This is the current release of the guideline.

This guideline updates a previous version: Expert Panel on Radiation Oncology– Prostate Work Group: Carlos A. Perez, MD; David C. Beyer, MD; John C. Blasko, MD; Jeffrey D. Forman, MD; David H. Hussey, MD; W. Robert Lee, MD; Shyam B. Paryani, MD; Alan Pollack, MD, PhD; Louis Potters, MD; Mack Roach III, MD; Peter Scardino, MD; Paul Schellhammer, MD; Steven Leibel, MD. ACR Appropriateness Criteria® definitive external beam irradiation in stage T1 and T2 prostate cancer. [online publication]. Reston (VA): American College of Radiology (ACR); 1999.

The appropriateness criteria are reviewed annually and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Stage T1 and T2 prostate cancer

To evaluate the appropriateness of treatment procedures for patients with stage T1 and T2 prostate cancer

Patients with stage T1 and T2 prostate cancer

The guideline developer performed literature searches of peer-reviewed medical journals, and the major applicable articles were identified and collected.

Not stated

Not stated

One or two topic leaders within a panel assume the responsibility of developing an evidence table for each clinical condition, based on analysis of the current literature. These tables serve as a basis for developing a narrative specific to each clinical condition.

Since data available from existing scientific studies are usually insufficient for meta-analysis, broad-based consensus techniques are needed for reaching agreement in the formulation of the appropriateness criteria. The American College of Radiology (ACR) Appropriateness Criteria panels use a modified Delphi technique to arrive at consensus. Serial surveys are conducted by distributing questionnaires to consolidate expert opinions within each panel. These questionnaires are distributed to the participants along with the evidence table and narrative as developed by the topic leader(s). Questionnaires are completed by participants in their own professional setting without influence of the other members. Voting is conducted using a scoring system from 1‒9, indicating the least to the most appropriate imaging examination or therapeutic procedure. The survey results are collected, tabulated in anonymous fashion, and redistributed after each round. A maximum of three rounds is conducted and opinions are unified to the highest degree possible. Eighty percent agreement is considered a consensus. This modified Delphi technique enables individual, unbiased expression, is economical, easy to understand, and relatively simple to conduct.

If consensus cannot be reached by the Delphi technique, the panel is convened and group consensus techniques are utilized. The strengths and weaknesses of each test or procedure are discussed and consensus reached whenever possible. If "No consensus" appears in the rating column, reasons for this decision are added to the comment sections.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

Criteria developed by the Expert Panels are reviewed by the American College of Radiology (ACR) Committee on Appropriateness Criteria.

ACR Appropriateness Criteria®

Clinical Condition: Definitive External Beam Irradiation in Stage T1 and T2 Prostate Cancer

Variant 1: 55-year-old male, asymptomatic in PSA screening program. PSA 5.2 ng/ml. Prostate within normal limits. No palpable lesions. Multiple needle biopsies of the prostate showed adenocarcinoma. Gleason score 3+3=6. Metastatic workup negative.

Note: Abbreviations used in the table are listed at the end of the "Major Recommendations" field.

Variant 2: 63-year-old male, minimal dysuria and urinary frequency, in PSA screening program. PSA a year ago was 3.2, recent PSA 8.2 ng/ml. Rectal exam showed no palpable abnormality in the prostate. Multiple quadrant biopsies demonstrate adenocarcinoma. Gleason score 3+2=5. Metastatic workup negative.

Note: Abbreviations used in the table are listed at the end of the "Major Recommendations" field.

Variant 3: 66-year-old male with minimal difficulty urinating. PSA 10.5 ng/ml. Rectal exam and ultrasound show 1 cm nodular lesion in the peripheral base, right lobe of the prostate. Needle biopsy positive in the nodule adenocarcinoma. Gleason score 3+2=5. Metastatic workup negative.

Note: Abbreviations used in the table are listed at the end of the "Major Recommendations" field.

Variant 4: 68-year-old male with minor difficulty urinating. PSA 12.3 ng/ml. Rectal exam shows moderate enlargement of the prostate (1.5 normal size). No palpable lesions noted. Findings confirmed on transrectal ultrasound. Biopsy of the prostate demonstrates adenocarcinoma. Gleason score 3+4=7. Metastatic workup negative.

Note: Abbreviations used in the table are listed at the end of the "Major Recommendations" field.

Variant 5: 73-year-old male, in screening program. PSA 15 ng/ml. History of arterial hypertension, under control with medication and incipient coronary disease. Rectal exam shows minimal enlargement of the prostate and no palpable lesions. Prostate biopsy shows adenocarcinoma. Gleason score 3+3=6 in 3 of 6 cores. Diagnostic workup negative.

Note: Abbreviations used in the table are listed at the end of the "Major Recommendations" field.

Variant 6: 69-year-old male with long-standing history of coronary disease. Coronary bypass 3 years ago with excellent cardiac status currently. Moderate difficulty urinating. Normal PSA on routine checkup (3.5 ng/ml), hyperplastic prostate (twice normal size) on rectal exam, without palpable nodules. Transurethral resection shows adenocarcinoma. Gleason score 2+2=4 in 10% of chips. Metastatic workup negative.

Note: Abbreviations used in the table are listed at the end of the "Major Recommendations" field.

Variant 7: 78-year-old male in excellent general health, minimal urinary frequency and nocturia. PSA 10 ng/ml. Rectal exam shows prostate somewhat enlarged (1.5 normal size) with 1 cm nodule at the base of the right lobe. Findings confirmed on ultrasound, and directed biopsy shows adenocarcinoma. Gleason score 2+2=4. Metastatic workup negative.

Note: Abbreviations used in the table are listed at the end of the "Major Recommendations" field.

Variant 8: 75-year-old male found to have abnormal PSA on routine checkup (24 ng/ml). Rectal exam shows prostate slightly enlarged without palpable nodularity. Multiple needle biopsies of prostate demonstrate adenocarcinoma. Gleason score 4+4=8. Metastatic workup negative.

Note: Abbreviations used in the table are listed at the end of the "Major Recommendations" field.

Variant 9: 70-year-old man who presented with 3-year history of moderate dysuria, urinary frequency, and nocturia. Rectal exam shows prostate 1.5 normal size. PSA 36 ng/ml. Six-quadrant biopsy of prostate shows adenocarcinoma. Gleason score 4+4=8 in both right and left lobes. Metastatic workup negative.

Note: Abbreviations used in the table are listed at the end of the "Major Recommendations" field.

Summary of Literature Review

The outcome for patients with localized prostate cancer depends upon multiple factors, including the natural history of the disease, the patient's age, and the efficacy and toxicity of a particular therapy. Due to these factors no single therapy is preferred for all prostate cancer patients. The Consensus Development Conference on Management of Localized Prostate Cancer 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 the long natural history; however, more recent studies show a benefit to definitive therapies. A randomized controlled trial comparing observation to 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 under 65 years of age.

The introduction and use of the prostate-specific antigen (PSA) has revolutionized the diagnosis, staging, and evaluation of treatment outcome for prostate cancer. The development and use of PSA in evaluation of treatment outcome has lead 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 includes: low risk (clinical stage T1c-T2a, PSA <10 ng/ml, Gleason score <7), intermediate risk (clinical stage T2b or PSA 10-20 ng/ml, or Gleason score =7), high risk (clinical stage T2c, or PSA >10 and Gleason score >7). Additionally, the use of the percentage of positive prostate biopsies has been proposed as a prognostic indicator of biochemical PSA control. One study demonstrated a significant difference in biochemical control in patients treated with external beam radiation or radical prostatectomy when stratified by <34% positive biopsies versus (vs)>50% positive biopsies.

Role of External Beam Irradiation

External beam irradiation 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. One study reported improved local control rates with doses greater than 6500 cGy, particularly in stage C patients. Another study with 1,348 patients with stage B and C tumors, reported actuarial 5-year local recurrence rates of approximately 35% for patients with stage C treated to doses of less than 6000 to 6490 cGy, 29% for doses of 6500 to 6990 cGy and, 19% for doses of 7000 cGy or higher. By 7 years, 32% of patients receiving 6500 to 6900 cGy and 24% treated with higher doses had local recurrences. More recently, a randomized controlled trial demonstrated a statistically significant improvement in freedom from PSA failure in patients treated to a total dose of 78 Gy compared to 70 Gy 3-dimensional radiation therapy. Patients treated to 78 Gy had a 5-year-freedom from failure rate of 79% vs 69% for the 70 Gy group. There is a generally accepted consensus that dose escalation is important in treatment of 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 within this document under the 3D 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.

Recently the Radiation Therapy Oncology Group (RTOG^®) 9413 evaluated the use of whole pelvic vs prostate-only radiation in a randomized controlled trial in patients with positive pelvic lymph nodes, seminal vesicle involvement, or a greater than 15% risk of having metastatic pelvic lymph nodes. Approximately 30% of the patients had clinical stage T1-T2b disease, and 30% had a Gleason score <7. Patients were additionally randomized to neoadjuvant vs concurrent androgen deprivation therapy in the 2x2 factorial designed trial. They reported that data from a 59-month follow-up demonstrated a significant improvement in biochemical control and disease progression with the use of whole pelvic radiation and androgen blockage. Patients treated with whole pelvic radiation combined with neoadjuvant and adjuvant androgen deprivation therapy experienced a 60% progression free-rate compared to 44% for prostate-only radiation with neoadjuvant and adjuvant androgen deprivation therapy. In subset analysis, the intermediate group (defined in this study as Gleason Score =6 and PSA >30 ng/ml or Gleason Score 7-10 and PSA <30 ng/ml) patients showed the largest improvement with the use of whole pelvic radiation and neoadjuvant androgen deprivation therapy.

Results of Treatment

The outcome for patients treated with external beam radiation 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 was 77% for external beam radiation 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. Other authors have also demonstrated that biochemical disease-free survival rate directly correlates with the pretreatment PSA and Gleason score, with a lower PSA and Gleason score resulting in an increased biochemical disease-free survival rate.

The biochemical control rates following prostate irradiation have also shown a direct relationship to radiation dose. One group of researchers reported on a study of 1,041 patients treated with external beam radiation that demonstrated a 5-year biochemical relapse-free survival rate of 87% in patients receiving a total dose greater than 72 Gy compared to 55% in patients receiving less than 72 Gy. Additionally, another group of researchers demonstrated that patients treated to doses of 75.6 Gy or greater had a 90% 5-year biochemical recurrence-free survival rate vs 77% for those treated to 64.8-70.2 Gy, in low-risk patients. The corresponding biochemical recurrence-free survival rates for intermediate patients was 70% vs 50%, and 47% vs 21% for high-risk patients, favoring the higher dose group.

Numerous reports have been published of results of treatment of localized carcinoma of the prostate with interstitial brachytherapy, using iodine (I) 123 (I-125), and palladium 103 (103Pd); 12- and 15-year results have been comparable to those obtained with external irradiation alone. Interstitial brachytherapy will be the subject of a separate statement.

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 underestimate patient-reported toxicity. One study has demonstrated that following radiation therapy, patients commonly report irritated bowel and bladder symptoms at 3 months, which most resolve by 12 months. Following radical prostatectomy, patients reported significant urinary incontinence (11%) and the need for absorptive pads (35%), symptoms which were rarely reported in patients undergoing radiation therapy. Sexual dysfunction was more commonly reported in surgery patients, but slightly improved with time in men less than 65 years of age. Another study reported that radiation therapy patients experienced a 29% decrease in sexual function at 24 months. Of those fully potent prior to 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.

In studies of physician-reported toxicity, the overall incidence of significant urinary or rectosigmoid sequelae is approximately 3% for severe toxicity and 7%-10% for moderate toxicity. Long-term urinary morbidity is rare with a 0.3% urinary incontinence rate following external beam prostate radiation reported in a multi-institutional review. A higher incidence of urethral stricture (about 5% vs. 3%) has been described in patients irradiated after a transurethral resection of the prostate. Some degree of urinary incontinence, sometimes related to stress, is noted in about 2% of patients, more frequently after transurethral resection. The incidence of severe anal/rectal injury requiring colostomy is less than 1%. (See original guideline for more information). The incidence of fatal complications in localized carcinoma of the prostate treated with external irradiation is rare, with a reported rate of 0.2%, demonstrating the low risk of this therapy.

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. A group of researchers 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. (See original guideline document for more information.)

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 to men with penile bulb doses below 52.5 Gy (p=0.039). The incidence of erectile dysfunctions depends on a patient's potency prior to prostate radiation, along with the time point and method in which potency is measured. Several series reported impotency rates ranging from 30%-45%, which increases with time in patients potent prior to radiation therapy.

The use of oral erectogenic agents such as Sildenafil has shown a benefit, more so in radiation patients in comparison to patients undergoing radical prostatectomy. One study demonstrated a 76% improvement in erectile function with the use of Sildenafil over a 5-week interval. Leg, scrotal, or penile edema is extremely rare in patients treated with irradiation alone (less than 1%), but its incidence ranges from 10%-30%, depending on the extent of lymph node dissection, in patients receiving "oral erectogenic agents."

The use of IMRT has further improved the therapeutic ratio. 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. (See original guideline document for more information.)

Impact of Surgical Staging on Therapeutic Results

Prior to the use of PSA, patients who underwent surgical staging and who were shown to have negative nodes experienced a better outcome from irradiation than those staged by imaging alone. One study investigated patients with clinical stage A2 and B carcinoma of the prostate. In an update, the 12-year disease-free survival (DFS) rate was 48% in patients surgically staged, compared with 38% in those staged by nonsurgical radiographic imaging (p=0.017), suggesting that in the latter group some patients had pathologically positive lymph nodes. (See original guideline document for more information.)

In the PSA era the rate of positive lymph nodes at the time of radical prostatectomy has been reported at less than 5% compared to previous rates of 20%-30%. A group of researchers demonstrated the low likelihood of pelvic lymph node metastasis in patients with low-risk disease, suggesting that the exclusion of pelvic lymph node dissection would not affect treatment outcome. Currently, pelvic lymph node irradiation is infrequently performed for stage T1 and T2 prostate cancer unless a patient has a 15% or greater risk of having positive pelvic lymph nodes. For these patients, pelvic radiation therapy has shown a benefit in biochemical control and disease progression.

Comparison of Outcome with Irradiation or Radical Prostatectomy

Little data exist directly comparing prostate radiation therapy and prostatectomy in a prospective randomized manner. Comparison of these modalities has been difficult due to selection bias, where traditionally older patients or those not surgical candidates were treated with radiation therapy and younger, healthier patients were selected for radical prostatectomy. Additionally 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.

The DFS and the cause-specified (CSS) survival rates reported in many radiation therapy series are comparable to those obtained with radical prostatectomy, as documented in several reports. Nonrandomized studies have compared outcomes using biochemical (DFS) rates for patients treated with external beam radiation therapy or radical prostatectomy. A group of authors 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 three different risk groups. The group expanded their analysis, comparing results in 766 patients treated with irradiation, 218 treated with implant with or without neoadjuvant androgen deprivation therapy, 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 three different risk groups. However, 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 prior to 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% - 30% after brachytherapy. (See the original guideline document for more information.)

Prostate-Specific Antigen (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 post treatment assessment of outcome. Screening of patients with PSA and digital rectal examination (DRE) has significantly increased the number of patients diagnosed with very small, microscopic lesions. A lower incidence of positive nodes (5%-17%) has been reported in patients with stage T1b, T1c, and T2 disease diagnosed in a PSA screening program compared with patients in RTOG protocols (20%-30% in stage T2) who were surgically or radiographically staged without PSA testing. (See original guideline document for more information.)

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. A group of researchers 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.

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 three consecutive increases in PSA. For clinical trials the date of failure should be the midpoint between the postirradiation nadir PSA (nPSA) and the first of the three 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 perhaps 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 following external beam radiation therapy for prostate cancer. This conference was held in Phoenix and is referred to as the "Phoenix definition." The original ASTRO definition of three 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 following external beam radiation therapy with or without androgen deprivation therapy, 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.

Presently, no definition of PSA failure has been shown to be a surrogate for clinical progression or survival. Nadir PSA after irradiation has a prognostic value similar to that of pretreatment PSA and other prognostic variables.

An additional complicating factor is the fluctuation in PSA that has been demonstrated following prostate radiation. This phenomenon, referred to as PSA bounce, can occur in up to 25% of men from 12 to 24 months following 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. (See the original guideline document for more information.)

Positive Biopsy of the Prostate after Definitive Radiation Therapy

The use of prostate biopsy following radiation therapy is not commonly recommended due to the slow death rate of prostate adenocarcinoma following irradiation. Several authors have reported histologic evidence of viable adenocarcinoma in the prostate at various times following completion of radiation therapy. One study noted that there was a decreasing incidence of positive biopsies as a function of time after irradiation (from 70% at 6 months to 20% after 24 months). These data should be interpreted in the light of radiobiological data indicating that cell death after radiation exposure is a post-mitotic event. In view of the long doubling time of many prostate tumors in early biopsies, cells that harbor lethal damage, but have not had an opportunity to morphologically express it may be misinterpreted as viable cells. There was no significant correlation between the status of the prostatic biopsies (positive or negative) and subsequent survival rates. (See original guideline document for more information.)

The rate of positive specimens is also related to the initial clinical stage of the tumor; one study noted a positivity of 28% for stage B1, 41% for stage B2, and 62% for stage C lesions. Likewise, another study reported no positive biopsies in patients with stages A2 and B, but rates of 38%, 59%, and 74% for small stage B2, large stage B2, and stage C tumors, respectively.

In a study of 94 patients with clinically negative digital examination of the prostate who did not receive hormonal therapy until documented evidence of recurrence and on whom routine biopsies of the prostate were performed 18 months or longer after irradiation, the incidence of positive biopsies was 1 of 10 (10%) for stage A2 lesions, 10 of 55 (18%) for stage B lesions, and 6 of 29 (21%) for stage C lesions. By 10 years 75% of the patients with positive biopsies developed clinical local failure; the DFS rate was 20% compared with 62.9% respectively, in patients with negative biopsies.

Postirradiation biopsy findings were closely related to the clinical status of the prostate gland in the experience of several authors, who reported 89% and 64% incidence, respectively, of positive biopsies in patients with suspected or definite clinical evidence of tumor regrowth, whereas the same authors reported 25% and 20% positivity, respectively, in patients with negative clinical examination of the prostate. In another publication, the local recurrence rate was 52% at 5 years with a positive biopsy vs. 12% with a negative specimen, and at 10 years, the rates were 72% and 30%, respectively (p<0.001). When only patients with a normal DRE were considered, the risk of local recurrence at 10 years was 50% with a positive biopsy and 25% with a negative biopsy.

Thus, timing of postirradiation biopsies and whether they are routinely performed only in patients with suspected recurrence will significantly affect the positivity of the examination and the correlation with outcome.

The prognosis is significantly better in patients with an isolated recurrence in the prostate gland compared with patients who also have distant metastases. One study reported 50% 5-year and 22% 10-year survival rates from diagnosis of failure after irradiation in 74 patients with initial isolated prostatic clinical recurrence, in contrast to 20% and 0%, respectively, when distant metastases were present (alone or associated with pelvic recurrence). (See original guideline document for more information.)

Three-Dimensional Treatment Planning and Conformal Therapy

With the advent of 3-dimensional (3D) treatment planning and conformal radiation therapy, it is feasible to deliver higher tumor doses to selected target volumes, thus improving tumor control probability without increasing treatment morbidity.

A group of authors 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). (See original guideline document for more information.)

Dose Escalation with 3D Conformal Irradiation

With the use of computed tomography-based 3D treatment planning software, dose escalation is possible without an increase in treatment-related morbidity. Additionally, the use of image guidance has further increased the ability to accurately target the prostate and avoid excess exposure to normal tissue. Several 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.

One study 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 (bNED) rate of 69% compared with 80% and 89% for patients treated with 75 or 80 Gy, respectively. In patients with PSA levels of 20 ng/ml or higher the corresponding bNED rates were 36%, 46%, and 57%. In 1998, results were updated, with bNED rates of 29% for patients treated with <7150 cGy, 57% with 7150 to 7574 cGy, and 73% with 7575 cGy or higher (p=0.02). (See original guideline document for more information.)

Another study updated results on 324 patients with carcinoma of the prostate irradiated with 3DCRT on a dose-escalation protocol (64.8-66.6 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% with stage T2b, 60% with stage T2c, and 43% with stage C tumors. (See original guideline document for more information.)

Intensity-Modulated Radiation Therapy

The use of IMRT has also provided a decrease in normal tissue toxicity while allowing an increase in radiation dose to the prostate. A group of researchers have shown a decrease in rectal toxicity compared to 3DCRT, with a reduction of grade 2-3 rectal bleeding from 15% to 3% with IMRT. In a 2002 report of 772 patients, the 3-year actuarial rectal grade 2 toxicity was 4%, and the urinary grade 2 toxicity was 15%, comparing favorably to 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 in 2006 of 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 prior to IMRT.

Irradiation and Androgen Deprivation Therapy

The use of androgen deprivation therapy has demonstrated a significant effect in the treatment of prostate cancer, but remains undefined in low-risk patients. One study presented laboratory data showing that withdrawing testosterone prior to irradiation of androgen-dependent adenocarcinoma cells significantly reduced the cell kill compared to radiation alone or testosterone withdraw following irradiation.

Initially a group of authors showed a lower rate of positive prostate biopsies at 12 and 24 months with the use of combined androgen blockade 3 months prior to and following 64 Gy external irradiation. The benefit of adjuvant androgen blockade was demonstrated by another group in the European Organisation for Research and Treatment of Cancer (EORTC) 22863 trial. Locally advanced patients were treated with pelvic and prostate irradiation to 70 Gy followed by 3 years of zoladex, with an overall survival benefit and disease-specific survival benefit at 66 months follow-up with the long-term use of zoladex. The benefit in survival and local control was additionally seen in RTOG 8531. (See original guideline document for more information.)

Neoadjuvant androgen deprivation has also shown to be beneficial in patients with greater than a 15% risk of lymph node involvement, when combined with whole pelvic radiation therapy.

Most recently a randomized trial demonstrated an overall survival benefit with the use of 6 months of androgen deprivation 3 months prior to, 3 months during, and 3 months following 3DCRT to 70 Gy (67 Gy prescribed to the 95% isodose line). The trial included patients with a PSA of 10?40 ng/ml or Gleason score 7 or greater. Low-risk patients were included if magnetic resonance imaging evidence of extraprostatic disease extension or seminal vesicle invasion was present. For patients with early localized disease the specific subgroups that will most benefit from the combination of androgen deprivation therapy and external prostate irradiation is undetermined. However, this was one of the smallest of the four trials yet with a radiotherapy-only control arm and the only study to show an overall survival advantage. Whether the use of higher doses of external beam radiotherapy might have obviated the need for androgen deprivation therapy is unknown.

Proton Therapy

The potential dosimetric benefit of the Bragg peak has lead to the investigation of proton therapy in treating prostate carcinoma. Most recently a group of researchers published a report on the use of proton boost combined with 3D 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 prior to a 50.4 Gy photon dose. This equated to a conventional total dose equivalent of 70.2 GyE (conventional dose) vs. 79.2 GyE (high dose). The results demonstrated a benefit of a high total equivalent dose, with 5-year biochemical failure rates of 37.3% (95% CI = 28.4%-46.3%) for the conventional-dose group and 19.1% (95% CI = 11.1%-27.1%) for the high-dose group (p=0.00001). These data demonstrate a biochemical control benefit for a cumulative higher prostate dose, which has been demonstrated by photon-only radiation as well. (See original guideline document for more information.)

Abbreviations

• 2D-CT, 2-dimensional computed tomography
• 3D-CT, 3-dimensional computed tomography
• CT, computed tomography
• HDR, high-dose rate
• IMRT, intensity-modulated radiation therapy
• LDR, low-dose rate
• PSA, prostate-specific antigen

None provided

The recommendations are based on analysis of the current literature and expert panel consensus.

Selection of appropriate treatment procedures for stage T1 and T2 prostate cancer

An American College of Radiology (ACR) Committee on Appropriateness Criteria and its expert panels have developed criteria for determining appropriate imaging examinations for diagnosis and treatment of specified medical condition(s). These criteria are intended to guide radiologists, radiation oncologists, and referring physicians in making decisions regarding radiologic imaging and treatment. Generally, the complexity and severity of a patient's clinical condition should dictate the selection of appropriate imaging procedures or treatments. Only those exams generally used for evaluation of the patient's condition are ranked. Other imaging studies necessary to evaluate other co-existent diseases or other medical consequences of this condition are not considered in this document. The availability of equipment or personnel may influence the selection of appropriate imaging procedures or treatments. Imaging techniques classified as investigational by the U.S. Food and Drug Administration (FDA) have not been considered in developing these criteria; however, study of new equipment and applications should be encouraged. The ultimate decision regarding the appropriateness of any specific radiologic examination or treatment must be made by the referring physician and radiologist in light of all the circumstances presented in an individual examination.

An implementation strategy was not provided.

Not applicable: The guideline was not adapted from another source.

The American College of Radiology (ACR) provided the funding and the resources for these ACR Appropriateness Criteria®.

Committee on Appropriateness Criteria, Expert Panel on Radiation Oncology–Prostate

Panel Members: David C. Beyer, MD; Daniel R. Reed, DO; Mack Roach III, MD; Gregory Merrick, MD; Jeff M. Michalski, MD, MBA; Brian J. Moran, MD; Seth A. Rosenthal, MD; Carl J. Rossi Jr, MD; Peter R. Carroll, MD; Celestia S. Higano, MD

Not stated

This is the current release of the guideline.

This guideline updates a previous version: Expert Panel on Radiation Oncology– Prostate Work Group: Carlos A. Perez, MD; David C. Beyer, MD; John C. Blasko, MD; Jeffrey D. Forman, MD; David H. Hussey, MD; W. Robert Lee, MD; Shyam B. Paryani, MD; Alan Pollack, MD, PhD; Louis Potters, MD; Mack Roach III, MD; Peter Scardino, MD; Paul Schellhammer, MD; Steven Leibel, MD. ACR Appropriateness Criteria® definitive external beam irradiation in stage T1 and T2 prostate cancer. [online publication]. Reston (VA): American College of Radiology (ACR); 1999.

The appropriateness criteria are reviewed annually and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site .

ACR Appropriateness Criteria® Anytime, Anywhere™ (PDA application). Available from the ACR Web site .

Print copies: Available from the American College of Radiology, 1891 Preston White Drive, Reston, VA 20191. Telephone: (703) 648-8900.

The following is available:

• ACR Appropriateness Criteria®. Background and development. Reston (VA): American College of Radiology; 2 p. Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site .

None available

This NGC summary was completed by ECRI Institute on September 15, 2009.

Instructions for downloading, use, and reproduction of the American College of Radiology (ACR) Appropriateness Criteria® may be found on the ACR Web site .