Abstract
Sensitivity to androgen suppression therapy (AST) is a key determinant of survival in patients with non-localized prostate cancer. While an incomplete response to AST is associated with poor survival, additional therapy is typically withheld until obvious cancer progression. It is not known if the application of additional therapy earlier can have a favorable impact on long-term outcomes. We present the case of a patient with biochemically relapsed prostate cancer treated with early docetaxel after initial incomplete response to AST who now has a prolonged response to therapy.
Most patients with prostate cancer have organ-confined disease at presentation and can be treated with surgery or radiation. However, approximately one-third of these patients eventually develop a detectable or rising prostate-specific antigen (PSA), also known as biochemical relapse. Response to androgen suppression therapy (AST) in these patients is a strong determinant of long-term survival, providing clinical evidence that sensitivity to hormonal interventions can be ascertained early in therapy.
Stewart et al. found that among men whose PSA nadir after initiation of AST for 8 months was >0.2 ng/dl, the 7-year prostate cancer-specific mortality ranged from 54 to 72%, depending on pre-treatment PSA doubling time. Patients who had a PSA nadir <0.2 ng/dl, had a much lower risk of dying from prostate cancer with a 7-year prostate cancer-specific mortality of 2 to 4%, regardless of pretreatment PSA doubling time (1). A similar relationship between depth of response to initial AST and survival has been shown for patients with radiographically detectable metastases (2).
Phase III trials in metastatic castrate-resistant prostate cancer have shown that docetaxel-based therapy not only prolongs life, but significantly improves symptom control and quality of life (3-5). Little is known about the potential of docetaxel and other agents to modify the natural history of biochemically relapsed prostate cancer.
Based on the hypothesis that androgen suppression-resistant clones are responsible for persistently detectable PSA following AST initiation, a clinical trial was designed to evaluate the feasibility of improving disease control with the addition of docetaxel at this early point in the evolution of castration-resistant prostate cancer. Patients initially treated with a radical prostatectomy or radiation therapy with PSA >0.2 ng/dl after 8 to 12 months of AST and no evidence of metastatic disease were given docetaxel at 75 mg/m2 i.v. every 21 days for 4-6 cycles. Docetaxel was to be continued for 2 cycles beyond achievement of an undetectable serum PSA for a minimum of 4 cycles or maximum of 6 cycles. This was an open label study designed for primary endpoint of complete response rate and PSA ≤0.2 ng/dl.
The trial proved difficult to accrue participants, in part because the relatively unconventional point of intervention meant that treating physicians were unaccustomed to referral for clinical trials until a later point in the natural history of the disease. Funding was pulled from the study prematurely by the study sponsor. Three patients were enrolled on this protocol. One proved ineligible, and another discontinued therapy after only two cycles due to unrelated uncontrolled atrial fibrillation. Only one patient met eligibility criteria and received all cycles of chemotherapy.
Case Report
This 68 year old man was treated with a radical retropubic prostatectomy for a pT3aN0M0 Gleason 3+4 adenocarcinoma of the prostate in 2002. While he had a positive surgical margin, his serum PSA remained undetectable until 2005 when it reached 0.3 ng/dl. PSA increased to 0.8 ng/dl in 2007. This relapse was then treated with 70 Gy of radiation delivered to the pelvis and prostatic bed using 4-field box and 6-field 3D conformal techniques. Post-radiation PSA never decreased and by early 2008 had reached 2.7 ng/dl. In response to this rise in serum PSA, AST was initiated in May of 2008. Following 11 months of therapy with goserelin, initially with bicalutamide, the nadir PSA was 0.5 ng/dl. The patient was then enrolled in the clinical trial, and he received six cycles of docetaxel 75 mg/m2 administered every 3 weeks beginning in May 2009. His therapy resulted in a PSA nadir of 0.2 ng/dl. One year following completion of chemotherapy, his PSA remains 0.2 ng/dl on continuing treatment with goserelin alone.
Conclusion
While this study only had one patient treated at our institution, this case illustrates the possibility of prolonged disease response with the use of early docetaxel in certain prostate cancer patients. Biochemical relapse after primary therapy is a common problem in prostate cancer (6), and many of these patients develop castration-resistance. This patient's experience suggests that the early application of chemotherapy is feasible and should be examined further in prospective trials. When compared to the 6-month median time to progression with chemotherapy in men with metastatic prostate cancer, continued PSA stability for over one year is encouraging. The growing understanding that an incomplete response to initial AST represents early hormone resistance and has prognostic importance enables us to contemplate novel strategies to interrupt the progression of recurrent prostate cancer before a fully developed castrate-resistant state is established.
- Received December 6, 2010.
- Revision received February 16, 2011.
- Accepted February 17, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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