Prostate Cancer - External Beam Radiotherapy Overview of EBRT

External beam radiation therapy (EBRT) remains one of the primary treatment modalities for patients with localized or locally advanced prostate cancer. The use of modern equipment has fostered greater interest in this form of treatment over the past 25 years; however, the origins of this therapy extend back to the early 20th century.

History of the procedure

Radiation therapy for prostate cancer was first introduced to the United States in 1915 in the form of radium applicators. These devices were positioned adjacent to the prostate (ie, in the urethra, bladder, or rectum). This form of therapy offered local treatment to the prostate but was associated with significant morbidity.

Over the next 3 decades, EBRT was used with greater frequency. Unfortunately, the early therapy machines generated low-energy x-ray beams that lacked the ability to penetrate deep into the pelvis. As a result, treatments were often palliative and commonly caused significant skin morbidity (ie, erythema, desquamation, or both). The technological limitations of low-energy radiation beams greatly restricted the use of radiotherapy in advanced prostate cancer throughout the first half of the 20th century.

The role of radiotherapy in the palliative treatment of prostate cancer also was limited by discoveries regarding the endocrine-sensitive nature of this malignancy. As the androgen dependence of this tumor became increasingly clear, clinical interest turned toward eliminating the primary source of hormone production in patients with advanced disease. Orchiectomy became an accepted form of therapy for advanced carcinoma of the prostate until estrogenic products were developed in the 1950s and 1960s.

The role of radiotherapy in the management of prostate carcinoma became clearer with technological advancements that followed World War II. Megavoltage (ie, energy >1000 kV) radiation resulted in x-ray beams that penetrated more deeply and that were associated with significantly less skin and subcutaneous morbidity. This property prompted further investigation of the role of radiotherapy in more deeply seeded tumors.

During the 1950s and 1960s, megavoltage radiation was more commonly available from the decay of radioactive isotopes (eg, cobalt-60 units, 1.25 MeV); however, the generation of high-energy x-rays became increasingly popular during the latter portion of the 20th century. The names of the equipment often indicated the mode by which the x-rays were created (eg, Betatron, Linear Accelerator, Proton Beam, and Neutron Beam). The role of the Linear Accelerator as the most common form of EBRT was established by the early 1980s.

Clinical use of higher-energy radiation beams allowed the science of radiation oncology to develop as an accepted mode of therapy for both advanced and early-stage prostate carcinoma. This experience was developed largely due to the work of Malcolm Bagshaw and colleagues at Stanford University.^[1]

In addition to allowing for deeper penetration into tissue, linear accelerators provided a beam with more sharply delineated borders. In turn, this allowed higher doses of radiation to be directed at the clinical target (eg, prostate, seminal vesicles, regional lymph nodes). Improved technology, treatment planning, and dosimetry allowed localized therapy with curative intent.

Heightened awareness of this disease and an apparent increase in the incidence of the disease during the early 1990s continued to serve as a further stimulus for more patients to consider EBRT in the management of this disease.

Current status

With the evolution of improved computer-based treatment planning, modern radiotherapy techniques have essentially replaced conventional radiotherapy treatments. These modern techniques include 3-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), and image-guided radiotherapy (IGRT).

The advantages of the newer forms of treatment are the abilities to escalate tumor dose and to minimize toxicity to normal tissue. The importance of the former attribute is enhanced disease control and the latter is improved patient compliance and satisfaction.

Despite this, a 2008 research summary by the Agency for Healthcare Research and Quality (AHRQ) reviewed 5 randomized controlled trials of EBRT and concluded that no regimen, whether conventional, high-dose conformal, dose fractionation, or hypofractionation, was superior in reducing overall or disease-specific mortality.^[2]

Future role of conventional radiotherapy

As biochemical endpoints of therapy replace clinical endpoints, conventional radiotherapy will likely have a diminished role in the management of localized prostate cancer. This is largely due to a number of variables, including an appreciation of the importance of dose escalation, the ability to offer patient's more precise target localization, and the use of combined treatment strategies (ie, adding hormonal manipulation or brachytherapy to the primary treatment).

Modern literature supports the role of conventional EBRT in the management of localized prostate carcinoma. In contrast to this view is historical information reported by Paulson et al, whose Veterans Administration trial showed that in early-stage disease, surgery offered better results than EBRT. However, randomization schema and statistical analysis of their data make definitive conclusions difficult.

Although the Paulson study was a prospective trial, it was conducted prior to the routine use of prostate-specific antigen (PSA) testing and pelvic imaging. No similar study has been conducted in the PSA era. In fact, an ongoing trial at the US National Cancer Institutes (NCI), the Prostate Intervention versus Observation Trial (PIVOT), failed to include radiotherapy as a treatment arm.

The 2 forms of therapy are unlikely to be directly compared in the future. Retrospective comparisons of the 2 treatment methods, using PSA-based outcomes, suggest no significant difference between the two treatments. The results for patients with T1/T2 disease who are treated with conventional EBRT are similar to results achieved after radical prostatectomy.

Both forms of therapy offer comparable rates of disease control. Ten-year survival rates for the 2 treatments are similar in studies by both Bagshaw^[3] and Perez^[4] . Each form of therapy offers 10-year survival rates in excess of 60%.

External beam radiation therapy (EBRT) is commonly used in the treatment of patients who have a greater likelihood of non–organ-confined disease. For patients who decide against surgical intervention, determining the presence of non–organ-confined disease is typically based on a review of tumor-related variables that have been shown to correlate with extraglandular disease extension (eg, high stage, high Gleason scores, high prostate-specific antigen [PSA] levels).

Certain patients may not be optimum candidates for external beam radiation therapy (EBRT) (eg, patients with a history of bowel disorders, including ulcerative colitis and diverticular disease, as well as those with poorly controlled diabetes).^[5] These patients are known to have preexisting conditions that may place them at risk for either more intense morbidity or more protracted morbidity.

Despite the decreasing frequency of conventional external beam radiation therapy (EBRT) radiotherapy in the management of prostate carcinoma, no significant body of medical literature indicates that this treatment should be abandoned. In fact, a recently completed Radiation Therapy Oncology Group (RTOG) trial (94-13) suggests that whole-pelvis radiotherapy (ie, conventional treatment) may improve the local regional control of disease in patients with increased risk of non–organ-confined cancer (ie, high Gleason score and high prostate-specific antigen [PSA] level).^[6] Regardless, a clear understanding of the former standard treatments allows a greater appreciation of more current techniques.

Simulation

Simulation is a process during which the patient is prepared for therapy. The patient is placed in the treatment position, and the radiation field or fields are marked. Simulation for conventional EBRT relies on fluoroscopy and plain radiographs. The use of these less sophisticated techniques is generally considered acceptable because the treatment borders (margins) are more inclusive than those used in 3-dimensional and IMRT treatments. CT-based simulation is becoming increasingly popular for 3D-CRT and IMRT.

Localization of the target and adjacent normal tissue is critical in the planning of both conventional therapy and 3-dimensional treatment. For conventional therapy, the patient is placed in the supine position. Radiographs of the AP, PA, and lateral fields are obtained. Typically, treatment fields are shaped with corner blocks only, and borders are based on bony landmarks.

Normal tissue is delineated using radiopaque contrast materials in the rectum and bladder. Retrograde urethrograms are used to establish the inferior margin of the prostate. Blocking of normal structures is performed in most cases; however, custom blocking is not always necessary.

Technique of EBRT

Conventional external beam radiation therapy (EBRT) is typically delivered using a 4-field technique. The 4 fields (anteroposterior [AP], posteroanterior [PA], left lateral, right lateral) are designed to include the prostate, seminal vesicles, and regional lymphatics. This technique is used for cumulative doses of 4500-5000 cGy delivered over 5-5.5 weeks. An additional dose of approximately 20 Gy to a smaller field (ie, a boost) is administered to the prostate and periprostatic tissues.

Total doses of 66.6-70 Gy were once typically used; however, these doses are too low to provide the same rates of local and regional controlled compared with modern standards (72-80 Gy).^{[7, 8]} The boost field is designed to limit treatment to the target volume (prostate, seminal vesicles, 1- to 2-cm margin) and to offer additional shielding to the posterior wall of the rectum, the urethra, and the small bowel. The reduced volume of normal tissue included within the radiation field is associated with a reduction in morbidity.

Whole-pelvis radiotherapy (ie, superior border at L5-S1 junction) is rarely used because of the increased bowel toxicity and lack of clear outcome improvement. Whole-pelvis radiotherapy is offered to some patients when extensive regional disease is either present or expected. A recently completed RTOG trial (94-13) suggests that large-field radiation treatment may be beneficial in patients with higher Gleason scores and in those who receive adjuvant hormonal blockade.^[6]

When regional lymph nodes are to be treated, the superior border of the pelvic field is at the level of the midsacroiliac joints, and the inferior border is usually 1-1.5 cm inferior to the junction of the membranous and prostatic urethra, as demonstrated on the urethrogram (ie, pencil point). The lateral borders on the AP and PA fields are 1.5-2 cm laterally to the pelvic brim.

The superior and inferior borders remain unchanged on the lateral fields. The posterior border of the lateral field is commonly placed at the S2/S3 interspace. The anterior border is established to include the anterior portion of the symphysis pubis. The field edges for cone-down, or boost-field treatments, share the same inferior border as the primary field.

Superiorly, the fields extend to the top of the acetabulum and laterally to include two thirds of the obturator foramen. Dose distributions for conventional treatment are typically generated in a single plane, and the dose is prescribed at the isocenter and normalized at the 100%-isodose line.

Outcome

One of the major determinants of outcome for clinically localized prostate cancer is tumor stage. Staging systems have always acknowledged the significance of extraglandular disease. In both the Whitmore classification schema and, more recently, the tumor-node-metastasis (TNM) system, the presence of disease beyond the prostate (ie, stage C and stage T3, respectively) has been recognized as indicative of a poor prognosis. This observation predates the use of modern prognostic variables associated with increased risk of extracapsular disease (ie, elevated PSA level and high Gleason score).

Although radiation therapy was used in the management of locally advanced lesions, the long-term results, even in the pre-PSA era, were relatively poor. Patients diagnosed with locally advanced disease (ie, stage C or T3 disease) who were treated with EBRT had acceptable disease-free survival (DFS) rates at 5 years, approaching 60%-65% in most series; however, 10-year DFS rates offered less encouraging results (30%-40%). At 15 years, failure rates continued to increase (70%-80%).

These results typify the experience gained through review of historic controls; however, they are significantly limited because of less-sophisticated treatment techniques, total dose offered, and inadequacies of staging. Newer information continues to be generated using modern radiotherapy techniques and increasing therapy doses. Similarly, the rates of disease control are more carefully reported (eg, PSA-based outcome in lieu of clinical failure endpoints).

Patients undergoing definitive radiotherapy are typically deemed as having achieved biochemical control of disease if the PSA level is not rising and the serum PSA level is less than 0.5 ng/mL. Several definitions of biochemical failure have been proposed in the radiation oncology literature; however, 3 consecutive rises in serum PSA level have been proposed as an accepted marker for failure in an American Society of Therapeutic Radiation Oncology (ASTRO) consensus conference.

Despite the increasing body of literature that considers PSA level a measurable determinant for treatment failure or success, this tumor marker has been in wide use for only 15 years. Prior to this time, endpoints for clinical outcome were largely subjective and included prostate assessments based on clinical examination (eg, digital rectal examination [DRE]) and several nonspecific serum markers, including alkaline phosphatase and acid phosphatase. The poor sensitivity of DRE has made this form of posttreatment assessment increasingly less useful.

As an increasing number of studies use serum PSA level to assess treatment outcome, comparison with larger historic series (including those of American College of Radiology's Patterns of Care Studies) becomes increasingly difficult. Several institutions have reported 5-year and 10-year PSA-based outcome; however, the limited follow-up with posttreatment PSA studies and the protracted natural history of the disease make comparisons with historical data difficult. In contrast to clinical outcome, PSA-based outcome suggests that long-term disease control can be difficult for locally advanced disease.

Complications of External Beam Radiation Therapy

Morbidity of radiation treatment is intimately linked to the volume of normal tissue treated. Conventional radiotherapy includes the irradiation of large volumes of tissue, including the skin, small bowel, bladder, large bowel, bones of the pelvis, and additional areas of soft tissue (including nerves). Each organ can experience irritation during a course and, potentially, following a course of radiotherapy.

A brief review of commonly encountered morbidities is appropriate. Patients are told that any of the following conditions may arise during the course of radiation treatments and may persist for up to 3 months following therapy (ie, acute morbidity). A significantly smaller proportion of all patients (3-5%) have persistence of symptoms beyond 3 months or develop new symptoms following the completion of therapy.

Skin complications

Because radiation can cause perturbation of the epidermis and dermis, reddening of the skin may develop during therapy. This is relatively uncommon, given the frequent use of high-energy photon beams (≥ 10 MV). Skin irritation is common in patients with a fair complexion; however, early intervention can limit progression to either dry or moist desquamation. Hair loss in the irradiated field (epilation) is commonly seen.

Small intestine complications

Radiation therapy can cause changes to the epithelial lining of the small intestine. In turn, absorption and transit can be impaired. Patients may experience more frequent bowel movements or less-formed stool. Minimizing the extent of the small bowel that is treated is the goal of treatment planning, but this is more difficult with conventional therapy than with conformal therapy or IMRT.

Patients undergoing radiotherapy are commonly advised to reduce their consumption of certain high-fiber foods (eg, fruits or uncooked vegetables), which can have a laxative effect. If dietary modifications do not correct frequent bowel movements, patients often receive prescriptions for antidiarrheal medications.

Bladder complications

During conventional radiotherapy, the entire bladder is usually treated, which can cause adverse effects, including urinary frequency, urgency, and, less frequently, incontinence. Patients commonly experience dysuria, which can be lessened with increased fluid consumption. Hematuria occasionally occurs but should be carefully evaluated to ensure that an occult urinary tract infection is not present.

Whether other associated urinary tract symptoms (eg, frequency, urgency) are due to bladder or urethral irritations is often difficult to discern. Regardless, both symptoms occur quite frequently during EBRT and are seen through the continuum of radiotherapy (ie, conventional therapy to IMRT). This observation supports the importance of urethral irritation to both urgency and frequency.

Large bowel complications

Toxicity, including proctitis, may develop in segments of the distal bowel included in the radiotherapy fields. This is observed more commonly with conventional radiotherapy than with conformal therapy. To minimize perianal inflammation, patients are encouraged to exercise good hygiene while receiving therapy.

Symptoms of proctitis can include fecal urgency, mucous discharge, and rectal bleeding. If rectal bleeding or mucous discharge is noted, treatment with steroid-containing suppositories may be necessary. Although rare, measurable changes in levels of hemoglobin and hematocrit may occur. Blood should be tested weekly to assess this possibility.

Pelvic bone complications

A number of pelvic bones receive radiation during the treatment of prostate cancer. As expected, patients receiving conventional radiotherapy have a large volume of bone tissue (ie, marrow reserve) irradiated. Weekly complete blood counts should be performed to review this possibility, which is typically noted in white blood cell and platelet counts. Cessation of therapy to allow for recovery of the blood count is rarely necessary.

Nerve complications

Pelvic irradiation exposes both sympathetic and parasympathetic nerves. Posttherapy defects with erectile and ejaculatory function are reported in 30-40% of patients undergoing a full course of EBRT (total doses of ≥ 6660 cGy). The etiology of this injury is not fully understood; however, current thinking suggests that the mechanism may be microvascular changes affecting the blood supply to the nerves.

In 3-dimensional conformal radiotherapy (3D-CRT), the radiation beam is shaped to include a 3-dimensional anatomic configuration of the prostate and any specified adjacent tissue. Adjacent structures include the seminal vesicles and periprostatic adventitial tissues. 3D-CRT allows for more precise delivery of therapy to the target organ or organs.

With increasing access to CT and MRI simulation equipment, as well as more powerful treatment-planning equipment, the use of 3D-CRT has markedly increased over the past decade. Indeed, 3D-CRT has essentially replaced conventional external beam radiation therapy (EBRT) in the management of early-stage prostate cancer.

The transition to this form of therapy has significantly reduced the number of treatment-associated toxicities. More importantly, conforming the radiation dose to a limited target has resulted in several successful dose escalation trials. The success of 3D-CRT is the result of multiple factors, including favorable dose-response relationships, increased ability to reduce radiation to neighboring normal tissue, the relative immobility of the organ (typically < 1 cm), and a high prevalence of disease.

Inherent to the discussion of 3D-CRT is a working knowledge of the terms gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV). The GTV is the delineation of the visible target using common imaging modalities (eg, CT imaging, MRI).

CTV describes the structures that may be beyond the easily visible anatomic structures delineated on CT imaging or MRI. Specifically, the CTV acknowledges the anticipated microscopic extent of tumor, as well as anticipated subclinical areas that may be at risk for disease involvement.

The PTV acknowledges that daily patient positioning and setup vary and should be addressed in creating radiation portals.

Although each of these terms is readily applied to single-organ structures (eg, prostate, seminal vesicles), how well the structures can be defined in the delineation of regional pelvic adenopathy is unclear.

Indications for 3D-CRT

Despite the successful completion of several prospective randomized trials in the management of prostate cancer, several issues remain unclear. Specifically, 3D-CRT is appropriate when (1) the probability that tumor remains within the anticipated target portals (ie, delineation of the GTV, CTV, and PTV for organs at risk) can be adequately determined and when (2) the importance of regional adenopathy in varying clinical settings can be delineated.

Technique of 3D-CRT

The process of 3D-CRT requires the acquisition of imaging data; the initial step is immobilization of the patient. Patients can be positioned in either the supine or prone position. Theoretic advantages of supine immobilization include the ease of daily setup for the patient and staff, the ability to fuse treatment-planning images with previously obtained diagnostic images (ie, MRI), and the relative ease of use when performing daily setup localization with ultrasound assistance.

Many centers have adopted prone positioning. Theoretic advantages of prone positioning relate to relative sparing of small bowel from the radiation portals and reproducibility of patient positioning on daily setup.

Following patient positioning, fabrication of the immobilization device is performed. This step becomes increasingly critical as the margin around the target is decreased (eg, when a 1.5-cm margin around the prostate is decreased to a 0.5-cm margin).

Numerous materials have been used to immobilize patients prior to acquiring CT imaging or MRI data for treatment planning. Commercially available products include thermoplastic casts (eg, Aquaplast), vacuum-shaping bags (eg, Vac-lock), and self-contained thermochemicals (eg, alpha cradle). Regardless of which device is chosen, the goal of immobilization is to reproduce the position in which the patient is treated each day.

Upon fabrication of the device or devices, axial images of the area of interest are obtained. Consecutive CT scans or MRIs are obtained, starting from 3 cm below the prostate and extending superiorly to 3 cm above the superior tip of the seminal vesicles.

Additional CT imaging or MRI data can be obtained above or below the areas of interest. However, this information has minimal impact on patient treatment or dose computation.

The targets (CTV, PTV, or both) are identified on each relevant axial CT slice. Similarly, normal structures, including the bladder wall, rectum, small bowel, bony structures, and skin surface, are outlined on each relevant CT slice.

The target volume and normal structures are then digitally reconstructed in 3 dimensions and displayed with the beam's eye view (BEV) technique. The adequacy of target coverage and normal tissue doses can be viewed using dose-volume histograms (DVHs) or serial 2-dimensional images superimposed with isodose curves.

Compared with conventional EBRT, 3D-CRT techniques implement a larger number of beams daily to improve the tumor–to–normal tissue dose ratio. Implementation of 3D-CRT requires the use of newer treatment machines capable of rapidly delivering a large number of precisely shaped fields under automated computer control (ie, multileaf collimators [MLCs]). (See the image below.)

MLCs are capable of automatically shaping the apertures of each treatment field in rapid succession under computer control. Treatment times are shortened, individual treatment blocks do not need to be fabricated, and more complex beam shaping can be attempted.

Results of 3D-CRT

The results of 3D-CRT demonstrate superior bNED (biochemical, no evidence of disease) control rates, largely because of the ability to escalate the dose with less concern over the toxicity to normal tissue. 3D-CRT allows higher doses of radiation to the prostate without significant complications to the normal tissue.

Even small degrees of dose escalation have been shown to improve the biochemical outcome in patients diagnosed with prostate cancer. Comparison studies have shown superior outcomes with doses of 78 or 79 Gy versus 70 Gy.^{[7, 8]}

Five- and 10-year follow-up results with 3d-CRT indicate increased rates of bNED control, especially in patients with intermediate prognostic factors (ie, Gleason score of 7 and PSA level of 10-20 ng/mL). bNED rates in patients with pretreatment PSA levels of 10-20 ng/mL are approximately 30% better than those in patients treated with conventional radiotherapy (5-y results).

Patients with more favorable prognostic factors (ie, Gleason score ≤6 and PSA level ≤10 ng/mL) may not benefit from dose escalation, although this issue remains highly controversial. Similarly, the bNED rates in patients at high risk for locally or regionally advanced disease (ie, Gleason scores of 8-10 and PSA ≥ 20 ng/mL) may not markedly improve after dose escalation. This is felt to be true because this group of patients is ultimately at higher risk for distant metastasis.

Intensity-modulated radiation therapy (IMRT) can achieve tightly conformal dose distributions with the use of nonuniform radiation beams. The intent of this form of therapy is to create highly conformal fields by treating the patient with multiple static portals (so-called step and shoot IMRT) or dynamic fields. In dynamic IMRT, a series of arcs are administered through the area of interest. Multileaf collimators (MLCs) are reshaped many times as the machine performs a series of arc rotations around the target. (See the image below.)

Complex treatment-planning software algorithms allow exceedingly high doses of radiation to be delivered to the target while significantly smaller doses of radiation are delivered to the adjacent normal tissue. In contrast to the traditional method of radiation planning, inverse treatment planning is commonly used for the calculation of doses during IMRT.

IMRT establishes a treatment plan following the establishment of acceptable doses to regional (normal) anatomy. For instance, in IMRT treatment planning, the maximum tolerable dose to be delivered to the involved segments of the bladder, bowel, and rectum is specified.

The desired target dose is then prescribed to the PTV. The computer, through a series of complex iterations, designs a treatment that maximizes delivered dose to the target and minimized dose to adjacent normal tissue. Implicit in the name of this form of therapy is the concept that the intensity of the radiation beam changes throughout the course of therapy.

IMRT has been successfully used to treat tumors when the target area is readily identifiable at the initiation of daily treatments and the desired dose for optimum tumor control is significantly higher than the acceptable dose limits for adjacent normal tissue. Tumors of the head and neck and tumors of the breast are clinical sites where this treatment has been successfully used.

IMRT is no longer considered an investigational technique in the management of prostate cancer. Rather, it has rapidly become a highly precise method of delivering increasing doses of radiotherapy to the prostate and immediate periprostatic tissues.

However, no multicenter, phase III, prospective, randomized trial has been performed to address the superiority of this form of therapy over well-designed 3D-CRT. Data from the Memorial Sloan Kettering Cancer Center have demonstrated the safe delivery of doses of more than 80 Gy using this technique. The value of dose escalation when additional adjuvant treatments are being considered (eg, hormonal blockade, chemotherapy) remains unclear.

IMRT in the treatment of prostate cancer continues to evolve; however, reproducible identification of the target (on daily treatments) remains challenging. The use of implantable fiducial markers and sonographic localization devices has become increasingly popular. Both techniques allow the treating therapists to identify the desired target immediately prior to each day's treatment. Without such specificity, the logic of using IMRT is questionable.

Image-guided radiotherapy (IGRT) refers to the use of additional verification tools in an attempt to ensure proper target localization during the course of radiotherapy. The term IGRT has been widely used to refer to imaging techniques as simple as daily port films to those as complicated as computer-assisted patient repositioning devices. Regardless, as highly conformal radiotherapy is administered with increasing frequency (eg, IMRT), accurate target localization becomes mandatory.

Historically, attempts to identify the target’s position have focused on imaging performed prior to each daily treatment, or fraction. Recent efforts have attempted to address the significance of organ movement during the daily treatment fraction.^[9]

Interfractional assessment (static)

As radiotherapy for prostate cancer has become increasingly conformal, dose escalation has become a standard approach to the management of early-stage disease,^[10] and accurate target and normal tissue localization has become increasingly important. Proper target identification becomes necessary in 3 distinct phases of treatment planning and treatment execution. When patients are selected for primary radiotherapy treatment, simulation is performed. CT-based imaging is most commonly used; however, some centers prefer MRI technology.^[11]

Accurate delineation of normal tissues in relation to the prostatic target is equally important in this phase of patient care. Physician review of axial CT images allows delineation of the prostate. As most radiation oncologists lack formal training in the interpretation of radiographic imaging, review with a diagnostic radiologist or extensive clinical experience is advised.

Following identification of the prostatic target (GTV), a clinical target volume and planning target volume are created. Although this phase of treatment planning allows for accurate target localization based on the gland’s location at the time of CT imaging, it does not address organ motion subsequent to that date.

Portal imaging

Early attempts to identify the location of the prostate prior to each daily treatment resulted in suboptimal target identification. A commonly used approach has included the performance of daily port films prior to therapy. This strategy provides limited value to the image guidance process.

Megavoltage imaging (portal imaging) of pelvic anatomy provides reasonable confidence that the patient’s fixed pelvic structures (bones) are in the same position as observed during CT simulation; however, it does not provide information regarding the prostate’s position in reference to these bony structures. Nevertheless, it remains an accepted method for approximating target localization in the absence of more sophisticated imaging.

An evolution from this simple form of therapy occurred with the placement of fiducial markers into the prostatic target. Using a series of implanted radio-opaque markers, a soft tissue target can be localized using portal imaging technology. Imaging of the implanted fiducial markers can be obtained with either megavoltage imaging (ie, port films) or with kilovoltage imaging. In the latter setting, low-energy x-ray equipment and detectors are mounted on the treatment machine.

Ultrasonography

Transabdominal ultrasonography is an accepted noninvasive method for obtaining detailed imaging of pelvic contents. It is regularly used by gynecologists and urologists in the daily assessment of their patients. This technology has been adapted for use in the management of target localization for patients undergoing radiation-based treatments.

In an attempt to displace normal tissue(s) from the radiation treatment portals and to facilitate the immobilization of the gland, patients are asked to undergo their daily treatments with a full urinary bladder and a relatively empty distal bowel. The increased volume within the bladder provides a good window for prostate target localization using ultrasonography.

Several commercially available systems allow the operator to identify the target’s localization based on CT data. Ultrasonographic images of the prostate are obtained on a daily basis to identify the gland’s relative position. If the gland is not identified in the anticipated location, a series of calculated shifts are proposed to correct the image. Following repositioning of the patient, repeat imaging can confirm that the target is correctly localized.^[12]

Limitations to this technology include the need to train staff to interpret sonographic images, variability in image quality each day, and the potential for organ movement while applying the ultrasound transducer to the patient’s lower abdominal wall. Although still used in many clinical centers, this added procedure increases the time patients are required to remain in the treatment position.

CT-based imaging

As discussed above, kilovoltage imaging devices have been successfully added to linear accelerators. They are normally mounted at 90° to the treatment head of the machine and are opposed by digital image detectors. These x-ray cameras can be used to generate axial images representative of the target area of interest, which are then compared with CT scans obtained previously during treatment planning.

Coordinated shifts can be made if positioning inaccuracies are detected in patient setup. Alternatively, and more simply, the radiation used for therapy (megavoltage) can be used to generate a CT image. Megavoltage images can be used to perform requisite shift to ensure that the patient’s position matches that obtained during initial simulation.^[9]

Radiofrequency localization

Newer forms of target tracking have become clinically available. Similar to radio-opaque fiducial markers, small radio transponders can be implanted into the prostate for facilitating patient setup. These transponders emit radiofrequency waves that can be detected and used to reposition the target prior to execution of therapy.

Intrafractional assessment (dynamic)

As information regarding the potential for interfractional organ movement has become increasingly well described, concern regarding the potential for intrafractional movement has developed. This issue is particularly important because many intensity-modulated radiation treatments can require 20-30 minutes or longer.

Of the devices listed above, only radiofrequency-based localization has been regularly used to obtain information regarding target localization during the course of linear accelerator–based radiotherapy. Newer generations of radiation-based equipment (eg, robotic arm linear accelerator–based therapy, Accuray CyberKnife) have unique treatment repositioning techniques that are not found in association with linear accelerator–based therapy.

The use of radiofrequency transponders can be valuable as each treatment fraction is administered. Following initial patient positioning using this image-guided technique, any potential target movement can be accurately tracked during treatment. In the simplest of models, when a discordance between expected location and exact location is detected, the machine can be stopped from delivering further radiotherapy.

In a more complicated system, an automatic patient repositioning can occur to correct for the measured change in target localization. As this technology is relatively new, phase 3, multi-institutional data reporting its overall benefit is ongoing.^{[13, 14]}

Conventional external beam radiation therapy (EBRT) is delivered using photon beams. Data from Loma Linda and Harvard suggest that prostate cancer can be effectively managed with conformal proton beam therapy.^[15] What is less clear is whether the overall cost-benefit ratio will make this form of therapy a continued source of clinical interest.

Photons are packets of energy that are capable of entering the body to a depth that is proportional to their energy (ie, higher energy equals deeper penetration). Photons are generated for clinical use in linear accelerators by accelerating electrons to varying potentials (speeds) and aiming them at a tungsten target.

The resultant collision of the electron with the target generates a photon beam whose energy is proportional to the accelerating potential of the electron. Energies of commonly used clinical beams range from 4-25 megavolts.

The electron is a relatively small particle with essentially no weight. As such, the equipment needed to accelerate the electron prior to target collision is comparatively small. In contrast, other charged particles (eg, protons) weigh as much as 2000 times the weight of an electron.

The equipment needed to accelerate these particles is significantly larger. In fact, this equipment can take up several thousand square feet of space. Recent technological advances in proton beam therapy have resulted in several centers being constructed throughout the United States. Although costs remain in excess of $100 million per unit, this technology has generated significant interest in the management of prostate carcinoma.

Proton beam therapy has been successfully used in the management of prostate cancer. Early work from the cyclotron center at Harvard formed an important basis for current clinical trials.^[16] A unique feature of proton beam therapy is the way in which it deposits its most concentrated radiation dose.

Unlike photon beam therapy, the entrance radiation dose tends to be significantly less than the maximum energy of the clinical beam. Proton beams have a characteristic Bragg peak. Beyond this point, where energy is at a maximum intensity level, radiation energy rapidly falls off, which is important in the management of normal tissue toxicity.

The radiotherapeutic approach to carcinoma has been relative consistent for more than 3 decades. Although refinements in treatment technique have allowed for higher doses of radiation treatment to be offered to patients with limited disease, at least two unique forms of external beam radiotherapy have gained increasing interest over the past 5 years.

The first is helical radiotherapy using a CT-like gantry and a rotating radiation beam that passes through the target area of interest. This form of therapy, termed tomotherapy, has been used in the management of primary CNS tumors and visceral-based malignancies. Although the CT-like gantry used in the treatment of patients generates megavoltage radiation, its design allows for the ready acquisition of CT-like images, which have been successfully used in the optimum patient positioning on a daily basis.^[17]

A completely distinct, yet clinically exciting, form of therapy involves the use of hypofractionated radiotherapy. In this model, radiation is delivered from an accelerator; however, the equipment is mounted to a computer-guided robotic arm. Because the machine is capable of treating the target at angles not possible with conventional rotational-based equipment, it yields the theoretical advantage of conforming the dose more closely to the target organ’s shape.

Unlike conventional forms of radiotherapy, this treatment process is administered over the course of approximately 1 week. This is in contrast to conventional IMRT/IGRT, which entails daily (Monday through Friday) treatment for 6-8 weeks.

Commercially available from Accuray, the CyberKnife is used in several clinical centers throughout the United States. Early clinical data suggest that the hypofractionated regimens may allow adequate dose delivery while providing similar and potentially reduced toxicity to normal tissue.^[18]

Accelerated hypofractionated radiotherapy may offer great promise in the management of prostate carcinoma. To date, however, the clinical use of this form of therapy has been insufficient to support its routine use in all patients.

The primary purpose of combining hormonal blockade with radiotherapy continues to evolve. Initial attempts combined treatment approaches centered on the obvious results of hormonal blockade (ie, prostate downsizing). The results of several phase III clinical trials suggest that the true benefit of combining radiotherapy and androgen blockade may lie in the potentially synergistic effects of the two treatments.

Data from the Radiation Therapy Oncology Group (RTOG) have shown a clear improvement in the biochemical control of disease in patients who are treated with a combination of radiotherapy and androgen suppressive therapy. Initial data suggest that patients with a Gleason score of 7 or higher may have an improved survival rate.

The mechanism by which hormonal blockade enhances the effects of radiotherapy is unclear; however, the induction of apoptosis may be an important component of its action. Others have proposed that cell cycle shifting (ie, to a more sensitive component of the cell cycles) may underlie the benefit of combined therapy.

The 5-year results of a trial (RTOG 86-10) in patients with bilobar and more severe prostate carcinoma demonstrated that 4 months of total androgen blockade (TAB) in conjunction with conventional external beam therapy was more beneficial than radiotherapy alone. Specifically, an improvement in PSA relapse-free survival, disease-free survival (DFS), and local control was observed. The overall survival rate was not better in the neoadjuvant androgen ablation arm than in the control group; however, many believe this was due to the lack of protracted follow-up.

The 5-year results from the European Organization for Research and Treatment of Cancer (EORTC) trial that compared radiotherapy alone for locally advanced disease (T1, T2 grade 3 disease, any T-T4 without pelvic lymph node involvement) with radiotherapy followed by adjuvant androgen ablation for 3 years demonstrated improved outcome, including a survival advantage for the combined modality arm.

A recently summarized RTOG trial (92-02) that evaluated the role of continued androgen blockade for 2 years found that PSA relapse-free survival, DFS, and local control were improved with combined therapy (ie, TAB and radiotherapy vs radiotherapy alone). In this trial, an overall survival advantage to combined therapy was not proven. As the data mature, a survival advantage to the combined therapy arm may be anticipated.

Preliminary analysis of a trial by Laverdiere et al showed a potential for marked improvement in outcome when patients with early-stage prostate cancer are offered combined therapy.^[19] In this prospective study, more than 120 patients with early-stage prostate carcinoma who were divided into 1 of 3 treatment arms. The first arm included radiotherapy alone. The second arm included 3 months of neoadjuvant antiandrogen therapy followed by radiotherapy. The third arm included 3 months of neoadjuvant antiandrogen therapy, followed by combined therapy (ie, radiotherapy and TAB), followed by 6 months of TAB (postradiotherapy).

The study followed both posttreatment PSA and gland biopsy. As expected, patients receiving TAB reached lower PSA nadirs. In addition, at 1 year posttherapy, the rate of repeat prostate biopsy was twice as high in patients not receiving TAB.

The RTOG 94-08 trial demonstrated definitively that the addition of short-term TAB to radiation therapy does not improve survival in patients with low-risk prostate cancer (T1/T2a). However, a subgroup analysis of the trial, presented at the 2010 Genitourinary Cancers Symposium in San Francisco, showed that patients with intermediate-risk prostate cancer obtained a significant survival benefit from TAB.^[20]

Nevertheless, full determination of the benefits of TAB for this group of patients may require more study. For example, RTOG 94-08 employed lower doses of radiation than are currently used.

At present, TAB is used primarily for volume reduction in early-stage disease. This can be of great importance for patients undergoing either brachytherapy or 3-dimensional conformal radiotherapy (3D-CRT).

Although the results of combined therapy continue to offer encouraging results, each component of therapy (ie, TAB, external beam radiation therapy [EBRT]) is associated with potential morbidity. Adverse effects from androgen ablation include anemia, decreased muscle tone, gynecomastia, hepatotoxicity, hot flashes, impotence, osteoporosis, and loss of libido. The morbidities rarely necessitate termination of therapy.

Radiation and adjuvant androgen ablation for T3 disease

Recent clinical trials have shown significant improvement in freedom from relapse in patients with advanced local-regional prostate cancer treated with radiation and adjuvant androgen ablation compared with those treated with radiation alone. Improved disease control, specifically in patients with stage III disease who were treated with combined radiation and estrogen, was noted in an earlier prospective randomized study. Despite the considerably more unfavorable disease characteristics among patients treated with both modalities, their outcome is significantly better than that of patients treated with radiation alone.

Adjuvant androgen ablation leads to the suppression of the postradiation rising PSA profile. Patients treated with both radiation and androgen ablation have a significantly decreased incidence of positive findings on postradiation prostate biopsy samples compared with those treated with androgen alone. Therefore, the combination of androgen ablation and radiation likely achieves greater local tumor cell killing than radiation alone. The number of patients who sustain metastatic relapse is low, and the incidence of patients who develop distant metastases is also low.

Conventional EBRT as the sole treatment has limited curative potential for patients with clinical stage III prostate cancer. Radiation doses of less than 68 Gy appear to be relatively ineffective. However, patients with pretreatment PSA levels that exceed 10 ng/mL have little chance for long-term freedom from PSA relapse, even when treated with the conventional dose limit of 70 Gy.

Such patients are best treated with combined radiation and adjuvant androgen ablation or with 3-dimensional conformal dose-escalation protocols. Patients with PSA levels of less than 10 ng/mL fare relatively better with conventional radiation to a dose-equivalent of 70 Gy in 7 weeks; however, their PSA outcome is also improved by adjuvant androgen ablation.

Additional debate regarding the use of antiandrogen therapy in conjunction with EBRT has arisen because of a recently published RTOG clinical trial. RTOG 94-13 was a phase III, prospective, randomized, clinical trial that compared the sequencing of androgen blockade (ie, pretherapy, during therapy, posttherapy) and the size of the radiation field (ie, large field, conventional EBRT vs limited field, 3D-CRT).

Initial analysis of this trial has demonstrated two trends. First, in patients presenting with high risk of non–organ-confined disease (ie, Gleason scores of 8-10), larger-field radiotherapy seems to carry a disease-control advantage (ie, treatment of regional pelvic lymph nodes). Second, in patients treated with limited-field radiotherapy (prostate only), sequencing of hormonal therapy (ie, neoadjuvant vs adjuvant) may not be a critical outcome variable.

Note that this trial has not had sufficient time for thorough maturation. Continued follow-up may alter these early results. More specifically, the initial observations may become increasingly significant after greater follow-up periods.

As stated above, patients with early-stage prostate cancer, a low Gleason score, and a low PSA level may also benefit from very localized conformal EBRT. This requires 3-dimensional CT-guided planning with specialized block cutting or multileaf collimation of the external beam in order to deliver the highest possible dose to the prostate gland and to protect the surrounding normal tissues. Results of treatment with this method of delivery are encouraging.

Combined prostate implant and EBRT

Current literature suggests that the clinical outcomes of patients treated with external beam radiation therapy (EBRT) or permanent prostate brachytherapy are comparable if patients are properly selected. This typically implies patients with T1 or T2 disease, prostate-specific antigen (PSA) level of less than 10 ng/mL, and Gleason score of 6 or less. An ongoing RTOG trial should clarify the difference between the two forms of therapy. Although permanent brachytherapy is widely accepted for patients with low risk of extracapsular disease, its role in other patients is less clear.

A well-performed prostate implant is perhaps the most conformal type of radiation treatment available. To this end, brachytherapy has been used more frequently for boost purposes in patients with more advanced disease (ie, T3a). Prospective data demonstrating an improved outcome compared with EBRT alone are scant; however, the logic of combined treatment is irrefutable.

Using brachytherapy alone is reasonable if one wishes to treat only the prostate and immediate periglandular tissue. However, if the patient is suspected to be at increased risk for extracapsular disease, brachytherapy may not adequately address all sites of potential disease. In this instance, many clinicians consider supplementing the brachytherapy dose with a shortened course of external beam therapy.

The proper sequence of the 2 treatments is uncertain; however, the authors believe that the biological effectiveness of the therapy is improved when EBRT follows permanent implant. In this setting, EBRT is offered 5-6 weeks following permanent prostate implant. Although by then the implanted radioisotopes have begun to decay, they contribute to the daily radiation dose from EBRT. This increased dose per day may improve the effectiveness of the radiotherapy in controlling the cancer.

Importantly, when EBRT is offered in conjunction with permanent implant, neither dose is at its maximum. Conventional prostate iodine-125 (I-125) prostate implants offer doses in the range of 14,400 cGy. Likewise, palladium-103 (Pd-103) implants offer doses of 11,000 cGy. Recent trials predict similar biologic outcome with cesium-131 (Cs-131), which is given in a dose of 11,500 cGy.

When implantation is followed by EBRT, the brachytherapy doses with I-125, Pd-103, and Cs-131 are reduced to 10,800 cGy, 9000 cGy, and 9000 cGy, respectively. When EBRT follows permanent prostate implant, the dose usually is limited to 4500 cGy per 5 weeks.

Selection of the isotope has varied widely in different practice settings. One of the strongest potential advantages to Cs-131 for combination radiotherapy is its markedly short half-life. This should allow for successful integration with external beam when EBRT is initiated several weeks postimplant.

Post-radical prostatectomy radiotherapy

Radiation therapy has been used as an adjuvant therapy following surgical therapy for prostate cancer (ie, radical prostatectomy). Selection of candidates for this approach is increasingly difficult. Prognostic variables that predict for extracapsular extension can be used prior to the selection of surgical candidates. Unfortunately, many of the clinical trials that attempted to answer the role of postsurgical radiotherapy were conducted prior to the PSA era.

Multi-institutional data from the American Society of Therapeutic Radiation Oncology (ASTRO) consensus conference suggest that in patients treated for a rising PSA level, postoperative radiotherapy (typically in a dose range of 60-65 Gy) offers a PSA remission rate of 70%. Unfortunately, the durability of this response varies widely from center to center, with averages of 25-67 months. The ASTRO panel also noted that the data support initiation of therapy when the PSA level is less than 1.5 ng/mL.

More recent data further support the use of adjuvant radiotherapy, indicating improved biochemical control of disease with immediate postoperative therapy compared with benefits seen when treatment is started for a rising PSA level. Lastly, the ASTRO panel noted that the use of hormonal therapy in this setting is investigational.

New techniques have significantly enhanced the ability of external beam radiation therapy (EBRT) to deliver high-dose radiation to the prostate and to minimize the dose to the surrounding structures. A new trend in well-localized radiotherapy, intensity-modulated radiotherapy (IMRT), has enhanced the precision of conformal therapy. IMRT further minimizes toxicities associated with conventional external beam therapy. Careful target assessment both prior to and during each fraction of therapy (ie, image-guided radiotherapy) has become a current standard of care. Whether image guidance will allow for more successful dose escalation is uncertain.

Doses previously considered unsafe for clinical use have become current standards. Patients with early-stage prostate carcinoma typically receive doses in the range of 72-78 Gy. Those with more advanced disease are commonly offered doses that approach 80-82 Gy.

Prospective data suggest that certain groups of patients have improved disease control with increasing dose; however, dose escalation can be safely used only with the use of modern technology (eg, IMRT and image-guided radiotherapy [IGRT]) and the assistance of technically proficient staff (including physicists, dosimetrists, and therapists). The role of chemotherapy in patients with locally advanced disease continues to evolve.

Current clinical trials are attempting to address the potential advantage of the addition of taxane-based therapy to EBRT and androgen blockade. Chemotherapy in conjunction with radiotherapy should not be considered a current standard; rather, it is the source of ongoing clinical investigation.

Patients with early-stage disease (ie, T1c/T2a) who are at a low risk of extracapsular disease extension (ie, PSA level of 10 ng/mL or lower and Gleason score of 6 or lower) may choose from either external beam therapy or permanent prostate implant if they do not wish to undergo surgery. Current literature suggests that conformal radiotherapy reduces the morbidity associated with EBRT. The latter statement may also be particularly true of IMRT.

An additional benefit of this form of therapy is the ability to offer an increased dose to the primary target. In turn, this should improve bNED (biochemical, no evidence of disease) control rates. Patients with early-stage disease who have either an increased PSA level (10 ng/mL or higher) or an elevated Gleason score (7 or higher) likely require aggressive therapy. Dose-escalation studies suggest that many of these patients may benefit from higher doses of local therapy. Data that assess the role of androgen blockade in this setting should be available within the next few years.

Patients with more advanced disease (T2b and higher) appear to benefit from combined treatment including total androgen blockade (TAB) and radiotherapy. Several prospective studies have shown improved bNED when both forms of therapy are offered. Protracted use of TAB following radiotherapy may also convey an improved survival advantage. This issue also awaits further clarification from the follow-up of recently completed clinical trials.

Patients at high risk and with poor prognostic features may be treated more effectively with the addition of systemic therapies and androgen ablation. The advent of new techniques such as patient immobilization devices, CT planning, beam's eye view (BEV) visualization and planning, 3-dimensional dose calculation, multileaf collimation, and electronic portal imaging has significantly improved the management of prostate cancer, resulting in increased radiation doses to the prostate. At the same time, these technologies have enabled a reduction in the normal tissue volume that receives clinically significant doses of radiation, thus minimizing complication rates.

Radiation oncology will continue to offer great promise to patients with carcinoma of the prostate. IGRT offers great promise in the management of this disease. Ongoing clinical trials should help solidify the role of this treatment strategy in the treatment of patients with prostate cancer.

The combined use of antiandrogen therapy with radiotherapy has been shown to markedly affect the bNED in patients with locally advanced disease. In the Radiation Therapy Oncology Group trial 94-08 (RTOG 94-08), patients with intermediate-risk prostate cancer obtained a significant survival benefit from antiandrogen therapy; survival was not improved in patients with low-risk disease.^[20]

Patient Education

For patient education information, see the Prostate Health Center, Cancer and Tumors Center, and Kidneys and Urinary System Center, as well as Prostate Cancer and Bladder Control Problems.