Editor in Chief Marc B. Garnick, M.D., discusses issues and controversies about early-stage prostate cancer
Thanks to more widespread prostate-specific antigen (PSA) testing, today nine out of 10 men diagnosed with prostate cancer have tumors that are detected at the earliest stage, when they are still confined to the prostate gland and are so small they can be detected only through a biopsy.
Maybe you are one of these men. If so, it is likely that you are feeling overwhelmed by your diagnosis and all the treatment options for early-stage prostate cancer, and are wondering what to do next. (See “What constitutes early-stage prostate cancer?” below.) You may even be feeling as though your life depends on making a treatment decision as quickly as possible. So it may surprise you to know that one respectable study indicates that you can take up to one year to evaluate the options before choosing a treatment, and it will not affect your long-term likelihood of remaining cancer-free (see “Time to decide,” below).
Time to decide
Researchers at Memorial Sloan-Kettering Cancer Center analyzed medical records of 3,149 men with early-stage prostate cancer who underwent a radical prostatectomy within a year of diagnosis. The time the men took to make a treatment decision did not affect likelihood of relapse (measured by a rising PSA level, known medically as a biochemical recurrence). This held true even for men at high risk for relapse, based on their clinical profile.
Source: Boorjian SA, Bianco FJ, Scardino PT, Eastham JA. Does the Time from Biopsy to Surgery Affect Biochemical Recurrence after Radical Prostatectomy? BJU International, 2005;96:773–6. PMID: 16153197.
Yet all too often when I meet with patients who are diagnosed with early-stage prostate cancer, I find that they want to rush into treatment without fully considering the ramifications of their decisions. What I often hear from patients who have just received a prostate cancer diagnosis are statements like “I want this out!” or “I just want to get on with my life.”
The emotional impact of cancer can be devastating — there’s no question of that. But you owe it to yourself to do whatever you need in order to remain calm and take things one step at a time. There is no one-size-fits-all treatment for early-stage prostate cancer. Even the experts do not agree about which men with such cancers should be treated, which treatment method is best — or whether, for some tumors, any treatment is even necessary.
At the same time, every doctor knows that some men who undergo treatment for early-stage prostate cancer, and are considered “cured” on the basis of follow-up PSA tests, suffer relapse or “biochemical recurrence” (as measured by PSA levels) years later — indicating that the original cancer spread (metastasized) without being detected and has become active. What is going on? It is likely in these situations that individual cancer cells (micrometastases) shed from the tumor early on, but at levels too small to be detected by computed tomography or bone scans or by physical examination (see “Likelihood of progression,” below). Such micrometastases cause no symptoms initially but may do so in future months to years, as they grow into tumors. Research is under way to find better methods of detecting micrometastases.
What constitutes early-stage prostate cancer?
Tumors with the following profile are considered early stage:
- Small tumor size (stage T2a or smaller)
- Low PSA (no more than 10 ng/ml)
- Low Gleason score (no more than 6)
Likelihood of progression
Investigators followed 81 men diagnosed with stage T1c prostate cancer for at least one year (some for nearly five years). The men underwent semiannual PSA tests and digital rectal exams and had annual prostate biopsies to see if the cancer had become active. At time of repeat biopsy, cancer had progressed in 25 men.
Source: Carter HB, Walsh PC, Landis P, Epstein JI. Expectant Management of Nonpalpable Prostate Cancer with Curative Intent: Preliminary Results. Journal of Urology 2002;167:1231–4. PMID: 11832703.
Complicating the matter still further, side effects of treatment can be devastating, destroying a man’s quality of life. For all these reasons, when I meet with patients, I encourage them to ask detailed questions and perform “due diligence” to ensure that they are making the right decisions about their medical care. Often used in a business context, the phrase “due diligence” means doing your homework, exploring all the options, and taking reasonable steps to protect yourself or someone else. When it comes to prostate cancer, due diligence begins with having the confidence to question your physician about treatment recommendations — after all, you are the person who has to live with the results.
Why due diligence is important
When you receive a diagnosis of prostate cancer, you are inundated with information. Chances are you know the basics about your prostate gland (if not, see Figure 1 for a refresher) and your “numbers” — your PSA level, your Gleason score, and the stage of your cancer. Take the time to process this information, and ask for more details.
Figure 1. Location of the prostate gland
The prostate gland, about the size of a walnut, produces fluid that forms part of the semen that is ejaculated during sexual activity. The prostate is located adjacent to the rectum and just below the bladder, and wraps around the upper part of the urethra, which carries urine from the bladder out of the body.
This location creates challenges in both diagnosis and treatment. During a digital rectal exam, for example, a doctor is able to feel only the back portion of the prostate. If cancer has developed in the apex, base, or deep inside the prostate, it may not be palpable.
Surgeons and radiation oncologists also face challenges in eradicating a tumor without causing lasting damage to surrounding organs and structures. When removing a tumor from the breast or colon, a surgeon is able to remove enough surrounding tissue to ensure “clean margins,” meaning that all the cancer has been removed. But when treating prostate cancer, a comparable amount of tissue cannot be removed surgically or targeted. It takes a skilled surgeon and radiation oncologist to eradicate diseased tissue without harming portions of the rectum, bladder, and penis, thereby minimizing the likelihood of complications.
As you evaluate treatment options, I’d suggest that you think not only about your situation today, but also about where you expect to be in five or 10 years — because chances are, you’ll still be alive. And you need to be sure that you would make the same treatment decision five or 10 years from now as you will right now.
Will you be able to deal with impotence if it occurs? What about incontinence (which is actually the more devastating complication, if you ask most men dealing with it)? How will the possible side effects of treatment affect your relationship with your wife or significant other — and your very sense of self? It’s vital to really think about these issues: In my experience, truly informed patients are much better able to deal with adverse consequences than patients who are uninformed or rush into making a decision.
As you evaluate various treatment options, keep in mind that studies show that patients do not always mention problems such as incontinence or impotence to their doctors. As a result, when your doctor cites numbers or percentages when trying to convey risk, the numbers may be on the low side. It’s not uncommon for a man to talk with other patients — at a support group or while searching for information — and to hear about higher proportions of people being affected by a particular problem.
It’s also important to understand the limits of current medical knowledge about prostate cancer.
Diagnostic tests are limited
We always knew that prostate cancer is common and that, until recently, it often went undiagnosed: Autopsies of men who died of other causes have shown that about one-third of men over age 50 have some cancerous cells in their prostate, while 90% of men over age 90 have such cells.
As PSA screening has grown more widespread, we are finding more tumors that otherwise would have escaped detection. Yet current diagnostic technology does not always enable urologists to determine which tumors will lie dormant and which will become active, spreading elsewhere in the body.
Studies estimate that anywhere from 16%–56% of men diagnosed with prostate cancer, generally because of an abnormal PSA test, have tumors that might never have caused problems had they not been found. And the landmark Prostate Cancer Prevention Trial (PCPT) unexpectedly yielded data that early-stage prostate tumors are incredibly common, even at PSA levels considered normal.
The PCPT was a randomized controlled study — the type considered to be the gold standard in research (see “Randomized controlled trials,” below). The study, which involved almost 19,000 healthy men, was designed to evaluate whether the drug finasteride (Proscar) could prevent prostate cancer from developing. Finasteride is a hormonal medication originally approved to treat benign prostatic hyperplasia (an enlarged prostate, which can cause problems with urination), but which has also been investigated as a potential treatment for prostate cancer.
Randomized controlled trials
In randomized controlled studies to determine a drug’s effectiveness, physicians randomly assign participants to either take the medication under investigation or join a control group whose members receive a placebo. In this way, physicians eliminate biases in both the selection of patients and interpretation of data that might otherwise lead them to conclude the treatment was more effective than it would be in a random collection of people.
All participants were ages 55 and older with PSA levels of no more than 3.0 nanograms per milliliter (ng/ml) and normal digital rectal exams — in other words, by the traditional testing standards, they showed no evidence of prostate cancer. Investigators randomly assigned participants to take finasteride or a placebo, and the men were followed for seven years. Every year, all participants underwent a digital rectal exam and had their PSA levels tested.
Every participant in the PCPT also agreed to undergo a prostate biopsy at the end of the study, whether he met the clinical criteria for such a biopsy or not. The reason investigators included this requirement was that they wanted to eliminate any “detection bias,” a technical term for unintended differences in diagnosis between comparison groups in a study — in this case, between the men randomly assigned to finasteride and those assigned to receive placebo.
At the end of seven years, investigators found that finasteride reduced the risk of developing prostate cancer by almost 25%. But they also found that the men taking finasteride who did develop prostate cancer were more likely to develop high-grade tumors and experience sexual dysfunction than the men taking placebo.
One aspect of the PCPT did not generate a lot of media attention, but sheds significant light on decisions about whether and how to treat early-stage prostate cancer. Of the 18,882 men enrolled in the study, 9,459 received a placebo. Of these men, 2,950 never had PSA levels greater than 4.0 ng/ml or abnormal digital rectal examinations — and so, normally, they would never have undergone a prostate biopsy. By all indications, they should have been cancer-free.
But when these supposedly healthy men underwent biopsies as a requirement of the study, investigators found something surprising: A significant number actually had cancer that otherwise would have gone undetected. And of the men who developed such tumors, high-grade cancers (those considered significant) were found even at the lowest detectable PSA levels (see Table 1).
Table 1. Why a low PSA does not mean you are “cancer-free”
The Prostate Cancer Prevention Trial included a provision that men randomized to receive placebo undergo a prostate biopsy at the end of the study, even if they had normal PSA levels and digital rectal exams. To their surprise, investigators found that many of these men had prostate cancer — in some cases, high-grade prostate cancer.
||Number of men (2,950 total)
||Men with prostate cancer
||Men with prostate cancer whose tumors were high grade (Gleason score 7 or more)
|up to 0.5 ng/ml
|*Note: A PSA level over 4.0 ng/ml traditionally triggers a biopsy.
|Adapted with permission from I.M. Thompson, et al. Prevalence of Prostate Cancer Among Men with a Prostate-Specific Antigen Level ≤4.0 ng per Milliliter. New England Journal of Medicine, May 27, 2004, Table 2.
This study inadvertently provided evidence not only that prostate cancer occurs more often than once believed, but also that PSA levels may not be a reliable indicator of which cancers are most aggressive. Both findings add weight to the growing consensus that many prostate tumors currently being detected may not need to have been diagnosed or treated in the first place.
For more information
To learn more about the PCPT:
Thompson IM, Goodman PJ, Tangen CM, et al. The Influence of Finasteride on the Development of Prostate Cancer. New England Journal of Medicine 2003;349:215–24. PMID: 12824459.
Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of Prostate Cancer among Men with a Prostate-Specific Antigen Level ≤4.0 ng per Milliliter. New England Journal of Medicine 2004;350:2239–46. PMID: 15163773.
Cancer staging may miss errant cells
Once a pathologist confirms that cancer is present, the doctor will next determine how far the cancer extends — a process known as cancer staging — and discuss the implications with you. This is perhaps the most important information of all for you to obtain, as it determines whether the cancer is likely to be curable, or whether it has already spread to additional tissues, making prognosis much worse.
If you were my patient, I would ask you to consider two important points. First, cancer staging actually occurs in two phases: clinical (based on information obtained preoperatively) and pathological (based on information obtained during surgery). Of the two, pathological staging is more accurate.
A second point to understand, however, is that even pathological staging can be inaccurate (see Figure 2). A cancer spreads, or metastasizes, once a primary tumor sheds cancer cells that travel elsewhere in the body and establish other tumor sites. Metastasis is a complex process that researchers do not fully understand. What is clear is that this process involves multiple genetic mutations and steps, and that each type of cancer spreads in a unique way.
Figure 2. Why understaging may occur
When the prostate is removed, a pathologist examines slices of the gland for evidence of cancer. A. Under a microscope, the pathologist can distinguish tiny tumors, consisting of clumps of visibly abnormal cells. B. With current imaging technology, it is not yet possible for a pathologist to identify micrometastases — individual cancer cells shed from the primary tumor — that have gone on to seed adjacent tissue. In this image, for example, cancer cells have already penetrated the capsule and migrated to adjacent tissue, even beyond the margin of tissue removed during surgery.
Individual prostate cancer cells can spread to more remote areas of the body in three ways (see “How prostate cancer spreads,” below). What’s more, they can do so without being detected with our current technology, essentially escaping “under the radar.” So it’s always possible — even if you are diagnosed with early-stage prostate cancer — that the cancer has already spread and will manifest in the coming years. How likely is it that an early-stage prostate cancer will become active without treatment? A small study provides some clues (see “Likelihood of progression,” above).
How prostate cancer spreads
- The cells escape into the bloodstream, initially by invading small blood vessels around the tumor, then traveling to larger blood vessels that enable the cells to circulate around the body (a situation known as vascular invasion).
- The cells are filtered through the body’s lymph system; although some are captured in lymph nodes, others may travel elsewhere in the body.
- The cells migrate along the length of a nerve, escaping from the prostate into adjacent soft tissue (a situation known as perineural invasion, or PNI).
Treatments may have side effects
The treatment options for early-stage prostate cancer fall into three broad categories: surgery, radiation therapy, and active surveillance. Your doctor will make a treatment recommendation based on your “numbers” as well as a mathematical tool known as a nomogram, which can help you and your doctor better assess how extensive your cancer is likely to be and whether it is likely to become active in the future.
Yet clinical studies have not provided any evidence that one treatment is better than another — or that any treatment at all actually prolongs life: The average 5-, 10-, and 15-year survival rates are virtually the same for all treatment options in early-stage prostate cancer, including active surveillance. It’s also important to understand that no mathematical model is foolproof, and some men diagnosed with early-stage, locally confined disease will later find out that their cancer was more extensive than originally believed.
If you are diagnosed with early-stage prostate cancer, you have a number of treatments to choose from. A brief comparison is listed in Table 2.
Table 2. What guides treatment recommendations
Both of the situations below involve men diagnosed with a tumor that is small in size (stage T2a or smaller), yet who may require quite different treatments, based on their PSA level and Gleason score. Of course, many men have clinical profiles that vary from these two extremes.
||Probable pathological stage
|Low PSA (less than 10 ng/ml)
Low Gleason score (no more than 6)
|80% of men with this profile probably have locally confined disease.
It is likely that fewer than 3% will have evidence of cancer in lymph nodes.
|Surgery, radiation, or active surveillance (depending on exact clinical profile).
|High PSA (more than 20 ng/ml)
High Gleason score (8–10)
|5% of men with this profile probably have locally confined disease.
More than 20% probably have evidence of cancer in the lymph nodes.
|Systemic therapy rather than surgery (may involve some combination of hormonal and radiation therapy).
Radical prostatectomy (surgery). The surgeon removes the prostate and seminal vesicles (saclike glands that release fluid that becomes part of semen). In some cases, pelvic lymph nodes are also sampled. This is most often performed through an abdominal incision; abdominal surgery may also be done with a laparoscope. A third option is the perineal technique, involving an incision in the area between the scrotum and the anus (the perineum). The most common side effects are
- impotence (affecting 30%–70% of men)
- mild to severe incontinence (2%–15%).
External beam radiation therapy. After a CT scan constructs a three-dimensional picture of the prostate and seminal vesicles, the radiation oncologist directs rays of high-energy radiation at the prostate tumor and sometimes at nearby lymph nodes. The most common side effects are
- impotence (30%–70%)
- mild to severe incontinence (1%–2%).
Brachytherapy. With ultrasound guidance, radioactive “seeds” or pellets are implanted in the prostate itself to irradiate the tumor. The most common side effects are
- impotence (30%–50%)
- mild to severe incontinence (2%).
Active surveillance. This involves an extended period of monitoring the cancer with regular digital rectal exams, PSA tests, and sometimes repeated prostate biopsies. If tests indicate cancer has become active, treatment options are offered. The major risk of active surveillance is that the cancer could become active during the period of surveillance, potentially making prognosis worse.
Side effect reporting
When thinking about side effects, it’s important to understand that patients don’t always talk openly with their doctors about the impact treatment has had on their quality of life — or sometimes, doctors don’t ask. The following studies are just a sampling of the patient-reported data that have been published, which may provide a more accurate assessment of side effects.
Fecal incontinence. A telephone survey of 227 men with prostate cancer revealed that 5% of those who underwent radical prostatectomy and 18% of those who had a perineal prostatectomy developed fecal incontinence afterward. Yet fewer than 50% told their physicians. (Source: Bishoff JT, Motley G, Optenberg SA, et al. Incidence of Fecal and Urinary Incontinence Following Radical Perineal and Retropubic Prostatectomy in a National Population. Journal of Urology 1998;160:454–8. PMID: 9679897.)
Erectile dysfunction. A mailed questionnaire returned by 1,236 men with localized prostate cancer who had undergone either prostatectomy or radiation therapy revealed that 36% had erectile dysfunction at the time of diagnosis. Yet when contacted an average of four years after treatment, more than twice as many men (85%) said they had erectile dysfunction. Only 13% were able to have firm, reliable erections spontaneously. Respondents indicated that they were as concerned about the loss of sexual desire and the ability to have an orgasm as they were about erectile dysfunction. (Source: Schover LR, Fouladi RT, Warneke CL, et al. Defining Sexual Outcomes after Treatment for Localized Prostate Carcinoma. Cancer 2002;95:1773–85. PMID: 12365027.)
Urinary incontinence. A retrospective analysis based on Medicare claims submitted by 11,522 men who underwent prostatectomy for prostate cancer found that more than one year after surgery, 18%–24% (the proportion increased with age) had suffered symptoms of urinary incontinence or had undergone procedures to correct urinary difficulties. (Source: Begg CB, Riedel ER, Bach PB, et al. Variations in Morbidity after Radical Prostatectomy. New England Journal of Medicine 2002;346:1138–44. PMID: 11948274.)
Rectal cancer risk. A retrospective analysis of the outcomes of 30,552 men who received radiation for prostate cancer found that they were almost twice as likely to develop rectal cancer as a comparison group of 55,263 men who treated their cancer with surgery. (Source: Baxter NN, Tepper JE, Durham SB, et al. Increased Risk of Rectal Cancer after Prostate Radiation: A Population-Based Study. Gastroenterology 2005;128:819–24. PMID: 15825064.)
On the horizon
Given the current limits in diagnosis, prognosis, and treatment, research advances become even more important. Here’s a brief look at other diagnostic and prognostic tests currently in development.
Prostate cancer “fingerprints”
New types of genetic diagnostic technology, known as gene chips or genetic microarrays, use computers to analyze the activity of hundreds and sometimes thousands of genes at a time. The tests can reveal certain telltale patterns that indicate whether inborn controls that inhibit cancer growth — such as controls of blood vessel growth (angiogenesis), cell differentiation and proliferation, and cell adhesion — remain in place or have failed. Think of these patterns as molecular fingerprints that help researchers identify which are the most aggressive cancers and therefore are most likely to spread. The technology is already commercially available for use in breast cancer. Several gene chips for prostate cancer are in development.
Other researchers are investigating whether it is possible to analyze blood samples for the presence of particular antibodies, immune system chemicals that attack cancer cells and other abnormal cells. One study published in the New England Journal of Medicine found that a computerized microarray device could use antibody detection to identify people with prostate cancer more accurately than a PSA test. Although more research has to be done, the hope is that antibody analysis will enable doctors to detect cancer at its earliest stages, when your own immune system has identified the abnormal growth and is trying to suppress it. (Source: Wang X, Yu J, Sreekumar A, et al. Autoantibody Signatures in Prostate Cancer. New England Journal of Medicine 2005;353:1224–35. PMID: 16177248.)
Originally published January 2007; Last reviewed April 20, 2011