Cancer of the prostate is the most common tumor in US men, with well over 300,000 new cases diagnosed annually. According to the American Cancer Society, the incidence of this cancer has increased 50% between 1989 and 1993. Paralleling this increase in incidence has been a heightened focus of the medical and research community on the disease, as demonstrated by the number of MEDLINE citations on prostate cancer, which rose from 166 in 1966 to a high of 1,643 in 1994 (Figure 1).
Despite this intense public and academic scrutiny, major questions about prostate carcinoma remain unresolved. In this review, we will briefly examine some of these issues and also review current studies designed to answer the most fundamental questions regarding this disease.
Recognizing the public health impact of prostate cancer, several options for control of this disease are available. At present, the major medical focus is on early diagnosis and treatment. While this is an attractive approach, it is associated with several potential confounding factors and problems. These include: (1) overdiagnosis, (2) unknown impact on mortality, (3) potential morbidity of treatment, and (4) significant costs of screening and treatment.
Another potential approach that centers on biologically significant disease would be to improve the outcomes of therapy for metastatic disease. Although 50 years have passed since the first description of hormonal therapy for prostate cancer, there is little evidence that survival of patients with metastatic disease has improved.
Potential Preventive Approaches
Given the problems inherent in both early detection and treatment and improving the treatment of metastatic disease, the prevention of prostate cancer has emerged as a very attractive option. Epidemiologic and observational evidence suggests a number of potential preventive approaches. These include:
- Dietary PreventionPopulations of patients with diets high in fiber or low in fat have a lower risk of prostate cancer mortality.
- Vitamin EA recent randomized trial from Finland, originally designed to determine whether vitamins E and/or A could prevent lung cancer in heavy smokers, demonstrated a significant reduction in the number of prostate cancers in patients receiving vitamin E(Drug information on vitamin e).
- Agents That Block or Suppress MutationOltipraz, selenium(Drug information on selenium), vitamin C, and isoflavenoids, all of which block or suppress gene mutation, have been suggested possible chemopreventive agents.
- DifluoromethylorithineRecognizing that the prostate has one
of the highest levels of polyamines in the body, that normal cell proliferation
is enhanced by these agents, and that the first step in mammalian synthesis
of polyamines is catalyzed by ornithine decarboxylase (ODC), difluoromethylorithine
(DFMO), a potent inhibitor of ODC, has been suggested as a potential preventive
Ongoing Clinical Trials
At present, at least two studies are addressing two of these potential prevention avenues (Table 1). One of these trials, coordinated through the University of Wisconsin, is designed to determine whether DFMO can modulate a number of markers for prostate carcinogenesis. In a model that may be applicable to the testing of a wide variety of agents, patients with prostate cancer who are scheduled for radical prostatectomy and those without prostate cancer who are to undergo cystoprostatectomy (eg, for muscle-invasive bladder cancer) receive DFMO prior to surgery. Analyses will be performed to ascertain the impact of treatment on prostate-specific antigen (PSA), as well as a number of cellular markers of disease.
A second, larger undertaking, the Prostate Cancer Prevention Trial, is testing the hypothesis that finasteride(Drug information on finasteride) (Proscar), which prevents the conversion of testosterone to the more potent dihydrotestosterone via inhibition of the enzyme 5-alpha-reductase, can prevent the development of prostate cancer. In this study, 18,000 healthy men over age 55 with a normal digital rectal examination (DRE) and a PSA level less than 3.0 ng/mL are randomly assigned to receive either finasteride or placebo. The study end point is the period prevalence (the number of tumors identified through biopsy during the 7-year period of the study) of prostate cancer over 7 years. All participants are scheduled to undergo prostate biopsy 7 years after beginning the study.
Although these two trials will provide tremendous information about potential methods for preventing prostate cancer, there will almost certainly be future studies that will examine the impact of other interventions in this patient population. Hopefully, these trials will identify preventive strategies that can reduce the morbidity and mortality of this common disease without the problems associated with treatment.
What is the Best Treatment for Localized Disease?
As stated above, the principal focus of current medical efforts is the early diagnosis and treatment of prostate cancer. Studies have demonstrated that the majority of tumors detected by screening tests, including PSA and DRE, are clinically confined to the prostate (T1-T2 tumors).
There have been conflicting opinions about the relative benefits of treating these clinically localized tumors. For example, various authors have provided evidence that, for organ-confined tumors, observation (also known as "watchful waiting" or "expectant management") will lead to acceptable outcomes during 5- and 10-year follow-up. A more recent analysis has suggested, however, that with longer follow-up, mortality from the disease increases dramatically. Similarly, while several authors have demonstrated excellent survival among patients with clinically localized prostate cancer treated with radical prostatectomy, concerns have been raised about the high rates of positive margins, PSA recurrence, and patient-reported morbidity.[10,11]
Ongoing Clinical Trials
In an effort to resolve this controversy, the Veterans Administration and National Cancer Institute are co-sponsoring the Prostate Cancer Intervention vs Observation Trial (PIVOT), which randomizes patients with clinically confined prostate carcinoma to either radical prostatectomy or observation. The arduous study has accrued well over 200 patients to date and is enrolling over 10 patients per month.
As PIVOT is powered to detect differences in survival, results will not be forthcoming for many years. Nonetheless, it promises to provide some of the most important answers regarding the management of early, localized disease.
Another ongoing study that may help resolve the controversy over secondary prevention (ie, early detection and treatment) of prostate cancer is the Prostate, Lung, Colorectal, Ovarian Cancer (PLCO) study. The aim of this trial is to determine whether annual screening will reduce mortality from prostate, lung, colorectal, and ovarian cancers. In this study of 148,000 men and women, patients randomized to the screening arm undergo PSA and DRE (prostate), chest x-ray (lung), flexible sigmoidoscopy (colorectal), and CA-125 and pelvic ultrasound (ovarian) during a screening period of 4 years. This cohort is then compared to a group who undergo whatever regular testing is available within the community.
Because PLCO does not mandate a specific treatment for detected prostate cancers, this study dovetails quite well with PIVOT. Possibly, the combination of the two trials may provide evidence of the relative efficacy of both screening and treatment.
Numerous trials are currently assessing various treatment modalities in patients with clinically localized prostate cancer (Table 2). Unfortunately, to the authors' knowledge, no ongoing phase III trial is evaluating the efficacy of newer treatment modalities; ie, no head-to-head comparisons are being performed to assess the relative worth of brachytherapy, cryotherapy, or other modalities compared to either radical prostatectomy or external-beam radiotherapy. The initial course of many newly diagnosed prostate cancers is indolent. Thus, it is difficult to reliably assess efficacy of any treatment from studies in which patients at relatively low risk of short-term progression are treated and in whom follow-up is less than 10 years.
What is the Best Treatment For Locally Advanced Disease?
The optimal treatment of patients with locally advanced (T3-T4) disease has been a polemic for 50 years. Various approaches have been advocated by many authors. Although external-beam radiotherapy may be the most common therapeutic modality used in this disease stage, evidence suggests that its long-term results may be less than satisfactory.[13a]
Ongoing and Recently Completed Clinical Trials
Accordingly, a number of approaches have been employed in the treatment
of T3-T4 disease, some of which are the focus of current clinical trials
(Table 3). These include neoadjuvant
hormonal therapy plus either radiotherapy or radical prostatectomy, increased doses of radiation (either through hyperfractionation or the use of conformal therapy), and the addition of systemic agents to radiation.
One very attractive ongoing trial is the JPR3 study of the National Cancer Institute of Canada, which is being activated in a number of US groups, including the Southwest Oncology Group (SWOG). This novel study is designed to determine whether radiation therapy positively contributes to the ultimate outcome of patients with T3-T4 disease who receive combined androgen ablation.
Several authors have explored the possibility of using neoadjuvant hormonal therapy plus definitive therapy (surgery or radiotherapy) for T3-T4 prostate carcinoma. A randomized, prospective trial of radiotherapy with or without neoadjuvant hormonal therapy for localized prostate cancer has recently been completed. Thus far, results demonstrate that the addition of neoadjuvant hormonal therapy reduces short-term local and biochemical disease progression. Whether neoadjuvant hormonal therapy will influence end points of importance to the patient (eg, metastatic disease-free recurrence and survival) requires further follow-up.
Similarly, a US randomized, prospective trial of patients with T2 disease has demonstrated that radical prostatectomy plus neoadjuvant hormonal therapy significantly reduces the rate of pT3 disease (as defined by positive margins). Of interest, however, are the 1-year follow-up data, which suggest that the addition of neoadjuvant hormonal therapy does not significantly reduce the PSA recurrence rate.
A phase II SWOG trial is currently assessing the impact of neoadjuvant hormonal therapy (a luteinizing hormone-releasing hormone [LHRH] agonist plus flutamide(Drug information on flutamide) [Eulexin]) in patients with T3 disease. Although some authors have suggested that this approach is of limited value in patients with T3 disease, phase III trials comparing this approach with alternative treatments will probably be needed to determine the optimal treatment for this disease stage.
What is the Best Treatment for Metastatic Disease?
Since the work of Huggins and Hodges in the 1940s, hormonal therapy has been the mainstay of therapy for D2 prostate cancer. Unfortunately, there is little evidence that significant advances in the treatment of metastatic disease have been made since that time.
A putative major advance was announced by Labrie and colleagues in the
early 1980s: the concept of "combined androgen deprivation"ie,
the use of primary monotherapy (LHRH
agonist or orchiectomy to ablate testicular androgens) plus an antiandrogen (to block remaining adrenal androgens). In 1989, the National Cancer Institute (NCI) and SWOG completed a trial comparing LHRH-agonist therapy with or without antiandrogen therapy. The results of the trial suggested that combined androgen deprivation significantly improved median time to progression in patients with metastatic disease.
Ongoing and Recently Completed Clinical Trials
A concern expressed about the NCI-SWOG trial was the fact that, since LHRH agonist therapy is associated with an initial disease flare (due to a transient testosterone increase) and that this flare may result in an exacerbation of the disease, the sole impact of antiandrogen therapy may be to block this temporary but adverse effect of LHRH agonist therapy. For this reason, SWOG 8894 was designed and implemented. This study compared orchiectomy with or without flutamide in patients with metastatic disease. The results of this trial should be available in the next few months.
Although a number of therapies for metastatic prostate cancer are currently being tested in clinical trials (Table 4), perhaps the most intriguing potential approach is the use of intermittent hormonal therapy. Intermittent therapy is not a new concept. (Whitmore employed intermittent diethylstilbestrol(Drug information on diethylstilbestrol) over 2 decades ago.) However, the advent of LHRH agonist therapy has afforded a more practical and less morbid means of achieving intermittent therapy.
Potential advantages of intermittent hormonal therapy include: (1) lower cost (compared to permanent LHRH therapy); (2) periods during which side effects are reduced (eg, potency and libido returns to normal after LHRH therapy is stopped); (3) lower risk of the long-term complications, such as osteoporosis and anemia; and (4) the possibility that survival may be enhanced by delaying the development of androgen-independent disease may. To that end, a recently opened SWOG study is randomizing patients who achieve an undetectable PSA following initial hormonal therapy to either continuous therapy or intermittent hormonal therapy. This trial will address one of the most important new potential treatment approaches for patients with metastatic disease.