NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
Prostate cancer has surpassed lung cancer as the most common cancer in men. Experts generally accept that these changes resulted from prostate-specific antigen (PSA) screening that detected many early-stage prostate cancers. An estimated 233,000 new cases will be diagnosed in 2014, accounting for 27% of new cancer cases in men in 2014.1 Fortunately, the age-adjusted death rates from prostate cancer have declined (-4.1% annually from 1994 to 2001). Researchers have estimated prostate cancer to account for 29,480 deaths in 2014.1 This comparatively low death rate suggests that, unless prostate cancer is becoming biologically less aggressive, increased public awareness with earlier detection and treatment has begun to affect mortality from this prevalent cancer. However, early detection and treatment of prostate cancers that do not threaten life expectancy result in unnecessary side effects, which impair quality of life and increase health care expenses, while decreasing the value of PSA and digital rectal exam (DRE) as early detection tests.
This guideline version includes NCCN Panel recommendations on treatment decisions for patients with localized disease. The full version of the guideline, including treatment of patients with advanced disease, can be found online at NCCN.org.
Estimates of Life Expectancy
Estimates of life expectancy have emerged as a key determinant of primary treatment, particularly when considering active surveillance or observation. Although estimating life expectancy for groups of men is possible, extrapolating these estimates to an individual patient is more difficult. Life expectancy can be estimated using the Minnesota Metropolitan Life Insurance Tables or the Social Security Administration Life Insurance Tables2 and adjusted for individual patients by adding or subtracting 50% based on whether one believes the patient is in the healthiest or unhealthiest quartile, respectively.3 As an example, the Social Security Administration Life Expectancy for a 65-year-old American man is 16 years. If he is judged to be in the upper quartile of health, a life expectancy of 24 years is assigned. If he is judged to be in the lower quartile of health, a life expectancy of 8 years is assigned. Thus, treatment recommendations could change dramatically using the NCCN Guidelines if a 65-year-old man was judged to be in either very poor or excellent health.
NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 2.2014
Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 5; 10.6004/jnccn.2014.0072
NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 2.2014
Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 5; 10.6004/jnccn.2014.0072
NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 2.2014
Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 5; 10.6004/jnccn.2014.0072
NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 2.2014
Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 5; 10.6004/jnccn.2014.0072
NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 2.2014
Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 5; 10.6004/jnccn.2014.0072
NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 2.2014
Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 5; 10.6004/jnccn.2014.0072
NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 2.2014
Version 2.2014, 04-01-14 ©2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 5; 10.6004/jnccn.2014.0072
Risk Stratification
Optimal treatment of prostate cancer requires assessment of risk: how likely is a given cancer to be confined to the prostate or to spread to the regional lymph nodes? How likely is the cancer to progress or metastasize after treatment? How likely is adjuvant or salvage radiation to control cancer after an unsuccessful radical prostatectomy? Prostate cancers are best characterized by clinical (TNM) stage determined by DRE, Gleason score in the biopsy specimen, and serum PSA level. Imaging studies (ultrasound, MRI) have been investigated intensively but have yet to be accepted as essential adjuncts to staging.
The NCCN Guidelines incorporate a risk stratification scheme that uses a minimum of stage, grade, and PSA to assign patients to risk groups. These risk groups are used to select the appropriate options that should be considered for treatment and to predict the probability of biochemical failure after definitive local therapy.4 Risk group stratification has been published widely and validated, and provides a better basis for treatment recommendations than clinical stage alone.5,6 The NCCN Prostate Cancer Panel recognized that heterogeneity exists within each risk group. For example, an analysis of 12,821 patients reported that men assigned to the intermediate-risk group by clinical stage (T2b-T2c) had a lower risk of recurrence than men categorized according to Gleason score (7) or PSA level (10-20 ng/mL).7 A similar trend of superior recurrence-free survival was seen in men placed in the high-risk group by clinical stage (T3a) compared with those assigned by Gleason score (8-10) or PSA level (>20 ng/mL), although it did not reach statistical significance.
The more clinically relevant information that is used in the calculation of time to PSA failure, the more accurate the result. The Partin tables8,9 were the first to achieve widespread use for counseling men with clinically localized prostate cancer. The tables give the probability (95% confidence intervals) that a patient with a certain clinical stage, Gleason score, and PSA will have a cancer of each pathologic stage. A nomogram is a predictive instrument that takes a set of input data (variables) and makes predictions about an outcome. Nomograms predict more accurately for the individual patient than risk groups, because they combine the relevant prognostic variables, regardless of value. Nomograms can be used to inform treatment decision-making for men contemplating active surveillance,10 radical prostatectomy,11-13 neurovascular bundle preservation,14-16 or omission of pelvic lymph node dissection (PLND) during radical prostatectomy,17 brachytherapy,11,18,19 or external beam radiation therapy (EBRT).11,20 Biochemical progression-free survival can be reassessed postoperatively using age, diagnostic serum PSA, and pathologic grade and stage.21,22 Potential success of adjuvant or salvage radiation therapy (RT) after unsuccessful radical prostatectomy can be assessed using a nomogram.11,23
None of the current models predict with perfect accuracy, and only some of these models predict metastasis11,22,24,25 and cancer-specific death.13,26 Given the competing causes of mortality, many men who sustain PSA failure will not live long enough either to develop clinical evidence of distant metastases or to die from prostate cancer. Those with a short PSA doubling time are at greatest risk of death. Not all PSA failures are clinically relevant; thus, PSA doubling time may be a more useful measure of risk of death.27 The NCCN Prostate Cancer Panel recommends that NCCN risk groups be used to begin discussing options for treatment of clinically localized prostate cancer and that nomograms be used to provide additional and more individualized information.
Imaging
Imaging techniques are useful for detecting metastases and tumor recurrence. Anatomic imaging techniques include radiographs, ultrasound, CT, and MRI. Functional techniques include radionuclide bone scan, PET, and advanced MRI such as spectroscopy and diffusion-weighted imaging.
Observation
Observation involves monitoring the course of prostate cancer with the expectation of providing palliative therapy when symptoms develop or a change in exam or PSA results suggest symptoms are imminent. Observation thus differs from active surveillance. The goal of observation is to maintain quality of life by avoiding noncurative treatment when prostate cancer is unlikely to cause mortality or significant morbidity. The main advantage of observation is avoiding possible side effects of unnecessary definitive therapy or androgen-deprivation therapy (ADT). But patients may be at risk for urinary retention or pathologic fracture without prior symptoms or increasing PSA level.
Observation is applicable to elderly men or frail patients with comorbidity that will likely out-compete prostate cancer. Johansson et al28 noted that only 13% of men developed metastases 15 years after diagnosis of T0 to T2 disease and only 11% had died of prostate cancer. Since prostate cancer will not be treated for cure for patients with shorter life expectancies, observation for as long as possible is a reasonable option based on physician discretion. Monitoring should include PSA and DRE. When symptoms develop or are imminent, patients can begin palliative ADT.
Active Surveillance
Active surveillance (also referred to as watchful waiting, expectant management, or deferred treatment) involves actively monitoring the course of the disease with the expectation to intervene if the cancer progresses. Unlike observation, active surveillance is mainly applicable to younger men with seemingly indolent cancer with the goal of deferring treatment and potential side effects. Because these patients have a longer life expectancy, they should be followed closely and treatment should start promptly if the cancer progressed, to avoid missing the chance for cure.
The advantages of active surveillance include 1) avoiding the side effects of definitive therapy that may not be necessary; 2) retaining quality of life and normal activities; 3) ensuring that small indolent cancers do not receive unnecessary treatment; and 4) decreasing initial costs. The disadvantages of active surveillance include 1) chance of missed opportunity for cure; 2) chance the cancer may progress or metastasize before treatment; 3) treatment of a larger, more aggressive cancer may be more complex with greater side effects; 4) nerve sparing at subsequent radical prostatectomy may be more difficult, which may reduce the chance of potency preservation after surgery; 5) increased patient anxiety of living with an untreated cancer;29 6) the requirement for frequent medical examinations and periodic prostate biopsies; 7) the uncertain long-term natural history of untreated prostate cancer; and 8) the timing and value of periodic imaging studies have not been determined.
Rationale
The panel remains concerned about the problems of overtreatment related to the increased frequency of diagnosis of prostate cancer from widespread use of PSA for early detection or screening (see NCCN Guidelines for Prostate Cancer Early Detection; available online at NCCN.org).
The debate about the need to diagnose and treat every man who has prostate cancer is fueled by the high prevalence of prostate cancer on autopsy of the prostate30; the high frequency of positive prostate biopsies in men with normal DREs and serum PSA values31; the contrast between the incidence and mortality rates of prostate cancer; and the need to treat an estimated 37 men with screen-detected prostate cancer32,33 or 100 men with low-risk prostate cancer34 to prevent one death from the disease. The controversy regarding overtreatment of prostate cancer and the value of prostate cancer early detection32-38 has been informed further by publication of the Goteborg study, a subset of the European Randomized Study for Screening of Prostate Cancer (ERSPC).39 Many believe that this study best approximates proper use of PSA for early detection because it was population based and involved a 1:1 randomization of 20,000 men who received PSA every 2 years and used thresholds for prostate biopsy of PSA greater than 3 and greater than 2.5 since 2005. The follow-up of 14 years is longer than the European study as a whole (9 years) and Prostate, Lung, Colorectal, and Ovarian (PLCO) (11.5 years).
Prostate cancer was diagnosed in 12.7% of the screened group compared with 8.2% of the control group. Prostate cancer mortality was 0.5% in the screened group and 0.9% in the control group, which gave a 40% absolute cumulative risk reduction of prostate cancer death (compared with ERSPC [20%] and PLCO [0%]). Most impressively, 40% of the patients were initially managed by active monitoring and 28% were still on active surveillance at the time these results were analyzed. To prevent a prostate cancer death, 12 men would need to be diagnosed and treated as opposed to the ERSPC in which 37 needed to be treated. Thus, early detection when applied properly should reduce prostate cancer mortality. However, that reduction comes at the expense of over-treatment that may occur in as many as 50% of men treated for PSA-detected prostate cancer.40
The best models of prostate cancer detection and progression estimate that 23% to 42% of all screen-detected cancers in the United States are overtreated41 and that PSA detection was responsible for up to 12.3 years of lead-time bias.42 The NCCN Prostate Cancer Panel responded to these evolving data with careful consideration of which men should be recommended for active surveillance. However, the panel recognizes the uncertainty associated with the estimation of chance of competing causes of death, the definition of very low- or low-risk prostate cancer, the ability to detect disease progression without compromising chance of cure, and the chance and consequences of treatment side effects.
Application
Epstein et al43 introduced clinical criteria to predict pathologically “insignificant” prostate cancer. Insignificant prostate cancer is identified by clinical stage T1c, biopsy Gleason score of 6 or lower, the presence of disease in fewer than 3 biopsy cores, 50% or less prostate cancer involvement in any core, and PSA density less than 0.15 ng/mL/g. Despite the usefulness of these criteria, physicians are cautioned against using these criteria as the sole decision point. Studies have shown that as many as 8% of cancers that qualified as insignificant using the Epstein criteria were not organ-confined based on postoperative findings.21,44
A new nomogram may be better.45 Although many variations on this definition have been proposed (reviewed by Bastian et al46), the panel reached a consensus that insignificant prostate cancer, especially when detected early using serum PSA, poses little threat to men with life expectancy less than 20 years. The confidence that Americans with very low-risk prostate cancer have a very small risk of prostate cancer death is enhanced by lead time bias introduced by PSA early detection that ranges from an estimated 12.3 years in a 55-year-old man to 6 years in a 75-year-old man.42
The role for active surveillance should increase with the shift toward earlier-stage diagnosis attributed to PSA testing. However, results from randomized or cohort studies comparing this deferral strategy with immediate treatment are mixed, partly due to heterogeneity of the patient populations (reviewed by Sanda and Kaplan47).
Ultimately, a recommendation for active surveillance must be based on careful individualized weighing of a number of factors, including life expectancy, general health condition, disease characteristics, potential side effects of treatment, and patient preference. Race is emerging as another important factor to consider, since African-American men who meet the criteria of very low-risk have been reported to show higher rates of upgrading and adverse pathology compared with men of other races.48
Surveillance Program and Reclassification Criteria
Each of the major active surveillance series has used different criteria for reclassification.49-53 Reclassification criteria were met by 23% of men with a median follow-up of 7 years in the Toronto experience,51 33% of men with a median follow-up of 3 years in the Johns Hopkins experience,53 and 16% of men with a median follow-up of 3.5 years in the UCSF experience50 (Table 1). Uncertainty regarding reclassification criteria and the desire to avoid missing an opportunity for cure have driven several reports in the past year that have dealt with the validity of commonly used reclassification criteria. The Toron- to group demonstrated that a PSA trigger point of a PSA doubling time less than 3 years could not be improved on using a PSA threshold of 10 or 20, PSA doubling time calculated in various ways, or PSA velocity greater than 2 ng/mL/yr.54
The Johns Hopkins group used biopsy-demonstrated reclassification to Gleason pattern 4 or 5 or increased tumor volume on biopsy as their only criteria for reclassification. Of 290 men on an annual prostate biopsy program, 35% demonstrated reclassification at a median follow-up of 2.9 years.55 Unfortunately, neither PSA doubling time (area under the curve [AUC], 0.59) nor PSA velocity (AUC, 0.61) was associated with prostate biopsy reclassification. Both groups have concluded that PSA kinetics cannot replace regular prostate biopsy, although treatment of most men who show reclassification on prostate biopsy prevents evaluation of biopsy reclassification as a criterion for treatment or reduction of survival.
Active Surveillance Experience in North America
Repeat biopsy is useful to determine whether higher-grade elements are evolving although the risks appear small.56 This may influence prognosis and, hence, the decision to continue active surveillance or to proceed to definitive local therapy. Treatment of all men who developed Gleason pattern 4 on annual prostate biopsies has thus far avoided a prostate cancer death among 769 men in the Johns Hopkins study.53 However, whether treatment of all men who progressed to Gleason pattern 4 was necessary remains uncertain. Studies are in progress to identify the best trigger points at which interventions with curative intent may still be successful.
The Toronto group published on 3 patients who died of prostate cancer in their experience with 450 men.51 These 3 deaths led to them to revise their criteria for offering men active surveillance, since each of these 3 men probably had metastatic disease at the time of entry onto active surveillance. In 450 men followed for a median of 6.8 years, overall survival was 78.6% and prostate cancer-specific survival was 97.2%.51 Of the 30% (n=145) of men who progressed, 8% showed an increase in Gleason score, 14% showed PSA doubling time less than 3 years, 1% showed development of a prostate nodule, and 3% expressed anxiety. One hundred and thirty-five of these 145 men were treated; 35 by radical prostatectomy, 90 by RT with or without ADT, and 10 with ADT alone. Follow-up is available for 110 of these men, and 5-year biochemical progression-free survival is only 62% for those undergoing radical prostatectomy and 43% for those undergoing radiation.
By comparison, among 192 men on active surveillance who underwent delayed treatment at a median of 2 years after diagnosis in the Johns Hopkins experience,53 5-year biochemical progression-free survival was 96% for those undergoing radical prostatectomy and 75% for those undergoing radiation. These experiences contrast with the UCSF experience, in which 74 men who progressed on active surveillance and underwent radical prostatectomy were compared with 148 men who were matched by clinical parameters. The two groups were similar by pathologic Gleason grade, pathologic stage, and margin positivity. All men treated using radical prostatectomy after progression on active surveillance had freedom from biochemical progression at a median follow-up of 37.5 months, compared with 97% of men in the primary radical prostatectomy group at a median follow-up of 35.5 months.
The panel believes there is an urgent need for further clinical research regarding the criteria for recommending active surveillance, the criteria for reclassification on active surveillance, and the schedule for active surveillance especially as it pertains to prostate biopsies, which unfortunately come within an increasing burden. Literature suggests that as many as 7% of men undergoing prostate biopsy will suffer an adverse event,36 those with urinary tract infection are often fluoroquinolone-resistant,57 and radical prostatectomy may become technically challenging after multiple sets of biopsies, especially as it pertains to potency preservation.58
Radical Prostatectomy
Radical prostatectomy is appropriate for any patient whose tumor is clinically confined to the prostate. However, because of potential perioperative morbidity, radical prostatectomy should be reserved for patients whose life expectancy is 10 years or more. Stephenson et al13 reported a low 15-year prostate cancer-specific mortality of 12% in patients who underwent radical prostatectomy (5% for low-risk patients), although it is unclear whether the favorable prognosis is due to the effectiveness of the procedure or the low lethality of cancers detected in the PSA era.
Radical prostatectomy was compared with watchful waiting in a randomized trial of 695 patients with early-stage prostate cancer (mostly T2).59 With a median follow-up of 12.8 years, those assigned to the radical prostatectomy group had significant improvements in disease-specific survival, overall survival, and risk of metastasis and local progression. Overall, 15 men needed to be treated to avert 1 death; that number fell to 7 for men younger than 65 years of age. The results of this trial offer high-quality evidence to support radical prostatectomy as a treatment option.
Some patients at high or very high risk may still benefit from radical prostatectomy. In an analysis of 842 men with Gleason scores 8 to 10 at biopsy who underwent radical prostatectomy, predictors of unfavorable outcome included PSA level over 10 ng/mL, clinical stage T2b or higher, Gleason score 9 or 10, higher number of biopsy cores with high-grade cancer, and over 50% core involvement.60 Patients without these characteristics showed higher 10-year biochemical-free and disease-specific survival after radical prostatectomy compared with those with unfavorable findings (31% vs 4% and 75% vs 52%, respectively).
Radical prostatectomy is a salvage option for patients experiencing biochemical recurrence after primary RT, but morbidity (incontinence, erectile dysfunction, and bladder neck contracture) remains significantly higher than when radical prostatectomy is used as initial therapy.61,62 Overall and cancer-specific 10-year survival ranged from 54% to 89% and 70% to 83%, respectively.61
Operative Techniques and Adverse Effects
Long-term cancer control has been achieved in most patients with both the retropubic and the perineal approaches; high-volume surgeons in high-volume centers generally provide superior outcomes.63,64 Laparoscopic and robot-assisted radical prostatectomy are used commonly and are considered comparable to conventional approaches in experienced hands.65,66 In a cohort study using US Surveillance, Epidemiology, and End Results (SEER) Medicare-linked data on 8837 patients, minimally invasive compared to open radical prostatectomy was associated with shorter length of hospital stay, less need for blood transfusions, and fewer surgical complications, but rates of incontinence and erectile dysfunction were higher.67 Oncologic outcome of a robotic versus open approach was similar when assessed by use of additional therapies67 or rate of positive surgical margins,68 although longer follow-up is necessary. A meta-analysis of 19 observational studies (n=3893) reported less blood loss and lower transfusion rates with minimally invasive techniques than with open surgery.68 Risk of positive surgical margins was the same. Two recent meta-analyses showed a statistically significant advantage in favor of a robotic approach compared with an open approach in 12-month urinary continence 69 and potency recovery.70
An analysis of the Prostate Cancer Outcomes Study on 1655 men with localized prostate cancer compared long-term functional outcomes after radical prostatectomy or RT.71 At 2 and 5 years, patients who underwent radical prostatectomy reported higher rates of urinary continence and erectile function but lower rates of bowel urgency. However, no significant difference was observed at 15 years. In a large retrospective cohort study involving 32,465 patients, patients who received RT had a lower 5-year incidence of urologic procedures than those who underwent radical prostatectomy but a higher incidence of hospital admissions, rectal or anal procedures, open surgical procedures, and secondary malignancies.72
Return of urinary continence after radical prostatectomy may be improved by preserving the urethra beyond the prostatic apex and by avoiding damage to the distal sphincter mechanism. Bladder neck preservation may allow more rapid recovery of urinary control.73 Anastomotic strictures that increase the risk of long-term incontinence are less frequent with modern surgical techniques. Recovery of erectile function is related directly to the degree of preservation of the cavernous nerves, age at surgery, and preoperative erectile function. Improvement in urinary function also was seen with nerve-sparing techniques.74 Replacement of resected nerves with nerve grafts does not appear to be effective for patients undergoing wide resection of the neurovascular bundles.75
PLND
The decision to perform PLND should be guided by the probability of nodal metastases. The NCCN Prostate Cancer Panel chose 2% as the cutoff for PLND because this avoids 47.7% of PLNDs at a cost of missing 12.1% of positive pelvic lymph nodes.76
PLND should be performed using an extended technique.77,78 An extended PLND includes removal of all node-baring tissue from an area bounded by the external iliac vein anteriorly, the pelvic side wall laterally, the bladder wall medially, the floor of the pelvis posteriorly, Cooper’s ligament distally, and the internal iliac artery proximally. Removal of more lymph nodes using the extended technique has been associated with an increased likelihood of finding lymph node metastases, thereby providing more complete staging.79-81 A survival advantage with more extensive lymphadenectomy has been suggested by several studies, possibly due to elimination of microscopic metastases.80,82-84 PLND can be performed safely laparoscopically, robotically, or open, and complication rates should be similar for the three approaches.
RT
EBRT
Over the past several decades, RT techniques have evolved to allow higher doses of radiation to be administered safely. Three-dimensional conformal radiation therapy (3D-CRT) uses computer software to integrate CT images of the patients’ internal anatomy in the treatment position, which allows higher cumulative doses to be delivered with a lower risk of late effects.24,85-87 The second-generation 3D technique, intensity-modulated radiation therapy (IMRT), is used increasingly in practice88 because compared with 3D-CRT it significantly reduces the risk of gastrointestinal toxicities and rates of salvage therapy without increasing side effects, although treatment cost is increased.89-91
Daily prostate localization using image-guided RT is essential with either 3D-CRT or IMRT for target margin reduction and treatment accuracy. Imaging techniques such as ultrasound, implanted fiducials, electromagnetic targeting and tracking, and endorectal balloon, can improve cure rates and decrease complications.
These techniques have permitted safer dose escalation, and results of randomized trials have suggested that dose escalation is associated with improved biochemical outcomes.92-95 Kuban et al95 published an analysis of their dose-escalation trial of 301 patients with stage T1b to T3 prostate cancer. Freedom from biochemical or clinical failure was higher in the group randomized to 78 compared with 70 Gy (78% vs 59%; P=.004) at a median follow-up of 8.7 years. The difference was even greater among patients with diagnostic PSA greater than 10 ng/mL (78% vs 39%; P=.001). In light of these findings, the conventional 70 Gy dose is no longer considered adequate. A dose of 75.6 to 79.2 Gy in conventional fractions to the prostate (with or without seminal vesicles) is appropriate for patients with low-risk cancers. Patients at intermediate and high risk should receive doses up to 81.0 Gy.89,96,97 Moderately hypofractionated image-guided IMRT regimens (2.4-4 Gy per fraction over 4-6 weeks) have been tested in randomized trials, and efficacy and toxicity have been similar to conventionally fractionated IMRT.98,99 These RT techniques can be considered as an alternative to conventionally fractionated regimens when clinically indicated.
EBRT of the primary prostate tumor shows several distinct advantages over radical prostatectomy. RT avoids complications associated with surgery, such as bleeding and transfusion-related effects, and risks associated with anesthesia, such as myocardial infarction and pulmonary embolus. IMRT and 3D-CRT techniques are available widely and are possible for patients at a wide range of ages. EBRT includes a low risk of urinary incontinence and stricture as well as a good chance of short-term preservation of erectile function.100
The disadvantages of EBRT include a treatment course of 8 to 9 weeks. Up to 50% of patients have some temporary bladder or bowel symptoms during treatment. There is a low but definite risk of protracted rectal symptoms from radiation proctitis, and the risk of erectile dysfunction increases over time.100,101 In addition, if the cancer recurs, salvage radical prostatectomy is associated with a higher risk of complications than primary radical prostatectomy.102 Contraindications to RT include prior pelvic irradiation, active inflammatory disease of the rectum, or a permanent indwelling Foley catheter. Relative contraindications include very low bladder capacity, chronic moderate or severe diarrhea, bladder outlet obstruction requiring a suprapubic catheter, and inactive ulcerative colitis.
EBRT for Early Disease: EBRT is one of the principle treatment options for clinically localized prostate cancer. The NCCN Prostate Cancer panel consensus was that modern RT and surgical series show similar progression-free survival in low-risk patients treated with radical prostatectomy or RT. In a study of 3546 patients treated with brachytherapy plus EBRT, disease-free survival remained steady at 73% between 15 and 25 years of follow up.103
EBRT for High-Risk or Very High-Risk Patients: EBRT has shown efficacy in patients at high risk and very high risk. One study randomized 415 patients to EBRT alone or EBRT plus 3-year ADT.104 In another study (RTOG 8531), 977 patients with T3 disease treated with RT were randomized to adjuvant ADT or ADT at relapse.105 Two other randomized phase III trials evaluated long-term ADT with or without radiation in mostly T3 patients.106,107 In all 4 studies, the combination group showed improved disease-specific and overall survival compared with single-modality treatment.
Stereotactic Body Radiotherapy
The relatively slow proliferation rate of prostate cancer is reflected in a low α/β ratio,108 most commonly reported between 1 and 4. These values are similar to that for the rectal mucosa. Since the α/β ratio for prostate cancer is similar to or lower than the surrounding tissues responsible for most of the toxicity reported with RT, appropriately designed radiation treatment fields and schedules using extremely hypo-fractionated regimens should result in similar cancer control rates without an increased risk of late toxicity.
Stereotactic body radiotherapy (SBRT) is an emerging treatment technique that delivers highly conformal, high-dose radiation in 5 or fewer treatment fractions, which are safe to administer only with precise, image-guided delivery.109 Single institution series with median follow-up as long as 6 years report excellent biochemical progression-free survival and similar early toxicity (bladder, rectal, and quality of life) compared with standard radiation techniques.108-114 According to a pooled analysis of phase II trials, the 5-year biochemical relapse-free survival rates are 95%, 84%, and 81% for low-, intermediate-, and high-risk patients, respectively.115 SBRT can be considered cautiously as an alternative to conventionally fractionated regimens at clinics with appropriate technology, physics, and clinical expertise. Longer follow-up and prospective multi-institutional data are required to evaluate longer-term results, especially since late toxicity theoretically could be worse in hypofractionated regimens compared with conventional fractionation (1.8-2.0 Gy per fraction).
Brachytherapy
Brachytherapy is used traditionally for low-risk cases since earlier studies found it less effective than EBRT for high-risk disease.6,116 However, increasing evidence suggests that technical advancements in brachytherapy may provide a role for contemporary brachytherapy in high-risk localized and locally advanced prostate cancer.117 Brachytherapy involves placing radioactive sources into the prostate tissue. There are currently 2 methods for prostate brachytherapy: low dose-rate (LDR) and high dose-rate (HDR).
LDR Brachytherapy: LDR brachytherapy consists of placement of permanent seed implants in the prostate. The short range of the radiation emitted from these low-energy sources allows delivery of adequate dose levels to the cancer within the prostate, whereas excessive irradiation of the bladder and rectum can be avoided. Current brachytherapy techniques attempt to improve the radioactive seed placement and radiation dose distribution.
The advantage of brachytherapy is that the treatment is completed in 1 day with little time lost from normal activities. In appropriate patients, the cancer-control rates appear comparable to radical prostatectomy (over 90%) for low-risk tumors with medium-term follow-up.118 In addition, the risk of incontinence is minimal in patients without a previous transurethral resection of the prostate (TURP), and erectile function is preserved in the short term.101 Disadvantages of brachytherapy include the requirement for general anesthesia and the risk of acute urinary retention. Irritative voiding symptoms may persist for as long as 1 year after implantation. The risk of incontinence is greater after TURP because of acute retention and bladder neck contractures, and many patients develop progressive erectile dysfunction over several years. IMRT causes less acute and late genitourinary toxicity and similar freedom from biochemical failure compared with iodine-125 or palladium-103 permanent seed implants.119,120
Permanent brachytherapy as monotherapy is indicated for patients with low-risk cancers (cT1c-T2a; Gleason grade, 2-6; PSA, <10 ng/mL). For intermediate-risk cancers, brachytherapy may be combined with EBRT (45 Gy) with or without neoadjuvant ADT, but the complication rate increases.121,122 Patients with high-risk cancers are generally considered poor candidates for permanent brachytherapy.
Patients with very large or very small prostates, symptoms of bladder outlet obstruction (high International Prostate Symptom Score), or a previous TURP are not ideal candidates for brachytherapy. These patients have an increased risk of side effects, and implantation may be more difficult with them. Neoadjuvant ADT may be used to shrink the prostate to an acceptable size, however, increased toxicity would be expected from ADT and prostate size may not decline. Postimplant dosimetry should be performed to document the quality of the implant.123 The recommended prescribed doses for monotherapy are 145 Gy for iodine-125 and 125 Gy for palladium-103.
HDR Brachytherapy: HDR brachytherapy, which involves temporary insertion of a radiation source, is a newer approach that provides a “boost” dose in addition to EBRT for patients at high risk of recurrence. Combining EBRT (40-50 Gy) and HDR brachytherapy allows dose escalation while minimizing acute or late toxicity in patients with high-risk localized or locally advanced cancer.124-127 Studies have demonstrated reduced risk of recurrence with the addition of brachytherapy to EBRT.128-130 Analysis of a cohort of 12,745 patients at high risk found that treatment with brachytherapy (hazard ratio [HR], 0.66; 95% CI, 0.49-0.86) or brachytherapy plus EBRT (HR, 0.77; 95% CI, 0.66-0.90) lowered disease-specific mortality compared with EBRT alone.131 Common boost doses include 9.5 to 11.5 Gy times 2 fractions, 5.5 to 7.5 Gy times 3 fractions, or 4.0 to 6.0 Gy times 4 fractions. A commonly used regimen for HDR treatment alone includes 13.5 Gy times 2 fractions.
Addition of ADT (2 or 3 years) to brachytherapy and EBRT is common for patients at high risk of recurrence. The outcome of trimodality treatment is excellent, with 9-year progression-free survival and disease-specific survival reaching 87% and 91%, respectively.132,133 However, it remains unclear whether the ADT component contributes to outcome improvement. D’Amico et al134 studied a cohort of 1342 patients with PSA over 20 ng/mL and clinical T3/T4 and/or Gleason score 8 to 10 disease. Addition of either EBRT or ADT to brachytherapy did not confer an advantage over brachytherapy alone. The use of all 3 modalities reduced prostate cancer-specific mortality compared with brachytherapy alone (adjusted HR, 0.32; 95% CI, 0.14-0.73). Other analyses did not find an improvement in failure rate when ADT was added to brachytherapy and EBRT.135,136
Two groups have observed a lower risk of urinary frequency, urgency, and rectal pain with HDR brachytherapy compared with LDR brachytherapy (permanent seed implant).137,138 Vargas et al139 reported that HDR brachytherapy results in a lower risk of erectile dysfunction than LDR brachytherapy.
Proton Therapy
Proton beams can be used as an alternative radiation source.140 The costs associated with proton beam facility construction and proton beam treatment are high.141 Two comparisons between proton beam therapy and EBRT show similar early toxicity rates.141,142 A single-center report of prospectively collected quality-of-life data 3 months, 12 months, and more than 2 years after treatment revealed significant problems with incontinence, bowel dysfunction, and impotence.142 Perhaps most concerning is that only 28% of men with normal erectile function maintained normal erectile function after therapy.
“Prostate cancer has the most patients treated with conformal proton therapy of any other disease site. The outcome is similar to IMRT therapy, however, with no clear advantage from clinical data for either technique in disease control or prevention of late toxicity. This is a site where further head-to-head clinical trials may be needed to determine the role of proton beam therapy. In addition, careful attention must be paid to the role of dosimetric issues including correction for organ motion in this disease. Based on current data, proton therapy is an option for prostate cancer, but no clear benefit over the existing therapy of IMRT photons has been demonstrated.”143
Other Local Therapies
Cryosurgery, also known as cryotherapy or cryoablation, is an evolving minimally invasive therapy that achieves damage to tumor tissue through local freezing. The reported 5-year biochemical disease-free rate after cryotherapy ranged from 65% to 92% in low-risk patients using different definitions of biochemical failure.144 A report suggests that cryotherapy and radical prostatectomy give similar oncologic results for unilateral prostate cancer.145 A study by Donnelly et al146 randomly assigned 244 men with T2 or T3 disease to either cryotherapy or RT. All patients received neoadjuvant ADT. No difference was seen in 3-year overall or disease-free survival. Patients who received cryotherapy reported poorer sexual function.147 For patients with locally advanced cancer, cryoablation was associated with lower 8-year biochemical progression-free rate compared with EBRT in a small trial of 62 patients, although disease-specific and overall survival were similar.148
Other emerging local therapies, such as high intensity focused ultrasound and vascular-targeted photodynamic therapy, also warrant further study.149
Androgen Deprivation Therapy
ADT for Low-Risk Patients
In the community, ADT has commonly been used as primary therapy for early-stage, low-risk disease, especially in the elderly. This practice was challenged in a study with a large cohort of 19,271 elderly men with T1 or T2 tumors.150 No survival benefit was found in patients receiving ADT compared with observation alone. Placing elderly patients with early prostate cancer on ADT should not be routine practice.
ADT for Intermediate-Risk Patients
The addition of short-term ADT to radiation improved overall and cancer-specific survival in 3 randomized trials including 20% to 60% of men with intermediate-risk prostate cancer (Tran Tasman Radiation Oncology Group [TROG] 9601, Dana Farber Cancer Institute [DFCI] 95096, and Radiation Therapy Oncology Group [RTOG] 9408).151-153 Only a cancer-specific survival benefit was noted in a fourth trial that recruited mostly high-risk men (RTOG 8610).154 The addition of short-course ADT to RT in men with intermediate-risk disease is an option.
ADT for High-Risk or Very High-Risk Patients
As discussed previously, ADT combined with RT is an effective primary treatment for patients at high risk or very high risk. Combination therapy was associated consistently with improved disease-specific and overall survival compared with single-modality treatment in randomized phase III studies.104-107
Increasing evidence favors long-term over short-term neoadjuvant, concurrent, or adjuvant ADT for high-risk patients. The RTOG 9202 trial included 1521 patients with T2c to T4 prostate cancer who received 4 months of ADT before and during RT.155 They were randomized to no further treatment or an additional 2 years of ADT. At 10 years, the long-term group was superior for all endpoints except overall survival. A subgroup analysis of patients with Gleason score 8 to 10 found an advantage in overall survival for long-term ADT (32% vs 45%; P=.0061). The EORTC 22961 trial also showed superior survival when 2.5 years of ADT were added to RT given with 6 months of ADT in 970 patients, most of whom had T2c to T3, N0 disease.156 In a secondary analysis of RTOG 8531 that mandated lifelong ADT, those who adhered to the protocol had better survival than those who discontinued ADT within 5 years.157
Adjuvant ADT after Radical Prostatectomy
Neoadjuvant or adjuvant ADT generally confers no added benefit in men who have undergone radical prostatectomy.158 The role of adjuvant ADT after radical prostatectomy is restricted to cases in which positive pelvic lymph nodes are found, although reports in this area reveal mixed findings. Messing et al159 randomly assigned patients to immediate ADT or observation who were found to have positive lymph nodes at the time of radical prostatectomy. At a median follow-up of 11.9 years, those receiving immediate ADT had a significant improvement in overall survival (HR, 1.84; 95% CI, 1.01-3.35). However, a meta-analysis resulted in a recommendation against ADT for pathologic lymph node metastatic prostate cancer in the ASCO guidelines.160 A cohort analysis of 731 men with positive nodes failed to demonstrate a survival benefit of ADT initiated within 4 months of radical prostatectomy compared with observation.161
Anti-androgen monotherapy (bicalutamide) after completion of primary treatment was investigated as an adjuvant therapy in patients with localized or locally advanced prostate cancer, but results did not support its use in this setting.162,163
NCCN Recommendations
Initial Clinical Assessment and Staging Evaluation
For patients with a life expectancy of 5 years or less and without clinical symptoms, further workup or treatment should be delayed until symptoms develop. If high-risk factors (bulky T3-T4 cancers or Gleason score 8-10) for developing hydronephrosis or metastases within 5 years are present, ADT or RT may be considered. Patients with advanced cancer may be candidates for observation if the risks and complications of therapy are judged to be greater than the benefit in terms of prolonged life or improved quality of life.
For symptomatic patients or those with a life expectancy of more than 5 years, a bone scan is appropriate for patients with any of the following: 1) T1 disease with PSA over 20 ng/mL or T2 disease with PSA over 10 ng/mL;164 2) a Gleason score of 8 or higher; 3) T3 to T4 tumors; or 4) symptomatic disease. Pelvic CT or MRI scanning is recommended in T3 or T4 disease, or if T1 or T2 disease and a nomogram indicate that a greater than 10% chance of lymph node involvement, although staging studies may not be cost effective until the chance of lymph node positivity reaches 45%.165 Biopsy should be considered for further evaluation of suspicious nodal findings. For all other patients, no additional imaging is required for staging. NCCN panelists voiced concern about inappropriate use of PET imaging in the community setting. FDG or fluoride PET is not recommended for initial assessment.
The staging workup is used to categorize patients according to their risk of recurrence or disease progression or recurrence into those with clinically localized disease at very low, low, intermediate, or high risk, or those with locally advanced disease at very high risk, or those with metastatic disease.
Very Low Risk
Men with all of the following tumor characteristics are categorized in the very low-risk group: clinical stage T1c, biopsy Gleason score 6 or lower, PSA lower than 10 ng/mL, presence of disease in fewer than 3 biopsy cores, 50% or less prostate cancer involvement in any core, and PSA density less than 0.15 ng/mL/g. Given the potential side effects of definitive therapy, men in this group who have an estimated life expectancy less than 10 years should undergo observation. Unlike active surveillance, observation schedules do not involve biopsies. Men with very low risk and a life expectancy of 10 to 20 years should undergo active surveillance. For patients who meet the very low-risk criteria but who have a life expectancy of 20 years or above, the NCCN Panel agreed that active surveillance, RT or brachytherapy, or radical prostatectomy are all viable options.
Low Risk
The NCCN Guidelines define the low-risk group as patients with tumors stage T1 to T2a, low Gleason score (≤6), and serum PSA level below 10 ng/mL. Observation is recommended for men with low-risk prostate cancer and life expectancy less than 10 years. If the patient’s life expectancy is 10 years or more, initial treatment options include 1) active surveillance; 2) RT or brachytherapy; or 3) radical prostatectomy with or without a PLND if the predicted probability of pelvic lymph node involvement is 2% or greater. ADT as a primary treatment for localized prostate cancer does not improve survival and is not recommended by the NCCN panel.
At this time, cryotherapy or other local therapies are not recommended as routine primary therapy for localized prostate cancer due to lack of long-term data comparing these treatments to radiation or radical prostatectomy.
Intermediate Risk
The NCCN Guidelines define the intermediate-risk group as patients with any T2b to T2c cancer, Gleason score of 7, or PSA value of 10 to 20 ng/mL. Patients with multiple adverse factors may be shifted into the high-risk category.
Options for patients with life expectancy less than 10 years include 1) observation; 2) RT with or without ADT (4 to 6 months), and with or without brachytherapy; or 3) brachytherapy alone. Initial treatment options for patients with an expected survival of 10 years or more include 1) radical prostatectomy, including a PLND if the predicted probability of lymph node metastasis is 2% or greater; 2) RT with or without 4 to 6 months of ADT and with or without brachytherapy; or 3) brachytherapy alone for patients with favorable factors (cT1c, Gleason score 7, low volume). Active surveillance is not recommended for patients with a life expectancy more than 10 years (category 1).
High Risk
Men with prostate cancer that is clinically localized stage T3a, Gleason score 8 to 10, or PSA level greater than 20 ng/mL are categorized by the NCCN Guidelines panel as high risk. Patients with multiple adverse factors may be shifted into the very high-risk category. The preferred treatment is RT in conjunction with 2 to 3 years of ADT (category 1); ADT alone is insufficient. In particular, patients with low-volume, high-grade tumor warrant aggressive local radiation combined with typically 2 or 3 years of ADT. The combination of EBRT and brachytherapy, with or without ADT (typically 2 or 3 years), is another primary treatment option. However, the optimal duration of ADT in this setting remains unclear.
Radical prostatectomy with PLND remains an option as a subset of men in the high-risk group may benefit from surgery.
Very High Risk
Patients at very high risk are defined by the NCCN Guidelines as those with clinical stage T3b to T4 (locally advanced). The options for this group include 1) RT and long-term ADT (category 1); 2) EBRT plus brachytherapy with or without long-term ADT; 3) radical prostatectomy plus PLND in selected patients with no fixation to adjacent organs; or 4) ADT for patients not eligible for definitive therapy.
Disease Monitoring
For patients who choose active surveillance, an appropriate active surveillance schedule includes a PSA determination no more often than every 6 months unless clinically indicated, a DRE no more often than every 12 months unless clinically indicated, and repeat prostate biopsy no more often than every 12 months unless clinically indicated. A repeat prostate biopsy within 6 months of diagnosis is indicated if the initial biopsy was less than 10 cores or if assessment results show discordance.
Reliable parameters of prostate cancer progression await the results of ongoing clinical trials. A change in prostate exam results or increase in PSA level may prompt consideration of a repeat biopsy at the discretion of the physician. A repeat biopsy can be considered as often as annually to assess for disease progression. Repeat biopsies are not indicated when life expectancy is less than 10 years or when men are on observation. Multiparametric MRI may be considered to exclude the presence of anterior cancer if the PSA level rises and systematic prostate biopsy remains negative.166 However, multiparametric MRI is not recommended for routine use. PSA doubling time is not considered reliable enough to be used alone to detect disease progression.167
If the repeat biopsy shows Gleason 4 or 5 disease or if tumor is found in a greater number of cores or in a higher percentage of a given core, cancer progression may have occurred.
For patients initially treated with intent to cure, a serum PSA level should be measured every 6 to12 months for the first 5 years and then annually. PSA testing every 3 months may be required for men at high risk of recurrence. When prostate cancer recurred after radical prostatectomy, Pound et al168 found that 45% of patients experienced recurrence within the first 2 years, 77% within the first 5 years, and 96% by 10 years. Because local recurrence may result in substantial morbidity and can, in rare cases, occur in the absence of a PSA elevation, an annual DRE also is appropriate to monitor for prostate cancer recurrence as well as to detect colorectal cancer. Similarly, after RT, the monitoring of serum PSA levels is recommended every 6 months for the first 5 years and then annually and a DRE is recommended annually. The clinician may opt to omit the DRE if PSA levels remain undetectable.
The intensity of clinical monitoring for patients presenting with nodal positive or metastatic disease is determined by the response to initial ADT, radiotherapy, or both. Follow-up evaluation of these patients should include a history and physical examination, DRE, and PSA determination every 3 to 6 months based on clinical judgment.
Patients being treated with either medical or surgical ADT are at risk for having or developing osteoporosis. A baseline bone mineral density study should be considered for these patients. Supplementation is recommended using calcium (500 mg) and vitamin D (400 IU). Men who are osteopenic or osteoporotic should be considered for bisphosphonate therapy.
Patients under observation should be monitored for symptom development at 6 to 12 month intervals. PSA, renal function, and red cell mass may be assessed.
Adjuvant Therapy after Radical Prostatectomy
Most patients who have undergone a radical prostatectomy are cured of prostate cancer. However, some men will experience pathologic or biochemical failure. Selecting men appropriately for adjuvant or salvage radiation is difficult. However, recently published trials provide high-level evidence that can be used to counsel patients more appropriately. Thompson et al169 reported the results of the SWOG 8794 trial enrolling 425 men with extraprostatic cancer treated with radical prostatectomy. Patients were randomized to receive either adjuvant RT or usual care, and follow-up has reached a median of 12.6 years. The initial study report revealed that adjuvant RT reduced the risk of PSA relapse and disease recurrence.170 An update reported improved 10-year biochemical failure-free survival for high-risk patients (seminal vesicle positive) receiving postprostatectomy adjuvant radiation compared with observation (36% vs 12%; P=.001).171
Another randomized trial conducted by the EORTC172 compared postprostatectomy observation and adjuvant RT in 1005 patients. All patients had extraprostatic extension or positive surgical margins. The 5-year biochemical progression-free survival significantly improved with RT compared with observation for patients with positive surgical margins (78% vs 49%), but benefit was not seen for patients with negative surgical margins.
A German study by Wiegel et al173 reported results for 268 patients. All participants had pT3 disease and undetectable PSA levels after radical prostatectomy. Postoperative radiation improved 5-year biochemical progression-free survival compared with observation alone (72% vs 54%; HR, 0.53; 95% CI, 0.37-0.79). Collectively, these trial results suggest that continued follow-up of these series of patients may show a survival advantage.
Although observation after radical prostatectomy is appropriate, adjuvant RT after recuperation from surgery (usually within 1 year) is likely beneficial in men with shorter PSA doubling times (<9 months) or adverse laboratory or pathologic features, which include positive surgical margin, seminal vesicle invasion, and extracapsular extension. Positive surgical margins are unfavorable especially if diffuse (>10 mm margin involvement or ≥3 sites of positivity) or associated with persistent serum levels of PSA. The defined target volumes include the prostate bed. The pelvic lymph nodes may be irradiated, but pelvic radiation is not necessary.
Several management options should be considered if positive lymph nodes are found during or after radical prostatectomy. ADT is a category 1 option. Another option is observation, which is a category 2A recommendation for very low-risk or low-risk patients but category 2B for patients at intermediate, high, or very high risk. A third option is addition of pelvic RT to ADT (category 2B). This is based on retrospective data demonstrating improved biochemical recurrence-free survival and cancer-specific survival with postprostatectomy RT and ADT compared with adjuvant ADT alone in 250 patients with lymph node metastases.174
Individual Disclosures for the NCCN Prostate Cancer Panel
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