Sequential intravesical mitomycin plus Bacillus Calmette-Guérin for non-muscle-invasive urothelial bladder carcinoma: translational and phase I clinical trial
To determine the safety and toxicities of sequential MMC (mitomycin C) + BCG (bacillus Calmette-Guérin) in patients with non-muscle-invasive bladder cancer (NMIBC) and explore evidence for potentiation of BCG activity by MMC. A 3 + 3 phase I dose-escalation trial of six weekly treatments was conduct...
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| Veröffentlicht in: | Clinical cancer research 2015-01, Vol.21 (2), p.303-311 |
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| creator | Svatek, Robert S Zhao, Xiang Ru Morales, Edwin E Jha, Mithilesh K Tseng, Timothy Y Hugen, Cory M Hurez, Vincent Hernandez, Javier Curiel, Tyler J |
| description | To determine the safety and toxicities of sequential MMC (mitomycin C) + BCG (bacillus Calmette-Guérin) in patients with non-muscle-invasive bladder cancer (NMIBC) and explore evidence for potentiation of BCG activity by MMC.
A 3 + 3 phase I dose-escalation trial of six weekly treatments was conducted in patients with NMIBC. MMC (10, 20, or 40 mg) was instilled intravesically for 30 minutes, followed by a 10-minute washout with gentle saline irrigation and then instillation of BCG (half or full strength) for 2 hours. Urine cytokines were monitored and compared with levels in a control cohort receiving BCG only. Murine experiments were carried out as described previously.
Twelve patients completed therapy, including 3 patients receiving full doses. The regimen was well tolerated with no treatment-related dose-limiting toxicities. Urinary frequency and urgency, and fatigue were common. Eleven (91.7%) patients were free of disease at a mean (range) follow-up of 21.4 (8.4-27.0) months. Median posttreatment urine concentrations of IL2, IL8, IL10, and TNFα increased over the 6-week treatment period. A greater increase in posttreatment urinary IL8 during the 6-week period was observed in patients receiving MMC + BCG compared with patients receiving BCG monotherapy. In mice, intravesical MMC + BCG skewed tumor-associated macrophages (TAM) toward a beneficial M1 phenotype.
Instillation of sequential MMC + BCG is safe tolerable up to 40-mg MMC plus full-strength BCG. This approach could provide improved antitumor activity over BCG monotherapy by augmenting beneficial M1 TAMs. |
| doi_str_mv | 10.1158/1078-0432.ccr-14-1781 |
| format | Article |
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A 3 + 3 phase I dose-escalation trial of six weekly treatments was conducted in patients with NMIBC. MMC (10, 20, or 40 mg) was instilled intravesically for 30 minutes, followed by a 10-minute washout with gentle saline irrigation and then instillation of BCG (half or full strength) for 2 hours. Urine cytokines were monitored and compared with levels in a control cohort receiving BCG only. Murine experiments were carried out as described previously.
Twelve patients completed therapy, including 3 patients receiving full doses. The regimen was well tolerated with no treatment-related dose-limiting toxicities. Urinary frequency and urgency, and fatigue were common. Eleven (91.7%) patients were free of disease at a mean (range) follow-up of 21.4 (8.4-27.0) months. Median posttreatment urine concentrations of IL2, IL8, IL10, and TNFα increased over the 6-week treatment period. A greater increase in posttreatment urinary IL8 during the 6-week period was observed in patients receiving MMC + BCG compared with patients receiving BCG monotherapy. In mice, intravesical MMC + BCG skewed tumor-associated macrophages (TAM) toward a beneficial M1 phenotype.
Instillation of sequential MMC + BCG is safe tolerable up to 40-mg MMC plus full-strength BCG. This approach could provide improved antitumor activity over BCG monotherapy by augmenting beneficial M1 TAMs.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.ccr-14-1781</identifier><identifier>PMID: 25424854</identifier><language>eng</language><publisher>United States</publisher><subject>Administration, Intravesical ; Aged ; Animals ; Carcinoma, Transitional Cell - therapy ; Carcinoma, Transitional Cell - urine ; Combined Modality Therapy ; Cytokines - urine ; Female ; Humans ; Immunization ; Macrophages - immunology ; Male ; Mice, Inbred C57BL ; Middle Aged ; Mitomycin - administration & dosage ; Mycobacterium bovis - immunology ; Neoplasm Transplantation ; Translational Medical Research ; Treatment Outcome ; Urinary Bladder Neoplasms - therapy ; Urinary Bladder Neoplasms - urine</subject><ispartof>Clinical cancer research, 2015-01, Vol.21 (2), p.303-311</ispartof><rights>2014 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-d7f11e9fdc69adf9963762e071d2ebc911f7bda6edfad7c6bb4eb82e320d8f473</citedby><cites>FETCH-LOGICAL-c477t-d7f11e9fdc69adf9963762e071d2ebc911f7bda6edfad7c6bb4eb82e320d8f473</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25424854$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Svatek, Robert S</creatorcontrib><creatorcontrib>Zhao, Xiang Ru</creatorcontrib><creatorcontrib>Morales, Edwin E</creatorcontrib><creatorcontrib>Jha, Mithilesh K</creatorcontrib><creatorcontrib>Tseng, Timothy Y</creatorcontrib><creatorcontrib>Hugen, Cory M</creatorcontrib><creatorcontrib>Hurez, Vincent</creatorcontrib><creatorcontrib>Hernandez, Javier</creatorcontrib><creatorcontrib>Curiel, Tyler J</creatorcontrib><title>Sequential intravesical mitomycin plus Bacillus Calmette-Guérin for non-muscle-invasive urothelial bladder carcinoma: translational and phase I clinical trial</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>To determine the safety and toxicities of sequential MMC (mitomycin C) + BCG (bacillus Calmette-Guérin) in patients with non-muscle-invasive bladder cancer (NMIBC) and explore evidence for potentiation of BCG activity by MMC.
A 3 + 3 phase I dose-escalation trial of six weekly treatments was conducted in patients with NMIBC. MMC (10, 20, or 40 mg) was instilled intravesically for 30 minutes, followed by a 10-minute washout with gentle saline irrigation and then instillation of BCG (half or full strength) for 2 hours. Urine cytokines were monitored and compared with levels in a control cohort receiving BCG only. Murine experiments were carried out as described previously.
Twelve patients completed therapy, including 3 patients receiving full doses. The regimen was well tolerated with no treatment-related dose-limiting toxicities. Urinary frequency and urgency, and fatigue were common. Eleven (91.7%) patients were free of disease at a mean (range) follow-up of 21.4 (8.4-27.0) months. Median posttreatment urine concentrations of IL2, IL8, IL10, and TNFα increased over the 6-week treatment period. A greater increase in posttreatment urinary IL8 during the 6-week period was observed in patients receiving MMC + BCG compared with patients receiving BCG monotherapy. In mice, intravesical MMC + BCG skewed tumor-associated macrophages (TAM) toward a beneficial M1 phenotype.
Instillation of sequential MMC + BCG is safe tolerable up to 40-mg MMC plus full-strength BCG. This approach could provide improved antitumor activity over BCG monotherapy by augmenting beneficial M1 TAMs.</description><subject>Administration, Intravesical</subject><subject>Aged</subject><subject>Animals</subject><subject>Carcinoma, Transitional Cell - therapy</subject><subject>Carcinoma, Transitional Cell - urine</subject><subject>Combined Modality Therapy</subject><subject>Cytokines - urine</subject><subject>Female</subject><subject>Humans</subject><subject>Immunization</subject><subject>Macrophages - immunology</subject><subject>Male</subject><subject>Mice, Inbred C57BL</subject><subject>Middle Aged</subject><subject>Mitomycin - administration & dosage</subject><subject>Mycobacterium bovis - immunology</subject><subject>Neoplasm Transplantation</subject><subject>Translational Medical Research</subject><subject>Treatment Outcome</subject><subject>Urinary Bladder Neoplasms - therapy</subject><subject>Urinary Bladder Neoplasms - urine</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkd9uFSEQh4nR2Fp9BA0vQAWWXXa9MNGN1iZNmvjnmrAweDAsHGH3JH2aXvc5-mKy1jb2iiEzv28IH0KvGT1lrO3fMip7QkXDT43JhAnCZM-eoGPWtpI0vGuf1vp-5gi9KOUXpUwwKp6jI94KLvpWHKPrb_B7hbh4HbCPS9YHKN7Uy-yXNF8ZH_E-rAV_1MaHrRh1mGFZgJyttze5tl3KOKZI5rWYAMTHgy7-AHjNadlB2MBT0NZCxkbnCkyzfofrpliCXnyKdUBHi_c7XQCfYxN8_PuCJdfsS_TM6VDg1b_zBP34_On7-IVcXJ6djx8uiBFSLsRKxxgMzppu0NYNQ9fIjgOVzHKYzMCYk5PVHVinrTTdNAmYeg4Np7Z3QjYn6P0dd79OM1gD218Etc9-1vlKJe3V4070O_UzHZTgg2z7vgLaO4DJqZQM7iHLqNqMqc2G2myocfyqmFCbsZp78__ih9S9ouYP3CGamw</recordid><startdate>20150115</startdate><enddate>20150115</enddate><creator>Svatek, Robert S</creator><creator>Zhao, Xiang Ru</creator><creator>Morales, Edwin E</creator><creator>Jha, Mithilesh K</creator><creator>Tseng, Timothy Y</creator><creator>Hugen, Cory M</creator><creator>Hurez, Vincent</creator><creator>Hernandez, Javier</creator><creator>Curiel, Tyler J</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20150115</creationdate><title>Sequential intravesical mitomycin plus Bacillus Calmette-Guérin for non-muscle-invasive urothelial bladder carcinoma: translational and phase I clinical trial</title><author>Svatek, Robert S ; Zhao, Xiang Ru ; Morales, Edwin E ; Jha, Mithilesh K ; Tseng, Timothy Y ; Hugen, Cory M ; Hurez, Vincent ; Hernandez, Javier ; Curiel, Tyler J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-d7f11e9fdc69adf9963762e071d2ebc911f7bda6edfad7c6bb4eb82e320d8f473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Administration, Intravesical</topic><topic>Aged</topic><topic>Animals</topic><topic>Carcinoma, Transitional Cell - therapy</topic><topic>Carcinoma, Transitional Cell - urine</topic><topic>Combined Modality Therapy</topic><topic>Cytokines - urine</topic><topic>Female</topic><topic>Humans</topic><topic>Immunization</topic><topic>Macrophages - immunology</topic><topic>Male</topic><topic>Mice, Inbred C57BL</topic><topic>Middle Aged</topic><topic>Mitomycin - administration & dosage</topic><topic>Mycobacterium bovis - immunology</topic><topic>Neoplasm Transplantation</topic><topic>Translational Medical Research</topic><topic>Treatment Outcome</topic><topic>Urinary Bladder Neoplasms - therapy</topic><topic>Urinary Bladder Neoplasms - urine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Svatek, Robert S</creatorcontrib><creatorcontrib>Zhao, Xiang Ru</creatorcontrib><creatorcontrib>Morales, Edwin E</creatorcontrib><creatorcontrib>Jha, Mithilesh K</creatorcontrib><creatorcontrib>Tseng, Timothy Y</creatorcontrib><creatorcontrib>Hugen, Cory M</creatorcontrib><creatorcontrib>Hurez, Vincent</creatorcontrib><creatorcontrib>Hernandez, Javier</creatorcontrib><creatorcontrib>Curiel, Tyler J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Svatek, Robert S</au><au>Zhao, Xiang Ru</au><au>Morales, Edwin E</au><au>Jha, Mithilesh K</au><au>Tseng, Timothy Y</au><au>Hugen, Cory M</au><au>Hurez, Vincent</au><au>Hernandez, Javier</au><au>Curiel, Tyler J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sequential intravesical mitomycin plus Bacillus Calmette-Guérin for non-muscle-invasive urothelial bladder carcinoma: translational and phase I clinical trial</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2015-01-15</date><risdate>2015</risdate><volume>21</volume><issue>2</issue><spage>303</spage><epage>311</epage><pages>303-311</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>To determine the safety and toxicities of sequential MMC (mitomycin C) + BCG (bacillus Calmette-Guérin) in patients with non-muscle-invasive bladder cancer (NMIBC) and explore evidence for potentiation of BCG activity by MMC.
A 3 + 3 phase I dose-escalation trial of six weekly treatments was conducted in patients with NMIBC. MMC (10, 20, or 40 mg) was instilled intravesically for 30 minutes, followed by a 10-minute washout with gentle saline irrigation and then instillation of BCG (half or full strength) for 2 hours. Urine cytokines were monitored and compared with levels in a control cohort receiving BCG only. Murine experiments were carried out as described previously.
Twelve patients completed therapy, including 3 patients receiving full doses. The regimen was well tolerated with no treatment-related dose-limiting toxicities. Urinary frequency and urgency, and fatigue were common. Eleven (91.7%) patients were free of disease at a mean (range) follow-up of 21.4 (8.4-27.0) months. Median posttreatment urine concentrations of IL2, IL8, IL10, and TNFα increased over the 6-week treatment period. A greater increase in posttreatment urinary IL8 during the 6-week period was observed in patients receiving MMC + BCG compared with patients receiving BCG monotherapy. In mice, intravesical MMC + BCG skewed tumor-associated macrophages (TAM) toward a beneficial M1 phenotype.
Instillation of sequential MMC + BCG is safe tolerable up to 40-mg MMC plus full-strength BCG. This approach could provide improved antitumor activity over BCG monotherapy by augmenting beneficial M1 TAMs.</abstract><cop>United States</cop><pmid>25424854</pmid><doi>10.1158/1078-0432.ccr-14-1781</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical cancer research, 2015-01, Vol.21 (2), p.303-311 |
| issn | 1078-0432 1557-3265 |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Administration, Intravesical Aged Animals Carcinoma, Transitional Cell - therapy Carcinoma, Transitional Cell - urine Combined Modality Therapy Cytokines - urine Female Humans Immunization Macrophages - immunology Male Mice, Inbred C57BL Middle Aged Mitomycin - administration & dosage Mycobacterium bovis - immunology Neoplasm Transplantation Translational Medical Research Treatment Outcome Urinary Bladder Neoplasms - therapy Urinary Bladder Neoplasms - urine |
| title | Sequential intravesical mitomycin plus Bacillus Calmette-Guérin for non-muscle-invasive urothelial bladder carcinoma: translational and phase I clinical trial |
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