Clinical Evidence for Second- and Third-Line Treatment Options in Advanced Non-Small Cell Lung Cancer

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1 Clinicl Evidence for Second- nd Third-Line Tretment Options in Advnced Non-Smll Cell Lung Cncer Filippo de Mrinis, Frncesco Grossi b Thorcic Oncology Unit I, Deprtment of Lung Diseses, Sn Cmillo nd Forlnini Hospitls, Rome, Itly; b Medicl Oncology A, Disese Mngement Tem Lung Cncer, Ntionl Institute for Cncer Reserch, Genov, Itly Key Words. NSCLC Second-line chemotherpy Pemetrexed Docetxel Erlotinib Disclosure: F.d.M. hs cted s consultnt to Eli Lilly nd Compny, Roche, nd Snofi-Aventis, nd hs received honorri from Pierre Fbre, Amgen, nd GlxoSmithKline. F.G. hs cted s consultnt to Eli Lilly nd Compny, GlxoSmithKline, nd Roche, nd hs received honorri from Snofi-Aventis. Abstrct In the U.S. nd Europe, the current options for the second- nd third-line tretment of dvnced non-smll cell lung cncer (NSCLC) re cytotoxic drugs nd trgeted gents. Docetxel ws the first drug pproved for second-line tretment fter two phse III trils demonstrted its superiority over best supportive cre (BSC) lone nd single-gent chemotherpy. Pemetrexed ws lso registered for use s second-line therpy fter it ws demonstrted to hve ctivity comprble with, nd more fvorble toxicity profile thn, docetxel. Introduction Pltinum-bsed chemotherpy with third-genertion gent (gemcitbine, pclitxel, docetxel, or vinorelbine) improves survivl nd qulity of life in ptients with dvnced non-smll cell lung cncer (NSCLC) [1]. Despite these fvorble results, most ptients receiving front-line chemotherpy experience disese progression. The vilbility of severl new ctive drugs nd tril results in secondline tretment suggests tht this strtegy cn now be considered stndrd of cre for ptients with good performnce sttus (PS) who re resistnt to first-line tretment [1]. Single-Agent Docetxel Every 3 Weeks Two phse III trils demonstrted tht docetxel cn produce longer survivl nd better qulity of life thn with best Erlotinib, n epiderml growth fctor receptor inhibitor, is the only biologicl gent to hve been pproved in the U.S. nd Europe for lung cncer tretment fter study showed its superiority over BSC in recurrent (second-/third-line) NSCLC ptients. This review focuses on these drugs, deling with the results supporting the choice mong docetxel, pemetrexed, nd erlotinib in second- nd/or third-line tretment. The Oncologist 2008;13(suppl 1):14 20 supportive cre (BSC) lone [2] nd single-gent chemotherpy [3] (Tble 1). In 2000, the results of these studies llowed the registrtion in the U.S. nd Europe of docetxel (75 mg/m 2 every 3 weeks) s the first cytotoxic gent for the second-line tretment of NSCLC. In these trils, docetxelrelted toxicity ws relevnt, despite the significntly better qulity of life scores concerning pin control, weight loss, nd PS obtined with docetxel in comprison with the control groups [4]. A phse II rndomized tril [5] confirmed tht docetxel t dose of 75 mg/m 2 hs more fvorble toxicity profile thn, nd similr efficcy to, docetxel t 100 mg/m 2. The current problem of this tretment remins hemtologic toxicity, which, in the registrtion trils [2, 3], represented the dose-limiting toxicity: neutropeni occurred in 54% 67% of ptients nd febrile neutropeni Correspondence: Filippo de Mrinis, M.D., Thorcic Oncology Unit I, Chief Crlo Forlnini Hospitl, Pz Forlnini 1, 00151, Rome, Itly. Telephone: ; Fx: ; e-mil: demrinis.filippo@virgilio.it Received September 10, 2007; ccepted for publiction October 25, AlphMed Press /2008/$30.00/0 doi: /theoncologist.13-S1-14 The Oncologist 2008;13(suppl 1):

2 de Mrinis, Grossi 15 Tble 1. Registrtion trils for the tretment of recurrent NSCLC: Survivl nd toxicity Study TAX 317 [2] TAX 320 [3] Arm n of ptients Response rte Medin survivl time (months) occurred in 1.8% 8.0%. Moreover, in these studies [2, 3], docetxel yielded significnt nonhemtologic toxicities, minly grde 3 4 stheni (12% 18%). Nuse nd vomiting were lso frequent but cn generlly be well controlled with modern ntiemetics. 1-Yer survivl rte Grde 3 4 neutropeni Febrile neutropeni Most frequent grde 3 4 nonhemtologic toxicity D Pulmonry events (37%) D Pulmonry events (20%) BSC Pulmonry events (30%) D Ftigue (17%) D Ftigue (12%) V/I Ftigue (11%) JMEI [8] Pem Ftigue (5.3%) D Ftigue (5.4%) ISEL [21] G250 1, Dirrhe (3%) BSC Astheni (3%) BR.21 [22] E Ftigue (19%) BSC Ftigue (23%) Abbrevitions: BSC, best supportive cre; D100, docetxel 100 mg/m 2 every 3 weeks; D75, docetxel 75 mg/m 2 every 3 weeks; E150, erlotinib 150 mg dily; G250, gefitinib 250 mg dily; ISEL, Iress Survivl Evlution in Lung cncer; NSCLC, non-smll cell lung cncer; Pem, pemetrexed 500 mg/m 2 every 3 weeks; TAX, Txotere ; V/I, vinorelbine or ifosfmide. Single-Agent Pemetrexed Pemetrexed, multitrgeted ntifolte, ws shown to be ctive in recurrent nd progressive NSCLC in lrge phse II tril [6], nd in mlignnt pleurl mesotheliom in phse III tril [7]. The phse III JMEI tril demonstrted tht pemetrexed nd stndrd 3-weekly docetxel (75 mg/m 2 ) hve similr efficcies when used s second-line tretments [8]. Over 1 yer, 571 ptients resistnt to first-line chemotherpy were rndomized into this study. Pemetrexed (500 mg/m 2 i.v.) plus vitmin supplementtion ws dministered every 3 weeks for medin of four cycles, nd ws shown to be comprble with docetxel in terms of efficcy: in both rms, the medin survivl time, response rte, nd 1-yer survivl rte were pproximtely 8 months, 9%, nd 30%, respectively (Tble 1). The most interesting dt from tht tril re the toxicity results: the sfety profile of pemetrexed ws significntly better thn tht of docetxel. As shown in Tble 1, ptients treted with docetxel were more likely to experience grde 3 4 neutropeni (p <.001), febrile neutropeni (p <.001), nd infections ssocited with neutropeni (3.3% versus 0%; p =.004) thn ptients treted with pemetrexed. Consequently, fewer ptients in the pemetrexed rm required one or more hospitliztions resulting from neutropenic fever (1.5% versus 13.4%; p <.001), nd more limited use of white blood cell growth fctors ws observed thn in ptients who received docetxel (2.6% versus 19.2%; p <.001). The superiority of pemetrexed over docetxel (75 mg/m 2 every 3 weeks) ws lso confirmed by noting tht ll of the other rndomized studies using this tretment rm found more neutropeni nd febrile neutropeni with docetxel tretment thn with pemetrexed (Fig. 1). Following these results, t the end of 2004, pemetrexed ws registered in the U.S. nd Europe for this indiction, nd ws included in the most recent guidelines on the tretment of NSCLC published by the Europen Society of Medicl Oncology, the Americn Society of Clinicl Oncology, nd the Ntionl Comprehensive Cncer Network [9, 10]. As result, pemetrexed is recommended for second-line tretment, prticulrly for ptients with good PS (becuse, in the phse III registrtion study, only 11% of ptients hd PS score of 2) but lso for ptients previously treted with pltinum-contining first-line chemotherpy who showed neutropeni or some other toxicity, becuse pemetrexed demonstrted efficcy with low incidences of hemtologic nd nonhemtologic toxicities.

3 16 Clinicl Evidence for Second-/Third-Line Advnced NSCLC Therpy Figure 1. Min grde 3 4 World Helth Orgniztion toxicities mesured in rndomized trils evluting docetxel t dose of 75 mg/m 2 given every 3 weeks in second-line nonsmll cell lung cncer, compred with those obtined with the pemetrexed rm in its registrtion tril [3]. The min nonhemtologic toxicity ws nuse nd vomiting. b First-line tretment only for elderly ptients nd/or ptients with performnce sttus score of 2. Abbrevitions: FN, febrile neutropeni; N, neutropeni; N-H, nonhemtologic toxicity (stheni). Pemetrexed cn lso be recommended for elderly ptients needing second-line chemotherpy. A recent retrospective nlysis [11] of the JMEI tril found tht 15% of ptients 70 yers old (n = 86) on pemetrexed hd longer time to progression nd longer medin survivl time (4.6 nd 9.5 months, respectively) thn their counterprts treted with docetxel (2.9 nd 7.7 months, respectively; p >.05). Febrile neutropeni ws less frequent in the pemetrexed rm (2.5%) thn in the docetxel rm (19%; p =.025). This nlysis [11] shows tht elderly ptients cn hve s much benefit from second-line cytotoxic chemotherpy with pemetrexed s younger ptients, nd tht this cn be chieved with cceptble toxicity rtes. Single-Agent Weekly Docetxel In order to reduce the hemtologic toxicity of docetxel from tht seen with 75 mg/m 2 given every 3 weeks, severl clinicl trils hve explored weekly dministrtion of the drug. In phse II tril, Lilenbum et l. [12] rndomized elderly chemotherpy-nïve ptients nd/or ptients with PS score of 2 with dvnced NSCLC to either 3-weekly docetxel or weekly schedule. The primry endpoint ws toxicity, nd secondry endpoints were response rte, time to progression, nd overll survivl. Approximtely 100 ptients were enrolled, with medin ge of 75 yers; 75% were elderly nd 50% hd PS score of 2. Regrding the overll toxicity, the weekly docetxel regimen demonstrted less neutropeni (0% versus 30%), less febrile neutropeni (0% versus 2%), nd less stheni (23% versus 37%). The medin survivl times in the weekly docetxel nd 3-weekly docetxel rms were 6.5 nd 2.5 months, respectively. The uthors concluded tht, in elderly ptients nd borderline PS ptients, weekly docetxel is preferble to 3-weekly docetxel in first-line chemotherpy. In terms of second-line tretment, following rndomized phse II study [13] with sfety s primry endpoint, weekly docetxel schedule ws compred with the stndrd schedule in three phse III trils. In Spnish study [14], more thn 250 ptients were rndomized between 3- weekly nd weekly docetxel (36 mg/m 2 for 6 weeks every 2 months). The results did not demonstrte significnt differences between 3-weekly nd weekly docetxel in either the 1-yer survivl rte or medin survivl time (27% versus 22% nd 6.6 versus 5.4 months, respectively; p =.076), but n dvntge ws seen with the weekly schedule in terms of febrile neutropeni (7.8% versus 0.8%; p =.01), lthough it ws ssocited with significntly higher incidences of nemi (p =.011), dirrhe (p <.05), nd grde 3 4 mucositis (p =.032). In Germn study [15], 208 ptients were rndomized to receive 3-weekly or weekly docetxel (35 mg/m 2 for 3 weeks every 28 dys), nd the primry endpoint ws overll survivl. A significntly lower rte of hemtologic toxicity ws recorded for the weekly rm (20.6% versus 4.8% ptients suffered from neutropeni), with significnt difference observed in the medin survivl time nd 1-yer survivl rte for the two schedules (6.3 versus 9.2 months nd 26.9% versus 39.5% in the 3-weekly nd weekly tretment groups, respectively; p =.07). Finlly, n Itlin study [16] investigted possible dvntge in terms of qulity of life using weekly docetxel (33.3 mg/m 2 for 6 weeks every 2 months) versus 3-weekly docetxel in ptients with recurrent NSCLC. No difference ws found in the globl qulity-of-life score t 3 weeks. The incidences of pin, cough, nd lopeci were significntly lower under the weekly schedule, while the incidence of dirrhe ws higher. The response rtes nd survivl times were similr, with medin survivl times of 29 nd The Oncologist

4 de Mrinis, Grossi weeks in the 3-weekly docetxel nd weekly docetxel rms, respectively. Becuse of the smple size in ech tril, there ws insufficient sttisticl power to detect cliniclly relevnt differences in overll survivl. Two met-nlyses [17, 18] were recently performed tht included these previous rndomized trils in order to evlute whether weekly docetxel cn result in longer survivl thn with the stndrd 3-weekly schedule in previously treted dvnced NSCLC ptients. In the first met-nlysis [17], significntly lower incidence of grde 3 4 neutropeni for weekly docetxel ws found (reltive risk [RR], 0.22; 95% confidence intervl [CI], ; p <.0001). This dvntge trnsltes into n bsolute benefit of 15% 19%, with nine ptients needing to be treted for one to receive benefit. When considering only the phse III rndomized trils (682 ptients), overll survivl did not differ significntly between the two regimens (RR, 1.01; 95% CI, ; p =.785). The second met-nlysis, recently published [18], is bsed on updted individul ptient dt from 865 ptients enrolled in three phse III nd two phse II rndomized trils. The results show no significnt difference in efficcy between weekly docetxel nd 3-weekly docetxel s second-line tretment in dvnced NSCLC ptients (medin survivl time, 26.1 versus 27.4 weeks, respectively; hzrd rtio [HR], 1.09; 95% CI, ; p =.245). The risk for febrile neutropeni ws significntly lower with the weekly schedule. The uthors concluded tht weekly docetxel represents vlid lterntive for ll ptients with NSCLC suitble for second-line chemotherpy, bsed on better toxicity profile nd no relevnt differences in survivl. In conclusion, the results of four rndomized trils [13 16] nd two met-nlyses [17, 18] demonstrte no difference in survivl, lthough there re some criticl issues becuse of the limited number of ptients (bout 700) nd the different endpoints considered (sfety, overll survivl, qulity of life) tht men tht no cler, conclusive definition of the role of weekly docetxel schedule cn be determined. The use of weekly docetxel schedule for relpsed NSCLC ptients is not supported by direct comprison with pemetrexed. If the results of rndomized trils using both 3-weekly nd weekly docetxel regimens re compred with the JMEI tril [8], it is possible to conclude tht the primry difference in toxicity (neutropeni nd febrile neutropeni) would not be significnt (Fig. 2). However, nonhemtologic toxicities nd dose scheduling re more fvorble with pemetrexed, nd ptients my not wnt to mke weekly hospitl visits. Moreover, it is importnt to note tht the weekly docetxel dose nd schedule hve not been pproved by regultory uthorities in the U.S. or Europe. Erlotinib in Second-/Third-Line Tretment Erlotinib is the only epiderml growth fctor receptor (EGFR) tyrosine kinse inhibitor (TKI) (Tble 1) pproved in Europe nd the U.S. for the tretment of recurrent NSCLC. Gefitinib, nother EGFR TKI, ws grnted ccelerted pprovl in the U.S. on the bsis of response rtes obtined in two phse II rndomized trils [19, 20], but one of the following confirmtory trils (Iress Survivl Evlution in Lung cncer tril 709), designed with survivl s primry endpoint, filed to meet its primry objective [21]. As consequence, the mrketing ppliction for gefitinib ws withdrwn in Europe, nd the U.S. indiction ws subsequently chnged in 2005 so tht it could be used only in ptients who were lredy receiving nd benefiting from it, or in ongoing clinicl trils. However, in similr tril, orl erlotinib t dose of 150 mg dily demonstrted survivl dvntge over BSC lone (medin survivl times nd 1-yer survivl rtes of 6.7 versus 4.7 months nd 31% versus 22% for the erlotinib nd plcebo groups, respectively) [22, 23]. Selecting Second-/Third-Line Tretment Some issues must be exmined before decision cn be mde on whether to use pemetrexed, docetxel, or erlotinib s second-line tretment. First, the lck of dt from comprison trils mkes the choice difficult, s does the nonhomogene- Figure 2. Min grde 3 4 World Helth Orgniztion toxicities mesured in rndomized trils evluting docetxel t dose of mg/m 2 given weekly in second-line non-smll cell lung cncer, compred with those obtined with the pemetrexed rm in its registrtion tril [3]. The min nonhemtologic toxicity ws nuse nd vomiting. b First-line tretment only for elderly ptients nd/or ptients with performnce sttus score of 2. Abbrevitions: FN, febrile neutropeni; N, neutropeni; N-H, nonhemtologic toxicity (stheni).

5 18 Clinicl Evidence for Second-/Third-Line Advnced NSCLC Therpy Tble 2. Second-line registered drugs: Clinicl prognostic fctors nd results Study TAX 317 [2] TAX 320 [3] JMEI [8] Medin ge (yers) Mle/ femle Adenocrcinom ECOG performnce sttus score 2/3 n of Response Arm ptients rte D /34 NA NA ity of prognostic chrcteristics between ptients enrolled in the JMEI [8] nd BR.21 [22] studies nd the lck of importnt dt such s ptients smoking history in the JMEI study (Tble 2), even if the predictive role of nonsmoking ttitude in ptients treted with chemotherpy is still uncler. A retrospective study from Singpore [24] observed no differences in response rtes between current nd former smokers, finding respective medin survivl times of 18.5 nd 13.6 months (p =.14). In nother study, Nordquist et l. [25] reported 5-yer survivl rte of 23% for ptients with denocrcinom of the lung who hd never smoked (neversmokers), compred with 16% for smokers (p =.004). With the use of EGFR TKIs, drmtic differences in response to therpy hve been reported between neversmokers nd smokers. A multivrite nlysis of the BR.21 tril [26] showed tht nonsmoking history ws significnt independent predictor of survivl, with medin survivl time of 12.3 months for never-smokers (n = 104) versus 5.5 months for former/current smokers (n = 358; HR, 0.54; 95% CI, ). The sme efficcy in never-smokers ws found in the Trcev Responses in Conjunction with Pclitxel nd Crbopltin (TRIBUTE) study [27], in which, in the subset nlysis of never-smokers, the group treted with erlotinib hd medin survivl time of 22.5 months, compred with only 10.1 months for smokers. All of these results confirm the need to better define the predictive role of nonsmoking ttitude in prospective trils compring cytotoxic gents with EGFR TKIs. 2 Previous chemotherpy regimens PFS/ TTP (weeks) Medin survivl time (months) 1-Yer survivl rte BSC /35 NA NA D / NA V/I / NA Pem / NA Neversmokers D / NA BR.21 E / / (6.3) 31 (32) 21.3 [22] (243) BSC / / (5.5) (121) (23) In the second-line setting only. Abbrevitions: BSC, best supportive cre; D75, docetxel 75 mg/m 2 every 3 weeks; E150, erlotinib 150 mg dily; NA, not vilble; Pem, pemetrexed 500 mg/m 2 every 3 weeks; PFS, progression-free survivl; TAX, Txotere ; TTP, time to progression; V/I, vinorelbine or ifosfmide. It is worthwhile emphsizing tht the mrketing pprovl for the two chemotherpy gents recommends use fter filure of previous chemotherpy tretment in the cse of docetxel nd fter previous chemotherpy for pemetrexed, while the use of erlotinib is dvised fter filure of t lest one previous chemotherpy regimen. Strictly conforming to these therpeutic recommendtions would men tht the two chemotherpy gents should be used only in second-line tretment, while erlotinib could be used in second- nd lso subsequent-line therpy. A retrospective nlysis hs shown tht improvement in survivl beyond second-line tretment using chemotherpy is only modest [28]. In the cse of erlotinib, benefits in response nd survivl re similr for those undergoing second- or subsequent-line tretment (medin survivl times of 6.3 months nd 6.8 months for second- nd third-line tretments, respectively) [22],so it seems rtionl to consider second-line tretment with docetxel or pemetrexed nd third-line tretment with erlotinib. In support of this ide, dt derived from direct comprison of second-line erlotinib tretment with the stndrd chemotherpy gents pemetrexed nd docetxel in phse III tril re still not vilble, nd the popultion treted in the erlotinib registrtion tril [22, 23] ws considered unsuitble for chemotherpy tretment [29]. The option of third-line erlotinib use is lso supported by the fct tht 50% of ptients enrolled in the BR.21 study hd lredy received two lines of chemotherpy, nd tht this drug, while hving The Oncologist

6 de Mrinis, Grossi 19 good tolerbility profile without hemtologic toxicity, hd lso shown positive results for both ptients with PS score of 0 1 nd those with PS score of 2 3 (the response rte ws 8% for ptients with PS score of 0 1 nd 11% for those with PS score of 2 3; the medin survivl times were 8.3, 4.3, nd 1.9 months in the PS score 0 1, PS score 2, nd PS score 3 groups, respectively) [22, 23]. In view of these results, it is resonble to suggest the use of erlotinib in third-line therpy, where the PS of ptients is usully diminished. However, certin fctors, either clinicl (never-smoker, denocrcinom or bronchiololveolr subtype, femle sex, Asin ethnicity) [30, 31] or moleculr (immunohistochemicl EGFR expression [26], mplifiction of EGFR mesured by fluorescence in situ hybridiztion [32], or EGFR muttions [33, 34]), hve been shown to be predictive of benefits in response nd, in some cses, survivl when using EGFR inhibitors s second-line tretments. Thus, even though the presence of EGFR muttions did not correlte with longer survivl in the BR.21 study [26], the use of EGFR inhibitors could be recommended for second-line therpy insted of chemotherpy. References 1 Pfister DG, Johnson DH, Azzoli CG et l. Americn Society of Clinicl Oncology tretment of unresectble non-smll-cell lung cncer guideline: Updte J Clin Oncol 2004;22: Shepherd FA, Dncey J, Rmlu R et l. Prospective rndomized tril of docetxel versus best supportive cre in ptients with non-smll-cell lung cncer previously treted with pltinum-bsed chemotherpy. J Clin Oncol 2000;18: Fossell FV, DeVore R, Kerr RN et l. Rndomized phse III tril of docetxel versus vinorelbine or ifosfmide in ptients with dvnced nonsmll-cell lung cncer previously treted with pltinum-contining chemotherpy regimens. The TAX 320 Non-Smll Cell Lung Cncer Study Group. J Clin Oncol 2000;18: Dncey J, Shepherd FA, Grll RJ et l. Qulity of life ssessment of second-line docetxel versus best supportive cre in ptients with nonsmll-cell lung cncer previously treted with pltinum-bsed chemotherpy: Results of prospective, rndomized phse III tril. Lung Cncer 2004;43: Quoix E, Lebeu B, Depierre A et l. Rndomised, multicentre phse II study ssessing two doses of docetxel (75 or 100 mg/m 2 ) s second-line monotherpy for non-smll-cell lung cncer. Ann Oncol 2004;15: Smit EF, Mttson K, von Pwel J et l. ALIMTA (pemetrexed disodium) s second-line tretment of non-smll-cell lung cncer: A phse II study. Ann Oncol 2003;14: Vogelzng NJ, Rusthoven JJ, Symnowski J et l. Phse III study of pemetrexed in combintion with cispltin versus cispltin lone in ptients with mlignnt pleurl mesotheliom. J Clin Oncol 2003;21; Hnn N, Shepherd FA, Fossell FV et l. Rndomized phse III tril of pemetrexed versus docetxel in ptients with non-smll-cell lung cncer previously treted with chemotherpy. J Clin Oncol 2004;22: Conclusions There re some issues tht should be considered when choosing between chemotherpy nd trgeted therpy in the second-line tretment of NSCLC [35]. Pemetrexed is the only drug tht hs been directly compred in the secondline setting with n ctive cytotoxic gent, docetxel, rther thn with BSC [8], s is the cse for gefitinib [21] nd erlotinib [22]. Moreover, the demonstrted superiority of trgeted gents over BSC for third-line tretment opens up the debte, in our opinion, bout whether second- nd third-line tretment options should be evluted seprtely. While we re witing for the results of phse III trils rndomizing ptients to receive either docetxel, pemetrexed, or EGFR inhibitors, the comprble ctivity of pemetrexed, together with its fvorble toxicity profile (versus docetxel), suggests tht pemetrexed my be the best option t present for second-line tretment. Erlotinib, therefore, represents the best third-line option in recurrent NSCLC, nd could lso be used s second-line tretment in ptients who re unsuitble for chemotherpy, or in those with fvorble moleculr nd/or clinicl prognostic profile. 9 Felip E, Sthel RA, Pvlidis N; ESMO Guidelines Tsk Force. ESMO Minimum Clinicl Recommendtions for dignosis, tretment nd follow-up of non-smll-cell lung cncer (NSCLC). Ann Oncol 2005;16(Suppl 1): i28 i Ntionl Comprehensive Cncer Network. Clinicl Prctice Guidelines in Oncology. Non-Smll-Cell Lung Cncer, Volume 2, Avilble t Accessed Mrch 28, Weiss GJ, Lnger C, Rosell R et l. Elderly ptients benefit from second-line cytotoxic chemotherpy: A subset nlysis of rndomized phse III tril of pemetrexed compred with docetxel in ptients with previously treted dvnced non-smll-cell lung cncer. J Clin Oncol 2006;24: Lilenbum R, Rubin M, Smuel J et l. A phse II rndomized tril of docetxel weekly or every 3 weeks in elderly nd/or poor performnce sttus (PS) ptients (pts) with dvnced non-smll-cell lung cncer (NSCLC). J Clin Oncol 2004;22(14 suppl): Gervis R, Ducolone A, Breton JL et l. Phse II rndomised tril compring docetxel given every 3 weeks with weekly schedule s second-line therpy in ptients with dvnced non-smll-cell lung cncer (NSCLC). Ann Oncol 2005;16: Cmps C, Mssuti B, Jiménez A et l. Rndomized phse III study of 3-weekly versus weekly docetxel in pretreted dvnced non-smllcell lung cncer: A Spnish Lung Cncer Group tril. Ann Oncol 2006;17: Schuette W, Ngel S, Blnkenburg T et l. Phse III study of second-line chemotherpy for dvnced non-smll-cell lung cncer with weekly compred with 3-weekly docetxel. J Clin Oncol 2005;23: Gridelli C, Gllo C, Di Mio M et l. A rndomised clinicl tril of two docetxel regimens (weekly vs 3 week) in the second-line tretment of non-smll-cell lung cncer. The DISTAL 01 study. Br J Cncer 2004;91:

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