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Many phase III trials are under way to evaluate anti-PD1 antibody in combination with a new generation hormone therapy (enzalutamide), docetaxel or olaparib.
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PARP (poly(ADP) ribose polymerase) is a family of nuclear proteins involved in the repair of single-strand DNA breaks.
&DQFHUV ZLWK GHÀFLWV LQ WKH KRPRORJRXV UHFRPELQDWLRQ involved in the repair of DNA double-strand breaks are highly sensitive to PARP inhibitors. PARP inhibitors are used in patients with BRCA1 and BRCA2 germline mutations and metastatic ovarian or breast cancer. The leading PARP inhibitor is olaparib [14]. Other PARP inhibitors are being developed (niraparib, talazoparib, rucaparib, etc.). They are taken orally. They are responsible for haematological and gastrointestinal side effects (nausea, diarrhoea).
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Management takes into account associated multiple patholo-JLHVWKDWLQÁXHQFHWKHSUREDELOLW\RIVXUYLYDOWKHLQIRUPDWLRQ given to the patient, and their preferences. This information LQFOXGHVSUHVHQWLQJWKHEHQHÀWVDQGULVNVRIHDFKWUHDWPHQW It takes into account the age at diagnosis (INSEE data in 2020:
OLIHH[SHFWDQF\RI\HDUVIRUPHQIXQFWLRQDOGLVRUGHUV competing morbidity factors, various contraindications and patient preferences. Low-risk progressive cancers are usually managed with active surveillance or curative treatment (radical prostatectomy, external beam radiation therapy or interstitial brachytherapy) with the same long-term oncologi-cal outcomes [140]. HIFU and cryotherapy are currently being evaluated, particularly in the context of focal therapies.
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The intermediate risk group is a heterogeneous group with very different prognoses. Patients in the intermediate group with a single intermediate risk factor, ISUP 2 and less than
50% positive biopsies were shown to have an excellent prog-nosis whether treated by surgery or radiotherapy [105]. The prognosis for patients with a favourable intermediate risk is close to the prognosis for a low risk, while those with an unfavourable risk have a prognosis close to the prognosis for a high risk [303].
7DEOHRecommendations: Treatment of low-risk PCA.
6WUHQJWK UDWLQJ Simple monitoring such as Watchful Waiting
(palliative treatment in case of progression) for patients not eligible for other options.
6WURQJ
Active surveillance 6WURQJ
Radical prostatectomy 6WURQJ
Radiotherapy 6WURQJ
Brachytherapy 6WURQJ
Cryotherapy and HIFU
(Lack of long-term data) :HDN
)RFDOWKHUDS\LQVXIÀFLHQWGDWDWRPDNH recommendations
Hormonal treatment: not recommended 6WURQJ
7DEOHRecommendations: treatment of intermediate-risk PCA.
6WUHQJWK UDWLQJ Simple monitoring such as Watchful Waiting
(palliative treatment in case of progression) for patients not eligible for other options with a probability of short survival.
6WURQJ
Active surveillance for selected patients
informed of the long-term risks :HDN Radical prostatectomy ± lymphadenectomy.
Patients with a life expectancy of > 10 years
6WURQJ
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– only if favourable intermediate – or associated with a short-term ADT (6 months) if unfavourable intermediate.
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Radiotherapy with brachytherapy boost :HDN Brachytherapy (favourable intermediate
group)
:HDN
Cryotherapy and HIFU (lack of long-term
data) :HDN
)RFDOWKHUDS\,QVXIÀFLHQWGDWDWRPDNH recommendations
Hormonal treatment: not recommended 6WURQJ
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Major AS series have a limited number of patients with intermediate-risk PCA [304]. In the main series, the risk of metastasis in this group compared to patients with a good prognosis was 3 times higher [305]. In the ProtecT trial, more than 20% of the patients were at intermediate or high risk [141]. While no difference was observed in the 10-year disease-specific survival, there was an increase in the risk of clinical progression or metastasis in the surveillance group. AS in the intermediate-risk patient group should be limited to patients who are selected and informed of the long-term risks. Among the selection criteria, the majority of the consensus groups agreed on a low percentage of grade 4 (< 10%), a limited number of positive biopsies, and a PSA < 10 ng/ml. MRI data also guide decisions concerning therapy, although strict selection and monitoring criteria cannot be defined at present [150].
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Studies on HIFU, cryotherapy and focal therapy in intermediate-risk PCA, regardless of the energy used, are observational studies with limited follow-up. No conclusion RQORQJWHUPRQFRORJLFDOHIÀFDF\FDQEHEDVHGRQWKHVH studies. Therefore, these techniques can only be offered to patients who are not eligible for surgery or radiotherapy, or in the framework of a study.
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Radical prostatectomy is one of the reference treatments for localised intermediate risk PCA, according to the D’Amico FODVVLÀFDWLRQDQGWKH&$35$VFRUH>@
5DQGRPLVHGWULDOVVKRZDVLJQLÀFDQWUHGXFWLRQLQRYHUDOO PRUWDOLW\DQGGLVHDVHVSHFLÀFPRUWDOLW\LQWKH53YVWKHVXU-YHLOODQFHJURXS,QWKH63&$*6VWXG\>@ZLWKD\HDU follow-up, the risk of death from PCA was 19.6% after pros-tatectomy and 31.3% in case of watchful waiting. The main ULVNIDFWRUVIRUGLVHDVHVSHFLÀFGHDWKZHUHSRVLWLYHPDUJLQV H[WUDFDSVXODUVSUHDGDQGPRVWRIDOODQ,683JUDGH
7KHUDWHVIRURYHUDOOGLVHDVHVSHFLÀFDQGPHWDVWDVLVIUHH VXUYLYDOZHUHDQGUHVSHFWLYHO\,QWKH PIVOT study, a 12% decrease in the overall risk of death was noted [138].
In terms of surgical technique, NVB preservation can be achieved depending on preoperative erectile function, in the absence of capsular penetration on the MRI.
The risk of lymph node involvement varies from 4 to 20%
in this group [112]. Extensive lymphadenectomy should be performed in case of a risk of positivity > 5% by nomogram HYDOXDWLRQ>@/HVVLQYDVLYHDSSURDFKHVFRXOGEHVXJJHVWHG for intermediate-risk patients [105].
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RT is one of the reference treatments for prostate cancer patients in the intermediate group. The PROTECT trial, with
more than 20% of the patients presenting an intermediate VWDJHRQGLDJQRVLVFRQÀUPVWKHHTXLYDOHQFHEHWZHHQVXU-JHU\DQGLUUDGLDWLRQDW\HDUVLQWHUPVRIGLVHDVHVSHFLÀF survival.
A short-term (6 months) ADT combined with prostate LUUDGLDWLRQRI*\LPSURYHVWKHRYHUDOOVXUYLYDORISDWLHQWV in the intermediate group compared to the conventional
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In the Boston randomised trial [308], overall survival at
\HDUVZDVVLJQLÀFDQWO\EHWWHUZLWKWKH57+7FRPELQD-WLRQYVS 7KLVEHQHÀWZDVQRWHGRQO\LQ patients without associated moderate or severe multiple pathologies.
The RTOG 94-08 study [309] showed an overall survival EHQHÀW DW \HDUV IRU WKH FRPELQDWLRQ WUHDWPHQW YVS ZLWKGLVHDVHVSHFLÀFPRUWDOLW\UDWHVDW
\HDUVRIDQGUHVSHFWLYHO\7KHEHQHÀWZDVEDVLFDOO\
pronounced in intermediate-risk patients with an improve-ment in overall survival at 10 years (from 54% to 61%) and DUHGXFWLRQLQGLVHDVHVSHFLÀFPRUWDOLW\IURPWR p < 0.01).
The EORTC 22991 study [208] included 819 patients ZKREHQHÀWHGIURPHLWKHU57DORQHRU*\RU 57FRPELQHGZLWKPRQWKVRI+77KHUHZDVDEHQHÀWLQ FOLQLFDOUHODSVHIUHHVXUYLYDODQGDVLJQLÀFDQWUHGXFWLRQLQ WKHRFFXUUHQFHRIPHWDVWDVHVEXWQREHQHÀWIRURYHUDOO survival. The higher the radiation dose, the greater was the EHQHÀWRIWKLV+7
GETUG 14 is a prospective dose escalation trial that UDQGRPLVHGSDWLHQWVZLWKDQLQWHUPHGLDWHSURJQRVLV into two arms: a neoadjuvant ADT (2 months) + prostate irradiation (2 months) arm and a prostate irradiation arm.
The irradiation dose was 80 Gy. Preliminary results with a PHGLDQIROORZXSRIPRQWKVFRQÀUPHGWKHYDOXHRID VKRUWWHUP$'7ZLWKDVLJQLÀFDQWEHQHÀWIRUELRORJLFDODQG clinical relapse-free survival at 5 years. [310]
It is important to differentiate the two subgroups already described within the intermediate risk group:
unfavourable intermediate risk patients could benefit from combined ADT while favourable intermediate risk patients could be treated with RT alone with a minimum GRVHRI*\7KHEHQHILWRIWKHGRVHLQFUHDVHDSSHDUV useful even in case of ADT [208]. The indication for this ADT should take into account the associated cardio-vascular co-morbidities.
A combination of external beam radiotherapy and brachy-therapy could be superior to external beam radiobrachy-therapy DORQH>@7KLVVKRXOGEHFRQÀUPHGE\IXUWKHUSURVSHFWLYH trials. Low dose rate brachytherapy alone can be offered to patients in the intermediate group if they have only one SRRUSURJQRVWLFIDFWRU36$QJPORU,683,QWKDW case, it is essential to have a good quality MRI that shows no extraprostatic extension.
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The group with high-risk tumours is heterogeneous. Based on the number of unfavourable factors (PSA > 20 ng/ml; clinical VWDJH77,683GLVHDVHVSHFLÀFVXUYLYDODIWHUVXUJHU\
and RT varies from 80 to 95% [311,312].
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If the local treatment is RT, it is imperative to combine it with an ADT for locally advanced tumours (T3-T4). Hormone therapy with radiotherapy is superior to RT alone for local control, biochemical control, the development of meta-stases and overall survival at 10 years – EORTC: 40 vs 58%
(p = 0.0004); RTOG 85-31: 38 vs (p = 0.0043) [313,314].
Hormone therapy with radiotherapy is superior to HT alone in biochemical control, metastasis-free survival and overall survival [315,316]. A local treatment must be added to optimize the management of these locally advanced tumours without distant metastases.
Long-term ADT (2 or 3 years) is superior to short-term ADT (4 or 6 months) for biochemical relapse-free survival, clinical UHODSVHIUHHVXUYLYDODQGPHWDVWDVLVIUHHVXUYLYDO$EHQHÀW in overall survival was observed for the subgroup of patients ZLWKDQ,683JUDGHLQWKH572*VWXG\)RUSDWLHQWVLQWKH high-risk group, long-term ADT (2 years) improves metastasis-free survival and overall survival compared to 4 months of
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One trial [318] compared 18 months of use versus PRQWKVDQGIRXQGQRVLJQLÀFDQWGLIIHUHQFHIRUDQ\RIWKH endpoints assessed. However, this was a superiority trial and not an equivalence trial. It has not yet been demonstrated that 18 months of use is equivalent to 3 years of use. For patients with a single high-risk factor or with associated multiple pathologies (especially cardiovascular related), ADT can be discontinued at 18 months. Eighteen months is the minimum duration to be considered in high-risk forms.
In the randomised trials, pelvic irradiation was routine ZLWKDGRVHRI*\GHOLYHUHGWRWKHSURVWDWHEXWWKHDFWXDO EHQHÀWRISHOYLFLUUDGLDWLRQUHPDLQVGHEDWDEOH
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RP can be performed in selected patients with high-risk prostate cancer who are at a negative stage. In case of unfavourable pathological factors, it should be considered as part of a multimodality treatment. The patient should be informed of this possibility preoperatively.
The presentation of high-risk tumours has changed.
Currently, the majority of patients are at high risk due to a high ISUP grade or extraprostatic extension on MRI, rather WKDQD36$YDOXHQJPORUWKHFOLQLFDOVWDJHF7 High-risk tumours account for 20-25% of the newly diagnosed 3&$VGHSHQGLQJRQWKHGHÀQLWLRQXVHG2QFRORJLFDOÀQGLQJV RI53IRUKLJKULVNGLVHDVHVDUHKHWHURJHQHRXVDQGGLIÀFXOW WRLQWHUSUHWEHFDXVHRIWKHPXOWLSOHGHÀQLWLRQVXVHGDQG variable combinations with adjuvant or salvage therapy. The S7UDWHLVKLJKLQUHFHQWVHULHV'LVHDVHVSHFLÀF survival at 10 years varies from 85 to 98%. There are no randomised studies that compare RP with radiotherapy and radiotherapy + hormonal therapy. Several comparative retro-spective series and a meta-analysis have suggested that RP might be equivalent to radiotherapy + hormonal therapy, and ZRXOGSURYLGHDGLVHDVHVSHFLÀFVXUYLYDOEHQHÀWFRPSDUHG to radiotherapy [193,319,320]. Conversely, an equivalence and even superiority of the RT/brachytherapy/hormonal therapy combination over surgery has been demonstrated in other more recent series [202,203]. But these studies are burdened by many biases, so no conclusions can be drawn.
A randomised trial (SGPCA-15) is under way.
Technically, extensive lymphadenectomy and comprehen-sive ablation of the prostate should be performed. The objective of surgery is an excision within healthy margins.
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It has been mainly evaluated in combination with radio-therapy + hormonal radio-therapy.
• The GETUG12 trial [321] compared a long-term (3-year) ADT alone or in combination with 4 cycles of docetaxel/
estramustine. Patients could undergo surgery, but only 5%
of the patients had a radical prostatectomy. With 8 years of follow-up, biochemical relapse-free survival was better LQWKHFKHPRWKHUDS\JURXSYVS EXWQR EHQHÀWIRUPHWDVWDVLVIUHHVXUYLYDORURYHUDOOVXUYLYDO was indicated.
• The STAMPEDE trial [289] is a randomised, multi-arm, multi-stage trial that included metastatic patients who were also at high-risk. At least two of the following FKDUDFWHULVWLFVZHUHUHTXLUHGF77,683JUDGH
DQG36$QJPO,QWKHDGMXYDQWGRFHWD[HODUPLQ the non-metastatic subgroup (1,145 patients, of whom 62% received radiation), chemotherapy improved bioche-mical relapse-free survival (HR: 0.6; p = 0.0002), without improving the other parameters.
• The NRG/RTOG0521 trial [322] evaluated an adjunctive treatment with docetaxel in combination with long-term 7DEOHRecommendations: treatment of high-risk PCA.
6WUHQJWK UDWLQJ Hormone therapy with radiotherapy
is superior to radiotherapy alone for local control, biochemical control, the development of metastases and overall survival at 10 years.
6WURQJ
Long-term ADT (2 or 3 years) is superior to short-term ADT (4 or 6 months) for biochemical relapse-free survival, clinical relapse-free survival, metastasis-free survival and overall survival. In some cases (elderly patient, co-morbidities), a duration of 18 months may be indicated.
6WURQJ
RP can be offered in the management of high-risk or locally advanced PCA in the framework of a multimodality approach.
6WURQJ
ADT alone is inferior to radiotherapy + hormonal therapy on biological control, metastasis-free survival and overall survival in patients without associated severe multiple pathology
6WURQJ
Local treatment should be offered in case of cN1 M0 disease (surgery or radiotherapy + hormonal therapy)
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$'7\HDUVDQGLUUDGLDWLRQWR*\,Q high-risk patients, docetaxel improved overall survival (at 6 years, 86.0% vs 80.6%; with a unilateral log-rank test, p = 0.034). However, there were more intercurrent deaths LQWKHDUPZLWKRXWGRFHWD[HOYVZLWKQREHQHÀW IRUGLVHDVHVSHFLÀFVXUYLYDO%LRFKHPLFDOUHODSVHIUHH survival was similar in both arms, and there was a slight improvement in the rate of metastases at 6 years (14%
vs. 9.1%; p = 0.044), which suggests a simple delay in the RQVHWRIPHWDVWDVLV$GHÀQLWLYHFRQFOXVLRQFDQQRWEH drawn on the usefulness of adjuvant docetaxel based on these various methodological considerations.
Chemotherapy seems to improve biochemical relapse-free survival in high-risk forms without impact on other parameters for the moment. Therefore, it is not routinely indicated.
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ADT alone is inferior to radiotherapy + hormonal therapy on biological control, metastasis-free survival and overall survival in patients without associated severe multiple pathology [315,323,324].
HT as monotherapy should only be offered as a last resort in patients with severe multiple pathology (level of evidence 2) who are not eligible for radiotherapy.
F1
Up until now, the treatment of cN1 patients considered to be metastatic has been ADT.
6HYHUDOUHFHQWVHULHVKDYHVKRZQWKHEHQHÀWRIORFDO treatment in this situation [325]: RP or RP+ADT [326] and 57$'7>@7KLVEHQHÀWRIDGGLQJORFDOWUHDWPHQWKDV been evaluated in various retrospective studies, summa-rized in a systematic review [325]. These studies show a EHQHÀWRIFRPELQLQJDQ$'7ZLWKDORFDOWUHDWPHQW57 RU53LQRYHUDOOVXUYLYDODQGLQGLVHDVHVSHFLÀFVXUYLYDO ZLWKWKH+5UDQJLQJIURPWRGHSHQGLQJRQWKH studies. This is particularly the case in the STAMPEDE study
>@)RUQRQPHWDVWDWLFSDWLHQWVLQFOXGLQJF1DQG0 patients, it was left to the clinician to decide whether or not to offer prostate irradiation with or without pelvic irradiation. The two groups were comparable. Relapse-free survival at 2 years was 89% in the irradiated group versus 64% without irradiation (HR: 0.35, IC: 0.19-0.65). This is a retrospective analysis, but in a prospective study. The EHQHÀWRI53LQF1SDWLHQWVZDVWKHQHYDOXDWHGLQDQRWKHU UHWURVSHFWLYHVWXG\WKDWFRQÀUPHGWKHVXUYLYDOEHQHÀWIRU patients who had undergone surgery [328]. The type of ORFDOWUHDWPHQW53YHUVXV57GLGQRWDSSHDUWRLQÁXHQFH oncological outcomes.
Based on these studies, local treatment is recommended in patients with cN1 disease at the time of diagnosis. This is particularly the case if lymph node involvement is only detected on the PET scan. If lymph node involvement is suspected during surgery, RP should be continued. Extensive lymphadenectomy remains the reference treatment in this situation.
6\VWHPLFWUHDWPHQWLQWHQVLÀFDWLRQKDVQRWEHHQVSHFLÀ-cally evaluated in the cN1 patient population. The STAMPEDE
study evaluated the addition of docetaxel and abiraterone, but in a non-metastatic sub-population, including both cN0 and cN1 patients [289,329]. Abiraterone acetate was DVVRFLDWHG ZLWK QRQVLJQLÀFDQW LPSURYHPHQW LQ RYHUDOO survival in these cN0/1M0 patients with survival data that are still preliminary. Adding docetaxel and/or zoledronic acid SURYLGHGQRRYHUDOOVXUYLYDOEHQHÀWLQWKHVHQRQPHWDVWDWLF patients treated with ADT.
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Local treatment by surgery or radiotherapy + hormonal therapy is indicated in case of cN1M0 cancer.
Augmentation of systemic treatment with
chemotherapy or NGHT is not indicated for cN1M0 cancer.
)ROORZXSDGMXYDQWDQGVDOYDJHWUHDWPHQWV DIWHUORFDOWUHDWPHQW
0RQLWRULQJPRGDOLWLHVGHÀQLWLRQDQGDVVHVVPHQW RIELRFKHPLFDOUHODSVH%5DIWHUORFDOWUHDWPHQW Monitoring modalities after local treatment
Monitoring after local treatment is intended to verify the absence of relapse and to assess the tolerability of treat-ment. In the event of a relapse, it makes it possible to discuss the merits of a second line of treatment.
36$DQG'5(DUHWKHÀUVWOLQHWHVWV$QLQLWLDOWRWDO36$
test is recommended within 3 months after the procedure.
If PSA undetectable, subsequent checks are recommended every 6 months for 3 to 5 years, then every year [330]. After RP, PSA becomes undetectable in 6 weeks since the half-life is 3.15 days [331].
There is no indication for systematic imaging after RP or RT, unless there is a biochemical or clinical relapse after local treatment.
'HÀQLWLRQRIELRFKHPLFDOIDLOXUHDIWHUORFDO treatment (Table 37)
%LRFKHPLFDOIDLOXUHLVGHÀQHGHLWKHUE\UHODSVH%&5RUE\
the persistence of a detectable PSA after the procedure.
7DEOH'HÀQLWLRQVRI%&5E\W\SHRISURVWDWHFDQFHU treatment.
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