For patients over 75 with metastatic gastric cancer, a common practice is to reduce the oxaliplatin dose from 85 to 65 mg/m² and universally omit the 5-FU bolus from the FOLFOX regimen. This pragmatic approach aims to maintain efficacy while minimizing toxicity in a more vulnerable population.

New targeted therapies like Zanidatamab and Zolbetuximab show great promise but cause significant side effects like diarrhea and nausea. Their successful clinical adoption hinges on proactive management using detailed guidelines and prophylactic medications, as toxicity can be severe enough to force treatment discontinuation despite the drug's efficacy.

As a practical standard of care for elderly patients, one clinician universally avoids the 5-FU bolus in metastatic settings and reduces the oxaliplatin dose in the FOLFOX regimen from 85 mg/m² to 65 mg/m² for most patients over age 75. This adjustment balances efficacy with improved tolerability in a more vulnerable population.

Despite being the backbone for new combination therapies in trials like Matterhorn, the FLOT chemotherapy regimen has significant toxicity. Approximately 30% of patients discontinue treatment due to adverse events, and only half manage to complete the post-surgery adjuvant portion, posing a major clinical challenge in real-world settings.

In a phase 2 trial, the combination of zanidatumab and FOLFOX achieved a remarkable 95% response rate after two key modifications were made: adding prophylactic loperamide and dropping the 5-FU bolus. This suggests the bolus adds toxicity without clear benefit in this specific, potent combination.

The TRILINX trial revealed Xevinapant's toxicity was so high that it forced reductions in standard, effective treatments like cisplatin and radiation. This compromised the foundational therapy, leading to worse patient outcomes and demonstrating a key risk in adding novel agents to established regimens.

As survival times for metastatic gastric cancer patients extend, managing long-term toxicity is paramount. Clinicians typically administer only 6-8 cycles of oxaliplatin to prevent severe, cumulative peripheral neuropathy, allowing for longer, better-tolerated maintenance therapy with biologics.

In third-line mCRC, drug selection is heavily guided by a patient's accumulated toxicities. For instance, a patient with bone marrow issues from prior chemotherapy might receive a VEGF inhibitor instead of another chemotherapy agent, prioritizing tolerability and quality of life.

Clinicians advise against continuing targeted agents like zolbituximab or trastuzumab after disease progression in gastroesophageal cancer. The biological heterogeneity of this cancer type means that if a targeted therapy isn't working, it's unlikely to provide benefit with a different chemotherapy backbone.