Prostate cancer is the most common internal malignancy in American men, and its death toll is second only to lung cancer’s. About 80,000 American men will be diagnosed with prostate cancer this year, and each will have an urgent need to know what treatment is best for him. It's a crucial question and a fair one. To answer it, the American Urological Association (AUA) convened an authoritative Prostate Cancer Clinical Guidelines Panel, but it was unable to establish standard-of-care recommendations. Instead, the experts recognized that there are many acceptable therapeutic options, and they suggested that doctors inform their patients about the advantages and disadvantages of each treatment, enabling every man to choose for himself. It's a sound position, but it puts men with prostate cancer in the very difficult position of making hard decisions about complex questions, often before the shock of the diagnosis has worn off. Fortunately, however, there is no need to rush into treatment, so men should take the time they need to gather information, digest the facts, and discuss them with relatives and friends. In many cases, the decision-making process will benefit from independent second and third opinions from doctors with different perspectives; urologists, radiation oncologists, and medical oncologists have their own views, and each can help. A diagnosis of prostate cancer calls for decisions that are difficult, but they should not be lonely.

Why the Debate?
In most forms of cancer, diagnosis and treatment go hand in hand; it may be hard for a doctor to diagnose a tumor, but once he knows it’s there he can offer a clear plan of treatment based on solid scientific evidence that’s backed by most experts. Why is prostate cancer so different? First, the disease is different. Most cancers behave predictably, but prostate cancer does not; sometimes it’s aggressive and dangerous, but often it’s indolent or even clinically silent.

Second, the disease grows slowly. In many cancers, a 5-year survival is tantamount to cure, so clinical trials can learn if a treatment is effective in a relatively short time. But most patients with prostate cancer survive for more than 5 years with any form of treatment or with no treatment at all. As a result, it may take 10 or 15 years for a study to learn how well a treatment works.

Third, the diagnosis of prostate cancer has changed dramatically in the past 5 years. Before 1992, the disease was most often discovered as the result of a digital rectal exam (DRE) or a pathological examination of tissue obtained during a transurethral resection of the prostate (TURP), performed to treat benign prostatic hyperplasia (BPH). At present, prostate cancer is most often diagnosed as the result of a prostate-specific antigen (PSA) blood test. Widespread PSA testing has produced an explosive rise in the number of cases detected, particularly in young men with early disease. Doctors don’t yet know if the cancers detected by the PSA screening will behave the same way as the cancers detected by older methods.

Fourth, the treatment is also changing. Until recently, the options for active therapy were limited to surgery, external beam radiation, or hormonal therapy. Doctors have developed improved techniques for each of these standard treatments and they have also developed entirely new approaches, such as brachytherapy with implanted radioactive seeds; cryotherapy, which kills prostate cells by freezing them; and neoadjuvant therapy, which combines radiation with hormonal treatment. It's a heartening progress, but these advances make a man's decisions even more complex.

Finally, and most important, solid scientific trials that compare treatment options are not yet available. When the AUA tried to compare the outcome of patients treated with watchful waiting, surgery, and radiation, they found they were comparing apples to oranges. The studies that have been completed to date differ so substantially in patient age, disease stage, and follow-up that comparisons are not possible. New studies to resolve these issues are already in progress, but they will not be completed for years. Until the results are in, the only option is to consider each treatment on its own merits.

The Natural History of Prostate Cancer
Scientists don’t know how prostate cancer gets started or what causes it, but several factors appear important. Genetics certainly plays a role: men with fathers or brothers who have prostate cancer are about twice as likely to get the disease as men with no family history, and HPCA1, a gene that increases risk, has recently been identified (see Harvard Men’s Health Watch, June 1997). In addition, genetic factors probably account for the increased incidence of prostate cancer in African-Americans; the lower risk in Asian-Americans, though, may hinge more on diet than heredity. Hormones also play a role; testosterone and other androgens (male hormones) stimulate the growth of prostate cells, both benign and malignant. New research suggests that diet may be very important. Dietary fat — especially saturated fat from animal products — appears to fuel the disease, whereas soy products, tomatoes and other vegetables that provide turopene, and supplements such as vitamin E, vitamin D, and selenium may slow its progress (see Harvard Men’s Health Watch, October 1996).

Many factors contribute to prostate cancer, but they act slowly. That's why the disease becomes much more common as men age; between the ages of 50 and 60, a man's chance of having microscopic traces of prostate cancer is 10-30 percent, but at ages 70-80, it's 30-65 percent. In all, only 1 percent of prostate cancers are diagnosed in men younger than 50; 83 percent of cases are diagnosed after age 64. The average age of diagnosis is 72, but in most men the disease starts many years earlier. That's because prostate cancer takes years to grow enough to be clinically evident. In many cases, in fact, prostate cancer progresses so slowly that it never produces any symptoms at all. An American man's risk of developing prostate cancer at some time during his life is about 30 percent, but his risk of developing symptomatically troublesome disease is only 10 percent, and his risk of dying from it is just 3 percent.

Although many prostate cancers are indolent, some are aggressive and lethal. This variable behavior is the main reason that planning treatment is so difficult. If all men were treated maximally, many would undergo invasive therapy for a disease that would never bother them - but if no treatment was given, some would die from a disease that could have been cured. Optimal decisions depend on the ability to distinguish aggressive from indolent prostate cancers. However, it's often impossible to make that distinction. Still, to plan treatment, doctors need to know the grade of the tumor and the stage of the disease.

Grading Prostate Cancer
Pathologists diagnose cancer by examining biopsy specimens under a microscope. But they also evaluate how malignant the cells look; well-differentiated cells look the closest to normal; poorly differentiated cells have a wilder, more malignant appearance; moderately differentiated cells lie between the two extremes. In general, well-differentiated cancers have the best prognosis, poorly differentiated, the worst.

Like other malignancies, prostate cancers are identified according to their cellular differentiation. But since that system provides only a rough guide, pathologists also use the Gleason grading system, which is based on the architectural relationship among cells rather than their appearance. In this method, pathologists assign a grade between 1 and 5 to the tumor. Grade 1 tumors look the most normal, with individual cells lined up in a nearly normal glandular pattern. Grade 5 tumors are distorted and irregular, with cells clumped into cords and tubes; Grades 2, 3, and 4 lie in between. But since cancer cells can look different in a single prostate biopsy, pathologists score the two most representative regions independently, then tally them to arrive at a single Gleason score between 2 and 10. Tumors rated 2, 3, and 4 have the best outlook; tumors rated 8, 9, or 10, the worst. Tumors rated 5, 6, and 7 behave variably; since two-thirds of prostate cancers are in this gray zone, it's very hard for doctors to predict if they will be aggressive or indolent. Scientists are working hard to develop better systems, but right now the Gleason grade is the best guide to a tumor's likely behavior.

Staging Prostate Cancer
Diagnosing prostate cancer and assigning a grade to the tumor are relatively simple; to plan therapy, though, doctors must determine the stage of the disease. That’s because prostate cancer begins in the prostate and then spreads, either to other areas within the gland, or through its capsule to the seminal vesicles and neighboring tissues, or to lymph nodes and bones. Different stages of the disease require different treatments.

Most prostate cancers are diagnosed by means of an ultrasound-guided transrectal core biopsy. In most cases, doctors will have three important pieces of information by the time they perform the biopsy that diagnoses the disease: the results of a digital rectal exam, a blood PSA level, and the results of a transrectal ultrasound (TRUS). Although these results may provide enough information to stage the tumor, additional testing is sometimes necessary. For example, computed tomographic (CT) scanning may be used to look for enlarged lymph nodes in the pelvis and abdomen, especially in men with PSAs above 10. If advanced disease is suspected, a bone scan can be used to look for metastatic disease. However, patients with negative CT and bone scans may still have a microscopic spread of the tumor through the capsule. It's a crucial distinction that determines if a man is eligible for surgery. Doctors are beginning to use magnetic resonance imaging (MRI) of the prostate using an endorectal probe to detect early spread (see Harvard Men’s Health Watch, November 1996), but even this sophisticated test is of limited value. As a result, complete and accurate staging is sometimes possible only at the time of surgery.

There are two major systems for staging prostate cancer, the original Whitmore-Jewett classification and the newer TNM method (see figure). The Whitmore-Jewett system assigns a letter from A to D to each cancer, with a number to indicate gradations within each stage. The TNM system also evaluates the primary tumor (T), the lymph nodes (N), and distant metastases (M).

Therapeutic Options
Prostate cancer can be managed conservatively or aggressively. At present, the major choices include observation alone (watchful waiting), surgery (radical prostatectomy), radiation (external beam or brachytherapy with implanted radioactive seeds), radiation plus hormonal manipulation (neoadjuvant therapy), and hormonal treatment (androgen-deprivation therapy). Doctors are also investigating cryotherapy for localized disease and chemotherapy and other new approaches to advanced disease.