Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer.

BACKGROUND: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. METHODS: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. RESULTS: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. CONCLUSIONS: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

Wedding Rigorous Scientific Methodology and Ancient Herbal Wisdom to Benefit Cancer Patients: The Development of PHY906.

Our research group has extensively characterized the preclinical and clinical activities of PHY906, a traditional Chinese herbal medicine, as a modulator of irinotecan-based chemotherapy for the treatment of colorectal cancer. This article reviews the critical issues of quality control and standardization of PHY906 and highlights the importance of high-quality material for the conduct of preclinical and clinical studies. Studies to investigate the potential biological mechanisms of action using a systems biology approach play a pivotal role in providing the preclinical rationale to move forward with clinical studies. For early-phase clinical studies, translational biomarkers should be incorporated to characterize the biological effects of the herbal medicine. These biomarkers include tumor mutational load, cytokine/chemokine expression, metabolomic profiling, and the presence of key herbal metabolites. Sophisticated bioinformatic approaches are critical for mining the data and identifying those biomarkers that can define the subset of patients who will benefit from PHY906 or any other herbal medicine, in terms of reduced treatment toxicity, improved quality of life, and/or enhanced clinical activity of treatment.