Gudrun Piringer

Summary: Adjuvant treatment of colorectal cancer (CRC) has traditionally been based on fluoropyrimidine- and oxaliplatin-based chemotherapy regimens, which remain the cornerstone of care for patients with resected stage III and selected high-risk stage II disease. However, despite substantial improvements in disease-free (DFS) and overall survival (OS), a considerable proportion of patients experience disease recurrence. More recently, attention has shifted toward novel adjuvant strategies aimed at further reducing the recurrence risk, including structured exercise, biomarker-guided aspirin therapy, immune checkpoint inhibition in mismatch repair-deficient (dMMR) CRC, and circulating tumor DNA (ctDNA)-based detection of molecular residual disease. The CHALLENGE trial demonstrated that a 3-year structured exercise intervention after completion of adjuvant chemotherapy significantly improves DFS and OS in patients with stage III and high-risk stage II colon cancer. The ALASCCA trial established low-dose aspirin as a promising precision medicine strategy in patients with phosphatidylinositol 3‑kinase (PI3K) pathway alterations. The ATOMIC trial provided the first phase III evidence supporting adjuvant immunotherapy in patients with dMMR stage III colon cancer. In parallel, ctDNA has emerged as a powerful prognostic marker, although randomized studies have also demonstrated that ctDNA-guided escalation or de-escalation cannot yet be considered a universal replacement for standard clinicopathological decision-making. This review summarizes the biological rationale, clinical background, pivotal phase III data, practical implementation, and remaining uncertainties of these emerging strategies.

Summary: Neoadjuvant therapy plays an increasingly important role in the multidisciplinary management of gastrointestinal cancers. While multimodal strategies are well established in rectal cancer, the role of neoadjuvant therapy in colon cancer remains under investigation. Recent advancements in molecular profiling and systemic therapies have underscored the biological heterogeneity of colorectal tumors, leading to more personalized approaches in the palliative setting but also in neoadjuvant strategies. This review explores the evolving role of neoadjuvant systemic treatment strategies in microsatellite stable (MSS) and high microsatellite instability (MSI-h) colorectal cancer, examining key clinical trials and future directions aimed at optimizing personalized treatment approaches for localized colorectal cancer.

Summary: Despite recent advances in therapy, certain subtypes of colorectal cancer, such as those that are microsatellite instability (MSI-high), mismatch repair deficient (dMMR) or tumor mutation burden high (TMB-H), remain a treatment challenge. In recent years, interest in neoadjuvant therapy strategies for localized colorectal cancer has increased—especially treatment with immunotherapies. At ASCO meeting 2024, updated data on 6‑month course of dostarlimab in patients with dMMR locally advanced rectal cancer as well as several trials investigating the use of neoadjuvant immunotherapy monotherapy or immunotherapy combinations in high-risk stage II–III dMMR colon cancer were presented.

Purpose: The aim of this retrospective analysis was to determine if the response to preoperative radio(chemo)therapy is predictive for survival among patients with locally advanced rectal cancer and may act as a potential surrogate endpoint for disease free survival and overall survival.Results: Eight hundred seventy-eight patients from five centers were analyzed. There were 304 women and 574 men; the median age was 64.7 years. 77.6% and 22.4% of patients received neoadjuvant radiochemotherapy or short-course radiotherapy, resulting in a pathological complete response in 7.3%. T-downstaging and N-downstaging occurred in 50.5% and 37% of patients after neoadjuvant therapy. In patients with T-downstaging, the 10-year DFS and 10-year OS were 64.8% and 66.8% compared to 37.1% and 45.9% in patients without T-downstaging. N-downstaging resulted in 10-year DFS and 10-year OS in 56.2% and 62.5% compared to 47.3% and 52.3% without N-downstaging. Based on routinely evaluated clinical parameters, an absolute risk prediction calculator was generated for 5-year disease-free survival, and 5-year overall survival.Conclusion: T-downstaging and N-downstaging after neoadjuvant radiochemotherapy or short-course radiotherapy resulted in better DFS and OS compared to patients without response. Based on clinical parameters, 5-year DFS, and 5-year OS can be predicted using a prediction calculator.

Metastatic BRAF^V600E mutated colorectal cancer is associated with poor overall survival and modest effectiveness to standard therapies. Furthermore, survival is influenced by the microsatellite status. Patients with microsatellite-stable and BRAF^V600E mutated colorectal cancer have the worst prognosis under the wide range of genetic subgroups in colorectal cancer. Herein, we present a patient case of an impressive therapeutic efficacy of dabrafenib, trametinib, and cetuximab as later-line therapy in a 52-year-old woman with advanced BRAF^V600E mutated, microsatellite-stable colon cancer. This patient achieved a complete response after 1 year of triple therapy. Due to skin toxicity grade 3 and recurrent urinary tract infections due to mucosal toxicity, a therapy de-escalation to dabrafenib and trametinib was performed, and the double therapy was administered for further 41 months with ongoing complete response. For 1 year, the patient was off therapy and is still in complete remission.