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Thu 17 Jul 2008 04:00 AM

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Treating prostate cancer: Determining its severity

Knowing the condition's severity is key to treating the disease.

Knowing the condition's severity is key to treating the disease.

How bad is it, Doc?"

It's the question most men ask when they get over the shock of learning that their prostate biopsy found cancer. And the very same question is just as important for doctors as for patients. Before doctors can tell a man what therapeutic options are available to him, they must determine the severity of the cancer.

It's a crucial question, but it can be hard to answer, particularly for prostate cancer. That's because the disease is so variable, ranging from indolent tumors that are all but harmless to aggressive tumors that are life-threatening. At the extreme ends of the spectrum, predicting the behavior of prostate cancer is fairly accurate, but in the far-more-common middle, it's a bit dicey. Still, doctors are making progress, and more will follow from new research.

Each man with prostate cancer should consider his options in detail.

To evaluate the severity of prostate cancer, doctors consider three factors: the anatomic stage of the disease, its microscopic grade, and biologic evidence of its likely behavior.

Anatomic staging

Prostate cancer usually begins in one area of the gland and then spreads, first within the prostate, then through its capsule to the seminal vesicles and neighboring tissues, and then 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. Doctors will already have three important pieces of information by the time they perform the biopsy that confirms a diagnosis of prostate cancer: the results of a digital rectal exam (DRE), a blood PSA (prostate-specific antigen) level, and the results of a transrectal ultrasound (TRUS).

For most men with PSAs below 10 nanograms per milliliter (ng/mL), bone scans, CTs, and MRIs are rarely positive - but even though they're not necessary, many doctors order them anyway. It's a waste of money, and it can produce as much worry as reassurance. On the other hand, men should have imaging tests if they have PSAs above 10, high-grade tumors, or worrisome symptoms such as back pain, weakness, or weight loss.

In such cases, magnetic resonance imaging (MRI) or computed tomographic (CT) scanning can be used to look for enlarged lymph nodes in the pelvis and abdomen. In addition, a bone scan can be employed to look for metastatic disease. Some centers also use a nuclear imaging test called the ProstaScint, but it appears less useful than standard imaging techniques.

Unfortunately, however, patients with negative scans may still have microscopic spread of the tumor through the capsule. It is a crucial distinction that determines if a man is a candidate for surgery, but until new MRI techniques prove their mettle, the only way to be sure is to remove the gland surgically and send it to a pathologist for evaluation.

There are two major systems for evaluating prostate cancer based on the location and size of the tumor. The older Whitmore-Jewett classification system assigns a letter from A to D to the cancer, with a number to indicate gradations within each stage. Although it served well for many years, it's been largely replaced by the TNM system, which evaluates the primary tumor (T stage), the lymph nodes (N stage), and distant metastases (M stage).

Before surgery, patients are assigned to a stage based on clinical criteria; clinical staging can be noted by a "c" placed before the T stage. Patients who undergo radical prostatectomy are staged pathologically based on an examination of their tissues; a "p" before the T stage denotes pathological staging.

Anatomic staging is crucial to planning treatment. Tumors that are confined to the prostate (stages T1 and T2) are associated with a better prognosis than more advanced cancers. Men with early, organ-confined disease also have the option of surgical treatment, which does not offer the possibility of cure to men with more extensive disease. Microscopic grading

A prostate biopsy establishes the diagnosis of cancer, but it also provides two additional types of information. Both are important.

When a urologist performs a transrectal biopsy, he doesn't do one biopsy but many. Typically, at least six and often 12 to 20 individual tissue specimens, or cores, are obtained. Pathologists examine each core individually; the fewer that have cancer cells, the better the outlook.In general, when at least two cores are positive and one contains at least 50% cancer cells, there is an increased risk that the tumor has spread beyond the gland to its capsule.

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 extremes. In general, those with well-differentiated cancers have the best prognosis, poorly differentiated, the worst.

Like other malignancies, prostate cancers are classified according to this 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 the appearance of individual cells. Using this method, pathologists first assign a grade between 1 and 5 to the tumor based on the cells' appearance.

About 186,320 American men will be diagnosed with prostate cancer this year.

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 between the extremes. But since cancer cells can look different in different parts of the biopsy specimen, pathologists score the two most representative patterns independently, then report them both, listing the most representative area first.

The two numbers are added together to provide a single Gleason "score" between 2 (1+1) and 10 (5+5). However, if pathologists find some aggressive-looking cells that are not the most common or second-most common pattern, they can report the grade of the aggressive cells separately as a "tertiary pattern."

Tumors with scores 2, 3, and 4 are the least aggressive, but pathologists rarely assign such low scores these days. Tumors with scores of 8, 9, and 10 are the most troublesome, while those with Gleason scores of 5, 6, and 7 behave variably. Since two-thirds of prostate cancers fall into this gray zone, it is very hard to predict if they will be aggressive or indolent. Some doctors give additional attention to the predominant pattern; by this reckoning, a score of 4+3=7 is more worrisome than 3+4=7.

Scientists are working hard to develop better systems, but until they succeed, the Gleason score will remain the best guide to a tumor's likely behavior. The table shows the relationship between Gleason score and outcome in a group of 767 patients from Connecticut; since these patients were diagnosed clinically in the pre-PSA era and did not receive surgery or radiation, the results do not strictly apply to men diagnosed today.

Biologic factors

Anatomic staging and microscopic grading are valuable ways to predict how a given prostate cancer will behave, but they are imperfect. New approaches focus on biologic markers.

The best established is the PSA. PSA is a protein produced by the prostate. Because men with cancerous prostates tend to have higher blood PSA levels than men with healthy prostates, the test is widely used to screen for early prostate cancer. But since all prostate cells, benign and malignant, produce PSA, the test produces many false-positive and false-negative results.

After men with prostate cancer receive treatment, rising PSA levels provide strong evidence that the disease has recurred and is progressing. But before treatment, PSA levels offer only a crude approximation of prognosis. In general, patients with PSAs below 10 ng/mL have the best outlook, men with levels between 10 and 20 ng/mL have an intermediate prognosis, and patients with PSAs above 20 are at high risk.

Because PSA screening is so popular in the United States, most cases of prostate cancer are diagnosed in men with PSAs well below 20. But even at low levels, the PSA has prognostic significance for men who have had annual tests. The PSA velocity reflects the rate at which PSA levels have risen; a PSA velocity above 2 ng/mL in the year prior to diagnosis suggests a relatively high risk of death from prostate cancer.

Newer biologic markers are being studied. The most promising rely on identifying the genetic abnormalities that fuel the growth of malignant cells. These tests are still experimental, but if they prove clinically useful, Harvard Men's Health Watch will set about explaining concepts like promoter hypermethylation, AR polymorphisms, and loss of heterozygosity. And you thought the Gleason score was complicated!

Interpreting the results

If the behavior of prostate cancers could be predicted simply and accurately, there would only be one prognostic indicator. Since the disease is unpredictable, however, there are many factors to consider. In general:

• Men with low-volume tumors that are too small to be felt on a DRE or seen on a TRUS have a better prognosis than those whose tumors are large enough to form detectable nodules.

• Men with cancer cells in only one region of the gland have a better outlook than those who have cancer cells in cores from several different regions of the prostate.• Men with low PSAs have a better prognosis than men with higher PSAs. PSAs below 10 usually reflect early, localized disease, whereas levels of 10 to 20 may signify local spread, and levels above 20 to 40 often indicate widespread disease.

• Men with PSA velocities below 2 have a better outlook than men whose PSAs have risen by more than 2 ng/mL in the year prior to diagnosis.

• Well-differentiated tumors with low Gleason scores are less aggressive than poorly differentiated tumors with high Gleason scores.

• Men whose cancers are confined to the prostate gland (stages T1 and T2) have a better prognosis than men with tumors that have extended beyond the gland (stages T3 and T4).

• Men without lymph node, bone, or other organ metastasis (stage N0, M0) fare better than men with metastatic spread (N1-3, M1).

Knowing the grade and stage of prostate cancer is one thing, knowing what to do about it, quite another thing. Unfortunately, treatment decisions are like most areas of prostate cancer, uncertain and even contentious.

Decisions, decisions

About 186,320 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 after reviewing more than 13,000 studies, it was unable to establish standard-of-care recommendations. When the panel tried to compare the outcome of patients treated with active surveillance, surgery, or radiation, it found it was comparing apples to oranges. The studies that have been completed to date differ so substantially in patient age, disease stage, and follow-up that direct 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 panel recognized that there are several acceptable ways to manage prostate cancer. It suggested that doctors inform their patients about the advantages and limitations of each treatment, enabling every man to choose among them for himself.

"Who shall decide," asked Alexander Pope, "when doctors disagree?" Here are some general guidelines to help men decide for themselves. Prostate cancer can be managed conservatively or aggressively. At present, the major choices include observation alone (active surveillance), surgery (radical prostatectomy), or radiation (external beam or brachytherapy with implanted radioactive seeds); hormonal manipulation followed by radiation (neoadjuvant therapy); and hormonal treatment (androgen-deprivation therapy).

Some centers also offer cryotherapy for localized disease, and high-frequency focused ultrasound is under study. New chemotherapy regimens are being developed for advanced disease, and immunotherapy is on the horizon.

To make a choice, a man must know the stage of his tumor and its Gleason score. But other factors are just as important; a man must also consider his age, his general health and life expectancy, and the experience and skills of his medical team. Last but not least, every patient should include quality of life considerations, including the side effects of treatment, in his decision.

In general, men with early disease (stages T1 and T2) have the widest range of options. Older men with small tumors and low Gleason scores often choose radiation or active surveillance; younger men with higher Gleason scores often choose surgery or radiation. Most men with locally advanced disease (stage T3) receive radiation, with or without hormonal treatment. Men with widespread disease (stage T4) usually benefit from androgen-deprivation therapy.

General guides, however helpful, do not apply to every man. Each man with prostate cancer should consider his options in detail.

This article is provided courtesy of Partners Harvard Medical International. © 2008 President and Fellows of Harvard College.

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