Until recently, men with metastatic prostate cancer were commenced on androgen deprivation therapy at diagnosis, followed by sequential lines of treatment with the development of castration resistance. However, the results of recent clinical trials, which revealed that the addition of radiotherapy to the prostate to a dose of 55 to 60 Gy in 20 fractions over 4 weeks in patients with low-volume metastatic hormone-sensitive prostate cancer, in addition to androgen deprivation therapy and another systemic treatment option, either docetaxel, abiraterone, enzalutamide, or apalutamide, has led to a paradigm change in the management of this disease.
Androgen deprivation therapy (ADT) (either orchiectomy or medically with gonadotropin-releasing hormone agonists or antagonists) has remained the mainstay of the management of metastatic prostate cancer since the discovery of its effect in prostate cancer by Huggins et al.1 in 1941. Androgen deprivation therapy has a response rate of nearly 80%, but all patients will eventually progress to a state of castration resistance, with a median duration of response of approximately 18 to 24 months.2
Until recently, men with metastatic prostate cancer were commenced on ADT at diagnosis, followed by sequential lines of treatment with the development of castration resistance. Docetaxel was the first therapeutic agent to improve overall survival (OS) in metastatic castration-resistant prostate cancer3 Subsequently, another taxane, cabazitaxel, and the antiandrogens, abiraterone and enzalutamide, demonstrated gains in OS in this setting.4–6 The radioisotope radium-223 and immunotherapy with Sipuleucel-T also have proven efficacy in metastatic castration-resistant prostate cancer.7,8
However, based on the principle of proportional reduction of hazards, where earlier initiation of a therapeutic agent would lead to larger absolute gains in survival, some of these agents were tested in the hormone-sensitive setting. These trials revealed that the addition of either docetaxel or one of the novel antiandrogens, abiraterone, enzalutamide, or apalutamide, to ADT improves OS, leading to a paradigm change in the management of metastatic hormone-sensitive prostate cancer (mHSPC).9–13
Local Treatment in Metastatic Disease
With a few exceptions, such as germ cell tumors and colorectal cancer with resectable liver metastases, metastatic disease in many solid organ cancers is incurable. The objective of treatment in metastatic cancer has largely focused on systemic treatment with a view to improving symptoms and prolonging survival while maintaining quality of life. In this context, local treatment of the primary tumor is undertaken only if there are symptoms attributable to it such as pain, bleeding, or obstruction.
Classically, the development of metastatic spread has been described as an orderly 1-dimensional sequence of local invasion, intravasation, survival in the circulation, extravasation, and colonization.14 However, it has long been recognized that the primary tumor prepares the “premetastatic niche” much before the dissemination of tumor cells into circulation, by producing signaling factors and recruiting bone marrow–derived progenitor cells to the distant homing site.15 These bone marrow–derived progenitor cells prepare a permissive milieu for the circulating tumor cells to lodge and proliferate.15 The primary tumor also recruits myeloid derived suppressor cells, which protect the tumor cells from the immune system.16 Circulatory tumor cells may reinfiltrate an established primary tumor, enriching the tumor with more aggressive malignant cells.17 In prostate cancer, the spread of metastases from the primary tumor can occur in temporally separated waves.18 Moreover, resistant clones that persist in the primary tumor after systemic treatment may undergo molecular alterations that drive them to a state of castration resistance.19
Despite its strong biological rationale, treatment of the primary tumor in metastatic cancer has had mixed success in terms of translating into tangible gains in survival. In renal cell carcinoma, cytoreductive nephrectomy was shown to improve OS in the interferon era.20,21 However, with the advent of tyrosine kinase inhibitors, there was no gain in OS with nephrectomy as shown by the results of the CARMENA trial, and a large phase III randomized trial evaluating the role of mastectomy in metastatic breast cancer also failed to show improvements in OS.22,23 In extensive stage small cell lung cancer, radiotherapy (RT) to the primary tumor in patients responding to palliative chemotherapy improved OS.24 Similarly in ovarian cancer, maximal cytoreductive surgery is of proven benefit in patients receiving platinum-based chemotherapy.25
Radiotherapy to the Prostate in mHSPC
Based on evidence of benefit from nonrandomized registry-based studies, RT to the prostate was offered by some clinicians to patients with mHSPC. The largest of these was an analysis of 6382 mHSPC patients in the National Cancer Database.26 In this study, 538 patients (8%) received prostate RT, and these patients had a significant improvement in OS on multivariate and propensity score–matched analysis (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.55–71; P < 0.001).26
The HORRAD trial was the first randomized study to report on the outcomes of addition of local radiation therapy in mHSPC.27 A total of 432 patients with histologically confirmed prostate adenocarcinoma and bone metastases on technetium-99m bone scan were randomized between ADT alone and ADT along with radiation to the prostate. Radiotherapy was delivered to the prostate gland and base of seminal vesicles with a 1-cm margin to a dose of 70 Gy in 35 fractions. A hypofractionated regimen of 57.76 Gy in 19 fractions was also permitted. At a median follow-up of 46 months, the primary endpoint OS did not differ between the treatment groups (HR, 0.90; 95% CI, 0.70–1.14). Biochemical disease-free survival was also not significant, even though there was a suggestion in favor of RT (HR 0.86; 95% CI 0.69–1.08 l; P = 0.2). However, an unplanned subgroup analysis pointed toward a possible benefit in selected “low volume” disease patients with less than five metastases (OS HR, 0.68; 95% CI, 0.42–1.10). The lack of benefit in the whole population could be due to the preponderance of patients with “high-volume” metastases in the study cohort. In addition, data on visceral metastases were not available, possibly underestimating the true disease burden.
The Systemic Therapy in Advancing and Metastatic Prostate cancer (STAMPEDE) trial also investigated the benefit of adding RT to the primary in this setting.28 More than 2000 patient enrolled in this multistage multiarm study were randomized to receive RT to the prostate gland in addition to standard systemic treatment versus standard systemic therapy alone with OS as the primary endpoint. Initially, all patients received ADT as standard-of-care system therapy, but addition of docetaxel to ADT was permitted once this became standard of care. At randomization, patients were stratified by World Health Organization performance status, age, nodal involvement, planned ADT use, docetaxel use, aspirin, and no steroidal anti-inflammatory drug use. Radiotherapy was delivered to the prostate gland with a margin of 10 mm (8 mm posteriorly). Two fractionation schedules were permitted—either 55 Gy in 20 fractions over 4 weeks or 36 Gy in 6 weekly fractions.
Before the analysis of its results, based on external data that suggested the effect of prostate RT will be more pronounced in patients with low-volume metastatic disease, the STAMPEDE investigators decided to perform a subgroup analysis by metastatic disease burden, in addition to the preplanned analysis by fractionation regimen. As in the CHAARTED trial, high-volume disease was defined as the presence of 4 or more bone metastases with at least 1 deposit outside the vertebral bodies and pelvis or visceral metastases or both.
A little above 40% (819/1939) of evaluable patients had low-volume disease, and there was near-equal selection of fractionation regimen (52% daily regimen vs 48% weekly regimen). Eighteen percent of patients received 6 cycles of docetaxel. There was no significant difference in OS in the whole study population (stratified log-rank test P = 0·451; HR, 0.92; 95% CI, 0.80–1.06; P = 0.266), although failure-free survival (FFS) was improved by the addition of RT (HR, 0.76; 95% CI, 0.68–0.84; P < 0.0001). On subgroup analysis, patients with low metastatic burden (40%) had an improvement in both FFS (HR, 0.59; 95% CI, 0.49–0.72; P < 0.0001) and OS (HR, 0.68; 95% CI, 0.52–0.90; P = 0.007).
Although there was no difference in OS on subgroup analysis by fractionation schedule, there was some evidence of heterogeneity in the effect on FFS in favor of the daily fractionation regimen. While only 18% of patients received upfront docetaxel with ADT, on exploratory subgroup analysis there was no suggestion of any interaction with prostate RT. Furthermore, RT was well tolerated, with only 5% or fewer acute and late grade 3 or more adverse events.
A meta-analysis of both these trials was performed by the Systemic Treatment Options for Cancer of Prostate collaborators.29 The group employed the framework of prospective adaptive meta-analysis (FAME) to synthesize the evidence. The eligible trials, review methods, outcome definitions, and subgroups were all prospectively specified before the publication of trial results.30 Subgroup analyses were performed by Gleason score, T stage, performance status, and metastatic disease burden. Because the HORRAD trial did not collect data on visceral metastases and data on bone deposits were only categorized as less than 5, 5 to 15, and more than 15, it was not possible to use the STAMPEDE definition of low-volume disease in this analysis.
In unselected patients, there was no significant difference in OS (HR, 0.92; 95% CI, 0.81–1.04; P = 0.195) with addition of RT to ADT. As in the original trials, FFS was significantly improved by the addition of RT with an absolute gain of nearly 10% in 3-year FFS (HR, 0.76; 95% CI, 0.69–0.84; P < 0.001). However, on prespecified subgroup analysis, it was shown that the effect of prostate RT varied with disease burden for OS (interaction HR, 1.47; 95% CI, 1.11–1.94; P = 0.007) and FFS (interaction HR, 1.35; 95% CI, 1.10–1.66; P = 0.004). Indeed, in men with fewer than 5 metastases, the addition of RT to ADT resulted in an absolute improvement in OS of 7% at 3 years (HR, 0.73; 95% CI, 0.58–0.92; P = 0.007).
If the primary mechanism of RT in this setting is eradication of disease in the primary tumor, cytoreductive prostatectomy should potentially improve survival in mHSPC. But the effect of RT is not limited to local control alone and includes potential activation of the antitumor immune response.28 As such, the benefit of RT cannot be readily extrapolated to surgery.
The evidence supporting cytoreductive prostatectomy in mHSPC is largely limited to nonrandomized studies. A Surveillance Epidemiology and End Results database study of a cohort of mHSPC showed that 5-year OS was significantly higher in patients treated with prostatectomy (67.4%) or brachytherapy (52.6%) compared with no local treatment (22.5%).31 Similarly, a study by Parikh et al.32 of patients in the National Cancer Database reported 5-year OS of 51.4% for prostatectomy in comparison to and 17.1% in patients receiving no local treatment. The major limitations of these studies include lack of data on salvage or adjuvant radiation treatment and case selection bias.
However, several trials are now underway to evaluate the role of cytoreductive prostatectomy in this setting. The TRoMbone (Testing Radical prostatectomy in men with prostate cancer and oligometastases to the bone) is a feasibility study comparing the addition of prostatectomy with pelvic lymph node dissection to standard-of-care treatment in mHSPC patients.33 Another phase III trial by the US South West Oncology Group 1802 evaluates the addition of local treatment of the prostate to standard systemic therapy. This study is flexible in allowing either RT or prostatectomy as local treatment. Two more randomized trials testing the benefit of prostatectomy in this setting are the German g-RAMMP trial and the North American SIMCAP trial.
The common adverse effects of prostatectomy include urinary incontinence, erectile dysfunction, bladder neck contracture, lymphocele, and anastomotic leak.34,35 In a multi-institutional small retrospective analysis of 106 patients, the overall complication rates of cytoreductive prostatectomy were comparable to standard radical prostatectomy.36 However, in another large series of 1173 men, patients who underwent cytoreductive prostatectomy had more complications.37 Notably, they had longer hospital stay and higher hospital costs.37 Therefore, until more robust data of efficacy and safety emerge, cytoreductive prostatectomy should not be performed outside a clinical trial.
Treating the Primary: The Current Standard of Care
The results of the STAMPEDE trial and that of the Systemic Treatment Options for Cancer of Prostate meta-analysis provide robust evidence to recommend RT to the prostate in addition to standard systemic treatment in patients with low-volume mHSPC, despite some inconsistency in characterizing disease burden.28,29 Although not part of the definition in the meta-analysis, patients with visceral metastases should be considered as having high-volume disease without regard to the number of bone deposits. In our opinion, these patients should not be offered RT to the prostate gland as its benefit is uncertain in this group of patients, and systemic therapy is likely to be key to their management.
There is also some uncertainty in the benefit of RT in patients with 5 or more bone deposits within the pelvis and/or vertebral bodies (and without visceral metastases) as these patients were categorized as high-volume disease in the meta-analysis and as having low-volume patients in the STAMPEDE trial. In essence, current evidence shows that the effect of RT to the prostate gland diminishes as the burden of disease increases, and clinicians should keep this principle in mind when considering treatment options.
More advanced and sensitive modalities such as prostate-specific membrane antigen (PSMA) PET may detect a higher volume of disease than with conventional imaging.38 This brings a degree of uncertainty into the clinical pathway. Nevertheless, patients with low-volume disease on bone scintigraphy and CT scans, but high-volume disease on PSMA-PET should be offered RT to the prostate gland because both trials used conventional imaging techniques to characterize disease burden.
And what of systemic therapies in addition to ADT in patients with low-volume disease? Although there was a suggestion from the CHAARTED trial that the benefit of docetaxel would be limited to patients with high-volume disease, the recent subgroup analysis of the much larger STAMPEDE trial did not show any evidence of heterogeneity of treatment effect with disease burden for docetaxel.39,40 The STAMPEDE and LATITUDE trials have also demonstrated an improvement in OS with the addition of abiraterone to ADT in mHSPC without regard to disease burden.10 The same holds true for enzalutamide and apalutamide.11,12 The heterogeneity of treatment effect with disease burden is uniquely limited to prostate RT in mHSPC, in contrast to the novel systemic treatment options. As such, ADT with either docetaxel, enzalutamide, or apalutamide in addition to prostate RT should be now considered as standard of care for patients with low-volume disease while we await the results of PEACE I, which will compare combinations of docetaxel, abiraterone, and RT to the prostate gland (NCT01957436).
Although subtle differences existed, there was broad concordance in the RT protocols in the 2 trials, and the prostate gland with a 10-mm margin (8 mm posteriorly) can be recommended as the planning target volume in this setting. There is a lack of consensus on the inclusion of pelvic lymph nodes in the clinical target volume of localized nonmetastatic prostate cancer patients treated with external beam RT.41 Patients with mHSPC may have a higher prevalence of clinical and occult lymph node metastases than those with localized disease, and there is strong rationale to include the pelvic lymph nodes in the clinical target volume of patients receiving prostate RT. This is unlikely to be tested in a future clinical trial, but because there is no unequivocal evidence of benefit even in localized disease, pelvic nodal RT cannot be recommended in mHSPC.
There is wide variety in the choice of fractionation regimen with 4 schedules: 70 Gy in 35 fractions over 7 weeks, 57.75 Gy in 19 fractions over 4 weeks, 55 Gy in 20 fractions over 5 weeks, and 36 Gy in 6 weekly fractions being used in the 2 trials. The STAMPEDE trial had the largest number of patients, and there was some suggestion of superiority on FFS with the use of the 55 Gy in 20-fraction regimen over the weekly fractionation regimen. With the publication of the CHHIP trial results, 60 Gy in 20 fractions has now become standard-of-care regimen for radical external beam RT in localized prostate cancer in the United Kingdom and many other countries.42 Furthermore, the CHHIP trial also showed that long-term serious adverse effects are rare with this schedule, and we have no hesitation in recommending the regimen of 60 Gy in 20 fractions over 4 weeks in mHSPC as well.
There are at least 2 randomized clinical trials that are evaluating the addition of cytoreductive prostatectomy to standard systemic therapy in this setting. With no randomization to prostate-only RT in these trials, if superiority of prostatectomy is proven, it would add another alternative local therapeutic option in mHSPC. Because primary tumors are likely to be more locally advanced in patients with metastatic prostate cancer, the adverse effects of surgery, especially urinary incontinence and sexual dysfunction, would need to be closely assessed in these patients. As in localized disease, patients with preexisting urinary and bowel symptoms may find prostatectomy a more suitable option than RT, with the choice eventually being determined upon a consideration of adverse effects and patients' preference.
Trials of stereotactic body RT in localized prostate cancer are likely to report survival outcomes soon.43 The convenience of shorter treatment courses with low toxicity would mean that this option is likely to become the treatment of choice in men with localized prostate cancer being offered external beam RT. Once stereotactic RT to the prostate gland has been proven to be effective in localized disease, we believe that stereotactic body RT could be considered in mHSPC.
Although not entirely synonymous with oligometastatic disease, most patients with low burden mHSPC would also fit the definition of oligometastatic disease. There are compelling nonrandomized data that have ignited an enthusiasm to answer the question of ablative RT to primary and oligometastases within phase III randomized clinical trials.44,45 Newer imaging modalities such as PSMA PET are likely to offer greater precision in determining disease spread, and there would be considerable interest in delivering ablative doses of RT to both the primary tumor and nodal and systemic metastases in these patients.
There is robust evidence in favor of RT to the prostate to a dose of 55 to 60 Gy in 20 fractions over 4 weeks in patients with low-volume mHSPC in addition to ADT and another systemic treatment option, either docetaxel, abiraterone, enzalutamide, or apalutamide. However, compared with the resources required for the delivery of many systemic treatments, local prostate treatment with external beam RT provides an economically viable, low-toxicity treatment, which should be deliverable within all health care models.46 In some countries, this will require initial investment in infrastructure, but given the significant gains that can be made for men with prostate cancer and beyond, this should be a cancer health care priority. We have the opportunity to improve the outcomes of these men across the globe.
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