Can the patient be switched to S‑1 (tegafur‑gimeracil‑oteracil) after completing bevacizumab (Avastin) plus capecitabine (Xeloda)?

Switching to S-1 After Bevacizumab Plus Capecitabine

Yes, S-1 (tegafur-gimeracil-oteracil) can be safely administered after bevacizumab plus capecitabine, particularly when capecitabine-related toxicities such as hand-foot syndrome or cardiotoxicity necessitate a fluoropyrimidine alternative. 1

Evidence-Based Rationale for the Switch

Guideline Support for S-1 as Fluoropyrimidine Alternative

• The 2023 ESMO guidelines explicitly state that in patients presenting with cardiotoxicity and/or hand-foot syndrome on 5-FU or capecitabine-based chemotherapy, S-1 may be used as an alternative [Level III, B]. 1

• The Pan-Asian ESMO consensus guidelines (2018) specifically include S-1 in combination with oxaliplatin for Asian patients as part of maintenance therapy strategies, demonstrating its established role in colorectal cancer treatment algorithms. 1

Clinical Evidence for S-1 After Capecitabine

• A Dutch prospective cohort study (2022) demonstrated that 47 patients with metastatic colorectal cancer who switched from capecitabine to S-1 experienced complete resolution or lower-grade symptoms of hand-foot syndrome in all cases, with only 13% discontinuing S-1 due to toxicity. 2

• The median time between last capecitabine dose and first S-1 dose was 11 days (range 1-49), and switching to S-1 did not compromise treatment efficacy. 2

• All patients with prior capecitabine-induced hand-foot syndrome (77% of cohort) or coronary artery vasospasms (21% of cohort) tolerated S-1 with either symptom resolution or non-recurrence. 2

Bevacizumab Continuation with S-1

Safety and Efficacy Data

• Bevacizumab can be safely combined with S-1 based on multiple clinical studies showing acceptable toxicity profiles and maintained efficacy. 3, 4

• A phase II trial (BASIC trial, 2015) evaluated bevacizumab plus S-1 in 56 elderly patients with metastatic colorectal cancer, demonstrating median PFS of 9.9 months, median OS of 25.0 months, and response rate of 57%, with main grade 3+ adverse events being hypertension (11%), diarrhea (9%), and neutropenia (7%). 4

• A case report documented bevacizumab combined with low-dose S-1 achieving stable disease for 25 months in a heavily pre-treated 84-year-old patient with advanced gastric cancer, with only grade I bleeding gums as a side effect. 3

Practical Implementation Algorithm

When to Consider the Switch

• Switch from capecitabine to S-1 when: 1, 2
  • Grade 2-3 hand-foot syndrome develops despite dose reduction
  • Cardiotoxicity (coronary vasospasm, chest pain) occurs
  • Gastrointestinal toxicity becomes dose-limiting
  • Patient requires continued fluoropyrimidine therapy but cannot tolerate capecitabine

Dosing Considerations

• S-1 dosing should follow standard protocols: typically 40-60 mg orally twice daily (based on body surface area) on days 1-28 of a 42-day cycle when combined with bevacizumab. 4

• Bevacizumab dosing remains unchanged: 5 mg/kg IV every 2 weeks or 7.5 mg/kg IV every 3 weeks, depending on the chemotherapy backbone. 5

• A washout period of 7-14 days between capecitabine discontinuation and S-1 initiation is reasonable based on clinical data, though shorter intervals (1-11 days) have been safely used. 2

Critical Safety Monitoring

Toxicity Profile Differences

• S-1 demonstrates significantly lower incidence of hand-foot syndrome compared to capecitabine due to the gimeracil component inhibiting dihydropyrimidine dehydrogenase, reducing toxic metabolite formation. 2

• Monitor for S-1-specific toxicities including diarrhea, neutropenia, and mucositis, though these are typically grade 1-2 and manageable. 4

• Continue standard bevacizumab monitoring for hypertension, proteinuria, bleeding, and thromboembolic events regardless of fluoropyrimidine partner. 5

Common Pitfalls to Avoid

• Do not assume S-1 is unavailable or inappropriate in Western populations—while more commonly used in Asian countries, clinical evidence supports its use when capecitabine toxicity occurs. 1, 2

• Do not discontinue bevacizumab unnecessarily—the fluoropyrimidine can be switched while maintaining bevacizumab, as the toxicity is capecitabine-specific, not bevacizumab-related. 2, 4

• Do not delay the switch—prolonged exposure to capecitabine despite toxicity worsens hand-foot syndrome and may lead to treatment discontinuation entirely. 2

• Verify renal function before S-1 initiation, as dose adjustments are required for creatinine clearance <50 mL/min. 4