Risk Stratification

There is significant heterogeneity in the biological behavior observed in prostate cancer. The risk of biochemical failure after local therapy has been explored in detail. Increasing stage at presentation, prostate specific antigen (PSA) level, and grade of tumor all predict for PSA recurrence after therapy with curative intent.

The National Comprehensive Cancer Network (NCCN) risk stratification ( Table 1 ) can be used to stratify patients by risk of biochemical failure after curative therapy (eg, low, intermediate, or high risk). It should also be realized that many men with low-risk disease have a low chance of prostate cancer death and may be candidates for active surveillance, and if more than 60 years of age are unlikely to die of prostate cancer irrespective of local treatment. Some patients with Gleason 7 disease more than 70 years of age may even be able to avoid treatment all together without a mortality penalty. In intermediate-risk disease, the benefits of therapy must be carefully weighed against the potential side effects of therapy and associated costs.

Conversely, the risk of prostate cancer death in patients with high-risk disease increases considerably. Despite a high baseline risk of micrometastatic disease, local therapy has an impact on long-term outcomes in this group. An absolute survival benefit of 10% at 7 years was demonstrated in the SPCG-7 randomized trial of androgen deprivation therapy with or without local radiation therapy. A comparable benefit was confirmed in a similarly structured Canadian study, further reinforcing the use of radiation in this setting.

Assessment, Comorbidities, and Contraindications

A thorough history and examination should be performed to assess the patient’s suitability for radiation therapy, especially given that the avoidance of therapy is intrinsically linked with anticipated life expectancy. Thus, patients with a low life expectancy because of either medical comorbidities or a life expectancy less than 10 years are less likely to benefit from therapy. The presence of comorbidities can significantly affect the choice of recommended therapy and treatment modality; for example, in the avoidance of anesthetic and postoperative risks in men with significant comorbidities. However, certain comorbidities may interact with radiotherapy, such as the presence of type 2 diabetes, or increase risk of rectal toxicity (especially with concurrent inflammatory bowel disease) after radiotherapy.

Assessment of urinary symptoms is central as symptomatic benign prostatic hypertrophy (BPH) often coexists with carcinoma. Qualitative as well as quantitative validated assessments, such as the American Urologic Association (AUA) Prostate Symptom Score or the identical International Prostate Symptom Score (IPSS), should be attained. Men with significant lower urinary tract obstructive symptoms are at higher risk of late genitourinary toxicity such as incontinence from both external beam and brachytherapy. Men with a higher IPSS are also more likely to experience urinary obstructive symptoms during external beam radiotherapy. These may also be mitigated with cytoreductive androgen suppression therapy before commencement of treatment. A transurethral resection of prostate (TURP) before radiation may be required in some to alleviate obstruction, but conflicting nonrandomized studies have been published regarding whether it is has a long-term deleterious effect on urinary continence.

Potency after local therapy for prostate cancer is an important end point. A sexual history should be taken, in terms of sexual activity, erectile function, and libido. Validated surveys such as the International Index of Erectile Function (IIEF) provide an objective measure of sexual function and health.

If testosterone manipulation is being considered, cardiovascular risk factors must be carefully assessed and aggressively managed, because of the potential for increased cardiovascular events in patients with significant underlying cardiac dysfunction. This could influence the decision about the prescription of endocrine therapy and its duration.

Radiation should be avoided in patients with active inflammatory bowel disease, which can increase the severity of gastrointestinal (GI) symptoms significantly. Previous pelvic surgery, particularly for rectal cancer, can result in loops of radiosensitive small bowel entering the pelvis and possibly being tethered by postoperative adhesions, which may limit the ability to administer a full therapeutic dose. Previous high-dose pelvic radiotherapy is a contraindication to further EBRT to respect the radiotolerance of normal tissues. In this case, other modalities such as surgery or brachytherapy should be considered.

In broad terms, patients with an increased risk of radiographic evidence of metastatic disease at presentation (eg, men with high-risk disease) should be staged with nuclear medicine bone scan and computed tomography (CT) of the abdomen and pelvis. Magnetic resonance imaging (MRI) of the pelvis is useful for detecting extraprostatic extension of tumor and defining the prostatic anatomy.

A full PSA history should be obtained. Apart from the impact of the current absolute PSA level, there may be prognostic significance to the pretreatment PSA dynamics. Similarly, the histopathology report may contain information of relevance beyond the Gleason score, with much attention focused on whether the burden of disease can be better captured using biopsy core volumetrics. The general consensus is that the metrics of a heavier cancer burden, such as an increasing number of cores involved, a higher percentage of biopsy cores positive for cancer, and increased core length, are all associated with poorer outcome and should be considered in the selection of treatment intensity.

Prostate and Seminal Vesicles

The extent of radiation fields is based on understanding the natural history and potential routes of spread. The multifocal nature of prostate cancer has typically suggested that a uniform radiation dose to the whole prostate is required. Tumors may also breach the capsule of the prostate and be found in the periprostatic fat, or involve the adjacent seminal vesicles. The risk of extraprostatic extension and seminal vesicle invasion (SVI) increases significantly in higher-risk groups, as reflected in published nomograms. In cases where extraprostatic extension is detected, the mean length of extension is 1.1 mm, and 90% of cases were within 3.8 mm in 1 series. This information affects treatment planning.

There are conflicting data regarding the distribution of SVI, which has resulted in variation in the amount of seminal vesicle (SV) included in the prophylactic volume. Davis and colleagues reported a cohort of patients in whom SVI was identified on prostatectomy, and 40% of specimens had tumor less than 0.5 cm from the SV tip. Conversely, Kestin and colleagues reported that a cohort of patients with low-risk disease had a 1% incidence of SVI, compared with 27% SVI incidence in those with high-risk disease. In those with SVI, only 7% were observed to have tumor extending beyond 1 cm of the base of the SV and 1% beyond 2 cm.

Taking these basic biological underpinnings into account, the whole prostate is generally defined as an area of clinical risk, and included in the clinical target volume (CTV). Gross tumor seen on correlative imaging is included in the CTV, and any visible extracapsular extension may entail using a small volume expansion to ensure coverage of regions of apparent disease as well as incorporate areas of subclinical spread. In the event of confirmed SVI, the whole seminal vesicle is typically incorporated into the high-dose volume. Similarly, with a high risk of subclinical SVI, a prophylactic dose is generally prescribed to either the proximal or whole SVs. SVs lie immediately adjacent to the anterior fascial plane of the mesorectum, and most treatment including the SV can entail a compromise between coverage of the SV and dose constraints of the rectum.

Whole Pelvic Irradiation

Prostate cancer dissemination is commonly ascribed to lymphovascular permeation, via largely stepwise spread through the pelvic nodes. Despite this, the prophylactic treatment of pelvic nodes is controversial, with no clear consensus on the subgroup of patients who derive benefit from treatment. Several randomized trials of whole pelvis radiotherapy (WPRT) have been conducted, and all concluded that there was no clear biochemical or clinical control improvement with the addition of whole pelvic therapy to prostate only radiotherapy. The major criticisms of these studies were that patients may have been either too low risk or too high risk to benefit from pelvic therapy. However, pelvic nodes may represent an important source of treatment failures if only the prostate is treated, especially in high-risk patients. New highly conformal therapy such as intensity-modulated radiotherapy (IMRT) has allowed adjuvant radiation to be delivered with acceptable toxicity. These observations infer that, in the right patient population, pelvic prophylaxis may be feasible with low toxicity and possible clinical benefit nomograms have been developed and refined, with the aim of identifying men most likely to benefit from WPRT. For those believed to potentially benefit from WPRT, consensus guidelines have been published and can guide treatment volume definition; further definitive trials are ongoing. The most commonly involved first echelon nodal regions are fully included in the target volume. These have been defined by MRI imaging studies, as well as sentinel node imaging. One study using sentinel node imaging found these to be the external iliac (34.3%), internal iliac (17.9%), common iliac (12.7%), sacral (8.6%), and perirectal (6.2%) regions. The paraaortic nodes were less commonly involved and are generally not included. Studies to define the role of nodal irradiation are ongoing, such as RTOG 09-24.

IMRT

IMRT is based on 2 principles: (1) dynamically changing the open area of each field during each fraction and (2) computer software to divide the planning CT into spatial units (voxels) and then determine the optimal solution to deliver the dose to each voxel for a given beam arrangement. This differs from conventional radiotherapy because target dose characteristics and normal tissue tolerances are specified before plan construction (inverse planning). IMRT prescriptions are highly proscriptive to adequately direct the resultant computer-generated dosimetry. Compared with three-dimensional conformal radiation therapy, prostate IMRT allows optimization of the therapeutic ratio through limiting areas of high dose outside the target volume while preserving tumor coverage. IMRT can be delivered using 7 to 9 static fields, or a single beam treating in an arc about the patient (volume-modulated arc therapy). Variants of IMRT include the Cyberknife (Accuray, Inc, Sunnyvale, CA), which uses a small 6 MV linear accelerator mounted on an articulated mechanical gantry and tomotherapy, using a therapy source moving in an arc that delivers treatment a slice at a time.

Image-Guided Radiation Therapy

One of the major technical hurdles in treating prostate cancer is target localization. The prostate is a deformable gland that is influenced by both bowel and bladder filling, and thus mobile within the pelvis. Traditional bony matching techniques do not account for day-to-day variation of prostate motion, which is independent of pelvic position. Failure to account for prostatic motion could result in underdosing of the target and overdosing of surrounding normal tissues. This uncertainly is translated into a larger planning target volume (PTV) margin.

Common methods of image guidance are implanted fiducial markers and cone-beam CT scan. Fiducial markers, usually implanted via the transrectal route, can account for prostate motion when used in conjunction with kilovoltage or orthovoltage daily imaging. The patient is set up on the treatment couch, a set of verification images taken, and then the three-dimensional shift required to account for prostatic motion is applied. This approach minimizes the systematic error in patient positioning, allowing for both dose escalation with isotoxic therapy and minimization of PTV margins. Clinical results indicate that such an approach can reduce toxicity significantly, including doses of up to 86.4 Gy.

An alternative to implanted fiducial markers is volumetric imaging such as cone-beam CT. The imaging apparatus on the linear accelerator is rotated about the patient while imaging to obtain a three-dimensional image. These systems can be used in patients who have a contraindication to implanted fiducial markers; acceptable levels of systematic error are maintained even when matching to prostate rather than implanted fiducials. Furthermore, direct monitoring of intrafraction motion is possible using sophisticated electronic transponders implanted into the prostate.

Dose-Escalated Radiotherapy

The ability to deliver higher doses of radiotherapy in contemporary practice is based on minimizing tumor localization uncertainties and minimizing the high-dose irradiated volume.

There is level 1 evidence that increasing radiation dose has a substantial positive effect on biochemical control. Increasing the prescribed dose of radiation from 68 to 70 Gy to more than 78 Gy can result in impressive PSA control rates. For example, the MD Anderson Cancer Center dose escalation trial reported that increasing the radiation dose from 70 Gy to 78 Gy improved biochemical control outcomes from 59% to 78% ( P = .004). This effect was more pronounced in intermediate and high-risk tumors, although other studies have also documented a response in all risk groups. Similar dose escalation trials were conducted in the United Kingdom and the Netherlands ( Table 2 ).

Although the biochemical outcome may be an indicator of clinical benefit, it is yet to be shown to be a potential surrogate for overall survival, and no overall survival benefit has ever been demonstrated with dose-escalated radiotherapy. Given that in many trials the risk of noncancer mortality is often double that of prostate cancer mortality, these studies are underpowered to show a relatively modest decrease in mortality brought about by the biochemical failure improvements.

Although photon-based EBRT is the most common method for delivering high biological doses to the prostate, other modalities, such as proton beam therapy and HDR brachytherapy, can also produce similar results. Particle beam therapy uses a large particle accelerator to produce a therapeutic beam of heavy ions such as protons or carbon nuclei. The major advantage in using protons as opposed to conventional high-energy photons is the ability of a proton beam to deposit a greater proportion of energy at depth, thus potentially protecting normal tissues.

One randomized trial has used proton beams to boost an EBRT dose of 50.4 Gy to a total of either 70.2 or 79.2 Gy (photon equivalent dose). The higher boost dose gave better 10-year freedom from biochemical relapse (83% v 68%) but also a somewhat higher grade 2 or more GI toxicity rate (24% vs 13%), analogous to the EBRT dose escalation experience. However, no direct comparisons have been conducted between proton beam and modern IMRT techniques, and nonrandomized comparisons are conflicting. Although planning studies suggest that dose distributions and subsequent toxicity are likely to be similar, larger observational studies have found higher rates of hip fractures and GI toxicity with proton therapy. Perhaps the most significant drawback of proton therapy is the substantial capital and running costs of proton facilities.

Toxicity

Increasing GI and genitourinary (GU) toxicity has been reported with dose-escalated regimens. The MD Anderson Cancer Center dose escalation trial reported a 10-year actuarial incidence of GI toxicity of grade 2 severity or greater as 26% for those who received 78 Gy compared with 13% for those who received 70 Gy ( P = .013). Likewise, there was a trend toward higher grade 2 GU toxicity in the high-dose arm, which was observed in 13% and 8% of those in the high-dose and low-dose arms, respectively. This trial did not have universal use of CT to delineate normal tissues or image-guided radiation therapy (IGRT) to minimize set up uncertainty. Modern approaches using these measures are likely to result in decreased toxicity.

Erectile dysfunction (ED) is the other major toxicity experienced by those treated with EBRT. The prostate lies just superior to the penile bulb, and sensitive neurovascular bundles controlling erectile function course posterolateral to the prostate. These structures can often be included in the high-dose irradiated volume and thus ED is likely to become an increasingly common issue with any form of dose-escalated therapy. The average time to ED after EBRT is 12 to 18 months, with institutional reports of 40% to 50% potency rates after 2 years ; a meta-analysis of EBRT data confirmed a potency rate of 55% at 1 year (95% confidence interval [CI] 52%–58%). Prospective quality-of-life surveys reported that 50% to 60% of irradiated men (including EBRT and brachytherapy) reported distress about perceived sexual health, which may peak after 2 to 6 months, stabilizing thereafter. This implies that other factors such as acute toxicity from radiotherapy and hormone therapy are likely to adversely affect quality of life before the onset of ED from radiotherapy alone. ED management with phosphodiesterase inhibitors has been shown to be effective after EBRT in randomized trials.

Role of Androgen Deprivation Therapy

Androgens are an important mitogen in prostate cancer in all phases of disease. There is level 1 evidence that the addition of androgen deprivation therapy (ADT) to radiotherapy improves biochemical and survival outcomes in patients with locally advanced disease or with poor risk factors. There seems to be a stepwise improvement in outcome with increasing length of adjuvant androgen deprivation. RTOG 86-10 randomized patients in all risk groups between 66.6 Gy EBRT with and without 2 months of neoadjuvant goserelin. Most impressively, statistically significant improvements in biochemical progression-free survival, distant metastasis rate, local control, and cause-specific survival were found. The Australian Trans-Tasman Radiation Oncology Group (TROG) 96.01 randomized study treated patients with 66 Gy of EBRT with and without neoadjuvant goserelin and flutamide (3 or 6 months) in a high-risk population. The addition of 6 months of neoadjuvant ADT to radiation resulted in improved distant progression (adjusted hazard ratio [aHR] 0.49, 95% CI 0.31–0.76; P = .001), prostate cancer-specific mortality (aHR 0.49, 95% CI 0.32–0.74; P = .0008), and all-cause mortality (aHR 0.63, 95% CI 0.48–0.83; P = .0008), a finding that was not reproduced in those who received 3 months of ADT.

Compared with 66 to 70 Gy of radiation alone, multiple trials demonstrate survival benefits for the addition of long-term adjuvant ADT, with 1 trial demonstrating an improvement in distant metastasis-free survival as well. However, the benefit for the incremental benefit of 2 or 3 years of ADT after neoadjuvant ADT is more modest. The European Organisation for the Research and Treatment of Cancer (EORTC) 22961 trial treated patients with 6 months of ADT and 70 Gy EBRT, with or without an additional 2.5 years of ADT. A small statistically significant difference in prostate cancer–specific survival was noted, but no additional overall survival benefit was found, consistent with ADT duration effect modeling. Likewise, the RTOG 92-02 trial treated patients with 2 months of goserelin, flutamide, and 65 to 70 Gy EBRT, randomizing patients between 24 months of goserelin versus no adjuvant therapy. Only a trend toward an overall survival benefit was found (80.0% vs 78.5% at 5 years, P = .73), although improvements in other end point surrogates such as disease-free survival and biochemical progression-free survival were found.

In addition to disease control benefits, a period of neoadjuvant ADT may also confer the added benefit of modulating lower urinary tract symptoms and decreasing prostate size, which has the potential to translate into improved long-term toxicity rates.

All these data have predated modern dose-escalated radiotherapy, IGRT, as well as the widespread use of PSA screening. It is postulated that the effect of neoadjuvant or adjuvant ADT may not be as large when combined with dose-escalated radiotherapy. However, it must be noted that no trial assessing increased radiation dose has ever demonstrated a survival advantage, in contradistinction to trials with ADT and radiotherapy. Randomized trials have been activated to address this issue in the intermediate-risk group (RTOG 08-15).

LDR Brachytherapy

LDR brachytherapy involves the permanent implantation of radioactive sources into the prostate to achieve high intraprostatic doses of radiation. The availability of real-time ultrasonography or MRI feedback to place seeds accurately, along with short-range radioisotopes that decay into inert substances form the basis for LDR brachytherapy. Isotopes such as iodine 125 ( ¹²⁵ I) and palladium 103 ( ¹⁰³ Pd) are commonly used in clinical practice. These seeds are placed under direct image guidance, following a predefined customized plan (done in real time, or via a previous volume study) that peripherally loads the prostate gland to deliver maximum radiation dose to the prostate while sparing the urethra. Seeds are implanted via the transperineal route by means of a template affixed to the perineum. Typical delivered doses prescribed to a minimum peripheral dose (MPD) are 145 Gy and 125 Gy for ¹²⁵ I and ¹⁰³ Pd, respectively. In patients at risk of nodal disease or extraprostatic extension, LDR brachytherapy may be combined with EBRT to the whole pelvis or limited fields to cover periprostatic tissues and SVs.

HDR Brachytherapy

HDR brachytherapy temporary implants are another method of delivering radiation via a radioactive source. In this case, the dose rate is high and can exceed 6 Gy per minute at calibration distances, with doses increasing exponentially closer to the source. These dose rates are similar to that deliverable via linear accelerator, and allow for the delivery of large radiation fractions, which may exploit the proposed sensitivity of prostate cancer to high fractional doses. The most common isotope used is iridium 192 ( ¹⁹² Ir). A series of hollow transfer catheters are inserted into the prostate facilitated by a perineal template similar to that of LDR brachytherapy, with transrectal ultrasonographic guidance to visualize the catheter track. During treatment, the ¹⁹² Ir source is sequentially introduced into each transfer catheter to deliver a composite dose to the prostate with high conformity while sparing surrounding critical structures.

Hoskin and colleagues reported the results of a randomized trial demonstrating increased biochemical control outcomes when an HDR boost to EBRT was compared with EBRT alone. The control arm received 55 Gy in 20 fractions of EBRT, and the experimental arm received 35.75 Gy in 13 fractions with an HDR boost of 17 Gy in 2 fractions. The 5-year freedom from biochemical failure estimates were 75% for HDR and 61% for the control arm, which was a statistically significant result. Although the radiation doses used in this study would no longer be considered optimal, well-controlled retrospective studies have also reproduced these findings with more contemporary dose fractionation schedules.

Given the improvement in outcomes and brevity of treatment, HDR monotherapy trials have been conducted to establish its efficacy in patients in all risk groups with encouraging results. For example, Demanes and colleagues reported the results of a cohort of 298 patients treated with HDR monotherapy (42 Gy in 6 fractions or 38 Gy in 4 fractions). With a median follow-up time of 5.2 years, the 8-year biochemical control rate was 97% and overall survival was 95% with acceptable toxicity.

PPRT Volume Delineation

Patterns of failure studies have identified that the most common area for local recurrence after surgery is the vesicourethral anastomosis (VUA), found in up to two-thirds of cases. The bladder trigone and bladder neck are also at risk. However, despite an intact prostatic capsule, surface secretions from prostatectomy specimens often contain detectable levels of PSA, implying that the whole surgical bed is at risk of recurrence. Several consensus guidelines exist detailing the subsequent volume at risk, but commonly include the VUA, SV remnant, and posterior wall of the bladder, encompassing any surgical clips. Irradiation of the pelvic nodes in this case is a controversial issue, as in definitive radiotherapy, and may be considered in those with high-risk disease.

Adjuvant Therapy

Immediate adjuvant therapy aims to identify patients at risk of local recurrence after RP, and offer treatment to this population based on their high propensity for recurrence. The theoretic advantage of immediate therapy is that if disease is present, it will be treated at the lowest possible levels. The disadvantage is that all at-risk patients receive treatment and are thus exposed to treatment side effects, although only a proportion of them will benefit.

Early salvage therapy foregoes the opportunity of immediate PPRT if the PSA decreases to undetectable levels, limiting treatment to those patients who subsequently develop a detectable level of PSA. The major theoretic advantage of this approach is in minimizing the number of patients subjected to the potential side effects of radiation. Practically, delaying radiation may also decrease the potential impact on continence recovery. One large multiinstitutional retrospective study demonstrated grade 3 GU toxicity rates at less than 1%, and grade 3 GI side effects of 0.4%, based on the practice of awaiting return of continence before commencing therapy.

Three randomized studies have compared immediate adjuvant therapy to a watchful waiting approach in men with T3N0 or pathology with a positive surgical margin (SM) ( Table 3 ). These studies were conducted by the Southwest Oncology Group (SWOG), Arbeitsgemeinschaft Radiologischer Onkologie (ARO), and EORTC cooperative trials groups. The SWOG trial demonstrated an improvement of metastasis-free survival at 10 years favoring immediate therapy from 61% to 71%, which was statistically significant. There was a corresponding improvement in overall survival with a hazard ratio of 0.72 (95% CI 0.55, 0.96; P = .023). However, the number needed to treat to prevent 1 case of metastatic disease at a median of 12.6 years was 12.2, underscoring the long-term nature of outcomes. The magnitude of the survival benefit was 1.7 years.

Table 3

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