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.
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For an older patient population, the ultimate goal in prostate cancer treatment might not be a traditional cure, but rather turning it into a quiescent, chronic disease manageable with well-tolerated therapy, similar to HIV. This reframes success as long-term control until a patient dies of other causes.
Historically, discussing adjuvant therapy for Stage III colon cancer was quick and straightforward, while Stage II was complex. The advent of ctDNA testing has reversed this dynamic. Stage II decisions are now clearer (treat if positive), while Stage III discussions have become much longer and more nuanced as clinicians integrate ctDNA data with patient preferences.
Medical progress isn't just about new therapies; it's also about de-escalation, such as reducing the number of radiotherapy sessions. This type of innovation significantly improves a patient's quality of life by minimizing the exhaustive and disruptive time spent in treatment, a benefit patients value highly.
A study switching therapy based on ctDNA-detected ESR1 mutations revealed patients felt significantly better after the switch, even without visible tumor progression on scans. This counterintuitive finding suggests molecular progression has a subclinical impact on quality of life, supporting proactive, biomarker-driven treatment changes before patients clinically deteriorate.
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.
Counterintuitively, adding palbociclib to maintenance therapy showed a favorable quality of life in the PATINA trial. Despite known toxicities, the drug delayed the time to first symptom progression. This suggests that the benefit of superior disease control can outweigh the negative impact of treatment side effects on patient-reported outcomes.
While depth of response strongly predicts survival for an individual patient, the FDA analysis concludes it cannot yet be used as a surrogate endpoint to replace overall survival in pivotal clinical trials. It serves as a measure of drug activity, similar to response rate, but is not sufficient for drug approval on its own.
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.
In the DESTINY-CRC02 trial, the lower 5.4 mg/kg dose of trastuzumab deruxtecan (TDXD) resulted in a higher response rate in colorectal cancer compared to the 6.4 mg/kg dose used in gastric cancer. This counter-intuitive finding suggests better tolerability led to longer treatment duration and superior outcomes.
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.