New Approaches Emerging for Advanced Prostate Cancer

NEW ORLEANS—Emerging strategies for treatment of advanced prostate cancer rest on precise classification of the hormone status of the disease and a range of developing techniques and agents aimed at increasing survival, according to experts at the 92nd Annual Meeting of the American Urological Association.

The dependency of prostate cancer growth on hormones has been known for over 50 years, Paul F. Schellhammer, MD, chairman of the Department of Urology, Eastern Virginia Medical School, said at a symposium sponsored by Zeneca Pharmaceuticals and held in conjunction with the meeting.

Although androgen deprivation has demonstrated good response in hormone-dependent prostate cancer, “the problem is that metastatic prostate cancer is a heterogeneous disease that has not been fully characterized,” Dr. Schell-hammer said.

The main problem facing urologists treating metastatic prostate cancer is to define the importance of blocking adrenal androgens in suppressing disease and delaying the appearance of hormone-refractory disease.

Dr. Schellhammer advocates using the following four fundamental categories, proposed by Scher et al (J Natl Cancer Inst 88:1623, 1966), to delineate the hormone-related nature of advanced prostate cancer:

• Hormone naïve (patient has received no previous hormonal manipulation).
• Androgen dependent (patient has received discontinuous hormonal treatment, known as intermittent androgen blockade).
• Androgen independent (patient has progressive disease despite castrate levels of testosterone).
• Hormone independent (patient has progressive disease despite castrate levels of testosterone and one or more additional hormonal manipulations).

Complicating the picture, Dr. Schellhammer said, is that fact that PSA levels and tumor activity do not necessarily correlate. For example, a differentiated cell produces more PSA than an undifferentiated cell, a fact that must be considered when new agents affecting differentiation are administered.

Dr. Schellhammer reviewed data from trials of androgen suppression showing statistically significant improvements in survival in the major trials, and some inconclusive results in other trials.

He acknowledged also that treatment side effects may be problematic. “Patients will accept the side effects of treatment if their progression-free survival and overall survival are significantly prolonged,” he said, emphasizing the importance of these endpoints in encouraging patient compliance as well as quality of life assessments.

Intermittent Androgen Blockade

Compliance problems with androgen blockade can be mitigated through discontinuous administration of androgens, said Kenneth J. Pienta, MD, associate professor of surgery, University of Michigan Medical School. “The androgen blockade side effects of hot flashes, breast tenderness, weight gain, and significant fatigue can be reduced through intermittent androgen blockade,” Dr. Pienta said.

He reviewed the available data indicating a potential benefit for intermittent androgen blockade, noting that ongoing studies indicate fewer side effects, and improved quality of life. Data on survival, however, are not yet available.

Although complete and intermittent androgen blockade remain as treatment options for advanced prostate cancer, patients who become resistant to treatment have had few treatment alternatives.

“Urologists and medical oncologists need to be aware that therapies for hormone-refractory prostate cancer exist. Several new chemotherapeutic regimens show promise and should be tried,” Dr. Pienta said.

For patients with rising PSA levels after radical prostatectomy or radiation and chemotherapy, peripheral androgen blockade has shown promise in a small series of 10 patients. After receiving a combination of finasteride (Proscar) (5 mg/day) and bicalutamide (Casodex) (50 mg/day), PSA dropped to undetectable levels in nine of 10 patients and has remained unchanged over a median follow-up of six months, Dr. Pienta said.

“While this peripheral scheme is still experimental, it can be considered an option. However,” Dr. Pienta cautioned, “experience with the regimen is too limited to assess its safety or efficacy.”

Other emerging therapies are progressing rapidly, Dr. Pienta observed. These include agents such as suramin, a cell growth inhibitor that blocks growth factor binding; estramustine plus vinblas-tine, inhibitors of microtubule-associated proteins (MAPs) and microtubule formation, respectively; and estramustine plus etoposide, a combination that targets tumor intracellular nuclear matrix and interferes with gene expression.

“Chemoprevention and chemotherapy rely on knowing the biology of the cell,” Dr. Pienta said, adding that many new strategies combine traditional chemotherapeutic agents with drugs that poison the internal cellular machinery.

New approaches mentioned by Dr. Schellhammer include strontium-89 for alleviation of bone pain; agents targeting signal transduction pathways within cells; agents that increase the endogenous levels of retinoids (promoting differentiation and thus forcing a tumor cell to adopt a less harmful phenotype); and radioimmunotherapy with isotopes linked to antibodies.

Another strategy involves “suicide gene” therapy using the herpes simplex virus thymidine kinase (HSV-tk) gene that converts intravenously administered ganciclovir (Cytovene) to a toxin within cells carrying this viral vector.

Therapies Keyed to Stage

In a thumbnail survey of current and future therapies keyed to the progressive stages of prostate cancer, Dr. Pienta provided the following outline:

• The normal prostate. No therapy, but for high-risk patients, future vaccine ablation may be used to target and destroy the prostate.
  
  
•  Small tumors. Present therapy involves chemoprevention and chemosup-pression strategies. Emerging approaches include vitamins E, A, and D, and selenium, with selenium showing strong potential as a chemopreventive agent for prostate cancer.
  
  
• Clinical tumor. Currently treated with surgery or radiation alone or with neoadjuvant hormone therapy. Future treatments may include neoadjuvant chemotherapy and combinations of chemotherapy with radiation therapy.
  
  
• Remission (after surgery or radiation as primary treatment). While no treatment is currently advocated, in the future, gene therapy or antimetastatic agents may be employed for minimal disease. For those patients in remission but with rising PSA concentrations, future vaccine-based approaches may be successful. A recombinant viral vector composed of vaccinia-PSA genes will be assessed in trials at the University of Michigan.
  
  
• Clinical recurrence with hormone-sensitive disease. While surgery and radiation are the currently recommended approaches, hormone ablation may also be an option. Dr. Pienta acknowledged that no definitive approaches have been identified. Once hormone-sensitive patients exhibit rising PSA levels, Dr. Pienta advocates the use of second-line hormone treatment, preceded possibly by chemotherapy.

Numerous trials are now evaluating strategies for treating clinical recurrence. “The bottom line is that there are a lot of new therapies emerging,” he said