, Filomena Pina3 and Leonor Ribeiro1
(1)
Medical Oncology Department, Centro Hospitalar de Lisboa Norte, Lisbon, Portugal
(2)
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035 Lisbon, Portugal
(3)
Radiation Oncology department of Centro Hospitalar de Lisboa Norte, Lisbon, Portugal
22.1 Introduction
The term prostate is originally derived from the Greek prostates, which means “one who stands before” and was first used by Herophilus of Alexandria in 335 B.C. to describe seminal vesicles and epididymis (prostatai adenoeides). However its first use within a medical context to describe the prostate took place more than 2,000 years afterwards, as the prostate was not discovered until then [1].
Anatomically it is divided in a peripheral zone, a central cone-shaped zone and the apex, at the confluence of the ejaculatory ducts and the prostatic urethra. Lateral to the urethra there are two portions of glandular tissue called the transitional zone.
22.2 Epidemiology and Risk Factors for Prostate Cancer
Prostate Cancer (PCa) is the most frequent cancer in males in economically developed countries and the second most frequently diagnosed cancer in the world, accounting for 14 % of all new cancer cases. It is also the sixth leading cause of death by cancer worldwide [2]. It is estimated that PCa will continually rise worldwide approximately by 3 % a year [3].
Since the availability of Prostate Cancer Antigen (PSA) measurement, PCa epidemiology has changed a lot. In fact prostate cancer incidence and mortality are greatly variable worldwide with two to five times higher rates in developed countries [2, 4] which is in part attributable to increased detection capability with widespread PSA testing of asymptomatic individuals and transrectal ultrasound (TRUS) in these regions.
PSA screening is the single most important risk factor for PCa diagnosis [5], with a relevant increase in asymptomatic PCa diagnosis and a concurrent decrease in the prevalence of latent PCa in autopsy studies from pre to post PSA era [6].
The risk of PCa increases with age, with both incidence and mortality higher in men over 70 years of age, and 97 % of PCa cases occurring in men over 50 years old [7]. In fact, while the probability of developing prostate cancer is 0.005 % for men younger than 39 years of age, it is 2.2 % for men aged 40–59 years old and 13.7 % for those aged 60–79 years old [8].
Ethnicity is also an irrefutable risk factor for PCa with higher incidence, younger age and more advanced anatomic stage at diagnosis and higher mortality rates reported in black men comparing to white men [9]. On the other hand PCa rates in Asia are among the lowest in the world, although there has been an increase in most of the countries [10].
Family history also plays a role as men with first-degree family history of PCa have a rate ratio of 2.48 [95 % confidence interval: 2.25–2.74] of developing PCa, that increases with an increasing number of affected family members. In fact almost 60 % of the prostate cancer incidence among men with first-degree family history is attributable to this risk factor [11].
Genetic characteristics have an important impact in these differences. BRCA 1 and 2 mutations are associated with poorer survival outcomes in men with PCa, as they confer a more aggressive phenotype with higher probability of nodal involvement and distant metastasis [12]. Patients carrying mutated DNA mismatch repair genes (Lynch Syndrome) are also at increased risk of PCa although PCa presence alone does not increase suspicion of Lynch Syndrome [13].
Several environmental risk and protective factors have been inconsistently reported with trends suggesting higher risk of PCa with consumption of carbohydrates, saturated and ω-6 fats and certain vitamin supplements (vitamin A and folate) [14]. On the other hand consumption of plant phytochemicals such as lycopene, phenolic compounds (such as those found in coffee), fiber and ω-3 fatty acids seem to decrease the risk and slow the progression of the disease [14].
Lifestyle factors like physical activity, and medication such as statins and non-steroid anti-inflammatory drugs have been reported do decrease the risk of PCa [14], while obesity seems to have a positive association with PCa [15]. High ejaculatory frequency seems to be protective [16]. Yet number of sexual partners and history of sexually transmitted infections might be deleterious [17].
22.3 Pathogenesis
Adenocarcinoma accounts for 95 % of PCa cases, although some men develop other histological types such as small-cell neuroendocrine, adenoid cystic and basal cell (basaloid), squamous cell, urothelial, and sarcomatoid carcinomas. Even more rare histological types comprise primary prostate sarcomas, germ cell tumors, rhabdoid tumors, phyllodes tumors, malignant peripheral nerve sheath tumors, nephroblastoma, primary malignant melanoma, and Wilms’ tumor, as well as primary hematopoietic malignancies [18].
Similar to other cancers, PCa results of the accumulation of genetic alterations in a cell originating malignant growth. However, there is a heterogeneous pattern of oncogene activation. Several gene alterations have been identified as relevant in the development or progression of sporadic PCa, such as gene mutations, hypermethylation, inactivation, aneuploidy or loss of heterozygosity of specific oncosupressor genes (for example GSTp1, PTEN, Rb and p27) [19]. The activation of oncogenes is also important in PCa (such as the amplification of MYC and increased expression of BCL2) and, combined with p53 and Androgen Receptor (AR) mutation plays a special role in cancer progression and metastasis [19, 20].
Prostate adenocarcinomas originate from acinar and proximal duct epithelium, typically in the peripheral zones of the prostate and are associated with high-grade prostatic intraepithelial neoplasia (HGPIN) – the only recognized premalignant prostatic lesion [21]. High grade carcinomas are frequently associated with HGPIN. Yet, low grade carcinomas are not, especially those that develop in the transition zone [18].
Although not considered a premalignant lesion, the presence of Atypical Small Acinar Proliferation (ASAP) is a significant predictor of subsequent carcinoma on repeated biopsy, as it refers to the presence of small atypical glands that display some features of carcinoma, yet not enough to render the diagnosis. In fact, up to 60 % of ASAP on repeated needle biopsy confirm the presence of carcinoma [21].
22.4 Presentation and Diagnosis
Before the widespread use of PSA PCa was diagnosed only when symptoms were present. With the advent of screening with PSA and Digital Rectal Examination (DRE) PCa is rarely symptomatic at diagnosis. Symptoms resulting from bladder outlet obstruction are among the most common ones and usually occur only in advanced stages as they tend to reflect prostate enlargement or invasion of the periprostatic tissues. There are two types of bladder outlet obstruction symptoms: voiding symptoms (hesitancy, intermittency, incomplete emptying and a diminished urinary stream) and storage symptoms (frequency, nocturia, urgency and urge incontinence). Hematuria might also occur. None of these symptoms is specific of PCa and might also be present in other diseases such as Prostatic Benign Hyperplasia (PBH) [22]. Although even less frequently PCa might also present with symptoms secondary to metastatic disease such as skeletal related events (for instance bone pain, bone fracture and hypercalcemia).
22.4.1 Screening
Screening of asymptomatic men with PSA has been for years accepted in most European countries and in the US. It is nevertheless a controversial subject.
PSA is an enzyme, produced mainly in prostatic epithelial cells, that liquefies the ejaculate being mainly released into the semen but also leaking into circulation in small amounts. It is thus produced by prostatic cells, both benign and malignant and its serum concentration increases in prostatic manipulation (biopsy) but also in the hyperplastic and neoplastic prostate. In PCa the secretion to prostatic ducts decreases due to derangement of architecture and polarization of the epithelial cells leading to loss of normal secretory pathways hence increasing the amount of circulating PSA about 30-fold in comparison to normal epithelium and 10-fold comparing to BPH [23, 24].
Serum PSA was first approved by the FDA in 1986 to monitor cancer progression and later in 1994 for cancer screening of asymptomatic men alongside DRE. The cutoff value of 3.0 μg/L was considered the threshold above which prostate biopsy was recommended with positive predictive value for PCa of 25 % (for World Health Organization–calibrated assays and 4.0 μg/L in traditionally calibrated assays, to achieve the same sensitivity and specificity), although PCa might be present with lower PSA values. The normal range of PSA rises with age as a result of gland enlargement and this should be taken into account [25].
The widespread use of PSA screening during the following decades greatly influenced PCa epidemiology, undoubtedly decreasing the frequency of advanced disease and disease specific mortality [26]. However it also increased the overdiagnosis or diagnosis of cases that, if left untreated would have not become clinically manifest over a patient’s lifetime or result in cancer-related death; the rate of overdiagnosis by PSA screening is still unknown ranging from 1.7 % to 67 % in different studies [27]. Overdiagnosis leads to overtreatment, which means a potential lack of benefit as well as unnecessary harm and cost from treatment of an overdiagnosed case [27]. This recent evidence generated controversy in PCa screening.
In order to evaluate the efficacy of PCa screening, two large randomized trials have been published: the Prostate, Lung, Colorectal and Ovary (PLCO) trial in the United States and the European Randomized Study of Screening for Prostate Cancer (ERSPCa) in Europe and based on the results most of the major urologic societies have recommended against widespread mass screening for PCa at present, favoring opportunistic screening offered to men that know and accept the potential risks instead [25].
When an elevated PSA value is obtained, the most common explanation is the presence of BPH, although there are other causes such as prostatic inflammation/infection and perineal trauma. Therefore PSA measurement should generally be repeated a few weeks later, before additional studies are performed. If a consistent increase in PSA value is detected or a high baseline value is obtained (>20 ng/ml) further examination is recommended.
Other strategies to improve PSA diagnostic performance, namely PSA ratios and dynamic PSA calculations, are useful in the diagnosis and assessment of tumor aggressiveness. The percentage of free PSA (f/t PSA) and PSA density (PSA/prostate volume) are examples of calculated ratios. The percentage of free PSA (free/total PSA) has been used to improve cancer detection sensitivity when total PSA ranges between 1 and 4 ng/mL with a suggested cut-off at 20 % for higher likelihood of cancer diagnosis (92 % sensitivity and 23 % specificity) [28]. PSA density (PSA per unit volume of prostate) >0.15 ng/mL/cc is suggestive of prostate cancer (when opposed to BPH) and used by some as a cut-off for biopsy [29]. Other emerging tests such as ACT-complexed PSA (cPSA) and the [-2]proPSA to free PSA ratio are still being assessed in clinical studies. PSA velocity (rate of PSA change over time in nanograms per milliliter per year) and PSA doubling time (number of months for a certain level of PSA to increase by a factor of two) are examples of PSA dynamic tests [30]. A PSA velocity cut-off of 0.75 ng/mL per year may provide information regarding the distinction of those with or without PCa [31]. PSA doubling time assessment is mainly used in the pre or post-treatment settings to predict aggressiveness [30].
22.4.2 Diagnosis and Staging
Besides serum PSA measurement, the main diagnostic tools for PCa are physical examination including DRE, and TRUS guided biopsy.
DRE provides information about the location, size and extent of the lesion (usually detected as a hard induration or nodularity) increasing the suspicion of cancer. Therefore it can be used for screening or further evaluation after an elevated PSA result. Presence of node spreading or skeletal involvement must also be accessed by inguinal node evaluation, palpation of the skeleton looking for tender spots and neurological examination looking for spinal cord compression.
PCa study should include:
1.
Routine studies: complete blood count (CBC), renal and liver function tests, calcium, alkaline phosphatase, urinalysis.
2.
PSA (previously discussed)
3.
Biopsy techniques. PCa diagnosis is given by histological examination [25]. Unlike PSA or DRE, TRUS is not used for screening but only for evaluation after a suspicion DRE or elevated PSA. The first elevated PSA level does not require an immediate biopsy and should instead be verified after a few weeks by the same assay. This, however, does not apply to high PSA values (>20 ng/ml) in which TRUS and biopsy are recommended, after prostatitis has been excluded [25].
PCa usually has a hypoechoic appearance in TRUS and a glandular volume of 30–40 mL should prompt the acquisition of 10–12 core samples, under antibiotic prophylaxis with quinolones, more frequently ciprofloxacin (oral or intravenous).
22.4.3 Gleason Score
The histologic sampling is usually graded using the Gleason Score, which is a grading system that classifies PCa according to the architectural pattern of the tumor, attributing a grade that is defined as the sum of the two most common grade patterns observed. It ranges from 2 (1 + 1), very well differentiated, to 10 (5 + 5), poorly differentiated. The change in tissue structure is good evidence for this differentiation [32]. However, nowadays the full Gleason spectrum is rarely used. In fact the attribution of Gleason scores from 2 to 5 is discouraged, as cancer with Gleason score less than 6 is rarely found in clinical practice [33].
22.4.4 TNM Staging
The decision to further proceed with diagnostic or staging work-up depends on which treatment options are available to the patient, taking the patient’s preference, age, and comorbidity into consideration [25].
TNM classification is used to stage PCa (Table 22.1
). Local or T staging is based on DRE findings, TRUS or Magnetic Ressonance Imaging (MRI). MRI is the best imaging exam to provide information about tumor size, prostate capsule integrity, extraprostatic invasion and seminal vesicle invasion. Further information is provided by the number and sites of positive prostate biopsies, the tumor grade, and the level of serum PSA. CT scan can also be used for local staging although it provides less information than MRI.
Table 22.1
TNM staging system for prostate adenocarcinoma. (Adapted from the American Joint Committee on Cancer (AJCC) 7th Edition)
Clinical staging | Pathological staginga | ||
|---|---|---|---|
Primary tumor – T | |||
Tx | Cannot access primary tumor | ||
T0 | No evidence of primary tumor | ||
T1 | Clinically unapparent tumor | ||
T1a | Incidental histologic finding in ≤ 5 % of tissue resected | ||
T1b | Incidental histologic finding in > 5 % of tissue resected | ||
T1c | Tumor identified in needle biopsy | ||
T2b | Prostate confined | ||
T2a | Unilateral, involving one-half of 1 lobe or less | ||
T2b | Unilateral involving more than one-half of 1 lobe | ||
T2c | Bilateral disease | ||
T3c | Extraprostatic extension (unilateral/bilateral) | ||
T3a | Extracapsular extension (one or both sides) | Extraprostatic extension/microscopic invasion of bladder neckd | |
T3b | Seminal vesicle invasion | ||
T4 | Tumor is fixed or invades other adjacent structures (external sphincter, rectum, bladder, levator muscles, pelvic wall) | Invasion of the bladder, levator muscles or pelvic wall | |
Lymph node – N | |||
Nx | Regional lymph nodes not assessed | ||
N0 | No regional lymph node metastasis | ||
N1 | Metastasis in regional lymph nodes | Metastasis in one or more lymph nodes | |
Distant metastasis – M e | |||
M0 | No distant metastasis | ||
M1 | Distant metastasis | ||
M1a | Nonregional lymph nodes | ||
M1b | Bone | ||
M1c | Other sites with or without bone disease or more than one site of metastasis present | ||
Lymph node status or N staging should only be assessed when curative treatment is planned as preoperative imaging has significant limitations in detection of small metastases (TRUS, CT and MRI are limited in detecting lymph node metastases <5 mm) and pelvic node dissection is the only reliable staging method for assessment of lymph nodes [25]. Patients with stage ≤T2, PSA <20 ng/ml, a Gleason score ≤6, and <50 % positive biopsy cores have a <10 % likelihood of having node metastases and can be spared nodal evaluation.
PCa metastases are most likely located in the bone. As such, M staging is best assessed by Bone Scintigraphy. Metastization is more frequent and bone scan is therefore recommended in symptomatic patients, if the serum PSA level is above 20 ng/ml or in the presence of undifferentiated tumor. PET Scan could be of value in equivocal cases, especially to differentiate active metastases from healing bones [25].
22.5 Treatment
The following sections will focus on the treatment of prostate adenocarcinoma. There is a great diversity of options in PCa treatment which have not always been clearly compared in clinical trials, especially for localized disease.
The adoption of a specific treatment along with its toxicity and morbidity depends on the risk level established by the life time expectancy, symptoms and tumor biology characteristics (such as Gleason score and PSA). Actively informing patients of advantages, pitfalls and relative contraindications of each treatment modality is therefore fundamental for a balanced intervention [34].
The approach used in this chapter is consistent with the National Comprehensive Cancer Network (NCCN) guidelines for the use of specific treatment modalities according to risk strategies based on several clinical variables.
At a first glance, the treatment for prostate cancer (PCa) can be directed to localized disease or metastatic disease.
22.6 Localized Prostate Cancer
22.6.1 Stratifying Risk and Treatment Options for PCa
Currently, practitioners have a limited set of tools to determine the risk/aggressiveness of localized PCa. The majority of risk stratification models used in clinical practice are based on [35]:
PSA values,
Gleason Score (GS),
TNM staging
Extension and number of biopsy cores involved
The variety of models can be presented as normograms, simple or complex formulas or fixed values in guidelines. We will use the current NCCN risk stratification system presented in Table 22.2. Table 22.3 compares NCCN stratification system to others [35].
Table 22.2
NCCN pre-treatment PCa risk group stratification system
Risk group | Very low | Low | Intermediatea | High | Very high (locally advanced) | Metastatic | |
|---|---|---|---|---|---|---|---|
Regional lymph node | Distant metastasis | ||||||
Criteria | T1c + Fewer than three prostate biopsy positive cores; ≤ 50 % cancer in each core + PSA density <0.15 ng/mL/g | T1-T2a + GS ≤6 + PSA <10 ng/mL | T2b-T2c or GS = 7 or PSA 10–20 ng/mL | T3a or GS 8–10 or PSA >20 ng/mL | T3b-T4 N0 M0; Any GS Any PSA | Any T, N1 M0 Any GS Any PSA | Any T, any N, M1 Any GS Any PSA |
Table 22.3
Comparison between risk group stratifications for PCa (adapted from Rodrigues et al. [35])
Institution/organization | Low risk | Intermediate risk | High risk |
|---|---|---|---|
Harvard (D’Amico) | T1-T2a and GS ≤6 and PSA ≤10 | T2b and/or GS =7 and/or PSA >10–20 not low-risk | ≥T2c or PSA >20 or GS 8–10 |
AUA | |||
EAU | |||
GUROC | T1-T2a and GS ≤6 and PSA ≤10 | T1-T2 and/or Gleason ≤7 and/or PSA ≤20 not low-risk | ≥T3a or PSA >20 or GS 8–10 |
NICE | |||
CAPSUREa | T1-T2a and GS ≤6 and PSA ≤10 | T2b and/or GS =7 and/or PSA >10–20 not low-risk | T3-4 or PSA >20 or GS 8–10 |
ESMO | T1-T2a and GS ≤6 and PSA≤10 | T2b and/or GS7 and/or PSA 10–20 | ≥ T2c or PSA >20 or GS 8–10 |
22.6.1.1 Very Low-Risk Patient Strategy
Active surveillance is recommended in this set of patients. Those who are not able to cope with the surveillance program due to anxiety or non-compliance should preferably be treated as low-risk PCa.
This risk subgroup is not widely used by expert groups other than NCCN [35].
22.6.1.2 Low Risk Patient Strategy
Local treatment options as surgery or radiotherapy (such as external beam therapy [EBRT], low-dose-rate brachytherapy [LDR-BT] or high-dose-rate brachytherapy [HDR-BT]) are recommended [36, 37].
The ESMO 2015 guidelines [37] consider surgery and EBRT techniques (CRT and IMRT) as equal options for localized PCa, however underline the lack of large RCTs comparing contemporary techniques of different treatment modalities on quality of life or long-term survival in patients with low-risk [38]. Non-randomized studies have shown superiority of radical prostatectomy over RT or brachytherapy in overall survival, although not demonstrating statistically significant differences in cancer-related mortality [39]. Selection bias and confounding variables in long-term analysis might have influenced overall survival results [40].
22.6.1.3 Intermediate-Risk Patient Strategy
These patients should undergo radical prostatectomy (with Pelvic Lymph Node Dissection [PLND] in patients with risk of lymph node invasion) or EBRT (including Whole Pelvic Radiotherapy [WPRT] if Roach formula for lymph nodes is superior to 15 %) plus Androgen Deprivation Therapy (ADT, 4–6 months) with or without complete/combined androgen blockade (CAB, which implies gonadotropin releasing hormone modulation with the addition of anti-androgen) [36]. The addition of brachytherapy (BT) as boost is optional. Most physicians do not use brachytherapy in monotherapy given the risk of potential undertreatment due to unfavourable coverage at distant peripheral zones.
22.6.1.4 High-Risk and Very High-Risk Patient Strategy
Prostatectomy combined with PLND for patients without tumor fixation to adjacent organs can be used. Other options include EBRT with BT boost (for patient with clinical and anatomical condition for BT). For those receiving RT, ADT with complete androgen blockage should also be given (2–3 years) [37].
22.6.2 Therapeutic Modalities
22.6.2.1 Active Surveillance
Active surveillance, also known as watchful waiting, expectant management or deferred treatment, is an option attempting to overcome overdiagnosis and overtreatment of PCa. Active surveillance is defined as a tight schedule follow-up with active clinical evaluation and exams (unless clinically indicated, PSA no more than every 6 months, DRE and prostate biopsy no more than every 12 months) with the objective to intervene with potential curative intent if the cancer progresses. These follow up recommendations are not based on randomized clinical trial results and therefore need further evidence. Treatment is required when, upon repeated biopsies, PCa samples with Gleason score 4 or 5 are found or when a greater number or extension of cores are involved [36]. PSA kinetics (PSA doubling-time and PSA velocity) is not an ideal trigger for biopsy because it is not associated with clinical important reclassification of biopsy results (pathology progression) [41, 42], therefore it should not be used to replace annual surveillance biopsy. In asymptomatic patients with a low life expectancy (<10 years) only observation is recommended until symptoms develop or are eminent (PSA >100 ng/ml). Subsequently, a palliative treatment is provided. ESMO guidelines further state that active surveillance with delayed intervention is an option in case of localized or locally advanced disease in men who are not suitable for, or unwilling to have, radical treatment [37].
22.6.2.2 Surgery
Radical prostatectomy (RP) is a treatment option when cancer can be completely excised surgically and no surgical contraindications are present. High-volume centers have best outcomes [43].
Laparoscopic radical prostatectomy has been increasing when compared to classic approaches to minimize invasiveness and open surgery related complications [44]. Most studies at the moment (non-Randomized Clinical Trials) do detect slight improved surgical margins and perioperative outcomes favoring minimal invasive techniques when compared to open surgery [44, 45]. Outcomes regarding tumor control are not well assessed due to short follow-up of patients treated with robotic surgery [46].
During RP a PLND is performed when the probability of nodal metastasis is >2 % according to the normogram created by Cagiannos et al. [47]. In clinical practice, this normogram reveals that only low-risk and few patients with intermediate risk should not be submitted to PLND. An extended technique should be the preferred option (excision of lymph nodes in the anterior portion of the external iliac vein, pelvic side wall, medial bladder wall, posterior floor of the pelvis, Cooper’s ligament distally and proximal internal iliac artery), given that twice as much nodal metastasis will be found.
Traditionally, RP for high-risk prostate cancer has been discouraged; however, some authors consider that a surgical approach in high-risk patients provides better staging and enhance the removal of micrometastatic lymph nodes through extended PLND [48].
The use of hormone therapy prior to surgery is discouraged in most guidelines. A systematic review by Kumar et al. found no improvement of overall survival (OR 1.11, 95 % CI 0.67–1.85, p = 0.69) [49]. However, there was a significant reduction in the proportion of patients with positive surgical margins (OR 0.34, 95 % CI 0.27 to 0.42, P < 0.001).
22.6.2.3 Radiotherapy
External Beam Radiation Therapy (EBRT)
EBRT is a radiation therapy technique in which the patient is treated with beams of external radiation that must cross through the body (skin and nearby organs) until they reach the desired target (i.e. prostate, seminal vesicles with or without the irradiation of regional lymph nodes) with the calculated dose and preserving adjacent organs at risk.
EBRT will require a certain fractionation schedule and the “splitting” of the dose by fields, i.e. “angles of entry” of the radiation beams in the body.
Radiotherapy departments have EBRT techniques based on computerized tomography (CT) simulation and devices emitting megavoltage photons that can be either used in three-dimensional conformal radiotherapy technique (3D-CRT) or intensity modulated radiation therapy (IMRT). CT-based simulation allows to better delineate volumes and to improve field settings, which contributes to optimize the preservation of adjacent organs at risk. A systematic review of the literature by Morris et al. reported that 3D-CRT decreases toxicity and improves therapeutic index when compared the conventional radiotherapy (non-CT-based) [50].
This technological achievement was the beginning of further evolution in the improvement of dose escalation specifically to the tumor with modulation of beams intensity and computerized inverse-planning optimization strategies, which culminated in the development of IMRT (3D-CRT refinement). Also, the optimization of safety/tolerance radiation margins, image guidance to improve reproducibility of treatment and preserve organs at risk and the standardization of delineation guidelines and dosimetry reports were other technological hallmarks that allowed dose escalation.
Prostate cancer is a dose-responsive tumor. Many trials reported better outcomes with dose escalation. One example is the study performed by Kuban et al. in which 301 patients with PCa staged from T1b to T3 were randomized to 70 Gy or to 78 Gy EBRT. Freedom from biochemical or clinical failure (FFF) was superior in the 78-Gy arm (78 %) as compared with the 70-Gy arm (59 %; p = 0.004). In this study, patients with initial PSA >10 ng/ml benefited even more (78 % vs. 39 %, p = 0.001) [51].
IMRT is a 3D-CRT refinement in which the radiation intensity is further modulated through the creation of beamlets of different intensities and by allowing shaping in each beam through multileaf collimators. Computerized inverse planning further optimizes field settings. Studies concerning IMRT use in PCa have shown that it was superior to 3D-CRT regarding rectum and bladder protection based on dosimetric studies and clinical data. Organ sparing was even more significant, namely for small bowel and colon, when WPRT was used [52].
The RTOG 0126 clinical trial demonstrated the added benefit from IMRT against 3D-CRT [53] for the same total prescribed dose (79.2 Gy) and the same planned volume structures in low risk prostate cancer patients. The dosimetric studies revealed less radiation exposure to unwanted organs as bladder and rectum in the IMRT arm. Finally, less severe acute and late gastrointestinal toxicity was shown.
Zelefesky et al. studied the toxicity incidence at 10 years after 3D-CRT and IMRT (total dose range 66–81 Gy) for localized prostate cancer during 1988 and 2000 using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) [54]. Proctitis was less frequent using IMRT. Other gastrointestinal (GI) and genitourinary (GU) toxicities were associated with higher doses and acute symptoms were a marker of late toxicity.
Xu et al. studied the toxicity profile of dose escalation from 189 patients treated with 75.6 Gy using 3D-CRT and 81.0 Gy using IMRT. In the 81.0 Gy IMRT group it was found:
GU toxicity: higher rates of grade 2 acute (P < 0.001) and late (P = 0.001) GU toxicities
GI toxicity: lower rate of acute (P = 0.002) and late (p = 0.082) GI toxicities
There were no differences in final GU (p = 0.551) or final GI (p = 0.194) toxicities compared with the 75.6 Gy group. Increased age (p = 0.019) and radiotherapy dose (p = 0.016) were correlated with acute GU toxicity, but only radiotherapy dose (p = 0.018) correlated with late GU toxicity. Only IMRT (p = 0.001) was correlated with acute GI toxicity; no factors correlated with late GI toxicity or final GU or GI toxicity [55].
Current evidence recommends IMRT with minimal prescription doses of 75.6–79.2 Gy to the prostate (including or not seminal vesicles) for low-risk PCa and doses up to 81 Gy for intermediate to high-risk patients [36, 37, 55].
Treatment protocols enforcing accuracy of treatment are a cornerstone. Image-guided radiotherapy (IGRT) (e.g. portal images, cone beam CT and/or fiducial markers) and physiological preparation (e.g. bowel and rectal deflation and bladder filing) are respectively important to reduce margins and risk of adjacent organ complication, as well as to reduce movements of the prostate gland, which the IMRT or 3D-CRT cannot predict.
A radiobiological feature of PCa is the low α/β ratio (ratio that depicts survival behaviour after a certain amount of radiation), which ranges between 1 and 4 with most studies considering 1.5 [56]. Cells with low alfa-beta are more resistant against small doses of radiation. This means that hypofractionation schemes (treatment in which total radiation dose is divided into larger doses and higher than conventional doses per fraction, thus reducing the overall days of treatment) are an appropriate option if technological feasible. However, further studies are needed in this regard.
IMRT with integrated boost and stereotactic treatments are possible options, however caution is advised. A recent systematic review and meta-analysis including nine trials [57] (total 2,702 patients) has shown similar freedom from biochemical failure between hypofractionation and conventional schemes (outcome reported in only three studies). The incidence of acute adverse gastrointestinal events was higher in the hypofractionated group (fixed effect, RR 2.02, 95 % CI 1.45–2.81; P < 0.0001) but the acute genitourinary toxicity was similar among the groups (fixed effect, RR 1.19, 95 % CI 0.95–1.49; P = 0.13), although there was a moderate to high-level of heterogeneity among these outcome assessments. The incidence of all late adverse events was the same in both groups for gastrointestinal and genitourinary. It should be noted that this analysis included few studies, mixed different external radiation techniques, some studies combined RT with ADT and the prescribed total dose for the conventional fractionation techniques was outdated. The main messages from this review were the confirmation that IMRT is feasible with no significant increase of late toxicity. A cost-effective alternative that exploits these radiobiological features is the combination of high-dose-rate brachytherapy that can be used in multiple settings (discussed later in chapter).
Complementary Pelvic Lymph Nodes Irradiation and Androgen Deprivation
The indications for complementary irradiation of pelvic lymph nodes (common iliac, external iliac vein, internal iliac and obturator lymph node region) and use of androgen deprivation therapy are not clear. The pivotal randomized study testing the indication for irradiation of pelvic lymph nodes in combination with ADT was the RTOG 9413 trial [58]. In this trial the combined ADT and whole pelvic radiation therapy (WPRT) followed by a boost to the prostate improved progression-free survival (PFS) by 7 % when compared to ADT and prostate-only (PO) RT (54 vs. 47 %, p = 0.022). Moreover, this trial failed to demonstrate an added benefit from neoadjuvant and concurrent hormonal therapy (NCHT) when compared with adjuvant hormonal therapy (AHT) only, which was also a main point of evaluation in this trial. Patients enrolled in the study had localized PCa with PSA ≤ 100 ng/mL and an estimated risk of lymph node involvement >15 % by the Roach Formula for lymph node risk involvement (LN). In this study, 1,323 patients were randomized in four arms: two in the WPRT group and two in the prostate-only irradiation (PORT) group; each group was subdivided in two ADT regimens: neoadjuvant and concurrent hormonal therapy (NCHT) versus adjuvant hormonal therapy (AHT). With a median follow-up of 59.5 months and when comparing all four arms, there was a progression-free difference in favor of WPRT + NCHT. The reported PFS for the four groups, WPRT + NCHT, PORT + NCHT, WPRT + AHT, and PORT + AHT were of 60 % vs. 44 % vs. 49 % vs. 50 %, respectively (p = 0.008).
The Roach formula for lymph node risk involvement was simple and derived empirically from the Partin normogram. This formula, which is calculated as LN = (2/3) * PSA + 10 * (Gleason Score – 6), was previously validated after reviewing the pathologic features of 282 patients who had undergone PR [59]. This means RTOG 9413 included high-risk but also a part of intermediate -risk patients which had a lymph node risk >15 %.
The updated results from this trial reported no difference when comparing neoadjuvant vs. adjuvant hormone therapy and WPRT vs. PORT regarding PFS or OS. However, an unexpected difference was noted in pairwise comparison in favour of WPRT + NCHT. Patients receiving WPRT + NCHT had a better trend over PORT + NHT (p = 0.023) and over WPRT + AHT (p = 0.014), but not different when compared with PO RT + AHT (p = 0.63). The overall survival was statistically significantly different amongst the four arms (p = 0.027) but pairwise comparison of the four arms in the study showed a worse trend for WPRT+ AHT than every other arm of this study [60]. It should be reminded that this study is underpowered for arm vs arm analysis since it had assumed there was no interaction between field size and timing of hormone therapy. Also the p-values were not adjusted for multiple comparisons. That said, this study demonstrated that aggressive treatment (combining WPRT and NCHT) should be offered to all high-risk and some intermediate-risk patients with a Roach formula for lymph node involvement >15 %.
The RTOG 9413 also opened a series of questions regarding the indications and quality of WPRT (field site) and also indication and timing for hormone therapy. The Roach formula for lymph node involvement is still the standard discriminator for WPRT according to all evidence available. A good delineation before pelvic irradiation is however a cornerstone [61]. Further results are awaited from the RTOG 0924 (NCT01368588).
In the 3D-CRT era and parallel to the race for better dose escalation techniques and hypo-fractionations schemes, a combined treatment with ADT was provided to high-risk patients to whom higher RT dose prescription was not possible [62]. Better outcomes were obtained if suppression started before RT and continued afterwards [63]. Clinically, the use of hormone therapy decreased PSA and prostate volume in short to medium-term (up to 33 % volume decrease in 3–4 months) prior to radiation [64]; It also improved treatment response. A metanalysis by Bria et al. [65] reports a significant improvement in terms of biochemical failure (RR 0.76; 95 % CI 0.70–0.82; P < 0.0001) and PFS (RR 0.81; 95 % CI 0.71–0.93; P = 0.002), with absolute differences of 10 % and 7.7 %, respectively. ADT also improved cancer-specific survival (RR 0.76; 95 % CI 0.69–0.83; P < 0.0001) and OS (RR, 0.86; 95 % CI, 0.80–0.93; P < 0.0001), with absolute differences of 5.5 % and 4.9 %, respectively. Furthermore, in a metanalysis by Nguyen et al. ADT was not associated with an increased risk of cardiovascular death for unfavorable-risk patients [66]. This means that ADT is to be considered in certain groups at risk: trials such as the RTOG 86-10, RTOG 85-31, TROG 96.01, RTOG 9413 and EORTC 22863 confirmed benefit from the addition of ADT for patients with intermediate-risk, high-risk or those with lymph node involvement [67–70]. The specific duration of treatment is still under investigation, however therapy is usually recommended to begin at least 3 months before RT and continue for 2–3 years in high-risk patients and 4–6 months in intermediate-risk patients [36].
ADT in conjunction with RT is only applicable for intermediate, high-risk and node positive patients. WPRT is mandatory in all high-risk and some intermediate-risk patients.
Brachyterapy
Prostate brachytherapy (BT) consists in placing definitive or temporary radioactive sources inside the prostate gland by transperineal insertion. These sources have a short range emission which means that a higher dose is delivered to the prostate instead of other regional organs. The implantation is done under transrectal ultrasound (TRUS) guidance but the dosimetry calculations can be done by either TRUS or other imaging exams (CT or MRI).
BT is an appropriate option for low-risk PCa, especially for patients without LUTS and who haven not undergone a TURP, to decrease the risk of urinary symptoms [71].
Most of the data concerning low-risk PCa were obtained with low-dose-rate brachytherapy (LDR-BT) since high-dose-rate brachytherapy (HDR-BT) is a more recent technique. Also, the majority of studies using HDR-BT were performed for dose escalation with EBRT on high-risk groups. Nevertheless, there are studies that indicate that monotherapy with either LDR-BT or HDR-BT in low-risk PCa may have equally favorable outcomes [72, 73].
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