Prostate radiotherapy in newly diagnosed metastatic prostate cancer
Prostate radiotherapy in newly diagnosed metastatic prostate cancer
Current Opinion in Urology
Shore Adnan Ali , Christopher C. Parker , and Noel W. Clarke
Purpose of review: The aim of this article is to review the role of prostate radiotherapy in the multimodal management of newly diagnosed metastatic hormone naïve prostate cancer.
Recent findings: Two randomized controlled trials have evaluated the role of prostate radiotherapy with systemic therapy (androgen deprivation therapy ± docetaxel) in newly diagnosed metastatic hormone-naive prostate cancer. In a combined cohort of over 2000 patients, prostate radiotherapy with systemic therapy improved survival over systemic therapy alone in patients with low metastatic burden but not in high-burden patients. Prostate radiotherapy with systemic therapy is now a recommended first-line option for newly diagnosed men with low metastatic burden prostate cancer. The current recommended definition for low metastatic burden is based on conventional imaging (99mTc bone scans and CT/MRI). Cross-correlative studies are required to pick an appropriate threshold for sensitive-imaging modalities such as PSMA PET or whole-body MRI. Ongoing trials are evaluating prostate radiotherapy in this setting combined with abiraterone/docetaxel and metastasis-directed therapy.
Summary: Prostate radiotherapy with systemic therapy improves survival in patients with newly diagnosed, low metastatic burden prostate cancer and is a recommended first-line treatment option. Ongoing trials are evaluating combination with metastasis-directed therapy and other systemic treatments.
In newly diagnosed high-risk localized prostate cancer, a multimodal approach is recommended whereby prostate radiotherapy with androgen deprivation therapy (ADT) results in improved survival compared with radiotherapy or ADT alone [1–3]. However, in the absence of evidence for benefit in metastatic prostate cancer, an international modus operandi was adopted wherein prostate radiotherapy was not recommended and systemic treatments alone were standard of care. Nevertheless, based on preclinical data and theories of an intermediate metastatic stage, the role of prostate radiotherapy in metastatic prostate cancer has now been evaluated in two phase III trials. In a combined cohort of over 2000 patients, the HORRAD and the STAMPEDE ‘M1|RT comparison’ trials have evaluated the therapeutic advantage associated with adopting a multimodal approach in men with newly diagnosed metastatic hormone naïve prostate cancer (mHNPC) [4▪▪,5▪▪]. In this review, we summarize the data from these trials to guide and expand the use of multimodal treatment in metastatic prostate cancer.
Evidence from randomized controlled trials
The HORRAD and the STAMPEDE ‘M1|RT comparison’ trials have evaluated the role of prostate radiotherapy in de-novo mHNPC (Table 1). HORRAD enrolled men with newly diagnosed mHNPC with bone metastasis on bone scintigraphy between 2004 and 2014. Overall, 432 patients were randomized in a 1:1 ratio to receive prostate radiotherapy and ADT or ADT alone [5▪▪]. At a median follow-up of 47 months, there was no evidence of improvement in overall survival associated with the radiotherapy intervention (hazard ratio = 0.90, 95% confidence interval [CI] 0.70–1.14). However, in a subgroup of 160 patients with less than 5 bone metastases, prostate radiotherapy and ADT showed some evidence of overall survival benefit over ADT alone (hazard ratio = 0.68, 95% CI 0.42–1.10), although statistical significance was not reached. A similar trend was not seen in patients with at least 5 bone metastases (hazard ratio = 1.06, 95% CI 0.80–1.39). However, both subgroups were inadequately powered to reach definitive conclusions. Furthermore, the presence of concomitant nonregional lymph node or visceral metastasis was not known. Therefore a contemporary metastatic burden definition could not be considered.
The STAMPEDE trial's M1|radiotherapy comparison (arm H) also assessed the role of prostate radiotherapy with ADT (±docetaxel) in newly diagnosed mHNPC [4▪▪]. Between, 2013 and 2016, 2061 patients underwent stratified 1:1 randomization to receive ADT (±docetaxel) or prostate radiotherapy and ADT (±docetaxel). At a median follow-up of 37 months, prostate radiotherapy improved failure-free survival (FFS) (hazard ratio = 0.76, 95% CI 0.68–0.84; P < 0.001) but not overall survival (hazard ratio = 0.92, 95% CI 0.80–1.06; P = 0.266). However, in a prespecified, directionally hypothesized, subgroup analysis by metastatic burden based on the CHAARTED definition , a significant heterogeneity was noted between the low and high-burden subgroups for overall survival (interaction P = 0.0098) and FFS (interaction P = 0.002). As hypothesized in the M1|radiotherapy comparison's prespecified statistical analysis plan, overall survival (hazard ratio = 0.68, 95% CI 0.52–0.90; P = 0.007) and FFS (hazard ratio = 0.59, 95% CI 0.49–0.72; P < 0.0001) were significantly improved in the low metastatic burden subgroup (n = 819) with prostate radiotherapy and ADT (±docetaxel) over ADT (±docetaxel) alone. No such benefit was noted in the high metastatic burden subgroup (n = 1120) for overall survival (hazard ratio = 1.07, 95% CI 0.90–1.28; P = 0.420) or FFS (hazard ratio = 0.88, 95% CI 0.77–1.01; P = 0.059). An interaction was also noted for prostate cancer-specific survival (interaction P = 0.007) with a statistically significant benefit associated with prostate radiotherapy and ADT (±docetaxel) in the low metastatic burden subgroup (hazard ratio = 0.65, 95% CI 0.47–0.90) but not in the high-volume subgroup (hazard ratio = 1.10, 95% CI 0.92–1.32). Based on the results of these trials, the 2019 NCCN, EAU and ESMO guidelines recommend prostate radiotherapy and ADT as a first-line option for newly diagnosed patients with low metastatic burden disease [2,3,7].
Prostate radiotherapy schedules
In both trials, the clinical target volume incorporated the prostate gland alone (±seminal vesicles if involved). Pelvic lymph nodes were not included in target volumes. In the HORRAD trial, treatment arm patients received a conventionally fractionated dose of 70 Gy in 2 Gy fractions over 7 weeks. During the study, a schedule of 57.76 Gy in 19 fractions of 3.04 Gy, three times a week for 6 weeks was also added, but outcomes by radiotherapy schedule were not evaluated. In the STAMPEDE trial's M1|radiotherapy comparison, the treatment arm patients were nominated for one of two schedules. A weekly schedule of 36 Gy in six consecutive weekly fractions of 6 Gy was designated for 48% (n = 497) and a daily schedule of 55 Gy in 20 daily fractions of 2.75 Gy over 4 weeks was chosen for 52% (n = 535) of the patients. No heterogeneity of effect on overall survival was noted between the weekly and daily schedules (interaction P = 0.27).
The radiotherapy schedules used in these trials differ from the ones currently used in localized prostate cancer. In 2012, when the STAMPEDE M1|radiotherapy comparison was designed, the standard radiotherapy schedule (74 Gy in 37 fractions over 7.5 weeks) used at the time for localized disease was felt to be too burdensome for patients with metastatic disease. Based on an investigator survey, the two more convenient schedules were chosen. Now, with evidence of benefit from prostate radiotherapy in low metastatic burden patients, the contemporary hypofractionation schedule of 60 Gy in 20 fractions, as used for high-risk localized prostate cancer, might be preferred . Further studies will be required to explore the role of dose escalation and optimization.
Safety and adverse events
There have been concerns that hypofractionation may increase the risk of late treatment-related toxicity [9,10]. In the STAMPEDE trial, grade 3 or 4 adverse events on the RTOG scale were modest in the prostate radiotherapy arm (5%); 5% patients reported their worst acute bladder toxic effect as grade 3 or 4, and 1% reported their worst acute bowel toxic effect as grade 3 or 4; grade 5 toxic effects were not observed. Furthermore, a low incidence of grade 3 and 4 late effects was reported by patients in both control and prostate radiotherapy arms (1% control versus 4% prostate radiotherapy). No difference was seen in CTCAE grade 3 or worse in between the control group (38%) and the prostate radiotherapy group (39%); with no evidence of a difference in time to first grade 3 or worse event (hazard ratio = 1.01, 95% CI 0.87–1.16; P = 0.941). Adverse events and toxicity outcomes were not reported in the HORRAD trial.
The M1|radiotherapy comparison also evaluated symptomatic local events (SLE). This was defined as a composite endpoint evaluating urinary tract infection, new urinary catheterization, acute kidney injury, transurethral resection of the prostate, urinary tract obstruction, ureteric stent, nephrostomy, colostomy or surgery for bowel obstruction. There was no difference in the frequency of SLE between the control and prostate radiotherapy arms and no evidence of a difference in time to first SLE by treatment allocation (hazard ratio = 1.07, 95% CI 0.93–1.22; P = 0.349). However, at current follow up it is too early to rule out a beneficial effect of prostate radiotherapy for preventing SLE as these tend to occur late during disease progression [4▪▪,11].
Sequencing of systemic therapies with prostate radiotherapy
In both the trials, patients started lifelong ADT prior to radiotherapy. In the HORRAD trial, patients were started on ADT within 2 weeks of randomization and received radiotherapy within 12 weeks of starting ADT. This trial enrolled between 2004 and 2014, well before the introduction of therapies such as abiraterone, enzalutamide and radium-223. A breakdown of subsequent life-prolonging treatments received in the trial's deceased population showed no significant difference between the arms. In the prostate radiotherapy arm, the majority of patients received docetaxel (46%), whereas other life-prolonging therapies such as abiraterone (18%), cabazitaxel (9%), enzalutamide (8%) and radium-223 (3%) were used less frequently.
In the STAMPEDE arm H, patients were randomised within 12 weeks of starting ADT and commenced radiotherapy as soon as possible thereafter. Docetaxel was also permitted following its approval in the United Kingdom in December 2015: 18% of the patients received ADT and docetaxel in both arms. It was administered as six 3 weekly cycles of 75 mg/m2, with or without prednisolone 10 mg daily. In the prostate radiotherapy arm, patients received docetaxel first followed by prostate radiotherapy within 4 weeks of the last docetaxel cycle. No significant heterogeneity in outcomes was noted based on docetaxel use (interaction P = 0.63). Furthermore, there was no difference in the use of subsequent life-prolonging therapies between the two arms. In the prostate radiotherapy arm, the majority of the patients received docetaxel (33%), enzalutamide (36%) or abiraterone (20%) at progression. Optimal sequencing of systemic therapies after failure of first-line therapy remains an ongoing area of research.
Currently, an incongruity exists between the NCCN, EAU and ESMO guidelines regarding the use of early docetaxel with prostate radiotherapy. The NCCN and EAU recommend prostate radiotherapy and ADT as a first-line option, whereas ESMO has made no such distinction, recommending prostate radiotherapy and systemic therapy (ADT + docetaxel) [2,3,7]. In the STAMPEDE M1|radiotherapy comparison, 18% of the patients received prostate radiotherapy and ADT and docetaxel and no evidence of heterogeneity was found based on docetaxel use [4▪▪]. However, patients receiving docetaxel were enrolled at a later stage of the trial (post-Dec-2015) and therefore had a shorter follow-up. Emerging data from phase 3 trials evaluating prostate radiotherapy and ADT and docetaxel in high-risk localized prostate cancer suggests that the triple combination improves relapse-free survival, but the results for overall survival are immature [12–15]. The GETUG-12 and the STAMPEDE trials have demonstrated statistically significantly improved relapse-free survival but no improvement in overall survival. By contrast, the RTOG-05201 trial has reported that prostate radiotherapy and ADT and docetaxel improved both overall (hazard ratio = 0.69, 90% CI 0.49–0.97) and disease-free survival (hazard ratio = 0.76, 95% CI 0.58–0.99) over prostate radiotherapy and ADT alone . Therefore, a combination of prostate radiotherapy with ADT and early docetaxel can be the preferred first-line option in low metastatic burden if patients are fit enough for it.
The imaging modality used to evaluate M stage in both HORRAD and STAMPEDE was standard CT/MRI and 99mTc bone scan. The STAMPEDE results show that the bone metastasis number on bone scan was predictive of treatment outcome regarding radiotherapy to the prostate using CHAARTED based criteria. This raises the question of which imaging modality should be used for staging in the modern era. Use of other imaging modalities, such as68Ga-PSMA PET or whole-body MRI, to evaluate metastatic burden has become widespread in some countries but it has not been validated in large-scale randomized studies and it is not currently recommended outside a clinical trial [2,18,19]. As these modalities have a higher sensitivity, they are likely to detect more metastases than those detected by conventional imaging [20–22]. Therefore, the threshold for low metastatic burden might differ substantially depending on the imaging modality used. Further study of the clinical utility of modern imaging and its influence on the natural history of disease and treatment outcome will require validation in properly conducted studies if this uncertainty is to be overcome. Additionally, future trials could and should evaluate quantitative measures of metastatic burden. Methods currently available include the automated bone scan index or maximum standardized uptake values as predictive biomarkers to select patients for multimodal treatment. These are currently underutilized despite their proven utility [23–25]. In future, the metastatic burden criteria are likely to require further optimization as our understanding of disease burden and metastatic distribution in relation to treatment benefit improves.
Biological rationale for impact of metastatic burden on efficacy of prostate radiotherapy
The section discusses plausible biological rationale by which metastatic progression could be reduced by using multimodal strategies in patients with low metastatic burden [26–28].
Disruption of metastatic dissemination
The metastatic cascade involves a number of steps, wherein cancer cells within the prostate acquire characteristics enabling invasion and migration to distant sites through haematogenous or lymphatic routes [27–29]. In the metastatic process, cancer cells within the primary and the metastatic sites undergo spatiotemporal evolution dictated by the tumour microenvironment and systemic treatment pressures. A number of studies have used whole genome or exome sequencing to infer metastatic phylogeny in prostate cancer [30–34]. Although all clones can be traced to the primary, complex modes of progression have been demonstrated in advanced disease with primary to metastasis, metastasis to metastasis and metastasis to primary all being possible [30,31]. Furthermore, metastatic dissemination can occur in temporally separated waves during disease progression . In patients with low metastatic burden, the prostate could be the predominant source of metastatic clones, whereas in high burden, metastasis to metastasis progression may be the dominant mode of spread. In this circumstance, treating the primary would have a limited effect on metastatic progression. Therefore, treatment of the primary in mHNPC could disrupt metastatic progression in low-burden patients but not in high-burden patients. This hypothesis is supported by the observed heterogeneity in metastasis progression-free survival in the STAMPEDE trial. In the low-burden subgroup, metastatic progression was delayed in patients treated with prostate radiotherapy and systemic therapy compared with systemic therapy alone (hazard ratio = 0.80, 95% CI 0.63–1.01; restricted means survival time [RMST] difference = 3.1 months, 95% CI 0.2–6 months). No such effect was observed in the high-burden subgroup (hazard ratio = 1.10, 95% CI 0.95–1.28). Similar heterogeneity in progression-free survival between low and high metastatic burden subgroups was also observed in the HORRAD trial .
Primary derived molecular components
A number of other primary-derived components such as exosomes, cytokines and other molecules have been shown to have a tropic action ‘preparing’ distant metastatic niches [36–39]. It may be hypothesized that prostate radiotherapy disrupts release of primary derived molecular components which have been shown to work in this way. In low metastatic burden patients, it is possible that the predominant source of such cytokines may be the prostate, whereas in high metastatic burden patients, distant metastases may become the major source as disease load increases beyond a biological threshold. In such circumstances, treating the primary might lower the circulating levels of such molecules significantly in low-burden patients but not in high burden. This notion can be further interrogated using FFS, which was largely driven by PSA failure. In the low metastatic burden subgroup, a statistically significant improvement in FFS was noted (hazard ratio = 0.59, 95% CI 0.49–0.72; RMST difference = 8.6 months). This suggests that the major source of PSA was the primary tumour. However, in the high metastatic burden subgroup, no significant difference was noted (hazard ratio = 0.88, 95% CI 0.77–1.01; RMST difference = 1.5 months), suggesting that the main source of PSA was the metastatic sites and not the primary tumour. Similar heterogeneity in FFS between low and high metastatic burden subgroups was also seen in the HORRAD trial . PSA through its serine protease activity been shown to promote cell invasion and induce an osteoblastic phenotype in vitro and in vivo[40–42]. It might therefore be speculated that reducing absolute PSA levels might limit the development of new bone metastases.
Radiotherapy induces cell death and secondary release of proinflammatory cytokines, tumour associated antigens (TAA), damage-associated molecular patterns and other chemokines [43,44]. Radiotherapy also upregulates MHC-I on cancer cells, leading to the recognition of TAAs by cytotoxic T cells, enabling them to mount an antitumour response [45,46]. Therefore, prostate radiotherapy can potentially initiate a systemic, or ‘abscopal’ immune response, resulting in antitumorigenic responses in distant metastases. Whilst this is possible, there might also be a threshold beyond which the immune system is unable to cope with a high burden of disease. This might explain the ‘threshold effect’ seen with metastasis number on bone scan and response to primary radiotherapy [4▪▪].
Future trials evaluating prostate radiotherapy with checkpoint blockade may demonstrate augmented immune-mediated antitumour effects . Again, this might be ‘burden’ related: a phase III trial in metastatic castration-resistant prostate cancer (mCRPC) evaluating metastasis-directed radiotherapy (8 Gy for at least one or up to five bone fields) followed by ipilimumab suggested that the combination was only beneficial in a subgroup of patients with lower disease burden (hazard ratio = 0.74, 95% CI 0.61–0.89) [48,49]. Another phase III trial evaluating ipilimumab monotherapy without radiotherapy did not demonstrate any such effect . This suggests that radiotherapy might be required to unmask the beneficial effect of immunotherapy. Two additional case reports of mCRPC patients from these trials reported long-term complete remission of disease in patients who received combined radiotherapy and Ipilimumab . However, identification of specific patients of this type remains investigational. Currently, a phase II study is evaluating ADT in combination with SBRT and pembrolizumab with or without a TLR9 agonist in newly diagnosed oligometastatic HNPC (NCT03007732) .
Prevention of systemic treatment-induced lineage plasticity in the primary
A number of genomic studies based on prostatectomy specimens have demonstrated multifocality and intratumour heterogeneity in prostate cancer [53–56]. This heterogeneity provides an environment where specifically directed systemic therapies such as ADT/docetaxel/abiraterone can act to invoke a ‘lineage crisis’, wherein cancer cells undergo transdifferentiation or dedifferentiation to a lethal phenotype which then develops as the dominant and progressive cell type . Prostate radiotherapy could prevent such crisis from occurring in the primary, thereby preventing spatiotemporally separated waves of lethal clones emerging from the primary to propagate new metastatic sites.
Genomic and transcriptomic deifferences based on metastatic burden
A recent study conducted single-cell transcriptomic profiling of metastatic cells obtained from low and high metastatic burden breast cancer xenografts has shown that metastatic cells from low-burden tissues were different from those arising from high-burden tissues and that they had increased expression of stem cell, epithelial-to-mesenchymal transition, prosurvival, and dormancy-associated genes . On the other hand, high metastatic burden was found to be associated with increased proliferation and MYC expression. Further in-vivo evaluation showed that progression to high burden could be attenuated by treatment with dinaciclib, a cyclin-dependent kinase inhibitor. These findings support a hierarchical model for metastasis, in which burden directed systemic treatment could delay progression. Currently, genomic analysis of primary prostate cancer samples allied to systemic genomic sampling, linked to accurate and quantified image analysis is ongoing within the STAMPEDE trial. It is hoped that this will also inform whether the metastatic burden criteria can be better understood with the use of genomic markers .
Ongoing phase III trials are evaluating prostate radiotherapy linked to additional systemic treatments (docetaxel/abiraterone) and/or metastasis-directed therapy in newly diagnosed mHNPC (Table 2). The PEACE-1 trial (NCT01957436) has completed its enrolment and the primary analysis is expected to be conducted in 2019 . It has randomized de-novo mHNPC patients in a 1:1:1:1 ratio to arm A (ADT + docetaxel), arm B (ADT + docetaxel + abiraterone), arm C (ADT + docetaxel + prostate radiotherapy) or arm D (ADT + docetaxel + abiraterone + prostate radiotherapy). This trial will provide new data regarding the benefit of adding abiraterone plus-minus docetaxel to prostate radiotherapy and ADT. Another trial, the SWOG 1802 (NCT03678025) is evaluating the efficacy of local treatment in de-novo mHNPC . It is a two-stage trial; in the first step, patients who are eligible to undergo radical prostatectomy are registered to receive best systemic therapy (BST) for at least 28 weeks. In the second step, patients who do not progress on BST for at least 28 weeks undergo a stratified randomization in a 1:1 ratio to BST or BST and radical prostatectomy/radiotherapy. Data from the phase 2 suggests that this approach enriches patients with low metastatic burden (78% low burden) . However, one could reason that patients who do not respond to systemic therapy alone would be the ones who would require treatment of the primary as well. Therefore, excluding patients with low-burden disease from treatment of the primary based on response to systemic therapy is investigational.
The planned arm M comparison within the STAMPEDE multiarm multistage trial will also evaluate the added value of metastasis-directed therapy and prostate radiotherapy in low-burden metastatic patients. This study has a recruitment target of approximately 2200 patients and it will combine standard treatment including radiotherapy to the prostate, with a randomization to receive SABR for men with metastases in extrapelvic lymph nodes and/or bone metastases up to a maximum of five lesions. It is expected that the arm M comparison of the STAMPEDE trial will commence in early 2020.
Prostate radiotherapy with ADT improves survival and is a recommended first-line option for men presenting with low metastatic burden prostate cancer. Currently, the recommended criteria to characterize metastatic burden is based on conventional imaging (99mTc bone scans and CT/MRI) and low burden can be defined as patients with only nonregional lymph nodes or less than 4 bone metastasis based (±lymph node) and no visceral metastasis on conventional imaging. Defining metastatic burden based on newer imaging modalities such as PSMA PET or whole body-MRI is currently investigational. Emerging data suggest that heterogeneity in metastatic disease and progression demands a multimodal approach which integrates local, systemic and possibly metastasis-directed therapy to achieve effective oncological control. On-going trials evaluating prostate radiotherapy with metastasis-directed therapy plus-minus other systemic agents will provide further data in the future which will establish the utility of this approach.
Financial support and sponsorship
The project was supported by the National Institute for Health Research Royal Marsden and Institute for Cancer Research Biomedical Research Centre.
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