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Docetaxel, Estramustine, and 15-Month Androgen Deprivation for Men With Prostate-Specific Antigen Progression After Definitive Local Therapy for Prostate Cancer

Mary-Ellen Taplin, Wanling Xie, Glenn J. Bubley, Marc S. Ernstoff, William Walsh, Daniel E. Morganstern, Meredith M. Regan

From the Dana-Farber Cancer Institute; Beth Israel Deaconess Medical Center; Harvard Medical School, Boston; University of Massachusetts Memorial Medical Center, Worcester, MA; and Dartmouth Hitchcock Medical Center, Lebanon, NH

Address reprint requests to Mary-Ellen Taplin, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: mtaplin{at}partners.org

	ABSTRACT

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PURPOSE: Androgen-deprivation therapy (ADT) is effective for relapsed prostate cancer, but is rarely curative. The purpose of this trial was to determine the feasibility, toxicity, and prostate-specific antigen (PSA) response of chemotherapy and limited ADT for men with PSA relapse.

PATIENTS AND METHODS: Eligible men had an increasing PSA and no metastases after prostatectomy and/or radiation for localized disease. Treatment consisted of four cycles of docetaxel (70 mg/m²) every 21 days and estramustine 280 mg tid on days 1 through 5. After chemotherapy, goserelin acetate and bicalutamide were prescribed for 15 months.

RESULTS: Sixty-two patients were enrolled. A complete PSA response (CR) was defined as PSA at or below the assay-specific lower limit. The proportion of patients with CR after chemotherapy, after ADT, and at 1 year after completion of ADT was 53%, 63%, and 36%, respectively. Testosterone was more than 100 ng/dL (median, 250 ng/dL) 1 year after completion of ADT in 97% of patients. Patients with a PSA less than 3.0 ng/mL at enrollment had a significantly longer time to progression (TTP; P = .0004). Of 56 patients who were observed at least 1 year after completion of ADT, 23 (41%) have not experienced progression as of their last follow-up. The median TTP is 34 months from treatment initiation (maximum, 74 months free from progression).

CONCLUSION: Chemotherapy plus ADT was feasible for early prostate cancer relapse. Forty-one percent of men who are at least 1 year after completion of ADT with recovered testosterone have not experienced progression. This approach is being tested in a randomized trial with investigation of predictors of response.

	INTRODUCTION

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Despite early detection and aggressive local therapy with prostatectomy and/or radiation, a substantial number of prostate cancer patients experience prostate-specific antigen (PSA) progression and a proportion will eventually die from prostate cancer. Adjuvant or salvage radiotherapy can result in favorable responses in a proportion of patients.^1-5 However in many cases these biochemical relapses are the result of occult systemic disease rather than local failure, and responses to salvage local therapy may not be durable.

The natural history of PSA relapse is diverse, and is based on heterogeneous tumor biology. Initially and for many years, the majority of these men have no symptoms or detectable metastases. In a retrospective review of prostatectomy patients at Johns Hopkins University (Baltimore, MD), it was observed that the median actuarial time to the development of metastases after PSA elevation was 8 years, but men with a high Gleason score (8 to 10), PSA recurrence within 3 years of prostatectomy or a short PSA doubling time (PSAdt) had increased risk of metastases and of dying as a result of prostate cancer.^6,7 In a retrospective analysis of 1,159 men treated with prostatectomy or radiation, Zhou et al found that a PSAdt less than 3 months was associated significantly with higher rates of prostate cancer–specific mortality at 5 years after PSA failure: 31% v 1% in surgical patients and 75% v 35% in radiation patients with Gleason score more than 7.⁸

At present, there is no single standard recommendation for patients with PSA progression. In appropriate patients salvage radiation and rarely salvage prostatectomy can be considered.³ Aside from investigational therapy, androgen-deprivation therapy (ADT) is the most commonly prescribed treatment. In men with lymph node and other metastases there has been some evidence that earlier therapy may be beneficial.⁹ Whether survival is improved by early versus delayed initiation of ADT in PSA recurrence is not known. Although the majority of patients initially respond well to ADT, in most patients, hormone-refractory prostate cancer (HRPC) and metastases will eventually develop.

The rationale for adjuvant chemotherapy is to maximize cytotoxic efficacy by treating the patient when tumor bulk is minimal.¹⁰ Adjuvant chemotherapy has become standard for many solid tumors including breast and colorectal cancers.¹¹ It is estimated that systemic relapse will be prevented in approximately 25% to 30% of patients who receive adjuvant chemotherapy for solid tumors.¹² Adjuvant chemotherapy trials for prostate cancer have been slow to accrue patients and randomized data are not available. In advanced HRPC, docetaxel (with or without estramustine) has been demonstrated to improve survival by 8 to 10 weeks compared to mitoxantrone and prednisone.^13,14 In HRPC approximately 50% will experience a PSA decline of 50%, and 17% will have an objective response to docetaxel.^13,14

We propose that the prostate cancer patient with PSA progression and microscopic systemic disease is analogous to the breast cancer patient after local therapy who is at high risk for relapse, and that the addition of chemotherapy before the development of HRPC may improve long-term outcomes. In the trial described herein, we investigated whether it was feasible (with acceptable toxicity) to treat patients with PSA-only progression with chemotherapy plus ADT. We also wished to determine if a proportion of patients would have a prolonged PSA remission after testosterone recovery.

	PATIENTS AND METHODS

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Eligibility
Written informed consent was obtained from men enrolled onto the University of Massachusetts Memorial Health Center (UMMHC; Worcester, MA), Beth Israel Deaconess Medical Center (BIDMC; Boston, MA), Lahey Clinic (Burlington, MA), and Dartmouth Hitchcock Medical Center (Lebanon, NH). A proportion of the UMMHC patients renewed their consent and were observed at Dana-Farber Cancer Institute (DFCI; Boston, MA) in 2003 when an investigator (M.E.T.) moved to DFCI. Eligible patients had histologically documented adenocarcinoma of the prostate, which was clinically or pathologically localized and treated with prostatectomy, radiotherapy, or both. Prior use of neoadjuvant or adjuvant ADT was allowed if the ADT had been for 6 months and was at least 6 months before enrollment, and testosterone recovery was documented. For prostatectomy patients, the PSA had to increase on at least two successive occasions at least 2 weeks apart and there was no specified minimum value for PSA. For radiation patients, the PSA had to increase on at least two successive measurements and had to have doubled from the nadir postradiation value.

Patients were required to have no metastases on bone scans, chest radiograph, and computerized tomography scan of abdomen and pelvis. Biopsies were required to exclude recurrence in any areas suggestive of disease on physical examination or radiographic studies. An Eastern Cooperative Oncology Group performance status of 0 to 1 was required. Required laboratory values included granulocytes more than 4,000/µL, platelets more than 100,000/µL, normal bilirubin, and alkaline phosphatase and hepatic aminotransferases less than 2.5x the upper limit of normal or alkaline phosphatase less than 4x the upper limit of normal with normal aminotransferases. Patients were not eligible if they had a second malignancy within 5 years, active treatment with corticosteroids, active infection, significant neuropathy, uncontrolled or severe cardiovascular disease, prior chemotherapy, or a thromboembolic event within 6 months.

Treatment
Patients were treated with estramustine 10 mg/kg/d (rounded to the nearest increment of 140) divided into three daily doses on days 1 through 5 and taken orally with an empty stomach. Docetaxel 70 mg/m² was administered intravenously during 1 hour on day 2 every 21 days for four treatment cycles. All patients received premedication with dexamethasone before docetaxel. After the third patient was enrolled, warfarin 1 mg daily was prescribed during the 3 months of chemotherapy as prophylaxis of thrombosis. Starting on week 13, patients were prescribed bicalutamide 50 mg orally per day and goserelin acetate 10.8 mg subcutaneously every 12 weeks for a total of 15 months of ADT. Equivalent luteinizing hormone-releasing hormone agonist therapy was allowed at standard dosing intervals.

During chemotherapy, granulocyte colony-stimulating factor was allowed at a dose of 300 µg subcutaneously daily for 5 to 10 days during the subsequent nadir period for grade 4 neutropenia with fevers or grade 4 neutropenia lasting more than 7 days. If a thromboembolic event occurred, estramustine was discontinued and docetaxel was continued per protocol.

PSA levels were measured every 3 weeks during chemotherapy and every 3 months during ADT, and then every 3 months for 5 years or until the initiation of a subsequent therapy. Serum was obtained for testosterone assessment at the completion of chemotherapy, at completion of ADT, and at 1 year after the completion of ADT. PSA at diagnosis and PSA values after the initial local therapy were recorded. PSAdt was calculated using all PSA values between the first increasing PSA after nadir on the most recent local therapy and the baseline PSA, and was estimated for each patient as natural log of 2 divided by the slope of linear regression of natural log of PSA on time.

Outcome Assessments
A complete response (CR) during therapy was defined as PSA level at or below the assay-specific limit of measurement. PSAs were measured using Immulite 2000 assay at UMMHC (lower limit, < 0.01), Abbott assay at BIDMC, and Lahey Clinic (< 0.3), Immulite PSA assay (Immulite 2000 and Immulite; Diagnostic Products Corporation, Los Angeles, CA) at Dartmouth (< 0.04), and Bayer Centaur Platform assay at DFCI (< 0.01). Progression was defined as two serial increases in PSA (at least 2 weeks apart), and the PSA had to be 2.0 ng/mL in radiation patients and 0.2 in prostatectomy patients (or 0.3 lower limit of Abbott PSA assay; Abbott Laboratory, Abbott Park, IL); the first date of increasing PSA was considered as the progression date. Reinitiation of ADT for increasing PSA before fulfillment of the definition of progression was also considered as a progression event, with the date of ADT reinitiation considered as the progression date. In prostatectomy patients this occurred after only one rise in PSA more than 0.2 (n = 5), and in radiation patients this occurred either after only one increase that was much greater than 2.0 (n = 1) or after the first or second increase in PSA more than 0.2 (n = 3). Time to progression (TTP) was defined from start of chemotherapy until the date of progression, which was censored at last follow-up if patients were still responding to treatments. Duration of response, among patients who achieved CR at 1 year after completion of ADT, was defined from the date of assessment 1 year after completion of ADT to the date of progression.

Statistical Analysis
The sample size of 62 patients provided 80% power to detect a 60% improvement in hazard rate for time to progression to a median of approximately 32 months (corresponding to 50% of patients free from progression at 1 year after completion of therapy) versus a median of 20 months from initiation of therapy, with two-sided = .05 and assuming an exponential distribution, accrual during 18 months, and 30 months of additional follow-up.

Variables were summarized as number (and percentage) of patients or median (and range) of values. Categoric variables were compared between patients who did and did not achieve CR using Fisher's exact test and extensions; continuous variables were compared using Wilcoxon rank sum test. TTP was compared according to patients' disease characteristics using log-rank tests; continuous variables were dichotomized at the median value. The statistical analysis was undertaken using SAS version 9 (SAS Institute Inc, Cary, NC) and P < .05 (two sided) was considered as statistically significant.

	RESULTS

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From May 1999 through October 2003, 62 patients were enrolled at four institutions (32 at UMMHC, five at BIDMC, seven at Dartmouth, and 18 at Lahey Clinic). Baseline patient characteristics are listed in Table 1. Forty-five patients had prior prostatectomy (22 with adjuvant or salvage radiation) and 17 patients had prior external-beam radiation as local therapy. The median age of prostatectomy patients was 62 years compared with 70 years for radiation patients. The median baseline PSA for the whole group was 3.01 ng/mL (range, 0.08 to 47 ng/mL), and was 1.50 ng/mL for prostatectomy patients and 8.20 ng/mL for radiation patients. Forty percent had Gleason score 8 to 10. PSAdt was shorter for prostatectomy patients compared with radiation-only patients. Risk assessment using initial stage, PSA, and Gleason score demonstrated that 8.1% were low risk, 27.4% were intermediate risk, and 62.9% were high risk.

The overall median TTP was 33.8 months (range, 15+ to 74+ months). In total, 33 of 62 patients have experienced PSA progression, including nine patients in whom ADT was reinitiated when the patients did not fulfill the definition of progression. Of 36 patients with PSA that did not reach assay lower limit at 1 year after completion of ADT, 25 had PSA progression as of their last follow-up. Of 20 patients with PSA at assay lower limit at 1 year after completion of ADT, eight have experienced PSA progression. Thus, 23 of 56 patients (41%) who are at least 1 year after completion of ADT remain free of progression or reinitiation of ADT as of their last follow-up; six patients who have not yet reached 1 year after completion of ADT did not experience PSA progression. Median time to ADT reinitiation from start of chemotherapy was 39.9 months (range, 14 to 74+ months); ADT was reinitiated in 29 of the 33 patients who experienced progression.

Table 4 summarizes univariate associations of patients' disease characteristics and treatment with TTP. TTP was significantly associated with patients' baseline PSA and prior hormone therapy. Median TTP was 30.8 months among patients with baseline PSA 3.0 ng/mL, and 39.3 months among patients with baseline PSA less than the median value of 3.0 ng/mL (P = .0004; Fig 1). Median time to progression was 27.1 months for patients with prior hormone therapy, and 36.5 months for patients who did not receive any hormone treatment (P = .0086).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Time to prostate-specific antigen (PSA) progression after initiation of chemotherapy by patient baseline PSA values.

Chemotherapy-associated toxicities were similar to those experienced in HRPC patients. There were four thromboses (one cerebrovascular event, three deep vein thromboses) and 38 patients (61%) had at least one episode of grade 3/4 neutropenia. There were five occurrences of non–life-threatening infections. There were 11 hospitalizations during chemotherapy and three during hormone therapy. One patient (concomitant lithium) stopped docetaxel after two doses because of elevated liver function tests (no progression was noted as of 2 years after completion of ADT). All other patients received four cycles of docetaxel.

	DISCUSSION

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In men with PSA relapse after local therapy, the prognosis is variable, with shorter survival estimates in the 4- to 5-year range and favorable estimates of several decades with indolent relapse.^7,8 In younger men with unfavorable features of PSA relapse such as a short PSAdt, there is an inclination toward more aggressive therapy such as early ADT despite a lack of randomized data. We have demonstrated that administering chemotherapy plus ADT was an accepted approach to referring urologists, radiation oncologists, and patients, especially patients in the 50- to 70-year age range.

Toxicity was similar to that described in HRPC, despite a younger, hormone-naïve population with low tumor burden.^13-15 The 6.5% rate of thrombosis (estramustine) despite low-dose warfarin prophylaxis is similar to published data and is a concern. All patients recovered completely from their thromboses and anticoagulation was eventually discontinued. Recent phase III studies suggest that in HRPC the estramustine may contribute little to the overall efficacy, and in HRPC single-agent docetaxel has become standard.^13,14

Whether estramustine specifically contributed to positive outcome or possibly simultaneous ADT could equally contribute to efficacy (of docetaxel) in hormone-naïve patients remains an unanswered question. In our patient cohort the hormonal effect of estramustine certainly contributed to the high early PSA response rate. During the same time period, Hussain et al¹⁶ enrolled 39 patients with PSA progression (18% with metastatic disease) to a trial of docetaxel alone (90% received six cycles), followed by 4 to 12 months of a luteinizing hormone-releasing hormone agonist and bicalutamide, followed by 8 months of bicalutamide and finasteride. In that trial, after docetaxel alone, 20% of patients had a PSA decline of 75% and 48% of patients had a PSA decline of 50%. Of these patients, no one was castrated after docetaxel alone compared with a 100% castration rate in our trial. Possible differential efficacy of simultaneous versus sequential chemotherapy and ADT in prostate caner has not been investigated.

At present, with a median follow-up of 37 months (start of chemotherapy), 23 of 56 patients who were observed 1 year after completion of ADT (and were not castrated) have not had PSA progression as of their last follow-up. The patient with the longest follow-up completed ADT 4.5 years previously and has not experienced progression. This duration of response compares favorably to published data from phase II trials of intermittent ADT. Reports of intermittent ADT suggest that the average time after completion of ADT in the first cycle ranges from 6 to 24 months (approximate median, 10 months).¹⁷ Most reports on intermittent treatment with ADT involve patients with more advanced disease than those in our cohort. However in a subset of 74 patients with increasing PSA (mean, 10.6 ng/mL) after local therapy, the average time in the cycle without ADT was 9.6 months (ADT restarted prostatectomy patients PSA > 4, in radiation therapy patients > 10).¹⁸ It is anticipated that with longer follow-up, additional patients in our cohort will experience PSA progression but it is likely that there will be a subset of men who remain in remission and possibly will be cured. Hussian et al¹⁶ also reported that five of 33 men in their study had not experienced progression (PSA 0.01 ng/mL) with a median follow-up of 18.9 months after therapy. Both of these phase II studies support a randomized comparison of early chemotherapy.

Our data demonstrated that patients who were treated with PSA less than 3.0 ng/mL (median of the group) compared with 3.0 ng/mL had a significantly longer median TTP of 39.3 months compared with 30.8 months (P = .0004). Although this result could reflect a lead time bias based on lower PSA because TTP also reflects nonprogression, we believe that the data support treatment with chemotherapy at lower PSA values. Whether there is a PSA (or other factors) beyond which this approach is unlikely to have a sustained effect is not known; however, none of our patients who remained PSA progression free for at least 1.5 years after completing ADT had a PSA more than 4.7 at entry. There was no association of TTP with Gleason score, stage, PSAdt, or prior local therapy. The other factor that significantly correlated with a longer TTP was no prior ADT compared with prior ADT with local therapy: median TTP was 36.5 v 27.1 months (P = .0086). Although prior ADT could have selected androgen-independent clones, the fact that previous ADT was 6 months would suggest that prior ADT likely reflected a group of patients with an initial poor prognosis in whom early chemotherapy plus hormonal therapy did not influence the natural history of progression.

We have demonstrated in this phase II trial that administering chemotherapy to patients with hormone-sensitive prostate cancer is feasible, has toxicity but no long-term serious toxicity, produces high PSA response rates, and yields a cohort of patients with freedom from progression at a median follow-up of 37 months since starting treatment. Conclusions regarding the overall impact of this approach are limited due to the phase II design, but these data support ongoing efforts investigating the administration of chemotherapy before development of HRPC. Important questions that remain include predictors of response, timing of therapy, and the optimal chemotherapy and ADT regimen.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Marc S. Ernstoff Chiron Chiron, Berlex, Schering Chiron, Berlex

	Author Contributions

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Conception and design: Mary-Ellen Taplin, Glenn J. Bubley, Daniel E. Morganstern Administrative support: Mary-Ellen Taplin Provision of study materials or patients: Mary-Ellen Taplin, Glenn J. Bubley, Marc S. Ernstoff, William Walsh, Daniel E. Morganstern Collection and assembly of data: Mary-Ellen Taplin, Marc S. Ernstoff, William Walsh Data analysis and interpretation: Mary-Ellen Taplin, Wanling Xie, Glenn J. Bubley, Marc S. Ernstoff, Meredith M. Regan Manuscript writing: Mary-Ellen Taplin, Glenn J. Bubley, Marc S. Ernstoff, Meredith M. Regan Final approval of manuscript: Mary-Ellen Taplin, Glenn J. Bubley, Marc S. Ernstoff, William Walsh, Daniel E. Morganstern, Meredith M. Regan

 

	NOTES

 
Supported by Aventis Pharmaceuticals (now sanofi-aventis), Bridgewater, NJ; bicalutamide (Casodex) and goserelin (Zoladex) were provided by AstraZeneca Pharmaceuticals, Wilmington, DE.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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5. Bolla M, van Poppel H, Collette L, et al: Postoperative radiotherapy after radical prostatectomy: A randomized controlled trial (EORTC trial 22911). Lancet 366:572-578, 2005[CrossRef][Medline]

6. Pound C, Partin A, Eisenberger M, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281:1591-1597, 1999[Abstract/Free Full Text]

7. Freedland SJ, Humphreys EB, Mangold LA, et al: Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 294:433-439, 2005[Abstract/Free Full Text]

8. Zhou P, Chen M, McLeod D, et al: Predictors of prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Clin Oncol 23:6992-6998, 2005[Abstract/Free Full Text]

9. Messing E, Manola J, Sarosdy M, et al: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341:1781-1788, 1999[Abstract/Free Full Text]

10. Goldie J: Scientific basis for adjuvant and primary (neoadjuvant) chemotherapy. Semin Oncol 14:1-7, 1987[Medline]

11. Carlson RW, Brown E, Burnstein HJ, et al: NCCN task force report: Adjuvant therapy breast cancer. J Natl Comprehensive Cancer Network 4(suppl 1):S1-S26, 2006

12. Trudeau M, Charbonneau F, Gelmon K, et al: Selection of adjuvant chemotherapy for treatment of node-positive breast cancer. Lancet Oncol 6:886-898, 2005[CrossRef][Medline]

13. Tannock I, de Wit R, Berry W, 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]

14. Petrylak D, Tangen C, Hussain M, 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]

15. Savarese D, Halabi S, Hars V, et al: Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: A final report of CALGB 9780—Cancer and Leukemia Group B. J Clin Oncol 19:2509-2516, 2001[Abstract/Free Full Text]

16. Hussain A, Dawson N, Amin P, et al: Docetaxel followed by hormone therapy in men experiencing increasing prostate-specific antigen after primary local treatments for prostate cancer. J Clin Oncol 23:2789-2796, 2005[Abstract/Free Full Text]

17. Grossfeld GD, Chaudhary UB, Reese DM, et al: Intermittent androgen deprivation: Update of cycling characteristics in patients without clinically apparent metastatic prostate cancer. Urology 58:240-245, 2001[CrossRef][Medline]

18. De La Taille A, Zerbib M, Conquy S, et al: Intermittent androgen suppression in patients with prostate cancer. BJU International 91:18-22, 2003[CrossRef][Medline]

Submitted March 23, 2006; accepted September 25, 2006.

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