26. Рак простаты

The American Cancer Society’s Oncology in Practice: clinical management (2018)

Edited by American Cancer Society


Заболеваемость и летальность

In the United States (US), an estimated 161,360 new cases of prostate cancer will be diagnosed in 2017, and approximately 26,730 men will die of prostate cancer. Given current screening practices, it is estimated that one in six American males will acquire the diagnosis in their lifetime, and one in 36 will die from the disease [1]. Much of the statistical information regarding prostate cancer in the US is derived from the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program.

Incidence rates have fluctuated in the recent past, most significantly affected by the introduction of prostate-specific antigen (PSA) testing in the mid-1980s. As availability and utilization of PSA testing became more widespread, detection of prostate cancer increased, resulting in substantial increases in incidence rates of approximately 16.5% a year between 1988 and 1992. The subsequent decline in incidence of about 1.5% per year until 1995 represented a time when the majority of prevalent detectable cases had already been identified (Figure 26.1).

The small and transient rise in incidence seen around the new millennium is thought to be the result of a combination of increased prostate cancer screening initiatives, and the transition from six-core (sextant) prostate biopsy to the more sensitive extended (10–12) core prostate biopsy as the standard of care. The incidence rate decline of approximately 10.7% annually from 2010 to 2013 is thought to be the result of reduced use of PSA testing [1,2]

Prostate cancer-specific mortality in the US has declined significantly since the early 1990s [1,2], and there are multiple factors likely contributing to its improvement. While large randomized, controlled trials have not shown a significant mortality benefit to PSA screening, some argue that the effects from the early implementation of PSA screening is delayed, and are only starting to become manifest now as mortality reduction. Treatments have also been refined and new therapies realized since the inception and completion of the clinical trials. Changes to the World Health Organization’s definition of death attributed to a specific cause, and morbidities such as increased cardiovascular risk secondary to hormonal therapy for prostate cancer treatment, need to be taken into consideration as well.

Worldwide, prostate cancer remains the second most common cancer in men. Incidence rates of prostate cancer vary widely across country borders, with developing countries having lower rates compared to industrialized nations.

Факторы риска

Из всех хорошо известных факторов риска развития рака предстательной железы возраст, безусловно, самый сильный. Рак простаты редко диагностируется у мужчин в возрасте до 40 лет. Согласно данным SEER базы с 2007 по 2009 год, вероятность диагноза рака простаты у мужчин-американцев в возрасте до 39 лет составляет всего 0,01%. Соответствующие вероятности для мужчин в возрасте 40-59, 60-69 и 70+ лет равняются 2,68%, 6,78% и 12,06% соответственно.

Ethnic background is an important prostate cancer risk factor. Among different races, African American men have the highest incidence of prostate cancer in the world. They present with higher PSAs, Gleason scores, and stages of disease, even after controlling for socioeconomic, clinical, and pathologic variables [2]. Prostate cancer is more common in Whites from North America and northwestern Europe, and less common in men in Asia and South America.

Family history and genetics are also strong risk factors. A meta-analysis of epidemiological studies found that having a first-degree relative with prostate cancer places a male at over 2.5Ч relative risk of developing prostate cancer in their lifetime [3]. An even greater risk has been observed in men with multiple relatives with prostate cancer, or a family history of early prostate cancer disease onset [3–5].

Further supporting the hypothesis that genetics is an important factor in driving prostate cancer pathogenesis, a Scandinavian study of male twins found a 21.1% concordance for monozygotic twins as compared to 6.4% for dizygotic twins. Hereditary factors may represent as much as 42% of the risk of prostate cancer, greater than that seen in colorectal (35%) and breast cancer (27%) [6]. Germline mutations in BRCA1 and BRCA2 account for small percentages of prostate cancer, but are associated with higher Gleason scores and overall worse prognosis [7–11].

Рисунок 26.1. SEER возраст-скорректированная заболеваемость раком простаты. Частота на 100,000 и возраст-скорректированная к 2000 Американской Стандартной Популяции. Regression lines are calculated using the Joinpoint Regression Program Version 4.2.0, April 2015, National Cancer Institute. Incidence source: SEER 9 areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta).

Through genome-wide association studies, multiple single nucleotide polymorphisms (SNPs) have been identified as markers for prostate cancer risk [12–21]. Many of these SNPs reside in regions of the genome not yet well understood. With further research, these SNPs may help yield further insights into prostate cancer biology, to be used in screening, or become future targets for therapeutics.

Many observations have suggested that environmental factors play a major role in the etiology of prostate cancer. As an example, Japanese immigrants in the US, while at lower risk for prostate cancer as compared to their White American counterparts, have a higher risk than Japanese men who reside in Japan. This and other similar risk patterns may be explained by different dietary habits and other lifestyle attributes.

The effects of dietary intake and nutritional factors on prostate cancer risk have been widely studied although the body of evidence is often difficult to interpret due to differences in individual trial designs and inconsistent tools for measuring intake. Diets high in cruciferous vegetables, such as broccoli and cauliflower, are associated with a decreased risk of aggressive prostate cancer [22]. A similar association has been shown in recent meta-analyses with certain soy products, such as tofu, which is thought to be due to phytoestrogens having an effect on reducing cell proliferation and angiogenesis [23], and decreasing concentrations of dihydrotestosterone via 5areductase inhibition. Other foods such as tomatoes, legumes, and fish have also been associated with reduced risk, although the evidence is not as convincing [24].

Dietary fat, particularly alpha-linoleic acids that are commonly found in red meats, has been implicated for increasing prostate cancer risk [25,26]. Increased dairy and calcium intake may also be modestly associated with increased risk of nonaggressive prostate cancer [27].

Selenium and vitamin E, which were initially thought to be protective based on early observational studies and post-hoc analyses of randomized trials evaluating risk of other cancers, was studied in a randomized, prospective chemoprevention trial called SELECT (Selenium and Vitamin E Cancer Prevention Trial); they were found to be not beneficial in reducing prostate cancer risk [28], and are no longer recommended as a preventative supplement.

With regards to dietary intake, the American Cancer Society advises eating at least 2.5 cups of a wide variety of vegetables and fruits each day [24]. No specific recommendations are made for calcium and dairy intake as they may play a role in decreasing colorectal cancer risk, however it is advisable to not exceed recommended daily intake levels [24].

The effects of hormonal factors on prostate cancer was studied in a pooled analysis of 18 prospective studies, which showed that prediagnosis serum androgen and estrogen levels were not associated with an increased risk of disease development [29]. The use of testosterone supplementation for treatment of medical conditions such as hypogonadism, were similarly found not to affect subsequent prostate cancer risk [29].

Metabolic factors affect prostate cancer risk as well. Prospective studies have demonstrated an association between obesity and prostate cancer specific mortality at diagnosis [30], and that it portends a worse prognosis following treatment [31]. These were confirmed in a large meta-analysis which found a 5 kg/m2 increase in body mass index at diagnosis was associated with a 15% higher risk of dying of prostate cancer (relative risk 1.15, 95% CI 1.06–1.25, P <0.01), as well as a 21% increased risk of biochemical recurrence for the same increase in body mass index following primary treatment (relative risk 1.21, 95% CI 1.11–1.31, P <0.01) [32]. Multiple studies also support a relationship between higher serum insulin levels and insulin resistance with higher prostate cancer risk. High circulating IGF-1 concentrations have been shown in meta-analysis to be associated with a moderately increased risk for prostate cancer, although more positively associated with low-grade than with high-grade disease [33].

Physical activity was demonstrated to have a small inverse association with prostate cancer risk in a meta-analysis of 19 cohort and 24 case-control studies [34]. Since other health benefits are derived from increased physical activity, men should be encouraged to maintain a healthy weight, pursue regular exercise, and stay active in their daily lives [24].

Скрининг

Although the majority of diagnoses in the US are made by PSA, routine PSA screening remains controversial. It is well established that PSA is an imperfect test for prostate cancer, as benign conditions such as benign prostatic hypertrophy and prostatitis commonly elevate PSA levels. At a PSA level of

4.0 ng/mL, the traditional limit set by laboratories as the upper limit of normal range, the positive predictive value for prostate cancer is only 30%. Attempts at enhancing PSA testing specificity and sensitivity using PSA velocity [35,36], density [37], and fractionation [38], have not consistently outperformed PSA alone when compared in retrospective series. An abnormal finding on digital rectal examination (DRE), however, adds to the positive predictive value of PSA testing [39].

Early PSA screening guidelines were adopted in the absence of prospective randomized data in the hopes that early detection would translate to decreased prostate cancer morbidity and mortality. Unfortunately, routine PSA screening uncovered many low-risk prostate cancers that would otherwise not become clinically meaningful during a man’s lifetime. The unnecessary treatment of these “clinically insignificant” cancers exposed men to significant morbidities, such as urinary, bowel, and sexual dysfunction, as well as the psychological distress that comes with a cancer diagnosis.

In 2009, two large randomized PSA screening trials were published, providing for the first time ever, clinical data to help guide prostate cancer screening. Both the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial found higher incidences of prostate cancer in their PSA screening arms as compared to the control arms. The two trials differed in that ERSPC found some long-term reduction in prostate cancer-specific mortality associated with PSA screening, whereas PLCO did not [40,41]. However, both trials underscored the high rate of false positives and significant risk of overdiagnosis associated with PSA-based screening. Additionally, both commented that the risks patients are subjected to from screening, diagnosis, and overtreatment can considerably compromise quality of life.

Despite data questioning the efficacy of prostate cancer screening and a lack of universally accepted screening guidelines, PSA testing has nevertheless become a standard of care in many medical practices. While different medical organizations have differing recommendations (Table 26.1), they all stress the importance of helping patients make informed personal decisions about whether or not to check screening PSA levels [42–45]. For a more detailed review of prostate cancer screening, please refer to Chapter 11 in the American Cancer Society’s Principles of Oncology: Prevention to Survivorship.

Диагноз

A PSA level of 4.0 ng/mL has historically been the accepted cutoff for referral for prostate biopsy, although the optimal threshold remains unclear. Subgroup analysis of the large, phase III, randomized Prostate Cancer Prevention Trial in which men underwent routine prostate biopsy at the completion of the trial, found that 26.9% of patients in the placebo arm over the age of 55 and with PSA levels 3.1–4.0 ng/mL, demonstrated prostate cancer on end-of-study biopsy. Even more striking is the fact that 25% of those cases were categorized as high-grade prostate cancer [46]. There continues to be debate whether the PSA cut-off for referral needs to be lowered in order to diagnose this subgroup of high-risk patients at the risk of increasing overdiagnosis.

Таблица 26.1. Руководства по скринингу рака простаты.

Организация Последний пересмотр Рекомендации
American Cancer Society (ACS) [42] 03/03/2010 ·         Informed decision for men with ≥10‐year life expectancy, starting at age 50 if average risk, age 45 if high risk (African American, one first degree relative), age 40 if appreciably higher risk (multiple family members with prostate cancer before age 65)

·         For men who choose screening, PSA test annually with optional DRE. In men whose PSA is <2.5 ng/mL, screening intervals can be extended to every 2 years

American College of Physicians (ACP) [43] 05/21/2013 ·         Informed decision for PSA screening in men aged 50–69

·         No clear evidence guides the periodicity or frequency of screening

·         Recommends against PSA screening in men age <50 at average risk, age ≥70, or life expectancy less than 10–15 years

American Urologic Association (AUA) [44] 05/06/2013 ·         Informed decision for men age 55–69 if average risk, or age 40–54 if higher risk (African American race, positive family history)

·         For men who choose PSA screening, a routine schedule of 2 years or more may be preferred over annual screening

·         Recommends against PSA screening in men age <55 at average risk, age ≥70, or life expectancy less than 10–15 years

United States Preventative

Services Task Force

(USPSTF) [45]

05/22/2012 ·         Informed decision for all men

·         Recommends against PSA based screening, regardless of age

DRE, пальцевое ректальное обследование; PSA, простата-специфичный антиген.

A definitive diagnosis of prostate cancer is made by transrectal ultrasound-guided prostate biopsy. The procedure is usually performed under local anesthesia in the outpatient setting. The current standard of care is for 10–14 core biopsies to be taken in order to establish diagnosis. In the past, the six-core (sextant) biopsy approach had been the standard; however, sextant biopsies were later shown in a systematic review of 87 studies to miss 31% of clinically significant cancers when compared to extended core (>6) biopsies. It also showed that taking more than 12 cores did not add significant benefit to cancer detection [47].

While generally well tolerated, prostate biopsy is not without its side effects. Many patients report pain and discomfort with the procedure. Local anesthesia reduces patient discomfort during prostate biopsy, and is not associated with an increase in rate of complications [48]. A retrospective review of 5,802 transurethral ultrasound-guided sextant biopsies, found that 22.6% of men had hematuria that lasted longer than 3 days, and 50.4% had hematospermia following biopsy [49]. Major complications were observed in small numbers, but notable for fever (3.5%), rectal bleeding (1.3%), and urinary retention (0.4%). Need for hospitalization due to complications of prostate biopsy was rare (0.5%), with most cases attributed to prostatitis or urosepsis.

More than 95% of prostatic malignancy is accounted for by adenocarcinoma. Other histologic diagnoses are rare, and are not limited to neuroendocrine tumors, sarcomas, lymphomas, small cell carcinomas, and transitional cell carcinomas (Table 26.2).

If prostatic adenocarcinoma is discovered on pathologic review of the core needle biopsy, the pathologist grades the most prevalent pattern of glandular architecture and differentiation on the Gleason scale of 1–5, with 1 being the most differentiated and 5 being the least differentiated. The second most prevalent pattern is similarly graded, with the sum of the two grades comprising the overall Gleason sum or score. While the Gleason score is based solely upon architectural features of prostate cancer cells, it is an important prognostic factor as it closely correlates with clinical behavior. In the most popular risk stratification (D’Amico criteria), a Gleason score of 6 (Gleason 3 + 3) or below is considered low-grade disease, 7 (Gleason 3 + 4 or 4 + 3) is considered intermediate-grade disease, and 8 (Gleason 4 + 4) or above is considered high-grade disease.

Стадийность

Prostate cancer is staged either clinically or pathologically according to the TNM staging system developed by the American Joint Committee on Cancer. Revised in 2016, the 8th edition combines anatomic (TNM) stage, pretreatment PSA levels, and histologic grade to define different prognostic groups (Tables 26.3 and 26.4).

Таблица 26.2. Гистологические подтипы рака простаты.

Эпителиальные опухоли

  • Ацинарная аденокарцинома
  • Протоковая аденокарцинома
  • Псевдогиперпластическая карцинома
  • Пенистая гландулярная карцинома
  • Перстневидноклеточная карцинома
  • Лимфоэпителиома-подобная карцинома
  • Саркоматоидная/ веретеноклеточная карцинома
  • Муцинозная аденокарцинома
  • Уротелиальная карцинома
  • Сквамозная/аденосквамозная карцинома
  • Базальноклеточная/аденоидная карцинома

Нейроэндокринные опухоли

  • Нейроэндокринная дифференцировка в пределах аденокарциномы
  • Мелкоклеточная карцинома
  • Карциноидная опухоль
  • Параганглиома
  • Нейробластома

Стромальные опухоли

  • Стромальная саркома

The clinical stage, PSA level, and biopsy Gleason score are used in combination for risk stratification [50] (Table 26.5). The combination of these clinicopathologic parameters has been demonstrated in multiple studies to strongly predict treatment outcome and risk for recurrence following definitive localized treatment. Low-risk disease is generally characterized by a serum PSA level  ≤10 ng/mL, Gleason score ≤6, and clinical stage less than T1c or T2. The disease is more commonly nonpalpable on DRE (T1c), with the only evidence of disease being found pathologically from transurethral resection of the prostate or prostate biopsy. Intermediate-risk disease patients have either PSA levels that range from 10 to ≤20 ng/mL, Gleason score 7, and/or clinical stage T2b. High-risk disease is defined by serum PSA values >20 ng/mL, Gleason score 8–10, and/or clinical stage T2c.

Since prostate cancer metastasizes preferentially to bone, radionuclide bone scans are the most widely used method to evaluate for skeletal metastases. Not all newly diagnosed prostate cancers require a bone scan for workup. A study of 631 prostate cancer patients demonstrated the importance of clinical stage, Gleason score, and PSA, in predicting the likelihood of bony metastasis. Their analysis found that only 1% (3/308) of men with disease stage T2b or less, Gleason score ≤7, and PSA ≤50 ng/mL had a positive bone scan [51]. In the subset of men within the previously defined group except with PSA levels ≤15 ng/mL, none had positive bone scans. This and other similar studies demonstrate that there is a group of low-risk patients that can be easily identified based on the three clinicopathologic factors, in whom bone scan could be omitted.

For patients with higher grade or stage of disease, bone scans and other imaging modalities such as computed tomography and magnetic resonance imaging are indicated for disease staging, and provide guidance for further management. Newer staging modalities such as NaF positron emission tomography scans demonstrate some promise for more sensitive detection of metastasis, without loss of specificity.

Таблица 26.3. TNM дефиниции Американского Объединенного Комитета по Раку.

Определение первичной опухоли (T)
Клинический T (cT)
T категория T критерий
TX Первичная опухоль не может быть оценена
T0 Нет свидетельства первичной опухоли
T1 Клинически бессимптомная не пальпируемая опухоль
T1a Случайное гистологическое выявление опухоли в 5% или менее резецированной ткани
T1b Случайное гистологическое выявление опухоли более чем в 5% резецированной ткани
T1c Tumor identified by needle biopsy found in one or both sides, but not palpable
T2 Tumor is palpable and confined within prostate
T2a Tumor involves one-half of one side or less
T2b Tumor involves more than one-half of one side but not both sides
T2c Tumor involves both sides
T3 Extraprostatic tumor that is not fixed or does not invade adjacent structures
T3a Extraprostatic extension (unilateral or bilateral)
T3b Tumor invades seminal vesicle(s)
T4 Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall
Патологический T (pT)1
T категория  T критерий
T2 Ограничена органом
T3 Распространение за границы простаты
T3a Распространение за границы простаты (унилатеральное или двустороннее) или микроскопическая инвазия в шейку мочевого пузыря
T3b Опухоль инвазирует в семенной пузырек(пузырьки)
T4 Опухоль фиксирована или инвазирует прилегающие структуры кроме семенных пузырьков, такие как наружний сфинктер, прямая кишка, мочевой пузырь, леваторные мышцы и/или стенка таза
Определение для регионального лимфатического узла (N)
N категория  N критерий
NX Региональные узлы не были оценены
N0 Нет позитивных региональных узлов
N1 Метастазы в региональный узел(узлы)
Определение для отдаленного метастаза (M)2
M категория M критерий
M0 Нет отдаленных метастазов
M1 Отдаленный метастаз
M1a Nonregional lymph node(s)
M1b Bone(s)
M1c Other site(s) with or without bone disease
Определение простата-специфичного антигена (PSA)
PSA значения

<10

≥10 < 20

<0

≥20

Любое значение

Определение групп гистологической злокачественности (G)
Grade group Gleason score Gleason pattern
1 ≤6 ≤3 + 3
2 7 3 + 4
3 7 4 + 3
4 8 4 + 4
5 9 или 10 4 + 5, 5 + 4, or 5 + 5

1 There is no pathological T1 classification. Positive surgical margin should be indicated by an R1 descriptor, indicating residual microscopic disease.

2 When more than one site of metastasis is present, the most advanced category is used. M1c is most advanced.

Лечение локализованного рака простаты

Опции лечения локализованного рака предстательной железы включают в себя активное наблюдение (AS), радикальную простатэктомию (RP), внешнюю лучевую терапию (EBRT) и брахитерапию.

Активное наблюдение

For men with low-risk disease that is unlikely to progress based on their clinicopathologic parameters, and in older men with significant comorbidities and/or limited life expectancies, active surveillance (AS) is a preferred option. AS entails regular office visits with PSA checks and DREs, as well as periodic repeat prostate biopsies to monitor the status of the disease. Optimal frequency for monitoring is not clearly established, but a reasonable surveillance protocol would be PSA evaluations every 6 months, DRE every 12 months, and repeat biopsies every 12–24 months, particularly during the initial monitoring period. Definitive therapy can be initiated only if there are significant laboratory or pathologic changes or clinical symptoms to suggest disease progression.

The comparative effectiveness of AS versus definitive therapy was demonstrated in a large prospective trial that randomized 1,643 men with predominantly Gleason 6 (77%) and T1c disease (76%), to receive either AS, radical prostatectomy, or radical radiotherapy. At a median 10 years of follow-up, no significant difference in prostate cancer-specific mortality was demonstrated between the three treatment arms (1.5 vs 0.9 vs 0.7 events per 1,000 person-years, respectively, P = 0.48) [52]. Higher rates of disease progression and metastases were seen in the AS cohort as compared to prostatectomy and radiotherapy cohorts however (22.9 vs 8.9 vs 9.0 events per 1,000 person-years, respectively, P <0.001) [52].

Таблица 26.4. Прогностические стадийные группы Американского Объединенного Комитета по Раку

Опухоль (T) Узел (N) Метастаз (M) PSA Градирующая группа (G) Стадийная группа
cT1a–c, cT2a N0 M0 <10 1 I
pT2 N0 M0 <10 1 I
cT1a–c, cT2a N0 M0 ≥10 < 20 1 IIA
cT2b–c N0 M0 <20 1 IIA
T1‐2 N0 M0 <20 2 IIB
T1‐2 N0 M0 <20 3 IIC
T1‐2 N0 M0 <20 4 IIC
T1‐2 N0 M0 ≥20 1–4 IIIA
T3‐4 N0 M0 Любой 1–4 IIIB
Любой T N0 M0 Любой 5 IIIC
Any T N1 M0 Любой Любая IVA
Any T N0 M1 Любой Любая IVB

When either prostate-specific antigen (PSA) or grade group is not available, grouping should be determined by T category and/or either PSA or grade group as available.

Таблица 26.5. Стратификация риска для локализованного рака простаты.

Risk PSA level (ng/mL) Gleason score Clinical stage
Low ≤10 и ≤6 и T1c или T2a
Intermediate >10–20 или 7 или T2b
High >20 или 8–10 или T2c

PSA, простата-специфичный антиген.

Subgroup analyses from two older studies, the Scandinavian Prostate Cancer Group Study 4 and the Prostate Cancer Interventions versus Observation Trial (PIVOT) suggest a possible benefit for RP over surveillance in younger men (<65 years old) [53] or those with PSA levels >10 [54], although taking into consideration that 20 RPs would need to be performed in order to prevent one death in 10 years, and the risk for RP-associated erectile dysfunction and urinary leakage, AS may still be favored.

Although AS allows men to avoid or defer the potential significant complications associated with the active treatment of prostate cancer, it can cause significant patient anxiety. The psychological toll of having a cancer diagnosis without receiving cancer treatment may – for some patients – outweigh the benefits that AS may bring to a patient’s quality of life. Many patients (and their physicians) opt out of an AS program in favor of starting definitive treatment, despite not having any signs of clinical disease progression.

Дефинитивное лечение локализованной болезни низкого-промежуточного риска

Once the decision is made to treat, there are two broad modalities of treatment that are considered definitive treatment for localized prostate cancer: RP or radiation therapy (RT). Surgical treatment with RP can be performed by either an open or robotassisted laparoscopic approach, whereas radiation therapy can be delivered as EBRT or brachytherapy (radiation seed implants).

No large randomized clinical trials have directly compared RP and RT, but historically, they have yielded similar outcomes in terms of freedom from local or distant recurrence. An observational study attempted to compare the two modalities of treatment; they retrospectively followed men who were diagnosed in the mid-1990s with localized prostate cancer that underwent subsequent treatment with either RP or EBRT over a follow-up period of 15 years. The study suggested a mortality benefit associated with RP as compared to EBRT [55]. However, these results need to be approached carefully as RT has evolved dramatically since the 1990s. Higher prostate radiation dosing, the advent of three-dimensional radiation therapy techniques, and the current practice of adding androgen deprivation therapy (ADT) to EBRT in high-risk localized prostate cancer, need to be taken into consideration. Residual selection bias in the EBRT group is also a potential confounder in this particular study. More likely, large case series suggest that cancer control and survival is comparable in risk-matched localized prostate cancer patients treated with either surgery or radiation.

Treatment selection is often based on age, patient preference, side effect profiles, and impact on quality of life. A multiinstitutional, observational study prospectively measured the outcomes reported by 1,201 patients and 625 spouses or partners before and after RP, brachytherapy, or EBRT. Notably, the use of adjuvant hormone therapy with brachytherapy or EBRT was associated with worse outcomes in multiple quality of life metrics [56]. Overall, both surgical and radiation approaches cause sexual dysfunction, but RP is associated with more urinary incontinence, while RT with more urinary and gastrointestinal irritation.

Лучевая терапия локализованной болезни высокого риска

The combination of ADT and EBRT has been shown in randomized trials to confer a benefit in localized high-risk disease. ADT in these studies consisted of chemical castration with a GnRH agonist either alone or in combination with an antiandrogen agent. The purpose behind the antiandrogen is to suppress the testosterone flare that is observed with the initiation of a GnRH agonist, although there is limited data documenting the frequency and clinical consequences of a testosterone flare. Whether an antiandrogen needs to be given adjunctively when starting a GnRH agonist in prostate cancer patients has not been properly addressed in prospective randomized trials. A retrospective study compared metastatic prostate cancer patients who received a GnRH agonist alone or with an oral antiandrogen, and found that antiandrogen use was not associated with any significant differences in fractures, spinal cord compression, bladder outlet obstruction, or narcotic prescriptions [57]. As discussed previously, ADT can significantly impact quality of life, potentially causing fatigue, hot flashes, erectile dysfunction, decreased libido, decreased bone density, and increased risk of cardiovascular events. The side effects are largely reversible upon discontinuation, although there is a moderate age and therapy duration-dependent risk of permanent testosterone suppression.

The RTOG 8610 trial randomized 471 men with bulky tumors with or without pelvic lymph node involvement to treatment with goserelin 2 months prior to and 2 months concurrent with EBRT vs EBRT alone. With median follow-up of 12.5 years, it was found that ADT significantly decreased 10-year prostate cancer mortality (23% vs 36%), distant metastases (23% vs 36%), and biochemical failure rates (65% vs 80%). Ten-year overall survival (OS) and median survival times favored the combination therapy, but did not reach statistical significance (P = 0.12) [58]. Similarly, the EORTC 22863 trial randomized 415 poorrisk prostate cancer patients to EBRT vs EBRT with 3 years of goserelin, and found that the 10-year disease-free survival was greatly improved with the prolonged combination treatment (47.7% vs 22.7%). The 10-year OS was also significantly better with ADT (58.1% vs 98.8%), with prostate cancer mortality decreased (10.3% vs 30.4%) [59].

Current standard of care for ADT treatment in high-risk patients receiving RT is a prolonged course of 2–3 years, but the optimal duration of androgen suppression is still being challenged. Prior attempts to minimize the duration of ADT have not definitively shown that a shorter course of ADT is as efficacious as the prolonged courses [60,61]. However, recently presented at the American Society of Clinical Oncology Annual Meeting in 2017, the final results of a trial of 630 men with highrisk, node negative prostate cancer randomized to EBRT with either 36 or 18 months of total ADT, showed similar 10-year OS rates between the 36-month and 18-month arms (62.4% vs 62.0%, respectively). QOL analysis showed a significant difference (P <0.001) in 6 scales and 13 items favoring the 18-month duration of ADT [62]. These results may lead to a shortening of the duration of ADT used in the near future for patients with high-risk disease receiving salvage RT.

In most studies, the current standard of care for neoadjuvant ADT is to start 2 months prior to the initiation of EBRT. Although ADT has been shown to augment EBRT, it has not been shown to have a similar effect in the setting of brachytherapy when used alone. Brachytherapy alone is primarily a treatment for lowand intermediate-risk disease, but it is increasingly being used in combination with ADT and EBRT for intermediateand high-risk prostate cancer as it allows for an escalation of effective radiation dose delivered to the prostate over what EBRT alone is able to provide. In a study cohort of 1342 men with high-risk prostate cancer who underwent brachytherapy, either alone, with supplemental ADT, with EBRT, or both ADT and EBRT, the prostate cancer-specific mortality rate was significantly decreased in the group that received both ADT and EBRT as compared to brachytherapy alone, but not in any other group [63]. Notably, the risk reduction was significant despite there being a higher proportion of higher grade and more clinically advanced cancers in the group that received both supplemental ADT and EBRT.

Радикальная простатэктомия для локализованной болезни высокого риска

The role of radical prostatectomy as monotherapy for high-risk localized disease is limited given the risk of local recurrence and micrometastasis. Evidence of extraprostatic extension, tumor fixation to adjacent structures, or lymph node involvement, suggests that RP will not be curative, and consideration should be given for treatment with ADT and RT. However, some men are only found to have high-risk disease on pathology after surgery has been performed.

While there is no established role for adjuvant ADT or chemotherapy following RP in a patient with high-risk disease, adjuvant RT appears to favorably influence the course of disease. It has been shown in multiple studies to decrease the risk of biochemical relapse and improve local control rates in men that have extraprostatic extension (stage pT3a), seminal vesicle involvement (stage pT3b), or positive margins following RP [64–66]. Of the three large randomized trials of adjuvant RT versus observation, the SWOG 8794 study found improved metastasis-free survival (hazard ratio (HR) 0.71, 95% CI 0.54–0.94, P = 0.016) and OS (HR 0.72, 95% CI 0.55–0.96, P = 0.023) in their long-term follow-up [67]. Other studies have not confirmed this, but may require longer follow-up to assess these outcomes accurately. Trials are also currently underway to evaluate the benefit of the combination of adjuvant ADT and RT following RP in high-risk patients.

The use of neoadjuvant ADT is known to reduce overall tumor burden and decrease the rate of positive margins following RP in high-risk localized prostate cancer patients. However, a review of seven prospective randomized trials showed that neoadjuvant ADT does not improve rates of seminal vesicle invasion, rates of lymph node metastasis, PSA-free survival, or OS [68]. The review also found no significant differences in operative time, operative blood loss, transfusion requirements, or length of hospital stay. There is currently no data to support the routine use of neoadjuvant hormonal therapy prior to prostatectomy. Neoadjuvant chemohormonal therapy (chemotherapy and ADT) is currently under investigation in a randomized phase III cooperative group trial.

Лечение рекуррентного и распространенного рака простаты

Unfortunately, definitive local therapy does not guarantee cure, and prostate cancer may recur as often as a third of the time. Recurrence can present either biochemically (rising PSA only), locally, or as disseminated metastatic disease. The approach to treatment depends on the site of recurrence.

Биохимический и локальный рецидив

Following definitive local therapy, serum PSA should be regularly monitored since the first sign of recurrent prostate cancer is usually a rising PSA without any other signs or symptoms. Often in biochemical recurrence, even after detailed evaluation and imaging, no evidence of locally recurrent or metastatic disease can be found, although new diagnostic tools are being explored in this space. Recently approved in patients with rising PSA after definitive therapy, is the PET radiotracer 18F-fluciclovine, which was found to outperform 11C-choline in detection rate of lesions, lymph nodes, bone lesions, and local relapse [69].

While PSA is a controversial test for screening and diagnosis of prostate cancer, it is an effective and highly sensitive biomarker that can be followed during and after treatment as it is elevated in 95% of men with advanced prostate cancer. The time to nadir in serum PSA differs depending on the modality of treatment that was undertaken initially. Patients reach nadir quickly following successful RP during which all prostatic tissue is removed, while the decline in PSA following RT is gradual and more variable, at around 12–18 months.

Local recurrences following definitive RT can be confirmed on prostate biopsy. After RP, recurrence rates in the prostate bed are reported to be anywhere from 20 to 40% in the medical literature, and should be considered in patients who had prostatic disease that extended beyond the prostate capsule or other high-risk features.

Treatment options for PSA-only and local recurrence include observation, salvage RT or RP, or systemic therapy with ADT. There are no randomized trials that directly compare the different modalities of salvage treatment to guide selection, although salvage therapy options depend upon what treatment the patient had initially undergone. Importantly, the disease must have a high likelihood of remaining locally confined for local salvage therapy to have a chance at durable long-term disease control. If clinical and pathologic parameters suggest a high risk of disease dissemination, local salvage therapy is unlikely to succeed. A patient’s overall performance status, as well as medical comorbidities, also influences whether aggressive local therapy would be a reasonable option.

Спасительная (salvage) терапия после начальной лучевой терапии

Salvage RP can provide durable disease control in a select group of confirmed, localized patients who recur after radiation therapy. A systematic review performed of the available medical literature showed that salvage RP is associated with significant surgical complications and morbidity, but with careful selection of patients and improvements in modern surgical techniques, outcomes with salvage RP have improved compared to the past. Published rates of positive surgical margins and pathologic organ-confined disease in recent studies show improvement [70]. Ten-year cancer-specific survival and OS with salvage RP ranged from 70 to 83% and 54 to 89%, respectively [70], making it a procedure worth considering in some men with an otherwise good life expectancy.

Quality of life continues to be a major factor, however. Rates of postoperative sexual and urinary dysfunction are significant. While rates of most surgical complications in salvage RP following radiation failure have improved as compared to the past, they are still significantly increased when compared to RPs without prior radiotherapy [71]. Occurrences of late urinary incontinence and anastomotic strictures are acceptable, but have not significantly improved despite better patient selection and advances to surgical techniques [72].

Cryoablation and brachytherapy have also been studied as treatments following RT failure. Efficacy of salvage cryoablation is difficult to ascertain, as only retrospective data is available. In a retrospective study of 98 men, it was found that salvage RP significantly outperformed salvage cryoablation in rates of biochemical disease-free survival (66% vs 42%) and OS (95% vs 85%), but not disease-specific survival at 5 years (98% vs 96%) [73]. Salvage cryoablation can be a consideration in older patients with significant comorbidities or in those unwilling to undergo salvage RP. Brachytherapy currently has limited studies to support its use following initial RT failure, and further studies will be needed to better understand its merits.

Спасительная (salvage) терапия после начальной радикальной простатэктомии

In patients with recurrence of disease following RP, salvage RT provides the potential for long-term cancer control. While early retrospective studies presented some conflicting findings, overall it was indicative that salvage RT provides long-term survival benefits, but should be initiated soon after biochemical relapse is found [74–76].

Prospective randomized data soon followed that demonstrated the benefit for concurrent ADT use along with salvage RT. In RTOG 9601, a double-blinded, placebo-controlled trial enrolling patients with pT2 or pT3 disease with a rising PSA ranging 0.2–4.0 after prostatectomy, 760 men received salvage RT with either bicalutamide 150 mg daily or a placebo, for a duration of 24 months. With a median follow up of 12.6 years, the study found that the addition of 24 months of bicalutamide to salvage RT resulted in a significantly higher actuarial rate of OS at 12 years (76.3% vs 71.3%, HR 0.77, 95% CI 0.59–0.99, P = 0.04), lower incidence of metastatic disease at 12 years (14.5% vs 23.0%, P = 0.005), and a lower 12-year incidence of death from prostate cancer (5.8% vs 13.4%, P <0.001). Notably, incidence of gynecomastia was much higher in the bicalutamide group (69.7% vs 10.9%, P <0.001) [77].

Another prospective study, GETUG-AFU 16, enrolled 743 men with pT2–pT4a prostate cancer with a rising PSA of 0.2–2.0 µg/L following radical prostatectomy, and randomized them to receive salvage RT with or without goserelin for 6 months. Patients receiving concurrent goserelin had a significantly higher rate of progression free survival at 5 years (80% vs 62%, HR 0.50, 95% CI 0.38–0.66, P <0.0001) [78]. While this study was not able to demonstrate a statistically significant improvement in its secondary endpoint of 5-year OS with the addition of goserelin (96% vs 95%, HR 0.7, 95% CI 0.4–1.2, P = 0.18) [78], the hazard ratio is similar to that of RTOG 9601 for its primary 12-year OS endpoint. Longer follow-up may be enlightening.

Андроген-депривирующая терапия для биохимического или локального рецидива

Systemic treatment with ADT can be considered in patients with biochemical or local recurrence, especially in those who have unfavorable disease characteristics such as short PSA doubling times or high initial Gleason scores. While ADT is not considered curative, over 90% of patients respond with decreases in PSA levels.

The optimal timing to initiating ADT after confirmation of biochemical recurrence remains controversial, as it is unclear whether early treatment delays progression to metastatic disease or confers a survival advantage. Practices vary widely, with some practitioners starting treatment immediately, while others defer until there are clinical signs or symptoms of metastatic disease to avoid the adverse effects of a treatment not shown to improve OS. A review of randomized trials in patients with prostate cancer finds that there is a decrease in relative risk for prostate cancer specific mortality, but no OS advantage to early initiation of ADT versus deferral until onset of symptoms [79]. There are limited data to suggest that early ADT may delay the onset of metastases in patients with aggressive high-risk disease. In the absence of more definitive data, most favor early intervention with ADT, especially in patients with long life expectancies, high-grade disease, or other high-risk clinicopathologic features to their disease.

ADT causes a host of side effects that can significantly affect quality of life, prompting the study of intermittent ADT as an alternative treatment option. Intermittent ADT can provide respite from short-term reversible side effects, as well as delay potential long-term complications such as osteoporosis and cardiovascular disease. An international, multicenter, controlled, intent-to-treat phase III study randomized 1,386 men with biochemical recurrence of prostate cancer to receive treatment with either intermittent ADT or continuous ADT. Intermittent ADT consisted of 8-month treatment cycles with a luteinizing hormone releasing hormone agonist and an upfront nonsteroidal antiandrogen for at least 4 weeks. A nontreatment interval was allowed after each 8-month cycle if there was no evidence of clinical disease progression and PSA levels were stably suppressed at <4 ng/mL. While off treatment, PSA levels were monitored every 2 months, with ADT restarted if PSA =10 ng/mL, or if there was evidence of disease progression. At a median follow-up of 6.9 years, median OS with intermittent ADT met significance for noninferiority when compared with continuous ADT (8.8 vs 9.1 years, P = 0.009) [80]. While the intermittent therapy group saw more disease-specific and treatment-related deaths, it had fewer deaths unrelated to prostate cancer as compared to the continuous arm.

The intermittent therapy arm scored better for overall quality of life than the continuous therapy arm, but the differences were not statistically significant. However, there were some individual aspects of quality of life that were observed. For individual symptoms, intermittent therapy scored significantly better for hot flashes, libido, and urinary symptoms, as well as trended towards significance in fatigue [80]. Testosterone and potency recovery were not universal. Only 35% of the intermittent ADT group had testosterone recovery to pretreatment levels within 2 years after the first period of treatment, with patients older than 75 years of age less likely to achieve pretreatment levels. Only 29% of men who were potent at baseline recovered potency [80].

Nonsteroidal antiandrogen monotherapy, such as with flutamide or bicalutamide, has also been studied as a potential treatment option. A meta-analysis of clinical trials comparing it with other androgen ablating treatments, including orchiectomy, diethylstilbestrol, and GnRH agonists, suggested inferiority of antiandrogen monotherapy, associating it with lower survival rates [81]. It may still be a consideration in selected men who have PSA-recurrence of previously low-risk disease, and who prefer to avoid castration.

The combination of an antiandrogen and a 5-alpha reductase inhibitor has some data supporting its use [82–84]. It is an attractive prospect since the combination works more selectively within the prostate, allowing for serum testosterone levels to be maintained, helping some men retain libido, potency, and muscle mass. Toxicity has been described by uncontrolled trials to be mild [85], and it has been shown in a nonrandomized trial of men with biochemical recurrence to perform better than antiandrogen monotherapy at lowering PSA levels and rates of progression [86]. Further studies will be needed to better validate its efficacy, especially as compared to ADT, the current standard of care.

Метастатическая болезнь

Prostate cancer has a predilection for bone, with a particular affinity for those in the axial skeleton. Over 90% of patients with metastatic prostate cancer will present with bone metastases, which are predominantly osteoblastic lesions. While initially asymptomatic, bone metastases can cause complications of pain, pathologic fractures, spinal cord compression, and calcium metabolism abnormalities over time. Bone scans are sensitive tests for osteoblastic metastases, but not for osteolytic disease. Plain film, computed tomography, and magnetic resonance imaging are useful modalities in the evaluation of other common sites of metastatic disease, which includes the lymph nodes, lung, liver, and adrenal glands.

Newly diagnosed metastatic prostate cancer in the absence of previous hormonal treatment is considered hormone sensitive, and the standard first-line therapy is continuous ADT. In a phase III noninferiority trial, men with newly diagnosed, metastatic, hormone-sensitive prostate cancer were randomized to receive either intermittent ADT or continuous ADT. The hazard ratio for death was 1.10, favoring the continuous ADT arm. However, the study was statistically inconclusive, unable to rule out a significant inferiority of intermittent therapy as compared to continuous ADT, but also unable to rule out a 20% greater risk of death with intermittent therapy [87]. As with PSA-only recurrence, optimal timing to initiation of continuous ADT in hormone-sensitive metastatic disease is unclear. Immediate ADT is associated with a statistically significant decrease in prostate cancer-related deaths, but no OS benefit as compared to delayed ADT [79].

The benefit of chemohormonal therapy in the upfront management of metastatic hormone-sensitive prostate cancer (mHSPC) was demonstrated in two phase III studies, CHAARTED and STAMPEDE. Study designs differed considerably; CHAARTED randomized 790 men with mHSPC to ADT plus docetaxel (75 mg/m2 every 3 weeks х 6 cycles) or ADT alone, whereas STAMPEDE randomized 2,962 men with metastatic (61%), node-positive (15%), or high-risk localized (24%) hormone-sensitive prostate cancer to four different treatment arms: ADT alone, ADT plus zoledronic acid, ADT plus docetaxel, or ADT plus zoledronic acid and docetaxel. A consistent OS benefit was seen in both studies with the addition of docetaxel to ADT (CHAARTED: 57.6 vs 44.0 months; HR 0.61; 95% CI 0.47–0.80; P = 0.001, STAMPEDE: 77 vs 67 months; HR 0.76; 95% CI 0.63–0.91; P = 0.003) [88,89]. Secondary endpoints of time to castration resistance, time to clinical progression, and achieving PSA levels <0.2 ng/mL at 6 and 12 months, all uniformly favored docetaxel in CHAARTED [88], and failure-free survival benefit was demonstrated by STAMPEDE in its overall study population [89].

Planned subgroup analyses of the CHAARTED data at initial interim analysis showed an unprecedented 17-month OS improvement with the addition of docetaxel in patients with high-volume disease (49.2 months vs 32.2 months; HR 0.60; 95% CI 0.45–0.81; P <0.001), but not in low-volume disease [88]. Updated survival data presented at ESMO 2016, suggests that early chemohormonal benefit is limited to high-burden disease (51.2 months vs 34.4 months; HR 0.63; 95% CI 0.50–0.79, P <0.0001), as low-volume patients were still without OS improvement (63.5 vs NR; HR 1.04; 95% CI 0.70–1.55, P = 0.86) [90].

There remains controversy whether low-volume patients should be offered early chemohormonal therapy despite the negative subgroup analysis because of the significantly positive overall study. For high-volume patients, early chemohormonal therapy has already been adopted by treatment guidelines, although selection of suitable candidates requires consideration of the inherent toxicities associated with docetaxel therapy.

Recently, two large randomized phase III studies also demonstrated a significant benefit for abiraterone in the management of mHSPC. LATITUDE randomly assigned 1199 men with high-risk mHSPC to receive either abiraterone 1000 mg and prednisone 5 mg daily or dual placebos. Patients were eligible for the study if their disease met at least two of three high-risk features: Gleason score of 8 or more, at least three bone lesions, and the presence of measurable visceral metastasis. At planned interim analysis with a median follow-up of 30.4 months, the addition of abiraterone was associated with significant improvements in the two primary efficacy endpoints of OS (NR vs 34.7 months, HR 0.62, 95% CI 0.51–0.76, P <0.001) and rPFS (33.0 months vs 14.8 months, HR 0.47, 95% CI 95% 0.39–0.55, P <0.001) [91].

Similarly, STAMPEDE randomized 1917 men with metastatic (52%), node-positive (20%), and nonmetastatic disease (28%) hormone sensitive prostate cancer to receive ADT alone or ADT plus abiraterone 1000 mg daily and prednisolone 5 mg daily. With median follow-up of 40 months, a significant advantage was seen in 3-year OS in the abiraterone arm for the overall study population (83% vs 76%, HR 0.63; 95% CI 0.52–0.76; P <0.001). Failure-free survival at 3 years also favored the combination group (75% vs 45%; HR 0.29; 95% CI 0.25–0.34; P <0.001) [92]. In analysis of the metastatic subgroup, OS and FFS benefits were statistically significant (HR 0.61 and 0.31, respectively) [92], consistent with the findings reported in LATITUDE.

Despite the initial effectiveness of ADT, regardless of the addition of docetaxel or abiraterone, the disease eventually progresses, becoming castration-resistant prostate cancer (CRPC). Time to the development of ADT resistance is variable, but the median duration is around 18–24 months in men with metastatic disease. There is a growing arsenal of effective treatments for CRPC, each with distinct mechanisms of actions, but the optimal selection, sequence, and timing are still unknown. In selection of treatment, consideration must be given regarding patient comorbidities, functional status, disease burden, rate of progression, organ functions, and potential adverse effects (Table 26.6).

Цитотоксическая химиотерапия

The early trials of traditional chemotherapeutic agents found poor responses in the treatment of prostate cancer leading to the initial belief that the disease was chemotherapy-resistant.

In the mid-1990s, mitoxantrone demonstrated a palliative benefit in both quality and duration of pain control when used in combination with prednisone compared to prednisone alone. No OS benefit was observed [93]. A second phase III trial randomized both symptomatic and asymptomatic men to mitoxantrone plus hydrocortisone versus hydrocortisone alone. While the addition of mitoxantrone appeared to delay time to treatment failure and disease progression, there was again no difference in OS. However, quality of life and pain control was again improved [94]. Mitoxantrone was thus approved for palliative treatment of CRPC based on the findings of these two randomized trials.

Taxanes, a class of microtubule inhibitors, are the only cytotoxic agents that have been demonstrated in clinical trials to prolong OS in men with CRPC. Multiple phase II trials suggested docetaxel as an active agent in metastatic CRPC [95–97], which led to the design of the pivotal phase III randomized TAX 327 trial comparing docetaxel plus prednisone versus mitoxantrone plus prednisone in the treatment of metastatic CRPC (mCRPC). Docetaxel plus prednisone demonstrated a superior survival compared with prednisone alone; in addition there were improved rates of pain response, serum PSA levels, and quality of life [98]. Final analysis of the TAX 327 study confirmed a significant survival advantage, with a difference in median survival time of 2.9 months (P = 0.004, HR 0.79), after treatment with docetaxel every 3 weeks as compared with mitoxantrone, across all subgroups of patients studied [99]. On the merits of this study, docetaxel every 3 weeks with prednisone was approved by the Food and Drug Administration (FDA) in 2004 for treatment of mCRPC and remains a standard first-line regimen.

Таблица 26.6. Системное лечение рака простаты.

LHRH агонист/антагонист Леупролид, гозерелин, дегареликс
Антагонист андрогенового рецептора Флутамид, бикалутамид, энзалутамид
Ингибиторы синтеза андрогенов Кетоконазол, абиратерон
Цитотоксическая химиотерапия Митоксантрон, эстрамустин, доцетаксел, кабазитаксел
Иммунотерапия Сипулеуцел-Т
Радионуклидная терапия Самарий-153, стронций-89, радий-223

LHRH, лютеинизирующий гормон-высвобождающий гормон.

Cabazitaxel is a semisynthetic taxane developed for treatment of patients with docetaxel-refractory disease. It was selected for clinical testing because of its poor affinity for ATPdependent drug efflux pump P-glycoprotein 1, a known mechanism of taxane resistance, as well as its ability to penetrate the blood–brain barrier. Preclinical and phase I studies demonstrated antitumor activity in various solid tumor types, with promising results in a small cohort of mCRPC patients. The randomized, multinational, open-label, phase III TROPIC trial was launched comparing cabazitaxel with mitoxantrone in men previously treated and progressed on docetaxel. A total of 755 men were randomized 1:1 to each arm and included in the intention-to-treat analysis, the primary outcome of the study being OS. All patients were concurrently treated with prednisone 10 mg daily. After a median follow-up of 12.8 months, cabazitaxel demonstrated superior OS compared with mitoxantrone (15.1 months vs 12.7 months, HR 0.70, P = 0.0001), as well as superiority in the secondary end points of progressionfree survival, PSA response, time to tumor progression, radiographic tumor response, and time to PSA progression [100]. However, cabazitaxel is associated with significant toxicities, most notably hematologic toxicity (80%), febrile neutropenia (7.5%), and treatment-related death (5%). Because of the high incidence of neutropenia, many practitioners commonly use G-CSF support. This study led to the FDA approval of cabazitaxel 25 mg/m2 every 21 days as a second-line chemotherapeutic agent for treatment of mCRPC after docetaxel. Lower treatment doses and use in combination with other therapies are currently being investigated.

Estramustine phosphate consists of estradiol, an estrogen derivative, and a nitrogen mustard moiety. As a single agent, estramustine demonstrates modest levels of activity in CRPC, but a meta-analysis showed that in combination with other chemotherapies, it significantly improves PSA progression-free survival (HR 0.74, P = 0.01) and OS (HR 0.77, P = 0.008) [101].

The combination of docetaxel and estramustine was studied in phase I and II trials in treatment of men with CRPC, and demonstrated significant declines in PSA levels and disease response [102,103]. A phase III trial randomized 674 patients with CRPC to receive docetaxel and estramustine or mitoxantrone and prednisone in an intention-to-treat analysis. Overall survival was significantly longer in the docetaxel/estramustine arm (17.5 months vs 15.6 months, HR 0.80, P = 0.02). The docetaxel/ estramustine combination was also associated with significantly improved time to progression, PSA declines, and objective tumor responses [104]. Although estramustine is FDA approved for use in combination with docetaxel for treatment of CRPC, it is associated with significant toxicity, most notably thromboembolic events. Prophylactic anticoagulation has not proven to be effective, leading to this agent being largely abandoned.

Other classes of cytotoxic chemotherapeutic agents that have been studied in CRPC include epothilones and platinums. Epothilones are a class of microtubule stabilizing drugs that are less susceptible to mechanisms that confer taxane resistance, such as microtubulin mutations and overexpression of P-glycoprotein efflux pumps [105–107]. Data suggests that taxanes and epothilones are not crossresistant, with epothilones still demonstrating efficacy in taxane-refractory prostate, breast, ovarian, and lung cancer [108–110]. Of the epothilones, ixabepilone is arguably the best studied, as it is already FDA approved for treatment of taxane and anthracycline refractory metastatic breast cancer. In phase II studies, ixabepilone has demonstrated modest activity in CRPC in both the chemotherapy naпve and taxane-refractory settings [111,112].

Platinum salts have long been studied in prostate cancer and may have a potential role in treatment of prostate cancer with neuroendocrine features. Hormonally independent neuroendocrine cells, which are classically platinum sensitive, are thought to be selected for by prolonged courses of androgen deprivation [113]. Recent studies show the combination of carboplatin and docetaxel to have significant activity in the first-line setting, and to have additional activity in docetaxel-refractory disease [114–116]. Satraplatin, a fourth generation platinum analogue, has demonstrated activity in cisplatin-resistant prostate cancer. SPARC was a multinational, double-blinded, placebocontrolled, phase III trial comparing satraplatin plus prednisone to prednisone alone. While satraplatin was associated with a 33% reduction in the risk of progression, and higher PSA response rates, there was no difference seen in OS between the two groups [117] and satraplatin is no longer under clinical development.

Phase III trials of cytotoxic chemotherapeutic agents in mCRPC are shown in Table 26.7.

Вторичная гормональная терапия

Prostate cancers that develop resistance to ADT were historically thought to have become totally independent of the androgen-signaling axis, but a better understanding of the androgen-signaling pathway suggests that the androgen pathway remains an important therapeutic target in CRPC. Targeting mechanisms of castration resistance such as nontesticular androgen production, androgen receptor (AR) binding, AR nuclear translocation, and AR gene amplification, has led to the development of novel therapies in CRPC. Two important new agents, abiraterone acetate and enzalutamide, have been recently approved for use in mCRPC (Table 26.8).

Abiraterone is an orally administered, selective, irreversible inhibitor of CYP17 that catalyzes two essential steps required for androgen biosynthesis in the testes, adrenals, and tumor. It was developed by rational design based on long time understanding that ketoconazole exhibits antitumor activity by inhibiting multiple CYP enzymes required for steroid and testosterone synthesis.

Phase I studies showed that abiraterone is effective at reducing serum testosterone and results in regression of disease, even in patients who had previously received ketoconazole [118]. Two phase II studies conducted in chemotherapy-naпve patients again showed significant antitumor activity by virtue of marked PSA declines, observed radiographic response, and delayed time to progression [119,120]. Two phase III randomized trials were subsequently designed to evaluate abiraterone in two different settings: docetaxel-treated mCRPC and chemotherapy-naпve mCRPC.

Table 26.7. Phase III trials of cytotoxic chemotherapeutic agents in metastatic castration resistant prostate cancer (mCRPC).

Treatment Study arms Primary outcome Secondary outcomes Approval
Mitoxantrone Mitoxantrone and prednisone vs prednisone alone [93] Pain palliation: 29% vs 12% (P = 0.01)

Duration of pain response: 43 weeks vs 18 weeks (P <0.0001)

Improvements in several dimensions of quality of life Palliative treatment of mCRPC
Mitoxantrone and hydrocortisone vs hydrocortisone alone [94] OS: 12.6 months vs 12.3 months (P = 0.77) Time to disease progression and treatment failure: 3.7 months vs 2.3 months (P = 0.0254, P = 0.0218)
Docetaxel Docetaxel q3wk vs docetaxel q1wk vs mitoxantrone (each with prednisone) [99] OS: 19.2 months vs 17.8 months vs 16.3 months (P = 0.004 for D3P vs MP) Treatment of mCRPC
Cabazitaxel Cabazitaxel and prednisone vs mitoxantrone vs prednisone [100] OS: 15.1 months vs 12.7 months (HR 0.70, P <0.0001) PFS: 2.8 months vs 1.4 months (HR 0.74, P <0.0001)

Higher rates of tumor and PSA response

Improvements in time to tumor and PSA progression

Treatment of mCRPC previously treated with docetaxel
Docetaxel/ estramustine Docetaxel and estramustine vs mitoxantrone and prednisone [104] OS: 17.5 months vs 15.6 months (P = 0.02) TTP: 6.3 vs 3.2 (P <0.001)

PSA decline: 50% vs 27% (P <0.001)

Objective tumor response: 17% vs 11% (P = 0.30)

Treatment of mCRPC
Satraplatin Satraplatin and prednisone vs prednisone alone [117] OS: 61.3 weeks vs 61.4 weeks (HR 0.98, P = 0.80)

PFS: 11.1 weeks vs 9.7 weeks (P <0.001)

Tumor response: 8% vs 0.7% (P = 0.002)

Pain response: 24.2% vs 13.8% (P = 0.005)

PSA response: 25.4% vs 12.4% (P <0.001)

Not FDA approved

FDA, Food and Drug Administration; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; q3wk, every 3 weeks; q1wk, once a week; TTP, time to progression.

Table 26.8. Phase III trials of hormonal therapies in metastatic castration resistant prostate cancer (mCRPC).

Treatment Study arms Primary outcome Secondary outcomes Approval
Abiraterone Abiraterone and prednisone vs prednisone alone [121] OS: 14.8 months vs 10.9 months (HR 0.66, P <0.001) Time to PSA progression: 10.2 months vs 6.6 months (HR 0.58, P <0.001)

Radiographic PFS: 5.6 months vs 3.6 months (HR 0.67, P <0.001)

PSA response rate: 29% vs 6% (P <0.001)

Treatment of mCRPC in both pre‐ and postchemotherapy settings
Abiraterone and prednisone vs prednisone alone [124] OS: median not reached vs

8.3 months (HR 0.43, P <0.001)

Radiographic PFS: 16.5 months vs 8.3 months (HR 0.53, P <0.001)

Time to PSA progression: 11.1 months vs 5.6 months (HR 0.49, P <0.001)

Time to initiation of cytotoxic chemotherapy:

25.2 months vs 16.8 months (HR 0.58, P <0.001) Time to ECOG score decline: 12.3 vs 10.9 (HR 0.82, P = 0.005)

Time to opiate use: median not reached vs 23.7 months (HR 0.69, P <0.001)

Enzalutamide Enzalutamide vs placebo [130] OS: 18.4 months vs 13.6 months (HR 0.63, P <0.001) Time to PSA progression: 8.3 months vs 3.0 months (HR 0.25, P <0.001)

Radiographic PFS: 8.3 months vs 2.9 months (HR 0.40, P <0.001)

Time to first skeletal‐related event: 16.7 months vs 13.3 months (HR 0.69, P <0.001)

PSA response rate: 54% vs 2% (P <0.001)

Soft tissue response rate: 29% vs 4% (P <0.001)

FACT‐P QOL response: 43% vs 18% (P <0.001)

Treatment of mCRPC previously treated with docetaxel

ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; OS, overall survival; PFS, progression free survival; PSA, prostate-specific antigen.

The COU-AA-301 trial randomized 1,195 patients in a 2:1 ratio to treatment with abiraterone and prednisone versus placebo and prednisone in CRPC patients previously treated with docetaxel. The abiraterone arm showed a statistically significant OS benefit (14.8 months vs 10.9 months, HR 0.65, P <0.0001), as well as significantly improved time to PSA progression, radiographic progression-free survival, and PSA response [121]. Additional analysis of this trial also found that the combination of abiraterone and prednisone resulted in significant improvements in fatigue and pain palliation over prednisone alone [122,123]. The second phase III trial, COU-AA-302, randomized patients with chemotherapy-naпve mCRPC to receive either abiraterone and prednisone or placebo and prednisone. The abiraterone arm showed superiority in terms of radiographic progression-free survival, one of two coprimary endpoints. There was an improvement in OS, although it did not reach the prespecified cut-off for significance, as well as time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, PSA progression, and decline in performance status [124]. Based on data from these two large randomized trials, the FDA has approved abiraterone for treatment of mCRPC in both the preand postchemotherapy setting, making it another first-line treatment option.

As mentioned previously, optimal sequencing of CRPC therapies remain the subject of further study. Some recent data raises the concern that the activity of docetaxel may be decreased following prior treatment with abiraterone, suggesting some degree of cross resistance [125].

While generally well tolerated, abiraterone can result in mineralocorticoid excess due to its inhibitory effect on steroid metabolism, leading to fluid retention and hypertension. The addition of low dose prednisone in phase II and III studies did not fully eliminate this effect, but the toxicities were mostly low grade and tolerable.

Enzalutamide is an orally administered androgen receptor signaling inhibitor that potently and competitively binds AR, leading to a twoto threefold reduction of binding affinity from the natural ligand dihydrotestosterone. In addition, it also prevents AR nuclear translocations, DNA binding, and coactivator recruitment by the ligand-receptor complex [126]. By inhibiting ligand-bound complex translocation, enzalutamide markedly reduces aberrant recruitment of coactivators to enhancer regions leading to target gene activation.

Its selection for clinical development was based on preclinical demonstration of activity even in the presence of AR amplification, a known mechanism of resistance to antiandrogens in CRPC [127]. It also differs from prior generation AR antagonists, such as bicalutamide, in that it does not confer any degree of agonist activity. Even when complexed with mutant AR protein W741C, which unmasks agonist qualities of bicalutamide [128], enzalutamide remains antagonistic [126].

In early clinical phase I/II trials in men with CRPC, enzalutamide exhibited significant antitumor activity in patients previously treated with docetaxel, ketoconazole, or both [129]. A PSA decline of 50% or more was observed in 56% of men, with radiographic responses in 22%. It also showed a favorable toxicity profile, although associated with small but increased risk for seizures. These results led to two randomized, placebocontrolled, phase III trials studying enzalutamide in the docetaxelrefractory mCRPC (AFFIRM) and chemotherapy-naпve mCRPC (PREVAIL) setting.

In the AFFIRM trial, 1199 men were randomized 2:1 to receive either enzalutamide 160 mg daily or placebo. At a planned interim analysis with median follow-up of 14.4 months, enzalutamide demonstrated superior OS as compared to placebo (18.4 months vs 13.6 months, HR 0.63, P <0.001). Enzalutamide was also associated with higher rates of PSA decline (54% vs 2%, P <0.001), soft-tissue response rate (29% vs 4%, P <0.001), quality-of-life response (43% vs 18%, P <0.001), time to PSA progression (8.3 months vs 3.0 months, HR 0.25, P <0.001), radiographic progression-free survival (8.3 months vs 2.9 months, HR 0.40, P <0.001), and time to first skeletal-related event (16.7 months vs 13.3 months, HR 0.69, P <0.001) [130]. Additionally, subsequent multivariate analysis showed a survival benefit in all studied subgroups of patients.

Similarly, PREVAIL randomized 1717 men with mCRPC to either enzalutamide 160 mg daily or placebo, in the prechemotherapy setting. There was significant improvement in both coprimary endpoints of radiographic PFS at 12 months followup (65% vs 14%, HR 0.19, 95% CI 0.15–0.23, P <0.001) and OS (HR 0.71, 95% CI 0.60–0.84, P <0.001) with the use of enzalutamide over placebo [131]. Multiple secondary endpoints of median time until initiation of cytotoxic therapy, time until PSA progression, time until first skeletal related event, and time until decline of quality of life, all favored enzalutamide as well [131]. Based on the merits of AFFIRM and PREVAIL, enzalutamide received FDA indication in both the preand post-chemotherapy setting for mCRPC.

Unlike abiraterone and other therapeutic options for CRPC, enzalutamide does not require the concurrent use of corticosteroids. This is an important factor to consider as corticosteroids may be relatively contraindicated in some men owing to its effects on muscle strength, skin integrity, bone density, glycemic control, and weight control. Optimal sequence and combination of the novel secondary hormone therapy agents are not yet defined.

Иммунотерапия

Another treatment approach for mCRPC utilizes immunotherapeutic strategies. Sipuleucel-T is an autologous dendritic cell vaccine produced by coculturing antigen-presenting cells, collected by leukapheresis, with a recombinant fusion protein consisting of prostatic acid phosphatase (PAP) and granulocyte macrophage colony-stimulating factor. The end product consists of activated dendritic cells specifically sensitized to the PAP antigen, which is specific to prostate cancer cells. The cells are infused back into the patient where they induce an augmented host antigen-specific cytotoxic T lymphocyte response against prostate cancer cells.

Three randomized phase III trials compared sipuleucel-T against placebo in men with asymptomatic or minimally symptomatic mCRPC. An integrated analysis of two of these trials (D9901 and D9902A) showed that the primary endpoint of improvement in time to disease progression was not met. However, the patients randomized to receive sipuleucel-T demonstrated a survival benefit, with a 33% reduction in the risk of death (HR 1.5, 95% CI 1.10–2.05, P = 0.011) [132]. The IMPACT study randomized 512 patients in a 2:1 ratio to either three infusions of sipuleucel-T administered every 2 weeks or reinfusion of peripheral blood mononuclear cells alone on the same schedule. With median follow-up of 34.1 months, the sipuleucel-T arm had a relative reduction of 22% in the risk of death (HR 0.78, P = 0.03), which represented a 4.1 month improvement in median survival (25.8 months vs 21.7 months) [133]. Again, time to objective disease progression did not differ significantly between the two groups. Based on the results of these trials, sipuleucel-T was approved by the FDA for the treatment of asymptomatic or minimally symptomatic mCRPC.

There are no data on the efficacy of sipuleucel-T in men whose only evidence of disease is an elevated PSA or in those with symptomatic metastatic disease. Currently, usage is not indicated in patients on steroids or opioids for cancer-related pain. Additionally, since treatment with sipuleucel-T does not usually affect serum PSA levels, it should not be used in patients with rapidly progressive disease where a brisk response to treatment is needed.

Other novel immunotherapies are being developed and entering advanced stages of clinical testing. Anti-CTLA-4 and antiPD1/PDL1 antibodies are the subjects of ongoing investigation in CRPC. New viral vector-based vaccines are also under clinical investigation.

Радионуклидная терапия

Prostate cancer is a disease that metastasizes preferentially to bone. Over 90% of patients with mCRPC have radiographic evidence of bony involvement that can often lead to pathologic fractures, functional impairment, pain, decreased quality of life, and bone marrow suppression. Two beta-particle emitting radiopharmaceuticals, strontium-89 chloride (89Sr) and samarium-153 lexidronam (153Sm), were previously approved by the FDA for only palliative management of pain secondary to bony metastases.

There is renewed interest in bone-targeting radionuclides with the introduction of radium-223 dichloride (223Ra). Radium-223 is a next generation, targeted alpha-emitter that  selectively binds to areas of increased bone turnover, such as in the environment of bone metastases. It emits high-energy alpha particles that produce high, linear energy transfer with a range of less than 100 µm. Its short half-life (11.4 days) and superficial tissue penetration translates into less toxic effects on adjacent healthy tissue.

Phase I and II trials demonstrated that radium-223 was well tolerated and had a favorable toxicity profile, most notably associated with minimal myelotoxicity [134,135]. Other phase II trials also showed that radium-223 significantly improved pain and decreased disease-related biomarkers, such as bone alkaline phosphatase [136,137].

Data from an initial phase II study suggested a survival advantage with radium-223 [135], which led to the design of the phase III, randomized, double-blinded, multinational ALSYMPCA study. Radium-223 dosed at 50 kBq/kg every 4 weeks for six doses was compared with placebo in 921 men with CPRC with symptomatic bone metastases randomized in a 2:1 ratio. Radium-223 was found to improve OS significantly, with a 30% reduction in the risk of death, as compared to placebo (14.0 months vs 11.2 months, HR 0.70, 95% CI 0.55–0.88, P = 0.002) [138]. Radium-223 also significantly prolonged the time to the first symptomatic skeletal event, as well as time to alkaline phosphatase and PSA level increase. Based on this study, the FDA approved radium-223 for treatment of mCRPC with symptomatic bone metastases without other visceral metastases.

Table 26.9 summarizes phase III trials of immunotherapy and radionuclide therapy for mCRPC.

Направленная на кости терапия

Other bone-targeting therapies can palliate pain and delay skeletal-related events (SRE), but do not confer an OS benefit.

For palliation of bone pain that is limited to one or a few discrete metastatic sites, EBRT is a good option. Large randomized trials have found that a single fraction of 8 Gy is as effective at providing pain relief as compared with higher radiation doses divided over multiple fractions [139–141]. Patients treated with a single fraction are more likely to require retreatment than those who were initially treated with a fractionated regimen (20% vs 8%) [142], but the majority can be successfully retreated with a single fraction.

Bisphosphonates, as a class of medications, have demonstrated efficacy in preventing osteoporosis from prolonged ADT use, but are not all equally effective in the management of prostate cancer bone metastases. Zoledronic acid has been well studied in mCRPC, demonstrating the ability to reduce frequency of SRE and improve median time to development of SRE [143], and is also associated with meaningful reductions in pain scores [144]. It is currently the only bisphosphonate approved for use in castrate-resistant disease with bone metastases.

Table 26.9. Phase III trials of immunotherapy and radionuclide therapy for metastatic castration resistant prostate cancer (mCRPC).

Treatment Study arms Primary outcome Secondary outcomes Approval
Sipuleucel‐T Sipuleucel‐T vs placebo [133] OS: 25.8 months vs 21.7 months (HR 0.78, P = 0.03) Time to objective disease progression:

14.6 months vs 14.4 months (HR 0.95, P = 0.63)

Treatment of asymptomatic or minimally symptomatic mCRPC
Radium‐223 dichloride Radium‐223 vs placebo [138] OS: 14.0 months vs 11.2 months (HR 0.70, P = 0.002) Time to first symptomatic skeletal event: 15.6 vs 9.8 months (HR 0.66, P <0.001)

Time to alkaline phosphatase level increase:

7.4 months vs 3.8 months (HR 0.17, P <0.001)

Time to PSA level increase: 3.6 months vs 3.4 months (HR 0.64, P <0.001)

Treatment of mCRPC with symptomatic bone metastases and no known visceral metastatic disease

HR, hazard ratio; OS, overall survival; PSA, prostate-specific antigen.

Denosumab, a monoclonal antibody that binds RANK ligand, is also effective at preventing ADT-associated osteoporosis [145,146]. When compared to placebo in a randomized phase III trial of nonmetastatic CRPC patients, denosumab significantly increased bone metastasis-free survival time (29.5 months vs 25.2 months, HR 0.85, 95% CI 0.73–0.98) and time to first bone metastasis (33.2 months vs 29.5 months, HR 0.84, 95% CI 0.71–0.98) [147]. Furthermore, when compared to zoledronic acid in a randomized phase III trial of mCRPC patients, denosumab significantly delayed time to first SRE (20.7 months vs 17.1 months, HR 0.82, 95% CI 0.71–0.95) [148]. No improvements to OS were observed in either trial. While generally well tolerated, hypocalcemia and osteonecrosis of the jaw occur more frequently with denosumab use than with zoledronic acid.

Заключение

An improved understanding of prostate cancer has paved the way for multiple novel therapies to be developed. However, there is still much that is still not fully understood about the biology of prostate cancer and its management. As drug development continues to accelerate and we acquire a wider breadth of therapy options, clinical trials will be needed to answer questions regarding how best to implement these new treatments in clinical practice. Optimal timing, sequencing, and combination of different treatment modalities need not only to be studied in the advanced metastatic disease setting, but also in the early disease stages where a cure may still be imminently attainable. Further research will also be needed to help clinicians better guide their patients along the fine line between improved survival and quality of life.

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