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Keywords:

  • COX-2;
  • cyclooxygenase;
  • prostate cancer;
  • PSA;
  • recurrence

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

OBJECTIVES

To evaluate the efficacy of the cyclooxygenase (COX)-2 inhibitor celecoxib in prostate-specific antigen (PSA) recurrent prostate cancer after definitive radiation therapy (RT) or radical prostatectomy (RP), as recent evidence showed that COX-2 inhibitors have potent antitumour activity in prostate cancer both in vitro and in vivo but there are no human trials.

PATIENTS AND METHODS

Twelve patients who had biochemical relapse after RT or RP were treated with celecoxib 200 mg twice daily. Follow-up PSA levels to assess efficacy were obtained at 3, 6 and 12 months after initiating treatment. Data were evaluated by calculating PSA doubling times and the slope of the curve of logPSA vs time, to assess rate of PSA rise before and after celecoxib treatment for each patient. Serum testosterone levels were also measured.

RESULTS

Eight of the 12 patients had significant inhibition of their serum PSA levels after 3 months of treatment; five had a decline in their absolute PSA level and three a stabilization of the level. Of the remaining four patients, three had a marked decrease in their PSA doubling time, with a mean increase (i.e. slowing) of 3.1 times that before treatment. The short-term responses at 3 months also continued at 6 and 12 months. From the slope of log PSA vs time there was a significant flattening of the rate of PSA rise (P = 0.001). There was a significant change of patients with rapid doubling times towards slower doubling times or even stable/declining PSA values after treatment with celecoxib (P = 0.029). There was no significant change in testosterone levels, suggesting an androgen-independent mechanism.

CONCLUSIONS

COX-2 inhibitors may have an effect on serum PSA levels in patients with biochemical progression after RT or RP. These results suggest that COX-2 inhibitors may help to delay or prevent disease progression in these patients, and thereby help extend the time until androgen deprivation therapy. Further study with more patients is currently underway to better evaluate the clinical potential of COX-2 inhibitors as an antitumour agents in prostate cancer.


Abbreviations
COX

cyclooxygenase

RT

radiation therapy

RP

radical prostatectomy.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Cyclooxygenase (COX)-2 is an inducible protein that catalyses the synthesis of prostaglandins from arachidonic acid. Aberrant or increased expression of COX-2 has been implicated in the pathogenesis of many diseases, including carcinogenesis. COX-2 expression is increased in association with decreased apoptosis, increased tumour invasiveness, immunosuppression and angiogenesis [1–8]. Furthermore, increased COX-2 expression correlates with poor differentiation, increased tumour size, increased nodal and distant disease, and decreased overall survival in a variety of cancers [7,9–11]. The precise in vivo mechanisms for the effect of COX-2 on tumour growth have not been determined, but may include influences on tumour angiogenesis or immune-mediated growth [1–8].

COX-2 inhibitors have been shown to have antitumour activities in human colon, breast, lung and prostate cancer tissues. Epidemiological and clinical data on the potential antitumour effects of COX-2 inhibitors have been best described for colon cancer, suggesting both a therapeutic and chemopreventive role. More recent studies have shown that COX-2 inhibitors may also have a role in prostate cancer. COX-2 expression is increased in prostate cancer tissue, with consistently high levels in lymph node metastasis, suggesting that in the prostate COX-2 may act early in tumour promotion and progression [12,13]. In prostate cancer cell lines, COX-2 is expressed in both androgen responsive (LNCaP) and androgen resistant (PC-3) cell lines, and exposure to COX-2 inhibitors results in the induction of apoptosis [14,15]. Some investigators have suggested that apoptosis occurs via down-regulation of bcl-2 (in LNCaP cell lines), while others have suggested a bcl-2-independent mechanism involving Akt inactivation in prostate cancer cell lines, including PC-3 [14,15]. More recently, in vivo studies on nude mice models injected with PC-3 cells have shown clearly that selective COX-2 inhibition has a dramatic antitumour effect, resulting in a more than 10-fold reduction in tumour surface area (93% reduction). This effect occurred via a combination of induction of tumour cell apoptosis and a downregulation of tumour vascular endothelial growth factor [4].

Whereas the precise mechanism remains under investigation, the clinical potential of COX-2 inhibitors as an antitumour medication in prostate cancer is promising. Selective COX-2 inhibitors are safe, nontoxic agents, first earning USA Food and Drug Administration approval in 1998. The ability of such drugs to selectively inhibit COX-2 (vs traditional NSAIDs which provide both COX-1 and COX-2 inhibition) allows for the specific anti-inflammatory benefits without the associated toxicity (gastrointestinal, renal, bleeding), which is derived from COX-1 inhibition. Currently available COX-2 inhibitors (celecoxib, rofecoxib and valdecoxib) are readily available as tablets taken in a once or twice daily dosing regimen. Long-term use (in arthritis or as a chemopreventive for colon cancer) has not been shown to have any adverse side-effects. These medications may provide a simple and safe alternative for both the treatment and prevention of prostate cancer.

Thus the present study was a pilot investigation to evaluate the efficacy of COX-2 inhibitors in PSA-recurrent prostate cancer after definitive radiation therapy (RT) or radical prostatectomy (RP).

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The 12 patients included in the study had had previous treatment with definitive RT (≥55 Gy, three) or RP (nine) for clinically localized disease (clinical stage T1 or T2). All patients had evidence of biochemical failure within 5 years (range 6–42 months) after definitive treatment, as (i) detectable and rising PSA levels after surgery (at least two values above the residual cancer detection limit of the assay), or (ii) at least two rising values of > 1 ng/mL or at least three rising values at any level after RT. Patients may have received neoadjuvant hormonal therapy, but not > 6 months and not within 6 months of entry into the study. Two men who had had salvage RT after surgery and who had further evidence of biochemical progression were included. Patients may have been on dietary treatments for prostate cancer, but were not taking any NSAIDs.

Patients who had received any adjuvant treatment (chemotherapy, hormonal therapy for > 6 months) after definitive RP or RT (except for salvage RT after surgery and except for neoadjuvant hormonal therapy as described above) were excluded. Patients with a contraindication or allergy to COX-2 inhibitors were also excluded.

The 12 patients has PSA levels of 0.8–19.4 ng/mL before taking celecoxib; they were treated with celecoxib 200 mg twice daily in an open-label, unblinded trial. PSA levels were measured to assess efficacy at 3, 6 and 12 months after starting treatment. Serum testosterone levels were also measured in 11 patients to confirm an androgen-independent mechanism of the COX-2 effect.

PSA outcome was evaluated in two ways: (i) the change in response with time, i.e. the slope of the line of logPSA vs time (days) before and at each sample time after treatment, and (Fig. 1); and (ii) as a change in the calculated PSA doubling time before and after treatment. The PSA doubling time was calculated as log2 × t/[log(final PSA) – log(initial PSA)][16]. The PSA doubling times and slopes of logPSA vs time after therapy were compared to those before for each patient descriptively, categorizing patients by high (<6 months), moderate (6–12 months) or slow (>12 months) PSA doubling time, or as a stable/declining absolute value before and after treatment.

image

Figure 1. A plot of the slope of logPSA vs time (× 0.001) before and at 3, 6 and 12 months from starting celecoxib. The slopes at the three times were significantly different from baseline (P < 0.001) by nonparametric one-way anova.

Download figure to PowerPoint

The nonparametric Jonckheere-Terpstra method was used to test for ordered differences among categories. With this test the null hypothesis is that the distribution of the response does not differ across ordered categories [17]. The nonparametric Wilcoxon signed-rank test was used on calculated paired difference scores and the sets of logPSA difference scores. All P values reported were adjusted using the Bonferroni method to account for multiple testing or comparisons.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Before initiating treatment no patient had a stable PSA level and seven had a PSA doubling time of < 6 months. At 3 months after starting treatment, eight patients had a decrease in their rate of PSA progression; five had an absolute decrease and three stabilization of their PSA values. Of the remaining four patients, three had substantial slowing in their PSA doubling time (i.e. an increase in their PSA but at a slower rate; mean increase 3.8-fold; range 2.0–5.7-fold). Only one had no change in the PSA doubling time.

At 6 months, five had a decrease or stabilization in their absolute PSA values vs before celecoxib; of the remaining seven the mean increase in PSA doubling time (calculated from the onset of treatment until the 6-month sample) was 2.8-fold (range 1.6–7.5). At 12 months one of the men had a decrease or stabilization of his absolute PSA value vs before celecoxib. Of the remaining 11 patients, eight had a PSA doubling time that was >1 year. The mean increase in PSA doubling time (calculated from onset of treatment until 12 months) was 4.0-fold (range 1.3–15.3).

PSA doubling time was assessed over the three sample times by categorizing the 12 patients as having a high, moderate or slow doubling time, or as a stable/declining absolute value before and after treatment. Table 1 shows the number in each category; there was a significant change from high and moderate to slow or stable/declining which was highly significant at all three sample times (P = 0.001, 0.022 and 0.029, respectively). The median PSA doubling time for all patients before treatment was 227 days, and this is reflected in most having high or moderate PSA doubling times. After treatment the doubling times clearly changed to slow or stable/declining at all three times. Table 1 also shows the mean and median slope of the logPSA vs time plots, categorized for each sample time; the differences were statistically significant at all.

Table 1.  The PSA doubling times of the 12 patients categorized by high, moderate or slow, or as a stable/declining absolute value before and after treatment. There was a significant redistribution from high and moderate to slow or stable/declining at 3, 6 and 12 months; the mean and median slope of the logPSA vs time (× 0.001) for the patients, categorized by before vs 3, 6 and 12 months is also listed; the differences were statistically significant at all three times (P = 0.001 and < 0.001, respectively)
CategoryTime
Before3612
High7111
Moderate2142
Slow3228
Stable/declining0851
Mean (median) slope of PSA vs time1.8 (1.8)0.2 (0)0.5 (0.5)0.5 (0.4)

There was no significant change in serum testosterone levels from before to after treatment in the 11 patients evaluated at 3 and 6 months, suggesting an androgen-independent mechanism for COX-2.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Despite improved cure rates with definitive therapy for clinically localized prostate cancer, it is estimated that up to half of patients will develop biochemical relapse (i.e. a detectable and rising serum PSA level) after surgery or RT [18–20]. Such patients with biochemical recurrence and who do not yet have clinical signs of relapse currently represent a substantial and growing group population among those with prostate cancer.

Currently there are no clear effective treatment options for patients with rising PSA levels after definitive RT or surgery. The use of chemotherapy in prostate cancer has been uniformly disappointing in both a primary or adjuvant role [21]. The lack of efficacy, combined with the toxicity of treatment, has made the use of chemotherapy in this setting only investigational. Furthermore, early hormonal (i.e. androgen-ablation) therapy in these patients has not been shown to affect disease progression, survival or quality of life, and may unnecessarily expose patients who are otherwise asymptomatic to the side-effects of hormonal therapy [21]. Currently many of these patients are simply watched expectantly until they develop clinically symptomatic or widely metastatic disease, when hormonal therapy is instituted. Therapeutic alternatives which are simple and not toxic but effective clearly need to be identified; COX-2 inhibitors may represent such an alternative for these patients.

In the present pilot study the COX-2 inhibitor celecoxib was used to treat patients with PSA recurrent prostate cancer after definitive RT or RP. The goal of such treatment is to help to delay or prevent disease progression in these patients, and thereby extend the time until androgen deprivation therapy. Extending the time between biochemical recurrence and clinical recurrence might thereby help to preserve the quality of life in these patients. In addition, slowing the PSA rise may also have some effect on patient survival.

The present results suggest that there was some inhibition of the logarithmic rise in PSA with celecoxib, at least in the short term. Eight of the 12 patients had significant inhibition of their serum PSA levels after 3 months of treatment. Indeed, five had a decline in their absolute PSA value, another three had stabilization of their PSA level and three had a dramatic slowing of their PSA doubling time, with a mean increase in doubling time of over three-fold from the initial value. The short-term responses at 3 months also continued at 6 and 12 months of treatment. Similarly, the slope of logPSA vs time was significantly flatter. Table 1 shows the effect of celecoxib on PSA in more clinically relevant terms; there was a significant redistribution of patients with rapid doubling times to slower doubling times or even stable/declining PSA values after treatment. Again, these results suggest an inhibition of PSA rise with treatment.

This pilot trial represents the first report of the clinical use of COX-2 inhibitors for treating prostate cancer, but the results should be interpreted cautiously for several reasons. First, there were few patients; although all had biochemically progressive disease before treatment, it is conceivable that some degree of PSA variability (either physiological or intra-assay) might affect the interpretation of the drug effect, and that this influence might be magnified with so few patients. Second, the follow-up was relatively short; truly beneficial effects of such an agent would potentially come from long-term treatment, thereby delaying the time to progression of clinically symptomatic disease. Third, the extrapolation of short-term PSA effects to long-term clinical outcome should always be cautious. Although PSA levels have correlated with disease burden and PSA doubling times correlated with disease progression and the development of metastatic disease, the ability of a treatment to affect such PSA endpoints does not necessarily constitute a long-term beneficial clinical response. As a result the beneficial antitumour effects of celecoxib should not be overestimated, based on this pilot study alone.

Nevertheless, the results suggest a consistent inhibition of PSA progression, apparent in all but one of the patients treated, suggesting a drug effect on PSA level. The effects were considered substantial for the slowing of the rate of PSA rise in the short-term; indeed, over half the treated patients had a stabilization or even a decline in their absolute PSA value. If the effect were a result of PSA variability alone a beneficial effect would be expected in only half the patients and mean doubling times should remain unchanged. As a result, the present findings warrant further investigation in more patients and with a longer biochemical and clinical follow-up; such a trial is currently underway.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
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