Small Cell Lung Cancer

Given the systemic nature of SCLC, chemotherapy is the keystone in the treatment. Despite the high chemosensitivity of SCLC, with an objective response achieved in approx 80% of the patients, remission is in general short, and relapses are frequently chemoresistant. Treatment strategies to prolong remission have therefore dominated clinical trials for SCLC in the past decade. The use of alternating non-crossresistant chemotherapy, maintenance chemotherapy, or dose intensification strategies were examined.

Most of the studies on rHuG-CSF and rHuGM-CSF in SCLC have concentrated on the primary administration of these agents. Far fewer data exist on the use of these CSFs in secondary prophylaxis (initiation of CSF subsequent to the occurrence of chemotherapy-induced prolonged neutropenia or FN in a previous cycle) or in the therapeutic setting (treatment of established neutropenia with or without fever).

The studies focusing on the primary administration are listed in Table 4. One group of these studies examined the question of whether the use of CSFs could reduce the incidence and consequences of chemotherapy-induced neutropenia, thereby improving

Table 4

Randomized Studies Focusing on the Primary Administration of White Blood Cell Colony-Stimulating Factors in Small-Cell Lung Cancer

Table 4

Randomized Studies Focusing on the Primary Administration of White Blood Cell Colony-Stimulating Factors in Small-Cell Lung Cancer

Primary

Attempt

Effect

Effect

Effect

Ref.

CSF

ED (%)

endpoint

to DI

on DI

Toxicity

FN

MST

2YS

92

G

72

FN

No

NA

i

i

None

na

93

G

64

FN

No

T

i

i

None

na

94

G

55

FN

No

T

i

i

None

None

95

GM

66

N

No

T

None

None

None

na

96

GM

0

N

No

i

T

NA

None

na

98

G

32

DI

T DD

None

i

na

NA

na

99

G

8

DI/FN

T DD

T

T

None

None

T

100

G

100

DI

T DD

T

i

na

T

T

101

G

100

DI

T DD

i

T

na

None

None

102

G

11

Survival

T DD

T

i

na

None

T

103

GM

100

Survival

T DS

i

T

None

i

i

104

GM

40

FN/DI

T DD

T

None

None

T

T

105

GM

92

Survival

T DD

T

T

na

None

None

106

G

43

Survival

T DS/DD

T

T

None

None

None

Abbreviations: CSF, colony-stimulating factor; G, granulocyte; GM, granulocyte-macrophage; ED, extensive disease; FN, febrile neutropenia; N, neutropenia; DI, dose Intensity; DD, dose density; DS, dose size; NA, not available; MST, median survival time; 2YS, 2-yr survival.

Abbreviations: CSF, colony-stimulating factor; G, granulocyte; GM, granulocyte-macrophage; ED, extensive disease; FN, febrile neutropenia; N, neutropenia; DI, dose Intensity; DD, dose density; DS, dose size; NA, not available; MST, median survival time; 2YS, 2-yr survival.

the acceptability of chemotherapy by reducing clinical infections (92-96). In these studies, the incidence of FN or neutropenia is the primary endpoint. Before the advent of rHuG-CSF and rHuGM-CSF, the problem of neutropenia was tackled by reduction and/or delay of the cytotoxic treatment, which may compromise the prognosis. This was shown in a randomized study done in patients with limited SCLC, in which patients were randomly assigned to what is now considered to be a rather low dose of cisplatin, cyclophosphamide, doxorubicin, and etoposide or to a regimen with a 20% increased dose of cisplatin and a 25% increased dose of cyclophosphamide, in the first cycle only (97). This relatively small difference in dose resulted in a statistically significant survival benefit for the last group (2-yr survival 43% vs 26%, p = 0.02).

Another group of studies examined whether the use of CSFs might allow an increase in dose intensity, to improve the prognosis (98-106). Dose intensity is defined as the dose per m2 per week. This dose can be increased either by increasing the dose itself (increase in dose size), by shortening the interval between cycles (increase in dose density), or both. In these strategies, the most common dose-limiting toxicity is neutrope-nia and its resultant potentially life-threatening infectious complications. It is clear that increasing the dose of a standard chemotherapy regimen or the administration of intensive weekly regimens require CSF support to avoid increased, sometimes unacceptable, toxicity. These trials have the possibility of administering an increased dose of chemotherapy or survival as primary endpoint.

Table 5

Randomized Studies on the Primary Use ofWhite Blood Cell Colony-Stimulating Factors in Standard-Dose Chemotherapy for Small-Cell Lung Cancer

Table 5

Randomized Studies on the Primary Use ofWhite Blood Cell Colony-Stimulating Factors in Standard-Dose Chemotherapy for Small-Cell Lung Cancer

Infectious

Dose

Neutropenia

Infection

episode

reduced

duration

duration

RR

MST

Ref.

No.

Chemo

Cohort

(% pts.)

(% pts.)

(d)

(d)

(%)

(mo)

92

211

CDEa

C

77

6

5

80

12.2

G

40

na

1

4

72

11.4

p < 0.001

p < 0.001

NS

NS

NS

93

130

CDEa

C

53

61

10

87

9.5

G

26

29

3

na

79

8.9

p < 0.002

p < 0.001

p < 0.001

NS

NS

94

280

CDEb

C

54

28

8

80

9.8

G

37

17

na

7

76

11.2

p = 0.004

p < 0.001

NS

NS

NS

95

283

CDEc

C

27

86

10

GM 5/10/20

25/22/36

na

na

na

58

10

NS

NS

NS

96

215

CiE +

C

27

85e

85

17

RT d

GM

42

75e

na

na

74

14

p = 0.03

p < 0.03

NS

NS

Abbreviations: C, control arm; G, arm with granulocyte CSF; GM, arm with granulocyte-macrophage CSF; NA, not available; RR, response rate; MST, median survival time.

a CDE, cyclophosphamide 1 g/m2 and doxorubicin 50 mg/m2 on d 1, etoposide 120 mg/m2 on d 1-3; G, G-CSF 230 |g/m2/d on d 4-18.

b CDE, cyclophosphamide 1 g/m2 and doxorubicin 45 mg/m2 on d 1, etoposide 100 mg/m2 on d 1-3; G, G-CSF 150 |g/m2/d on d 4-13.

c CDE, cyclophosphamide 1g/m2 and doxorubicin 40 mg/m2 on d 1, etoposide 80 mg/m2 on d 1-3; GM-CSF at 5,10, or 20 |g/kg on d 4-13.

d CiE+RT, cisplatin 25 mg/m2 and etoposide 60 mg/m2 on day 1-3; GM-CSF 250 |g/m2; chest radiotherapy 45 Gy.

e In this study, expressed as % of planned dose.

Abbreviations: C, control arm; G, arm with granulocyte CSF; GM, arm with granulocyte-macrophage CSF; NA, not available; RR, response rate; MST, median survival time.

a CDE, cyclophosphamide 1 g/m2 and doxorubicin 50 mg/m2 on d 1, etoposide 120 mg/m2 on d 1-3; G, G-CSF 230 |g/m2/d on d 4-18.

b CDE, cyclophosphamide 1 g/m2 and doxorubicin 45 mg/m2 on d 1, etoposide 100 mg/m2 on d 1-3; G, G-CSF 150 |g/m2/d on d 4-13.

c CDE, cyclophosphamide 1g/m2 and doxorubicin 40 mg/m2 on d 1, etoposide 80 mg/m2 on d 1-3; GM-CSF at 5,10, or 20 |g/kg on d 4-13.

d CiE+RT, cisplatin 25 mg/m2 and etoposide 60 mg/m2 on day 1-3; GM-CSF 250 |g/m2; chest radiotherapy 45 Gy.

e In this study, expressed as % of planned dose.

2.1.1. Primary Use of CSFs in Support of Standard-Dose Chemotherapy for SCLC

The use of rHuG-CSF in a standard three-weekly regimen of cyclophosphamide-doxorubicin-etoposide (CDE) chemotherapy has been investigated in three large, randomized, placebo-controlled phase 3 trials, in which incidence of chemotherapy-induced infection was the primary endpoint. In two of these studies, a significant reduction of the incidence of FN in the rHuG-CSF cohort was observed, 77% in the placebo groups compared with 40% in the rHuG-CSF group (p < 0.001) in one study, and 53% vs 26% in the other study (p < 0.002) (92,93) (Table 5). Secondary endpoints such as the incidence and median duration of grade 4 neutropenia and the number of hospitalization days were also significantly reduced by 50% in the rHuG-CSF group in both trials. This reduction resulted in significantly less chemotherapy delays and dose reductions in one study (93). Tumor response rate and survival were not significantly different across groups. The third randomized trial, in which a lower dose of rHuG-CSF was administered for a shorter period, had similar findings regarding the primary endpoint but did not show a reduction in the duration of neutropenia (94).

The use of rHuGM-CSF in standard chemotherapy for SCLC has been less beneficial on the incidence of FN than rHuG-CSF. In one randomized trial, 283 patients with SCLC were treated with CDE chemotherapy without or with rHuGM-CSF at different dose levels (5, 10, or 20 |g/kg) (95). rHuGM-CSF at 5 or 10 |g/kg significantly reduced chemotherapy-induced neutropenia and the duration of neutropenia in cycle 1. However, the incidence of FN in cycle 1 was not significantly changed, except for a favorable trend in the subgroup of rHuGM-CSF 10 |g/kg. In later cycles, the neutropenia nadirs were equivalent in all groups. rHuGM-CSF at dosages of 5 |g/kg (cycles 2 and 3) and 10 |g/kg (cycles 1-4) were able to increase significantly the amount of planned chemotherapy administrations and thus dose intensity, but this may have led to an observed significantly higher incidence of thrombocytopenia. Nevertheless, response rate and median survival time were not improved in the rHuGM-CSF cohort. The second randomized trial failed to demonstrate any benefit of rHuGM-CSF in 215 patients with limited SCLC receiving concomitant chemoradiotherapy (cis-platin-etoposide) with or without rHuGM-CSF (96). rHuGM-CSF reduced the number of infectious episodes, but significantly more patients had life-threatening thrombocy-topenia, more hospitalization days, more iv antibiotic administration, more nonhema-tologic toxicity, and more toxic deaths (nine vs one; p < 0.01) in the rHuGM-CSF group compared with placebo. The total dose of chemotherapy given across all six cycles was significantly smaller in the rHuGM-CSF group. It was concluded that concurrent use of rHuGM-CSF plus chemotherapy and daily radiotherapy should be avoided, as co-administration of rHuGM-CSF and radiotherapy might accelerate stem cell exhaustion.

2.1.2. Primary Use of CSF for Dose Intensification for SCLC

In a small, prospective, randomized trial, 40 patients were treated with weekly courses of dose-dense cisplatin and etoposide alternating with ifosfamide and doxorubicin, with or without rHuG-CSF (98) (Table 6). Although significantly less grade 3-4 neutropenia and dose reductions owing to neutropenia occurred in the rHuG-CSF group, this result did not contribute to a reduction in FN or an increase in received dose intensity compared with the control group. The small sample size precludes outcome analysis.

Sixty-five patients with SCLC received chemotherapy with vincristine, ifosfamide, carboplatin, and etoposide (VICE) with or without rHuG-CSF at a treatment interval determined by hematologic recovery in a slightly larger randomized trial (99). Dose intensity and incidence of FN were the primary endpoints. In both treatment groups, the received dose intensity was significantly higher than that in the standard 4-weekly VICE regimen of that center. In contrast to studies with standard CDE chemotherapy supported by rHuG-CSF, incidence of FN was not reduced in rHuG-CSF-supported, accelerated VICE chemotherapy. This finding may be explained by the high percentage of patients with limited disease in this study compared with other studies, as well as the higher dose intensity in the rHuG-CSF group. Survival analysis was an additional endpoint and showed no significant difference in median survival but a significantly better 2-yr survival rate for rHuG-CSF group.

Randomized Studies on the Primary Use ofWhite Blood Cell Colony-Stimulating Factors to Increase Dose Intensity of Chemotherapy for Small-Cell Lung Cancer

FN

Toxic

RR

MST

2YS

Ref.

No.

Chemo

Cohort

(% pts.)

deaths

DI

(%)

(mo)

(%)

98

40

CE/IDa

C

2

0.82

71

G

NA

0

0.84

74

na

na

NS

NS

NS

NS

99

65

VICEb

C

65

1

1.18

94

15

15

G

70

6

1.25

93

16

32

NS

p = 0.03

NS

NS

S

100

63

CODEc

C

4

0.72

84

7.2

6.5

G

NA

4

0.84

97

13.3

31.3

NS

p = 0.03

NS

p = 0.004

S

101

227

CE/CODd

C

9

0.82

77

10.9

8.5

CODE

I + G

19

NA

0.72

84

11.6

11.7

p = 0.031

p = 0.001

NS

NS

NS

102

403

CDEe

C

1.00

79

11

8

I + G

NA

na

1.32

78

12

13

NA

NS

NS

S

103

125

CDE-C/

C

7j

5

72

10.8

I + GM

34'

8

NA

71

8.9

na

p = 0.005

NS

NS

p = 0.0005

104

300

VICEĀ«

C

51

5

na

77

12

18

C + GM

53

5

na

78

I

55

5

na

91

15

33

I + GM

56

5

na

88

NS

NS

NS

NS

p = 0.014

S

105

233

EVIh

C

5'

5

0.87

59

9.4

5

I + GM

7'

4

0.73

76

8.7

6

I + ab

3'

3

0.61

70

8.7

6

NS

NS

NS

0.04

NS

NS

106

244

CDE''

C

24

3

0.99

79

12.5

15

I + G

34

6

1.70

84

12

18

NS

NS

S

NS

NS

NS

Abbreviations: C, control arm; AB, arm with antibiotic prophylaxis; I, dose-intensified arm; FN, febrile neutropenia; NA, not available; DI, relative dose intensity; RR, response rate; MST, median survival time; 2YS 2-yr survival; G, arm with granulocyte CSF; GM, arm with granulocyte-macrophage CSF.

a CE/ID, cisplatin 50 mg/m2 on d 1 and etoposide 75 mg/m2 on d 1-2 alternating weekly with ifosfamide 2 g/m2 and doxorubicin 25 mg/m2 on d 1; G-CSF 5 ^g/kg/d when no chemotherapy.

b VICE, carboplatin 300 mg/m2 and ifosfamide 5 g/m2 on d 1, etoposide 120 mg/m2 on d 1-2, vincristine 1 mg on d 15; G-CSF 5 ^g/kg/d from d 4 to 48 h before next cycle.

c CODE, cisplatin 25 mg/m2 weekly and vincristine 1 mg/m2 on wk 1, 2, 4, 6 and doxorubicin 40 mg/m2 + etoposide 80 mg/m2 on wk 1, 3, 5, 7; G-CSF 50 ^g/m2 on days when no chemotherapy.

d CE/COD, 3-weekly cisplatin 80 mg/m2 on d 1 and etoposide 100 mg/m2 on d 1-3 alternating with cyclophosphamide 800 mg/m2 and doxorubicin 50 mg/m2 and vincristine 1.4 mg/m2 on d 1.

e CDE, cyclophosphamide 1g/m2 and doxorubicin 40 mg/m2 on d 1, etoposide iv 120 mg/m2 on d 2-3 and etoposide po 240 mg/m2 d 4-14 either 3-weekly (standard) or 2-weekly (intensified) with G-CSF.

f CDE-C (standard), cyclophosphamide 1.2 g/m2 and doxorubicin 40 mg/m2 and etoposide 225 mg/m2 and cisplatin 100 mg/m2; CDE-C (intensified), cyclophosphamide 1.8 g/m2 and doxorubicin 60 mg/m2 and etoposide 330 mg/m2 and cisplatin 120 mg/m2; GM-CSF 5 ^g/kg/d for 10 d.

g VICE, vincristine 0.5 mg/m2 on d 15, ifosfamide 5 g/m2 and carboplatin 300 mg/m2 and etoposide 120 mg/m2 on d 1-2 every 4 (standard) or 3 (intensified) wk; GM-CSF 250 ^g/m2/d for 14 d.

h EVI, epirubicin 60 mg/m2 and vindesine 3 mg/m2 and ifosfamide 5 g/m2 on d 1 every 3 weeks (standard) or every 2 wk (intensified); GM-CSF 5 ^g/kg d 3-13; or cotrimoxazole d 3 until end of cycle.

' CDE, (standard) cyclophosphamide 1 g/m2 and doxorubicin 45 mg/m2 on d 1, etoposide 100 mg/m2 on d 1-3 every 3 wk; (intensified) cyclophosphamide 1.25 g/m2 and doxorubicin 55 mg/m2 on d 1, etoposide 125 mg/m2 on d 1-3 every 2 wk with G-CSF 5 ^g/kg/d on d 4-13. j In this study expressed as grade 3 + 4 infections.

Sixty-three patients with extensive disease SCLC were treated with weekly chemotherapy with cisplatin, oncovin, doxorubicin, and etoposide (CODE) with or without rHuG-CSF during 9 wk in a small randomized trial in Japanese patients (100). Dose intensity was the primary endpoint. The trial demonstrated a significantly higher delivered dose intensity in the rHuG-CSF-supported weekly CODE regimen. This result also significantly prolonged median and 2-yr survival rates. In a larger randomized trial, 227 Japanese patients with extensive SCLC were given weekly CODE with rHuG-CSF or standard 3-weekly cisplatin and etoposide alternating with cyclophosphamide, oncovin, and doxorubicin (101). This study could not confirm the previous results, and the received dose intensity in the weekly cohort was lower than in the standard cohort, with no significant differences in median survival or 2-yr survival rates. Patients who received the weekly CODE regimen with rHuG-CSF support had a significant higher incidence of thrombocytopenia and neutropenic fever.

Standard CDE chemotherapy given every 3 wk was compared with accelerated CDE every 2 wk with support of rHuG-CSF in a large randomized trial in 403 patients with SCLC (mainly limited disease) (102). The rHuG-CSF support in the accelerated cohort significantly increased the dose intensity by 32%, but this did not result in a difference in response rate or median survival compared with the standard cohort. Nevertheless, it led to a better survival rate in the intensified cohort, which started at approx 1 yr after treatment and was not associated with worsening of QOL.

The administration of rHuGM-CSF to dose-escalate chemotherapy in patients with SCLC has been studied in three randomized trials. In one of these, a 4-weekly standard-dose cyclophosphamide, doxorubicin, etoposide, and cisplatin (CDE-C) was compared with a 4-weekly high-dose CDE-C with rHuGM-CSF support in patients with extensive SCLC (103). It was concluded that rHuGM-CSF did not allow the delivery of a higher cumulative dose of the four-drug regimen, owing to significantly greater hematologic toxicity (grade 4 neutropenia and thrombocytopenia). Treatment outcome was significantly affected, with a median survival of 8.9 mo in the intensive cohort vs 10.8 mo in the standard cohort (p = 0.0005).

Three hundred patients were studied in a trial with a 2 x 2 factorial design with randomization between a slightly modified VICE schedule every 3 wk (intensified) or every 4 wk (standard), and between rHuGM-CSF or placebo (104). FN and dose intensification were the primary endpoints. The intensified-treatment cohort received a 26% higher dose intensity than the standard cohort, with a nonsignificant trend for greater dose intensity for those who received rHuGM-CSF. Nevertheless, the incidence of FN, blood culture-confirmed sepsis, and toxic mortality were not significantly affected by chemotherapy schedule or rHuGM-CSF use. No significant difference in response rate was seen among the four treatment groups. Median survival and 2-yr survival rate were significantly increased in the intensified cohorts compared with the standard cohorts, but not in the rHuGM-CSF group vs the placebo group. The authors concluded that there is a potential survival benefit from dose intensification but that rHuGM-CSF, compared with placebo, did not reduce the incidence of hematologic complications and had no significant impact on either response or survival.

In a three-armed, randomized study with survival as primary endpoint, a 3-weekly chemotherapy course with epirubicin, vindesine, and ifosfamide (EVI) was compared with accelerated 2-weekly EVI chemotherapy supported with rHuGM-CSF or oral antibiotics (105). The administration of EVI chemotherapy could be accelerated with rHuGM-

CSF support. The response was significantly higher in the rHuGM-CSF cohort compared with the control cohort (p = 0.04), but the study failed to demonstrate a survival benefit. In contrast to the findings of Steward et al. (104), it was impossible to accelerate chemotherapy without rHuGM-CSF support. Hematologic toxicity, consisting mainly of severe thrombocytopenia and nonsevere infections, was increased in the rHuGM-CSF cohort.

Only one randomized phase 3 trial examined the effect of dose intensification based on increasing both the dose density and dose size (106). The combined effect of increased dose (by 25%) and increased dose density (by 33%) led to a 70% increase in dose intensity. No statistically significant difference was seen in response rate, median survival time, or 2-yr survival rate. Hematologic and nonhematologic toxicity was increased: grade 4 leukopenia occurred significantly more in the intensified group (79% vs 50%), despite the use of rHuG-CSF, and the incidence of grade 3-4 thrombocytopenia and anemia was significantly higher (p = 0.001). A 70% dose increase of CDE chemotherapy thus did not lead to improved outcome in patients with SCLC.

2.1.3. Primary Use of CSF in High-Dose Chemotherapy for SCLC With Stem Cell Support

Approaches used to increase cytotoxic dose intensity can be performed not only with support of CSF, but also with sequential infusion of hematopoietic progenitors in whole blood or autologous bone marrow transplantation. Classic high-dose chemotherapy with support of autologous bone marrow transplantation has been abandoned because of excessive toxicity and conflicting results. A randomized phase

2 trial demonstrated that chemotherapy with ifosfamide, carboplatin, and etoposide can be given at a significant higher dose intensity when it is supported by rHuG-CSF injections and hematopoietic progenitor cell infusion (107). No significant difference was seen between the treatment arms in time to progression or overall survival. A sufficiently powered, randomized, phase 3 trial, with survival as primary endpoint, is needed to answer this question.

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