 Home: PCU 1|2004:Arif Hussain, MD
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| Edited comments by Arif Hussain, MD |
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Treatment approaches for PSA relapse
A PSA recurrence can precede clinical progression by several months to years. No standard treatment exists for these patients, in terms of when to intervene and with what therapy.
Hormone ablation therapy
One approach is hormone ablation therapy, which is the standard treatment for men diagnosed with metastatic disease based on imaging studies. Hormone ablation therapy works in over 80 percent of men with metastatic disease, but it invariably fails over time. Men with PSA-only relapse after surgery or radiation therapy and negative imaging studies have a much lower tumor burden. Therefore, it makes sense to use a therapy that works well in patients with metastatic prostate cancer.
In the community, urologists often use hormonal therapy when the PSA starts rising. Hormonal therapy is likely to provide excellent PSA control, but it is unlikely to be curative in PSA-only failures. Like patients with metastatic disease, hormonal therapy eventually fails in patients with PSA-only recurrence. However, it may take longer to fail because the amount of disease burden is much lower.
Chemotherapy
Traditionally, chemotherapy has been used in men with hormone-resistant metastatic prostate cancer. However, hormone-resistant prostate cancer is also chemotherapy resistant. Two-thirds of men with hormone-resistant prostate cancer have increased Bcl-2, which is involved in the apoptotic pathway.
Bcl-2 expression is associated with resistance to a variety of cytotoxic drugs. Chemotherapy drugs might be useful in patients with hormone-sensitive prostate cancer before they are exposed to hormonal therapy.
Sequential chemohormonal therapy for PSA relapse
We conducted a pilot study in 39 patients who experienced PSA recurrence (Figure 2.1). Prior to trial entry, imaging studies (e.g., CAT scans and bone scans) were obtained. Thirty-two of the 39 patients had negative imaging studies. In contrast, seven of the 39 patients had metastatic disease; amazingly the PSA levels in these men were in the teens. This underscores the heterogeneity of prostate cancer. PSA levels don’t necessarily predict the extent of disease.
We treated all of these hormone-naive men with up-front chemotherapy —single-agent docetaxel every three weeks for four to six cycles — followed by hormone ablation therapy for 12 to 20 months. We administered four months of total androgen suppression (LHRH agonist and bicalutamide) in the 32 patients with negative imaging studies, and 12 months of total androgen suppression in six patients with positive imaging studies. One patient dropped out of the study. Then, we administered an additional eight months of peripheral androgen blockade (finasteride and bicalutamide).
Of the 33 men followed for a median of 20 months after the end of treatment, 25 have had a rise in their PSA, but eight have maintained their PSA at less than 0.1 ng/mL. Of those eight men, three previously had metastatic soft tissue disease and are now in complete remission based on imaging studies. In these three men, imaging studies performed after treatment with docetaxel revealed a greater than 50 percent reduction in tumor size. After four months of total androgen suppression, the tumors had completely disappeared.
Clearly, a subgroup of men exists in which long-term disease control is possible, even in metastatic disease. It is hard to predict a priori those groups of men. This approach is similar to the strategies with adjuvant systemic therapy in early breast cancer. In prostate cancer, we are behind in terms of integrating chemotherapy with hormonal therapy.
Case history: A 54 year-old man with PSA progression
Ten years ago this man had a prostatectomy for a Gleason 7 prostate cancer with negative margins, seminal vesicles and lymph nodes. His preoperative PSA was about 7 or 8 ng/mL, and his postoperative PSA was less than 0.1 ng/mL. Three years postprostatectomy, at the age of 54, his PSA began to rise to about 1.5 or 1.8 ng/mL. He underwent salvage radiation therapy, and his PSA became less than 0.1 ng/mL. After another four or five years, his PSA began to rise again to 3, 4, 7, and then 8 ng/mL.
Follow-up
He was referred to me by a urologist. The patient continued with observation until his PSA was 11 ng/mL; then he wanted to participate in our trial. On prestudy imaging evaluations, the bone scan was negative but the CAT scan revealed multiple bilateral pulmonary nodules, which I thought represented prostate cancer metastases. He underwent a lung biopsy, which proved to be recurrent prostate cancer.
I treated him with single-agent docetaxel for six cycles, and he had a 78 percent reduction in his PSA. At that point, most, but not all, of his pulmonary nodules had disappeared. Then he received one year of total androgen suppression. After four months of total androgen suppression, the residual pulmonary nodules had completely disappeared. I continued the hormonal therapy and treated him with peripheral androgen blockade. While on chemotherapy, this patient was able to work four out of the five days and, in fact, insisted on going to the gym. He developed neutropenia but did not develop any infections. He also experienced Grade II fatigue.
Discussion
This man had failed radical prostatectomy and salvage radiation therapy. His options included hormone ablation therapy but he knew that it eventually would fail, so he elected to enroll in our trial. He received single-agent docetaxel and had a greater than 50 percent response in his pulmonary nodules, which completely disappeared after hormonal therapy. I have followed him for a year — all his CAT scans are negative, his PSA is less than 0.1 ng/mL and his testosterone levels are noncastrate. He is my success story.
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| Dr Hussain is an Associate Professor of Medicine at the University of Maryland Greenebaum Cancer Center in Baltimore, Maryland. |
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