Clinical application of DT and SGR Discordant results

Mehrara retrieved data from two previously published clinical studies [70]. The first by Guess et al. [38] Table 1 who studied the effect of modified citrus pectin (MCP) on PSA-DT of 12 prostate cancer patients. Mehrara extracted data and analyzed for both PSA-DT and PSA-SGR before and after therapy. The difference between PSA-DT before and after treatment was not found to be statistically significant by the paired t-test (p = 0.27). Nevertheless, when transforming PSA-DT to PSA-SGR the difference before and after MCP treatment is statistically significant by the paired t-test (p = 0.003) and nonparametric Wilcoxon matched pairs signed rank test: p = 0.002. Thus, a therapy initially deemed ineffective by PSA-DT analysis, when analyzed for a group of patients based on PSA-SGR proved to be highly significant Table 1.

Effect of modified citrus pectin (MCP) on PSA-DT and PSA-SGR

Patient

Before Rx PSA-DT (mo)

After Rx PSA-DT (mo)

Before Rx PSA-SGR (%/mo)

After Rx PSA-SGR (%/mo)

A

3.97

13.34

17.46

5.16

B

5.67

10.11

12.22

6.86

C

1.14

2.91

60.80

23.82

D

3.37

7.71

20.57

8.99

E

1.58

16.49

43.87

4.20

F

10.5

7.97

6.60

8.70

G

2.66

11.95

26.06

5.80

H

3.64

3.27

19.04

21.20

I

2.04

4.96

33.98

13.97

J

2.33

3.24

29.75

21.39

K

6.29

-155.49

11.02

-0.45

L

5.12

-645.51

13.54

-0.11

Nonparametric Wilcoxon matched pairs signed Nonparametric Wilcoxon matched pairs signed

rank: p = 0.42

rank: p

= 0.002

Parametric Paired t-test

p = 0.2704

Parametric Paired t-test p = 0.0027

Table 1. Guess et al. [38] studied the effect of modified citrus pectin (MCP) on PSA-DT of 12 prostate cancer patients. Mehrara extracted that data and analyzed both PSA-DT and PSA-SGR before and after therapy. The difference between PSA-DT before and after treatment was not statistically significant by the paired t-test (p = 0.27). Nevertheless, when transforming PSA-DT to PSA-SGR the difference before and after MCP treatment is statistically significant by the paired t-test (p = 0.003) and nonparametric Wilcoxon matched pairs signed rank test: p = 0.002.

Table 1. Guess et al. [38] studied the effect of modified citrus pectin (MCP) on PSA-DT of 12 prostate cancer patients. Mehrara extracted that data and analyzed both PSA-DT and PSA-SGR before and after therapy. The difference between PSA-DT before and after treatment was not statistically significant by the paired t-test (p = 0.27). Nevertheless, when transforming PSA-DT to PSA-SGR the difference before and after MCP treatment is statistically significant by the paired t-test (p = 0.003) and nonparametric Wilcoxon matched pairs signed rank test: p = 0.002.

A second analysis of original data by Nishida et al. (1999) [78] was based on a study of the correlation of tumor volume and the CA19-9 tumor marker of pancreatic cancer patients Ta ble 2. The correlation between CA19-9-DT and tumor volume-DT was statistically significant (p<0.0001). However, after converting tumor-volume-DT to TV-SGR and CA19-9-DT to CA19-9-SGR, correlation between CA19-9-SGR and TV-SGR was no longer statistically significant (p>0.3). Since SGR is the preferred parameter, the initial analysis of Nishida may benefit from a second look.

Relationship between CA19-9-DT and TV-DT vs. CA19-9-SGR and TV-SGR

Patient

CA19-9 DT (Days)

Tumor-DT (Days)

CA19-9-SGR %/day

Tumor-SGR %/day

A

8.3

34.8

8.4

2

B

39.7

44.6

1.7

1.6

C

46.3

34.5

1.5

2

D

36.5

21.2

1.9

3.3

E

30.4

47.7

2.3

1.5

F

67.1

112.8

1

0.6

G

44.7

70.6

1.6

1

H

24.7

18.4

2.8

3.8

I

42.7

50.6

1.6

1.4

J

137.5

231.6

0.5

0.3

K

42.3

39.3

1.6

1.8

Linear regression: i

'2 = 0.89

Linear regression:

r2 = 0.09

p < 0.0001

p = 0.37

Table 2. This table displays the extracted data from Nishida's study [78] of the correlation of tumor volume and the CA19-9 tumor marker of pancreatic cancer patients. The correlation between CA19-9-DT and tumor volume-DT was statistically significant (p<0.0001). However, after converting tumor-volume-DT to TV-SGR and CA19-9-DT to CA19-9-SGR, correlation between CA19-9-SGR and TV-SGR was no longer statistically significant (p>0.3).

Table 2. This table displays the extracted data from Nishida's study [78] of the correlation of tumor volume and the CA19-9 tumor marker of pancreatic cancer patients. The correlation between CA19-9-DT and tumor volume-DT was statistically significant (p<0.0001). However, after converting tumor-volume-DT to TV-SGR and CA19-9-DT to CA19-9-SGR, correlation between CA19-9-SGR and TV-SGR was no longer statistically significant (p>0.3).

Most prostate cancer studies employ changes in the PSA-DT. PSA-DT values are not normally distributed and thus not readily subject to more sensitive parametric statistical analysis. However, PSA-specific growth rate is normally distributed and parametric statistics can be applied. Nonparametric statistical methods lose discriminatory power especially for clinical studies of smaller groups of patients [77].

During a cursory review of the literature we found two additional studies, one dealing with the effects of celecoxib on PSA-DT Figure 11 and the other investigating the effects of a combination of calcitriol and naproxin on PSA-DT of prostate cancer patients Figure 12.

Smith et al. [79] Figure 11 studied the biologic activity of celecoxib, a selective cyclooxyge-nase-2 inhibitor, in men with recurrent prostate cancer using change in PSA-DT as the primary outcome variable. We carefully extracted the data from his graphic report. We applied the Wilcoxon matched-pairs signed rank test [two tailed] (for nonparametric distribution of

PSA-DT) to the data. PSA-DT before versus after celecoxib was highly significant: p = 0.0006. After transformation of PSA-DT to PSA-SGR, the Paired t-test [two tailed] for parametric distribution of PSA-SGR suggests that the celecoxib effect lacked statistical significance p = 0.213!

A second study by Srinivas [80] Figure 12 evaluated naproxen in combination with calcitriol in patients with early recurrent prostate cancer. All patients received 45 |g of calcitriol (DN101, Novacea, South San Francisco, CA, USA) orally once a week with naproxen 375 mg twice a day and were evaluated for a biochemical PSA response and a change in PSA doubling time (PSA-DT). Testing the efficacy of the combination therapy using changes of PSA-DT by the non-parametric Wilcoxon matched-pairs signed rank test [two tailed] p = 0.037 a significant difference. However, after transforming PSA-DT to PSA-SGR (SGRpsa = ln(2)/ DTpsa), analysis with the parametric Paired t-test [2-tailed] indicate naproxen plus calcitriol was not effective in slowing tumor growth, p = 0.213.

c

50

O OOO

E

E o

40

O

30

0

O

.a

20 10

O

O o

0 0

£L

0

5

10 15

20 25 30 35 40 45 50

Pre-therapy baseline PSA-DT (months)

Figure 11. Smith et al. [79] studied the biologic activity of celecoxib, a selective cyclooxygenase-2 inhibitor, in men with recurrent prostate cancer using change in PSA-DT as the primary outcome variable. We retrieved their graphic data for our own analysis. A histogram of the PSA-DT paired differences for before and after celecoxib appears normally distributed. Applying the parametric Paired t-test statistic for significance of the difference yields p = 0.0002. Next, we transformed the same (before-after celecoxib PSA-DT data with to PSA-SGR before and after pairs and applied the paired t-test. Contrary to the statistical analysis for celecoxib induced change of PSA-DT, changes of PSA-SGR revealed that the celecoxib difference was no longer significant, p = 0.213!

Figure 11. Smith et al. [79] studied the biologic activity of celecoxib, a selective cyclooxygenase-2 inhibitor, in men with recurrent prostate cancer using change in PSA-DT as the primary outcome variable. We retrieved their graphic data for our own analysis. A histogram of the PSA-DT paired differences for before and after celecoxib appears normally distributed. Applying the parametric Paired t-test statistic for significance of the difference yields p = 0.0002. Next, we transformed the same (before-after celecoxib PSA-DT data with to PSA-SGR before and after pairs and applied the paired t-test. Contrary to the statistical analysis for celecoxib induced change of PSA-DT, changes of PSA-SGR revealed that the celecoxib difference was no longer significant, p = 0.213!

Figure 12. Sinivras and Feldman [80] evaluated naproxen in combination with calcitriol in patients with early recurrent prostate cancer. All patients received 45 |jg of calcitriol (DN101, Novacea, South San Francisco, CA, USA) orally once a week with naproxen 375 mg twice a day and were evaluated for a biochemical PSA response and a change in PSA doubling time (PSA-DT). Applying the paired t-test for statistical significance (before PSA-DT and after PSA-DT) resulted in p = 0.034. Nevertheless, after transforming PSA-DT to PSA-SGR (PSA-SGR = ln(2)/PSA-DT), analysis with the paired t-test [2-tailed] suggested naproxen plus calcitriol was not effective in slowing tumor growth, p = 0.213.

Figure 12. Sinivras and Feldman [80] evaluated naproxen in combination with calcitriol in patients with early recurrent prostate cancer. All patients received 45 |jg of calcitriol (DN101, Novacea, South San Francisco, CA, USA) orally once a week with naproxen 375 mg twice a day and were evaluated for a biochemical PSA response and a change in PSA doubling time (PSA-DT). Applying the paired t-test for statistical significance (before PSA-DT and after PSA-DT) resulted in p = 0.034. Nevertheless, after transforming PSA-DT to PSA-SGR (PSA-SGR = ln(2)/PSA-DT), analysis with the paired t-test [2-tailed] suggested naproxen plus calcitriol was not effective in slowing tumor growth, p = 0.213.

The non-linear relationship between the SGR and DT may be responsible for erroneous interpretations of treatment effects reported in prior prostate cancer trials that published results solely in terms of changes in PSA-DT Figure 10.

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