Safe administration of irinotecan, oxaliplatin and raltitrexed in a DPD-deficient patient with metastatic colon cancer

Abstract

Dihydropyrimidine dehydrogenase deficiency is diagnosed more frequently and is now generally accepted as a potentially life-threatening condition. It predisposes patients receiving treatment with fluoropyrimidines such as 5-fluorouracil (5-FU) to severe and, in case of complete dihydropyrimidine dehydrogenase deficiency, often fatal toxicity. A patient who had severe side effects following standard dose adjuvant 5-FU exposure was diagnosed of having hereditary partial dihydropyrimidine dehydrogenase deficiency. When the patient relapsed with liver metastases, we treated him with the non-fluoropyrimidine cytotoxic agents irinotecan, oxaliplatin and raltitrexed in sequential manner, and were able to show that these drugs can be safely applied in patients with this metabolic defect.

A randomized phase II study to compare oxaliplatin plus 5-fluorouracil and leucovorin (FOLFOX4) versus oxaliplatin plus raltitrexed (TOMOX) as first-line chemotherapy for advanced colorectal cancer

“…Given that TOMOX does not seem to be associated with any additional safety and tolerability concerns compared with FOLFOX4, the relative convenience of raltitrexed administration may make TOMOX an attractive option for first-line treatment of patients with advanced CRC, particularly in patients who find it difficult to meet the scheduling commitments for FOLFOX4 infusions, who cannot tolerate 5-FU-based regimens, or who cannot have a central venous catheter [33, 34]. …”

Acute hyperammonemic encephalopathy after 5-fluorouracil based chemotherapy

“…Thus, it is very difficult to make a decision as to what we should choose as alternative treatment modality. A few centers performed single-agent chemotherapy with oxaliplatin or irrinotecan, raltitrexed without 5-FU, but the outcomes were disappointing [ 8 ]. On the other hand, according to a report about the application of tegafur-uracil (tegafur, uracil in a molar ratio 1:4), taking tegafur (oral 5-FU prodrug) with uracil, which is a natural substrate for DPD, 5-FU is slowly released by the inclusion of uracil thus reducing the side effects of 5-FU catabolite by preventing rapid degradation of 5-FU [ 9 ].…”

Personalizing Colon Cancer Therapeutics: Targeting Old and New Mechanisms of Action

“…These inhibitors are referred to as antifolate inhibitors (Figure 1). Tomudex (Raltitrexed ® , Astra Zeneca) is an antifolate TS inhibitor that is now used in clinics outside the USA as an alternative to 5-FU for patients who are sensitive to 5-FU and the 5-FU oral prodrug form, capecitabine, including in a patient with DPD deficiency [96,97,98]. Tomudex has been shown to have similar efficacy as 5-FU in combination with other agents used with 5-FU (e.g., oxaliplatin) [99].…”