- Email: [email protected]
Effect on Overall Survival of Locoregional Treatment in a Cohort of De Novo Metastatic Prostate Cancer Patients: A Single Institution Retrospective Analysis From the Royal Marsden Hospital
Accepted Manuscript Impact on Overall Survival (OS) of loco-regional treatment (LRT) in a cohort of de novo metastatic prostate cancer (mPCa) patients: a single institution retrospective analysis from the Royal Marsden Hospital D. Bianchini, D. Lorente, P. Rescigno, Z. Zafeiriou, E. Psychopaida, H.O.' Sullivan, M. Alaras, M. Kolinsky, S. Sumanasuriya, M Sousa Fontes, J. Mateo, R. Perez, N. Tunariu, N. Fotiadis, P. Kumar, A. Tree, N. Van As, V. Khoo, C. Parker, R. Eeles, A. Thompson, D. Dearnaley, J.S. de Bono PII:
S1558-7673(17)30097-6
DOI:
10.1016/j.clgc.2017.04.013
Reference:
CLGC 826
To appear in:
Clinical Genitourinary Cancer
Received Date: 27 January 2017 Revised Date:
3 April 2017
Accepted Date: 14 April 2017
Please cite this article as: Bianchini D, Lorente D, Rescigno P, Zafeiriou Z, Psychopaida E, Sullivan HO', Alaras M, Kolinsky M, Sumanasuriya S, Fontes MS, Mateo J, Perez R, Tunariu N, Fotiadis N, Kumar P, Tree A, Van As N, Khoo V, Parker C, Eeles R, Thompson A, Dearnaley D, de Bono J, Impact on Overall Survival (OS) of loco-regional treatment (LRT) in a cohort of de novo metastatic prostate cancer (mPCa) patients: a single institution retrospective analysis from the Royal Marsden Hospital, Clinical Genitourinary Cancer (2017), doi: 10.1016/j.clgc.2017.04.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Impact on Overall Survival (OS) of loco-regional treatment (LRT) in a cohort of de novo
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metastatic prostate cancer (mPCa) patients: a single institution retrospective analysis from the
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Royal Marsden Hospital.
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Authors: D Bianchini2, D Lorente 1,3, P Rescigno1, Z Zafeiriou1, E Psychopaida1, H O' Sullivan1,
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M Alaras1, M Kolinsky1, S Sumanasuriya2, M Sousa Fontes2, J Mateo1, R Perez1, N Tunariu2, N
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Fotiadis2, P Kumar2, A Tree2, N Van As2, V Khoo2, C Parker1, R Eeles1, A Thompson2, D
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Dearnaley1, JS de Bono1
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Affiliations:
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1
The Institute of Cancer Research, London, UK
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The Royal Marsden NHS Foundation Trust, London, UK
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Medical Oncology Service, Hospital Universitario La Fe, Valencia, Spain
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*Corresponding author:
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Professor Johann S de Bono, Division of Clinical Studies, The Institute of Cancer Research, London
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SM2 5NG
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Telephone: +44 (0)2087224028
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Fax: +44 (0)2086427979
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Email: [email protected]
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Abstract word count:
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Manuscript word count:
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ACCEPTED MANUSCRIPT Abstract
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Background:
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The optimal management of the primary tumour in metastatic at diagnosis (M1) prostate cancer (PCa)
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patients is not yet established. We retrospectively evaluated the impact of LRT on OS hypothesizing
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that this could improve outcome through better local disease control and the induction of an antitumor
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immune response (abscopal effect).
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Methods:
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M1 at diagnosis PCa patients referred to the Prostate Targeted Therapy Group at the Royal Marsden
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between 06/2003 and 12/2013 were identified. LRT was defined as either surgery, radiotherapy (RT)
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or transurethral prostatectomy (TURP) administered to the primary tumour at any time point from
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diagnosis to death. Kaplan-Meier analyses generated OS data. The association between LRT and OS
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was evaluated in univariate (UV) and multivariate (MV) Cox regression models.
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Results:
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Overall 300 patients were identified; 192 patients (64%) experienced local symptoms at some point
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during their disease course; 72 patients received LRT (56.9%TURP, 52.7%RT). None of the patients
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were treated by prostatectomy. LRT was more frequently performed in patients with low volume
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disease (35.4% vs 16.2%; p<0.001), lower PSA at diagnosis (median PSA: 75 vs 184ng/mL; p=0.005)
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and local symptoms (34.2% vs 4.8%; p<0.001). LRT was associated in UV and MV analysis with
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longer OS (62.1 vs 55.8 months; HR: 0.74;p=0.044) which remained significant for RT (69.4 vs 55.1
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months; HR:0.54;p=0.002) but not for TURP. RT associated with better OS independent of disease
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volume at diagnosis.
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Conclusion
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These data support the conduct of randomized Phase III trials evaluating the benefit of local control in
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patients with M1 disease at diagnosis.
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ACCEPTED MANUSCRIPT Introduction:
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The standard management of de novo metastatic prostate cancer (mPCa) has recently changed to
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combine docetaxel chemotherapy with androgen deprivation therapy (ADT) for fit patients (1, 2, 3).
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Definitive treatment of the local prostate tumour in the form of surgery or radiotherapy (RT) is not
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generally contemplated for asymptomatic patients in the metastatic setting; rather it is usually
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reserved for patients with organ-confined or locally advanced prostate cancer. The role of LRT such
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as surgery, RT or transurethral prostatectomy (TURP) in mPCa is mostly used for the palliation of
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local symptoms such as haematuria or urinary obstruction, and its impact on overall survival (OS)
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remains undefined.
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This treatment paradigm has been challenged by a growing body of evidence based on several
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retrospective studies (4, 5, 6, 7, 8) suggesting a potential OS benefit from radical prostatectomy or RT
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for patients with mPCa at diagnosis. For several other malignancies, including colorectal, kidney and
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ovarian cancer, maximal cytoreduction including removal of the primary tumour has been shown to
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provide an OS advantage (9, 10, 11, 12, 13). In breast cancer, despite several retrospective series
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suggesting a similar favourable effect, a recently published randomized controlled trial failed to
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confirm such evidence (14).
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Beside the more intuitive rationale for treating the primary tumour, whereby the reduction of the
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overall tumour burden may limit the risk of metastatic spread, emerging preclinical evidence now
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supports a more aggressive treatment approach for the local prostate tumour even in the metastatic
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setting. The “tumour self-seeding theory” suggests that circulating tumour cells may spread and
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metastasize not only from the primary site to distant organs but also in the opposite direction, re-
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infiltrating the site of origin which could become a reservoir of tumour cells with metastatic potential
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(15). Moreover, LRT of the primary tumour could act as an effective endogenous vaccine through
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tumour antigen shedding, resulting in the regression not only of the directly treated local tumour but
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also of the distant metastatic sites through “abscopal effects” (16). RT-induced inflammation and
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tumour necrosis is also postulated to cause the acute release of multiple tumour-associated antigens
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which in turn elicit a specific CD8+T-cell mediated antitumor immunological effect (16). This
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secondary immunological response could potentially convert RT into a potent systemic treatment
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with unexplored clinical benefits which go beyond mere local control or symptom palliation. Primary
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tumour-derived exosomes and cytokines have also been postulated to contribute to the creation of a
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receptive microenvironment (“pre-metastatic niche”) for the subsequent development of metastatic
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sites in specific organs. It has been suggested that the untreated primary disease continues to impact
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the growth of the metastatic disease in an endocrine manner (17).
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Several ongoing large prospective Phase II and III trials are investigating whether LRT should be
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recommended in mPCa patients (Clinical trial gov NCT01751438, NCT02138721, NCT01957436,
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ACCEPTED MANUSCRIPT NCT 00268476). In the present study we aimed to determine the survival of patients undergoing LRT
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administered at any time point along the course of the disease in a retrospective study evaluating a
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population of patients diagnosed with mPCa at presentation. Secondarily, we described the type and
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the incidence of local symptoms in this population, their management and the treating physician’s
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rationale for prescribing LRT.
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Patients and Methods
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Study population and data collection:
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PCa patients with metastatic disease at diagnosis referred to the Prostate Targeted Therapy Group at
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the Royal Marsden NHS Foundation Trust between June 2003 and December 2013 were selected. The
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time of data cut off was 16th of January 2016. Clinical patient data was collected from the Electronic
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Patients Record (EPR). Variables including age, diagnostic Gleason score, Eastern Cooperative
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Oncology Group (ECOG) performance status (PS) at diagnosis or first referral, post castration
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resistant prostate cancer (CRPC) lines of standard therapies received, PSA at diagnosis, metastatic
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sites and volume of disease at diagnosis or first referral and at the time of LRT, were retrospectively
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recorded. Information on local symptoms (pelvic pain, haematuria, urinary frequency, urinary
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retention, hydronephrosis), intervention (medications, TURP, surgery, RT, cystoscopy, suprapubic
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catheterization, ureteric stenting, hospitalization and catheterization) at diagnosis and/or at any time
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point along the course of the disease, the physician decision rationale and treatment intent for LRT
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were also collected.
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LRT was defined as the receipt of treatment to the primary tumour consisting in either surgery
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(radical prostatectomy), RT (administered at any dose and fractionation) or TURP at any time point
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along the disease course from diagnosis to death. The volume of disease was classified according to
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CHAARTED criteria (1) into high (presence of visceral metastases or ≥ 4 bone lesions of which at
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least one beyond the vertebral bodies and pelvis) or low volume (< 4 bone lesions without visceral
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metastases). The intent of RT was categorized as either palliative (palliation of local symptoms) or
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radical (definitive local RT only or in combination with external beam radiation therapy (EBRT)
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directed to the metastatic sites in the context of oligometastatic or oligorecurrent disease) (21).
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Statistical Analysis:
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A descriptive analysis of clinical variables was performed. Categorical variables were presented as
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proportions (%) and continuous variables were presented by the median values with interquartile
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ranges (IQR). Differences in baseline variables between LRT+ and LRT- groups were evaluated using
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Chi-square (categorical values) and t-Student (continuous variables) tests.
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ACCEPTED MANUSCRIPT 1 Median survival values for each of the groups were calculated by Kaplan-Meier analyses. The
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association of LRT with survival was evaluated by univariable and multivariable Cox-regression
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models. Variables in the multivariable model included LRT, age, PSA (log-transformed), Gleason
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score, tumour volume and the presence of symptoms. Cox-regression models were estimated for LRT
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(RT and Surgery) and for RT and surgery as LRT separately. Only p-values <0.05 were considered
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statistically significant. No correction for multiple testing was performed.
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Results Patient Characteristics and Local Symptoms
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Overall 300 PCa patients with metastatic disease at diagnosis were identified. Patient characteristics
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at diagnosis or first referral are summarized in Table 1. Most patients (95.6 %) presented with good
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baseline ECOG PS (0 or 1) and received a median of 3 lines of treatment for metastatic CRPC. In
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total 192 patients (64%) experienced local symptoms at some point during their disease course with
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99 patients (33%) having these at diagnosis and 148 patients (49.3%) developing symptoms later on
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during the course of the disease. Clinical data on local symptoms during the course of the disease
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were not available in 4 of the 192 symptomatic patients.
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Follow up of these local symptoms in the 99 patients who were symptomatic at diagnosis, indicated
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that 42 of these patients (42/99, 42.4%) did not report any further local symptoms during the course of
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the disease of which only 20 had received a specific intervention for their local symptoms Fifty-three
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patients (53/99, 53.5%) continued to experience local symptoms with 19 reporting the same (19/53,
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35.8%), 32 worsening (32/53, 60.3%), and 2 improving local symptoms (2/53, 3.7%). Follow up data
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on these local symptoms were not available for 4 patients. Of the 99 patients presenting with local
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symptoms at diagnosis, 44 patients (44.4%) received medical intervention to manage their local
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symptoms while 55 patients (55.5%) did not. In the 44 patients receiving medical intervention, local
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symptoms resolved during the course of the disease in 19 (19/44, 43.1%), improved in 3 (3/44, 6.8%)
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and persisted or worsened in 18 patients (18/44, 40.9%).
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Urinary frequency was the most commonly reported symptom at diagnosis (20%), followed by
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urinary retention (7.3%), haematuria (4.3%), pelvic pain (4%) and hydronephrosis (2%) (Table 2).
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During the course of the disease, urinary frequency remained the most frequently reported local
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symptom (37.7%) followed by pelvic pain (12.7%), urinary retention (12%), haematuria (11%) and
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hydronephrosis (8.7%).
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Loco-regional treatment
2 Overall 72 (24%) patients received LRT to the primary tumour (Table 3);18 (25%) patients
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received this at diagnosis and 54 (75%) patients later during the course of the disease. Of these, the
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majority were symptomatic with only 13 (18%) being free of local symptoms from the primary
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tumour at the time LRT was performed. For those receiving LRT during the course of the disease,
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median time from diagnosis to LRT was 41.6 months (range: 6.9-170.1).
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The most common form of LRT was TURP in 41 (56.9%) patients followed by RT in 38 (52.7%)
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patients; 8 (11.6%) patients underwent both TURP and RT; one (1.4%) patient had focal surgical
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intervention (laser prostatectomy) but none of the patients received radical prostatectomy.
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All patients treated with TURP reported local symptoms at the time of treatment; 15 (38.5%)
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patients had a TURP performed at diagnosis and 26 (63.4%) patients later during the course of
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treatment. For those treated during the course of the disease, median time from diagnosis to TURP
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was 38.9 months (range: 8-119 months).
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Of those treated with RT, 63.2% were symptomatic from the local tumour at the time of local RT; 5
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(13.2%) patients received RT at diagnosis and 33 (86.8%) patients later during the course of the
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disease. In those treated during the course of the disease, median time from diagnosis to RT was 46.7
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months (range: 6.9-170.1). Among these 33 patients treated with local RT along the disease course,
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24 patients were symptomatic from the local tumour at the time of administration of RT. Following
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local irradiation, local symptoms improved or resolved in 12 patients (12/24, 50%) but persisted or
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worsened in the other 12 patients (12/24, 50%). Of the 156 patients with local symptoms but not
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treated with RT, 27 patients (17.3%) required multiple treatments to control local progression.
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RT with radical intent was administered to the primary tumour to 16 (42.1%) patients with
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oligometastatic or oligorecurrent disease (21) of which 8 patients were treated with synchronous
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external beam RT (EBRT) to additional bone or nodal metastatic lesions. Twenty-one (55.3%)
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patients received RT with the intent to palliate local symptoms or improve the local control of the
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disease. Data on one of these patients was missing. Twenty-six patients (76.5%) received at least 30
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Gy, and 6 patients (15.8%) were treated with doses of 60 Gy or higher; the dose was unknown in 4
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(10.5%) patients and fractionation was inconsistently reported.
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LRT was more frequently performed in patients with low volume metastatic disease (35.4% vs
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16.2%; p<0.001), lower PSA at diagnosis (median PSA: 75 vs 184 ng/mL; p=0.005) and with local
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symptoms (34.2% vs 4.8%; p<0.001). No significant association was found with age (median age:
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63.1 vs 62.2 years; p=0.409) or Gleason Score ≥8 (24.6% vs 27.5%; p=0.657). The pattern of
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metastatic spread was not clearly associated with LRT. Although there was a non-significant trend
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towards patients with lymph node only disease reciving LRT in higher proportion (37% vs 21.5%;
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p=0.068), no differences were observed in patients with visceral (22.7% vs 26.7%; p=0.725) or bone
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only (28.7% vs 20.5%; p=0.125) metastases.
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Median follow-up was 54.6 months (range: 11.9-227.8), with 266 (88.7%) deaths. Median OS for
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the whole cohort was 57.9 months (95%CI: 51.9-63.9) (Fig.1A). In univariate analysis, LRT was
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associated with better OS (62.1 vs 55.8 months; HR: 0.74; p=0.044). LRT was also associated with
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improved survival in a multivariable model including age, Gleason Score, PSA, volume of disease
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(low vs high) at diagnosis and presence of symptoms as co-variates (Table 4A). We then evaluated
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whether the type of LRT (radiotherapy or TURP/surgery) would have an equivalent effect on OS. In
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univariate analysis, TURP/surgery was associated with a non-significant decrease in OS (54.3 vs 58.8
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months; HR: 1.23; p=0.239) (Fig.1B), while patients receiving local RT appeared to have a significant
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OS advantage (69.4 vs 55.1 months; HR: 0.54; p=0.002)(Fig.1C), which was maintained in the
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multivariable Cox-regression model (Table 4B). There was no significant interaction between RT
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treatment administration and disease volume evaluated at diagnosis or first referral (CHAARTED
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criteria) (1) (p=0.958). Higher RT doses were associated with increased OS independently of the
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volume of disease assessed at diagnosis or first referral (p<0.001).
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Discussion
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The past decade has seen a major change in therapeutic options for mPCa patients with several novel
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and effective drugs receiving regulatory approval, resulting in significant OS improvements. As a
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consequence, in our experience, an increasing number of patients are developing symptoms secondary
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to local progression of untreated primary disease. Furthermore, although the local tumour tends to
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respond well to initial ADT, the adaptive resistance mechanisms induced by subsequent lines of
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hormonal or chemotherapy treatment impair the chances of achieving adequate local control. Small
30
increases in size of the local prostate tumour frequently result in urinary outflow obstruction and the
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invasion of adjacent organs that may manifest clinically with macroscopic haematuria, tenesmus or
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hydronephrosis. In our study, more than a half of de novo mPCa patients had locally symptomatic
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disease at some point between diagnosis and death. The appropriate management of these local
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prostate cancer complications remains challenging. Furthermore, therapeutic interventions may
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themselves be, in some cases, the cause of long term side-effects such as erectile dysfunction, urinary
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proportion of the patients presenting with local symptoms at diagnosis (18/44, 40.9%) reported
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persistent or worsening local symptoms despite local interventions. Nearly one in five M1 at diagnosis
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patients with local symptoms who did not receive definitive treatment to the primary tumour in the
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form of radical surgery or RT required multiple local interventions. This suggests that not treating the
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primary may not only have implications to patient morbidity and longevity but also health economics.
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However, RT treatment was efficacious in improving the local symptoms in only half of the treated
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patients, suggesting that this local intervention may have been administered too late in the disease
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course. The timing of administration of LRT should not necessarily coincide with the development of
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local symptoms but probably at the first evidence of radiological progression.
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A recent paper published in the New England Journal of Medicine analysed patient-reported
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outcomes based on questionnaires in patients with localized prostate cancer treated with radical
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prostatectomy, RT or active surveillance. Sexual dysfunction and urinary incontinence were the most
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frequently reported adverse events among patients treated with radical prostatectomy whereas RT
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more often induced changes in bowel habits especially in the long term (24). The appropriate
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identification and timely management of patients with locally-advanced disease that are most likely to
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develop clinically relevant local symptoms is therefore key to prevent patient morbidity.
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This retrospective analysis suggests the possibility of an OS benefit from LRT in patients presenting
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with mPCa at diagnosis. This hypothesis has already been proposed by other retrospective case series
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from different centres, with similar positive results (4, 5, 6, 7, 8). Current guidelines for kidney,
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ovarian and colorectal cancer recommend, whenever technically and clinically feasible, the surgical
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removal of the primary tumour and the metastatic sites (9, 10, 11, 12, 13).
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Here we explored the effect on OS of different local treatments analysing RT and TURP as separate
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single interventions. As already mentioned before, the primary tumour releases in the circulation
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tumour cytokines which may have a role in stimulating tumour growth at the metastatic sites (15).
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This implies that any intervention to the local disease may favourably or unfavourably alter this
30
mechanism and ultimately affect OS. Here we suggest the hypothesis that the administration of RT to
31
the local tumour may improve OS through not only the suppression of the aforementioned paracrine
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cytokines but also the dissemination of tumour-derived neoantigens triggering an antitumoral immune
33
response (abscopal effect). On the contrary, the effect of TURP is more unpredictable with
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mechanical trauma disrupting the anatomic barriers surrounding the tumour and favouring not only
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the circulation of tumour-derived cytokines and circulating tumour cells but also tumour neoantigens
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with consequent antitumor-immune responses (16, 17). The effect of TURP on OS may therefore be
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different depending on which one of these two processes predominates. Non-definitive LRT such as
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TURP may fail to fully abrogate the release of tumour-derived paracrine factors but still promote the
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intravascular dissemination of circulating tumour cells (18). In fact, prostate cancer cells can be
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detected in the circulation during the peri-operative period in patients undergoing TURP and other
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studies have suggested an association of this procedure with disease progression (18, 19, 20). In our study, while local treatment (LRT) overall conferred a survival advantage (62.1 vs 55.8
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months; HR: 0.74; p=0.044), this was almost entirely restricted to patients receiving radiotherapy
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(69.4 vs 55.1 months; HR: 0.54; p=0.002) as opposed to those receiving TURP (54.3 vs 58.8 months;
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HR: 1.23; p=0.239). The survival benefit from local radiotherapy appeared to be independent of other
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known prognostic variables (age, Gleason Score, PSA, volume of disease and presence of symptoms)
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included in multivariable Cox-regression models. Importantly, the survival benefit was independent of
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the volume of bone metastases, suggesting that both patients with a low and a high burden of
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metastases could potentially benefit from local RT. These results, although limited by the small
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number of patients and its retrospective nature, may indicate that the overall biological effect of
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TURP on OS is negligible whereas RT may instead have a favourable impact on OS. The different
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effect on OS between these two main local treatment modalities (RT or TURP) may be, in part,
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explained by the different rationale for treatment indication. While TURP was generally carried out to
17
resolve urinary symptoms such as urinary obstruction and/or urinary frequency, the rationale for
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administering RT in nearly half the patients was primarily not to palliate local symptoms but rather to
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improve local control and prevent the subsequent development of local symptoms.
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We acknowledge that our study has a number of limitations including its retrospective nature and
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our population heterogeneity. Relatively few patients received local treatment, which is consistent
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with current clinical practice, since local treatment in asymptomatic metastatic patients is not the
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current standard. With this, as with other similar retrospective studies published to date, treatment
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selection bias (i.e. the selection of patients with better baseline prognostic features for local treatment
26
at baseline) may significantly alter the interpretation of results. In our study, however, RT to the
27
primary tumour was associated with significantly increased OS independently of other important
28
baseline prognostic factors such as the volume of metastatic disease, Gleason Score or PSA.
29
Furthermore, the role of an “abscopal effect”, suggested as a possible biological mechanism to
30
support the role of LRT in advanced prostate cancer, cannot be supported in our series due to the
31
different timing of local therapy in our patients. The fact that not all patients had local treatment at
32
baseline may have also led to the selection of those with favourable responses for local treatment
33
along the course of the disease. Other studies previously published supporting the role of local therapy
34
in advanced prostate cancer come from large databases that, unfortunately, do not contain most of the
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clinical parameters that are evaluated here. This is one of the first studies that takes into account the
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clinical heterogeneity of patients treated with local therapy, the very important methodological
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limitations to conducting similar analyses, therefore supporting the notion that well conducted,
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randomized prospective clinical trials are needed to correctly answer this very important clinical
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question.
4 Conclusion
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Although this is a retrospective study limited by a risk of selection bias with the possibility of
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overestimating the OS impact of local radiation, these data support the rationale for conducting large
8
randomized Phase III trials to determine whether local treatment improves outcome for metastatic at
9
diagnosis PCa patients. Moreover, our data make clear that not treating local disease in mPCa patients
10
at diagnosis results in significant local disease morbidities during their lifetime with these patients
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commonly requiring invasive interventions with significant health economic implications particularly
12
as patients with mPCa live longer with better systemic therapies.
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interventions with significant impact in terms of morbidity and health economics •
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Local symptoms in de novo mPCa patients are common and often require multiple invasive
The definitive treatment of the primary tumour may favourably affect outcome and prevent local symptoms
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Large randomized prospective clinical trials to investigate the OS benefit of RT to the primary tumour in de novo mPCa patients such as STAMPEDE are ongoing and results are
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eagerly awaited.
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References 1. Sweeney CJ, Chen YH, Carducci M et al, Chemohormonal Therapy in Metastatic HormoneSensitive Prostate Cancer. N Engl J Med. 2015 Aug 20; 373(8):737-46. 2. James ND, Sydes MR, Clarke NW et al, Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from
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an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar 19;
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387 (10024):1163-77.
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3. Parker CC, Sydes MR, Mason MD et al., Prostate radiotherapy for men with metastatic
disease: a new comparison in the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial. BJU Int. 2013 May;111(5):697-9. 4. Culp SH Schellhammer PF, Williams MB., Might men diagnosed with metastatic prostate
12
cancer benefit from definitive treatment of the primary tumour? A SEER-based study Eur
13
Urol 65 (2014) 1058-1066.
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5. Fossati N, Trinh QD, Sammon J et al. Identifying optimal candidates for local treatment of
15
the primary tumour among patients diagnosed with metastatic prostate cancer: a SEER-based
16
study (2015) Eur Urol. Jan; 67(1):3-6.
17 18
6. Engel J, Bastian PJ, Baur H Survival benefit of radical prostatectomy in lymph node-positive patients with prostate cancer (2010) Eur Urol.; 57, 754-761.
7. Patrikidou A, Brureau L, Casenave J et al. Locoregional symptoms in patients with de novo
20
metastatic prostate cancer: morbidity, management and disease outcome (2015)Urol Oncol.
21
May; 33(5).
22
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8. Rusthoven CG, Jones BL, Flaig TW et al. Improved Survival with Prostate Radiation in Addition to Androgen Deprivation Therapy for Men with Newly Diagnosed Metastatic
24
Prostate Cancer. J Clin Oncol(2016) Aug 20; 34(24):2835-42.
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9. Glehen O, Mohamed F, Gilly FN., Peritoneal carcinomatosis from digestive tract cancer: new
26
management by cytoreductive surgery and intraperitoneal chemohypertermia(2004) Lancet
27 28 29 30 31
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Oncol; 5:219-28.
10. Bristow RE Tomacruz RS, Armstrong DK et al., Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a metanalysis(2002) J Clin Oncol; 20:1248-59.
11. Flanigan RC, Salmon SE, Blumenstein BA et al, 2001 Nephrectomy followed by interferon
32
alfa-2b compared with interferon alfa-sb alone for metastatic renal-cell cancer. N Engl J Med
33
345, 1655-1659.
34
12. Mickisch GH, Garin A, van Poppel H et al. 2001 Radical nephrectomy plus interferon-alfa-
35
based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma:
36
a randomised trial. Lancet 358, 966-970.
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13. Temple LK, Hsieh L, Wong WD et al. Use of surgery among elderly patients with stage IV colorectal cancer. J Clin Oncol. 22, 3475-3484. 14. Badwe R, Hawaldar R, Nair N et al., Locoregional treatment versus no treatment of the
4
primary tumour in metastatic breast cancer: an open-label randomised controlled trial. Lancet
5
Oncol (2015) Oct; 16(13):1380-8.
7
15. Kim MY, Oskarsson T, Acharyya S et al. Tumor self-seeding by circulating cancer cells. Cells (2009) 139, 1315-1326.
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16. Demaria S1, Ng B, Devitt ML et al., Ionizing radiation inhibition of distant untreated tumors
9
(abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys, (2004) 58, 862-870.
11
17. Hoshino A, Costa-Silva B, Shen TL et al., Tumour exosome integrins determine organotropic metastasis. Nature (2015) Nov 19; 527(7578):329-35.
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18. Krupski TL, Stukenborg GJ, Moon K et al., The relationship of palliative transurethral
13
resection of the prostate with disease progression in patients with prostate cancer. BJU
14
International (2010), 106, 1477-1483
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19. Heung YMM, Walsh K, Sriprasad S et al., The detection of prostate cells by the reverse
16
transcription-polymerase chain reaction in the circulation of patients undergoing transurethral
17
resection of the prostate. BJU International (2000), 85, 65-69.
18
20. Forman JD, Order SE, Zinreich ES et al., The correlation of pretreatment transurethral resection of prostate cancer with tumor dissemination and disease-free survival. A univariate
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and multivariate analysis. Cancer(1986) Oct 15;58(8):1770-8.
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21. Tosoian JJ, Gorin MA, Ross AE et al. Oligometastatic prostate cancer: definitions, clinical outcomes, and treatment considerations. Nat Rev Urol(2016) Oct 11. 22. Kyrdalen AE, Dahl AA, Hernes E, et al. A national study of adverse effects and global quality of life among candidates for curative treatment for prostate cancer. BJU
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Int.(2013) Feb; 111(2):221-32.
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23. Elsamra SE, Leavitt DA, Motato HA et al. Stenting for malignant ureteral obstruction: Tandem, metal or metal-mesh stents. Int J Urol(2015) Jul; 22(7):629-36.
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24. Donovan JL, Hamdy FC, Lane JA et al., Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. N Engl J Med.(2016) Oct 13; 375(15):14251437.
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ACCEPTED MANUSCRIPT Table 1. Patient Characteristics LRT (+) 62.2 (56.9-66.5)
LRT (-) 63.1 (57.8-68.6)
0-1 2
287 (95.7%) 13 (4.3%) 150 (55-500)
64 (92.8%) 5 (7.2%) 75 (35 - 381)
217 (96.4%) 8 (3.6%) 184 (65.3-533.5)
≥8 <8 Unknown Metastatic sites Bone Lymph nodes Visceral Tumor Burden (CHAARTED criteria) High Low Post-CRPC lines of treatment
164 (54.7%) 66 (22%) 70 (23.3%)
44 (63.8%) 16 (23.2%) 9 (13%)
265 (88.3%) 83 (27.7%) 15 (5%)
54 (78.3%) 23 (33.3%) 4 (5.8%)
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181 (60.3%) 117 (39%) 3 (2-3)
116 (51.6%) 49 (21.8%) 60 (26.7%) 207 (92%) 56 (24.9%) 11 (4.9%)
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PSA Gleason
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All patients 63 (57.7-68.5)
Age (yr) ECOG PS
29 (42%) 40 (58%) 3 (2-3)
150 (66.7%) 73 (32.4%) 3 (2-3)
Table 2. Local Symptoms
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All patients (n=294) At During diagnosis disease 96 147 (32%) (49.3%) 12 38 (4%) (12.7%) 13 33 (4.3%) (11%) 60 113 (20%) (37.7%) 22 36 (7.3%) (12%) 6 26 (2%) (8.7%)
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At least one symptom Pelvic Pain
Hematuria Urinary Frequency Urinary Retention
Hydronephrosis
LRT (+) LRT (-) (n=69) (n=225) At During At During diagnosis disease diagnosis disease 32 56 60 91 (46.4%) (81.2%) (26.7%) (40.4%) 4 14 6 23 (5.8%) (20.3%) (2.7%) (10.2%) 4 18 9 14 (5.8%) (26.1%) (4%) (6.2%) 17 42 41 71 (24.6%) (60.9%) (18.2%) (31.6%) 11 18 9 18 (15.9%) (26.1%) (4%) (8%) 3 18 3 8 (4.3%) (26.1%) (1.3%) (3.6%)
Information on symptoms was missing for 6 (2%) patients.
ACCEPTED MANUSCRIPT Table 3. Loco-Regional Treatment During course of the disease (n=54) 20 (37%) 0 28 (51.9%) 1 (1.9%) 5 (9.3%) 0
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TURP only Surgery only Radiotherapy only TURP + Surgery TURP + Radiotherapy Radiotherapy + Surgery
At diagnosis (n=18) 13 (72,2%) 0 3 (16.7%) 0 2 (11.1%) 0
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*3 patients had LRT at diagnosis and during the course of the disease: 2 patients had TURP at diagnosis and TURP during the course of the disease and 1 patient had TURP at diagnosis and RT during the course of the disease.
Table 4. Multivariable Survival Analysis
4A) LRT including both Radiotherapy and TURP
p-value 0.030 0.766 0.001 0.132 <0.001 0.303
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LRT Age PSA at Dx* Gleason Score** Volume of metastases*** Symptoms at Diagnosis
HR (95% CI) 0.68 (0.48-0.96) 1 (0.98-1.02) 0.69 (0.55-0.86) 1.23 (0.93-1.76) 1.89 (1.39-2.58) 1.04 (0.97-1.11)
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4B) LRT when only Radiotherapy is considered
LRT Age PSA at Dx* Gleason Score** Volume of metastases*** Symptoms at Diagnosis
HR (95% CI) 0.53 (0.33-0.85) 1 (0.97-1.02) 0.7 (0.56-0.87) 1.29 (0.94-1.77) 1.8 (1.32-2.45) 1.03 (0.96-1.1)
p-value 0.008 0.644 0.002 0.120 <0.001 0.406
*PSA at diagnosis was log-transformed **Gleason Score: ≥8 vs <8 **Volume of metastatic disease: high vs low as per CHAARTED criteria
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Figure 1A: LRT and Survival (TURP + RT)
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Figure 1B: LRT and Survival (TURP only)
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Figure 1C: LRT and Survival (RT only)
S1558-7673(17)30097-6
DOI:
10.1016/j.clgc.2017.04.013
Reference:
CLGC 826
To appear in:
Clinical Genitourinary Cancer
Received Date: 27 January 2017 Revised Date:
3 April 2017
Accepted Date: 14 April 2017
Please cite this article as: Bianchini D, Lorente D, Rescigno P, Zafeiriou Z, Psychopaida E, Sullivan HO', Alaras M, Kolinsky M, Sumanasuriya S, Fontes MS, Mateo J, Perez R, Tunariu N, Fotiadis N, Kumar P, Tree A, Van As N, Khoo V, Parker C, Eeles R, Thompson A, Dearnaley D, de Bono J, Impact on Overall Survival (OS) of loco-regional treatment (LRT) in a cohort of de novo metastatic prostate cancer (mPCa) patients: a single institution retrospective analysis from the Royal Marsden Hospital, Clinical Genitourinary Cancer (2017), doi: 10.1016/j.clgc.2017.04.013. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Impact on Overall Survival (OS) of loco-regional treatment (LRT) in a cohort of de novo
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metastatic prostate cancer (mPCa) patients: a single institution retrospective analysis from the
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Royal Marsden Hospital.
4
Authors: D Bianchini2, D Lorente 1,3, P Rescigno1, Z Zafeiriou1, E Psychopaida1, H O' Sullivan1,
5
M Alaras1, M Kolinsky1, S Sumanasuriya2, M Sousa Fontes2, J Mateo1, R Perez1, N Tunariu2, N
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Fotiadis2, P Kumar2, A Tree2, N Van As2, V Khoo2, C Parker1, R Eeles1, A Thompson2, D
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Dearnaley1, JS de Bono1
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Affiliations:
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1
The Institute of Cancer Research, London, UK
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2
The Royal Marsden NHS Foundation Trust, London, UK
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3
Medical Oncology Service, Hospital Universitario La Fe, Valencia, Spain
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*Corresponding author:
13
Professor Johann S de Bono, Division of Clinical Studies, The Institute of Cancer Research, London
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SM2 5NG
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Telephone: +44 (0)2087224028
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Fax: +44 (0)2086427979
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Email: [email protected]
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Abstract word count:
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Manuscript word count:
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ACCEPTED MANUSCRIPT Abstract
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Background:
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The optimal management of the primary tumour in metastatic at diagnosis (M1) prostate cancer (PCa)
4
patients is not yet established. We retrospectively evaluated the impact of LRT on OS hypothesizing
5
that this could improve outcome through better local disease control and the induction of an antitumor
6
immune response (abscopal effect).
7
Methods:
8
M1 at diagnosis PCa patients referred to the Prostate Targeted Therapy Group at the Royal Marsden
9
between 06/2003 and 12/2013 were identified. LRT was defined as either surgery, radiotherapy (RT)
10
or transurethral prostatectomy (TURP) administered to the primary tumour at any time point from
11
diagnosis to death. Kaplan-Meier analyses generated OS data. The association between LRT and OS
12
was evaluated in univariate (UV) and multivariate (MV) Cox regression models.
13
Results:
14
Overall 300 patients were identified; 192 patients (64%) experienced local symptoms at some point
15
during their disease course; 72 patients received LRT (56.9%TURP, 52.7%RT). None of the patients
16
were treated by prostatectomy. LRT was more frequently performed in patients with low volume
17
disease (35.4% vs 16.2%; p<0.001), lower PSA at diagnosis (median PSA: 75 vs 184ng/mL; p=0.005)
18
and local symptoms (34.2% vs 4.8%; p<0.001). LRT was associated in UV and MV analysis with
19
longer OS (62.1 vs 55.8 months; HR: 0.74;p=0.044) which remained significant for RT (69.4 vs 55.1
20
months; HR:0.54;p=0.002) but not for TURP. RT associated with better OS independent of disease
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volume at diagnosis.
22
Conclusion
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These data support the conduct of randomized Phase III trials evaluating the benefit of local control in
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patients with M1 disease at diagnosis.
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ACCEPTED MANUSCRIPT Introduction:
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The standard management of de novo metastatic prostate cancer (mPCa) has recently changed to
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combine docetaxel chemotherapy with androgen deprivation therapy (ADT) for fit patients (1, 2, 3).
4
Definitive treatment of the local prostate tumour in the form of surgery or radiotherapy (RT) is not
5
generally contemplated for asymptomatic patients in the metastatic setting; rather it is usually
6
reserved for patients with organ-confined or locally advanced prostate cancer. The role of LRT such
7
as surgery, RT or transurethral prostatectomy (TURP) in mPCa is mostly used for the palliation of
8
local symptoms such as haematuria or urinary obstruction, and its impact on overall survival (OS)
9
remains undefined.
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This treatment paradigm has been challenged by a growing body of evidence based on several
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retrospective studies (4, 5, 6, 7, 8) suggesting a potential OS benefit from radical prostatectomy or RT
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for patients with mPCa at diagnosis. For several other malignancies, including colorectal, kidney and
13
ovarian cancer, maximal cytoreduction including removal of the primary tumour has been shown to
14
provide an OS advantage (9, 10, 11, 12, 13). In breast cancer, despite several retrospective series
15
suggesting a similar favourable effect, a recently published randomized controlled trial failed to
16
confirm such evidence (14).
17
Beside the more intuitive rationale for treating the primary tumour, whereby the reduction of the
18
overall tumour burden may limit the risk of metastatic spread, emerging preclinical evidence now
19
supports a more aggressive treatment approach for the local prostate tumour even in the metastatic
20
setting. The “tumour self-seeding theory” suggests that circulating tumour cells may spread and
21
metastasize not only from the primary site to distant organs but also in the opposite direction, re-
22
infiltrating the site of origin which could become a reservoir of tumour cells with metastatic potential
23
(15). Moreover, LRT of the primary tumour could act as an effective endogenous vaccine through
24
tumour antigen shedding, resulting in the regression not only of the directly treated local tumour but
25
also of the distant metastatic sites through “abscopal effects” (16). RT-induced inflammation and
26
tumour necrosis is also postulated to cause the acute release of multiple tumour-associated antigens
27
which in turn elicit a specific CD8+T-cell mediated antitumor immunological effect (16). This
28
secondary immunological response could potentially convert RT into a potent systemic treatment
29
with unexplored clinical benefits which go beyond mere local control or symptom palliation. Primary
30
tumour-derived exosomes and cytokines have also been postulated to contribute to the creation of a
31
receptive microenvironment (“pre-metastatic niche”) for the subsequent development of metastatic
32
sites in specific organs. It has been suggested that the untreated primary disease continues to impact
33
the growth of the metastatic disease in an endocrine manner (17).
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Several ongoing large prospective Phase II and III trials are investigating whether LRT should be
35
recommended in mPCa patients (Clinical trial gov NCT01751438, NCT02138721, NCT01957436,
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ACCEPTED MANUSCRIPT NCT 00268476). In the present study we aimed to determine the survival of patients undergoing LRT
2
administered at any time point along the course of the disease in a retrospective study evaluating a
3
population of patients diagnosed with mPCa at presentation. Secondarily, we described the type and
4
the incidence of local symptoms in this population, their management and the treating physician’s
5
rationale for prescribing LRT.
6
Patients and Methods
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Study population and data collection:
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PCa patients with metastatic disease at diagnosis referred to the Prostate Targeted Therapy Group at
10
the Royal Marsden NHS Foundation Trust between June 2003 and December 2013 were selected. The
11
time of data cut off was 16th of January 2016. Clinical patient data was collected from the Electronic
12
Patients Record (EPR). Variables including age, diagnostic Gleason score, Eastern Cooperative
13
Oncology Group (ECOG) performance status (PS) at diagnosis or first referral, post castration
14
resistant prostate cancer (CRPC) lines of standard therapies received, PSA at diagnosis, metastatic
15
sites and volume of disease at diagnosis or first referral and at the time of LRT, were retrospectively
16
recorded. Information on local symptoms (pelvic pain, haematuria, urinary frequency, urinary
17
retention, hydronephrosis), intervention (medications, TURP, surgery, RT, cystoscopy, suprapubic
18
catheterization, ureteric stenting, hospitalization and catheterization) at diagnosis and/or at any time
19
point along the course of the disease, the physician decision rationale and treatment intent for LRT
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were also collected.
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LRT was defined as the receipt of treatment to the primary tumour consisting in either surgery
23
(radical prostatectomy), RT (administered at any dose and fractionation) or TURP at any time point
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along the disease course from diagnosis to death. The volume of disease was classified according to
25
CHAARTED criteria (1) into high (presence of visceral metastases or ≥ 4 bone lesions of which at
26
least one beyond the vertebral bodies and pelvis) or low volume (< 4 bone lesions without visceral
27
metastases). The intent of RT was categorized as either palliative (palliation of local symptoms) or
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radical (definitive local RT only or in combination with external beam radiation therapy (EBRT)
29
directed to the metastatic sites in the context of oligometastatic or oligorecurrent disease) (21).
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Statistical Analysis:
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A descriptive analysis of clinical variables was performed. Categorical variables were presented as
34
proportions (%) and continuous variables were presented by the median values with interquartile
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ranges (IQR). Differences in baseline variables between LRT+ and LRT- groups were evaluated using
36
Chi-square (categorical values) and t-Student (continuous variables) tests.
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ACCEPTED MANUSCRIPT 1 Median survival values for each of the groups were calculated by Kaplan-Meier analyses. The
3
association of LRT with survival was evaluated by univariable and multivariable Cox-regression
4
models. Variables in the multivariable model included LRT, age, PSA (log-transformed), Gleason
5
score, tumour volume and the presence of symptoms. Cox-regression models were estimated for LRT
6
(RT and Surgery) and for RT and surgery as LRT separately. Only p-values <0.05 were considered
7
statistically significant. No correction for multiple testing was performed.
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Results Patient Characteristics and Local Symptoms
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Overall 300 PCa patients with metastatic disease at diagnosis were identified. Patient characteristics
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at diagnosis or first referral are summarized in Table 1. Most patients (95.6 %) presented with good
13
baseline ECOG PS (0 or 1) and received a median of 3 lines of treatment for metastatic CRPC. In
14
total 192 patients (64%) experienced local symptoms at some point during their disease course with
15
99 patients (33%) having these at diagnosis and 148 patients (49.3%) developing symptoms later on
16
during the course of the disease. Clinical data on local symptoms during the course of the disease
17
were not available in 4 of the 192 symptomatic patients.
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Follow up of these local symptoms in the 99 patients who were symptomatic at diagnosis, indicated
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that 42 of these patients (42/99, 42.4%) did not report any further local symptoms during the course of
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the disease of which only 20 had received a specific intervention for their local symptoms Fifty-three
22
patients (53/99, 53.5%) continued to experience local symptoms with 19 reporting the same (19/53,
23
35.8%), 32 worsening (32/53, 60.3%), and 2 improving local symptoms (2/53, 3.7%). Follow up data
24
on these local symptoms were not available for 4 patients. Of the 99 patients presenting with local
25
symptoms at diagnosis, 44 patients (44.4%) received medical intervention to manage their local
26
symptoms while 55 patients (55.5%) did not. In the 44 patients receiving medical intervention, local
27
symptoms resolved during the course of the disease in 19 (19/44, 43.1%), improved in 3 (3/44, 6.8%)
28
and persisted or worsened in 18 patients (18/44, 40.9%).
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Urinary frequency was the most commonly reported symptom at diagnosis (20%), followed by
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urinary retention (7.3%), haematuria (4.3%), pelvic pain (4%) and hydronephrosis (2%) (Table 2).
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During the course of the disease, urinary frequency remained the most frequently reported local
33
symptom (37.7%) followed by pelvic pain (12.7%), urinary retention (12%), haematuria (11%) and
34
hydronephrosis (8.7%).
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Loco-regional treatment
2 Overall 72 (24%) patients received LRT to the primary tumour (Table 3);18 (25%) patients
4
received this at diagnosis and 54 (75%) patients later during the course of the disease. Of these, the
5
majority were symptomatic with only 13 (18%) being free of local symptoms from the primary
6
tumour at the time LRT was performed. For those receiving LRT during the course of the disease,
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median time from diagnosis to LRT was 41.6 months (range: 6.9-170.1).
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The most common form of LRT was TURP in 41 (56.9%) patients followed by RT in 38 (52.7%)
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patients; 8 (11.6%) patients underwent both TURP and RT; one (1.4%) patient had focal surgical
11
intervention (laser prostatectomy) but none of the patients received radical prostatectomy.
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All patients treated with TURP reported local symptoms at the time of treatment; 15 (38.5%)
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patients had a TURP performed at diagnosis and 26 (63.4%) patients later during the course of
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treatment. For those treated during the course of the disease, median time from diagnosis to TURP
16
was 38.9 months (range: 8-119 months).
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(13.2%) patients received RT at diagnosis and 33 (86.8%) patients later during the course of the
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disease. In those treated during the course of the disease, median time from diagnosis to RT was 46.7
21
months (range: 6.9-170.1). Among these 33 patients treated with local RT along the disease course,
22
24 patients were symptomatic from the local tumour at the time of administration of RT. Following
23
local irradiation, local symptoms improved or resolved in 12 patients (12/24, 50%) but persisted or
24
worsened in the other 12 patients (12/24, 50%). Of the 156 patients with local symptoms but not
25
treated with RT, 27 patients (17.3%) required multiple treatments to control local progression.
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RT with radical intent was administered to the primary tumour to 16 (42.1%) patients with
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oligometastatic or oligorecurrent disease (21) of which 8 patients were treated with synchronous
29
external beam RT (EBRT) to additional bone or nodal metastatic lesions. Twenty-one (55.3%)
30
patients received RT with the intent to palliate local symptoms or improve the local control of the
31
disease. Data on one of these patients was missing. Twenty-six patients (76.5%) received at least 30
32
Gy, and 6 patients (15.8%) were treated with doses of 60 Gy or higher; the dose was unknown in 4
33
(10.5%) patients and fractionation was inconsistently reported.
34
LRT was more frequently performed in patients with low volume metastatic disease (35.4% vs
35
16.2%; p<0.001), lower PSA at diagnosis (median PSA: 75 vs 184 ng/mL; p=0.005) and with local
36
symptoms (34.2% vs 4.8%; p<0.001). No significant association was found with age (median age:
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63.1 vs 62.2 years; p=0.409) or Gleason Score ≥8 (24.6% vs 27.5%; p=0.657). The pattern of
2
metastatic spread was not clearly associated with LRT. Although there was a non-significant trend
3
towards patients with lymph node only disease reciving LRT in higher proportion (37% vs 21.5%;
4
p=0.068), no differences were observed in patients with visceral (22.7% vs 26.7%; p=0.725) or bone
5
only (28.7% vs 20.5%; p=0.125) metastases.
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Median follow-up was 54.6 months (range: 11.9-227.8), with 266 (88.7%) deaths. Median OS for
10
the whole cohort was 57.9 months (95%CI: 51.9-63.9) (Fig.1A). In univariate analysis, LRT was
11
associated with better OS (62.1 vs 55.8 months; HR: 0.74; p=0.044). LRT was also associated with
12
improved survival in a multivariable model including age, Gleason Score, PSA, volume of disease
13
(low vs high) at diagnosis and presence of symptoms as co-variates (Table 4A). We then evaluated
14
whether the type of LRT (radiotherapy or TURP/surgery) would have an equivalent effect on OS. In
15
univariate analysis, TURP/surgery was associated with a non-significant decrease in OS (54.3 vs 58.8
16
months; HR: 1.23; p=0.239) (Fig.1B), while patients receiving local RT appeared to have a significant
17
OS advantage (69.4 vs 55.1 months; HR: 0.54; p=0.002)(Fig.1C), which was maintained in the
18
multivariable Cox-regression model (Table 4B). There was no significant interaction between RT
19
treatment administration and disease volume evaluated at diagnosis or first referral (CHAARTED
20
criteria) (1) (p=0.958). Higher RT doses were associated with increased OS independently of the
21
volume of disease assessed at diagnosis or first referral (p<0.001).
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Discussion
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The past decade has seen a major change in therapeutic options for mPCa patients with several novel
25
and effective drugs receiving regulatory approval, resulting in significant OS improvements. As a
26
consequence, in our experience, an increasing number of patients are developing symptoms secondary
27
to local progression of untreated primary disease. Furthermore, although the local tumour tends to
28
respond well to initial ADT, the adaptive resistance mechanisms induced by subsequent lines of
29
hormonal or chemotherapy treatment impair the chances of achieving adequate local control. Small
30
increases in size of the local prostate tumour frequently result in urinary outflow obstruction and the
31
invasion of adjacent organs that may manifest clinically with macroscopic haematuria, tenesmus or
32
hydronephrosis. In our study, more than a half of de novo mPCa patients had locally symptomatic
33
disease at some point between diagnosis and death. The appropriate management of these local
34
prostate cancer complications remains challenging. Furthermore, therapeutic interventions may
35
themselves be, in some cases, the cause of long term side-effects such as erectile dysfunction, urinary
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2
proportion of the patients presenting with local symptoms at diagnosis (18/44, 40.9%) reported
3
persistent or worsening local symptoms despite local interventions. Nearly one in five M1 at diagnosis
4
patients with local symptoms who did not receive definitive treatment to the primary tumour in the
5
form of radical surgery or RT required multiple local interventions. This suggests that not treating the
6
primary may not only have implications to patient morbidity and longevity but also health economics.
7
However, RT treatment was efficacious in improving the local symptoms in only half of the treated
8
patients, suggesting that this local intervention may have been administered too late in the disease
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course. The timing of administration of LRT should not necessarily coincide with the development of
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local symptoms but probably at the first evidence of radiological progression.
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A recent paper published in the New England Journal of Medicine analysed patient-reported
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outcomes based on questionnaires in patients with localized prostate cancer treated with radical
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prostatectomy, RT or active surveillance. Sexual dysfunction and urinary incontinence were the most
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frequently reported adverse events among patients treated with radical prostatectomy whereas RT
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more often induced changes in bowel habits especially in the long term (24). The appropriate
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identification and timely management of patients with locally-advanced disease that are most likely to
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develop clinically relevant local symptoms is therefore key to prevent patient morbidity.
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This retrospective analysis suggests the possibility of an OS benefit from LRT in patients presenting
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with mPCa at diagnosis. This hypothesis has already been proposed by other retrospective case series
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from different centres, with similar positive results (4, 5, 6, 7, 8). Current guidelines for kidney,
23
ovarian and colorectal cancer recommend, whenever technically and clinically feasible, the surgical
24
removal of the primary tumour and the metastatic sites (9, 10, 11, 12, 13).
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Here we explored the effect on OS of different local treatments analysing RT and TURP as separate
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single interventions. As already mentioned before, the primary tumour releases in the circulation
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tumour cytokines which may have a role in stimulating tumour growth at the metastatic sites (15).
29
This implies that any intervention to the local disease may favourably or unfavourably alter this
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mechanism and ultimately affect OS. Here we suggest the hypothesis that the administration of RT to
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the local tumour may improve OS through not only the suppression of the aforementioned paracrine
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cytokines but also the dissemination of tumour-derived neoantigens triggering an antitumoral immune
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response (abscopal effect). On the contrary, the effect of TURP is more unpredictable with
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mechanical trauma disrupting the anatomic barriers surrounding the tumour and favouring not only
35
the circulation of tumour-derived cytokines and circulating tumour cells but also tumour neoantigens
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with consequent antitumor-immune responses (16, 17). The effect of TURP on OS may therefore be
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different depending on which one of these two processes predominates. Non-definitive LRT such as
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TURP may fail to fully abrogate the release of tumour-derived paracrine factors but still promote the
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intravascular dissemination of circulating tumour cells (18). In fact, prostate cancer cells can be
3
detected in the circulation during the peri-operative period in patients undergoing TURP and other
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studies have suggested an association of this procedure with disease progression (18, 19, 20). In our study, while local treatment (LRT) overall conferred a survival advantage (62.1 vs 55.8
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months; HR: 0.74; p=0.044), this was almost entirely restricted to patients receiving radiotherapy
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(69.4 vs 55.1 months; HR: 0.54; p=0.002) as opposed to those receiving TURP (54.3 vs 58.8 months;
8
HR: 1.23; p=0.239). The survival benefit from local radiotherapy appeared to be independent of other
9
known prognostic variables (age, Gleason Score, PSA, volume of disease and presence of symptoms)
10
included in multivariable Cox-regression models. Importantly, the survival benefit was independent of
11
the volume of bone metastases, suggesting that both patients with a low and a high burden of
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metastases could potentially benefit from local RT. These results, although limited by the small
13
number of patients and its retrospective nature, may indicate that the overall biological effect of
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TURP on OS is negligible whereas RT may instead have a favourable impact on OS. The different
15
effect on OS between these two main local treatment modalities (RT or TURP) may be, in part,
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explained by the different rationale for treatment indication. While TURP was generally carried out to
17
resolve urinary symptoms such as urinary obstruction and/or urinary frequency, the rationale for
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administering RT in nearly half the patients was primarily not to palliate local symptoms but rather to
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improve local control and prevent the subsequent development of local symptoms.
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We acknowledge that our study has a number of limitations including its retrospective nature and
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our population heterogeneity. Relatively few patients received local treatment, which is consistent
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with current clinical practice, since local treatment in asymptomatic metastatic patients is not the
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current standard. With this, as with other similar retrospective studies published to date, treatment
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selection bias (i.e. the selection of patients with better baseline prognostic features for local treatment
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at baseline) may significantly alter the interpretation of results. In our study, however, RT to the
27
primary tumour was associated with significantly increased OS independently of other important
28
baseline prognostic factors such as the volume of metastatic disease, Gleason Score or PSA.
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Furthermore, the role of an “abscopal effect”, suggested as a possible biological mechanism to
30
support the role of LRT in advanced prostate cancer, cannot be supported in our series due to the
31
different timing of local therapy in our patients. The fact that not all patients had local treatment at
32
baseline may have also led to the selection of those with favourable responses for local treatment
33
along the course of the disease. Other studies previously published supporting the role of local therapy
34
in advanced prostate cancer come from large databases that, unfortunately, do not contain most of the
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clinical parameters that are evaluated here. This is one of the first studies that takes into account the
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clinical heterogeneity of patients treated with local therapy, the very important methodological
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limitations to conducting similar analyses, therefore supporting the notion that well conducted,
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randomized prospective clinical trials are needed to correctly answer this very important clinical
3
question.
4 Conclusion
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Although this is a retrospective study limited by a risk of selection bias with the possibility of
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overestimating the OS impact of local radiation, these data support the rationale for conducting large
8
randomized Phase III trials to determine whether local treatment improves outcome for metastatic at
9
diagnosis PCa patients. Moreover, our data make clear that not treating local disease in mPCa patients
10
at diagnosis results in significant local disease morbidities during their lifetime with these patients
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commonly requiring invasive interventions with significant health economic implications particularly
12
as patients with mPCa live longer with better systemic therapies.
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15 •
17 18
interventions with significant impact in terms of morbidity and health economics •
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Local symptoms in de novo mPCa patients are common and often require multiple invasive
The definitive treatment of the primary tumour may favourably affect outcome and prevent local symptoms
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Large randomized prospective clinical trials to investigate the OS benefit of RT to the primary tumour in de novo mPCa patients such as STAMPEDE are ongoing and results are
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eagerly awaited.
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References 1. Sweeney CJ, Chen YH, Carducci M et al, Chemohormonal Therapy in Metastatic HormoneSensitive Prostate Cancer. N Engl J Med. 2015 Aug 20; 373(8):737-46. 2. James ND, Sydes MR, Clarke NW et al, Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from
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an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar 19;
7
387 (10024):1163-77.
8 9 10
RI PT
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3. Parker CC, Sydes MR, Mason MD et al., Prostate radiotherapy for men with metastatic
disease: a new comparison in the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial. BJU Int. 2013 May;111(5):697-9. 4. Culp SH Schellhammer PF, Williams MB., Might men diagnosed with metastatic prostate
12
cancer benefit from definitive treatment of the primary tumour? A SEER-based study Eur
13
Urol 65 (2014) 1058-1066.
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14
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5. Fossati N, Trinh QD, Sammon J et al. Identifying optimal candidates for local treatment of
15
the primary tumour among patients diagnosed with metastatic prostate cancer: a SEER-based
16
study (2015) Eur Urol. Jan; 67(1):3-6.
17 18
6. Engel J, Bastian PJ, Baur H Survival benefit of radical prostatectomy in lymph node-positive patients with prostate cancer (2010) Eur Urol.; 57, 754-761.
7. Patrikidou A, Brureau L, Casenave J et al. Locoregional symptoms in patients with de novo
20
metastatic prostate cancer: morbidity, management and disease outcome (2015)Urol Oncol.
21
May; 33(5).
22
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19
8. Rusthoven CG, Jones BL, Flaig TW et al. Improved Survival with Prostate Radiation in Addition to Androgen Deprivation Therapy for Men with Newly Diagnosed Metastatic
24
Prostate Cancer. J Clin Oncol(2016) Aug 20; 34(24):2835-42.
EP
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9. Glehen O, Mohamed F, Gilly FN., Peritoneal carcinomatosis from digestive tract cancer: new
26
management by cytoreductive surgery and intraperitoneal chemohypertermia(2004) Lancet
27 28 29 30 31
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Oncol; 5:219-28.
10. Bristow RE Tomacruz RS, Armstrong DK et al., Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a metanalysis(2002) J Clin Oncol; 20:1248-59.
11. Flanigan RC, Salmon SE, Blumenstein BA et al, 2001 Nephrectomy followed by interferon
32
alfa-2b compared with interferon alfa-sb alone for metastatic renal-cell cancer. N Engl J Med
33
345, 1655-1659.
34
12. Mickisch GH, Garin A, van Poppel H et al. 2001 Radical nephrectomy plus interferon-alfa-
35
based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma:
36
a randomised trial. Lancet 358, 966-970.
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13. Temple LK, Hsieh L, Wong WD et al. Use of surgery among elderly patients with stage IV colorectal cancer. J Clin Oncol. 22, 3475-3484. 14. Badwe R, Hawaldar R, Nair N et al., Locoregional treatment versus no treatment of the
4
primary tumour in metastatic breast cancer: an open-label randomised controlled trial. Lancet
5
Oncol (2015) Oct; 16(13):1380-8.
7
15. Kim MY, Oskarsson T, Acharyya S et al. Tumor self-seeding by circulating cancer cells. Cells (2009) 139, 1315-1326.
RI PT
6 8
16. Demaria S1, Ng B, Devitt ML et al., Ionizing radiation inhibition of distant untreated tumors
9
(abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys, (2004) 58, 862-870.
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17. Hoshino A, Costa-Silva B, Shen TL et al., Tumour exosome integrins determine organotropic metastasis. Nature (2015) Nov 19; 527(7578):329-35.
SC
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18. Krupski TL, Stukenborg GJ, Moon K et al., The relationship of palliative transurethral
13
resection of the prostate with disease progression in patients with prostate cancer. BJU
14
International (2010), 106, 1477-1483
15
M AN U
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19. Heung YMM, Walsh K, Sriprasad S et al., The detection of prostate cells by the reverse
16
transcription-polymerase chain reaction in the circulation of patients undergoing transurethral
17
resection of the prostate. BJU International (2000), 85, 65-69.
18
20. Forman JD, Order SE, Zinreich ES et al., The correlation of pretreatment transurethral resection of prostate cancer with tumor dissemination and disease-free survival. A univariate
20
and multivariate analysis. Cancer(1986) Oct 15;58(8):1770-8.
21 22 23
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21. Tosoian JJ, Gorin MA, Ross AE et al. Oligometastatic prostate cancer: definitions, clinical outcomes, and treatment considerations. Nat Rev Urol(2016) Oct 11. 22. Kyrdalen AE, Dahl AA, Hernes E, et al. A national study of adverse effects and global quality of life among candidates for curative treatment for prostate cancer. BJU
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Int.(2013) Feb; 111(2):221-32.
27 28 29 30
23. Elsamra SE, Leavitt DA, Motato HA et al. Stenting for malignant ureteral obstruction: Tandem, metal or metal-mesh stents. Int J Urol(2015) Jul; 22(7):629-36.
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24. Donovan JL, Hamdy FC, Lane JA et al., Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer. N Engl J Med.(2016) Oct 13; 375(15):14251437.
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ACCEPTED MANUSCRIPT Table 1. Patient Characteristics LRT (+) 62.2 (56.9-66.5)
LRT (-) 63.1 (57.8-68.6)
0-1 2
287 (95.7%) 13 (4.3%) 150 (55-500)
64 (92.8%) 5 (7.2%) 75 (35 - 381)
217 (96.4%) 8 (3.6%) 184 (65.3-533.5)
≥8 <8 Unknown Metastatic sites Bone Lymph nodes Visceral Tumor Burden (CHAARTED criteria) High Low Post-CRPC lines of treatment
164 (54.7%) 66 (22%) 70 (23.3%)
44 (63.8%) 16 (23.2%) 9 (13%)
265 (88.3%) 83 (27.7%) 15 (5%)
54 (78.3%) 23 (33.3%) 4 (5.8%)
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181 (60.3%) 117 (39%) 3 (2-3)
116 (51.6%) 49 (21.8%) 60 (26.7%) 207 (92%) 56 (24.9%) 11 (4.9%)
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PSA Gleason
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All patients 63 (57.7-68.5)
Age (yr) ECOG PS
29 (42%) 40 (58%) 3 (2-3)
150 (66.7%) 73 (32.4%) 3 (2-3)
Table 2. Local Symptoms
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All patients (n=294) At During diagnosis disease 96 147 (32%) (49.3%) 12 38 (4%) (12.7%) 13 33 (4.3%) (11%) 60 113 (20%) (37.7%) 22 36 (7.3%) (12%) 6 26 (2%) (8.7%)
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At least one symptom Pelvic Pain
Hematuria Urinary Frequency Urinary Retention
Hydronephrosis
LRT (+) LRT (-) (n=69) (n=225) At During At During diagnosis disease diagnosis disease 32 56 60 91 (46.4%) (81.2%) (26.7%) (40.4%) 4 14 6 23 (5.8%) (20.3%) (2.7%) (10.2%) 4 18 9 14 (5.8%) (26.1%) (4%) (6.2%) 17 42 41 71 (24.6%) (60.9%) (18.2%) (31.6%) 11 18 9 18 (15.9%) (26.1%) (4%) (8%) 3 18 3 8 (4.3%) (26.1%) (1.3%) (3.6%)
Information on symptoms was missing for 6 (2%) patients.
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TURP only Surgery only Radiotherapy only TURP + Surgery TURP + Radiotherapy Radiotherapy + Surgery
At diagnosis (n=18) 13 (72,2%) 0 3 (16.7%) 0 2 (11.1%) 0
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*3 patients had LRT at diagnosis and during the course of the disease: 2 patients had TURP at diagnosis and TURP during the course of the disease and 1 patient had TURP at diagnosis and RT during the course of the disease.
Table 4. Multivariable Survival Analysis
4A) LRT including both Radiotherapy and TURP
p-value 0.030 0.766 0.001 0.132 <0.001 0.303
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LRT Age PSA at Dx* Gleason Score** Volume of metastases*** Symptoms at Diagnosis
HR (95% CI) 0.68 (0.48-0.96) 1 (0.98-1.02) 0.69 (0.55-0.86) 1.23 (0.93-1.76) 1.89 (1.39-2.58) 1.04 (0.97-1.11)
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4B) LRT when only Radiotherapy is considered
LRT Age PSA at Dx* Gleason Score** Volume of metastases*** Symptoms at Diagnosis
HR (95% CI) 0.53 (0.33-0.85) 1 (0.97-1.02) 0.7 (0.56-0.87) 1.29 (0.94-1.77) 1.8 (1.32-2.45) 1.03 (0.96-1.1)
p-value 0.008 0.644 0.002 0.120 <0.001 0.406
*PSA at diagnosis was log-transformed **Gleason Score: ≥8 vs <8 **Volume of metastatic disease: high vs low as per CHAARTED criteria
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Figure 1A: LRT and Survival (TURP + RT)
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Figure 1B: LRT and Survival (TURP only)
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Figure 1C: LRT and Survival (RT only)