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Pacientesoligometastásicos:¿hay untratamientodiferenciado? Dr.MiguelAngel Climent FundaciónInstitutoValencianodeOncología Esquemaquevamosaseguir… • Definicion delasituación • Esunaenfermedaddiseminadadelaquevemosel principioo… • Esunasituaciónconcaracterísticasclinicobiológicas propias • Numeroylocalización(abarcablesportto.único) • Nuevaspruebasdeimagen:PET • TratamientodelaenfermedadlocalenM1 • Linfadenectomía (cirugía)derescate • RTenoligometastasico sites could be treated using local therapy. Oligometastasis yoligorrecurrencia SYSTEMIC THERAPY AND LOCAL THERAPY 108 Oligometastases and oligo-recurrence Improvement of systemic chemotherapy including molecular-targeted therapy has allowed micrometastases thera sion inclu be er state (rang powe eradic Table 1. Oligometastases and oligo-recurrence Oligometastases Oligo-recurrence Reference Hellman and Weichselbaum (1) Niibe et al. (2,3,4) Primary lesion Uncontrolled/controlled Controlled No. of distant/metastases/ recurrences One to several One to several (one is better) to be almost completely absent clinically. Theoretically, if several gross metastatic or recurrent sites could be eradiated by local therapy, these patients could be cured with concomitant systemic chemotherapy. Punglia et al. (5) reported that if systemic therapy improved, the role of local therapy would improve and proposed a figure for this Figure correlation. figure of Schema the correlation 2. This is Here, a schemaa ofnew oligo-recurrence. 1 shows one distant metastasis/recurrence with a controlled primary lesion. Schema 2 shows two between local therapy and systemic therapy is proposed Figure 1. This is a schema of oligometastases. Schema 1 shows one distant distant metastases/recurrences with a controlled primary lesion. The biggest (Fig. 3), showing that the role of local therapy is initially metastasis/recurrence with a primary lesion. Schema 2 shows two distant difference between oligometastases and oligo-recurrences lies in the unconincreasingly important as lesion. systemic therapy requires improves, metastases/recurrences with a primary lesion. trolled or controlled primary Oligo-recurrence a controlled stases and oligo-recurrence depending on the sigmoid curve. The current status of primary lesion. cancer therapy lies in the range between 0 and between oligometastasis and oligo-recurrence are listed in A. However, in the future, extreme improvements in sysTable 1. Oligometastases oligo-recurrence Table 1. In the state of oligo-recurrence, recurrent orand metatemic therapy will decrease the importance of local static sites with a controlled primary lesion were treated withOligometastases Oligo-recurrence therapy, because cancers will be diminished by systemic local therapy, meaning that all gross recurrent or metastatic Reference Hellman and Niibe et al. therapy alone such as intravenous anti-cancer drug infusites could be treated using local therapy. Weichselbaum (1) (2,3,4) sion or oral Controlled anti-cancer drugs. All cancerous lesions Primary lesion Uncontrolled/controlled including gross tumors and microinvasive tumors could No. of distant/metastases/ One to several One to several be eradicated (one withis better) systemic therapy alone. This desirable SYSTEMIC THERAPY ANDrecurrences LOCAL THERAPY state is shown as B in Fig. 3. In the present status Figure Until improv temic t therapy ¿existecomoentidadoesunpuntodecorte? ¿existe como entidad o es un punto de corte? Comportamiento biológico del CPRC Tto. Local AB,ENZ DOCE CBZ,AB, ENZ,Rd EXITUS M1 PSA CPRC M0 M1 Asintomático Sintomático 16-19ms 30-35ms 20-44ms MedianasSupervivencia Comportamiento del CPRC ¿existe como entidad biológico o es un punto de corte? Comportamiento biológico del CPRC Tto oligometa Tto. Local DOCE CBZ,AB, ENZ,Rd EXITUS M1 PSA CPRC M0 M1 Asintomático Sintomático 16-19ms 30-35ms 20-44ms MedianasSupervivencia Platinum Opinion w.sciencedirect.com ‘‘Gotta Catch ’em All’’, or e: www.europeanurology.com Do We? Pokemet Approach to Metastatic Prostate Cancer Declan G. Murphy a,b,c,*, Christopher J. Sweeney d, Bertrand Tombal e a Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia; b Australian Prostate Cancer Research Centre, Epworth Healthcare, c Richmond, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; d Dana-Farber Cancer Institute, e Harvard Medical School, Boston, MA, USA; Institut de Recherche Clinique, Cliniques Universitaires Saint-Luc, Brussels, Belgium ‘‘Gotta catch ’em all’’ is the catch-cry of location-based augmented reality game Pokemon Go, which caused a worldwide sensation when it was launched in July 2016. Within 1 wk, it had become the most downloaded app in the history of Apple’s App Store; within 2 mo it had reached 500 million downloads; within 5 mo its users had taken over 8.7 billion steps in their quest to catch Pokemon; and despite a drop-off in users since launch, more than 20 million people still spend hours each day trying to catch Pokemon using their smartphones. ‘‘Pokemania’’ does seem an appropriate term to describe the phenomenon whereby users chase around various locations trying d to trap a,b,c, e Pokemon in a fruitless effort to ‘‘catch ’em all’’. In the world of metastatic prostate cancer, there is ery, Peter MacCallum Cancer Centre,inMelbourne, Australia; b Australian Prostate Cancer Research Centre, Epworth Healthcare, considerable interest at present aggressive therapeutic approaches to oligometastatic cancer.University The term of Melbourne, Melbourne, Australia; d Dana-Farber Cancer Institute, e Sir Peter MacCallum Department prostate of Oncology, metastasis-directed therapy (MDT) has been used to describe Boston, MA, USA; e Institut de Recherche Clinique, Cliniques Universitaires Saint-Luc, Brussels, Belgium surgical resection of, or stereotactic radiation therapy to, low-volume oligometastatic lesions in selected prostate cancer patients [1]. On the basis of experience in other ll’’ is the catch-cry of location-based tumour types, it has been suggested that ablative approaches to oligometastatic (typically game Pokemon Go, whichcancer caused a defined as up to 3 synchronous metastases, bone and/or lymph nodes) on when it orwas in July may defer enhancelaunched the need for systemic therapy in some with perhaps some patients never requiring further it hadpatients, become the most downloaded treatment [2]. Androgen deprivation therapy (ADT) alone on ch ’em All’’, or Do We? Pokemet Approach to Prostate Cancer hy *, Christopher J. Sweeney , Bertrand Tombal py (SABR) with ongoing biochemical and clinical progression. Images for a 67-yreason grade group 2 prostate cancer with negative pathological margins. (A) Declan G. Murphy a,b,c,*, Christopher J. Sweeney d, Bertrand Tombal e ¿quéesprimero…elhuevoolagallina? a Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia; c b Australian Prostate Cancer Research Centre, Epworth Healthcare, Richmond, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; d Dana-Farber Cancer Institute, e Harvard Medical School, Boston, MA, USA; Institut de Recherche Clinique, Cliniques Universitaires Saint-Luc, Brussels, Belgium ‘‘Gotta catch ’em all’’ is the catch-cry of location-based augmented reality game Pokemon Go, which caused a worldwide sensation when it was launched in July 2016. Within 1 wk, it had become the most downloaded app in the history of Apple’s App Store; within 2 mo it had reached 500 million downloads; within 5 mo its users had taken over 8.7 billion steps in their quest to catch Pokemon; and despite a drop-off in users since launch, more than 20 million people still spend hours each day trying to catch Pokemon using their smartphones. ‘‘Pokemania’’ does seem an appropriate term to describe the phenomenon whereby users chase around various locations trying to trap Pokemon in a fruitless effort to ‘‘catch ’em all’’. In the world of metastatic prostate cancer, there is considerable interest at present in aggressive therapeutic approaches to oligometastatic prostate cancer. The term metastasis-directed therapy (MDT) has been used to describe surgical resection of, or stereotactic radiation therapy to, low-volume oligometastatic lesions in selected prostate cancer patients [1]. On the basis of experience in other tumour types, it has been suggested that ablative approaches to oligometastatic cancer (typically defined as up to 3 synchronous metastases, bone and/or lymph nodes) may defer or enhance the need for systemic therapy in some patients, with perhaps some patients never requiring further treatment [2]. Androgen deprivation therapy (ADT) alone has limited efficacy, in contrast to ADT combined with radiation in high-risk localized disease. In parallel, there is much interest in aggressive approaches to the primary cancer in men presenting with metastatic cancer, with a number of studies ongoing in what is an experimental Fig. 1 – The growth in publications on oligometastatic prostate cancer is paralleled by the growth in publications on prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) imaging of prostate cancer. • PaCents!data!from!8,820!men!with!mCRPC)enrolled)onto)9)phase)III)trials.) • Site!of!metastases:!!lymph)node)only,!bone)with)or)without)LN,!any!lung!metastases!(but! no!liver),!and!any!liver!metastases.! • Specific!sites!of!metastases!in!men!with!mCRPC!are!associated!with!differenCal!OS:!LN>Bone>lung>liver)) • These!data!may!help!in!treatment)decisions,!!design)of)clinical)trials,!and!understanding!the!variaIon) in)biology)of)different)sites)of)metastases)in!men!with!mCRPC.! Eur)Urol.) 2016)Mar)19) Post hoc. Overall Survival according to disease extension (<4)vs)≥4)bone)mets.)) Podemossóloestarescogiendolas mejores… Abstract #5018 #5018 Ext vs. Lim PLND ¿Cómoeselfenómenodelasmetastasis? I. Halsted 1907: Ca. de mama siempre se disemina vía linfática locorregional la enfermedad se puede curar si se dx en un estadío precoz. II. Hellman 1994: Ca. de mama siempre metastatiza aparecen tan precozmente, que las terapias locales son menos importantes que el microambiente tumoral o terapias sistémicas. I. Fisher, Hellman 2005 “Spectrum hypothesis”: rango entre enf. local y la enf. diseminada en el momento del diagnóstico. ¿Cómoeselfenómenodelasmetastasis? Las metástasis surgen de una expansión clonal, los clones con ventajas selectivas dan lugar a metástasis si estos clones son destruidos (p.e. con SBRT ) teóricamente podríamos reducir el potencial metastásico. and polymetastatic groups in the an two-tailed Background: Fisher Exact Cancer Test). These that stagingdata and demonstrate treatment presumes abetween divisionthe intooligometastatic localized or metastatic disease. We proposed intermediate state defined by #5from cumulative termeddataset oligometastases. In tumor contrast to widespread metastatic tumor and the primary set independently detected patterns of microRNA expression metastaticmetastasis(es), may benefit from metastasis-directed local treatments. many29patients using a two-tailed Student t-test (P,0.05). However, We prioritized and samples arepolymetastases, dominated byoligometastatic oligometastaticpatients or polymetastatic initially present with S1). oligometastases progress to polymetastases. Predictors of progression could improve patient 17 microRNAs that characterized oligometastatic or polymetaprogression who of disease (Fig. 1, Table In contrast, unsuperselection for metastasis-directed static progression in the two datasets, respectively (Table 1, vised hierarchical clustering using microRNA therapy. expression of tissue 1,5. Yves A. Lussier1,2,3,4*,exclusively H. Rosie obtained Xing1,2,5,6. , Joseph K. Salama8., Nikolai N. Khodarev , Yong Huang1,3., Fig. 1, Figure S1). We designated these sets as 29 M-miRs from primary tumors of patients failed to 7. 3. 5. 5 from oligometastatic patients treated with Methods: Here, we identified patterns D. of microRNA expression of tumor samples A. Khan Yang , Michael Hasselle E. prioritized Darga , from Renuka Qingbei Zhang3,6., Sajid (microRNAs metastatic tumors, Table 1a) and accurately separate, Xinan oligometastatic and polymetastatic patients , Thomas high-dose5 radiotherapy. 5 6 5 5 3 17 Pr-miRs (microRNAs prioritized (Fig. S1). Perakis Indeed, unsupervised not designed to , Matthewmethods Filippoare, Kimberly Corbin , Younghee Lee , Mitchell C. from primary tumors, Malik , Hanli Fan , Samantha Table 1b). To validate Pr-miR and M-miR, we applied them identify5a phenotype, such as the subtle distinction between oligo- 1,2,5 7 2,5 Results: Patients who failed to develop polymetastases are characterized by unique prioritized features of a microRNA * Posner , Steven J. Chmura , Samuel Hellman , Ralph R. Weichselbaum to patients in the alternative dataset (ie Pr-miR wasmodel tested in in which the and poly-metastases, while the primary tumor cells family. are more classifier that includes the microRNA-200 We created an oligometastatic-polymetastatic xenograft 1 Comprehensive Cancer Center, University of Chicago, Chicago, United States ofWe America, Center for Metastasis Research, University Chicago, and M-miR in the patients patients with metastatic tissueofobtained heterogeneous than thoseIllinois, of microRNAs metastases. thus2 Ludwig obtained the patient-derived discriminated between the two metastatic outcomes. MicroRNA-200c enhancement in an Chicago, Illinois, United States of America, 3 Department of Medicine Center for Biomedical Informatics, University of Chicago, Chicago, Illinois, United States of America, with primary tissue profiled). This analysis was performed using microRNA oligometastatic profiles of 5 patients whom in both primary andprogression. cell lineforresulted polymetastatic 4 Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, United States of America, 5 Department of Radiation and Cellular Oncology, the unsupervised first component of a principal component metastatic samples were collected. In MicroRNA four of fiveCharacterizes patients primary Oligometastasis(es) University of Chicago, Chicago, Illinois, United States of America, 6 Department of Pathology Committee on Biology,basis University ofoligometastases Chicago, Chicago, Illinois, United Conclusions: These demonstrate a Cancer biological for(PCA) a potential for different using microRNA analysis (Methods, and Methods S1). At cutoff and metastatic tumor samples, theresults microRNA of the same patient States of America, 7 Department of Surgery, University of Chicago, Chicago, Illinois, United States of America, 8 Department of Radiation Oncology Duke University expression to identify patients most likely to remain oligometastatic after metastasis-directed treatment. MicroRNA Expression Characterizes Oligometastasis(es) Medical Center, Durham, North Carolina, United States of America Abstract andb.metastasis(es) sample sitesby of Expression the same patient andof (ii)Oligooligo vs Polymetastases in Human Metastatic and Primary Table 1. a(Pr) and Prioritized microRNAs Analysis Citation: YA, Xing HR,(Pol-) Salama JK, Khodarevphenotype NN, Huang across Y, et al. patients. (2011) MicroRNA Expression Characterizes Oligometastasis(es). PLoS ONE 6(12): e28650. (Ol-) vsLussier polymetastatic progression Tumors.doi:10.1371/journal.pone.0028650 doi:10.1371/journal.pone.0028650.g001 Editor: Mikhail V. Blagosklonny, Roswell Park Cancer Institute, United States of America Background: Cancer staging and a division intoof11, localized or metastatic Received Octoberpresumes 10, 2011; Accepted November 2011; Published Decemberdisease. 13, 2011 We proposed an Table 1a. Oligo vs polymetastases progression in metastatic tumor samples (M-miRs) Intreatment vivo assessment of the effect microRNA-200c intermediate state defined byCopyright: #5 cumulative metastasis(es), oligometastases. In contrast tothewidespread ! 2011 Lussier et al. This is antermed open-access article distributed under the terms of Creative Commons Attribution License, which permits miRIDIAN mimics treatment metastatic progression in However, MicroRNA FC pon (t-test) MicroRNA FC patients p (t-test) polymetastases, oligometastatic patients maydistribution, benefit from metastasis-directed local treatments. unrestricted use, and reproduction in any medium, provided the original author andmany source are credited. two mouse models who initially present with oligometastases progress to polymetastases. Predictors of progression could improve patient Funding: This work28.3 was supported by the Ludwig Research Grant, the Center for Radiation Therapy, the Chicago miR-654-3p 0.028 Center for MetastasismiR-95 2.4 0.029 Tumor Institute, Dr. Lloyd 40% confluent L1-R2-435-GFP cells orLung B16F1 were selection for metastasis-directedOld, therapy. Mr. and Mrs. Vincent Foglia and the Foglia foundation, Cancer cells Research Foundation, the Cancer Research Foundation and the following NIH Grants: K22 miR-654-5p 24.6 0.041 miR-500 22.1 LM008308-04, 5UL1RR024999-04, Chicago(Cat#110CN-001000Comprehensive Cancer Center (5P30CA014599-35), National Center 0.047 for the Multi Scale Analysis of transfected with 100 nMUniversity Control ofmimics Genomicof and Cellular Networks (MAGNeT; 5U54CA121852-5). The funders had no role in study design, collection and analysis, Methods: Here, we identified patterns microRNA expression of tumor samples from oligometastatic patients treated miR-200c 20.1 0.029 miR-328 22.2datawith 0.002 decision to publish, or 01), or species-specific miR-200c miRIDIAN mimics (L1-R2-435of the manuscript. high-dose radiotherapy. miR-105 preparation GFP: #C-300646-05-0010; B16F1: (Dhar15.9 0.023 # MIMAT0000039) miR-125a-3p 22.2 0.048 Competing Interests: The authors have declared that no competing interests exist. macon, Lafeyette, CO, USA) using Oligofectamine (Invitrogen, miR-375 14.9 0.027 miR-140-5p 0.024 Results: Patients who failed to* develop polymetastases are characterized by unique prioritized features of a 22.2 microRNA E-mail: [email protected] [email protected] Carlsbad, CA, USA) as we(RRW); previously described(YAL) [22]. Transfection miR-135b 0.013 miR-29c xenograft model 22.4 0.008 classifier that includes the microRNA-200 family.7.8We created an oligometastatic-polymetastatic in which . These authorswas contributed equally to this work. to be .90%. In vivo tailefficiency optimized the patient-derived microRNAs theand twoestimated metastatic outcomes. MicroRNA-200c enhancement miR-200b discriminated between 5.7 0.032 miR-140-3p 22.4 in an 0.018 injection of progression. control or specific mimics-treated L1-R2-GFP oligometastatic cell line miR-410 resulted invein polymetastatic 6 5 5.4 0.01 miR-489 22.7 0.008 (2610 cells/mouse) or B16F1 cells (1610 cells/mouse) was it has only recently received attention Introduction miR-376a 4.7 0.049 miR-331-5p 23.6 0.046 as a defined subset o performed at 48 h after transfection. Conclusions: These results demonstrate a biological basis for oligometastases and a potential for using microRNA metastasis [1,7,8]. Employing radiotherapy improvements, terme For model, tumor-cell mice expression to identify patients most likelythe to remain oligometastatic metastasis-directed treatment. miR-323-3p 4.1 0.023after miR-193a-3p 26.7 0.036 Metastases areL1-R2-435-GFP the leading cause of cancer death.inoculated Standard hypofractionated image-guided radiotherapy (HIGRT) or stereo were monitored and scored for tumor metastasis development and miR-539 4 0.045 miR-199b-5p 29.5 0.043 therapies for most metastatic cancers are systemic chemotherapy, tactic body radiotherapy (SBRT), we [9] and others [8] treate progression as3.6 above. For the therapies. B16F1 mouse melanoma Citation: Lussier YA, Xing HR, Salama JK, Khodarev NN, Huang Y,described et al.or (2011) MicroRNA Expression Characterizes Oligometastasis(es). PLoS ONE 6(12): e28650. miR-642 0.024 miR-502-5p 218.3 0.034 hormonal manipulation newer targeted However, metastatic lesions using a few high-doses of radiotherapy i weeks curative. C57BL/6We female mice that wereduring obtained doi:10.1371/journal.pone.0028650 these model, agents 4–6 are rarely proposed the frominoperable patients Initial reports demon miR-370 3.2 0.031 miR-545 220.2with #5 metastasis(es). 0.022 labs (Indianapolis, IN, USA). The care and treatment of Editor: Mikhail V. Blagosklonny, Roswellevolution Park Harlan CancerofInstitute, United States of America some tumors, an intermediate metastatic state exists strated long-term disease free survival in some treated patien miR-127-3p experimental 3 animals was in 0.04 miR-363 221.6 0.012 accordance with institutional Received October 10, 2011; Acceptedcalled November 11, 2011; Published 13, 2011 that these patients, oligometastasis(es). WeDecember hypothesized [8,9,10,11]. However, many oligometastatic patients develope miR-212 2.7 University of Chicago. 0.002 guidelines the Mice were sacrificed 14 a less at aggressive biology with cumulative widespread cancer and were subsequently classified a Copyright: ! 2011 Lussier et al. This exhibiting is an open-access article distributed under the limited terms of[1,2,3] the Creative Commons Attribution License, whichprogression permits days after tail vein injections. The thoracic cavity of each (Pr-miRs) mouse unrestricted use, distribution, andTable reproduction in any medium, provided the original author and source are credited. 1b. Oligo vs polymetastases progression in primary tumor samples metastasis(es) in less than 4 months from time of first metastatic polymetastatic (.5 new metastatic sites, see methods). W was opened andpotentially lungs werebenefit removed in their entirety and surface progression, from Funding: This work was supported by the Ludwig Centercould for Metastasis Research Grant, Centermetastasis-directed for Radiation Therapy, the Chicago Tumor Institute, Lloyd hypothesized that molecular markers could be developed fo MicroRNA FC were p the (t-test) MicroRNA FC Dr. p (t-test) lung metastasis(es) scored using methods previously describedand the following NIH Old, Mr. and Mrs. Vincent Foglia and the Foglia foundation, Lung Cancer Research Foundation, Research Foundation Grants: therapy [1,3]. This hypothesis was based the on Cancer long-term survival identifying patients whoK22 would fail to become polymetastatic. W LM008308-04, 5UL1RR024999-04,miR-654-3p University of[23]. Chicago Comprehensive Cancer Center (5P30CA014599-35), National Center for the Multi Scale of 0.018 miR-127-3p 1.7Analysis 0.036 from paraffin blocks o following surgical 17 resection liver or and analyzed microRNA expression derived Genomic and Cellular Networks (MAGNeT; 5U54CA121852-5). The funders of hadlimited no role inlung study[2], design, data[4,5], collection analysis, decision to publish, or After being excised from each mouse, the lung tissue was fixed 14.3 from a variety 0.014 of primary sites.miR-24 21.5 oligometastatic0.014 adrenal metastases[6] An patients who were at time of treatment wit preparation of the manuscript. miR-542-3p in 10% formalin, embedded inclinical paraffin, cut into 5 micrometerscurative intent radiotherapy. We report unique prioritized feature oligometastatic common miR-548c-3p 10 is a interests 0.001 presentation although miR-27b 21.6 0.025 Competing Interests: The authors have declared that nostate competing exist. sections, stained with hematoxylin and eosin and examined for miR-758 8.8 0.045 miR-197 21.9 0.032 * E-mail: [email protected] (RRW); [email protected] macro- or (YAL) micrometastases. 5 mice were examined from each miR-483-5p 3.6 0.038 miR-330-3p 22 0.01 . These authors contributed equally to this work. group. PLoS ONE | www.plosone.org 1 December 2011 | Volume 6 | Issue 12 | e2865 miR-369-3p 3.6 0.047 miR-671-3p 22.2 0.012 REVIEWS Definicióndeoligometástasis Table 1 | Studies defining oligometastatic prostate cancer Author/Site n Number of Sites of metastases metastases Detection Tabata et al.27 35 ≤5 Bone only; each site <50% size of vertebral body Bone scan Ahmed et al.28 17 ≤5 NS 11 Berkovic et al.29 24 ≤3 Bone or LN • Bone scan + 18F-FDG PET–CT(n = 20) • Bone scan + 11C-choline PET–CT(n = 4) Schick et al.30 50 ≤4 NS • Bone scan + 18F-choline PET–CT • Bone scan + 11C-acetate PET–CT Decaestecker et al.31 50 ≤3 Bone or LN • 18F-FDG PET–CT(n = 32) • 18F-choline PET–CT (n = 18) Ost et al.32 119 ≤3 Any 18 NR Any except brain —JJ.Nature rev Urology,2016 Tososian Original studies C-choline PET–CT (n = 7), MRI (n = 6), biopsy (n = 1), CT (n = 1), 11C-choline PET–CT and MRI (n = 2) F-FDG PET–CT (n = 24) or 18F-choline PET–CT (n = 92) Prospective trials (NCTI) University of Florida (NCT01859221)33 NS Schick et al.30 50 ≤4 NS • Bone scan + 18F-choline PET–CT • Bone scan + 11C-acetate PET–CT Decaestecker et al.31 50 ≤3 Bone or LN • 18F-FDG PET–CT(n = 32) • 18F-choline PET–CT (n = 18) Ost et al.32 119 ≤3 Any 18 University of Florida (NCT01859221)33 NR NS Any except brain or CNS — Sunnybrook Health Sciences Centre (NCT02563691)34 NR ≤5 Outside the prostate and pelvic lymph nodes — Sidney Kimmel Comprehensive Cancer NR Center (NCT02489357)35 ≤4 Extrapelvic — Mayo Clinic (NCT01777802)36 NR ≤3 NS — Grupo de Investigación Clínica en Oncología Radioterapia (NCT02192788)37 NR ≤4 Bone, LN — University Hospital, Ghent (NCT01558427)38 NR ≤3 NS (N1, M1a/b)* — Technische Universität Dresden (NCT02264379)39 NR ≤5 NS — City of Hope Medical Center (NCT00544830)40 NR ≤5 NS (N1–3, M1) — Memorial Sloan Kettering Cancer Center (NCT02020070)41 NR ≤10 Bone, LN — ≤3 Bone, LN — Definicióndeoligometástasis F-FDG PET–CT (n = 24) or 18F-choline PET–CT (n = 92) Prospective trials (NCTI) Sidney Kimmel Comprehensive Cancer NR Center (ORIOLE) (NCT02680587)42 CNS, central nervous system; FDG, fluorodeoxyglucose; LN, lymph node; NCTI, national clinical trial identifier; NR, not reported; NS, not specified; ORIOLE, Phase II randomized Observation versus stereotactic ablative RadiatIon for OLigometastatic Prostate Tososian JJ.Nature rev CancEr. *N1 = Metastases in regional lymph nodes; M1 = Distant metastasis; M1a = Non-regional lymph nodes; M1bUrology,2016 = Bone; ¿quéopinanlosexpertos? PSADTyriesgodemetástasis RelaIonship)between)PSADT)and)the)risk)of)metastasis)or)death) From!a!PSAUDT!<6!months!the!risk!of!metastasis!increases!exponenCally was that conventional imaging tools—contrast enhanced abdominopelvic computed tomography (CT) and Tc99mmethylene diphosphonate bone scintigraphy—perform poorly in accurate staging of metastatic prostate cancer. Clearly, if one fails to identify all sites of disease, then an aggressive MDT approach to only those sites identified may result in futile use of MDT ablative therapy [4]. MDT strategies have seen an enormous boost with the advent of superior imaging such as whole-body magnetic resonance imaging (MRI) or positron-emission tomography (PET)/CT with 18F and 11C-choline or 68Ga–prostate-specific membrane antigen (PSMA), as this would appear to perform much better in identification of metastatic prostate cancer, particularly at low levels of prostate-specific antigen (PSA) in step with growth in publications regarding Ga-PSMA PET/CT in recent years (Fig. 1). One might speculate that enthusiasm for MDT is being fed by enthusiasm for Ga68!PSMA PET imaging; a type of ‘‘oligometmania’’ akin to the ‘‘Pokemania’’ described above. Physicians should be reminded, however, that better does not mean perfect. Diagnostic accuracy is indeed a key factor for success: is what you see cancer and, more importantly, is there no more cancer? In a recent paper by Montorsi et al [6], only two-thirds of patients with positive 11C-choline or PSMA PET/CT with oligo recurrent lymph nodes had cancer at final pathology. However, improved ability to identify metastatic lesions does not necessarily imply that aggressive approaches to Diagnósticodelaenfermedadoligometastásica • • • • • • PSA TAC R.óseo MRI MRcuerpocompleto PET: • • • • • • • Glucose consumption:(18)F]FDG Cell membrane proliferation (phospholipids):(11)C](18)Fcholine ] Synthesis offatty acids:(11)Cacetato. Transp.Aminoacids andprotein synt.:(11)CmeIonine Expres.Androgenic Receptor:(18)F]FDHT. Osteoblast AcCvity:(18)F]fluoride.Na Prostare specific membrane antigen:PSMA • CTC • DNAcirculante Fig. 2 – ‘‘Pokemet’’ strategy using stereotactic ablative body radiotherapy (SABR) with ongoing biochemical and clinical progression. Images for a 67-yrold male at 2 yr after robot-assisted radical prostatectomy for pT3a Gleason grade group 2 prostate cancer with negative pathological margins. (A) Prostate-specific antigen (PSA) 0.4 ng/ml; prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) demonstrates avidity in a solitary 5-mm left obturator lymph node (in green); the patient underwent SABR. (B) PSA continued to rise to 0.6 ng/ml; repeat PSMA PET revealed no avidity in the treated node, but a newly avid node in the left external iliac region, which was treated with a further course of SABR. (C,D) PSA further increased to 1.1 ng/ml and PSMA PET revealed newly avid presacral nodes, with no avidity in previously treated nodes. Androgen deprivation therapy was then offered. (E) Graph of biochemical progression for the 68Ga PSMA scans depicted in (A–D). Please cite this article in press as: Murphy DG, et al. ‘‘Gotta Catch ’em All’’, or Do We? Pokemet Approach to Metastatic Prostate Cancer. Eur Urol (2017), http://dx.doi.org/10.1016/j.eururo.2017.02.036 0 2 5 5 cue treatments while also scientifically establishing their Whole-body resonance imaging 0 2 diffusion-weighted 2 2 magnetic true role in properly assessing the disease. (WB-DW-MRI) vs choline-positron emission It is essential to keep in mind that to select these tomography-computed tomography (choline-PET/CT) patients, in addition for selecting treatments prostate cancerto the latest imaging techniques, ess evidence available regarding in the recurrent use of clinical predictors of limited disease must also be considRI. Even though is it1 is estimated to be equally 1 1 A. G. Herrando-Parreño R. Muelas-Soria ered. These include the time from primary tumour treat11 J. Conde-Moreno2 3 2 C-choline-PET/CT at detecting M.bone J. Ferrer-Rebolleda R. Broseta-Torres P. Cozar-Santiago ment to the appearance metastases, the type of primary F. Garcı́a-Piñón4 C. Ferrer-Albiach1 • • • • • • • Received: 20 September 2016 / Accepted: 11 October 2016 / Published online: 31 October 2016 ! Federación de Sociedades Españolas de Oncologı́a (FESEO) 2016 ivity, specificity, Choline-PET/CT in lymph node metastases Abstract Valuewith (%) multipleCI 95% WB-DW-MRI were excluded Valuefrom (%) the study. CI 95% WB-DW-MRI and choline-PET/CT was then performed on Objective To determine the effectiveness of whole-body each patient within 1 week. The results were interpreted by diffusion-weighted magnetic resonance imaging (WB-DWSensitivity 100.00 98.98–100.00 18.37 6.51–30.23 specialists in nuclear medicine and MRI. If they were MRI) in detecting metastases by comparing the results with candidates for69.98–100.00 treatment with ablative100.00 SBRT (SABR), they those from choline-positron emission tomography-com-88.24 Specificity 97.09–100.00 were then evaluated every three months with both tests. puted tomography (choline-PET/CT) in patients with bioPositive predictive value and no96.08Results Choline-PET/CT 89.77–100.00 100.00in 16 patients 94.44–100.00 detected lesions chemical relapse after primary treatment, observable using WB-DW-MRI. metastases in bone scintigraphy, CT and/orvalue pelvic MRI, or Negative predictive 100.00that were not 96.67–100.00 29.82 The results 17.07–42.58 were consistent in seven patients and in three cases, a metastatic/oligometastatic prostate cancer (PCa). Patients lesion was observed using WB-DW-MRI that was not with this disease profile who could benefit from treatment detected with choline-PET/CT. The Kappa value obtained with stereotactic body radiation therapy (SBRT) were Clin Transl Oncol (2017) 19:553–561 559 was 0.133 (p = 0.089); the sensitivity, specificity, positive selected and their responses to these techniques were rated. predictive value (PPV) and negative predictive value Materials and methods This was a prospective, controlled, Table involving 6 Sensitivity, PPV and NPV in bone metastases (NPV) of WB-DW-MRI were estimated at 44.93, 64.29, unicentric study, 46specificity, consecutive patients from 86.11, and WB-DW-MRI 19.15%, respectively. For choline-PET/CT our centre who presented biochemical relapse after adjuCholine-PET/CT Bone scintigraphy patients, the sensitivity, specificity, PPV, and NPV were vant, salvage or radical treatment with external beam Value (%) CI 95%97.10, 58.33, Value (%) and 77.78%, CI 95% respectively. Value (%) CI 95% 93.06, radiotherapy, or brachytherapy. After initial tests (bone Conclusions Choline-PET/CT has a high global sensitivity scintigraphy, CT, pelvic MRI), 35 patients with Sensitivity 88.00 11 patients 73.26–100.00 72.00 52.40–91.60 80.95 while WB-DW-MRI has a high specificity, and so they are 61.78–100.00 oligometastases or without them were selected. Specificity 88.46 74.26–100.00 70.37 51.29–89.45 61.29 42.53–80.05 Positive predictive value 88.00 73.26–100.00 69.23 49.57–88.89 58.62 38.97–78.27 88.46 74.26–100.00 73.08 [email protected] 54.10–92.05 82.61 64.94–100.00 & A. J. Conde-Moreno Negative predictive [email protected] G. Herrando-Parreño [email protected] R. Muelas-Soria [email protected] J. Ferrer-Rebolleda [email protected] value C. Ferrer-Albiach 1 Radiation Oncology Department, Consorcio Hospitalario Provincial de Castellón, Castellón, Spain 2 Nuclear Medicine Department, Eresa Hospital General de Valencia, Valencia, Spain 3 MRI Department, Eresa-Hospital General de Castellón, 2016) 16!arCcles!1,309!paCents!were!analysed.! •!✚!68Ga!PSMAUPET:!! ! 40%!primary!staging!!! ! 76%))for)biochemical)recurrence)(BCR).! •!✚!68Ga!PSMAUPET!!for!BCR!increased!with!higher! preUPET!PSA:! $ !0U0.2ng/ml:!42%! $ 0.2U1ng/ml:58%! $ !1U2!ng/ml:76%!! $ >!2!ng/ml:95%! • A!shorter)PSA)doubling)Ime,!resulted!in!a!92%!68Ga! PSMAPET!posiCvity!compared!to!65%!from!corresponding! choline!PET!metaUanalyCcal!data.! ! European!!Urology!7!0!(!2!0!1!6!)!9!2!6!–!9!3!7! ¿quéopinanlosexpertos? FalsospositivosconPETcolina yPSMA-PET • Correlacion PET-linfadenectomía: • Passoni etal:PETcolina • 35%falsospositivos • 35%N+enlamismaárea • 30%N+enotraárea • Pfister etal:PETcolinayPSMAPET • 21,9%falsospositivosPETcolina • 17,9%falsospositivosPSMA-PET • PSMAmejorquePETcolinaentodoslosparámetros • Monstorsi etal:PETcolina • 31,2%falsospositivos tion differences), and treated men comprised <5% of the study population. Nonetheless, consistent findings were obtained using two different sophisticated analyses. Of note, patients who underwent external beam radiation therapy (EBRT) were excluded from these studies owing to the lack of organ-site-specific coding for EBRT in SEER data. radiation, and 440 men (28.6%) who underwent other treatment. Whether the study distinguished between definitive or palliative treatment in the radiation therapy group was not reported; this omission might explain why outcomes in the radiation group mirrored the primary ADT and other treatment groups, and why radiation therapy was not considered in the same Tratamientolocalenenf.metastásica Table 2 | Retrospective data for local consolidative therapy of the primary tumour Source Study design Inclusion Intervention OS* CSS* MVA Additional information Culp et al.44 Population-based, n = 8,185, median follow-up period: 16 months M1a–M1c • RP (n = 245) • BT (n = 129) • NLT (n = 7811) • 67.4% • 52.6% • 22.5% P <0.001 • 75.8% • 61.3% • 48.7% P <0.001 SHR (CSM) • 0.38 (0.27–0.53; RP) • 0.68 (0.49–0.93; BT) • 1.00 (ref; NLT) MVA includes: Gleason score ≥8, T4, PSA ≥20 ng/ml, AJCC N1 (versus N0), AJCC M stage (versus M1a), year of diagnosis Antwi et al.45 Population-based, n = 7,858, median follow-up period: NR M1a–M1c • RP (n = 222) • BT (n = 120) • NSR (n = 7516) • 82.0% • 66.7% • 43.6% P <0.0001 • 84.7% • 71.7% • 54.6% P <0.0001 aHR (CSM) • 0.22 (0.27–0.28; RP) • 0.40 (0.32–0.51; BT) • 1.00 (ref; NSR) MVA includes: age, race, marital status, tumour grade, PSA level, and cancer registry Gratzke et al.46 Population-based, n = 1,538, median follow-up period: NR M+ • RP (n = 74) • RT (n = 389) • ADT (n = 635) • Other (n = 440) • 55% (RP) • 21% (other therapy) P <0.01 • NR NR Overall survival compared between RP patients and non-RP patients (including RT, ADT, and other) Satkunasivam et al.47 Population-based, n = 4,069, median follow-up period: NR • M+ • Age ≥65 years • RP (n = 47) • IMRT (n = 88) • CRT (n = 107) • NLT (n = 3827) • 73% • 72% • 37% • 34% • 79% • 82% • 49% • 46% aHR (CSM) • 0.48 (0.27–0.85; RP) • 0.38 (0.24–0.61; IMRT) • 0.85 (0.64–1.14; CRT) • 1.00 (ref; NLT) • MVA includes: sociodemographics, primary tumour characteristics, CCI, ADT, and bone radiation within 6 months of diagnosis. • On CRR: SHR (95% CI) for PCSM versus NLT: • RP 0.58 (0.35–0.95), IMRT 0.43 (0.27–0.68) Heidenreich et al.48 Case-control, n = 61, median follow-up period: • 40.6 months (RP) • 44.0 months (no RP) Limited M1 • RP (n = 23) • No RP (n = 38) • 91.3% • 78.9% P = 0.048 • 95.6% • 84.2% P = 0.043 • NR Inclusion criteria: ≤3 lesions on bone scan; absence of visceral or extended LN metastases; PSA nadir <1 ng/ ml after 6 months of neoadjuvant ADT Cho et al.49 Case-control, n = 140 (38 cases), median follow-up period: 34 months M1 • RT (n = 38) • No RT (n = 102) • 69% • 43% • NR HR (OM) • 0.43 (P = 0.015) MVA includes: ECOG status, site of metastasis ADT, androgen deprivation therapy; aHR, adjusted hazard ratio; AJCC, American Joint Committee on Cancer; BT, brachytherapy; CCI, Charlson comorbidity index; VOLUME14|JANUARY2017 Methods! The!NCDB!was!queried!for!men!with!newly!diagnosed!mPCa,!all!treated!with!ADT,!with! complete!datasets!for!RT,!surgery,!prostateUspecific!anCgen!(PSA)!level,!Gleason!score,!and! CharlsonUDeyo!comorbidity!score.!OS!was!analyzed!using!the!KaplanUMeier!method,!logUrank! test,!Cox!proporConalhazards!models,!and!propensity!scoreUmatched!analyses.! Results! From2004!to!2012,!6,382menwithmPCawere!idenCfied,!including!538!(8.4%)!receiving!prostate! RT.!At!a!median!followUup!of!5.1!years,!the!addiCon!of!prostate!RT!to!ADT!was!associated!with! improved!OS!on!univariate!(P!,!.001)!and!mulCvariate!analysis!(hazard!raCo,!0.624;!95%!CI,! 0.551!to!0.706;!P!,!.001)!adjusted!for!age,!year,!race,!comorbidity!score,!PSA!level,!Gleason! score,!T!stage,!N!stage,!chemotherapy!administraCon,!treaCng!facility,!and!insurance!status.! Propensity!score!analysis!with!matched!baseline!characterisCcs!demonstrated!superiormedian! (55!v!37months)!and!5Uyear!OS!(49%!v!33%)!with!prostate!RT!plus!ADT!compared!with!ADT! alone!(P,!.001).!Landmark!analyses!limited!to!longUterm!survivors!of!$1,!$3,!and!$5!years! demonstrated!improved!OS!with!prostate!RT!in!all!subsets!(all!P!,!.05).!Secondary!analyses! comparing!the!survival!outcomes!for!paCents!treated!with!therapeuCc!dose!RT!plus!ADT!versus! prostatectomy!plus!ADT!during!the!same!Cme!interval!demonstrated!no!significant!differences! in!OS,!whereas!both!therapies!were!superior!to!ADT!alone.! Conclusion! In!this!large!contemporary!analysis,!men!with!mPCa!receiving!prostate!RT!and!ADT!lived! substanCally!longer!than!men!treated!with!ADT!alone.!ProspecCve!trials!evaluaCng!local! therapies!for!mPCa!are!warranted.! • Time to next skeletal-related event defined by even a fracture or bone pain requiring radiation therapy or spinal cord compression or preventive surgery to the bones. Events will be evaluated by investigators. No systematic X-Ray will be perform. Time to chemotherapy Time to severe local symptoms (grade 3 and 4 events according to NCI-CTCAE v4.0) Impact of the radiotherapy protocol on outcome (PFS and local symptoms) Toxicity (with a specific focus on the use of long-term low-dose steroids) according to NCICTCAE v4.0 Prostate cancer specific survival ValortratamientolocalenpacientesM1: PEACE-1TRIAL • • • • • STUDY SCHEME: Metastatic hormone-naïve prostate cancer patients Verification of the eligibility criteria RANDOMIZATION Arm A: ADT Arm B: ADT + abiraterone 1000mg/day+ prednisone 5mg bid Arm C: Arm A + radiotherapy Arm D: Arm B + radiotherapy Linfadenectomía derescate:experiencias Reviews; OligoM+ ganglionar; LDN de rescate Abdollah etal;Eur Urol 2015;67:839-849 Supervivenciasegúnlocalizacion delas metástasis Site of Visceral Metastases Predicts Overall Survival A 1.0 Median OS (months, 95% CI) LN 31.6 (27.9 to 35.5) Bone 21.3 (20.8 to 21.9) Lung 19.4 (17.8 to 20.7) Liver 13.5 (12.7 to 14.4) OS (probability) 0.8 0.6 0.4 0.2 0 6 12 24 30 36 42 48 Time Since Random Assignment (months) No. at risk LN 18 565 510 424 345 250 162 91 50 37 Bone 6,356 5,602 4,406 3,079 1,932 1,083 556 278 165 Lung 791 669 508 347 225 126 65 36 16 Liver 752 551 367 219 128 66 27 13 5 B Study SWOG 9916 No. of patients (No. of deaths) TAX 327 Median OS (months, 95% CI) Bone (+/– LN) Lung 17.3 (15.9 to 20) 245 (160) 21.1 (18.9 to 26.1) 16.2 (11.2 to NR) 25 (16) 20.9 (13.0 to NR) Hazard Ratio* (95% CI) 1.12 (0.67 to 1.88) J Clin Oncol 34:1652-1659. 1.19 (0.73 to 1.94) Resultadosdelinfadenectomía derescatecon PETcolinapositivos Metastasis surgery Table 1. Main results of studies reporting on salvage lymph node dissection in patients with PET/CT scan detected nodal recurrence of prostate cancer Study Pts. (n) Jilg et al. [26] 47 Tilki et al. [27] 58 Rigatti et al. [25] 72 PET/CT tracer 11 C-/18F choline Rate of Mean PSA ADT prior sLND limited Mean no. 5-year 5-year Median at sLND to sLND to pelvic of LNs cBR BCR-free CR-free follow-up (ng/ml) (%) area (%) removed rate (%) rate (%) rate (%) CSS (%) (months) 11.1 78.7 54.0 12 46.0 8.7 25.6 77.7 35.5 F-choline 9.8 47.0 39.7 18.6 22.4 0 35.9 71.1 39 C-choline 3.73 55.5 22.2 30.6 56.9 19.0 48.6 75.0 39.8 59.3 29.4 52.0 89.1 76.6 – 45.5a 46.9a 92.5a 20 18 11 11 C-choline 3.95 62.7 23.7 11.7 Suardi 59 Role of[15] salvage lymph node dissection in prostate cancer Heidenreich et al. et al. Karnes et al. [29] 52 11 C-choline 4.0 34.7 76.9 23.8 local treatment Table 2. Pre- and postoperative parameters associated 29.6ADT, months, androgen deprivation BCR,oncological biochemical recurrence; completesalvage biochemical response; CR, clinical recurrence; CSS, cancer-specific survival; withtherapy; beneficial outcomecBR, following LND LNs,the lymph nodes; no, number; PSA, prostate-specific antigen; Pts, patients; sLND, salvage lymph node dissection. ction of first based on multivariate analysis of various patient cohorts a Three-year rate. ithin or outside Preoperative parameters Postoperative parameters 4.3% of patients T were free of 11 PSA <4 Complete biochemical based on evidence ofng/ml C-choline/18F-choline PET/ specific mortality rate was 3.7%. Three-year BCRery only group response to our cohort and all other free, systemic therapy-free and clinical recurrencedationCTof [10]. adju-In contrast Positive PET/CT signals in the <3 positive lymph nodes at studies to date, 27 patients received adjufree survival rates for patients with cBR were 69.3, it needs to published be small pelvis only salvage LND vant radiotherapy of regions with histopathological 77.0, and 75%, respectively. ly resected the Gleason score <8 Absence of retroperitoneal confirmation of lymph node metastases lymph and node six metastases The largest U.S. study of sLND was published by spicious on the etal.CO-urology.2016 patients had additional evidence of local PCA recurKarnes et al.Heidenreich [35] and included 52 patients. During a ghlighted by the Long-Term Outcome After Radical Prostatectomy for Patients With Lymph Node Positive Prostate Cancer in the Prostate Specific Antigen Era Stephen A. Boorjian, R. Houston Thompson, Sameer Siddiqui, Stephanie Bagniewski, Erik J. Bergstralh, R. Jeffrey Karnes, Igor Frank and Michael L. Blute* From the Department of Urology and Division of Biostatistics (SB, EJB), Mayo Medical School and Mayo Clinic, Rochester, Minnesota Purpose: While the incidence of lymph node positive prostate cancer has decreased during the prostate specific antigen era, the optimal treatment of these in question.PROSTATE We the impact of lymph node metastases on LYMPH the UTCOME AFTER PROSTATECTOMY FORpatients LYMPHremains NODE POSITIVE CANCER 868 examined OUTCOME AFTER PROSTATECTOMY FOR NODE POSITIVE PROSTATE CA outcome of patients following radical prostatectomy and investigated prognostic factors that affect survival. Materials and Methods: We identified 507 men treated with radical prostatectomy between 1988 and 2001 who had lymph node positive disease. Of the 507 patients 455 (89.7%) were treated with adjuvant hormonal therapy. Median followup was 10.3 years (IQR 6.1–13.5). Postoperative survival rates were estimated using the Kaplan-Meier method and the impact of various clinicopathological factors on outcome was analyzed using Cox proportional hazard regression models. Results: Ten-year cancer specific survival for patients with positive lymph nodes was 85.8% with 56% of the men free from biochemical recurrence at last followup. On multivariate analysis pathological Gleason score 8 –10 (p ! 0.004), positive surgical margins (p ! 0.016), nondiploid tumor ploidy (p ! 0.023) and 2 or greater positive nodes (p ! 0.001) were adverse predictors of cancer specific survival. Tumor stage, year of surgery and total number of nodes removed did not significantly affect outcome. Adjuvant hormonal therapy decreased the risk of biochemical recurrence (p "0.001) and local recurrence (p ! 0.004) but it was not associated with systemic progression (p ! 0.4) or cancer specific survival (p ! 0.4). Conclusions: Radical prostatectomy may offer long-term survival to patients with lymph node positive prostate cancer. Gleason score, margin status, tumor ploidy and the number of involved nodes predict survival, while the role of adjuvant hormonal therapy continues to be defined. Key Words: prostate, prostatic neoplasms, lymph node dissection, prostate-specific antigen, prostatectomy A s part of the stage migration in prostate cancer durNevertheless, a potential importance for addressing the priing the PSA era,1 the incidence of positive lymph mary tumor in patients with advanced prostate cancer has nodes in patients undergoing RRP has decreased to been suggested. approximately 4% in recent series.2,3 While lymph node Moreover, because most patients with positive lymph metastases adversely impact the prognosis of patients folnodes are currently 1. Outcome following RRP for patients with positive lymph nodes. LR, local recurrence. SP, systemic progressionfound to have microscopic disease on . 5. Postoperative CSS according to degree of lymph node involvement lowing surgery, extended postoperative survival in a subset pathological examination ofFIG the nodes after RRP, the appro2–7 of these men was reported. However, studies to date of priate postoperative treatment of such patients similarly nodes waslargely 56%, 89%, and BCR, local recurRRP, of which all were given at systemic patients with lymph node disease have been com-80% remains We86% next examined risk factors for the disease progression infor question. In particular optimal time toininiti-stage, year of surgery and the total rence, systemic progression patients and cancer death, respectively. including chemotherapy in 1, strontium in 1 11,12 with therapy positive lymph nodes. In debated. a multivariate Coxiden-examined did not affect survival. posed of pre-PSA and early PSA era cohorts, when the clinate hormone continues to be The Postoperative survival was thenonly stratified for allpreoperative patients in 2. AHT was associated with a decrea model increased PSA (p ! 0.036) and icopathological features of prostate cancer tend to be more tificationof of risk factors for disease progression in patients who underwent RRP by the nondiploid number positive lymph an followup after RRP1of 10.3 years (IQR 6.1– (p "0.001) and local recurrence (p ! 0.0 tumor ploidy (p nodes ! 0.006) were significant predicadvanced. with nodal disease may help individualize treatment for (figs. 2 to 5). Although a single node significantly ents had BCR, 51 experienced local recurrence, significantly impact systemic progression torsmetastatic of BCR, while pathological Gleason score 8 –10 was While mendied, withincluding lymph node continue to be these patients. increased the risk of BCR (HR 1.4, 95% CI 1.1–1.7,BCR (p ! 0.078, table 3). A mic relapse and 200 had 72 ofmetastases (p ! 0.43). Ten-year event-free survival fo associated with a trend toward J.Urol,2007 Experienciasrestrospectivas conSBRT REVIEWS Table 3 | Retrospective data for metastasis-directed radiotherapy Source Study design Treated cohort (% of lesions) Muacevic et al.55 Case series, n = 40, 64 lesions, median follow-up per od ont s Bone (100%) Median dose (range) and fractions 1 fraction (80% of patients) Toxicity per CTCAE (% of lesions) Median Clinical outcomes* ADT-FS (months) NR NR 2-year local control: 95.5% Ahmed et al.28 Case series, n = 17, 21 • Bone (90%) lesions, median follow- • LN (5%) p per od ont s • Liver (5%) • Dose: bone 20 Gy (8–24); LN 50 Gy; liver 60 Gy • Median fractions: bone 1 (1–3), LN 5, liver, 3 • Grade 1 (9.5%) • Grade 2 (9.5%) • rade NR • Local control: 100% • 1-year FFDP: 40% • 1-year CSS: 100% Berkovic et al.29 Case series, n = 24, 29 • Bone (55%) lesions, median follow- • LN (45%) p per od ont s • 50 Gy (40–50) • Median fractions 10, range 8–10 • Grade 2 GI (8%) • Grade 2 GU (6%) • rade 38 • 2-year local control: 100% • 2-year CPFS: 42% Schick et al.30 Case series n = 50, 79 • Bone (31.5%) • 64 Gy (44–78) lesions, median follow- • LN (63.5%) • Fractions NR p per od ont s • Viscera (5%) NR • 3-year bRFS: 54.5% • 3-year CPFS: 58.6% • 3-year OS: 92% 25 • Local control: 100% • Median PFS: 19 months • 1-year and 2-year PFS: 64%, 35% • 1-year and 2-year CSS: 96%, 90% Decaestecker Case series, n = 50, et al.31 70 lesions, median follow-up period: ears • Bone (44%) • LN (54%) • Viscera (2%) • Schedule 1: 50 Gy, 10 fractions • Schedule 2: 30 Gy, 3 fractions rade • Grade 1 (14%)‡ • Grade 2 (6%) ‡ ‡ • rade ADT, androgen deprivation therapy; ADT-FS, androgen deprivation therapy-free survival; bRFS, biochemical-relapse-free survival; CPFS, clinical progression-free survival, CSS, cancer-specific survival; CTCAE, Common Terminology Criteria for Adverse Events; FFDP, failure from distant progression; LN, lymph node; NR, not reported; NS, not specified; OS, overall survival; PCSM, prostate cancer-specific mortality; PFS, progression-free survival. *In cases of unspecified time frame, values refer to proportion experiencing outcome during total follow-up period. ‡Percentage of patients. or lymph node metastases using SBRT. Again, 2-year rates of local control were 100%; clinical-progression past few years have witnessed a flurry of research into VOLUME14|JANUARY2017 REVIEWS | UROLOGY novel PETNATURE radiotracers targeting lesions of the bone and Experienciasrestrospectivas conSBRT REVIEWS Table 3 | Retrospective data for metastasis-directed radiotherapy Source Study design Treated cohort (% of lesions) Muacevic et al.55 Case series, n = 40, 64 lesions, median follow-up per od ont s Bone (100%) Median dose (range) and fractions 1 fraction (80% of patients) Toxicity per CTCAE (% of lesions) Median Clinical outcomes* ADT-FS (months) NR NR 2-year local control: 95.5% Ahmed et al.28 Case series, n = 17, 21 • Bone (90%) lesions, median follow- • LN (5%) p per od ont s • Liver (5%) • Dose: bone 20 Gy (8–24); LN 50 Gy; liver 60 Gy • Median fractions: bone 1 (1–3), LN 5, liver, 3 • Grade 1 (9.5%) • Grade 2 (9.5%) • rade NR • Local control: 100% • 1-year FFDP: 40% • 1-year CSS: 100% Berkovic et al.29 Case series, n = 24, 29 • Bone (55%) lesions, median follow- • LN (45%) p per od ont s • 50 Gy (40–50) • Median fractions 10, range 8–10 • Grade 2 GI (8%) • Grade 2 GU (6%) • rade 38 • 2-year local control: 100% • 2-year CPFS: 42% Schick et al.30 Case series n = 50, 79 • Bone (31.5%) • 64 Gy (44–78) lesions, median follow- • LN (63.5%) • Fractions NR p per od ont s • Viscera (5%) NR • 3-year bRFS: 54.5% • 3-year CPFS: 58.6% • 3-year OS: 92% 25 • Local control: 100% • Median PFS: 19 months • 1-year and 2-year PFS: 64%, 35% • 1-year and 2-year CSS: 96%, 90% Decaestecker Case series, n = 50, et al.31 70 lesions, median follow-up period: ears • Bone (44%) • LN (54%) • Viscera (2%) • Schedule 1: 50 Gy, 10 fractions • Schedule 2: 30 Gy, 3 fractions rade • Grade 1 (14%)‡ • Grade 2 (6%) ‡ ‡ • rade ADT, androgen deprivation therapy; ADT-FS, androgen deprivation therapy-free survival; bRFS, biochemical-relapse-free survival; CPFS, clinical progression-free survival, CSS, cancer-specific survival; CTCAE, Common Terminology Criteria for Adverse Events; FFDP, failure from distant progression; LN, lymph node; NR, not reported; NS, not specified; OS, overall survival; PCSM, prostate cancer-specific mortality; PFS, progression-free survival. *In cases of unspecified time frame, values refer to proportion experiencing outcome during total follow-up period. ‡Percentage of patients. or lymph node metastases using SBRT. Again, 2-year rates of local control were 100%; clinical-progression past few years have witnessed a flurry of research into VOLUME14|JANUARY2017 REVIEWS | UROLOGY novel PETNATURE radiotracers targeting lesions of the bone and ROPEAN UROLOGY 69 (2016) 9–12 nodal dissection (n = 2), or chemotherapy (n = 3). The Progression-free Survival FollowingE UStereotactic Body median time from first SBRT to the start of palliative Radiotherapy for Oligometastatic Prostate Cancer ADT was 28 mo (95% CI, 16.2–69.7). Reasons for starting available at www.sciencedirect.com Treatment-naive palliativeAnalysis ADT were biochemical progression (n = 2), oligoj o u r n a lRecurrence: h o m e p a g e : w w w . e uA r o pMulti-institutional eanurology.com UROLOGY urvival beam n very pically [4]. into a usions is a diagstases entral 2014/ which llows: elapse t, and s were /ml at rogen SBRT, t with rmone maxiceived n = 24) with onance isease. astatic t least ) of at of the ion of iation dicate radionation owing 39 Gy SBRT e, and rately n-free astatic ogrese. The DPFS, (OS). ential nivarf SBRT ely. All metastatic progression (n = 18), or polymetastatic progresa, b c d sion (n = 37). Piet Ost *, Barbara Alicja Jereczek-Fossa , Nicholas Van As , Thomas Zilli , e f c g Seven patients , from PCa, and one patient died from Alexander Muacevic , Kenneth Olivier , Daniel Henderson , Franco Casamassimadied b b f c pancreatic cancer. The , Alessia Surgo , Lindsay Brown , Alison Tree , Raymond Miralbell d3, and 5-yr OS was 95% and 88%, 6Roberto 9 ( 2 0 1 6 )Orecchia 9–12 respectively. Late grade 1 and 2 toxicity was observed in Gert De Meerleer a 14% (n = 17) and 3% of patients (n = 3), respectively. The a Table 1 – Patient characteristics Department of Radiotherapy, Ghent University Hospital, Belgium; b University of Milan and European Institute of Oncology, Milan Italy; c Department of d reported toxicity was due to gastrointestinal Radiotherapy Royal Marsden NHS Foundation Trust, London, Department of Radiation Oncology, Geneva University grade Hospital,2Geneva, Switzerland; Characteristics AllUK; patients (n = 119) e g Cyberknife Center Munich Grosshadern, Munich, Germany; f Department of Radiation Oncology, Mayocomplaints Clinic, Rochester, MN, USA;treated Ecomedica in patients for nodal metastases. No Platinum Priority – Brief Correspondence Age at PCa diagnosis, yr Radioterapia, Empoli, Italy Median (IQR) 61 (56–65) toxicity of grade "3 was observed. Follow-up from PCa diagnosis, yrEditorial by Vincent Khoo on pp. 13–14 of this issue Median (IQR) 7.2 (5.0–9.3) Primary therapy, n (%) Article info Abstract Radical prostatectomy alone 21 (17.6) Radical prostatectomy with postoperative RT 37 (31.1) Radical prostatectomy with 31 (26.1) Article history: The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) postoperative RT and ADT recurrence consists of small heterogeneous studies. This study aimed to reduce the Accepted July 2, 2015 Radiotherapy and ADT 22 (18.5) heterogeneity by pooling individual patient data from different institutions treating Radiotherapy alone 8 (6.7) oligometastatic PCa recurrence with stereotactic body radiotherapy (SBRT). We focussed Associate Editor: PSA at initial diagnosis, ng/ml on patients who were treatment naive, with the aim of determining if SBRT could delay Mean (range) 18.1 (1.3–180) Giacomo Novara Median (IQR) 10.7 (6.8–19) disease progression. We included patients with three or fewer metastases. The KaplanUnknown 9 Meier method was used to estimate distant progression-free survival (DPFS) and local EAU prognostic grouping at initial diagnosis, n (%) Keywords: progression-free survival (LPFS). Toxicity was scored using the Common Terminology Low 5 (4.2) Criteria for Events. In total, 163 metastases were treated in 119 patients. The Prostatic neoplasms Intermediate 30Adverse (25.2) median DPFS was 21 mo (95% confidence interval, 15–26 mo). A lower radiotherapy dose High 51 (42.9) Neoplasm metastasis Very high (25.2)local recurrence rate with a 3-yr LPFS of 79% for patients treated with predicted 30 a higher Oligometastasis Unknown 3 (2.5) a biologically effective dose !100 Gy versus 99% for patients treated with >100 Gy Interval from diagnosis to metastases, yr Neoplasm recurrence (p = 0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three Mean (range) 5.0 (0.2–16.8) patients (3%) Radiosurgery Median (IQR) 4.7developed (2.7–6.6) grade 2 toxicity. No grade "3 toxicity occurred. These results should serve as a benchmark for future prospective trials. PSA level at first documented metastases, ng/ml Stereotactic body radiotherapy Patient summary: This multi-institutional study pools all of the available data on the Mean (range) 9.6 (0.1–116.7) Median (IQR) 4.0 (1.6–8.8) use of stereotactic body radiotherapy for limited prostate cancer metastases. We Unknown 1 a metastases, mo concluded that this approach is safeb and associated with a prolonged treatment PSA DT at first documented progression-free survival. Mean (range) 5.6 (1.0–30.0) d # 2015 Median (IQR) 3.9Published (2.9–6.9) by Elsevier B.V. on behalf of European Association of Urology. Unknown 36 e f No. of lesions at diagnosis of metastases, n (%) * Corresponding author. Department of Radiotherapy, Ghent University Hospital, De Pintelaan 185, One metastasis 86 (72.3) B-9000 Ghent, Belgium. Tel. +32 3322411; Fax: +32 93323040. Two metastases 22 (18.5) E-mail address: [email protected] (P. Ost). Three metastases 11 (9.2) Primary site of metastases, n (%) Lymph nodes 72 (60) Pelvic 53 (45) state of cancer spread while avoiding or delaying the toxicity Metastasis-directed therapy is a lesion-targeted approach Obturator 12 (10) Internal for iliac 9 (8) associated with the use of systemic therapies [1]. A few reserved a subset of patients with a limited number of External iliac 17 (14) small studies using stereotactic body radiotherapy (SBRT) for metastases (typically three or fewer or five or fewer), Presacral 2 (2) soCommon iliac 6 (5) oligometastatic prostate cancer (PCa) recurrences have been called oligometastases, and it aims to control an intermediate Combination of nodal sites 7 (6) Extrapelvic 12 (10) http://dx.doi.org/10.1016/j.eururo.2015.07.004 Fig. 1 – Kaplan-Meier analysis depicting time Both 7 (6) 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology. Bones, n (%) 43 (36) Axial 22 (18) Appendicular 17 (14) Both 4 (3) Viscera, n (%) Liver 1 (1) Lung 1 (1) Node and/or bone and/or viscera, n (%) 2 (2) Imaging modality at recurrence, n (%) Choline PET-CT 92 (77) FDG PET-CT 24 (20) MRI 3 (3) Adjuvant ADT, n (%) No 59 (50) Yes 60 (50) Duration of ADT, mo, median (range) 2 mo (1–8 mo) Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis b c Drafting of the Critical revision Jereczek-Fossa sima, Orecchia Statistical analy Obtaining fundi Administrative, Supervision: Os Other (specify) ia, stock owne filed, received, the Prostate C Urology Young of the Researc Daniel Hender of the Royal M Centre. Funding/Suppo Department of Radiation Oncology, Geneva University Hospital, Geneva, Switzerland; g Appendix A Ecomedica Radioterapia, Empoli, Italy Article info Analysis and in (eg, employme d Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA; Meerleer. relevant to the Department of Radiotherapy, Ghent University Hospital, Belgium; University of Milan and European Institute of Oncology, Milan Italy; c Department of Cyberknife Center Munich Grosshadern, Munich, Germany; Henderson, Ca including spec Piet Ost *, Barbara Alicja Jereczek-Fossa , Nicholas Van As , Thomas Zilli , Alexander Muacevic e, Kenneth Olivier f, Daniel Henderson c, Franco Casamassima g, Roberto Orecchia b, Alessia Surgo b, Lindsay Brown f, Alison Tree c, Raymond Miralbell d, Gert De Meerleer a Radiotherapy Royal Marsden NHS Foundation Trust, London, UK; Acquisition of d Financial discl [(Fig._1)TD$IG] a, Study concept a Abstract Article history: Accepted July 2, 2015 The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) recurrence consists of small heterogeneous studies. This study aimed to reduce the heterogeneity by pooling individual patient data from different institutions treating oligometastatic PCa recurrence with stereotactic body radiotherapyto(SBRT). focussed distant We progression. Associate Editor: on patients who were treatment naive, with the aim of determining if SBRT could delay Giacomo Novara disease progression. We included patients with three or fewer metastases. The KaplanMeier method was used to estimate distant progression-free survival (DPFS) and local Keywords: progression-free survival (LPFS). Toxicity was scored using the Common Terminology Criteria for Adverse Events. In total, 163 metastases were treated in 119 patients. The Prostatic neoplasms median DPFS was 21 mo (95% confidence interval, 15–26 mo). A lower radiotherapy dose Neoplasm metastasis predicted a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with Oligometastasis a biologically effective dose !100 Gy versus 99% for patients treated with >100 Gy Neoplasm recurrence (p = 0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three patients (3%) developed grade 2 toxicity. No grade "3 toxicity occurred. These results Radiosurgery should serve as a benchmark for future prospective trials. Stereotactic body radiotherapy ADT = androgen-deprivation therapy; EAU = European Association of Urology; Patient summary: This multi-institutional study pools all of the available data on the DPFS21meses:18vs25siADT MedianatiempoADT:28m 3yDPFS31% Supplement found, in the eururo.2015 References [1] Hellman S 13:8–10. ¿quéopinanlosexpertos? ¿quéopinanlosexpertos? Estudiosenmarcha… Standard Arm Patient Group E o c l/l 13 "rd cn m~ T3 QJ O rd <N XJ OJ CL 3 c =3 m u~i O 0. Q O CD o fM CO CO ID bd O p Ibo c j rd 2 c co~ o (N QJ JD E QJ l_j QJ Q o m m bd c ft QJ cj '5 G? rd — i/ i CO o o "u u CJ _3 l l CO t/i L_ 1— U 1— UJ CL bd c 4-J cj '3 QJ *“ K O fN QJ C 3 fN ID T- QJ QJ rd LL QJ _3 LU CL CJ ID fN ° g >~ +3 U U rd qj 3 tu CJ "O u < LJ CD rd rd bb LJ Q LJ qj o I— U 2 00 LD LD m ai 4-> cn 4-J a CD < in < o cl 00 o CO ID ID LD o hLJ 2 m O CM r\i 'o >CJ rd 3 CJ CJ < in < CL qj m m LD fN O I— LJ ~Z. 1— u 1— LU CL qj O O fN rd ID O >u rd 3 CJ u < CL < CL 1— LU CL E +-* oj F bp Q aj SB P x— l d LD fN m CO r^ o 1— U 2 “ Volume 13 / Issue 1 / January 2017 • Journal of Oncology Practice ClinicalTrials.gov Identifier and Trial Marne Wo- Estimated Experimental Arm(s) Primary End Point Patients Completion Date Clement and Sweeney 14 Table 1, Summary of Select Clinical Trials Investigating Evaluation and Treatment of Oligometastatic Prostate Cancer -C O O m CL QJ >• rd £ cl 3 ^ n p ^ O '5= _Q c +3 o l d o p +3 nT 2 LD r- <r fN o i— U CO LD r-> ^ ain fO e. 3> -D » Q. E 3 -q cl i C F a> g > m LD (N O >- o n i i1—j QJ £° 2 3 in L o 4-J rd TD rd CL 00 ID CL CD (N or CO 00 2 t— fN O 1— D 3 ID o- E CL CO in o CL n00 ID o o CO LD fN O 1— LJ 2 Copyright © 2017 by American Society of Clinical O ORIOLETRIAL:randomized phase II. Eligibility • ≤3 metastatic lesions (≤5 cm) • Hormone-sensitive disease • PSADT <15 months • ECOG ≤2 Randomization Observation Day 1: PSA, LDH, AP, T, ctDNA, and rectal swab Days 1–30: Observation Day 90: PSA, LDH, AP, T, and ctDNA Day 180: Bone scan, CT, PSA, LDH, AP, T, and ctDNA 1:2 SBRT DCFPyL-PET–MRI or DCFPyL-PET–CT, PSA,LDH, AP, T, CTC/ctDNA assays, PBMC (ImmunoSEQ), and rectal swab SABR PSA, LDH, AP, T, ctDNA, and PBMC (ImmunoSEQ) Bone scan, CT, and DCFPyL-PET–MRI or DCFPyL-PET–CT, PSA, LDH, AP, T, CTC/ctDNA assays Patients progressing on observation can be crossed over o protocol to receive SBRT Figure 2 | Schema for the phase II Randomized Observation versus Stereotactic Nature Reviews | Urology Ablative RadiatIon for OLigometastatic Prostate CancEr (ORIOLE) trial. Men with metachronous hormone-naive oligometastatic disease will be enrolled and dynamically randomized to the schema as shown. AP, alkaline phosphatase; CTCs, circulating tumour cells; ctDNA, cell-free circulating tumour DNA; LDH, lactate dehydrogenase; PBMC, peripheral blood mononuclear cells; SABR, stereotactic ablative radiation; SBRT, stereotactic radiation therapy; T, serum testosterone. ORIOLE is sponsored by the National Cancer Institute (NCI) 1U01CA183031 and a Movember-PCF Challenge Award. R from surrogate measures such as th these studies notably lack a compa definitive data will become available tion and reporting of prospective ra (TABLE 1) such as the Belgian STOM Baltimore ORIOLE trial42 (FIG. 2), whi to assess clinical progression in me receive SBRT versus observation. Sec include local control, ADT-free surv quality-of-life outcomes. We would encourage future retro spective studies to clearly distingui men using ADT at baseline, and to pr 1-year ADT-free survival in those wh pose that future studies define clinical detection of a new metastatic lesion of a clinically significant event (such fracture) in a previously detected st the limited time course over which su would be reasonable to share median, values for these outcomes. Future directions and recommend Existing data suggest that local and m therapies are safe in men with metasta Whether we should take an aggressive static disease simply because it is avai this approach actually helps patients s ing. Only retrospective data exist in th of these studies provide an appropri for comparison. Thus, the reality is th beginning to answer this question. In ation, we make the following recomm sidering an aggressive treatment appr known metastatic disease. As in other settings, only those suffer mortality or substantial morb disease should be considered for agg Ensayobelga:FASEIISTOMP Patients with an oligometastatic recurrence, diagnosed on choline PET/CT after localtreatment with curative intent R A N D O M 1: 1 A:activesurveillance B:MTDfollowed by active surveillance Stratified: location ofmetastasis (node vs.bone metastases)andPSAdoubling time (≤3vs.>3months). Both surgery andSBRTareallowed asMDT. Activesurveillance means 3-monthlyPSAtesting andre-imaging atPSAprogression. Primary endpoint : ADT-freesurvival.ADTwill bestarted inboth arms attimeof polymetastatic disease (>3metastatic lesions),localprogression or symptoms. Secondary endpoints:progression-freesurvival,quality oflife,toxicity andprostatecancer specific survival. Amododeconclusiones… • Faltanresultadosclarossobreelposiblevalor terapéuticodeltratamientolocalsobre oligometástasis. • Paraobtenerresultadosesnecesariohacerestudios quetenganencuenta: • Laspruebasdiagnósticas • Losdiferentestratamientos • Lasdiferentessituacionesclínicasylocalizacionesdelas metástasis • Mientrastantocuidadocon… ‘subirsealcarro’deformaacrítica The bandwagon effect Antonarakis Localized Disease Therapy Surgery/ Radiation Systemic Therapy Oligometastatic Disease Widely Metastatic Castrate-Resistant Disease