PSA is a serine protease enzyme secreted by prostate epithelial cells. Large quantities are present in seminal fluid, and only a fraction escapes into the bloodstream. PSA elevations can be secondary to benign prostate hyperplasia. However, due to the disorganization of gland and duct structure associated with cancer, greater increases are more common. A PSA > 4.0 ng/mL has been considered the standard cutpoint in defining an abnormal PSA level, but as a tumor marker it lacks specificity; eg, in the 4- to 10-ng/mL range, only 30% of biopsies will be positive for cancer; in the 10- to 20-ng/mL range, approximately 50% of biopsies will be positive for cancer. If the total PSA elevation had no prognostic significance, screening of an enriched population might be an easier proposition. The urologist could wait until the PSA level was quite high, thereby increasing specificity before advising a biopsy. However, PSA is prognostic for all treatment modalities, such that the likelihood of cure diminishes as pretreatment PSA increases.[ 2] For example, Pollack et al cite a 50% to 80% incidence of biochemical failure after radiation, surgery, or androgen deprivation monotherapy when pretreatment PSA is > 20 ng/mL. Gleason Pattern
Albertsen et al published an informative study from the Connecticut Surveillance, Epidemiology, and End Results (SEER) cancer registry. Men with prostate cancer who elected not to be treated with curative therapy were followed for 15 years to determine the incidence of death from prostate cancer vs death from any cause. Not surprisingly, the risk of death from prostate cancer is closely related to age at diagnosis and biopsy Gleason score. For men with a Gleason score of 6, the prostate cancer death rate at 15 years was 18% to 30%; for a Gleason score of 7, it was 42% to 70%; and for a Gleason score of 8 to 10, it was 60% to 87%. The lower end of these ranges occurred among men diagnosed in their 70s, whereas the higher death rates occurred among men diagnosed in their 50s. Thus, if not treated with curative intent, a 50-yearold man with a Gleason score of 8 to 10 had a very high risk-nearly 90%-of dying from prostate cancer. Clinical Stage
Clinical stage is determined by the physician's digital rectal examination. This designation is highly subject to interobserver interpretation and is the least prognostic variable. The incidence of clinical stage T1c (cT1c) disease (or nonpalpable lesions) has markedly increased with PSA screening. Patients rarely present with bulky lesions that are clearly extraprostatic (cT3a) or that invade the seminal vesicle (cT3b) or the bladder (cT4). Combination of Prognostic Factors
Combining prognostic factors to construct tables was initiated and popularized by Partin et al. Based on radical prostatectomy data, they combine clinical stage, pretreatment PSA level, and biopsy Gleason score to predict extracapsular extension, seminal vesicle invasion, and lymph node involvement. Men with "low-risk" disease, ie, PSA < 10 ng/mL, Gleason score of 3+3, and cT1c disease, have a 67% chance of organ confinement and only a 1% risk of lymph node involvement. On the other hand, a patient with a Gleason score of 8, PSA of 25 ng/mL, and cT2a disease is predicted to have an organ-confined rate of 5% and a 24% risk of lymph node involvement. Overall, high-risk disease is defined by any of the following features: PSA > 20 ng/mL, Gleason score 8 to 10, or clinical stage T2c/3 disease. Approximately 35% of newly diagnosed cancers, a significant minority, fall into this category.[6,7] Although the Partin tables predict for pathologic stage, it is well known that some patients with an adverse pathology after radical prostatectomy will never experience biochemical failure.[ 5] To more accurately predict 5-year PSA recurrence-free survival, Nelson et al have added the greatest percentage of cancer on any biopsy core to Gleason score, PSA level, and disease stage. The key concept is that while the presence of a single high-risk factor is certainly adverse, additional high-risk factors dramatically worsen prognosis. For example, for a PSA > 20 ng/mL, stage cT1c disease, and no single biopsy core percentage < 60%, the 5-year recurrencefree survival rates for Gleason score 8-10 was 19%. PSA survival dropped to 9% if any biopsy core percentage was > 60%, and further to 3% if the clinical stage was advanced to T2. Looking at the wide range of these outcomes, it may be reasonable to consider truly high-risk prostate cancer as the presence of one high-risk factor plus a second intermediate- or high-risk factor. An exact definition of "high-risk" prostate cancer is therefore somewhat relative and better described in gradients rather than absolutes. Treatment Options for High-Risk Prostate Cancer Radical Prostatectomy
Radical prostatectomy alone can on occasion be successful in treating men with high-risk disease.[9,10] In the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database, 547 patients with high-risk disease underwent radical prostatectomy; with a median follow-up of 3.1 years, 68% maintained an undetectable PSA. Although PSA level, Gleason score, and percent positive biopsy were each significant predictors of failure, together they increased the odds of biochemical failure. Mian et al from M. D. Anderson Cancer Center recently reported a PSA-era series of patients who underwent radical prostatectomy as monotherapy for Gleason 8-10 disease. They cite pre-PSA series that reported a high (70%-100%) incidence of nodal metastases and poor survival rates.[12-14] By contrast, in their series of 188 patients with specimen Gleason scores of 8 to 10 and no neo- adjuvant or adjuvant therapy, PSA recurrence- free survival was 68% at a median of 5 years follow-up. Pathologic staging of the series showed organ- confined and margin-negative disease in 31%, specimen-confined disease (pT2/pT3, margin-negative) in 57%, extraprostatic extension with positive margins in 9%, seminal vesicle invasion in 21%, and positive lymph nodes in 6%. A pretreatment PSA < 10 ng/mL was more likely to correlate with organ- and specimenconfined disease than a PSA > 10 ng/mL. The median time to recurrence was 36 months. A striking finding of this study was that the 5-year biochemical disease-free survival was similar for 84% of patients with organconfined disease, with or without positive margins, and for those with negative-margin pT3a disease. However, where disease was both extraprostatic and margin-positive, biochemical recurrence-free survival dropped to 50%. Thus, although rates of extraprostatic disease were high, as one would expect with Gleason 8-10 disease, achieving a negative margin resulted in a significant PSA recurrencefree survival benefit. In this setting, surgeons would not risk a positive margin with a nerve-sparing procedure. In the Mayo clinic surgical series of Gleason 8-10 prostate cancer patients reported by Lau et al, biochemical progression-free 5- and 10-year survival rates were 49% and 36%. Organ-confined disease was seen in 25%, 54% had positive margins, 48% had positive seminal vesicles, and 27% had positive lymph nodes. Organ- confined tumors, some with positive margins, had 5- and 10-year progression-free survival rates of 53% and 28%. By comparison, the highrisk surgical series reported by Tefilli et al showed a less optimistic 3-year biochemcial disease-free rate of 33%. Their series had a higher proportion of patients with a pretreatment PSA level > 10 ng/mL and lower proportions of organ-confined and specimenconfined disease. In conclusion, prostate cancer with high-risk features that is organ confined, or at least specimen confined, and of low volume on pathologic examination, may be cured by surgical monotherapy. Radical Prostatectomy With Adjuvant or Neoadjuvant Therapy
If nodal metastases are found at the time of radical prostatectomy, early application of adjuvant androgen deprivation therapy has been shown to prolong survival in a randomized trial. Messing et al randomized 98 node-positive patients to immediate or delayed androgen deprivation therapy after radical prostatectomy-commencing only at the time of metastatic occurrence, ie, not for asymptomatic rises in PSA. After a median follow- up of 7.1 years, disease progression was reduced from 77% to 18%, and survival increased from 65% to 85%. (The strategy of initiating androgen deprivation therapy at the onset of a rising PSA was not tested and may be as efficacious as initiating therapy immediately after surgical removal of the prostate.) This trial did not reach its accrual goal of 220 patients due to the decreasing incidence of nodal metastases with PSA detection. Nevertheless, a statistically significant survival benefit was realized in this small trial. These findings combined with those of the Medical Research Council study and the European Organization for Research and Treatment of Cancer (EORTC) trials reported by Bolla provide evidence-based data for early rather than delayed treatment of high-risk patients with androgen deprivation therapy.[17-19] Although adjuvant androgen deprivation for node-positive disease has demonstrated a survival benefit in clinical trials testing, neoadjuvant androgen deprivation prior to radical prostatectomy has not demonstrated any clinical benefit. Soloway et al reported extended follow-up of a trial comparing 3 months of neoadjuvant androgen deprivation for cT2b, NX, M0 disease. In the prostatectomy- only group, positive margins were detected in 48% with a 5-year biochemical recurrence-free survival of 68%. In the neoadjuvant hormonal group, while the positive margins were reduced to 18%, the 5-year biochemical recurrence-free survival was a similar 65%. Thus, neoadjuvant androgen deprivation decreased the recognition of positive margins but did not affect recurrence-free survival. Patients with higher PSA levels and Gleason scores had higher relapse rates that were unaffected by neoadjuvant therapy. The Canadian Uro-Oncology Group recently reported follow-up of a trial comparing 3 vs 8 months of neoadjuvant androgen deprivation followed by radical prostatectomy. The investigators postulated that the 8-month schedule would prove more efficacious, as this regimen was associated with further declines in PSA nadir and reduction of positive margins when compared to the 3-month schedule. However, with 4-year follow- up, both arms had a similar PSA progression-free survival. Adjuvant irradiation is a common strategy used after surgery for prostate cancer with high-risk features. As reviewed by Syed et al, while improved local control may be a benefit, no randomized trial has demonstrated a survival advantage for adjuvant radiation in this setting.[23-27] A Southwest Oncology Group (SWOG) phase III trial randomized patients with extraprostatic extension, positive margins, or seminal vesicle involvement to either observation or 62-64 Gy of adjuvant radiation. This trial is designed to evaluate a survival benefit; the outcome analysis is still pending. External-Beam Radiation Therapy
In 1999, we reported our experience with external-beam irradiation as monotherapy delivered between 1976 and 1995 at Eastern Virginia Medical School. Our technique during that era was described as follows: "Patients were treated with 4-MV photons in the earliest years and 10-18 MV photons in the last 10 years of the study period. A minimum dose of 62-65 Gy was delivered to the entire prostatic volume, with 40-45 Gy to the lymph node drainage sites of the pelvis for poorly differentiated > T2b staged cancers. A typical four-field technique was used to treat the whole pelvis and the initial prostatic fields, while an anterior and two lateral fields or 120o bilateral arc rotation was used for the prostate boost." The sensitivity of PSA as a followup tool after local treatment made it clear that this technique was inadequate, especially for high-risk disease. In the past decade, radiation oncologists have radically updated their techniques to deliver increased doses to the prostate while sparing the surrounding bowel and bladder. We will review these efforts and their surrounding controversies.
- Field Size-Considerable controversy remains regarding the role of elective pelvic lymph node irradiation in clinically localized high-risk prostate cancer. Retrospective reports support[ 29,30] and refute a benefit for elective pelvic radiation therapy in this setting. The issue was first prospectively evaluated by Radiation Therapy Oncology Group (RTOG) protocol 7706.[32,33] In this study, 445 patients with clinical stage A2 or B disease (cT1b or cT2) and no clinical or pathologic evidence of pelvic lymph node involvement were randomized to receive either 45 to 50 Gy of pelvic nodal irradiation followed by a 20-Gy boost to the prostate, or 65 to 72 Gy to the prostate only. Elective pelvic irradiation failed to improve local control, freedom from distant metastases, and disease-specific or overall survival. However, this trial had several weaknesses: The doses used were moderate, the field size was small (6 * 6 cm to 7 * 7 cm) prior to computed tomography (CT) localization of the prostate, a "sandwich technique" was allowed whereby treatment of the pelvic nodes was given in a split-course fashion, and the definition of failure was clinical (ie, not PSA failure). More significantly, the patient population analyzed had a low risk of occult lymph node involvement. Recent randomized data have shed new light on this decades-old issue. RTOG 9413 evaluated elective pelvic nodal irradiation in clinically staged patients with greater than a 15% risk of lymph node involvement. In this study, nearly 1,300 patients were randomized to receive either 50.4 Gy to the pelvis followed by a 19.8 Gy prostate boost (70.2 Gy total to prostate) or 70.2 Gy to the prostate alone. All patients were also treated with 4 months of total androgen deprivation therapy, which they were randomized to receive either 2 months prior to and during radiation therapy or 4 months following the completion of radiation therapy. With a median follow-up of 5 years, a significant improvement in 4-year progression-free survival was shown (54% vs 47%) when elective pelvic irradiation was compared with prostate-only irradiation in patients also receiving neoadjuvant and concurrent total androgen suppression. An overall survival benefit has not yet been demonstrated, and it will be important to follow this critical end point. Therefore, pelvic irradiation when given in the context of neoadjuvant and concurrent androgen deprivation therapy may be of benefit for patients at high risk for lymph node involvement.
- Dose Response-A dose response in locally advanced prostate cancer was recognized with evidence that delivery of conventional doses of radiation therapy-ie, 65 to 70 Gy- results in poor local control, high biochemical failure rates, and positive postradiation biopsies. A patternof- care outcomes survey found that patients with stage C (cT3) tumors had improved local control with doses ≥ 70 Gy. Zietman et al analyzed the long-term outcome of over 1,000 patients with localized prostate cancer who received 68.4 Gy to the prostate. Using a strict definition of biochemical failure, only 20% of men with either cT3/4 or cT1/2 disease and a Gleason score of 8 to 10 were disease-free at 10 years. Crook et al reported the results of postradiation prostate biopsies in 226 patients after doses of 65 to 66 Gy to the prostate. At 30 months' followup, 38% of T3 and 83% of T4 patients had positive or indeterminate biopsies. Despite the realization that higher doses were necessary, dose escalation above 70 Gy using conventional treatment techniques resulted in significant rectal and bladder toxicity. Fortunately, advances in computer technology have made the necessary transition to dose escalation a reality.
- 3D CRT and IMRT-Three-dimensional conformal radiotherapy (3D CRT) starts with acquiring a CT scan of the patient in the desired treatment position. The resulting two-dimensional axial images are stacked into a virtual 3D representation of the entire treatment area, including the prostate and adjacent critical organs. These structures can be projected as if one were viewing them along the path of a radiation beam from any angle (beam's-eye view). Each beam used during treatment can thus be shaped to maximally conform to the target while excluding adjacent normal tissue. The result is a marked improvement in dose conformation around the target compared with a classic four-field technique. Intensity-modulated radiation therapy (IMRT) is a further refinement of 3D CRT. This technique uses computer- optimized nonuniform beam intensities to conform the dose even more closely to the target volume. IMRT systems generally utilize inverse planning, a plan optimization process that first considers the desired outcome (adequate dose to the target and minimum dose to surrounding critical structures) and then designs a treatment scheme to achieve that outcome. This is in contrast to forward planning on most 3D CRT systems, in which a trial-and-error method of arranging beam combinations and blocking must be performed to arrive at the desired solution. As with all new technology, the successful implementation of IMRT requires an understanding of its potential drawbacks. Increasingly, conformal dose delivery means that margins around the target become smaller and dose gradients around the tumor become steeper. Despite strict immobilization of the patient, some daily variation in both patient position and internal prostate motion will occur, which needs to be considered in treatment planning. In rigidly immobilized prostate cancer patients receiving conformal radiation therapy, Rosenthal found a median patient position variability of 4 mm between simulation and treatment. Ten Haken observed an average prostate movement of 5 mm in 50 patients due to differential filling of the rectum and bladder. Daily localization of the prostate with transabdominal ultrasound imaging or implanted radiopaque seed markers can significantly improve the accuracy of treatment and should be utilized when treating with tight margins.
- Dose Escalation: Retrospective or Nonrandomized Studies-Investigators at Fox Chase Cancer Center described the results in 618 patients treated with different doses of 3D CRT alone. Patients were grouped by pretreatment PSA level (< 10 ng/mL, 10-19.9 ng/mL, or ≥ 20 ng/mL) and further subgrouped by unfavorable risk if they had T2b/3 disease, Gleason score ≥ 7, or perineural invasion. Favorable-risk patients lacked any of these features. Among unfavorablerisk patients with a PSA < 10 ng/mL, any patient with a PSA between 10 and 19.9 ng/mL, and the favorable PSA ≥ 20 ng/mL group, an increase in the median dose from approximately 73 to 77.5 Gy resulted in a 14% to 40% improvement in 5-year biochemical freedom from failure. Outcome was poor in the unfavorable group with PSA > 20 ng/mL regardless of dose, suggesting that disease is present outside the local field and additional therapy such as androgen deprivation is necessary. Zelefsky and colleagues reported on the long-term outcome of 1,100 patients with stage T1c-3 disease treated with 3D CRT and IMRT. The radiation dose was incrementally increased from 64.8 to 86.4 Gy. Unfavorablerisk patients were defined as having at least two of the following factors: PSA > 10 ng/mL, stage T3 disease, or a Gleason score ≥ 7. For the 416 patients with unfavorable risk criteria, 81 Gy significantly improved 5-year PSA relapse- free survival to 67%, compared to 43% for 75.6 Gy and 21% for 64.8- 70.2 Gy. Posttreatment biopsies were obtained at least 2.5 years after treatment in 108 of the 416 men. The incidence of positive biopsies decreased steadily as the radiation dose was escalated in increments of 5.4 Gy.
- Dose Escalation: Randomized Studies-Shipley et al randomized 202 patients with T3/4 tumors to 67.2 Gy or 75.6 cobalt gray equivalent, using a conformal perineal proton boost. No patient received androgen deprivation therapy. In the subset of 57 patients with poorly differentiated tumors, local control was significantly improved (84% vs 19%) with the higher dose. In the M. D. Anderson dose escalation trial, over 300 patients with T1-3 disease were randomized to a radiation dose of 70 or 78 Gy as monotherapy. A preliminary analysis revealed that among patients with a pretreatment PSA > 10 ng/mL, a dose of 78 Gy increased 5-year freedom from clinical or biochemical failure from 48% to 75% (P = .011). A subsequent analysis at 60 months' median follow- up confirmed the benefit for these intermediate- to high-risk patients; dose escalation significantly improved the 6-year freedom from clinical or biochemical failure rate from 43% to 62%.