Prostate Cancer

Treatment

There are several treatment options for localized prostate cancer, including radical prostatectomy, EBRT, brachytherapy (interstitial radiation/seeds), and cryotherapy. Multiple treatment series with each modality have documented the validity of the risk-stratification model based on clinical palpation stage, Gleason score, and serum PSA level. More recently, it has been suggested that biopsy quantification may also be an important factor. Specifically, counting the number of involved needle biopsy cores or the percentage of each core involved by cancer may be prognostic. Low-risk patients experience a favorable 85% to 90% freedom from recurrence, compared with approximately 75% and 35% to 50% for the intermediate- and high-risk patients, respectively. Although very few randomized studies have been performed, contemporary series, which stratify patients by the risk model, demonstrate remarkably similar outcomes independent of the treatment modality. For this reason, treatment recommendations should be individualized based on patient preference, life expectancy, and discussion of potential toxicities.

Sidebar: The multidisciplinary approach is becoming increasingly encouraged but little is known about the multidisciplinary experience compared with routine care. A study by Stewart et al compared utilization determinants between a multidisciplinary vs a urology prostate cancer clinic at Duke University Medical Center and identified factors associated with pursuing treatment at the university medical center for multidisciplinary clinic patients. The authors retrospectively analyzed data on patients referred for primary prostate cancer treatment evaluation at Duke University Medical Center from 2005 to 2009. Comparisons between 701 multidisciplinary clinic patients and 1,318 urology prostate cancer clinic patients were examined. Compared with patients at the urology prostate cancer clinic, those at the multidisciplinary clinic were more likely to be younger and white, have a higher income and travel a longer distance for evaluation. Of multidisciplinary clinic patients, 58% pursued primary treatment at the university medical center. They were more likely to be younger, black and physician referred, have a lower income and reside closer to the medical center. Factors predictive of pursuing treatment at the medical center included high-risk disease and physician referral. Factors predictive of not receiving care at the university medical center were income greater than $40,000 and a distance traveled of greater than 100 miles. A different patient demographic is using the multidisciplinary approach. However, when treatment is pursued at the institution providing multidisciplinary services, the patient demographic resembles that of the treating institution (Stewart SB et al: J Urol 187:103-108, 2012).

Clinically Localized Disease: T1, T2

Active surveillance

Active surveillance in very low–risk to low-risk patients who have a limited life expectancy (< 10 to 15 years) also is emerging as an important initial treatment modality. Ongoing studies (Cancer and Leukemia Group B [CALGB]/National Cancer Institute of Canada [NCIC] START study) are examining the necessity of immediate vs deferred active definitive therapy. At this time, hHowever, the majority of men in the United States receive initial radical surgery or radiation as treatment of localized prostate cancer.

This is fast becoming an initial treatment selection of low and very low–risk men (Gleason score of 6 or less, low volume disease, PSA level < 10, ng/mL T1c disease). Most studies have suggested a less than 5% to 10% prostate cancer–specific mortality rate for men in this category who choose initial deferred therapy, particularly those with slow PSA doubling times (> 3 years). In these men, non-prostate cancer–specific mortality far outweighs prostate cancer–specific mortality, illustrating the need to assess age, comorbidities, and life expectancy in the initial treatment decisions of a man with prostate cancer. Approximately 25% to 30% of men will progress during this period and require definitive therapy, and this time, it is not known whether deferred active therapy results in inferior outcomes for these men compared with immediate therapy. Because level 1 multicenter prospective studies of active surveillance are lacking, there is still quite a bit of uncertainty in a defined protocol on follow-up of men on active surveillance. Recent studies have suggested that following PSA alone is inaccurate for assessing progression, and periodic repeat prostate biopsies are needed. The exact interval for repeat biopsy; however, remains uncertain. Younger and otherwise healthy men may warrant repeat biopsy as often as annually, while older and unhealthy men may never warrant rebiopsy. The biopsy pathologic criteria for progression are still somewhat uncertain as well. Patients who have clear-cut Gleason grade progression are relatively easy to define as having "failed" active surveillance, but sometimes more subtle changes on repeat biopsy are difficult to reconcile as constituting progression on active surveillance, or stability.

Radical prostatectomy

Radical prostatectomy can be performed retropubically through a lower midline incision—an approach that may include pelvic lymph node dissection. Robotic-assisted laparoscopic prostatectomy (RALP) is now the most popular form of radical prostatectomy in the United States. Radical perineal prostatectomy is uncommon but remains a viable option.

Sidebar: The effectiveness of surgery vs observation for men with localized prostate cancer detected by prostate-specific antigen (PSA) remains controversial. Investigators from the Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group recently reported on radical prostatectomy versus observation for localized prostate cancer. From November 1994 through January 2002, a total of 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng/mL) were randomized to radical prostatectomy or observation and followed through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. During the median follow-up of 10 years, 171 of 364 men (47%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio [HR] = 0.88; 95% CI, 0.71–1.08; P = .22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (HR = 0.63; 95% CI, 0.36–1.09; P = .09; absolute risk reduction, 2.6 percentage points). Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng/mL (P = .04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P = .07 for interaction). Critics of the study cite limitations including short follow-up and the fact that most patients were enrolled from VA (US Department of Veterans Affairs) health care centers, which may not reflect characteristics of patients in other health settings (Wilt TJ et al: N Engl J Med 367:203-213, 2012).

Sidebar: A 2011 study by Scandinavian Prostate Cancer Group Study 4 (SPCG-4) investigators reported on radical prostatectomy vs watchful waiting in early prostate cancer. In 2008, this group reported that radical prostatectomy, as compared with watchful waiting, reduced the rate of death from prostate cancer. After an additional 3 years of follow-up, they now reported estimated 15-year results. From October 1989 through February 1999, a total of 695 men with early prostate cancer were randomized to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009. During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P = .007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (95% CI = 0.44–0.87; P = .01). The number needed to treat to avert 1 death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was seven times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI = 2.6–18.4). These results showed a continuing benefit with radical prostatectomy after 9 years of follow-up (Bill-Axelson A et al: N Engl J Med 364:1708-1717, 2011).

Although the morbidity of radical prostatectomy was a major concern in the past, improvements were made during the 1980s. Among the various treatment options for prostate cancer, only radical prostatectomy has been demonstrated to confer a survival advantage over no treatment. The hazards of anesthesia, risk of blood loss, and hospital stay have all been minimized. Nationwide, Medicare data suggest that surgical outcomes are significantly better at those centers performing > 40 prostatectomies per year than at other hospitals with a lower surgical volume.

Transfusion is usually unnecessary, and treatment-related mortality is < 0.05% at leading prostate cancer centers. The average hospital stay of a man undergoing radical prostatectomy is now approximately 1 to 2 days at leading referral centers in the United States; several institutions routinely discharge patients within 24 hours. Although urinary incontinence is common in the first few months after prostatectomy, most men recover urinary control; at some leading centers, 90% to 98% of men report few or no long-term urinary problems.

Nerve-sparing radical prostatectomy. Nerve-sparing radical prostatectomy is appropriate for men with small-volume disease. It offers men with good potency prior to surgery the probability of recovering that function following the operation. By permitting better visualization of Santorini's dorsal venous plexus, the apical prostate, the urethra, and the striated urethral sphincter, the nerve-sparing technique also reduces blood loss and improves recovery of urinary continence. In appropriately selected individuals, a nerve-sparing procedure confers no greater risk of prostate cancer recurrence after considering other relevant clinical information (PSA level, Gleason score, margin status, seminal vesicle involvement, and the presence of extraprostatic spread).

Referral centers have reported that 50% to 90% of patients who are fully potent prior to surgery recover erections following a nerve-sparing procedure, but the quality (rigidity and duration) of these recovered erections may be compromised compared with preoperative erections. Erection recovery rates can be higher than 80% in patients < 60 years of age and lower in older men. Potency may return anywhere from 2 to 24 months following surgery. Regardless of potency, sensation of the penis is not changed after this procedure, and men still experience orgasm. Nerve-sparing radical prostatectomy has not compromised cancer control outcomes in well-selected men with early-stage disease. Also, recent studies have suggested that early postoperative use of sildenafil(Drug information on sildenafil) (Viagra), tadalafil(Drug information on tadalafil) (Cialis), vacuum entrapment device (VED), and/or intracavernosal injection (ICI) of vasoactive medications, such as papaverine, may facilitate the return of natural erections more quickly. Generally speaking, recovery of erectile function after radical prostatectomy is mediated by age (the younger, the better), pretreatment erectile function (the stronger, the better), and a nerve-sparing approach (bilateral is better than unilateral, which is better than none [which is better than wide dissection]).

Robotic radical prostatectomy

Laparoscopic prostatectomy was initially described by Schuessler in 1997 but was abandoned because of its technical difficulty and long operative time with little apparent benefit over the conventional technique. A resurgence in the technique was prompted by improved instrumentation and refinements in the procedure itself, although the laparoscopically naive urologist must endure a substantial learning curve (with attendant perioperative morbidity) prior to meeting the outcome standards set by the open technique.

Robot-assisted laparoscopic prostatectomy (RALP) was developed to overcome some of the difficulties of the standard laparoscopic prostatectomy (eg, intracorporeal suturing). The robotic technique allows for three-dimensional (3D) visualization of the operative field and provides for a significantly wider range of movements intracorporeally than do standard laparoscopic instruments. This advance has prompted the assimilation of the technique into the armamentarium of many urologists.

Current evidence suggests that in experienced hands, the laparoscopic and robotic techniques have oncologic efficacy similar to that of the open procedure. However, the length of follow-up (usually < 24 months) in these studies is limited, suggesting that a measure of caution be taken when interpreting the results. Furthermore, recent studies suggest the learning curve is prolonged, with 200 to 250 cases necessary before results can be compared with those of experienced surgeons. Long-term effects of these modalities on sexual and urinary health (as measured by a psychometrically valid survey) have not been reported, and such data are critical in the context of the prostatectomy patient when evaluating technical results. Although vision with robotic prostatectomy is excellent, the current-generation robotic device does not allow tactile sensation for the operating surgeon. Furthermore, the vast majority of robotic prostatectomies are performed via a transabdominal approach, whereas the open retropubic approach avoids the peritoneal cavity. A 2010 systematic review by Murphy et al showed the learning curve to be steep, and few published reports have reported outcomes in a standardized manner. The cost of the technology is substantial and little is known of the cost-effectiveness compared with the open technique.

Pelvic lymph node dissection. Studies now indicate that regional pelvic lymph node dissection may not be necessary for patients with stage T1c disease if the total Gleason score is < 7 and the PSA level is < 10 ng/mL, that is, low-risk individuals. Selected intermediate-risk men may also not require this staging procedure, but in high-risk men, it is still considered imperative. In addition, for high-risk and very high–risk men, there is growing use of extended pelvic lymphadenectomy which includes more nodal regions that the standard obterator fossa.

Neoadjuvant hormonal therapy

Approximately 15% to 35% of men who undergo radical prostatectomy for clinical stage T2 prostate cancer will be found to have pathologic T3 disease following surgery. This finding led some investigators to evaluate the efficacy of neoadjuvant androgen deprivation therapy in prospective clinical trials. Early data from these trials suggested that neoadjuvant hormonal therapy led to a reduction in positive surgical margins. However, these findings need to be considered in a technical context: Androgen deprivation therapy causes artifactual changes in prostate morphology that cause difficulties for the pathologic identification of prostate cancer foci.

Indeed, more recent data from prospective studies have shown no benefit of neoadjuvant therapy with regard to progression-free survival. At present, therefore, it appears that neoadjuvant hormonal therapy does not improve the curative potential of radical prostatectomy but instead is associated with morphologic alterations that complicate the prognostic utility of standard pathology. Neoadjuvant hormonal therapy is sometimes used for technical downsizing to facilitate surgical resectability. However, it is not routinely recommended to improve cancer control. With the approval of more effective hormonal agents, such as enzalutamide, the role of neoadjuvant hormonal therapy prior to surgery may be revisited.

Adjuvant therapy post prostatectomy

The potential indications for adjuvant therapy following radical prostatectomy in patients with clinical T1 or T2 malignancy include pathologic evidence of T3 disease, positive nodes, a rising PSA level, and positive surgical margins, among others.

Radiation therapy. Men with positive margins or pathologic T3 disease following radical prostatectomy are potential candidates for early adjuvant EBRT. Some controversy exists as to the efficacy of early postoperative therapy vs intervention once a biochemical failure has been documented in patients who achieve an undetectable PSA level following surgery.

Three randomized trials have been completed demonstrating a benefit to early adjuvant radiation therapy for men with positive margins, seminal vesicle invasion, or extracapsular extension. Typically, this treatment is offered after continence is restored, to allow healing to take place after surgery. With a median follow-up of 12 years, the most mature study (Southwest Oncology Group [SWOG] 8794), by Thompson et al, confirmed a significant improvement in the risk of metastasis (43% vs 54%) and overall survival (41% vs 52%) among patients randomized to adjuvant radiation. The largest trial, by Bolla et al, included 1,000 patients with T3 disease randomly assigned to 60 Gy of radiation vs observation. At 5 years, progression-free survival was significantly improved (74% vs 53%), with no demonstration of an overall survival benefit. A subsequent update suggested that the benefit might be limited to patients with positive surgical margins. A German trial of 395 patients also demonstrated a biochemical progression-free survival benefit (72% vs 54%) to early radiation therapy in this pT3 group. The benefit of therapy was observed with or without positive margins (Wiegel et al, J Clin Oncol 2009).

An alternate approach to early adjuvant radiation therapy is salvage radiation therapy for PSA recurrence. It remains unclear whether early salvage radiation based on PSA thresholds is inferior to the adjuvant approach, but it has the benefit of not treating all men with T3 disease with radiation. Of note, in the SWOG trial approximately one-third of patients initially assigned to observation ultimately received salvage radiation largely for PSA recurrence. In a retrospective analysis, there was a 5-year bNED (biochemical no evidence of disease, or undetectable PSA levels) advantage (77% vs 38%) to early vs salvage therapy. Based on this emerging evidence and a relatively low toxicity to radiation, the use of early adjuvant radiation in this high-risk group should be considered.

The use of salvage radiation after a PSA recurrence in the other patient groups should be based on the risk of having an isolated local/regional failure. Approximately 60% to 70% of patients with favorable disease after surgical failure (PSA level < 2 ng/mL, a slow PSA doubling time, and a long interval to failure after surgery) will experience durable disease-free survival after salvage radiotherapy, presumably due to a smaller tumor burden and a lower likelihood of occult metastatic disease.

Stephenson et al evaluated a large number of patients with salvage EBRT and persistent or increasing PSA levels after surgery from five American academic institutions. Forty-five percent of patients were free of disease at 4 years after salvage EBRT. Patients with no adverse risk features achieved a 4-year progression-free probability of 77%. The authors subsequently developed a nomogram based on established risk factors to more accurately identify patient-specific risks to assist in clinical decision-making. Patients who experience PSA failure after radical prostatectomy generally should be restaged with pelvic CT, bone scan, and DRE. Patients with no evidence of metastatic disease should be evaluated for radiotherapy.

Hormonal therapy. Significant controversy exists within the academic community as to the timing of initiating androgen deprivation following radical prostatectomy. Clinical trials have documented a survival benefit only for patients with nodal involvement.

Treatment recommendations for postprostatectomy recurrence

Following radical prostatectomy, it is expected that serial PSA levels will become undetectable. Any detectable PSA level (> 0.2 ng/mL) following surgery indicates possible recurrent disease and the need for restaging and possible salvage therapies, including radiation or hormonal therapy, experimental protocols, or observation. However, some patients can develop low levels of detectable PSA after prostatectomy without cancer recurrence, presumably due to small foci of benign prostate tissue in situ. Although there is concern about recurrence when the PSA level is > 0.2 ng/mL, most clinicians will wait until a PSA threshold > 0.4 ng/mL is reached to assume that the rise in PSA level represents meaningful recurrence.

Recent findings have suggested that tumor grade, time to PSA recurrence after surgery, and PSA doubling time predict the 5-, 10-, and 15-year risks of prostate cancer mortality and can help to guide the timing of and need for androgen ablation. Although these findings do not prove that early androgen ablation is more beneficial than delayed androgen ablation based on a PSA threshold or development of metastatic disease, it does help to risk-stratify patients into those most likely to derive benefit from androgen ablation early. Moreover, men with a PSA doubling time of less than 15 months may be more likely to die of prostate cancer than of other competing causes, suggesting that these men should be evaluated in controlled trials of hormonal or novel therapeutic agents.

Definitive radiation therapy

EBRT. EBRT utilizes high-energy photons to destroy cancer cells by damaging cellular DNA. Traditional EBRT utilized bony landmarks and standard-beam arrangements to deliver dose to the pelvic region. Technologic advances in treatment planning, driven by improved computing power and the incorporation of individualized patient anatomy, have led to dramatic improvements in treatment delivery.

3D conformal EBRT. 3D conformal EBRT creates 3D representations of target structures (ie, the prostate) and designs highly tailored treatment portals utilizing various angles to create a volume of high radiation dose that conforms to the target shape. The anatomic information used to define the target is generally derived from CT images obtained while the patient is placed in an immobilization device in the precise treatment position. With the selective delivery of dose to the target and avoidance of the surrounding normal tissue, the therapeutic ratio is improved. This approach has permitted the use of doses far higher than are tolerable with traditional therapy, with fewer bowel and bladder complications.

Treatment volumes in patients with low-risk disease are designed to encompass the prostate plus a margin for daily variations. Patients with a high risk for periprostatic extension and/or regional lymph node metastasis have historically received initial pelvic treatment of 45 to 50 Gy, followed by a coned-down boost to the prostate.

Radiation Therapy Oncology Group (RTOG) 9413 was designed to test the addition of whole pelvic radiation and the timing of androgen deprivation in the treatment of high-risk patients (lymph node-positive potential > 15% or locally advanced [Gleason score ≥ 6 and > stage cT2c disease] cancers). At a median follow-up of 59.5 months, Roach et al (reporting in J Clin Oncol, 2003) noted an improved 4-year progression-free survival (60%) among those receiving whole pelvic radiotherapy in conjunction with neoadjuvant androgen deprivation, compared with other treatment arms (44% to 50%). In a subsequent update, the value of whole pelvic fields was limited to only patients receiving hormonal therapy, and the benefit became nonsignificant with a trend toward improved outcomes. Furthermore, a European randomized trial (GETUG-01) did not show a benefit to larger pelvic fields. Therefore, at this time, there is no consensus as to the use of whole pelvic or more limited prostate-only fields in the intermediate-/high-risk patient groups.

EBRT dose. The previous standard radiation dose with conventional therapy was 70 Gy given over 7 weeks; however, more recent work has suggested a positive dose response, particularly in the intermediate- and high-risk patient populations. Multiple single-institution experiences have demonstrated that 3D conformal EBRT techniques with doses of 75 Gy and higher can be delivered with minimal toxicities.

A randomized trial from the MD Anderson Cancer Center compared 70 Gy given conventionally vs 78 Gy delivered with a conformal boost. With a median follow-up of 8.7 years, it showed an advantage in freedom from failure for the higher-dose arm in patients with a PSA level > 10 ng/mL (78% vs 39%). Kupelian et al (in Int J Radiat Oncol Physiol, 2005) presented pooled data for nearly 5,000 patients from 9 institutions over a narrow time range (1994-1995) to remove treatment technique, stage migration, and lead-time bias. They demonstrated favorable biochemical control outcomes for doses higher than 72 Gy in all risk groups.

The RTOG has completed a dose-escalation trial to assess toxicity with 3D conformal EBRT. In this multi-institutional trial, 78 Gy (prescribed as a minimum to the tumor volume in 2-Gy fractions) was well tolerated, with only 3% of patients experiencing significant (grade 3+) acute gastrointestinal/genitourinary morbidity and a 6% rate of significant late toxicity. A comparison trial is being conducted by the RTOG (P0126); it will accrue 1,520 cases and provide information regarding any beneficial effect on mortality with higher radiation doses. Although no standard ≥ 75 Gy with 3D conformal EBRT techniques appear to be well tolerated and improve biochemical response rates.

Intensity-modulated radiation therapy (IMRT). Intensity-modulated radiation therapy (IMRT) is becoming a widely used treatment for prostate cancer. This refinement of conformal therapy employs high nonuniform beam intensity profiles and dynamic multileaf collimation to create even more conformal dose distributions. Further improving the therapeutic index compared with 3D conformal EBRT, IMRT is associated with reduced toxicity, permitting further dose escalations previously unattainable.

IMRT was pioneered in several major centers, and Zelefsky et al from Memorial Sloan-Kettering Cancer Center reported a series of 772 patients treated with doses between 81 and 86.4 Gy (Int J Radiat Oncol Biol Phys, 2002). With a median follow-up of 24 months, the side-effect profile was improved, despite these higher doses, with less than 1% of patients experiencing late grade 3+ gastrointestinal/genitourinary toxicity. The early PSA relapse-free survival rates for favorable-intermediate-and unfavorable-risk groups were 92%, 86%, and 81%, respectively. Although IMRT is quickly becoming the standard of care at most institutions, some caution should be exercised. The precision of dose delivery and the complexity of treatment planning demand a strong commitment by both physicians and physics personnel to ensure high-quality IMRT.

Proton therapy. Technically a form of EBRT, proton therapy has been utilized in clinical practice for more than 10 years. It offers a potential advantage over photon-based IMRT by exploiting superior dose distributions of the Bragg peak effect. The routine implementation of this technology has been hampered by the staggering costs of building and maintaining a facility. The largest experience, involving 1,277 patients at the Loma Linda proton facility, was reported in 2004 and demonstrated "comparable control rates with minimal toxicity" compared with other local therapies. Although there are theoretical benefits and ongoing trials evaluating the possibility of further safe dose escalation with protons, to date there is little clinical evidence to support a significant benefit over IMRT. With several new centers now under construction or online, and a published economic evaluation questioning its cost-effectiveness, the future of eventual widespread application of proton therapy remains unclear.

Stereotactic body radiotherapy (SBRT). Stereotactic body radiotherapy (SBRT) is being investigated as a method to treat early-stage prostate cancers. Utilizing several highly focused fractions, this method exploits the alpha/beta ratio typical of slowly growing malignancies. The technique, which employs high-dose radiotherapy (approximately 700 cGy) for several fractions (typically 5), can be delivered by several specialized methods, including linear accelerator-based models, tomotherapy, and CyberKnife. A pooled cohort of 41 patients with a median follow-up of 5 years demonstrated both the efficacy and safety of this approach utilizing the CyberKnife. This methodology represents a major paradigmatic shift over the typical 8-week course of IMRT. This approach is gaining favor with patients intrigued by the convenience of a short course of therapy. It is important to recognize that while results from several ongoing studies appear promising, further data maturation in a large patient population will likely be necessary to promote this as a standard technique. Additionally, several investigators are employing a hybrid of these approaches with hypofractionated (higher dose/fraction) IMRT to reduce treatment times by approximately 2 weeks. The extent to which the inverse relationhship of smaller treatment fields to higher doses per fraction can be delivered with comparative morbidity to conventional therapy requires further study.

Androgen ablation with EBRT. Two potential benefits of the use of transient androgen ablation prior to EBRT have been identified. First, there may be some synergy between the apoptotic response induced by androgen deprivation and radiotherapy that may increase local tumor control.

Second, androgen deprivation results in an average 20% decrease in prostate volume. This volume reduction not only may reduce the number of target cells, and thereby improve tumor control, but also may shrink the prostate and, thus, diminish the volume of rectum and bladder irradiated during conformal therapy. Complete androgen blockade can be achieved with luteinizing hormone-releasing hormone (LHRH) agonists plus an oral antiandrogen or LHRH antagonist therapy.

The survival benefits of androgen suppression therapy (AST) for patients with intermediate-risk disease have been uncertain. A single-institution prospective trial by D'Amico et al randomized patients with a PSA level > 10 ng/mL, a Gleason score ≥ 7, or radiographic evidence of extraprostatic disease to receive EBRT (70 Gy) alone or the same EBRT with 6 months of AST. After a median follow-up of 4.5 years, patients treated with combined EBRT and AST were found to have improved progression-free, prostate cancer–specific, and overall survival (P = .04). Although hormone therapy for 3 years has been shown to be beneficial in locally advanced cases, this trial in men with more localized disease showed a benefit to a shorter duration of hormone therapy. However, it is not known whether high-dose radiotherapy will obviate the need for AST in this group of patients. The survival benefit in this study was largely confined to men with few cardiovascular comorbidities, illustrating the importance of patient selection for AST.

Recent secondary findings from a large randomized study (RTOG 9202) suggest that men with high-grade tumors (Gleason score 8-10) and high-risk (T2c-T4) localized disease benefit from long-term androgen ablation (2 years) compared with short-term androgen ablation (4 months), based on improved prostate cancer–specific and overall survival. A caveat to these findings has been the increased incidence or acceleration of incident cardiovascular death in men older than 65 years of age starting androgen ablation compared with men who did not receive androgen ablation. These findings suggest that cardiac evaluation should be considered in men older than age 65 with cardiovascular risk factors prior to undergoing androgen ablation. RTOG 94-08 was presented at the American Society for Therapeutic Radiology and Oncology (ASTRO) meeting in April 2010. This study examined a short course (4 months) of androgen deprivation (flutamide plus either goserelin(Drug information on goserelin) [Zoladex] or leuprolide [Lupron]) with EBRT (66.6 or 68.4 Gy) in 1,979 men. For intermediate-risk men, the 8-year survival rate was 66% in men who received radiation therapy alone and 72% in men who also received hormones. There was no benefit observed to hormonal therapy in low-risk men.

Interstitial radiotherapy. In the 1970s, the use of permanently placed radioactive iodine(Drug information on iodine) implants produced initial results as good as those obtained with other available radiotherapy techniques and posed a small risk of impotence and other morbidity when compared with conventional EBRT and radical prostatectomy. However, ultimate control rates were unacceptable. The technique used (freehand placement of seeds during laparotomy) was found to distribute the radioactive seeds unevenly throughout the gland; cold regions may have contributed to the relatively poor outcome.

The advent of improved imaging and seed placement techniques coupled with better patient selection has resulted in vast improvements in cancer control. The perception of fewer side effects in a single outpatient treatment has also contributed to some popularity of this treatment modality. Transrectal ultrasonography is now utilized to guide seed placement from a transperineal approach, which has corrected the problem of poor seed placement in experienced hands. Two radioactive seed isotopes have been used: iodine (I-125), with a half-life of 60 days, and palladium (Pd-103), with a shorter half-life (17 days) and subsequent higher dose rate. The advantage of the brachytherapy technique is that substantial dose can be delivered to the prostate with minimal effect on the surrounding tissue.

Although concentrating dose with brachytherapy represents a potential advantage over EBRT, it also highlights the need for appropriate patient selection. Significant dose falloff 2 to 3 mm beyond placement of the seeds within the gland limits the application of seed monotherapy in patients with potential periprostatic or regional disease extension. Large studies from several leading institutions have now matured and confirm the long-term effectiveness and safety of this approach in low-risk populations. Favorable results have also been reported in selected intermediate-risk patients. Typical monotherapy doses of 145 Gy for I-125 and 125 Gy for Pd-103 are utilized. To date, the data do not support the use of either isotope over the other.

In addition to disease risk factors, certain patient selection factors are important in considering implants. A large prostate size (> 60 cc) may make the procedure more challenging, both from the perspective of increased prostate gland swelling due to the increased number of needles and the difficulty of the pubic bone obstructing needle placement. Patients with outlet obstruction symptoms and an International Prostate Symptom Score (IPSS) > 15 have an increased risk of requiring catheterization following implantation. Patients who have undergone prior transurethral resection of prostate (TURP) have been reported to have an increased risk of incontinence; recognizing this risk and placing seeds farther from the defect may help to minimize this risk. Therefore, with proper counseling, patients with small TURP defects may still be considered implant candidates.

For patients with intermediate-risk or high-risk disease, implants may be combined with EBRT. There is sound logic in combining high-dose radiotherapy to the prostate with an implant and moderate doses of EBRT to the regional tissues to sterilize micrometastatic disease. In this situation, an implant (110 Gy of I-131 or 100 Gy of Pd-104) usually either precedes or follows 20 to 45 Gy delivered to the pelvis. Some reports have suggested an increase in rectal toxicity with this approach; however, this is likely due to the poor quality of the implant. At least one study from a leading implant center suggested no significant increase in severe early or late gastrointestinal/genitourinary morbidity with combination therapy. The value of supplemental EBRT needs to be evaluated in comparison to full-dose EBRT in terms of long-term morbidity and cancer control.

High-dose-rate (HDR) devices. Besides permanent implants, which deliver low-dose-rate (LDR) radiotherapy, brachytherapy for prostate cancer has been delivered using temporary HDR devices, usually in patients with locally advanced disease. In this technique, a high dose (minimum, approximately 5 Gy) is delivered to the prostate over ≤ 1 hour by remotely inserting a highly radioactive source into catheters placed into the prostate using ultrasonographic guidance while the patient is under anesthesia. Several treatments are given on separate occasions, and EBRT is used for approximately 5 weeks as well.

More reports are accumulating on the application of HDR brachytherapy to prostate cancer. Various dose-fractionation combinations of HDR with or without combined pelvic EBRT have been employed, with a dose-response relationship apparent in biochemical control. Although the follow-up is short and no prospective randomized trials evaluating this approach have yet been published, it appears that HDR prostate brachytherapy in combination with pelvic EBRT may be effective. The long-term consequences to normal tissue of delivering large doses per fraction using this technique are unclear.

Medications and devices to manage impotence after prostatectomy, EBRT, or brachytherapy

Treatment for postprostatectomy impotence includes the phosphodiesterase inhibitors sildenafil, vardenafil (Levitra), and tadalafil, and prostaglandin E1, administered as a urethral suppository (MUSE [Medicated Urethral System for Erections; alprostadil(Drug information on alprostadil)]); intercavernosal injection (Caverject, Edex); or VEDs that are useful for improving erections in men who have poor erectile function after prostatectomy, radiation therapy, or brachytherapy. These therapies are effective in 15% to 40% of men with postprostatectomy impotence and in 50% to 75% of men with postradiotherapy erectile dysfunction. Insertion of a penile prosthesis is typically offered to patients only after unsuccessful trials with the previously mentioned less invasive interventions.

Sidebar: Sexual function is the health-related quality-of-life (HRQOL) domain most commonly impaired after prostate cancer treatment. The aim of this study was to predict long-term erectile function following prostate cancer treatment based on individual patient and treatment characteristics. Pretreatment patient characteristics, sexual HRQOL, and treatment details measured in a longitudinal academic multicenter cohort (Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment; enrolled from 2003 through 2006) were used to develop models predicting erectile function 2 years after treatment. A community-based cohort (community-based Cancer of the Prostate Strategic Urologic Research Endeavor [CAPSURE]; enrolled 1995 through 2007) externally validated model performance. Patients in US academic and community-based practices whose HRQOL was measured pretreatment (N = 1,201) underwent follow-up after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer. Sexual outcomes among men completing 2 years' follow-up (n = 1,027) were used to develop models predicting erectile function that were externally validated among 1,913 patients in a community-based cohort. Two years after prostate cancer treatment, 368 (37% [95% CI, 34%-40%]) of all patients and 335 (48% [95% CI, 45%–52%]) of those with functional erections prior to treatment reported functional erections. Pretreatment sexual HRQOL score, age, serum prostate-specific antigen level, race/ethnicity, body mass index, and intended treatment details were associated with functional erections 2 years after treatment. Multivariable logistic regression models predicting erectile function estimated 2-year function probabilities from as low as 10% or less to as high as 70% or greater depending on the individual's pretreatment patient characteristics and treatment details (Alemozaffar M et al: JAMA 306:1205-1214, 2011).