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Gastric Cancer

, Volume 22, Issue 3, pp 577–586 | Cite as

Prognostic factors in patients treated with second-line chemotherapy for advanced gastric cancer: results from the randomized prospective phase III FFCD-0307 trial

  • Y. TouchefeuEmail author
  • R. Guimbaud
  • C. Louvet
  • L. Dahan
  • E. Samalin
  • E. Barbier
  • K. Le Malicot
  • R. Cohen
  • J. M. Gornet
  • T. Aparicio
  • S. Nguyen
  • A. Azzedine
  • P. L. Etienne
  • J. M. Phelip
  • P. Hammel
  • N. Chapelle
  • D. Sefrioui
  • L. Mineur
  • C. Lepage
  • O. Bouche
Original Article

Abstract

Aim

The aim of this study was to determine prognostic factors in patients treated with second-line therapy (L2) for locally advanced or metastatic gastric and gastro-esophageal junction (GEJ) adenocarcinoma in a randomized phase III study with predefined L2.

Methods

In the FFCD-0307 study, patients were randomly assigned to receive in L1 either epirubicin, cisplatin, and capecitabine (ECX arm) or fluorouracil, leucovorin, and irinotecan (FOLFIRI arm). L2 treatment was predefined (FOLFIRI for the ECX arm and ECX for the FOLFIRI arm). Chi square tests were used to compare the characteristics of patients treated in L2 with those of patients who did not receive L2. Prognostic factors in L2 for progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox model.

Results

Among 416 patients included, 101/209 (48.3%) patients in the ECX arm received FOLFIRI in L2, and 81/207 (39.1%) patients in the FOLFIRI arm received ECX in L2. Patients treated in L2, compared with those who only received L1 had : a better ECOG score (0–1: 90.4% versus 79.7%; p = 0.0002), more frequent GEJ localization (40.8% versus 27.6%; p = 0.005), and lower platelet count (median: 298000 versus 335000/mm3; p = 0.02). In multivariate analyses, age < 60 years at diagnosis (HR 1.49, 95% CI 1.09–2.03, p = 0.013) and ECOG score 2 before L2 (HR 2.62, 95% CI 1.41–4.84, p = 0.005) were the only significant poor prognostic factors for OS.

Conclusion

Age ≥ 60 years at diagnosis and ECOG score 0/1 before L2 were the only favorable prognostic factors for OS.

Keywords

Gastric neoplasm Survival Prognosis Second-line chemotherapy 

Introduction

Worldwide, gastric cancer is the third leading cause of cancer-related mortality. Though the incidence has decreased over the last 20 years, the prognosis remains poor [1]. In patients with advanced or metastatic disease, 5-year overall survival remains less than 5%. In first-line, chemotherapy, regimens can improve overall survival. Doublets or triplet chemotherapy regimen, and trastuzumab in patients with human epidermal growth factor receptor (HER)-2 positive tumors, have demonstrated clinical benefits on overall survival and quality of life [2, 3, 4, 5]. Other studies have also demonstrated the potential benefits on overall survival of a second-line treatment, with irinotecan, taxanes, ramucirumab alone or combined with paclitaxel, and more recently nivolumab in third-line therapy and beyond [6, 7, 8, 9, 10, 11]. In published clinical trials evaluating first-line treatments without pre-planned second line, the percentage of patients receiving a second line, when reported, is heterogenous, e.g., 14% in the REAL-2 trial, 45% in the ToGA trial, 75% in the SPIRITS trial; with a higher proportion in Asian trials compared to non-Asian trials [2, 3, 4]. Thus, few data are available to help the selection of patients for a second-line treatment. The aim of our study was to evaluate the prognostic factors in patients who received second-line therapy in a randomized prospective trial in which the first- and second-line treatments were planned [12].

Materials and methods

Patients and study design

Patients from the FFCD-0307 trial had locally advanced or metastatic gastric or gastro-esophageal junction (GEJ) locally advanced or metastatic adenocarcinoma and were randomly assigned (1:1) to receive either epirubicin, cisplatin, and capecitabine (ECX) chemotherapy in the first line (ECX arm) with a predefined second-line therapy with fluorouracil, leucovorin, and irinotecan (FOLFIRI) or to receive FOLFIRI in the first line (FOLFIRI arm) with a predefined ECX second-line therapy. Other inclusion criteria were: age 18 years or older, measurable and/or assessable lesions according to RECIST criteria, WHO performance score (PS) ≤ 2, ability to take oral medications, no previous palliative chemotherapy (≥ 6 months from adjuvant chemotherapy was allowed), ≥ 3 weeks from previous radiotherapy, sufficient bone marrow function, creatininemia ≤ 110 μmol/l, and bilirubinemia ≤ 35 μmol/l.

Treatment and evaluation

The ECX regimen consisted of epirubicin 50 mg/m2 [15-min intravenous (IV) infusion] plus cisplatin 60 mg/m2 (1-h IV infusion) on day 1 followed by oral capecitabine 1 g/m2 twice per day from day 2 to day 15 every 3 weeks; the maximum authorized cumulative dose of epirubicin was 900 mg/m2. The FOLFIRI regimen consisted of irinotecan 180 mg/m2 (90-min IV infusion) and leucovorin 400 mg/m2 (2-h IV infusion) followed by a fluorouracil 400 mg/m2 IV bolus and then fluorouracil 2400 mg/m2 as a 46-h continuous infusion every 2 weeks.

Tumor response was evaluated by investigators and classified according to RECIST criteria. CT scans were performed before the start of treatment and then every 8 weeks until disease progression for each treatment line and in each arm.

Statistical analyses

Progression-free survival (PFS) was defined as the time from the start of the second line to the first progression or death (all causes). Patients alive without progression were censored at the last follow-up. Overall survival (OS) was defined as the time between the start of the second line and death (all causes). The disease control rate (DCR) was defined as the proportion of patients with a complete or partial response, or stable diseases during the second line according to RECIST criteria.

Qualitative and continuous variables were described using the usual descriptive statistics: numbers and percentages and medians with min–max, respectively. Comparison of baseline characteristics of the two arms was made with the χ2 test or nonparametric Wilcoxon test, depending on the type and distribution of variables.

Survival analyses (OS, PFS) were done using the Kaplan–Meier method and described using medians with 95% two-sided confidence intervals (95% CI). Cox models were used to estimate hazard ratios (HR) and logistic regressions were performed for DCR. All variables significant at 10% in univariate analyses were included in the multivariate analyses. Two multivariate models were made: the first one with factors assessed before the start of first-line therapy and the second one with factors assessed before the start of second-line therapy. Analyses were performed using SAS software 9.4 (SAS Institute, Cary, NC).

Results

Probability of receiving a second-line chemotherapy according to baseline characteristics

Among the 416 patients included in the FFCD-0307 trial, 182 patients received the preplanned second-line chemotherapy, 101/209 (48.3%) patients in the ECX arm received FOLFIRI in L2, and 81/207 (39.1%) of patients in the FOLFIRI arm received ECX in L2. No other second-line regimen was administered.

The baseline (before first line) clinical characteristics of patients are presented in Table 1. At baseline, patients with GEJ tumors (versus gastric tumors, p = 0.005), ECOG 0–1 (versus ECOG 2, p = 0.0002) were more likely to receive the second-line chemotherapy. There was no significant difference according to the first-line regimen (55.5% ECX, 44.5% FOLFIRI, p = 0.06).

Table 1

Clinical characteristics of the population at baseline

 

Second line

Yes

No

Number of patients, n = 182

%

Number of patients, N = 234

%

First-line treatment

 ECX

101

55.49

108

46.15

 FOLFIRI

81

44.51

126

53.85

Sex

 Male

134

73.63

175

74.79

 Female

48

26.37

59

25.21

Median age (min–max) in years

60 (28–82)

62 (29–84)

 < 60 years

93

51.10

103

44.21

 ≥ 60 years

89

48.90

130

55.79

 

n = 178

 

n = 227

 

ECOG score

 0

75

42.13

57

25.11

 1

86

48.31

124

54.63

 2

17

9.55

46

20.26

Body mass index (kg/m2)

 < 18.5

19

10.44

37

15.81

 18.5–25

100

54.95

126

53.85

 25–30

51

28.02

58

24.79

 ≥ 30

12

6.59

13

5.56

 

n = 179

 

n = 228

 

Localization

 Gastro-esophageal junction

73

40.78

63

27.63

 Stomach

106

59.22

165

72.37

 

n = 180

 

n = 227

 

Linitis plastica

 Yes

42

23.33

56

24.67

 No

138

76.67

171

75.33

 

n = 177

 

n = 224

 

Metastases

 Yes

157

88.70

192

85.71

 No

20

11.30

32

14.29

 

n = 178

 

n = 227

 

Primary tumor resection

 Yes

40

22.47

62

27.31

 No

138

77.53

165

72.69

 

n = 179

 

n = 225

 

Previous treatment

 Yes

19

10.61

24

10.67

 No

160

89.39

201

89.33

ECX epirubicin, cisplatin and capecitabine, FOLFIRI irinotecan, leucovorin, fluorouracil bolus and 46-h continuous infusion every 2 weeks

The baseline biological results were analyzed. The group of patients who received the second-line treatment had a lower baseline-platelet count (median 298,000/mm3 versus 335,000/mm3, p = 0.02). There were no significant differences according to the hemoglobin and neutrophils counts, and to serum levels of bilirubin, alkaline phosphatase, carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA19.9) (Table 2).

Table 2

Biological characteristics at baseline

 

Second Line

Yes, N = 182

No, N = 234

Hemoglobin (g/dl)

 n

179

228

 Minimum

7.00

7.10

 Median

12.20

12.05

 Maximum

16.50

16.30

Creatinine (µmol/l)

 n

175

227

 Minimum

32.00

5.50

 Median

76.00

71.00

 Maximum

115.00

118.00

Neutrophils (/mm3)

 n

178

224

 Minimum

2109.00

10.00

 Median

5410.50

5698.50

 Maximum

18737.00

22404.00

Platelets (× 1000/mm3)

 n

179

228

 Minimum

141.00

108.00

 Median

298.00

335.00

 Maximum

922.00

1080.00

Total bilirubin (µmol/l)

 n

175

223

 Minimum

1.70

1.70

 Median

8.60

8.00

 Maximum

108.00

85.00

Alkaline phosphatase

 n

176

219

 ≤ 1.5× normal value

130 (76.8%)

151 (68.9%)

 > 1.5× normal value

46 (26.1%)

68 (31.0%)

CEA

 n

167

205

 ≤ 2× normal value

105 (62.9%)

134 (65.4%)

 > 2× normal value

62 (37.1%)

71 (34.6%)

CA 19.9

 n

167

203

 ≤ 2× normal value

99 (59.3%)

120 (59.1%)

 > 2× normal value

68 (40.9%)

83 (40.9%)

Prognostic factors for disease control from the start of second line

The disease control rate (DCR) was assessable in 150 patients. The DCR was 45/83 (54.2%) for patients treated with FOLFIRI L2 versus 31/67 (46.3%) for patients treated with ECX L2.

In univariate analysis, the neutrophil count < 5000/mm3 (p = 0.028) and ECOG score 0/1 before L2 (p = 0.008) were the only significant good prognostic factor (Table 3). There was no correlation between the response rates in first and second lines (p (Fisher) = 0.156 for patients treated with FOLFIRI L2, p (Fisher) = 0.687 for patients treated with ECX L2).

Table 3

Prognostic factors for disease control rate in second-line therapy, univariate analysis

 

Disease control (yes/no)

Odd ratio

95% Confidence interval

p value

Factors from the start of first-line therapy

 Treatment

  ECX second line

31/67

0.73

0.38

1.39

0.334

  FOLFIRI second line

45/83

Ref

 

 Sex

  Male

53/105

0.97

0.48

1.98

0.940

  Female

22/43

Ref

 

 Tumor localization

  GEJ

29/62

0.75

0.39

1.44

0.380

  Stomach

46/85

Ref

 

 ECOG score

  1–2

43/80

1.31

0.68

2.52

0.415

  0

31/66

Ref

 

 Body mass index (kg/m2)

  < 18.5

7/14

1.45

0.44

4.78

0.221

  18.5–25

37/85

1.88

0.92

3.84

 

  ≥ 25

29/49

Ref

 

 Linitis plastica

 No

58/117

0.81

0.37

1.79

0.602

 Yes

17/31

Ref

 

 Metastasis

  No

10/16

1.67

0.57

4.85

0.349

  Yes

65/130

Ref

 

 Primary tumor resection

  No

56/113

0.93

0.43

2.01

0.843

  Yes

17/33

Ref

 

 Age

  < 60 years

35/72

0.85

0.45

1.62

0.625

  ≥ 60 years

40/76

Ref

 

 Hemoglobin

  < 12 g/dl

31/65

0.81

0.42

1.55

0.521

  ≥ 12 g/dl

44/83

Ref

 

 Neutrophils

  < 5000/mm3

37/60

2.12

1.08

4.14

0.028

  ≥ 5000/mm3

38/88

Ref

 

 Platelets

  < 300,000/mm3

42/73

1.72

0.90

3.31

0.101

  ≥ 300,000/mm3

33/75

Ref

 

 Alkaline phosphatases

  ≤ 1.5× normal value

53/109

1.37

0.66

2.85

0.405

  > 1.5× normal value

22/39

Ref

 

 CEA

  ≤ 2× normal value

41/85

1.16

0.58

2.31

0.676

  > 2× normal value

27/52

Ref

 

 CA 19.9

  ≤ 2× normal value

45/82

0.69

0.35

1.36

0.283

  > 2× normal value

26/57

Ref

 

Factors from the start of second-line therapy

 ECOG score

  ≥ 2

8/26

0.14

0.04

0.49

0.008

  1

21/39

0.37

0.12

1.12

 

  0

19/25

Ref

 

 Body mass index (kg/m2)

  < 18.5

11/18

1.85

0.59

5.82

0.576

  18.5–25

44/87

1.20

0.56

2.60

 

  ≥ 25

17/37

Ref

 

 CEA

  ≤ 2× normal value

30/52

0.79

0.34

1.82

0.576

  > 2× normal value

26/41

Ref

 

 CA 19.9

  ≤ 2× normal value

31/51

1.27

0.55

2.94

0.579

  > 2× normal value

22/40

Ref

 

Bold—p value < 0.05

Prognostic factors for PFS from the start of the second-line therapy

Median PFS was 2.8 months with FOLFIRI L2 and 2.1 months with ECX L2 (Fig. 1a). In univariate analysis, age ≥ 60 years and ECOG score 0/1 before L2 were the only significant good prognostic factors (Table 4).

Fig. 1

a Progression-Free Survival from the start of the second-line treatment (PFS L2). b Overall Survival from the start of the second-line treatment (L2)

Table 4

Prognostic factors for PFS after second-line therapy, univariate analysis

 

N events/N

Hazard ratio

95% Confidence interval

p value

From the start of first-line therapy

 Treatment

  ECX second line

77/81

1.17

0.86

1.58

0.312

  FOLFIRI second line

97/101

Ref

 

 Sex

  Male

127/134

1.12

0.80

1.57

0.502

  Female

47/48

Ref

 

 Tumor localization

  GEJ

71/73

1.17

0.87

1.59

0.302

  Stomach

100/106

Ref

 

 ECOG score

  1–2

99/103

0.93

0.69

1.27

0.658

  0

71/75

Ref

 

 Body mass index (kg/m2)

  < 18.5

19/19

0.85

0.51

1.43

0.674

  18.5–25

94/100

0.87

0.63

1.21

 

  ≥ 25

61/63

Ref

 

 Linitis plastica

  No

132/138

0.99

0.69

1.41

0.944

  Yes

40/42

Ref

 

 Metastasis

  No

20/20

0.86

0.54

1.38

0.540

  Yes

149/157

Ref

 

 Primary tumor resection

  No

133/138

1.23

0.86

1.77

0.255

  Yes

38/40

Ref

 

 Age

  < 60 years

91/93

1.38

1.03

1.87

0.034

  ≥ 60 years

83/89

Ref

 

 Hemoglobin

  < 12 g/dl

76/81

1.19

0.88

1.61

0.268

  ≥ 12 g/dl

95/98

Ref

 

 Neutrophils

  < 5000/mm3

70/75

0.82

0.60

1.12

0.209

  ≥ 5000/mm3

100/103

Ref

 

 Platelets

  < 300,000/mm3

87/91

0.74

0.54

1.00

0.051

  ≥ 300,000/mm3

84/88

Ref

 

 Alkaline phosphatases

  ≤ 1.5× normal value

126/130

0.94

0.66

1.34

0.737

  > 1.5× normal value

42/46

Ref

 

 CEA

  ≤ 2× normal value

101/105

1.04

0.75

1.45

0.799

  > 2× normal value

58/62

Ref

 

 CA 19.9

  ≤ 2x normal value

96/99

1.12

0.81

1.53

0.506

  > 2x normal value

63/68

Ref

 

From the start of second-line therapy

 PFS in the first line

  ≤ 6 months

98/100

Ref

0.559

  > 6 months

76/82

0.91

0.68

1.24

 

 ECOG score

  ≥ 2

36/36

3.18

1.85

5.47

< 0.001

  1

44/45

1.53

0.91

2.58

 

  0

24/27

Ref

 

 Body mass index (kg/m2)

  < 18.5

23/24

0.94

0.56

1.58

0.403

  18.5–25

102/105

1.21

0.84

1.75

 

  ≥ 25

41/45

Ref

 

 CEA

  ≤ 2× normal value

59/62

0.85

0.56

1.28

0.431

  > 2x normal value

42/45

Ref

 

 CA 19.9

  ≤ 2× normal value

53/56

0.76

0.51

1.14

0.184

  > 2× normal value

46/48

Ref

 

Bold—p value < 0.05

Prognostic factors for OS from the start of second-line therapy

The median OS was 5.4 months with FOLFIRI L2 and 4.8 months with ECX L2 (Fig. 1b). The median OS in the third quartile (subgroup of longer survivors), was 10.48 months (95% CI 8.84–12.39) for FOLFIRI in L2, and 8.02 months (95% CI 6.80–10.25) for ECX in L2. In univariate analysis, platelet count < 300,000/mm3 (p = 0.025), age ≥ 60 years (p = 0.008) and ECOG score before L2 were the only significant good prognostic factors (Table 5). In multivariate analyses, in the first model, age < 60 years at diagnosis (versus ≥ 60 years) (HR 1.49, 95% CI 1.09–2.03, p = 0.013) and in the second model ECOG score ≥ 2 before L2 (HR 2.62, 95% CI 1.41–4.84, p = 0.005) were the only significant poor prognostic factors (Table 6).

Table 5

Prognostic factors for overall survival after second-line therapy, univariate analysis

 

N death/N

Hazard ratio

95% Confidence interval

p value

From the start of first-line therapy

 Treatment

  ECX second line

74/81

1.25

0.91

1.70

0.167

  FOLFIRI second line

91/101

Ref

 

 Sex

  Male

120/134

1.21

0.86

1.70

0.285

  Female

45/48

Ref

 

 Tumor localization

  GEJ

66/73

0.91

0.66

1.25

0.554

  Stomach

97/106

Ref

 

 ECOG score

  1–2

94/103

0.96

0.70

1.32

0.812

  0

67/75

Ref

 

 BMI (kg/m2)

  < 18.5

18/19

0.90

0.53

1.53

0.779

  18.5–25

89/100

0.89

0.64

1.24

 

  ≥ 25

58/63

Ref

 

 Linitis plastica

  No

125/138

0.96

0.67

1.39

0.843

  Yes

38/42

Ref

 

 Metastasis

  No

20/20

0.96

0.60

1.54

0.871

  Yes

140/157

Ref

 

 Primary tumor resection

  No

126/138

1.24

0.86

1.80

0.257

  Yes

36/40

Ref

 

 Age

  < 60 years

87/93

1.52

1.12

2.08

0.008

  ≥ 60 years

78/89

Ref

 

 Hemoglobin

  < 12 g/dl

72/81

1.31

0.96

1.80

0.093

  ≥ 12 g/dl

90/98

Ref

 

 Neutrophils

    

0.174

  < 5000/mm3

67/75

0.80

0.59

1.10

 

  ≥ 5000/mm3

94/103

Ref

 

 Platelets

  < 300,000/mm3

81/91

0.70

0.51

0.96

0.025

 ≥ 300,000/mm3

81/88

Ref

 

 Alkaline phosphatase

  ≤ 1.5N

121/130

0.85

0.59

1.23

0.398

  > 1.5N

38/46

Ref

 

 CEA

  ≤ 2× normal value

97/105

1.01

0.72

1.41

0.951

  > 2× normal value

53/62

Ref

 

 CA 19.9

  ≤ 2× normal value

90/99

1.18

0.85

1.64

0.334

  > 2× normal value

60/68

Ref

 

From the start of second-line therapy

 PFS in first line

  ≤ 6 months

95/100

Ref

0.096

  > 6 months

70/82

0.77

0.56

1.05

 

 ECOG score

  ≥ 2

36/36

2.82

1.64

4.83

0.0003

  1

40/45

1.36

0.81

2.29

 

  0

22/27

Ref

 

 Body mass index (kg/m2)

  < 18.5

22/24

0.94

0.56

1.58

0.593

  18.5–25

95/105

1.15

0.79

1.67

 

  ≥ 25

40/45

Ref

 

 CEA

  ≤ 2× normal value

55/62

0.88

0.57

1.34

0.536

  > 2× normal value

38/45

Ref

 

 CA 19.9

  ≤ 2× normal value

47/56

0.69

0.46

1.06

0.088

  > 2× normal value

44/48

Ref

 

Bold—p value < 0.05

Table 6

Multivariate analyses for overall survival (OS) from the start of the second-line therapy, investigating factors assessed before the first-line therapy and factors assessed before the second-line therapy

 

Hazard ratio

95% Confidence interval

p value

Factors assessed before the start of first-line therapy (n = 179)

 Age at diagnosis

  < 60 years

1.49

1.09

2.03

0.013

  ≥ 60 years

Ref

 

 Hemoglobin

  < 12 g/dl

1.20

0.87

1.66

0.268

  ≥ 12 g/dl

Ref

 

 Platelets

  < 300,000/mm3

0.73

0.53

1.01

0.056

  ≥ 300,000/mm3

Ref

 

Factors assessed before the start of second-line therapy (n = 87)

 PFS in first line

  ≤ 6 months

Ref

0.372

  > 6 months

0.81

0.51

1.29

 

 ECOG score

  ≥ 2

2.62

1.41

4.84

 

  1

1.38

0.76

2.49

 

  0

Ref

0.005

 CA 19.9

  ≤ 2× normal value

0.75

0.47

1.19

0.219

  > 2× normal value

Ref

 

Bold—p value < 0.05

Discussion

Second-line treatment is seldom administered and results in all studies in limited efficacy on tumor growth. In the FFCD-0307 trial, only 43% of patients received a second-line therapy. From baseline, patients more likely to receive this second line more frequently had GEJ tumors and an ECOG score 0–1. Nonetheless, the clinical benefits were still limited, with median overall survival following the second line of around 5 months. For the second line, age ≥ 60 years and ECOG score 0/1 were the only significant good prognostic factors for OS in multivariate analyses.

The proportion of patients receiving a second line was closer to that observed in the ToGA trial (45%), than in the REAL-2 trial (14%), which illustrates the differences in clinical approaches in different centers [3, 5]. A planned second-line therapy in the FFCD-0307 may have favored the prescription of the second-line therapy. Median PFS (2.8 months with FOLFIRI L2 and 2.1 months with ECX L2) are in the same range as other published data: 2.3 months with irinotecan and 3.6 months with docetaxel [13], 2.1 months with ramucirumab alone in the REGARD trial [9], 2.9 months with paclitaxel and 4.4 months with paclitaxel combined with ramucirumab in the RAINBOW trial [10]. Median OS was 5.4 months with FOLFIRI L2 and 4.8 months with ECX L2. In other trials, median OS was 4–8.4 months with irinotecan and 9.5 months with docetaxel, 5.3 months with ramucirumab alone in the REGARD trial, 7.4 months with paclitaxel and 9.4 months with paclitaxel combined with ramucirumab in the RAINBOW trial.

Other studies have investigated prognostic factors in patients with metastatic gastric adenocarcinoma treated in the first or second line. In a large retrospective analysis, ECOG ≥ 2, bone metastases, ascitis, alkaline phosphatase > 85UI/l, albumin < 3.6 g/dl and no resected primary tumor were identified as poor prognostic factors for OS for patients receiving first-line chemotherapy [14]. In a pooled analysis of three randomized trials, ECOG ≥ 2, liver metastases, peritoneal metastases, and alkaline phosphatase ≥ 100UI/l were poor prognostic factors [15]. In second-line therapy, a retrospective analysis identified ECOG ≥ 2, hemoglobin ≤ 11.5 g/dl, CEA > 50 ng/ml, ≥ 3 metastatic sites, and time to progression ≤ 6 months under first-line treatment as independent poor prognostic factors [16]. Another retrospective study identified the following as prognostic factors in second-line chemotherapy: the PFS in the first-line chemotherapy, the performance status, serum levels of albumin and alkaline phosphatase and no resected primary tumor [17]. In a retrospective study that included 126 patients, a good performance status, a higher hemoglobin level and a longer time to progression in the first-line chemotherapy were good prognostic factors in the second-line chemotherapy [18]. More recently, a large retrospective multicenter analysis included 868 patients treated with second-line therapy. Median PFS was 2.8 months and median OS was 5.6 months. Patients received various treatments, but mostly single-agents or doublets with fluoropyrimidines, irinotecan, and taxanes. The ECOG score, an LDH level > 480UI/l, a neutrophil/lymphocyte ratio ≥ 2.7 and PFS ≤ 6.8 months in the first line were the four independent factors for poor OS [19]. In our study, PFS in L1 was not a prognostic factor (HR 0.81 95% IC 0.51–1.29). The relative efficacy of the two investigated regimen may partly explain this result, an efficient second-line therapy may be able to counterbalance a short PFS in L1 in patients in good general condition. Age (≥ 60 years or as a continuous variable) was an independent good prognostic factor for PFS and OS. In a meta-analysis comparing elderly with young patients, elderly patients had more diffuse-type cancer, but better 5-year OS [20]. There are few data in the literature about age as a prognostic factor in L2. In the study investigating prognostic factors in L2 in 868 patients, patients ≥ 40 years had a 5.8 months median OS versus 3.9 for patients < 40 years (p = 0.001 in univariate analysis), and patients ≥ 75 years had a 6.9 median OS versus 5.6 for patients < 75 (p = 0.08). However, there were no significant differences in the multivariate analysis [19]. In our study, our hypothesis is that most patients ≥ 60 years died in L1 (51%, versus 40% of patients < 60 years), leading to the selection of particularly fit elderly patients in L2. The platelet count at baseline was borderline significant in the multivariate analysis for OS (p = 0.056). The prognostic impact of thrombocytosis has also been suggested in other studies, as in the MRC-COIN trial. In this trial including patients with metastatic colorectal cancer, patients with raised baseline-platelet counts receiving intermittent chemotherapy had impaired survival and quality of life [21].

The main strength of our study is that the second-line therapy was planned in the protocol. Our study has some limits. Some data, such as lymphocyte counts and serum LDH levels, are missing from our database. The use of epirubicin in the treatment of gastric cancer is now controversial. A recent study that included 1002 patients from a national registry did not demonstrate any benefit of adding epirubicin to a platinum-fluoropyrimidine doublet chemotherapy, but greater toxicity [22]. There is a need to identify patients who will benefit from antiangiogenic drugs, but no predictive factors have been identified so far.

In conclusion, the benefits of second-line chemotherapy remain limited, with age ≥ 60 years at diagnosis and ECOG score 0/1 before the start of L2 being the only good prognostic factors in this study. Robust prognostic and predictive factors still need to be confirmed in prospective trials.

Notes

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval

All participants gave their written informed consent before inclusion in the FFCD-0307 trial. The study was approved by relevant ethics committees.

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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Y. Touchefeu
    • 1
    Email author
  • R. Guimbaud
    • 2
  • C. Louvet
    • 3
  • L. Dahan
    • 4
  • E. Samalin
    • 5
  • E. Barbier
    • 6
  • K. Le Malicot
    • 6
  • R. Cohen
    • 7
  • J. M. Gornet
    • 8
  • T. Aparicio
    • 9
  • S. Nguyen
    • 3
  • A. Azzedine
    • 10
  • P. L. Etienne
    • 11
  • J. M. Phelip
    • 12
  • P. Hammel
    • 13
  • N. Chapelle
    • 1
  • D. Sefrioui
    • 14
  • L. Mineur
    • 15
  • C. Lepage
    • 16
  • O. Bouche
    • 17
  1. 1.Gastrointestinal Oncology UnitInstitut des Maladies de l’Appareil Digestif, University HospitalNantes Cedex 1France
  2. 2.Digestive Medical Oncology IUCT RangueilCHU de ToulouseToulouseFrance
  3. 3.Oncology Multidisciplinary Research Group (GERCOR)ParisFrance
  4. 4.Digestive Oncology Unit, AP-HMLa Timone Hospital, Aix-Marseille UniversitéMarseilleFrance
  5. 5.Digestive Oncology DepartmentInstitut du Cancer de MontpellierMontpellierFrance
  6. 6.Fédération Francophone de Cancérologie Digestive-EPICAD INSERM LNC-UMR 1231University of Burgundy and Franche ComtéDijonFrance
  7. 7.Department of OncologySorbonne Université, AP-HP, hôpital Saint-AntoineParisFrance
  8. 8.Department of GastroenterologyAP-HP Hôpital Saint LouisParisFrance
  9. 9.Department of Gastroenterology and Digestive OncologySaint Louis Hospital, APHP, University Denis Diderot, Sorbonne Paris CitéParisFrance
  10. 10.Department of oncologyCH MontélimarMontélimarFrance
  11. 11.Oncology DepartmentCARIO, HPCAPlérinFrance
  12. 12.Service HGE et Oncologie Digestive, CHU de Saint EtienneUnité HESPER EA-7425 Université Jean Monnet/Claude Bernard Lyon 1VilleurbanneFrance
  13. 13.Digestive Oncology Unit, Beaujon HospitalAssistance Publique-Hôpitaux de ParisClichyFrance
  14. 14.Digestive Oncology Unit, Department of Hepato-Gastroenterology, Rouen University Hospital, UNIROUEN, Inserm U1245, IRON groupNormandie UniversityRouenFrance
  15. 15.Institut Sainte CatherineAvignonFrance
  16. 16.Gastroenterology Department, INSERM UMR1231, CHU de DijonUniversity Bourgogne Franche-ComtéDijonFrance
  17. 17.Digestive OncologyCHU REIMSReimsFrance

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