Oral topotecan given once or twice daily for ten days: a phase I pharmacology study in adult patients with solid tumors
Prolonged exposure to topotecan (TPT) in in vitro experiments and in vivo studies in animals yielded the highest antitumor efficacy. An oral bioavailability of TPT of 32-44% enables convenient prolonged administration. Because of unpredictable diarrhea in the third week of the twice daily (b.i.d.) 2...
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| Veröffentlicht in: | Clinical cancer research 1998-05, Vol.4 (5), p.1153-1158 |
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| creator | GERRITS, C. J. H BURRIS, H FIELDS, S VON HOFF, D. D VERWEIJ, J SCHELLENS, J. H. M ECKARDT, J. R PLANTING, A. S. T VAN DER BURG, M. E. L RODRIGUEZ, G. I LOOS, W. J VAN BEURDEN, V HUDSON, I |
| description | Prolonged exposure to topotecan (TPT) in in vitro experiments and in vivo studies in animals yielded the highest antitumor
efficacy. An oral bioavailability of TPT of 32-44% enables convenient prolonged administration. Because of unpredictable diarrhea
in the third week of the twice daily (b.i.d.) 21-day schedule of p.o. administered TPT and the finding of optimal down-regulation
of topoisomerase I level after 10-14 days in mononuclear peripheral blood cells, a shorter period of administration (10 days)
was chosen for Phase I and pharmacological studies of oral administration of TPT. Adult patients with malignant solid tumors
that were refractory to standard forms of chemotherapy were entered. Two dose schedules were studied: once daily (o.d.) and
b.i.d. administration for 10 days every 3 weeks. TPT o.d. for 10 days was studied at dose levels 1.0, 1.4, and 1.6 mg/m2/day,
and dose levels were 0.5, 0.6, 0.7, and 0.8 mg/m2 with the 10-day b.i.d. schedule. Pharmacokinetics were performed on days
1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic
methods. Nineteen patients were entered in the 10-day o.d. schedule, with a total of 48 courses given. Dose-limiting toxicity
(DLT) was reached at 1.6 mg/m2/day and consisted of common toxicity criteria (CTC) grade IV thrombocytopenia and CTC grade
III diarrhea. The maximum tolerated dose was 1.4 mg/m2/day. In the 10-day b.i.d. administration of TPT, a total of 64 courses
were studied in 20 patients. DLT was reached at a dose of 0.8 mg/m2 b.i.d. and consisted of CTC grade IV myelosuppression
and CTC grade IV diarrhea. The maximum tolerated dose was 0.7 mg/m2 b.i.d. Nonhematological toxicities with both schedules
included mild nausea and vomiting, fatigue, and anorexia. Pharmacokinetics revealed a substantial variation of the area under
the plasma concentration-time curve of TPT lactone in both schedules. Significant correlations were observed between the myelotoxicity
parameters and the area under the plasma concentration-time curve at day 1 of TPT lactone o.d. and b.i.d. The DLT of 10 daily
administrations of oral topotecan every 3 weeks consisted of a combination of myelosuppression and diarrhea for both schedules
studied. The recommended doses for Phase II studies are 1.4 mg/m2/day for 10 days for the o.d. administration and 0.7 mg/m2
for the b.i.d. schedule. |
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efficacy. An oral bioavailability of TPT of 32-44% enables convenient prolonged administration. Because of unpredictable diarrhea
in the third week of the twice daily (b.i.d.) 21-day schedule of p.o. administered TPT and the finding of optimal down-regulation
of topoisomerase I level after 10-14 days in mononuclear peripheral blood cells, a shorter period of administration (10 days)
was chosen for Phase I and pharmacological studies of oral administration of TPT. Adult patients with malignant solid tumors
that were refractory to standard forms of chemotherapy were entered. Two dose schedules were studied: once daily (o.d.) and
b.i.d. administration for 10 days every 3 weeks. TPT o.d. for 10 days was studied at dose levels 1.0, 1.4, and 1.6 mg/m2/day,
and dose levels were 0.5, 0.6, 0.7, and 0.8 mg/m2 with the 10-day b.i.d. schedule. Pharmacokinetics were performed on days
1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic
methods. Nineteen patients were entered in the 10-day o.d. schedule, with a total of 48 courses given. Dose-limiting toxicity
(DLT) was reached at 1.6 mg/m2/day and consisted of common toxicity criteria (CTC) grade IV thrombocytopenia and CTC grade
III diarrhea. The maximum tolerated dose was 1.4 mg/m2/day. In the 10-day b.i.d. administration of TPT, a total of 64 courses
were studied in 20 patients. DLT was reached at a dose of 0.8 mg/m2 b.i.d. and consisted of CTC grade IV myelosuppression
and CTC grade IV diarrhea. The maximum tolerated dose was 0.7 mg/m2 b.i.d. Nonhematological toxicities with both schedules
included mild nausea and vomiting, fatigue, and anorexia. Pharmacokinetics revealed a substantial variation of the area under
the plasma concentration-time curve of TPT lactone in both schedules. Significant correlations were observed between the myelotoxicity
parameters and the area under the plasma concentration-time curve at day 1 of TPT lactone o.d. and b.i.d. The DLT of 10 daily
administrations of oral topotecan every 3 weeks consisted of a combination of myelosuppression and diarrhea for both schedules
studied. The recommended doses for Phase II studies are 1.4 mg/m2/day for 10 days for the o.d. administration and 0.7 mg/m2
for the b.i.d. schedule.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>PMID: 9607572</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic agents ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - therapeutic use ; Biological and medical sciences ; Chemotherapy ; Drug Administration Schedule ; Female ; Hematologic Diseases - chemically induced ; Humans ; Male ; Medical sciences ; Middle Aged ; Neoplasms - drug therapy ; Neoplasms - metabolism ; Pharmacology. Drug treatments ; Topotecan - administration & dosage ; Topotecan - adverse effects ; Topotecan - pharmacokinetics ; Topotecan - therapeutic use</subject><ispartof>Clinical cancer research, 1998-05, Vol.4 (5), p.1153-1158</ispartof><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2241149$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9607572$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>GERRITS, C. J. H</creatorcontrib><creatorcontrib>BURRIS, H</creatorcontrib><creatorcontrib>FIELDS, S</creatorcontrib><creatorcontrib>VON HOFF, D. D</creatorcontrib><creatorcontrib>VERWEIJ, J</creatorcontrib><creatorcontrib>SCHELLENS, J. H. M</creatorcontrib><creatorcontrib>ECKARDT, J. R</creatorcontrib><creatorcontrib>PLANTING, A. S. T</creatorcontrib><creatorcontrib>VAN DER BURG, M. E. L</creatorcontrib><creatorcontrib>RODRIGUEZ, G. I</creatorcontrib><creatorcontrib>LOOS, W. J</creatorcontrib><creatorcontrib>VAN BEURDEN, V</creatorcontrib><creatorcontrib>HUDSON, I</creatorcontrib><title>Oral topotecan given once or twice daily for ten days: a phase I pharmacology study in adult patients with solid tumors</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Prolonged exposure to topotecan (TPT) in in vitro experiments and in vivo studies in animals yielded the highest antitumor
efficacy. An oral bioavailability of TPT of 32-44% enables convenient prolonged administration. Because of unpredictable diarrhea
in the third week of the twice daily (b.i.d.) 21-day schedule of p.o. administered TPT and the finding of optimal down-regulation
of topoisomerase I level after 10-14 days in mononuclear peripheral blood cells, a shorter period of administration (10 days)
was chosen for Phase I and pharmacological studies of oral administration of TPT. Adult patients with malignant solid tumors
that were refractory to standard forms of chemotherapy were entered. Two dose schedules were studied: once daily (o.d.) and
b.i.d. administration for 10 days every 3 weeks. TPT o.d. for 10 days was studied at dose levels 1.0, 1.4, and 1.6 mg/m2/day,
and dose levels were 0.5, 0.6, 0.7, and 0.8 mg/m2 with the 10-day b.i.d. schedule. Pharmacokinetics were performed on days
1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic
methods. Nineteen patients were entered in the 10-day o.d. schedule, with a total of 48 courses given. Dose-limiting toxicity
(DLT) was reached at 1.6 mg/m2/day and consisted of common toxicity criteria (CTC) grade IV thrombocytopenia and CTC grade
III diarrhea. The maximum tolerated dose was 1.4 mg/m2/day. In the 10-day b.i.d. administration of TPT, a total of 64 courses
were studied in 20 patients. DLT was reached at a dose of 0.8 mg/m2 b.i.d. and consisted of CTC grade IV myelosuppression
and CTC grade IV diarrhea. The maximum tolerated dose was 0.7 mg/m2 b.i.d. Nonhematological toxicities with both schedules
included mild nausea and vomiting, fatigue, and anorexia. Pharmacokinetics revealed a substantial variation of the area under
the plasma concentration-time curve of TPT lactone in both schedules. Significant correlations were observed between the myelotoxicity
parameters and the area under the plasma concentration-time curve at day 1 of TPT lactone o.d. and b.i.d. The DLT of 10 daily
administrations of oral topotecan every 3 weeks consisted of a combination of myelosuppression and diarrhea for both schedules
studied. The recommended doses for Phase II studies are 1.4 mg/m2/day for 10 days for the o.d. administration and 0.7 mg/m2
for the b.i.d. schedule.</description><subject>Administration, Oral</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - adverse effects</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Chemotherapy</subject><subject>Drug Administration Schedule</subject><subject>Female</subject><subject>Hematologic Diseases - chemically induced</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Topotecan - administration & dosage</subject><subject>Topotecan - adverse effects</subject><subject>Topotecan - pharmacokinetics</subject><subject>Topotecan - therapeutic use</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtqwzAURE1pSdO0n1DQotCVQU8r6q6EPgKBbNq1uZbkWMW2jCQ3-O_rkNDVzOUMA3eusiURQuaMFuJ69liuc8wZvc3uYvzBmHCC-SJbqAJLIekyO-4DtCj5wSeroUcH92t75HttkQ8oHd1sDLh2QvXpnpmBKb4gQEMD0aLtSUMH2rf-MKGYRjMh1yMwY5vQAMnZPkV0dKlB0bfOoDR2PsT77KaGNtqHi66y7_e3r81nvtt_bDevu7yhhUp5BZraojZazQ-RgiprmJZWSUZobSSlmNSU8boiSsiCr4HaSguusVDYikKxVfZ47h3GqrOmHILrIEzlZYCZP104RA1tHaDXLv7HKOWE8FPN8znWuENzdMGW81jahmCjhaCbkpeiJEQw9gfMTHOh</recordid><startdate>19980501</startdate><enddate>19980501</enddate><creator>GERRITS, C. J. H</creator><creator>BURRIS, H</creator><creator>FIELDS, S</creator><creator>VON HOFF, D. D</creator><creator>VERWEIJ, J</creator><creator>SCHELLENS, J. H. M</creator><creator>ECKARDT, J. R</creator><creator>PLANTING, A. S. T</creator><creator>VAN DER BURG, M. E. L</creator><creator>RODRIGUEZ, G. I</creator><creator>LOOS, W. J</creator><creator>VAN BEURDEN, V</creator><creator>HUDSON, I</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>19980501</creationdate><title>Oral topotecan given once or twice daily for ten days: a phase I pharmacology study in adult patients with solid tumors</title><author>GERRITS, C. J. H ; BURRIS, H ; FIELDS, S ; VON HOFF, D. D ; VERWEIJ, J ; SCHELLENS, J. H. M ; ECKARDT, J. R ; PLANTING, A. S. T ; VAN DER BURG, M. E. L ; RODRIGUEZ, G. I ; LOOS, W. J ; VAN BEURDEN, V ; HUDSON, I</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h269t-bac2e6fdc92651629ed3c7e97312fd72201f234fb1957648a2ebc54c0590e5693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Administration, Oral</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - adverse effects</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Chemotherapy</topic><topic>Drug Administration Schedule</topic><topic>Female</topic><topic>Hematologic Diseases - chemically induced</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Topotecan - administration & dosage</topic><topic>Topotecan - adverse effects</topic><topic>Topotecan - pharmacokinetics</topic><topic>Topotecan - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GERRITS, C. J. H</creatorcontrib><creatorcontrib>BURRIS, H</creatorcontrib><creatorcontrib>FIELDS, S</creatorcontrib><creatorcontrib>VON HOFF, D. D</creatorcontrib><creatorcontrib>VERWEIJ, J</creatorcontrib><creatorcontrib>SCHELLENS, J. H. M</creatorcontrib><creatorcontrib>ECKARDT, J. R</creatorcontrib><creatorcontrib>PLANTING, A. S. T</creatorcontrib><creatorcontrib>VAN DER BURG, M. E. L</creatorcontrib><creatorcontrib>RODRIGUEZ, G. I</creatorcontrib><creatorcontrib>LOOS, W. J</creatorcontrib><creatorcontrib>VAN BEURDEN, V</creatorcontrib><creatorcontrib>HUDSON, I</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GERRITS, C. J. H</au><au>BURRIS, H</au><au>FIELDS, S</au><au>VON HOFF, D. D</au><au>VERWEIJ, J</au><au>SCHELLENS, J. H. M</au><au>ECKARDT, J. R</au><au>PLANTING, A. S. T</au><au>VAN DER BURG, M. E. L</au><au>RODRIGUEZ, G. I</au><au>LOOS, W. J</au><au>VAN BEURDEN, V</au><au>HUDSON, I</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oral topotecan given once or twice daily for ten days: a phase I pharmacology study in adult patients with solid tumors</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>1998-05-01</date><risdate>1998</risdate><volume>4</volume><issue>5</issue><spage>1153</spage><epage>1158</epage><pages>1153-1158</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Prolonged exposure to topotecan (TPT) in in vitro experiments and in vivo studies in animals yielded the highest antitumor
efficacy. An oral bioavailability of TPT of 32-44% enables convenient prolonged administration. Because of unpredictable diarrhea
in the third week of the twice daily (b.i.d.) 21-day schedule of p.o. administered TPT and the finding of optimal down-regulation
of topoisomerase I level after 10-14 days in mononuclear peripheral blood cells, a shorter period of administration (10 days)
was chosen for Phase I and pharmacological studies of oral administration of TPT. Adult patients with malignant solid tumors
that were refractory to standard forms of chemotherapy were entered. Two dose schedules were studied: once daily (o.d.) and
b.i.d. administration for 10 days every 3 weeks. TPT o.d. for 10 days was studied at dose levels 1.0, 1.4, and 1.6 mg/m2/day,
and dose levels were 0.5, 0.6, 0.7, and 0.8 mg/m2 with the 10-day b.i.d. schedule. Pharmacokinetics were performed on days
1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic
methods. Nineteen patients were entered in the 10-day o.d. schedule, with a total of 48 courses given. Dose-limiting toxicity
(DLT) was reached at 1.6 mg/m2/day and consisted of common toxicity criteria (CTC) grade IV thrombocytopenia and CTC grade
III diarrhea. The maximum tolerated dose was 1.4 mg/m2/day. In the 10-day b.i.d. administration of TPT, a total of 64 courses
were studied in 20 patients. DLT was reached at a dose of 0.8 mg/m2 b.i.d. and consisted of CTC grade IV myelosuppression
and CTC grade IV diarrhea. The maximum tolerated dose was 0.7 mg/m2 b.i.d. Nonhematological toxicities with both schedules
included mild nausea and vomiting, fatigue, and anorexia. Pharmacokinetics revealed a substantial variation of the area under
the plasma concentration-time curve of TPT lactone in both schedules. Significant correlations were observed between the myelotoxicity
parameters and the area under the plasma concentration-time curve at day 1 of TPT lactone o.d. and b.i.d. The DLT of 10 daily
administrations of oral topotecan every 3 weeks consisted of a combination of myelosuppression and diarrhea for both schedules
studied. The recommended doses for Phase II studies are 1.4 mg/m2/day for 10 days for the o.d. administration and 0.7 mg/m2
for the b.i.d. schedule.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>9607572</pmid><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Clinical cancer research, 1998-05, Vol.4 (5), p.1153-1158 |
| issn | 1078-0432 1557-3265 |
| language | eng |
| recordid | cdi_pubmed_primary_9607572 |
| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Administration, Oral Adult Aged Aged, 80 and over Antineoplastic agents Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - therapeutic use Biological and medical sciences Chemotherapy Drug Administration Schedule Female Hematologic Diseases - chemically induced Humans Male Medical sciences Middle Aged Neoplasms - drug therapy Neoplasms - metabolism Pharmacology. Drug treatments Topotecan - administration & dosage Topotecan - adverse effects Topotecan - pharmacokinetics Topotecan - therapeutic use |
| title | Oral topotecan given once or twice daily for ten days: a phase I pharmacology study in adult patients with solid tumors |
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