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Adjuvant chemotherapy for T3 prostate cancer: not ready for prime time
EDITORIAL
ADJUVANT CHEMOTHERAPY FOR T3 PROSTATE CANCER: NOT READY FOR PRIME TIME MICHAEL A. CARDUCCI
R
ecent reviews of prostatectomy as monotherapy for T3 prostate cancer have suggested that adjuvant therapy is required.1– 4 In limited and uncontrolled series, adjuvant therapy has meant the addition of external beam radiation or endocrine therapy. Few or no published studies on the use of adjuvant chemotherapy for T3 prostate cancer exist that have adequate follow-up to allow for an appropriate interpretation of the results. The question of adjuvant chemotherapy for T3 prostate cancer stems from two impulses. First, it is easy to extrapolate successes in adjuvant therapy from other tumor types. Second, chemotherapy is seen to be emerging as a viable, tolerable, and efficacious strategy in advanced refractory prostate cancer. Despite the perceived improvements in the management of advanced prostate cancer, no clinical justification has emerged for the use of adjuvant chemotherapy in patients with T3 prostate cancer after surgery. T3 PROSTATE CANCER: THE PROBLEM WITH STAGING
T3 disease is defined as tumor that extends through the prostatic capsule, including focal extracapsular penetration and/or invasion of the seminal vesicles. Clinical staging is often inaccurate, with both overstaging and understaging noted. Understaging by clinical findings is demonstrated by the many reports in which up to 26% of patients with T1b, 33% of patients with T2a, and 68% of those with T2b-T2c tumors will prove to have extracapsular disease (pathologic T3).5 Each year many patients have more advanced disease than is believed curable by surgical resection alone. Predictive models, such as the Partin Tables, help to clarify the risk of extraprostatic disease extension From the Division of Medical Oncology and Experimental Therapeutics, Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland Reprint requests: Michael A. Carducci, M.D., Johns Hopkins Oncology Center, 720 Rutland Avenue, Ross 359, Baltimore, MD 21205 Submitted: May 4, 1999, accepted: July 15, 1999 © 2000, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
at the time of surgery.6 Despite a measurable risk of pT3 disease, a number of factors bring many men to prostatectomy, including a potential for overstaging, young age, and patient desire. Men with pT3 disease may be divided into prognostically distinct subgroups by the histologic features and by the presence or absence of a detectable postoperative prostate-specific antigen (PSA) level. Admittedly, all pT3 subgroups are at higher risk of local and distant relapse than patients with organconfined disease, but the degree of risk varies. A number of studies with long-term clinical follow-up point out that extracapsular disease predisposes to local failure. Independent predictors of local failure are positive surgical margins and high tumor grade. Seminal vesicle involvement is a better predictor of distant metastasis. Up to 75% of men with extensive extracapsular disease, positive margins, or seminal vesicle involvement will have a PSA relapse within 5 years of surgery.1– 4 Many groups have drawn a prognostic distinction between focal and extensive positive surgical margins. Focally positive margins are associated with a 40% risk of progression at 5 years; patients with extensive positive margins have a 65% risk of progression.7,8 Patients with T3N0 disease with the highest progression rates are those with seminal vesicle involvement, a poorly differentiated phenotype, and a detectable PSA postoperatively.1– 8 These patients are the ones most likely to be selected for trials of adjuvant chemotherapy. Adjuvant radiation and endocrine therapy may be of some benefit to this patient population in terms of morbidity and survival, but even these adjuvant strategies have not been rigorously studied. A CASE FOR “CLINICAL CONSERVATISM” The cancer-specific survival rate at 15 years in patients with clinical Stage T3 after prostatectomy is 69%. In a review by Lerner et al.,3 the overall rate of nonprogression (systemic plus local) was 61% and 50% at 10 and 15 years of follow-up, respectively. When follow-up PSA was included as a criterion for progression, an additional 20% of paUROLOGY 55: 157–160, 2000 • 0090-4295/00/$20.00 PII S0090-4295(99)00366-0 157
tients manifested a subclinical progression at 10 and 15 years of follow-up. In these studies, 60% of patients with clinical Stage T3 undergoing prostatectomy received adjuvant therapy with radiation or hormonal therapy. Given these 15-year survival rates for patients with T3 disease who underwent prostatectomy, with more than half receiving adjuvant radiation or endocrine therapy, it has been suggested that monotherapy is suboptimal.1–3 On the other hand, more than 50% of patients are alive 15 years after surgery when treated in the described manner. Clearly there is room for improvement. A better understanding or standardization of clinical practice for patients with T3 prostate cancer may be used to optimize and select the patients requiring more than just surgical therapy. Little reported data exist regarding the addition of chemotherapy to this patient population. Most of the chemotherapy studies in combination with hormonal therapy for patients with newly diagnosed metastatic prostate cancer have looked at patients with D1 or nodal disease.9 –12 What should be done for the patient with Stage T3 disease and seminal vesicle involvement, high Gleason score (8 or greater), and an elevated PSA postoperatively? Surgical summaries suggest favorable long-term results, often with the addition of adjuvant radiation or androgen ablative therapies. With such procedures, long-term morbidity may be reduced because local progression, with extension into the bladder, and other local symptoms are often prevented. Neoadjuvant hormonal therapy for this patient population undergoing primary radiation therapy has clinical trial evidence of efficacy, including improvement in local control and reduction in disease progression.13 However, neoadjuvant endocrine therapy before prostatectomy has met with disappointing results.14 The reduction in prostate size and reduced incidence of positive surgical margins has had little clinical impact on survival or progression rates. A patient’s prognosis relates primarily to the pathologic stage before hormonal therapy. Stage pT3 disease is not an immediate death sentence, yet warrants concern for its potential for morbidity, psychosocial distress, and mortality. The role of adjuvant therapy is to lengthen the time to progression, to improve survival, and to have a positive impact on the quality of life in the long run. For patients older than 70, the benefits of adjuvant therapy will be hard to document in terms of years prolonged or quality of life improved. For the younger patient, pT3 cancer is likely to shorten that individual’s life, despite a 30% to 69% 15-year disease-specific survival rate based on prognostic factors.5 The impact of adjuvant therapy on such parameters needs to be quite dramatic to show a benefit in survival and quality of life. 158
ADJUVANT CHEMOTHERAPY IN OTHER TUMOR TYPES Adjuvant chemotherapy has been shown to be beneficial in patients with locally advanced breast and colon carcinoma. Progression and mortality rates of greater than 50% at 5 years exist for these patients at the time of adjuvant therapy. Multiple large-scale clinical trials were required to demonstrate the clinical efficacy of adjuvant chemotherapy in these patient populations. For example, adjuvant therapy for Stage III colon carcinoma reduces recurrence rates by nearly 20%.15 Most chemotherapy regimens used in the adjuvant setting have demonstrated clinical activity in advanced metastatic disease. For breast cancer, agents like cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) showed an 8% reduction in death from breast cancer when used in the adjuvant setting.16 This benefit is not exactly a huge improvement for an individual; however, the societal benefits of saving 8% of women with high-risk breast cancer means thousands of lives saved. However, it has been hard to prove the benefit of adjuvant therapy in other tumor types. In bladder cancer, methotrexate/vinblastine/doxorubicin/cisplatinum (MVAC) has nearly a 65% response rate in patients with advanced metastatic bladder cancer.17 When the regimen has been used adjuvantly in patients with muscle-invasive bladder cancer (T3 or T4, node-positive bladder cancer), it has been difficult to demonstrate an improvement in survival or a delay in time to progression. CHEMOTHERAPY FOR HORMONEREFRACTORY PROSTATE CANCER Advances in chemotherapy for hormone-refractory prostate cancer prompted the development of clinical trials for early-stage prostate cancer. Chemotherapy regimens used in the 1980s by the National Prostate Cancer Project and other academic centers demonstrated low response rates and no effect on survival. For the most part, chemotherapy has been viewed as only adding to the unpleasantness of having prostate cancer. Agents used in the past include single-agent estramustine, cyclophosphamide, doxorubicin, and cis-platinum. In the PSA era, today’s regimens typically combine cytotoxic agents with a hormonal-type agent and are administered to patients on an outpatient basis. Responses are defined by declines in PSA, most often a PSA decline of greater than 50% for at least 8 weeks. Agents inducing a clinical benefit have been approved for symptomatic hormone-refractory prostate cancer, such as mitoxantrone/ prednisone, despite a low PSA response rate. Regimens under investigation and in wide clinical practice include estramustine/etoposide, adriamyUROLOGY 55 (2), 2000
cin/ketoconazole/estramustine/vinblastine, paclitaxel/estramustine, docetaxel/estramustine, and single-agent docetaxel.18 –21 PSA response rates for these regimens are consistently greater than 50% in recent reports, with measurable disease response rates greater than 40%. The taxane/estramustine regimens have reported 17 to 24-month median survival times in nonrandomized Phase I and Phase II trials in patients with hormone-refractory prostate cancer. This apparent improvement in survival has yet to be tested in multi-institution, randomized clinical trials. One caveat concerning the current chemotherapy regimens for advanced prostate cancer is that most of the regimens have a hormonal agent, like estramustine, ketoconazole, or prednisone, as the backbone. By using these chemotherapy/hormonal therapy regimens in hormonal-naive patients, the early results look promising because progression appears delayed as a result of the hormonal agent. True benefits to the cytotoxic or chemotherapy arm of the therapy are unlikely to be fully assessed unless regimens that exclude hormonal therapy are tried in the adjuvant setting. The interpretation of clinical trials in the adjuvant setting must consider the agents selected for testing to determine the real benefits of such therapies. Further evaluation of these regimens in advanced disease is required. Moving these regimens to earlier disease stages should only be done in the context of well-designed clinical trials. Extrapolation of results and clinical trial successes from other tumor types has not always met with success in the next tumor type. The appropriate, rational selection of patients likely to “benefit” and requiring “benefit” is important to the design of adjuvant chemotherapy trials for patients with locally advanced T3 prostate cancer. NONTOXIC, ANTIPROGRESSION AGENTS FOR T3 PROSTATE CANCER The term “chemotherapy” has come to have multiple meanings and at times is inclusive or exclusive of newer treatment strategies such as antiprogression agents (eg, vitamin D, vitamin A, phenylbutyrate, matrix metalloproteinase inhibitors, and angiogenesis inhibitors) or immunotherapy agents.22–24 As a result of their inherent propensity for low toxicity, these agents have been and are continuing to move to clinical testing in men with early stages of prostate cancer as moderators of disease progression. These agents may skip testing in advanced disease altogether. The daunting task of showing a survival benefit in patients with a long natural history before clinical progression makes clinical trials costly and difficult to interpret, unless the benefits to the patient population treated are large. The use of nontoxic UROLOGY 55 (2), 2000
agents that can be administered chronically is more palatable for such trials. Altering the time until PSA progression, delaying the time until hormonal therapy is instituted, and delaying the time until radiation or systemic therapy is required all may be meaningful end points to patients. Demonstrating a survival benefit is a more long-term end point. CONCLUSIONS The expansion of basic science knowledge, improved prognostication of patients with prostate cancer, and the availability of new, potentially active chemotherapy regimens prompts the question before us today. Can we use all this information to recommend that patients with T3 prostate cancer receive adjuvant chemotherapy routinely? It is likely that patients with T3 prostate cancer will have tailored therapy in the future that lengthens survival, maintains quality of life, and can be administered with minimal toxicity. Such therapies are currently under development and should be evaluated in the setting of well-designed, rational clinical trials to determine the end points that patients and physicians would agree are beneficial. Outside of a clinical trial, it is unclear as to who should be treated and with what agents for what duration. Routine adjuvant chemotherapy for T3 cancer cannot be recommended on the basis of the information on hand in 2000. REFERENCES 1. van den Ouden D, Hop WC, and Schroder FH: Progression in and survival of patients with locally advanced prostate cancer (T3) treated with radical prostatectomy as monotherapy. J Urol 160: 1392–1397, 1998. 2. Gerber GS, Thisted RA, Chodak GW, et al: Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis. Eur Urol 32: 385– 390, 1997. 3. Lerner SE, Blute ML, and Zincke H: Extended experience with radical prostatectomy for clinical stage T3 prostate cancer: outcome and contemporary morbidity. J Urol 154: 1447–1452, 1995. 4. Yamada AH, Lieskovsky G, Petrovich Z, et al: Results of radical prostatectomy and adjuvant therapy in the management of locally advanced, clinical stage TC, prostate cancer. Am J Clin Oncol 17: 277–285, 1994. 5. Zietman AL: The role of radiation as adjuvant or salvage therapy following radical prostatectomy, in Vogelzang NJ, Scardino PT, Shipley WU, et al (Eds): Comprehensive Textbook of Genitourinary Oncology. Baltimore, Williams & Wilkins, 1996, pp 782–790. 6. Partin AW, Kattan MA, Subong EN, et al: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 277: 1445–1451, 1997. 7. Epstein JI, Partin AW, Sauvageot J, et al: Prediction of progression following radical prostatectomy. A multivariate analysis of 721 men with long term follow-up. Am J Surg Pathol 20: 286 –292, 1996. 159
8. Weider JA, and Soloway MS: Incidence, etiology, location, prevention and treatment of positive surgical margins after radical prostatectomy for prostate cancer. J Urol 160: 299 –315, 1998. 9. Pilepich MV, Al-Sarraf M, Rotman M, et al: Adjuvant chemotherapy with adriamycin, cytoxan, and cis-platinum in high-grade carcinoma of the prostate treated with definitive radiotherapy. Am J Clin Oncol 9: 135–138, 1986. 10. Freeman JA, Lieskovsky G, Grossfeld G, et al: Adjuvant radiation, chemotherapy, and androgen deprivation therapy for pathologic stage D1 adenocarcinoma of the prostate. Urology 44: 719 –725, 1994. 11. Loening S, and Narayana A: Adjuvant chemotherapy to definitive treatment of prostate cancer. Prostate 1: 321–335, 1980. 12. Seifter EJ, Bunn PA, Cohen MH, et al: A trial of combination chemotherapy followed by hormonal therapy for previously untreated metastatic carcinoma of the prostate. J Clin Oncol 4: 1365–1373, 1986. 13. Roach M III: Neoadjuvant total androgen suppression and radiotherapy in the management of locally advanced prostate cancer. Semin Urol Oncol 14: 32–37, 1996. 14. Amling CL, Blute ML, Bergstralh EJ, et al: Preoperative androgen-deprivation therapy for clinical stage T3 prostate cancer. Semin Urol Oncol 15: 222–229, 1997. 15. Moertel CG, Fleming TR, MacDonald JS, et al: Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med 12: 321–326, 1995. 16. Early Breast Cancer Trialists’ Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000
160
recurrences and 24,000 deaths among 75,000 women. Lancet 339: 1–15, 1992. 17. Sternberg CN, Yagoda A, Scher HI, et al: M-VAC for advanced transitional cell carcinoma of the urothelium: efficacy and patterns of response and relapse. Cancer 64: 2448 – 2458, 1989. 18. Ellerhorst JA, Tu SM, Amato RJ, et al: Phase II trial of alternating weekly chemohormonal therapy for patients with androgen-independent prostate cancer. Clin Cancer Res 3: 2371–2376, 1997. 19. Petrylak DP, MacArthur RB, O’Connor J, et al: Phase I trials of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 17: 958 –967, 1999. 20. Hudes GH, Greenberg R, Krigel R, et al: Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone refractory prostate cancer. J Clin Oncol 15: 3156 –3163, 1997. 21. Pienta KJ, Redman B, Hussain M, et al: Phase II evaluation of oral estramustine and oral etoposide in hormonerefractory adenocarcinoma of the prostate. J Clin Oncol 12: 2005–2012, 1994. 22. Getzenberg RH, Light BW, Lapco PE, et al: Vitamin D inhibition of prostate adenocarcinoma growth and metastasis in the Dunning rat prostate model system. Urology 50: 999 – 1006, 1997. 23. Carducci MA, Nelson JB, Chan-Tack K, et al: Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate. Clin Cancer Res 2: 379 –385, 1996. 24. Slovin SF, Kelly WK, and Scher HI: Immunological approaches for the treatment of prostate cancer. Semin Urol Oncol 16: 53–59, 1998.
UROLOGY 55 (2), 2000
ADJUVANT CHEMOTHERAPY FOR T3 PROSTATE CANCER: NOT READY FOR PRIME TIME MICHAEL A. CARDUCCI
R
ecent reviews of prostatectomy as monotherapy for T3 prostate cancer have suggested that adjuvant therapy is required.1– 4 In limited and uncontrolled series, adjuvant therapy has meant the addition of external beam radiation or endocrine therapy. Few or no published studies on the use of adjuvant chemotherapy for T3 prostate cancer exist that have adequate follow-up to allow for an appropriate interpretation of the results. The question of adjuvant chemotherapy for T3 prostate cancer stems from two impulses. First, it is easy to extrapolate successes in adjuvant therapy from other tumor types. Second, chemotherapy is seen to be emerging as a viable, tolerable, and efficacious strategy in advanced refractory prostate cancer. Despite the perceived improvements in the management of advanced prostate cancer, no clinical justification has emerged for the use of adjuvant chemotherapy in patients with T3 prostate cancer after surgery. T3 PROSTATE CANCER: THE PROBLEM WITH STAGING
T3 disease is defined as tumor that extends through the prostatic capsule, including focal extracapsular penetration and/or invasion of the seminal vesicles. Clinical staging is often inaccurate, with both overstaging and understaging noted. Understaging by clinical findings is demonstrated by the many reports in which up to 26% of patients with T1b, 33% of patients with T2a, and 68% of those with T2b-T2c tumors will prove to have extracapsular disease (pathologic T3).5 Each year many patients have more advanced disease than is believed curable by surgical resection alone. Predictive models, such as the Partin Tables, help to clarify the risk of extraprostatic disease extension From the Division of Medical Oncology and Experimental Therapeutics, Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland Reprint requests: Michael A. Carducci, M.D., Johns Hopkins Oncology Center, 720 Rutland Avenue, Ross 359, Baltimore, MD 21205 Submitted: May 4, 1999, accepted: July 15, 1999 © 2000, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
at the time of surgery.6 Despite a measurable risk of pT3 disease, a number of factors bring many men to prostatectomy, including a potential for overstaging, young age, and patient desire. Men with pT3 disease may be divided into prognostically distinct subgroups by the histologic features and by the presence or absence of a detectable postoperative prostate-specific antigen (PSA) level. Admittedly, all pT3 subgroups are at higher risk of local and distant relapse than patients with organconfined disease, but the degree of risk varies. A number of studies with long-term clinical follow-up point out that extracapsular disease predisposes to local failure. Independent predictors of local failure are positive surgical margins and high tumor grade. Seminal vesicle involvement is a better predictor of distant metastasis. Up to 75% of men with extensive extracapsular disease, positive margins, or seminal vesicle involvement will have a PSA relapse within 5 years of surgery.1– 4 Many groups have drawn a prognostic distinction between focal and extensive positive surgical margins. Focally positive margins are associated with a 40% risk of progression at 5 years; patients with extensive positive margins have a 65% risk of progression.7,8 Patients with T3N0 disease with the highest progression rates are those with seminal vesicle involvement, a poorly differentiated phenotype, and a detectable PSA postoperatively.1– 8 These patients are the ones most likely to be selected for trials of adjuvant chemotherapy. Adjuvant radiation and endocrine therapy may be of some benefit to this patient population in terms of morbidity and survival, but even these adjuvant strategies have not been rigorously studied. A CASE FOR “CLINICAL CONSERVATISM” The cancer-specific survival rate at 15 years in patients with clinical Stage T3 after prostatectomy is 69%. In a review by Lerner et al.,3 the overall rate of nonprogression (systemic plus local) was 61% and 50% at 10 and 15 years of follow-up, respectively. When follow-up PSA was included as a criterion for progression, an additional 20% of paUROLOGY 55: 157–160, 2000 • 0090-4295/00/$20.00 PII S0090-4295(99)00366-0 157
tients manifested a subclinical progression at 10 and 15 years of follow-up. In these studies, 60% of patients with clinical Stage T3 undergoing prostatectomy received adjuvant therapy with radiation or hormonal therapy. Given these 15-year survival rates for patients with T3 disease who underwent prostatectomy, with more than half receiving adjuvant radiation or endocrine therapy, it has been suggested that monotherapy is suboptimal.1–3 On the other hand, more than 50% of patients are alive 15 years after surgery when treated in the described manner. Clearly there is room for improvement. A better understanding or standardization of clinical practice for patients with T3 prostate cancer may be used to optimize and select the patients requiring more than just surgical therapy. Little reported data exist regarding the addition of chemotherapy to this patient population. Most of the chemotherapy studies in combination with hormonal therapy for patients with newly diagnosed metastatic prostate cancer have looked at patients with D1 or nodal disease.9 –12 What should be done for the patient with Stage T3 disease and seminal vesicle involvement, high Gleason score (8 or greater), and an elevated PSA postoperatively? Surgical summaries suggest favorable long-term results, often with the addition of adjuvant radiation or androgen ablative therapies. With such procedures, long-term morbidity may be reduced because local progression, with extension into the bladder, and other local symptoms are often prevented. Neoadjuvant hormonal therapy for this patient population undergoing primary radiation therapy has clinical trial evidence of efficacy, including improvement in local control and reduction in disease progression.13 However, neoadjuvant endocrine therapy before prostatectomy has met with disappointing results.14 The reduction in prostate size and reduced incidence of positive surgical margins has had little clinical impact on survival or progression rates. A patient’s prognosis relates primarily to the pathologic stage before hormonal therapy. Stage pT3 disease is not an immediate death sentence, yet warrants concern for its potential for morbidity, psychosocial distress, and mortality. The role of adjuvant therapy is to lengthen the time to progression, to improve survival, and to have a positive impact on the quality of life in the long run. For patients older than 70, the benefits of adjuvant therapy will be hard to document in terms of years prolonged or quality of life improved. For the younger patient, pT3 cancer is likely to shorten that individual’s life, despite a 30% to 69% 15-year disease-specific survival rate based on prognostic factors.5 The impact of adjuvant therapy on such parameters needs to be quite dramatic to show a benefit in survival and quality of life. 158
ADJUVANT CHEMOTHERAPY IN OTHER TUMOR TYPES Adjuvant chemotherapy has been shown to be beneficial in patients with locally advanced breast and colon carcinoma. Progression and mortality rates of greater than 50% at 5 years exist for these patients at the time of adjuvant therapy. Multiple large-scale clinical trials were required to demonstrate the clinical efficacy of adjuvant chemotherapy in these patient populations. For example, adjuvant therapy for Stage III colon carcinoma reduces recurrence rates by nearly 20%.15 Most chemotherapy regimens used in the adjuvant setting have demonstrated clinical activity in advanced metastatic disease. For breast cancer, agents like cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) showed an 8% reduction in death from breast cancer when used in the adjuvant setting.16 This benefit is not exactly a huge improvement for an individual; however, the societal benefits of saving 8% of women with high-risk breast cancer means thousands of lives saved. However, it has been hard to prove the benefit of adjuvant therapy in other tumor types. In bladder cancer, methotrexate/vinblastine/doxorubicin/cisplatinum (MVAC) has nearly a 65% response rate in patients with advanced metastatic bladder cancer.17 When the regimen has been used adjuvantly in patients with muscle-invasive bladder cancer (T3 or T4, node-positive bladder cancer), it has been difficult to demonstrate an improvement in survival or a delay in time to progression. CHEMOTHERAPY FOR HORMONEREFRACTORY PROSTATE CANCER Advances in chemotherapy for hormone-refractory prostate cancer prompted the development of clinical trials for early-stage prostate cancer. Chemotherapy regimens used in the 1980s by the National Prostate Cancer Project and other academic centers demonstrated low response rates and no effect on survival. For the most part, chemotherapy has been viewed as only adding to the unpleasantness of having prostate cancer. Agents used in the past include single-agent estramustine, cyclophosphamide, doxorubicin, and cis-platinum. In the PSA era, today’s regimens typically combine cytotoxic agents with a hormonal-type agent and are administered to patients on an outpatient basis. Responses are defined by declines in PSA, most often a PSA decline of greater than 50% for at least 8 weeks. Agents inducing a clinical benefit have been approved for symptomatic hormone-refractory prostate cancer, such as mitoxantrone/ prednisone, despite a low PSA response rate. Regimens under investigation and in wide clinical practice include estramustine/etoposide, adriamyUROLOGY 55 (2), 2000
cin/ketoconazole/estramustine/vinblastine, paclitaxel/estramustine, docetaxel/estramustine, and single-agent docetaxel.18 –21 PSA response rates for these regimens are consistently greater than 50% in recent reports, with measurable disease response rates greater than 40%. The taxane/estramustine regimens have reported 17 to 24-month median survival times in nonrandomized Phase I and Phase II trials in patients with hormone-refractory prostate cancer. This apparent improvement in survival has yet to be tested in multi-institution, randomized clinical trials. One caveat concerning the current chemotherapy regimens for advanced prostate cancer is that most of the regimens have a hormonal agent, like estramustine, ketoconazole, or prednisone, as the backbone. By using these chemotherapy/hormonal therapy regimens in hormonal-naive patients, the early results look promising because progression appears delayed as a result of the hormonal agent. True benefits to the cytotoxic or chemotherapy arm of the therapy are unlikely to be fully assessed unless regimens that exclude hormonal therapy are tried in the adjuvant setting. The interpretation of clinical trials in the adjuvant setting must consider the agents selected for testing to determine the real benefits of such therapies. Further evaluation of these regimens in advanced disease is required. Moving these regimens to earlier disease stages should only be done in the context of well-designed clinical trials. Extrapolation of results and clinical trial successes from other tumor types has not always met with success in the next tumor type. The appropriate, rational selection of patients likely to “benefit” and requiring “benefit” is important to the design of adjuvant chemotherapy trials for patients with locally advanced T3 prostate cancer. NONTOXIC, ANTIPROGRESSION AGENTS FOR T3 PROSTATE CANCER The term “chemotherapy” has come to have multiple meanings and at times is inclusive or exclusive of newer treatment strategies such as antiprogression agents (eg, vitamin D, vitamin A, phenylbutyrate, matrix metalloproteinase inhibitors, and angiogenesis inhibitors) or immunotherapy agents.22–24 As a result of their inherent propensity for low toxicity, these agents have been and are continuing to move to clinical testing in men with early stages of prostate cancer as moderators of disease progression. These agents may skip testing in advanced disease altogether. The daunting task of showing a survival benefit in patients with a long natural history before clinical progression makes clinical trials costly and difficult to interpret, unless the benefits to the patient population treated are large. The use of nontoxic UROLOGY 55 (2), 2000
agents that can be administered chronically is more palatable for such trials. Altering the time until PSA progression, delaying the time until hormonal therapy is instituted, and delaying the time until radiation or systemic therapy is required all may be meaningful end points to patients. Demonstrating a survival benefit is a more long-term end point. CONCLUSIONS The expansion of basic science knowledge, improved prognostication of patients with prostate cancer, and the availability of new, potentially active chemotherapy regimens prompts the question before us today. Can we use all this information to recommend that patients with T3 prostate cancer receive adjuvant chemotherapy routinely? It is likely that patients with T3 prostate cancer will have tailored therapy in the future that lengthens survival, maintains quality of life, and can be administered with minimal toxicity. Such therapies are currently under development and should be evaluated in the setting of well-designed, rational clinical trials to determine the end points that patients and physicians would agree are beneficial. Outside of a clinical trial, it is unclear as to who should be treated and with what agents for what duration. Routine adjuvant chemotherapy for T3 cancer cannot be recommended on the basis of the information on hand in 2000. REFERENCES 1. van den Ouden D, Hop WC, and Schroder FH: Progression in and survival of patients with locally advanced prostate cancer (T3) treated with radical prostatectomy as monotherapy. J Urol 160: 1392–1397, 1998. 2. Gerber GS, Thisted RA, Chodak GW, et al: Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis. Eur Urol 32: 385– 390, 1997. 3. Lerner SE, Blute ML, and Zincke H: Extended experience with radical prostatectomy for clinical stage T3 prostate cancer: outcome and contemporary morbidity. J Urol 154: 1447–1452, 1995. 4. Yamada AH, Lieskovsky G, Petrovich Z, et al: Results of radical prostatectomy and adjuvant therapy in the management of locally advanced, clinical stage TC, prostate cancer. Am J Clin Oncol 17: 277–285, 1994. 5. Zietman AL: The role of radiation as adjuvant or salvage therapy following radical prostatectomy, in Vogelzang NJ, Scardino PT, Shipley WU, et al (Eds): Comprehensive Textbook of Genitourinary Oncology. Baltimore, Williams & Wilkins, 1996, pp 782–790. 6. Partin AW, Kattan MA, Subong EN, et al: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 277: 1445–1451, 1997. 7. Epstein JI, Partin AW, Sauvageot J, et al: Prediction of progression following radical prostatectomy. A multivariate analysis of 721 men with long term follow-up. Am J Surg Pathol 20: 286 –292, 1996. 159
8. Weider JA, and Soloway MS: Incidence, etiology, location, prevention and treatment of positive surgical margins after radical prostatectomy for prostate cancer. J Urol 160: 299 –315, 1998. 9. Pilepich MV, Al-Sarraf M, Rotman M, et al: Adjuvant chemotherapy with adriamycin, cytoxan, and cis-platinum in high-grade carcinoma of the prostate treated with definitive radiotherapy. Am J Clin Oncol 9: 135–138, 1986. 10. Freeman JA, Lieskovsky G, Grossfeld G, et al: Adjuvant radiation, chemotherapy, and androgen deprivation therapy for pathologic stage D1 adenocarcinoma of the prostate. Urology 44: 719 –725, 1994. 11. Loening S, and Narayana A: Adjuvant chemotherapy to definitive treatment of prostate cancer. Prostate 1: 321–335, 1980. 12. Seifter EJ, Bunn PA, Cohen MH, et al: A trial of combination chemotherapy followed by hormonal therapy for previously untreated metastatic carcinoma of the prostate. J Clin Oncol 4: 1365–1373, 1986. 13. Roach M III: Neoadjuvant total androgen suppression and radiotherapy in the management of locally advanced prostate cancer. Semin Urol Oncol 14: 32–37, 1996. 14. Amling CL, Blute ML, Bergstralh EJ, et al: Preoperative androgen-deprivation therapy for clinical stage T3 prostate cancer. Semin Urol Oncol 15: 222–229, 1997. 15. Moertel CG, Fleming TR, MacDonald JS, et al: Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med 12: 321–326, 1995. 16. Early Breast Cancer Trialists’ Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000
160
recurrences and 24,000 deaths among 75,000 women. Lancet 339: 1–15, 1992. 17. Sternberg CN, Yagoda A, Scher HI, et al: M-VAC for advanced transitional cell carcinoma of the urothelium: efficacy and patterns of response and relapse. Cancer 64: 2448 – 2458, 1989. 18. Ellerhorst JA, Tu SM, Amato RJ, et al: Phase II trial of alternating weekly chemohormonal therapy for patients with androgen-independent prostate cancer. Clin Cancer Res 3: 2371–2376, 1997. 19. Petrylak DP, MacArthur RB, O’Connor J, et al: Phase I trials of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 17: 958 –967, 1999. 20. Hudes GH, Greenberg R, Krigel R, et al: Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone refractory prostate cancer. J Clin Oncol 15: 3156 –3163, 1997. 21. Pienta KJ, Redman B, Hussain M, et al: Phase II evaluation of oral estramustine and oral etoposide in hormonerefractory adenocarcinoma of the prostate. J Clin Oncol 12: 2005–2012, 1994. 22. Getzenberg RH, Light BW, Lapco PE, et al: Vitamin D inhibition of prostate adenocarcinoma growth and metastasis in the Dunning rat prostate model system. Urology 50: 999 – 1006, 1997. 23. Carducci MA, Nelson JB, Chan-Tack K, et al: Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate. Clin Cancer Res 2: 379 –385, 1996. 24. Slovin SF, Kelly WK, and Scher HI: Immunological approaches for the treatment of prostate cancer. Semin Urol Oncol 16: 53–59, 1998.
UROLOGY 55 (2), 2000