[Raltitrexed and oxaliplatin in colorectal cancer: in vitro and in vivo study of a synergistic cytostatic combination].
To evaluate the efficacy of combined raltitrexed and oxaliplatin in vitro using 4 colorectal cell-lines and subsequently in vivo in 36 patients with advanced colorectal cancer failing palliative 5-fluorouracil/leucovorin-based chemotherapy. In the preclinical phase of this study, the efficacy of oxaliplatin and of raltitrexed as well as of 5-FU alone and in combination was evaluated in 4 different human colorectalcarcinoma cell-lines with the MTT-test (Microculture Tetrazolium Assay). In the clinical phase 36 patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after withholding palliative chemotherapy with 5-FU/leucovorin +/- irinotecan were enrolled in this study. Treatment consisted of oxaliplatin 130 mg/m2 and raltitrexed 3.0 mg/m2 both given on day 1 every 3 weeks for a total of 8 courses unless prior evidence of progressive disease. A supraadditive effect was found for the experimental combination of oxalipatin and raltitrexed in 3/4 of cell lines. In the clinical phase the overall response rate was 33.3% for all 36 evaluable patients. Seventeen additional patients (47.2%) had stable disease, and only 7 (19.5%) progressed. The median progression-free survival was 6.5 months (range, 1.2 to 14.0). After a median follow-up time of 12 months, 23 patients (63.8%) are still alive. The tolerance of treatment was acceptable with only 8/36 (22%) experiencing grade 3 or 4 neutropenia. Grade 3 nonhematologic adverse reactions included peripheral sensory neuropathy in 3, asthenia in 1, diarrhea in 2, and clinically insignificant increase in serum transaminases in 2 patients, respectively. Our data suggest that the combination of oxaliplatin and raltitrexed has not only in vitro, but also in vivo in patients with progressive fluoropyrimidine/leucovorine +/- irinotecan pretreated colorectal cancer antitumor activity. Because of its favorable toxicity profile and its convenient 3-weekly outpatient administration schedule, further evaluation of this regimen seems warranted.
Schüll
Birgit
B
Klinische Abteilung für Onkologie, Universitätsklinik für Innere Medizin I, Währingergürtel 18-20, A-1090 Wien.
Scheithauer
W
W
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D006801:Humans; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use* / Q000633:toxicity; D000077150:Oxaliplatin; D011799:Quinazolines / Q000627:therapeutic use* / Q000633:toxicity; D013876:Thiophenes / Q000627:therapeutic use* / Q000633:toxicity; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D011799:Quinazolines; D013876:Thiophenes; D000077150:Oxaliplatin; C068874:raltitrexed