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Treatment of Localized Prostate Cancer With Intermittent Triple Androgen Blockade: Preliminary ROBERT L. LEIBOWITZ, STEVEN J. TUCKER
Compassionate Oncology Medical Group, Los Angeles, California, USA Key Words. Prostate cancer · Triple androgen blockade
ABSTRACT
Objectives. To determine the effectiveness of triple
PSA level was 13.2 ± 1.2 ng/ml (range, 0.39-100 ng/ml), and
androgen blockade as an alternative to watchful wait-
mean Gleason score was 6.6 ± 0.1 (range, 4-10). During
ing, radical prostatectomy or radiation therapy in the
treatment, PSA levels declined to ≤0.1 ng/ml in all patients,
management of patients with clinical stage T1 to T3
with a median time of 3 months. After a median follow-up
prostate cancer.
of 36 months since initiation of treatment, PSA levels have
Methods. The records of 110 consecutive patients
remained stable in 105 of 110 patients (95.5%). At a
were retrospectively evaluated. Patients were treated
median follow-up of 55 months (range, 38-125 months), the
with a three-drug androgen blockade regimen, consisting
mean PSA level for the first 57 patients treated in this
of a luteinizing hormone-releasing hormone agonist
series is 1.88 ± 0.1 (range, 0-11.0 ng/ml). Only 9 of 110
(leuprolide or goserelin) plus an antiandrogen (flutamide
(8.1%) patients have a PSA level ≥4.0 ng/ml. To date, no
or bicalutamide) plus finasteride (a 5-alpha-reductase
patient has received a second cycle of hormone blockade.
inhibitor), followed by finasteride maintenance therapy,
Conclusions. Although median follow-up is short,
as the sole intervention. All patients refused local therapy
triple androgen blockade therapy followed by finas-
and had their prostates intact. Determinants of efficacy
teride maintenance appears to be a promising alterna-
included serum prostate-specific antigen (PSA) levels and
tive for the management of patients with clinically
disease-specific survival.
localized or locally advanced prostate cancer. Further
Results. Patients were treated for a median of 13
study of this approach is warranted. The Oncologist
months with triple androgen blockade. At baseline, mean
INTRODUCTION
an overall survival benefit with a median follow-up of 23 Current treatment options for clinically localized or years for patients undergoing prostatectomy compared to locally advanced cancer of the prostate include radical prosta- patients receiving no initial treatment [1, 2]. Moreover, tectomy, radiation therapy, brachytherapy, cryotherapy, or reported 10-year disease-specific survival rates for prostatec- “watchful waiting” (i.e., surveillance). Approximately two- tomy (88% to 93%) and external beam radiotherapy (66% to thirds of patients are treated with either prostatectomy or 86%) are not different from those reported for surveillance radiotherapy. Although local therapies are potentially cura- (84% to 85%) [3, 4]. The curative potential of surgery or radi- tive, they are associated with long-term, often permanent, side ation has been further called into question by measurements effects, and to date none have been demonstrated to provide a of prostate-specific antigen (PSA), which indicate persistent statistically significant survival benefit compared with sur- or recurrent disease in up to 27% to 53% of patients treated veillance in prospectively randomized trials. In the only for clinically localized prostate cancer [5-7]. This implies that prospective randomized trial comparing placebo to radical only a limited number of patients treated with local therapy prostatectomy plus placebo, the Veterans Administration will enjoy long-term PSA failure-free survival. For men pre- Cooperative Urological Research Group failed to demonstrate senting with known adverse risk factors such as Gleason Correspondence: Robert L. Leibowitz, M.D., Compassionate Oncology Medical Group, 2080 Century Park East, #601, LosAngeles, California 90067, USA. Telephone: 310-229-3555; Fax: 310-229-3554; e-mail: [email protected] October 18, 2000; accepted for publication January 4, 2001. AlphaMed Press 1083-7159/2001/$5.00/0 The Oncologist 2001;6:177-182
scores [8-10], PSA values greater than 10 ng/ml, or locally patients with localized prostate cancer [28, 29]. In this trial, advanced disease and treated with radical prostatectomy or 59 patients were randomized to an LHRH agonist plus an radiotherapy, the 5-year PSA biochemical failure-free sur- antiandrogen with or without the addition of finasteride.
vival is only between 21% and 32% [7-9]. Sensitive PSA Finasteride was added both as part of the three-drug induc- assays, including reverse-transcriptase polymerase chain tion regimen and maintenance therapy. Patients who reaction for PSA, suggest that a large proportion of patients received the three-drug combination plus finasteride main- with clinically localized disease have occult micrometastatic tenance had a significantly shorter median time to unde- disease in peripheral blood, lymph nodes, and/or bone mar- tectable PSA (three versus five months; p = .0095) and a row prior to prostatectomy [10-14]. Given these data and the significantly longer median time to relapse, defined as PSA well-documented morbidity associated with surgery and increase to ≥2.5 ng/ml (34 versus 19 months; p = .013).
radiation, including impotence and urinary incontinence, the These data suggest that this three-drug combination andro- clinical benefit of local therapy for prostate cancer continues gen-blockade regimen may be a highly effective alternative to prostatectomy, radiotherapy, or watchful waiting for the Combination hormone blockade has been suggested as treatment of localized prostate cancer.
an option in the management of patients with clinically We have treated 110 consecutive patients who presented localized or locally advanced prostate cancer. The combi- with clinical stage T1 to T3 prostate cancer and refused local nation of the 5-alpha-reductase inhibitor finasteride and a therapy with this three-drug combination androgen-blockade pure antiandrogen such as flutamide (Eulexin®, Schering- regimen in a community-based medical oncology practice.
Plough Corporation; Kenilworth, NJ) is an effective form Preliminary results suggest that the majority of patients of androgen blockade. Finasteride inhibits the intraprostatic maintain long-term, stable, low PSA levels following triple conversion of testosterone to 5-alpha-dihydrotestosterone, androgen blockade therapy with finasteride maintenance.
whereas flutamide blocks the interaction of androgens withtheir cytoplasmic receptors [5]. The advantage of this com- MATERIALS AND METHODS
bination over traditional hormone therapy (e.g., chemical orsurgical orchiectomy) is that it does not affect plasma con- Patients
centrations of testosterone, thereby maintaining potency The records of 110 consecutive patients presenting with and quality of life. Long-term treatment (i.e., four years) clinical stage T1 to T3 prostate cancer and treated between with finasteride monotherapy has been shown to produce June 1990 and June 1999 were retrospectively reviewed. All continuous improvement in PSA over time in patients with patients had biopsy-proven adenocarcinoma of the prostate; benign prostatic hyperplasia in the PLESS Study Group biopsies were performed and interpreted at each patient’s local trial [15], and finasteride in combination with flutamide has institution. Routine staging with bone scans, magnetic reso- been shown to substantially decrease PSA levels in patients nance imaging, computer tomography, and/or indium-111 with metastatic prostate cancer [16].
capromab pendetide (ProstaScint®; Cytogen Corporation; Antiandrogens are typically used in combination with Princeton, NJ) was not performed. Any patient with clinical luteinizing hormone-releasing hormone (LHRH) super-ago- evidence of metastatic disease was excluded from study.
nists such as leuprolide or goserelin. This combination has Patients were not surgically staged to differentiate clinically been shown to provide a substantial survival benefit in patients localized (stage T1 and T2) from locally advanced (stage T3) with metastatic prostate cancer compared with an LHRH ago- disease, nor were baseline scans routinely ordered. No patient nist or orchiectomy alone [17-19]. While these studies suggest had undergone any form of local therapy. All patients, in fact, a benefit for combined androgen blockade, other well- refused local therapy and were offered triple androgen block- designed studies dispute the benefit including four large meta- ade therapy. Patients were informed of the risks, benefits, and analyses [17, 20-24]. Some authors suggest that patients with alternatives to hormone blockade before therapy was initiated.
minimal disease burden receive a more pronounced survivalbenefit with combined androgen ablation [19, 25, 26]. In Treatment
patients with localized or locally advanced prostate cancer, Patients were treated with an LHRH agonist (either long-term treatment with flutamide plus an LHRH agonist leuprolide acetate [7.5 mg] or goserelin acetate [3.6 mg] every reduced PSA to undetectable levels in 39 of 46 (85%) patients 28 days) plus an antiandrogen (either flutamide [750 mg] or with stage T2 and T3 disease who were treated continuously bicalutamide [150 mg] daily) plus finasteride (5 mg daily) for for a median of 7.2 and 9.9 years, respectively [27].
a median of 13 months [30]. Induction therapy was followed The triple combination of an LHRH agonist, an antian- by maintenance therapy with finasteride (5 mg daily) for an drogen, and finasteride has also recently been studied in Preliminary Results in 110 Consecutive Patients Table 1. Baseline patient demographics
Standard error
n
Efficacy variables included: A) PSA levels; B) time to comprised 16% of the study population. Fifteen patients had achieve undetectable PSA level (defined as ≤0.1 ng/ml), and Gleason scores of 8 to 10; 25 patients had PSA 10-20; and 20 C) disease-specific survival. Measurements of PSA were patients had a baseline PSA >20. The mean PSA for patients made at 3-month intervals or less during treatment with triple presenting with a baseline PSA greater than 20 was 35 ng/ml.
androgen blockade and at approximately 3-month intervalsduring maintenance therapy. Blood samples were assayed for Efficacy
PSA at our clinic or by local community laboratories. The The median duration of triple androgen blockade therapy AIA® 600 immunoassay analyzer (Tosoh Medics, Inc.; South was 13 months. All 110 patients in this series achieved unde- San Francisco, CA) was used at our clinic, which employed tectable PSA levels (≤0.1 ng/ml). The median time to achieve a two-site immunoenzymetric assay and Tosoh AIA-PACK undetectable PSA was 3 months (range, 1-10 months).
methodology. Baseline and follow-up testosterone levels With a median follow-up of 36 months from the start of were also measured at 3-month intervals until testosterone hormone blockade therapy, the majority of patients have main- levels reached baseline levels or a plateau. Testosterone was tained low PSA levels. As shown in Table 3, the mean PSA also measured during finasteride maintenance to assess level for the entire cohort is 1.3 ± 0.1 ng/ml (range, 0-11.0 ng/ml). Eighty-five patients have now been off triple hormone At the majority of patient visits, clinical symptoms and blockade therapy for ≥12 months and have a mean PSA level adverse effects were recorded. In addition, complete blood of 1.6 ± 0.1 ng/ml. These men continue to receive finasteride counts and comprehensive chemistry panels including liver 5 mg daily. For the first 57 patients who completed therapy, the mean PSA level is 1.88 ± 0.1 ng/ml at a median follow-upof 55 months (range, 38-125 months). Only 9 out of 110 patients (8%) have a PSA level ≥4.0 ng/ml. Moreover, six ofeight patients who have been off therapy for >5 years have Patients
maintained stable low PSA levels without relapse. As of May Baseline patient characteristics are shown in Table 1 for 2000, no patient in this series has required further treatment.
110 consecutive patients who completed treatment by May Disease-specific survival is 100%. Although 10 2000. The median age was 67 years (range, 51 to 86 years), patients have died, none of these deaths were considered to and the mean Gleason score was 6.6 ± 0.1 (range, 4-10). The have resulted from prostate cancer or a treatment-related mean baseline PSA level was 13.2 ± 1.2 ng/ml (range, 0.39-100 ng/ml). Mean baseline serum testosterone level was Table 2. Clinical characteristics of 110 men treated with triple
available in 54 patients and was 373 ng/dl (range, 154-819 ng/dl). Table 2 summarizes the Gleason score, clinical stage, Clinical stage
Gleason score
PSA risk group
and PSA risk group (PSA <10, 10-20, and >20 ng/ml) for men receiving triple androgen blockade. Forty-four percent of patients had clinical stage T1c and 40% of patients had clinical stage T2a. Patients with higher stages (T2b/T3) Table 3. Post-treatment PSA levels
Mean PSA(ng/ml)
Standard error
Range (ng/ml)
Median follow-up (months)
n
T3 prostate cancer treated only with an LHRH agonist plus Table 4. Baseline and post-treatment testosterone values
flutamide for a median of 7 to 10 years, all patients achieved Testosterone
n
and maintained undetectable PSA levels; PSA failure occurred in only seven (15%) patients (two patients with stage T2 disease and five patients with T3 disease) after amedian of 3 years. Moreover, Strum et al. have recently complication. In each case, prostate cancer was reported by reported that intermittent androgen deprivation with an the local attending physician to be controlled and in remission.
antiandrogen, an LHRH agonist, and finasteride (given dur-ing induction therapy and as maintenance) resulted in signif- Safety and Toxicity
icantly prolonged time off intermittent androgen blockade in Nearly all patients reported adverse events typically asso- patients with clinically localized prostate cancer; only 5 of 27 ciated with hormone blockade therapy, including hot flashes, (19%) patients required retreatment after a median of 36 loss of libido, and loss of potency; however, these side effects resolved in nearly all patients on discontinuation of hormone Unlike the regimen described by Strum et al., we have blockade. No unexpected adverse events were reported.
used triple androgen blockade with finasteride maintenance Return of testosterone to greater than 180 was attained by all for all our patients. Additionally we recommend utilizing men who had a normal baseline testosterone level; the mean “high-dose” bicalutamide,150 mg orally all at one time daily, pretreatment testosterone level was 373 (n = 54); the mean rather than the 50 mg daily as used by Strum. Pharmaco- post-treatment testosterone level is 412 ng/dl (range, 9-942 dynamic studies of bicalutamide demonstrate an increasing ng/dl; n = 91) among patients who have been off treatment PSA response with higher dosing [33]. Studies suggest bicalu- for ≥12 months. Available testosterone data are summarized tamide monotherapy at 150 mg daily may be equivalent to sur- gical castration or dual androgen blockade, and is associatedwith fewer side effects such as hot flashes, sexual interest, and DISCUSSION
The results observed in this series indicate that patients Thus far, none of our patients treated with this regimen with clinically localized or locally advanced prostate cancer have required retreatment with hormone blockade. Recur- can achieve undetectable PSA levels with short-term triple rences to PSA ≥ 4.0 ng/ml have occurred in 8% of patients androgen blockade and maintain stable low PSA levels with (9/110), consistent with what others have observed [27, 29].
finasteride maintenance. The advantage of finasteride mainte- Follow-up PSA levels appear to have reached a stable PSA nance is that it may prolong time to relapse [29]. Despite the plateau in the majority of patients. However, if a patient retrospective nature of this study and the relatively short dura- experienced a progressive increase in PSA levels and his tion of follow-up, these results are provocative and, in con- PSA was at or above pretreatment levels, retreatment with junction with other published reports, support a reassessment hormone blockade should be considered. Patients with PSA of currently accepted approaches to the treatment of localized levels greater than 10 ng/ml may be candidates for further The clinical benefits of androgen blockade therapy appear Although PSA levels increased in nearly all patients when to be greatest when patients are treated early. This conclusion hormone blockade therapy was discontinued, one cannot is supported by a study in patients with locally advanced or assume that the relatively low levels of PSA observed in these asymptomatic metastatic disease that showed early interven- patients result from residual or occult metastatic prostate can- tion with hormone blockade was more effective than deferred cer cells. At least some of this PSA is likely to originate from intervention [31]. Messing et al. [32] also reported that imme- normal prostate-gland cells, as all of the men in this series still diate hormone blockade therapy following radical prostatec- have their prostate glands intact. Therefore, as testosterone tomy in pathologically node-positive patients significantly levels recover, as was the case in nearly all patients, normal prolongs survival compared with either observation or delayed prostate-gland cells will be stimulated to produce PSA.
hormone therapy. This suggests that men with low tumor bur- Remarkably, 18 patients (16%) in this series continue to have den might be expected to have prolonged survival with the PSA levels less than 0.1 ng/ml, and seven of these patients early use of hormone blockade and supports the rationale for have documented testosterone recovery to normal levels.
A particular benefit of the approach described here is its Labrie has reported that combined hormone blockade is tolerability. The morbidities associated with radical prosta- highly effective in controlling clinically localized or locally tectomy or other forms of local treatment can substantially advanced prostate cancer [27]. In 46 patients with stage T2 to affect quality of life and are often permanent. While on Preliminary Results in 110 Consecutive Patients treatment most men reported loss of libido and potency as CONCLUSION
well as the occurrence of hot flashes. Surprisingly, six men The current series has demonstrated that a single cycle in this series remained sexually active throughout the entire of 13 months of triple androgen blockade followed by treatment period. No patients developed urinary inconti- finasteride maintenance therapy yielded promising prelimi- nence or leakage. Approximately 25% of patients com- nary results. Since the median follow-up is short, it is pre- plained of some or all of the so-called “androgen mature to form definitive conclusions about triple androgen deprivation syndrome” symptoms [37], including hot blockade with finasteride maintenance as primary therapy flushes, mood swings, mild arthralgias, and mild gyneco- for localized prostate cancer. Nevertheless, 57 patients have mastia. Mild to moderate reductions in maximal athletic now been followed for a median of 55 months without stamina were subjectively reported in our patients. These requiring a second cycle of androgen blockade. If these androgen deprivation symptoms generally resolved within results can be confirmed in prospective randomized clinical a few months of testosterone recovery. With recovery of trials, it may suggest a new paradigm for the treatment of androgen production, patients reported an improved overall clinically localized or locally advanced prostate cancer.
sense of well-being. Approximately 5% of patients reportedpersistent loss of libido and/or potency. While on therapy ACKNOWLEDGMENT
and during the testosterone recovery period, the use of We would like to express our gratitude to Joni and Howard Viagra® often improved sexual function and restored Miller for their assistance in data management and preparation REFERENCES
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