- Email: [email protected]
Timing hormonal therapy in prostate cancer
Urol Clin of N Am 29 (2002) 223–227
Timing hormonal therapy in prostate cancer Annette E. Sessions, MD, Edward M. Messing, MD, FACS* Department of Urology, University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY 14642, USA
Six decades have passed since Huggins and Hodges [1] set the stage for androgen ablation in the treatment of prostate cancer. The fact that hormonal suppression delays recurrence and slows progression of prostate cancer is now well accepted; however, the appropriate time to initiate such therapy remains controversial. The myriad of published studies addressing this concern has yet to offer definitive answers. Meaningful clinical studies must meet several basic design standards to allow any truly valid assessment of the benefits of early treatment. First, the studies must be randomized, prospective, and controlled. Only by following this format can the treatment and control groups be considered identical and the intervention alone shown to be the cause of any difference in outcome. Furthermore, the type of hormonal therapy in both arms of the study and the timing of its initiation in the observed patients must be described and preferably defined by the protocol. For example, the indication to begin treatment could be a rise in prostate-specific antigen (PSA) level, more objective evidence of disease progression (e.g., on nucleotide bone scan), or symptomatic progression. The most meaningful endpoint in assessing the effectiveness of therapy for patients with moderately advanced to far-advanced prostate cancer is its impact on overall survival. When one uses survival as a study endpoint, there is no ambiguity in defining the time from cancer diagnosis to death, and the prolongation of survival becomes the chief goal of treatment. If a patient quickly dies of an unrelated disease, even if he is free of * Corresponding author. E-mail address: [email protected] (E.M. Messing).
prostate cancer, it should be determined whether the therapy received for prostate cancer provided benefit. Advantages for early endocrine therapy for other endpoints, such as the time to biochemical failure, local control of disease, disease-free survival, and progression-free survival, are preordained because no one contends that androgen ablation therapy does not slow the disease. The question is whether the therapy will permit the patient to live longer. Although cause-specific survival might be a reasonable endpoint (although not as important as overall survival), it cannot always be clearly established in the population most affected by that prostate cancer, that is, elderly men with multiple comorbidities. In evaluating these endpoints, the use of projected statistical methods, such as actuarial survival for a disease with a long time course that occurs in the elderly, is a suspect practice and one that, all too often, is used to permit the premature publication of data. As a general rule, it would make more sense to present differences in the endpoints at whatever median follow-up duration has actually occurred and to let readers decide whether this time frame is long enough. None of these issues even begins to address the elusive comparisons of morbidity, quality of life, and expense for early versus delayed therapy, whether physical, fiscal, or emotional. Hormonal therapy with diethylstilbestrol One of the earliest randomized prospective clinical trials confirming that early hormonal therapy delays disease progression was conducted by the Veterans Administration Co-operative Urological Research Group (VACURG) [2]. A total of 2052 patients newly diagnosed with prostate cancer and who had not undergone previous therapy
0094-0143/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 9 4 - 0 1 4 3 ( 0 2 ) 0 0 0 0 7 - 1
224
A.E. Sessions, E.M. Messing / Urol Clin N Am 29 (2002) 223–227
were randomized according to clinical stage. Patients with stage I and stage II disease (no prostatic induration and localized-nodule disease, respectively) underwent prostatectomy and were then randomized to receive either 5 mg of diethylstilbestrol (DES) daily or a placebo. Patients with stage III or IV disease (extraprostatic extension or metastatic disease, as assessed on the basis of staging assessments appropriate for the time, that is, physical examination and plain radiographs of the skeleton) were randomized to receive 5 mg of DES alone, orchiectomy plus placebo, orchiectomy plus DES, or placebo alone. Cancer progression was delayed in patients with stage III and IV disease who were treated with DES, orchiectomy, or both, but no benefit in survival was seen with any early hormonal therapy. Patients treated with DES had a lower cancer-specific mortality rate, but this benefit was outweighed by increased cardiovascular and cerebrovascular mortality associated with the 5-mg DES dose. A second VACURG study revealed that 1 mg of DES daily provided the same delay in disease progression as the 5-mg dosage and did not carry with it the same cardiovascular toxicity [3]. Moreover, 1 mg of DES provided at diagnosis actually increased overall survival in patients with stage III and IV disease when compared with patients receiving 0.2 mg or 5 mg of DES or placebo. The investigators, who were influenced by the first VACURG trial, withheld additional therapy in patients who progressed on assigned treatment either completely or until there was very advanced disease; consequently, the study actually tested early versus no hormonal therapy and led the VACURG not to recommend early therapy for all patients, reserving it primarily for younger patients with high-grade tumors. Results of a randomized study combining androgen ablation therapy with pelvic radiation were published in 1988 by investigators at the M.D. Anderson Tumor Institute, with 15 years of follow-up [4]. Approximately 80 patients with clinical stage T3 prostate cancer were randomized into one of two study arms: (1) radiotherapy alone versus (2) DES daily (initially, a 5-mg dosage that was later decreased to 2 mg because of the cardiovascular risks and the publication of the first VACURG trial) immediately at the completion of radiotherapy. No staging pelvic lymphadenectomy was performed, and the protocol did not specify treatment at relapse. Again, hormonal treatment was associated with a prolonged disease-free survival, but no overall survival advan-
tage was identified. This study and the conclusions from the VACURG trials established the longheld tenet that early androgen ablation therapy delays recurrence or progression of prostate cancer but offers no survival advantage over delayed treatment. More recent trials of androgen ablation therapy Since the VACURG studies have been carried out, significant improvements have occurred in treating and preventing cardiovascular and cerebrovascular disease. Newer and less morbid forms of castrative and androgen ablative therapy have been developed, and the role of PSA in early diagnosis and monitoring of patients with prostate cancer now is recognized. In part motivated by these changes, several more recent prospective, randomized studies retested the tenet regarding early androgen ablation. In 1997, the Medical Research Council of Great Britain studied 938 men with advanced local (T2–T4) or asymptomatic metastatic (M1) disease who were randomized to receive either immediate hormonal monotherapy (within 6 weeks of enrollment, either orchiectomy or a luteinizing hormone–releasing hormone [LHRH] agonist) or deferred treatment until progression, at which time the treatment and the timing of its initiation were determined by the individual practitioner [5]. Similar to the findings in previous studies, androgen ablation was associated with a statistically significant delay in progression. For 434 patients with confirmed metastatic disease (M1, n ¼ 261) or without radiographic evidence to confirm the absence of metastatic disease (Mx, n ¼ 173), no overall survival advantage was observed with early treatment; however, in 500 patients with radiographically confirmed absence of metastatic disease (M0), early hormonal therapy was associated with a statistically significant, albeit modest, survival advantage. Because 11% of patients assigned to deferred therapy died of unrelated causes before an indication to treat was thought to exist, it was concluded that elderly patients without metastatic disease would be the population most likely to benefit from deferred treatment. Perhaps the most impressive benefit of early therapy as recognized by the Medical Research Council was the finding that the rare but catastrophic sequelae of disease progression, such as spinal cord compression, ureteral obstruction, and pathologic fractures, could be deferred or prevented.
A.E. Sessions, E.M. Messing / Urol Clin N Am 29 (2002) 223–227
Hormonal therapy with radiation A study conducted by the European Organization for Research and Treatment of Cancer (EORTC) pointed to prolonged survival in patients with advanced, localized cancer receiving an LHRH agonist (goserelin) initiated on the first day of radiotherapy and continued for 3 years [6]. Control patients received radiotherapy alone, with goserelin deferred until recurrence. The actuarial 5-year survival rate was 79% in the immediate treatment group versus 62% in the control group (P ¼ 0.001); however, because the median follow-up was only 45 months (20%–25% of patients had been followed-up for 5 years), the accuracy of the projected survival results is uncertain and awaits longer follow-up. Furthermore, because hormonal therapy was initiated at the beginning of radiotherapy, the former therapy may have enhanced the efficacy of the latter therapy by reducing the size of the gland (creating a smaller target for radiation) rather than by eradicating persistent or micrometastatic disease. In a smaller study that also tested hormonal therapy and radiation in advanced local or regional disease, 91 patients with T1–4, pN0–3, and M0 prostate cancer were prospectively randomized to receive radiotherapy beginning 5 to 6 weeks after staging pelvic lymphadenectomy or orchiectomy 3 weeks after staging lymphadenectomy and then, 4 weeks later, radiotherapy [7]. Median follow-up was 9.3 years (range, 6.0–11.4 years). Analysis revealed a significant survival benefit among patients with node-positive disease undergoing combined (orchiectomy and radiation) therapy (61% versus 38%, P ¼ 0.007); however, it took nearly 9 years to see a significant survival benefit, and combination therapy in N0 patients (most of the participants in the trial) did not provide a significant survival advantage. Conversely, other prospective, randomized studies could not confirm a survival advantage for radiation with immediate hormonal therapy. The Radiation Therapy Oncology Group (RTOG) randomized 945 patients with advanced local or regional disease to immediate combined radiation and androgen ablation therapy (goserelin begun at the end of radiotherapy and then continued indefinitely) or definitive radiation with hormonal therapy when disease progressed [8]. This study, RTOG 85-31, was similar to the two studies discussed previously in which combined treatment was associated with survival prolongation, except for the fact that hormonal therapy in the RTOG
225
study was initiated at the end of radiation rather than at the beginning (EORTC) or before beginning radiation (Granfor study [7]). No significant survival advantage was identified in either arm of RTOG 85-31. Although a subgroup of men with cancers of Gleason score of 8 to 10 who had not had previous prostate surgery survived longer (P ¼ 0.03), this subgroup included less than one third of all participants. As a general rule, subgroup analyses at odds with the results of an overall trial almost always confirm findings of the original study and rarely can be substantiated when tested independently [9]. Another study by the RTOG (92-02) has not shown a survival benefit to date. Hanks and coworkers [10] studied patients with locally advanced prostate cancer (T2C–T4 with PSA <150 ng/mL) who received goserelin and flutamide for 2 months before and during radiotherapy and compared that group with men who had the same treatment and who continued the same hormonal therapy for 2 years. Median follow-up was 4.8 years. There was no significant difference in the actuarial 5-year survival. Comparison of the subset of patients having cancers with Gleason scores of 8 to 10 revealed a statistically significant survival advantage in the patients receiving long-term therapy (80% versus 69%; P ¼ 0.02). Again, conclusions from these subset analyses must be viewed with caution, particularly when they yield results different from those of the entire cohort analysis for which the study was designed.
Androgen ablation in presence of minimal disease burdens Messing and co-workers [11] recently presented data from a prospective, randomized Eastern Cooperative Oncology Group (ECOG) study comparing immediate versus deferred androgen ablation therapy (goserelin or bilateral orchiectomy) in patients with node-positive disease after they had undergone radical prostatectomy and pelvic lymphadenectomy. Ninety-eight patients were followed-up for a median of 7.1 years (range, 3–10 years). Immediate therapy was associated with statistically significant advantages in overall survival (P ¼ 0.02), prostate cancer-specific survival (P ¼ 0.001), and recurrence-free survival (P < 0.001). This study has been criticized for several reasons [12]. With rising recognition of the important role of PSA in diagnosing and following prostate
226
A.E. Sessions, E.M. Messing / Urol Clin N Am 29 (2002) 223–227
cancer, the initial accrual goal was not met, and, perhaps because of the small size of the study, an imbalance of risks between the two arms existed despite randomization. One proposed possible imbalance was in the Gleason score, which was not a significant predictor of outcome for the entire study cohort and not assessed by a centralized pathology review. Nevertheless, for men in the study’s deferred arm, Gleason score predicted the likelihood of failure, making it unlikely that Gleason grades were inaccurately read by pathologists at institutions participating in the study. Because Gleason sums assigned by institutional pathologists were evenly distributed in both arms, it is unlikely that this characteristic was truly unequally balanced. Additionally, three small, retrospective, single-institution series [13– 15] of radical prostatectomy in men with nodepositive disease reported better disease-specific survivals than that in observed patients in the ECOG study, implying that men in this arm may have been at unusually high risk; however, cause-specific survivals in these retrospective series all fell well within the pointwise 95% confidence intervals of observed patients in the ECOG trial. This fact indicates that outcomes in men randomized to observation in this trial were not significantly poorer than would be expected, and this outcome could not explain the benefits of early androgen ablation as a result of bias or aberrant patient selection. A critical difference between the ECOG study and the others previously discussed is that men entered the ECOG study with tiny quantities of cancer; 80% had undetectable PSAs after prostatectomy at entry. This fact alone may explain the dramatic benefits of early androgen deprivation in the ECOG study when compared with the other trials in which modest, if any, benefits were seen. Early endocrine therapy may be most effective under such circumstances. It is cautioned that the success of this immediate therapy cannot be directly extrapolated to other clinical scenarios, including patients with greater tumor burdens (even with lower stage disease). Two retrospective series have tried to compare node-positive patients undergoing immediate androgen ablation alone with patients undergoing androgen ablation and prostatectomy [16,17]. Both reviews independently found that men receiving combined surgical and hormonal treatment fared significantly better than men undergoing solely hormonal ablation. Although the small patient numbers and retrospective design
of these series may introduce biases, the cohorts seemed to be well matched, and the findings further suggest that minimizing tumor burden may be critical in optimizing the efficacy of androgen deprivation against prostate cancer. This conclusion is supported by experimental data in studies using animal and human prostate cancer cells [18,19]. Over the past 5 years, an increasing number of studies have pointed to the benefits of initiating androgen ablation therapy earlier in the treatment of prostate cancer. These findings suggest that the greatest benefits of antiandrogen therapy may be reaped when there are minuscule amounts of prostate cancer. Hormonal therapy, once reserved for palliation of symptomatic disease in select settings, is beginning to have a more prominent role in increasing longevity. References [1] Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941;1: 293–7. [2] Veterans Administration Co-operative Urological Research Group. Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 1967;124:1011–7. [3] Byar DP, Corle DK. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group Studies. Natl Cancer Inst Monogr 1988;7:165–70. [4] Zagars GK, Johnson DE, von Eschenbach AC, Hussey DH. Adjuvant estrogen following radiation therapy for stage C adenocarcinoma of the prostate: long-term results of a prospective randomized study. Int J Radiat Oncol Biol Phys 1988;14:1085–91. [5] The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. Br J Urol 1997;79:235–46. [6] Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295–300. [7] Granfors T, Modig H, Damber JE, Tomic R. Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol 1998;159:2030–4. [8] Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher MJ, Mesic JB, et al. Phase III trial of
A.E. Sessions, E.M. Messing / Urol Clin N Am 29 (2002) 223–227
[9]
[10]
[11]
[12]
[13]
androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85–31. J Clin Oncol 1997;15:1013–21. Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:93–8. Hanks GE, Lu J, Machtay M, Venkatesan V, Pinover W, Byhardt R. RTOG Protocol 92–02: A phase III trial of the use of long term androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate [abstract 1284]. Proc Am Soc Clin Oncol 2000;19:327a. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999;341:1781–8. Eisenberger MA, Walsh PC. Early androgen deprivation for prostate cancer? N Engl J Med 1999;341: 1837–8. Cadeddu JA, Partin AW, Epstein JI, Walsh PC. Stage D1 (T1–3, N1–3, M0) prostate cancer: a casecontrolled comparison of conservative treatment versus radical prostatectomy. Urology 1997;50: 251–5.
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[14] DeKernion JB, Neuwirth H, Stein A, Dorey F, Stenzl A, Hannah J, et al. Prognosis of patients with stage D1 prostate carcinoma following radical prostatectomy with and without early endocrine therapy. J Urol 1990;144:700–3. [15] Zincke H, Bergstralh EJ, Larson-Keller JJ, Farrow GM, Myers RP, Lieber MM, et al. Stage D1 prostate cancer treated by radical prostatectomy and adjuvant hormonal treatment: evidence for favorable survival in patients with DNA diploid tumors. Cancer 1992;70:311–23. [16] Brausi M, Tognoni P, Scattoni V, Montorsi, F, Guazzoni G, Blanco S, et al. Radical prostatectomy and immediate hormone treatment vs. immediate hormonal treatment alone for N+ prostate cancer: a matched comparison [abstract MP6.1.02]. BJU Int 2000;86(suppl 3):218. [17] Ghavamian R, Bergstralh EJ, Blute ML, Slezak J, Zincke H. Radical retropubic prostatectomy plus orchiectomy versus orchiectomy alone for pTxN+ prostate cancer: a matched comparison. J Urol 1999;161:1223–8. [18] Eng MH, Charles LG, Ross BD, Chrisp CE, Pienta KJ, Greenberg NM, et al. Early castration reduces prostatic carcinogenesis in transgenic mice. Urology 1999;54:1112–9. [19] Isaacs JT. Relationship between tumor size and curability of prostatic cancer by combined chemohormonal therapy in rats. Cancer Res 1989;49: 6290–4.
Timing hormonal therapy in prostate cancer Annette E. Sessions, MD, Edward M. Messing, MD, FACS* Department of Urology, University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY 14642, USA
Six decades have passed since Huggins and Hodges [1] set the stage for androgen ablation in the treatment of prostate cancer. The fact that hormonal suppression delays recurrence and slows progression of prostate cancer is now well accepted; however, the appropriate time to initiate such therapy remains controversial. The myriad of published studies addressing this concern has yet to offer definitive answers. Meaningful clinical studies must meet several basic design standards to allow any truly valid assessment of the benefits of early treatment. First, the studies must be randomized, prospective, and controlled. Only by following this format can the treatment and control groups be considered identical and the intervention alone shown to be the cause of any difference in outcome. Furthermore, the type of hormonal therapy in both arms of the study and the timing of its initiation in the observed patients must be described and preferably defined by the protocol. For example, the indication to begin treatment could be a rise in prostate-specific antigen (PSA) level, more objective evidence of disease progression (e.g., on nucleotide bone scan), or symptomatic progression. The most meaningful endpoint in assessing the effectiveness of therapy for patients with moderately advanced to far-advanced prostate cancer is its impact on overall survival. When one uses survival as a study endpoint, there is no ambiguity in defining the time from cancer diagnosis to death, and the prolongation of survival becomes the chief goal of treatment. If a patient quickly dies of an unrelated disease, even if he is free of * Corresponding author. E-mail address: [email protected] (E.M. Messing).
prostate cancer, it should be determined whether the therapy received for prostate cancer provided benefit. Advantages for early endocrine therapy for other endpoints, such as the time to biochemical failure, local control of disease, disease-free survival, and progression-free survival, are preordained because no one contends that androgen ablation therapy does not slow the disease. The question is whether the therapy will permit the patient to live longer. Although cause-specific survival might be a reasonable endpoint (although not as important as overall survival), it cannot always be clearly established in the population most affected by that prostate cancer, that is, elderly men with multiple comorbidities. In evaluating these endpoints, the use of projected statistical methods, such as actuarial survival for a disease with a long time course that occurs in the elderly, is a suspect practice and one that, all too often, is used to permit the premature publication of data. As a general rule, it would make more sense to present differences in the endpoints at whatever median follow-up duration has actually occurred and to let readers decide whether this time frame is long enough. None of these issues even begins to address the elusive comparisons of morbidity, quality of life, and expense for early versus delayed therapy, whether physical, fiscal, or emotional. Hormonal therapy with diethylstilbestrol One of the earliest randomized prospective clinical trials confirming that early hormonal therapy delays disease progression was conducted by the Veterans Administration Co-operative Urological Research Group (VACURG) [2]. A total of 2052 patients newly diagnosed with prostate cancer and who had not undergone previous therapy
0094-0143/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 9 4 - 0 1 4 3 ( 0 2 ) 0 0 0 0 7 - 1
224
A.E. Sessions, E.M. Messing / Urol Clin N Am 29 (2002) 223–227
were randomized according to clinical stage. Patients with stage I and stage II disease (no prostatic induration and localized-nodule disease, respectively) underwent prostatectomy and were then randomized to receive either 5 mg of diethylstilbestrol (DES) daily or a placebo. Patients with stage III or IV disease (extraprostatic extension or metastatic disease, as assessed on the basis of staging assessments appropriate for the time, that is, physical examination and plain radiographs of the skeleton) were randomized to receive 5 mg of DES alone, orchiectomy plus placebo, orchiectomy plus DES, or placebo alone. Cancer progression was delayed in patients with stage III and IV disease who were treated with DES, orchiectomy, or both, but no benefit in survival was seen with any early hormonal therapy. Patients treated with DES had a lower cancer-specific mortality rate, but this benefit was outweighed by increased cardiovascular and cerebrovascular mortality associated with the 5-mg DES dose. A second VACURG study revealed that 1 mg of DES daily provided the same delay in disease progression as the 5-mg dosage and did not carry with it the same cardiovascular toxicity [3]. Moreover, 1 mg of DES provided at diagnosis actually increased overall survival in patients with stage III and IV disease when compared with patients receiving 0.2 mg or 5 mg of DES or placebo. The investigators, who were influenced by the first VACURG trial, withheld additional therapy in patients who progressed on assigned treatment either completely or until there was very advanced disease; consequently, the study actually tested early versus no hormonal therapy and led the VACURG not to recommend early therapy for all patients, reserving it primarily for younger patients with high-grade tumors. Results of a randomized study combining androgen ablation therapy with pelvic radiation were published in 1988 by investigators at the M.D. Anderson Tumor Institute, with 15 years of follow-up [4]. Approximately 80 patients with clinical stage T3 prostate cancer were randomized into one of two study arms: (1) radiotherapy alone versus (2) DES daily (initially, a 5-mg dosage that was later decreased to 2 mg because of the cardiovascular risks and the publication of the first VACURG trial) immediately at the completion of radiotherapy. No staging pelvic lymphadenectomy was performed, and the protocol did not specify treatment at relapse. Again, hormonal treatment was associated with a prolonged disease-free survival, but no overall survival advan-
tage was identified. This study and the conclusions from the VACURG trials established the longheld tenet that early androgen ablation therapy delays recurrence or progression of prostate cancer but offers no survival advantage over delayed treatment. More recent trials of androgen ablation therapy Since the VACURG studies have been carried out, significant improvements have occurred in treating and preventing cardiovascular and cerebrovascular disease. Newer and less morbid forms of castrative and androgen ablative therapy have been developed, and the role of PSA in early diagnosis and monitoring of patients with prostate cancer now is recognized. In part motivated by these changes, several more recent prospective, randomized studies retested the tenet regarding early androgen ablation. In 1997, the Medical Research Council of Great Britain studied 938 men with advanced local (T2–T4) or asymptomatic metastatic (M1) disease who were randomized to receive either immediate hormonal monotherapy (within 6 weeks of enrollment, either orchiectomy or a luteinizing hormone–releasing hormone [LHRH] agonist) or deferred treatment until progression, at which time the treatment and the timing of its initiation were determined by the individual practitioner [5]. Similar to the findings in previous studies, androgen ablation was associated with a statistically significant delay in progression. For 434 patients with confirmed metastatic disease (M1, n ¼ 261) or without radiographic evidence to confirm the absence of metastatic disease (Mx, n ¼ 173), no overall survival advantage was observed with early treatment; however, in 500 patients with radiographically confirmed absence of metastatic disease (M0), early hormonal therapy was associated with a statistically significant, albeit modest, survival advantage. Because 11% of patients assigned to deferred therapy died of unrelated causes before an indication to treat was thought to exist, it was concluded that elderly patients without metastatic disease would be the population most likely to benefit from deferred treatment. Perhaps the most impressive benefit of early therapy as recognized by the Medical Research Council was the finding that the rare but catastrophic sequelae of disease progression, such as spinal cord compression, ureteral obstruction, and pathologic fractures, could be deferred or prevented.
A.E. Sessions, E.M. Messing / Urol Clin N Am 29 (2002) 223–227
Hormonal therapy with radiation A study conducted by the European Organization for Research and Treatment of Cancer (EORTC) pointed to prolonged survival in patients with advanced, localized cancer receiving an LHRH agonist (goserelin) initiated on the first day of radiotherapy and continued for 3 years [6]. Control patients received radiotherapy alone, with goserelin deferred until recurrence. The actuarial 5-year survival rate was 79% in the immediate treatment group versus 62% in the control group (P ¼ 0.001); however, because the median follow-up was only 45 months (20%–25% of patients had been followed-up for 5 years), the accuracy of the projected survival results is uncertain and awaits longer follow-up. Furthermore, because hormonal therapy was initiated at the beginning of radiotherapy, the former therapy may have enhanced the efficacy of the latter therapy by reducing the size of the gland (creating a smaller target for radiation) rather than by eradicating persistent or micrometastatic disease. In a smaller study that also tested hormonal therapy and radiation in advanced local or regional disease, 91 patients with T1–4, pN0–3, and M0 prostate cancer were prospectively randomized to receive radiotherapy beginning 5 to 6 weeks after staging pelvic lymphadenectomy or orchiectomy 3 weeks after staging lymphadenectomy and then, 4 weeks later, radiotherapy [7]. Median follow-up was 9.3 years (range, 6.0–11.4 years). Analysis revealed a significant survival benefit among patients with node-positive disease undergoing combined (orchiectomy and radiation) therapy (61% versus 38%, P ¼ 0.007); however, it took nearly 9 years to see a significant survival benefit, and combination therapy in N0 patients (most of the participants in the trial) did not provide a significant survival advantage. Conversely, other prospective, randomized studies could not confirm a survival advantage for radiation with immediate hormonal therapy. The Radiation Therapy Oncology Group (RTOG) randomized 945 patients with advanced local or regional disease to immediate combined radiation and androgen ablation therapy (goserelin begun at the end of radiotherapy and then continued indefinitely) or definitive radiation with hormonal therapy when disease progressed [8]. This study, RTOG 85-31, was similar to the two studies discussed previously in which combined treatment was associated with survival prolongation, except for the fact that hormonal therapy in the RTOG
225
study was initiated at the end of radiation rather than at the beginning (EORTC) or before beginning radiation (Granfor study [7]). No significant survival advantage was identified in either arm of RTOG 85-31. Although a subgroup of men with cancers of Gleason score of 8 to 10 who had not had previous prostate surgery survived longer (P ¼ 0.03), this subgroup included less than one third of all participants. As a general rule, subgroup analyses at odds with the results of an overall trial almost always confirm findings of the original study and rarely can be substantiated when tested independently [9]. Another study by the RTOG (92-02) has not shown a survival benefit to date. Hanks and coworkers [10] studied patients with locally advanced prostate cancer (T2C–T4 with PSA <150 ng/mL) who received goserelin and flutamide for 2 months before and during radiotherapy and compared that group with men who had the same treatment and who continued the same hormonal therapy for 2 years. Median follow-up was 4.8 years. There was no significant difference in the actuarial 5-year survival. Comparison of the subset of patients having cancers with Gleason scores of 8 to 10 revealed a statistically significant survival advantage in the patients receiving long-term therapy (80% versus 69%; P ¼ 0.02). Again, conclusions from these subset analyses must be viewed with caution, particularly when they yield results different from those of the entire cohort analysis for which the study was designed.
Androgen ablation in presence of minimal disease burdens Messing and co-workers [11] recently presented data from a prospective, randomized Eastern Cooperative Oncology Group (ECOG) study comparing immediate versus deferred androgen ablation therapy (goserelin or bilateral orchiectomy) in patients with node-positive disease after they had undergone radical prostatectomy and pelvic lymphadenectomy. Ninety-eight patients were followed-up for a median of 7.1 years (range, 3–10 years). Immediate therapy was associated with statistically significant advantages in overall survival (P ¼ 0.02), prostate cancer-specific survival (P ¼ 0.001), and recurrence-free survival (P < 0.001). This study has been criticized for several reasons [12]. With rising recognition of the important role of PSA in diagnosing and following prostate
226
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cancer, the initial accrual goal was not met, and, perhaps because of the small size of the study, an imbalance of risks between the two arms existed despite randomization. One proposed possible imbalance was in the Gleason score, which was not a significant predictor of outcome for the entire study cohort and not assessed by a centralized pathology review. Nevertheless, for men in the study’s deferred arm, Gleason score predicted the likelihood of failure, making it unlikely that Gleason grades were inaccurately read by pathologists at institutions participating in the study. Because Gleason sums assigned by institutional pathologists were evenly distributed in both arms, it is unlikely that this characteristic was truly unequally balanced. Additionally, three small, retrospective, single-institution series [13– 15] of radical prostatectomy in men with nodepositive disease reported better disease-specific survivals than that in observed patients in the ECOG study, implying that men in this arm may have been at unusually high risk; however, cause-specific survivals in these retrospective series all fell well within the pointwise 95% confidence intervals of observed patients in the ECOG trial. This fact indicates that outcomes in men randomized to observation in this trial were not significantly poorer than would be expected, and this outcome could not explain the benefits of early androgen ablation as a result of bias or aberrant patient selection. A critical difference between the ECOG study and the others previously discussed is that men entered the ECOG study with tiny quantities of cancer; 80% had undetectable PSAs after prostatectomy at entry. This fact alone may explain the dramatic benefits of early androgen deprivation in the ECOG study when compared with the other trials in which modest, if any, benefits were seen. Early endocrine therapy may be most effective under such circumstances. It is cautioned that the success of this immediate therapy cannot be directly extrapolated to other clinical scenarios, including patients with greater tumor burdens (even with lower stage disease). Two retrospective series have tried to compare node-positive patients undergoing immediate androgen ablation alone with patients undergoing androgen ablation and prostatectomy [16,17]. Both reviews independently found that men receiving combined surgical and hormonal treatment fared significantly better than men undergoing solely hormonal ablation. Although the small patient numbers and retrospective design
of these series may introduce biases, the cohorts seemed to be well matched, and the findings further suggest that minimizing tumor burden may be critical in optimizing the efficacy of androgen deprivation against prostate cancer. This conclusion is supported by experimental data in studies using animal and human prostate cancer cells [18,19]. Over the past 5 years, an increasing number of studies have pointed to the benefits of initiating androgen ablation therapy earlier in the treatment of prostate cancer. These findings suggest that the greatest benefits of antiandrogen therapy may be reaped when there are minuscule amounts of prostate cancer. Hormonal therapy, once reserved for palliation of symptomatic disease in select settings, is beginning to have a more prominent role in increasing longevity. References [1] Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941;1: 293–7. [2] Veterans Administration Co-operative Urological Research Group. Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 1967;124:1011–7. [3] Byar DP, Corle DK. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group Studies. Natl Cancer Inst Monogr 1988;7:165–70. [4] Zagars GK, Johnson DE, von Eschenbach AC, Hussey DH. Adjuvant estrogen following radiation therapy for stage C adenocarcinoma of the prostate: long-term results of a prospective randomized study. Int J Radiat Oncol Biol Phys 1988;14:1085–91. [5] The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. Br J Urol 1997;79:235–46. [6] Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295–300. [7] Granfors T, Modig H, Damber JE, Tomic R. Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol 1998;159:2030–4. [8] Pilepich MV, Caplan R, Byhardt RW, Lawton CA, Gallagher MJ, Mesic JB, et al. Phase III trial of
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androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85–31. J Clin Oncol 1997;15:1013–21. Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:93–8. Hanks GE, Lu J, Machtay M, Venkatesan V, Pinover W, Byhardt R. RTOG Protocol 92–02: A phase III trial of the use of long term androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate [abstract 1284]. Proc Am Soc Clin Oncol 2000;19:327a. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999;341:1781–8. Eisenberger MA, Walsh PC. Early androgen deprivation for prostate cancer? N Engl J Med 1999;341: 1837–8. Cadeddu JA, Partin AW, Epstein JI, Walsh PC. Stage D1 (T1–3, N1–3, M0) prostate cancer: a casecontrolled comparison of conservative treatment versus radical prostatectomy. Urology 1997;50: 251–5.
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[14] DeKernion JB, Neuwirth H, Stein A, Dorey F, Stenzl A, Hannah J, et al. Prognosis of patients with stage D1 prostate carcinoma following radical prostatectomy with and without early endocrine therapy. J Urol 1990;144:700–3. [15] Zincke H, Bergstralh EJ, Larson-Keller JJ, Farrow GM, Myers RP, Lieber MM, et al. Stage D1 prostate cancer treated by radical prostatectomy and adjuvant hormonal treatment: evidence for favorable survival in patients with DNA diploid tumors. Cancer 1992;70:311–23. [16] Brausi M, Tognoni P, Scattoni V, Montorsi, F, Guazzoni G, Blanco S, et al. Radical prostatectomy and immediate hormone treatment vs. immediate hormonal treatment alone for N+ prostate cancer: a matched comparison [abstract MP6.1.02]. BJU Int 2000;86(suppl 3):218. [17] Ghavamian R, Bergstralh EJ, Blute ML, Slezak J, Zincke H. Radical retropubic prostatectomy plus orchiectomy versus orchiectomy alone for pTxN+ prostate cancer: a matched comparison. J Urol 1999;161:1223–8. [18] Eng MH, Charles LG, Ross BD, Chrisp CE, Pienta KJ, Greenberg NM, et al. Early castration reduces prostatic carcinogenesis in transgenic mice. Urology 1999;54:1112–9. [19] Isaacs JT. Relationship between tumor size and curability of prostatic cancer by combined chemohormonal therapy in rats. Cancer Res 1989;49: 6290–4.