Radiation Therapy for Genitourinary Malignancies: A Practical and Technical Guide

This book is a comprehensive guide to the use of modern radiation therapy techniques for prostate cancer and other common and rare genitourinary malignancies. It will be an ideal resource for clinicians and trainees wishing to delve more deeply into the practical and technical aspects of radiotherapy for these malignancies and will serve to enhance day-to-day management in clinical practice. The first section is devoted to prostate cancer and includes coverage of low dose rate and high dose rate brachytherapy, conventionally fractionated, moderately hypofractionated, and ultra-hypofractionated external beam radiotherapy, and proton therapy. The second section focuses on radiotherapy considerations in relation to bladder cancer, testicular cancer, renal cell carcinoma, and rare malignancies such as penile cancer and urethral cancer. Radiotherapeutic treatment of patients with genitourinary malignancies now involves unprecedented precision and complexity, and this book will enable readers to exploit fully the exciting advances that have been achieved in recent years. 

• Language: English
• Publisher: Springer
• Release date: Mar 24, 2021
• ISBN: 9783030651374

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Part IProstate Cancer

© Springer Nature Switzerland AG 2021

A. A. Solanki, R. C. Chen (eds.)Radiation Therapy for Genitourinary Malignancies Practical Guides in Radiation Oncologyhttps://doi.org/10.1007/978-3-030-65137-4_1

1. The Management of Prostate Cancer

Robert T. Dess¹  , William C. Jackson¹   and Daniel E. Spratt¹  

(1)

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

Robert T. Dess

Email: [e-mail]

William C. Jackson

Email: [e-mail]

Daniel E. Spratt (Corresponding author)

Email: [e-mail]

1.1 Epidemiology

1.2 Anatomy and Physiology

1.3 Pathology

1.3.1 Histology

1.3.2 Prostate Adenocarcinoma Grading

1.4 Diagnosis

1.5 Staging and Risk Groupings

1.6 Management of Intact Prostate Cancer

1.6.1 Low Risk

1.6.2 Favorable Intermediate Risk

1.6.3 Unfavorable Risk (Unfavorable Intermediate to Very High Risk)

1.7 Post-prostatectomy Radiation Therapy

1.8 Treatment of Metastatic Prostate Cancer

1.9 Technological Advancements in Radiotherapy

1.10 Focus on Patient Reported Quality of Life

1.11 Follow-Up and Survivorship

References

Keywords

Prostate cancerRadiotherapySurgeryPSAAndrogen-deprivation therapy

1.1 Epidemiology

Prostate cancer is the most common cancer diagnosed in men in the United States with over 165,000 new cases per year [1]. Worldwide over 1.2 million men are diagnosed with prostate cancer. Although the majority of men will not die from their disease, prostate cancer remains the second leading cause of cancer death in the United States [1]. In 2015, there were an estimated 3,120,000 men alive in the United States with prostate cancer [2]. Furthermore, given the high incidence, long natural history, and frequent treatment-related morbidity, prostate cancer remains the most common cause of cancer associated years lived with disability worldwide [3].

The median age of diagnosis is 66 years old, and the largest risk factor is age. Autopsy studies have shown that ~10% of men in their 20s and >25% of men in their 40s can harbor prostate cancer [4, 5]. With increasing age, beyond 80 years, the majority of men will harbor some form of prostate cancer, most commonly indolent low grade disease [5]. In contrast, men under 45 years old rarely are diagnosed with prostate cancer, comprising only 0.5% of all new cases [1]. The majority of men who die from prostate cancer are >75 years old, with only approximately 10% of deaths from prostate cancer occurring in men under 65 years old.

Prostate cancer is diagnosed 1.7-fold more often in black than white men in the United States [1]. This is despite the known social disparities that exist in the United States between black and white men, where black men undergo less PSA screening, have less insurance, and are less likely to have a primary care physician [6]. Thus, the difference in new cases would likely be even larger if these social disparities were minimized. Additionally, black men have a 2.2-fold greater likelihood of dying of prostate cancer than white men [1]. The difference in mortality appears to largely be driven by social factors as well, including being diagnosed at a later stage of disease, receiving less guideline concordant treatment, and receipt of heterogeneous follow-up and monitoring. In contrast, Asian-Americans are nearly half as likely to be diagnosed with prostate cancer as white men and are more than twofold less likely to die from prostate cancer [7].

Other risk factors beyond age and race include a Western diet and obesity [8]. There is mixed evidence regarding the impact of diabetes on the development of prostate cancer, as well as the impact of diabetic medications on prostate cancer aggressiveness [9, 10]. By reducing circulating dihydrotestosterone (DHT), 5-alpha reductase inhibitors decrease the development and diagnosis of prostate cancer, but there is debate whether men who take these medications develop more aggressive prostate cancer [11, 12]. Approximately one in ten men with prostate cancer have a hereditary or underlying genetic risk for the development of prostate cancer [13]. Similar to breast cancer, mutations in multiple DNA damage repair genes, such as BRCA2, are associated with an increased predisposition for the development of prostate cancer [14]. There are now established recommendations for germline screening in men newly diagnosed with prostate cancer that are predominately guided based on family history and stage of their prostate cancer (Table 1.1) [15].

Table 1.1

ISUP grade groups

1.2 Anatomy and Physiology

The prostate, which is part of the male reproductive system, is a small exocrine gland of approximately 30 cc in size located within the true pelvis. The primary function of the prostate gland is to secrete fluid that is combined with the spermatozoa from the seminal vesicles to constitute the majority of the semen contents. This secretion is known to facilitate sperm motility and survival. The prostate is regulated by testosterone and DHT.

The urethra passes through the prostate. The bladder sits superior to the prostate with the prostatic base approximating the bladder neck. The rectum is posterior to the prostate and seminal vesicles. The pubic symphysis is anterior to the prostate. The gland is responsible for production of the majority of the contents of the male ejaculate, which is stored in the connecting seminal vesicles.

The prostate is commonly divided based on zonal anatomy into three zones: peripheral zone, central zone, and the transitional zone. Additionally, although rarely a site of prostate cancer, the anterior aspect of the prospect is comprised by fibromuscular stroma. Prostate cancer mostly commonly resides within the peripheral zone, which makes up ~70% of the prostate gland. The peripheral zone abuts the anterior rectal wall and is most easily accessible via trans-rectal ultrasound guided biopsy and digital rectal examination.

The central zone covers 25% of the prostate gland and contains approximately one-third of the ducts that secrete fluid that helps create semen. It is cone-shaped and is located at the base of the prostate adjacent to the seminal vesicles. The transition zone comprises the remaining 5% of the prostate and surrounds the urethra. The prostate gland is enclosed by a fibrous tissue layer and is named as the prostate capsule. Although most cancer resides in the peripheral zone, other prostatic zones may harbor prostate cancer at a lesser frequency and are not routinely sampled with a standard templated biopsy.

1.3 Pathology

1.3.1 Histology

Based on the 2016 World Health Organization classification of tumors of the prostate, there are over ten types of prostate cancer, with multiple histologic variants of each tumor type [16]. The most common histologic type of prostate cancer is acinar adenocarcinoma. Other types include ductal adenocarcinoma, urothelial carcinoma, squamous neoplasms, basal cell carcinoma, mesenchymal tumors, hematopoetic tumors, and neuroendrocrine tumors. Acinar adenocarcinomas, as most prostate adenocarcinomas do, typically express PSA and PSMA and have a functional androgen receptor (AR) present. There are numerous acinar variants of unclear significance, including atrophic, pseudohyperplastic, microcystic, foamy, mucinous, signet-ring, pleomorphic giant cell, and sarcomatoid.

Another common type of prostate cancer is intraductal carcinoma, a distinct entity from ductal adenocarcinoma [17], which is present in ~17% of radical prostatectomy cases but only 3% of needle biopsies. It is associated with a worse prognosis, BRCA2 mutations, PTEN loss, loss of heterozygosity of TP53 or RB1, and SChLAP1 dysregulation.

Neuroendocrine tumors are a rare type of prostate cancers that are binned into four groups: adenocarcinoma with neuroendocrine differentiation, well-differentiated neuroendocrine tumor (carcinoid tumor), small cell, and large cell neuroendocrine tumors [16, 18]. Pure small cell or neuroendocrine prostate cancers are uncommon and are associated with very poor outcomes [19]. This entity should be distinguished from treatment-induced neuroendocrine prostate cancer after years of androgen-deprivation therapy. Pure small cell prostate cancer often has lost either or both PSA and PSMA expression and has over expressed neuroendocrine markers, such as chromogranin and synaptophysin.

1.3.2 Prostate Adenocarcinoma Grading

Prostate adenocarcinoma is graded conventionally using the Gleason grading system, which most recently has been converted into the 2014 International Society of Urologic Pathology (ISUP) grade groupings (grade 1–5) shown in Table 1.1 [20, 21]. Grade groups are based on the histologic architectural pattern observed and are assigned based on the most common and second most common pattern seen. The higher the grade group, the worse the prognosis and higher risk for the development of metastatic disease.

1.4 Diagnosis

The diagnosis of prostate cancer must be made by tissue confirmation. The most common reason for undergoing a prostate biopsy is due to a rising PSA. Although there are age adjusted PSA thresholds, simplified National Comprehensive Cancer Network (NCCN) guidelines typically recommend that if a man has a PSA ≥3 ng/mL this should prompt further testing based on a patients age [22]. This includes ruling out benign causes of a PSA rise such as infection. This also should prompt a digital rectal exam to determine if a palpable abnormality can be felt or if there is increased pain on prostate exam indicative of prostatitis.

The PSA should be repeated to determine if it remains elevated. Based on the PSA, DRE findings, and estimated PSA density, one should determine the patient’s pretest probability of harboring clinically significant cancer. There are multiple available blood and urine-based assays that can help improve the pretest probability of detecting clinically significant cancer [23]. While not recommended for routine use for the detection of prostate cancer by the NCCN, these tests can be useful for increasing the specificity of cancer detection or aiding in decision making regarding the need for additional biopsies in men with an initial negative biopsy. There are several commercially available assays. The Prostate Health Index combines total PSA, free PSA, and p2PSA to improve the sensitivity of detecting prostate cancer and is FDA-approved for use in men with serum PSA values between 4 and 10 ng/mL [24]. The Progensa PCA3 test which combines PCA3 and PSA mRNA has FDA approval for use in men with an elevated PSA and a previously negative biopsy [25]. Tests available to predict the likelihood of observing a Gleason score of 7 or higher on biopsy include the 4Kscore [26], which measures free PSA, total PSA, human kallikrein 2, and intact PSA, as well as the Mi-Prostate score [27], which combines serum PSA and post-DRE urine expression of PCA3 and the TMPRSS2:ERG fusion mRNA.

In addition to blood and urine-based biomarkers, recently multiple randomized controlled trials have shown that multiparametic MRI can significantly improve the detection of clinically significant cancer while reducing unnecessary biopsies and the detection of low grade cancers [28, 29]. However, there is significant heterogeneity in the inter-reader reliability using the current PI-RADS version 2, even among experts [30]. Other factors that increase the likelihood of harboring cancer are PSA density, strong family history, African-American race, or known familial cancer mutation (e.g., BRCA2).

Once a patient has a sufficiently high pretest probability, they should undergo a transrectal ultrasound-guided sextant biopsy with at least 12 templated cores. If an MRI were already performed, several systems are available to enhance the yield and accuracy of the biopsy by performing MRI-targeted biopsies to any regions of interest. Importantly, the templated and targeted biopsies should both be performed as MRI-targeted biopsy alone may miss 10% of clinically significant cancers when the templated systematic biopsies are omitted [31].

Other methods for the diagnosis of prostate cancer are incidental. These most commonly include detection of prostate cancer during a trans-urethral resection of the prostate or cystoprostatectomy.

1.5 Staging and Risk Groupings

Once a histologic diagnosis of prostate cancer is made, a full staging workup is appropriate based on the patient’s stage and NCCN risk group [32]. Nearly all cancers of the human body are staged using the American Joint Committee on Cancer (AJCC) 8th edition. However, for prostate cancer, these stage groupings are rarely utilized for multiple reasons. First and foremost, the prostate cancer stage grouping system is one of the few that is based not from specific outcomes data but rather expert consensus. Second, national guidelines and most clinical trials use NCCN risk groups [33] to bin patients into similar prognostic groups. However, the basic TNM staging used in the AJCC staging system is a critical component to determining a patient’s NCCN risk group.

The three most important clinicopathologic prognostic factors that comprise both the AJCC stage groupings and NCCN risk groups are a patient’s pre-treatment PSA, ISUP Grade group, and TNM stage. Cancers can be first divided into localized, locally advanced, node positive, and metastatic [32]. Within localized and locally advanced prostate cancer, NCCN subdivides them into six risk groups: very low, low, favorable intermediate, unfavorable intermediate, high, and very high. This expanded NCCN classification has evolved from the original D’Amico risk groups of low, intermediate, and high [34], which are still used by many today. The current AJCC 8th edition staging and the 2018 NCCN risk groups are shown in Tables 1.2, 1.3 and 1.4.

Table 1.2

AJCC 8th Edition TNM Definitions

Table 1.3

NCCN risk groups

Table 1.4

AJCC 8th edition and NCCN risk groups

Other risk grouping systems include CAPRA, which similar to recent expansions of NCCN, includes percent positive cores, which is one of the most prognostic variables in addition to grade [35]. CAPRA also includes age in their model, as older age is consistently shown to correlate with more aggressive disease [35].

For patients that have chosen to undergo radical prostatectomy as their definitive treatment, there are also pathologic staging systems. The AJCC clinical and pathologic staging systems are essentially identical, with the main exception being that patients must have at least pT2 disease if they undergo surgery, where clinically many patients are cT1c. CAPRA also has a commonly used post-operative risk grouping system termed CAPRA-S [36]. Other frequently used nomograms to predict prognosis are the widely used Memorial Sloan Kettering nomograms available online (www.​mskcc.​org/​nomograms/​prostate).

Recently, Medicare began covering select genomic classifiers (e.g., Decipher) for the use in the pre-treatment and post-operative setting to improve risk stratification [32]. These tests have been shown to independently improve the discriminatory capability of identifying which patients within each NCCN risk group are more or less likely to recur, develop metastatic disease, or die from prostate cancer [37, 38]. Prospective studies of these tests are ongoing (NCT02783950, NCT03070886).

1.6 Management of Intact Prostate Cancer

The initial management of newly diagnosed intact prostate cancer depends principally on two factors. The first is life expectancy. This can be estimated using actuarial tables such as those provided by the Social Security Administration which can be adjusted upward or downward by clinical judgment (e.g., patient comorbidities). For men with a life expectancy of 5 years or less, observation is the preferred strategy. Prostate cancer in elderly or frail men is unlikely to cause disease-specific mortality or significant morbidity. Local treatment is therefore deferred and reserved for only those who develop symptomatic disease. The second factor that helps determine the appropriate initial management strategy is NCCN clinical risk assessment (Table 1.3). Recommended curative local treatment options vary by risk group. For those with very low- and low-risk disease, disease monitoring (active surveillance) is the preferred strategy. For those with favorable intermediate-risk disease, a range of options are appropriate including radical prostatectomy (RP), external-beam-radiation therapy (EBRT), or brachytherapy. For those with unfavorable intermediate-risk, high-risk, or very high-risk disease, multimodality treatment is most often the treatment of choice.

EBRT for localized prostate cancer is commonly delivered in three dose/fractionation schemes: (1) conventional fractionation (1.8–2 Gy per fraction to ~80 Gy), (2) moderate hypofractionation (2.5–3 Gy per fraction to 60–70 Gy), or (3) stereotactic body radiotherapy (SBRT) (7–9.5 Gy per fraction to 36–40 Gy in 4–5 fractions).

1.6.1 Low Risk

For men with very-low risk or low risk prostate cancer, deferring upfront initial treatment is a safe, effective strategy [39, 40]. The intensity of active surveillance varies by institution and individual but generally involves following PSA levels no more frequent than every 6 months and repeat biopsies no more frequent than every 12 months. Most men with very-low or low risk disease classification harbor indolent cancer that is unlikely to ever spread outside the prostate; distant metastatic rates at 10–15 years are 1–3%, and even fewer have died from prostate cancer [41]. Disease monitoring spares men the side effects of immediate treatment and preserves baseline quality of life. Approximately 50% of men can avoid radical treatment at 10–15 years with this strategy [39, 42]. At disease progression, often defined by an upgrade Gleason score to Grade group 2 (Gleason 3 + 4) or above, definitive treatment is offered and the opportunity for cure is not lost. The ProtecT trial, a randomized comparison of PSA monitoring to immediate treatment with RP or EBRT with 3–6 months of androgen deprivation (ADT), demonstrated no difference in prostate cancer-specific mortality at 10 years in all three arms [42]. Approximately 80% of men had low risk disease. Immediate treatment with RP or EBRT was associated with a small benefit in distant metastasis, but most of those events were in those who had intermediate risk disease.

For those who are felt to warrant treatment with EBRT, SBRT, or moderate hypofractionation are preferred for this population given the reduced costs and increased convenience over conventional fractionation and are endorsed by national guidelines [32, 43].

Low-dose-rate (LDR) brachytherapy is also a treatment option for men with low risk prostate cancer. LDR brachytherapy involves transrectal ultrasound (TRUS) based interstitial permanent implantation of radioactive seeds [iodine-125 (¹²⁵I), palladium-103 (¹⁰³Pd), or cesium-131] into the prostate via the perineum. Supplementary EBRT added to brachytherapy is unnecessary in this population [44, 45]. High-dose-rate (HDR) brachytherapy, first reported in the early 1990s, is also a treatment option [46, 47]. HDR similarly involves TRUS-guided interstitial implantation. Temporary catheters are placed instead of radioactive seeds, and treatment is delivered with iridium-192 via an afterloader.

1.6.2 Favorable Intermediate Risk

For men with favorable intermediate risk prostate cancer and a life expectancy beyond 10 years, definite treatment is typically recommended. The two most common treatment options for these men are RP and EBRT. RP involves surgical removal of the prostate and seminal vesicles with or without sampling of the pelvic lymph nodes. EBRT involves external treatment most often with high-energy X-rays generated from a linear accelerator. The ProtecT randomized trial demonstrated no difference in efficacy of radical treatment between these two modalities in men with low and intermediate risk disease.

For those who are felt to warrant treatment with EBRT, SBRT, or moderate hypofractionation are preferred for this population given the reduced costs and increased convenience over conventional fractionation and are endorsed by national guidelines [32, 43].

Low-dose-rate (LDR) brachytherapy is also a treatment option for men with favorable intermediate risk prostate cancer. LDR brachytherapy involves transrectal ultrasound (TRUS) based interstitial permanent implantation of radioactive seeds [iodine-125 (¹²⁵I), palladium-103 (¹⁰³Pd), or cesium-131] into the prostate via the perineum. Supplementary EBRT added to brachytherapy is unnecessary in this population [44, 45]. High-dose-rate (HDR) brachytherapy, first reported in the early 1990s, is also a treatment option [46, 47]. HDR similarly involves TRUS-guided interstitial implantation. Temporary catheters are placed instead of radioactive seeds, and treatment is delivered with iridium-192 via an afterloader.

1.6.3 Unfavorable Risk (Unfavorable Intermediate to Very High Risk)

For men with unfavorable intermediate-risk, high-risk, and very-high risk prostate cancer (collectively unfavorable risk disease), multimodality treatment is often required. No randomized trials have directly compared RP to EBRT (with or without ADT) in this population. However, many retrospective studies have shown mixed results—some report better outcomes with RT [48, 49] and some showed RP is better [50, 51]. Historically, RP was the most common treatment modality for those with low and favorable intermediate risk disease, and EBRT was the dominant treatment modality for men with unfavorable risk disease. Recent estimates suggest, however, that RP is the most common treatment even in men with unfavorable risk disease [52]. For these men with higher risk disease, up to 50% or more will have biochemical recurrence even at high volume surgical centers [53, 54]. Thus, many require adjuvant or salvage radiation treatment at time of PSA recurrence. For those with unfavorable risk disease, the addition of EBRT to ADT has improved overall survival in several trials [55, 56]. The converse is also true. The addition of ADT to EBRT improved OS in multiple trials. In the unfavorable intermediate-risk group, 6 months of ADT is recommended [57, 58], and in those with high or very-high risk disease, 18–36 months is recommended [59–61]. ADT is given concurrently with EBRT and as adjuvant treatment. Prolonged neoadjuvant ADT has not improved outcomes [62]. Dose escalation with EBRT plus a brachytherapy boost improves biochemical control in those treated without ADT [63] and with ADT [64, 65] but has not been demonstrated to lower distant metastasis or improve survival endpoints. To date, no randomized evidence demonstrates reduction in metastasis or improvement in survival when the pelvic lymph nodes are added to the radiation field [66, 67]. The ongoing study, RTOG 0924, aims to answer this question in the modern era.

For those who are felt to warrant treatment with EBRT without brachytherapy for unfavorable intermediate risk disease, SBRT or moderate hypofractionation are preferred for this population given the reduced costs and increased convenience over conventional fractionation and are endorsed by national guidelines [32, 43]. For patients with high or very high risk, there is less data for SBRT, and thus use of moderate hypofractionation should be the preferred strategy, with ongoing studies assessing nodal irradiation in the setting of moderate hypofractionation [43].

1.7 Post-prostatectomy Radiation Therapy

As mentioned, prostatectomy is an initial local treatment option for men with newly diagnosed prostate cancer [52, 68]. While many men are cured with this approach, some will ultimately develop a rising PSA after prostatectomy, known as biochemical recurrence, signaling recurrent prostate cancer [69]. For men with high-risk prostate cancer undergoing radical prostatectomy, the risk of future recurrence often exceeds 50% [54]. Pathologic features associated with an increased risk of post-prostatectomy biochemical failure include a positive surgical margin, extracapsular extension, seminal vesicle invasion, and involvement of lymph nodes, among others [70].

Four randomized trials have demonstrated that for men with any or multiple of these three pathologic features (positive surgical margin, extracapsular extension, seminal vesicle invasion), adjuvant radiation therapy (ART) reduces the risk of future biochemical recurrence by approximately 50% [71–73]. One trial additionally demonstrated a reduction in development of metastatic disease and improved overall survival in men receiving adjuvant radiation therapy [73]. Based on the findings of these randomized trials, national guidelines endorse offering ART to men with a positive surgical margin, extracapsular extension, and/or seminal vesicle invasion following prostatectomy [74, 75]. Despite this recommendation and the known benefits of ART for these men, <10% of men with any of these adverse pathologic features receive adjuvant post-prostatectomy radiation therapy [76, 77]. The cause of this low utilization is multifactorial in nature, but likely driven by concerns of overtreatment, additive treatment-related toxicity, and the lack of a clear survival benefit when looking at the findings from all three adjuvant radiation trials in whole.

An alternative to planned adjuvant radiation therapy following prostatectomy is for a selective treatment approach with salvage radiation therapy (SRT) for men who develop biochemical recurrence following prostatectomy. While no randomized trial has ever compared SRT to observation for men who develop post-prostatectomy biochemical recurrence, well-performed retrospective analyses suggest that salvage radiation therapy improves outcomes over observation for men with biochemical recurrence [78, 79]. For men receiving SRT, early SRT, most commonly defined as initiation of treatment with a PSA level <0.5 ng/mL, has been associated with improved outcomes, with no apparent lower threshold [80, 81]. A large multi-institutional study suggests that SRT given when PSA is ≤0.2 ng/mL results in the best long-term oncologic outcomes [82]. Ongoing trials are directly comparing the effectiveness early SRT to ART, with preliminary results recently presented in abstract [83, 84]. Early combined results of the Radiotherapy-Adjuvant Versus Early Salvage (RAVES) trial, Radiotherapy and Androgen Deprivation in Combination After Local Surgery (RADICALS) trial, and GETUG-AFU 17 trial, all which compared adjuvant and early salvage radiation therapy, were presented in the ARTISTIC meta-analysis [85]. This analysis included 1074 men randomized to ART and 1077 randomized to SRT. With a median follow-up ranging from 47 to 61 months, there was no difference in event free survival between these two treatment approaches [85].

While the role of ADT with external beam radiation therapy is well established, it is less clear which men receiving post-prostatectomy benefit from the addition of ADT. RTOG 9601 randomized men receiving SRT to 2 years of high-dose bicalutamide versus placebo and demonstrated an improvement in overall survival 12 years post-treatment, with the benefit driven by receipt of ADT in men with a pre-SRT PSA level >0.7 ng/mL [86]. GETUG-AFU 16 assessed adding 6 months of ADT to SRT, and with 5-years follow-up, demonstrated improved biochemical control only [87]. Overall, the men in GETUG-AFU 16 had lower PSA values than those enrolled on RTOG 9601. As the survival benefit achieved with ADT was in men with PSA values >0.7 ng/mL, future studies will attempt to assess whether select men with lower PSA values may benefit from ADT, and what the appropriate duration of ADT is in this setting. The use of ADT with ART is even less clear with no reported randomized trial in this setting.

An exciting development moving forward is the incorporation of genomic biomarkers and novel molecular imaging techniques to aid in risk stratification and treatment selection for men receiving post-prostatectomy radiation therapy. Predictive genomic biomarkers have been proposed that can discriminate which men are most likely to benefit from post-prostatectomy radiation therapy, as well as identify men that may benefit from adjuvant radiation therapy over salvage radiation therapy [88, 89]. It is probable that genomic classifiers such as these will dramatically alter the way in which treatment decisions are made for men potentially eligible for post-prostatectomy radiation therapy. Similarly, new molecular imaging techniques, such as prostate-specific membrane antigen positron emission tomography (PSMA-PET), ¹¹C-choline PET, and fluciclovine F18 PET (Axumin®), may allow for identification of men with distant metastatic disease near the time of initial biochemical recurrence. Indeed, even with PSA values <0.5 ng/mL, approximately 50% of men will have a positive finding on PSMA-PET [90], and incorporation of imaging modalities such as this into routine clinical practice could prevent delivering potentially futile local-only therapy in men found to have distant metastatic disease.

1.8 Treatment of Metastatic Prostate Cancer

For men with newly diagnosed castration-sensitive metastatic prostate cancer, androgen deprivation therapy (ADT) forms the backbone of treatment. Historically, androgen deprivation has been achieved through orchiectomy or treatment with a gonadotropin-releasing hormone (GnRH) agonist, and these treatment approaches improved survival for men with clinically evident metastatic disease. ADT is commonly supplemented with anti-androgen therapy, and these two forms of treatment given together are referred to as combined androgen blockade. The treatment landscape of metastatic hormone-sensitive prostate cancer is rapidly evolving, with multiple new standard of care first-line treatment options available. Docetaxel in addition to ADT has been demonstrated to improve survival for at least a subset of men with newly diagnosed metastatic disease in three randomized trials [91–93]. Similarly, two randomized trials have demonstrated improved overall survival in men with newly diagnosed metastatic prostate cancer when adding abiraterone to ADT [94, 95]. New forms of anti-androgen therapy and systemic therapies continue to emerge at a rapid pace, and it is likely that available first-line treatment options for men with metastatic prostate cancer will continue to expand in the near future.

While the current treatment paradigm of metastatic prostate cancer relies on systemic therapies, radiation therapy also plays an important role in the treatment of these men as a palliative or preventative therapy. Radiation in this setting is commonly used to treat painful bony lesions, locally advanced disease resulting in lower urinary tract symptoms, bleeding, or pain; in the treatment of spinal cord compression, and to reduce fracture risk, among others, and is quite effective. Additionally, there is a growing body of evidence suggesting that radiation therapy may have a role in improving outcomes for men with oligometastatic prostate cancer. The STOMP trial demonstrated that in men with three or fewer metastases that metastasis directed therapy with surgery or radiation therapy improved the primary outcome of ADT-free survival by an absolute difference of 8 months at 3-years [96]. Conversely, the STAMPEDE trial demonstrated that in men with low burden metastatic disease that radiation therapy to the prostate improved overall survival [97]. Ongoing and future trials will hopefully better define which men with limited volume metastatic disease truly derive benefit from radiation therapy to local and/or distant sites of disease.

1.9 Technological Advancements in Radiotherapy

Over the past few decades, several technical advances have improved the delivery of EBRT. Mega-voltage-based EBRT was developed in the 1960s and treatment was based on two-dimensional imaging with limited, if any, soft tissue delineation [98]. Smaller fraction sizes of 1.8–2 Gy per fraction per day were used and cumulative doses were limited based on normal tissue toxicity. The first major technological advance involved the incorporation of 3D-dimensional imaging into treatment planning [99]. This was followed by the development of intensity-modulated radiation therapy (IMRT), a technology that allows for more conformal treatment of the prostate while better sparing normal tissue [100]. The development of daily image-guided radiation therapy (IGRT), such as implanted fiducials, electromagnetic tracking, and cone-beam computed-tomography, has further allowed for increased reproducibility and target margin reduction [101]. Investigators have taken advantage of these collective advances to deliver higher daily doses of EBRT more precisely. Dose-escalated treatment above 70 Gy in conventional fractionation is now standardly used [102]. In addition, several large-scale trials have demonstrated non-inferiority of shorter hypofractionated 4–6 week regimens delivering 2.5–3 Gy per fraction compared to conventionally fractionated treatment [103–105]. Hypofractionated treatment is now endorsed by ASTRO guidelines [43]. Ultrahypofractionation, most commonly using stereotactic-body-radiation therapy (SBRT) technology, further shortens the treatment course, often delivered in just 4–5 fractions. SBRT is a growing treatment option with several randomized clinical trials underway [106–108].

1.10 Focus on Patient Reported Quality of Life

Patient reported health quality of life instruments are the main tool used to compare the side effects of local curative treatment options. Questionnaires such as the Expanded Prostate Cancer Index Composite (EPIC) interrogate patient function and bother post-treatment and are organized by urinary, bowel, sexual, and hormonal domains [109]. The ProtecT trial is the only major randomized trial with long-term follow-up that compared active monitoring, RP, and 3D conformal EBRT with 3–6 months of ADT [110]. Surgery had the greatest negative effect on urinary continence and sexual function both short-term and long-term to 6 years of follow-up. Sexual function also declined with EBRT, but improved as patients recovered testosterone function after ADT. EBRT patients also had a decrease in bowel function which recovered after 6 months, except for bloody stools which persisted in approximately 7% of patients [110]. Several groups have also created large-scale prospective population-based cohorts which provide additional comparative toxicity profiles. The CAESAR study highlights several differences between men undergoing active surveillance or treated with surgery or EBRT [111]. Men treated with EBRT were older and had lower baseline sexual function. Similar to ProtecT, men treated with RP had larger declines in urinary incontinence and sexual function but had improved urinary irritative symptoms. Bowel function was similar across modalities after 12 months. A similar study from North Carolina reported quality of life outcomes after radical prostatectomy, EBRT, brachytherapy, and active surveillance [112]. A different validated instrument was used (Prostate Cancer Symptom Indices) [113], but it contained similar domains (sexual dysfunction, urinary obstruction and irritation, urinary incontinence, and bowel problems). At 3 months, compared to active surveillance, sexual function was worse with RT, EBRT, and brachytherapy; urinary incontinence was worse with surgery; urinary irritation was worse with EBRT and brachytherapy; and bowel symptoms were worse with EBRT. By 2 years, scores were similar between EBRT and brachytherapy with active surveillance.

1.11 Follow-Up and Survivorship

The vast majority of men treated with definitive or post-prostatectomy radiation therapy will die from something other than prostate cancer. As such, while surveillance for disease recurrence is important, maximizing post-treatment quality of life becomes essential. Men are commonly followed post-treatment every 6–12 months for the first 5 years post-treatment, and then annually each year thereafter, with PSA values checked at each visit. A digital rectal exam is usually performed annually as another method by which to monitor for recurrent disease. PSA values and kinetics vary by the modality of radiation therapy utilized for treatment, and definitions of biochemical recurrence differ between definitive