Phase III trial of intermittent MAB vs continuous MAB
Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Last Modified: June 5, 2006
Presenter: F.M. Calais Da Silva
Presenter's Affiliation: Hospital Desterro, Lisbon, Portugal
Type of Session: Scientific
- Androgen deprivation relieves symptoms and causes a reduction of PSA level in men with locally advanced and metastatic prostate cancer.
- Men with metastatic prostate cancer have a median progression free survival from 12 to 33 months and a median overall survival from 23 to 37 months.
- Androgen deprivation is associated with significant costs and side effects.
- The doubling time of prostate cancer is usually slow, but its response to therapy is usually rapid.
- It has been suggested that intermittent therapy may be possible, depending on the percentages of hormone sensitive cells in the tumor.
Materials and Methods
- 766 patients with locally advanced or metastatic prostate cancer were initially treated with three months of induction therapy (2 weeks of 200mg cyproterone acetate (CPA) and then monthly injections of an LHRH agonist with continued daily CPA).
- 626 of these patients had their PSA fall to either <4ng/ml or <80% of its initial value and were then randomized to either intermittent or concurrent androgen deprivation.
- Patients had either T3/4M0 or M1 disease with a WHO performance status of 0-2.
- Patients had to have histologically proven prostate cancer and could not have received any previous therapy (including radiation therapy).
- Patients were followed with PSAs every 3 months.
- For the intermittent patients, androgen deprivation was restarted when their PSA rose to >10ng/ml with symptoms, or >20ng/ml without symptoms, or above 20% of the nadir value.
- For the intermittent group, androgen deprivation was stopped when the PSA fell to <4ng/ml.
- Patients were well balanced in terms of demographic and disease related factors.
- The median PSA at time of randomization was 1.2ng/ml for the intermittent group and 1.3ng/ml for the continuous group.
- 22% patients randomized had PSA in excess of 4ng/ml.
- 50% of intermittent patients have been off of therapy for at least 52 weeks following the initial LHRH therapy, and 29% have been off therapy for at least 36 months.
- For the 197 patients whose PSA fell below 2ng/ml at initial randomization, the median time off of therapy was 74 weeks.
- When patients returned to treatment, they had a median duration of therapy of 14 weeks followed by a second period off therapy with a median of 70 weeks.
- Patients with a PSA <2ng/ml at randomization have spent a median of 82% of their time off of therapy.
- Patients with a PSA >4ng/ml at randomization are off of therapy for a median of 16 weeks.
- The main difference in quality of life between the two arms of the study was confined to sexual function.
- Sexual activity was significantly greater in the intermittent arm (p<0.01).
- The most commonly reported side effect was hot flashes, which was reported by 8% of patients.
- The patients in the continuous arm complained of more side effects.
- 30% of continuous patients reported at least 1 hot flash, while only 20% of intermittent patients reported at least 1 hot flash (p<0.01).
- There was either subjective or objective disease progression in 110 intermittent patients and 99 continuous patients.
- There was no significant difference seen in overall survival (HR continuous 0.99, 95%CI 0.8-1.23, p=0.84).
- The median time off therapy for patients in the intermittent arm was 52 weeks.
- Patients with PSA less than 2ng/ml on randomization spent a median of 82% of their time receiving no therapy.
- There is no evidence that intermittent therapy leads to an elevated risk of dying.
- Intermittent therapy is associated with improved quality of life and decreased side effects.
- The use of intermittent therapy is a feasible option in the clinic.
The authors presented a well designed phase III randomized trial of continuous versus intermittent androgen deprivation in patients with advanced or metastatic prostate cancer. The authors’ conclusions are valid for the cohort of patients that were studied. In