AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Background
• Conventional External Beam Radiotherapy
• Three-dimensional Conformal Therapy
• Intensity-Modulated Radiation Therapy
• Radiotherapy In Combination With Androgen Ablation
• Particle Therapy And Radiation Alone For T3 Disease
• Radiation And Adjuvant Androgen Ablation For T3 Disease
• Conclusion
• Multimedia
• References

BACKGROUND

Section 2 of 11  

• Authors and Editors
• Background
• Conventional External Beam Radiotherapy
• Three-dimensional Conformal Therapy
• Intensity-Modulated Radiation Therapy
• Radiotherapy In Combination With Androgen Ablation
• Particle Therapy And Radiation Alone For T3 Disease
• Radiation And Adjuvant Androgen Ablation For T3 Disease
• Conclusion
• Multimedia
• References

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.

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 associated with significant skin morbidity (ie, erythema, desquamation, or both). The technological limitations of low-energy radiation beams greatly restricted the use of radiotherapy in the management of 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 was directed at 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 subsequent trials that incorporated estrogenic products were developed in the 1950s and 1960s.

The role of radiotherapy in the management of prostate carcinoma became more clear with technological advancements that followed World War II. Megavoltage (ie, energy >1000 kV) radiation resulted in x-ray beams that penetrated more deeply, which 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, 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. 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.

Prostate cancer is the most common cancer among men in the United States, with more than 220,000 patients diagnosed in 2005. It is the second leading cause of cancer deaths in the United States, where mortality rates are in excess of 30,000 persons per year. Although this disease carries still carries high mortality rates, the mortality associated with prostate cancer has declined over the past 5 years. A detailed description of the presumed causes for this observation are beyond the scope of this article; however, improved treatments and detection of disease at earlier stages are believed to be important factors.

An apparent increase in the incidence of this disease through the early 1990s is largely associated with the routine use of prostate-specific antigen (PSA) testing. This trend plateaued by 1997, suggesting that the prevalence of disease is remaining constant. The disease is observed with increased frequency in African American males compared with white American males. African American males are known to present with more advanced disease and have increased mortality rates, regardless of stage. Although the pathophysiology of this observation is not completely understood, both genetic and environmental issues have been suggested to contribute to the phenomenon.

Treatment for prostate cancer is broadly determined by the absence of metastatic disease. Patients with distant metastatic disease are not candidates for curative therapy. Treatment for this cohort of patients largely consists of total androgen suppression (TAS), which commonly includes the use of a luteinizing hormone-releasing hormone (LHRH) agonist and, at times, a peripheral antiandrogen (total androgen blockade [TAB]).

This combination of treatments is considered standard therapy; however, variations in TAS therapy are being investigated (ie, LHRH agonist monotherapy, peripheral antiandrogen monotherapy, pulse TAS therapy). Patients who become refractory to conventional hormonal blockade are offered second-line hormonal therapy with agents such as ketoconazole and megestrol acetate (Patel, 1990; Dawson, 2000). Recent reports from medical oncology literature support the routine use of systemic therapy in the management of hormone-refractory disease (Petrylak, 2000; Savarese, 2001). Both taxane-based chemotherapy and conjugated chemotherapy agents (eg, estramustine) have shown great promise.

Current treatment options for nonmetastatic carcinoma of the prostate include radical prostatectomy, EBRT, temporary and permanent prostate implants (brachytherapy), cryosurgery, androgen suppressive therapy, and watchful waiting. Therapies are designed to address the known extent of disease and the likelihood of extraglandular (ie, non–organ-confined) disease. Surgery remains a preferred therapeutic treatment option for younger patients who present with a high likelihood of organ-confined disease. In contrast, 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 PSA levels).

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).

Evidence-based medicine mandates more objective methods of assessing response to therapy. Treatment endpoints of disease control are now measured primarily through serial posttherapy PSA studies. The expression "biochemical, no evidence of disease" (bNED) has become the most commonly used term to describe clinical control of disease following therapy. The term is based on the review of serial PSA studies following a course of treatment. The results that define success for surgical treatments are, by definition, more stringent (ie, posttherapy PSA level <0.2 ng/mL).

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.

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

CONVENTIONAL EXTERNAL BEAM RADIOTHERAPY

Section 3 of 11  

• Authors and Editors
• Background
• Conventional External Beam Radiotherapy
• Three-dimensional Conformal Therapy
• Intensity-Modulated Radiation Therapy
• Radiotherapy In Combination With Androgen Ablation
• Particle Therapy And Radiation Alone For T3 Disease
• Radiation And Adjuvant Androgen Ablation For T3 Disease
• Conclusion
• Multimedia
• References

Despite the decreasing frequency of conventional 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 PSA level). Regardless, a clear understanding of the former standard treatments allows a greater appreciation of more current techniques.

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) (Vicini, 2001; Pollack, 2000; Zietman, 2005). 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 certain patients may benefit from large-field radiation treatment. A report by Roach et al details the benefit of this form of treatment in patients with higher Gleason scores and in those who receive hormonal blockade in the adjuvant setting (Roach, 2003).

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.

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. They presented the results of a Veterans Administration trial that compared EBRT with surgery in early-stage disease. Although they concluded that surgery offered improved results when compared with EBRT, randomization schema and statistical analysis of their data make definitive conclusions difficult.

The Paulson study was a prospective trial; however, it was conducted prior to the routine use of PSA testing and routine pelvic imaging of patients. 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 two forms of therapy are unlikely to be directly compared in the future. Retrospective comparisons of the two 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 both treatments are similar in studies by both Bagshaw and Perez. Each form of therapy offers 10-year survival rates in excess of 60%.

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.

Certain patients may not be optimum candidates for radiotherapy (eg, patients with a history of bowel disorders, including ulcerative colitis and diverticular disease, as well as those with poorly controlled diabetes) (Small, 2006). These patients are known to have preexisting conditions that may place them at risk for either more intense morbidity or more protracted morbidity.

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: Because radiation can cause perturbation of the epidermis and dermis, patients may develop a reddening of their skin 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 with the use of therapeutic doses of treatment.
• Small intestine: 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 diminish the consumption of certain high-fiber foods (eg, excess of 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: 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: 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, patients may experience measurable changes in levels of hemoglobin and hematocrit. Blood should be tested weekly to assess this possibility.
• Pelvic bones: 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 CBC counts should be performed to review this possibility, which is typically noted in WBC and platelet counts. Cessation of therapy to allow for recovery of the blood count is rarely necessary.
• Nerves: Pelvic irradiation involves the treatment of 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.

Conventional EBRT provided the basis for all other forms of radiotherapy treatments. Continued use of this form of therapy is limited.

THREE-DIMENSIONAL CONFORMAL THERAPY

Section 4 of 11  

• Authors and Editors
• Background
• Conventional External Beam Radiotherapy
• Three-dimensional Conformal Therapy
• Intensity-Modulated Radiation Therapy
• Radiotherapy In Combination With Androgen Ablation
• Particle Therapy And Radiation Alone For T3 Disease
• Radiation And Adjuvant Androgen Ablation For T3 Disease
• Conclusion
• Multimedia
• References

Three-dimensional conformal radiotherapy (3D-CRT) has essentially replaced conventional external beam radiation therapy (EBRT) in the management of early-stage prostate cancer. 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.

The past decade has seen significant changes in the radiotherapeutic management of prostate carcinoma. 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. This technique allows for more precise delivery of therapy to the target organ or organs. 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.

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. Finally, the PTV acknowledges 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.

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.

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 and to treat the patient 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.

Three-dimensional treatment 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]). 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.

The results of 3D-CRT demonstrate superior bNED 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.

Five- and 10-year follow-up results 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 £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.

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. CT-based simulation is becoming increasingly popular because of the use of both 3D-CRT and IMRT. Simulation for conventional EBRT relies on less sophisticated techniques (eg, fluoroscopy and plain radiographs). This is generally considered acceptable because the treatment borders (margins) are more inclusive than those used in 3-dimensional and IMRT treatments.

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.

Recently completed trials involving 3D-CRT clearly demonstrated a number of relevant and important facts, as follows:

• Limited-field (conformal) radiotherapy is associated with less morbidity than conventional radiotherapy.
• Dose escalation to the target organ or organs is possible because of the limited morbidity.
• Dose escalation has been shown to improve the biochemical outcome in patients diagnosed with prostate cancer. This was well documented in a trial by MD Anderson in which the outcomes following 70-Gy and 78-Gy doses were compared. MGH reported similar data, with dose comparisons of 70 Gy and 79 Gy (Pollack, 2000; Zietman, 2005).

INTENSITY-MODULATED RADIATION THERAPY

Section 5 of 11  

• Authors and Editors
• Background
• Conventional External Beam Radiotherapy
• Three-dimensional Conformal Therapy
• Intensity-Modulated Radiation Therapy
• Radiotherapy In Combination With Androgen Ablation
• Particle Therapy And Radiation Alone For T3 Disease
• Radiation And Adjuvant Androgen Ablation For T3 Disease
• Conclusion
• Multimedia
• References

Intensity-modulated radiation therapy (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 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.

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 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.

RADIOTHERAPY IN COMBINATION WITH ANDROGEN ABLATION

Section 6 of 11  

• Authors and Editors
• Background
• Conventional External Beam Radiotherapy
• Three-dimensional Conformal Therapy
• Intensity-Modulated Radiation Therapy
• Radiotherapy In Combination With Androgen Ablation
• Particle Therapy And Radiation Alone For T3 Disease
• Radiation And Adjuvant Androgen Ablation For T3 Disease
• Conclusion
• Multimedia
• References

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 combined therapy (ie, radiotherapy and androgen blockade) may lie in the potentially synergistic effects of the two treatments.

Data from the RTOG has 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 certain subgroups of patients receiving combined treatment may have an improved survival rate (ie, patients with a Gleason score of >7). 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 explained that cell cycle shifting (ie, to a more sensitive component of the cell cycles) may vary in the benefit of combined therapy.

In the early 1980s, the RTOG began a cooperative trial that assessed the role of antiandrogen therapy in the management of prostate carcinoma. The promising results from this study prompted further investigations into the role of combined antiandrogen therapy and radiotherapy. The RTOG study, 86-10, evaluated the role of 4 months of TAB in conjunction with conventional external beam therapy for patients with bilobar and more severe disease.

The 5-year results from this trial demonstrate a benefit for patients receiving both antiandrogen therapy and radiotherapy when compared with those receiving radiotherapy alone. Specifically, an improvement in PSA relapse-free survival, DFS, and local control was observed. The overall survival rate for the neoadjuvant androgen ablation arm was not improved compared with 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) evaluated the role of continued androgen blockade for 2 years. PSA relapse-free survival, DFS, and local control were once again 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.

The role of radiotherapy and TAB in early-stage prostate cancer should be more clear upon review of the data from the recently completed RTOG (94-08) trial. This trial compared conventional radiotherapy with and without androgen blockade in patients diagnosed with early-stage prostate carcinoma (T1/T2a). The trial attempted to prove a biologic advantage to combined therapy (ie, radiotherapy/antiandrogen therapy).

Laverdiere has reviewed the use of antiandrogen therapy in early-stage disease. This prospective study observed 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. The length of TAB therapy also predicted for a lower PSA nadir. The second endpoint for analysis was based on repeat biopsies of the glands. At 1 year posttherapy, the rate of rebiopsy was twice as high in patients not receiving TAB. Although this study suggests a potential for marked improvement in the outcome when patients with early-stage tumor are offered combined therapy, it remains the results of a single institution.

While we await the results of the RTOG 94-08 study, the role of combined therapy in this group of patients remains less clear. At the present time, 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. The below morbidities rarely necessitate termination of therapy. Nevertheless, a brief review is appropriate.

Adverse effects

Adverse effects from androgen ablation include anemia, decreased muscle tone, gynecomastia, hepatotoxicity, hot flashes, impotence, osteoporosis, and loss of libido.

EBRT can cause adverse effects observed shortly after the initiation of therapy (ie, acute) and those that occur following treatment (ie, late). Acute adverse effects (ie, within 90 d of radiotherapy) include irritation to the following organs or organ systems: urinary tract (eg, urgency, frequency, dysuria), large bowel (eg, tenesmus, fecal urgency, mucus discharge), and small bowel (eg, frequent, less-formed stool). Late adverse effects (ie, after 90 d of radiotherapy) include a persistence of acute adverse effects and the following problems related to organ or organ system injury: urinary tract (eg, cystitis, hematuria, urethral stricture, bladder contracture) and large bowel (eg, chronic diarrhea, proctitis, rectal or anal stricture, rectal bleeding, ulcer, bowel obstruction, visceral perforation).

Radiation is also associated with subsequent difficulty with sexual function. Sexual dysfunction largely results from problems with erectile function. This problem is observed with relative frequency and has been reported to lead to a loss of sexual function in 18-27% of patients who were monitored for 1-1.5 years after radiotherapy. Patients who present with preexisting erectile difficulties experience similar problems, but with greater frequency (57% lost sexual function). Radiation-induced erectile dysfunction is caused by vascular disruption resulting from treatment. Doppler studies of corporal vasculature reveal arteriogenic, rather than cavernosal or neurogenic, dysfunction.

PARTICLE THERAPY AND RADIATION ALONE FOR T3 DISEASE

Section 7 of 11  

• Authors and Editors
• Background
• Conventional External Beam Radiotherapy
• Three-dimensional Conformal Therapy
• Intensity-Modulated Radiation Therapy
• Radiotherapy In Combination With Androgen Ablation
• Particle Therapy And Radiation Alone For T3 Disease
• Radiation And Adjuvant Androgen Ablation For T3 Disease
• Conclusion
• Multimedia
• References

Particle therapy

External beam radiation therapy (EBRT) may also be delivered using particle therapy. Examples include trials with particles such as neutrons or protons. The use of neutron beam or proton beam therapy has not gained wide acceptance because of the clinical difficulty in creating these particles. Large cyclotrons are found in few centers throughout the United States.

Potential advantages of both treatments are biologic in nature. A tumor's response to neutron beam therapy depends less on the radiation's interaction with neighboring water molecules than is observed with photon external beam therapy (ie, direct action rather than indirect action). In turn, greater effective damage per unit of radiation is delivered (ie, higher radiobiological effectiveness than that of conventional photon beam therapy).

Proton therapy has also been used successfully to treat patients with localized prostate cancer. The benefit of this therapy is related to the energy deposition of the radiation beam, which is associated with a minimum dose at entry and maximal energy deposition at the stopping region located within the target volume. Whether the results from the use of these particles are better than the high-dose conformal photon radiotherapy remains unclear because the biochemical outcome and tolerance of both of these forms of therapy are excellent.

Radiation alone for T3 disease

The overall outcome in patients treated with conventional radiation therapy alone is poor. At 5 years after treatment, approximately two thirds of patients experience a disease relapse as detected based on a rising postradiation PSA profile. By 10 years, the failure rate is approximately 75%. Continued follow-up suggests the limitations of monotherapy for treating advanced disease. Several studies of patients with T3 disease who were irradiated report high relapse rates (82% at 8 y, 80% at 4 y, 90% at 10 y, 85% at 4 y). These poorer outcomes are largely the result of more sophisticated measurements of success (ie, PSA failure vs clinical failure).

In the pre-PSA era, when only clinical-radiographic endpoints were available, such high failure rates were rarely observed, and then only at follow-up times that exceeded 10 years. As a result, treatment failure can be detected many years before it is clinically evident. Because of high relapse rates, conventional radiotherapy as the sole treatment has little curative potential in patients with clinical stage III prostate cancer.

Radiation therapy may also be used as a salvage therapy following surgery. A complex issue in this group of patients is the timing of therapy for patients with known extracapsular disease following surgery.

RADIATION AND ADJUVANT ANDROGEN ABLATION FOR T3 DISEASE

Section 8 of 11  

• Authors and Editors
• Background
• Conventional External Beam Radiotherapy
• Three-dimensional Conformal Therapy
• Intensity-Modulated Radiation Therapy
• Radiotherapy In Combination With Androgen Ablation
• Particle Therapy And Radiation Alone For T3 Disease
• Radiation And Adjuvant Androgen Ablation For T3 Disease
• Conclusion
• Multimedia
• References

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 external beam radiation therapy (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).

Two trends appear to have arisen during the analysis of this trial. 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.

CONCLUSION

Section 9 of 11  

• Authors and Editors
• Background
• Conventional External Beam Radiotherapy
• Three-dimensional Conformal Therapy
• Intensity-Modulated Radiation Therapy
• Radiotherapy In Combination With Androgen Ablation
• Particle Therapy And Radiation Alone For T3 Disease
• Radiation And Adjuvant Androgen Ablation For T3 Disease
• Conclusion
• Multimedia
• References

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 the well-localized radiotherapy, intensity-modulated radiotherapy (IMRT), has enhanced the precision of conformal therapy. IMRT further minimizes toxicities associated with conventional external beam therapy.

Doses previously considered unsafe for clinical use have become current standards. Patients with early-stage prostate carcinoma typically receive doses in the range of 72-74 Gy. Those with more advanced disease are commonly offered doses that approach 80 Gy. Several centers have argued for doses in excess of 80 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 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 have a low risk of extracapsular disease extension (i.e, PSA £10 ng/mL and Gleason score £6) 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. Patients with early-stage disease who have either an increased PSA level (>10 ng/mL) or an elevated Gleason score (>7) 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 nextfewyears.

Patients with more advance disease (T2b and higher) appear to benefit from combined treatment including 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. IMRT 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 affect the bNED markedly for patients with locally advanced disease. The results of the recently closed RTOG trial (94-08) should confirm if a similar benefit is observed in patients with early-stage disease.

Combined prostate implant and external beam therapy

Current literature suggests that the clinical outcomes of patients treated with surgery, EBRT, and permanent prostate brachytherapy are comparable if patients are properly selected. This typically implies patients with T1 or T2 disease, 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 implant is widely accepted for patients with low risk of extracapsular disease, its role in other patients is less clear.

Permanent prostate brachytherapy is typically performed using 1 of 3 radioisotopes (iodine-125 [I-125]; palladium [Pd-103]; cesium 131 [Cs-131]). All sources offer low-level radiation treatment to the target in which they are implanted. The energy level of cesium and iodine are comparable; however, the half-life of the two sources varies greatly (9.7 d vs 57 d). 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 at this point the radioisotopes have begun to decay, they contribute to the daily radiation dose (when added to the external beam dose). 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 I-125 prostate implants offer doses in the range of 14,400 cGy. Likewise, Pd-103 implants offer doses of 11,000 cGy. Recent trials predict similar biologic outcome with Cs-131 (prescribed dose of 11,500 cGy). When implantation is followed by EBRT, the brachytherapy doses 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. Limited data compare I-125 with Pd-103 in the setting of a clinical trial. Neither source appears to be superior. Because Cs-131 remains a relatively new source, limited data are available that compare its use with either Pd-103 or I-125. One of the strongest potential advantages to Cs-131 is its markedly short half-life. This should allow for more rapid cell kill when used as a monotherapy. Moreover, it 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.

The results of the American Society for Therapeutic Radiology and Oncology (ASTRO) have been published. The results of multi-institution data suggest that postoperative radiotherapy doses (typically in a range of 60-65 Gy) offer a PSA remission rate of 70% to patients treated for a rising PSA level. Unfortunately, the durability of this response varies widely from center to center, with averages of 25-67 months. The 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 upon a rising PSA level. Lastly, they note that the use of hormonal therapy in this setting is investigational.

For excellent patient education resources, visit eMedicine's Prostate Health Center, Cancer and Tumors Center, and Kidneys and Urinary System Center. Also, see eMedicine's patient education articles Prostate Cancer and Bladder Control Problems.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Background
• Conventional External Beam Radiotherapy
• Three-dimensional Conformal Therapy
• Intensity-Modulated Radiation Therapy
• Radiotherapy In Combination With Androgen Ablation
• Particle Therapy And Radiation Alone For T3 Disease
• Radiation And Adjuvant Androgen Ablation For T3 Disease
• Conclusion
• Multimedia
• References

Media file 1:  Adenocarcinoma of the prostate. Note the atypical hyperchromatic epithelium lining the glands and the pleomorphic nature of the malignant cells.
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Media file 2:  Conformal radiation therapy. A linear accelerator equipped with a multileaf collimator is a device that can decrease the time a patient spends in the treatment room and one that improves treatment accuracy.
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Media file 3:  Unit used to deliver conventional external beam radiotherapy.
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Media file 4:  Multileaf intensity-modulating collimator (MIMiC) unit. This is used to deliver intensity-modulated radiotherapy.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Background
• Conventional External Beam Radiotherapy
• Three-dimensional Conformal Therapy
• Intensity-Modulated Radiation Therapy
• Radiotherapy In Combination With Androgen Ablation
• Particle Therapy And Radiation Alone For T3 Disease
• Radiation And Adjuvant Androgen Ablation For T3 Disease
• Conclusion
• Multimedia
• References

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