High-Risk Localized Prostate Cancer: A Case for Early Chemotherapy Martin Gleave and W. Kevin Kelly

NUMBER NOVEMBER VOLUME 23 d 32 d 10 2005 JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E High-Risk Localized Prostate Cancer: A Case for Early Chemotherapy Martin Gleave and W. Kevin Kelly From the Department of Surgery, University of British Columbia Director, Clinical Research, The Prostate Centre, Vancouver General Hospital Vancouver, British Columbia, Canada; and Yale University, Yale Cancer Center, New Haven, CT. Submitted June 30, 2005; accepted August 3, 2005. Authors disclosures of potential conflicts of interest are found at the end of this article. Address reprint requests to Martin Gleave, FRCSC, FACS, Department of Surgery, University of British Columbia, D-9, 2733 Heather St, Vancouver, BC, Canada V5Z 3J5; e-mail: gleave@interchange.ubc.ca. 2005 by American Society of Clinical Oncology A B S T R A C T High-risk tumors exhibit a more aggressive natural history and have higher positive margin and recurrence rates after radical prostatectomy or radiotherapy alone, where unimodality therapy likely represents undertreatment. Hence, the therapeutic ratio (patients who actually realize a survival benefit from a therapeutic intervention) may, therefore, be greater in high-risk disease if its natural history can be altered by multimodality therapy. It is, thus, important to investigate therapies that optimize complete extirpation of all cancer cells and reduce the incidence of positive surgical margins and disease recurrence. Neoadjuvant therapy extends the logic of early adjuvant therapy further by applying systemic therapy earlier in the course of the disease before definitive locoregional therapy. In prostate cancer, outcomes have not been improved significantly when neoadjuvant hormone therapy is used before surgery; although outcomes are improved when androgen ablation is combined with radiotherapy, many patients remain at risk for systemic recurrence. With recent data confirming improved survival data with docetaxel chemotherapy in metastatic disease, future trials are now focusing on earlier combinations of chemohormonal or biologic therapies in high-risk patients. J Clin Oncol 23:8186-8191. 2005 by American Society of Clinical Oncology 0732-183X/05/2332-8186/$20.00 DOI: 10.1200/JCO.2005.03.3068 INTRODUCTION Despite remarkable advances in surgical techniques and delivery of radiotherapy over the last two decades, residual disease at the primary site or the presence of microscopic disease outside the surgical or radiotherapy fields ultimately lead to biochemical and/or disease recurrence in most patients with high-risk disease. 1-3 Today, clinicians are better able to identify these poor-risk patients through the use of nomograms. 1-3 The use of early and prolonged androgen ablation therapy with radiotherapy delays disease progression and improves overall survival; however, most patients still relapse, develop androgenresistant disease, and eventually die as a result of their cancer. 4-6 More effective therapy is needed in these high-risk patients that target the local and distant disease and the androgen-dependent and -independent (hormone-refractory) subpopulations of malignant cells (Fig 1). Introducing systemic cytotoxic chemotherapy earlier in these highrisk patients has been hampered by the lack of effective chemotherapy in hormonerefractory prostate cancer (HRPC). 7,8 More recently, docetaxel-based regimens have shown a clinical benefit and survival advantage in patients with HRPC, allowing us to move cytotoxics forward in the treatment of patients with localized HRPC. PRIOR EXPERIENCE WITH EARLY CHEMOTHERAPY IN PATIENTS WITH HIGH-RISK LOCALIZED PROSTATE CANCER AND RADICAL PROSTATECTOMY There are no adequately powered randomized studies that have been completed using adjuvant or neoadjuvant chemotherapy in conjunction with surgery or radiotherapy. Numerous small trials with variable inclusion criteria have evaluated the use of early chemotherapy, and used a microtubule-based chemotherapy regimen such as docetaxel or 8186

Chemotherapy for Localized High-Risk Prostate Cancer Chemotherapy (novel agents: anti-angiogenesis, HDACI, anti-sense, monoclonal abs) Decrease the risk of distant metastasis Androgen sensitive Androgen insensitive Cytoreduction prior to surgery/radiotherapy Control local residual disease Fig 1. Improving the outcomes in patients with locally advanced prostate cancer. Abs, antibodies; HDACI, histone deacetylase inhibitor. paclitaxel with or without androgen ablation (Table 1). The primary outcomes for these trials were feasibility and safety. Secondary end points assessed the pathologic response in the primary tumor and post-therapy changes in biochemical markers. Consistent in all trials is that the addition of chemotherapy increased the morbidity of the therapy, but most of the adverse effects were reversible once the treatment was discontinued. Toxicities included mild to moderate anemia, neutropenia, fatigue, nausea and vomiting. However, more serious complications such as deep-vein thrombosis occurred in up to 22% of patients who received an estramustine-based regimen. 9-12 These adverse events were manageable and not significantly different from what has been experienced in the more advanced disease setting. Importantly, these trials confirmed the safety and feasibility of administering chemotherapy before radical prostatectomy. The systemic therapy in general did not complicate the surgical procedure; however, some studies reported an increase in periprostatic fibrosis that increased the average difficulty of surgery compared with non chemotherapy-treated patients. 9,13,14 These observations may also reflect that fact that patients with more locally advanced tumors were enrolled in these trials. The mean surgical time, estimated blood loss, or the median hospital stay werenot increased compared with non chemotherapytreated patients. 9,13,14 The reported rates of erectile Author Table 1. Neoadjuvant and Adjuvant Chemotherapy Trials in Patients With Locally Advanced Prostate Cancer No. of Patients Inclusion Criteria Neoadjuvant trials Pettaway et al 11 33 ct1-2, GL $ 8; ct2b-c, GL $ 7; PSA 10 ng/ml Clark et al 10 18 ct2b-c or T3 with PSA $ 15 ng/ml or GL $ 8 Konety et al 9 36 ct1-2 with PSA $ 20 ng/ml; Local Therapy Hormonal Therapy Chemotherapy Regimen Clinical Outcome RP Yes KAVE 12 weeks No P0 50% achieved PSA NMA after chemotherapy RP Yes EMP\VP-16 12 No P0 50% achieved PSA weeks NMA after chemotherapy RP Yes TEC 12-16 weeks No P0 Median PSA nadir 0.17 ng/ml ct3-4; GL $ 8 Ko et al 26 12 ct3; PSA $ 20 ng/ml; GL 8-10; RP Yes EMP docetaxel No P0 75% achieved PSA NMA after chemotherapy Hussain et al 12 21 $ ct2b; PSA $ 15 ng/ml; GL 8 RP Yes EMP docetaxel No P0 100% achieved PSA 50% decline after chemotherapy Gleave et al 18 72 GL $ 8 or PSA $ 20 plus $ 2 positive cores; or T3a or GL $ 7 plus PSA $ 10 plus $ 3 positive cores RP Yes Docetaxel weekly LHRH analog 2 complete responders (p0), 14 microfoci pt2 Oh et al 15 15 ct3; PSA 20 ng/ml; GL $ 8 RP No Docetaxel weekly 67% achieved PSA 50% decline after chemotherapy Beer et al 13 22 ct2c; ct3a; PSA $ 15 ng/ml; RP No Docetaxel weekly Median PSA decline of 41% GL $ 4 3 mitoxantrone Drecier et al 27 29 T2b-T3; PSA 15 ng/ml; GL $ 8 RP No Docetaxel weekly 24% achieved PSA 50% decline after chemotherapy Khil et al 23 65 T2-4; GL 4-10; locally advanced prostate cancer Radiotherapy (65-70 Gy) Yes EMP vinblastine 7 weeks prior to 5-yr BFS: T2, 49%; T3, 38%; T4, 17% Zelefsky et al, 23 GL $ 8 plus PSA 10 ng/ml GL7 Ryan et al 24,25 plus PSA 20 ng/ml T3 plus PSA 20 ng/ml T4N0M0 TxN1M0 Radiotherapy 75.6 Gy Yes radiotherapy EMP vinblastine 16 weeks prior and concomitant Adjuvant trials Schmidt et al 21 184 Locally advanced prostate cancer RP Cyclophosphamide 2 years v EMP 2 years v observation Wang et al 28 96 ct3 localized or metastatic disease RP Yes Mitoxantrone LHRH agonist\antiandrogen v LHRH agonist\ antiandrogen Increase grade 2 late GI\GU toxicity 5-year BFS, 25% 48% No additional therapy 10-year FU: EMP has improved RFS, no difference in OS Median OS and DSS 80 and 84 months v 36 and 41 months Abbreviations: GL, Gleason score; RP, radical prostatectomy; KAVE, ketoconazole, doxorubicin, vinblastine, and estramustine phosphate; PSA, prostatespecific antigen; NMA, no measurable amount; EMP, estramustine phosphate; VP-16, etoposide; TEC, paclitaxel, estramustine phosphate, carboplatin; LHRH, leutenizing hormone releasing hormone; BFS, biochemical-free survival; GI, gastrointestinal; GU, genitourinary; FU, follow-up; RFS, relapse-free survival; OS, overall survival; DSS, disease-specific survival. www.jco.org 8187

Gleave and Kelly dysfunction and incontinence were similar to patients undergoing wide bilateral or unilateral resection of neurovascular bundles who did not received chemotherapy. 9,13,14 Identifying benefit in clinical outcomes is difficult due to the absence of a control arm in all of these trials. As expected, post-therapy declines in prostate-specific antigen (PSA) were observed universally in studies that combined androgen ablation with chemotherapy. Of interest are the studies with docetaxel-based therapies alone that demonstrated post-therapy declines in PSA ranging from 24% to 60% after the administration of the chemotherapy, indicating an independent antitumor effect on hormonenaive prostate cancer. 13-15 In patients who have recurrent or metastatic androgen-sensitive prostate cancer, Hussain et al 16 reported that 49% and 20% of patients had a $ 50% or $ 75% decline in PSA after docetaxel treatment, respectively. Serum testosterone levels were not altered significantly by chemotherapy, further providing evidence of the activity of chemotherapy in early prostate cancer. Theoretical concerns regarding a potential risk of detriment rather than benefit from the concurrent administration of hormonal and cytotoxic therapies has raised questions regarding the sequence of administration of chemo-/hormonal therapies. Recently, preclinical data evaluating the optimal timing and combination of androgen withdrawal with cytotoxic chemotherapy in LNCaP and Shionogi prostate cancer xenografts reported that mice receiving simultaneous chemo-hormonal therapy had a significant improvement in median time to progression versus best sequential therapy. 17 Interestingly, a marked lack of response to castration was observed after initial paclitaxel therapy, and transcriptional profiling identified increased expression of several survival genes known to play a role in androgen independence after paclitaxel exposure. These findings support simultaneous chemo-hormonal therapy in future neoadjuvant and adjuvant trials. In neoadjuvant studies, pathologic specimens were noted in some cases to have marked tumor regression, but complete eradication of the tumor was rare. Gleave et al 18 reported that two of 64 patients treated with docetaxel plus androgen ablation for 24 weeks had a complete pathologic response (no tumor in final pathologic specimen). Histologic changes observed in specimens included disintegration of the acinar/glandular arrangement of the neoplastic epithelium, cytoplasmic clearing, and vacuolation. 12 Squamous metaplasia was also observed with the estramustine-based therapies, likely the result of estrogenic and castration-inducing effects of this compound. The use of neoadjuvant hormonal and chemotherapy has been shown to be feasible and safe, but more importantly it has provided a platform for understanding prostate cancer biology and drug discovery. The radical prostatectomy tissues from these trials are a valuable resource for changes in expression levels of critical regulators of cell cycle and apoptosis after castration and chemotherapy. Tissue microarray and transcriptional profiling can define treatment-induced changes in gene expression (eg, stress-activated cytoprotective chaperones like clusterin and Hsp27; Fig 2), which are, in turn, being targeted to enhance chemo- and hormonal responsiveness. 19,20 Future studies such as the randomized Intergroup Cancer and Leukemia Group B study will randomize patients with high-risk localized prostate cancer to androgen ablation with docetaxel-based therapy before radical prostatectomy or immediate radical prostatectomy and provide the opportunity to further study the molecular changes associated with chemotherapy. ADJUVANT CHEMOTHERAPY AND HORMONE THERAPY AFTER RADICAL PROSTATECTOMY In the mid-1980s, Schmidt et al 21 from the National Prostate Cancer Group randomly assigned 184 patients with localized advanced prostate cancer to one of the three arms: 2 years of oral cyclophosphamide, estramustine phosphate for 2 years, or observation. After 10 years of follow-up, the estramustine-phosphate group had an improvement in relapse-free survival but there was no difference in overall survival, likely reflecting insufficient power of small sample size. It is important to point out that some of the clinical outcomes observed are likely due to the castrating effect of estramustine. A more contemporary trial by Wang et al 22 randomly assigned 96 patients with clinical T3 or T4 disease or metastatic disease to mitoxantrone plus combined androgen blockade versus combined androgen blockade alone. In the 38 patients without metastatic disease, a higher initial objective response (95% v 53%; P Z.008) and median survival (80 v 36 months; P Z.04) was observed in patients treated with mitoxantrone plus combined androgen ablation. In contrast, no survival advantage was seen with combination chemo- plus hormonal therapy for the patients with documented metastatic disease. Although these results are interesting, the sample size is too small to confirm any clinical benefit from the mitoxantrone therapy. An ongoing Southwest Oncology Group trial randomly assigning patients with high-risk features after radical prostatectomy to 2 years of combined androgen ablation with or without mitoxantrone therapy is adequately powered to address the role of mitoxantrone in this setting. NEOADJUVANT CHEMOTHERAPY AND HORMONAL THERAPY WITH RADIOTHERAPY Androgen ablation, as well as chemotherapy, are potent radiosensitizers that can enhance local tumor control in many other malignancies. Numerous preclinical and clinical trials document improved outcomes in patients treated with 8188 JOURNAL OF CLINICAL ONCOLOGY

Chemotherapy for Localized High-Risk Prostate Cancer A B C D Fig 2. The expression levels of stress-activated cytoprotective chaperones, Hsp27 (A and C) and clusterin (B and D) increase substantially in residual prostate cancer cells after 6 months of neoadjuvant chemohormonal therapy (C and D) compared with untreated prostate cancers (A and B). neoadjuvant hormone therapy plus radiotherapy compared with radiation monotherapy. Many investigators are now studying whether the addition of chemotherapy will further enhance the outcomes in high-risk patients treated with radiation therapy. Khil et al 23 reported the results of 65 men with a clinical stage T2 to T4, Gleason score of 4 to 10, with locally advanced prostate cancer that were treated with 16 weeks of estramustine phosphate and vinblastine concomitantly with external beam radiotherapy (65 to 70 Gy). Therapy was well tolerated, undetectable PSA at 6 weeks was observed in 86% of the patients, and 5-year biochemicalfree survival for T2 were 49%, for T3 were 38%, and T4 were 17%. Zelefsky et al 24 evaluated 23 patients with locally advanced prostate cancer defined as Gleason scores of 7 to 10 with a PSA of 10 to 20; clinical T3 disease with a PSA 20; or T4 N0 or TXN1M0 disease. Estramustine phosphate and vinblastine were administered before and concurrently with high-dose conformal radiotherapy (75.6 Gy). There was an increase incidence of late grade two gastrointestinal and genitourinary toxicities observed with this combination. The 5-year biochemical-free survival was 25% and 48% of the patients had asymptomatic rise in the PSA without evidence of metastatic disease at 5 years that required no additional therapy. 25 www.jco.org 8189

Gleave and Kelly Table 2. Ongoing or Planned Phase III Clinical Trial in Patients with Locally Advanced Prostate Cancer No. of Protocol Sponsor Treatment Patients Adjuvant androgen deprivation v mitoxantrone plus prednisone plus androgen deprivation in selected high risk prostate cancer patients after radical prostatectomy, Phase III: SWOG 9921 Adjuvant phase III yrial for high risk of recurrence prostate cancer after radical prostatectomy Chemotherapy after prostatectomy for high-risk prostate carcinoma: A phase III randomized study Randomized phase III trial of neoadjuvant docetaxel and ADT followed by RP v neoadjuvant ADT followed by RP in patients with high risk localized prostate cancer: CALGB 90203 A phase III protocol of AS and 3DCRT/ IMRT v AS and 3DCRT/IMRT followed by chemotherapy with docetaxel and prednisone for localized, high-risk prostate cancer Docetaxel plus 6 months of AS and radiation therapy v 6 months of AS and radiation therapy for patients with high-risk localized or locally advanced prostate cancer: A randomized controlled trial NCI/SWOG Sanofi-Aventis Department of Veterans Affairs NCI\CALGB\NCIC NCI\RTOG Sanofi-Aventis CAB 2 years v mitoxantrone plus prednisone plus CAB 2years First random assignment: observation v early treatment with LHRH agonist or LHRH plus docetaxel 6 cycles; Second random assignment of the observation arm at disease progression: LHRH agonist or LHRH plus docetaxel 6 cycles Docetaxel plus prednisone 18 weeks v standard of care (observation) Docetaxel 6 cycles plus ADT 6 months followed by RP v ADT 6 months followed by RP AS 24 months plus radiotherapy v AS 24 months plus radiotherapy followed by docetaxel plus prednisone 6 cycles Docetaxel plus AS 6 months plus radiotherapy v AS 6 months plus radiotherapy Primary Trial End Point 1,360 Overall survival 2,172 Progression-free survival 636 Progression-free survival 750 Progression-free survival at 5 years 600 Overall survival 350 Overall survival Abbreviations: SWOG, Southwest Oncology Group; NCI, National Cancer Institute; CAB, combined androgen blockade; LHRH, leutenizing hormone releasing hormone; ADT, androgen-deprivation therapy; RP, radical prostatectomy; CALGB, Cancer and Leukemia Group B; NCIC, National Cancer Institute of Canada; AS, androgen suppression; 3DCRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiation therapy. EARLY CHEMOTHERAPY IN LOCALLY ADVANCED PROSTATE CANCER: CONTROVERSIES AND FUTURE DIRECTIONS Studies to date confirm that neoadjuvant and adjuvant chemotherapy therapy are feasible, safe and do not significantly complicate surgery or radiotherapy. Whether we actually improve overall survival still needs to be explored in appropriately powered randomized studies (Table 2). Therelativebenefit ofthechemotherapyadministered neoadjuvantly or adjuvantly needs further exploration and should not be used outside of a study setting. The potential for chronic adverse effects from chemotherapy and their negative impact on quality of life need to be better quantified. Adjuvant therapy has the advantage of limiting the morbidity of additional therapy to only the highest-risk patients, who typically can be defined more precisely after examining the final pathologic specimen. This approach will not interfere with the primary therapy of surgery or radiotherapy, but may delay the administration of systemic therapy. The use of neoadjuvant therapy may make the interpretation of the pathologic specimen more difficult to interpret; however, it can enhance the effects of radiotherapy and provide researchers an opportunity to investigate the molecular changes associated with therapy. Regardless of the approach in administering early chemotherapy, the relative benefits on residual disease are similar. Over the years there have been accumulating clinical and most recently preclinical data that would suggest that the use of early chemotherapy will improve the outcomes in patients with high-risk localized prostate cancer. However, the use of early chemotherapy remains investigational until the risks and benefits are better defined in the randomized studies. - - - 8190 JOURNAL OF CLINICAL ONCOLOGY

Chemotherapy for Localized High-Risk Prostate Cancer Authors Disclosures of Potential Conflicts of Interest 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 Martin Gleave AstraZeneca (A) Oncogenex (B) W. Kevin Kelly AstraZeneca (A) TAP Pharmaceutical Products Inc (A) Oncogenex (A) Astra-Zeneca (A) AstraZeneca (A) TAP Pharmaceutical Products Inc (A) Dollar amount codes: (A) $10,000 (B) $10,000-99,999 (C) $ $100,000 (N/R) Not Required Sanofi-Aventis (B) Oncogenex (B) REFERENCES 1. Kattan MW, Eastham JA, Stapleton AMF, et al: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 90:766-771, 1998 2. D Amico AV, Whittington R, Malkowicz SB, et al: Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 280:969-974, 1998 3. D Amico AV, Whittington R, Malkowicz SB, et al: A multivariate analysis of clinical and pathological factors that predict for prostate specific antigen failure after radical prostatectomy for prostate cancer. J Urol 154:131-138, 1995 4. 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Urology 63:1138-1142, 2004 28. Wang J, Halford S, Rigg A, et al: Adjuvant mitozantrone chemotherapy in advanced prostate cancer. BJU Int 86:675-680, 2000 www.jco.org 8191