Oligometastatic bone disease in prostate cancer patients treated on the TROG 03.04 RADAR trial

Radiotherapy and Oncology xxx (2016) xxx–xxx

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Original article

Oligometastatic bone disease in prostate cancer patients treated on the TROG 03.04 RADAR trial Swetha Sridharan a, Allison Steigler b, Nigel A. Spry c, David Joseph c, David S. Lamb d, John H. Matthews e, Chris Atkinson f, Keen-Hun Tai g, Gillian Duchesne g, David Christie h, John Attia b,i, Elizabeth G. Holliday b,i, James W. Denham b,⇑ a

Calvary Mater Newcastle, Waratah; b School of Medicine and Public Health, University of Newcastle; c Sir Charles Gairdner Hospital, Perth, Australia; d Wellington Cancer Centre; Auckland Hospital; f St Georges Cancer Care Centre, Christchurch, New Zealand; g Peter MacCallum Cancer Centre, Melbourne; h Genesiscare, Tugun; and i Hunter Medical Research Institute, Newcastle, Australia

e

a r t i c l e

i n f o

Article history: Received 23 May 2016 Received in revised form 20 July 2016 Accepted 24 July 2016 Available online xxxx Keywords: Oligometastasis Prostate cancer Bone metastasis Androgen suppression Radiotherapy

a b s t r a c t Background: It remains unclear whether eradication of oligometastases by stereotactic body radiation therapy or other means will result in cure or prolongation of survival in some cases, or merely provide palliation. We address this issue with prospectively collected progression and treatment data from the TROG 03.04 RADAR randomised controlled trial for men with locally advanced prostate cancer (PC). Methods: Three Fine and Gray competing risk survival models with time-dependent covariates were used to determine whether metastatic progression status at first diagnosis of bony metastases, i.e. number of bony sites involved and presence of prior or simultaneous other sites of progression, impacts on prostate cancer-specific mortality (PCSM) when adjusted for baseline prognostic factors and allocated primary treatment. Results: Between 2003 and 2014, 176 of the 1071 subjects developed bone metastases, 152 developed other sites of progression and 91 died of PC. All subjects received secondary treatment using androgen suppression but none received extirpative treatments. The three models found evidence: 1 – of a clear prognostic gradient according to number of bony metastatic sites; 2 – that other sites of progression contributed to PCSM to a lesser extent than bone progression; and 3 – that further bony metastatic progression in men with up to 3 bony metastases had a major impact on PCSM. Conclusion: Randomised trials are essential to determine the value of extirpative treatment for oligometastatic bony metastases due to PC. Ó 2016 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2016) xxx–xxx

Prostate cancer is the most common cancer in men and when death is attributable to prostate carcinoma, metastatic disease is invariably present. In 1995 Hellman and Weichselbaum proposed that oligometastatic presentations are either a transition state between localised cancer and disseminated metastatic cancer, in which case the eradication of oligometastases could result in cure, or that they are an early manifestation of a widespread largely subclinical metastatic process that would not result in cure by eradicative treatments [1]. Since then improvements in therapeutic techniques have greatly increased interest in oligometastatic disease as a treatable entity. One example is the emergence of stereotactic body radiation therapy, which has enabled ablative doses of radiotherapy to be delivered safely to patients with low volume ⇑ Corresponding author at: University of Newcastle, Locked Bag 1, Hunter Region Mail Centre, NSW 2310, Australia. E-mail address: [email protected] (J.W. Denham).

metastatic disease [2]. However evidence is yet to emerge that progression of the metastatic process is altered by the ablation of apparently limited metastatic disease [3]. In fact the natural history of oligometastatic prostatic bone disease is poorly described in the literature and is limited by a paucity of prospectively collected data. In this post-hoc secondary substudy of the TROG 03.04 RADAR trial for men with locally advanced non-metastatic prostate cancer, we present prospectively collected data from all participants in order to determine the natural history of subsequent bony metastatic disease managed with androgen suppression (AS) ± anti-androgens ± palliative radiotherapy doses. Outcomes were analysed taking into account the long known prognostic characteristic of bone metastases, i.e. number of bony metastases at first diagnosis by bone scan, X-ray or CT scan following biochemical relapse or clinical suspicion of metastatic disease [4]. In this report we study the impact of both bone metastases (solitary,

http://dx.doi.org/10.1016/j.radonc.2016.07.021 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Sridharan S et al. Oligometastatic bone disease in prostate cancer patients treated on the TROG 03.04 RADAR trial. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.07.021

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Bone oligometastases in prostate cancer

2–3 or >3 metastases) and the presence of non-bony disease progression on prostate cancer-specific mortality. Methods The TROG 03.04 RADAR trial is a randomised 2X2 factorial trial investigating the role of adjuvant AS and zoledronic acid (Z) in patients with intermediate and high risk prostate cancer. A total of 1071 patients were enrolled between 2003 and 2007. Details of the trial were presented in Lancet Oncology in 2012 [5] and 2014 [6]and in Radiotherapy and Oncology in 2012 [7] and 2015 [8]. Participants with histologically confirmed adenocarcinoma of the prostate without lymph node or systemic metastases and with primary tumours T stage 2b and above, or T stage 2a, Gleason score (GS) P 7 and baseline PSA levels P 10 ng/mL were eligible to participate after providing informed consent. All received 6 months of leuprorelin (22.5 mg i.m. 3 monthly) commencing at randomisation, 5 months before RT to the prostate and seminal vesicles, but excluding pelvic lymph nodes. In the control arm (short term AS [STAS]) participants received no further treatment. In the second AS only treatment arm participants received an additional 12 months of adjuvant leuprorelin (22.5 mg i.m. 3 monthly) (intermediate term AS [ITAS]). Participants allocated to the two bisphosphonate treatment arms received Z 4 mgs i.v. every 3 months for 18 months starting at randomisation with STAS (STAS + Z) or with ITAS (ITAS + Z). Participants were routinely followed up at 3 monthly intervals to 30 months, then 6 monthly to 60 months, then annually with PSA measures and clinical examinations. If signs of progression were observed, clinicians were encouraged to follow a set of relapse diagnosis guidelines which recommended that secondary therapeutic intervention (STI) be delayed until clinical progression occurred or until the PSA reached 20 lg/L. Investigations such as biopsy, CT scan, chest X-ray and bone scintigraphy were performed at the treating clinician’s discretion. The protocol did not mandate the type of STI administered on progression. All endpoint imaging reports and causes of death were monitored at source and reviewed centrally by a group of senior clinician investigators, blinded to patient and treatment identity. In this secondary analysis endpoint data to 28th February 2014 were retrospectively re-reviewed by SS and JWD to confirm the timing, site and number of bone metastases shown on whole body bone scans and computerised tomography. Participants were classified according to number of bone sites involved at first diagnosis of metastases. As imaging reports were not detailed enough to be reproducible for men with more than four bone metastases, bone metastases (BM) were defined as solitary, 2–3 sites or >3 sites, or else no BM if not diagnosed during follow-up. In addition the timing and sites of further bony progression metastatic deposits were recorded in those presenting with solitary and 2–3 metastases. Other sites of progression documented included local prostatic progression and all metastatic progressions in soft tissues ie including in lymph nodes, liver, lung, adrenal, brain, etc. Statistical methods The endpoint for this study was prostate cancer-specific mortality (PCSM). Death was attributed to prostate cancer if it occurred in the context of progressive metastatic disease or recurrent primary cancer causing urinary obstruction, without reasonable alternative unrelated causes. Competing risks were defined as deaths due to other or unknown causes. Three Fine and Gray competing risk models [9] for PCSM were used to determine the impact of number of bone metastases: (1) at first presentation, (2) with or without non-bony progression at, or prior to, first presentation, and (3)

for men with <4 bone sites, at subsequent bony progression. Bony metastases were treated as a time-dependent categorical covariate. In Model 1 this was defined as a 4-level covariate (no BM, solitary BM [reference category], 2–3 BM sites, >3 BM sites); in Model 2 as an 8-level covariate (Model 1 covariate ± non-bony progression, with solitary BM only as reference category); and in Model 3 as a 4-level covariate (no BM, solitary BM without further bony progression [reference category], 2–3 BM sites without further bony progression, solitary or 2–3 BM sites plus further bony progression). All models were adjusted for the baseline Gleason score (67 [reference category], >7), T stage (T2 [reference category], T3/4), PSA (log-transformed), trial arm (STAS [reference category], STAS + Z, ITAS, ITAS + Z), and age. Since these were secondary analyses, a significance level of 0.05 was used for each analysis.

Results Median follow up for the 1071 participants was 7
4 years at data closeout on 28 February 2014. A total of 243 deaths were reported, 91 from prostate cancer (PC) and 152 from other causes. Bone metastases were identified in 176 subjects of whom 83/176 (47%) died of PC, 16/176 (9%) died of other causes and 77/176 (44%) remained alive at last follow-up. All participants who developed bony metastases received secondary therapeutic intervention (STI) using either continuous or intermittent androgen suppression. In addition 77 participants were treated with modest doses of palliative radiotherapy at diagnosis of bone metastasis or when symptoms developed. In the 176 men diagnosed with bone metastases, 45 presented with a solitary metastasis, 49 had 2–3 sites of metastases and 82 had greater than 3 sites. Non-bony progression was also diagnosed in 78/176 (44%) of men at or prior to first presentation of bone metastases. Table 1 enables some insight into the prognostic features at baseline that were associated with subsequent metastatic progression status when bone metastases were first diagnosed. As anticipated, high stage and high Gleason score tumours were more likely to develop bone metastases, however there did not appear to be any association with the number of bone sites at time of diagnosis for these high risk tumours. Of the four trial arms, participants treated on the STAS + Z arm were of the most likely to develop bone metastases. Results from the three multivariable models for PCSM presented in Table 2 show a clear prognostic gradient according to the extent of progression involved. In all models tumour stage was a significant, independent prognostic factor for PCSM. However none of the other baseline covariates (including Gleason score, PSA, age and treatment arm) was significantly associated with PCSM. In Model 1, compared to those with solitary BM, the risk of PCSM was decreased for men with no BM (SHR 0.02, 95% CI 0.01–0.07, p < 0.001) and increased for men presenting with 2–3 BM sites (SHR 2.32, 95% CI 1.15–4.70, p = 0.019) and >3 BM sites (SHR 4.98, 95% CI 2.57–9.67, p < 0.001). Furthermore the PCSM risk was increased for >3 BM sites when compared to 2–3 BM sites (SHR 2.14, 95% CI [1.27–3.62], p = 0.004). Model 2 demonstrates that the diagnosis of non-bony progression at or prior to bone metastases was also associated with a modest increase in PCSM. For men with >3 BM sites and non-bony progression, this increase was significant compared to those with >3 BM sites only (SHR 2.23, 95% CI 1.29–3.87, p = 0.004). Model 3 shows the impact of the diagnosis of subsequent bone progression following solitary or 2–3 BM sites. Men who experienced further bony progression had a significantly increased risk of PC death compared to men with a solitary BM (SHR 21.60, 95% CI 6.73–69.32, p < 0.001) as well as to those with 2–3 BM sites (SHR 4.45, 95%CI 1.66–11.95, p = 0.003). The adjusted PCSM cumulative incidence graphs (i.e. averaged across

Please cite this article in press as: Sridharan S et al. Oligometastatic bone disease in prostate cancer patients treated on the TROG 03.04 RADAR trial. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.07.021

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S. Sridharan et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx Table 1 Important baseline prognostic factors and their relationships with metastatic progression status. Metastatic progression status

Bone metastases

Number of bone sites at first diagnosis

No

Yes

Solitary

2–3 sites

>3 sites

895 (83.6) 831 (77.6) 64 (6.0)

176 (16.4) 98 (9.2) 78 (7.3)

45 (4.2) 28 (2.6) 17 (1.6)

49 (4.6) 27 (2.5) 22 (2.1)

82 (7.7) 43 (4.0) 39 (3.6)

Baseline factors T stage: T2 T3/T4

594 (55.5) 301 (28.1)

86 (8.0) 90 (8.4)

18 (1.7) 27 (2.5)

19 (1.8) 30 (2.8)

49 (4.6) 33 (3.1)

Gleason score 67 >7

622 (58.1) 273 (25.5)

78 (7.3) 98 (9.2)

19 (1.8) 26 (2.4)

25 (2.3) 24 (2.2)

34 (3.2) 48 (4.5)

Total number diagnosed Non-bone progression* present prior to or at time of first bone metastases

No Yes

PSA ng/ml, median (IQR)

14.0 (9.1–23.0)

19.0 (12.0–33.4)

21.0 (16.0–37.0)

18.0 (10.9–36.0)

17.8 (11.7–27.5)

Age years, median (IQR)

69.1 (63.9–73.0)

68.1 (61.7–73.0)

64.2 (59.8–71.4)

68.9 (61.9–74.2)

69.1 (63.3–73.1)

Allocated treatment: STAS STAS + Z ITAS ITAS + Z

222 211 231 231

46 57 37 36

15 (1.4) 15 (1.4) 4 (0.4) 11 (1.0)

8 (0.7) 17 (1.6) 16 (1.5) 8 (0.7)

23 25 17 17

(20.7) (19.7) (21.6) (21.6)

(4.3) (5.3) (3.5) (3.4)

(2.1) (2.3) (1.6) (1.6)

Data are n (%) unless otherwise stated. Percentages for each categorical covariate represent proportions of the total 1071 participants. Abbreviations: STAS, short term androgen suppression; ITAS, intermediate term androgen suppression; Z, zoledronate; IQR, interquartile range; PSA, prostate-specific antigen. * Local, nodal or soft tissue progression.

Table 2 Sub-hazard ratios for time to prostate cancer-specific mortality from randomisation according to number of bone metastases in multivariable models adjusted for baseline age, tumour stage, Gleason score, PSA, and trial arm. Adjusted SHR*

95% CI

p-Value

Model 1y (n = 1071) No BM Solitary BM 2–3 BM sites >3 BM sites

0.02 1 2.32 4.98

0.01–0.07

<0.001

1.15–4.70 2.57–9.67

0.019 <0.001

Model 2y,à (n = 1071) No clinical progression No BM + other progression Solitary BM only Solitary BM + other progression 2–3 BM sites only 2–3 BM sites + other progression >3 BM sites only >3 BM sites + other progression

0.00 0.60 1 1.15 2.06 2.28 3.32 7.41

0.00–0.00 0.23–1.53

<0.001 0.28

0.35–3.82 0.90–4.72 1.00–5.18 1.61–6.83 3.51–15.65

0.81 0.09 0.05 0.001 <0.001

Model 3y,§ (n = 989) No BM Solitary BM not progressing 2–3 BM sites not progressing Further bone progression

0.10 1 4.85 21.60

0.02–0.43

0.002

1.14–20.58 6.73–69.32

0.032 <0.001

Abbreviations: SHR, sub-hazard ratio; CI, confidence interval; BM, bone metastases; STAS, short-term (6 months) androgen suppression and radiotherapy; ITAS, intermediateterm (18 months) androgen suppression and radiotherapy; Z, zoledronic acid. * Reference group: solitary bone metastases. y Multivariable competing risks models: number of bone metastases (time-dependent covariate), age (years, continuous), tumour stage (T2, T3/T4), Gleason score (67, >7), PSA (continuous), trial arm (STAS, STAS + Z, ITAS, ITAS + Z). à Other progression defined as progression at non-bony sites (i.e. local, nodal or soft tissue) diagnosed prior to or at time of first appearance of bone metastases. § The subgroup of men diagnosed with >3 BM sites were excluded from this model due to the difficulty in determining if further bone progression had occurred.

the covariates) for these three models are shown in Figs. 1–3 respectively.

Discussion To our knowledge this is the first study in the literature to report the natural history of oligo-metastatic disease in bone using prospectively collected data for men with prostate cancer, whose bone metastases have been managed definitively with androgen suppression therapy and in some cases by palliative doses of radiotherapy. The results from our study indicate that patients with oli-

gometastatic bone disease either at one site alone or 2 to 3 sites at the time of first diagnosis of metastases experience longer time to prostate cancer-specific mortality than patients who are diagnosed with 4 or more bone metastases. Importantly this prognostic gradient persists in spite of the presence of other non-bony sites of progression, as well as the absence of attempts to prolong remission by applying ablative therapies, such as stereotactic radiotherapy. However the study does not indicate whether these oligometastases are merely early expressions of a more widespread phenomenon or whether they differ biologically from the metastases that participate in more numerous metastatic presentations [3].

Please cite this article in press as: Sridharan S et al. Oligometastatic bone disease in prostate cancer patients treated on the TROG 03.04 RADAR trial. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.07.021

Bone oligometastases in prostate cancer 1.0

Cumulative incidence of prostate cancer-specific mortality

Cumulative incidence of prostate cancer-specific mortality

4

0.8 0.6 0.4 0.2 0.0 0

12

24

36

48

60

72

1.0 0.8 0.6 0.4 0.2 0.0 0

84

12

36

48

60

72

84

877

690

Number at risk

Number at risk 1071

1052

1034

1004

961

no BM 2-3 BM sites

933

877

690

1.0 0.8 0.6 0.4 0.2 0.0 0

12

24

36

48

60

72

84

877

690

Time from randomisation (months)

Number at risk 1071

1052

1034

1004

no clinical progression >3 BM sites only solitary BM only 2-3 BM sites only >3 BM sites only

961

933

1071

1052

1034

1004

no BM 2-3 BM sites

solitary BM further BM

Fig. 1. Evidence of a prostate cancer-specific mortality gradient in men with solitary, two or three, and more than three bony metastatic presentations (n = 1071). Abbreviations: BM, bony metastasis.

Cumulative incidence of prostate cancer-specific mortality

24

Time from randomisation (months)

Time from randomisation (months)

non-BM only+ non-BM >3 BM sites solitary BM + non-BM 2-3 BM sites + non-BM >3 BM sites + non-BM

Fig. 2. Evidence that non-bony sites of progression at or prior to diagnosis of bony metastasis also contribute to the prostate cancer-specific mortality gradient (n = 1071). Abbreviations: BM, bony metastasis.

Molecular profiling of a large number of bone metastases would be necessary to address this issue [10–12]. Moreover although our study also provides evidence that further progression within bone of the oligometastatic process is associated with shorter times to PCSM, we must emphasise that this does not necessarily mean that attempts to eliminate oligometastases will improve PCSM further. Randomised trials comparing standard treatments of oligometastases, such as androgen suppression, with the same treatment plus ablative treatments, such as stereotactic radiotherapy, are necessary to determine that treatment escalation of this type can delay further metastatic progressions and PCSM. The present study is however helpful in this regard because it suggests that careful stratification of such trials is necessary to ensure that credible results are forthcoming. Our study indicates that number of sites of bone metastases determined using a pre-specified imaging protocol, the primary tumour stage, and presence of local or metastatic disease at soft tissue sites are all essential stratification factors. So too should be the most powerful predictor of PCSM, PSA doubling time [13]. However after PSA progression, baseline factors such as Gleason score, T stage and PSA seem to have

961

933

solitary BM further BM

Fig. 3. Evidence that further progression in the bony skeleton of solitary and two or three bony metastatic presentations is associated with a substantial increase in prostate cancer-specific mortality (n = 989). Abbreviations: BM, bony metastasis.

reduced prognostic utility [14]. A number of randomised studies assessing the benefit of ablative treatments are already in the process of development but few are adopting this design. Of course prolongation of survival is not the only potential benefit that stereotactic radiotherapy can achieve in the treatment of oligometastatic disease in bone. Several non-randomised studies have focussed on the effects of increasing doses of radiotherapy. These have shown that higher radiation doses produce more rapid, complete and durable responses in bone pain resulting in less interference with everyday life [15–17]. These improvements may be accompanied by larger and more durable PSA responses [17,18]. Some investigators have also suggested that high dose stereotactic radiotherapy to oligometastatic disease prior to androgen suppression therapy (AS) is advantageous to the patient because it will delay the need for AS even though it does not lead to cure [19,20]. However, while some reports have indicated that high doses are more effective, none have shown that ablative doses alter metastatic progressions or prolong survival. The only published literature exploring the natural history of oligometastatic disease to date is a retrospective review by Singh et al that analysed the patterns and behaviour of metastatic lesions in prostate cancer patients who were initially treated with radiation therapy [21]. They analysed outcomes for 369 patients of whom 74 developed metastasis and investigated whether patients with less than 5 lesions had an improved outcome relative to patients with greater than 5 lesions. When the number of metastasis was considered, less than 5 lesions had superior survival relative to greater than 5 (5 year survival of 73% vs 45% p = 0.02). Interval from date of diagnosis of bone metastases to the date of death was similar in both groups irrespective of number of lesions. Pelvis as the site of metastasis had poorer outcome compared to vertebral metastases. In the present study anatomic site of metastasis in the skeleton was collected but small numbers precluded the identification of especially dangerous anatomical sites. Further limitations of the study include the under-diagnosis of very small metastatic deposits due to the insensitivity of the imaging equipment used across Australia and New Zealand between 2003 and 2014. The use of more sensitive and specific scanning technologies, such as prostate specific membrane antigen (PSMA) PET, would likely have identified further sub-centimetre metastatic deposits that may have altered the characteristics of the prognostic gradient reported herein. There is little doubt however that the use of PSMA PET in future randomised trials will improve their precision and, in doing so, help to unravel the true natural

Please cite this article in press as: Sridharan S et al. Oligometastatic bone disease in prostate cancer patients treated on the TROG 03.04 RADAR trial. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.07.021

S. Sridharan et al. / Radiotherapy and Oncology xxx (2016) xxx–xxx

history of oligometastatic bone and non-bone disease. Another limitation to the accuracy of the present study was our inability to review the original imaging investigations due to the great dispersion of the trial population across Australia and New Zealand. Finally it must be pointed out that these analyses were secondary ones not pre-specified in the RADAR protocol and thus the findings should be interpreted cautiously. Because the timing of bony metastatic progression was not known at randomisation we could not treat progression as fixed, requiring the use of time-dependent covariates in our models to avoid time-dependent bias. These findings will require confirmation in further studies. Conclusion Properly stratified randomised trials are necessary to determine which of Hellman and Weichselbaum’s competing theories of the natural history of oligometastatic disease is correct. From a patient’s perspective they will determine whether the attempted eradication of oligometastatic bone metastases will limit the metastatic process and improve times to PCSM. Trial number The TROG 03.04 Trial is registered with the National Institutes of Health Clinical Trials Registry, number NCT00193856 and has approval from Hunter New England Human Research Ethics Committee (Trial ID. 03/06/11/3.02). Role of funding source This study received support from the National Health and Medical Research Council of Australia (NHMRC) (Project Application IDs 300705, 455521 and 1099149) and Calvary Health Care (Calvary Mater Newcastle Radiation Oncology Fund). Conflict of interest There are no author conflicts of interest to disclose. Acknowledgement We thank Rosemary Bradford (Prostate Cancer Trials Group, University of Newcastle, Australia) once again for her expert preparation of the manuscript.

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Please cite this article in press as: Sridharan S et al. Oligometastatic bone disease in prostate cancer patients treated on the TROG 03.04 RADAR trial. Radiother Oncol (2016), http://dx.doi.org/10.1016/j.radonc.2016.07.021