents such as vinorelbine,gem-citabine,paclitaxel,or docetaxel to a platinum agent,no combi-nation has emerged as a gold standard.4,5Survival data with the newer combinations have been encouraging,with median sur-vival times of8.4to14.2months,and1-year survival rates as high as54%.6-9

In an analysis of more than2,500patients with advanced NSCLC treated in the Southwest Oncology Group(SWOG) trials between1974to1988,cisplatin emerged as an independent prognostic variable predicting improved survival.10Vinorelbine plus cisplatin(VC)is frequently used as?rst-line chemotherapy in patients with advanced disease(on the basis of results from four large controlled studies conducted in North America and Europe),with a median survival of8.0to9.2months;however, it results in considerable toxicity.11-14

There remains a need to provide patients with treatment that not only prolongs survival,but also has acceptable toxicity and improves quality of life(QoL).Docetaxel and the platinums are active as single chemotherapeutic agents in NSCLC.15-17Phase III trials have proven the activity of docetaxel in advanced NSCLC,including platinum-resistant disease.18-20The combina-

From the M.D.Anderson Cancer Center,Houston,TX;Instituto do

Ca?ncer Arnaldo Vieira de Carvalho,Sao Paulo,Brazil;Asklepios Fachklini-

ken Mu¨nchen-Gauting,Gauting,Germany;M.Kopernik Memorial Hospital,

Lodz,Poland;Cancer Research Center RAMS,Moscow,Russia;AK-

Hamburg-Harbug,Hamburg,Germany;Helsinki University Central Hospi-

tal,Helsinki,Finland;Regional Lung Diseases Center,Poznan′;Regional

Lung Diseases Hospital,Otwock,Poland;Massachusetts General Hospital,

Boston,MA;Sydney Cancer Centre,Camperdown,Australia;University of

Pittsburgh Cancer Institute,Pittsburgh,PA.

Submitted December9,2002;accepted May1,2003.

Supported by a grant from Aventis Pharma.

Previously presented in part at the Annual Meeting of the American

Society of Clinical Oncology(ASCO),San Francisco,CA,May12-15,2001;

the Annual Meeting of ASCO,Orlando,FL,May18-21,2002;and the

Congress of the European Society for Medical Oncology,Nice,France,

October18-22,2002.

Address reprint requests to Chandra P.Belani,MD,Division of Medical

Oncology,University of Pittsburgh Cancer Institute,University of Pittsburgh

Medical Center Cancer Pavilion,5150Center Ave,Suite570,Pittsburgh,PA

15232;email:belanicp@https://www.wendangku.net/doc/8613992254.html,.

?2003by American Society of Clinical Oncology.

0732-183X/03/2116-3016/$20.00

3016Journal of Clinical Oncology,Vol21,No16(August15),2003:pp3016-3024

DOI:10.1200/JCO.2003.12.046

tion of docetaxel with a platinum agent has yielded response rates of30%to67%and median survival of8.4to13.9months in phase II and III trials of chemotherapy-naive patients,indi-cating that docetaxel plus platinum combinations are active in the?rst-line treatment of NSCLC.6,21-27We conducted a large, randomized,phase III study in chemotherapy-naive patients with stage IIIB or IV NSCLC to compare the effect of docetaxel plus cisplatin(DC)and docetaxel plus carboplatin(DCb)against an accepted11,28standard regimen of VC.The primary end point was overall survival.Secondary end points included overall response rate,time to progression,safety,and QoL.

PATIENTS AND METHODS

This was a multicenter,international,prospective,open-label,randomized phase III study.The study protocol was approved by the review board or ethics committee at each of the participating centers.An independent data-monitoring committee ensured that the trial was conducted in an ethical manner.All patients provided written informed consent before enrollment. Eligibility Criteria

Adults(age?18years)with histologically or cytologically con?rmed locally advanced or recurrent(stage IIIB)or metastatic(stage IV)NSCLC, Karnofsky performance status(KPS)?70%,and at least one measurable or assessable lesion were recruited.Adequate organ function was required,as evidenced by absolute neutrophil count?1.5?109/L,platelet count?100?109/L,hemoglobin?9.0g/dL,hepatic enzyme levels?2?the upper limit of the normal range(ULN),alkaline phosphatase levels?5?the ULN,total bilirubin levels no more than the ULN,and serum creatinine levels?1.5mg/dL(or creatinine clearance?60mL/min).

Exclusion criteria included prior treatment with a biologic response modi?er or chemotherapeutic agent,previous or concurrent malignant disease(except cone-biopsied carcinoma-in-situ of the cervix or adequately treated basal or squamous cell carcinoma of the skin),history of brain or leptomeningeal metastases(except if adequately treated and radiologically stable for at least4weeks),peripheral neuropathy of National Cancer Institute common toxicity criteria grade2or above,major surgery within2 weeks of study entry,radiotherapy within4weeks of study entry,or other serious concomitant illness.

Strati?cation and Treatment Plan

Before random assignment to treatment,patients were strati?ed according to disease stage(IIIB v IV)and geographic region(North America v South Africa,New Zealand and Australia v Europe,Lebanon and Israel v South America).Random assignment to treatment was conducted by an indepen-dent research organization using computer-generated lists.

Patients were randomly assigned to one of three treatment groups:DC (docetaxel75mg/m2immediately followed by cisplatin75mg/m2,both as 1-hour intravenous infusions on day1,repeated every3weeks);DCb (docetaxel75mg/m2as a1-hour intravenous infusion immediately followed by carboplatin administered intravenously at a dose calculated to produce an area under the concentration-time curve of6mg/mL?min,both on day1, repeated every3weeks);VC(vinorelbine25mg/m2as a6-to10-minute intravenous infusion on days1,8,15,and22,plus cisplatin100mg/m2 administered intravenously on day1,repeated every4weeks).A total of six doses of dexamethasone8mg were given orally to all patients with each docetaxel treatment for prophylaxis against?uid retention and hypersensi-tivity reactions.The?rst8-mg dose was given on the evening before treatment.Three8-mg doses were given on the day of treatment(day1)in the morning,1hour before the docetaxel infusion,and in the evening.The last two doses were given the day after treatment(day2),in the morning and evening.Antiemetic prophylaxis was given routinely,and patients receiving cisplatin also received adequate hydration.Secondary prophylaxis with granulocyte colony-stimulating factor was allowed as needed after comple-tion of cycle1.If toxicity occurred,patients were allowed a maximum of two dose reductions of docetaxel,cisplatin,or vinorelbine(dose reductions of carboplatin were not allowed).

Patients were treated for six cycles(which corresponds to18weeks for DC and DCb,and24weeks for VC)or until progressive disease,death,or an unacceptable adverse event.Patients could continue treatment beyond six cycles at the discretion of the treating physician.Second-line therapies,also at the treating physician’s discretion,were permitted after the study treatment was discontinued.The nature of any second-line therapies was recorded. After discontinuation of study treatment,patients were monitored at2-month intervals until death.

Response,Survival,and Toxicity Criteria

Response was determined in comparison with baseline assessment of measurable disease(identi?able tumor margins,measurable in two dimen-sions)or assessable disease(one identi?able measurable margin).SWOG response criteria were applied and all responses were con?rmed by the next treatment cycle(3weeks later for DC and DCb,and4weeks later for VC). The overall response rate was the number of patients with a con?rmed response occurring at any point between the start of treatment and their removal from treatment.Time to progression was de?ned as the time from random assignment to?rst documentation of progressive disease.Disease was evaluated every6weeks(two cycles)in patients who received DCb or DC,and every8weeks(two cycles)for patients who received VC.Survival was measured from the time of random assignment to date of death or date of last patient contact if lost to follow-up.Toxicities were assessed at the end of every cycle using the National Cancer Institute common toxicity criteria; toxicities that could not be graded by these criteria were assessed as mild, moderate,severe,or life threatening.Hematologic assessments were carried out on a weekly basis for all treatment arms.

QoL and Other Clinical Assessments

Instruments used for the self-administered QoL assessments included the validated,disease-speci?c,Lung Cancer Symptom Scale(LCSS),29and the global QoL scale,EuroQol.30The LCSS concentrates on physical and functional QoL dimensions.The EuroQol is a validated general measure of health status,and allows the calculation of quality-adjusted survival.QoL assessments were completed before each treatment cycle,at the end of study treatment,and every other month after the end of study treatment.QoL assessments were performed only in the countries in which a translated version of the QoL tool with validation was available.Other clinical bene?t parameters included body weight and KPS,which were measured at baseline and at every cycle;changes were compared using a longitudinal analysis model. Statistical Analysis

The primary end point was overall survival.Both noninferiority and superiority hypotheses were tested.The noninferiority criterion was based on historic data.12Noninferiority could be concluded if the lower bound of the con?dence interval(CI)of the hazard ratio for survival was greater than0.85, which means that the test treatment preserves at least50%of the control treatment effect observed in the historic data.The planned sample size of360 patients per treatment group provided the study with88%power to detect an increase in median survival from8months in the control arm to10.5months in either docetaxel arm(ie,an absolute improvement of2.5months),with a type I error of0.05.The same sample size provided85%power to test the noninferiority hypothesis.

The planned analyses for survival consisted of two independent compar-isons of each docetaxel combination versus VC.The Hochberg method31was applied to account for the two treatment comparisons.Statistical signi?cance would be declared if both comparisons achieved P?.05or if only one of them achieved P?.028.This corresponds to the use of a97.2%CI if noninferiority was achieved for one comparison only.In addition,the type I error rate for each pair-wise comparison was adjusted to0.047to account for a prespeci?ed interim analysis.

In the evaluation of the ef?cacy end points,every patient enrolled onto the study was included and analyzed according to the intention-to-treat principle.

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CHEMOTHERAPY FOR NSCLC

Only patients who actually received treatment were assessed for safety.A Cox proportional hazards model strati?ed for stage of disease and region of centers and adjusted for important prognostic variables(described below) was used to compare the survival curves and to estimate the hazard ratios and respective CIs.The survival estimates(median and survival rates at1and2 years)were adjusted for the following prognostic variables:age,perfor-mance status,time from diagnosis of disease to random assignment of treatment,weight loss in the prior6months,histologic subtype,level of lactate dehydrogenase,sex,baseline QoL score,liver involvement,bone involvement,prior radiotherapy,and prior surgical procedure.Minor differ-ences in the distribution of prognostic variables for the two independent comparisons could lead to slightly different point estimates for the control group.Superiority was tested using a nonparametric covariate-adjusted log-rank test.32The survival curves were plotted on the basis of the nonparametric covariate-adjusted survival estimates.Fisher’s exact test was used to compare frequencies of response rates.

RESULTS

Patients and Treatment Administration

A total of1,218patients with NSCLC from140institutions in 28countries were enrolled and randomly assigned to treatment between July1998and January2000.Of the1,218patients,15 did not receive treatment(nine were ineligible,four withdrew consent,and two died of malignant disease before the?rst drug infusion)and were excluded from the safety analysis.The median follow-up period was10months.Baseline characteristics of patients were well balanced across the three treatment groups with regard to the strati?cation factors of stage and geography,as well as sex,age,and performance status(Table1).Approxi-mately67%of the patients in each treatment group had stage IV disease,and33%of patients had stage III

B disease.A total of 4.9%(DC),6.7%(DCb),and4.5%(VC)of patients were staged with IIIB disease on the basis of malignant pleural effusion.The 28%of stage IIIB patients without pleural effusion were con-sidered unresectable,and therefore,surgery was not deemed an option.Only2.2%(DC),1.2%(DCb),and1.5%(VC)of patients had stable brain metastases.

Patients received between one and13cycles of treatment during the study.The median number of treatment cycles delivered was?ve(over15weeks)for DC,six(18weeks)for DCb,and four(16weeks)for https://www.wendangku.net/doc/8613992254.html,pliance to treatment was excellent,particularly for DC and DCb,as indicated by the combined relative dose-intensities,which approached1(DC, 0.94;DCb,0.93;VC,0.78).A total of541patients completed at least six treatment cycles;more patients in the DC(49.8%)and DCb(51.4%)groups completed six cycles of treatment as compared with those in the VC group(33.6%).The main reasons for treatment discontinuation were completion of protocol-planned treatment(DC,36.0%;DCb,37.2%;VC,22.0%)and disease progression(DC,30.1%;DCb,36.9%;VC,32.2%),with only13patients(1.1%)in total discontinuing because of a major protocol violation.Patients who received DC or DCb experi-

Table1.Patient Characteristics

DC(n?408)DCb(n?406)VC(n?404)

No.of

Patients%No.of

Patients%

No.of

Patients%

Age,years

Median615961

Range30-8123-8735-80

Sex

Male29472.129271.930274.8

Female11427.911428.110225.2

Karnofsky performance status,%

1006515.96616.36816.8

80-9032880.432479.832079.2

7015 3.716 3.916 4.0

Histologic subtype of tumor

Adenocarcinoma18144.416941.616440.6

Large cell4110.04811.84912.1

Squamous cell13232.413633.514034.7

Bronchioalveolar15 3.711 2.711 2.7

Other399.64210.3409.9

Extent of disease*

Locally advanced,stage IIIB13533.113232.513332.9

Metastatic,stage IV27366.927467.527167.1

Pretreatment weight loss,%

0-521452.519848.819548.3

?512530.615437.913433.1

Not available6916.95413.37518.6

Prior anticancer therapies?

Radiotherapy alone24 5.927 6.722 5.4

Surgery alone7718.97217.79022.3

Radiotherapy and surgery19 4.7307.4297.2

Abbreviations:DC,docetaxel plus cisplatin;DCb,docetaxel plus carboplatin;VC,vinorelbine plus cisplatin.

*At time of randomization.

?The remaining patients did not receive prior anticancer therapy.

3018FOSSELLA ET AL

enced fewer treatment delays than VC-treated patients (11.8%,11.2%,and 16.1%,respectively).Granulocyte colony-stimulat-ing factor use was higher for patients on the VC arm (18.9%of patients)than for those on the DC (13.8%)and DCb (15.0%)arms.RBC transfusion was required by a greater number of patients treated with VC (19.4%)compared with DC (10.3%)and DCb (10.5%).

After discontinuation or completion of the study,the number of patients who received second-line therapy and the nature of the second-line therapy were well balanced among the groups.In total,444patients (36.5%)went on to receive additional chemo-therapy (DC,35.3%;DCb,36.0%;VC,38.1%),498patients (40.9%)received radiotherapy (DC,40.9%;DCb,41.1%;VC,40.6%),and 41patients (3.4%)underwent surgery (DC,3.4%;DCb,2.5%;VC,4.2%).The most common second-line chemo-therapies were gemcitabine monotherapy (123patients;27.7%),docetaxel monotherapy (56patients;12.6%),and gemcitabine plus cisplatin (41patients;9.2%).A higher number of patients from the VC study group received docetaxel as second-line therapy (35patients;8.7%)as compared with patients from the DC group (14patients;3.4%)and DCb group (seven patients;1.7%).Survival

In the ?rst pair-wise comparison of DC versus VC,the median overall survival was 11.3months for DC-treated patients and 10.1months for VC-treated patients.The hazard ratio was 1.183(97.2%CI,0.989to 1.416).The test for superiority using a nonparametric covariate-adjusted log-rank test resulted in P ?.044.The survival curves separate beginning at 4months from random assignment and remain nonoverlapping for the duration of the follow-up period (Fig 1).One-and 2-year survival rates were 46%v 41%,and 21%v 14%(DC and VC,respectively;Table 2).

In the second pair-wise comparison of DCb versus VC,the overall median survival was 9.4v 9.9months,respectively (Fig 2).The hazard ratio was 1.048(97.2%CI,0.877to 1.253).The test for superiority using a nonparametric covariate-adjusted log-rank test resulted in P ?.657.One-and 2-year survival rates

for DCb versus VC were 38%v 40%,and 18%v 14%,respectively (Table 2).Response

In the ?rst pair-wise comparison,the response rate for DC was 31.6%v 24.5%for VC (P ?.029;Table 3).In the second pair-wise comparison of DCb versus VC,the response rates were similar (23.9%v 24.5%;P ?.870).Median time to disease progression for DC was 22weeks (95%CI,21to 25weeks),compared with 23weeks (95%CI,21to 27weeks)for VC (P ?.805).Similarly,median time to disease progression for DCb was 20weeks (95%CI,19to 23weeks)compared with 22weeks (95%CI,19to 25weeks)for VC (P ?

.235).

Fig 1.Nonparametric covariate-adjusted estimates of overall survival for

docetaxel plus cisplatin (DC)versus vinorelbine plus cisplatin (VC).

Table 2.

Survival Analyses in Intention-to-Treat Population

DC versus VC*DC (n ?408)

VC (n ?404)

Overall median survival,months 11.310.195%CI

10.1to 12.49.2to 11.3

Nonparametric covariate-adjusted log-rank test P ?.044Hazard ratio 1.183

97.2%CI

0.989to 1.4161-year survival estimate,%464195%CI

42to 5136to 462-year survival estimate,%211495%CI

16to 2510to 18

DCb versus VC*

DCb (n ?406)

VC (n ?404)

Overall median survival,months 9.49.995%CI

8.7to 10.69.0to 11.3

Nonparametric covariate-adjusted log-rank test P ?.657Hazard ratio 1.048

97.2%CI

0.877to 1.2531-year survival estimate,%384095%CI

33

to 4335to 452-year survival estimate,%181495%CI 13to 2210to 18

Abbreviations:CI,con ?dence interval;DC,docetaxel plus cisplatin;DCb,

docetaxel plus carboplatin;VC,vinorelbine plus cisplatin.

*Minor differences in the distribution of prognostic variables for the two indepen-dent comparisons (DC v VC and DCb v VC)resulted to slightly different point estimates for the control group.

Fig 2.Nonparametric covariate-adjusted estimates of overall survival for docetaxel plus carboplatin (DCb)versus vinorelbine plus cisplatin (VC).

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CHEMOTHERAPY FOR NSCLC

Toxicity

Fewer patients in both the DC(41.4%)and DCb groups (39.9%)experienced grade3to4adverse events compared with the VC group(48.0%).No differences were seen among the three treatment groups with regard to grade3to4neutropenia, thrombocytopenia,or infection(Table4).Febrile neutropenia occurred in less than5%of patients in each arm(4.9%DC;3.7% DCb;4.5%VC).A higher percentage of patients in the VC arm experienced grade3to4anemia,nausea,and vomiting com-pared with patients in either docetaxel arm(P?.01;Table4). Grade3to4diarrhea occurred more frequently in DC(6.7%) and DCb(5.2%)patients compared with VC patients(2.8%), though the majority of these events were grade3,and they had a negligible in?uence on treatment delays and treatment discon-tinuation.The incidence of grade3to4sensory neuropathy was 3.8%in the control arm,3.9%in the DC arm,and0.7%in the DCb arm.Grade1to4edema(DC,32.3%;DCb,22.7%;VC, 16.2%),nail disorders(DC,13.5%;DCb,10.2%;VC,0.5%),and hypersensitivity reactions(DC,11.8%;DCb,11.2%;VC,4.0%), as well as grade1to3alopecia(DC,73.6%;DCb,68.3%;VC, 41.4%)occurred more frequently with the docetaxel-containing treatments compared with VC;however,the incidence of these adverse events at grade3to4was similarly low for all treatment arms(?1%for alopecia[grade1to3],edema,and nail disorders;?3%for hypersensitivity reactions).Fewer patients treated with DC(0.9%)experienced treatment delays caused by hematologic toxicity compared with those treated with VC (4.8%)and DCb(3.1%).Hospitalizations because of adverse events were less frequent in the DC and DCb arm(40.8%and 39.4%,respectively)compared with the VC arms(46.7%). Furthermore,more patients on the VC arm(22.5%)discontinued treatment because of adverse events compared with those on the DC(15.7%)and DCb arms(9.1%).

QoL and Other Clinical Assessments

Translation of the QoL assessment tools into the patient’s native language was available for926patients.The baseline EuroQol questionnaire was completed by831patients(DC,281; DCb279;VC,271),and811patients(DC,279;DCb,269;VC, 263)completed the baseline LCSS questionnaire.Patients treated with either docetaxel regimen reported consistently improved global QoL compared with patients treated with VC, who generally experienced a deterioration in QoL(Figs3and4). Longitudinal analyses showed that for patients treated with DCb,

Table3.Overall Response Rates in Intention-to-Treat Population

DC(n?408)DCb(n?406)VC(n?404)

No.of Patients%No.of Patients%No.of Patients%

Overall response rate*12931.69723.99924.5 95%CI27.1to36.419.8to28.320.4to29.0 Complete response8 2.05 1.28 2.0 Partial response12129.79222.79122.5 No change or stable disease17643.118846.317042.1 Progressive disease7217.68821.78621.3 Not assessable?317.6338.14912.1

Abbreviations:CI,con?dence interval;DC,docetaxel plus cisplatin;DCb,docetaxel plus carboplatin;VC,vinorelbine plus cisplatin.

*P?.029for DC versus VC,and P?.870for DCb versus VC,by Fisher’s exact test.

?18of31of DC,13of33of DCb,and27of49of VC-treated patients did not receive two cycles of treatment required for response determination.

Table4.Grade3and4Toxic Effects*

DC(n?406)DCb(n?401)VC(n?396)

No.of

Patients%No.of

Patients%

No.of

Patients%

Hematologic

Leukopenia17342.819749.521354.5

Neutropenia30274.829474.430979.0

Thrombocytopenia11 2.7287.015 3.8

Anemia28 6.94210.59424.0?

Infection348.44411.0317.8

Nonhematologic

Asthenia5012.34310.75714.4

Nausea409.925 6.26516.4?

Pulmonary399.65413.54511.4

Pain327.9369.0338.3

Vomiting327.917 4.26416.2?

Diarrhea27 6.721 5.211 2.8

Anorexia22 5.412 3.019 4.8

Abbreviations:DC,docetaxel plus cisplatin;DCb,docetaxel plus carboplatin;VC,vinorelbine plus cisplatin.

*Occurring in?5%patients in at least one arm.

?P?.01for both DC versus VC and DCb versus VC by Fisher’s exact test.

3020FOSSELLA ET AL

this overall advantage in global QoL was statistically signi ?cant according to both LCSS (P ?.016)and EuroQol (P ?.001)assessments.For patients treated with DC,the advantage in global QoL was statistically signi ?cant when evaluated by EuroQol (P ?.016)but not when evaluated by the LCSS (P ?.064).

Patients treated with DC or DCb experienced signi ?cantly less mean weight loss from baseline through the last on-treatment assessment than those treated with VC (0.29,0.01,and 2.35kg,respectively;P ?.001for both comparisons with VC).A separate analysis indicated that ?uid retention observed as an adverse event did not account for the maintenance of weight.Furthermore,VC-treated patients experienced a modest but consistently greater decline (of ?20%from baseline)in KPS than those treated with DC (P ?.028)and DCb (P ?.001).

DISCUSSION

This phase III trial of 1,218chemotherapy-naive patients with stage IIIB to IV NSCLC examined the effect of two docetaxel plus platinum regimens against a standard reference regimen of VC.Patients bene ?ted from a better safety pro ?le,improved QoL,and a higher 2-year survival rate in the docetaxel plus platinum arms,as well as a more convenient dosing schedule.In this study,de ?nitive conclusions can be drawn on the effective-

ness of the docetaxel plus platinum regimens because both noninferiority and superiority were tested.With the application of a rigorous statistical methodology and the use of conservative criteria to establish noninferiority,it has been demonstrated that DC,at minimum,retained the effect of the control regimen VC.Although superiority was not demonstrated using a signi ?cance level of.028,the lower bound of the 97.2%CI of 0.989indicated that DC was nearly superior to VC.The survival estimates clearly favored DC,with a longer median survival (11.3v 10.1months)and a more favorable 2-year survival rate (21%v 14%)than those of VC.DC-treated patients also experienced a higher overall response rate (31.6%v 24.5%;P ?.029).Overall response and survival rates were similar for patients treated with DCb and VC.The lower bound of the 97.2%CI of the hazard ratio of 0.877met the noninferiority margin of 0.85.However,sensitivity analyses indicated that the survival results for DCb were not as robust as those for DC;a formal conclusion could not be reached on noninferiority.We prospectively recorded the nature of second-line treatment and established that this did not confound survival results in favor of therapy with docetaxel plus platinum.Because the role of chemotherapy in advanced NSCLC is primarily palliative,the in ?uence on patients ’QoL is an impor-tant consideration in determining the true value of any

new

Fig 3.Global quality-of-life assessment using the Lung Cancer Symptom Scale instrument.(A)Docetaxel plus cisplatin (DC)versus vinorelbine plus cisplatin (VC).(B)Docetaxel plus carboplatin (DCb)versus VC.Vertical bars represent plus or minus a unit of standard

error.Fig 4.Global quality-of-life assessment using the EuroQol instrument.(A)Docetaxel plus cisplatin (DC)versus vinorelbine plus cisplatin (VC).(B)Docetaxel plus carboplatin (DCb)versus VC.Vertical bars represent plus or minus a unit of standard error.

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CHEMOTHERAPY FOR NSCLC

therapy.The complete evaluation of the effects of chemotherapy on health status in metastatic NSCLC requires assessment of chemotherapy on domains of patient health,lung cancer–speci?c symptoms,and treatment-related toxicity.In this study,the use of both a lung cancer–speci?c QoL scale(LCSS),and a global health scale(EuroQol),demonstrated that patients treated with DC or DCb had consistently improved QoL,whereas VC-treated patients suffered a deterioration in QoL(for DC v VC,P?.064 [LCSS]and P?.016[EuroQol];for DCb v VC,P?.016 [LCSS]and P?.001[EuroQol]).Thus,the bene?ts observed in this study extended beyond survival to an improvement in global QoL.Furthermore,patients treated with either docetaxel plus platinum regimen experienced signi?cantly less weight loss and decline in KPS than did VC-treated patients.

This study also showed that the overall safety pro?le of both DC and DCb compared favorably with that of VC,as indicated by fewer adverse events leading to hospitalizations,treatment discontinuations caused by side effects,and grade3to4 toxicities.Speci?cally,grade3and4anemia,nausea,and vomiting were more prevalent in patients who received VC than in those who received DC or DCb.The incidence of infection and febrile neutropenia was similar across the three treatment arms.There was little grade3to4neurosensory toxicity associated with DCb or DC in the current trial(1%and4%, respectively).Grade1to4edema,nail disorders,and hypersensi-tivity reactions occurred more frequently in the docetaxel-contain-ing arms;however,the incidence of these adverse events at grade3 to4was similarly low for all treatment arms(?1%for edema and nail disorders;?3%for hypersensitivity reactions).

Three recently published,large,phase III trials also compared modern platinum-based regimens in the?rst-line treatment of advanced NSCLC,but found no clear advantage for any regi-men.5,14,33SWOG study9509enrolled408patients and com-pared the standard regimen of VC,the identical reference regimen used in our study,to paclitaxel plus carboplatin(PCb).14 The median survival was similar for both regimens,8.1and8.6 months(P?.87).One-and2-year survival rates were also similar:36%and16%for VC,and38%and15%for PCb.There were grade3to4toxicity differences between the regimens:VC was associated with signi?cantly more leukopenia,neutropenia, nausea,and vomiting;PCb was associated with signi?cantly more grade3sensory neuropathy.QoL,which was measured using the Functional Assessment of Cancer Therapy–Lung questionnaire,showed no statistically signi?cant differences between the arms.Similarly,a study by the Italian Lung Cancer Project(612patients)compared PCb and gemcitabine plus cisplatin(GC)against VC,and found no signi?cant differences in median survival(9.9,9.8,and9.5months,respectively), 1-year survival rate(43%,37%,and37%,respectively),or QoL.33The survival data from the Italian Lung Cancer Project and SWOG trials are similar to the results observed in our trial and that of other randomized trials using new agent plus platinum combinations,with median survivals of7.4to13.2 months and1-year survivals in the range25%to61%.11,12,34-36 In the Eastern Cooperative Group(ECOG)study1594,a control arm of paclitaxel and cisplatin(PC)was compared against GC,DC,or PCb.5A total of1,155patients were assessable.None of the regimens tested showed any improve-ment in median,1-,or2-year survivals as compared with the control regimen.For the entire study population,the overall median survival was7.9months,and1-and2-year survival rates were33%and11%,respectively.There were grade3to4toxicity differences between each comparator and the control.GC was associated with signi?cantly less febrile neutropenia,but signi?-cantly more thrombocytopenia,anemia,and renal toxicities than PC.DC was associated with signi?cantly more hypersensitivity reactions than PC.The PCb arm was associated with signi?cantly less febrile neutropenia,nausea,vomiting,and overall grade3to4 toxicities than PC.QoL evaluations were not a part of this study.5 Differences in trial design,patient characteristics,and treat-ment delivery between ECOG1594and this study may account for the differences in survival outcome of the respective DC https://www.wendangku.net/doc/8613992254.html,pared with ECOG1594,this study included approx-imately100more patients per treatment arm,enrolled a higher proportion of stage IIIB patients(33%v13%),and had a lower proportion of patients with brain metastases(2%v13%). DC-treated patients in our study received a median of?ve cycles compared with four cycles in ECOG1594.Furthermore,unlike this study,the nature of second-line chemotherapy in ECOG 1594was not documented,and thus may have contributed in obscuring potential survival differences among the treatments. Recent reports indicate that chemotherapy in advanced lung cancer has reached a plateau,with few differences in survival among the various combinations of chemotherapeutic agents.5,14,33,37,38ECOG1594,SWOG9509,and the Italian Lung Cancer Project trial showed similar survival and response rates across all arms,with an average gain of2months for median survival in comparison with historic controls.There were some toxicity trade-offs between arms,but no clear advantage with regard to response rate,survival,or QoL(in SWOG9509 and the Italian Lung Cancer Project trial)emerged.5,14,33In contrast,this study demonstrated clinically meaningful bene?ts with the two docetaxel plus platinum regimens.Because this trial was not designed to compare formally cisplatin with carboplatin, the choice of exactly which platinum should be used in combi-nation with docetaxel is likely to be based on the clinician’s preference and individual patient characteristics.There was a strong trend favoring improved survival in patients receiving DC as compared with VC.In addition,patients in either docetaxel arm experienced a more favorable toxicity pro?le than those in the VC arm.Perhaps most notable was the observation that patients who received either docetaxel regimen also experienced a consistent improvement in QoL and other measures of clinical bene?t,including weight loss and performance status.This QoL bene?t appears to be unique to docetaxel plus platinum chemo-therapy.Randomized clinical trials of paclitaxel combined with either cisplatin or carboplatin failed to detect any signi?cant QoL bene?t of paclitaxel plus platinum therapy in patients with advanced NSCLC.14,33,34These results demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for use in?rst-line therapy of patients with advanced or metastatic NSCLC.Although cytotoxic chemo-

3022FOSSELLA ET AL

therapeutic agents are currently the mainstay of treatment for advanced NSCLC,it is important to explore concurrent or sequen-tial administration of novel targeted therapies to determine whether treatment can be taken to the next level.

ACKNOWLEDGMENT

We thank Francis C.Gamza,MD,Jocelyne Berille,MD,and Yong S. Kim,PhD(statistician),for planning and implementing the study;Antoinette Wozniak,MD,Lionel Bosquee,MD,and Claude Ramazeilles, PhD,for their valuable insights;Luz Hammershaimb,MD,Antoine Yver, MD,and Jean-Pierre Bizzari,MD,for their support of the study;Mark R. Green,MD(Chairman),Lucio Crino,MD,and Boris Iglewicz,PhD,from the Independent Data Monitoring Committee;and Wendy Crist(interna-tional study manager),Isabelle Dancy,PhD(study manager),Anthony Rodgers,PhD(statistician),Martin Roessner,MSc(statistician),San-drine Anneheim-Herbelin,PhD(study manager),and Jean-Luc Schmidt (data manager).

APPENDIX

The appendix is included in the full text version of this article only,available on-line at https://www.wendangku.net/doc/8613992254.html,.

It is not included in the PDF version.

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2020年高考英语书面表达专项训练05申请信万能句式和模板

申请信 一、申请信写作技巧 二、常用句型 （一）开头——自我介绍和写信目的 1.I’m a student who is studying in …… School. 自我介绍 2. I’m glad to learn that you want a……我很高兴得知你们需要一名…… 3. I am writing to apply for the job/position. 我写信的目的是申请这个工作/职位。 4. I’m quite interested in this job. 我对这个工作非常感兴趣。 5.I am writing this letter to recommend myself. 我写信推荐自己。 （二）中间——介绍个人优势 1.I graduated from ……university three years ago/just now. 毕业于… 2.I major in English/Computer/Chinese medicine… so I have a good command of… 优势一：专业对口 3.Additionally, no one can deny I get along well with all my classmates, enjoy a harmonious interpersonal relationship and am always ready to help others. 优势二：情商高 https://www.wendangku.net/doc/8613992254.html,st but not least, I have some relevant experience before, considering that I once worked in a similar company/for a similar activity as a….优势三：有相关经验

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补充1.在提出申请或应聘时，应适时展现的良好性格，以下是表示性格品质的形容词

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