General treatment strategies for early-stage prostate cancer include radical prostatectomy, external beam radiation therapy, brachytherapy, androgen deprivation therapy, and watchful waiting per NCCN Version 1.2015 guidelines for prostate cancer treatment. External beam radiation therapy, brachytherapy, and androgen deprivation therapy are often used as bi- or trimodality therapy combinations based on the aggressiveness of the disease in terms of probability of locoregional spread.

Prostate cancer patients with localized, organ-confined disease or limited extraprostatic extension are candidates for prostate brachytherapy. Table 14.2 summarizes general treatment guidelines for patients to be treated with brachytherapy. Patients with NCCN low-risk group disease are candidates for brachytherapy as monotherapy, patients with intermediate-risk group disease are candidates for brachytherapy with or without supplemental external beam radiotherapy, and patients with high-risk group disease should receive supplemental external beam radiotherapy and androgen deprivation therapy [5].

When deciding whether or not to use brachytherapy, either alone or in combination with EBRT, it is useful to consider pretreatment urologic symptoms and prostate size. Acute urologic symptoms may also be more severe with brachytherapy, which makes it less ideal for patients with significant symptoms of benign prostatic hypertrophy (BPH) and those with large glands, the general cutoff being 50 cubic centimeters. Urinary symptoms are commonly rated using the AUA IPSS, which is the same as the BPH symptom score but with a quality-of-life (QOL) question added. In the phase III trial, RTOG 0815, patients with an AUA score of greater than 15 are not candidates for brachytherapy, and the size cutoff is less than 60 g. Also, a history of transurethral resection of the prostate (TURP) is considered a relative contraindication for brachytherapy because of the increased risk of urethral toxicity, including incontinence [6]. Other factors that may contribute to higher acute toxicity include a greater number of needles used to do the implant and the use of hormonal therapy [7].

The American Brachytherapy Society recommends the following absolute contraindications to TRUS-guided PPB: limited life expectancy, unacceptable operative risks including poor suitability for general or spinal anesthesia, presence of distant metastases, anatomic or surgical absence of the rectum such that TRUS guidance is not possible, large TURP defects which preclude seed placement and acceptable radiation dosimetry, and a history of ataxia-telangiectasia. Recommended relative contraindications include: IPSS >20, history of prior pelvis radiotherapy, prior TURP, prominent median lobe architecture, prostate volume >60 cubic centimeters, and history of inflammatory bowel disease [5]. It is emphasized that published reports demonstrate excellent clinical results in patients with relative contraindications if meticulous patient selection is used and treatment is performed by an experienced brachytherapy team in a multidisciplinary environment.

In theory, the higher incidence of extracapsular extension and seminal vesicle invasion in intermediate- to high-risk patients is more adequately covered by EBRT than brachytherapy, which is the rationale for combining EBRT and brachytherapy alone in these patients. On the other hand, certain intermediate-risk patients are likely to be candidates for brachytherapy alone. In a retrospective review of 668 brachytherapy patients, there was no statistically significant difference in the 8-year actuarial biochemical relapse-free survival (BRFS) between low- and intermediate-risk patients, 98.4 and 98.2 %, respectively [8]. These data suggest that most intermediate-risk patients have a low risk of micrometastatic disease in the pelvis. Even though the risk of extracapsular disease is higher in these patients, these areas may be adequately covered by an implant, since most extracapsular disease is located within 5 mm of the prostate capsule. In another series of combination therapy, where 63.4 % of the intermediate-risk patients had 50 % or more positive biopsy needle cores, there was an 80 % 15-year BRFS [8]. These data suggest excellent long-term control with the combined approach. However, despite high control rates, the additional use of EBRT may be detrimental in terms of higher rates of morbidity. Therefore, additional pathologic factors, such as number or percentage of positive cores, may be helpful to determine whether or not combination treatment should be used. There is a national trial RTOG 0232, which has accrued and closed at the time of publication, that randomized intermediate-risk group patients to brachytherapy alone versus combination therapy. The results of this trial will inform decision making regarding this patient group.

Transrectal ultrasound (TRUS) was the first modality widely to evaluate the local extent of prostate cancer and remains the most widely used imaging modality for biopsy guidance and image-guided treatments including brachytherapy source placement. However, even with improvements in ultrasound technology such as color Doppler, color power Doppler, microbubble contrast enhancement, and ultrasound elastography, TRUS is unable to reliably differentiate prostate cancer from normal prostate glandular tissue, and TRUS-guided biopsy can miss up to one-third of clinically significant prostate cancers [9, 10].

MRI of the prostate gland was first performed in the mid-1980s with excellent anatomic visualization [11]. The T2-weighted images provide excellent spatial resolution and can differentiate the more hyperintense peripheral from the lower signal intensity central and transition zones. In the T2 images, a focus of prostate cancer can appear with low signal intensity in the area of hyperintense parenchyma of the normal peripheral zone [12]. Hypointense lesions can also represent foci of benign hyperplasia, prostatitis, focal prostate atrophy, or post-biopsy hemorrhage or similar processes. The degree of signal reduction in a cancer lesion correlates, in some cases, with the grade and growth pattern of the tumor [13, 14]. T2-weighted MRI also offers the enormous benefit of assessing the extent of local disease. Extracapsular extension can be identified through asymmetry of the neurovascular bundles, obliteration of the rectoprostatic angle, irregular bulging of the prostatic margin, and low-signal tumor in the periprostatic fat. Seminal vesicle invasion can be similarly identified. Figure 14.1 demonstrates a T2 hypointense lesion with extracapsular extension.

More recently, the ability to obtain functional information from the MRI refined prostate cancer diagnosis and staging. Specifically, dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted MRI (DW-MRI), and proton magnetic resonance spectroscopic imaging (MRSI) are all becoming more widely used in the evaluation of a potential prostate brachytherapy patient. DCE-MRI is able to detect changes in the local vasculature as prostate tumors secrete pro-angiogenic agents, such as vascular endothelial growth factor, leading to recruitment of neovasculature, increased vascular permeability, and increase in volume of the tumor interstitial space [15, 16]. With microcompartmental modeling, the time versus intensity curves of contrast enhancement can be plotted, and the parametric images can be fused with T2-weighed images. DWI-MRI is based on the thermally induced ransom molecular displacement (Brownian motion). An organ’s diffusion properties are related to the amount of interstitial free water and tissue permeability. A prostatic neoplasm generally has more restricted diffusion due to higher cell densities and cancer cell membrane characteristics [17]. MRSI provides metabolic information by determining the chemical concentration of various compounds and metabolites in the prostate architecture. In prostate cancer, the choline-to-citrate ratio is generally used to identify lesions that are at high risk of representing prostate cancer [18].

Each of the MRI techniques offers distinct advantages and limitations, so the ideal use of MRI in prostate cancer is to use a combined multiparametric MRI (mpMRI) approach, where information from each technique is used to complement the information gained from the others. Modern software algorithms are able to register and fuse the information from different techniques to allow functional and anatomic colocalization. Typical mpMRI sequences include T1- and T2-weighted images combined with functional imaging techniques. There is increasing use of mpMRI in the diagnosis and staging of prostate cancer, but no formal recommendations of guidelines are available [19]. Efficient detection of prostate cancer is improved with performing targeted biopsies with MRI guidance, and sampling of the most abnormal area on a prostate MRI is likely to yield a positive diagnosis of prostate cancer [20, 21]. Accurate delineation of the prostate cancer lesions improves patient staging and also informs important brachytherapy treatment decisions regarding the need for supplemental external beam radiation therapy or androgen deprivation therapy.

TRUS has been the mainstay imaging modality for intraoperative brachytherapy imaging and treatment planning due to its portability, ease of use, low cost, and safety. Suboptimal source placement, in the past, was frequently a result of poor TRUS imaging during the procedure, a problem that is being mitigated with improvements in ultrasound technology and the ability to fuse ultrasound images with other modalities including CT and ultrasound.

Several institutions are exploring the concept of focal boost treatment strategies, where the whole prostate gland is treated but areas of dominant tumor are given a boost dose. In local failures after primary radiation therapy, there is a body of evidence that suggests the local recurrence happens at the dominant tumor locations [22, 23]. A focal brachytherapy boost could improve the therapeutic ratio of brachytherapy treatments by dose-escalating areas of bulky tumor while still allowing minimal increased dose to adjacent normal tissues.

Due to the multifocal nature of prostate cancer, the use of any definitive radiotherapy has included the whole prostate gland as a target volume. With the advent of PSA screening and advanced imaging techniques, outlined above, that improve staging and finely hone risk group stratification, whole-gland treatment may represent overtreatment of low-grade, well-defined disease. Therefore, the concept of focal brachytherapy is being explored for patients with unifocal dominant lesions [24] with the assumption that the dominant lesion is responsible for total tumor volume, risk of recurrence, and Gleason score. In addition to brachytherapy, a variety of other focal ablative approaches are being explored, including photodynamic therapy, high-intensity ultrasound, cryotherapy, and thermal laser ablation.

A successful prostate implant demonstrates adequate coverage of the prostate gland and limitation of dose to adjacent normal tissues including the rectum, bladder, urethra, and neurovascular bundles. As detailed above, the ABS recommends post-implant dosimetry for all patients undergoing prostate brachytherapy. In this process, implanted sources are localized and correlated with prostatic anatomy to calculate the dosimetric parameters of interest. This process allows the radiation oncologist to correct systematic deficiencies in overall implant technique while identifying patients who are at risk for local failure or toxicity development. It is acknowledged that given the real-time nature of brachytherapy, there will be spatial variation in source placement from the intraoperative plan to the post-plan, and therefore a range of post-plan variabilities is to be anticipated.

The first published report of CT for post-implant dosimetry was in the 1990s, which allowed for the representation of organ and dose distribution together in spatial registration [25]. In contemporary practice, CT is recommended to evaluate post-implant dosimetry and is used in the vast majority of cases [26]. While CT is inexpensive and widely available and allows for easy identification for implant prostate seeds, it is not optimal for identification of the periphery of the prostate, particularly at the apex and base of the gland. Several authors have reported large uncertainties in prostate contours in post-implant CT scans [27, 28]. Additionally, the CT volume is generally different from the intraoperative volume and remains a confounding issue in the analysis and reporting of dosimetric outcomes [29].