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Originally published as JCO Early Release 10.1200/JCO.2005.11.111 on February 28 2005

Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3352-3357
© 2005 American Society of Clinical Oncology.
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Effect of Docetaxel in Patients With Hormone-Dependent Prostate-Specific Antigen Progression After Local Therapy for Prostate Cancer

Susan Goodin, Patrick Medina, Terry Capanna, Weichung J. Shih, Sybil Abraham, Jessica Winnie, Susan Doyle-Lindrud, Mary Todd, Robert S. DiPaola

From the Department of Medicine, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School; Division of Biostatistics, The Cancer Institute of New Jersey; The Dean and Betty Gallo Prostate Cancer Center; Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ

Address reprint requests to Robert S. DiPaola, MD, The Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08901; e-mail: dipaolrs{at}umdnj.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors’ Disclosures of...
 REFERENCES
 
PURPOSE: To evaluate docetaxel in the treatment of patients with early-stage prostate cancer with prostate-specific antigen (PSA) progression after local therapy without androgen ablation therapy.

PATIENTS AND METHODS: Twenty-five patients with adenocarcinoma of the prostate with PSA progression despite local therapy were treated with 70 mg/m2 docetaxel every 21 days. Treatment was planned for eight cycles. Patients were followed up for effects on PSA, testosterone, and toxicity.

RESULTS: Twenty-three of 25 patients completed at least one full cycle of therapy. Ten (43%) of 23 patients demonstrated a decrease in PSA by ≥ 50% for at least 4 weeks. The nadir decrease in PSA occurred beyond 150 days of therapy in most patients. Therapy was well tolerated. Grade 4 neutropenia with fever occurred in only six cycles (4.5%). Two patients required 25% dose reductions, both occurring with cycle 6, secondary to increased transaminases in one patient, and grade 3 lacrimation in the other patient. Two patients were removed after the first cycle of therapy due to toxicity (deep venous thrombosis, chest palpitations). Mean testosterone levels were not reduced in 17 patients assessed before and during therapy (P = .12).

CONCLUSION: This study demonstrated the activity of docetaxel alone, without androgen ablation, in patients with PSA progression after completion of local therapy. Treatment with docetaxel in this population with early disease progression was well tolerated, biochemically active, and was not androgen ablative. Accrual to national phase III studies in early disease is now critical and should be strongly encouraged to determine the ability of early chemotherapy to improve survival.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors’ Disclosures of...
 REFERENCES
 
One in six men will be diagnosed with prostate cancer, and one in 30 will die of prostate cancer in their lifetime.1 Androgen deprivation is only temporarily effective secondary to the development of tumor resistance.2 Following androgen deprivation therapy, we are limited in our treatment options by noncurative chemotherapy regimens secondary to the development of additional molecular mechanisms of resistance.3-9 Since many known mechanisms of chemotherapy resistance increase as cancer progresses, a treatment approach that targets prostate tumors early, before hormonal therapy, may result in an improved outcome.

Few studies have assessed chemotherapy in patients with hormone-sensitive prostate-specific antigen (PSA) progression without metastatic disease. In a prior study, we treated hormone-naive patients and patients with PSA progression with mitoxantrone and demonstrated that mitoxantrone is well tolerated and decreased PSA in this population of patients.5 Although active, all patients eventually progressed, and we concluded that newer agents should be tested. In fact, docetaxel has been recently studied for the treatment of hormone-refractory metastatic prostate cancer (HRPC), with improvement in survival over mitoxantrone in phase III studies.6-8 In the current study, we tested the hypothesis that docetaxel would demonstrate biochemical activity and be well tolerated in patients with hormone-sensitive micrometastatic disease, which could support and encourage the approach of testing docetaxel-based chemotherapy in phase III studies in this earlier-stage patient population. To test this hypothesis, we treated patients with PSA progression after local therapy before metastasis and assessed for toxicity and biochemical response. Of additional importance, we tested serum testosterone levels to determine if this cytotoxic agent would induce androgen ablation in this hormone sensitive population.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors’ Disclosures of...
 REFERENCES
 
Patients
Patients with histopathologically proven adenocarcinoma of the prostate, with tumors limited to the prostate (no radiographic evidence of metastatic disease) who completed local therapy and had an elevated PSA after surgery or rising PSA after radiation therapy without any androgen ablation therapy were eligible. Patients with prior surgically resected T3 or stage D1 disease were eligible. PSA values for patients after surgery were greater than 2 ng/mL, determined by two measurements, at least 1 month apart. The PSA value for patients after radiation therapy was greater than 7 ng/mL with a velocity of at least 0.4 ng/mL/mo, determined by two values, each at least 1 month apart. Patients may not have received prior androgen ablation, except in the neoadjuvant setting, and must have been off therapy for at least 3 months. Other inclusion criteria were: WBC count ≥ 3,500/µL and a platelet count ≥ 100,000/µL; normal liver function tests defined as total bilirubin below the upper limit of normal (ULN) and transaminases (AST, ALT) ≤ 2.5 x the ULN; an estimated life expectancy of at least 6 months; and an Eastern Cooperative Oncology Group (ECOG) performance status less than 2. Full recovery from any effects of surgery or radiation therapy was required. We excluded patients with active infections, patients with unstable or coexisting medical or social conditions precluding full compliance with the study, or HIV-positive patients who met the Centers for Disease Control and Prevention criteria for AIDS. Patients were also excluded if prior irradiation included more than 30% of the marrow-containing skeleton, if they had ≥ grade 2 peripheral neuropathy, if they received an investigational drug within 3 weeks of registration, or if there was any known contraindication or hypersensitivity reaction to dexamethasone, polysorbate 80, or Escherichia coli–derived products. The study was reviewed and approved by the institutional review board of the University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, and all patients signed written informed consent.

Evaluations
Pretreatment evaluation included a complete history, physical examination, ECOG performance status determination, body-surface area, full staging studies (chest radiograph, computed tomography scan of the abdomen if abnormal liver function tests were present), bone scan, measurement of serum PSA, serum testosterone, serum biochemistry, and CBC. Patients returned to the clinic weekly for a CBC. On day 1 of each 3-week cycle, patients were re-evaluated and assessed for performance status, toxicity, serum biochemistry, CBC, and a PSA. All other tests and evaluations were performed as clinically necessary.

Treatment Plan
Patients received docetaxel (Taxotere; Aventis, Bridgewater, NJ) 70 mg/m2 as a 1-hour infusion every 3 weeks on day 1. All patients received dexamethasone 8 mg twice daily starting 1 day before the docetaxel infusion and continuing for 2 additional days. Each cycle was 3 weeks in duration. Treatment was continued for eight cycles unless there was documented disease progression or patients experienced toxicity requiring removal from the trial.

Dose Modifications
Chemotherapy was held in patients with an absolute neutrophil count less than 1,500/µL or platelets less than 100,000/µL on day 1 of the cycle. Patients with grade 4 (according to the National Cancer Institute Common Toxicity Criteria version 2.0, revised April 30, 1999) neutropenia for ≥ 7 days, or grade 4 neutropenia or leukopenia associated with fever (one reading of oral temperature > 38.5°C, or three readings of oral temperature > 38.0°C in a 24-hour period) were treated on subsequent cycles with the same dose but with the administration of prophylactic filgrastim (Neupogen; Amgen, Thousand Oaks, CA) 5 µg/kg. Grade 1, 2, and 3 myelosuppression (leukopenia, neutropenia, thrombocytopenia) and grade 4 leukopenia or neutropenia except as previously defined, did not require a dose reduction when recovery was within 21 days.

Patients who developed abnormal liver functions for any reason required a dose adjustment. Patients with a bilirubin less than the ULN and transaminases 1.6 x to 5 x the ULN required a dose reduction of docetaxel by 25%. A dose was held for up to 3 weeks if the bilirubin was greater than ULN or transaminases were greater than 5 x ULN. When the liver enzymes recovered, the docetaxel dose was reduced by 25%. A maximum of two dose reductions per patient, for any reason, was allowed.

Criteria for Response
Biochemical response was determined by the measurement of patient’s PSA every 3 weeks while receiving therapy. A complete biochemical response was defined as normalization of PSA maintained for 1 month in patients with a prior history of radiation or prior prostatectomy. A partial biochemical response was defined as a reduction of PSA by 50% and maintained for at least 4 weeks. An increase in PSA of less than 25% was considered stable disease. Disease progression was defined as an increase in PSA greater than 25%.

Statistical Analysis
This study had a two-stage design based on a modified Simon’s method, in which the maximal sample size was 14 for the first stage.9 Although the initial design was planned for 30 total patients, response was sufficient after 11 additional patients in the second stage (total of 25) for 80% power to test the hypothesis that the PSA response rate was ≥ 30%. Log (PSA) linear relationship with time was fitted using a mixed-effects model with intercept and slope as the random effects, and time as the fixed effect. The estimated doubling time (when slope was positive) or halving time (when the slope was negative) = (log2)/b, where b was the estimated slope. The random effects covariance matrix is chosen as unspecified. This model provides the average estimate of intercept and slope. The standard deviation (SD) of the doubling time (DT) or halving time (HT) is derived by the delta method as the SD of DT (or HT) = (log2) x (SD of b)/(mean of b). Log (testosterone) linear relation with time was fitted using a mixed effects model with intercept, and slope as the random effects and time as the fixed effect, and reported as the mean ± the SD.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors’ Disclosures of...
 REFERENCES
 
Twenty-five men were enrolled on the study and pretreatment characteristics are summarized in Table 1. The median age was 64 years (range, 36 to 77 years). The median baseline PSA was 31.5 ng/mL (range, 2.2 to 160.6 ng/mL), and the median baseline Gleason score was 7 (range, 6 to 9). Prior local therapy included prostatectomy (n = 14), radiation therapy (n = 6), or both prostatectomy and radiation therapy (n = 5).


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  		Table 1. Baseline Patient Characteristics

 
Toxicity
The regimen was generally well tolerated. A total of 132 cycles of chemotherapy were administered. Grade 3 or 4 neutropenia without fever or hospitalization occurred in 55 cycles (42%), while grade 4 neutropenia with fever occurred in only six cycles (4.5%). Six patients received filgrastim per protocol. Two patients required 25% dose reductions, both occurring with cycle 6 secondary to increased transaminases in one patient, and grade 3 lacrimation in the other patient. Other nonsignificant toxicities included grade 2 fatigue (3.8%) and diarrhea (3%). Three patients were removed for adverse events: one patient experienced a deep vein thrombosis after the first cycle, one patient developed chest palpitations after the first cycle, and one patient developed shortness of breath after five cycles of therapy. Five patients were removed from study before completing eight cycles of therapy because of disease progression.

Biochemical Response
Twenty-three of the 25 patients completed one full cycle of therapy and had follow-up PSA values to assess response. Two patients were removed before completing a full cycle of therapy; one was removed secondary to the occurrence of a deep vein thrombosis, and one, secondary to chest palpitations. Figure 1 displays the data by plots of individual patient’s PSA over time for the 23 patients with at least 2 PSA data points. It can be seen from the graphs that 18 of the 23 patients had a decrease in PSA during the docetaxel treatment period. Five patients had progression defined only by PSA. Ten (43%) of 23 patients demonstrated a decrease in PSA by ≥ 50% confirmed at least 4 weeks later. Three (13%) patients had a greater than 75% decrease in PSA. The estimated median PSA halving time was 152 days in patients with a decrease in PSA (n = 18), and the median doubling time was 214 days in patients with increased PSA (n = 5). As shown in Figure 1, the effect of docetaxel to decrease PSA in this population of patients, who were not on any form of androgen ablation, typically required at least 150 days to nadir, suggesting that future approaches to study therapy of micrometastatic disease may require at least 5 months of therapy. This is best illustrated in patients 1 to 3, 5, 6, 14 to 18, 21, 24, and 25. Testosterone data at baseline and during therapy were available in 17 patients, as shown in Figure 2. The baseline testosterone was 306.7 ± 162 ng/dL. In contrast to the effect of docetaxel on PSA, mean testosterone levels were not reduced during therapy; mean testosterone increased 48 ng/dL (SD, ±150) over the treatment period (P = .12).



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  		Fig 1. Effect of docetaxel on prostate-specific antigen (PSA) values for 23 patients plotted over time. As shown, 18 patients had some decrease in PSA throughout the study period, but only 10 patients with ≥ a 50% decrease maintained this level for 4 weeks.

 


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  		Fig 2. Effect of docetaxel on testosterone values for 17 patients in whom values were obtained at baseline and during therapy. Values are plotted over time. The mean baseline testosterone (± standard deviation [SD]) was 306.7 ± 162 ng/dL. Mean testosterone increased 48 ng/dL (SD, ± 150) over the treatment period (P = .12).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors’ Disclosures of...
 REFERENCES
 
The results of this study indicate that docetaxel is well tolerated and decreases PSA in patients with PSA progression after local therapy, before androgen ablation. To our knowledge, this study is the first to demonstrate the biochemical activity and safety of docetaxel when administered alone without concurrent or sequential androgen ablation in patients with increasing PSA after local therapy, complementing prior studies on the use of docetaxel in patients with advanced HRPC, and supporting phase III studies in this patient population.

The optimal treatment for men with biochemical relapse has not been established. However, recent published studies demonstrating a survival advantage with docetaxel-containing regimens in metastatic HRPC support the study of docetaxel in this earlier patient population.6-9 We demonstrated that the use of docetaxel will reduce PSA in 43% of patients by 50% or greater. A prior study using mitoxantrone in this same population revealed a ≥ 50% reduction in PSA in 18% of patients.5 Our study does not allow for a direct comparison to these historical data, but support and encourage enrollment on phase III studies. Our results also indicate that the treatment of micrometastasis in early prostate cancer likely requires more than 5 months of therapy. As shown on Figure 1, most patients with decreased PSA reached a nadir beyond 150 days. This finding is interesting and may be secondary to less effective induction of apoptosis or may represent a more accurate correlation to tumor cell death in patients than the rapid PSA decline expected with successful hormone therapy, since PSA production can be regulated by testosterone.13 Further studies would be needed to prove this possibility. This may have important implications to use of PSA as a marker in future studies that target the treatment of micrometastasis.14

Although clinical outcome is difficult to measure in this population of patients, the effect of therapy on PSA is likely a reasonable surrogate of antitumor activity. One possible confounding variable considered at the onset of the study was the possibility of chemotherapy-induced androgen ablation, since prior studies that include estramustine in a hormone-naive population have caused castration levels of testosterone.10,11 In contrast to the effect achieved with an estramustine-containing regimen, we demonstrated that docetaxel as a single agent did not induce androgen ablation, as measured by serum testosterone levels over the course of the study in a small number of patients (Fig 2). Further studies in larger numbers of patients would be needed to prove this finding. Although additional reasons for a reduction in PSA independent of chemotherapy-induced tumor cell apoptosis are possible, prior studies demonstrate a correlation of PSA reduction and survival in patients with HRPC treated with cytotoxic agents.12 These data, therefore, provide a strong rationale for phase III studies in patients with early-stage disease.

Overall, this study demonstrates clinical activity and tolerability of docetaxel in patients with biochemical progression after local therapy without androgen ablation therapy. Since this study excluded the use of androgen ablation with hormone therapy or estramustine, we were able to assess the effect of a cytotoxic agent alone; these data, therefore, can be used to guide and support therapy of such agents in early micrometastatic disease.


   Authors’ Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors’ Disclosures of...
REFERENCES
 
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Susan Goodin, Aventis; Robert S. DiPaola, Aventis. Honoraria: Susan Goodin, Aventis; Robert S. DiPaola, Aventis. Research Funding: Robert S. DiPaola, Aventis. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.


   NOTES
 
Supported by a grant from Aventis, and National Cancer Institute grant No. CCSG 72,720.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors’ Disclosures of...
 REFERENCES
 
1. Stewart AK, Bland KI, McGinnis LS, et al: Clinical highlights from the National Cancer Data Base, 2000. CA Cancer J Clin 50:171-183, 2000[Abstract]

2. DiPaola RS, Patel J, Rafi MM: Targeting apoptosis in prostate cancer. Hematol Oncol Clin North Am 15:509-524, 2001[CrossRef][Medline]

3. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative end points. J Clin Oncol 14:1756, 1996[Abstract/Free Full Text]

4. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with and without mitoxantrone in men with hormone-refractory prostate cancer: Results of the cancer and leukemia Group B. J Clin Oncol 17:2506-2513, 1999[Abstract/Free Full Text]

5. DiPaola RS, Chenven ES, Shih WJ, et al: Mitoxantrone in patients with prostate specific antigen progression after local therapy for prostate carcinoma. Cancer 92:2065-2071, 2001[CrossRef][Medline]

6. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004[Abstract/Free Full Text]

7. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004[Abstract/Free Full Text]

8. Berry W, Dakhil S, Gregurich MA, et al: Phase II trial of single-agent weekly docetaxel in hormone refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol 28:8-15, 2001 (suppl 15)[CrossRef]

9. Lin Y, Shih WJ: Adaptive two-stage designs for single-arm phase IIA cancer clinical trials. Biometrics 60:482-490, 2004[Medline]

10. Talpin M, Bubley GJ, Rajeshkumar B, et al: Docetaxel, estramustine, and short-term androgen withdrawal for patients with biochemical failure after definitive local therapy for prostate cancer. Semin Oncol 28:32-39, 2001 (suppl 15)[CrossRef]

11. Hussain A, Dawson N, Amin P, et al: Docetaxel followed by hormone therapy in men who fail biochemically after definitive local treatments for prostate cancer. Proc Am Soc Clin Oncol 20:160b, 2001 (abstr 2392)

12. Scher HI, Kelly WM, Zhang ZF, et al: Post-therapy prostate-specific antigen level and survival in patients with androgen-independent prostate cancer. J Natl Cancer Inst 91:244-251, 1999[Abstract/Free Full Text]

13. Riegman PH, Vlietstra RJ, van der Korput JA, et al: The promoter of the prostate specific antigen gene contains a functional androgen responsive element. Mol Endocrinol 5:1921-1930, 1991[Abstract]

14. Scher HI, Eisenberger M, D’Amico AV, et al: Eligibility and outcomes reporting guidelines for clinical trials for patients in the state of a rising prostate-specific antigen: Recommendations from the prostate-specific antigen working group. J Clin Oncol 22:537-556, 2004[Abstract/Free Full Text]

Submitted November 19, 2003; accepted August 7, 2004.


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