PHASE II STUDY OF ALL-TRANS RETINOIC ACID ADMINISTERED INTERMITTENTLY FOR HORMONE REFRACTORY PROSTATE CANCER
Identifieur interne : 000A44 ( Istex/Corpus ); précédent : 000A43; suivant : 000A45PHASE II STUDY OF ALL-TRANS RETINOIC ACID ADMINISTERED INTERMITTENTLY FOR HORMONE REFRACTORY PROSTATE CANCER
Auteurs : S. Culine ; A. Kramar ; J. P. Droz ; C. TheodoreSource :
- The Journal of Urology [ 0022-5347 ] ; 1999.
Abstract
Purpose We assess the efficacy and toxicity of all-trans retinoic acid administered intermittently for hormone refractory prostate cancer.Materials and Methods A total of 26 patients with histologically confirmed adenocarcinoma of the prostate and manifestations of progressive metastatic disease, despite at least 1 hormonal therapy, were included in the study. Patients received a single oral dose of 45 mg./m. [2] all-trans retinoic acid daily for 7 days followed by 7 days of no treatment, and then resumed treatment on day 14. This schedule was continued until progression or limiting toxicity occurred. Response was assessed based on serial measurement of serum prostate specific antigen and pain scores every other week. In addition, objective responses were evaluated every 12 weeks in patients with bi-dimensionally measurable metastases.Results All-trans retinoic acid was administered for 168 weeks (median 6 weeks per patient, range 2 to 21). Toxicity was mild. No patient stopped therapy because of toxicity. Of the patients 4 (15) demonstrated a biological response of 50 or greater serum prostate specific antigen decrease. No objective response was observed among 11 patients with measurable metastases. Of 17 patients who required analgesics at the onset of all-trans retinoic acid treatment only 1 achieved a significant reduction of pain. Median survival time from the onset of all-trans retinoic acid treatment was 19 months (range 2 to 24).Conclusions All-trans retinoic acid has minimal activity in hormone refractory prostate cancer.
Url:
DOI: 10.1016/S0022-5347(01)62090-1
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>PHASE II STUDY OF ALL-TRANS RETINOIC ACID ADMINISTERED INTERMITTENTLY FOR HORMONE REFRACTORY PROSTATE CANCER</title><author><name sortKey="Culine, S" sort="Culine, S" uniqKey="Culine S" first="S." last="Culine">S. Culine</name><affiliation><mods:affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</mods:affiliation></affiliation></author><author><name sortKey="Kramar, A" sort="Kramar, A" uniqKey="Kramar A" first="A." last="Kramar">A. Kramar</name><affiliation><mods:affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</mods:affiliation></affiliation></author><author><name sortKey="Droz, J P" sort="Droz, J P" uniqKey="Droz J" first="J. P." last="Droz">J. P. Droz</name><affiliation><mods:affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</mods:affiliation></affiliation></author><author><name sortKey="Theodore, C" sort="Theodore, C" uniqKey="Theodore C" first="C." last="Theodore">C. Theodore</name><affiliation><mods:affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:1348E4C826B5B92D3DA34D1BE4A3944020B097DC</idno><date when="1999" year="1999">1999</date><idno type="doi">10.1016/S0022-5347(01)62090-1</idno><idno type="url">https://api.istex.fr/document/1348E4C826B5B92D3DA34D1BE4A3944020B097DC/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000A44</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000A44</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">PHASE II STUDY OF ALL-TRANS RETINOIC ACID ADMINISTERED INTERMITTENTLY FOR HORMONE REFRACTORY PROSTATE CANCER</title><author><name sortKey="Culine, S" sort="Culine, S" uniqKey="Culine S" first="S." last="Culine">S. Culine</name><affiliation><mods:affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</mods:affiliation></affiliation></author><author><name sortKey="Kramar, A" sort="Kramar, A" uniqKey="Kramar A" first="A." last="Kramar">A. Kramar</name><affiliation><mods:affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</mods:affiliation></affiliation></author><author><name sortKey="Droz, J P" sort="Droz, J P" uniqKey="Droz J" first="J. P." last="Droz">J. P. Droz</name><affiliation><mods:affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</mods:affiliation></affiliation></author><author><name sortKey="Theodore, C" sort="Theodore, C" uniqKey="Theodore C" first="C." last="Theodore">C. Theodore</name><affiliation><mods:affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">The Journal of Urology</title><title level="j" type="abbrev">JURO</title><idno type="ISSN">0022-5347</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999">1999</date><biblScope unit="volume">161</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="173">173</biblScope><biblScope unit="page" to="175">175</biblScope></imprint><idno type="ISSN">0022-5347</idno></series><idno type="istex">1348E4C826B5B92D3DA34D1BE4A3944020B097DC</idno><idno type="DOI">10.1016/S0022-5347(01)62090-1</idno><idno type="PII">S0022-5347(01)62090-1</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-5347</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Purpose We assess the efficacy and toxicity of all-trans retinoic acid administered intermittently for hormone refractory prostate cancer.Materials and Methods A total of 26 patients with histologically confirmed adenocarcinoma of the prostate and manifestations of progressive metastatic disease, despite at least 1 hormonal therapy, were included in the study. Patients received a single oral dose of 45 mg./m. [2] all-trans retinoic acid daily for 7 days followed by 7 days of no treatment, and then resumed treatment on day 14. This schedule was continued until progression or limiting toxicity occurred. Response was assessed based on serial measurement of serum prostate specific antigen and pain scores every other week. In addition, objective responses were evaluated every 12 weeks in patients with bi-dimensionally measurable metastases.Results All-trans retinoic acid was administered for 168 weeks (median 6 weeks per patient, range 2 to 21). Toxicity was mild. No patient stopped therapy because of toxicity. Of the patients 4 (15) demonstrated a biological response of 50 or greater serum prostate specific antigen decrease. No objective response was observed among 11 patients with measurable metastases. Of 17 patients who required analgesics at the onset of all-trans retinoic acid treatment only 1 achieved a significant reduction of pain. Median survival time from the onset of all-trans retinoic acid treatment was 19 months (range 2 to 24).Conclusions All-trans retinoic acid has minimal activity in hormone refractory prostate cancer.</div></front></TEI><istex><corpusName>elsevier</corpusName><author><json:item><name>S. CULINE</name><affiliations><json:string>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</json:string></affiliations></json:item><json:item><name>A. KRAMAR</name><affiliations><json:string>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</json:string></affiliations></json:item><json:item><name>J.P. DROZ</name><affiliations><json:string>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</json:string></affiliations></json:item><json:item><name>C. THEODORE</name><affiliations><json:string>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</json:string></affiliations></json:item></author><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>Purpose We assess the efficacy and toxicity of all-trans retinoic acid administered intermittently for hormone refractory prostate cancer.Materials and Methods A total of 26 patients with histologically confirmed adenocarcinoma of the prostate and manifestations of progressive metastatic disease, despite at least 1 hormonal therapy, were included in the study. Patients received a single oral dose of 45 mg./m. [2] all-trans retinoic acid daily for 7 days followed by 7 days of no treatment, and then resumed treatment on day 14. This schedule was continued until progression or limiting toxicity occurred. Response was assessed based on serial measurement of serum prostate specific antigen and pain scores every other week. In addition, objective responses were evaluated every 12 weeks in patients with bi-dimensionally measurable metastases.Results All-trans retinoic acid was administered for 168 weeks (median 6 weeks per patient, range 2 to 21). Toxicity was mild. No patient stopped therapy because of toxicity. Of the patients 4 (15) demonstrated a biological response of 50 or greater serum prostate specific antigen decrease. No objective response was observed among 11 patients with measurable metastases. Of 17 patients who required analgesics at the onset of all-trans retinoic acid treatment only 1 achieved a significant reduction of pain. Median survival time from the onset of all-trans retinoic acid treatment was 19 months (range 2 to 24).Conclusions All-trans retinoic acid has minimal activity in hormone refractory prostate cancer.</abstract><qualityIndicators><score>5.081</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 792 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1556</abstractCharCount><pdfWordCount>2321</pdfWordCount><pdfCharCount>14507</pdfCharCount><pdfPageCount>3</pdfPageCount><abstractWordCount>230</abstractWordCount></qualityIndicators><title>PHASE II STUDY OF ALL-TRANS RETINOIC ACID ADMINISTERED INTERMITTENTLY FOR HORMONE REFRACTORY PROSTATE CANCER</title><pii><json:string>S0022-5347(01)62090-1</json:string></pii><refBibs><json:item><author><json:item><name>N.A. 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Oncol.</title></host><title>Pharmacokinetics of all-trans retinoic acid administered on an intermittent schedule</title></json:item></refBibs><genre><json:string>research-article</json:string></genre><host><volume>161</volume><pii><json:string>S0022-5347(01)X0006-2</json:string></pii><pages><last>175</last><first>173</first></pages><issn><json:string>0022-5347</json:string></issn><issue>1</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><title>The Journal of Urology</title><publicationDate>1999</publicationDate></host><categories><wos><json:string>science</json:string><json:string>urology & nephrology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>urology & nephrology</json:string></scienceMetrix></categories><publicationDate>1999</publicationDate><copyrightDate>1999</copyrightDate><doi><json:string>10.1016/S0022-5347(01)62090-1</json:string></doi><id>1348E4C826B5B92D3DA34D1BE4A3944020B097DC</id><score>0.18515053</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/1348E4C826B5B92D3DA34D1BE4A3944020B097DC/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/1348E4C826B5B92D3DA34D1BE4A3944020B097DC/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/1348E4C826B5B92D3DA34D1BE4A3944020B097DC/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">PHASE II STUDY OF ALL-TRANS RETINOIC ACID ADMINISTERED INTERMITTENTLY FOR HORMONE REFRACTORY PROSTATE CANCER</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>ELSEVIER</publisher><availability><p>©1999 American Urological Association, Inc.</p></availability><date>1999</date></publicationStmt><notesStmt><note type="content">Section title: Clinical Urology: Original Articles</note><note type="content">Table 1: Patient characteristics</note><note type="content">Table 2: Toxicity</note><note type="content">Table 3: Pain score after therapy</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">PHASE II STUDY OF ALL-TRANS RETINOIC ACID ADMINISTERED INTERMITTENTLY FOR HORMONE REFRACTORY PROSTATE CANCER</title><author xml:id="author-1"><persName><forename type="first">S.</forename><surname>CULINE</surname></persName><affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</affiliation></author><author xml:id="author-2"><persName><forename type="first">A.</forename><surname>KRAMAR</surname></persName><affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</affiliation></author><author xml:id="author-3"><persName><forename type="first">J.P.</forename><surname>DROZ</surname></persName><affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</affiliation></author><author xml:id="author-4"><persName><forename type="first">C.</forename><surname>THEODORE</surname></persName><affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</affiliation></author></analytic><monogr><title level="j">The Journal of Urology</title><title level="j" type="abbrev">JURO</title><idno type="pISSN">0022-5347</idno><idno type="PII">S0022-5347(01)X0006-2</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999"></date><biblScope unit="volume">161</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="173">173</biblScope><biblScope unit="page" to="175">175</biblScope></imprint></monogr><idno type="istex">1348E4C826B5B92D3DA34D1BE4A3944020B097DC</idno><idno type="DOI">10.1016/S0022-5347(01)62090-1</idno><idno type="PII">S0022-5347(01)62090-1</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1999</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Purpose We assess the efficacy and toxicity of all-trans retinoic acid administered intermittently for hormone refractory prostate cancer.Materials and Methods A total of 26 patients with histologically confirmed adenocarcinoma of the prostate and manifestations of progressive metastatic disease, despite at least 1 hormonal therapy, were included in the study. Patients received a single oral dose of 45 mg./m. [2] all-trans retinoic acid daily for 7 days followed by 7 days of no treatment, and then resumed treatment on day 14. This schedule was continued until progression or limiting toxicity occurred. Response was assessed based on serial measurement of serum prostate specific antigen and pain scores every other week. In addition, objective responses were evaluated every 12 weeks in patients with bi-dimensionally measurable metastases.Results All-trans retinoic acid was administered for 168 weeks (median 6 weeks per patient, range 2 to 21). Toxicity was mild. No patient stopped therapy because of toxicity. Of the patients 4 (15) demonstrated a biological response of 50 or greater serum prostate specific antigen decrease. No objective response was observed among 11 patients with measurable metastases. Of 17 patients who required analgesics at the onset of all-trans retinoic acid treatment only 1 achieved a significant reduction of pain. Median survival time from the onset of all-trans retinoic acid treatment was 19 months (range 2 to 24).Conclusions All-trans retinoic acid has minimal activity in hormone refractory prostate cancer.</p></abstract></profileDesc><revisionDesc><change when="1999">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/1348E4C826B5B92D3DA34D1BE4A3944020B097DC/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier doc found" wicri:toSee="Elsevier, no converted or simple article"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 5.0.1//EN//XML" URI="art501.dtd" name="istex:docType"></istex:docType><istex:document><article docsubtype="fla"> <item-info> <jid>JURO</jid> <aid>62090</aid> <ce:pii>S0022-5347(01)62090-1</ce:pii><ce:doi>10.1016/S0022-5347(01)62090-1</ce:doi> <ce:copyright type="other" year="1999">American Urological Association, Inc.</ce:copyright> <!-- 0005392-199901000-00049 G99901000040 2005-10-28T18:00:31+5.30 --> </item-info> <ce:floats> <ce:table id="tbl1" frame="topbot" rowsep="0" colsep="0"> <ce:label>Table 1</ce:label> <ce:caption> <ce:simple-para>Patient characteristics</ce:simple-para> </ce:caption> <tgroup cols="3" altimg="si1.gif"> <colspec colnum="1" colname="col1"></colspec> <colspec colnum="2" colname="col2"></colspec> <colspec colnum="3" colname="col3"></colspec> <tbody> <row valign="top"> <entry align="left" namest="col1" nameend="col2">No. response:</entry> <entry colname="col3" align="left"></entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Objective</entry> <entry colname="col3" align="char" char=".">11</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Biological</entry> <entry colname="col3" align="char" char=".">26</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Toxicity</entry> <entry colname="col3" align="char" char=".">26</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Median pt. age (range)</entry> <entry colname="col3" align="char" char=".">65 (45–76)</entry> </row> <row valign="top"> <entry align="left" namest="col1" nameend="col2">No. WHO performance status:</entry> <entry colname="col3" align="char" char="."></entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">0</entry> <entry colname="col3" align="char" char=".">7</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">1</entry> <entry colname="col3" align="char" char=".">17</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">2</entry> <entry colname="col3" align="char" char=".">2</entry> </row> <row valign="top"> <entry align="left" namest="col1" nameend="col2">No. sites measurable lesions:</entry> <entry colname="col3" align="char" char="."></entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Retroperitoneal lymph nodes</entry> <entry colname="col3" align="char" char=".">8</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Liver</entry> <entry colname="col3" align="char" char=".">2</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Lung</entry> <entry colname="col3" align="char" char=".">1</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Mediastinal nodes</entry> <entry colname="col3" align="char" char=".">1</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Supraclavicular nodes</entry> <entry colname="col3" align="char" char=".">1</entry> </row> <row valign="top"> <entry align="left" namest="col1" nameend="col2">No. extent skeletal metastases:</entry> <entry colname="col3" align="char" char="."></entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">1</entry> <entry colname="col3" align="char" char=".">6</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">2</entry> <entry colname="col3" align="char" char=".">8</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">3</entry> <entry colname="col3" align="char" char=".">11</entry> </row> <row valign="top"> <entry align="left" namest="col1" nameend="col2">No. pain score:</entry> <entry colname="col3" align="char" char="."></entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">0</entry> <entry colname="col3" align="char" char=".">9</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">1</entry> <entry colname="col3" align="char" char=".">8</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">2</entry> <entry colname="col3" align="char" char=".">9</entry> </row> <row valign="top"> <entry align="left" namest="col1" nameend="col2">No. prior treatments:</entry> <entry colname="col3" align="char" char="."></entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Prostatectomy</entry> <entry colname="col3" align="char" char=".">4</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Radiation to prostate</entry> <entry colname="col3" align="char" char=".">10</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Radiation to metastases</entry> <entry colname="col3" align="char" char=".">8</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Bilat. orchiectomy</entry> <entry colname="col3" align="char" char=".">9</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Luteinizing hormone releasing hormone analogues</entry> <entry colname="col3" align="char" char=".">17</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Antiandrogens</entry> <entry colname="col3" align="char" char=".">23</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Second hormonal treatment</entry> <entry colname="col3" align="char" char=".">13</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Chemotherapy:</entry> <entry colname="col3" align="char" char=".">16</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Estramustine phosphate</entry> <entry colname="col3" align="char" char=".">8</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Estramustine phosphate + doxorubicin</entry> <entry colname="col3" align="char" char=".">6</entry> </row> <row valign="top"> <entry colname="col1" align="left"></entry> <entry colname="col2" align="left">Others</entry> <entry colname="col3" align="char" char=".">2</entry> </row> <row valign="top"> <entry align="left" namest="col1" nameend="col2">Median PSA (range)</entry> <entry colname="col3" align="char" char=".">138 (9–1,518)</entry> </row> <row valign="top"> <entry align="left" namest="col1" nameend="col2">Median IU./l. alkaline phosphatase (range)</entry> <entry colname="col3" align="char" char=".">166 (49–2,963)</entry> </row> </tbody> </tgroup> </ce:table> <ce:table id="tbl2" frame="topbot" rowsep="0" colsep="0"> <ce:label>Table 2</ce:label> <ce:caption> <ce:simple-para>Toxicity</ce:simple-para> </ce:caption> <tgroup cols="5" altimg="si2.gif"> <colspec colnum="1" colname="col1"></colspec> <colspec colnum="2" colname="col2"></colspec> <colspec colnum="3" colname="col3"></colspec> <colspec colnum="4" colname="col4"></colspec> <colspec colnum="5" colname="col5"></colspec> <thead> <row valign="top"> <entry colname="col1" align="left">Toxicity</entry> <entry align="center" rowsep="1" namest="col2" nameend="col5">Grade</entry> </row> <row valign="top" rowsep="1"> <entry colname="col1" align="center"></entry> <entry colname="col2" align="center">0</entry> <entry colname="col3" align="center">1</entry> <entry colname="col4" align="center">2</entry> <entry colname="col5" align="center">3</entry> </row> </thead> <tbody> <row valign="top"> <entry colname="col1" align="left">Cheilosis</entry> <entry colname="col2" align="center">124</entry> <entry colname="col3" align="right">36</entry> <entry colname="col4" align="right">8</entry> <entry colname="col5" align="center">0</entry> </row> <row valign="top"> <entry colname="col1" align="left">Headache</entry> <entry colname="col2" align="center">140</entry> <entry colname="col3" align="right">12</entry> <entry colname="col4" align="right">15</entry> <entry colname="col5" align="center">1</entry> </row> <row valign="top"> <entry colname="col1" align="left">Nausea/vomiting</entry> <entry colname="col2" align="center">156</entry> <entry colname="col3" align="right">6</entry> <entry colname="col4" align="right">6</entry> <entry colname="col5" align="center">0</entry> </row> <row valign="top"> <entry colname="col1" align="left">Fever</entry> <entry colname="col2" align="center">164</entry> <entry colname="col3" align="right">1</entry> <entry colname="col4" align="right">3</entry> <entry colname="col5" align="center">0</entry> </row> </tbody> </tgroup> </ce:table> <ce:table id="tbl3" frame="topbot" rowsep="0" colsep="0"> <ce:label>Table 3</ce:label> <ce:caption> <ce:simple-para>Pain score after therapy</ce:simple-para> </ce:caption> <tgroup cols="4" altimg="si3.gif"> <colspec colnum="1" colname="col1"></colspec> <colspec colnum="2" colname="col2"></colspec> <colspec colnum="3" colname="col3"></colspec> <colspec colnum="4" colname="col4"></colspec> <thead> <row valign="top" rowsep="1"> <entry colname="col1" align="center">Score</entry> <entry align="center" namest="col2" nameend="col4">No. Pts.</entry> </row> </thead> <tbody> <row valign="top"> <entry colname="col1" align="center">0</entry> <entry colname="col2" align="center">6</entry> <entry colname="col3" align="center">2</entry> <entry colname="col4" align="center">1</entry> </row> <row valign="top"> <entry colname="col1" align="center">1</entry> <entry colname="col2" align="center">0</entry> <entry colname="col3" align="center">6</entry> <entry colname="col4" align="center">2</entry> </row> <row valign="top"> <entry colname="col1" align="center">2</entry> <entry colname="col2" align="center">0</entry> <entry colname="col3" align="center">1</entry> <entry colname="col4" align="center">8</entry> </row> </tbody> </tgroup> </ce:table> </ce:floats> <head> <ce:dochead> <ce:textfn>Clinical Urology: Original Articles</ce:textfn> </ce:dochead> <ce:title>PHASE II STUDY OF ALL-TRANS RETINOIC ACID ADMINISTERED INTERMITTENTLY FOR HORMONE REFRACTORY PROSTATE CANCER</ce:title> <ce:author-group> <ce:author> <ce:given-name>S.</ce:given-name> <ce:surname>CULINE</ce:surname><ce:cross-ref refid="cor1"><ce:sup>*</ce:sup></ce:cross-ref> </ce:author> <ce:author> <ce:given-name>A.</ce:given-name> <ce:surname>KRAMAR</ce:surname> </ce:author> <ce:author> <ce:given-name>J.P.</ce:given-name> <ce:surname>DROZ</ce:surname> </ce:author> <ce:author> <ce:given-name>C.</ce:given-name> <ce:surname>THEODORE</ce:surname> </ce:author> <ce:affiliation> <ce:textfn>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</ce:textfn> </ce:affiliation> <ce:correspondence id="cor1"> <ce:label>*</ce:label> <ce:text>Requests for reprints: Department of Medical Oncology, CRLC Val d’ Aurelle 34298 - Montpellier Cedex 5, France.</ce:text> </ce:correspondence> </ce:author-group> <ce:date-accepted day="10" month="7" year="1998"></ce:date-accepted> <ce:abstract> <ce:section-title>Abstract</ce:section-title> <ce:abstract-sec> <ce:section-title>Purpose</ce:section-title> <ce:simple-para>We assess the efficacy and toxicity of all-trans retinoic acid administered intermittently for hormone refractory prostate cancer.</ce:simple-para> </ce:abstract-sec> <ce:abstract-sec> <ce:section-title>Materials and Methods</ce:section-title> <ce:simple-para>A total of 26 patients with histologically confirmed adenocarcinoma of the prostate and manifestations of progressive metastatic disease, despite at least 1 hormonal therapy, were included in the study. Patients received a single oral dose of 45 mg./m. <ce:cross-ref refid="bib2"><ce:sup>[2]</ce:sup></ce:cross-ref> all-trans retinoic acid daily for 7 days followed by 7 days of no treatment, and then resumed treatment on day 14. This schedule was continued until progression or limiting toxicity occurred. Response was assessed based on serial measurement of serum prostate specific antigen and pain scores every other week. In addition, objective responses were evaluated every 12 weeks in patients with bi-dimensionally measurable metastases.</ce:simple-para> </ce:abstract-sec> <ce:abstract-sec> <ce:section-title>Results</ce:section-title> <ce:simple-para>All-trans retinoic acid was administered for 168 weeks (median 6 weeks per patient, range 2 to 21). Toxicity was mild. No patient stopped therapy because of toxicity. Of the patients 4 (15%) demonstrated a biological response of 50% or greater serum prostate specific antigen decrease. No objective response was observed among 11 patients with measurable metastases. Of 17 patients who required analgesics at the onset of all-trans retinoic acid treatment only 1 achieved a significant reduction of pain. Median survival time from the onset of all-trans retinoic acid treatment was 19 months (range 2 to 24).</ce:simple-para> </ce:abstract-sec> <ce:abstract-sec> <ce:section-title>Conclusions</ce:section-title> <ce:simple-para>All-trans retinoic acid has minimal activity in hormone refractory prostate cancer.</ce:simple-para> </ce:abstract-sec> </ce:abstract> </head> <body> <ce:sections> <ce:para>Key Words: prostatic neoplasms, tretinoin, hormones</ce:para> <ce:para>The treatment of metastatic prostate cancer remains a complex and difficult problem. The suppression of androgenic activity is considered the most adequate first line treatment. However, hormonal therapy is successful in only 70 to 80% of cases and median duration of response is no longer than 12 to 18 months. <ce:cross-ref refid="bib1"><ce:sup>[1]</ce:sup></ce:cross-ref> The prognosis for men with metastatic prostate cancer that has progressed after initial androgen ablative therapy remains poor as reported median survival ranges from 6 to 12 months. Various second line hormonal treatments as well as multiple cytotoxic agents, alone or in combination, have failed to demonstrate a significant impact on survival. There is no current consensus on the optimal medical treatment in this setting and new agents are needed. <ce:cross-refs refid="bib2 bib3"><ce:sup>[2,3]</ce:sup></ce:cross-refs> We report the results of a phase II trial of all-trans retinoic acid, a natural retinol metabolite formed by enterocytes from beta-carotene, and tissue metabolism of retinol and retinaldehyde, in patients with hormone refractory prostate cancer.</ce:para> <ce:section> <ce:section-title>PATIENTS AND METHODS</ce:section-title> <ce:section> <ce:section-title>Patient eligibility.</ce:section-title> <ce:para>A total of 26 patients with histologically confirmed prostatic adenocarcinoma and manifestations of progressive disease, despite 1 or several hormonal therapies and chemotherapy, entered our study from September 1994 to December 1996. Progression was defined as the development of new metastatic sites, objective evidence of progression at previous sites of metastases or increasing serum prostate specific antigen (PSA) on 2 consecutive determinations. In addition, eligibility criteria included an Eastern Cooperative Oncology Group performance status of 2 or less, adequate bone marrow reserve (white blood count greater than 4,000 and platelet count greater than 100,000/mm. <ce:cross-ref refid="bib3"><ce:sup>[3]</ce:sup></ce:cross-ref>), normal renal (serum creatinine less than 120 micro mol./l.) and hepatic (bilirubin and transaminases less than 1.5 times normal) functions, and cardiac ejection fraction greater than 50%. Moreover, men who had not undergone orchiectomy were required to have serum testosterone concentration within the castrate range, that is less than 20 ng./ml.</ce:para> <ce:para>Pretreatment evaluation included a complete medical history, clinical examination, blood count, serum chemistry profile (including glycemia, cholesterol and triglycerides), serum PSA and testosterone, chest x-ray, radionuclide bone scan, computerized tomography of the abdomen and pelvis, and echocardiographic or radionuclide cineangiography. Clinical examination included assessment of performance status and pain score of 0 for no analgesics, 1 for nonnarcotic analgesics and 2 for narcotics required. A significant reduction in pain score was defined as a decrease of at least 1. Radionuclide bone scan enabled categorization of extent of disease according to Soloway et al. <ce:cross-ref refid="bib4"><ce:sup>[4]</ce:sup></ce:cross-ref> Regular followup tests included serum PSA, blood count, serum chemistry studies, toxicity evaluation, performance status and pain score every other week. Bone and other scans to assess tumor status were repeated every 12 weeks.</ce:para> </ce:section> <ce:section> <ce:section-title>Treatment.</ce:section-title> <ce:para>All-trans retinoic acid was supplied as 10 mg. opaque gelatin capsules and treatment consisted of a single oral dose of 45 mg./m. <ce:cross-ref refid="bib2"><ce:sup>[2]</ce:sup></ce:cross-ref> daily for 7 days. Capsules were self-administered with fatty substance enriched breakfasts to improve digestive absorption. Therapy was interrupted for 7 days before resuming on day 14. This schedule was continued until progression or limiting toxicity occurred. Toxicity was assessed every other week. Doses were scheduled to be reduced in cases of grade 2 or greater (World Health Organization [WHO] criteria) toxicity. <ce:cross-ref refid="bib5"><ce:sup>[5]</ce:sup></ce:cross-ref> Patients receiving medical therapy with luteinizing hormone releasing hormone analogues continued this treatment to maintain serum testosterone within the castrate range. Other hormonal agents had to be discontinued at least a month before treatment initiation to eliminate withdrawal responses.</ce:para> </ce:section> <ce:section> <ce:section-title>Response assessment.</ce:section-title> <ce:para>Response was mainly assessed by serial measurements of serum PSA every other week. Partial response was defined as a 50% or greater decrease in PSA from baseline on 4 successive measurements in patients with stable or improved performance status. Patients were considered to have progressive disease if PSA increased 50% or greater from baseline on 4 determinations. Patients who had no deterioration in performance status and who did not meet PSA criteria for response or progression were considered to have stable disease. Progression was defined as 4 consecutive increases in PSA 50% or greater from the minimal value achieved in patients with responding or stable disease. Pain scores were assessed every other week. In addition, objective response was evaluated according to WHO criteria every 12 weeks in patients with bi-dimensionally measurable metastases. <ce:cross-ref refid="bib5"><ce:sup>[5]</ce:sup></ce:cross-ref> Overall survival was measured from the first day of all-trans retinoic acid intake to the date of death or last followup.</ce:para> </ce:section> </ce:section> <ce:section> <ce:section-title>RESULTS</ce:section-title> <ce:section> <ce:section-title>Patients.</ce:section-title> <ce:para>Pretreatment characteristics of the 26 patients are listed in <ce:cross-ref refid="tbl1">Table 1</ce:cross-ref><ce:float-anchor refid="tbl1"></ce:float-anchor>. Median patient age was 65 years. Median time from initial diagnosis of prostate cancer was 45 months (range 20 to 124). Of the patients 13 (50%) had received 2 or 3 successive hormone treatments (antiandrogens in 4, estrogens in 9) and 1 line of chemotherapy had been administered in 16 (61.5%). All patients except 1 had skeletal and 11 (38.5%) presented with measurable metastases. Nine patients (29%) required no analgesics. All 26 patients could be evaluated for subjective and biological responses and toxicity.</ce:para> </ce:section> <ce:section> <ce:section-title>Treatment delivery and toxicity.</ce:section-title> <ce:para>All-trans retinoic acid was administered for 168 weeks (median 6 weeks per patient, range 2 to 21). Treatment was administered for at least 4 weeks to 21 patients (81%) and more than 6 weeks to 8 (31%). Therapy was stopped within the first 6 weeks in 8 patients, that is before first tumor assessment, because of early progression after 3 weeks in 5, 4 in 1 and 5 in 2.</ce:para> <ce:para>Toxicity was mild (<ce:cross-ref refid="tbl2">Table 2</ce:cross-ref><ce:float-anchor refid="tbl2"></ce:float-anchor>). Cheilosis developed in 11 patients (42%) and vomiting during therapy occurred in 1. A 30% all-trans retinoic acid dose reduction was required in 1 patient because of severe headache with vomiting on treatment day 1. Modifications were only observed in serum triglyceride, and after transient increase in 8 patients (as much as 3 times normal) levels returned to normal within 3 to 6 weeks despite continuation of all-trans retinoic acid. No patient stopped therapy because of toxicity.</ce:para> </ce:section> <ce:section> <ce:section-title>Responses and survival.</ce:section-title> <ce:para>Biological response was demonstrated in 4 patients (50%) with a 50% or greater serum PSA decrease. In these patients baseline serum PSA was 25, 62, 138 and 376 ng./ml., respectively. Only the first patient achieved a biological complete response as serum PSA returned to normal. This patient had asymptomatic minimal bone disease with normal serum alkaline phosphatases at the onset of all-trans retinoic acid treatment. Duration from start of treatment to maximal biological response in 4 patients was 8, 12, 14 and 14 weeks, respectively. Biological response lasted 8, 10 and 12 weeks in 3 patients but could not be assessed in 1 as liver metastases concurrently occurred and alternative chemotherapy was initiated. No objective response was observed among 11 patients with measurable metastases. Of 17 patients who required analgesics at the onset of treatment only 1 achieved a significant but transient (2 months) reduction in pain (<ce:cross-ref refid="tbl3">Table 3</ce:cross-ref><ce:float-anchor refid="tbl3"></ce:float-anchor>). After median followup of 23 months 16 patients died of progressive prostate cancer. Median survival time from the onset of all-trans retinoic acid treatment was 19 months (range 2 to 24).</ce:para> </ce:section> </ce:section> <ce:section> <ce:section-title>DISCUSSION</ce:section-title> <ce:para>The retinoids are a class of chemical compounds structurally related to vitamin A, and comprised of natural and synthetic analogues, which have important effects on growth and development of mammalian epithelial tissues. Enthusiasm for retinoids in oncology was renewed after recent reports of a dramatic antitumor effect of all-trans retinoic acid in patients with acute promyelocytic leukemia. In addition, significant clinical responses have been observed in patients with other hematological or dermatological malignancies. <ce:cross-ref refid="bib6"><ce:sup>[6]</ce:sup></ce:cross-ref> Cumulative evidence in in vivo prostate systems suggests that retinoids could be useful in the management of prostatic cancer. Fenretinide, a derivative of retinoic acid, prevented, primary prostate cancer in the Lobund-Wistar rat model. <ce:cross-ref refid="bib7"><ce:sup>[7]</ce:sup></ce:cross-ref> Pienta et al reported that fenretinide was effective in the treatment of established tumors in Dunning rats with prostatic adenocarcinoma. <ce:cross-ref refid="bib8"><ce:sup>[8]</ce:sup></ce:cross-ref></ce:para> <ce:para>These encouraging preclinical data prompted the initiation of phase II trials of retinoids in human prostate cancer. Preliminary results of 13-cis-retinoic acid in combination with alpha-interferon indicated limited efficacy as no objective response was observed, although some patients had a decrease in serum PSA. <ce:cross-refs refid="bib9 bib10"><ce:sup>[9,10]</ce:sup></ce:cross-refs> Similar disappointing results were observed in our study with all-trans retinoic acid as well as 2 negative trials using different delivery schedules. <ce:cross-refs refid="bib11 bib12"><ce:sup>[11,12]</ce:sup></ce:cross-refs> At the Memorial Sloan-Kettering Cancer Center 14 patients received 50 mg./m.<ce:sup>2</ce:sup> all-trans retinoic acid 3 times daily for 8 weeks and no major response was observed. <ce:cross-ref refid="bib11"><ce:sup>[11]</ce:sup></ce:cross-ref> Trump et al recently reported experience with 17 patients who received 50 mg./m.<ce:sup>2</ce:sup> all-trans retinoic acid 3 times daily on days 1 to 14, repeated every 22 days and no objective response occurred. <ce:cross-ref refid="bib12"><ce:sup>[12]</ce:sup></ce:cross-ref></ce:para> <ce:para>Initial pharmacokinetic studies suggested that failure following therapy with a chronic daily schedule of all-trans retinoic acid could be related to enhanced mechanisms of all-trans retinoic acid clearance. In fact, the area under the plasma concentration time curve after 1 month of therapy was as low as a fifth of that on day 1. <ce:cross-refs refid="bib13 bib14"><ce:sup>[13,14]</ce:sup></ce:cross-refs> Preclinical studies in rhesus monkeys demonstrated a decrease in plasma concentrations of all-trans retinoic acid as early as day 3 of daily intravenous administration. 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Oncol.</sb:maintitle> </sb:title> <sb:volume-nr>13</sb:volume-nr> </sb:series> <sb:date>1995</sb:date> </sb:issue> <sb:pages> <sb:first-page>1238</sb:first-page> </sb:pages> </sb:host> </sb:reference> </ce:bib-reference> </ce:bibliography-sec> </ce:bibliography> </tail></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>PHASE II STUDY OF ALL-TRANS RETINOIC ACID ADMINISTERED INTERMITTENTLY FOR HORMONE REFRACTORY PROSTATE CANCER</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>PHASE II STUDY OF ALL-TRANS RETINOIC ACID ADMINISTERED INTERMITTENTLY FOR HORMONE REFRACTORY PROSTATE CANCER</title></titleInfo><name type="personal"><namePart type="given">S.</namePart><namePart type="family">CULINE</namePart><affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A.</namePart><namePart type="family">KRAMAR</namePart><affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J.P.</namePart><namePart type="family">DROZ</namePart><affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">C.</namePart><namePart type="family">THEODORE</namePart><affiliation>Departments of Medicine and Biostatistics, Institut Gustave Roussy, Villejuif, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1999</dateIssued><copyrightDate encoding="w3cdtf">1999</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Purpose We assess the efficacy and toxicity of all-trans retinoic acid administered intermittently for hormone refractory prostate cancer.Materials and Methods A total of 26 patients with histologically confirmed adenocarcinoma of the prostate and manifestations of progressive metastatic disease, despite at least 1 hormonal therapy, were included in the study. Patients received a single oral dose of 45 mg./m. [2] all-trans retinoic acid daily for 7 days followed by 7 days of no treatment, and then resumed treatment on day 14. This schedule was continued until progression or limiting toxicity occurred. Response was assessed based on serial measurement of serum prostate specific antigen and pain scores every other week. In addition, objective responses were evaluated every 12 weeks in patients with bi-dimensionally measurable metastases.Results All-trans retinoic acid was administered for 168 weeks (median 6 weeks per patient, range 2 to 21). Toxicity was mild. No patient stopped therapy because of toxicity. Of the patients 4 (15) demonstrated a biological response of 50 or greater serum prostate specific antigen decrease. No objective response was observed among 11 patients with measurable metastases. Of 17 patients who required analgesics at the onset of all-trans retinoic acid treatment only 1 achieved a significant reduction of pain. Median survival time from the onset of all-trans retinoic acid treatment was 19 months (range 2 to 24).Conclusions All-trans retinoic acid has minimal activity in hormone refractory prostate cancer.</abstract><note type="content">Section title: Clinical Urology: Original Articles</note><note type="content">Table 1: Patient characteristics</note><note type="content">Table 2: Toxicity</note><note type="content">Table 3: Pain score after therapy</note><relatedItem type="host"><titleInfo><title>The Journal of Urology</title></titleInfo><titleInfo type="abbreviated"><title>JURO</title></titleInfo><genre type="journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">199901</dateIssued></originInfo><identifier type="ISSN">0022-5347</identifier><identifier type="PII">S0022-5347(01)X0006-2</identifier><part><date>199901</date><detail type="volume"><number>161</number><caption>vol.</caption></detail><detail type="issue"><number>1</number><caption>no.</caption></detail><extent unit="issue pages"><start>1</start><end>376</end></extent><extent unit="pages"><start>173</start><end>175</end></extent></part></relatedItem><identifier type="istex">1348E4C826B5B92D3DA34D1BE4A3944020B097DC</identifier><identifier type="DOI">10.1016/S0022-5347(01)62090-1</identifier><identifier type="PII">S0022-5347(01)62090-1</identifier><accessCondition type="use and reproduction" contentType="copyright">©1999 American Urological Association, Inc.</accessCondition><recordInfo><recordContentSource>ELSEVIER</recordContentSource><recordOrigin>American Urological Association, Inc., ©1999</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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