Neoadjuvant Advantage, Adjuvant Challenge: Clinical Evidence and Hypothetical Biological Mechanisms Behind Divergent Tolerability.
6 affiliations
- 1Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
- 2Mechanistic Pharmacology and Pharmacotherapy, UCIBIO Applied Molecular Biosciences Unit, Associate Laboratory i4HB, Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
- 3Research Center in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sports, University of Porto (FADEUP), 4200-450 Porto, Portugal.
- 4Laboratory for Integrative and Translational Research in Population Health (ITR), 4050-600 Porto, Portugal.
- 5Experimental Pathology and Therapeutics Group, Research Centre of IPO Porto and RISE@CI-IPOP (Health Research Network), 4200-072 Porto, Portugal.
- 6Department of Surgical Oncology, Portuguese Oncology Institute of Porto, Porto Comprehensive Cancer Centre, 4200-072 Porto, Portugal.
Abstract
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.
Related
- Efficacy and safety of neoadjuvant chemotherapy with toripalimab in locally advanced nasopharyngeal carcinoma: a phase II trial and biological correlate analysis
- Long-Term Outcomes of Anatomical and Biological Borderline Resectable Pancreatic Ductal Adenocarcinoma After Gemcitabine/S-1-Based Neoadjuvant Chemoradiotherapy
- Ultra-Processed Foods in Early Life: Biological Mechanisms, Developmental Programming and Childhood Obesity—A Narrative Review
- The Dark Side of Radiotherapy: Experimental Evidence, Biological Mechanisms, and Preventive Strategies for Radiation-Induced Tumor-Promoting Niches
- A pathomics model for predicting lactate-related prognostic risk groups and their biological mechanisms in lung adenocarcinoma
BibTeX
@article{dias2026neoadjuvant,
title = {{Neoadjuvant Advantage, Adjuvant Challenge: Clinical Evidence and Hypothetical Biological Mechanisms Behind Divergent Tolerability.}},
author = {Patrícia Dias and Joaquim Faria Monteiro and Maria João Rocha and Daniel Moreira-Gonçalves and Lúcio Lara Santos and Jorge Gonçalves and Jorge Gonçalves and Paula Fresco},
journal = {Cancers},
year = {2026},
month = sep,
doi = {10.3390/cancers18193137},
url = {https://europepmc.org/article/MED/42882832},
note = {CC BY},
}
RIS
TY - JOUR
TI - Neoadjuvant Advantage, Adjuvant Challenge: Clinical Evidence and Hypothetical Biological Mechanisms Behind Divergent Tolerability.
AU - Patrícia Dias
AU - Joaquim Faria Monteiro
AU - Maria João Rocha
AU - Daniel Moreira-Gonçalves
AU - Lúcio Lara Santos
AU - Jorge Gonçalves
AU - Jorge Gonçalves
AU - Paula Fresco
PY - 2026
DA - 2026/09/28
JO - Cancers
DO - 10.3390/cancers18193137
UR - https://europepmc.org/article/MED/42882832
AB - 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.
SN - 2072-6694
ER -