Cross-trial comparisons cannot establish either treatment timing or MRD status as a causal determinant of efficacy

The gap

Evidence profile

Sourced from the limitations section and future work of the source papers, classified as general, drawn from work published between 2025 and 2026, spanning 3 journals. Those papers have been cited 31 times in total.

Supporting evidence — 3 representative gaps

• Beyond a negative trial: timing, molecular residual disease, and antibody biology in adjuvant immunotherapy for resected NSCLC (2026) · Frontiers in Oncology · doi

  cross-trial comparisons cannot establish either treatment timing or MRD status as a causal determinant of efficacy, - the wide confidence interval, limited number of events, and immature follow-up require caution in interpreting the results of NADIM-Adjuvant, - analytical and biological heterogeneity pose significant obstacles to the clinical utility of post-operative ctDNA measurements, - sensitivity is especially problematic in patients who have low-volume residual disease or tumors with minimal ctDNA shedding

  generallimitations sectionevidence 5/5
  Keywords: cross-trial comparisons cannot establish either treatment timing mrd
• Resect first in resectable colorectal liver metastases: recalibrating the default (2026) · Annals of Hepato-Biliary-Pancreatic Surgery · doi

  ctDNA is emerging as a prognostic and potentially predictive biomarker in CRLM. Multiple studies have demonstrated that ctDNA positivity following curative resection is associated with early recurrence and inferior survival, while ctDNA neg- ativity identifies patients with more indolent disease biology [33,34]. Prospective trials [35,36] are now exploring the role of ctD- NA-guided adjuvant therapy. In practical terms, ctDNA offers a route beyond broad clinicopathologic surrogates toward molecular residual disease stratification. This would involve enriching postoperative systemic therapy for patients with persistent ctDNA positivity while identifying lower-risk pa- tients in whom treatment could potentially be de-escalated or withheld. Therefore, ctDNA may help define which patients are most likely to benefit from perioperative chemotherapy. Integrating ctDNA with clinicopathologic and molecular risk factors may further refine individualized treatment sequencing in the future. Treatment sequencing in resectable CRLMwww.ahbps.org4 CONCLUSION In resectable CRLM, the routine use of perioperative chemo- therapy reflects a strong biological rationale, but its benefit is unlikely to be uniform across all patients. Patients with clearly resectable, low-volume, and biologically favourable disease may be well served by upfront liver-directed treatment, particularly when timely local therapy can be delivered without compro- mising future options. By contrast, perioperative systemic ther- apy remains appropriate in selected patients with synchronous presentation, technically complex disease, or adverse biological features. The challenge is to move away from a single default approach and instead align the treatment sequence with anato- my, tumour biology, and emerging molecular markers of resid- ual risk. in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 2020;21:398-411. 4. Kanemitsu Y, Shimizu Y, Mizusawa J, Inaba Y, Hamaguchi T, Shida D, et al. Hepatectomy followed by mFOLFOX6 versus hepatectomy alone for liver-only metastatic colorectal cancer (JCOG0603): a phase II or III randomized controlled trial. J Clin Oncol 2021;39:3789-3799. 5. André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109-3116. 6. André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343-2351. 7. Morris VK, Kennedy EB, Baxter NN, Benson AB 3rd, Cercek A, Cho M, et al. Treatment of metastatic colorectal cancer: ASCO guideline. J FUNDING Clin Oncol 2023;41:678-700. None. CONFLICT OF INTEREST 8

  generalfuture workevidence 5/5
  Keywords: treatment ctdna patients disease therapy resectable oncol cancer adjuvant molecular risk perioperative liver colorectal trial
• Anti-EGFR Therapy in Metastatic Colorectal Cancer: Identifying, Tracking, and Overcoming Resistance (2025) · Cancers · cited 31× · doi

  Its sensitivity is affected by tumor biology and assay performance - False-negative results may occur in cases with low tumor burden, limited tumor shedding, or metastases located in compartments with restricted access to the bloodstream, such as the peritoneum or central nervous system - Turnaround time, although generally shorter than that of tissue-based sequencing, may still be suboptimal due to logistical delays in sample handling and reporting - Financial and infrastructural barriers also limit access to ctDNA testing in many healthcare settings - Clinically, the interpretation of ctDNA results is not always straightforward

  generallimitations sectionevidence 5/5
  Keywords: sensitivity affected tumor biology assay performance false-negative results

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