Second-line treatment for advanced non-small cell lung cancer: A systematic review

Lung Cancer (2006) 51, 159—172

REVIEW

Second-line treatment for advanced non-small cell lung cancer: A systematic review Fabrice Barl´ esi a,∗, William Jacot b, Philippe Astoul a, Jean-Louis Pujol b a

Faculty of Medicine, Universit´ e de la M´ editerran´ ee, Assistance Publique Hˆ opitaux de Marseille, Thoracic Oncology, F´ ed´ eration des Maladies Respiratoires, Sainte-Marguerite Hospital, 270 Bd de sainte-Marguerite, 13274 Marseille Cedex 09, France b Montpellier Academic Hospital, Unit´ e d’Oncologie Thoracique, Hˆ opital Arnaud de Villeneuve, Avenue du Doyen Giraud, 34295 Montpellier Cedex 5, France Received 21 April 2005; accepted 17 August 2005 KEYWORDS Chemotherapy; Non-small cell lung cancer; Second-line; Docetaxel; Pemetrexed; Weekly schedule; Targeted therapy

∗

Summary Background: Among advanced non-small cell lung cancer (NSCLC) patients, most will resist or relapse after first-line chemotherapy. As a result, second-line therapy has been a major focus for clinical research. Materials and methods: A systematic review was carried out from 1996 to February 2005. Results: Second-line chemotherapy provides pre-treated NSCLC patients with a clear survival advantage. Docetaxel 75 mg/m2 every 3 weeks is the present standard second-line chemotherapy. Despite promising results regarding efficacy and toxicity in phase III studies, a docetaxel weekly schedule could not be recommended. Pemetrexed recently emerged as an alternative with similar efficacy and less toxicity. Although the combination of two drugs was not associated with a survival benefit when compared with single-agent chemotherapy, such regimens induced a dramatic increase in toxicities and therefore mono-chemotherapy remains the standard as second-line therapy. Finally, few new agents were reported with better results than those used previously and clinical research on second-line therapy currently focuses on combinations with targeted therapies. Conclusion: Second-line chemotherapy offers NSCLC patients a small but significant survival improvement. However, this field of clinical research needs further investigations in order to answer certain remaining questions especially concerning targeted therapies. © 2005 Elsevier Ireland Ltd. All rights reserved.

Corresponding author. Tel.: +33 491 74 47 36; fax: +33 491 74 55 24. E-mail address: [email protected] (F. Barl´ esi).

0169-5002/$ — see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2005.08.017

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Contents 1. 2.

3.

4.

Introduction ................................................................................................ Materials and methods...................................................................................... 2.1. Screening of trials ................................................................................... 2.2. Eligibility criteria .................................................................................... 2.3. Quality assessment................................................................................... 2.4. Extraction of data.................................................................................... Results ..................................................................................................... 3.1. Does chemotherapy improve survival?................................................................ 3.2. Is one single-agent chemotherapy superior to another? .............................................. 3.3. Is a combination of two or more drugs superior to single-agent chemotherapy? ...................... 3.4. Is a weekly schedule better than a three- or four-weekly administration of chemotherapy? .......... 3.5. How many cycles of second-line chemotherapy should NSCLC patients receive? ...................... 3.6. Do any new second-line treatments appear? ......................................................... Discussion .................................................................................................. References..................................................................................................

1. Introduction Chemotherapy improves survival of non-small cell lung cancer (NSCLC) patients suffering from stage IV or stage 1MB disease with pleural effusion. Randomized studies comparing best supportive care (BSC) versus BSC plus chemotherapy have suggested a moderate improvement for patients receiving cytotoxic agents, and meta-analyses concluded positively in favour of chemotherapy in this setting [1,2]. However, among these patients, most will present either a refractory NSCLC to chemotherapy or a relapse after having been sensitive to chemotherapy. As a result, the question of a second-line therapy in pre-treated NSCLC patients has been a major focus for clinical research. The aim of this systematic review is twofold. Primarily to consider clinical trials leading to the current recommendations regarding second-line therapy in pre-treated NSCLC patients, and clinical trials which became available thereafter. Secondly, to look at the results of the numerous available phase II trials in order to discuss the possibilities of further clinical research in this setting.

2. Materials and methods 2.1. Screening of trials A computerised bibliography was extracted from the PUB-MED database using medical subject headings of the following terms: lung neoplasm, non-small cell lung cancer, randomised trials, chemotherapy, second-line, refractory, relapse, gemcitabine, paclitaxel, docetaxel, vinorelbine

160 160 160 160 160 161 161 161 161 163 165 166 167 168 168

and pemetrexed. The search was carried out from January 1996 to February 2005 inclusive. Afterwards, the manual selection of relevant trials was based on summary analysis. In addition to the above-mentioned procedure, bibliographies of selected full papers were screened in order to disclose other relevant articles. Finally, both a manual and an electronic search of available abstracts from the latest ‘‘American Society of Clinical Oncology’’ (ASCO), ‘‘International Association for the Study of Lung Cancer’’ and ‘‘European Society of Medical Oncology’’ meetings were carried out.

2.2. Eligibility criteria To be included in this review, trials have to fulfil the following criteria: clinical trials reported in English language involving patients suffering from histologically or cytologically proven advanced NSCLC, previously treated by chemotherapy whatever the first line.

2.3. Quality assessment A number of quality-control items of publication were taken into account, in particular: definition of hypothesis in the statistics section of each article, definition of the patients characteristics in regard to fundamental prognostic factors (sex, performance index, weight loss, stage of the disease, previous radiotherapy), definition of the treatment protocol and definition of survival. A minimal of 1-year median follow-up was required. Trials were also screened regarding the report of evaluable patients, response assessment procedure and toxicity, particularly toxic-deaths. Finally, the presence of confusing additional variables such

Second-line treatment for advanced non-small cell lung cancer as the number of patients lost to follow-up was checked.

2.4. Extraction of data The following general items were independently recorded by two observers (F.B. and W.J.): year of publication, hypothesis, method of randomisation when applicable and method of analyses (intent to treat or fully-eligible population). In addition, the following variables were recorded: number of accrual patients, number of eligible patients, and number of patients lost to follow-up, mean age, sex ratio, proportion of patients with good performance status (0 or 1), proportion of patients with stage IIIB. Feature outcomes for each treatment arm were assessed as follows: percentage of patients achieving a partial or complete response, median survival and overall survival at 1 year when available, number of toxic-deaths and number of patients with grade 3—4 haematological (i.e. leucopenia, neutropenia, febrile neutropenia and thrombocytopenia) and non-haematological toxicities.

3. Results The results of this systematic review are presented in order to answer the six following questions: Does chemotherapy improve survival? If yes, is one single-agent chemotherapy superior to another? Is a combination of two or more drugs superior to single-agent chemotherapy? Is a weekly schedule better than a three- or four-weekly administration of chemotherapy? How many cycles of second-line chemotherapy should the patients receive? Do any new second-line treatments (including alternatives to chemotherapy) emerge from the literature?

3.1. Does chemotherapy improve survival? Only one randomised phase III study compared chemotherapy plus BSC versus BSC alone. In the classical study by Shepherd et al. [3] previously platinum-based treated NSCLC patients were randomly assigned to receive BSC alone or BSC plus docetaxel every 3 weeks (initially at the 100 mg/m2 dosage, then 75 mg/m2 ). Disease progressed more slowly in patients randomised in the docetaxel group when compared with those assigned to BSC (respective median times to progression: 10.6 and 6.7 weeks, p = 0.001). In the docetaxel group patients proved to have a longer median survival (7.0 months versus 4.6 months, p = 0.04) and a

161

higher 1-year survival (37% versus 12%, p = 0.03) than patients in the BSC group. Moreover, toxicities were manageable when using docetaxel 75 mg/m2 . No toxic death occurred and only one patient experienced febrile neutropenia (1.8%). Grade 3—4 neutropenia were frequent (67.3% of patients) contrary to anaemia (5.5%). In addition, patients receiving docetaxel plus BSC experienced a significantly better quality of life (QOL) when compared with BSC alone. QOL assessed by the Lung Cancer Symptom Scale (LCSS) essentially showed lower patient-rated pain scores in the docetaxel arm. Accordingly, QOL assessed by the EORTC QLQ-C30 showed a non-significant lower impairment in pain-control, physical functioning and global health scores for patients treated with docetaxel when compared with patients receiving BSC only [4]. Furthermore, the survival and symptom benefits related to docetaxel in the previous phase III study have been proven to be in the same when used in daily practice as demonstrated in subsequent studies [5,6]. Finally, docetaxel 75 mg/m2 was found to be cost-effective with approximately 30,000$ per year of life gained, although the authors from the Canadian healthcare system identified no cost savings in the chemotherapy arm when compared with BSC alone [7]. In conclusion, 2003 ASCO recommendations stated that ‘‘docetaxel is recommended as secondline therapy for patients with locally advanced or metastatic NSCLC with adequate performance status who have progressed on first-line, platinumbased therapy’’ [8].

3.2. Is one single-agent chemotherapy superior to another? Several phase II trials based on four single agents of chemotherapy including docetaxel [9—13], paclitaxel [14,15], gemcitabine [16—18] and pemetrexed [19] are available (Table 1). Assuming that docetaxel 75 mg/m2 could be considered as a reasonable standard therapy for NSCLC patients who experienced first-line failure, three randomized studies compared docetaxel with a single agent of chemotherapy: vinorelbine or ifosfamide [20], paclitaxel [21] and pemetrexed [22] (Table 2). Only the latter was designed to detect a non-inferiority of the experimental arm regarding survival. Patients receiving docetaxel 75 mg/m2 had a better 1-year survival when compared with patients treated with vinorelbine or ifosfamide (32% versus 19%, p = 0.02) [20], and similar 1-year sur-

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Table 1 Phase II studies of single-agent chemotherapy as second-line therapy in pre-treated NSCLC patients published in their mature results N

Treatment arm

ORR (%)

MS (months)

1-Yr S (%)

Crino Sculier Gridelli Gandara Fossella Gridelli Robinet

83 82 30 80 44 23 27

GMZ 1 g/m2 d1,8,15 q4ws GMZ 1 g/m2 d1,8,15 q4ws GMZ 1 g/m2 d1,8,15 q4ws TXT 100 mg/m2 d1 q3ws TXT 100 mg/m2 d1 q3ws TXT 100 mg/m2 d1 q3ws (+CSF) TXT 100 mg/m2 d1 q3ws

19 6.2 20 16 21 21.7 24

7.8 3.9 5.0 7 9.6 5 8.5

45 NA NA 25 — — —

Quoix

89 93

TXT 100 mg/m2 d1 q3ws TXT 75 mg/m2 d1 q3ws

7.6 7.4

6.7 4.7

NA NA

Sculier Socinski Smit

67 13 81

TXL 225 mg/m2 d1 q3ws TXL 140 mg/m2 over 96 h q3ws PMX 500 mg/m2 d1 q3ws

3 0 8.9

4.5 3/8 5.7

19 NA NA

ORR: overall response rate; MS: median survival; 1-Yr S: 1-year survival; GMZ: gemcitabine; TXT: docetaxel; TXL: paclitaxel; PMX: pemetrexed; CSF: colony stimulating factor; NA: non available.

vival when compared with patients receiving pemetrexed alone (29.7% for each arm) [22]. The phase II randomized trial aimed at comparing docetaxel with paclitaxel was based on a weekly schedule of drug administration for both drugs [21]. However, the study was under-powered with regards to the survival insofar as the 1-year survival rate was poor (6%), and the number of patients (n = 71) in the investigational arm was low. Therefore, the efficacy of paclitaxel in second-line therapy of pre-treated NSCLC patients is not firmly defined. In the study comparing docetaxel and pemetrexed safety profiles differed significantly. Patients treated with a three-weekly schedule of docetaxel experienced significantly more grade 3—4 neutropenia (40.2 versus 5.3%, p < 0.001) and febrile neutropenia (12.7% versus 1.9%, p < 0.001) lead-

ing to more hospitalization for neutropenic fever (13.4% versus 1.5%, p < 0.001) and increased use of granulocyte colony-stimulating factors (19.2% versus 2.6%, p < 0.001) when compared with patients treated with pemetrexed [22]. Although a comparison of two populations treated with the same regimen (docetaxel 75 mg/m2 , every 3 weeks) accrued in two different trials is speculative, one can observe that the rate of febrile neutropenia (12.7%) reported for patients treated with docetaxel 75 mg/m2 in the study by Hanna was higher than that reported in previous phase III studies (1.8—5%) [3]. NSCLC patients treated with either docetaxel or pemetrexed as second-line single-agent chemotherapy experienced a similar symptom alleviation. Patients achieving tumour response or stable disease have a greater likelihood of

Table 2 Randomised phase II and III studies of single-agent chemotherapy as second-line therapy in pre-treated NSCLC patients n Shepherd

104 100

Treatment arm

ORR (%) 2

TXT 100 then 75 mg/m d1 q3ws BSC

MS (months) *

1-Yr S (%)

7.1 —

7.0 4.6

37.0* 11.0

Fossella

60 59 60

TXT 100 mg/m2 d1 q3ws TXT 75 mg/m2 d1 q3ws VNR 30 mg/m2 d1,8,15 q3ws or IFM 2 gr/m2 d1-3 q3ws

10.8** 6.7* 0.8

5.5 5.7 5.6

21.0 32.0* 19.0

Esteban

35 36

TXT 36 mg/m2 wly × 6 q8ws TXL 80 mg/m2 wly × 6 q8ws

3.0 14.03

6.0 3.4

6.0 6.0

8.8 9.1

7.9 8.3

29.7 29.7

Hanna

288 283

TXT 75 mg/m2 d1 q3ws PMX 500 mg/m2 d1 q3ws

ORR: overall response rate; MS: median survival; 1-Yr S: 1-year survival; TXT: docetaxel; BSC: best supportive care; VNR: vinorelbine; IFM: ifosfamide; TXL: paclitaxel; PMX: pemetrexed. * p < 0.05. ** p < 0.001.

Second-line treatment for advanced non-small cell lung cancer reporting a better symptom control than those with progressive disease [23]. In conclusion, docetaxel and pemetrexed shared comparable efficacy regarding survival and quality of life, with however a putative better safety profile for pemetrexed.

3.3. Is a combination of two or more drugs superior to single-agent chemotherapy? Numerous phase II trials explored a two-drug combination for second-line therapy of pre-treated NSCLC patients. Among these phase II studies, both platinum-based [24—35] and non-platinum [36—55] regimens were used (Tables 3 and 4). Four randomized studies compared a single-agent chemotherapy versus a two-drugs regimen [56—59] (Table 5). Three trials compared docetaxel with a combination chemotherapy of docetaxel plus gemcitabine

163

[58] or docetaxel plus irinotecan [56,57]. The last one compared irinotecan as a single agent with a combination of irinotecan plus gemcitabine [59]. In the first study, the combination of docetaxel with gemcitabine led to a significantly higher rate of interstitial lung toxicity (21% versus 2%) responsible for a 5% rate of toxic-deaths and commanding an early discontinuation of the trial [58]. Similarly, the combination of docetaxel with irinotecan in the second study led to additional haematological (grade 3—4 thrombocytopenia, 17% versus 6%, p = 0.04) and extra-haematological (grade 3—4 diarrhoea, 12% versus 3%, p = 0.05) toxicities when compared with docetaxel alone. Also, while the combination of docetaxel with irinotecan prolonged time to progression (5.6 months versus 4.8 months, p = 0.06), it did not significantly improve the response rate (20% versus 14%, p = 0.3), median survival (6.5 versus 6.4, p = 0.4) or 1-year survival

Table 3 Two-drugs phase II studies with a platinum compounds for the second-line therapy of pre-treated NSCLC patients

Agelaki De Pas Chen Kakolyris Laack Wachters Seto Oka Stathopoulos

n

Treatment arm

ORR (%)

37

CBDCA 300 mg/m2 d1 plus VNR 30 mg/m2 d1,8 q4ws

16

8.5

38

17

CDDP 80 mg/m2 d1 plus VNR 25 mg/m2 d1,8 q3ws

18

8.0

NA

22

CDDP 50 mg/m2 d1 plus VNR 20 mg/m2 d 1,8,15 q4ws

9.5

7.6

12.3

22

CDDP 80 mg/m2 d8 plus CPT11 100—110 mg/m2 d1 8a q3ws

16.7

8.0

41

26

CBDCA AUC5 d1 plus TXT 75 mg/m2 d1 q3ws

19.2

7.9

25.9

57

CBDCA AUC6 d1 plus TXT 75 mg/m2 d1 q3ws

37

7.1

32

25

CDDP 60 mg/m2 d1 plus TXT 60 mg/m2 d1 q3ws

32

8.4

—

16

CBDCA AUC5 d1 plus TXT 40—60 mg/m2 d1 q3-4ws

31

—

—

36

CDDP 90 mg/m2 d1 plus TXL 175 mg/m2 d1 q3ws

40

—

—

26

CDDP 50 mg/m2 d1,8 plus TXL 125 mg/m2 d1,8 plus GMZ 1 g/m2 d1,8 q3ws

27

5.5

—

48

NDDP 80 mg/m2 d1 plus VDS 3 mg/m2 d1,8 q3-4ws

10.0

40

27

CDDP 60 mg/m2 d1 plus EPI 135 mg/m2 d1 q2ws

6.2

NA

Rosati

Takigawa Huisman

7.5 33

MS (months)

1-Yr S (%)

ORR: overall response rate; MS: median survival; 1-Yr S: 1-year survival; CBDCA: Carboplatin; AUC: area under the curves, mg/(ml min); VNR: vinorelbine; CDDP: cisplatin; CPT11: irinotecan; EPI: epirubicin; TXT: docetaxel; GMZ: gemcitabine; NDDP: nedaplatin; VDS: vindesine; NA: not available. a Phase I—II trials.

164

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Table 4 Two-drugs phase II studies without a platinum compounds for the second-line therapy of pre-treated NSCLC patients

Hainsworth Camps Kosmas Park Chen Pectasides Iaffaioli Koizumi Androulakis Niho Spiridonidis Kakolyris Tas Kosmas Chen Leu Chen Rinaldi Gonzalez Pectasides

n

Treatment arm

ORR (%)

55

VNR 20 mg/m2 d1,8,15 plus GMZ 1 g/m2 d1,8,15 q4ws

18

16

VNR 25 mg/m2 d1,8 plus GMZ 1250 mg/m2 d1,8,15 q4ws

40

GMZ 1 g/m2 d1,8 plus VNR 25 mg/m2 d1,8 q3ws

38

MS (months)

1-Yr S (%)

6.5

20

5.7

NA

22.5

7

17

VNR 30 mg/m2 d1,8 plus GMZ 1 g/m2 d1,8,15 q3ws

21

8.1

13.2

17

GMZ 800 mg/m2 d1,8,15 plus VNR 20 mg/m2 d 1,8,15 q4ws

31.3

8.3

34.3

39

GMZ 800 mg/m2 d1,8 plus VNR 25 mg/m2 d1,8 q3ws

2.6

7.3

35

37

GMZ 1 g/m2 d1,8 plus TXL 90—240a mg/m2 d1 q3ws

39

9.2

NA

18

GMZ 1 g/m2 d1,15 plus TXL 110—170a mg/m2 d1,15

22

—

—

49

GMZ 900 mg/m2 d1,8 plus TXL 175 mg/m2 d8 q3ws

18

11.0

37

42

GMZ 800a mg/m2 d1,8 plus TXT 60 mg/m2 d1 q3ws

28

11.1

41

40

GMZ 800 mg/m2 d1,8,15 plus TXT 100 mg/m2 d1 q4ws

32.5

8.1

32

GMZ 900 mg/m2 d1,8 plus TXT 100 mg/m2 d8 q3ws

15.6

6.5

27.6

33

GMZ 1.2 g/m2 d1,8 plus TXT 85 mg/m2 d1 q3ws

30.3

7.3

—

43

GMZ 1 g/m2 d1,8 plus TXT 100 mg/m2 d1 q3ws

33

8.5

28

36

GMZ 800 mg/m2 d1,8 plus TXT 30 mg/m2 d1,8 q3ws

36.1

6.9

—

30

TXT 60 mg/m2 d1 plus VNR 15 mg/m2 d1,8,15 q3ws

13

10.8

50

50

TXT 60 mg/m2 d1 plus IFM 3 g/m2 d1 q3ws

10

8.2

NA

35

TPT 0.75 mg/m2 d1-5 plus GMZ 400 mg/m2 d1,5 q3ws

11

7

20

33

CPT11 300 mg/m2 d1 plus VNR 30 mg/m2 d1,15 q4ws

9

6.0

—

50

CPT11 150 mg/m2 d1,8 plus GMZ 1800 mg/m2 d1,8 q4ws

16

8.1

36

6.2

ORR: overall response rate; MS: median survival; 1-Yr S: 1-year survival; VNR, vinorelbine; CPT11, irinotecan; TPT: topotecan; GMZ: gemcitabine; TXL: paclitaxel; TXT: docetaxel; IFM: ifosfamide; NA: not available. a Phase I—II trials.

Second-line treatment for advanced non-small cell lung cancer Table 5

165

Randomised studies including a two-drug combination as second-line chemotherapy for NSCLC patients n

Treatment arm

ORR (%)

2

MS (months)

1-Yr S (%)

Pectasides

65 65

TXT 75 mg/m d1 q3ws TXT 30 mg/m2 d1,8 plus CPT11 60mg/m2 d1,8 q3ws

14 20

6.4 6.5

34 37

Wachters

56 52

TXT 75 mg/m2 d1 q3ws TXT 60 mg/m2 d1 plus CPT11 200 mg/m2 d1 q3ws

16 10

7.3 6.2

26 30

Takeda

65 65

TXT 60 mg/m2 d1 q3ws TXT 60 mg/m2 d1 plus GMZ 800 mg/m2 d1,8 q3ws

NA NA

10.1 11.3

38 47

Georgoulias

75 79

CPT11 300 mg/m2 d1 q3ws CPT11 300 mg/m2 d8 q3ws GMZ 1000 mg/m2 d1,8 q3ws

4.2 18.4*

7.0 9.0

29 24.5

TXT 30 mg/m2 d1,8,15 plus GMZ 800 mg/m2 d1,8,15 q4ws TXT 30 mg/m2 d1,8,15 plus VNR 20 mg/m2 d1,8,15 q4ws

10.0

6.0

20

0

8.0

22

40 Hainsworth 23

ORR: overall response rate; MS: median survival; 1-Yr S: 1-year survival; TXT: docetaxel; CPT11: irinotecan; GMZ: gemcitabine; VNR: vinorelbine; NA: not available. * p < 0.05.

(37% versus 34%, p = 0.7) when compared with docetaxel alone [56]. The second study comparing the combination of docetaxel plus irinotecan versus docetaxel alone demonstrated the lack of benefit for the two-drug regimen with regards to the response rate (10% versus 16%), median survival (6.2 versus 7.3, p = 0.6) and 1-year survival (30% versus 26%, p = 0.4, respectively) [57]. In the fourth trial, irinotecan plus gemcitabine demonstrated a higher response rate (18.4 versus 4.2, p = 0.009) and a better symptom alleviation than irinotecan alone. However, there was no median survival improvement (9.0 months versus 7.0 months, p = 0.5) [59]. An additional study compared docetaxel combined with either gemcitabine or vinorelbine [60]. The combination of docetaxel with gemcitabine appeared feasible and well-tolerated. More importantly, no interstitial lung disease was reported among the 40 accrued patients. Response rate (10%) and median survival (6 months) were in the same range as those observed with docetaxel singleagent chemotherapy. On the other hand, the combination of docetaxel and vinorelbine was associated with severe myelosuppression insofar as 70% of the patients experienced a neutropenic fever and no major response was observed. Consequently, an early discontinuation of the trial was compulsory [60]. In conclusion, a two drug combination regimen was not shown to improve survival and toxicities were frequently increased, sometimes leading to

toxic-deaths which is in contradiction with the primary aim of second-line treatment, i.e. prolong survival and quality of life in patients with incurable disease. Although attractive the doublet of gemcitabine and docetaxel needs further evaluation of its safety profile particularly regarding severe pulmonary events [61]. For the moment, single-agent chemotherapy should be preferred.

3.4. Is a weekly schedule better than a three- or four-weekly administration of chemotherapy? Several phase II studies aimed at improving both haematological and extra-haematological safety by adopting a weekly delivery schedule for secondline chemotherapy. Docetaxel and paclitaxel were extensively studied in this setting, either alone [62—71] or in combination with gemcitabine [72], vinorelbine [73] or irinotecan [74] (Table 6). Overall response rate varied markedly for single-agent chemotherapy (0—37.5%) as well as for combination of two drugs (6—21%). Accordingly, 1-year survival rate also varied from 9.5% to 53% throughout the above-mentioned studies. The substantial heterogeneity of the designs precluded any firm conclusion regarding the mentioned analyses. Three randomised trials (one phase II and two phase III studies), compared a weekly docetaxel delivery schedule versus the classical schedule (every 3 weeks) [75—77]. The results reported in the phase II study were as follows: response

166 Table 6

F. Barl´ esi et al. Phase II and III studies with weekly schedule of second-line chemotherapy for NSCLC patients n

Treatment arm

ORR (%)

MS (months)

1-Yr S (%)

Phase II studies with single agent Juan 40 TXL 80 mg/m2 wly until PRG Socinsky 62 TXL 80 mg/m2 wly until PRG Buccheri 38 TXL 100 mg/m2 wly × 21 ws Ceresoli 53 TXL 80 mg/m2 d1,8,15 q4ws × 4 Yasuda 39 TXL 80 mg/m2 d1,8,15 q4ws Vazquez 45 TXT 50 mg/m2 biwly Rossi 21 TXT 40 mg/m2 wly × 6 q8ws Lilenbaum 31 TXT 36 mg/m2 wly × 6 q8ws Serke 36 TXT 35 mg/m2 wly × 6 q8ws × 3 Ardizzoia 42 TXT 25 mg/m2 wly × 12

37.5 8.0 15.7 15.0 31.0 20.0 0 10.0 11.0 10.5

9.7 5.2 13.3 8.0 9.9 4.0 3.0 8.0 5.2 2.9

37.7 20.0 53.0 18.0 — 23.0 9.5 31.0 23.0 —

Phase II and III randomized studies with single agent 125 TXT 40 mg/m2 wly × 6 q8ws Gervaisa versus TXT 75 mg/m2 d1 q3ws 220 TXT 33 mg/m2 wly × 6 q8ws Gridelli versus TXT 75 mg/m2 d1 q3ws 216 TXT 35 mg/m2 d1,8,15 q4ws Schuette versus TXT 75 mg/m2 d1 q3ws

3.2 4.8 5.5 2.7 11.6 10.5

5.5 5.8 6.7 5.8 NR 5.8

6 18 31 21 NA NA

12

6.4

23

21

8

30

6

8

30

Phase II studies with two agents 34 TXL 80 mg/m2 d1,8,15 Dongiovanni plus GMZ 1 g/m2 d1,8 q3ws 24 TXT 25 mg/m2 wly Nelli plus VNR 20 mg/m2 wly 51 TXT 25 mg/m2 d 1,8,15 Font plus CPT11 70 mg/m2 d1,8, 15 q4ws

ORR: overall response rate; MS: median survival; 1-Yr S: 1-year survival; PRG, progression; TXL: paclitaxel; TXT: docetaxel; GMZ: gemcitabine; VNR, vinorelbine; CPT11: irinotecan; NA: not available; NR: not reached. a Phase II randomised study.

rate (3.2% versus 4.8%, respectively), median survival (5.5 months versus 5.8 months, respectively) and 1-year survival (6% versus 18%, respectively). None of these results seems to favour the weekly schedule for docetaxel infusion [75]. Similarly, the results of the first phase III study reported comparable results regarding survival (median survival 6.7 months versus 5.8 months, respectively). However, better safety and quality of life profiles were reported for patients receiving the weekly schedule [76]. In contrast, the results of the second phase III study showed that response rates did not significantly differ between the two regimens, whereas a trend towards better survival (>8 months versus 5.8 months, p = 0.08) for patients in the weekly arm was observed [77]. Although methodologically debatable, a sub-group analysis restricted to those patients who had not received paclitaxel in the first-line regimen, suggest a statistically significant overall survival improvement with docetaxel second-line weekly schedule (p = 0.003). In addition, the weekly schedule was associated with fewer grade 3—4 haematological toxicities. Mature results are eagerly awaited in order to define the

putative benefit associated with a docetaxel weekly schedule in second-line NSCLC therapy.

3.5. How many cycles of second-line chemotherapy should NSCLC patients receive? Up till now, this question has not been formally addressed. When considering the results reported in the aforementioned phase III trials, the mean number of delivered cycles was as follows: docetaxel 100 mg/m2 : two cycles [3]; docetaxel 40 mg/m2 weekly: two cycles [75]; two-drugs regimens [24]: two cycles; docetaxel 75 mg/m2 : three to four cycles; pemetrexed: four cycles [3,20,22]. The reason leading to treatment discontinuation has been inconsistently reported throughout the studies but drug-related toxicity as well as progressive disease are possible explanations. Inasmuch as time to progression reported in the same aforementioned phase III trials mainly ranges between 2 and 3 months [3,20,22,75] corresponding with three or four 3-weekly cycles, disease progression might be

Second-line treatment for advanced non-small cell lung cancer considered as the main reason for second-line treatment discontinuation.

3.6. Do any new second-line treatments appear? The great majority of NSCLC patients who relapse suffer from metastatic disease at time of secondline therapy. Conversely, few patients have a refractory disease confined to the lungs. Some pilot studies investigated the case of regional chemotherapy for these patients [78,79]. While the results reported by the authors are promising (response rate of 35—56% and 1-year survival of 36—75%), the lack of control for distant metastases and the difficulty associated with the technique show the strong limitations regarding such a second-line therapy. In addition, the effectiveness of systemic chemotherapy in this highly selected population of patients (affected lower tumour burden) is unknown precluding any comparison. On the other hand, several new chemotherapeutic agents have been studied in a second-line setting including an alkylating agent [80], platinum compounds [34], taxanes [81], I and/or II topo-isomerase inhibitors [82], ifosfamide derivative [83,84], vinca-alkaloid derivative [85] or capecitabine combined with irinotecan [86] (Table 7). The results reported for all these new agents are either in the range of those recorded with standard single-agent chemotherapies or sometimes inefficient in this setting. Currently, only vinflunine has been investigated in a phase III trial. Cyclooxygenase-2 enzyme (COX-2) appeared to play a role in cancer. COX-2 is over-expressed in lung cancer and might be related to poor survival. Accordingly, COX-2 inhibitors such as celecoxib have been studied for the management of NSCLC patients. In a phase II study on 41 pre-

Table 7

Dowell Dittrich Giaccone Han Miller Bennouna Camps Takigawa

167

treated NSCLC patients, celecoxib 400 mg daily combined with docetaxel 75 mg/m2 provided a 10.2% response rate. The median survival was 11.3 months with an interesting 1-year survival of 48%, without increased toxicity [87]. However, the risk of cardio-vascular events recently reported for COX-2 inhibitors raised questions concerning this research. Nevertheless, recent clinical research for second-line therapy in NSCLC patients focused more particularly on targeted therapy and mainly on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKI) such as gefitinib or erlotinib. Phase II studies of gefitinib in advanced NSCLC were called Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) 1 and 2 [88,89]. In the IDEAL 1 trial, 210 patients were randomly assigned to receive gefitinib 250 or 500 mg daily. Among them up to 56% received gefitinib as second-line therapy and reached a global response rate of 18.4% and 19%, median survival of 7.6 and 8.0 months and 1-year survival of 35% and 29%, respectively. That leads to an international extended access programme for this drug in routine practice. More recently, the results of a randomised placebo-controlled trial of gefitinib after failure of first or second-line chemotherapy in NSCLC patients called IRESSA Survival Evaluation in Lung cancer (ISEL) with 1692 patients were reported [90]. Gefitinib failed to significantly prolong survival in comparison to placebo in the overall population (Hazard Ratio 0.89, p = 0.11; median survival, 5.6 months versus 5.1 months) or in patients with adenocarcinoma (HR 0.83, p = 0.07; median survival 6.3 months versus 5.4 months). Contrarily, a similarly-designed study of erlotinib showed a better progression free (2.23 months versus 1.84 months, p < 0.001) and overall survival (6.7 months versus 4.7 months,

Phase II studies including a novel agent of chemotherapy as second-line chemotherapy for NSCLC patients n

Treatment arm

15 15 39

Irofulven 11 mg/m2 dly q4ws XR5000 3010 mg/m2 q3ws Glufosfamide 5000 mg/m2 q3ws

37

ORR (%)

MS (months)

1-Yr S (%)

0 0 3.0

— NA 5.8

— NA NA

Irinotecan 90—100 mg/m2 d 1,8 + Capecitabine 1 g/m2 d1-14 q3ws

11.4

7.4

12.4

55 63 56

Karenitecin 1 mg/m2 d1-5 q3ws Vinflunine 320 mg/m2 q3ws BMS-184476 60 mg/m2 q3ws

4.0 8.0 14.3

8.6 NA 10.0

29.0 NA ?

48

Nedaplatine 80 mg/m2 d1 plus VDS 3 mg/m2 d1,8 q3-4ws

7.5

10.0

40.0

ORR: overall response rate; MS: median survival; 1-Yr S: 1-year survival; VDS, vindesine; NA: not available.

168 p = 0.001) for patients receiving erlotinib when compared with placebo [91]. In addition, EGFR-TKI demonstrated a favourable toxicity profile with only 1.5—4.7% grade 3—4 adverse events in the IDEAL 1 trial [88]. While numerous studies are currently ongoing, no comparison of a standard single-agent chemotherapy with EGFR-TKI nor any study of a standard single-agent chemotherapy combined with EGFR-TKI, have been reported to date. There is a clear need to strictly define the population that could benefit the best from antiEGFR targeted therapy as a prerequisite to such treatment. In this setting, efforts attempting to defined deletions and mutations of the tyrosine kinase gene exon 18—19—21 which confer the increase affinity between EGFR-TKI and tyrosinekinase domain must be generalised in routine practice. As a first step the re-appraisal of EGFR-TKI studies [90,91] with regards to those mutations and deletions in the accrued population should be considered.

4. Discussion This systematic review highlights the current position of second-line chemotherapy for the management of NSCLC patients throughout the large number of phase II and III trials. Second-line chemotherapy provides the pre-treated NSCLC patients with a clear survival advantage. While docetaxel 75 mg/m2 is the present standard secondline chemotherapy, pemetrexed recently emerged as an alternative with similar efficacy and an eventual best safety profile. Although the combination of two drugs was not associated with a survival benefit when compared with single-agent chemotherapy, such regimens led to a dramatic increase in toxicities. Currently, a weekly secondline chemotherapy schedule should not be recommended despite promising results regarding efficacy and the safety profile in a preliminary report of a phase III study. Finally, none of the new agents tested reported with better results than those previously used and the clinical research on secondline therapy currently focuses on combination with targeted therapies. Response rate observed with second-line therapy for pre-treated NSCLC patients is in the same range than the response rate usually reported for refractory or relapsing metastatic colon cancer patients with recommended regimens. At present, response rates obtained with second-line chemotherapies for colon cancer patients ranged from 4% to 15% [92,93], and is strongly influenced by the previ-

F. Barl´ esi et al. ously applied first-line regimen [92]. This is in contrast with the investigation of second-line therapy for NSCLC which did not disclose a difference pending on first line. On the other hand, the case of metastatic breast cancer could not be compared with lung cancer insofar as hormonal therapy remains an additional second line for women with hormono-dependent disease status. While additional toxicity related to secondline therapy is firmly counterbalanced by a survival advantage, further investigations taking into account QALY analyses are strongly needed as well as cost-effectiveness studies. Only one published study addresses this question and reports quite a high level of cost-effectiveness per year of life gained [7]. Thus, studies based on new agents as well as different health care systems are mandatory. Less than 50% of NSCLC patients received second-line treatment [94]. Therefore, development of new schedules associated with better safety profile is warranted in order to offer more to patients than supportive care alone. In conclusion, second-line chemotherapy offers NSCLC patients with refractory disease after firstline treatment an opportunity to prolong survival and alleviate frequently disabling symptoms. However, this field of clinical research needs further investigation in order to resolve the unanswered questions.

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