Clinical Oncology 32 (2020) 156e162 Contents lists available at ScienceDirect
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Overview
Salvage Radiotherapy for Prostate Cancer K. Rans *, C. Berghen *, S. Joniau y, G. De Meerleer * * Department y
of Radiation Oncology, University Hospitals Leuven, Leuven, Belgium Department of Urology, University Hospitals Leuven, Leuven, Belgium
Received 6 December 2019; received in revised form 23 December 2019; accepted 8 January 2020
Abstract For patients experiencing biochemical recurrence in the absence of distant metastasis, salvage radiotherapy (SRT) with or without androgen deprivation therapy (ADT) is currently the only possible curative treatment option. Prostate-specific antigen (PSA) monitoring and the selected use of SRT has some advantages when compared with adjuvant radiotherapy. The most important one is avoidance of a potential overtreatment of patients who would never have disease progression, even in the presence of high-risk pathological features. The identification of a specific PSA cut-off seems to be incorrect. In patients with more adverse pathological features, early SRT administered at the very first sign of a PSA rise granted better disease control. Dose-intensified SRT is feasible and well tolerated with no significant difference in grade 2 or more acute and late toxicity. At least 66 Gy must be given in the salvage setting. ADT has a radio-sensitising effect on the radiotherapy by inhibiting the repair of DNA double-strand breaks. The use of ADT in the salvage setting results in a better oncological outcome. Hormonal therapy is associated with a decrease in quality of life and side-effects depending on the duration of hormone therapy. The oncological benefit of hormone therapy duration depends on their clinical and pathological characteristics. 68-Ga-prostate-specific membrane antigen positron emission tomography-computed tomography is the gold standard in staging prostate cancer patients with biochemical persistence or recurrence after radical prostatectomy. The implementation of 18F-labelled PSMA tracers can provide a further improvement. Ó 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Key words: Adjuvant radiotherapy; androgen deprivation therapy; prostate cancer; prostate-specific antigen; PSMA PET-CT; salvage radiotherapy
Introduction Prostate cancer is the most common malignancy in men worldwide and the third leading cause of cancer-related death [1]. Radical prostatectomy is, together with radiotherapy, considered to be a state-of-the-art treatment resulting in long-term disease control for most patients with localised disease. At 10 years of follow-up there is an overall risk of biochemical recurrence of 30e50%, depending on the initial risk state. This results in an increased risk of distant metastasis and cancer-related death [2,3]. According to the European Association of Urology guidelines, biochemical recurrence is defined as an increase in prostate-specific antigen (PSA) after radical prostatectomy to >0.2 ng/ml, confirmed at least once [4,5]. For patients experiencing biochemical recurrence in the absence of distant metastasis, salvage radiotherapy (SRT) with or Author for correspondence: K. Rans, Department of Radiation Oncology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel: þ3216346670; Fax: þ32-16347623. E-mail address:
[email protected] (K. Rans).
without androgen deprivation therapy (ADT) is currently the only possible curative treatment option. Both adjuvant radiotherapy (ART) and SRT are defined as irradiation of the post-prostatectomy prostate and seminal vesicle bed aimed at avoiding local relapse or eradicating (microscopic) local relapse, respectively. ART is defined as radiotherapy delivered after surgery without a period of observation at an undetectable PSA level and in case of unfavourable pathological features on the radical prostatectomy specimen, such as extracapsular extension, seminal vesicle invasion (SVI), positive surgical margins (R1) or a combination of those features [6]. This overview summarises the optimal timing and dosage of ART and SRT, the use of concomitant ADT and the potential impact of new imaging modalities.
Adjuvant Radiotherapy versus Salvage Radiotherapy Three randomised trials, the Southwest Oncology Group (SWOG) 8794 trial [7], the European Organization for
https://doi.org/10.1016/j.clon.2020.01.003 0936-6555/Ó 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
K. Rans et al. / Clinical Oncology 32 (2020) 156e162
Research and Treatment of Cancer (EORTC) 22,911 trial [8] and the ARO 96-02 trial [9] showed that ART significantly improved biochemical relapse-free survival when compared with observation. The results on metastasis-free survival were not unequivocal: the ARO 96-02 trial failed to show a benefit of ART concerning metastasis-free survival [9]. Also, in the EORTC 22911 trial, the initial significant improvements in clinical progression could not be maintained [8]. However, in the SWOG trial, long-term results for a median follow-up of 12.7 years showed a hazard ratio of 0.71 (95% confidence interval 0.5e0.9) with a P-value of 0.0016 [7]. In terms of overall survival, ART failed to show a significant improvement in both the EORTC and ARO trials, although the ARO 96-02 study was underpowered concerning both metastasis-free survival and overall survival [9]. SWOG showed a significant improvement in 10-year overall survival, with a median survival of 13.3 years and 15.2 years for the SRT and ART groups, respectively (P ¼ 0.023) [7]. The inclusion criteria for patients in these studies were, however, rather heterogeneous. Although extracapsular extension, R1 disease and SVI were considered inclusion criteria in the three trials, up to 30% of the patients in the SWOG and the EORTC trials included had a detectable PSA >0.2 ng/ml, rendering these patients no longer purely ‘adjuvant’. Another major point of criticism towards these trials was the lack of standard management for relapsing patients in the ‘watch and wait’ arm. As only 35e55% of these patients received SRT (often at a PSA >1 ng/ml), the results in the watch and wait arms are probably not the ones we would achieve nowadays with SRT at an early timing post-radical prostatectomy. Moreover, about 50% of patients randomised to the observational arm in the randomised trials remained free of biochemical recurrence at 5 years of follow-up [7e9]. ART to these patients would have led to overtreatment and the accompanying side-effects. The choice for SRT might prevent overtreatment of patients and guard them from potential side-effects, such as urinary leakage, development urethral strictures, haematuria and several bowel symptoms [10e12]. Additionally, a longer interval between surgery and radiotherapy allows for better recovery of urinary incontinence [13]. Taking all this together, clinicians raised the pertinent question whether early SRT could not achieve the same results as ART. Therefore, efforts to define better the patients who would probably benefit from ART were undertaken [14]. These results suggest that ART should not be recommended in the case of negative surgical margins [15]. It is important to emphasise the word ‘early’ in this setting, as cure is the aim of SRT. Indeed, several retrospective studies have shown that the pre-radiotherapy PSA level was significantly associated with disease control after SRT [16e22]. Stish et al. [18] showed a doubling of the development of distant metastasis when PSA at SRT was above 0.5 ng/ml (hazard ratio 1.89, P < 0.001). Each doubling of pre-SRT PSA resulted in a significant 32% increase in the relative risk of distant metastasis and an
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increased risk for cause-specific mortality of 40%. Also, Stephenson et al. [20] concluded that a PSA <0.5 ng/ml resulted in the best long-term responses. This was confirmed by the studies of Tendulkar et al. [21] and Abugharib et al. [22], who both even suggested a further benefit when SRT was applied at PSA levels <0.2 ng/ml. Although retrospective, these studies included >4000 patients and clearly concluded: when SRT is the treatment of choice, time is ticking [16,17]. Not only PSA at referral determines disease outcome. Pathological T-stage and Gleason score are other well-known determinants of disease progression. Both Rodin et al. [23] and Fossati et al. [19] showed pathological SVI (pT3b) to be a very significant predictor for disease progression, with hazard ratios >2.5 higher when compared with pT2 disease. The presence of Gleason score 8e10 also reached a high significance, with Pvalues <0.01. The presence of positive surgical margins was not unequivocally predictive for disease progression [19]. Fossati et al. [19] included 716 node-negative patients with undetectable postoperative PSA who experienced a PSA rise after radical prostatectomy; all patients received SRT with a PSA level <0.5 ng/ml. He concluded that in patients with more adverse pathological features, such as pT3b, Gleason score of 8 or more and negative surgical margins, early SRT administered at the very first sign of a PSA rise granted better disease control. The identification of a specific PSA cut-off seems to be incorrect, as the prognostic significance of PSA level varies according to pathological characteristics. There are three prospective trials comparing ART versus early SRT: RADICALS (ISRCTN40814031), RAVES (NCT00860652) and GETUG-AFU 17 (NCT00667069). Across the three trials, 2051 patients were included. RADICALS is a multi-arm randomised phase III trial, comparing immediate radiotherapy with early SRT, followed by a subsequent randomisation for hormone therapy duration (no hormonal therapy versus radiotherapy with short-term hormonal treatment versus radiotherapy with long-term hormonal therapy). Early results on the comparison of immediate versus SRT were presented at the European Society for Medical Oncology (ESMO) congress 2019 [24]. The investigators reported no difference in biochemical recurrence-free survival at 5 years of follow-up between the two treatment groups. Of interest, only a minority of the patients had Gleason 8e10 disease or had SVI, suggesting that this population might not reflect the highrisk patients who are surgically treated elsewhere in Europe. Also, no information on the nodal status (pNx versus pN0) was given. The primary end point of distant metastases-free survival at 10 years has not yet been met. Publication of the results is still awaited. RAVES is a randomised phase III non-inferiority trial comparing ART with SRT [25], with biochemical recurrencefree survival as the primary end point. Similar biochemical recurrence-free survival rates were shown in the ART arm and the SRT arm: 86% and 88%, respectively. SRT spares 50% of the patients from pelvic radiotherapy and is associated with significantly lower levels of genitourinary toxicity [25]. GETUG-AFU-17 is a randomised trial that compares ART þ ADT with SRT þ ART, with the primary end point
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being event-free survival. The results of the GETUG-AFU-17 trial are still awaited. A prospective preliminary meta-analysis, ARTISTIC [26], pooled the available data of these three prospective trials. There was no improvement in event-free survival with ART when compared with SRT (hazard ratio ¼ 1.09).
Radiotherapy Dose and Fields Although there is level I evidence that the use of higher radiotherapy doses improves local control and metastasisfree survival in the treatment of primary prostate cancer [27e32] this evidence is less straightforward in the case of ART and SRT, although retrospective studies have suggested the same benefit of dose escalation after radical prostatectomy [33e35]. These studies used a radiotherapy dose of at least 66 Gy and suggested a dose of 70 Gy as the optimal dose. Two meta-analyses estimated a biochemical recurrence-free survival increase of 2% for each additional 1 Gy of SRT [36,37]. The European Association of Urology guidelines consequently advise a dose of at least 66 Gy in the salvage setting [6]. The delivery of a higher dose in the post-radical prostatectomy setting must be weighed against the risk of increasing toxicity, certainly when >70 Gy is delivered. Using intensity-modulated radiotherapy or volumetric arc therapy, delivering >70 Gy seems not to increase late rectal and urinary toxicity, at least after a moderate follow-up time [38,39]. Data on urethral and/or bladder toxicity after a long follow-up are still awaited. The phase III clinical trial of the Swiss Group for Clinical Cancer Research (SAKK 09/ 10) [40] was the first randomised prospective trial that compared two dose levels of SRT to the prostate bed: 64 Gy versus 70 Gy. Patients in the 70 Gy group reported overall low rates of acute grade 2e3 gastrointestinal and genitourinary toxicity and a minor impact on health-related quality of life, except for a significant increase in patientreported urinary symptom burden. The trial included a significant proportion of patients with pre-treatment incontinence, but severe incontinence after SRT was rare [37]. A recently published study that made a comparison between 66 and 72 Gy confirmed that high-dose radiotherapy is well tolerated. The study showed no difference in grade 2 or more acute and late toxicity. After 4 years of follow-up, no difference was shown for biochemical recurrence-free survival. However, in patients with a high Gleason score of 8 or more there was a significant improvement in biochemical progression-free survival for the high dose group [41]. When the prostate and seminal bed are the target areas for ART and SRT, recommendations on target volume delineation can be found in guidelines of several international scientific organisations: the EORTC [42], the Australian and New Zealand Radiation Oncology Genito-Urinary Group (FROGGRANZCR) [43], the Princess Margaret Hospital (PMH) [44] and the Radiation Therapy Oncology Group (RTOG) [45]. Whether the pelvic nodes should electively be irradiated remains a matter of debate, as it is the case in the primary setting. Recently, the results of the SPPORT trial
were presented at international congresses, showing a significant advantage concerning progression-free survival when pelvic radiotherapy was added to the prostate bed only [46].
Hormonal Therapy ADT has a radio-sensitising effect by inhibiting the androgen receptor-mediated repair of radiotherapyinduced DNA damage in the prostate cancer cell [47]. ADT blocks the androgen receptor, which is known to stimulate the translation of DNA repair genes. A decrease in the number of DNA repair genes results in a decreased ability for the prostate cancer cell to recover from radiotherapyinduced damage [47]. There is level I evidence that the addition of ADT to primary radiotherapy improves overall survival for intermediate- and high-risk prostate cancer [48,49]. However, the use of ADT in the salvage setting remains less clear. A prospective randomised phase III GETUG-AFU 16 trial [50] compared early SRT alone with early SRT plus 6 months in patients experiencing biochemical recurrence after radical prostatectomy with PSA <0.5 ng/ml. Patients receiving the combination treatment were significantly more likely to be free of biochemical recurrence and clinical progression at 5 years (hazard ratio 0.5; P < 0.0001). These results were confirmed by the RTOG 9601 trial [51]. In this double-blind placebocontrolled phase III trial, patients were randomised between SRT alone or SRT plus 2 years of bicalutamide 150 mg daily. After 12 years of follow-up, overall survival was 5% higher in the SRT plus bicalutamide group (hazard ratio 0.77; P ¼ 0.04) with the difference most pronounced in the patient group with pre-treatment PSA >1.5 ng/ml (hazard ratio 0.45; P ¼ 0.007). Death from prostate cancer and the development of distant metastases were significantly lower in the combination group (hazard ratio 0.49 and 0.63, respectively; P < 0.01). Despite the results of the two abovementioned trials, there is still debate concerning the optimal duration of ADT or anti-androgens when associated with SRT. It is well known that the rate and extent of toxicity caused by ADT or anti-androgens depends on their duration. In the GETUG-AFU 16 trial, there were more significant acute adverse events observed in the radiotherapy plus ADT group, but most of these were grade 1 or 2. No additional late adverse events occurred [50]. Recently, Fossati et al. [52] published a multi-institutional retrospective study that tried to assess the optimal duration of ADT, depending on three risk factors: pT stage pT3b, Gleason score 8 and PSA level at SRT > 0.5 ng/ml. This trial showed a significant benefit of 36 months of ADT for patients with two or more risk factors. Conversely, short-term ADT of less than 12 months was sufficient for patients with a single risk factor, whereas patients without any adverse features did not show a significant benefit from concomitant ADT. It has been suggested by Jackson et al. [53] that for men with highrisk disease features receiving ADT with SRT, an extended course of ADT of 12 months or more may be preferable. A multicentre randomised phase II trial coordinated by the
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University Hospitals of Leuven will compare 6 versus 24 months of ADT together with high-dose SRT in the case of biochemical recurrence after radical prostatectomy in pN0 prostate cancer patients (LOBSTER trial, recruitment starting soon). Hormone therapy should be offered to patients in the SRT setting. It is necessary to discuss the possible longand short-term side-effects with the patient as well as the potential benefits of preventing recurrence [54].
New Kids on the Block Recently, the use of new molecular imaging has increasingly changed the management of patients after radical prostatectomy. Choline positron emission tomography-computed tomography (PET-CT) was the ‘first’ gamechanger. Different retrospective studies [55e58] showed that using choline PET-CT changed the management in 33% of prostate cancer patients with biochemical recurrence. Gallium Ga 68-labelled prostate-specific membrane antigen PET-CT (68-Ga-PSMA PET-CT) is even more sensitive and specific when compared with choline [59] and fluciclovine [60]. PSMA is a cell surface glycoprotein and folate hydrolase highly expressed on prostate cancer cells [61]. Its expression increases with Gleason score [62]. Today, 68 Ga-PSMA PET-CT has emerged as the gold standard in staging prostate cancer patients with biochemical persistence or recurrence after radical prostatectomy. Calais et al. [63] showed a rate of 50% positive PSMA PET-CT scans in patients with biochemical recurrence after radical prostatectomy and a median PSA of 0.48 ng/ml. In about 20%, the lesion was outside the clinical target volume that is recommended by the RTOG guidelines. The most common sites of recurrence in these patients were bone and perirectal lymph nodes. A quarter of the patients had a local recurrence, whereas 51% had PSMA-positive glands in the pelvis without distant metastases. This paper underlines the potential benefit of treatment of the pelvic lymph nodes. In a retrospective study [64], 57.3% of the patients had a positive PSMA PET-CT without any suspicious correlates according to the Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria on magnetic resonance imaging or CT. However, this does not mean that SRT can be postponed until the appearance of visible lesions on imaging. Emmett et al. [65] showed that a negative PSMA PET-CT was an independent predictor of a good response to SRT. In a retrospective study, Farolfi et al. [66] showed that in patients with a PSA level <0.5 ng/ml, 68Ga-PSMA PET-CT causes a change in treatment in 30%. A retrospective study also showed that 68Ga-PSMA11 PET-CT is a sensitive tool for restaging prostate cancer and has a high detection efficacy, even in patients with very low PSA levels of <0.2 ng/ ml [67]. Currently, PSMA PET-CT is the best diagnostic tool available for patients with PSA recurrence after surgery. Yet, it may still underestimate the true extent of disease, in particular for the detection of small volume lymph nodes below 4 mm due to the inherent limitations of PET imaging [68,69], as well as for lesions close to the prostate fossa overshadowed by the standardised uptake value and
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radioactivity concentration within the bladder [70,71]. The implementation of 18F-labelled PSMA tracers may overcome this issue because of low clearance via the urinary tract. A head-to-head pilot study showed that 18F-PSMA1007 may detect additional low-grade lesions of limited clinical relevance [72]. New imaging modalities ensure a change in management, but this does not always mean an improvement in clinical outcome. Therefore, randomised trials incorporating new imaging modalities are urgently needed in the postoperative setting.
Conclusion Early SRT is the best treatment for patients with biochemical recurrence after radical prostatectomy and should be done as early as possible. In patients with clinical or pathological risk factors it is necessary to combine the SRT with ADT. We are waiting for prospective trials to define the optimal duration of the hormonal therapy. New imaging modalities should be used with ease in the postoperative setting. Further research is necessary to improve management in patients and avoid overtreatment.
Conflict of interest No conflict of interest.
Acknowledgement C. Berghen is a PhD student in the Department of Radiation Oncology at KU Leuven and is funded by a Kom op tegen Kanker (reference 0010048) (Stand Up to Cancer) grant from the Flemish Cancer Society. G. De Meerleer received a research grant from the Stichting Tegen Kanker (FAF-C/2018/1309).
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