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A distinction is made between brachytherapy alone and exter-nal beam radiation therapy-brachytherapy combinations.
Interstitial brachytherapy alone Two techniques are currently used:
Interstitial brachytherapy of the prostate consists of the permanent implantation of Iodine pellets, usually Iodine 125 in France (LDR brachytherapy).
High dose rate interstitial brachytherapy with Iridium 192 in monotherapy (HDR brachytherapy) consists of implanting needles in the prostate which are subsequently connected to a source projector.
Brachytherapy is a treatment option for prostate tumours with a low risk on the D’Amico scale, therefore biochemical control at 10 years is approximately 90% [195]. A large body of data provides support for offering brachytherapy alone in cancers with a favourable intermediate prognosis (ISUP2) [196-198]. The oncological outcomes are therefore equivalent to those obtained for tumours with a good pro-gnosis [195]. In a prospective phase II study, the biochemical FRQWUROUDWHDW\HDUVZDV>@&RQWUDLQGLFDWLRQV related to the technique are: prostate volume > 50-60 ml, the existence of a median lobe, a history of endoscopic prostate resection and pre-existing urinary disorders. Being young should not be a contraindication for brachytherapy as the results in patients less than 60 years of age are the same as those in older patients. Neoadjuvant androgen deprivation is not recommended.
Low dose rate interstitial brachytherapy exposes to immediate and delayed urinary complications. On the other hand, it appears to be one of the best radiotherapy tech-niques to preserve erectile function [200].
HDR brachytherapy in monotherapy cannot be routinely offered due to the low number of patients included and the limited follow-up of these studies [201].
Brachytherapy in combination with external beam RT
One method that appears particularly effective for increasing the prostate dose is to administer a brachytherapy boost, either by permanent Iodine-125 implants or by high dose rate brachytherapy. This is of interest for patients with an
unfavourable intermediate or high risk [202,203]. Three randomised trials compared external beam radiation the-rapy with or without brachythethe-rapy booster [204]. But two of those trials had an underdosed control arm. Only one randomised trial (ASCENDE-RT) shows that LDR brachytherapy ERRVWLPSURYHVELRFKHPLFDOFRQWUROYVS ZLWKQREHQHÀWLQWHUPVRIPHWDVWDVLVIUHHVXUYLYDOFRPSDUHG to external beam radiation therapy [205], and at the cost of increased urinary toxicity [206]. For this indication, HDR brachytherapy appears to show similar results to LDR EUDFK\WKHUDS\>@
([WHUQDOEHDPUDGLDWLRQWKHUDS\(%57 EBRT: technique
RT should be performed by a three-dimensional conformal technique and if possible, with intensity modulated radiation therapy (IMRT). Image-guided RT is required for dose increases DERYH *\ ,057 PDNHV LW SRVVLEOH WR UHGXFH GHOD\HG
7DEOHRecommendations for radiotherapy.
6WUHQJWK UDWLQJ Technique The recommended
technique is irradiation with intensity modulation
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3D-RT remains an option in case of prostate irradiation alone.
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Fractionation Moderately hypofractionated radiotherapy is equivalent to normo-fractionated RT, in case of prostate irradiation alone
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Dose ,UUDGLDWLRQ*\LV recommended, in the absence of a combination with HT
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In case of short or long-term HT, irradiation
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Lymph node irradiation
Lymph node irradiation is recommended for patients in the high-risk group according to the D’Amico FODVVLÀFDWLRQ
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In this case, IMRT is recommended.
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Brachytherapy combined with radiotherapy
After external beam radiation therapy at a dose of 45-50 Gy, a boost by prostatic brachytherapy is possible for lesions FODVVLÀHGDV77
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toxicity compared to conventional RT at an equivalent dose and to increase the dose delivered to the tumour without VLJQLÀFDQWO\LQFUHDVLQJWR[LFLW\7KHWHUPVDQGFRQGLWLRQV of RT are established in the RECORAD procedures guide and in the Siriade delineation reference system, on the SFRO website (http://www.sfro.org/). Quality assurance plays a major role and requires the commitment of all professionals.
Dose escalation
7KHGRVHLQFUHDVH*\DFKLHYHGE\SKRWRQVSURWRQV or brachytherapy was compared to a conventional dose
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IUDFWLRQLQWKHIUDPHZRUNRIUDGLRWKHUDS\DORQH6LJQLÀFDQW improvement in biochemical control, relapse-free survival, DQG GLVHDVHVSHFLÀF VXUYLYDO ZDV UHSRUWHG EXW ZLWKRXW improvement in overall survival. The usefulness of increa-sing the dose has not been demonstrated for combinations with short or long-term HT, although there are indirect arguments in favour of combining both HT and RT at high doses [208,209].
Hypofractionation
Hypofractionation consists of delivering doses of more than 2 Gy per fraction, and makes it possible to reduce the number of sessions. A distinction is made between moderate hypofractionation (between 2.5 and 6 Gy/fraction) and H[WUHPHK\SRIUDFWLRQDWLRQ'RVH*\IUDFWLRQ
Moderate hypofractionation has been the subject of several phase III randomised trials to verify the superiority of this approach. The results were negative [210,211].
Équivalence trials [212-215] have been published which show that hypofractionated treatments with doses of approximately 2.5 to 3.5 Gy per fraction allow equivalent biochemical control without any major increase in toxi-FLW\>@,WVKRXOGEHQRWHGWKDWUHFWDODQGXULQDU\
toxicity are more frequent, particularly in the RTOG 0415 study where intensity-modulated RT was not required [215].
Hypofractionation is a therapeutic option with a slightly higher risk of toxicity and therefore requires a strict tech-nique that combines intensity modulation with daily control of prostate positioning (image-guided RT). The GETUG has published recommendations on dose constraints for suscep-tible organs, with the 60 Gy in 20 fractions regime being the most widely accepted [218]. This hypofractionation has only been validated for low or intermediate risk cancers without lymph node irradiation.
Extreme hypofractionation (stereotactic RT) has been the subject of few comparative trials. Long-term tolerability, in particular urinary tolerability, appears satisfactory. These studies mainly involved patients in the favourable and inter-mediate groups. Only one randomised trial is published [219].
,WFRPSDUHGDGRVHRI*\LQIUDFWLRQVWRVWHUHRWDFWLF UDGLRWKHUDS\*\LQIUDFWLRQVVHVVLRQVSHUZHHN without associated androgen deprivation. Between 2005 and 2015, 1,054 patients were included, most from the inter-mediate group (89%). With a median follow-up of 5 years, there was no difference between the two groups regarding any of the endpoints (biochemical and/or clinical control:
84% in both groups). Initially designed as a superiority trial, it was later transformed into an equivalence trial, with a SUHVSHFLÀHGOLPLW7KHDXWKRUVFRQFOXGHGWKDWWKHWZR irradiation schemes are equivalent.
Irradiation volume
The initial volume includes the prostate. It is customary to DOVRLQFOXGHWKHVHPLQDOYHVLFOHVDWOHDVWWKHÀUVWFHQWL-metre) for intermediate and high-risk groups. Irradiation of O\PSKQRGHDUHDVVKRZHGFRQÁLFWLQJUHVXOWVZLWKQREHQHÀW GHPRQVWUDWHGLQWKHWZRSKDVH,,,WULDOVWKDWVSHFLÀFDOO\
evaluate their importance (GETUG P01; RTOG 94-13). The randomised trials that demonstrate the value of irradiation in high-risk or locally advanced tumours have all included lymph node irradiation.
Complications
Toxicity was rigorously evaluated in the recent randomised WULDOVRIK\SRIUDFWLRQDWLRQWKDWLQFOXGHGDVLJQLÀFDQWQXPEHU of patients (> 500 patients per arm). In summary, grade 2 late urinary toxicity was noted in 9-20% of the cases and grade 3 in 1-3% of the cases. In terms of the digestive V\VWHPJUDGHODWHWR[LFLW\ZDVUHSRUWHGLQRIWKH cases and grade 3 in 1-3% of the cases. Evaluating grade 2 toxicities (diagrammatically, leading to minor disorders but UHTXLULQJPHGLFDWLRQUHPDLQVGLIÀFXOWZKLFKH[SODLQVWKH wide ranges observed. An important parameter is function prior to irradiation. This is particularly true for urinary toxicity. Patients with lower urinary tract symptoms prior to irradiation are at a higher risk for urinary toxicity after irradiation [211,212,219,220].
Contraindications
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disease, and scleroderma are contraindications for external beam RT. Severe obstructive urinary symptoms increase the risk of bladder retention during RT and of subsequent complications. Prostate adenoma can be surgically treated before starting RT (agreement of experts). After surgical treatment, RT should be delayed for 6 to 8 weeks to reduce the risk of urinary complications including urethral stricture.
Hip prosthesis (especially bilateral) is not a contraindication for RT but requires an adapted technique and dosimetry.
Adjuvant or salvage radiotherapy
The standard dose is 66 Gy. The irradiated volume usually includes the prostate capsule. Irradiation of lymph node chains can be discussed according to the initial tumour characteristics and the extent of the lymphadenectomy. The most frequent complications are urinary and digestive, but the incidence remains limited if the total dose prescribed is 66 Gy and if irradiation is not started until continence is stabilised (after 3 months). Five to 10% grade 3 complica-tions are reported. An increase in the volume of irradiation probably increases the risk of late side effects, especially related to the digestive system. IMRT improves digestive and urinary dosimetric and clinical results.
Palliative radiotherapy
External beam RT has an important role in palliative care, particularly when there are symptomatic bone metastases.
1RGLIIHUHQFHLQDQDOJHVLFHIÀFDF\ZDVIRXQGEHWZHHQVLQJOH fraction RT (8 Gy in 1 fraction) and multifraction RT (30 Gy LQIUDFWLRQVEXWVLJQLÀFDQWO\PRUHUHSHDWWUHDWPHQWVLQ the single fraction arm. Single fraction radiotherapy should be chosen when there is no visible fracture or neurological compression.
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By evaluating PROs (patient reported outcomes) [200,221], adverse effects can be analysed according to the stages of the disease and the treatments. At 6 months, radiotherapy (combined with androgen deprivation) affected sexual function, particularly erectile function, only slightly less than prostatectomy. Bowel and urinary disorders increased in the radiotherapy group, with good recovery in the following months. Most urinary, intestinal and sexual disorders were alleviated in 5 years. Prostatectomy was associated with a risk of urinary incontinence compared to other options for men with a favourable or unfavourable PCA risk.
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,QGLFDWLRQVConsidering the high technicity of HIFU, which prevents WUHDWPHQWRIH[WUDSURVWDWLFIRUPVRUWKRVHDWVLJQLÀFDQW risk of being so, and in the absence of consensus, treatment of high-risk or unfavourable intermediate-risk prostate cancers by this method is not recommended (Low level).
The three major total treatment series that have been published show a higher failure rate according to the risk [222,223,224].
In addition, cases concerning apex lesions are not to be considered because of the need to maintain a safety margin to avoid incontinence [225]. Prostate volume can be reduced by prior surgical reduction.
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HIFU is a non-surgical therapy that has developed for 20 years for selected patients with localised PCA. Two mechanisms predominate in tissue damage, the thermal effect and cavitation. It is performed by endorectal ultrasound and currently includes preoperative MRI.
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A case-control study in 2015 compared HIFU and brachytherapy. Biochemical relapse-free survival was better in the brachytherapy arm, with no difference for PHWDVWDVLVIUHHGLVHDVHVSHFLÀFDQGRYHUDOOVXUYLYDOEXW the follow-up remained limited (83 months) and the numbers ZHUHORZSDWLHQWVLQHDFKJURXS>@$UHYLHZ of the literature on 4,000 patients found that biochemical relapse-free survival was worse in one year with HIFU than with radiotherapy, but this difference disappeared in 5 years.
This literature review is particularly biased [229].
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The rate of complication increases with the number of sessions. The rate of urinary incontinence varies from 1% to 25% depending on the series, according to the severity and the measurement tool. Lower urinary tract obstruction varies from 10% to 30%. For approximately 20-50% of the patients who had sexual intercourse without the assistance of drugs before treatment this function remains intact (Table 28).
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Cryotherapy is currently under evaluation and is envisaged as an alternative treatment to reference treatments for localised PCA. Patients who are potential candidates have prostates less than 40 ml in volume, a tumour at the localised VWDJH36$OHVVWKDQQJPODQGDQ,683JUDGH>@
Cryotherapy is mainly offered in salvage radiotherapy.
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The method is based on freezing (-40°) the tissue, which results in protein denaturing, rupture of the cell membranes
7DEOHOncological results of treatment by whole-gland HIFU.
3DWLHQWV 5LVNORZLQWHUPHGLDWHKLJK 26 '66 %5)6E\VWDJH
Crouzet S. et al [222] 1,002 44%, 42% and 14% 80% 80-60%°°
Thuroff S. et al [224] 22%, 38% and 40% 83% 99% 68-60%°°
Ganzer R et al [223] 538 DQG 86% DQG
Uchida T et al [226] 918 26%, 40% and 30% 89% 63%, 52% and 32%
5RXJHW%HWDO>@ 191 55%, 34% and 12% 90%°°° 98%°°° 88%, 69% and 39%
* OS: overall survival
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°in 10 years °°in 8 years, °°°in 5 years
by ice crystals, and vascular micro-thromboses with apop-tosis. Cryotherapy needles are introduced by perineal route under transrectal ultrasound guidance.
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,QLQDUHWURVSHFWLYHVWXG\RISDWLHQWVZLWKDW ORZULVNDWLQWHUPHGLDWHULVNDQGDWKLJKULVN Cohen et al reported biochemical relapse-free survival in
\HDUVDFFRUGLQJWRWKH3KRHQL[FULWHULDRI and 45.5% depending on the risk group. [232]
In 2015, based on a retrospective study of the Cryo On-Line Database with 2,242 hormone-naive patients com-SULVHGRIDWORZULVNDWLQWHUPHGLDWHULVNDQG 42.2% at high risk, Elshafei et al showed a 5-year biochemical UHODSVHIUHHVXUYLYDO3KRHQL[RIDQG respectively [233]. In 2009, in a retrospective study based on the Cryo On-Line Database, Levy et al reported results IURPSDWLHQWV7KHIDLOXUHUDWH3KRHQL[ZDV DQGUHVSHFWLYHO\DFFRUGLQJWRWKHULVN>@
In Ramsay’s literature review of almost 4,000 cryothera-pies, the results on 1-year clinical relapse-free survival were poorer compared to radiotherapy or surgery [229].
The development of this technique is essentially North American. The main studies are from a single registry and although the number of patients treated is up to several thousand, lack of follow-up and the type of studies mean that this treatment is not offered as an alternative but only when the recommended options are not possible. In a recent Cochrane review, the level of evidence remained too low in terms of both oncological and functional outcomes to change the current recommendations [235].
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7KHUDWHRIFRPSOLFDWLRQVKDVGHFUHDVHGVLJQLÀFDQWO\ZLWK technical improvements. The rate of urinary incontinence varies from 1% to 8% depending on the severity and the mea-surement tool. Obstruction varies from 4% to 10%. The risk of
sexual impotence is 30% to 100%. The risk of prostatic-rectal ÀVWXODLVWR>@