{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:57:15Z","timestamp":1790744235653,"version":"4.1.0"},"reference-count":99,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers18193137","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:35:59Z","timestamp":1790595359000},"page":"3137","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neoadjuvant Advantage, Adjuvant Challenge: Clinical Evidence and Hypothetical Biological Mechanisms Behind Divergent Tolerability"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4169-1667","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Dias","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Mechanistic 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1635-8811","authenticated-orcid":false,"given":"Joaquim Faria","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Mechanistic 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7382-7226","authenticated-orcid":false,"given":"Maria Jo\u00e3o","family":"Rocha","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7404-7405","authenticated-orcid":false,"given":"Daniel","family":"Moreira-Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Research Center in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sports, University of Porto (FADEUP), 4200-450 Porto, Portugal"},{"name":"Laboratory for Integrative and Translational Research in Population Health (ITR), 4050-600 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00facio","family":"Lara Santos","sequence":"additional","affiliation":[{"name":"Experimental Pathology and Therapeutics Group, Research Centre of IPO Porto and RISE@CI-IPOP (Health Research Network), 4200-072 Porto, Portugal"},{"name":"Department of Surgical Oncology, Portuguese Oncology Institute of Porto, Porto Comprehensive Cancer Centre, 4200-072 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3045-2150","authenticated-orcid":false,"given":"Jorge","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Mechanistic 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6705-7798","authenticated-orcid":false,"given":"Paula","family":"Fresco","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"Mechanistic 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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1002\/bjs.5894","article-title":"Neoadjuvant chemotherapy for operable breast cancer","volume":"94","author":"Mieog","year":"2007","journal-title":"Br. J. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"547","DOI":"10.55730\/1300-0144.6002","article-title":"Comparative efficacy of adjuvant FOLFOX vs. FLOT following neoadjuvant FLOT in patients with locally advanced gastric cancer","volume":"55","author":"Ceylan","year":"2025","journal-title":"Turk. J. Med. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1002\/jso.27934","article-title":"The New Era of Total Neoadjuvant FLOT Therapy for Locally Advanced, Resectable Gastric Cancer: A Propensity-Matched Comparison with Standard Perioperative Therapy","volume":"131","author":"Rencuzogullari","year":"2025","journal-title":"J. Surg. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1055\/s-0041-1733349","article-title":"An Analysis of Tolerance and Early Survival Outcomes with Perioperative Modified FLOT in Gastric Cancers","volume":"11","author":"Bhargava","year":"2022","journal-title":"South. Asian J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.ejca.2018.11.006","article-title":"Oxaliplatin, 5-Fluorouracil and Nab-paclitaxel as perioperative regimen in patients with resectable gastric adenocarcinoma: A GERCOR phase II study (FOXAGAST)","volume":"107","author":"Watson","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa055531","article-title":"Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer","volume":"355","author":"Cunningham","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1016\/S0140-6736(18)32557-1","article-title":"Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): A randomised, phase 2\/3 trial","volume":"393","author":"Homann","year":"2019","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1038\/s41416-025-03199-8","article-title":"Adverse events of postoperative adjuvant chemotherapy predict survival outcomes in locally advanced colorectal cancer: A pooled analysis of Japanese clinical trials","volume":"133","author":"Kawamura","year":"2025","journal-title":"Br. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1200\/JCO.2009.25.8541","article-title":"Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study","volume":"28","author":"Pericay","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1093\/annonc\/mdv223","article-title":"Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: Long-term results of the Spanish GCR-3 phase II randomized trial\u2020","volume":"26","author":"Pericay","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1200\/JCO.2008.19.2567","article-title":"Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer","volume":"27","author":"Gianni","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"van der Hage, J.H., van de Velde, C.J.H., Mieog, S., and Charehbili, A. (2007). Preoperative chemotherapy for women with operable breast cancer. Cochrane Database Syst. Rev., CD005002.","DOI":"10.1002\/14651858.CD005002.pub2"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s12957-020-01907-7","article-title":"Survival outcomes of neoadjuvant versus adjuvant chemotherapy in triple-negative breast cancer: A meta-analysis of 36,480 cases","volume":"18","author":"Xia","year":"2020","journal-title":"World J. Surg. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"18055","DOI":"10.1038\/s41598-024-68719-7","article-title":"Evaluation of neoadjuvant chemotherapy for clinical T1 triple-negative breast cancer","volume":"14","author":"Hao","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"oyaf356","DOI":"10.1093\/oncolo\/oyaf356","article-title":"Survival outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer patients","volume":"30","author":"Wang","year":"2025","journal-title":"Oncologist"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1007\/s10549-026-07983-9","article-title":"Retrospective study of comparable survival after neoadjuvant versus adjuvant chemotherapy in cT1-2N0M0 triple-negative breast cancer","volume":"217","author":"Olsson","year":"2026","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"104460","DOI":"10.1016\/j.breast.2025.104460","article-title":"Comparison of neoadjuvant and adjuvant chemotherapy for operable triple-negative breast cancer before the era of immune checkpoint inhibitors: A retrospective study from the Japanese National Clinical Database-Breast Cancer Registry","volume":"81","author":"Taji","year":"2025","journal-title":"Breast"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4890","DOI":"10.1245\/s10434-025-17297-7","article-title":"Long-term Outcomes for Neoadjuvant Versus Adjuvant Chemotherapy in ER+\/HER2- Locally Advanced Breast Cancer","volume":"32","author":"Wang","year":"2025","journal-title":"Ann. Surg. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"21580","DOI":"10.1038\/s41598-026-45873-8","article-title":"Neoadjuvant versus adjuvant chemotherapy in locally advanced hormone receptor-positive, HER2-negative invasive lobular carcinoma: A retrospective cohort study based on the SEER database","volume":"16","author":"Xu","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"104821","DOI":"10.1016\/j.breast.2026.104821","article-title":"Toxicity profile and tolerability of immune checkpoint inhibitors for the treatment of early-stage breast cancer: A systematic review and meta-analysis","volume":"88","author":"Dacoregio","year":"2026","journal-title":"Breast"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e14621","DOI":"10.1200\/JCO.2025.43.16_suppl.e14621","article-title":"Adverse events and tolerability of immune checkpoint inhibitors (ICI) for the treatment of early stage of breast cancer (BC): A systematic review and meta analysis","volume":"43","author":"Dacoregio","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s10549-019-05303-y","article-title":"HER2+ breast cancer treatment and cardiotoxicity: Monitoring and management","volume":"177","author":"Jerusalem","year":"2019","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s13058-025-02013-w","article-title":"Pharmacovigilance study of adverse reactions of anti-HER-2 drugs for the treatment of HER-2-positive breast cancer based on the FAERS database","volume":"27","author":"Han","year":"2025","journal-title":"Breast Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e000361","DOI":"10.1136\/esmoopen-2018-000361","article-title":"Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: A systematic review and meta-analysis","volume":"3","author":"Poggio","year":"2018","journal-title":"ESMO Open"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15330338251350630","DOI":"10.1177\/15330338251350630","article-title":"Efficacy and Safety of Poly (ADP-Ribose) Polymerase Inhibitors in Combination with Chemotherapy for Advanced Breast Cancer: A Systematic Review and Meta-Analysis","volume":"24","author":"Duan","year":"2025","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"21s","DOI":"10.1177\/0148607113496117","article-title":"The surgically induced stress response","volume":"37","author":"Finnerty","year":"2013","journal-title":"JPEN J. Parenter. Enter. Nutr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2165\/00003088-199835040-00003","article-title":"Effects of surgery on the pharmacokinetic parameters of drugs","volume":"35","author":"Kennedy","year":"1998","journal-title":"Clin. Pharmacokinet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1097\/01.cad.0000203382.07114.0f","article-title":"Effect of gastrectomy on the pharmacokinetics of 5-fluorouracil and gimeracil after oral administration of S-1","volume":"17","author":"Tsuruoka","year":"2006","journal-title":"Anticancer Drugs"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s00280-007-0415-x","article-title":"Effect of gastrectomy on the pharmacokinetics of S-1, an oral fluoropyrimidine, in resectable gastric cancer patients","volume":"60","author":"Kochi","year":"2007","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1002\/jcph.499","article-title":"Postgastrectomy pharmacokinetic changes of S-1 in patients with localized advanced gastric cancer","volume":"55","author":"Lim","year":"2015","journal-title":"J. Clin. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1111\/j.1349-7006.2007.00573.x","article-title":"Alternative pharmacokinetics of S-1 components, 5-fluorouracil, dihydrofluorouracil and alpha-fluoro-beta-alanine after oral administration of S-1 following total gastrectomy","volume":"98","author":"Kim","year":"2007","journal-title":"Cancer Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"eabk2901","DOI":"10.1126\/sciadv.abk2901","article-title":"Real-time monitoring of drug pharmacokinetics within tumor tissue in live animals","volume":"8","author":"Seo","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s11912-007-0006-3","article-title":"Drug distribution in tumors: Mechanisms, role in drug resistance, and methods for modification","volume":"9","author":"Bocci","year":"2007","journal-title":"Curr. Oncol. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Thurber, G.M., and Weissleder, R. (2011). A systems approach for tumor pharmacokinetics. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024696"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"517","DOI":"10.2967\/jnumed.118.219352","article-title":"Dosimetry of (177)Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: Correlations Between Pretherapeutic Imaging and Whole-Body Tumor Dosimetry with Treatment Outcomes","volume":"60","author":"Violet","year":"2019","journal-title":"J. Nucl. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"226","DOI":"10.2967\/jnumed.121.261906","article-title":"Tumor Sink Effect in (68)Ga-PSMA-11 PET: Myth or Reality?","volume":"63","author":"Gafita","year":"2022","journal-title":"J. Nucl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Burgard, C., Rosar, F., Marlowe, R.J., Bartholom\u00e4, M., Dewes, S., Schaefer-Schuler, A., Linxweiler, J., Khreish, F., and Ezziddin, S. (2023). Tumor Sink Effect with Prostate-Specific Membrane Antigen-Targeted Theranostics in Patients with Metastatic Castration-Resistant Prostate Cancer: Intra-Individual Evaluations. Cancers, 15.","DOI":"10.3390\/cancers15092592"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13550-025-01319-2","article-title":"Tumor sink effect on melanin-ligand [(131)I]ICF01012 in melanoma and its implications for targeted radionuclide therapy","volume":"15","author":"Jouberton","year":"2025","journal-title":"EJNMMI Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Nikmaneshi, M.R., Jain, R.K., and Munn, L.L. (2023). Computational simulations of tumor growth and treatment response: Benefits of high-frequency, low-dose drug regimens and concurrent vascular normalization. PLoS Comput. Biol., 19.","DOI":"10.1371\/journal.pcbi.1011131"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"67","DOI":"10.4161\/mabs.2.1.10781","article-title":"Target mediated disposition of T84.66, a monoclonal anti-CEA antibody: Application in the detection of colorectal cancer xenografts","volume":"2","author":"Urva","year":"2010","journal-title":"MAbs"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Monteiro, J.F., Fernandes, A., Tato, D.G., Moreira, E., Ribeiro, R., Reguengo, H., Gon\u00e7alves, J., and Fresco, P. (2025). Optimizing Anti-PD1 Immunotherapy: An Overview of Pharmacokinetics, Biomarkers, and Therapeutic Drug Monitoring. Cancers, 17.","DOI":"10.3390\/cancers17193262"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/nrc1893","article-title":"Drug penetration in solid tumours","volume":"6","author":"Minchinton","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_43","first-page":"482","article-title":"Identification and partial characterization of an unusual distribution of the photosensitizer meta-tetrahydroxyphenyl chlorin (temoporfin) in human plasma","volume":"69","author":"Hopkinson","year":"1999","journal-title":"Photochem. Photobiol."},{"key":"ref_44","first-page":"538","article-title":"MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation","volume":"56","author":"Koya","year":"1996","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Koren, J., Miyata, Y., Kiray, J., O\u2019Leary, J.C., Nguyen, L., Guo, J., Blair, L.J., Li, X., Jinwal, U.K., and Cheng, J.Q. (2012). Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance. PLoS ONE, 7, Correction in PLoS ONE\u00a02012, 7, 10-1371. https:\/\/doi.org\/10.1371\/annotation\/7493e5d2-4c1a-43eb-a83f-16814861ff13.","DOI":"10.1371\/annotation\/7493e5d2-4c1a-43eb-a83f-16814861ff13"},{"key":"ref_46","first-page":"878","article-title":"Limited penetration of anticancer drugs through tumor tissue: A potential cause of resistance of solid tumors to chemotherapy","volume":"8","author":"Tannock","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8782","DOI":"10.1158\/1078-0432.CCR-05-1664","article-title":"The distribution of the anticancer drug Doxorubicin in relation to blood vessels in solid tumors","volume":"11","author":"Primeau","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1093\/jnci\/djm135","article-title":"Drug resistance and the solid tumor microenvironment","volume":"99","author":"Galmarini","year":"2007","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1091\/mbc.e14-04-0916","article-title":"How Taxol\/paclitaxel kills cancer cells","volume":"25","author":"Weaver","year":"2014","journal-title":"Mol. Biol. Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1091\/mbc.10.4.947","article-title":"Taxol Suppresses Dynamics of Individual Microtubules in Living Human Tumor Cells","volume":"10","author":"Wadsworth","year":"1999","journal-title":"Mol. Biol. Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/nrc2167","article-title":"The resurgence of platinum-based cancer chemotherapy","volume":"7","author":"Kelland","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_52","first-page":"775","article-title":"Therapeutic attack of hypoxic cells of solid tumors: Presidential address","volume":"48","author":"Sartorelli","year":"1988","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1056\/NEJM198311033091805","article-title":"The pharmacology and clinical use of methotrexate","volume":"309","author":"Jolivet","year":"1983","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1016\/S0959-8049(98)00058-6","article-title":"Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue","volume":"34","author":"Miwa","year":"1998","journal-title":"Eur. J. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s002800050043","article-title":"Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients","volume":"45","author":"Cassidy","year":"2000","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.18632\/oncotarget.2732","article-title":"Lysosomal sequestration of hydrophobic weak base chemotherapeutics triggers lysosomal biogenesis and lysosome-dependent cancer multidrug resistance","volume":"6","author":"Zhitomirsky","year":"2015","journal-title":"Oncotarget"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6949","DOI":"10.1021\/jm500766w","article-title":"Ado-trastuzumab Emtansine (T-DM1): An antibody-drug conjugate (ADC) for HER2-positive breast cancer","volume":"57","author":"Lambert","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_58","first-page":"6387","article-title":"A new concept for macromolecular therapeutics in cancer chemotherapy: Mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs","volume":"46","author":"Matsumura","year":"1986","journal-title":"Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0168-3659(99)00248-5","article-title":"Tumor vascular permeability and the EPR effect in macromolecular therapeutics: A review","volume":"65","author":"Maeda","year":"2000","journal-title":"J. Control Release"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nrc1074","article-title":"5-fluorouracil: Mechanisms of action and clinical strategies","volume":"3","author":"Longley","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1073\/pnas.87.1.492","article-title":"Tumor trapping of 5-fluorouracil: In vivo 19F NMR spectroscopic pharmacokinetics in tumor-bearing humans and rabbits","volume":"87","author":"Wolf","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1200\/JCO.1990.8.11.1868","article-title":"Human tumor fluorouracil trapping: Clinical correlations of in vivo 19F nuclear magnetic resonance spectroscopy pharmacokinetics","volume":"8","author":"Presant","year":"1990","journal-title":"J. Clin. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/sj.bjc.6600809","article-title":"Penetration of capecitabine and its metabolites into malignant and healthy tissues of patients with advanced breast cancer","volume":"88","author":"Mader","year":"2003","journal-title":"Br. J. Cancer"},{"key":"ref_64","first-page":"131","article-title":"Tissue Penetration of Capecitabine and Its Tumor-Selective Delivery of 5-FU in Advanced Breast Cancer Patients","volume":"3","author":"Ye","year":"2006","journal-title":"J. Chin. Pharm. Sci."},{"key":"ref_65","first-page":"3415","article-title":"Pharmacokinetic analysis of 5-[18F]fluorouracil tissue concentrations measured with positron emission tomography in patients with liver metastases from colorectal adenocarcinoma","volume":"57","author":"Kissel","year":"1997","journal-title":"Cancer Res."},{"key":"ref_66","first-page":"507","article-title":"Link between dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells and liver","volume":"2","author":"Chazal","year":"1996","journal-title":"Clin. Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1016\/S0959-8049(98)00175-0","article-title":"Autoregulation of 5-fluorouracil metabolism","volume":"34","author":"McLeod","year":"1998","journal-title":"Eur. J. Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00280-016-3105-8","article-title":"Effects of a bolus injection of 5-fluorouracil on dihydropyrimidine dehydrogenase activity in rats receiving continuous infusion of 5-fluorouracil","volume":"78","author":"Kobuchi","year":"2016","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"10651","DOI":"10.1039\/b913896j","article-title":"Non-traditional platinum compounds for improved accumulation, oral bioavailability, and tumor targeting","volume":"48","author":"Lovejoy","year":"2009","journal-title":"Dalton Trans."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"14298","DOI":"10.1073\/pnas.162491399","article-title":"Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals","volume":"99","author":"Ishida","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"15584","DOI":"10.3390\/molecules191015584","article-title":"Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview beyond Cisplatin","volume":"19","author":"Spreckelmeyer","year":"2014","journal-title":"Molecules"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"8847","DOI":"10.1158\/0008-5472.CAN-06-0769","article-title":"Organic cation transporters are determinants of oxaliplatin cytotoxicity","volume":"66","author":"Zhang","year":"2006","journal-title":"Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1038\/s41467-023-36334-1","article-title":"Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy","volume":"14","author":"Linares","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"101223","DOI":"10.1016\/j.drup.2025.101223","article-title":"Novel insights into taxane pharmacology: An update on drug resistance mechanisms, immunomodulation and drug delivery strategies","volume":"81","author":"Beretta","year":"2025","journal-title":"Drug Resist. Updat."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/s41580-022-00473-y","article-title":"Mechanisms of microtubule organization in differentiated animal cells","volume":"23","author":"Akhmanova","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/S1359-6349(06)80002-9","article-title":"Head-to-head: Docetaxel challenges paclitaxel","volume":"4","author":"Jones","year":"2006","journal-title":"Eur. J. Cancer Suppl."},{"key":"ref_77","first-page":"357","article-title":"Benefit risk assessment and update on the use of docetaxel in the management of breast cancer","volume":"5","author":"Alken","year":"2013","journal-title":"Cancer Manag. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1634\/theoncologist.9-suppl_2-3","article-title":"Preclinical pharmacology of the taxanes: Implications of the differences","volume":"9","author":"Gligorov","year":"2004","journal-title":"Oncologist"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1111\/IGC.0b013e3181a130db","article-title":"Intravenous paclitaxel is specifically retained in human gynecologic carcinoma tissues in vivo","volume":"19","author":"Koshiba","year":"2009","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"322","DOI":"10.4103\/0975-1483.90245","article-title":"Pharmacokinetic evaluation of Paclitaxel in South Indian cancer patients: A prospective study","volume":"3","author":"Vasantha","year":"2011","journal-title":"J. Young Pharm."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"7737","DOI":"10.1039\/C4CS00477A","article-title":"Pharmaceuticals that contain polycyclic hydrocarbon scaffolds","volume":"44","author":"Stockdale","year":"2015","journal-title":"Chem. Soc. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/0959-8049(95)00357-O","article-title":"Preclinical pharmacology of docetaxel","volume":"31","author":"Bissery","year":"1995","journal-title":"Eur. J. Cancer"},{"key":"ref_83","first-page":"305","article-title":"Pharmacokinetics and metabolism of Taxotere (docetaxel)","volume":"17","author":"Bruno","year":"1993","journal-title":"Cancer Surv."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"101205","DOI":"10.1016\/j.mam.2023.101205","article-title":"Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming","volume":"93","author":"Mattioli","year":"2023","journal-title":"Mol. Asp. Med."},{"key":"ref_85","first-page":"1221","article-title":"Doxorubicin distribution in human breast cancer","volume":"71","author":"Rossi","year":"1987","journal-title":"Cancer Treat. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"e70104","DOI":"10.1002\/pon.70104","article-title":"Patient and Family Caregiver Perspectives on Therapy De-Escalation in Cancer: A Scoping Review","volume":"34","author":"Hamilton","year":"2025","journal-title":"Psychooncology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.annonc.2022.03.273","article-title":"Risk-adapted modulation through de-intensification of cancer treatments: An ESMO classification","volume":"33","author":"Trapani","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1016\/S0140-6736(24)00054-0","article-title":"3-year invasive disease-free survival with chemotherapy de-escalation using an (18)F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): A randomised, open-label, phase 2 trial","volume":"403","author":"Colleoni","year":"2024","journal-title":"Lancet"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e2400068","DOI":"10.1200\/OA-24-00068","article-title":"Randomized Trial of Fixed-Dose Capecitabine Compared with Standard-Dose Capecitabine in Metastatic Breast Cancer: X-7\/7 Trial","volume":"2","author":"Khan","year":"2025","journal-title":"JCO Oncol. Adv."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/bjc.2013.86","article-title":"Adjuvant chemotherapy for gastric cancer: A randomised phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201)","volume":"108","author":"Kang","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Donada, M., Bonin, S., Barbazza, R., Pettirosso, D., and Stanta, G. (2013). Management of stage II colon cancer\u2014The use of molecular biomarkers for adjuvant therapy decision. BMC Gastroenterol., 13.","DOI":"10.1186\/1471-230X-13-36"},{"key":"ref_92","first-page":"4949","article-title":"Prognostic markers in early-stage colorectal cancer: Significance of TYMS mRNA expression","volume":"34","author":"Koumarianou","year":"2014","journal-title":"Anticancer. Res."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Gibbs, P., Hong, W., and Tie, J. (2023). Re: Molecular testing to deliver personalised chemotherapy recommendations. BMC Med., 21.","DOI":"10.1186\/s12916-023-03036-w"},{"key":"ref_94","first-page":"746","article-title":"Use of molecular biomarkers to inform adjuvant therapy for colon cancer","volume":"27","author":"Mettu","year":"2013","journal-title":"Oncology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s00280-016-3054-2","article-title":"Therapeutic drug monitoring of 5-fluorouracil","volume":"78","author":"Lee","year":"2016","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ejca.2019.01.102","article-title":"Therapeutic drug monitoring as a tool to optimize 5-FU-based chemotherapy in gastrointestinal cancer patients older than 75 years","volume":"111","author":"Macaire","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1080\/17425255.2021.2029403","article-title":"Current status and future outlooks on therapeutic drug monitoring of fluorouracil","volume":"17","author":"Schmulenson","year":"2021","journal-title":"Expert. Opin. Drug Metab. Toxicol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.2217\/pgs.12.95","article-title":"Pharmacogenetic markers of toxicity for chemotherapy in colorectal cancer patients","volume":"13","author":"Cortejoso","year":"2012","journal-title":"Pharmacogenomics"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"pkaf092","DOI":"10.1093\/jncics\/pkaf092","article-title":"Leveraging real-world evidence to personalize adjuvant therapy in HR+\/HER2- early breast cancer","volume":"9","author":"Bar","year":"2025","journal-title":"JNCI Cancer Spectr."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3137\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:14:14Z","timestamp":1790741654000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3137"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":99,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cancers18193137"],"URL":"https:\/\/doi.org\/10.3390\/cancers18193137","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]}}}