Prostate cancer is the most common visceral malignancy among American men. In the year 2003, there are expected to be 220,000 new cases and nearly 29,000 deaths in the United States attributable to prostate cancer. Despite advances in prevention and early detection, refinements in surgical technique, and improvements in radiation and chemotherapy, the ability to cure many patients with prostate cancer remains elusive. The continuing challenge of cancer treatment is the successful management and eradication of recurrent metastatic disease.
While the majority of men presenting with prostate cancer will not die from their cancer, a substantial minority will develop disseminated and, eventually, hormone-refractory disease. Few effective palliative and no curative therapies are currently available for these unfortunate men. These men are not only at risk of dying from prostate cancer, but often become debilitated and incapacitated from the sequelae of advanced disease, including severe pain bone fractures, and spinal cord compression, all of which result in significant disability, discomfort, and distress.
The term “prostate” was originally derived from the Greek word prohistani, which means “to stand in front of,” and has been attributed to Herophilus of Alexandria who used the term in 355 B.C.E. to describe the small organ located in front of the bladder. The prostate gland is a small firm organ, about the size of a chestnut, located below the bladder and in front of the rectum. The urethra, the channel that carries urine from the bladder and through the penis, runs through the prostate.
The primary function of the prostate gland is to produce fluid which helps transport and nourish sperm as it passes from the testes, through the ejaculatory ducts and prostate, and out the urethra.
Traditionally, prostate cancer was considered a disease of “older men.” As such, people never died from prostate cancer, they died of other conditions. Hence, treatment was generally conservative and geared toward palliation: keeping the cancer in-check and preventing the emergence of debilitating and painful sequelae. In addition, diagnosis was generally made on the basis of palpating a rock-hard and nodular prostate on digital rectal exam [DRE]. By this point, most tumors had already disseminated and, therefore, were incurable.
In the mid-1980s, with the advent of PSA [Prostate-specific antigen] screening, prostate cancer began to be diagnosed in younger men; men who, if not treated aggressively, could die from their prostate cancer. Thus began the “modern era” of prostate cancer, when tumors are diagnosed while still contained within the prostate and, therefore, curable.
Because of our abilities to diagnose prostate cancer earlier and more reliably, more men are amenable to attempts at curative therapies. Consequently, we have developed improved surgical and radiation-based treatment approaches with which we are able to treat local lesions with greater curative success. Although advances in the diagnosis and treatment of localized disease have become well-established, the optimal approach to the diagnosis and management of these lesions remains controversial due to the variable biologic course of prostatic malignancy, imperfect staging modalities, and difficulty predicting the biologic outcome of both organ-confined and locally-invasive disease.
Between the men who fail attempts at cure, those who chose to not treat their cancers when diagnosed at a curable stage, and those with metastases when initially diagnosed, the majority of men with prostate cancer eventually develop clinically significant metastatic disease.
The approach to treating a given individual with prostate cancer depends on several factors.
(1) Has the tumor spread beyond the confines of the prostate (Stage)?
- First it must be determined whether the cancer is localized (contained within the prostate), locally-advanced (spread beyond the prostate, but not invading other organs or vital structures), or disseminated (metastatic lesions in bone, lymph nodes, or other viscera). This process is called Staging (see Table 1, next page).
- All cancers have "staging systems" that physicians use to describe the extent of the cancer or the degree to which it has progressed. These staging systems have changed over the years as we have learned more about cancer. We currently use the TNM system. The T stage of the disease refers to the form of the primary tumor within the prostate. The N stage refers to the status of the lymph nodes near to the prostate (the pelvic lymph nodes). Finally, the M stage refers to the degree of metastasis -- the degree to which prostate cancer has traveled out of the immediate area of the prostate to other organs of the body.
- Stage T1 disease is always found incidentally, either in men who have received a surgical procedure called a TURP to help them urinate with greater ease because their prostate is enlarged (stage T1a and 1b), or if cancer is found as a consequence only of the patient having a positive result to a PSA test but no other clinical sign of disease (stage T1c).
- When a physician says a patient has stage T2 disease, it means the physician can feel the tumor in one side (one lobe) of the prostate (T2a and T2b) when he does DRE. Stage T2c disease involves palpable tumor in both sides or lobes of the prostate.
- Stage T3 disease requires extension of prostate cancer tissue through the so-called "prostatic capsule" and out of the prostate into the immediately surrounding tissue. At the University of Chicago, we offer special treatment for men with clinical stage T3 prostate cancer.
- A stage T4 tumor is still localized to the pelvic region, but has definitely escaped from the prostate and seminal vesicles.
- N+ means that microscopic amounts of prostate cancer can be recognized in the pelvic lymph nodes. If metastases are clearly evident outside the pelvic area, the disease is classified as M+. Radionuclide bone scans and CT scans are used to evaluate for the presence of skeletal, lymph node or visceral metastases. Prostate cancer has a predilection for bone, which is where metastases most often occur, as osteoblastic lesions.
Treatment Options based on Stage
- Radical prostatectomy and radical radiotherapy can cure patients with localized (T1 and T2; N0; M0) prostate cancer and its use in treating such tumors in younger and healthy men is generally undisputed. Nonetheless, almost 30 percent of patients with pathologically organ-confined cancer will experience an early relapse with recurrent disease despite successful treatment of the primary lesion. Additionally, current screening modalities fail to identify a significant subset of patients with locally-invasive disease, and recent studies report that up to 40 percent of patients who were thought to have organ-confined lesions were found to be understaged subsequent to surgery.
- In younger patients (those with a greater than a 5 to 10-year life expectancy), locally-advanced (T3a; N0; M0) lesions (tumors that have spread beyond the prostate, but do not invade other vital structures), may be treated aggressively with surgery or radiation. Unfortunately, many of these men will already have occult metastatic disease and will experience relapses. These men will then be treated as those who present with metastatic disease (see below).
- Once prostate cancer has disseminated (M+ and/or N+), it is no longer considered curable and treatment is geared towards palliation. Since prostate tumors are initially very sensitive to male hormones (androgens, primarily testosterone), this treatment involves castration, the process of removing the major sources of testosterone. This is called hormonal therapy and can consist of surgical castration (removing the testes) or chemical castration (giving a combination of injections and pills which block testosterone production and activity). Both approaches have similar efficacies and produce the same end-effect: depleting the body of male hormones.
- Unfortunately, the effect of hormonal ablation therapy is of limited duration. Within 3 to 5 years, hormone-refractory cells become established with the tumor. These tumor cells are resistant to the effects of castration and they proliferate and disseminate rapidly. Within a year, most men with such hormone-refractory prostate cancer will die of their disease, or its sequelae. No curative treatments currently exist for hormone-refractory disease.
(2) Does the tumor have an aggressive behavior (Grade)?
- The outcome of a patient with prostate cancer ultimately depends upon the tumor’s capacity for un-hindered growth, local invasion, and the establishment of distant metastasis.
- Our abilities to predict the metastatic behavior of a given prostate cancer are limited and consist primarily of histologic factors observed under light microscopy. The process of assigning behavioral characteristics based on histologic findings is called Grading. For prostate cancer, we use the Gleason grading system. Originally developed by Dr. Donald Gleason, this system has became the gold standard for histologic analysis of prostatic adenocarcinoma.
- Based on architectural patterns, adenocarcinoma is assigned a value between 1 and 5, with higher numbers representing less differentiated and more aggressive tumors. A single prostate can harbor multiple foci of different histologic subtypes of adenocarcinoma. It is possible to have Gleason grade 3, 4 and 5 tumors in the same specimen. The transition from Gleason 3 to Gleason 4 appears to be a common event and represents a critical juncture in which a relative indolent tumor is converted into an aggressive tumor. Table 2 summarizes several important aspects regarding Gleason grading.
- The Gleason score (or Gleason sum) is generated by combining the values of the first and second most predominant grades (for example in a tumor with mostly Gleason 3 and substantial Gleason 4, the Gleason score will be 3+4 = 7. Gleason grades or scores are strongly related to the tumor stage and clinical prognosis and are used to counsel patients with regard to management strategies.
(3) If the tumor is treatable (potentially curable), what is the risk of recurrence?
- One particular group of patients at risk for succumbing to prostate cancer are those men who experience a recurrence of disease after attempted curative therapy.
- Although radical prostatectomy can cure patients with localized prostate cancer, recurrence rates after surgery can approach 25%. Men with established adverse prognostic factors (i.e. PSA?10 ng/ml, Gleason grade 4 or greater) have a significantly increased risk for treatment failure, due to associated increases in tumor volume, pathologic evidence of extraprostatic extension, and the presence of occult metastases. Relapse rates in these patients approach 50%, generally within 3 years. Adjuvant radiotherapy can prolong survival in some of these men. In addition, adjunctive experimental medical therapies are becoming available to reduce the risk of recurrence.
- Cancer recurrence post-prostatectomy is indicative of disseminated disease. Post-prostatectomy relapse occurs locally in 10% of cases, at a distant site in 20%, both distant and locally in 9%, and evidenced by PSA elevation alone in 61%. Tumor cells disseminate into the circulation early in the course of prostate carcinogenesis. The significance of “micrometastatic disease” is unclear, yet it is apparent that some tumor cells are detectable in bone and soft tissue at a time when the primary tumor is amenable to resection. Growth control mechanisms at the secondary site determine if further propagation occurs and macrometastatic lesions develop.
- Since 1986, prostate-specific antigen (PSA) has been utilized for the clinical diagnosis of prostate cancer. The PSA test or prostate specific antigen test has revolutionized the detection of prostate cancer and monitoring of the effects of treatment. Once a prostate cancer is diagnosed, PSA tests can help guide both the physician and patient in choosing the most appropriate and efficacious treatment approach. However, the greatest utility of PSA is to screen men for the presence of prostate cancer.
- PSA screening is recommended for all men older than 50 years. Because prostate cancer tends to be most prevalent among first-degree male relatives, PSA screening should begin by ages 40 to 45 in men whose brothers, parents, or grandparents have prostate cancer. Likewise, because prostate cancer is more prevalent in men with African-American ancestry and tends to be more aggressive among African-Americans, screening in this community should also begin by ages 40 to 45.
- Although serum PSA assays have been invaluable in improving the early detection of men with curable lesions, both the specificity and sensitivity of these assays are only average. Furthermore, because PSA values vary widely within a given tumor stage and over-lap between different stages, the predictive value of PSA in determining pathologic stage is weak. The combined use of digital rectal exam, serum PSA, and transrectal ultrasound is paramount to properly estimating the stage of an individual tumor. Unfortunately, even this approach is inexact.
- Using the most common type of PSA test currently available in the USA, the average, normal, healthy, 50-year-old male is generally believed to have a PSA of less than 4.0 ng/ml. However, some men with cancers present with normal PSA values (<4.0 ng/ml). Moreover, several conditions can result in an elevated PSA (>4.0 ng/ml), of which cancer is only one: increases in PSA are associated with infection (prostatitis) and benign enlargement of the prostate gland, know as benign prostatic hypertrophy [BPH]. BPH is not a malignant or premalignant condition.
- The free/total PSA test can help discriminate between patients with indeterminate PSA levels (4-10.0 ng/ml) who are at the greatest risk of having prostate cancer (and therefore need a prostate biopsy), and those patients who are more likely to have BPH. This test measures the amount of PSA that is free in the blood stream, and compares it to the amount that is bound to proteins. The lower the ratio of free to total PSA, the higher the likelihood that the patient has prostate cancer as opposed to benign prostatic hyperplasia.
- PSA velocity measures the speed at which a series of PSA values increases in value over a period of time. Some physicians believe that use of PSA velocity allows them to tell more about the way prostate cancer may be developing in individual patients. Any change in PSA of more than 0.75 ng/ml in a year, is highly suspicious for cancer. Hence, a 50 year-old man with a PSA which increases from 1.5 ng/ml to 3.0 ng/ml in 18 months should be biopsied, despite the fact that his total PSA is less than 4.0 ng/ml.
- PSA density is a measure of the concentration of PSA in a man's prostate. It compares the value of his PSA and the size of his prostate. Neoplastic prostate tissue produces more PSA than normal or hypertrophied (BPH) tissue. Subsequently, a PSA of 5.0 ng/ml in a twenty gram prostate is more worrisome for cancer that a PSA of 5.0 ng/ml in a sixty gram prostate. To determine the PSA density, a PSA level is obtained and is divided by the volume of the prostate, as estimated by trans-rectal ultrasound (a non-invasive imaging technique). A value >0.15 ng/ml per gram of prostate tissue is considered worrisome for prostate cancer.
- Prostatic intraepithelial neoplasia (PIN) is believed to be a precursor of prostate cancer, given the strong association between high grade PIN and prostatic adenocarcinoma. The presence of high grade PIN is often indicative of the presence of prostate cancer. It has been shown that more than 80% of prostates with adenocarcinoma also contain PIN. PIN has cytologic features resembling cancer and carries many genetic alteration of prostate cancer.
- Although a diagnosis of high-grade PIN is insufficient by itself for performing surgery or radiotherapy, men with high grade PIN on a biopsy specimen must be followed very closely with serial PSA tests and re-biopsy.
(1) Prostatectomy (Surgery):
Surgical removal of the prostate gland is the most common form of therapy for younger patients at an early stage of the disease. For most patients, the ten-year post-prostatectomy disease specific survival rate is 88-93%.
At the University of Chicago, both open and laparoscopic nerve-sparing radical prostatectomies are offered to our patients.
Aside from the normal risks associated with anesthesia and any major surgical procedure, complications of radical prostatectomy can include urinary incontinence and impotence. Those with other medical problems (i.e.: hypertension, diabetes, atherosclerosis). Reported complications vary significantly due to differences in the experience of the treating surgeon and due to variations in the size and location of each tumor.
(2) Radiation Therapy:
Radiation therapy is a viable treatment option for men with early stage and low Gleason grade disease.
With external beam radiation, daily treatments are given Monday through Friday over an eight week period, are painless, take 20 minutes to deliver, and have few immediate after effects. Significant advancements in computer technology have led to the development of CT based simulation and 3-Dimensional radiation treatment. Patients treated with external beam radiation can experience fatigue, increased frequency of urination, and minor diarrhea. Impotence is also common.
Brachytherapy (also known as seed implantation) is another form of radiation therapy in which radioactive sources are placed directly into the prostate gland either as a permanent Palladium-103 or Iodine-125 seed implants. Over the past 10-15 years, technical improvements in ultrasound imaging and preplanning brachytherapy software have improved the efficacy of this procedure.
(3) Watchful Waiting or Observation:
As the name implies, no treatment is offered and patients are monitored with repeat PSA's and DRE's. Those who choose this option assume that theirs is a slow-growing cancer that won't progress beyond the initial stages and one in which the patient will probably outlive. It should be noted, however, that we cannot distinguish between and indolent cancers, and withholding treatment may cause an otherwise curable cancer to become a clinically active one that is refractory to treatment.
Watchful waiting has generally been reserved for older patients with significant medical illnesses who are not expected to derive benefit from treatment.