title: Impact of serum caffeine monitoring on adverse effects and chemotherapeutic responses to caffeine-potentiated chemotherapy for osteosarcoma.
abstract: BACKGROUND
  Caffeine can safely enhance the cytocidal effects of anticancer drugs through its DNA repair-inhibiting effect. We have demonstrated in several studies that caffeine-potentiated chemotherapy induces a high complete response rate in patients with osteosarcoma. The present study focused on monitoring and adjusting serum caffeine levels during caffeine-potentiated chemotherapy to reduce adverse effects.
  
  
  METHODS
  We utilized a method for rapidly determining caffeine concentration by high-performance liquid chromatography. The maximum caffeine concentration was predicted from the measured concentrations at 24 and 48 h after the beginning of caffeine administration. The caffeine infusion rate was then modified accordingly to prevent the expected final concentration from exceeding 80 microg/ml. The study involved 22 American Joint Committee on Cancer (AJCC) stage IIB high-grade osteosarcoma patients treated with caffeine-potentiated chemotherapy. Nine patients underwent monitoring of their serum caffeine levels (monitoring group), and the remaining 13 patients were not monitored (nonmonitoring group). Toxicities were graded according to the Japan Clinical Oncology Group Toxicity Criteria.
  
  
  RESULTS
  Hematological toxic events were well tolerated in both groups. Grade 4 leukocyte toxicity events occurred in both groups. In the nonmonitoring group grade 2 or higher toxicities included 5 elevated aspartate aminotransferase/alanine aminotransferase level events and 17 hyponatremia events versus 1 hyponatremia event in the monitoring group. Histological examination of excised tumor samples after preoperative chemotherapy revealed that chemotherapeutic efficacy in the monitoring group was as good as in the nonmonitoring group. The median follow-up period in all patients was 72 months. Event-free survival was 76%, and overall survival was 100%.
  
  
  CONCLUSIONS
  Monitoring and adjusting caffeine levels were achieved without apparent loss of chemotherapeutic efficacy.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8641, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Shirai
authors.forename: Kensuke
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Masami
authors.initials: M
authors.lastname: Kawahara
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Katsuro
authors.initials: K
authors.lastname: Tomita
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood; D002110:Caffeine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D012516:Osteosarcoma / Q000097:blood / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D002110:Caffeine; D004317:Doxorubicin; D002945:Cisplatin