An Evidence-Based Approach to Early-Stage Prostate Cancer: The Role of Active Surveillance
An Evidence-Based Approach to Early-Stage Prostate Cancer: The Role of Active Surveillance
Authors: Jessica Mary Clement, MD, Clinical Fellow in Hematology-Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School; and Marc Bennett Garnick, MD, Clinical Professor of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Medical Director, Cancer Programs, NorthEast Hospital Corporation, Editor in Chief, Perspectives on Prostate Disease
Peer Reviewer: Safwat Zaki, MD, FACS, South Dayton Urological Associates, Director of Robotic and Minimally Invasive Urologic Surgery, Kettering Health Network, Kettering, OH; Volunteer Assistant Professor of Urology, University of Cincinnati, OH.
Case Example
A healthy 67-year-old man, Mr. C, comes to your office for his annual examination, which includes a check of his serum prostate specific antigen (PSA). A few days later, his PSA returns elevated at 5 ng/ml (normal range 0-4 ng/ml). Upon review of his records, you note that during the preceding 6 years, his PSA value ranged from 3.7 to 4.3 ng/ml, and he underwent a prostate biopsy 5 years prior when his PSA was noted to be above 4. Twelve core biopsies were taken at that time without any evidence of malignancy. Since his PSA is trending up, you refer him to the urologist.
At the urologist's visit, Mr. C is feeling well, with an American Urological Association symptom score of 3/35, which is in the mild range. On examination, he is well appearing, with a body mass index of 24. His blood pressure is 134/78, with a regular heart rate of 69. His cardiopulmonary examination is normal. His abdomen is soft, flat, and non-tender. The external genitalia are normal in appearance. His rectal examination reveals normal sphincter tone and a benign prostate examination without any palpable abnormalities. Due to the rise in his PSA, Mr. C and his urologist decide to proceed with a repeat prostate biopsy. Mr. C undergoes 20 prostate needle biopsies; one of the 20 cores is positive, with 40% of the core containing adenocarcinoma. The Gleason score is 3+3 (6). The patient, thus, is diagnosed at this time as cT1cNXMX.
Since Mr. C has a PSA less than 10, a Gleason score less than 7, and no palpable disease on digital rectal examination (DRE), which all portend a low likelihood of distant disease, he does undergo a bone scan or a CT of the abdomen/pelvis. The patient also seeks the opinion of a medical oncologist who is concerned about the possibility of local extension of the primary tumor that would preclude prostatectomy, so an endorectal MRI is performed. The endorectal MRI reveals two foci within the prostate suspicious for prostate carcinoma but no definite evidence for extracapsular disease. His urologist then states that he has a low volume of prostate cancer localized to the gland and tells Mr. C that he has a few treatment options, including prostatectomy, radiation, or active surveillance.
He returns to your office to discuss these options and asks you, "Why am I a candidate for active surveillance? Is that the same as watchful waiting? What does it involve?"
Introduction
In 2008, it was estimated that prostate cancer would be diagnosed in 186,320 men in the United States and would be the second leading cause of cancer-related deaths in men behind lung cancer.1 In 1986, the United States Food and Drug Administration approved the use of the serum PSA test as a tumor marker for prostate cancer. In the early 1990s, it was approved for screening.2 In the two decades following the introduction of the serum PSA as a screening tool, the number of men screened has continued to increase. This initially resulted in an increase in the incidence of new prostate cancer cases diagnosed from 1988-1992, which has leveled off since 1995.1 It has been estimated that since the introduction of PSA screening in 1986, approximately 1.3 million additional men have been diagnosed with prostate cancer. Of those, about 1 million have received definitive therapy for their disease.3 Because of the ambiguities of outcomes (and associated morbidity of various treatments for screen-detected cancers) associated with detecting, diagnosing, and treating PSA screen-detected prostate cancer, the United States Preventive Services Task Force (USPSTF) reported in 2002 that there was insufficient evidence in the literature to recommend either for or against screening for prostate cancer with serum PSA. The USPSTF recommendation statement for prostate cancer screening was subsequently updated in August 2008, documenting that there remained insufficient evidence either for or against screening in men younger than 75 years old. In addition, the USPSTF recommended against screening for prostate cancer in men aged 75 years or older because the harms outweigh the benefit.4 This recommendation was based on evaluation of a Cochrane meta-analysis5 that used an intention-to-screen analysis and found no difference in prostate cancer mortality between men invited to screen for prostate cancer and the control group of patients. Moreover, there was some suggestion of adverse psychological effects associated with false-positive PSA tests. The USPSTF did not discuss the negative effects associated with subsequent prostate biopsies or testing that followed from PSA testing.
Overall, estimates suggest 1 in 6 men will be diagnosed with prostate cancer, but the lifetime risk of death from it is only 3%.6,7 Since the institution of PSA screening, approximately 9 out of 10 men diagnosed with prostate cancer will have so-called "early-stage disease" in which the cancer is detected by an elevated PSA and biopsy, not by DRE. This is known as clinical stage T1c. (See Figure 1.) The natural history of early-stage prostate cancers suggests that many of these patients will not ultimately die of their cancer, thus suggesting overdetection of indolent cancer that may not necessarily cause any morbidity during the patient's lifetime. Overdetection describes the situation in which a screening test discovers indolent cancers that, if diagnosed, would remain clinically silent throughout a patient's lifetime. The rate of prostate cancer overdetection due to the institution of PSA screening has been estimated to be between 27% and 56%.8,9
In addition, randomized controlled trials looking at PSA screening have not demonstrated a survival benefit.5 Two large screening trials were published in 2009. One was the American Prostate, Lung, Colorectal and Ovarian Cancer Screening (PLCO) Trial, which recruited 76, 693 men, and the other was the European Randomized Study of Screening for Prostate Cancer (ERSPC), which recruited 182, 000 men.10,11 The PLCO trial found that, at 7 years, screening was associated with a relative increase in prostate cancer diagnosis of 22% but no reduction in prostate cancer mortality when compared with the control group.10 With a median follow-up of 9 years, the ERSPC study reported that PSA screening reduced the rate of prostate cancer deaths by 20%, but also noted that 1,410 men would need to be screened and 48 additional men would need to be treated for prostate cancer to prevent 1 death.11 This supports the postulation that early-stage prostate cancer is being overdiagnosed and overtreated.
PSA screening is also associated with adverse outcomes with relation to prostate biopsies. Although prostate biopsies are generally benign procedures, they are associated with pain, bleeding, and occasionally sepsis.12 The anxiety associated with testing also must be acknowledged.13 Thus, PSA screening remains controversial due to its lack of proven survival benefit and its physical and psychological ramifications.
Side Effects of Treatments for Early Prostate Cancer
The concern regarding overdetection of these early-stage prostate cancers with PSA screening lies with the morbidity and mortality associated with the standard local therapies recommended for this disease; brachytherapy, external beam radiation therapy (EBRT), and radical prostatectomy (RP), as well as other modalities, including cryotherapy.
Brachytherapy. Brachytherapy involves placing radioactive "seeds" into the prostate gland. Potential side effects include urinary retention or incontinence, irritative voiding symptoms, increased frequency of bowel movements, urgency of bowel movements, rectal bleeding, and, rarely, prostatorectal fistula. Long-term urinary incontinence is under 20%, and erectile dysfunction (ED) has been reported in 14-52% of patients.14,15
External Beam Radiation. For men undergoing external beam radiation, about half will experience acute toxicity including urinary urgency, frequency, and dysuria. Late urinary complications are infrequent, but incontinence can present and worsen over time, though only approximately 5% of patients report "significant" incontinence at 2 years. ED also increases over time following EBRT, such that 50% of previously potent men will have ED at two years following treatment. Additionally, radiation proctitis may be seen in 2-39% of men.16,17
Surgical Approaches (Radical Prostatectomy). For patients who select radical prostatectomy, mortality rates of the procedure are low (< 1%), so there are two main adverse effects to consider: impotence and urinary incontinence.18 The rates of incontinence and impotence vary by the experience of the surgeon, but the Prostate Cancer Outcomes Study (PCOS) reported 1.6% men without urinary control at 2 years following surgery. Seven percent of men had frequent leakage, whereas 42% had occasional leakage. The rate of incontinence is highest just after surgery and improves with time. Likewise, impotence improves with time following surgery, but in the PCOS report, 60% of men were unable to have erections firm enough for sexual intercourse 2 years out.19
Many men with early-stage prostate cancer, therefore, are being diagnosed with a disease that has a low likelihood of impacting their survival, yet they are undergoing treatments that have side effects that can be significant. Thus, the important question of determining whether there is a subset (with certain clinical and pathological parameters) of men for whom immediate treatment with either a radiation or surgical modality could possibly be avoided or delayed thus supporting the concept of active surveillance. The goal of active surveillance is to provide curative treatment to patients with early-stage disease that has the potential to progress while delaying or avoiding the morbidity associated with definitive therapy. This is in contrast to the policy of "watchful waiting," which historically meant deferring definitive therapy entirely in patients and then instituting palliative therapy once there are symptoms of local progression or metastatic disease. This usually was limited to men older than 75 years with limited life expectancy or men with significant co-morbidities that precluded primary treatment.
This Primary Care Reports article will review the presentation and evaluation of men with newly diagnosed prostate cancer and discuss the clinical and pathologic characteristics (and the application of such information to clinical decision making) that would allow consideration of active surveillance, rather than radical treatment.
Critical Appraisal of the Literature
The literature review was launched with a PubMed search using the MESH heading "prostatic neoplasms," followed by "watchful waiting" or "active surveillance." This search, limited to English-language publications, yielded 360 articles, from which a manual literature search was based. More than 250 articles were reviewed, with 118 included here for the reader's reference. The point of care reference from the American College of Physicians' (ACP) Physician's Information and Education Resource (PIER) provided an excellent outline of the topics "Screening for Prostate Cancer" and "Prostate Cancer," both with editorial updates in 2008. In addition, The Cochrane Collaboration provided a protocol on "Watchful waiting versus prostatectomy for prostate cancer" in 2008 with a review of pertinent literature. "Up-to-Date" also presented outlines on the diagnosis of prostate cancer and treatment options of early-stage disease, which were used as guides for further literature search. All of these sources provided a guide from which the relevant information here was analyzed and presented.
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Long-Term Outcomes Data. The information regarding the long-term outcomes of patients with early-stage prostate cancer have been from observational studies published in early 2000. There was one randomized controlled trial performed in Sweden comparing radical prostatectomy to watchful waiting initially published in 2002, then published in 2005,20 and now updated in 2008.21 This paper does not clearly reflect the population of prostate cancer patients here in the United States, since many of the men in the Swedish study were not detected by PSA elevation noted on screening as is the case in this country, but by clinically detected disease. On the horizon are the U.S. study "Prostate Cancer Intervention Versus Observation Trial" (PIVOT), which is a randomized control trial comparing radical prostatectomy with watchful waiting in men who are 75 years old or younger with localized prostate cancer, and the British study "Prostate testing for cancer and Treatment (ProtecT) trial, which is a randomized controlled trial comparing radical prostatectomy, radiation, and active surveillance that completed recruitment in 2008. Follow-up of these studies is expected to be 10-15 years; thus it will be some time before we have more robust, prospective data on which to base our patient care decisions.
Epidemiology and Etiology
Prostate cancer is the sixth most common cancer in the world, and in the United States, it represents approximately 29% of the cancers diagnosed in men each year. Approximately 1 in 6 men in the United States will be diagnosed with prostate cancer in their lifetime. It is the second leading cause of cancer-related deaths in men after lung cancer.6 Age, ethnicity, genetic factors, and diet have been linked with the development of prostate cancer, some more strongly than others.
Age is a well-known risk factor for developing prostate cancer. According to the National Cancer Institute's SEER database, the median age at diagnosis is 68 years. For the years 2001-2005, 8.6% of men with prostate cancer were diagnosed between the ages of 45 and 54, 28.0% between 55 and 64; 36.1% between 65 and 74; 22.0% between 75 and 84; and 4.7% 85+ years of age. The decrease in rates of prostate cancer diagnosis after the age of 74 is postulated to be from the decrease in screening of older patients.6 But autopsy studies show that the prevalence of occult prostate cancer is much higher than of clinically diagnosed disease and, again, the rates increase dramatically with age. A review of multiple studies across the globe demonstrates rates of occult prostate cancer in up to 31% of men aged 31-40 years, 5-46% of men aged 51-60 years, and up to 83% of men in the 71-80 year-old age group.22
Race/Ethnicity. There is a higher incidence of prostate cancer in African-American patients compared with whites, which is attributed to genetic factors and possibly dietary factors as well. In African-Americans, the incidence is 258.3 per 100,000 men compared to 163.4 per 100,000 white men, giving a rate ratio of 1.6.1 Moreover, African-Americans tend to have a younger age of onset, present with more advanced disease, and have a higher than expected rate of having a rising PSA after definitive therapy, even when adjusting for differences in socioeconomic status as well as clinical and pathologic factors.23 Hispanic-Americans are 20% less likely to be diagnosed with prostate cancer compared with white men, but are still more likely to die from the disease when correcting for age and stage.1
Family history is also a predictor for the development of prostate cancer, providing evidence for a genetic component to the etiology of this disease. Men with one first-degree relative with prostate cancer have a two-fold increase in risk, whereas those with two first-degree relatives affected have a five-fold increased risk. There was an 11-fold increased risk of developing prostate cancer if the patients had three first-degree relatives with prostate cancer. In addition, there is an increased risk in men with a history of a family member with early onset of disease (younger than age 65).24-28
Breast cancer 1 (BRCA1) and breast cancer 2 (BRCA 2) are tumor suppressor genes that, when mutated, have been shown to increase the risk of breast cancer and other malignancies. In fact, BRCA1 or 2 mutations may increase the risk of developing prostate cancer two- to five-fold. The BRCA2 mutation appears to be associated with a higher risk of prostate cancer compared to BRCA1 carriers and the development of a more aggressive phenotype than in patients without the mutation.29,30
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Diet. Dietary habits that have been linked to the development of prostate cancer include high animal fat intake and low vegetable intake. A prospective cohort study demonstrated that there was not an increase in prostate cancer risk with fish or fat from dairy products. Saturated fat, monounsaturated fat, and alpha-linolenic acid were associated with an advanced risk of prostate cancer. These are found in animal fat, especially in red meat.31 However, another large prospective study of men in Europe did not find a relationship between animal fat and prostate cancer.32 It has been postulated that the risk may be due to mutagens related to the cooking process of the meat, and one study showed that those who eat well-done or very well-done meat have a higher incidence of prostate cancer.33 Those with either lycopene-rich diets or diets high in soy products may derive a slight protective benefit against prostate cancer.34-36 Specific vitamins and minerals have been evaluated to see if they impact the development of prostate cancer. Patients taking large doses of multivitamins should be counseled that two reports noted an increased risk in advanced and fatal cases of prostate cancer, although there was not an increase in the number of men developing the disease.37,38 Other observational studies have suggested that taking zinc over a long period of time and diets heavy in dairy products or calcium supplementation may increase the risk of prostate cancer. The relationship between calcium and prostate cancer has been postulated to be due to decreased vitamin D levels in those with higher serum calcium levels.39-41 Studies looking at vitamin E and selenium have been controversial, with some showing a benefit, and others without a protective benefit.42,43 In January 2009, the "Selenium and Vitamin E Cancer Prevention Trial" (SELECT) was published. The SELECT trial enrolled 35,533 men and found that together or alone, vitamin E and selenium did not prevent prostate cancer in this population. In addition, there were two trends that were concerning but not statistically significant. In the vitamin E-only arm, more cases of prostate cancer were detected, and in the selenium-only arm, more cases of diabetes were reported.44 Thus, at this time, neither vitamin E nor selenium should be taken for prevention of prostate cancer.
Other factors, both endogenous and exogenous, that may influence the incidence of prostate cancer have been suggested. These include, but are not limited to, testosterone supplementation, insulin and insulin-like growth factor, statins, aspirin, non-steroidal anti-inflammatory medications, obesity, physical activity, Agent Orange, vasectomy, and prostatitis.
Serum levels of testosterone or DHT have not been correlated with an increased risk of prostate cancer. Likewise, supplemental testosterone for hypogonadism has not been associated with an increased risk, but evaluation for prostate abnormalities both before and during treatment is recommended.45 Insulin and insulin-like growth factor, along with higher waist-hip ratios, have shown a relationship to an increased risk of prostate cancer.46 A high body mass index, on the other hand, has been associated with more aggressive tumors and recurrence but not an increased incidence.47 Physical activity has not demonstrated a protective effect on prostate cancer risk.48 Aspirin may have a slight protective benefit, but there is no clear evidence with regard to NSAIDs or statins.49,50
Vasectomy and its link to prostate cancer has been controversial. Earlier studies demonstrated a link between the two that increased with time, but more recent data show that the procedure does not change a man's risk.51 Prostatitis appears to be implicated due to the increased number of biopsies this population gets due to an elevated PSA from the inflammation.52 The data on Agent Orange exposure is suggestive of a link with prostate cancer, but the National Academy of Sciences concluded that this evidence is limited and not definitive.53
Increased ejaculatory frequency has been associated with a decreased risk of prostate cancer in two case control studies. In one study, a decreased risk was seen in men who had 5 or more ejaculations per week while in their 20s.54 In the other study, if men in their 40s had 20 or more ejaculations per month, they also had a lower risk.55 This association has been called into question due to the lack of benefit seen in other age groups and the concern about recall biases. This link also has been questioned due to a lack of protection against prostate cancer seen in married patients or those with more sexual partners.56
Differential Diagnosis
In the United States, prostate cancer usually is diagnosed following a biopsy for an elevated PSA. There are other diagnostic considerations besides prostate cancer when a PSA test returns abnormal. The differential diagnosis for this situation includes benign prostatic hypertrophy (BPH), which is the most common cause of an elevated PSA, prostatic inflammation/prostatitis, and more broadly, perineal trauma. The trauma can range from the relatively benign DRE to cystoscopy, prostate biopsy, and transurethral resection of the prostate (TURP). Energetic bicycle riding and other activities that place pressure on the perineum, as well as sexual activity, also have been shown to raise the serum PSA level.
Following DRE, the rise is minimal and returns to normal quickly.57,58 It takes 48-72 hours for the PSA to decline following ejaculation.59,60 The most persistent elevations follow prostate biopsies, TURPs, and cystoscopies.61 The median time for PSA to return to baseline following a biopsy is 15-17 days, and 18 days following TURP. Thus, it is recommended not to check a PSA level until 6 weeks following such procedures.
PSA velocity, the rate of change of PSA over a period of time, may help differentiate between prostate cancer and benign processes like BPH. If the PSA rises by 0.75 ng/mL per year, especially in patients with lower PSA levels, prostate cancer is more likely to be the cause.62
Patient Presentation. Prior to the institution of screening with PSA, patients presented with urinary urgency, frequency, and hesitancy, nocturia, or incomplete sensation of bladder emptying, for example. Sudden-onset erectile dysfunction due to cancer involvement of neurovascular bundles also was seen. Rarely, hematuria or hematospermia triggered an evaluation for prostate cancer. In some cases, men presented with symptoms of metastatic disease such as bony pain or cord compression. While these presentations still are possible, the large majority of men in the United States now present with asymptomatic rises in their PSA, leading to a prostate biopsy and a diagnosis of prostate cancer.
Patient Evaluation. The patient evaluation should focus on specific aspects of the history, such as determining whether the patient has any new urinary symptoms, recent onset of erectile dysfunction, or symptoms to suggest metastatic disease, such as new bone or back pain. A good way to evaluate some of these symptoms is by utilizing the American Urologic Association symptom score, a validated scoring system for BPH that often is used to assess symptoms for prostate cancer. Patients are asked 7 specific questions, each of which can be rated on a scale from 0 (no symptoms), to 5 (almost always have symptoms). (See Table 3.) The range of possible scores is zero to 35, and there is a quality-of-life assessment as well. Patients with a score of 0-7 are deemed to have mild symptoms, those with a score of 8-19 have moderate symptoms, and men with a score greater than 20 have severe symptoms.63
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A detailed family history should be taken to determine if other first-degree relatives have been diagnosed with prostate cancer or malignancies associated with the BRCA1 and 2 gene mutations that will help guide other family members with appropriate cancer screening. Other data that should be documented is a dietary history. As for the physical exam, the digital rectal exam is crucial to accurately assign a clinical stage of disease to the patient. (See Figure 1.)
Diagnostic Studies
Laboratory Evaluation. Beyond obtaining serum PSA for initial screening, the level of the elevation is helpful in determining the likelihood of extraprostatic extension. If the PSA is < 4 ng/mL, about 80% of prostate cancers will be clinically localized. Conversely, if the PSA is > 10 ng/mL, the rate of extraprostatic disease is 24- to 50-fold higher.64-67
It is important to think of PSA values and the risk of finding prostate cancer as being on a continuum. The Prostate Cancer Prevention Trial (PCPT) performed end-of-study prostate biopsies on men with PSA levels below 4 ng/mL, a level considered to be normal. The biopsies demonstrated a 27% risk of prostate cancer in men with a PSA value between 3.1 and 4, 24% risk of prostate cancer between 2.1 and 3, 17% risk at PSA levels of 1.1 to 2, 10% risk for men with PSA levels between 0.6 and 1, and there was even a 7% risk of finding cancer with a PSA < 0.5 ng/mL. Therefore, there is not a "normal" PSA value at which prostate cancer cannot be found.68 Thus, monitoring of PSA velocity may be more important than the actual starting PSA value. Once again, if a PSA level increases more than 0.75 ng/mL per year, especially in the lower range of PSA values, it is more likely to be due to prostate cancer.62 Another way to evaluate PSA levels is by determining the PSA density, which is the PSA value divided by the volume of the prostate in grams as estimated by ultrasound. PSA density values greater than 0.15 ng/mL/gm, are seen more frequently in prostate cancer, while lower values are associated with BPH.69
Other laboratory tests should be dictated by the patient's history. If a patient is describing urinary retention or frequency, blood urea nitrogen (BUN) and creatinine may be evaluated to see if there is renal insufficiency. An abdomen/pelvis CT scan or CT urogram to evaluate hydronephrosis also may be indicated. Urinalysis may be performed to evaluate for infection or hematuria. Alkaline phosphatase also may be considered if a patient is reporting bone pain.
Prostate Biopsy. A prostate biopsy is indicated in any patient with a palpable abnormality on DRE. Patients with a rising PSA without a palpable abnormality should be referred to a urologist to discuss whether a prostate biopsy is indicated. The goal of the prostate biopsy is to evaluate for the presence and the extent of prostate cancer, and to determine the Gleason score of the cancer.
The Gleason score is found on the pathology report and describes the architectural features of the prostate cancer. A number from 1-5 is used to describe the level of differentiation, with 1 being the most differentiated and 5 being the least differentiated. A pathologist will find the two most common patterns within the prostate cancer and assign each a score. The first score lists the most dominant pattern, and the second score lists the next most common pattern. The pathologist then add these two scores to get the Gleason score. An example would be 3+4, giving a total Gleason score of 7. It is important to recognize that 3+4 is not equivalent to 4+3 even though both add to 7, since the latter score describes a tumor with a predominant area of cancer that is more poorly differentiated. The Gleason score closely correlates with clinical behavior of the tumor, such that those with a higher Gleason score are more likely to have extra-prostatic spread after local therapy.70 The high-grade Gleason scores are 8-10, moderate scores are 5-7, and low scores are less than 5.
Prostate biopsies can be done either blindly or guided by DRE or transrectal ultrasound (TRUS). Traditionally, sextant biopsies would be performed, obtaining a core from the base, midzone, and apex of the prostate on the right and the left for a total of 6 cores. Over time, this has been replaced by a biopsy schema that includes lateral aspects of the prostate. With higher numbers of cores taken, the detection of cancer also goes up. A prospective study looked at adding biopsies of the lateral biopsies of the peripheral zone at the base and mid-gland to the standard sextant biopsy plan. The patients who had 10 cores taken had a cancer detection rate of 96%. Twenty percent of the cancers were missed by the standard 6-core biopsy.71,72 Some groups suggest that up to 20 core biopsies should be taken to optimize cancer detection, also called "saturation" biopsies. A review performed of 87 studies looking at cancer detection based on the number of cores concluded that 12-core biopsies seemed to create a reasonable balance between cancer detection and the likelihood of finding a significant cancer and rate of adverse events.73 Of course, more extensive biopsies may also reveal small and clinically insignificant prostate cancers.
Complications from TRUS-guided prostate biopsies include hematospermia, hematuria, fever, and rectal bleeding. Patients infrequently require hospitalization for either urinary difficulties or urosepsis post procedure.12 The rate of urinary tract infections (UTIs) following prostate biopsies may be decreased with prophylactic antibiotics. A prospective study of 400 men reviewed the number of UTIs in men who received prophylactic levofloxacin 500 mg orally before undergoing a biopsy. Men who were deemed high risk were given an additional 2 days of 500 mg of levofloxacin post-biopsy. High-risk patients were defined as those with large prostates (75 mL in volume or greater), diabetes mellitus, recent steroid use, significant voiding dysfunction at baseline, or immune compromise. None of the 23 high-risk patients had any complications post-biopsy. One of the 377 low-risk patients had a symptomatic UTI.74
Patients who undergo saturation biopsies tend to have more rectal bleeding and hematospermia. There does not appear to be an increased risk of pain, urinary complications, or urosepsis.73 Some patients express concern that either exposing the tumor to air or putting a needle into it will make the cancer spread. There are no data to support these theories, and reassurance should be provided.
Pain is a side effect of the procedure, and local anesthesia may be used for prostate biopsies. A nonrandomized retrospective study of 100 men showed decreased amounts of pain recorded in men with no increase in complications compared to historical controls.75 Alternatively, a randomized prospective study of 100 men comparing periprostatic local anesthesia, demonstrated increased rates of fever greater than 101.6 and bacteriuria in the men who received anesthesia, although they experienced less rectal bleeding.75 Urethral bleeding was the same in both groups.76
Transrectal Ultrasound (TRUS). TRUS is used most often as a guide for the urologist when performing prostate biopsies, although many early-stage cancers cannot be visualized via this modality. This is its main use, as many studies failed to demonstrate accuracy in detecting discrete tumor nodules.
Endorectal Coil Magnetic Resonance Imaging (MRI). Endorectal MRI also may be used to determine whether there is extraprostatic extension of disease and/or seminal vesicle involvement. It is clearly more accurate than DRE and also is more accurate than an MRI of the pelvis since the endorectal coil allows the acquisition of thinner slices, which leads to better spatial resolution of the prostate and periprostatic tissues (neurovascular bundle, seminal vesicles, and lymph nodes). Endorectal MRI also has been shown to incrementally add to prognostic factors in patients with intermediate or high-grade disease, but it has not been shown to help in predicting which patients with low-grade disease will progress.77 Endorectal MRIs can be helpful when a patient has a rising PSA and multiple negative prostate biopsies, oftentimes detecting "anterior" tumors. Anterior tumors are those tumors that lie anterior to the urethra. This test is not routinely used and its role is still being determined.
Radionuclide Bone Scan. A bone scan is used to evaluate for metastatic disease of the bones. If present, curative therapies are not indicated. Some practitioners will obtain baseline bone scans at the time of diagnosis, although many recommend obtaining bone scans only in those patients who have clinical factors that would predict for extraprostatic disease. For example, in one series of men with prostate cancer, if the clinical stage was T2b or less, the Gleason score was 7 or less, and the PSA was less than or equal to 50 ng/mL, the chance of having a positive bone scan was only 1%.78 Thus, bone scans should be reserved for those patients with Gleason scores greater than 7, a tumor that has spread beyond the prostate, and a markedly elevated PSA.
Computed Tomography (CT) scan. The role of the CT scan in prostate cancer, like bone scans, is limited to the patients expected to have a high rate of extraprostatic spread. A CT abdomen/pelvis then is used to evaluate for regional lymph node involvement or other soft-tissue disease. This should not be routinely ordered for low-risk patients since nodal involvement usually occurs late in the progression of disease. It is reasonable to stage patients with a CT scan if their PSA is greater than 20 ng/mL, they have a T3 or T4 tumor, or they have a Gleason score greater than 7.79
Positron Emission Tomography (PET). Currently, there is no clinical indication to use PET scanning in patients with prostate cancer. At present, bone scans are more sensitive than PET for metastatic bone disease, and PET does not reliably pick up soft-tissue or lymph node disease.80
Prostascint. Prostascint (capromab pendetide) is a monoclonal IgG antibody against prostate-specific membrane antigen (PSMA) radiolabeled with indium-111. It is another tool that may be used to detect metastatic disease either before primary therapy or if there is evidence of early recurrence.81 As with bone scans and CT scans, its use should be reserved in patients with high-risk disease. Its use today is limited to centers that have a special interest in this technology. The accuracy and false-positive and false-negative rates have precluded its widespread acceptance as a staging tool.
Treatments
Once a patient has been diagnosed with localized prostate cancer, he has many decisions to make. He needs to decide whether to proceed with an intervention right away, consider deferment of treatment with either watchful waiting or active surveillance, or proceed with newer, focused therapies. The three most standard interventions for local prostate cancer are radical prostatectomy, external beam radiotherapy and brachytherapy. There is no study that confirms that any of the standard therapies is better than another. Unfortunately, there is significant bias in the observational studies looking at this question since older patients with more co-morbidities are usually funneled toward radiation therapy, and younger, healthier men undergo prostatectomy. Moreover, it is unlikely that a randomized study comparing these modalities will be completed, since most physicians and patients would not like to give up the opportunity to make their own decision regarding therapy.
Radical Prostatectomy. Radical prostatectomy is the treatment most often selected by men in the United States. It involves removing the prostate gland, seminal vesicles, and, occasionally, the regional lymph nodes. It can be performed as an open retropubic procedure, by a perineal approach, laparoscopically, or with robot assistance. Lymph node evaluations for metastatic disease can be undertaken in all of these approaches except the perineal approach; thus this procedure usually is reserved for patients with low-risk disease. Once again, for patients who choose to undergo radical prostatectomy, there are two main adverse effects to consider, impotence and urinary incontinence, since the mortality rates of this procedure are low.
Complications. The rates of incontinence and impotence vary by the experience of the surgeon, but the Prostate Cancer Outcomes Study (PCOS) reported 1.6% men without urinary control at 2 years following surgery. Seven percent of men had frequent leakage, whereas 42% had occasional leakage. The rate of incontinence is highest just after surgery and improves with time. Likewise, impotence improves with time following surgery, but in the PCOS reports, 60% of men were unable to have erections firm enough for sexual intercourse 2 years out.18,19
ED rates are lower if surgeons are able to perform nerve-sparing procedures, but this cannot be guaranteed for all patients.17 The location, size, and grade of the tumor may prohibit a nerve-sparing procedure, and the greatest patient outcomes following RP are for those patients who have no residual disease after surgery. Therefore, the neurovascular bundles may need to be removed to ensure negative margins.82 For patients who undergo a perineal prostatectomy, increased incidence of fecal soilage has been reported due to the inability to spare nerves, along with higher rates of biochemical failure (rising PSA following prostate removal), since many surgeons leave the seminal vesicles in.83
Laparoscopic prostatectomies and robot-assisted prostatectomies have been shown to have similar outcomes to each other with regard to length of hospital stay, postoperative pain, or blood transfusion requirement. More importantly, though, there are no long-term data on outcomes related to tumor control or rates of incontinence or impotence. These data were based on a prospective, single-surgeon study comparing robot-assisted prostatectomies to standard open radical prostatectomies.84
Patients should be encouraged to meet with many urologists to discuss their surgical approach, amount of experience, whether they plan to use a laparoscopic or robot-assisted approach, and how comfortable they are converting to open radical prostatectomies if necessary.
RP outcomes most often are described in terms of biochemical disease-free survival, which is the time without a rising serum PSA. On average, 70% of men will be free from biochemical recurrence at 10 years. Many patients are interested in robot-assisted surgery, but it is important to point out that there are no data to support clinically significant improvements in either disease-related outcomes or adverse events with robot-assisted surgery.85,86
It is important to note that biochemical disease-free survival does not correlate directly with overall survival. Results vary with pathologic findings at surgery such as positive or negative margins, involvement of lymph nodes, as well as PSA doubling time once there is biochemical recurrence.82-84,87-89 A prospective study of quality-of-life outcomes demonstrated that patients with a large prostate at baseline have improved urinary symptoms after prostatectomy, although overall 7% of prostatectomy patients had moderate to worse distress from urinary symptoms at 1 year, compared to 18% of patients following brachytherapy and 11% of patients who had EBRT. Patient-reported adverse outcomes on sexual function were mitigated by nerve-sparing procedures.90
External Beam Radiotherapy (EBRT) is the most common type of radiation therapy used. Using a linear accelerator, radiation can be given to the prostate gland and periprostatic tissues over a course of 5-8 weeks, depending on the dose. This therapy often is used in patients with medical co-morbidities that would make them poor surgical candidates.
Complications. Fifty percent of men undergoing external beam radiation will experience acute toxicity, including urinary urgency, frequency, and dysuria. Late urinary complications are infrequent, but incontinence can present and worsen over time, although only approximately 5% of patients report significant incontinence at two years. ED also increases over time following EBRT, such that 50% of previously potent men will have ED at two years following treatment. Additionally, radiation proctitis may be seen in 2-39% of men.16,17 Two technical improvements in EBRT, intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT), have allowed the sparing of normal tissues like the bladder and rectum, which can limit the toxicities experienced.91,92 For men with early-stage disease, the 5-year biochemical disease-free survival is in the 80-90% range.93,94 With regard to quality-of-life measures, effects on urinary symptoms were resolved at 12 months, but 11% of patients had moderate or worse distress from urinary symptoms. The majority of patients were improved from baseline at 24 months. In 9% of patients, disturbances in bowel function continued to cause distress at 12 months.
These symptoms included rectal urgency, frequency, pain, fecal incontinence, or hematochezia. For intermediate- and high-risk patients who received adjuvant hormone therapy, quality-of-life measures related to sexual function and vitality were worse and persisted up to two years.90
Brachytherapy involves placing radioactive "seeds" into the prostate gland. This therapy is best for men who do not have obstructive urinary symptoms, who wish to avoid surgery, and those who may be unable to make daily radiation therapy.
Side effects. Potential side effects include urinary retention or incontinence, late formation of urethral strictures, irritative voiding symptoms, increased frequency of bowel movements, urgency of bowel movements, rectal bleeding, and, rarely, prostatorectal fistula. Long-term urinary incontinence is under 20%, and erectile dysfunction (ED) has been reported in 14-52% of patients.14,15 For low-risk patients, outcomes appear to be similar to patients who receive EBRT or RP.94 For patients with higher-risk disease, EBRT is added to brachytherapy to provide more coverage to periprostatic tissues. There is an ongoing phase III trial comparing brachytherapy alone or combined with EBRT. There has been no benefit to the addition of adjuvant hormone therapy.
Hormone Therapy. Hormone therapy, also know as androgen deprivation therapy, is used to decrease testosterone levels and, therefore, decrease the stimulation of the androgen receptors of the prostate cancer cells. GnRH agonists may be used alone or in combination with anti-androgens. In metastatic disease, androgen deprivation therapy has been shown to prolong survival, but it is considered palliative therapy. Most men will progress to androgen-independent disease within 2-3 years.95 The full scope of hormone therapy in prostate cancer is beyond the scope of this article.
For patients with early-stage prostate cancer, hormone monotherapy alone traditionally is reserved for patients too ill to be considered for either RP or radiation therapy with either EBRT or brachytherapy, although there are no data that document a clear benefit.96 It can be given at the time of diagnosis, though often it is reserved until signs of progression appear for patients undergoing a watchful waiting approach. The conundrum is that many patients are ill from cardiovascular disease, and prolonged hormone therapy has been shown to increase cardiovascular risk and diabetes.97,98 For patients with intermediate- or high-risk local disease, hormone therapy may be used as an adjuvant therapy to EBRT. Eighty percent of patients will experience an improvement of symptoms and a decrease in PSA with the use of hormone therapy. In addition to the cardiovascular effects, the side effects of hormone therapy are related to the decrease in testosterone, resulting in hot flashes, gynecomastia, fatigue, decreased libido, muscle atrophy, and osteoporosis.
Cryotherapy is a process by which tumor cells are destroyed by freezing. The physician inserts several small needles into the prostate gland through the perineum via ultrasound guidance. Argon gas then is infused through the needles to cool the tips to - 40º F and rapidly freeze the surrounding tissue, which then is thawed slowly. The cells are destroyed by ice crystal formation and through cell disturbances from the freezing and thawing cycles.99 Warming catheters are inserted into the urethra and rectum to decrease the local side effects of incontinence, urinary obstruction from swelling, and fistula formation. The major side effect is impotence due to freezing of the nerves; 80-95% of men were unable to achieve an erection following therapy. On average, 60% of men with low-risk disease will have no evidence of biochemical recurrence at 5 years, and even though this therapy is FDA-approved, it is not considered a standard therapy.100-102
High-Intensity Focused Ultrasound (HIFU) uses a trans-rectal transducer to focus sound waves on the prostate. The focused sound waves create a large amount of energy and heat (up to 140º F) that damages cells. A small area of tissue is treated at a time, so MRI-guidance is used to ensure that all of the prostatic tissue is treated.99 Side effects are primarily urinary symptoms of obstruction either from swelling or dead tissue in the urethra blocking flow, incontinence, infections, and urinary frequency or urgency. Rates of impotence were reported to be in the 20-50% range. Effects were reported to be temporary. The biochemical outcomes for patients treated with HIFU suggest disease-free rates of 66% at five years.103,104 This therapy is not FDA-approved but is available in Canada and Mexico.
Because of both the side effects and ambiguities regarding outcomes, and the issue of overdiagnosis, deferred intervention strategies, typically described as watchful waiting (WW) or active surveillance (AS), are gaining in popularity.
Watchful Waiting. Traditionally, patients undergoing watchful waiting are monitored for signs of progressive disease, either local or distant. When this occurs, hormone therapy usually is instituted and the intent of treatment is palliative. Thus, the population selected for this plan usually is made up of patients with significant co-morbidities that preclude radiation or surgery, or predict a life expectancy of less than 10 years. A study of patients in Connecticut demonstrated patients with low-grade prostate cancer had a low risk of dying from prostate cancer at 15 years due to competing risks.105 In Sweden, a randomized control trial comparing radical prostatectomy to watchful waiting was performed on patients with prostate cancer diagnosed by transurethral resection of the prostate or clinically significant local disease. This study demonstrated a modest improvement in overall survival at 10 years for patients who underwent a prostatectomy, but those patients had a more significant decrease in the rates of local tumor progression and distant metastases. A 2008 update of this study found no further increase in benefit of prostate cancer mortality after 10 or more years after surgery.20,21
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Active Surveillance. In contrast to watchful waiting, the goal of active surveillance is to monitor patients until signs of progression and then proceed with curative intent. The theory behind active surveillance is that the majority of low-risk, early-stage patients will never have clinically significant disease, yet a few do progress. Therefore, by following these patients closely, physicians can select the patients with signs of progression and then proceed with therapy while sparing the majority the morbidity related to the therapies discussed above. Thus far, there have been no differences in adverse features found in men who underwent delayed prostatectomy after a period of surveillance compared with those who had immediate surgical intervention.106 The ProtecT trial is underway in Britain, which will compare immediate radical prostatectomy with active surveillance in a randomized, prospective manner. It has been estimated that if all low-risk patients appropriate for active surveillance were offered radical prostatectomy, the number needed to treat would be 100 for each patient who does not die from prostate cancer.107
To select low-risk patients who are appropriate for active surveillance, the following criteria (see Table 4) are most commonly used: Gleason score of 6 or less, PSA level of 10 or less, clinical stage T2a disease or less, PSA density of < 0.15 ng/mL/gm, less than one-third of prostate biopsy cores positive and no core with more than 50% involvement by malignancy, and stable PSA kinetics before diagnosis.95,108,109 Some consider age as a factor and would consider active surveillance in patients 60 years of age or older with multiple co-morbidities, or 65 years old or older if healthy. The best way to predict progression is still under debate. At this time, the surveillance algorithm for these patients includes serum PSA and DRE every 3 months, and repeat prostate biopsy one year after initial diagnosis to evaluate for high-grade disease that may have been missed initially, then every 4-5 years.107 The Johns Hopkins group recommends repeat prostate biopsies annually or with a rising PSA.110
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Therapy is indicated if the DRE changes, the PSA doubling time decreases to less than 3 years, the Gleason score increases to 7 or higher, more than one-third of the number of biopsy cores are positive, or if more than 50% of one core is involved. While there are no prospective data to validate these triggers, they represent a transition to intermediate-grade disease and, therefore, evidence to support progression.
Special Circumstances. It is important to focus on each patient's personal medical history and family history to select the appropriate intervention. Patients with germline BRCA mutations tend to have more aggressive phenotypes; thus they may not be candidates for surveillance.29,30 Radiation therapy would not be recommended for a patient with active inflammatory bowel disease due to radiation proctitis. Since the standard therapies are essentially equivalent based on the best available data, therapy can be individualized to each patient depending on his own special circumstances.
Controversies
The main controversy rests with the question of what are the most effective therapies for early-stage, low-risk prostate cancer. Unfortunately, this question is unlikely to be answered due to poor accrual for studies comparing standard therapies of radiation and prostatectomy due to physician and patient biases and unwillingness to be randomized to a therapy. Yet, given the huge number of observational studies, it is unlikely that there is a real difference between radiation and prostatectomy. Moreover, answering this type of question is not likely to alter practices, since there will always be a patient (and physician) preference based upon the known side effects of the treatments. Studies evaluating different forms of radiation and those comparing the varied surgical approaches, such as open versus robotic, prostatectomy, may be more enlightening and useful. The most relevant controversy at this time is the safety of active surveillance and how it compares to immediate definitive therapies. The ProtecT trial may bring us closer to answering this question.
Cutting Edge. Endorectal coil MRI as described in the treatment section remains on the cutting edge of diagnostic evaluation in prostate cancer. We await studies that correlate the findings on MRI with pathologic specimens to help determine the accuracy of the MRI images in finding extraprostatic disease.
Other diagnostic modalities that are not yet standard are molecular assays for urinary detection of prostate cancer, more specific blood tests, and genomic assays. In oncology, genomic assays are being developed as tools to predict tumor behavior. In the realm of breast cancer care, BRCA 1 and 2 are mutations that help predict the risk of a patient developing breast cancer. In addition, Oncotype Dx, a multi-gene assay, is available to help predict the risk of distant recurrent disease and assess the benefit of chemotherapy. Prostate cancer does not yet have these tools, but some are on the horizon. TMPRSS2 gene translocations have been discovered in advanced prostate cancer. Further studies may help determine whether this is present in early-stage disease and will represent a marker for risk of advanced disease and may lead to future targeted therapies.111
The urine assays for telomerase activity, GTSP 1 methylation, and uPM3 appear to have high specificity on initial testing, which may be helpful in differentiating BPH from prostate cancer.112-114 In addition, the blood tests pro-PSA and EPCA-2 are on the horizon.115,116 Both appear to be more specific for prostate cancer than standard PSA, which may help determine which patients are appropriate for further evaluation with prostate biopsy.
In the realm of treatment, focal therapies with radiation, cryotherapy, HIFU, and photodynamic therapy are being investigated. Photodynamic therapy is employed by giving patients a photosensitizer and then inserting optical fibers into the prostate. The light from the fibers triggers the photosensitizer to release toxic substances that will kill local cells.99 These therapies are being used to target areas within the prostate gland that have the primary tumor, not the entire gland. The thought is that by targeting the main tumor, it will prevent clinically significant progression while limiting local toxicities. This approach has been suggested as an intermediate therapy between surveillance and definitive curative therapy. However, there have been few studies evaluating the concept of focal therapy.117
What Does the Evidence Tell Us?
The literature has shown that by introducing the serum PSA as a screen for prostate cancer, we are finding more cases at an earlier stage.2,8 The data also provide us with good evidence that the majority of men with early-stage, local prostate cancers will do well most for greater than 10 years, and many for their lifetimes without intervention.9,105 It also emphasizes that, as of the current time, there is no randomized clinical level 1 evidence indicating that patients who undergo PSA testing and have their prostate cancer treated live any longer than those who are not screened.
Moreover, if patients and clinicians wish to proceed with immediate intervention, they have multiple, reasonable options to choose from, such as radical prostatectomy or radiation therapy, either external beam or brachytherapy. The literature also clearly demonstrates that these interventions do have associated morbidities, with the most predominant ones being incontinence and impotence, and they are not clinically insignificant.14-19 Quality-of-life studies have clearly documented the impact of these treatments and their side effects, not only on patients but also on their significant others.91
In light of these findings, the issues of overdetection and overtreatment have come to the forefront of discussions related to early-stage prostate cancer, which has allowed promotion of the concept of active surveillance. Again, active surveillance is based on the premise that the majority of these patients will not have cancers that will interfere with their overall health for a decade or more; thus, many men can defer therapy until they declare themselves to have progressive disease. Studies have shown that delayed, curative intention does not have worse outcomes than those patients who undergo intermediate intervention for their disease, therefore active surveillance is a viable and safe option for this population of men.106,109
It is important to note that the randomized study comparing watchful waiting, a plan with a non-curative intent, to radical prostatectomy, did show that men on the watchful waiting arm had worse prostate cancer outcomes due to more local progression and metastatic disease after 10 years of study.20,21 But, it is critical to appreciate that the men at baseline are a different population than we see here in the United States. The men in the Swedish trial were diagnosed via TURPs or having other clinically suggestive symptoms that prompted evaluation, not the asymptomatic men we diagnose here after a screening PSA returns elevated. Clinically, the men in the Swedish study were more locally advanced by virtue of their presenting symptoms.
In addition, the distinction between watchful waiting and active surveillance is important. Watchful waiting is instituted in men with significant comorbidities who have a short life expectancy and/or cannot tolerate curative therapy. Once they have evidence of disease progression, the treatment given is palliative in nature. This is in contrast to active surveillance, which is monitoring patients closely to then intervene with curative intent once they show signs of a more aggressive phenotype of prostate cancer. This is a critical distinction.
Clearly, the literature still leaves unanswered questions. More rigorous studies of novel diagnostics are needed to help predict the men with early-stage disease who will progress to more aggressive disease so that they can be targeted for early intervention. Furthermore, we do not have any prospective, randomized trials comparing the standard therapies of radical prostatectomy and radiation to each other to clearly determine which outcomes are better. Investigators have tried, but studies have not been completed due to poor accrual. We do have some mature data on the outcomes of patients undergoing active surveillance. A prospective cohort of 331 patients has a median follow-up time of 8 years and shows an overall survival of 85%, and disease-specific and metastatic-free survival of 99%.107,118 The results of the ProtecT trial will also be helpful in answering this question.
Summary
Screening with serum PSA and the detection of early-stage prostate cancer has created a "glass half-full, glass half-empty" scenario. On one hand, we are now finding cancers in men before they have a chance to have either local progression or widespread disease; thus ,we potentially can provide better outcomes to patients with our current therapies. But at what cost? Men with early-stage prostate cancer may be overtreated for a disease that may not ever cause any symptoms or have an impact on their overall survival, but they are sacrificing quality of life. Thus, it behooves us to consider patients for active surveillance and a chance to avoid or delay side effects of treatments while not giving up their chance to enjoy similar survivals. In the meantime, further research into improving our prognostic information for individual patients needs to continue.
Case Conclusions
After carefully exploring all of his options, Mr. C decides to proceed with active surveillance. His PSA levels are monitored every three months, and they fluctuate from 4.8 ng/mL to a peak of 5.3 ng/mL. At present, his PSA remains stable at 5.0 ng/mL. A repeat endorectal MRI shows no evidence of extracapsular invasion. He undergoes repeat saturation biopsies of the prostate after 1 year, and then after 2 years on active surveillance to evaluate for progression of his prostate cancer. The follow-up biopsy at 1 year demonstrates only 1 out of 20 cores positive for Gleason 3+3 prostate adenocarcinoma in less than 10% of the core. In the 2-year follow-up biopsy, 2 out of 20 cores are positive, for Gleason 3+3 prostate adenocarcinoma. One core has 10% involvement; the other has 15% involvement. Since he has had a stable PSA without any follow-up biopsies demonstrating greater than one-third of the cores positive for cancer, or any cores with more than 50% involved, and no Gleason 4 or 5 disease, he currently remains on a program of active surveillance.
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