{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:23:52Z","timestamp":1785435832909,"version":"3.56.0"},"reference-count":31,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Advanced Oncology, Kawasaki Medical School"},{"id":[{"id":"https:\/\/ror.org\/059z11218","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Platinum-based doublets are standard first-line therapy for advanced gastric cancer (GC) in the Western Pacific region, but oxaliplatin frequently induces persistent peripheral sensory neuropathy (PSN). Whether residual PSN compromises the feasibility and efficacy of subsequent paclitaxel (PTX)-based therapy remains unclear. Methods: The IVY study was a prospective, multicenter observational trial conducted across 16 Japanese institutions. Patients with advanced GC progressing after fluoropyrimidine\u2013platinum therapy received second-line PTX \u00b1 ramucirumab. Baseline PSN was assessed by CTCAE, PNQ, and FACT\/GOG-Ntx. The primary endpoint was the incidence of grade \u2265 3 PSN during second-line therapy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), tumor response, and patient-reported outcomes. Results: Among 156 patients (90 PSN-positive, 66 PSN-negative), grade \u2265 3 PSN occurred more frequently in the PSN-positive group (16.7% vs. 4.5%; p = 0.02). Median PFS was 4.0 vs. 3.9 months (p = 0.20), and median OS was 10.3 vs. 8.1 months (p = 0.04). In multivariable analysis, residual PSN was not an independent predictor of OS (HR = 0.68 for PSN-positive vs. PSN-negative, 95% CI [0.46\u20131.01]; p = 0.06). Patient-reported instruments captured greater and earlier QoL impairment in PSN-positive patients, though trajectories stabilized by 12 weeks. Conclusions: Residual PSN increases the risk of clinically relevant neurotoxicity\u2014particularly in patients with baseline grade \u2265 2\u2014but, in this cohort, did not appear to preclude paclitaxel-based second-line therapy when monitoring and dose modification were available. The apparent survival difference was exploratory and, after adjustment for baseline imbalance, should not be interpreted as a benefit attributable to residual PSN. Residual neuropathy should therefore prompt structured baseline assessment and early-cycle monitoring rather than routine reassurance.<\/jats:p>","DOI":"10.3390\/cancers18142243","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:55:21Z","timestamp":1783990521000},"page":"2243","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Residual Platinum-Induced Neuropathy and the Feasibility of Second-Line Paclitaxel\u2013Ramucirumab Therapy in Advanced Gastric Cancer: Prospective Multicenter Evidence from Japan"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4236-350X","authenticated-orcid":false,"given":"Takeshi","family":"Nagasaka","sequence":"first","affiliation":[{"name":"Department of Clinical Oncology, Kawasaki Medical School Hospital, Kurashiki 701-0192, Japan"},{"name":"Department of Advanced Oncology, Kawasaki Medical School, Kurashiki 701-0192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4717-5196","authenticated-orcid":false,"given":"Yoshiyasu","family":"Kono","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Kito","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ishikawa Prefectural Central Hospital, Kanazawa 920-8530, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Ando","sequence":"additional","affiliation":[{"name":"Third Department of Internal Medicine, University of Toyama, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Negoro","sequence":"additional","affiliation":[{"name":"Department of Oncological Medicine, Kochi Health Sciences Center, Kochi 781-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Steel Memorial Muroran Hospital, Muroran 050-0076, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidekazu","family":"Kuramochi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, NTT Medical Center Tokyo, Tokyo 141-8625, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5015-0379","authenticated-orcid":false,"given":"Shogen","family":"Boku","sequence":"additional","affiliation":[{"name":"Cancer Treatment Center, Kansai Medical University Hospital, Hirakata 573-1191, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8564-5080","authenticated-orcid":false,"given":"Tomohiko","family":"Mannami","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, NHO Okayama Medical Center, Okayama 701-1192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichiro","family":"Nasu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Okayama Saiseikai General Hospital, Okayama 700-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Okayama Red Cross Hospital, Okayama 700-8607, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Aizawa Comprehensive Cancer Center, Aizawa Hospital, Nagano 390-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Okita","sequence":"additional","affiliation":[{"name":"Department of Cancer Center, Kagawa University Hospital, Kagawa 761-0793, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Shindo","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Nakadori General Hospital, Akita 010-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1436-7482","authenticated-orcid":false,"given":"Takeshi","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Nippon Medical School, Tokyo 113-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Surgery, Konko Hospital, Asakuchi 719-0104, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yudai","family":"Shinohara","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Fukuoka 806-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Tanioka","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Kawasaki Medical School Hospital, Kurashiki 701-0192, Japan"},{"name":"Department of Advanced Oncology, Kawasaki Medical School, Kurashiki 701-0192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lin, J.L., Lin, J.X., Lin, G.T., Huang, C.M., Zheng, C.H., Xie, J.W., Wang, J.B., Lu, J., Chen, Q.Y., and Li, P. (2024). Global incidence and mortality trends of gastric cancer and predicted mortality of gastric cancer by 2035. BMC Public Health, 24.","DOI":"10.1186\/s12889-024-19104-6"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhang, T., Zhang, Y., and Leng, X. (2024). Global, regional, and national trends in gastric cancer burden: 1990\u20132021 and projections to 2040. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1468488"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e74389","DOI":"10.2196\/74389","article-title":"Burden and Future Trends of Gastric Cancer in 5 East Asian Countries from 1990 to 2036: Epidemiological Study Analysis Using the Global Burden of Diseases Study 2021","volume":"11","author":"Guo","year":"2025","journal-title":"JMIR Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1093\/annonc\/mdu472","article-title":"Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer","volume":"26","author":"Yamada","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_5","first-page":"1","article-title":"Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition)","volume":"26","year":"2023","journal-title":"Gastric Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"102226","DOI":"10.1016\/j.esmoop.2023.102226","article-title":"Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer","volume":"9","author":"Shitara","year":"2024","journal-title":"ESMO Open"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3325","DOI":"10.1200\/JCO.20.01399","article-title":"Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update","volume":"38","author":"Loprinzi","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1001\/jama.2013.2813","article-title":"Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial","volume":"309","author":"Smith","year":"2013","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4438","DOI":"10.1200\/JCO.2012.48.5805","article-title":"Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial","volume":"31","author":"Hironaka","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1016\/S1470-2045(14)70420-6","article-title":"Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial","volume":"15","author":"Wilke","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0140-6736(13)61719-5","article-title":"Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial","volume":"383","author":"Fuchs","year":"2014","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S2468-1253(16)30219-9","article-title":"Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): An open-label, randomised, non-inferiority, phase 3 trial","volume":"2","author":"Shitara","year":"2017","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1007\/s12325-024-02838-5","article-title":"Real-World Effectiveness and Safety of Ramucirumab as a Second-Line Treatment for Patients with Unresectable Advanced or Metastatic Gastric\/Gastroesophageal Junction Adenocarcinoma in Japan and South Korea: A Systematic Literature Review","volume":"41","author":"Zhang","year":"2024","journal-title":"Adv. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1093\/jnci\/djp386","article-title":"Adverse symptom event reporting by patients vs clinicians: Relationships with clinical outcomes","volume":"101","author":"Basch","year":"2009","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1200\/JCO.2014.57.9334","article-title":"Symptomatic toxicities experienced during anticancer treatment: Agreement between patient and physician reporting in three randomized trials","volume":"33","author":"Gallo","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_16","first-page":"1483","article-title":"Feasibility and validity of the Patient Neurotoxicity Questionnaire during taxane chemotherapy in a phase III randomized trial in patients with breast cancer: N-SAS BC 02","volume":"17","author":"Shimozuma","year":"2009","journal-title":"Support Care Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1136\/ijgc-00009577-200311000-00003","article-title":"Psychometric evaluation of the Functional Assessment of Cancer Therapy\/Gynecologic Oncology Group-Neurotoxicity (Fact\/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy","volume":"13","author":"Calhoun","year":"2003","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1158\/1078-0432.CCR-15-2035","article-title":"Focusing on Core Patient-Reported Outcomes in Cancer Clinical Trials: Symptomatic Adverse Events, Physical Function, and Disease-Related Symptoms","volume":"22","author":"Kluetz","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tanioka, H., Nagasaka, T., Uno, F., Inoue, M., Okita, H., Katata, Y., Kanzaki, H., Kuramochi, H., Satake, H., and Shindo, Y. (2019). The relationship between peripheral neuropathy and efficacy in second-line chemotherapy for unresectable advanced gastric cancer: A prospective observational multicenter study protocol (IVY). BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6163-6"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1080\/00273171.2011.568786","article-title":"An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies","volume":"46","author":"Austin","year":"2011","journal-title":"Multivar. Behav. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1200\/JCO.2014.55.2208","article-title":"Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis","volume":"32","author":"Uno","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1016\/S0140-6736(17)31827-5","article-title":"Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): A randomised, double-blind, placebo-controlled, phase 3 trial","volume":"390","author":"Kang","year":"2017","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/S1470-2045(18)30739-3","article-title":"Trifluridine\/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): A randomised, double-blind, placebo-controlled, phase 3 trial","volume":"19","author":"Shitara","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1001\/jamaoncol.2020.3370","article-title":"Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients with First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial","volume":"6","author":"Shitara","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0140-6736(21)00797-2","article-title":"First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial","volume":"398","author":"Janjigian","year":"2021","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1016\/S0140-6736(23)00620-7","article-title":"Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): A multicentre, randomised, double-blind, phase 3 trial","volume":"401","author":"Shitara","year":"2023","journal-title":"Lancet"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1038\/s41591-023-02465-7","article-title":"Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: The randomized, phase 3 GLOW trial","volume":"29","author":"Shah","year":"2023","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/s41586-021-04161-3","article-title":"The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer","volume":"600","author":"Janjigian","year":"2021","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1016\/S0140-6736(23)02033-0","article-title":"Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: Interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial","volume":"402","author":"Janjigian","year":"2023","journal-title":"Lancet"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/S1470-2045(24)00580-1","article-title":"Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line oxaliplatin-based chemotherapy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer (ARMANI): A randomised, open-label, multicentre, phase 3 trial","volume":"25","author":"Randon","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1080\/13645706.2024.2359705","article-title":"Robotic versus laparoscopic surgery for colorectal cancer in older patients: A systematic review and meta-analysis","volume":"34","author":"Wang","year":"2025","journal-title":"Minim. Invasive Ther. Allied Technol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2243\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T01:00:38Z","timestamp":1783990838000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":31,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cancers18142243"],"URL":"https:\/\/doi.org\/10.3390\/cancers18142243","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]}}}