Famous) Kak 3

Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: The Fragmin Advanced Malignancy Outcome Study (FAMOUS) Reported by: Kakkar AK et al. J Clin Oncol. 2004;22:1944-1948.

Results: Survival at 1, 2, and 3 years after randomization was 46%, 27%, and 21%, respectively, for patients receiving dalteparin and 41%, 18%, and 12%, respectively, for patients receiving placebo (P=.19). In a post-hoc analysis, survival was examined in a subgroup of patients who had a better prognosis and who were alive 17 months after randomization. In these patients, survival at 2 and 3 years was significantly improved for dalteparin patients compared with placebo patients (78% v 55% and 60% v 36%, respectively, P=.03). Conclusions: Dalteparin did not significantly improve 1-year survival rates in patients with advanced malignancy. In a post-hoc analysis, dalteparin improved survival in patients with a better prognosis. In summary, these data suggest but do not prove that dalteparin may have a modifying effect on tumor biology.

INTRODUCTION ! Thrombosis is a complication of solid tumor malignancy and may be related to development of a systemic hypercoagulable state as a result of tumor elaboration of tissue factor ! !

In experimental models, coagulation proteases have been shown to enhance tumor cell motility, invasion, angiogenesis, and growth Heparins have multiple effects on the coagulation pathway, including release of tissue factor pathway inhibitor, an inhibitor of the tissue factor pathway

Survival ! At 1 year, survival (primary end point) was 46% and 41% in the dalteparin and placebo groups, respectively (P=.19)

RESULTS Patients ! A total of 385 patients were enrolled in the study, of whom 190 were randomized to dalteparin and 184 were randomized to placebo

!

At 2 years, survival was 27% and 18% in the dalteparin and placebo groups, respectively

!

At 3 years, survival was 21% and 12% in the dalteparin and placebo groups, respectively

The percentage of patients who received concomitant chemotherapy, radiotherapy, or surgery were 33.7%, 8.4%, and 1.6% in the dalteparin group and 31.0%, 7.6%, and 1.1% in the placebo group

!

The Kaplan-Meier survival curve for the intent-to-treat population is shown in Figure 1

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Relevant baseline characteristics of the study population are shown in table 1

Table 1. Baseline demographic and disease characteristics Characteristic

Dalteparin (n=190) n %

Age, years (median)

62.0

Female

113

Placebo (n=184) n % 60.9

59.5

100

54.3

Primary cancer diagnosis Breast

40

21.1

26

14.1

Colorectal

35

18.4

35

19.0

Ovarian

33

17.4

28

15.2

Pancreatic

18

9.5

24

13.0

Other

64

34.0

71

39.0

Well

13

7.0

17

9.4

Moderate

61

32.8

57

31.1

Poor

69

37.1

56

31.1

Not known

47

24.7

54

29.3

It is therefore reasonable to hypothesize that interference with coagulation serine proteases may influence tumor biology

!

Previous clinical studies suggest that agents that influence coagulation, including warfarin and unfractionated heparin (UFH), prolong survival in patients with small-cell lung carcinoma

I

3

1.6

1

0.5

II

3

1.6

3

1.6

In this randomized, double-blind, placebo-controlled study, the effect of dalteparin, a LMWH, on survival rates in patients with advanced malignancies was assessed

III

71

37.4

52

28.3

IV

113

59.5

128

69.6

METHODS Patients ! Adult patients with advanced stage III or IV (locally advanced or metastatic) malignant disease of the breast, lung, gastrointestinal tract, pancreas, liver, genitourinary tract, liver, ovary, or uterus were included in the study ! !

Stage

Sites with metastasis 0

29

15.3

23

12.5

1

101

53.2

117

63.6

2

49

25.8

37

20.1

3

10

5.3

6

3.3

4

1

0.5

1

0.5

Previous treatment

Patients with bleeding disorders, hypersensitivity to heparin, or low platelet counts were excluded

Chemotherapy

122

64.2

108

58.7

Radiotherapy

78

43.2

77

42.4

All patients had an expected survival period of at least 3 months from time of randomization

Surgery

105

55.3

101

55.4

Hormonal

36

18.9

25

13.6

Other

7

3.7

7

3.8

Treatments ! Patients were permitted to receive any active chemotherapy or radiotherapy !

Patients were randomized to either 1) once-daily dalteparin 5000 IU, administered subcutaneously or 2) placebo

!

Therapy was scheduled to last 1 year or until the patient died

1.0

Dalteparin Placebo

0.9

Symptomatic Venous Thromboembolism ! The rates of symptomatic venous thromboembolism were 2.4% and 3.3% for dalteparin and placebo, respectively !

CONCLUSIONS ! In the overall patient population, dalteparin did not influence survival to a significant extent !

In a subset of patients with more indolent disease (eg, those who survived beyond 17 months from randomization), dalteparin appeared to confer a survival advantage

!

These results are at least partly consistent with previous studies, in which warfarin and UFH were shown to extend survival in patients with small-cell lung cancer

!

Administration of dalteparin at a dosage of 5000 IU once daily was safe in the overall population, with only 1 episode of major bleeding observed

0.8 0.7 0.6

Median survival [months] and its 95% Cl Dalteparin: 10.8 [9.27, 13.5] Placebo: 9.14 [7.33, 11.5]

0.5

P=0.19

0.4 0.3

Bleeding rates were 4.7% and 2.7% for dalteparin and placebo patients, respectively ! There was only 1 episode of major bleeding

0.2 0.1 0.0 0

12

24

36

48

60

72

84

Time to event from randomization [months] No. at Risk: 190 184

85 72

30 15

22 9

12 8

5 5

4 2

Dalteparin Placebo

Histologic grade

!

!

Figure 1. Kaplan-Meier survival curve for all intent-to-treat population patients

Kaplan-Meier Survival Distribution Function Estimate

Methods: A total of 385 patients with advanced malignancy were randomized to receive the LMWH dalteparin or placebo for 1 year.

Outcome measures ! The primary outcome measure was mortality after 1 year of therapy

!

In a post-hoc analysis, survival was examined in a subgroup of patients who had a better prognosis and who were alive 17 months after randomization ! In these patients, survival at 2 and 3 years was significantly improved for dalteparin patients compared with placebo patients (78% v 55% and 60% v 36%, respectively, P=.03) ! The median survival time in the dalteparin group was 43.5 months, compared with 24.3 months in the placebo group ! The Kaplan-Meier survival curve for this population is shown in Figure 2

Figure 2. Kaplan-Meier survival curve for the subgroup of patients with a better prognosis (those who survived beyond 17 months after randomization)

Kaplan-Meier Survival Distribution Function Estimate

ABSTRACT Background: In experimental models, interference with coagulation appears to affect tumor biology. In this study, the effect of dalteparin, a low-molecular weight heparin (LMWH), on survival rates in patients with advanced malignancies was assessed.

1.0

Dalteparin Placebo

0.9 0.8 0.7 0.6

Median survival [months] and its 95% Cl Dalteparin: 43.5 [33, 52.3] Placebo: 24.3 [22.4, 41.5]

0.5

P=0.03

0.4 0.3 0.2 0.1 0.0 17

23

29

35

41

47

53

59

65

71

77

83

Time to event from randomization [months] No. at Risk: 55 47

31 17

26 10

22 9

20 9

13 8

8 8

5 5

5 3

5 2

3 0

Dalteparin Placebo

For educational purposes only. These were not prepared or reviewed by the primary author.