Raltitrexed (Tomudex) for Mesothelioma

Raltitrexed, marketed as Tomudex, is an antifolate chemotherapy drug that serves as an alternative to pemetrexed in the treatment of malignant pleural mesothelioma, particularly in countries where it is more readily available. Like pemetrexed, raltitrexed targets folate-dependent enzymes, but it specifically and potently inhibits thymidylate synthase (TS), the enzyme responsible for converting deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) — a critical step in DNA synthesis.¹

A phase III randomized trial led by van Meerbeeck and colleagues, conducted by the European Organisation for Research and Treatment of Cancer (EORTC), demonstrated that raltitrexed combined with cisplatin significantly improved overall survival compared to cisplatin alone in patients with malignant pleural mesothelioma. The combination achieved a median overall survival of 11.4 months versus 8.8 months for cisplatin monotherapy — a result broadly comparable to the pemetrexed/cisplatin data from the Vogelzang trial.²

Raltitrexed offers several practical advantages over pemetrexed. It does not require the folic acid and vitamin B12 supplementation that is mandatory with pemetrexed, simplifying the treatment protocol. It also has a shorter infusion time (15 minutes vs. 10 minutes, but without the extensive pre-medication and vitamin regimen). These factors make raltitrexed an attractive option in healthcare systems where cost, availability, or supplementation compliance are concerns.³

A significant limitation of raltitrexed is its lack of availability in the United States, where pemetrexed is the established standard of care. Raltitrexed is approved and used in Europe, Australia, and several other countries for colorectal cancer, and its use in mesothelioma is based on the EORTC trial data. For patients outside the US — or US patients seeking treatment options abroad — raltitrexed/cisplatin represents a well-validated alternative to pemetrexed/cisplatin. More recently, raltitrexed has been combined with oxaliplatin (the ROMESO regimen) as an alternative platinum partner.⁴

Raltitrexed is used as the antifolate component in platinum-based combination regimens for mesothelioma:²

Raltitrexed + Cisplatin (EORTC Regimen)

The validated first-line regimen from the van Meerbeeck phase III trial:²

• Raltitrexed — 3 mg/m² intravenously over 15 minutes on Day 1
• Cisplatin — 80 mg/m² intravenously on Day 1
• Cycle length — 21 days for up to 6 cycles
• No vitamin supplementation required — Unlike pemetrexed, raltitrexed does not require folic acid or B12 supplementation

Phase III Trial Results (van Meerbeeck/EORTC)

The randomized trial enrolled 250 patients with unresectable malignant pleural mesothelioma:²

• Median overall survival — 11.4 months (raltitrexed + cisplatin) vs. 8.8 months (cisplatin alone)
• Objective response rate — 23.6% vs. 13.6%
• Median time to progression — 5.3 months vs. 4.0 months
• Hazard ratio — 0.76 (favoring the combination)

Raltitrexed + Oxaliplatin (ROMESO)

More recently, raltitrexed has been combined with oxaliplatin as an alternative platinum partner:⁴

• Dosing — Raltitrexed 3 mg/m² + oxaliplatin 130 mg/m² every 21 days
• Rationale — Oxaliplatin has less nephrotoxicity and ototoxicity than cisplatin, making it better tolerated
• Phase II data — Response rates of 20–35% and median survival of 11–15 months in published studies

Raltitrexed-based regimens show efficacy comparable to pemetrexed-based regimens in mesothelioma:²

• Median overall survival — 11.4 months with raltitrexed/cisplatin, comparable to the 12.1 months with pemetrexed/cisplatin (different trials, not directly comparable)
• Response rate — 23.6% with raltitrexed/cisplatin vs. 41.3% with pemetrexed/cisplatin (noting different trial populations and methodology)
• Epithelioid histology — As with pemetrexed, patients with the epithelioid subtype tend to have better outcomes with raltitrexed-based therapy
• International relevance — In countries where pemetrexed is unavailable or prohibitively expensive, raltitrexed/cisplatin provides a validated alternative with similar survival outcomes

Raltitrexed's side effect profile is similar to other antifolate drugs, with some important differences from pemetrexed:²

• Diarrhea — The most significant toxicity, affecting 25–35% of patients (grade 3–4 in 10–15%). Adequate hydration and prompt anti-diarrheal treatment are essential. Severe diarrhea can be life-threatening and may require hospitalization
• Fatigue and malaise — Common, affecting 30–50% of patients. Usually manageable with rest and activity modification
• Nausea and vomiting — Related primarily to the cisplatin component. Standard anti-emetic protocols apply
• Myelosuppression — Neutropenia and thrombocytopenia occur in 15–25% of patients at grade 3–4 severity. Blood counts are monitored before each cycle
• Liver enzyme elevation — Transient ALT/AST elevations occur in 10–20% of patients. Usually reversible and rarely dose-limiting
• Renal monitoring — Raltitrexed is renally excreted, so kidney function must be assessed before each cycle. Creatinine clearance below 25 mL/min is a contraindication. Combined with cisplatin, renal monitoring is particularly important
• No vitamin supplementation needed — Unlike pemetrexed, raltitrexed does not require daily folic acid or periodic B12 injections, reducing the complexity of the treatment regimen