Prostate Cancer Treatment
PSA and digital rectal exam. Until about 2008, doctors recommended that most men over 50 be screened for prostate cancer yearly with a PSA test along with a digital rectal exam (NCI 2017d; USPSTF 2008; NCI 2018a). PSA is a protein produced by cells of the prostate gland (NCI 2018a; Malatesta 2000), and high blood levels of PSA are often seen in men with prostate cancer. However, PSA levels can also be elevated as a result of benign prostate conditions, such as prostatitis and BPH (USPSTF 2008; NCI 2018a).
Controversy and new guidelines. Prostate cancer screening guidelines have been controversial (Wilt 2015; Etzioni 2014; Payton 2012; Tabayoyong 2015). As increasing numbers of men were being screened, critics became concerned that too many men were undergoing invasive diagnostic procedures only to find out they did not have cancer (NCI 2017d; USPSTF 2008; USPSTF 2017). A second concern was that some cancers detected during routine screening might not have become clinically significant in the man’s lifetime (Howrey 2013; Etzioni 2002; Andriole 2012).
In 2008, the United States Preventative Service Task Force (USPSTF) recommended against routine screening for men over 75 (USPSTF 2008). In 2012, they expanded this recommendation to men of all ages (Moyer 2012). A review of the literature from 2012 to 2016 found that the use of PSA testing had declined, and not as many prostate biopsies were being performed as previously (Lee, Mallin 2017).
As routine screening has declined, there are new concerns that men will be diagnosed in later and less treatable stages of prostate cancer (Lee, Mallin 2017; Eapen 2017; Fleshner 2017). The most recent draft of prostate cancer screening guidelines released by the USPSTF in 2017 states that “the decision about whether to be screened for prostate cancer should be an individual one” (Bibbins-Domingo 2017; USPSTF 2017). This statement highlights the importance of personal and informed decision-making when it comes to prostate cancer screening (Eapen 2017).
New screening tests. PSA testing and digital rectal exam have been the primary prostate cancer screening methods. Several variations of the basic PSA test, described below, have been developed to improve its usefulness (Saini 2016; Hatakeyama 2017).
The PSA level at a single time point may not be as informative as changes in PSA levels over time (Salman 2015; Adhyam 2012). PSA velocity measures how quickly PSA is rising, and PSA doubling time measures how long it takes for PSA levels to rise twofold (Ponholzer 2010; Loughlin 2014). Both doubling time and velocity have been primarily studied for monitoring prostate cancer after diagnosis. These tests can indicate how quickly a tumor is growing, whether the cancer has metastasized, and how the disease is responding to treatment (Howard 2017; Freiberger 2017; Vickers 2014).
Some PSA is free in the blood, and some is bound to, or complexed with, other proteins (NCI 2018a). The standard PSA test detects both forms, while a newer test measures free PSA, and complexed PSA can be calculated using these values (NCI 2018a; Brawer 1998; Brawer 2003). Complexed PSA, free PSA, and tests that include information about both may provide a more accurate reflection of prostate cancer activity than total PSA alone (Wang, Li 2017; Strittmatter 2011; NCI 2018a).
Another version of the PSA test looks at a precursor form of PSA called pro-PSA (Peyromaure 2005; Ito 2014; Ayyildiz 2014). This form of PSA may be better than total PSA at determining which men with borderline total PSA may really have cancer (Boegemann 2016). The Prostate Health Index (PHI) is a test that combines information from total PSA, free PSA, and pro-PSA (Loeb, Catalona 2014). This test was approved by the Food and Drug Administration (FDA) in 2012, for men age 50 and older with a total serum PSA between 4 and 10 ng/mL and a normal digital rectal exam, to reduce the number of unnecessary prostate biopsies (Loeb, Catalona 2014; Sartori 2014). One recent study found that total PSA was 47% accurate for identifying men with cancer while the PHI test was 72% accurate (Tosoian, Druskin 2017).
While some research has focused on improving the PSA test, other research has developed completely new tests. For the PCA3 test, for example, urine is collected after a digital rectal exam (NCI 2018a; Martignano 2017). The cells in the urine are tested for the prostate cancer-specific gene PCA3 (Hessels 2003). PCA3 testing is not currently used as a general screening test. Instead, for men with high PSA levels but no cancer detected in a biopsy, PCA3 testing can help determine which men should have a repeat biopsy and which should be monitored using active surveillance (Rubio-Briones 2017; Wang, Chen 2017; Galasso 2010).
Doctors diagnose prostate cancer by examining tissue from a biopsy (Bjurlin 2014; NCCN 2016b; Small 2015). The biopsy is most often collected through the wall of the rectum. Typically, at least 12 cores (different areas) of tissue are removed to check all areas of the prostate (NCCN 2016b). Some men experience adverse effects or complications such as soreness, infection, or bleeding after prostate biopsy (NCCN 2016b; Bjurlin 2014; Jones, Radtke 2016).
Imaging techniques are commonly used during the biopsy procedure (Woodrum 2017). Transrectal ultrasonography uses sound waves to produce images of the prostate (NCI 2018b). The doctor uses these images to ensure biopsy samples are obtained from the targeted regions of the prostate (NCCN 2016b).
Doctors may also use magnetic resonance imaging (MRI) along with transrectal ultrasonography (Marks 2013; Woodrum 2017; NCI 2018b; Jambor 2017). MRI images are taken before the procedure to assess the patient’s risk of prostate cancer, possibly preventing unnecessary biopsies (Porpiglia 2017; Ahmed 2017). If a biopsy is needed, these highly sensitive MRI images can be used to identify the region of the prostate to target (NCCN 2016b), improving diagnosis of more dangerous forms of cancer (Bjurlin 2017). In a study that enrolled 601 men who were scheduled for prostate biopsy, MRI-guided biopsy identified greater than 30% more cases of high-grade prostate cancer than traditional biopsy methods (Meng 2016).
A prognostic test can help guide treatment decisions by providing information on how aggressive a tumor is or how likely it is to spread (Terada 2017). Tissue obtained during biopsy or surgery is analyzed by a pathologist who assesses the characteristics of the cells and determines the Gleason score (Litwin 2017). The Gleason scoring system has been used for decades to indicate how aggressive a tumor is and guide treatment decisions (Chen 2016; Slager 2003; Wright 2009; Humphrey 2004).
The Gleason Score
The Gleason score is an established system for grading tumors and plays an important role in treatment selection. To determine the Gleason score, a pathologist first analyzes tumor cells in a biopsy or surgery sample under a microscope to determine how much they differ from normal cells and express this as a number between one and five (NCI 2018b). Lower numbers indicate that the characteristics of the cells are closer to those of normal cells and higher numbers indicate that the cells have more cancerous characteristics. The pathologist assigns a number, or a grade, to the two areas that make up most of the tumor. The sum of these two numbers is called the Gleason score. The Gleason score can range from 2 to 10 (although only Gleason scores of 6 – 10 are reported clinically in most cases) (NCCN 2016c; ACS 2017). Also, the individual numbers are usually provided (such as 3+4=7). The number listed first is the grade that is most common in the tumor (ACS 2017).
Tumors that are Gleason score 6 or lower are likely to grow slowly and may not require invasive treatment right away (NCCN 2016b). Patients with higher Gleason score tumors have a worse prognosis and may benefit from more aggressive treatment plans (NCCN 2017b). In 2014, new guidelines were released for grouping patients by Gleason score (Gordetsky 2016; Epstein 2017):
- Grade Group 1 = Gleason score ≤ 6
- Grade Group 2 = Gleason score 3 + 4 = 7
- Grade Group 3 = Gleason score 4 + 3 = 7
- Grade Group 4 = Gleason score 8
- Grade Group 5 = Gleason scores 9 and 10
This new grouping system was validated in a study in over 20,000 men undergoing radical prostatectomy. Using PSA levels alone as the measure of recurrence, the rates of 5-year survival without recurrence in men in Groups 1, 2, 3, 4, and 5 were 96%, 88%, 63%, 48%, and 26%, respectively (Epstein 2016).
A commonly used system of staging is called the TNM system. The “T” component describes how much the tumor has grown in and around the prostate gland; the “N” component of staging indicates whether the cancer has spread to lymph nodes; and the “M” component indicates whether the cancer has metastasized (NCCN 2016b; Small 2015).
After being diagnosed with prostate cancer, patients typically undergo further testing to determine whether the cancer has spread to the lymph nodes and other organs (ie, to assess their TNM status) (Bhindi 2017; Rodgers 2017). Selecting which type of additional testing is appropriate depends on each man’s clinical status. Men with higher PSA values or Gleason scores or larger tumors may be candidates for additional imaging such as a bone scan with technetium-99m, pelvic computed tomography (CT) scan, or pelvic MRI to check for cancer spread (NCCN 2016b). Men whose PSA is above 10‒20 ng/mL are often advised to undergo the technetium-99m bone scan. The American College of Radiology has developed guidelines to help guide the selection of imaging tests for men with prostate cancer, based on variables such as “T” stage, Gleason score, PSA level, and number of positive biopsy cores (National Guideline 2016).
One challenge with both MRI and CT scans is they have a relatively high rate of inaccurately identifying the extent of the disease, which may lead to a suboptimal course of treatment. The development of techniques such as multiparametric MRI and sophisticated types of positron emission tomography (PET) scans has expanded the repertoire of tools available to physicians for use during prostate cancer evaluation (Bednarova 2017; Fulgham 2017). Results from these tests can be used to assess cancer stage and guide treatment decisions (NCCN 2017b; NCCN 2016b; Bhindi 2017; Rodgers 2017). Other techniques combining PET and MRI technologies have been investigated; these newer modalities may improve treatment planning in the near future (Eiber 2013). However, as previously mentioned, each man’s clinical status and unique situation must be taken into consideration when determining which testing strategies are optimal.
Importantly, given the numerous and complex strategies available for investigating the extent of prostate cancer, it is important that each patient undergo careful and thoughtful evaluation. Some experienced physicians have noted that lack of attention to detail in assessing a man’s clinical status may lead to inaccurate TNM staging and thus suboptimal treatment. Men in the midst of prostate cancer diagnosis and staging should ask lots of questions of their medical team and be sure they are confident that sufficient detail is being gathered to carefully plan their treatment.
Nomograms are tools that combine available clinical information from large numbers of patients and use mathematical calculations to estimate an individual’s risk of various events. In the case of prostate cancer, these events may include the spread (metastasis) of prostate cancer or mortality after specific treatments. Nomograms, when used appropriately by knowledgeable clinicians, can help individualize the treatment decision-making process (NCCN 2016b; Beauval 2017; Kim 2017; Lowrance 2009; Caras 2014). Nomograms can be informative about many aspects of prostate cancer care, including estimating the need for biopsy and the choice for adjuvant therapy (Caras 2014). However, because it is difficult to standardize these assessments (ie, different nomograms are appropriate for different patients), practitioners may prefer different nomograms or interpret them slightly differently.
In recent years, imaging studies, such as MRI, have been incorporated into prostate cancer nomograms (Caras 2014). Several research studies have revealed that incorporating multiparametric MRI into nomograms could improve their predictive value (Watson 2016). While nomograms may be very useful in addressing a specific question, they also have several shortcomings (eg, cost), and they are not perfectly accurate. Moreover, nomograms are only valid if used on a treatment population that is similar to the population from which the nomogram data were collected (Caras 2014). Given the complexity of properly employing nomograms, they may be underutilized, even though they have demonstrated value when used appropriately. Men in the treatment-planning stages of prostate cancer management should ask their care team whether these valuable tools have been incorporated into the decision-making process for their care.