Neoadjuvant Advantage, Adjuvant Challenge: Clinical Evidence and Hypothetical Biological Mechanisms Behind Divergent Tolerability

Adjuvant chemotherapy is a cornerstone of curative treatment for solid tumours; however, its benefit is frequently limited by poor tolerability and low treatment completion rates after surgery. Importantly, tolerability decreases from neoadjuvant to adjuvant regimens, a phenomenon particularly evident in gastrointestinal malignancies and observed in breast cancer, despite the latter generally involving less extensive surgery. Moreover, the mechanisms underlying this reduced tolerability remain a conundrum in clinical practice. This narrative review explores the discrepancy between neoadjuvant and adjuvant chemotherapy tolerability in gastrointestinal and breast cancers, focusing on potential biological and pharmacological determinants. Clinical and translational evidence is analysed, including treatment completion, dose intensity, and toxicity profiles in perioperative settings (i.e., any chemotherapy around the time of surgery, e.g., preoperative, intraoperative, and immediately postoperative chemotherapy), with emphasis on conventional cytotoxic regimens. Across tumour types, neoadjuvant chemotherapy is consistently associated with higher completion rates and greater dose intensity than adjuvant treatments. Although postoperative morbidity, nutritional impairment, sarcopenia, organ dysfunction and delayed recovery contribute to reduced tolerance and may prevent the initiation or completion of postoperative chemotherapy, particularly in gastrointestinal cancers, these factors may not fully account for the observed differences across treatment settings. We therefore discuss additional pharmacokinetic and tumour-related hypotheses as complementary explanations requiring clinical validation. Emerging evidence indicates that tumour burden and surgical resection may modify systemic drug handling, including pharmacokinetics and tissue distribution. The removal of a tumour could decrease the sequestration of drugs and change the interactions between the host and the drugs, which might narrow the therapeutic index after surgery. Consequently, the tolerability of adjuvant chemotherapy could be linked to both postoperative vulnerability and potential biological changes resulting from tumour removal. Optimising treatment sequencing will require integration of pharmacological, physiological, and tumour-specific factors to develop personalised strategies that balance treatment efficacy and quality of life.