Clinical investigation
Prostate
Mature Results of the Ottawa Phase II Study of Intermittent Androgen-Suppression Therapy in Prostate Cancer: Clinical Predictors of Outcome

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Purpose: To present the mature experience of a phase II trial of intermittent androgen suppression (IAS).

Methods and Materials: Intermittent androgen-suppression therapy was initiated in prostate-cancer patients to delay hormone resistance and minimize potential side effects of androgen-deprivation therapy (ADT). Patients received cyclical periods of ADT and observation (off-treatment interval [OTI]). Androgen-deprivation therapy was reinitiated when the level of prostate-specific antigen (PSA) rose above 10 ng/ml, or for disease progression. Associations between clinical factors and eligibility for OTI were measured. Kaplan-Meier and Cox regression analyses were used to determine factors predicting the duration of OTIs.

Results: Ninety-five patients completed 187 cycles of treatment. The median duration of OTIs was 8.5 months. Patients with higher PSA and metastatic disease were less likely to be eligible for the first OTI (p < 0.01). In multivariate analysis, patients with higher PSA and local relapse had significantly longer OTIs (p < 0.01) compared with metastatic patients. The median time to withdrawal from the study was 37 months.

Conclusions: Intermittent androgen suppression appears to be a favorable treatment option for patients with biochemically (according to level of PSA) or locally recurrent prostate cancer with favorable long-term survival, a high probability of eligibility for OTIs, and durable OTIs.

Introduction

Androgen-deprivation therapy (ADT) is the standard treatment for metastatic and recurrent prostate cancer. The majority of patients with metastatic prostate cancer respond to hormone therapy, with a median response duration between 14 and 30 months. Patients with biochemically (according to level of prostate-specific antigen [PSA]) recurrent disease have a more prolonged response duration (>60 months). Despite a primary response rate of 80% to 90% with hormonal ablation, almost all patients advance to a state of androgen independence as manifested by PSA progression, and/or clinical tumor progression at local and/or distant sites. Once a patient becomes hormone-refractory, the median survival ranges from 9 to 19 months (1, 2). For hormone-refractory disease, treatment consists of supportive care, chemotherapy, bisphosphonate therapy, and radiotherapy.

Androgen-deprivation therapy produces a constellation of symptoms that can negatively influence patient quality of life. This ADT syndrome is well-documented and includes vasomotor side effects, increased weight and cholesterol levels, and reduced sexual function, energy levels, and hemoglobin levels (3). The long-term effects of ADT include reduced muscle mass and decreased bone-mineral density (4, 5). Because of the high incidence of prostate cancer, the earlier use of ADT, and the prolonged duration of therapy, the preponderance of ADT syndrome has increased and cannot be ignored.

Strategies to improve the duration of hormone response and minimize the side effects of ADT have been pursued. Intermittent androgen suppression (IAS) is a cyclic therapy consisting of active treatment periods followed by observation periods. During these observation or off-treatment intervals (OTIs), patients are closely monitored for disease control; evidence of progression triggers the initiation of the next active treatment cycle.

In the Shionogi carcinoma mouse model, a well-characterized model of androgen-dependent neoplasia, Bruchovsky et al. (6) and Akakura et al. (7) demonstrated that IAS could delay the development of androgen independence. The laboratory data produced by Bruchovsky et al. (6) and Akakura et al. (7) provided the stimulus for early human trials of IAS. Results of phase II studies demonstrated the clinical feasibility of IAS (8, 9, 10, 11, 12, 13, 14), and other studies reported reduced side effects and improvements in quality of life during OTIs (9, 15, 16, 17).

Intermittent hormone therapy is initiated in advanced prostate-cancer patients to delay the development of hormone resistance and to help minimize the side effects of ADT. The feasibility of IAS is due to the reliable detection of disease activity with the use of PSA testing; failure to respond to treatment can be easily evaluated, and patients can be prescribed an alternative treatment. In addition, because testosterone recovery is typically slow during OTIs, there is little concern about rapid tumor flare during the off-treatment phase of the cycle.

A phase II trial of IAS at the Ottawa Hospital Regional Cancer Centre (Ottawa, Ontario, Canada) was initiated in 1994. Crook et al. reported their initial clinical experience with 54 patients in 1999 (13). This report presents the mature experience with 95 patients, highlighting the typical course of therapy, clinical factors predicting eligibility for IAS treatment, and patient and tumor factors predicting the duration of OTIs.

Section snippets

Patients

Ninety-five patients were entered into this phase II study between October 1993 and April 2000. The Research Ethics Board of the Ottawa Hospital (Ottawa, Ontario, Canada) reviewed and approved the protocol. All patients gave written informed consent before entry into the study. The trial was limited to four patient groups: (1) PSA-proven recurrent disease after radiotherapy, (2) biopsy-proven local recurrence after definitive radiotherapy, (3) metastatic disease after radiotherapy, and (4)

Demographics

All patients entered into the study were diagnosed with prostate cancer between November 1984 and September 1998. The median age at diagnosis was 66 years (range, 49–80 years). Patient status at diagnosis, as presented in Table 1, demonstrates that 50% of the sample had PSA at baseline of >20 ng/ml, and that 56% had Stage III disease or higher. Seventy-two patients received radical radiotherapy as initial management (median dose, 6,600 cGy; range, 4,500–6,900 cGy). The median time from the end

Discussion

Although ADT is standard for metastatic and recurrent prostate cancer, the optimal timing in asymptomatic patients with biochemical relapse is unknown. Patients with recurrent prostate carcinoma, after the failure of local therapy, have a long life expectancy (median life expectancy, approximately 7–10 years), while patients with metastatic disease have a median survival of only 3 years (18). The median survival for patients with hormone-refractory disease is 9 to 18 months. If IAS were to

Conclusions

The data from our phase II study demonstrate the feasibility of IAS in patients with prostate cancer. In our study, a significant percentage of patients had durable OTIs. Patients with PSA or locally recurrent prostate cancer have long-term survival, and a high probability for eligibility for OTIs. Patients who presented with metastatic disease had an increased probability of being ineligible for an OTI. We await the mature results of phase III trials of IAS to determine if IAS delays the onset

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    Conflict of interest: none.

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