American Journal of Clinical Oncology:
ACR Appropriateness Criteria® Definitive External Beam Irradiation in Stage T1 and T2 Prostate Cancer
Expert Panel on Radiation Oncology-Prostate:; Moran, Brian J. MD*; DeRose, Paul MD†; Hsu, I-Chow Joe MD‡; Abdel-Wahab, May MD, PhD§; Arterbery, V. Elayne MD∥; Ciezki, Jay P. MD¶; Frank, Steven J. MD#; Mohler, James Lloyd MD**; Rosenthal, Seth A. MD††; Rossi, Carl J. Jr MD‡‡; Yamada, Yoshiya MD§§; Merrick, Gregory S. MD∥∥
*Chicago Prostate Cancer Center, Westmont, IL
†University of Texas Southwestern Medical Center, Dallas, TX
#MD Anderson Cancer Center, Houston, TX
‡University of California San Francisco, San Francisco, CA
††Radiological Associates of Sacramento, Sacramento
‡‡Loma Linda University Medical Center, Loma Linda, CA
§University of Miami, Miami, FL
∥Karmanos-Crittenton Cancer Center, Rochester Hills, MI
¶Cleveland Clinic Foundation, Cleveland, OH
**Roswell Park Cancer Institute, Buffalo, New York, American Urological Association, NY
§§Memorial Sloan Kettering Cancer Center, New York, NY
∥∥Schiffler Cancer Center and Wheeling Jesuit University, Wheeling, WV
The authors declare no conflicts of interest.
The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply society endorsement of the final document.
This article is a revised version of the American College of Radiology Appropriateness Criteria Definitive External Beam Irradiation in Stage T1 and T2 Prostate Cancer excerpts of which are reprinted here with permission. Practitioners are encouraged to refer to the complete version at www.acr.org/ac.
Reprints: Brian J. Moran, MD, American College of Radiology, Reston VA 20191. E-mail: email@example.com.
Purpose: External beam radiation therapy is a standard of care treatment for men who present with clinically localized (T1-T2) prostate cancer. The purpose of this review was to provide clarification on the appropriateness criteria and management considerations for the treatment of prostate cancer with external beam radiation therapy.
Methods: A panel consisting of physicians with expertise on prostate cancer was assembled and provided with a number of clinical scenarios for consensus treatment and management guidelines. Prostate cancer patient vignettes were presented along with specific management recommendations based on an extensive review of the modern external beam radiotherapy literature. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances, where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.
Results: Modern external beam radiation therapy series demonstrate favorable biochemical control rates for patients with localized prostate cancer. Morbidity profiles are also favorable and it is clear that this is enhanced by modern techniques like 3-dimensional conformal radiation therapy and intensity-modulated radiation therapy. An active area of investigation is evaluating the use of hypofractionated dosing.
Conclusions: Continued investigation to refine patient selection, external beam radiation technology application, and alternative dosing schedules should result in further improvements in biochemical outcome and decreased morbidity with external beam radiation treatment for localized prostate cancer.
SUMMARY OF LITERATURE REVIEW
The outcome for patients with localized prostate cancer depends on multiple factors, including the natural history of the disease, and the efficacy and toxicity of a particular therapy. Owing to these factors, no single therapy is preferred for all prostate cancer patients. The Consensus Development Conference on Management of Localized Prostate Cancer1 concluded that radical prostatectomy and radiation therapy are clearly effective treatments for tumors limited to the prostate in appropriately selected patients. It was further asserted that patients should be informed of the various options of therapy with the accompanying side effects and that physicians must make an effort to properly select patients for a given type of treatment.
Historically, observation or watchful waiting has been considered a reasonable option for early-stage prostate cancer patients due to its long natural history; however, more recent studies show a benefit to definitive therapies. Initially, Johansson et al2 reported observation data from Sweden at 10-year follow-up in which only 9% of men died of prostate cancer, although 53% had progressive disease. In 2004, Johansson et al3 reported their results with 21 years of follow-up in which 50% of men had developed metastatic disease and 64% had progressive disease. In addition, the prostate cancer mortality rate increased from 1.5% person-years for the first 15 years to 4.4% person-years after 15 years. It was concluded that patients with 15 years or greater life expectancy would benefit from prostate cancer treatment. A randomized controlled trial comparing observation with radical prostatectomy demonstrated a significantly higher death rate in the observation group, along with an increased rate of metastatic disease and death due to prostate cancer in men younger than 65 years of age.4
The introduction and use of the prostate-specific antigen (PSA) have revolutionized the diagnosis, staging, and evaluation of treatment outcome for prostate cancer. Its use in evaluating treatment outcomes has led to risk stratification groups that combine PSA, Gleason score, and clinical stage. These risk groupings allow the grade of the disease (Gleason score), and burden of disease (PSA and clinical stage) to be combined to stratify patients as low, intermediate, or high risk, supporting therapy recommendations and comparison within clinical trials and treatment modalities. The most commonly used risk grouping proposed by D’Amico et al5 includes low risk (clinical stage T1c-T2a, PSA <10 ng/mL, Gleason score <7), intermediate risk (clinical stage T2b or PSA 10 to 20ng/mL, or Gleason score ≥7), or high risk (clinical stage T2c, or PSA >20 and Gleason score >7). In addition, the percentage of positive prostate biopsies has been proposed as a prognostic indicator of biochemical PSA control. D’Amico et al5 demonstrated a significant difference in biochemical control in patients treated with external beam radiation therapy (EBRT) or radical prostatectomy when stratified by <34% positive biopsies versus >50% positive biopsies.
ROLE OF EBRT
EBRT is used as definitive therapy in patients with early and locally advanced disease. Defining the appropriate dose to be delivered to the prostate gland has been the subject of many decades of study. Several early retrospective studies indicate that dose has an impact on the local tumor control. Perez et al6,7 reported improved local control rates with doses >6500 cGy, particularly in stage C patients. Hanks et al8 in a study of 1348 patients with stage B and C tumors, reported actuarial 5-year local recurrence rates of approximately 35% for patients with stage C who were treated to doses of <6000 to 6490 cGy, 29% for doses of 6500 to 6990 cGy and, 19% for doses of ≥7000 cGy. By 7 years, 32% of patients receiving 6500 to 6900 cGy and 24% treated with higher doses had local recurrences. More recently, an update of a randomized controlled trial by Pollack et al9 demonstrated a statistically significant improvement in freedom from PSA failure in patients treated to a total dose of 78 Gy compared with 70 Gy 3-dimensional radiation therapy. Patients treated to 78 Gy had a 5-year freedom from biochemical failure rate of 78% versus 59% for the 70 Gy group. The trial also demonstrated a lower rate of clinical failure in the higher dose group of 7% as opposed to 15%. There is a generally accepted consensus that dose escalation is important in treating the prostate primary disease. Dose escalation to the prostate, enabled by 3-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiation therapy (IMRT) is addressed further in this document under the Three-Dimensional Treatment Planning and Conformal Therapy heading.
The role of radiation of the lymph nodes is less well established in T1 and T2 cancers. Pelvic lymph node radiation has demonstrated a benefit in patients with advanced local disease in early studies. McGowan et al10 reported improved survival and fewer pelvic failures in patients with stage B2 or C tumors treated with larger fields encompassing the pelvic lymph nodes, compared with patients treated to the prostate and periprostatic tissues only. To prospectively evaluate this issue, the Radiation Therapy Oncology Group (RTOG) 9413 trial evaluated the use of whole pelvic versus prostate-only radiation in a randomized controlled trial in patients with positive pelvic lymph nodes, seminal vesicle involvement, or a >15% risk of having metastatic pelvic lymph nodes.11 Approximately 30% of the patients had clinical stage T1-T2b disease, and 30% had a Gleason score <7. Patients were additionally randomized to neoadjuvant versus concurrent androgen depravation therapy in the 2×2 factorial-designed trial. A recent update on the results of this trial showed that neoadjuvant hormone therapy and pelvic node irradiation resulted in a better overall survival than neoadjuvant hormone therapy and prostate-only irradiation. This finding is confounded by the fact that neoadjuvant hormone therapy and pelvic node irradiation combination was not found to be superior to prostate-only irradiation and short-term adjuvant hormone therapy.12 Pommier et al13 has also reported results of a trial that included patients with T1c-T3 prostate cancer who were then randomized to irradiation of the whole pelvis or the prostate only. The data from this study showed no difference in progression-free survival or quality of life at 42 months follow-up. Further studies are needed to clearly define the role of pelvic node irradiation in this group of patients (Table 1)
RESULTS OF TREATMENT
The outcome for patients treated with EBRT compares favorably with the outcomes for other treatment modalities. In an analysis of T1-T2 patients treated to a dose of 70 Gy or greater, the 7-year freedom-from-biochemical-failure rates were 77% for EBRT patients, 79% for radical prostatectomy patients, and 74% for patients treated with prostate brachytherapy.
On multivariate analysis, treatment modality was not an independent predictor of outcome, only initial PSA and Gleason score.14 Other investigators have also demonstrated that biochemical disease-free survival (DFS) rates directly correlate with the pretreatment PSA and Gleason score, with a lower PSA and Gleason score resulting in an increased biochemical DFS rate.15,16
The biochemical control rates after prostate irradiation have also shown a direct relationship to radiation dose. Kupelian et al17 reported on a study of 1,041 patients treated with EBRT that demonstrated a 5-year biochemical relapse-free survival rate of 87% in patients receiving a total dose >72 Gy compared with 55% in patients receiving <72 Gy. In addition, Zelefsky et al18 demonstrated that low-risk patients treated to doses of 75.6 Gy or greater had a 90% 5-year biochemical recurrence-free survival rate versus 77% for those treated to 64.8 to 70.2 Gy. The corresponding biochemical recurrence-free survival rates were 70% versus 50% for intermediate patients and 47% versus 21% for high-risk patients, thus favoring the higher dose group. In addition, Zietman et al19 have shown a benefit in dose escalation using a combination of photon and proton radiation. Patients were initially treated with a proton boost dose of 19.8 gray equivalent (GyE) or 28.8 GyE, followed by a photon dose of 50.4 Gy for a combined dose of 70.2 GyE versus 79.2 GyE. Their update reported that the freedom from biochemical failure rates at 10 years favored the high-dose group (79.2 GyE), which had a 16% risk of failure as opposed to 32% for the low-dose group.
MORBIDITY OF EXTERNAL IRRADIATION
Health-related quality of life studies have helped reveal more accurately the morbidity patients experience with the treatment of prostate cancer. Physician-reported toxicity has been shown to understate patient-reported toxicity.20 Talcott et al20 demonstrated that after radiation therapy, patients commonly report irritated bowel and bladder symptoms at 3 months, most of which resolve by 12 months. After radical prostatectomy, patients reported significant urinary incontinence (11%) and the need for absorptive pads (35%), symptoms that were rarely reported in patients undergoing radiation therapy. Two recent studies of patient assessment of quality of life after radical prostatectomy, EBRT, and permanent seed implant revealed significantly more bowel bother with EBRT, significantly worse urinary incontinence with radical prostatectomy, and increased urinary irritation with permanent I-125 implant.21,22 Sexual dysfunction was more commonly reported in surgery patients, but slightly improved with time in men younger than the age of 65 years. Hamilton et al23 reported that radiation therapy patients experienced a 29% decrease in sexual function at 24 months. Of those fully potent before radiation therapy, 43% were impotent after 24 months of follow-up. Reported bowel function declined 5%, and urinary function remained stable at 24-month follow-up. Nevertheless, approximately two thirds of these men were satisfied with their quality of life at 24 months and would chose radiation as their treatment again.
Potosky et al24 reviewed 2-year and 5-year quality of life data on patients undergoing EBRT or radical prostatectomy. Patients treated with prostatectomy reported a greater rate of urinary incontinence and impotency. Patients treated with radiation reported a higher rate of bowel dysfunction, including bowel urgency and painful hemorrhoids. Between the second and fifth years, incontinency rates increased from 9.6% to 16% in surgery patients, and from 3.5% to 4% in radiation therapy patients. Impotency rates remained stable in surgery patients at 79%, and radiation therapy patients reported a 2% increase from 62% to 64%, from 2 to 5 years.
The use of modern radiation therapy techniques with computed tomography-based 3-dimensional planning has lowered treatment-related toxicity, even when higher than standard irradiation doses are administered. Hanks et al25 reported 34% grade 2 toxicity in 247 patients treated with conformal radiation therapy compared with 57% in 162 patients receiving standard radiation therapy. Only 12 gastrointestinal or genitourinary grade 3 complications were noted in the entire group of 409 patients. Patients in both the conformal radiation therapy and standard radiation therapy groups receiving pelvic irradiation had a greater incidence of treatment toxicity. Only the volume treated (prostate±whole-pelvis irradiation) and the techniques were significant prognostic factors affecting the incidence of morbidity on multivariate analysis. Total tumor dose was not a significant factor in the incidence of grade 2 morbidity.
Sandler et al26 in an update of their experience in 721 patients treated with 3DCRT, noted only a 3% incidence of grade 3 and 4 rectal morbidity. Lee et al27 observed grade 2 and 3 rectal morbidity in 46 of 257 patients (18%) treated with 3DCRT; most cases consisted of some rectal bleeding. The incidence of rectal morbidity increased when higher doses of irradiation were delivered, particularly above 76 Gy (actuarial rate of 23% at 18 mo compared with 7% and 16% at lower doses). However, when a rectal block on the lateral fields was interposed for the last 10 Gy of treatment, rectal morbidity decreased to 10%.
Zelefsky et al28 reported the following 5-year actuarial rates of gastrointestinal toxicity in patients treated with 3DCRT to 75.6 Gy or higher: 11% for grade 2 toxicity and 0.75% for grade 3 toxicity. The corresponding rates for grade 2 and 3 urinary toxicity were 10% and 3%, respectively.
Lu et al29 correlated rectal morbidity with conformal radiation therapy to the rectal surface area irradiated instead of volume and noted that morbidity increased significantly when more than 20% of the area was irradiated to at least 65 Gy. Dale et al30 reported a correlation of late rectal effects with higher doses delivered to small volume fractions as shown on the dose-volume histogram, suggesting a more serial organization of the rectal tissue architecture than previously reported.
Erectile dysfunction can be a significant treatment side effect affecting quality of life. Data from RTOG 9406, a dose escalation trial, demonstrates that penile bulb dose plays an important role in potency rates. Patients with median penile bulb doses ≥52.5 Gy had higher impotency rates compared with those with doses below 52.5 Gy (P=0.039).31 The incidence of erectile dysfunction depends on a patient’s potency before prostate radiation, along with the time point and method in which potency is measured. Several series reported impotency rates ranging from 30% to 45%, which increases with time in patients potent before radiation therapy.23,24,32
The use of oral erectogenic agents such as sildenafil has shown a benefit, more so in radiation patients in comparison with patients undergoing radical prostatectomy.33,34 Weber et al34 demonstrated a 76% improvement in erectile function with the use of sildenafil over a 5-week interval (Table 2).
COMPARISON OF OUTCOME WITH IRRADIATION OR RADICAL PROSTATECTOMY
Little date exist directly comparing prostate radiation therapy and prostatectomy in a prospective randomized manner. Comparison of these modalities has been difficult due to selection bias, in which traditionally older patients or those not surgical candidates were treated with radiation therapy and younger, healthier patients were selected for radical prostatectomy. In addition, in the PSA era, defining a common endpoint has been difficult, with differing biochemical failure definitions for surgical and radiation series. Early attempts to conduct definitive comparisons of radiation to radical prostatectomy were largely unsuccessful.35–40
The DFS and the cause-specified survival rates reported in many radiation therapy series are comparable to those obtained with radical prostatectomy, as documented in several reports.41,42 Nonrandomized studies have compared outcomes using biochemical (DFS) rates for patients treated with EBRT or radical prostatectomy. D’Amico et al43 compared results in 513 patients treated with irradiation and 582 treated with surgery. The biochemical DFS rates, using pretreatment PSA and biopsy Gleason score to determine prognosis, were comparable for 3 different risk groups. D’Amico et al44 expanded their analysis, comparing results in 766 patients treated with irradiation, 218 treated with implant with or without neoadjuvant androgen deprivation therapy (ADT), and 888 treated with surgery.
The biochemical DFS rates, using pretreatment PSA to determine prognosis, were comparable for radical prostatectomy or external irradiation for the 3 different risk groups. But in the intermediate-risk and high-risk groups, patients treated with interstitial brachytherapy had lower biochemical DFS rates. However, this report should be considered far from a definitive analysis because it had relatively short follow-up, there was no information about postimplant dosimetry, and it was published before the recognition of the phenomenon of benign “spikes” or “bounces” in the PSA that is now known to result in false-positive failure rate of 20% to 30% after brachytherapy.
Other retrospective interspecialty comparisons have been reported. Vicini et al45 reported on a pooled series involving 6877 men treated at 7 different institutions with radiation therapy, surgery, or brachytherapy. Using uniform risk group stratification, no difference in 5-year biochemical outcomes was seen favoring any specific therapy. Another retrospective review, from the Cleveland Clinic and Memorial Sloan Kettering, compared almost 3000 patients with prostate cancer who received EBRT, radical surgery, or brachytherapy.17 For all patients receiving modern therapy to a dose above 72 Gy, no differences were seen in cancer control rates using PSA-based endpoints. Another recent retrospective comparison from Aizer et al46 examined the results of radical prostatectomy or radiation therapy with IMRT to a dose of ≥72 Gy with hormone therapy also when appropriate. They found no difference in biochemical DFS between radical prostatectomy and IMRT with the exception of patients with a poor pretreatment prognosis, where radiation therapy with hormone therapy was superior to radical prostatectomy (62.2% vs. 38.4%) (Table 3).
PSA IN SELECTION OF PATIENTS FOR THERAPY AND POSTTREATMENT EVALUATION
The use of PSA has substantially altered the apparent prevalence of prostatic carcinoma, the age at which the cancer is diagnosed, the distribution of clinical stages, the selection of patients for therapy, and the posttreatment assessment of outcome.47–49 Screening of patients with PSA and digital rectal examination has significantly increased the number of patients diagnosed with very small, microscopic lesions. A lower incidence of positive nodes (5% to 17%) has been reported in patients with stage T1b, T1c, and T2 disease diagnosed in a PSA screening program50 compared with patients in RTOG protocols (20% to 30% in stage T2) who were surgically or radiographically staged without PSA testing.51
The use of PSA testing has also greatly improved the ability to predict which patients present with localized disease. Clinical staging has been shown to be relatively ineffective in predicting prostate-confined disease, with up to 50% of clinically T1 and T2-staged patients demonstrating extraprostatic disease at the time of surgery.52 Patients with PSA levels <10 ng/mL have a 70% to 80% probability of having prostate-limited disease, in contrast to patients with PSA >10 ng/mL, who have <50% rate of prostate-confined disease if their Gleason score exceeds 6.53 In addition, initial pretreatment PSA levels directly correlate with 5-year biochemical DFS rates.16 Shipley et al16 demonstrated a 5-year failure-free rate of 81% in patients with PSA levels <9 ng/mL compared with a failure-free rate of 69% in patients with PSA levels 9 to 20 ng/mL.
The combination of PSA, Gleason score, and clinical stage has provided the greatest advancement in predicting the extent of disease and the probability of biochemical disease control. Partin et al54 have published nomograms (Partin tables) combining PSA, Gleason score, and clinical stage to predict the extent of disease spread in men undergoing radical prostatectomy, including the probability of organ-confined disease, extraprostatic extension, seminal vesicle involvement, and lymph node involvement. These variables, along with the use of androgen ablation and conformal radiation dose, are combined in the Kattan nomograms.55,56
In any comparison of treatment series, stratification for PSA is as important as stratification for tumor stage and grade. Thirty-three percent of stage T1 and T2 patients receiving irradiation at Massachusetts General Hospital between 1988 and 1992 had serum PSA values >15 ng/mL compared with only 16% in the prostatectomy series reported by the Johns Hopkins group.57 The proportion of radiation-treated patients with occult micrometastatic disease is also correspondingly higher in the Massachusetts General Hospital study, with 65% of patients with preirradiation PSA levels <15 ng/mL exhibiting freedom from chemical failure 4 years after treatment, a value comparable to that following radical prostatectomy, when there are no known metastases in the pelvic lymph nodes.52,58,59
The American Society for Therapeutic Radiology and Oncology (ASTRO) published consensus guidelines in which it was agreed that a reasonable definition of biochemical failure after radiation therapy is 3 consecutive increases in PSA.60 For clinical trials, the date of failure should be the midpoint between the postirradiation nadir PSA (nPSA) and the first of the 3 consecutive rises. Since the publication of this consensus definition, there has been a continual effort to improve upon it, based on concerns regarding the backdating and whether another definition might better serve as a surrogate for more clinical endpoints. In 1996 an ASTRO consensus conference was held to establish an improved definition for biochemical failure after EBRT for prostate cancer. This conference was held in Phoenix and is referred to as the “Phoenix definition.” The original ASTRO definition of 3 consecutive rises was revised, and the panel recommended that a rise of 2 ng/mL or more above the nPSA level should be considered biochemical failure after EBRT with or without ADT, and that the date of failure should not be backdated. The importance of adequate follow-up was also stressed in patients treated without hormonal therapy.61
Presently, no definition of PSA failure has been shown to be a surrogate for clinical progression or survival. nPSA after irradiation has a prognostic value similar to that of pretreatment PSA and other prognostic variables. According to Zagars et al62 nPSA is defined as the lowest serum PSA achieved in the 12 months after radiation therapy.
An additional complicating factor is the fluctuation in PSA that has been demonstrated after prostate radiation.63 This phenomenon, referred to as PSA bounce, can occur in up to 25% of men from 12 to 24 months after radiation therapy and has been reported with both brachytherapy and conformal radiation.
There is a close correlation between pretreatment PSA and stage, histologic differentiation of the tumor, and postirradiation nPSA. Patients with pretreatment PSA of ≤10 ng/mL have significantly higher biochemical failure-free survival rates than those with higher PSA levels, in all clinical stages. Time to clinical appearance of local recurrence or distant metastasis were 5 years and 3 years, respectively, after a biochemical failure (postirradiation PSA of ≥1 ng/ml) was detected. It will be important to follow these patients for at least 10 years to better assess the significance of and the relationship between biochemical and clinical failures. Pound et al64 found that metastatic disease occurred at a median of 5 years after PSA failure in patients undergoing radical prostatectomy. The effect of biochemical failure on overall survival is unclear. Jhaveri et al65 demonstrated similar overall survival rates in patients with biochemical failure compared with patients with biochemical control with 10-year follow-up.
THREE-DIMENSIONAL TREATMENT PLANNING AND CONFORMAL THERAPY
With the advent of 3-dimensional treatment planning and conformal radiation therapy, it is feasible to deliver higher doses to selected target volumes, thus improving tumor control probability without increasing treatment morbidity.66
Leibel et al67 updated preliminary results for 324 patients with carcinoma of the prostate who were irradiated to the prostate, seminal vesicles, and adjacent tissues with a 1 cm margin around the identifiable prostate gland, except at the interface with the rectum, where a 0.6 cm margin was used on a dose-escalation protocol. Doses of irradiation were 6480 to 6660 cGy in 70 patients, 7020 cGy in 102 patients, 7560 cGy in 57 patients, and 8100 cGy in 25 patients. With a median 18-month follow-up, 48 patients (15%) had postirradiation increasing PSA, and 29 (9%) showed clinical relapse (7 local recurrences, 22 distant metastases). Corn et al68 who updated the experience of Hanks et al,69 reported that in patients receiving only prostatic field irradiation, 12-month PSA values returned to normal in 96% and 85% of conformally and conventionally treated patients, respectively, when normalization was defined as ≤4 ng/mL (P<0.03), and in 76% and 55% of patients when normalization was defined as ≤1.5ng/mL (P<0.02). Among those receiving pelvic irradiation before prostatic cone down, PSA normalization (≤4 ng/mL) occurred in 82% and 61% (P<0.01) of conformally and conventionally treated patients, respectively, and in 56% and 38% of patients when normalization was defined as ≤1.5ng/mL (P<0.05).
The use of IMRT has also reduced normal tissue toxicity while allowing an increase in radiation dose to the prostate. This technologic advance permits a decrease in the normal tissue radiation dose, with a simultaneous increase in the prostate planning target volume dose, potentially improving biochemical control rates. Zelefsky et al28 have shown a decrease in rectal toxicity compared with 3DCRT, with a reduction of grade 2 to 3 rectal bleeding from 15% to 3% with IMRT. In a 2002 report by Zelefsky et al70 involving 772 patients, the 3-year actuarial rectal grade 2 toxicity was 4%, and the urinary grade 2 toxicity was 15%, comparing favorably with the results of 3DCRT. Ninety percent of those patients were treated to 81 Gy, and 10% to 86.4 Gy. The 3-year actuarial PSA biochemical control rates were 92% for favorable disease, 86% for intermediate disease, and 81% for unfavorable disease.
An update by Zelefsky et al71 in 2006 involving 561 patients treated to 81 Gy with IMRT reported 8-year actuarial PSA relapse-free survival rates of 85%, 76%, and 72% for favorable, intermediate, and unfavorable risk groups using the ASTRO definition (P<0.025). The 8-year grade 2 rectal bleeding rate was 1.6%, and the grade 3 rectal bleeding rate was 0.1%. There was no reported grade 4 rectal toxicity. The urinary toxicity rates were also low at 9% and 3% for grades 2 and 3, respectively. The erectile dysfunction rate was 49% in men who were potent before IMRT.
There is further evidence that the use of IMRT has further improved the therapeutic ratio. Matzinger et al72 compared the toxicity resulting from 3DCRT and IMRT of patients treated on the European Organization for Research and Treatment of Cancer 22991 trial. They found an increased Dmax for the bladder and D50% for the rectum in patients treated with 3DCRT. There was a correlative reduction in toxicity in patient treated with IMRT compared with those treated with 3DCRT. Lips et al73 reported a prospective longitudinal study of the quality of life of patients treated with 3DCRT to 70 Gy and patients treated with IMRT to 76 Gy. On the basis of their data, quality of life was similar between the 2 groups despite the higher dose in the IMRT group, and the IMRT group had significantly better quality of life in terms of pain, role functioning, and urinary symptoms. Al-Mamgani et al74 demonstrated an improvement in toxicity when IMRT with a simultaneous integrated boost was used. They demonstrated that IMRT with an integrated boost was superior to 3DCRT in terms of grade 2 or greater gastrointestinal toxicity (20% vs. 61%). A study reported by Chung et al75 also addressed the additional technical improvement of implanted fiducial markers. In this study, prostate margins were reduced from 1 cm to 2 to 3 mm with the placement of fiducials, and this resulted in a decrease in grade 2 rectal toxicity (80% to 13%) and bladder toxicity (60% vs. 13%). Further improvement is anticipated with the use of fiducial markers that act as radiofrequency transponders.
The potential dosimetric benefit of the Bragg peak has lead to the investigation of proton therapy in treating prostate carcinoma. Most recently Zietman et al76 updated a report on the use of proton boost combined with 3-dimensional conformal photon radiation to the prostate, seminal vesicles, and periprostatic tissues. Patients with T1b-T2b disease and PSA <15 ng/mL were randomized to an initial proton boost of either 19.8 or 28.8 GyE before a 50.4 Gy photon dose. This equated to a conventional total dose equivalent of 70.2 GyE (conventional dose) versus 79.2 GyE (high dose). The results demonstrated a benefit of a high total equivalent dose. With a median follow-up of 8.9 years, biochemical failure rates were 32.4% for the conventional-dose group and 16.7% for the high-dose group (P=0.0001). On subgroup analysis, this difference only held for low-risk patients, although there was a trend toward significance for intermediate-risk patients. There was no difference in overall survival or toxicity between the 2 groups.77 These data demonstrate a biochemical control benefit for a cumulative higher prostate dose, which has been demonstrated by photon-only radiation as well.78
Unfortunately, there are only limited data comparing proton therapy with other methods of irradiation or radical prostatectomy. There are no randomized trials, but a recent retrospective comparison performed by Jabbari et al79 did investigate the efficacy of proton therapy. In this review, patients from the previously mentioned proton boost trial were compared with a cohort of patients treated with 3DCRT and permanent prostate implant. This comparison showed that, in similar patients, permanent prostate implant seemed to offer at least equivalent biochemical control to EBRT with a conformal proton boost (Table 4).
With the use of computed tomography-based 3-dimensional treatment planning software, dose escalation is possible without an increase in treatment-related morbidity. In addition, the use of image guidance has further increased the ability to accurately target the prostate and avoid excess exposure to normal tissue.80,81 Several institutions,25,80,81 the RTOG, and 9 institutions are conducting phase I and II dose-escalation studies under cooperative agreement with the National Cancer Institute. Depending on the results, the cost and benefit of 3DCRT must be further evaluated in a larger, multi-institutional protocol, comparing it with standard techniques to determine whether its initial increased cost is justified.
Hanks et al69 noted that patients with localized prostate cancer and PSA levels of 10 to 19.9 ng/mL treated with 70 Gy had a 3-year chemical disease-free survival (biochemical no evidence of disease) rate of 69% compared with 80% and 89% for patients treated with 75 or 80 Gy, respectively. In patients with PSA levels ≥20 ng/mL, the corresponding biochemical no evidence of disease rates were 36%, 46%, and 57%. In 1998, results were updated,82 with biochemical no evidence of disease rates of 29% for patients treated with <7150 cGy, 57% with 7150 to 7574 cGy, and 73% with ≥7575 cGy (P=0.02).
Zelefsky et al28 in a study involving 743 patients, found a 5-year relapse-free survival rate of 78% in patients with intermediate risk and 50% in high-risk groups receiving doses of 75.6 to 81 Gy, compared with 52% and 20%, respectively, for patients treated with 64.8 to 70.2 Gy (P=0.04 and 0.03, respectively).
Leibel et al67 updated results on 324 patients with carcinoma of the prostate irradiated with 3DCRT on a dose-escalation protocol (64.8 to 66.6 Gy in 70 patients, 70.2 Gy in 102 patients, 75.6 Gy in 57 patients, and 81 Gy in 25 patients). The overall 3-year actuarial PSA normalization rate was 97% in patients with stage T1c-T2a, 86% in those with stage T2b, 60% in those with stage T2c, and 43% in those with stage C tumors. Hanks et al83 observed higher 4-year actuarial survival (50%) in 373 patients treated with 3DCRT than in 129 patients (39% survival) receiving stereotactic radiation therapy (SRT). Median follow-up was short (14 mo for 3DCRT patients and 50 mo for the SRT group). Corn et al68 reported on 170 patients treated with 3DCRT and 90 patients treated with SRT for locally advanced prostate cancer, using a PSA level of 1.5 ng/mL as an endpoint. With a minimum follow-up of 12 months, biochemical DFS rates were 76% for the 3DCRT patients and 55% for the SRT patients. In a subgroup of patients receiving pelvic irradiation, the corresponding survival rates were 56% and 38%, respectively. Later, Hanks et al41 updated these data and noted that biochemical DFS rates (using 1.5 ng/mL as endpoint) for patients treated with CRT according to pretreatment PSA levels were comparable to those reported for radical prostatectomy.
Dearnaley et al84 recently reported the results of a larger multi-institutional dose-escalation trial conducted in the United Kingdom. Patients with localized prostate cancer were randomized to receive either 64 Gy in 32 fractions or 74 Gy in 37 fractions using a 3DCRT technique. A total of 843 patients were enrolled, and at 5 years the dose-escalated group’s high risk for biochemical progression free survival was 0.67 (P=0.0007). There was also a trend toward improved clinical progression for the dose-escalated group with a high risk of 0.69 (P=0.064). This trend was counterbalanced by significant increase in late bowel toxicity from 24% to 33%. The results of this large multi-institutional study support the benefit of dose escalation in preventing prostate cancer progression. Longer follow-up is necessary to determine if it increases survival.
The M.D. Anderson Cancer Center also conducted a trial to investigate dose escalation with EBRT. Kuban et al68 recently reported the long-term results of this trial, which had a median follow-up of 8.7 years. A group of 301 patients was enrolled and treated to either 70 Gy or 78 Gy. The higher dose arm had a higher freedom from biochemical or clinical failure (78% vs. 59%, P=0.001) and a lower rate of clinical failure only (7% vs. 15%, P=0.014). Patients in the higher-dose arm had higher grade 2 or greater gastrointestinal toxicity (26% vs. 13%) but lower grade 2 or greater genitourinary toxicity (8% vs. 13%).The results of this trial provide further evidence that dose escalation of EBRT reduces clinical progression, but at the cost of some increase in treatment morbidity.
IRRADIATION AND ADT
The use of ADT has demonstrated a significant benefit in the treatment of prostate cancer, but remains undefined in low-risk patients. Zietman et al85 presented laboratory data showing that withdrawing testosterone before irradiation of androgen-dependent adenocarcinoma cells significantly reduced the cell kill compared with radiation alone or testosterone withdraw after irradiation.
Initially, Laverdiere et al86 showed a lower rate of positive prostate biopsies at 12 and 24 months with the use of combined androgen blockade 3 months before and after 64 Gy external irradiation. The benefit of adjuvant androgen blockade in addition to radiation therapy was demonstrated by Bolla et al87 in the European Organization for Research and Treatment of Cancer 22863 trial. Locally advanced patients were treated with pelvic and prostate irradiation to 70 Gy followed by 3 years of goserelin, with an overall survival benefit and disease-specific survival benefit at 66 months follow-up with the long-term use of goserelin. The benefit in survival and local control was additionally seen in RTOG 8531.88 The benefit of neoadjuvant ADT was observed in RTOG 8610, demonstrating a survival benefit with androgen withdrawal 2 months before and during pelvic and prostate radiation in comparison with radiation alone.89 In a RTOG meta-analysis, Roach et al90 demonstrated this benefit in patients with clinically localized disease.
The survival benefit of radiation therapy combined with androgen blockade over androgen blockade alone in high-risk patients with localized disease has been established. In a recent abstract, Warde et al91 reported the results of a multi-institution randomized trial that showed an overall survival benefit of radiation therapy combined with androgen blockade over long-term androgen blockade alone. The duration of androgen blockade in localized high-risk patients was also recently addressed in a randomized trial reported by Bolla et al.92 Patients with high-risk T2 disease were randomized to either 6 months or 3 years of androgen blockade in addition to EBRT in this noninferiority trial. At a median follow-up of 6.2 years, the short-term androgen blockade was found to be inferior to long-term androgen blockade.
Neoadjuvant androgen deprivation has also proved to be beneficial in patients with >15% risk of lymph node involvement, when combined with whole pelvic radiation therapy. A randomized trial by D’Amico et al93 demonstrated an overall survival benefit with the use of 6 months of androgen deprivation 3 months before, 3 months during, and 3 months after 3DCRT to 70 Gy (67 Gy prescribed to the 95% isodose line). The trial included patients with a PSA of 10 to 40 ng/mL or Gleason score ≥7. Low-risk patients were included if magnetic resonance imaging evidence of extraprostatic disease extension or seminal vesicle invasion was present. In a recent update of the data, D’Amico et al93 reported that at a median follow-up of 7.6 years, there was superior survival in the group that underwent androgen deprivation, but on subgroup analysis this benefit only remained intact for patients with minimal comorbidity as opposed to moderate or severe comorbidity. It is important to note that this was one of the smallest of the 4 trials yet with a radiotherapy-only control arm and the only study to show an overall survival advantage for ADT.86,89,94,95 Whether the use of higher doses of EBRT might have obviated the need for such therapy is unknown (Table 5).
Improvements in the delivery of EBRT have also led to an increased interest in hypofractionated radiotherapy regimens. There is particular interest in using hypofractionation in the treatment of prostate cancer, as it theoretically may be more efficacious based on prostate cancer radiobiology. The safety and efficacy of hypofractionation were first addressed when Kupelian et al96 reported on a group of 770 patients that were treated to a dose of 70 Gy at 2.5 Gy per fraction. The biochemical relapse-free survival rate was 83%, and the rate of grade 3 early or late urinary or rectal toxicity was <2%. It is important to note that despite this low rate of toxicity, 10 patients in the study did have late rectal ulcerations. A phase II trial conducted by Marzi et al97 investigated the safety of 62 Gy in 20 fractions compared with 80 Gy in 40 fractions and found similar rates of late rectal toxicity. Both Coote et al98 and Martin et al99 reported results of treatment with a hypofractionated regimen of 60 Gy in 20 fractions, and both had only 1 grade 3 urinary toxicity. Lim et al100 used a different method of hypofractionation where a simultaneous integrated boost was used to deliver 67.5 Gy in 25 fractions to the prostate. Using this technique, 66 patients were treated and there were 5 cases of acute grade 3 urinary toxicity and no other grade 3 or 4 toxicity. There is less data available regarding the efficacy of hypofractionated treatment regimens, but Norkus et al101 did a small randomized trial comparing 74 Gy in 37 fractions with 13 fractions of 3 Gy with 4 fractions of 4.5 Gy for a total dose of 57 Gy. They found that at 1 year the biochemical response rates were similar, but further follow-up is needed. Leborgne et al102 performed a retrospective comparison of patients treated with either hypofractionation (3 Gy per fraction) or standard fractionation (2 Gy per fraction). Their results showed similar 5-year biochemical control rates of 96% and 84% for low-risk and intermediate-risk disease patients with no statistically significant difference in toxicity. On the basis of the results of these phase I and II trials, hypofractionation seems to be a safe and possibly efficacious way to treat prostate cancer, but this approach should continue to be used with caution until more mature studies have been performed.
Another approach to hypofractionation that is receiving significant attention is stereotactic body radiation therapy (SBRT). Improvements in techniques and technology have made it possible to perform SBRT—a technique that sends very precisely targeted radiation to a tumor while minimizing radiation to adjacent normal tissue. The treatment is typically delivered in a significantly hypofractionated manner consisting of 3 to 5 fractions. Madsen et al103 described the experience of a phase I/II trial at the Virginia Mason Medical Center. Implanted fiducials and daily stereotactic localization were used to deliver 33.5 Gy in 5 fractions. They treated 40 patients with only 1 acute grade 3 urinary toxicity and had a 48-month actuarial biochemical control rate of 90%. A phase I/II trial reported by Tang et al104 included T1-T2b tumors treated with IMRT using implanted fiducial markers and daily imaging to give 35 Gy in 5 fractions. A group of 30 patients was treated, and no grade 3 or 4 toxicity had occurred after at least 6 months of follow-up. A phase II trial by King et al105 using the CyberKnife system was described in which patients were treated with 5 fractions of 7.25 Gy for a total dose of 36.25 Gy. There were 2 late grade 3 urinary toxicities in this 32-patient group, and no patient had biochemical failure after at least 12 months minimum follow-up. The use of hypofractionation in general and a stereotactic approach looks very promising, but more robust studies with longer follow-up clearly are needed.
Well designed clinical trials are highly desirable to compare radical prostatectomy and irradiation, taking into account patient selection, staging methods, tumor characteristics, prognostic factors, etc. Endpoints should include survival, clinical or chemical failure, morbidity, and quality of life, and the cost-effectiveness of either therapeutic modality.
* Definitive EBRT for the treatment of stage T1 and T2 prostate cancer is as effective as other treatment modalities (eg, radical prostatectomy, brachytherapy).
* Dose escalation using IMRT has an improved therapeutic ratio with improved PSA relapse-free survival rates and reduced gastrointestinal and genitourinary toxicity.
* Pelvic lymph node irradiation is beneficial for treating stage T1 and T2 prostate cancer; however, a 15% or greater risk of having positive pelvic lymph nodes should exist.
* The role of androgen blockade remains undefined in low-risk patients; however, it benefits patients with high-risk stage T1 and T2 prostate cancer.
* The “Phoenix definition”—a posttreatment rise of PSA ≥2 ng/mL above the nPSA—has been considered biochemical failure after EBRT. This, however, can be confounded by a PSA bounce that can occur in up to 25% of men from 12 to 24 months after treatment. Therefore, caution must be exercised in defining failure after prostate irradiation.
* There are only limited data comparing proton beam therapy with other methods of irradiation or to radical prostatectomy for treating stage T1 and T2 prostate cancer. Further studies are needed to clearly define its role for such treatment.
* Hypofractionation, including SBRT, seems to be safe and efficacious based on phase I and II trials; however, this approach should continue to be used with caution until more mature studies have been performed.
* The use of oral erectogenic medication is beneficial for some patients with erectile dysfunction after irradiation for prostate cancer.
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