Japanese Journal of Clinical Oncology 30:21-26 (2000)
© 2000 Foundation for Promotion of Cancer Research
A Pilot Study of Intermittent Androgen Ablation in Advanced Prostate Cancer in Japanese Men
Departments of 1Urology and 2Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: Permanent androgen ablation has been the mainstay of treatment for advanced prostate cancer. However, the favorable outcome seen in recent pilot studies of intermittent androgen ablation raises the possibility of overtreatment.
Methods: This study included 35 Japanese men with advanced prostate cancer. Initial androgen ablation continued for 2 months after PSA levels decreased to <4.0 ng/ml, then was withdrawn. Androgen ablation was reinstituted 2 months after PSA reached levels >10 ng/ml, when indicated clinically or on patient request. Cycling continued until androgen independence was reached.
Results: Mean follow-up was 21.0 months, representing an average of 2.5 cycles. Nine patients developed androgen independence at an average of 16.0 months following androgen ablation; three of these have died. Six of the nine patients with early biochemical progression had elevated alkaline phosphatase levels at entry; five of these exhibited a flare in alkaline phosphatase activity after initiation of androgen ablation. Mean bone mineral density (BMD) in the lumbar spines of 17 patients was 81.5 mg/cm3 at 23 months following therapy. The BMD of 10 of these patients was normal for their age. Four patients suffered bone fractures, none pathological.
Conclusions: Intermittent androgen ablation may be an option for patients with advanced prostate cancer and may be especially beneficial for those with initially low BMD levels. Patients with elevated alkaline phosphatase levels at entry or a flare in its activity may not be ideal candidates. Whether prolonging time to androgen independence will provide benefit remains to be investigated in a randomized, prospective study.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The incidence of prostate cancer is currently increasing. This disease is now the ninth leading cause of male cancer death in Japan (1–3). There were 8200 cases in 1991, with the number anticipated to increase to as many as 12,783 in 2000. Despite efforts toward early detection, up to 30% of patients present with metastases and a large proportion of the remainder develop metastatic lesions during the course of their disease (4,5).
Since the introduction of hormonal therapy by Huggins and Hodges in 1941, permanent androgen withdrawal has been the mainstay in treatment of advanced prostate cancer (6). Despite a high initial response rate of 70–80%, however, more than 50% of patients relapse after an average of 2 years (7,8). Disease progression in these patients is characterized by the proliferation of androgen-independent cells, so responses to second-line hormonal agents are uncommon and transitory. Bruchovsky et al. (9) demonstrated in their experiments that cyclic androgen withdrawal can delay the time to androgen independence and resulting tumor progression. Akakura et al. reported on seven patients who had a total of 12 episodes of hormone therapy after achieving PSA-complete remission, with further response after each re-exposure (10). Since then, several clinical reports have described investigations of the efficacy and limitations of this new treatment strategy (11–17). In this paper, we describe our initial clinical experience with 35 Japanese patients with advanced prostate cancer treated with intermittent androgen ablation.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patients
Between March 1996 and October 1998, 40 consecutive Japanese males diagnosed with advanced prostate cancer were invited to join this prospective trial at Kitasato University Hospital. Before registration in the study all patients gave signed informed consent after discussion. Five of these exhibited a poor response to androgen ablation that did not allow transfer to intermittent cycling and were therefore excluded from further study (Table 1). Patients were eligible for this study if they had performance status 0 to 1(18) and had histologically confirmed adenocarcinoma of the prostate with or without distant metastases. Patients with biochemical failure following radical prostatectomy were also included. No patients had previously received any form of hormonal manipulation. Two patients were kept on oral fluorouracil (200 mg/day) for prophylaxis following radical surgery for colon and laryngeal carcinoma, respectively.
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Treatment Schedule
Hormonal therapy was commenced with a combination of luteinizing hormone-releasing hormone agonist (LHRH agonist, leuprolide acetate 3.75 mg or goserelin acetate 3.6 mg) and antiandrogen (flutamide 375 mg/day, 33 patients) or with LHRH agonist alone (two patients). Two of the 33 patients on combined blockade were later switched to LHRH agonist monotherapy owing to flutamide-induced transient liver dysfunction. Irrespective of the pretreatment PSA levels, the initial treatment period continued for 2 months after PSA decreased to <4.0 ng/ml. Patients then became eligible for withdrawal of androgen ablation treatment and commencement of the off-treatment phase. Androgen ablation was reinstituted 2 months after PSA reached levels >10 ng/ml, when indicated clinically or on patient request. Patients were seen in monthly follow-up visits to determine treatment-related side effects and to measure serum PSA and testosterone levels, as well as for other biochemical tests. The length of one treatment cycle was defined as the number of months of androgen ablation (on-therapy period) followed by the number of months that treatment was withdrawn (off-therapy period). Cycling was continued until androgen independence was reached.
Response Criteria
Androgen independence was defined as three successive serum PSA increases of at least 25% above the 4.0 ng/ml cut-off level while testosterone levels were in the castration range. Time to androgen independence was taken as the time to the first PSA increase. Disease progression was also defined clinically as finding biopsy-proven local recurrent tumor, evidence of malignant disease or appearance of new lesions on a bone scan or appearance of soft-tissue metastasis indicated by biopsy.
Staging and Clinical Tests
Rectal examination was conducted and all patients were followed prospectively by one of the authors (S.E.), who staged the tumors clinically according to the 1997 revision of the unified tumor node metastasis (TNM) classification (19).
Prebiopsy serum PSA was quantitated by Dainapack IMx PSA assay (Dinabot, Tokyo, Japan) up to June 1997 and by AxSYM PSA assay (Dinabot) thereafter. Results of the two assays are considered virtually identical (20). Prostate scanning and transrectal ultrasound-guided biopsy were done using a Bruel & Kjaer (Gentofte, Denmark) Model 1846 scanner equipped with a 7 MHz multiplanar transducer as described previously. Prostatic volume was determined as prostatic length x width x height x (
/6).
Post-therapy lumbar spine bone mineral density (BMD) was measured in selected patients by quantitative computed tomography (QCT) (21) using a Quantex Plus (Yokokawa Medical Systems, Hachiohji, Japan). Measurements were performed by obtaining scans through lumbar vertebra L3. A QCT value was calculated and expressed as mg/cm3.
The Mann–Whitney U-test or Kruskal–Wallis test was conducted for comparison of variables with p values <0.05 as significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Baseline Clinical Findings and Clinical Outcomes
Mean ( ± standard deviation) patient age at entry was 68.4 ± 7.0 years (range, 49–80). At the initiation of therapy, 10 had metastases to bone and/or lymph nodes (M1), nine without previous treatment and one following radical prostatectomy. Of the remaining 25 tumors (non-metastatic, M0), 14 had biochemical progression following radical surgery and/or salvage radiation therapy, three following definitive radiotherapy and eight without previous therapy. The 20 patients without previous surgery included three classified as T2a, two as T2b, two as T3a, 10 as T3b and three as T4. Tumor grade was classified as moderately differentiated (Gleason sum 5 or 6) in nine (25.7%) patients. Nineteen (54.3%) and seven (20.0%) patients had poorly differentiated tumors with respective Gleason sums of 7 and 8–10.
The mean follow-up time was 21.0 ± 9.5 months (range, 2.8–35.3). The pretreatment PSA values ranged from 10.7 to 558.0 ng/ml (mean, 96.5 ± 127.3). The pretreatment alkaline phosphatase levels ranged from 93.0 to 1590.0 ng/ml (mean, 269.8 ± 301.1; normal, 73.0–248.0). The mean testosterone level prior to treatment was 409.5 ± 130.8 ng/ml (range, 186.0–735.0; normal, 270–1070).
These patients have completed an average of 2.5 treatment cycles to date (range, 1–5.5). Five patients are still in the ‘off-therapy’ portion of cycle 1. Nine patients (five, M0; four, M1; Gleason score 5 in one patient, 7 in five patients, 8–10 in three patients) developed androgen independence at an average of 16.0 ± 7.2 months (range, 7–30) following initiation of androgen ablation. Of these, three patients died of prostate cancer and six are alive with (four patients) or without (two patients) bone metastases. One patient died of an intercurrent cause. Six of the nine patients with early biochemical progression had elevated alkaline phosphatase levels at entry (mean, 828.2 ± 442.8). Five of these six exhibited a flare in alkaline phosphatase activity 1 month after initiation of androgen ablation (mean, 2179.4 ± 1185.2; mean% increase, 46.7; range, 16.4–65.9%). All five developed androgen independence, four during cycle 2 and one during cycle 3.
The BMD of the lumbar spines in 17 patients at 23 months following therapy averaged 81.5 ± 32.1 mg/cm3 (range, 5.1–134.4). Ten of these patients had sustained BMD levels that were normal for their age. Five and four patients, respectively, had normal or low levels of BMD measured while ‘on therapy’, while the other five and three, respectively, had normal and low levels of BMD measured while ‘off therapy’. Four patients suffered bone fractures, two ulnar, one tibial and one femoral head. None of them had indications of pathologic fracture. BMD was measured only in one patient with an ulnar fracture, showing substantial loss compatible with osteoporosis.
The patient characteristics in each cycle are summarized in Table 2. Data from those who had completed the cycles or had had disease progression were used to calculate PSA values. Other figures are for those who completed the cycles.
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Cycle 1 Characteristics
To date, 30 patients have completed cycle 1 while five are still in the ‘off-therapy’ portion of cycle 1. The mean PSA values at the start of cycle 1 in these 30 patients were 108.3 ± 134.8 ng/ml. The mean PSA nadir during androgen ablation was 1.0 ± 0.9 ng/ml. The nadir of PSA values was reached within an average of 4.1 months from the commencement of treatment. The mean lengths of cycle 1 for these patients were 9.3 ± 4.2 months. On average, patients spent 46.2% of the time ‘on therapy’ and 53.8% of the time ‘off therapy’. All patients regained testosterone levels above the castrate range at an average of 3.4 (range 2–5) months after discontinuation of androgen ablation.
Cycle 2 Characteristics
To date, 20 patients have completed cycle 2. Four patients developed disease progression during the ‘on-therapy’ portion of cycle 2. The mean PSA values at the start of cycle 2 in these 20 patients were 54.9 ± 70.9 ng/ml. Six patients currently remain in this cycle. The time interval from the commencement of androgen ablation to androgen independence was 10.4 months on average. The mean PSA nadir values of the 20 patients during androgen ablation were 4.7 ± 12.6 ng/ml. Nadir PSA was reached within an average of 3.7 months from the commencement of treatment. The mean lengths of cycle 2 for these patients were 7.4 ± 2.1 months. On average, patients spent 50.0% of the time ‘on therapy’ and 50.0% of the time ‘off therapy’. All patients regained above-castrate testosterone levels at an average of 3.4 (range 1–4) months after discontinuation of androgen ablation.
Cycle 3 Characteristics
Nine patients have completed cycle 3 and five patients developed disease progression during the ‘on-therapy’ portion. The mean PSA values at the start of cycle 3 in these 14 patients were 64.8 ± 108.3 ng/ml. Six patients currently remain in cycle 3. The time interval from the commencement of androgen ablation to androgen independence was 20.5 months on average. One of these patients died of an intercurrent cause at 15.9 months following initiation of therapy. The mean PSA nadir values during androgen ablation were 4.6 ± 8.5 ng/ml. Nadir PSA was reached within an average of 3.5 months from commencement of treatment. The mean cycle lengths of cycle 3 for these patients were 7.6 ± 1.1 months. On average, patients spent 48.7% of the time ‘on therapy’ and 51.3% of the time ‘off therapy’. All patients regained testosterone levels above the castrate range at an average of 3.8 (range 1–4) months after discontinuation of androgen ablation.
Cycle 4 Characteristics
Two patients have completed cycle 4. No patients have developed disease progression to date. Seven patients currently remain in that cycle. The mean PSA values at the start of cycle 4 were 33.2 ± 16.8 ng/ml. Nadir PSA was reached within an average of 4.1 months from commencement of treatment. All patients regained above-castrate testosterone levels at an average of 5.0 months after discontinuation of androgen ablation.
Cycle 5 Characteristics
One patient has completed cycle 5 to date while the other currently remains in that cycle. The PSA value at the start of cycle 5 was 20.9 ng/ml.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Permanent or continuous androgen ablation, introduced by Huggins and Hodges (6) more than 50 years ago, has been routinely employed as first-line treatment for advanced prostate cancer. Based on experiments using the androgen-dependent Shionogi carcinoma cell line model, Bruchovsky et al. recently attempted to delay the development of hormone independence by replacing androgens early in the course of treatment (9,10). They suggested that it might be safe to avoid continuous use of hormone therapy in prostate cancer. Their observation raised a serious concern that, in some men, surgical castration and other forms of continuous androgen blockade amount to overtreatment of the disease. Since then, several clinical reports have described investigations of the efficacy and limitations of this new treatment strategy (11–17). To our knowledge, this report represents the first study in an oriental population.
The timing for deciding whether patients with prostate cancer are eligible for interruption of endocrine therapy remains to be determined. Bruchovsky et al. suggested that only patients whose PSA at 24 and 32 weeks had reached a stable or decreasing value within the normal range should be considered eligible for intermittent suppression at 36 weeks (22). In their view, this strategy facilitates apoptotic elimination of PSA-producing cells following cessation of androgen-regulated PSA gene expression. Theoretically, however, androgen ablation should be stopped before constitutive development of the androgen-independent phenotype.
Table 3 summarizes literature reports of intermittent androgen ablation. Despite the wide variability in duration of androgen suppression (induction period), there are relatively small differences in ‘off-therapy intervals’ or ‘% off-therapy values’. Castrate levels of testosterone and suppressed luteinizing hormone (LH) may persist as long as 1 year after cessation of prolonged LHRH agonist administration lasting more than 24 months (23). However, all patients in our study regained normal levels of testosterone within 5 months after discontinuation of androgen ablation. This is compatible with another report using a 9-month androgen ablation induction phase (testosterone recovery within 8 weeks, range 1–26 weeks) (24). Hence induction periods <9 months seem to have little impact on recovery of function by the hypothalamic–pituitary–testicular axis. The degree of response after stopping androgen ablation may be affected by other factors, but it seems that prolonged androgen suppression is not always needed for all types of prostate cancer.
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A certain subgroup of patients responded with an extended off-therapy period of slow tumor regrowth, even after a short interval of androgen ablation therapy (Fig. 1). Interestingly, prolonged PSA suppression and most likely tumor suppression can occur in the presence of normal-range testosterone levels in these patients. Especially in such patients, continuous androgen ablation may be an overtreatment. The results of clinical trials incorporating neoadjuvant/adjuvant androgen ablation should thus be interpreted with caution. The favorable outcome may be solely derived from the endocrine therapy rather than effects of combination treatment.
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The ideal candidate for intermittent androgen ablation has not yet been well defined. Nine patients developed androgen independence at an average of 16.0 months following initiation of androgen ablation. Six of these had elevated alkaline phosphatase levels at entry and five exhibited flares in alkaline phosphatase activity 1 month after treatment. Flare in alkaline phosphatase activity within 1 month of orchiectomy has been shown to permit early identification of patients in whom the disease is likely to progress rapidly (25). Thus, patients who have elevated levels of alkaline phosphatase before treatment and particularly those with flare, may not be ideal candidates for this type of endocrine manipulation.
Most of these patients were symptomatic (with bone pain) at entry. They usually returned to the clinic with recurrent pain accompanied by rising PSA levels after a typically short ‘off-therapy’ interval. We recommend patients with bone pain not to be involved in the current form of intermittent androgen ablation. By prolonging androgen ablation, those who are destined to suffer early failure may safely be excluded and thus tumors that are more sensitive to endocrine therapy may possibly be selected. Modifications in the intermittent protocol, such as maintenance with finasteride or antiandrogen but without an LH–RH agonist, may be another option in these patients (26).
Post-therapy lumbar spine BMD was measured in 17 patients who gave consent for evaluation. The mean BMD of the lumbar spine at a mean of 23 months following therapy was 81.5 mg/cm3. Ten of these 17 patients had sustained normal levels of BMD for their age (five measured ‘on therapy’ and five ‘off therapy’). Four patients suffered bone fractures, one of them with decreased BMD. It has been shown that an approximately 2–7% trabecular bone loss in the spine occurs after 6 months of treatment with a LHRH agonist (27). Although BMD values at entry were unknown in our patients, intermittent cycles may possibly be beneficial in some patients in terms of maintaining BMD, thus delaying osteoporosis (21,27). The long-term impact of the current findings needs to be confirmed by further investigation, however.
The cost of medical treatment has recently become a significant issue in Japan with respect to economy of resources and establishment of financial policy. The estimated cost for continuous endocrine therapy using combined androgen blockade is 1,384,697 yen/year/patient, while that for intermittent therapy is 756,044 yen. In 1995, Medicare patients spent $480 million for leuprolide acetate and the administration of leuprolide acetate was the thirteenth largest category of physician reimbursement by Medicare (28). Once the intermittent protocol proves feasible, this would certainly impact the worldwide medical economy substantially. However, reductions in drug costs may to some extent be balanced by a greater need for PSA monitoring.
Detailed analysis of patient survival was not possible since our study represented a non-randomized pilot study. The benefit of intermittent androgen ablation has not yet been established. Several groups have launched a prospective randomized trial to assess the feasibility of this treatment (15). Hence we need to wait longer before we may know whether any advantage in patient survival can be gained by delaying time to androgen independence. Until that time, this treatment should be considered merely investigational. Further study is warranted.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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This work was supported in part by a Grant from the Ministry of Health and Welfare of Japan and the Foundation for Promotion of Cancer Research in Japan. We thank Dr W.A. Thomasson for expert editorial assistance.
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FOOTNOTES |
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+ For reprints and all correspondence: Shin Egawa, Department of Urology, Kitasato University School of Medicine, 1–15–1 Kitasato, Sagamihara, Kanagawa 228–8555, Japan. E-mail: s-egpro@sa2.so-net.ne.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received August 9, 1999; accepted September 30, 1999.
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