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.
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While precision medicine has focused on tumor biology, this research suggests a broader "precision care" approach is needed. This involves tailoring treatment, such as drug dosage, based on patient-specific factors like physiology, functional reserve, and personal goals, not just genomic markers.
An ADC may show better response rates than chemotherapy, but its true benefit is compromised if toxicities lead to treatment discontinuation. As seen with failed PARP/IO combinations, if patients cannot tolerate a drug long enough, the regimen's overall effectiveness can become inferior to standard therapy.
Retesting for biomarkers with liquid biopsy in the third-line setting is crucial. It can uncover new, actionable mutations that have emerged during treatment or confirm the absence of resistance mutations, potentially allowing patients to benefit from re-challenging with a previously used targeted therapy.
When treating elderly patients (e.g., age 80+) with metastatic breast cancer, clinicians may prioritize quality of life over marginal overall survival gains seen in clinical trials. This justifies using a better-tolerated CDK4/6 inhibitor like palbociclib, even though ribociclib has demonstrated a statistical survival benefit, especially when patients have comorbidities or a preference for fewer side effects.
The development of PARP-1 selective inhibitors like seriparib signals a shift in drug innovation. Instead of only chasing higher efficacy, these new agents aim for a more favorable toxicity profile (less GI toxicity, fewer dose discontinuations) to improve patient quality of life and treatment adherence.
Data on Enfortumab Vedotin suggests that for modern therapies, maintaining patients on treatment longer via a lower, more tolerable starting dose is more important than administering the maximum labeled dose upfront, a concept inherited from the cytotoxic chemotherapy era.
In late-stage metastatic colorectal cancer, the goal shifts from achieving significant tumor shrinkage to stabilizing the disease. This recalibration of 'success' focuses on maintaining quality of life and managing symptoms for patients who have undergone multiple prior therapies.
The O11 trial (Len-Belzutafan vs. Cabozantinib) presents the first randomized Phase 3 data for a VEGF/HIF inhibitor combination. Its results will be pivotal in determining if this more toxic doublet approach is justified over monotherapy for IO-refractory kidney cancer, weighing the magnitude of benefit against increased side effects.
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.
As more effective targeted therapies move into first- and second-line treatment, patients live longer. A paradoxical outcome is that more patients will survive long enough to become candidates for third-line therapy, potentially expanding this patient population rather than shrinking it.