Abstract | BACKGROUND: METHODS: Patients with AJCC Stage IIIB or IIIC extremity melanoma who failed previous LPAM-based RC were treated with TMZ via isolated limb infusion (ILI) according to a modified accelerated titration design. Drug pharmacokinetic (PK) analysis, tumor gene expression, methylation status of the O6-methylguanine methyltransferase (MGMT) promoter, and MGMT expression were evaluated. Primary objectives were to (1) determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of TMZ via ILI and (2) explore biomarker correlates of response. RESULTS: 28 patients completed treatment over 2.5 years at 3 institutions. 19 patients were treated at the MTD defined as 3,200 mg/m(2) [multiplied by 0.09 (arm), 0.18 (leg)]. Two of five patients had DLTs at the 3,600 mg/m(2) level while only grade 1 (n = 15) and grade 2 (n = 4) clinical toxicities occurred at the MTD. At 3-month post-ILI, 10.5 % (2/19) had CR, 5.3 % (1/19) had PR, 15.8 % (3/19) had SD, and 68.4 % (13/19) had PD. Neither PK parameters of TMZ nor MGMT levels were associated with response or toxicity. CONCLUSION: In this first ever use of intra-arterial TMZ in ILI for melanoma, the MTD was determined. While we could not define a marker for TMZ response, the minimal toxicity of TMZ ILI may allow for repeated treatments to increase the response rate as well as clarify the role of MGMT expression.
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Authors | Georgia M Beasley, Paul Speicher, Christina K Augustine, Paul C Dolber, Bercedis L Peterson, Ketan Sharma, Paul J Mosca, Richard Royal, Merrick Ross, Jonathan S Zager, Douglas S Tyler |
Journal | Annals of surgical oncology
(Ann Surg Oncol)
Vol. 22
Issue 1
Pg. 287-94
(Jan 2015)
ISSN: 1534-4681 [Electronic] United States |
PMID | 25145500
(Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents, Alkylating
- RNA, Messenger
- Tumor Suppressor Proteins
- Dacarbazine
- DNA Modification Methylases
- MGMT protein, human
- DNA Repair Enzymes
- Temozolomide
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Topics |
- Aged
- Aged, 80 and over
- Antineoplastic Agents, Alkylating
(administration & dosage, pharmacokinetics)
- Cohort Studies
- DNA Methylation
- DNA Modification Methylases
(genetics)
- DNA Repair Enzymes
(genetics)
- Dacarbazine
(administration & dosage, analogs & derivatives, pharmacokinetics)
- Extremities
- Female
- Follow-Up Studies
- Humans
- Infusions, Intra-Arterial
- Male
- Maximum Tolerated Dose
- Melanoma
(drug therapy, genetics, pathology)
- Middle Aged
- Neoplasm Staging
- Prognosis
- Promoter Regions, Genetic
- RNA, Messenger
(genetics)
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Skin Neoplasms
(drug therapy, genetics, pathology)
- Temozolomide
- Tissue Distribution
- Tumor Suppressor Proteins
(genetics)
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