Update of the Andalusian Association of Urology protocol for the management of metastatic castration-resistant prostate cancer

Álvarez-Ossorio, J.L.; Cozar-Olmo, J.M.; Juárez-Soto, Á.; Medina-López, R.; Moreno-Jiménez, J.; Requena-Tapia, M.J.
doi:10.1016/j.acuroe.2019.09.001
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including the essential aspects of the patients&#8217; baseline assessment&#44; the choice and sequence of treatments and monitoring&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Baseline assessment</span><p id="par0015" class="elsevierStylePara elsevierViewall">Baseline evaluation of the patient with mCRPC should include clinical&#44; biochemical and imaging determinations &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Clinical assessment</span><p id="par0020" class="elsevierStylePara elsevierViewall">Based on medical history&#44; anamnesis and patient-reported outcomes&#46; The instruments and scales used for patients&#39; assessment are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Pain is the symptom with highest impact on quality of life in these cases&#46; Other evaluations include symptom interference in daily life&#44; health-related quality of life &#40;HRQOL&#41;&#44; the presence of comorbidities and analgesic use&#46; The Comprehensive Geriatric Assessment &#40;CGA&#41; of the older patient with cancer G8 questionnaire<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> is applied for the evaluation of men older than 70 years&#46; In case of recurrence&#44; the patient would be submitted to a new assessment&#44; which would also include information on the sequence of previous treatments&#44; the type of progression and adverse effects&#46; These assessment instruments are included in the national<span class="elsevierStyleSup">4</span> and European<span class="elsevierStyleSup">1</span> guidelines of mCRPC&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Imaging</span><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleSup">99m</span>Tc Bone scan and abdominopelvic computed tomography &#40;CT&#41; are the standard imaging tests for baseline evaluation&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> Based on the extent of metastasis&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> clinical subtypes with heterogenous prognosis and management are identified &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Laboratory tests</span><p id="par0030" class="elsevierStylePara elsevierViewall">The parameters to be included in this assessment are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Treatment</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Treatment for bone disease</span><p id="par0035" class="elsevierStylePara elsevierViewall">The algorithm presented in <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> refers to ECOG 0-1 patients and includes the latest modifications performed in the updated version of the European guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Initial treatment is based on patients&#39; symptoms &#40;pain&#41;&#46; The use of the different agents in painless or mildly symptomatic patients is based on the evidence provided by the COU-AA-302<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> &#40;abiraterone&#41; and PREVAIL<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> &#40;enzalutamide&#41; studies&#44; and for those with moderate-severe pain&#44; therapy is based on the TAX 327<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> &#40;docetaxel&#41; and ALSYMPCA<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> &#40;radium-223&#41; studies &#40;in case of ineligibility for treatment with docetaxel&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Although abiraterone and enzalutamide are the most commonly used as 1st line treatment&#44; patients will eventually present recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Several studies suggest the existence of cross-resistance between abiraterone and enzalutamide&#44; which discourages sequencing&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The use of drugs with different mechanisms of action to progression allows a more complete approach to the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Second and 3rd line recommendations are based on the evidence provided by the COU-AA-301<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> &#40;abiraterone&#41;&#44; AFFIRM<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> &#40;enzalutamide&#41; and ALSYMPCA<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> &#40;radio-223&#41; studies&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">This treatment scenario convolutes as the patient&#39;s therapeutic approach evolves&#44; especially with regard to the use of abiraterone and docetaxel in hormone-sensitive PC or the use of enzalutamide&#44; apalutamide and darolutamide in non-metastatic CRPC&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> which could result in a 2nd line treatment administration for the management of mCRPC in the future&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The use of bone protective agents &#40;denosumab&#44; zoledronic acid&#41; together with calcium and vitamin D is recommended for the prevention of skeletal-related events&#44; with the corresponding toxicity assessment&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Recently&#44; the Spanish Agency of Medicine and Medical Devices has warned about the increased risk of vertebral fractures after discontinuation of denosumab&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Treatment for nodal disease</span><p id="par0060" class="elsevierStylePara elsevierViewall">Specific scientific evidence is scarce&#46; Treatment options are shown in <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Monitoring</span><p id="par0065" class="elsevierStylePara elsevierViewall">It is based on the follow-up of parameters analyzed at baseline&#44; taking into account the specific toxicity indicators for each treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; An indicative monitoring algorithm is proposed in <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">On-treatment progression can be defined as &#8220;a convincing and consistent increase in prostate specific antigen &#40;PSA&#41;&#44; evidence of radiographic progression or the presence of clinical symptoms while the patient is being treated&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The decision to discontinue therapy must be based on at least two of these 3 criteria&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The &#8220;no longer clinically benefiting&#8221; &#40;NLCB&#41; reporting metric highlights the distinction between the first evidence of progression and the clinical need to discontinue&#47;change treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The decision on whether or not to continue treatment depends on the pursued therapeutic objective&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Clinical monitoring</span><p id="par0080" class="elsevierStylePara elsevierViewall">It is recommended to ignore changes in pain or HRQL occurred during &#60;12 weeks after treatment initiation in the absence of convincing evidence of progression&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Increased pain related to mCRPC is considered a progression criterion &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Imaging monitoring</span><p id="par0085" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a> shows the recommended frequency for imaging monitoring according to treatment response&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Bone progression is not considered unless at least 2 new lesions were seen on the first on-treatment scan&#44; followed by 2 or more additional lesions on the second post-treatment scan &#40;rule 2&#8239;&#43;&#8239;2&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4</span></a> Ambiguous lesions can be confirmed by CT or MRI&#46; In the absence of new lesions&#44; it is recommended to continue treatment if there are no other signs of progression&#46; Soft tissue progression would be assessed according to RECIST 1&#46;1 criteria&#46; Treatment should be discontinued in the event of unequivocal progression of visceral disease without PSA or clinical progression&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Biochemical monitoring</span><p id="par0095" class="elsevierStylePara elsevierViewall">PSA cannot be considered an absolute marker of disease activity&#59; it must be completed with clinical and imaging tests&#44; if necessary &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46; The efficacy of radium-223 is not demonstrated by immediate PSA decline&#46; However&#44; androgen axis inhibitors or chemotherapy produce wide fluctuations&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;15</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Recent studies suggest that markers of total bone alkaline phosphatase &#40;tALP&#41; and lactate dehydrogenase &#40;LDH&#41; may be good candidates for biochemical monitoring&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Clinical trials define PSA response as &#8805;50&#37; PSA decline confirmed by a second evaluation at least 3 weeks after treatment initiation&#46; This threshold is used to classify patients treated with abiraterone or enzalutamide as &#34;good responders&#34; &#40;PSA decline of &#8805;50&#37;&#41; or &#34;partial responders&#34; &#40;PSA decline of &#60;50&#37;&#41;&#46; PSA would not act as a marker of efficacy in patients treated with radium-223&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;15</span></a> Regular evaluation of tALP and LDH is recommended for the interpretation of discordant results &#40;e&#46;g&#46;&#44; elevated PSA and clinical improvement&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conclusions</span><p id="par0110" class="elsevierStylePara elsevierViewall">The analysis of the most recent evidence together with clinical experience&#44; allow the elaboration of protocols like the present one&#44; conveniently improving the management of the patient with mCRPC&#44; consolidating aspects regarding baseline assessment&#44; appropriate treatment selection and patient monitoring&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">Bayer Hispania sponsored the creation and writing of this work&#46; However&#44; the company has not been involved in the contents of the study&#46;</p></span></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; &#193;lvarez-Ossorio JL&#44; et al&#46; Actualizaci&#243;n del protocolo de manejo del c&#225;ncer de pr&#243;stata resistente a la castraci&#243;n metast&#225;sico de la Asociaci&#243;n Andaluza de Urolog&#237;a&#46; Actas Urol Esp&#46; 2020&#59;44&#58;125&#8211;130&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Algorithm of treatment for patients with bone and lymph node mCRPC&#46; Bone metastasis group&#58; bone -with or without nodal- involvement and no evidence of visceral disease&#59; Nodal metastasis group&#58; &#40;pelvic or extrapelvic&#41; nodal involvement with no evidence of bone or visceral affectation&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4</span></a> The presence of symptoms is based on the Brief Pain Inventory Short Form &#40;BPI-SF&#41; or the World Health Organization &#40;WHO&#41; analgesic ladder&#46; &#42;The ineligibility criteria for systemic therapies include &#40;a&#41; frail patients&#44; &#40;b&#41; the existence of multiple comorbidities which could increase the risk of adverse effects&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> &#40;c&#41; patient or family refusal&#44; d&#41; when efficacy or safety of the subsequent lines of treatment is conditioned&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The provider&#8217;s clinical opinion must be taken into account when choosing the most appropriate treatment scheme for the patient&#46; <span class="elsevierStyleSup">&#8224;</span>Radium-223 must be used before the development of visceral metastases&#46; Delayed administration of radium-223 may affect the patient&#39;s benefit provided by the whole treatment &#40;6 injections&#41;&#46;</p>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Algorithm for monitoring mCRPC patients treated with radium-223 or abiraterone&#47;enzalutamide&#46; &#42;Disregard PSA rise before 12 weeks &#40;flare&#41; which can be due to a transient effect on its production&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> PSA is not a reliable biomarker for radium-223 treatment&#46; <span class="elsevierStyleSup">&#8224;</span>Symptoms&#44; especially pain&#44; may increase &#40;flare&#41; during first treatment cycle&#46; &#42;&#42;In the ALSYMCA study&#44; the reduction of these two biomarkers was related to increased survival rates&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Although the value of these biomarkers has not been validated&#44; monitoring is recommended in the absence of other validated biomarkers&#46; <span class="elsevierStyleSup">&#35;</span>Imaging tests should be performed in the face of progression suspicion by clinical or biochemical evaluation during this period&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">BPI-SF&#58; Brief Pain Inventory Short Form&#59; ECOG&#58; Eastern Cooperative Oncology Group&#59; EQ-5D&#58; EuroQoL-5D &#40;5 dimensions&#41;&#59; VAS&#58; visual analog scale&#59; FACT-P&#58; Functional Assessment of Cancer Therapy-Prostate&#59; BS&#58; bone scan&#59; BMI&#58; body mass index&#59; LDH&#58; lactate dehydrogenase&#59; WHO&#58; World Health Organization&#59; PSADT&#58; PSA doubling time&#59; GOT&#58; glutamic-oxalacetic transaminase&#59; GPT&#58; glutamic-pyruvic transaminase&#59; MRI&#58; magnetic resonance imaging&#59; tALP&#58; total alkaline phosphatase&#59; CT&#58; computed tomography&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Assessment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="8" align="left" valign="\n
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                  \t\t\t\t">Clinical</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pain &#40;question 3 of the BPI-SF&#44; WHO analgesic ladder&#44; VAS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Performance status &#40;ECOG&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Health-related quality of life &#40;EQ-5D&#44; FACT-P&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Signs and symptoms related to bone metastases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Comorbidities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Analgesic use<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prior systemic treatments&#47;adverse effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="9" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Imaging</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bone&#58; <span class="elsevierStyleSup">99m</span>Tc bone scan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Use the first post-treatment scan as baseline&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Nodal&#58; contrast CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">In cases of intolerance to contrast&#58; abdominopelvic MRI and CT without contrast&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathologic and measurable lesions&#58; &#8805;1&#46;5&#8239;cm in short axis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathologic lesions according to clinical discretion&#58; 1&#8211;1&#46;5&#8239;cm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Visceral&#58; contrast CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In cases of intolerance to contrast&#58; abdominopelvic MRI and CT without contrast&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathologic&#44; measurable lesions&#58; &#8805;1&#8239;cm in long axis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Laboratory tests &#40;blood and urine&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complete blood count&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Testosterone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tumor markers &#40;PSA&#44; PSADT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bone activity markers&#58; tALP&#44; LDH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evaluation of liver function &#40;Child-Pugh&#44; GOT&#44; GPT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Assessment of kidney function &#40;glomerular filtration and electrolytes&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2280550.png"
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Regarding patients &#62;70 years&#44; these aspects are included in the G8 questionnaire&#44; which also contains nutritional status&#44; weight loss&#44; BMI&#44; motor skills and psychological status&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Baseline assessment of the patient with mCRPC&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0020"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Subtype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bone disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bone -with or without nodal- involvement and no evidence of visceral disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nodal disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lymph node involvement &#40;pelvic&#44; with lymph nodes &#62; 1&#8239;cm&#44; or extrapelvic&#41; without evidence of bone or visceral involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Visceral disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Visceral involvement with or without bone or nodal disease&#46; Includes lung&#44; liver&#44; adrenal or central nervous system&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2280551.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Clinical subtypes of the mCRPC according to the extent of metastases&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4</span></a></p>"
        ]
      ]
      4 => array:9 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Taken from Scher et al&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#44; Loizaga-Iriarte et al&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#44; Crawford et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and Gillessen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>"
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0025"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">BPI-SF&#58; Brief Pain Inventory Short Form&#59; VAS&#58; visual analog scale&#59; LDH&#58; lactate dehydrogenase&#59; WHO&#58; World Health Organization&#59; PSA&#58; prostate specific antigen&#59; tALP&#58; total alkaline phosphatase&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Androgen axis inhibitors &#40;abiraterone&#47;enzalutamide&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Targeted alpha therapy &#40;radium-223&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monitoring protocol</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#91;0&#46;2&#8211;3&#93; <span class="elsevierStyleItalic">Clinical</span>&#58; new signs&#44; symptoms and changes since the last review &#40;related to the disease as well potentially associated with the administered treatment &#40;toxicity&#41;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Progression criterion&#58; increased pain related to mCRPC &#40;&#62;3 points in the BPI-SF questionnaire&#44; &#8805;1 step rise in the WHO analgesic ladder or increased VAS&#41;</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Toxicity must be classified according to the Common Terminology Criteria for Adverse Events system</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Biochemical</span>&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Biochemical</span>&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PSA assessment&#58; reduction &#8805;50&#37; considered &#8220;good responder&#8221;&#44; &#8220;partial responder&#8221; if &#60;50&#37;&#46; Progression&#58; increase &#8805;25&#37; and &#8805;2&#8239;ng&#47;ml vs&#46; baseline value after 12 weeks of starting treatment in patients without an initial rise in PSA&#44; or with respect to nadir and confirmed in a second determination &#8805; 3 weeks in patients with an initial rise in PSA<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PSA changes do not correspond to treatment response&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Transient PSA and tALP rises have been described up to 3 months after treatment initiation with abiraterone&#46; Wait 3 months before making therapeutic decisions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">LDH and especially tALP could be response markers<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Imaging&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Imaging&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Partially responding patients&#58; suspicion of progression in monthly or every three months routine reviews&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Suspicion of progression in monthly visits during treatment or quarterly at post-treatment follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Responding patients&#58; suspicion of progression every 3 or 6 months in visits on a routine basis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Routinely&#44; at 6 months after the end of treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Possible radiographic <span class="elsevierStyleItalic">flare</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">When to stop&#47;change treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The decision to abandon treatment must be based on at least two of the three progression criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complete treatment includes 6 cycles&#46; All 6 must be completed in order to obtain the maximum benefit&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">The absence of PSA &#40;stable or &#60;30&#37; decrease&#41; or radiological response 3 months after treatment initiation may be indicative of resistance<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">To radiographic and clinical progression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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            0 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">It should not be evaluated based only on PSA&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Monitoring and therapeutic change criteria&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:16 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Mottet N&#44; van den Bergh RCN&#44; Briers E&#44; Cornford P&#44; de Santis M&#44; Fanti S&#44; et al&#46; EAU-ESTRO-SIOG Guidelines on Pros-tate Cancer 2019 &#91;consultado 9 Juk 2019&#93;&#46; Disponible en&#58; <a target="_blank" href="https://uroweb.org/guideline/prostate-cancer/">https&#58;&#47;&#47;uroweb&#46;org&#47;guideline&#47;prostate-cancer&#47;</a>&#46;"
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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