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Prostate-Specific Antigen and Pain Surrogacy Analysis in Metastatic Hormone-Refractory Prostate Cancer

Andrew J. Armstrong, Elizabeth Garrett-Mayer, Yi-Chun Ou Yang, Michael A. Carducci, Ian Tannock, Ronald de Wit, Mario Eisenberger

From the Duke Comprehensive Cancer Center, Durham, NC; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD; Department of Medical Oncology, Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada; and the Department of Medical Oncology, Rotterdam Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands

Address reprint requests to Andrew J. Armstrong, MD, ScM, DUMC Box 3850, Durham, NC 27710; e-mail: andrew.armstrong{at}duke.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose It is currently unclear if early prostate-specific antigen (PSA) or pain improvements are adequate surrogates for overall survival in men with metastatic hormone-refractory prostate cancer (HRPC). Here we examined various degrees of PSA decline and pain response as surrogates for the survival benefit observed in the TAX327 trial.

Patients and Methods In the TAX327 trial, 1,006 men with HRPC were randomly assigned to receive docetaxel in two schedules, or mitoxantrone, each with prednisone: 989 men provided data on 3-month PSA decline. Surrogacy was examined for post-treatment changes in PSA and pain response using Cox proportional hazards models to calculate the proportion of treatment effect (PTE) explained by each potential surrogate.

Results A 30% PSA decline within 3 months of treatment initiation provides the highest degree of surrogacy, with a PTE of 0.66 (95% CI, 0.23 to 1.0), and was associated with a hazard ratio (HR) of 0.50 (95% CI, 0.43 to 0.58) for overall survival after adjusting for treatment effect. Introduction of a 30% PSA decline is predictive of survival regardless of treatment arm. Other changes in PSA or PSA kinetics, PSA normalization, and pain responses were highly prognostic but weaker surrogates for survival.

Conclusion In the TAX327 trial, a PSA decline of 30% within 3 months of chemotherapy initiation had the highest degree of surrogacy for overall survival, confirming data from the Southwest Oncology Group 9916 trial. However, given the wide CIs around the estimate of this moderate surrogate effect, overall survival should remain the preferred end point for phase III trials of cytotoxic agents in HRPC.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Men with metastatic hormone-refractory metastatic prostate cancer (HRPC) have a median survival of 16 to 18 months, despite modern chemotherapy, and prostate cancer is the second most common cause of cancer death among men in 2007.^1-3 The identification of a surrogate marker for overall survival (OS) in HRPC patients treated with chemotherapy would represent an important advance in improved palliation and in the early identification of active therapies. OS is currently the only valid end point in phase III trials of men with HRPC, and while many efforts have established a correlation of tumor, prostate-specific antigen (PSA), or pain responses with OS, these end points have not been systematically evaluated as surrogates for the OS benefits associated with chemotherapy.^4-10

The most thorough analysis for surrogacy of postchemotherapy PSA declines was conducted using the Southwest Oncology Group (SWOG) 9916 database.^3,6 In this phase III study, 770 men were randomly assigned to docetaxel and estramustine, or mitoxantrone and prednisone (MP), and a range of PSA declines was analyzed for surrogacy. A PSA decline 30% within 3 months met several surrogacy criteria, while a decline 50% did not meet all surrogate criteria.^6,11-13 Here, we report a surrogacy analysis of various levels of PSA decline and pain response for OS in TAX327, a multinational phase III trial of men with HRPC who were randomly assigned to one of two different schedules of docetaxel and prednisone (DP) or MP.² This trial demonstrated a survival advantage for three-weekly DP, which represents the current standard chemotherapy in men with HRPC, and provides an opportunity to address surrogacy questions.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Subjects and Treatment
TAX327 was a randomized phase III study involving 1,006 men with progressive metastatic HRPC, conducted from March 2000 through June 2002. Full details of the protocol have been described.² Briefly, eligible men had histologically documented metastatic prostatic adenocarcinoma despite castrate serum testosterone levels ( 50 ng/dL), with disease progression defined as clinically or radiographically measurable disease, or by PSA criteria. No prior chemotherapy other than estramustine was allowed, and subjects were required to have stable pain scores at entry. An institutional review board approved the study at each participating institution.

Participants were randomly assigned to one of three arms: every-3-weeks docetaxel (every-3-weeks, 75 mg/m²), weekly docetaxel (weekly, 30 mg/m² 5 weeks of 6), or every-3-weeks mitoxantrone (12 mg/m²), all with prednisone 5 mg twice daily. Treatment was planned for 30 weeks in the absence of progression. The primary end point was OS; the present analysis is based on updated survival as of November 7, 2006, at which time 800 deaths had occurred. Serum PSA and pain scores were measured at baseline and every 3 weeks.

Analysis of PSA Declines
A PSA decline was defined within 3 months following treatment, using baseline PSA and the minimum PSA measure during this interval, calculated as percent decline. PSA declines ranging from 0% to 90% were evaluated for surrogacy. Moreover, post-treatment PSA velocity was calculated as the rate of change in PSA over time during the initial 3 months, and was estimable for 942 subjects using a subject-specific linear regression model among those with three or more PSA values during this time.

Besides PSA decline and post-treatment PSA velocity, pretreatment PSA velocity was evaluated using individual linear regression on 676 subjects with three or more pretreatment PSA measures separated by more than 1 week. The ratio of post-treatment to pretreatment PSA velocity was calculated for 646 subjects.¹⁴

For PSA normalization, all post-treatment PSA values were analyzed while subjects were on protocol treatment. PSA nadir was measured and considered to be normalized if it dropped to 4 ng/mL and was lower than baseline PSA, which was required to be 20 ng/mL for this exploratory subset analysis.

Pain Response
Baseline pain was measured using the Present Pain Intensity (PPI) score from the McGill-Melzack questionnaire or an analgesic score (AS), with a PPI of 2 and an AS of 10 as indicative of significant pain.^2,15 A response was assessable in 456 subjects and was defined as a 2 point reduction from the baseline PPI without an increase in the AS or a more than 50% reduction in the AS without an increase in the PPI.

Surrogacy Evaluation
Statistical surrogacy was evaluated for PSA and pain end points using several methods. The primary measure of surrogacy was defined by Prentice operational criteria, and quantified as a proportion of treatment effect (PTE), explained by each surrogate measure, similar to the SWOG 9916 analysis.^6,11 Prentice criteria define a surrogate as a factor that fully explains the effect of treatment on survival.¹² To test this, Cox proportional hazards models, including treatment and PSA decline, were calculated with time-to-death as the outcome, and the assumptions of these models were tested using Schoenfeld residual analysis. After confirming the proportional hazards assumption, a series of Cox models were estimated with the following covariates: model 1, treatment arm; model 2, surrogate marker; and model 3, treatment arm + surrogate. In this analysis, a reasonable surrogate will be statistically associated (P < .05) with survival in both univariate and multivariate models, and will negate the effects of treatment when introduced into the multivariate model. All results were confirmed by landmark analysis.

The degree of surrogacy, or PTE, was calculated for each degree of PSA decline and pain response.¹³ The PTE ranges from 0 to 1, with 1 being a perfect surrogate, and 0 indicating lack of surrogacy. Specifically, PTE is one minus the ratio of the treatment coefficient in the adjusted Cox regression model to the treatment coefficient in the unadjusted model, where adjustment refers to a model that includes the surrogate. For the 95% CI of the PTE, we used the approximation suggested by Lin et al.¹³ Our comparison of interest was the every-3-weeks DP arm versus the every-3-weeks MP arm, given that the survival benefit was limited to this arm of the trial. However, we included the indicator for every-3-weeks DP versus weekly DP in the model to adjust for potential differences in survival in the two docetaxel arms.

An exploratory surrogacy measure that was analyzed is the Nagelkerke R², which estimates the degree of variation in survival explained by the surrogate.^16,17 A rising R² from the treatment-only Cox model to the surrogate-only model to the adjusted model is indicative of surrogacy.

	RESULTS

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Updated survival results as of November 2006 were used in this analysis, with 1,006 subjects followed up to 70.1 months, for a total follow-up time of 18,887 person-months, and with 800 subjects known to have died. A detailed analysis of updated survival results for the TAX327 trial will be published elsewhere, but the differences in survival between treatment arms are similar to those in the original study report.² Seventeen subjects were censored at random assignment due to lack of receipt of protocol treatment, and were thus excluded from analysis, leaving 989 subjects for analysis with PSA data within 3 months of baseline. In addition, 63 subjects had less than three post-treatment PSA values and were not included in the PSA velocity subset analysis. Subjects in this analysis were similar to the overall TAX327 cohort (Appendix Table A1, available online only, and Table 1). In general, the men were predominantly white with a median age of 68 years and had metastatic disease involving bone, and more than 45% were symptomatic with pain. The median baseline PSA doubling time was 55 days, and the median baseline PSA was 113 ng/mL.

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier estimates of overall survival in TAX327 according to 30% prostate-specific antigen (PSA) decline status within first 3 months of treatment initiation. Survival is updated as of November 2006. HR, hazard ratio.

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier estimates of overall survival according to a range of percent prostate-specific antigen (PSA) decline in TAX327, among all treatment groups. Median survivals and numbers of patients who achieved the corresponding PSA decline are listed in the legend.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Plot of the proportion of treatment effect explained (PTE) according to percent prostate-specific antigen (PSA) decline within the first 3 months of therapy. Bars represent 95% CIs of the PTE estimate.

We considered two additional approaches for estimating the PTE. In the first, we combined the two docetaxel arms and compared this group with mitoxantrone. This analysis also indicated that a 30% cutoff for PSA decline was optimal, with a PTE of 0.85 (95% CI, 0.24 to 1.00). Our second approach dropped the weekly DP arm and compared the every-3-weeks DP and MP arms directly without adjustment. This resulted in a PTE of 0.64 (95% CI, 0.22 to 1.00) at the optimal cutoff of a 30% PSA decline, confirming the robustness of our analysis.

Degree of Variance in Survival Explained by PSA Declines
The Nagelkerke R² criteria for surrogacy were evaluated and were found to increase with each model, from 0.009 using treatment alone, to 0.085 using 30% PSA decline as a surrogate alone to 0.087 in the adjusted model using both treatment and surrogate.^16,17 The overall proportion of explained variance is low, indicating that this degree of PSA decline is likely a modest surrogate. All other PSA decline values were tested in a similar fashion, with R² values that did not exceed levels for a 30% decline.

Changes in PSA Velocity
Post-treatment PSA velocity was calculated within 3 months of random assignment, and analyzed for surrogacy based on a declining PSA post-treatment (velocity 0 ng/mL/mo), or a decline faster than the median post-treatment velocity (–1.15 ng/mL/mo). These measures demonstrated significant prognostic ability. A rising PSA within 3 months (primary PSA progression) occurred in 269 subjects and was associated with a median survival of 12.2 months as compared with the 674 men who experienced at least some PSA decline or had stable PSA values, who had a median survival of 20.3 months (HR, 0.53; 95% CI, 0.45 to 0.62; P < .0001). A negative post-treatment PSA velocity was a modest surrogate, with a PTE of 0.59 (95% CI, 0.20 to 0.97). In addition, a PSA velocity decrease faster than the median post-treatment velocity was prognostic, but also a modest surrogate (PTE, 0.55; 95% CI, 0.19 to 0.91; Table 2 and Appendix Table A2, online only). Likewise, the absolute value of the ratio of post-treatment PSA velocity to pretreatment PSA velocity was prognostic but demonstrated weak surrogacy (n = 646; PTE, 0.23; 95% CI, 0.08 to 0.38).

PSA Normalization
As an exploratory measure, PSA normalization was investigated for surrogacy. Of 763 subjects who had a sufficiently elevated baseline PSA and follow-up PSA data, 115 subjects experienced normalization (0 to 4 ng/mL) of their PSA with treatment and had a median survival of 33.3 months, compared with those who did not normalize, with a median of 15.8 months (Table 2, Appendix Table A2, and Figs 2 and 4). In Cox modeling, PSA normalization was significantly prognostic (HR, 0.30; 95% CI, 0.23 to 0.39; P < .0001), but given its relative rarity as an outcome, it displayed weak surrogate properties (PTE, 0.08; 95% CI, 0.03 to 0.13). PSA normalization occurred in 14%, 18%, and 8% of men randomly assigned to every-3-weeks DP, weekly DP, and every-3-weeks MP, respectively. Landmark analysis up to 12 months confirmed these results, as the HR estimates did not significantly change.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Kaplan-Meier estimates of overall survival according to prostate-specific antigen (PSA) normalization at any point after random assignment, while receiving study chemotherapy. Hazard ratio for overall survival is 0.30 (95% CI, 0.23 to 0.39) for those men who achieved PSA normalization (n = 115) compared with those who did not (n = 333).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
We have demonstrated that PSA declines following chemotherapy for men with metastatic HRPC have modest surrogacy for OS, with the optimal level being a 30% 3-month decline. This work confirms that of Petrylak et al who conducted a similar analysis of another phase III randomized trial and identified a 30% post-treatment decline in serum PSA as an acceptable surrogate for OS.⁶ In these trials, this level of decline paralleled the effects of treatment; in TAX327, 67% of patients receiving every-3-weeks docetaxel regimens achieved this level of decline as compared with 44% of patients receiving every-3-weeks mitoxantrone, while in the SWOG 9916 trial, the proportions of patients achieving a 30% PSA decline were 76% and 40%, respectively.³ In SWOG 9916, the proportion of treatment effect explained (PTE) for this surrogate was 1.0, with a 95% CI that ranged from 0.73 to 1.0, indicating a high level of surrogacy.⁶ In the current analysis, however, more modest surrogacy was noted with a PTE of 0.66 (95% CI, 0.23 to 1.0).

The reasons for this discrepancy are unclear, but may relate to the stronger correlation of PSA declines with survival in the SWOG trial.⁶ The estrogenic activity of estramustine may confer a greater PSA decline compared with MP, thus providing greater distinction between treatments. Thus, for the combination of docetaxel and estramustine, PSA declines may have improved surrogacy for survival. Conversely, in TAX327, the PSA declines with DP were less pronounced compared with MP, despite a survival advantage that was similar to that achieved in SWOG 9916, thus reducing the surrogate properties of PSA declines in this trial. Additionally, factors beyond a 3-month time window may differentially influence survival.¹⁸

The identification of an early clinical or biomarker surrogate that captures the treatment effect on survival among men with HRPC would be significant for several reasons. The natural history of men with metastatic HRPC is heterogeneous and difficult to estimate solely using baseline prognostic factors, such as pain, performance status, PSA and PSA kinetics, hemoglobin, lactate dehydrogenase, and alkaline phosphatase.^19-21 An intermediate outcome may refine prognosis and allow optimization of treatment directed at those most likely to benefit, and assist in identifying active experimental therapeutics at an early stage of development.

We evaluated a range of intermediate outcomes for surrogacy of the survival benefit seen with every-3-weeks DP in men with HRPC. We found that while PSA and pain end points were prognostic, they did not meet strict surrogacy criteria. For example, a man with HRPC treated with docetaxel-based therapy who achieves a 30% 3-month PSA decline may expect a median survival of 21.6 months, as compared with 13.0 months if this threshold is not met. While this difference is large, only two-thirds of the survival difference observed was explained through this PSA decline. The fact that weekly DP demonstrated greater PSA declines compared with every-3-weeks DP despite a lack of survival advantage over MP argues that the survival benefit was not related to the initial 3-month PSA decline. Additional factors that may explain the survival benefit of every-3-weeks DP include mode of disease progression or composites of pain, tumor, and PSA response to treatment.^4,21 Finally, this analysis is limited to cytotoxic chemotherapy, and is not generalizable to different stages of prostate cancer or to agents with other mechanisms of action. Cytostatic and antiangiogenic agents may have therapeutic effects independent of PSA.^12,22

The current study indicates that PSA declines are prognostic but not sufficiently rigorous to be guides for modification of treatment. Prospective validation of PSA declines should be performed before use as surrogates for OS in phase III clinical trials in men with HRPC. A 30% PSA decline in a phase II trial of men with HRPC may be evidence of early activity of a cytotoxic agent; however, this estimate may be incorrect in nearly one third of cases. The early cessation of therapy due to a biologically arbitrary threshold of PSA decline may prevent a large fraction of men from achieving the survival benefits associated with docetaxel. Conversely, a significant proportion of men have a survival benefit with docetaxel despite the absence of baseline pain. In conclusion, OS should remain the primary end point of phase III trials of men with HRPC.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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.

Employment: N/A Leadership: N/A Consultant: Michael A. Carducci, Sanofi-aventis, Centocor, Abbott, Methylgene, MGI Pharma, Dendreon, Merck, GlaxoSmithKline; Ronald de Wit, Sanofi-aventis; Mario A. Eisenberger, Sanofi-aventis, Merck, ImClone, Bristol Myers Squibb, Celgene, Cytogen Stock: N/A Honoraria: N/A Research Funds: Michael A. Carducci, Funds, Abbott, Sanofi-aventis; Ian F. Tannock, Funds, Immunex; Ronald de Wit, Funds, Sanofi-aventis; Mario A. Eisenberger, Funds, Sanofi-aventis, Celgene, Cytogen Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Andrew J. Armstrong, Ian F. Tannock, Mario Eisenberger

Financial support: Andrew J. Armstrong

Administrative support: Andrew J. Armstrong

Provision of study materials or patients: Ian F. Tannock, Ronald de Wit, Mario Eisenberger

Collection and assembly of data: Andrew J. Armstrong, Yi-Chun Ou Yang, Ian F. Tannock, Ronald de Wit, Mario Eisenberger

Data analysis and interpretation: Andrew J. Armstrong, Elizabeth S. Garrett-Mayer, Yi-Chun Ou Yang, Ian F. Tannock, Mario Eisenberger

Manuscript writing: Andrew J. Armstrong, Elizabeth S. Garrett-Mayer, Michael A. Carducci, Ian F. Tannock, Mario Eisenberger

Final approval of manuscript: Andrew J. Armstrong, Elizabeth S. Garrett-Mayer, Michael A. Carducci, Ian F. Tannock, Ronald de Wit, Mario Eisenberger

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
M.A. Rosenthal from Australia; D. Campos (Argentina); H. Gurney and M. Stockler (Australia); M. Rauchenwald (Austria); T. Gil, Y. Humblet, and A. van Oosterom (Belgium); D. Herchenhorn (Brazil); S. Ernst, L. Lacombe, M. Moore, F. Saad, D. Soulieres, P. Venner, and E. Winquist (Canada); M. Urban (Czech Republic) P. Kellokumpu-Lehtinen (Finland); G. Deplanque, B. Duclos, I. Krakowski, and L. Mignot, S Oudard and C. Theodore (France); J. Breul and R. Paul (Germany); I. Bodrogi (Hungary); S. Bracarda (Italy); G. Chahine (Lebanon); J.L. Bruins and J.A. Witjes (the Netherlands); T. Demkow and K. Bar (Poland); O. Kariakine and M. Matveev (Russia); I. Andrasina (Slovak Republic); D. Vorobiof (South Africa); J. Bellmunt and J.-R. Germa (Spain); I. Turesson and A. Widmark (Sweden); A. Horwich, T. Roberts, N.D. James, and J. Wylie (United Kingdom); and L. Baez, W. Dugan, and N. Tirumali (United States).

	ACKNOWLEDGMENTS

 
We thank the many patients who volunteered to participate in the TAX-327 study and the investigators who recruited them and managed their care. Some of these investigators are listed in the online-only Appendix.

	NOTES

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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10. Bubley GJ, Carducci MA, Dahut W, et al: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: Recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 17:3461-3467, 1999[Abstract/Free Full Text]

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18. Armstrong AJ, Garrett-Mayer ES, de Wit R, et al: Limitations of the current progression-free survival (PFS) definition in hormone-refractory prostate cancer (HRPC): Benefit associated with continuation of docetaxel beyond TAX327 protocol-defined progression. Am Soc of Clin Oncol Prostate Cancer Symposium 2007 (abstr 20113)

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Submitted March 2, 2007; accepted June 14, 2007.

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				A. J. Armstrong, E. L. Garrett-Mayer, and M. Eisenberger Re: Adaptive Therapy for Androgen-Independent Prostate Cancer: A Randomized Selection Trial of Four Regimens J Natl Cancer Inst, May 7, 2008; 100(9): 681 - 682. [Full Text] [PDF]

				D. R. Berthold, G. R. Pond, M. Roessner, R. de Wit, M. Eisenberger, a. I. F. Tannock, and on behalf of the TAX-327 investigators Treatment of Hormone-Refractory Prostate Cancer with Docetaxel or Mitoxantrone: Relationships between Prostate-Specific Antigen, Pain, and Quality of Life Response and Survival in the TAX-327 Study Clin. Cancer Res., May 1, 2008; 14(9): 2763 - 2767. [Abstract] [Full Text] [PDF]

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				A. Berruti, M. Tucci, A. Mosca, M. Ardine, M. Poggio, A. Saini, L. Russo, F. Vana, and L. Dogliotti Could the Efficacy of Docetaxel in Prostate Cancer Patients Be Potentiated by Concomitant High-Dose Calcitriol Administration? J. Clin. Oncol., April 10, 2008; 26(11): 1900 - 1901. [Full Text] [PDF]

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				H. I. Scher, S. Halabi, I. Tannock, M. Morris, C. N. Sternberg, M. A. Carducci, M. A. Eisenberger, C. Higano, G. J. Bubley, R. Dreicer, et al. Design and End Points of Clinical Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group J. Clin. Oncol., March 1, 2008; 26(7): 1148 - 1159. [Abstract] [Full Text] [PDF]

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				A. J. Armstrong, E. Garrett-Mayer, M. Eisenberger, I. Tannock, and R. de Wit In Reply J. Clin. Oncol., December 10, 2007; 25(35): 5674 - 5674. [Full Text] [PDF]

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