Introduction

This is the third year for the American Society of Clinical Oncology (ASCO) Prostate Cancer Symposium, held February 22-24, 2007 in Orlando, Florida. This meeting is a very informative symposium that gathers an international multidisciplinary group. The meeting is a product of collaboration among three major organizations, ASCO, the American Society for Therapeutic Radiology and Oncology (ASTRO), and the Society of Urologic Oncology (SUO).

This three day meeting covered a number of areas related to prostate cancer including risk factors, screening, prevention, prostate-specific antigen (PSA) as a marker, risk assessment, local treatments, biochemical failure, complications of therapy, and developmental therapeutics.

Inflammation and Prostate Cancer Carcinogenesis

Approximately 20% of all human cancers in adults result from chronic inflammatory states that can be triggered by infectious agents, environmental exposures or the combination of the two. Hepatitis, gastritis, chronic colitis, schistosomiasis, and HPV cervical infections are all known to be associated with subsequent development of cancer. Prostate cancer is another cancer which appears to be associated with inflammation.

Researchers from Johns Hopkins in Baltimore discussed epidemiological links between prostate cancer and consumption of red meats and fats.[1] Heterocyclic amines (HCAs) are formed by cooking meats at high temperatures. These HCAs can be metabolized to biologically active metabolites that can adduct to DNA, one such metabolite is PhIP.[2] Researchers have shown that PhIP can induce prostate lobe specific cell proliferation and death. This outstanding research is leading to a better understanding of why prostate cancer involves certain lobes and also relates to inflammation atrophy and subsequent cancers.

“Is prostate cancer a viral disease?” was discussed by Eric Klein, M.D. from the Cleveland Clinic. A number of different viruses have been identified in the prostate. MuLV-related virus, or XMRV, is a xenotropic retrovirus that is sexually transmitted and has been isolated in the prostate stroma. XMRV may increase the risk of prostate cancer.[3] It is postulated that the viral agent induces inflammation, which in turn promotes carcinogenesis. A screening test for this agent is being evaluated and in the future may help to predict those at higher risk.

Beyond PSA:  Risk Prediction in the Next Decade

PSA has been labeled the most important tumor marker in oncology, yet it lacks specificity for the diagnosis of prostate cancer. ECPA-2, a nuclear matrix protein, is a novel new marker that is highly specific for prostate cancer and also can help in stratifying men into organ confined and non-confined following diagnosis. Getzenberg reported that this marker has a sensitivity of 94% and specificity of 97%.[4] There are a large number of outcome predictive models for various stages of prostate cancer. Dr. Kevin Slawin from Baylor College of Medicine in Houston reviewed a number of these and discussed pitfalls of the nomograms. Electronic tools help to manage and interpret data such as PSA doubling time, a log based calculation.

Circulating tumor cells (CTC) are cells detected in the circulation in contrast to disseminated tumor cells (DTC) that have deposited in a distant site. All tumor cells emanate from shed tumor cells. However all CTC do not result in overt metastasis. In breast cancer, patients with more than 5 CTC have a worse survival.[5] Levels of CTC/DTC are being evaluated in prostate cancer and seem to be clinically informative.

Several abstracts in this session dealt with PSA velocity and percent free PSA, concluding that in men with PSA < 4 ng/ml that a velocity change of .3 -.5ng/ml/year was suggestive of prostate cancer.[6] In a similar cohort of men with PSA levels of < 2.5 ng/ml, percent free of less than 25% was a predictive factor for prostate cancer.

Who doesn’t need treatment?

More men are being diagnosed with low-risk prostate cancer. Many of these cancers are indolent in nature and will have no impact on health or longevity. Men diagnosed with prostate cancer are faced with a choice between immediate radical treatment versus active surveillance. In a mature prospective study from Toronto, 231 men with a median age of 71, 78% having a Gleason score of <7 and 84% having a PSA of < 10 ng/ml, were followed. At 8 years the disease specific survival was 98%.[7] Drs. Parker and Scardino argued for both sides, active surveillance versus immediate treatment. In some series, 33% of patients will undergo some sort of treatment within 5 years, and many of those undergoing delayed treatment have unfavorable pathology. An indolent cancer nomogram has been developed by Scardino’s group and may be helpful in selecting men who are candidates for observation, active surveillance, or aggressive local therapies.[8]

Tertiary prevention, which is preventing progression of a prostate cancer, could result in improvements in disease-specific outcomes.  A number of non-invasive approaches can be employed. The use of 5 alpha reductase agents (5ARI) that in theory might slow down progression of the disease was discussed by Dr. Neil Fleshner. A clinical trial called REDEEM  will accrue over 300 patients to address whether the 5ARI, dutasteride will prevent progression of diagnosed prostate cancer. Additionally, dietary and dietary micronutrients may play a role.

Additional Treatment for Pathologic T3 Disease: Now, Later, or Never

Adjuvant radiation therapy was the topic discussed in two large randomized clinical trials reported by Drs. Michel Bolla and Gregory Swanson. The EORTC trial enrolled 1,005 men between 1992-2001.[9] Eligibility criteria included capsular invasion, positive surgical margins, or seminal vesicle invasion. The median age of randomized men was 65 years.

The mean biochemical progression free survival was 74% for the immediate treatment group and 52% for the wait and see group. Toxicities were minimal and positive margin status was predictive of response.

The Southwest Oncology Group protocol 8794 evaluated radiation versus observation in 425 men with pathologic T3 disease.[10] The primary endpoint was metastasis free survival and there was a benefit in that category as well a significant reduction in the need for hormonal therapy.

Several abstracts presented dealt with active surveillance and PSA metrics. What level or change in the serum PSA is a trigger for treatment? PSA DT(doubling time) is commonly used but may result in over treatment. A PSA of 20 ng/ml is a better bench mark for institution of therapy but risks more advanced disease.

Androgen Deprivation for Advanced Disease

Drs. Derek Raghavan, Urs Studer, and E. David Crawford debated the diagnosis and management of men with biochemical failure. It is estimated that more than 50,000 patients annually will develop biochemical recurrence. Correctly defining PSA recurrence remains a challenge. Following radical prostatectomy, PSA should theoretically be undetectable; however, not all patients with minimal elevation experience disease progression. Different definitions of recurrence have been used, and in most studies, they range from a level of more than 0.2 ng/mL to more than 0.4 ng/mL. The definition following radiation remains even more controversial. PSA levels do not always fall to undetectable levels, and varying periods of time are required to achieve a nadir, usually 18 months. The nadir may take longer to occur following brachytherapy, and transient elevations (also known as PSA bounce) are not uncommon. The current definition for recurrence states that failure is defined as a greater than 2 ng/mL increase above the nadir.[11]

A number of factors are associated with treatment failure including age, race, obesity, family history, initial PSA level, PSA nadir, PSA kinetics, percentage of free PSA, PSA density, prostate size, number and percentage of positive biopsies, Gleason score, perineural invasion, tumor stage, tumor volume, lymphovascular invasion, seminal vesicle invasion, positive surgical margins, bladder neck invasion, lymph node status, multifocality, and transition zone cancers. There are numerous tables and neural networks that can be used to predict failure; however, the three most prominent predictors are Gleason score, initial PSA, and clinical stage.

Once a man has been identified as having biochemical failure, it is evident that local treatments have failed to cure the disease; however, that does not mean the person will die from prostate cancer. Biochemical failure studies from Johns Hopkins describe that the median time to metastases is 8 years, and the median time to death from metastatic disease is 5 years later.[12] Recently, the role of PSA doubling time has been introduced to identify groups of patients at risk of early death. Unfortunately, there is no standard technique to determine PSA doubling time. In general, those with doubling time of less than 1 year are at a higher risk of developing metastatic disease and of subsequent death. In addition, time to failure usually defined as less than 2 to 3 years is a prognostic factor. Whether the biochemical failure reflects local failure, distant failure, or a combination of both is an important issue that needs to be examined.

A number of imaging studies have been utilized to determine the location of the cancer. These include bone scan, computerized tomography scan, ProstaScint scan, and prostatic biopsy. Unfortunately, none of these tests are infallible, and it is this author’s opinion that approximately two-thirds of failures represent distant failure and one-third represent local failure. As one-third of failures are believed to be local, this represents an opportunity for a second chance at a “cure,” which can be achieved by local radiation therapy, cryotherapy, and salvage prostatectomy.

A raging controversy exists regarding the utilization of early compared with delayed hormone therapy and the use of chemotherapy for patients with biochemical failure. Additionally, some promising immunotherapeutic agents are being evaluated. Investigators must strive to determine if hormone therapy, immunotherapy and/or chemotherapy can effectively cure prostate cancer. Most clinicians doubt these hypotheses. However, the Eastern Cooperative Oncology Group positive node study and a number of adjuvant radiation trials would lead researchers to believe otherwise.[13] Dr. Studer provided an overview of this and his own study.[14] There are a number of strong arguments for the integration of early therapy. Investigators have observed improved outcome for various other cancer types when early treatment is used. Researchers opposed to early therapy highlight the side effect profile and often point to the lead time bias that this represents. Basic biology supports the concept that radiation, chemotherapy, and surgery are most effective when the number of cancer cells is the lowest and that host factors are such that the tolerance and effectiveness correlate with performance status. Large breast cancer clinical trials have demonstrated that patients who receive hormone therapy early in their treatment benefit more than patients who receive hormone therapy once relapse occurs; long-term hormone therapy is more effective than short–term therapy; early chemotherapy is superior to chemotherapy at relapse; and immediate salvage therapy is often offered at time of relapse. Breast cancer does not have a marker as definite as PSA; therefore, many believe that parallels between breast cancer and prostate cancer do not exist.

Chemotherapy: Soup to Nuts

This was one of the final sessions that highlighted the progress that has been made in the past few years in the chemotherapeutic approach for prostate cancer. Of interest was the discussion of targets for investigational therapies by Johann Bono, M.D. from the Royal Marsden Hospital in the UK. Several potential targets discussed included the androgen receptor (AR), Vitamin D receptor, and cell signaling.[15] Trials in these areas were discussed, including an interesting clinical study with Calcitriol, which is the basis for an ongoing Phase III trial in the US.

Immune therapy represents a new frontier for the treatment of prostate cancer. Immunotherapy has evolved from moderately to highly toxic treatments such as interleukin-2 or interferon to newer modalities such as active cellular immunotherapy and vaccine therapy. During this year’s ASCO Prostate Cancer Symposium, the role of immunotherapy was again discussed, particularly in advanced disease where there are few viable treatment options.  In this setting, immunotherapies may represent a non-cytotoxic approach and thus have the potential for a low incidence of serious adverse events. Preliminary studies demonstrate that asymptomatic men with hormone-refractory prostate cancer who are administered the dendritic cell product sipuleucel-T (APC8015, or Provenge®) have improved survival.

An interesting poster presented by W. Gerritsen presented the results of a novel Phase I trial evaluating the GM-CSF secreting immunotherapy for prostate cancer (GVAX®) and ipilimumab in hormone refractory prostate cancer. Ipilimuab is a monoclonal antibody specific for the CTLA-4 receptor on T cells that augments immune actions. Twelve patients completed the treatment and 5 patients attained PSA reductions.[16] Immunomonitoring studies demonstrated that T cell and dendritic cell activation were  more pronounced at higher doses. However, patients did develop endocrinopathies and alveolitis. Researchers in prostate cancer are encouraged by the activity of these immunotherapies which are paving the way for regulatory approval.

The challenge for the future will be how to best sequence prostatectomy, radiation therapy, hormone therapy, and chemotherapy with these new treatments.