Multicenter Phase II Study of Combined Neoadjuvant Docetaxel and Hormone Therapy Before Radical Prostatectomy for Patients With High Risk Localized Prostate Cancer

Article Outline

• Abstract
• Patients and Methods
• Results
  • Patient Characteristics
  • Adverse Events
  • Surgical Outcomes
  • Survival
• Discussion
• Conclusions
• Acknowledgments
• References
• Copyright

Purpose

We assessed pathological outcomes as well as the feasibility of combined docetaxel and androgen deprivation therapy in men with prostate cancer before undergoing prostatectomy.

Materials and Methods

In this phase II multicenter study of newly diagnosed patients with untreated clinically localized prostate cancer and high risk features, all patients received androgen deprivation therapy (6.3 mg buserelin acetate every 8 weeks for 3 doses and antiandrogen for 4 weeks) with docetaxel (35 mg/m² weekly for 6 of 8 weeks for 3 doses).

Results

A total of 72 men with a median age of 59 years (range 46 to 78) were enrolled in the study. Baseline characteristics included clinical stage T1C, T2 or T3 in 14%, 47% and 39%, and Gleason score 7 or less, 8 and 9 in 40%, 29% and 31% of patients, respectively. Median baseline prostate specific antigen was 10.8 μg/l (range 1.6 to 65.6). Eight patients did not complete protocol therapy because of toxicity (4), withdrawal of consent (1) and other reasons (3). Of the 64 patients completing protocol therapy 2 had a complete pathological response. Pathological stage was T2 in 53% and T3 in 44% of patients. Four patients had N1 disease and positive surgical margins were identified in 27%. At a median followup of 42.7 months (range 25.6 to 65.6) 19 patients (30%) had disease relapse.

Conclusions

Combined androgen deprivation and docetaxel before prostatectomy was feasible, and resulted in encouraging recurrence-free survival. While pathological down staging was observed, pathological complete response rates were rare.

Key Words: prostatic neoplasms, drug therapy, prostatectomy

Abbreviations and Acronyms: CALGB, Cancer and Leukemia Group B, CUOG, Canadian Urologic Oncology Group, ECOG, Eastern Cooperative Oncology Group, PSA, prostate specific antigen

Prostate cancer is the most frequently diagnosed malignancy in men and the third leading cause of cancer death in men in the United States.¹ Although many patients with localized prostate cancer enjoy a long disease-free and overall survival after diagnosis and treatment, a significant number of patients can be identified with a high risk of treatment failure exceeding 50% at 3 years. This figure includes those who present with an initially increased PSA greater than 20 μg/l, a Gleason score greater than 7, multiple positive biopsies and clinical extraprostatic extension of disease.² Single modality therapy is insufficient for most of these patients. Neoadjuvant androgen deprivation therapy before radical prostatectomy has been tested in several trials demonstrating improved pathological end points such as positive margin rates.³ However, complete pathological responses are infrequent especially in those patients with high risk disease, and progression-free survival has not been improved with neoadjuvant androgen deprivation therapy of up to 8 months before prostatectomy.⁴, ⁵

Potential explanations for the lack of demonstrated benefit on recurrence include underpowered study designs compounded by the inclusion of mostly favorable risk patients, and a short duration of therapy that may have been insufficient to eradicate micrometastatic disease. Another fundamental limitation is the preexistence and emergence of androgen independent subpopulations of cells after androgen deprivation therapy. Indeed, surviving prostate cancer cells in prostate cancer xenografts and prostatectomy specimens after neoadjuvant androgen deprivation therapy have increased expression of pro-survival proteins associated with androgen independent progression and treatment resistance.⁶

Combined chemohormonal therapy has not been shown to improve outcomes for patients with prostate cancer, but previous trials have been hampered by the lack of an effective chemotherapy and/or adequate sample size.⁷, ⁸ Docetaxel is now standard first line therapy in metastatic hormone refractory disease based on randomized trials demonstrating improved overall survival compared to mitoxantrone.⁹ These data provide a rationale to study docetaxel earlier in the natural history of prostate cancer in conjunction with androgen deprivation therapy to eradicate micrometastatic and hormone resistant disease. This approach is further supported by preclinical evidence in the androgen dependent Shionogi and LNCaP tumor models, in which simultaneous chemotherapy plus castration was more effective than the sequential therapies of castration followed by chemotherapy or vice versa.¹⁰

In this phase II trial we evaluated a chemohormonal approach in conjunction with definitive local therapy. A neoadjuvant approach was adopted because it builds on the previous multicenter Canadian Urologic Oncology Group experience with androgen deprivation therapy before prostatectomy and provides an early primary end point in the form of pathological response to evaluate antitumor activity.⁵, ¹¹ A weekly administration schedule for docetaxel was used rather than an every 3 week schedule because at the time of the study inception, phase II data suggested similar rates of posttreatment PSA decreases but less hematological toxicity in patients with hormone refractory disease.¹² Secondary objectives of the trial were to determine the tolerability of the regimen and the feasibility of this multimodality, multicenter trial.

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Patients and Methods 

This was a phase II study conducted at 6 sites in Canada and coordinated by the CUOG. Patients with localized, pathologically confirmed prostate cancer judged to be candidates for radical prostatectomy were eligible. Patients had to have 2 or more positive core biopsies and high risk disease clinical/pathological features defined as clinical stage T3, PSA 20 μg/l or greater and/or Gleason score greater than 7. Patients with clinical T2 disease and Gleason score 7 with 3 or more positive core biopsies, Gleason score 7 and a PSA greater than 10 μg/l, or PSA greater than 10 μg/l and more than 3 positive core biopsies were also eligible. Staging was according to the TNM classification (UICC 1997). Other eligibility criteria included a serum testosterone greater than 6 nmol/l, white blood cell count greater than 3 × 10⁹/l, hematocrit greater than 30%, platelets greater than 100 × 10⁹/l, normal hepatic function, creatinine less than 2 × upper limit of normal and an ECOG performance status of 0 or 1. Patients were excluded from participating if they received prior therapy for prostate cancer, or had prior invasive malignancy or any serious comorbidity. All patients provided written informed consent. The study was approved by the institutional review boards of participating centers.

At baseline, patients underwent history and physical examination, clinical staging, baseline blood tests, urinalysis, electrocardiogram and transrectal ultrasound. Computerized tomography of the abdomen and pelvis, bone scans and chest x-rays were performed as per standard of care guidelines at the participating centers. During protocol therapy patients were assessed weekly for performance status and complete blood counts, biweekly with history and physical examinations, and monthly for PSA, testosterone, and renal and hepatic function. After prostatectomy patients were seen in followup at 3, 6, 9, 12, 18 and 24 months, and then yearly. PSA recurrence was defined as a PSA of 0.4 μg/l or greater on 2 successive measurements.

Protocol treatment consisted of neoadjuvant androgen deprivation therapy with 6.6 mg buserelin acetate subcutaneously every 8 weeks for 3 doses and 150 mg nilutamide orally, daily for the first 4 weeks. After 2 occurrences of pneumonitis, the protocol was amended to exclude nilutamide, which was replaced with 250 mg flutamide 3 times daily or 50 mg bicalutamide daily for the same duration. Docetaxel was administered at 35 mg/m² intravenously, weekly for 6 consecutive weeks followed by a 2-week rest (8-week cycle) for 3 cycles. Two dose reductions by 5 mg/m² increments were allowed for toxicity and 2 weeks were permitted for recovery of side effects, otherwise patients were taken off protocol therapy. Docetaxel (supplied by Sanofi-Aventis) was started within 2 weeks of buserelin administration. Radical prostatectomy and lymphadenectomy were performed according to investigator standard of practice within 2 weeks after the last dose of docetaxel. Standard pathological examination of prostatectomy specimens was performed at the local institution.

The primary purpose of the study was to determine the pathological complete response rate defined as no microscopic evidence of malignancy in the prostatectomy specimen. Pathological complete response rates in several studies of neoadjuvant androgen deprivation therapy before radical prostatectomy were reported to be approximately 5%, with most of the patients in these trials having low risk disease.³ This study used a 2-stage design as described by Simon to distinguish a response rate of 20% signifying efficacy, from a response rate of 5% or less, with an alpha error of 0.05 and beta error of 0.10, which required at least 41 evaluable patients to be enrolled.¹³ Due to rapid accrual and to account for potentially inevaluable patients, this accrual target was exceeded. Other objectives were to determine feasibility, toxicity, assess effects on PSA before surgery and determine postoperative PSA recurrence rates. All patients who received any treatment were included in the analysis of toxicity. PSA progression-free survival was defined as the time of the first treatment with docetaxel to the date of first PSA recurrence, and calculated using the Kaplan-Meier method. Univariate and multivariate Cox regression and chi-square analyses were performed using SPSS® version 14.0 for Windows. All tests were 2-sided and used a 5% alpha level to determine significance.

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Results 

Patient Characteristics 

A total of 72 patients were accrued to the study from July 2001 to May 2003 at 6 centers. Two complete responses were seen in the first stage and the study continued to the second stage. Baseline patient characteristics are listed in table 1. Eight patients did not complete protocol therapy because of toxicity (4 patients), withdrawal of consent (1 patient) and diagnosis of metastatic disease (1 patient) or other cancer (1 patient with carcinoid tumor, 1 patient with small cell lung cancer). Of the 72 patients 63 (88%) had clinical stage T3, Gleason score 8 or greater and/or PSA 20 μg/l or greater at baseline. Of these 63 patients 41 (65%) had 1 of these factors, 19 (30%) had 2 and 3 (5%) had all 3 factors. Nine patients (12%) had Gleason score 7 disease and either 3 or more positive biopsies or a PSA greater than 10 μg/l.

Table 1. Baseline patient characteristics

Median pt age (range)	59 (46–78)
No. clinical stage (%):
T1	10 (14)
T2	34 (47)
T3	28 (39)
Median μg/l PSA (range)	10.8 (1.6–65.6)
No. PSA (%):
Less than 10	34 (47)
10–20	17 (24)
Greater than 20	21 (29)
No. Gleason score(%):
6	7 (10)
7	22 (31)
8	21 (29)
9	22 (31)

Adverse Events 

Adverse events are summarized in table 2. In general, toxicity was as expected with a weekly docetaxel schedule with a low incidence of hematological toxicity. Four patients discontinued therapy because of toxicity, 2 because of severe hypersensitivity reactions and 2 because of pneumonitis (grades 3 and 4). No further cases of pneumonitis were observed after the protocol amendment that substituted flutamide or bicalutamide in place of nilutamide. One patient experienced a myocardial infarction the day after surgery and 1 patient was diagnosed with a deep venous thrombosis approximately 1.5 months after prostatectomy. No other major postoperative complications were reported.

Table 2. Adverse events in more than 10% of patients considered possibly, probably or definitely related to protocol therapy

Surgical Outcomes 

A total of 64 patients completed protocol therapy and underwent prostatectomy. Median PSA before surgery was 0.14 μg/l (range 0.02 to 3.8) representing a median decrease of 98.4% (range 69.2 to 99.9), measured a median of 11 days before surgery (range 1 to 54). There were 34 patients (53%) who had pathological T2 disease, 14 (22%) with pathological T3a disease (extracapsular extension) and 14 (22%) with seminal vesicle involvement (T3b). Seventeen patients (27%) had positive margins and 4 were found to have involvement of regional lymph nodes (table 3). Two patients (3%) had no detectable cancer and 16 had an estimated 5% tumor or less by volume in prostatectomy specimens including 3 with just a single or 2 microfoci of disease. The baseline tumor characteristics for these patients are summarized in table 4.

Table 3. Pathological outcomes in 64 patients

Pathological Staging	No. Pts (%)
T0	2 (3)
T2	34 (53)
T3a	14 (22)
T3b	14 (22)
Marginpos	17 (27)
N1	4 (6)

Table 4. Baseline characteristics of patients with 5% or less tumor volume in prostatectomy specimen

Gleason Score	Clinical Stage	Baseline PSA
0% Tumor vol:
9	3A	7.9
8	2B	4.3
5%orLess tumor vol:
9	3A	4.7
9	2A	7.1
9	2A	4.3
8	3A	8.3
8	2B	7.8
8	2A	39.2
8	1C	23.6
8	1C	5.4
7	3B	56.7
7	3A	33
7	3A	9
7	2A	26.1
7	2A	16.4
7	2A	9.8
7	1C	18.8
6	3B	11

Survival 

Median followup of the 64 patients who completed protocol therapy was 42.7 months (range 25.6 to 65.6, SD 6.8). A total of 19 patients (30%) had PSA recurrence, 18 met the predefined criteria and 1 was considered to have relapse after a PSA increase to 0.4 μg/l or greater but went on to receive salvage radiotherapy before obtaining a confirmatory PSA. Adjuvant hormone or radiation therapy was not otherwise administered during followup. Median PSA recurrence-free survival has not been reached and is estimated to be 65.1 months (fig. 1). PSA recurrence-free survival for the 2 patients with a pathological complete response and the 16 patients with 5% or less tumor by volume in the prostatectomy specimens was 89%.

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• Fig. 1. 

  PSA recurrence-free survival

On univariate analysis Gleason score (6 or 7 vs 8 or 9, log rank p = 0.009) and pathological stage (T0 or T2 vs T3, log rank p = 0.019) were significantly associated with PSA recurrence-free survival (fig. 2). A preoperative PSA greater than 0.33 μg/l was also associated with a worse PSA recurrence-free survival (PSA greater than 0.33 vs 0.33 μg/l or less, p = 0.018) (fig. 2). Only baseline Gleason score remained significant on Cox regression analysis (HR 4.58, 95% CI 1.32–15.93). Three patients died at 32.0, 40.0 and 40.3 months, all of prostate cancer. Two of the patients who died had node positive disease at prostatectomy.

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• Fig. 2. 

  PSA recurrence-free survival by Gleason score (GS) (A), pathological stage (B) and preoperative PSA (C).

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Discussion 

To our knowledge this study is the largest phase II trial to date evaluating a combination of neoadjuvant docetaxel and androgen deprivation therapy before radical prostatectomy. Several smaller studies have reported on the use of neoadjuvant docetaxel based chemotherapy with and without estramustine or hormonal therapy before prostatectomy in patients with high risk localized prostate cancer, and have similarly demonstrated the safety and feasibility of the approach with respect to the subsequent surgery.¹⁴ As expected, in studies with a chemohormonal approach significant posttreatment PSA decreases were observed in most patients. Studies that did not incorporate estramustine or hormonal therapy demonstrated that docetaxel on its own has an antitumor effect, at least by posttreatment PSA reduction parameters, which further supports the rationale of a combination chemohormonal strategy to deal with potentially noncross-resistant clones.¹⁵, ¹⁶ Despite these encouraging preoperative PSA decreases, pathological complete responses have not been reported except for a single case in 1 trial, which may simply reflect the shorter duration of treatment and the smaller sample size of these studies.¹⁷

In this study neoadjuvant docetaxel appeared to be well tolerated with adverse events similar to those experienced by patients with advanced hormone refractory disease. Pneumonitis was observed in 2 patients when prescribed docetaxel and nilutamide, but not in subsequent patients after the exclusion of nilutamide. Pneumonitis has been described with docetaxel and nilutamide, and these agents should not be combined in future cases.¹⁸ The trial was feasible involving multidisciplinary collaboration, and acceptable to patients and physicians with brisk accrual once all centers were activated.

Two patients had a pathological complete response and 16 additional patients had less than 5% tumor volume involvement in prostatectomy specimens, including 3 with only microfoci of disease. These data suggest a down staging effect of neoadjuvant therapy as all these patients had high risk features and/or a significant pretreatment disease burden. However, the study did not meet the primary end point predefined criterion for success of a 20% pathological complete response rate. Pathological complete response serves as a convenient and easily assessable early end point for a 2-stage phase II design, but was ambitious given the high risk patient population. Our study had a 27% margin positive rate which is consistent with the previous literature, but there was significant site-site variability in margin status with 8 of 17 positive margins at a center that enrolled 9 patients. Intersurgeon variability has been previously well described and these observations emphasize the importance of stratifying by surgical center in future randomized trials.¹⁹

It is not clear what the optimal primary end point should be for neoadjuvant phase 2 trials. For example, if we had selected major response defined as less than 5% tumor volume in the prostatectomy specimen, then the response rate in this study would be 28%. However, it is important to note that improvement in pathological outcomes has not translated into a disease-free survival benefit in randomized trials of neoadjuvant androgen deprivation therapy.⁵, ¹¹ Rather than pathological stage or positive margin rates, a more relevant indicator of activity in single arm trials of neoadjuvant therapy may be progression-free survival. For patients in this study after a median followup of more than 43 months, PSA progression occurred in 30%. This finding compares favorably to the results from the CUOG study of 3 vs 8 months of neoadjuvant hormonal therapy before radical prostatectomy. In that study 97 of 502 patients had high risk disease (clinical stage T3, PSA greater than 20 μg/l and/or Gleason 8 or greater) and after a mean followup of 37.7 months there was PSA recurrence in 53%,⁵ which is also consistent with the progression rate reported in other trials of high risk patients undergoing prostatectomy.¹⁷, ²⁰

Another potential phase II end point that could be used for neoadjuvant studies is the PSA nadir achieved preoperatively. It was previously observed that patients with advanced prostate cancer who achieve lower a PSA after hormone therapy have a better prognosis.²¹ In this study we found that a preoperative PSA of 0.33 μg/l or less was associated with improved PSA recurrence-free survival on univariate analysis. This finding requires further validation.

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Conclusions 

Combined androgen deprivation therapy and docetaxel before prostatectomy was feasible, and resulted in encouraging recurrence-free survival compared to the literature. While pathological down staging was observed, pathological complete response rates were rare. Several phase III trials have been initiated which are evaluating neoadjuvant and adjuvant chemohormonal approaches around prostatectomy or radiotherapy. For example, CALGB 90203 is a randomized study of neoadjuvant docetaxel and androgen deprivation before radical prostatectomy vs immediate radical prostatectomy in 750 patients with high risk, clinically localized prostate cancer. These studies require our collective support to definitively determine the efficacy of a chemohormonal approach.

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Acknowledgments 

In addition to the listed authors Canadian Uro-Oncology Group investigators who contributed to this study are S. Larry Goldenberg, Scott Berry, Paul Perrotte, J. Dean Ruether, John Trachtenberg and Malcolm Moore.

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